Background
Methods
Materials
OAIs | Supplier |
L-arginine | Fagron, Waregem, Belgium |
L-carnitine | Fagron, Waregem, Belgium |
Chenodesoxycholic acid | BOC Sciences Creative Dynamics, Shirley, United States |
Primaquine phosphate | BOC Sciences Creative Dynamics, Shirley, United States |
Pyridoxal phosphate | Inresa, Bartenheim, France |
Sodium benzoate | Fagron, Waregem, Belgium |
Sodium perchloratea | Merck, Darmstadt, Germany |
Sodium phenylbutyrate | Fyrklovern Scandinavia AB, Mönsteras, Sweden |
Excipients | Supplier |
Aurantii amari epicarp et mesocarp tinctura | Conforma, Destelbergen, Belgium |
Sirupus simplex | Conforma, Destelbergen, Belgium |
Methyl paraben | Fagron, Waregem, Belgium |
Propyl paraben | Fagron, Waregem, Belgium |
Mannitol | Fagron, Waregem, Belgium |
Colloidal silicon dioxide | Fagron, Waregem, Belgium |
Packaging | Supplier |
Hard gelatine capsules | Capsugel, Bornem, Belgium |
Glass bottles 100 ml | Aca Pharma, Nazareth, Belgium |
Plastic opaque cups | Aca Pharma, Nazareth, Belgium |
Methods
Selection of orphan active ingredients
A (2) | B (4) | C (3) | D (2) | E (1) | total | |
---|---|---|---|---|---|---|
Amifampridine | 6 | 12 | 9 | 6 | 3 | 36 |
Sodium phenylbutyratea | 6 | 12 | 9 | 2 | 3 | 32 |
Pyridoxal phosphatea | 6 | 8 | 9 | 6 | 3 | 32 |
Chenodesoxycholic acida | 2 | 12 | 9 | 6 | 3 | 30 |
Primaquine phosphatea | 2 | 12 | 9 | 6 | 3 | 30 |
Fenfluramine | 2 | 12 | 6 | 6 | 3 | 29 |
Sodium hydroxybutyrate | 2 | 12 | 3 | 6 | 3 | 26 |
Difencyprone | 6 | 4 | 6 | 6 | 3 | 25 |
Bimyconase | 2 | 8 | 6 | 2 | 1 | 19 |
Development of compounding formulations
Orphan disease | Prevalence (/100.000) or number of published cases [15] | Recommended dose | Reference | Developed dosage form with OAI concentration (solutions) or OAI mass per dosage unit (capsules) | |
---|---|---|---|---|---|
L-arginine, sodium benzoate, sodium phenylbutyrate | Hyperammonemia: carbamoyl Phosphate synthase deficiency | 0.31P | L-arginine: < 20 kg: 100–200 mg/kg/day; > 20 kg: 2.5–6 g/m2/day (max. 6 g/day) Sodium benzoate: up to 250 mg/kg/day (max. 12 g/day) Sodium phenylbutyrate: < 20 kg: ≤ 250 mg/kg/day; > 20 kg: 5 g/m2/day (maximum: 12 g/day) | [17] | L-arginine: 10 g/100 ml solution Sodium benzoate: 10 g/100 ml solution Sodium phenylbutyrate: 20 g/100 ml solution |
Hyperammonemia: ornithine transcarbamylase deficiency | 1.4P* | ||||
Hyperammonemia: citrillinaemia or argininosuccinate synthase deficiencyHyperammonemia: argininosuccinic aciduria or argininosuccinate lyase deficiency | 2.4P*1.0P* | L-arginine: < 20 kg: 100–300 mg/kg/day; > 20 kg: 2.5–6 g/m2/day (max. 6 g/day) Sodium benzoate: up to 250 mg/kg/day (max. 12 g/day)Sodium phenylbutyrate: < 20 kg: ≤ 250 mg/kg/day; > 20 kg: 5 g/m2/day (maximum: 12 g/day) | [17] | ||
Hyperammonemia due to N-acetylglutamate synthase deficiency | 12a | L-arginine: < 20 kg: 100–200 mg/kg/day; > 20 kg: 2.5–6 g/m2/day (max. 6 g/day) Sodium benzoate: up to 250 mg/kg/day (max. 12 g/day) | [17] | ||
L-carnitine | Carnitine palmitoyl transferase1A deficiency | 50 cases | N.A. | 20 g/100 ml solution | |
Carnitine-acylcarnitine translocase deficiency | 60 cases | N.A. | |||
Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency | 3.2 BPa | 100 mg/kg/day | [18] | ||
