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in parallel with the small size of the patient population on an EU basis, even more on a national basis. The batch being by definition small, packaging in 25 different languages becomes immediately a nightmare. It is therefore of the utmost importance to rationalize the packaging and a specific box has been developed which allows having all different languages on the same box. This will allow having only one pack for the whole EU, making it manageable from batch release and logistic point of view. The final hurdle will be the negotiation of an acceptable price from the various social systems to make the whole project viable. The current financial environment is not the most favorable but we are hoping to be able to give you next year the conclusion of this presentation that this was a successful development. Fig. 1. Structure of the NaPB two-step coated granule.
Reference To be able to take the right dose prescribed, a specific CE-labeled dosing spoon was developed and validated (Fig. 2) to allow a wide flexibility in the dose ranging; fitting the needs of all patients. The bioequivalence of this formulation with the reference powder was a prerequisite to the whole development and the curves between the reference and the new formulation can hardly be distinguished (Guffon et al., 2012). Moreover the taste characteristics were evaluated in healthy volunteers and confirmed the statistical differences in palatability in favor of this new formulation vs. the reference on bitterness, saltiness and general acceptability. Eventually, the adverse events reported showed 5 ageusia and 1 dropout for severe vomiting after the reference product, and none with ours, all these results confirming the previous in vitro results. Going towards success. An ODD was granted in February 2012 to this new formulation, even though a reference product was registered in the EU since 1999. This ODD was based on a significant clinical benefit over the reference product. A Marketing Authorization Application was introduced in March 2012, and responses to D120 questions are under preparation. Still some hurdles before talking about a successful development, among which the packaging. There are more than 24 different languages in the EU and soon 25 (+Croatian). This has to be put
Guffon, N., Kibleur, Y., Copalu, W., et al., 2012. Developing a new formulation of sodium phenylbutyrate. Arch. Dis. Child. 97, 1081–1085, http://dx.doi.org/10.1136/archdischild-2012-302398.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.066 Microparticulates as drug carriers for pediatric use Norbert Pöllinger Glatt GmbH, Pharmaceutical Services Europe, Binzen, Germany
1. Background “An appropriate drug formulation is the basis of an efficient drug therapy for children. It should allow administering medicines to children accurately and safely. If children refuse to take their medicine or if the formulation concept fails due to a pediatric particularity, the efficacy of the therapy is at risk and medication errors are possible.” (Tuleu et al., 2010). Therefore, the goal is to develop relevant and acceptable pediatric formulations with convenient and precise dosing characteristics in an industrial scale suitable for marketing at affordable cost. The oral administration is the preferred route of administration. It is well accepted in all age groups if administered in a suitable form and allows accurate and flexible dosing. When the taste is acceptable, oral liquids are favored by children. Ideally, medicines should be available in both liquid and solid oral dosage forms. Palatability has become an integral part of formulation development to ensure acceptability of medicines by children (quality part of PIP). While adults can overcome the innate reluctance to swallow a bitter pill, small children cannot make that educated decision. In particular bitter taste lingers longer than other tastes and cannot be simply overcome by adding other taste like a flavor. Therefore, a bad taste must be encapsulated to render the taste imperceptible. Micropellets are considered to be an interesting concept to realize a broad spectrum of pediatric drug products. 2. Considerations on pediatric drug products
Fig. 2. CE-labeled NaPB specific spoon.
When oral pediatric drug products shall be developed a number of important aspects such as the dosage form, the topic of fixed or individualized doses, the potential combination of APIs, the excipients to be used and the taste must be considered in depth. In addition, the specific age of the pediatric patients, the specific conditions to be treated and the specific cultural and treatment settings must be taken into account.
352
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
Fig. 1. Process technologies for drug layered and matrix micropellets.
