principles of dosage form design paediatric formulations · 2015. 12. 14. · principles of dosage...

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Principles of dosage form design

& paediatric formulations

assist. prof. dr. Alenka Zvonar Pobirk, M. Pharm.

University of Ljubljana, Faculty of pharmacy

CEMCD, Ljubljana, 19-22.11.2015 1

Part 1

Principles of dosage form design

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DF design: Active pharmaceutical ingredient

� Active pharmaceutical ingredient (API)

... „any component of medicine intended to provide pharmacological

activity or another direct effect in the diagnosis, treatment or

prevention of disease, or to affect the structure or function of the

human or animal body by pharmacological means.“

Synonyms: active ingredient, active substance, drug substance, medicinal substance

� Active substances are rarely administered to patients as a pure chemical substance, but are almost always given as formulated preparations (medicine).

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� Besides the choice of the API, you need to make a responsible decision regarding

� route of administration and

� dosage form (DDS).

DF design: Administration route and dosage form

http://www.newhealthadvisor.com/Routes-of-Drug-Administration.html

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� …“any component, other than the API(s), present

in a medicine or used in its manufacture.“

� Functions: act as API(s) carrier and contribute to product stability, biopharmaceutical profile, appearance and patient acceptability.

� Diluents/fillers, binders, disintegrants, lubricants, coatings, preservatives, colorants, flavouringagents,…

� Safety of excipents in pediatric medicines!

Production process

DF design: Excipient

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� Pharmaceutical DF� Determines the physical form of the final

pharmaceutical preparation.

� Is a DDS formed by technological processing (drug formulation).

� Must reflect therapeutic inentions, route of administration, dosing, etc.

� Pharmaceutical preparation � Particular pharmaceutical product containing

API and inactive pharmaceutical ingredients formulated into the particular DF.

� Packed and labelled appropriately

� According to the origin: � manufactured in large scales by pharmaceutical

industry (innovative and generic medicines)

� compounded individually in compounding pharmacies (extemporaneous preparations, galenic preparations)

Dosage form & medicine

1° and 2°

packaging, labelling

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Dosage form design consideration

The following parameters have to be considered � Drug factors - physical and chemical

properties of the API(s)

� Biopharmaceutical and pharmacokinetic factors, including factors affecting rate and extent of drug absorption from different administration routes

� Therapeutic factors, including consideration of the disease to be treated and patient factors

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DF design consideration:API-factors

Properties of API important in DF design and potential stresses occurring during production, with range of manufacturing procedures

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� Administration route and distribution

� Local or systemic action required?

� How quickly a response is needed?

DF design consideration: Biopharmaceutical & PK factors

Variation in time of onset of action for different dosage forms

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DF design: Formulation aims

� To produce a dosage form (drug delivery system) with:

� The right API

� in the right amount,

� distributed to the right place,

� at the right time,

� for right duration of effect.

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Officially monographed dosage forms

European Pharmacopoeia: vol. 1, General Chapter

� 5. General Texts

� Monographs on dosage forms

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Dosage forms

Route of administration(systemic / local)

Physical form

Solid

Semisolid

Liquid

Gaseous

Classification according to

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Dosage forms

Route of administration(systemic / local)

Physical form

Solid

Semisolid

Liquid

Gaseous

Classification according to

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Part 2

Paediatric dosage forms

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Why paediatric formulations?

� Children can not be regarded as small adults!

� Childhood – period of fast growth and development - differences in absorption, distribution, metabolism and elimination (ADME) of API

� Children are heterogeneous population - there is not only one DF being ideal for all children respecting their age, body height/mass,…

Definitions (CPMP/ICH 2711/99 Age range

Preterm newborn infants 37 weeks gestation

Term newborn infants 0 - 1 month

Infants and toddlers 2 - 23-month

Children 2 - 11 years

Adolescent 12 -16/18 years15


Current situation:

� Only a few medicines registered for paediatric use!

� Frequent use of „off label“ or unlicensed medicines

� Preparation mostly from solid DF for adults with respect to:� Difficulties of swallowing solid DF

� Adopting dosing

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The options available to administer oral medicines to children who cannot swallow whole solid DF or need dose volume adjustment:

Standing JF, Tulou C. Paediatric Formulations – Getting to the heart of the problem. Int.J Pharm, 2005: 56-66


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Ideal paediatric formulation?

