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.
354
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
Table 1 Suggested consequences of hypovitaminosis D for skeletal and non skeletal health. • Skeletal effects Rickets and osteomalacia Fractures (forearm fractures in children, stress fractures in girls, fractures in subjects >65 years of agea ) Dental caries • Extraskeletal effects Diabetes mellitus types 1 and 2 Infectious diseases (influenza, upper respiratory tract infections, bronchiolitis, pneumonia, tuberculosis) Inflammatory diseases such as allergy, atopic dermatitis, asthma, multiple sclerosis, systemic lupus erythematosus, juvenile idiopathic arthritis, liver fibrosis associated with hepatitis C, inflammatory bowel diseases Cancer (breast, colon, prostate[?], ovary[?], pancreas[?], Hodgkin’s lymphoma[?]) Cardiovascular disease (atherosclerosis, thromboembolic stroke, congestive heart failure in children) Chronic kidney disease (accelerated progression, increased mortality in dialysis patients) Neurologic and psychiatric diseases (autism spectrum disorders, childhood language disorders, multiple sclerosis, Alzheimer’s disease and depression) Pain (muskuloskeletal pain, knee osteoarthritis, dysmenorrhea) Falls in the elderly age infants) Pregnancy (gestational diabetes mellitus, pre-eclampsia, small-forgestational-
• Decreased skin synthesis of vitamin D (poor sunlight exposure, physical agents blocking sun exposure such as sunscreen and clothing, dark-skinned individuals, geographic factors such as latitude, season, air pollution, clouds) • Nutritional vitamin D deficiency (exclusively breast-fed infants, eating disorders including anorexia nervosa and child neglect) • Secondary vitamin D deficiency Malabsorption (cholestatic liver disease, inborn errors of bile acid metabolism, exocrine pancreatic insufficiency including cystic fibrosis, celiac disease, inflammatory bowel diseases, intestinal lymphangiectasia, bowel resection) Pathologically increased degradation of vitamin D (anticonvulsants such as phenobarbital, phenytoin and carbamazepine, antimicrobials such as isoniazid and rifampicin, some antiretroviral drugs) Reduced liver 25-hydroxylase activity (hepatopathy with loss of liver function >90%) Chronic kidney disease and reduced renal 1␣-hydroxylase activity • Connatal vitamin D deficiency (poor sun exposure and insufficient maternal intake of vitamin D during pregnancy, closey spaced pregnancies) • Inborn defects in vitamin D metabolism (1␣-hydroxylase deficiency, vitamin D receptor deficiency) • Overweight
A circulating 25(OH)-vitamin D level of ≥75 nmol/L is generally needed for preventing these fractures. a
cents in relation to circulating 25(OH)-vitamin D levels have been suggested (Table 2) (Misra et al., 2008). To prevent hypovitaminosis D, in most industrialized countries, healthy infants are prescribed vitamin D supplementation (Dratva et al., 2006; Wagner et al., 2008; Paunier, 1991). Furthermore, also older children who are at risk for vitamin D insufficiency are supplemented (Table 3). Unfortunately, in Switzerland most families do not appropriately supplement their children with vitamin D (Bartoli et al., 2006; Dratva et al., 2006; Pronzini et al., 2008). In our experience (Bartoli et al., 2006) palatability characteristics of vitamin D preparations play a crucial role in modulating the adherence to vitamin D regimen. Hence, we performed three different studies evaluating the palatability (taste (Martínez et al., 2006; Lava et al., 2011) and consistency (Bianchetti et al., 2010)) of different vitamin D preparations. In the present article, we present the results of our trials in a renewed fashion. In a first trial, we recruited 40 healthy newborn infants (24 boys and 16 girls) aged between 2 and 15 days and their caregivers. Acceptance was evaluated by administering two liquid cholecalciferol formulations: (1) one drop of Vi-De3® , which contains cholecalciferol dissolved in ethanol 65% (alcoholic vitamin D3 , produced by Wild AG, Basel, Switzerland, containing 113 g/mL, corresponding to 2.5 g per drop), and (2) one drop of Oleovit D3 ® , Table 2 Standards for defining vitamin D status in children and adolescents in relation to circulating 25(OH)-vitamin D levels (endorsed by American Academy of Pediatrics). 25(OH)-vitamin D level
Severe deficiency Deficiency Insufficiency Sufficiency Desirable valuea Excess Intoxication a
Table 3 Conditions that predispose to hypovitaminosis D in children.