Systemic primary carnitine deficiency | 6.85 P | 100–400 mg/kg/day | [19] | ||
Sodium Benzoate | Non-ketotic hyperglycemia Glycine encephalopathy | 0.17 P* | 250–750 mg/kg/day | [20] | 10 g/100 ml solution |
Chenodesoxycholic acid | Cerebrotendinous xanthomatosis | < 5 P | 750 mg/day | 250 mg capsules | |
Primaquine phosphate | Malaria | 3.0 P* | 500 μg/kg and 250 μg/kg daily for 14 days | 30 mg capsules | |
Pneumocystis carinii pneumonia | N.A. | 15 mg/day | |||
Pyridoxal phosphate | Pyridoxamine 5′-oxidase deficiency | 0.2 P* | 30 – 50 mg/kg/day | 10 mg capsules | |
Sodium perchloratea | Prophylactic thyroid protection during radiological examination using iodine contrast agents | N.A. | 1 g/day | [29] | 50 mg/ml solution |
Stability testing
Column HPLC | Mobile phase | Flow rate (ml/min) | UV detection wavelength (nm) | Column oven temperature (°C) | Injection volume (μl) | |
---|---|---|---|---|---|---|
L-arginine | Nucleodur NH2-RP, 5 μm, 4.6 mm × 150 mm | Isocratic: phosphate buffer pH 7.0/acetonitrile 47/53 | 0.8 | 210 | 30 | 20 |
L-carnitine | Nucleodur NH2-RP, 5 μm, 4.6 mm × 150 mm | Isocratic: phosphate buffer pH 4.7/acetonitrile 40/60 | 0.8 | 205 | 30 | 20 |
Primaquine phosphate | Symmetry C8, 3.5 μm, 3 mm × 150 mm | Isocratic: acetonitrile/tetrahydrofuran/trifluoro acetic acid/water 9/1/0.1/90 | 0.75 | 265 | 30 | 10 |
Pyridoxal phosphate | Prevail C18, 5 μm, 4.6 mm × 250 mm | Isocratic: 25 mM KH2PO4 pH 3/acetonitrile 97/3 | 1 | 212 | 25 | 20 |
Sodium benzoate | Prevail Organic acid, 5 μm, 4.6 mm × 250 mm | Isocratic: Water/acetonitrile 75/25 + 0.1% (m/V) formic acid | 1.0 | 225 | 25 | 20 |
Sodium perchlorate | Primesep D column, 5 μm, 3.2 mm × 150 mm equipped with suitable guard column | Gradient with A: 10/90 acetonitrile/water (V/V) + 30 mM ammonium formate, B: 40/60 acetonitrile/water + 80 mM ammonium formate | 0.6 | -a | 30 | 1 |
Sodium phenylbutyrate | C18, end-capped, base-deactivated, 5 μm | Isocratic: glacial acetic acid/methanol/water 1/49/50 | 1.1 | 245 | 35 | 20 |
MBA, PBA | C18, 5 μm, 4.6 mm × 150 mm | Gradient with A: 95/5 0.62% (m/V) KH2PO4 in water/methanol (V/V), B: 5/95 0.62% (m/V) KH2PO4 in water/methanol (V/V) | 1.2 | 245 | 25 | 10 |
Results
Selection of orphan active ingredients
Stability testing
Assay | T0 | T3_5°C | T1_25°C/60%RH | T3_25°C/60%RH | Shelf life |
---|---|---|---|---|---|
L-arginine solution | 98.7; 98.8 | 100.3; 99.9a | 100.8; 99.9a | 98.5; 97.4a | 1 week refrigerated (5 °C) |
L-carnitine solution | 98.6; 100.8 | 102.7; 102.8 | 103.5; 102.9 | 99.3; 99.9 | 3 months |
Chenodesoxycholic acid capsules | 96.9; 96.3; 96.6 | 97.6; 97.6; 97.6 | 98.9; 99.4; 99.3 | 101.2; 100.4b | 3 months |
Primaquine phosphate capsules | 105.7; 101.8 | 98.4; 99.7 | 95.3; 96.7 | 95.3; 99.7 | 3 months |
Pyridoxal phosphate capsules | 104.9; 104.6 | 105.5; 101.8 | 100.3; 100.3 | 101.2; 100.2 | 3 months |
Sodium benzoate solution | 99.0; 99.5 | 101.8; 101.6 | 100.2; 100.1 | 100.6; 97.2 | 3 months |
Sodium perchlorate solution | 90.4; 96.18 | 92.1; 90.1 | 90.6; 93.2 | 91.7; 89.12 | 3 months |
Sodium phenylbutyrate solution | 99.7; 99.5 | 99.4; 101.5 | 100.0; 100.9 | 96.7; 99.7 | 3 months |