� Minimal dosage and frequency

� One DF to a wide range of age

� Minimal impact on patient’s lifestyle

� Use of safe and non toxic excipients

� Acceptable organoleptic properties (palatability!)

� Convenient, easy and reliable administration

� Simple technology of preparations, suitable stability and appearance

� Economic aspects

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Challenges of developing paediatric formulations

We have to ensure :

� Consistent legislation

� Adequate capacity of pharmaceutical industry

� Education of all involved staff

trgu.

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Legislation

� Paediatric regulation EC 1901/2006 – valid from Jan. 2007

� To improve quality and ethical research into medicines for children

� To increase the availability of authorized medicines for children

� To increase available information on medicines of children without unnecessar studies in children and wihout delaying authorization for adults.

� Paediatric Committee (PDCO)

� Paediatric Investigation Plan – PIP

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Legislation

� Paediatric regulation EC 1901/2006 – valid from Jan. 2007

� To improve quality and ethical research into medicines for children

� To increase the availability of authorized medicines for children

� To increase available information on medicines of children withoutunnecessar studies in children and wihout delaying authorization foradults.

� Paediatric Committee (PDCO)

� Paediatric Investigation Plan – PIP

� Submission of a PIP to the EMA for agreement by its PDCO

� Since 2008 all applications for new market authorisation (since 2009 alsofor new indication, routes of administration or DF) must contain resultsof studies conducted in compliance with agreed PIP, unless a waiver or deferral was granted

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Pharmaceutical industry

Research & development

� Acceptability� Flexibility� Taste masking (and analysis)� Excipients� Drug delivery devices

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Choice of paediatric formulations

� Ability of taking medicine is age dependent!

Dosing Choice of DF

Choice and amount of excipients Need for suitable applicator

� Properties of API (stability, solubility and especially taste) can represent limiting factors for choice

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� Safety of excipients!

� The number of excipients and their quantitiy in DF should be minimum required


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EMEA 2006.

EMA, 2006 25


EMEA 2006.

EMA, 2006 26

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� Frequent route of administration

� Numerous medicines, formulated in various solid as well as liquid DF: solutions, syrups, suspensions, powders, granules, effervescent tablets, orodispersible tablets, mini tablets, multiple dose DF, modified release DF…

� Palatable taste is critical parameter � must be considered since the early beginning of formulation development

Oral paediatric formulations

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Oral paediatric formulations – taste assessment

Problems

� Different taste between adults and children and among different cultures

Taste assessment - current approaches:� Adults test panels – relevant?

� Clinical testing with children – ethical?

� Regulation authorities do not allow children enrollment in strudy that can beconducted with adults

� “Swill and Spit” approach is allowed, depending on drug safety profile� Better embedding taste assessment in clinical studies with ill children� Concernes about design and outcome of studies with children

� in vitro methods (electronic tongues) – reliable?

Ambitions

� Development and validation of robust and reliable methods for taste assessment and for taste prediction fitting for early develop. phases

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� Create pleasant taste stimulation „cancelling“ that of API

� sweeteners and flavouring agents - only for API(s) with slightly unpleasant taste

� Enhancers

� Prevent/reduce direct contact between drug and taste buds

� Physical barrier around DF/drug particles >> coating, complexation

with CD or ion exchange resins, microencapsulation

� Solublility reduction >> suspensions

� Suppress taste bud response to drug stimulation� Substances competing with API at taste bud receptor sites

� Use of other advance technologies

� Development of flexible formulations enabling taste preference29

Oral paediatric formulations – taste masking approaches

Oral paediatric formulations - taste

Adding of medicines info food or baverige?

� One of possibilities

� Could be compatibility problem?

� In most cases no – it is sufficient that manufacturer inform the users which kind of food have to be avoided!

