342
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
(e.g. once a day, 4 times a day), the selected administration device, the primary and secondary packaging, the mode of administration (e.g. patient alone or care giver needed). There are cases when the product is mixed with food/beverages to further improve its acceptability – but it is not considered as a necessity, it is more a common practice – therefore this is considered as “off-label” use and beyond the remit of the Regulators. This was not discussed in the presentation. But there are other cases, when it was not possible to obtain an acceptable medicine after trying several formulations (e.g. coating, use of sweeteners or flavours, complexing), mixing with food/beverages is considered as a necessity. In this case, it needs to be detailed in the marketing authorization application and in the product information. This scenario is within the remit of the Regulators. This scenario raised many questions such as: the range of food to could be used (standard food/beverage or a limited range or unlimited options), the kind of studies that would need to be performed (e.g. compatibility studies with the food/beverages), and the level of details that would be expected in the product information SmPC. To illustrate the reality of medicines mixed with food/beverages before administration those points were briefly discussed and an overview of the literature Strickley (2008) and Richey et al. (2011) was given. A presentation of recent case studies was also given: 5 recent Paediatric Investigation Plans (PIPs) and one hybrid application reviewed by the Paediatric Committee Formulation Group (PDCO FWG) and/or the Committee of Human Products (CHMP) The main issues in the PIPs and the hybrid application focused on the need to give the details of the compatibility (e.g pH effect) and stability studies carried out with the food/beverages tested and to conduct acceptability testing. It was highlighted that no standard food/beverages was defined since it is not possible to cover the entire range of food products and there was no final agreement related to the type of methods for the taste assessment (e.g. questionnaire-type method, electronic tongue, adult panels, paediatric panels) to be used to conduct the acceptability of the mixed medicines. However the PDCO FWG encourages the applicants to conduct acceptability testing in the paediatric clinical trials unless justified. Regarding the details expected in the SmPC, it was agreed that the following information would be relevant: the type of food/beverages that have been tested (especially the ones with positive results), the known incompatible food/beverages, the quantities of food/beverage to be used (small quantity expected), the mixing time and mixing instruction, the conditions (storage time and temperature) where the mix of medicine and food/beverage is stable, and the defined time to administer this mix. The conclusion of this presentation was that there is no consensus yet with regard to the type of food/beverages or the type of methods for the taste assessment. In order to improve and share the knowledge in this area, collaboration between the Regulators, the Industry and the Academia was encouraged. In addition, it was noted that during the consultation phase of the draft Paediatric guideline, many comments were raised on mixing medicines with food/beverages. The outcome is under finalisation and it will be possible to look at the overview of comments and the responses from the Quality working Party (QWP) and PDCO FWG (published at a later stage on the EMA website).
References EMA Guideline on pharmaceutical development of medicines for paediatric use. May 2011, EMA/CHMP/QWP/180157/2011, http://www.ema.europa. eu/docs/en GB/document library/Scientific guideline/2011/06/WC500107908. pdf. Strickley, R.G., et al., 2008. Paediatric drugs – a review of commercially available oral formulations. J. Pharm. Sci. 97, 1731. Richey, R.H., Donnell, C., Shah, U.U., Barker, C.E., Craig, J.V., Ford, J.L., Peak, M., Turner, M.A., Nunn, A.J., 2011. An investigation of drug manipulation for dose accuracy in paediatric practice: the Modric study. Arch. Dis. Child. 96, e1, http://dx.doi.org/10.1136/adc.2011.211243.20 (Archives of Disease in Childhoodadc.bmj.com).
http://dx.doi.org/10.1016/j.ijpharm.2013.08.062 Evidence based design of face masks for infants Israel Amirav Department of Pediatrics, Ziv Medical Center, Safed, Israel E-mail address: [email protected]. Most devices used to administer aerosol medications to infants are adapted from devices that were originally designed for adults. Infants however, are different, as there are various anatomical, physiological and behavioral factors peculiar to infants and toddlers that present significant difficulties and challenges in regard to face-mask design. The infant larynx is situated much higher in the upper respiratory tract, very close to the base of the infant’s tongue. Additionally, the epiglottis which is narrow and floppy is located near the palate (see figure).
