Supply, pharmaceutical grading and biopharmaceutical consideration of amyloglucosidase (AMG) solution in congenital sucrase-isomaltase deficiency (CSID) treatment

28 September 2021

R. Lambert1, A. Lachaux3, A. Louguet1, C. Dupuis1, B. Lapras1, C. Paillet2, C. Pivot2, S. Filali1, C. Merienne1, F. Pirot1
1 Unité de Préparation et de Contrôle des Médicaments, plateforme FRIPHARM, Pharmacie à usage intérieur, Groupement Hospitalier Edouard Herriot - Hospices Civils de Lyon
2 Pharmacie à usage intérieur, Groupement Hospitalier Edouard Herriot - Hospices Civils de Lyon
3 Service de gastroentérologie, hépatologie et nutrition pédiatrique, Hôpital Femme Mère Enfant - Hospices Civils de Lyon et Université Claude Bernard Lyon 1, Lyon, France

Congenital SID is a rare genetic condition, which appears during food diversification. An acquired deficit is also possible in association with various digestive diseases. It affects the ability to hydrolyze sucrose and starch into monosaccharides. Primary or secondary deficiency are responsible of a wide variety of phenotypes that reveal after ingestion of sucrose or starch, by stomach cramps, bloating, diarrhea and vomiting. These digestive problems can lead to failure to thrive and malnutrition. Enzyme replacement therapy offers an alternative to sucrose and starch free diets to treat symptoms in SID. Our pharmaceutical platform already proposes an invertase solution (11 600 IU/mL) to improve sucrose digestion. AMG, an enzyme derived from Aspergillus niger strains, widely used in brewing and alcohol distillation, hydrolyzing starch and maltose to glucose, is proposed as supplement to invertase solution for completing SID treatment. However, taking into account its origin, a pharmaceutical qualification is required.

To propose a PQ of a food grade AMG solution and to evaluate its risks and specifications as an enzyme replacement therapy.

Material and methods
According to the European Pharmacopoeia (EP), several characteristics were measured, such as density (calculated by weighing), pH, osmolality (measurement by depression of freezing point). Enzyme activity (EA) dosages were performed by a validated method using the Megazyme R-AMGR3 reagent, in two conditions : (i) at 40°C and pH = 4.5, in strict accordance with the Megazyme assay conditions, (ii) at 37°C and pH = 6, to evaluate the enzyme activity expected in physiological conditions of the duodenum [1] and to define the optimum dose.

Results and discussion
Osmolality (400 ± 2 mOsm/kg, 1/10 diluted solution) and pH (4.5 ± 0.5) were conformed to the supplier specifications. Because of high osmolality, the AMG solution has to be diluted ten times before use. EA was 5275 ± 400 IU/mL at (i) and 1320 ± 70 IU/mL at (ii). Some further tests will be performed to check residual solvents and bioburden. Considering the starch amount ingested per day by children depending on weight [2], the optimum dosage of AMG solution was defined as follow : 2 mL per meal for children under 15 kg, 4 mL per meal for children over 15 kg.

In order to improve SID, AMG solution will be proposed to 25 patients already treated by invertase solution.

[1] Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Dan Med Bull.1999 Jun;46(3):183-96
[2] Fantino M, Gourmet E. Apports nutritionnels en France en 2005 chez les enfants non allaités âgés de moins de 36 mois. Archives de pédiatrie. 2008;15(4):446-455

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