Project topics and materials
Get Complete Project Material File(s) Now! »
Regulatory aspects of pediatric medicines
The pediatric population comprises about one-third of the world population (1); however, from the economical perspective, the pediatric market is unprofitable to pharmaceutical companies, because children represent a small proportion of the sick population (2). Therefore, for many years and up to date, the number of medical products labelled for pediatric use is limited. Hence, pediatricians have no alternative to prescribe off-label or unlicensed medicines to their patients. In consequence, the lack of information on dosage, potential toxicity, safety and efficacy in children increases the risk to develop adverse or undesired effects and to do not achieve or overpass the therapeutic drug concentrations (3–5). As a result, several initiatives around the world promote the development of pediatric medicines focusing on the suitability of age, size, physiological condition and treatment requirements for this population.
U.S. perspective
In the United States the first legislative initiative was put in effect in 1994 when the “Pediatric Labeling Rule” allowed pharmaceutical companies to review existing data in literature and determined whether they were sufficient to justify their pediatric use, but clinical trials were not required (6). Since, this approach was voluntary and it had a few impact, the FDA introduced the Pediatric Rule in 1997 and concluded in 1998.
At the same time in 1997, the Food and Drug Administration Modernization Act (FDAMA) published a list of drugs which included additional information that could be beneficial for pediatric use and also provided a financial incentive, exclusivity for six months, if the pharmaceutical companies conducted clinical trials to expand the benefit in pediatric use through a Written Request (7,8). This program expired in 2002 and was reauthorized the same year by the Best Pharmaceuticals for Children Act (BPCA) which renewed the exclusivity incentives and also expanded the provision to off-patent drugs involving government contracts for pediatric studies (9). Additionally in 2003, this regulatory framework was complemented by the Pediatric Research Equity Act (PREA) which required mandatory pediatric clinical trials, assessment for all new drug applications and biological license applications except orphan drugs and also addressed development of an age-appropriate formulation (10).
Both legislations the PREA and the BPCA were reauthorized from 2007 to October 2012. Additionally, the FDAAA introduced the Pediatric Review Committee (PeRC) which provides the preparation of consultation on and general review in pediatric plans, assessments, and pediatric studies to ensure quality and consistency (11). Also the PeRC is in charge to review all WRs, deferrals and waivers, and submitted studies in response to a WR (12).
As a response of the mandatory of the BPCA of 2002 and 2007, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), created in 2005 the Pediatric Formulation Initiative (PFI), this project aims: (i) to identify the scientific issues needed to develop appropriate pediatric medicines, (ii) to identify both international and national regulatory issues which affects the development and availability of pediatric medicines, (iii) to seek solutions to facilitate the development and approval for pediatric medications, and (iv) to promote interactive discussions, data exchange forums between academia, industry, sponsors and regulatory agencies (13).
Palatability and taste-masking of oral dosage forms
Another important aspect to be considered at the moment to develop an oral pediatric medicine is the palatability, which is an influential factor to acceptance and compliance of the patient.
Palatability is described as the overall perception of a medicinal product which is related to its smell, taste, texture and after taste specially in oral dosage forms (76).
The taste sense in humans is a chemosensory perception that comes from the stimulation of the taste receptors composed of modified epithelial cells located on the papillae of the tongue and all over the oral cavity. When compounds interact with these receptors once they are dissolved in saliva, one of the following five taste qualities are produced: sweet, sour, bitter, umami or salty (77).
During the 7th and 8th week of gestation taste receptors are developed and achieve their maturity by the 13th and 15th weeks. After birth, newborns are able to detect and tend to reject bitterness and prefer sweet or umami tastes (77).
As many active principles present a bitter taste, the taste-masking of the drug becomes a critical factor in patient compliance, especially in the case of acute or chronic illnesses, where the acceptability of the treatment is related to the pleasant taste of the medicines to be administered (78). The addition of sweeteners and flavors is often used to mask the undesirable taste of drug in pediatric formulations, especially in oral liquid forms (79).
Others techniques have been used to mask the undesirable taste of the active ingredients such as coating, complexation of the active ingredient with cyclodextrins or ion exchange resins, etc. The excipients used with these techniques should provide a safety profile and their bioavailability when are used in children (80).