These anatomic differences may explain why babies are preferentially nose breathers. Airways of infants are narrower and more susceptible to obstruction from any cause which results in an additional barrier to aerosol penetration into more peripheral airways. With a breath-hold the aerosol has more time to undergo gravitational sedimentation and be deposited in the lung. Since infants are unable to hold their breath, there is less time available for sedimentation and thus deposition is decreased and a greater proportion of the inhaled medication is exhaled. By labeling aerosol particles with radioactive agents it is possible to quantify deposition dose and distribution in the respiratory tract. The few available lung deposition studies in infants are strikingly similar with only 2–5% deposition (Table 1). All of these studies were done under the close supervision of medical personnel to ensure compliance & a tight facemask seal. Table 1 Lung deposition in various diseases in infants. Author
Disease
Age (mean, m)
n
% lung deposition
Chua et al. (1994) Mallol et al. (1996) Fok et al. (1996) Wildhaber et al. (1999) Amirav et al. (2002)
CF CF BPD Asthma Bronchiolitis
9 12 3 33 8
12 5 13 8 12
1.3 2.0 1.7 5.4 1.5
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
343
Table 2 Behaviour and lung deposition. Author
Age (mean, m) % deposition during crying
% deposition without crying
Tal et al. (1996) Murakami et al. (1990) Wildhaber et al. (1999) Iles et al. (1999) Amirav et al. (2003)
15 0–24 24 13 8
2.0 ? 5.4 0.4a Low URT-GIT
0.3 Neglible 1.3 0.1a High URT-GIT
URT – upper respiratory tract; GIT – gastro intestinal tract. a By urine analysis.
The infrequent real-world studies, are much more relevant to general pediatric practice and outcomes are, for the most part, more dependent on caregiver adherence to the treatment plan, infant behavior, and acceptance of treatments. In this regard, we need to remember that children can reliably use a mouth piece only from the age of about 3 years. Until then, the only way to deliver aerosol is to apply a mask and ensure a tight seal with the face. The face mask seal, crying, and the child’s acceptance of the prescribed treatment program are crucial if the therapy is to be successful. For efficient aerosol delivery, a tight seal between the mask and the face is critical. It is likely that the relatively high pressure applied by increasingly frustrated parents in order to achieve a tight fit between currently available masks and the face is the main reason that infants cry and fight mask application to the face. In published studies, crying occurs in 38–50% of infants and this dramatically reduces the efficiency of aerosol therapy (Table 2). Current face masks, that are simply a smaller version of those designed for adults, are sub-optimal for infants and poorly accommodate the behavioral problems as well as fundamental design deficiencies related to mask size, dead space, facial seal and contour in small children Amirav and Newhouse (2008). With regard to improving compliance we have introduced the SootherMaskTM concept that incorporates sucking on the infant’s own pacifier to reduce fear of the mask (Amirav et al., 2012). With regard to design, it was necessary to obtain anthropometric data of infants’ faces to account for their rapid developmental growth and constantly variable contour most marked in the first 2–3 years of life. The most important data determining mask design are the coronal dimension (i.e. the vertical distance from the bridge of the nose to the tip of the chin [H]) and rim contour. These dimensions were quantified in a clinical study of 272 infants and young children (0–4 years) using 3D photography structured light technology (Figs. 1–4) Heike et al. (2010). This method has submillimeter accuracy with texture-less surfaces like faces. It enables quick acquisition of non-invasive and accurate images which can be analyzed subsequently off site. H vs age showed great variability (Fig. 5), indicating that age, frequently used in the past, should not be used as a predictor of infants’ facial dimensions for mask design. H and the horizontal closed mouth aperture provided much more reliable and reproducible indices from which the scans could be divided into ‘small’, ‘medium’ and ‘large’ clusters (Fig. 6). All faces within each cluster were aligned to develop an “average” (representative) face model using the iterative closest point (ICP) numerical algorithm. Each 3D image provided thousands of points in 3D space, serving as triangular vertices that, when combined, formed a triangulated mesh surface (Fig. 7). The ICP method starts with an initial ‘guesstimate’ relating the position of one surface with respect to the other and iteratively rotates and translates the surface for improving the alignment between the shapes. Two unaligned faces are shown on the left of Fig. 8, where one face is represented as a smooth template, while the second is represented as a triangulated mesh surface. Alignment
Fig. 1.