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Examples of good praxis – dose sipping technology

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Examples of good praxis – Flavor Creator

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Solid formulations

+ easier to select non toxic excipients

+ various possibilities of taste masking

+ good stability

+ ability of modified release

- Difficulties with swallowing and/or dose adaptations

Liquid formulations

+ easy administration anddose addaptation

- Difficult finding of nontoxic excipients

- Microbiological stability problems

- Difficult to maskunpleasant taste

- Problematic measuring of precise dose

Oral dosage forms

Liquid versus solid

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� Monograph - Liquid dosage forms for oral use (Ph. Eur)

� Categories� Oral solutions, emulsions and suspensions� Powders and granules for oral solutions and

suspensions � Oral drops � Powders for oral drop � Syrups� Powders and granules for syrups

Liquid preparations

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� Appropriate for children < 8 years (6 years) being unable of swallowing solid formulations

� Volume - the most important parameter!

� Targeted volume:

≤≤≤≤ 5 ml for children younger than 5 years, and

≤≤≤≤10 ml for children older than 5 years

� Need for standardized measuring devices (measuring spoons, syringe, glasses) for accurate dosing

Liquid preparations

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� Appropriate for APIs with unpleasant taste

� Enable large amount of incorporated API in comparison withsolutions � smaller volume

� Critical parameters of preparations:

� Size of suspending particles and

� their distribution, influencing on:

� Appearance

� Sedimentation rate

� Absorption rate

� Capability of redispersing.

Paediatric suspensions

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� Very popular dosage form

� Known since Arabian times

� Older definition – only sugar solutions or liquid preparations based on sucrose

� Novel pharmacopoeias (Ph.Eur): spread the definition on all liquid preparations containing high conc. (min 45%) of sugars, polios and other sweeteners

� Specific characteristics:

� Increased viscosity

� Increased density

� Microbiological stability without adding preservatives

� Better taste

Syrups

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� Oral powders (Ph. Eur.- Powders, oral)

� Effervescent granules and tablets (Ph. Eur - Granules, Tablets)

� Orodisperzible forms (Ph. Eur – Tablets /Orodispersible tablets)

� Medicated chewing gum (Ph. Eur - Chewing gum, medicated)

� Capsules and tablets (Ph. Eur - Capsules, Tablets)

� Multiparticulate dosage forms

� Modified release dosage forms

Solid preparations

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Multiparticulate dosage forms

� granules (0.3 – 1.2 mm)

� pellets (0.5 – 2 mm)

� microcapsules (0.001 – 1 mm)

� mini tablets (1,5 – 3 mm).

� They can be put directly into mouth or mixed in small amount of food or beverage before application

� What age?

� Widely acceptable for children of 4 years

� Age 2-4 years generally swallowed but were also likely to chew

Solid preparationsNew drug delivery concepts

Pediatric drug products with micropellets; from: D.Bar-Shalom,R.Klaus (Eds.). Pediatric Formulations: A Roadmap.

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Orodispersible preparations

� Orodispersible tablets � disintegrate in mouth immediately without water and being chewed

� Disintegration time: less than 3 minutes

� They can be taken immediately, anywhere, anytime

� Chronic diseases: better adherence

� Easy swallowing, pleasant texture, palatable taste, easy dosing for children, elder and mentally handicapped people

Limitations

� Hard to incorporate higher amount of API ( > 500 mg)

� Complicate to mask extremely unpleasant taste

Fast dissolving dosage forms

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Suitability of oral dosage forms

EMEA 2006. Reflection paper: Formulations of choice for the pediatric population

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Other routes of applications

EMEA 2006. Reflection paper: Formulations of choice for the pediatric population

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Literature

� M.E. Aulton (Ed.). Aulton`s Pharmaceutics The design and manufacture of medicines 3rd. Ed. Churchill Livingstone, 2007.

� European Pharmacopoeia 8th. Ed.

� Cram A. Et all. Chalanges of developing palatable oral paediatric formulations. Int. J. Pharm. 365 (2009)1-3.

� EMEA 2006. Reflecton paper: Formulations of choice for the paediatric population.

� Sagraves R. Pediatric dosing and dosage forms. In: Encyclopedia of pharmaceutical technology. Informa Healthcare 2007. 2629-2649.

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Thank you for your attention! Questions?

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principles of dosage form design paediatric formulations · 2015. 12. 14. · principles of dosage...

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