In other cases, the palatability of the medicine might be improved by mixing it in soft food or beverages, nevertheless the aspects of acceptability, compatibility and stability of the product must be guaranteed (81).
Since the EU legislation on medicines for children became effective in 2007, the taste-making aspects are required by regulatory agencies, despite of the lack of guidance on the evaluation is still poor. Therefore, analytical in-vitro and in-vivo methods have been developed to assess the taste-masking efficacy.
Table of contents :
List of abbreviations
List of tablets
List of figures
GENERAL INTRODUCTION
Research context
Objectives
Presentation of the work
CHAPTER I- INTRODUCTION
1. Regulatory aspects of pediatric medicines
1.1 U.S perspective
1.2 E.U perspective
1.3 ICH of technical requirements for pharmaceutical for human use
1.4 Other initiatives
2. Oral drug development for pediatric populatio
2.1. Pediatric population
2.2. Pharmacokinetic aspects
2.2.1 Absorption
2.2.2 Distribution
2.2.3 Metabolism
2.2.4 Elimination
2.3. Excipients
2.4. Palatability and taste masking of oral dosage forms
2.5. Considerations for pediatric clinical trials
3. Oral age dosage forms
3.1. Liquid dosage forms
3.2. Solid dosage forms
3.3. Flexible oral solid dosage forms
3.3.1. Mini-tablets
3.3.2. Multiparticulate systems
3.3.3. Orodispersible forms
3.3.4. Chewable formulations
4. Oral delivery devices
4.1 Oral pediatric devices
Conclusion
References
CHAPTER II- MATERIALS AND METHODS
1. Materials
2. Methods
2.1 Formulation and evaluation of acetaminophen pellets: influence of the matrix system on the controlled release
2.1.1 Preparation of drug load pellets
2.1.2 Pellet characterization
2.2 Design and development of multiple-unit orodispersible tablets
2.2.1 Preparation of orodispersible granules
2.2.2 Preparation of free-drug pellets
2.2.3 Compression of multiple-unit orodispersible tablets
2.2.4 Powder physical properties
2.2.5 Tablet testing
2.2.6 Drug content of MUP-ODT
2.2.7 In-vitro drug release study
2.3 Development of controlled release of multiple-unit orodispersible tablet
2.3.1 Preparation of drug load pellets
2.3.2 Preparation of orodispersible granules
2.3.3 Compression of MUP-ODTs
2.3.4 Pellet characterization
2.3.5 Tablet testing
2.3.6 In-vitro drug release study
2.3.7 Taste masking evaluation
2.4 Feasibility to compress orodispersible pellets for pediatric use
2.4.1 Preparation of orodispersible pellets
2.4.2 Preparation of free-drug MCC pellets
2.4.3 Pellet physical characterization
2.4.4 Experimental design
2.4.5 Tableting of MUP-ODTs
2.4.6 Tableting testing
2.4.7 Statistical analysis of data
References
CHAPTER III- RESULTS AND DISCUSSIONS
3.1 Formulation and evaluation of acetaminophen pellets: influence of the matrix system on the controlled-release
3.1.1 Yield process and particle size distribution of pellets
3.1.2 Pellet shape
3.1.3 Pellet characterization
3.1.4 Drug release
3.1.5 Taste masking
Conclusions
3.2 Design and development of multiple-unit orodispersible tablets
3.2.1 Development of placebo orodispersible formulations…
3.2.2 Design of multiple-unit orodispersible tablets
3.2.3 Influence of disintegrant on drug pellet release
Conclusions
3.3 Development of controlled release multiple-unit orodispersible tablets…
3.3.1 Pellet characterization
3.3.2 Influence of the matrix formulation on drug dissolution
3.3.3 MUP-ODT compression
3.3.4 Taste masking
Conclusions
3.4 Feasibility to compress orodispersible pellets for pediatric use
3.4.1 Drug-free mannitol based pellets
3.4.2 Compression properties of MUP-ODT
Conclusions
References
CHAPTER IV- GENERAL DISCUSSION AND CONCLUSION
Perspectives