of these two faces, using the ICP numerical algorithm, is shown on the right. A representative face was thus constructed by averaging the location of corresponding points for each cluster (Fig. 9). Further analysis utilizing a software engine aligned masks to each of the average faces resulting in an optimally sealing range of small, medium, and large sizes with minimal dead space (Fig. 10). Evidence-based, height and contour-fitting small, medium and large face masks have been specifically developed for infants and toddlers. These evidence-based masks accurately follow facial contours, gently seal to the child’s face, thus minimizing leakage of medication and providing a minimal dead space with relatively little application pressure.
344
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
Fig. 2.
Fig. 3.
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
345
Fig. 6.
Fig. 7.
Fig. 4.
Fig. 8.
Fig. 5.
Fig. 9.
Fig. 10.
346
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
References Amirav, I., Balanov, I., Gorenberg, M., Groshar, D., Luder, A.S., 2003. Nebulizer hood compared to mask in wheezy infants: aerosol therapy without tears! Arch. Dis. Child. 88, 719–723. Amirav, I., Balanov, I., Gorenberg, M., Luder, A.S., Newhouse, M.T., Groshar, D., 2002. Beta agonist aerosol distribution in RSV bronchiolitis in infants. J. Nucl. Med. 43, 487–491. Amirav, I., Luder, A., Chleechel, A., Newhouse, M.T., Gorenberg, M., 2012. Lung aerosol deposition in suckling infants. Arch. Dis. Child. 97, 497–501. Amirav, I., Newhouse, M.T., 2008. Review of optimal characteristics of face-masks for Valved-Holding Chambers (VHCs). Pediatr. Pulmonol. 43, 268–274. Chua, H.L., Collis, G.G., Newbury, A.M., et al., 1994. The influence of age on aerosol deposition in children with cystic fibrosis. Eur. Respir. J. 7, 2185–2191. Fok, T.F., Monkman, S., Dolovich, M., et al., 1996. Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia. Pediatr. Pulmonol. 21, 301–309. Heike, et al., 2010. 3D digital stereophotogrammetry: a practical guide to facial image acquisition. Head Face Med. 6, 18. Iles, R., Lister, P., Edmunds, A.T., 1999. Crying significantly reduces absorption of aerosolised drug in infants. Arch. Dis. Child. 81, 163–165. Mallol, J., Rattray, S., Walker, G., Cook, D., Robertson, C.F., 1996. Aerosol deposition in infants with cystic fibrosis. Pediatr. Pulmonol. 21, 276–281. Murakami, G., Igarashi, T., Adachi, Y., Matsuno, M., Adachi, Y., Sawai, M., Yoshizumi, A., Okada, T., 1990. Measurement of bronchial hyperreactivity in infants and preschool children using a new method. Ann. Allergy 64, 383–387. Tal, A., Golan, H., Grauer, N., Aviram, M., Albin, D., Quastral, M.R., 1996. Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction. J. Pediatr. 128, 479–484. Wildhaber, J.H., Dore, N.D., Wilson, J.M., Devadason, S.G., LeSouef, P.N., 1999. Inhalation therapy in asthma: nebulizer or pressurized metered-dose inhaler with holding chamber? In vivo comparison of lung deposition in children. J. Pediatr. 135, 28–33.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.063 Challenges of pediatric formulations: A FDA science perspective夽 Abhay Gupta, Mansoor A. Khan ∗ Food and Drug Administration, Center for Drug Evaluation and Research, Division of Product Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States E-mail address: [email protected] (M.A. Khan). Drugs prescribed to children have historically been those that were approved for and prescribed to adult patients, although they were rarely testing in the pediatric subpopulation. As a result, over 80% of product labeling did not provide directions for safe and effective use in pediatric patients. This changed with the introduction of pediatric regulations in 1994 that required sponsor to review available pediatric data to determine whether existing data was adequate to support pediatric labeling. No clinical studies were however required. The regulations introduced the concept of extrapolation of efficacy data from adults to children. The Food and Drug Administration Modernization Act (FDAMA) of 1997 (FDA, 1997) created pediatric exclusivity incentives for the sponsors of certain products based on Written Request (WR) from the Food and Drug Administration (FDA), but required that sponsor provide sufficient data and information to support direction of pediatric use for the claimed indications. Pediatric exclusivity was granted as an additional six-month period during which the sponsor retained exclusive marketing control of all forms of the drug product, thereby delaying the introduction of generic products in the market. The act, however, required the sponsor to hold an exist-
夽 Disclaimer: The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. ∗ Corresponding author. Tel.: +1 301 796 0016; fax: +1 301 796 9816.