Normal-size tablets or capsules are no applicable to children. On one hand breaking tablets is often not precise and functional coating would be destroyed. On the other hand tablets smaller than 3 mm are better accepted by children. Powders, granules, pellets and micropellets being smaller than 1 mm are normally accepted from the moment an infant is able to accept solid food and if the taste is not prohibitive. For children younger than 6 months the administration in a liquid form is preferred – as long as drinking water is available. For pediatric drug products the spectrum of pharmaceutical excipients is limited. To make a choice for an excipient not only the technological characteristics and properties are to be considered. Safety, the duration of treatment, potential side effects like allergies and sensitization must be taken into account. Well-known excipients should be preferred but novel excipients cannot be excluded completely (e.g. coating polymers). In pediatric formulations, the concentration of excipients should be limited as much as possible. 3. The micropellets concept Microparticulates are considered to be a promising pediatric formulation approach allowing many different formulation variations. In particular micropellets (spherical particles with a particle size < 500 m) allow access to a broad variability of formulation options:
Fig. 3. Matrix type antibiotic micropellets mad with MicroPx technology and particle size distribution.
• Immediate release/gastro-resistant/modified release micropellets including taste masking. • Micropellets containing the API as a coprecipitate, adsorbate or solubilisate; the solubility of poorly soluble APIs and by this means the bioavailability can be improved (Fig. 1). The API can be provided as a drug layer on neutral starter beads such as sugar pellets or cellulose beads applying the Glatt Wurster fluid bed technology. High API loaded matrix micropellets can be achieved with the continuous Glatt MicroPx fluid bed technology providing a drug load of 95%. With both technologies, drug microparticles in a size range of ∼100–500 m are achieved. A particular processing knowhow and experience is required for the processing of such tiny particles. Spherical micropellets of said size are an ideal substrate for Wurster fluid bed coating applications of any kind. Due to their spherical shape and smooth surface and thereby not too big surface area, less coating material is required than for the coating of powders or irregular shaped granules. Applying the established Glatt Wurster fluid bed technology, a broad spectrum of micropellet forms can be achieved. Using the
Fig. 2. Drug products with micropellets.
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
353
Fig. 4. Taste masked antibiotic micropellets.
MicroPx technology matrix pellet concept is introduced as an additional option. With described micropellets different drug delivery platforms for children are in place: • Oral suspensions (ready to use, to be prepared from a dry suspension). • Sachets and stickpacks. • Dispersible tablets. • Orally dispersible tablets (ODTs). • MUPS tablets. • Fixed dose combinations. • Capsules. • Application of micropellets with devices (e.g. drinking straw, dose sipping syringe) (Fig. 2). • The development of taste-masked antibiotic micropellets for an oral liquid – a case study. In a case study, the development of taste masked micropellets containing a high-dosed extremely bitter antibiotic drug was demonstated. A 250/500 mg dose should be presented in an oral liquid. The particle size of the high drug loaded micropellets was specified to be smaller than 500 m. The taste masking of the micropellets should be stable for 14 days in an aqueous suspension. Nevertheless, a fast dissolution of the antibiotic at neutral pH was requested. The basic formulation concept is based on two main processing steps: • Matrix micropellets manufactured out of the crystalline API using the Glatt MicroPx pelletisation technology; particle size of the spherical and smooth matrix micropellets: ∼200–400 m; yield: ∼95% (Fig. 3). • Application of a seal coat and a taste masking coat on top of the matrix micropellets with the Glatt Wurster fluid bed technology resulting in a particle size of 95% (Fig. 4). • Flexibility with microparticulates – a summary. • Different dosage strengths with one micropellet quality. • Fixed and individualized doses. • API combinations. • Enhancement of solubility and bioavailability. • A broad variability of drug release profiles can be achieved. • Taste masked micropellets allow for different application forms such as oral liquids, sachets, stickpacks, dispersible tablets, ODTs, MUPS, minitablets, capsules.
• Micropellets may be sprinkled on food or applied with devices like straws and sipping syringes. • Micropellet formulations can be achieved with accepted excipients and cost-effective industrial processes.