nmol/L
ng/mL
375
150
This value was extrapolated from observational data obtained in adulthood.
which contains cholecalciferol dissolved in peanut oil (oily vitamin D3 , produced by Fresenius Kabi AG, Bad Homburg, Germany, containing 450 g/mL, corresponding to 10.0 g per drop) (Martínez et al., 2006). Briefly, following procedure was used. One drop of each preparation was placed in the child’s mouth. Immediately thereafter, caregivers were asked to rate the facial reaction of their infants by pointing on a scale that depicts 4 degrees of pleasure. Between tasting of the two formulations, the baby received some milk to rinse its mouth. Thirty-eight mothers indicated that the infant prefers the oily cholecalciferol (P < 0.0001), while the remaining two mothers identified no difference between the tested preparations (Fig. 1, left panel). The left panel depicts the acceptance of vitamin D3 dissolved in alcohol and in peanut-oil among mothers of 40 newborns (16 girls, 24 boys). The differences in palatability score between alcoholic and oily cholecalciferol were statistically significant (P < 0.0001). The right panel depicts the acceptance of vitamin D3 dissolved in alcohol and in medium-chain triglycerides among mothers of 41 newborns (20 girls and 21 boys). The difference between the two preparations was highly significant (P < 0.0001). Considering the increasing prevalence of peanut allergy, some authors recommend to avoid introducing peanuts (and, therefore, Oleovit D3 ® ) during the first 6 months of life. Consequently, the aforementioned study design was applied to investigate the palatability of the traditional alcoholic preparation (Vi-De3 ® ) as compared to a recently developed formulation containing vitamin D3 dissolved in medium-chain triglycerides (Vitamin D3 Wild® , which contains 500 g/mL, corresponding to 12.5 g per drop). For this purpose, we recruited 42 healthy newborn infants (20 boys, 22 girls), aged between 2 and 7 days (Lava et al., 2011). 41 mothers completed the comparison (Fig. 1, right panel): 38 of them assigned a superior facial score to the oily vitamin D3 preparation (P < 0.0001), while the remaining three participants identified no difference between the two tested preparations. Nobody positively rated the alcoholic vitamin D3 preparation. For evaluating formulations of different consistency, we recruited 20 children aged 8–11 years (11 boys and 9 girls) and 20 children aged 4 to 7 years (13 boys and 7 girls) who were at risk of reduced bone mineralization (Bianchetti et al., 2010). Acceptance was determined after administration of two different formulations that contain 500 mg of calcium combined with 10 g of vitamin D3 : (1) a single-serving sachet (Calcium Sandoz D3f, Sandoz, Holzkirchen, Germany) containing a lemon-flavored non-
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
355
Fig. 1. Comparative palatability of liquid vitamin D3 Preparations among Newborns, depicted by means of facial hedonic scales.