Table 1 Best Pharmaceuticals for Children Act (2002) vs. Pediatric Research Equity Act (2003). BPCA
PREA
Studies are voluntary Covers drugs only Written request may be issued for orphan drugs Studies encompass the entire active moiety
Studies are mandatory Covers biologics and drugs Studies for orphan drugs and indications not required Studies limited to drug/indication under review
ing patent or exclusivity on the drug. FDAMA was replaced by the Best Pharmaceuticals for Children Act (BPCA) in 2002 (FDA, 2002) which renewed the FDA’s authority to grant six months of marketing exclusivity to sponsors who conduct and submit studies in response to a WR from the agency. The act also included a mechanism for obtaining information on the off-patent drugs for use in pediatric patients. Pediatric Research Equity Act (PREA) of 2003 (FDA, 2003) made the pediatric assessment of certain applications of drug and biological products mandatory, unless the requirement was waived or deferred by the FDA. The act required pediatric assessment for application containing a new ingredient, a new indication, a new dosage form, a new dosing regimen or a new route of drug administration. The waiver was granted in case the necessary studies were impossible or highly impracticable; or, strong evidence suggested that the drug or biologic would be ineffective or unsafe; or, the product did not represent a meaningful therapeutic benefit over existing therapies and was not likely to be used in a substantial number of pediatric patients. A partial waiver was granted if reasonable attempts by the sponsor to produce a pediatric formulation necessary for that age group failed. The act was not applicable to drugs with Orphan designation. The major differences between the Best Pharmaceuticals for Children Act (2002) and the Pediatric Research Equity Act (2003) are summarized in Table 1. Now, over half of all currently marketed drug products include pediatric information on the product labeling. Both, BPCA and PREA, were reauthorized as part of the FDA Amendments Act of 2007 (FDA, 2007). Several approaches, including patient’s age, weight, body surface area etc., have been used to determine the appropriate dose for pediatric population. However additional pharmacokinetic factors should also be considered since the gastric pH, permeability and emptying time are highly variable. Additional considerations include the surface area of the site of drug absorption, the biliary functions and the amount of body water and adipose tissues. The product itself should be easy-to-swallow or dissolvable dosage form with good palatability. It should be prepared using minimal of safe excipients and allow for titration of dose without a need for extemporaneous compounding. The product should also provide adequate bioavailability in the target patient population and be stable under high heat/humidity conditions. Pediatric drug products are currently marketed as a variety of dosage forms, including tablets, capsules, solutions, injections, suspensions, etc. The selection of the dosage form depends on a number of factors, including the aqueous solubility and intestinal permeability of the drug substance. These two factors, along with the drug dissolution, are the most important factors that govern the rate and extent of drug absorption from immediate release solid oral dosage forms. Biopharmaceutics Classification System (BCS) (FDA, 2000) is a scientific framework that classifies drug substances into four classes based on their aqueous solubility and intestinal permeability (Table 2). It plays an important role in the selection of formulation components and product dosage form. Solution dosage forms, because of the ease of drug administration and dose titration, are the preferred dosage form for the pediatric population,
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