Reference Tuleu, C., Solomonidou, D., Breitkreutz, J., 2010. Paediatric Formulations. In: Rose, K., Van Den Anker, J.N. (Eds.), Guide to Paediatric Drug Development and Clinical Research. Karger, Basel, pp. 117–127, http://dx.doi.org/10.1159/000315580.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.067 Prevention of vitamin D insufficiency in Switzerland: A never-ending story Sebastiano A.G. Lava 1,2,∗ , Giacomo D. Simonetti 2 , Alessandra A. Bianchetti 1 , Alessandra Ferrarini 1 , Mario G. Bianchetti 1 1 Department of Pediatrics, Bellinzona and Mendrisio, and University of Bern, Bern, Switzerland 2 Division of Pediatric Nephrology, University Children’s Hospital Bern and University of Bern, Bern, Switzerland E-mail address: [email protected] (S.A.G. Lava).
At the turn of the 20th century, rickets, an extreme form of vitamin D deficiency, was rampant among children living in industrialized and polluted cities. With the discovery that sunlight is important in the prevention of rickets and the delineation of the anti-rachitic properties of cod-liver oil, it became possible to both prevent and treat vitamin D deficiency. In addition to its role in maintaining calcium-phosphate homeostasis and bone health, vitamin D might also play a positive role in a variety of other physiologic processes such as susceptibility to diabetes, cancer, infections and cardiovascular, neurologic or psychiatric diseases and modulation of inflammatory pathways (Table 1) (Holick, 2007; DeLuca, 2004; Rosen, 2011; Shaw and Mughal, 2013; Hyppönen et al., 2001; Chesney, 2010; Dobnig et al., 2008; Devereux et al., 2007). Hence, new standards for defining vitamin D status in children and adoles-
∗ Corresponding author at: Department of Pediatrics, San Giovanni Hospital, 6500 Bellinzona, Switzerland. Tel.: +41 91 811 86 68; fax: +41 91 811 80 26.
351
in parallel with the small size of the patient population on an EU basis, even more on a national basis. The batch being by definition small, packaging in 25 different languages becomes immediately a nightmare. It is therefore of the utmost importance to rationalize the packaging and a specific box has been developed which allows having all different languages on the same box. This will allow having only one pack for the whole EU, making it manageable from batch release and logistic point of view. The final hurdle will be the negotiation of an acceptable price from the various social systems to make the whole project viable. The current financial environment is not the most favorable but we are hoping to be able to give you next year the conclusion of this presentation that this was a successful development. Fig. 1. Structure of the NaPB two-step coated granule.
Reference To be able to take the right dose prescribed, a specific CE-labeled dosing spoon was developed and validated (Fig. 2) to allow a wide flexibility in the dose ranging; fitting the needs of all patients. The bioequivalence of this formulation with the reference powder was a prerequisite to the whole development and the curves between the reference and the new formulation can hardly be distinguished (Guffon et al., 2012). Moreover the taste characteristics were evaluated in healthy volunteers and confirmed the statistical differences in palatability in favor of this new formulation vs. the reference on bitterness, saltiness and general acceptability. Eventually, the adverse events reported showed 5 ageusia and 1 dropout for severe vomiting after the reference product, and none with ours, all these results confirming the previous in vitro results. Going towards success. An ODD was granted in February 2012 to this new formulation, even though a reference product was registered in the EU since 1999. This ODD was based on a significant clinical benefit over the reference product. A Marketing Authorization Application was introduced in March 2012, and responses to D120 questions are under preparation. Still some hurdles before talking about a successful development, among which the packaging. There are more than 24 different languages in the EU and soon 25 (+Croatian). This has to be put
Guffon, N., Kibleur, Y., Copalu, W., et al., 2012. Developing a new formulation of sodium phenylbutyrate. Arch. Dis. Child. 97, 1081–1085, http://dx.doi.org/10.1136/archdischild-2012-302398.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.066 Microparticulates as drug carriers for pediatric use Norbert Pöllinger Glatt GmbH, Pharmaceutical Services Europe, Binzen, Germany