effervescent powder (administered mixed with 100 mL of water and a spoon); and (2) a banana-flavored suspension (Colecalcium, Humana Italia SpA, Milan, Italy) containing the mentioned quantities of calcium and vitamin D3 in 12.5 mL. The sachet and the suspension were only identified by letters, but we did not disguise the preparations. The study procedure was similar to that used in the newborn studies, but in this comparison we employed a facial hedonic scale that depicts 5 degrees of pleasure. Out of the 40 participants, 38 children completed the comparison (Fig. 2). Fifteen out of the 20 (75%) children 8–11 years of age preferred the lemonflavored sachet, 4 (20%) did not express a clear-cut preference and 1 (5%) preferred the banana-flavored suspension (P < 0.001). On the other side, 12 out of the 18 (67%) children 4–7 years of age who completed the comparison preferred the banana-flavored suspension, 5 (28%) did not express a clear-cut preference and 1 (5%) preferred the lemon-flavored sachet (P < 0.002). The results were not affected by the presentation’s order of the two preparations. In children 8–11 years of age, the score assigned to the sachet was significantly higher than that assigned to the suspension (P < 0.001). Conversely, in children 4–7 years of age, the rated score
assigned to the sachet was significantly lower than that assigned to the suspension (P < 0.002). A first strength of our trials is their carefully randomized design. Actually, other studies investigated protective and risk factors for low adherence to vitamin D supplementation, but this was done retrospectively, using surveys among parents or healthcare workers (Dratva et al., 2006). To the best of our knowledge, our investigations represent the first studies providing interventional evidence for a better acceptability of oily vitamin D preparations as compared to alcoholic vitamin D formulations. A second relevant strength of the newborn trials (Martínez et al., 2006) resides in the recruitment of healthy newborns and infants selected at discharge from a well-baby nursery. They represent the vast majority of infants and the population at major risk for low adherence (Dratva et al., 2006), thus avoiding selection biases. Our studies have some limitations. Firstly, the study performed in children (Bianchetti et al., 2010) was not blinded, as the preparations were not disguised. Secondly, our explorative trials were performed among a small number of infants. Nevertheless, number of participants was chosen according to what is currently believed
Fig. 2. Facial hedonic scales of 2 different commercially available formulations containing calcium and vitamin D3 as banana-flavored suspension or as a lemon-flavored sachet.
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to be adequate for palatability studies (Davies and Tuleu, 2008). Thirdly, only one socio-cultural region of Switzerland was analyzed (the Italian-speaking region). As some relevant regional differences in vitamin D supplementation adherence have been found among different sociocultural regions in this country (Dratva et al., 2006), our results cannot be automatically generalized to the French and German-speaking regions of Switzerland and Europe. Fourthly, assessment of palatability among newborns and infants is traditionally considered difficult. Actually, facial-hedonic scales are not yet validated in these age groups. On the other side, however, such scales are validated for palatability assessment among older children (Davies and Tuleu, 2008). Furthermore, they have been often used to determine appreciation of food and beverages in older children (Birch, 1999; Chen et al., 1996; Peyram and Pilgrim, 1957) and for pain-measurements among newborns and infants (Slater et al., 2010). Finally, we repeatedly used them with extremely consistent results (Martínez et al., 2006; Lava et al., 2011; Bianchetti et al., 2010; Meier et al., 2007; Milani et al., 2010; Zgraggen et al., 2012). Finally, our trials were performed using facial hedonic scales that depict either an odd or an even number of rated pleasures. We currently prefer the use of scales that contain an even (and rather small) number of possible answers because this straightforward strategy requires participants to express a preference. It has been speculated that the need for palatability trials in children will increase in the next decade and that taste acceptability will need to be assessed also in infancy and early childhood (Winzenburg and Desset-Brèthes, 2012). With this respect, we feel that the presented data teach us two interesting methodological aspects. Firstly, facial hedonic scales appear more and more reliable tools for assessing palatability (or, at least, formulations acceptability) among newborns and infants. Secondly, the trial performed among children (Bianchetti et al., 2010) shows that, in evaluating pediatric formulations, it is crucial to distinguish among children of different ages (Chen et al., 1996). In conclusion, our results demonstrate that acceptability of vitamin D supplementation is modulated by taste and consistency characteristics of the prescribed formulation. Addressing such practical issues is pivotal in pediatric care, and particularly in preventive pediatric medicine, where the need of taking drugs is not as immediately perceived as in front of a sick child. Furthermore, our experience provides some methodological clues for further research evaluating palatability of pediatric drug formulations.