(e.g. once a day, 4 times a day), the selected administration device, the primary and secondary packaging, the mode of administration (e.g. patient alone or care giver needed). There are cases when the product is mixed with food/beverages to further improve its acceptability – but it is not considered as a necessity, it is more a common practice – therefore this is considered as “off-label” use and beyond the remit of the Regulators. This was not discussed in the presentation. But there are other cases, when it was not possible to obtain an acceptable medicine after trying several formulations (e.g. coating, use of sweeteners or flavours, complexing), mixing with food/beverages is considered as a necessity. In this case, it needs to be detailed in the marketing authorization application and in the product information. This scenario is within the remit of the Regulators. This scenario raised many questions such as: the range of food to could be used (standard food/beverage or a limited range or unlimited options), the kind of studies that would need to be performed (e.g. compatibility studies with the food/beverages), and the level of details that would be expected in the product information SmPC. To illustrate the reality of medicines mixed with food/beverages before administration those points were briefly discussed and an overview of the literature Strickley (2008) and Richey et al. (2011) was given. A presentation of recent case studies was also given: 5 recent Paediatric Investigation Plans (PIPs) and one hybrid application reviewed by the Paediatric Committee Formulation Group (PDCO FWG) and/or the Committee of Human Products (CHMP) The main issues in the PIPs and the hybrid application focused on the need to give the details of the compatibility (e.g pH effect) and stability studies carried out with the food/beverages tested and to conduct acceptability testing. It was highlighted that no standard food/beverages was defined since it is not possible to cover the entire range of food products and there was no final agreement related to the type of methods for the taste assessment (e.g. questionnaire-type method, electronic tongue, adult panels, paediatric panels) to be used to conduct the acceptability of the mixed medicines. However the PDCO FWG encourages the applicants to conduct acceptability testing in the paediatric clinical trials unless justified. Regarding the details expected in the SmPC, it was agreed that the following information would be relevant: the type of food/beverages that have been tested (especially the ones with positive results), the known incompatible food/beverages, the quantities of food/beverage to be used (small quantity expected), the mixing time and mixing instruction, the conditions (storage time and temperature) where the mix of medicine and food/beverage is stable, and the defined time to administer this mix. The conclusion of this presentation was that there is no consensus yet with regard to the type of food/beverages or the type of methods for the taste assessment. In order to improve and share the knowledge in this area, collaboration between the Regulators, the Industry and the Academia was encouraged. In addition, it was noted that during the consultation phase of the draft Paediatric guideline, many comments were raised on mixing medicines with food/beverages. The outcome is under finalisation and it will be possible to look at the overview of comments and the responses from the Quality working Party (QWP) and PDCO FWG (published at a later stage on the EMA website).
References EMA Guideline on pharmaceutical development of medicines for paediatric use. May 2011, EMA/CHMP/QWP/180157/2011, http://www.ema.europa. eu/docs/en GB/document library/Scientific guideline/2011/06/WC500107908. pdf. Strickley, R.G., et al., 2008. Paediatric drugs – a review of commercially available oral formulations. J. Pharm. Sci. 97, 1731. Richey, R.H., Donnell, C., Shah, U.U., Barker, C.E., Craig, J.V., Ford, J.L., Peak, M., Turner, M.A., Nunn, A.J., 2011. An investigation of drug manipulation for dose accuracy in paediatric practice: the Modric study. Arch. Dis. Child. 96, e1, http://dx.doi.org/10.1136/adc.2011.211243.20 (Archives of Disease in Childhoodadc.bmj.com).
http://dx.doi.org/10.1016/j.ijpharm.2013.08.062 Evidence based design of face masks for infants Israel Amirav Department of Pediatrics, Ziv Medical Center, Safed, Israel E-mail address: [email protected]. Most devices used to administer aerosol medications to infants are adapted from devices that were originally designed for adults. Infants however, are different, as there are various anatomical, physiological and behavioral factors peculiar to infants and toddlers that present significant difficulties and challenges in regard to face-mask design. The infant larynx is situated much higher in the upper respiratory tract, very close to the base of the infant’s tongue. Additionally, the epiglottis which is narrow and floppy is located near the palate (see figure).