1. Background “An appropriate drug formulation is the basis of an efficient drug therapy for children. It should allow administering medicines to children accurately and safely. If children refuse to take their medicine or if the formulation concept fails due to a pediatric particularity, the efficacy of the therapy is at risk and medication errors are possible.” (Tuleu et al., 2010). Therefore, the goal is to develop relevant and acceptable pediatric formulations with convenient and precise dosing characteristics in an industrial scale suitable for marketing at affordable cost. The oral administration is the preferred route of administration. It is well accepted in all age groups if administered in a suitable form and allows accurate and flexible dosing. When the taste is acceptable, oral liquids are favored by children. Ideally, medicines should be available in both liquid and solid oral dosage forms. Palatability has become an integral part of formulation development to ensure acceptability of medicines by children (quality part of PIP). While adults can overcome the innate reluctance to swallow a bitter pill, small children cannot make that educated decision. In particular bitter taste lingers longer than other tastes and cannot be simply overcome by adding other taste like a flavor. Therefore, a bad taste must be encapsulated to render the taste imperceptible. Micropellets are considered to be an interesting concept to realize a broad spectrum of pediatric drug products. 2. Considerations on pediatric drug products
Fig. 2. CE-labeled NaPB specific spoon.
When oral pediatric drug products shall be developed a number of important aspects such as the dosage form, the topic of fixed or individualized doses, the potential combination of APIs, the excipients to be used and the taste must be considered in depth. In addition, the specific age of the pediatric patients, the specific conditions to be treated and the specific cultural and treatment settings must be taken into account.
352
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
Fig. 1. Process technologies for drug layered and matrix micropellets.
Normal-size tablets or capsules are no applicable to children. On one hand breaking tablets is often not precise and functional coating would be destroyed. On the other hand tablets smaller than 3 mm are better accepted by children. Powders, granules, pellets and micropellets being smaller than 1 mm are normally accepted from the moment an infant is able to accept solid food and if the taste is not prohibitive. For children younger than 6 months the administration in a liquid form is preferred – as long as drinking water is available. For pediatric drug products the spectrum of pharmaceutical excipients is limited. To make a choice for an excipient not only the technological characteristics and properties are to be considered. Safety, the duration of treatment, potential side effects like allergies and sensitization must be taken into account. Well-known excipients should be preferred but novel excipients cannot be excluded completely (e.g. coating polymers). In pediatric formulations, the concentration of excipients should be limited as much as possible. 3. The micropellets concept Microparticulates are considered to be a promising pediatric formulation approach allowing many different formulation variations. In particular micropellets (spherical particles with a particle size < 500 m) allow access to a broad variability of formulation options:
Fig. 3. Matrix type antibiotic micropellets mad with MicroPx technology and particle size distribution.
• Immediate release/gastro-resistant/modified release micropellets including taste masking. • Micropellets containing the API as a coprecipitate, adsorbate or solubilisate; the solubility of poorly soluble APIs and by this means the bioavailability can be improved (Fig. 1). The API can be provided as a drug layer on neutral starter beads such as sugar pellets or cellulose beads applying the Glatt Wurster fluid bed technology. High API loaded matrix micropellets can be achieved with the continuous Glatt MicroPx fluid bed technology providing a drug load of 95%. With both technologies, drug microparticles in a size range of ∼100–500 m are achieved. A particular processing knowhow and experience is required for the processing of such tiny particles. Spherical micropellets of said size are an ideal substrate for Wurster fluid bed coating applications of any kind. Due to their spherical shape and smooth surface and thereby not too big surface area, less coating material is required than for the coating of powders or irregular shaped granules. Applying the established Glatt Wurster fluid bed technology, a broad spectrum of micropellet forms can be achieved. Using the
Fig. 2. Drug products with micropellets.