References Bartoli, F., Martínez, J.M., Ferrarini, A., Recaldini, E., Bianchetti, M.G., 2006. Poor adherence to the prophylactic use of vitamin D3 in Switzerland. J. Pediatr. Endocrinol. Metab. 19, 281–282. Bianchetti, A.A., Lava, S.A., Bettinelli, A., Rizzi, M., Simonetti, G.D., Bianchetti, M.G., 2010. Preference for formulations containing calcium and vitamin D(3) in childhood: a randomized-sequence, open-label trial. Clin. Ther. 32, 1083–1087. Birch, L.L., 1999. Development of food preferences. Annu. Rev. Nutr. 19, 41–62. Chen, A.W., Resurrecion, A.V.A., Paguio, L.P., 1996. Age appropriate hedonic scales to measure food preferences of young children. J. Sens. Stud. 11, 141–163. Chesney, R.W., 2010. Vitamin D and The Magic Mountain: the anti-infectious role of the vitamin. J. Pediatr. 156, 698–703. Davies, E.H., Tuleu, C., 2008. Medicines for children: a matter of taste. J. Pediatr. 153, 599–604. DeLuca, H.F., 2004. Overview of general physiologic features and functions of vitamin D. Am. J. Clin. Nutr. 80 (Suppl.), 1689S-96S. Devereux, G., Litonjua, A.A., Turner, S.W., Craig, L.C., McNeill, G., Martindale, S., Helms, P.J., Seaton, A., Weiss, S.T., 2007. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am. J. Clin. Nutr. 85, 853–859. Dobnig, H., Pilz, S., Scharnagl, H., Renner, W., Seelhorst, U., Wellnitz, B., Kinkeldei, J., Boehm, B.O., Weihrauch, G., Maerz, W., 2008. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch. Intern. Med. 168, 1340–1349. Dratva, J., Merten, S., Ackermann-Liebrich, U., 2006. Vitamin D supplementation in Swiss infants. Swiss. Med. Wkly. 136, 473–481. Holick, M.F., 2007. Vitamin D deficiency. N. Engl. J. Med. 357, 266–281.
Hyppönen, E., Läärä, E., Reunanen, A., Järvelin, M.R., Virtanen, S.M., 2001. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 1500–1503. Lava, S.A., Caccia, G., Osmetti-Gianini, S., Simonetti, G.D., Milani, G.P., Falesi, M., Bianchetti, M.G., 2011. Acceptance of two liquid vitamin D3 formulations among mothers with newborn infants: a randomized, single-blind trial. Eur. J. Pediatr. 170, 1559–1562. Martínez, J.M., Bartoli, F., Recaldini, E., Lavanchy, L., Bianchetti, M.G., 2006. A taste comparison of two different liquid colecalciferol (vitamin D3) preparations in healthy newborns and infants. Clin. Drug Investig. 26, 663–665. Meier, C.M., Simonetti, G.D., Ghiglia, S., Fossali, E., Salice, P., Limoni, C., Bianchetti, M.G., 2007. CHIld Project, Palatability of angiotensin II antagonists among nephropathic children. Br. J. Clin. Pharmacol. 63, 628–631. Milani, G., Ragazzi, M., Simonetti, G.D., Ramelli, G.P., Rizzi, M., Bianchetti, M.G., Fossali, E.F., 2010. Superior palatability of crushed lercanidipine compared to amlodipine among children. Br. J. Clin. Pharmacol. 69, 204–206. Misra, M., Pacaud, D., Petryk, A., Collett-Solberg, P.F., Kappy, M., Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society, 2008. Vitamin D deficiency in children and its management: review of current knowledge and recommendations. Pediatrics 122, 398–417. Paunier, L., 1991. Prevention of rickets. In: Nestlé Nutr Workshop Ser Pediatr Program, vol. 21, pp. 263–272. Peyram, D.R., Pilgrim, F.J., 1957. Hedonic scales method of measuring food preferences. Food Technol. 11, 9–14. Pronzini, F., Bartoli, F., Vanoni, F., Corigliano, T., Ragazzi, M., Balice, P., Bianchetti, M.G., 2008. Palatability of vitamin D3 preparations modulates adherence to the supplementation in infancy. Clin. Pediatr. Endocrinol. 17, 57–60. Rosen, C.J., 2011. Clinical practice. Vitamin D insufficiency. N. Engl. J. Med. 364, 248–254. Shaw, N.J., Mughal, M.Z., 2013. Vitamin D and child health: part 2 (extraskeletal and other aspects). Arch. Dis. Child. 98, 368–372. Slater, R., Cornelissen, L., Fabrizi, L., Patten, D., Yoxen, J., Worley, A., Boyd, S., Meek, J., Fitzgerald, M., 2010. Oral sucrose as an analgesic drug for procedural pain in newborn infants: a randomised controlled trial. Lancet 376, 1225–1232. Wagner, C.L., Greer, F.R., American Academy of Pediatrics Section on Breastfeeding, American Academy of Pediatrics Committee on Nutrition, 2008. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122, 1142–1152. Winzenburg, G., Desset-Brèthes, S., 2012. Industry perspective on palatability testing in children-two case studies. Int. J. Pharm. 435, 139–142. Zgraggen, L., Faré, P.B., Lava, S.A., Simonetti, G.D., Fossali, E.F., Amoruso, C., Bianchetti, M.G., 2012. Palatability of crushed ß-blockers, converting enzyme inhibitors and thiazides. J. Clin. Pharm. Ther. 37, 544–546.