These anatomic differences may explain why babies are preferentially nose breathers. Airways of infants are narrower and more susceptible to obstruction from any cause which results in an additional barrier to aerosol penetration into more peripheral airways. With a breath-hold the aerosol has more time to undergo gravitational sedimentation and be deposited in the lung. Since infants are unable to hold their breath, there is less time available for sedimentation and thus deposition is decreased and a greater proportion of the inhaled medication is exhaled. By labeling aerosol particles with radioactive agents it is possible to quantify deposition dose and distribution in the respiratory tract. The few available lung deposition studies in infants are strikingly similar with only 2–5% deposition (Table 1). All of these studies were done under the close supervision of medical personnel to ensure compliance & a tight facemask seal. Table 1 Lung deposition in various diseases in infants. Author
Disease
Age (mean, m)
n
% lung deposition
Chua et al. (1994) Mallol et al. (1996) Fok et al. (1996) Wildhaber et al. (1999) Amirav et al. (2002)
CF CF BPD Asthma Bronchiolitis
9 12 3 33 8
12 5 13 8 12
1.3 2.0 1.7 5.4 1.5
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
343
Table 2 Behaviour and lung deposition. Author
Age (mean, m) % deposition during crying
% deposition without crying
Tal et al. (1996) Murakami et al. (1990) Wildhaber et al. (1999) Iles et al. (1999) Amirav et al. (2003)
15 0–24 24 13 8
2.0 ? 5.4 0.4a Low URT-GIT
0.3 Neglible 1.3 0.1a High URT-GIT
URT – upper respiratory tract; GIT – gastro intestinal tract. a By urine analysis.
The infrequent real-world studies, are much more relevant to general pediatric practice and outcomes are, for the most part, more dependent on caregiver adherence to the treatment plan, infant behavior, and acceptance of treatments. In this regard, we need to remember that children can reliably use a mouth piece only from the age of about 3 years. Until then, the only way to deliver aerosol is to apply a mask and ensure a tight seal with the face. The face mask seal, crying, and the child’s acceptance of the prescribed treatment program are crucial if the therapy is to be successful. For efficient aerosol delivery, a tight seal between the mask and the face is critical. It is likely that the relatively high pressure applied by increasingly frustrated parents in order to achieve a tight fit between currently available masks and the face is the main reason that infants cry and fight mask application to the face. In published studies, crying occurs in 38–50% of infants and this dramatically reduces the efficiency of aerosol therapy (Table 2). Current face masks, that are simply a smaller version of those designed for adults, are sub-optimal for infants and poorly accommodate the behavioral problems as well as fundamental design deficiencies related to mask size, dead space, facial seal and contour in small children Amirav and Newhouse (2008). With regard to improving compliance we have introduced the SootherMaskTM concept that incorporates sucking on the infant’s own pacifier to reduce fear of the mask (Amirav et al., 2012). With regard to design, it was necessary to obtain anthropometric data of infants’ faces to account for their rapid developmental growth and constantly variable contour most marked in the first 2–3 years of life. The most important data determining mask design are the coronal dimension (i.e. the vertical distance from the bridge of the nose to the tip of the chin [H]) and rim contour. These dimensions were quantified in a clinical study of 272 infants and young children (0–4 years) using 3D photography structured light technology (Figs. 1–4) Heike et al. (2010). This method has submillimeter accuracy with texture-less surfaces like faces. It enables quick acquisition of non-invasive and accurate images which can be analyzed subsequently off site. H vs age showed great variability (Fig. 5), indicating that age, frequently used in the past, should not be used as a predictor of infants’ facial dimensions for mask design. H and the horizontal closed mouth aperture provided much more reliable and reproducible indices from which the scans could be divided into ‘small’, ‘medium’ and ‘large’ clusters (Fig. 6). All faces within each cluster were aligned to develop an “average” (representative) face model using the iterative closest point (ICP) numerical algorithm. Each 3D image provided thousands of points in 3D space, serving as triangular vertices that, when combined, formed a triangulated mesh surface (Fig. 7). The ICP method starts with an initial ‘guesstimate’ relating the position of one surface with respect to the other and iteratively rotates and translates the surface for improving the alignment between the shapes. Two unaligned faces are shown on the left of Fig. 8, where one face is represented as a smooth template, while the second is represented as a triangulated mesh surface. Alignment
Fig. 1.
