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Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations Tallinn, Estonia, 15 - 19 Octob

Pharmaceutical Development. Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations Tallinn, Estonia, 15 - 19 October 2007. Pharmaceutical Development. Suitable dosage forms for pediatric medicine Presenter: Jean-Marc AIACHE Emeritus Professor,

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Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations Tallinn, Estonia, 15 - 19 Octob

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  1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations Tallinn, Estonia, 15 - 19 October 2007

  2. 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@wanadoo.fr

  3. 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

  4. What are the problems? • 1) Children characteristics: • Children are “SPECIFIC patients”, and not “small ADULTS • Classification

  5. 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

  6. 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

  7. 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

  8. 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

  9. Example : Cancers • Cancers are rare Disease in the child (1-2 cases/ 10000 < 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”).

  10. 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.

  11. 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.

  12. 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 issue for children is the 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 water……but the capsules must be opened and the pellets transferred.

  13. 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.

  14. 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!!

  15. 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

  16. 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 ….

  17. 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

  18. Acute or common illness: The most important prescriptions Bones Hormones Eyes…. Respiratory dis. 2% Dermatology 4% 3% 4% 6% 32% Digestive tract. Metabolism 13% 14% 22% Nervous.C.S Antibiotics

  19. 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…) • :

  20. Dosage forms fornewborns, 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.

  21. Dosage forms fornewborns, infants ,toddlers • a) D.F to help the parents for drug administration: • Active administration :powders, solutions, suspensions introduced inpacifiers, 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!!!!

  22. Dosage forms fornewborns, 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 oralliquids, “Med-T-Spoon”, Intelligent” single doses. The graduations are presented in Kg, body area in m²,age (day ,month, years)

  23. Dosage forms forchildren(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 !

  24. Dosage forms forchildren(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 oral route, the taste will represent the main issue of all the developed D.F..

  25. Dosage forms forchildren(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.

  26. Dosage forms forchildren(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…..

  27. Dosage forms forchildren(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

  28. 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.!

  29. 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

  30. But all these developments must be under the control of two very important factors :

  31. NON-OBSERVANCE FACTORS KIDS-DRIVEN SUPER SERVICE EMPOWERMENT PARADOXE ENABLING EXPECTATIONS INCOHERENT EXPECTATIONS SECURITY FACTORS OBSERVANCE FACTORS REMINDER EFFECT MOSAIC FAMILY EXPERT-USER SYNDROME DISPERSION PHENOMENON RISK BLINDNESS SUB-ATTENTION NON-SECURITY FACTORS

  32. 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.

  33. 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 d’une enquête réalisée auprès des pédiatres

  34. 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 Administration—Center 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 Administration—Center for Drug Evaluation and Research [on-line] 1997; http://www.fda.gov/cder/guidance/105-115.htm (November 2002, date last accessed).

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