http://dx.doi.org/10.1016/j.ijpharm.2013.08.068
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.
354
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
Table 1 Suggested consequences of hypovitaminosis D for skeletal and non skeletal health. • Skeletal effects Rickets and osteomalacia Fractures (forearm fractures in children, stress fractures in girls, fractures in subjects >65 years of agea ) Dental caries • Extraskeletal effects Diabetes mellitus types 1 and 2 Infectious diseases (influenza, upper respiratory tract infections, bronchiolitis, pneumonia, tuberculosis) Inflammatory diseases such as allergy, atopic dermatitis, asthma, multiple sclerosis, systemic lupus erythematosus, juvenile idiopathic arthritis, liver fibrosis associated with hepatitis C, inflammatory bowel diseases Cancer (breast, colon, prostate[?], ovary[?], pancreas[?], Hodgkin’s lymphoma[?]) Cardiovascular disease (atherosclerosis, thromboembolic stroke, congestive heart failure in children) Chronic kidney disease (accelerated progression, increased mortality in dialysis patients) Neurologic and psychiatric diseases (autism spectrum disorders, childhood language disorders, multiple sclerosis, Alzheimer’s disease and depression) Pain (muskuloskeletal pain, knee osteoarthritis, dysmenorrhea) Falls in the elderly age infants) Pregnancy (gestational diabetes mellitus, pre-eclampsia, small-forgestational-
• Decreased skin synthesis of vitamin D (poor sunlight exposure, physical agents blocking sun exposure such as sunscreen and clothing, dark-skinned individuals, geographic factors such as latitude, season, air pollution, clouds) • Nutritional vitamin D deficiency (exclusively breast-fed infants, eating disorders including anorexia nervosa and child neglect) • Secondary vitamin D deficiency Malabsorption (cholestatic liver disease, inborn errors of bile acid metabolism, exocrine pancreatic insufficiency including cystic fibrosis, celiac disease, inflammatory bowel diseases, intestinal lymphangiectasia, bowel resection) Pathologically increased degradation of vitamin D (anticonvulsants such as phenobarbital, phenytoin and carbamazepine, antimicrobials such as isoniazid and rifampicin, some antiretroviral drugs) Reduced liver 25-hydroxylase activity (hepatopathy with loss of liver function >90%) Chronic kidney disease and reduced renal 1␣-hydroxylase activity • Connatal vitamin D deficiency (poor sun exposure and insufficient maternal intake of vitamin D during pregnancy, closey spaced pregnancies) • Inborn defects in vitamin D metabolism (1␣-hydroxylase deficiency, vitamin D receptor deficiency) • Overweight
A circulating 25(OH)-vitamin D level of ≥75 nmol/L is generally needed for preventing these fractures. a
cents in relation to circulating 25(OH)-vitamin D levels have been suggested (Table 2) (Misra et al., 2008). To prevent hypovitaminosis D, in most industrialized countries, healthy infants are prescribed vitamin D supplementation (Dratva et al., 2006; Wagner et al., 2008; Paunier, 1991). Furthermore, also older children who are at risk for vitamin D insufficiency are supplemented (Table 3). Unfortunately, in Switzerland most families do not appropriately supplement their children with vitamin D (Bartoli et al., 2006; Dratva et al., 2006; Pronzini et al., 2008). In our experience (Bartoli et al., 2006) palatability characteristics of vitamin D preparations play a crucial role in modulating the adherence to vitamin D regimen. Hence, we performed three different studies evaluating the palatability (taste (Martínez et al., 2006; Lava et al., 2011) and consistency (Bianchetti et al., 2010)) of different vitamin D preparations. In the present article, we present the results of our trials in a renewed fashion. In a first trial, we recruited 40 healthy newborn infants (24 boys and 16 girls) aged between 2 and 15 days and their caregivers. Acceptance was evaluated by administering two liquid cholecalciferol formulations: (1) one drop of Vi-De3® , which contains cholecalciferol dissolved in ethanol 65% (alcoholic vitamin D3 , produced by Wild AG, Basel, Switzerland, containing 113 g/mL, corresponding to 2.5 g per drop), and (2) one drop of Oleovit D3 ® , Table 2 Standards for defining vitamin D status in children and adolescents in relation to circulating 25(OH)-vitamin D levels (endorsed by American Academy of Pediatrics). 25(OH)-vitamin D level
Severe deficiency Deficiency Insufficiency Sufficiency Desirable valuea Excess Intoxication a
Table 3 Conditions that predispose to hypovitaminosis D in children.
