Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Ion exchange resin
Reexamination Certificate
1999-01-15
2001-01-30
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Ion exchange resin
C514S814000
Reexamination Certificate
active
06180094
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a medicament which comprises a weakly basic anion exchange resin chelating with ferric ions as an active ingredient. The medicament is useful as a medicament for therapeutic and/or preventive treatment of hyperphosphatemia.
BACKGROUND ART
Patients of chronic renal failure are unavoidably treated by dialysis normally at regular intervals over a prolonged period of time, and pathological conditions of increased plasma phosphate concentrations (4.5 mg/dl or more), i.e., hyperphosphatemia, are often appeared in the patients. Because no direct etiological treatment of hyperphosphatemia has been developed so far, diet therapy to lower phosphate absorption, or as a symptomatic therapy, treatment by oral administration of a medicament for hyperphosphatemia which adsorbs phosphate ions in the digestive tract are generally applied. As medicaments for therapeutic treatment of hyperphosphatemia, aluminum hydroxide gel and precipitated calcium carbonate are commonly used.
International Publication WO95/05184 discloses a method for eliminating phosphate ions in vivo by using a polymer such as polyallylamine, polyethylenimine or other, preferably a cross-linked polymer obtained by using a crosslinking agent such as epichlorohydrin or the like. The publicaition teaches that strongly basic anion exchange resins such as Dowex are not preferred from viewpoints that doses are inevitably high because of their weak adsorbability of phosphate ions and the resins may adsorb salts of bile acids. The publication also teaches that the aforementioned polymers are improved in these points compared to the conventional resins.
Aluminum hydroxide gel used as a medicament for therapeutic treatment of hyperphosphatemia has problems of high daily dosage, and moreover, bad taste, which cause difficulty in administration by a patient. Additionally, aluminum ions, formed by dissociation from the aluminum hydroxide gel in contact with gastric hydrochloric acid, are absorbed from the intestinal tract, and as a result, prolonged administration may sometimes cause precipitation of aluminum in the brain and bones and induces so-called osteopathic aluminosis or encephalopathic aluminosis, microcytic anemia or other. On the other hand, precipitated calcium carbonate used as a medicament for therapeutic treatment of hyperphosphatemia also has a problem that calcium ions formed by dissociation in contact with gastric hydrochloric acid may cause hypercalcemia.
In pathologic conditions of chronic renal failure accompanied by hyperphosphatemia, complications such as iron deficiency anemia, metabolic acidosis or other may often appear in patients. It is well known that administration of aluminum hydroxide gel under these conditions may further deteriorate the anemia. In addition, it is also known that cholestyramine (a preparation comprising a polystyrene-type strongly basic anion exchange resin: “Questran”, Bristol Myers Squibb Co.), which is used as a cholesterol depressant that adsorbs bile acids, also adsorbs iron ions and suppresses the iron absorption from the intestinal tract to reduce the iron concentration in blood and tissues and lower the hematocrit level. which advances iron deficiency anemia (Digestive Diseases, Vol. 17, No. 3, p.263-269, 1972; and Clin. Res. Vol. 18, p.38, 1970). In addition, international Publication WO94/27621 discloses a method for binding iron ions by using a polymer having amino groups. Accordingly, if polystyrene resins and acrylic resins having amino groups, per se, are administered, the aforementioned adverse effect (iron deficiency anemia) may possibly be generated.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a medicament useful for therapeutic and/or preventive treatment of hyperphosphatemia, and free from adverse effects. More specifically, the object is to provide a medicament for therapeutic and/or preventive treatment of hyperphosphatemia which has excellent phosphate eliminating ability and can selectively eliminate phosphate. In addition, another object of the present invention is to provide a method for therapeutic and/or preventive treatment of hyperphosphatemia.
The inventors of the present invention conducted various researches to achieve the foregoing objects. As a result, they found that weakly basic anion exchange resins chelating with ferric ions can efficiently adsorb phosphate ions in vivo, and when the resins were used as medicaments, no adverse effect such as osteopathic aluminosis, encephalopathic aluminosis, hypercalcemia, iron deficiency anemia or other were generated. The present invention was achieved on the basis of these findings.
The present invention thus provides a medicament which comprises a weakly basic anion exchange resin chelating with ferric ions as an active ingredient, preferably, it provides the aforementioned medicament used as a medicament for therapeutic and/or preventive treatment of hyperphosphatemia.
According to a preferred embodiment of the present invention, there is provided the aforementioned medicament which comprises a polyamine-type weakly basic anion exchange resin chelating with ferric ions as an active ingredient. According to another preferred embodiment, there is also provided the aforementioned medicament which comprises an acrylic-type weakly basic anion exchange resin chelating with ferric ions as an active ingredient.
These medicaments, preferably the medicaments for therapeutic and/or preventive treatment of hyperphosphatemia, are typically provided in the form of pharmaceutical compositions which comprise the aforementioned active ingredient together with pharmaceutically acceptable additives.
According to another aspect of the present invention, there is provided use of a weakly basic anion exchange resin chelating with ferric ions for the manufacture of the medicaments defined above, preferably a medicament for therapeutic and/or preventive treatment of hyperphosphatenia. According to preferred embodiment of the invention, there is provided the aforementioned use wherein the weakly basic anion exchange resin is a polyamine-type or an acrylic-type resin.
According to further aspect of the present invention, there is provided a method for therapeutic and/or preventive treatment of hyperphosphatemia which comprises the step of administering to a patient a therapeutically and/or preventively effective amount of a weakly basic anion exchange resin chelating with ferric ions. According to a preferred embodiment of the invention, there is provides the aforementioned method wherein the weakly basic anion exchange resin is a polyamine-type or an acrylic-type resin.
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patent: 5496545 (1996-03-01), Holmes-Earley et al.
patent: 5980881 (1999-11-01), Mitsuka et al.
patent: 94/27621 (1994-12-01), None
patent: 95/05184 (1995-02-01), None
Thomas et al. “Inhibition of Iron Absorption by Cholestyramine”, Digestive Diseases, vol. 17, No. 3, pp. 263-269, 1972.
Clinical Research, vol. 18, p. 38, 1970.
Bursaux et al., “Oxygen Transport in Children on Maintenance Haemodialysis”, Clin. Sci. Mol. Med., vol. 54, No. 1, pp. 85-91, 1978.
Brown et al., “Design of Iron (III) Chelates in Oral Treatment of Anemia: Solution Properties and Absorption of Iron(III) Acetohydroxamate in Anemic Rats”, Bioinorg. Chem., 1978, vol. 9, No. 3, pp. 255-275.
Ishii Yutaka
Sasaki Yoshiyuki
Greenblum & Bernstein P.L.C.
Kulkosky Peter F.
Nikken Chemicals Co., Ltd.
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