of these two faces, using the ICP numerical algorithm, is shown on the right. A representative face was thus constructed by averaging the location of corresponding points for each cluster (Fig. 9). Further analysis utilizing a software engine aligned masks to each of the average faces resulting in an optimally sealing range of small, medium, and large sizes with minimal dead space (Fig. 10). Evidence-based, height and contour-fitting small, medium and large face masks have been specifically developed for infants and toddlers. These evidence-based masks accurately follow facial contours, gently seal to the child’s face, thus minimizing leakage of medication and providing a minimal dead space with relatively little application pressure.
344
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
Fig. 2.
Fig. 3.
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
345
Fig. 6.
Fig. 7.
Fig. 4.
Fig. 8.
Fig. 5.
Fig. 9.
Fig. 10.
346
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
References Amirav, I., Balanov, I., Gorenberg, M., Groshar, D., Luder, A.S., 2003. Nebulizer hood compared to mask in wheezy infants: aerosol therapy without tears! Arch. Dis. Child. 88, 719–723. Amirav, I., Balanov, I., Gorenberg, M., Luder, A.S., Newhouse, M.T., Groshar, D., 2002. Beta agonist aerosol distribution in RSV bronchiolitis in infants. J. Nucl. Med. 43, 487–491. Amirav, I., Luder, A., Chleechel, A., Newhouse, M.T., Gorenberg, M., 2012. Lung aerosol deposition in suckling infants. Arch. Dis. Child. 97, 497–501. Amirav, I., Newhouse, M.T., 2008. Review of optimal characteristics of face-masks for Valved-Holding Chambers (VHCs). Pediatr. Pulmonol. 43, 268–274. Chua, H.L., Collis, G.G., Newbury, A.M., et al., 1994. The influence of age on aerosol deposition in children with cystic fibrosis. Eur. Respir. J. 7, 2185–2191. Fok, T.F., Monkman, S., Dolovich, M., et al., 1996. Efficiency of aerosol medication delivery from a metered dose inhaler versus jet nebulizer in infants with bronchopulmonary dysplasia. Pediatr. Pulmonol. 21, 301–309. Heike, et al., 2010. 3D digital stereophotogrammetry: a practical guide to facial image acquisition. Head Face Med. 6, 18. Iles, R., Lister, P., Edmunds, A.T., 1999. Crying significantly reduces absorption of aerosolised drug in infants. Arch. Dis. Child. 81, 163–165. Mallol, J., Rattray, S., Walker, G., Cook, D., Robertson, C.F., 1996. Aerosol deposition in infants with cystic fibrosis. Pediatr. Pulmonol. 21, 276–281. Murakami, G., Igarashi, T., Adachi, Y., Matsuno, M., Adachi, Y., Sawai, M., Yoshizumi, A., Okada, T., 1990. Measurement of bronchial hyperreactivity in infants and preschool children using a new method. Ann. Allergy 64, 383–387. Tal, A., Golan, H., Grauer, N., Aviram, M., Albin, D., Quastral, M.R., 1996. Deposition pattern of radiolabeled salbutamol inhaled from a metered-dose inhaler by means of a spacer with mask in young children with airway obstruction. J. Pediatr. 128, 479–484. Wildhaber, J.H., Dore, N.D., Wilson, J.M., Devadason, S.G., LeSouef, P.N., 1999. Inhalation therapy in asthma: nebulizer or pressurized metered-dose inhaler with holding chamber? In vivo comparison of lung deposition in children. J. Pediatr. 135, 28–33.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.063 Challenges of pediatric formulations: A FDA science perspective夽 Abhay Gupta, Mansoor A. Khan ∗ Food and Drug Administration, Center for Drug Evaluation and Research, Division of Product Quality Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993, United States E-mail address: [email protected] (M.A. Khan). Drugs prescribed to children have historically been those that were approved for and prescribed to adult patients, although they were rarely testing in the pediatric subpopulation. As a result, over 80% of product labeling did not provide directions for safe and effective use in pediatric patients. This changed with the introduction of pediatric regulations in 1994 that required sponsor to review available pediatric data to determine whether existing data was adequate to support pediatric labeling. No clinical studies were however required. The regulations introduced the concept of extrapolation of efficacy data from adults to children. The Food and Drug Administration Modernization Act (FDAMA) of 1997 (FDA, 1997) created pediatric exclusivity incentives for the sponsors of certain products based on Written Request (WR) from the Food and Drug Administration (FDA), but required that sponsor provide sufficient data and information to support direction of pediatric use for the claimed indications. Pediatric exclusivity was granted as an additional six-month period during which the sponsor retained exclusive marketing control of all forms of the drug product, thereby delaying the introduction of generic products in the market. The act, however, required the sponsor to hold an exist-
夽 Disclaimer: The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. ∗ Corresponding author. Tel.: +1 301 796 0016; fax: +1 301 796 9816.