nmol/L
ng/mL
375
150
This value was extrapolated from observational data obtained in adulthood.
which contains cholecalciferol dissolved in peanut oil (oily vitamin D3 , produced by Fresenius Kabi AG, Bad Homburg, Germany, containing 450 g/mL, corresponding to 10.0 g per drop) (Martínez et al., 2006). Briefly, following procedure was used. One drop of each preparation was placed in the child’s mouth. Immediately thereafter, caregivers were asked to rate the facial reaction of their infants by pointing on a scale that depicts 4 degrees of pleasure. Between tasting of the two formulations, the baby received some milk to rinse its mouth. Thirty-eight mothers indicated that the infant prefers the oily cholecalciferol (P < 0.0001), while the remaining two mothers identified no difference between the tested preparations (Fig. 1, left panel). The left panel depicts the acceptance of vitamin D3 dissolved in alcohol and in peanut-oil among mothers of 40 newborns (16 girls, 24 boys). The differences in palatability score between alcoholic and oily cholecalciferol were statistically significant (P < 0.0001). The right panel depicts the acceptance of vitamin D3 dissolved in alcohol and in medium-chain triglycerides among mothers of 41 newborns (20 girls and 21 boys). The difference between the two preparations was highly significant (P < 0.0001). Considering the increasing prevalence of peanut allergy, some authors recommend to avoid introducing peanuts (and, therefore, Oleovit D3 ® ) during the first 6 months of life. Consequently, the aforementioned study design was applied to investigate the palatability of the traditional alcoholic preparation (Vi-De3 ® ) as compared to a recently developed formulation containing vitamin D3 dissolved in medium-chain triglycerides (Vitamin D3 Wild® , which contains 500 g/mL, corresponding to 12.5 g per drop). For this purpose, we recruited 42 healthy newborn infants (20 boys, 22 girls), aged between 2 and 7 days (Lava et al., 2011). 41 mothers completed the comparison (Fig. 1, right panel): 38 of them assigned a superior facial score to the oily vitamin D3 preparation (P < 0.0001), while the remaining three participants identified no difference between the two tested preparations. Nobody positively rated the alcoholic vitamin D3 preparation. For evaluating formulations of different consistency, we recruited 20 children aged 8–11 years (11 boys and 9 girls) and 20 children aged 4 to 7 years (13 boys and 7 girls) who were at risk of reduced bone mineralization (Bianchetti et al., 2010). Acceptance was determined after administration of two different formulations that contain 500 mg of calcium combined with 10 g of vitamin D3 : (1) a single-serving sachet (Calcium Sandoz D3f, Sandoz, Holzkirchen, Germany) containing a lemon-flavored non-
Short papers / International Journal of Pharmaceutics 457 (2013) 337–358
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Fig. 1. Comparative palatability of liquid vitamin D3 Preparations among Newborns, depicted by means of facial hedonic scales.
