1136
Gastric delivery system for iron
gastric delivery system (GDS) for iron supplementation was evaluated. Radioisotopic A
studies in 9 volunteers demonstrated a three-fold higher absorption of GDS iron compared with ferrous sulphate elixir. A double-blind placebo controlled trial was done in 200 women to the compare gastrointestinal side-effects associated with 50 mg iron daily given either as GDS or conventional ferrous sulphate. The conventional preparation was associated with a significantly higher frequency of nausea and anorexia, whereas there were no significant differences in reported side-effects between subjects receiving GDS or placebo. A single GDS capsule daily provides the same amount of absorbed iron as conventional ferrous sulphate given three times daily, and does not produce gastrointestinal side-effects.
Introduction
deficiency continues to be the most prevalent nutrient deficiency in the world.l,2 Because food fortification is impractical for many developing countries and is not fully effective when iron deficiency is severe, iron supplementation is the preferred intervention in pregnant women. Iron tablets are usually effective in pilot studies but sustained efficacy in applied programmes is uncommon. This may be due to an inadequate distribution system or poor absorption of the iron supplement but the major difficulty is poor compliance related to gastrointestinal side-effects.3 A variety of preparations are available that delay the solubilisation of iron in the gastrointestinal tract. However, absorption is usually 10wer4 because iron release is delayed until the preparation is beyond the area of maximum intestinal uptake. An alternative method of sustaining delivery is to alter the hydrodynamic properties of the delivery system to retain the drug in the stomach.5 This approach is particularly suited to substances that are more soluble in acid. Iron is one such compound and we have therefore incorporated ferrous sulphate into a gastric delivery system (GDS). Iron
Subjects and methods Subjects All subjects gave written, informed consent. The investigation approved by the Human Subjects Committee at the Kansas University Medical Center.
supplementation
infections or gastrointestinal disorders that are known to influence iron assimilation. GDS contains hydroxypropyl methylcellulose, hydrogenated vegetable oil, crospovidone, microcrystalline cellulose, xanthan gum, talcum powder, magnesium stearate, and colloidal silicone dioxide (P. R. Sheth, J. Tossounian, US patent 4126 672) to which ferrous sulphate is added. When a capsule containing the ingredients is placed in aqueous solution, the gelatin coating dissolves but the matrix remains intact. Buoyancy is conferred by the hydrocolloids which form a hydrated boundary layer that impedes the entry of water into the core. By altering the composition the rate of dissolution can be delayed for several hours. Since the stomach never fully empties, the matrix floats there until final
disintegration. Iron was given as ferrous sulphate either in an elixir or GDS. In the first 3 subjects GDS containing 50 mg elemental iron was prepared in slow, intermediate, and fast release forms ; absorption was compared with that from 50 mg ferrous sulphate elixir. In the other 6 men, 10 and 25 mg GDS were compared with equivalent elixir. These preparations were trace-labelled with 15 Fe or S9Fe sulphate. The total dose of administered radioactivity for each test was 37 kBq 59Fe or 93 kBq 55Fe. For the first pair of tests, one preparation labelled with either 55Fe or 59Fe was given on days 1 and 3, and the other preparation tagged with the alternative label was given on days 2 and 4. Blood was collected on day 18 to measure the radioactivity incorporated into circulating red cells. Two additional tests with preparations tagged separately with 55Fe or 59Fe, were done on days 19-22. A blood sample was collected on day 36 to measure increase in red cell radioactivity from the second pair of tests.
All test doses were given between 0700 h and 0900 h after a 10-h fast. No intake of food or drink was allowed for the following 3 h. All iron preparations were taken with a breakfastb of egg (79 g), muffin (59 g), 40% bran flakes (28 g), sugar (5 g), 2% low-fat milk (227 g), and coffee (170 g). The meal contained 2470 kj (590 kcal) and 4-7 mg non-haem iron. The radiolabelled elixir or GDS was ingested midway through the meal. Radioactivity was measured in duplicate 10 ml samples of whole blood with a modification of the method of Eakins and Brown.’.7 Sufficient counts were obtained to reduce the counting error to within 2% in subjects who absorbed more than 1 % of the test dose. Percentage absorption was calculated assuming that 80% of the absorbed radioactivity was incorporated into circulating red cells 14 days after administration. Total blood volume was estimated from the height and weight of the subject.8 Serum ferritin was also measured.9 Because of the skewed distribution of iron absorption data, the mean and standard deviations were expressed as logarithms and the results retransformed to recover the original units of percentage absorption.’O Statistical comparisons of any two absorption tests were based on t tests to establish whether the mean logarithm of absorption ratios differed from zero.
was
Absorption studies Four separate absorption tests were done with sSFe and 59Fe in each of 9 men. A small pilot study was done in 3 subjects to compare the effect of altering the dissolution rate of GDS. In the other 6 subjects, absorption from varying doses of iron was evaluated. All the men were in good health and denied having had recent
ADDRESSES: Division of Hematology, Department of Medicine, Kansas University Medical Center, Kansas City, Kansas, USA (J D Cook, MD, M Carriaga, MD B. S. Skikne, MD); Agency for International Development, Washington DC, USA (S. G. Kahn, PhD); and F. Hoffman-La Roche Ltd, Basel, Switzerland (W Schalch, PhD) Correspondence to Dr J D Cook, Department of Medicine, Kansas University Medical Center, 39th & Rainbow, Kansas City, Kansas 66103, USA.
