U.S. patent application number 10/221585 was filed with the patent office on 2003-05-15 for preventives and/or remedies for hyperphosphatemia.
Invention is credited to Goto, Takeshi, Moriyama, Kazuteru, Sorimachi, Hiroshi, Yoshitake, Kazuhisa.
Application Number | 20030091530 10/221585 |
Document ID | / |
Family ID | 18587082 |
Filed Date | 2003-05-15 |
United States Patent
Application |
20030091530 |
Kind Code |
A1 |
Goto, Takeshi ; et
al. |
May 15, 2003 |
Preventives and/or remedies for hyperphosphatemia
Abstract
Provided in a phosphate ion adsorbent containing a weakly basic
anion exchange resin as an active ingredient which aims at
providing preventives and/or remedies for hyperphosphatemia having
a high selectivity for the adsorption of phosphate ion and showing
an effect of lowering blood phosphorus level and another effect of
suppressing phosphorus excretion into the urine.
Inventors: |
Goto, Takeshi; (Tsukuba-shi,
JP) ; Yoshitake, Kazuhisa; (Tsukuba-shi, JP) ;
Sorimachi, Hiroshi; (Tsukuba-shi, JP) ; Moriyama,
Kazuteru; (Tsukuba-shi, JP) |
Correspondence
Address: |
Jane Massey
Licata & Tyrrell
66 East Main Street
Marlton
NJ
08053
US
|
Family ID: |
18587082 |
Appl. No.: |
10/221585 |
Filed: |
September 12, 2002 |
PCT Filed: |
March 12, 2001 |
PCT NO: |
PCT/JP01/01900 |
Current U.S.
Class: |
424/78.15 ;
424/78.16; 521/32 |
Current CPC
Class: |
A61P 3/00 20180101; A61P
3/12 20180101; Y10S 514/891 20130101; Y10S 514/814 20130101; A61K
31/787 20130101; A61K 31/78 20130101; Y10S 514/824 20130101; A61P
13/12 20180101 |
Class at
Publication: |
424/78.15 ;
424/78.16; 521/32 |
International
Class: |
A61K 031/785; C08F
002/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 13, 2000 |
JP |
2000-67964 |
Claims
1. A phosphate ion adsorbent comprising as an active ingredient a
weakly basic anion exchange resin.
2. The phosphate ion adsorbent according to claim 1, characterized
in that the weakly basic anion exchange resin is a copolymer
containing as monomer components an acrylic acid type compound
having a tertiary amino group and divinylbenzene.
3. The phosphate ion adsorbent according to claim 2, characterized
in that the copolymer further contains as monomer components one or
more components selected from the group consisting of
acrylonitrile, vinylimidazole, vinylhistidine, vinylpyrazine and
diaminodiphenylmethane.
4. The phosphate ion adsorbent according to any one of claims 1-3,
characterized in that the weakly basic anion exchange resin has
porous bead structure.
5. The phosphate ion adsorbent according to claim 4, characterized
in that the weakly basic anion exchange resin is Ionac A-365 (trade
name; Sybron Chemicals Co.).
6. A preventive and/or a remedy for hyperphosphatemia,
characterized in that it contains the phosphate ion adsorbent
according to any one of claims 1-5.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The invention relates to a phosphate ion adsorbent and a
preventive and/or a remedy for hyperphosphatemia.
BACKGROUND ART
[0002] In patients of renal function disorder, disorder of
phosphorus excretion in the urine is observed, and in the early
stages of renal failure a renal compensation mechanism works to
keep phosphorus homeostasis, temporarily showing increase of
phosphorus excretion by inhibiting a phosphorus re-absorption due
to increase of PTH (parathyroid hormone). However, it becomes
impossible to keep the homeostasis due to aggravation of a renal
lesion and lowering of a renal function. As a result,
hyperphosphatemia due to reduction of phosphorus excretion and a
remarkable increase of PTH occurs. The accumulated phosphorus
induces, as direct actions, lowering of blood calcium, acceleration
of PTH production/secretion, ectopic calcification and renal
osteodystrophy due to suppression of vitamin D activation. Also, as
indirect actions via high PTH level, central and peripheral nerve
disorders, myocardial disorders, hyperlipemia, saccharometabolism
disorders, muscle disorders, growth retardation, cardiac conduction
disorders, alveolar diffusion disorders, arteriosclerosis and
immunodeficiency are shown. Further, as to phosphorus the aspect as
a uremic substance and its direct or indirect involvement for
complications of renal failure are known (Jin to Toseki, 37, 2:
321, 1994).
[0003] Even if treatment is changed to a dialysis therapy due to
renal failure, the above disease conditions and complications
continue unless the phosphorus homeostasis is maintained.