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
353
Fig. 4. Taste masked antibiotic micropellets.
MicroPx technology matrix pellet concept is introduced as an additional option. With described micropellets different drug delivery platforms for children are in place: • Oral suspensions (ready to use, to be prepared from a dry suspension). • Sachets and stickpacks. • Dispersible tablets. • Orally dispersible tablets (ODTs). • MUPS tablets. • Fixed dose combinations. • Capsules. • Application of micropellets with devices (e.g. drinking straw, dose sipping syringe) (Fig. 2). • The development of taste-masked antibiotic micropellets for an oral liquid – a case study. In a case study, the development of taste masked micropellets containing a high-dosed extremely bitter antibiotic drug was demonstated. A 250/500 mg dose should be presented in an oral liquid. The particle size of the high drug loaded micropellets was specified to be smaller than 500 m. The taste masking of the micropellets should be stable for 14 days in an aqueous suspension. Nevertheless, a fast dissolution of the antibiotic at neutral pH was requested. The basic formulation concept is based on two main processing steps: • Matrix micropellets manufactured out of the crystalline API using the Glatt MicroPx pelletisation technology; particle size of the spherical and smooth matrix micropellets: ∼200–400 m; yield: ∼95% (Fig. 3). • Application of a seal coat and a taste masking coat on top of the matrix micropellets with the Glatt Wurster fluid bed technology resulting in a particle size of 95% (Fig. 4). • Flexibility with microparticulates – a summary. • Different dosage strengths with one micropellet quality. • Fixed and individualized doses. • API combinations. • Enhancement of solubility and bioavailability. • A broad variability of drug release profiles can be achieved. • Taste masked micropellets allow for different application forms such as oral liquids, sachets, stickpacks, dispersible tablets, ODTs, MUPS, minitablets, capsules.
• Micropellets may be sprinkled on food or applied with devices like straws and sipping syringes. • Micropellet formulations can be achieved with accepted excipients and cost-effective industrial processes.
Reference Tuleu, C., Solomonidou, D., Breitkreutz, J., 2010. Paediatric Formulations. In: Rose, K., Van Den Anker, J.N. (Eds.), Guide to Paediatric Drug Development and Clinical Research. Karger, Basel, pp. 117–127, http://dx.doi.org/10.1159/000315580.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.067 Prevention of vitamin D insufficiency in Switzerland: A never-ending story Sebastiano A.G. Lava 1,2,∗ , Giacomo D. Simonetti 2 , Alessandra A. Bianchetti 1 , Alessandra Ferrarini 1 , Mario G. Bianchetti 1 1 Department of Pediatrics, Bellinzona and Mendrisio, and University of Bern, Bern, Switzerland 2 Division of Pediatric Nephrology, University Children’s Hospital Bern and University of Bern, Bern, Switzerland E-mail address: [email protected] (S.A.G. Lava).
At the turn of the 20th century, rickets, an extreme form of vitamin D deficiency, was rampant among children living in industrialized and polluted cities. With the discovery that sunlight is important in the prevention of rickets and the delineation of the anti-rachitic properties of cod-liver oil, it became possible to both prevent and treat vitamin D deficiency. In addition to its role in maintaining calcium-phosphate homeostasis and bone health, vitamin D might also play a positive role in a variety of other physiologic processes such as susceptibility to diabetes, cancer, infections and cardiovascular, neurologic or psychiatric diseases and modulation of inflammatory pathways (Table 1) (Holick, 2007; DeLuca, 2004; Rosen, 2011; Shaw and Mughal, 2013; Hyppönen et al., 2001; Chesney, 2010; Dobnig et al., 2008; Devereux et al., 2007). Hence, new standards for defining vitamin D status in children and adoles-
∗ Corresponding author at: Department of Pediatrics, San Giovanni Hospital, 6500 Bellinzona, Switzerland. Tel.: +41 91 811 86 68; fax: +41 91 811 80 26.