1137
TABLE I-EFFECT OF RATE OF DISSOLUTION OF GDS ON IRON ABSORPTION
’p
Gastric delivery system for iron
gastric delivery system (GDS) for iron supplementation was evaluated. Radioisotopic A
studies in 9 volunteers demonstrated a three-fold higher absorption of GDS iron compared with ferrous sulphate elixir. A double-blind placebo controlled trial was done in 200 women to the compare gastrointestinal side-effects associated with 50 mg iron daily given either as GDS or conventional ferrous sulphate. The conventional preparation was associated with a significantly higher frequency of nausea and anorexia, whereas there were no significant differences in reported side-effects between subjects receiving GDS or placebo. A single GDS capsule daily provides the same amount of absorbed iron as conventional ferrous sulphate given three times daily, and does not produce gastrointestinal side-effects.
Introduction
deficiency continues to be the most prevalent nutrient deficiency in the world.l,2 Because food fortification is impractical for many developing countries and is not fully effective when iron deficiency is severe, iron supplementation is the preferred intervention in pregnant women. Iron tablets are usually effective in pilot studies but sustained efficacy in applied programmes is uncommon. This may be due to an inadequate distribution system or poor absorption of the iron supplement but the major difficulty is poor compliance related to gastrointestinal side-effects.3 A variety of preparations are available that delay the solubilisation of iron in the gastrointestinal tract. However, absorption is usually 10wer4 because iron release is delayed until the preparation is beyond the area of maximum intestinal uptake. An alternative method of sustaining delivery is to alter the hydrodynamic properties of the delivery system to retain the drug in the stomach.5 This approach is particularly suited to substances that are more soluble in acid. Iron is one such compound and we have therefore incorporated ferrous sulphate into a gastric delivery system (GDS). Iron
Subjects and methods Subjects All subjects gave written, informed consent. The investigation approved by the Human Subjects Committee at the Kansas University Medical Center.
supplementation
infections or gastrointestinal disorders that are known to influence iron assimilation. GDS contains hydroxypropyl methylcellulose, hydrogenated vegetable oil, crospovidone, microcrystalline cellulose, xanthan gum, talcum powder, magnesium stearate, and colloidal silicone dioxide (P. R. Sheth, J. Tossounian, US patent 4126 672) to which ferrous sulphate is added. When a capsule containing the ingredients is placed in aqueous solution, the gelatin coating dissolves but the matrix remains intact. Buoyancy is conferred by the hydrocolloids which form a hydrated boundary layer that impedes the entry of water into the core. By altering the composition the rate of dissolution can be delayed for several hours. Since the stomach never fully empties, the matrix floats there until final
disintegration. Iron was given as ferrous sulphate either in an elixir or GDS. In the first 3 subjects GDS containing 50 mg elemental iron was prepared in slow, intermediate, and fast release forms ; absorption was compared with that from 50 mg ferrous sulphate elixir. In the other 6 men, 10 and 25 mg GDS were compared with equivalent elixir. These preparations were trace-labelled with 15 Fe or S9Fe sulphate. The total dose of administered radioactivity for each test was 37 kBq 59Fe or 93 kBq 55Fe. For the first pair of tests, one preparation labelled with either 55Fe or 59Fe was given on days 1 and 3, and the other preparation tagged with the alternative label was given on days 2 and 4. Blood was collected on day 18 to measure the radioactivity incorporated into circulating red cells. Two additional tests with preparations tagged separately with 55Fe or 59Fe, were done on days 19-22. A blood sample was collected on day 36 to measure increase in red cell radioactivity from the second pair of tests.
All test doses were given between 0700 h and 0900 h after a 10-h fast. No intake of food or drink was allowed for the following 3 h. All iron preparations were taken with a breakfastb of egg (79 g), muffin (59 g), 40% bran flakes (28 g), sugar (5 g), 2% low-fat milk (227 g), and coffee (170 g). The meal contained 2470 kj (590 kcal) and 4-7 mg non-haem iron. The radiolabelled elixir or GDS was ingested midway through the meal. Radioactivity was measured in duplicate 10 ml samples of whole blood with a modification of the method of Eakins and Brown.’.7 Sufficient counts were obtained to reduce the counting error to within 2% in subjects who absorbed more than 1 % of the test dose. Percentage absorption was calculated assuming that 80% of the absorbed radioactivity was incorporated into circulating red cells 14 days after administration. Total blood volume was estimated from the height and weight of the subject.8 Serum ferritin was also measured.9 Because of the skewed distribution of iron absorption data, the mean and standard deviations were expressed as logarithms and the results retransformed to recover the original units of percentage absorption.’O Statistical comparisons of any two absorption tests were based on t tests to establish whether the mean logarithm of absorption ratios differed from zero.
was
Absorption studies Four separate absorption tests were done with sSFe and 59Fe in each of 9 men. A small pilot study was done in 3 subjects to compare the effect of altering the dissolution rate of GDS. In the other 6 subjects, absorption from varying doses of iron was evaluated. All the men were in good health and denied having had recent
ADDRESSES: Division of Hematology, Department of Medicine, Kansas University Medical Center, Kansas City, Kansas, USA (J D Cook, MD, M Carriaga, MD B. S. Skikne, MD); Agency for International Development, Washington DC, USA (S. G. Kahn, PhD); and F. Hoffman-La Roche Ltd, Basel, Switzerland (W Schalch, PhD) Correspondence to Dr J D Cook, Department of Medicine, Kansas University Medical Center, 39th & Rainbow, Kansas City, Kansas 66103, USA.
1137
TABLE I-EFFECT OF RATE OF DISSOLUTION OF GDS ON IRON ABSORPTION
’p