Consequently, treatment of hyperphosphatemia is essential for
dialysis patients of renal failure or patients before dialysis. At
present, in the treatment of hyperphosphatemia a diet therapy or an
oral phosphorus adsorbent are used. In the diet therapy low protein
diet is used, though the intake for long period is difficult, and
protein intake of a certain degree is unavoidable, wherefore the
effect to lower phosphorus in blood cannot necessarily be
expected.
[0004] As oral phosphorus adsorbents, mainly three types in the
following are currently used.
[0005] 1) Aluminum preparation (aluminum hydroxide)
[0006] 2) Calcium preparation (calcium carbonate, calcium
acetate)
[0007] 3) Magnesium preparation (magnesium carbonate)
[0008] In 1) side effects of aluminum encephlopathy and aluminum
osteopathy due to aluminum absorption are problems; in 2) the
adsorbability is inferior compared with the aluminum preparation,
and additionally the dose is also high, giving a problem of
inducing hypercalcemia due to calcium absorption; further, in 3)
there is a problem of inducing hypermagnesemia as in the calcium
preparation.
[0009] Methods for using an anion exchange resin as an oral
phosphorus adsorbent have been reported in recent years. In JP, A,
9-504782 (WO95/05184) an anion exchange resin in which polyallyl
amine is crosslinked with epichlorohydrin is reported as a
phosphoric acid adsorbent. Also, in JP, A, 8-506846, WO96/25440, it
is reported that the anion exchange resin having a guanythidyl
group selectively adsorbs phosphoric acid. Further, in JP, A,
9-295941, 2-methylimidazole-epichloro- hydrin copolymer and
cholestyramine which are bile acid adsorbents are applied as oral
phosphorus adsorbents. However, all have a defect that use of a
high dose is necessary because of a remarkable reduction of
phosphate absorption.
[0010] As described above, in a currently carried out
hyperphosphatemia treatment, bad effects are concerned in any
method. Therefore, the present situation is such that a better
remedy for hyperphosphatemia has not been found out up to now.
[0011] On the other hand, although it is known that a weakly basic
anion exchange resin known under the trade name, for example, such
as Ionac A-365 (Sybron Chemicals Co.) is used to remove
hydrochloric acid in an aqueous system and a non-aqueous system,
there has been no report to date in which this is used as a
phosphoric acid adsorbent.
DISCLOSURE OF THE INVENTION
[0012] The invention is accomplished in view of the problems of the
above prior art, and is to provide a preventive and/or a remedy for
hyperphosphatemia having a high selectivity toward a phosphate ion
adsorption action, further having a lowering action of blood
phosphorus concentration and a lowering action of urinary
phosphorus excretion.
[0013] The inventors made extensive researches to solve the above
problems and found out that a weakly basic anion exchange resin ,
which was only used as main uses for removal of hydrochloric acid
in an aqueous system and a non-aqueous system, surprisingly has a
phosphoric acid adsorption action, a lowering action of blood
phosphoric acid concentration and a lowering action of urinary
phosphorus excretion, and accomplished the invention.
[0014] Namely, the invention relates to a phosphate ion adsorbent
comprising as an active ingredient a weakly basic anion exchange
resin.
[0015] Also, the invention relates to the above phosphate ion
adsorbent, characterized in that the weakly basic anion exchange
resin is a copolymer containing as monomer components an acrylic
acid type compound having a tertiary amino group and
divinylbenzene.
[0016] Further, the invention relates to the above phosphate ion
adsorbent, characterized in that the copolymer further contains as
monomer components one or more components selected from the group
consisting of acrylonitrile, vinylimidazole, vinylhistidine,
vinylpyrazine and diaminodiphenylmethane.
[0017] The invention also relates to the above phosphate ion
adsorbent, characterized in that the weakly basic anion exchange
resin has porous bead structure.
[0018] Also, the invention relates to the above phosphate ion
adsorbent, characterized in that the weakly basic anion exchange
resin is Ionac A-365 (trade name; Sybron Chemicals Co.).
[0019] Further, the invention also relates to a preventive and/or a
remedy for hyperphosphatemia, characterized in that it contains the
above phosphate ion adsorbent.
[0020] A phosphate ion adsorbent and a preventive and/or a remedy
for hyperphosphatemia according to the invention not only can
overcome bad effects shown in usual weakly basic anion exchange
resins and the aluminum, calcium and magnesium preparations that
have been used as a preventive and/or a remedy for
hyperphosphatemia, but also have an extremely high selectivity
toward a phosphorus adsorption action compared with oral phosphorus
adsorbents reported so far in which anion exchange resins are
used.