effervescent powder (administered mixed with 100 mL of water and a spoon); and (2) a banana-flavored suspension (Colecalcium, Humana Italia SpA, Milan, Italy) containing the mentioned quantities of calcium and vitamin D3 in 12.5 mL. The sachet and the suspension were only identified by letters, but we did not disguise the preparations. The study procedure was similar to that used in the newborn studies, but in this comparison we employed a facial hedonic scale that depicts 5 degrees of pleasure. Out of the 40 participants, 38 children completed the comparison (Fig. 2). Fifteen out of the 20 (75%) children 8–11 years of age preferred the lemonflavored sachet, 4 (20%) did not express a clear-cut preference and 1 (5%) preferred the banana-flavored suspension (P < 0.001). On the other side, 12 out of the 18 (67%) children 4–7 years of age who completed the comparison preferred the banana-flavored suspension, 5 (28%) did not express a clear-cut preference and 1 (5%) preferred the lemon-flavored sachet (P < 0.002). The results were not affected by the presentation’s order of the two preparations. In children 8–11 years of age, the score assigned to the sachet was significantly higher than that assigned to the suspension (P < 0.001). Conversely, in children 4–7 years of age, the rated score
assigned to the sachet was significantly lower than that assigned to the suspension (P < 0.002). A first strength of our trials is their carefully randomized design. Actually, other studies investigated protective and risk factors for low adherence to vitamin D supplementation, but this was done retrospectively, using surveys among parents or healthcare workers (Dratva et al., 2006). To the best of our knowledge, our investigations represent the first studies providing interventional evidence for a better acceptability of oily vitamin D preparations as compared to alcoholic vitamin D formulations. A second relevant strength of the newborn trials (Martínez et al., 2006) resides in the recruitment of healthy newborns and infants selected at discharge from a well-baby nursery. They represent the vast majority of infants and the population at major risk for low adherence (Dratva et al., 2006), thus avoiding selection biases. Our studies have some limitations. Firstly, the study performed in children (Bianchetti et al., 2010) was not blinded, as the preparations were not disguised. Secondly, our explorative trials were performed among a small number of infants. Nevertheless, number of participants was chosen according to what is currently believed
Fig. 2. Facial hedonic scales of 2 different commercially available formulations containing calcium and vitamin D3 as banana-flavored suspension or as a lemon-flavored sachet.
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to be adequate for palatability studies (Davies and Tuleu, 2008). Thirdly, only one socio-cultural region of Switzerland was analyzed (the Italian-speaking region). As some relevant regional differences in vitamin D supplementation adherence have been found among different sociocultural regions in this country (Dratva et al., 2006), our results cannot be automatically generalized to the French and German-speaking regions of Switzerland and Europe. Fourthly, assessment of palatability among newborns and infants is traditionally considered difficult. Actually, facial-hedonic scales are not yet validated in these age groups. On the other side, however, such scales are validated for palatability assessment among older children (Davies and Tuleu, 2008). Furthermore, they have been often used to determine appreciation of food and beverages in older children (Birch, 1999; Chen et al., 1996; Peyram and Pilgrim, 1957) and for pain-measurements among newborns and infants (Slater et al., 2010). Finally, we repeatedly used them with extremely consistent results (Martínez et al., 2006; Lava et al., 2011; Bianchetti et al., 2010; Meier et al., 2007; Milani et al., 2010; Zgraggen et al., 2012). Finally, our trials were performed using facial hedonic scales that depict either an odd or an even number of rated pleasures. We currently prefer the use of scales that contain an even (and rather small) number of possible answers because this straightforward strategy requires participants to express a preference. It has been speculated that the need for palatability trials in children will increase in the next decade and that taste acceptability will need to be assessed also in infancy and early childhood (Winzenburg and Desset-Brèthes, 2012). With this respect, we feel that the presented data teach us two interesting methodological aspects. Firstly, facial hedonic scales appear more and more reliable tools for assessing palatability (or, at least, formulations acceptability) among newborns and infants. Secondly, the trial performed among children (Bianchetti et al., 2010) shows that, in evaluating pediatric formulations, it is crucial to distinguish among children of different ages (Chen et al., 1996). In conclusion, our results demonstrate that acceptability of vitamin D supplementation is modulated by taste and consistency characteristics of the prescribed formulation. Addressing such practical issues is pivotal in pediatric care, and particularly in preventive pediatric medicine, where the need of taking drugs is not as immediately perceived as in front of a sick child. Furthermore, our experience provides some methodological clues for further research evaluating palatability of pediatric drug formulations.
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http://dx.doi.org/10.1016/j.ijpharm.2013.08.068