Table 1 Best Pharmaceuticals for Children Act (2002) vs. Pediatric Research Equity Act (2003). BPCA
PREA
Studies are voluntary Covers drugs only Written request may be issued for orphan drugs Studies encompass the entire active moiety
Studies are mandatory Covers biologics and drugs Studies for orphan drugs and indications not required Studies limited to drug/indication under review
ing patent or exclusivity on the drug. FDAMA was replaced by the Best Pharmaceuticals for Children Act (BPCA) in 2002 (FDA, 2002) which renewed the FDA’s authority to grant six months of marketing exclusivity to sponsors who conduct and submit studies in response to a WR from the agency. The act also included a mechanism for obtaining information on the off-patent drugs for use in pediatric patients. Pediatric Research Equity Act (PREA) of 2003 (FDA, 2003) made the pediatric assessment of certain applications of drug and biological products mandatory, unless the requirement was waived or deferred by the FDA. The act required pediatric assessment for application containing a new ingredient, a new indication, a new dosage form, a new dosing regimen or a new route of drug administration. The waiver was granted in case the necessary studies were impossible or highly impracticable; or, strong evidence suggested that the drug or biologic would be ineffective or unsafe; or, the product did not represent a meaningful therapeutic benefit over existing therapies and was not likely to be used in a substantial number of pediatric patients. A partial waiver was granted if reasonable attempts by the sponsor to produce a pediatric formulation necessary for that age group failed. The act was not applicable to drugs with Orphan designation. The major differences between the Best Pharmaceuticals for Children Act (2002) and the Pediatric Research Equity Act (2003) are summarized in Table 1. Now, over half of all currently marketed drug products include pediatric information on the product labeling. Both, BPCA and PREA, were reauthorized as part of the FDA Amendments Act of 2007 (FDA, 2007). Several approaches, including patient’s age, weight, body surface area etc., have been used to determine the appropriate dose for pediatric population. However additional pharmacokinetic factors should also be considered since the gastric pH, permeability and emptying time are highly variable. Additional considerations include the surface area of the site of drug absorption, the biliary functions and the amount of body water and adipose tissues. The product itself should be easy-to-swallow or dissolvable dosage form with good palatability. It should be prepared using minimal of safe excipients and allow for titration of dose without a need for extemporaneous compounding. The product should also provide adequate bioavailability in the target patient population and be stable under high heat/humidity conditions. Pediatric drug products are currently marketed as a variety of dosage forms, including tablets, capsules, solutions, injections, suspensions, etc. The selection of the dosage form depends on a number of factors, including the aqueous solubility and intestinal permeability of the drug substance. These two factors, along with the drug dissolution, are the most important factors that govern the rate and extent of drug absorption from immediate release solid oral dosage forms. Biopharmaceutics Classification System (BCS) (FDA, 2000) is a scientific framework that classifies drug substances into four classes based on their aqueous solubility and intestinal permeability (Table 2). It plays an important role in the selection of formulation components and product dosage form. Solution dosage forms, because of the ease of drug administration and dose titration, are the preferred dosage form for the pediatric population,