[0021] As described above, considering that in general, a weakly
basic anion exchange resin is a resin that has been used up to now
at the industrial level for the purpose of decoloring,
demineralization or hazardous substance removal for solvent, a
supplied water or a waste water, the effect attained by the
invention is totally surprising.
[0022] Weakly basic anion exchange resins used in the invention
typically have as its main backbone copolymers of an acrylic acid
type compound, which have a tertiary amino group, for example, such
as acrylamide or acrylate, and divinylbenzene, and further may
contain as other monomer components acrylonitrile, vinylimidazole,
vinylhistidine, vinylpyrazine, diaminodiphenylmethane or the like
further in a range that it is pharmaceutically acceptable and does
not reduce the effect. Preferably they are weakly basic
polyacrylate type resins having porous bead structure.
[0023] Although preparation of a weakly basic anion exchange resin
used in the invention can be carried out by a conventional method
known by publications, etc., specifically it can be carried out by
copolymerization of a monovinyl monomer such as acrylic acid or its
alkyl ester and divinylbenzene and reaction of this copolymer with
polyalkylene polyamine. Additionally, this copolymer can be
copolymerized with other monomers such as acrylonitrile,
vinylimidazole, vinylhistidine, vinylpyrazine or
diaminodiphenylmethane in a range that it is pharmaceutically
acceptable and does not lose the effect.
[0024] Illustrative of such a weakly basic anion exchange resin is,
for example, Ionac A-365 (trade name; Sybron Chemicals Co.) which
is being marketed with the main use for removal of, hydrochloric
acid in an aqueous system and a non-aqueous system.
[0025] The phosphoric acid adsorbent and the preventive and/or the
remedy for hyperphosphatemia according to the invention lower blood
phosphorus concentration and urinary phosphorus excretion.
Therefore, the preventive and/or the remedy for hyperphosphatemia
according to the invention are expected to have a preventive and/or
therapeutic effect toward a renal function disorder, chronic renal
failure, dialysis, hypocalcemia, excess secretion of parathyroid
hormone (PTH), suppression of vitamin D activation , ectopic
calcification or the like wherein hyperphosphatemia is considered
to be the cause of disease. Further, the preventive and/or remedy
for hyperphosphatemia of the invention are expected to exert a
remarkable preventive effect and/or therapeutic effect toward PTH
increase due to hyperphosphatemia, secondary hyperparathyroidism
via vitamin D lowering, renal osteodystrophy, uremia, central and
peripheral nerve disorders, anemia, myocardial disorders,
hyperlipemia, saccharometabolism disorders, itch, dermal ischemic
ulcer, tendon rupture, reproductive dysfunction, muscle disorder,
growth retardation, cardiac conduction disorders, alveolar
diffusion disorders, arteriosclerosis, immunodeficiency, etc.
BRIEF DESCRIPTION OF DRAWINGS
[0026] FIG. 1 is a figure which shows the bound amounts with
phosphoric acid of the weakly basic anion exchange resin (Ionac
A-365; Sybron Chemicals Co.) and that of calcium carbonate with
phosphoric acid in Example 1.
[0027] FIG. 2 is a figure which shows the increased amounts of
urinary phosphorus excretion calculated from the difference between
before and after the drug administration in Example 2; in the
figure * and ** show significant differences compared with control
(p<0.05 and p<0.01 respectively, student-t test). Further, in
the figure # shows a significant difference compared with the
calcium carbonate administration group ((p<0.05, student-t
test).
[0028] FIG. 3 is a figure which shows the blood phosphorus
concentrations after the drug administration in Example 3, and in
the figure * shows a significant difference compared with control
(p<0.05, student-t test).
[0029] FIG. 4 is a figure which shows the amounts of urinary
protein excretion before and after the drug administration in
Example 3, and in the figure * and ** show significant differences
compared with control (p<0.05 and p<0.01 respectively,
student-t test).
[0030] FIG. 5 is a figure which shows the adsorption amounts of
phosphoric acid toward Ionac A-365 and Renagel in Example 4.
[0031] FIG. 6 is a figure which shows the adsorption amounts of
bile acid toward Ionac A-365 and Renagel in the example 4.
MODE FOR CARRYING OUT THE INVENTION
[0032] In the following described is an embodiment on a phosphate
ion adsorbent which uses the above weakly basic anion exchange
resin and a preventive and/or a remedy for hyperphosphatemia of the
invention.
[0033] As a phosphate ion adsorbent and a preventive and/or a
remedy for hyperphosphatemia of the invention, although the above
ion exchange resin itself can be used as an active ingredient,
since this has a particle size of 0.3-1.2 mm, preferably vacuum
drying is appllied at room temperature, further being followed by a
step of removing impurities with a sieve after pulverization to
produce a pharmaceutical composition using an ordinarily used
additive for a pharmaceutical preparation. Illustrative of dosage
forms of such a pharmaceutical composition are tablets, capsules,
fine granules, pills, troches, liquids or the like, and these are
administered orally.
[0034] An oral pharmaceutical composition can be prepared by
ordinarily used conventional methods such as mixing, filling and
compressing. Further, by use of a repetitive blend procedure an
effective ingredient can be distributed using a large amount of
filler in a pharmaceutical composition. For example, tablets or
capsules used for oral administration are favorably administered as
a dosage unit form, which may contain conventionally used carriers
for preparations such as binders, fillers, diluents, compressing
agents, lubricants, disintegrators, colorants, flavoring agents and
wetting agents. Tablets can be made as coated tablets using, for
example, a coating agent according to widely known methods.
[0035] Illustrative of preferable fillers are cellulose, mannitol,
lactose, etc., and disintegrators such as starch,
polyvinylprrolidone and a starch derivative such as sodium starch
glycolate or lubricants such as sodium laurylsulfate can be used as
additives for preparations. A pharmaceutical composition of an oral
liquid form is provided as, for example, aqueous or oil
suspensions, solutions, emulsions, syrups or elixirs, or as a dry
pharmaceutical composition which can be redissolved before use by
water or an appropriate medium.
[0036] In such liquids can be blended conventional additives, for
example, such as precipitation preventing agents including
sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose,
carboxymethylcellulose, aluminum stearate gel or hydrogenated
edible fat; emulsifiers such as lecithin, sorbitan monooleate or
gum arabic; oily esters such as almond oil, finely distilled
coconut oil or glycerin ester; non-aqueous solvents such as
propylene glycol or ethyl alcohol (edible oil can also be
contained); preservatives such as methyl ester of p-hydroxybenzoic
acid or sorbic acid, and conventional flavoring agents or colorants
if needed.
[0037] In the case of the above oral pharmaceutical compositions,
for example, such as tablets, capsules or fine granules, usually
contain 5-95 wt. %, preferably 25-90 wt. % of the effective
ingredient. The remedy of the invention is useful for prevention
and/or treatment of hyperphosphatemia caused by diseases of a renal
function disorder and among them, is particularly useful for
prevention and/or treatment of hyperphosphatemia accompanied by
renal function disorders. The doses of the preventive and/or the
remedy for hyperphosphatemia of the invention may appropriately be
determined according to the age, health condition, body weight and
disease severity of the patient, the kind and frequency of therapy
and treatment simultaneously carried out, the nature of the desired
effect, and the like. Generally, the daily dose for an adult may be
1-60 g in the active ingredient amount and may be administered once
or several times a day.
[0038] In the following, the invention is explained concretely by
the examples. However, the invention is not limited thereto. Here,
Ionac A-365 (trade name; Sybron Chemicals Co.) pulverized and dried
for purification as the weakly basic anion exchange resin and
calcium carbonate described in Japanese Pharmacopeia were used.
[0039] Further, Renagel (Renagel.RTM.; manufactured by Geltex Co.,
U.S.) was used as a comparative drug.
EXAMPLE 1
Adsorption Test of Phosphoric Acid at the Ion Concentration of
Intestinal Juice
[0040] Considering the ion concentration of intestinal juice, the
weakly basic anion exchange resin (Ionac A-365; Sybron Chemicals
Co.) or calcium carbonate was added to an aqueous solution in which
NaH.sub.2PO.sub.4 5 mM was dissolved in such a way that each became
1 mg/ml, adjusted to pH 6.8 by sodium hydroxide, and stirred at
37.degree. C. for 1 hour. Then, the resin was removed by a filter,
and phosphoric acid which was not bound to the resin was measured
by an inorganic phosphrus measurement reagent (P Test Wako),
whereby the amount of phosphoric acid bound to the resin was
calculated based on its value. the results are shown in FIG. 1.
Ionac A-365 showed a higher binding amount with phosphoric acid
compared with calcium carbonate.
EXAMPLE 2
Effects on Amount of Blood and Urinary Phosphorus in Normal
Rats
[0041] Using male SD rats (aged 8 weeks), the experiments on
suppressive effects for the increase of urinary phosphorus amount
in the weakly basic anion exchange resin (Ionac A-365; Sybron
Chemicals Co.) or calcium carbonate were carried out as
follows.
[0042] Namely, after the rats were given with feed (20 g/rat/day)
containing 0.3% phosphorus for 7 days, feed (20 g/rat/day)
containing 0.58% phosphorus was mixed with 0.5 g of Ionac A-365 or
calcium carbonate and the mix feed was further administered to the
rats for 5 days. Further, urine was collected for 24 hours before
the drug administration and 5 days after the drug administration,
and the amount of urinary phosphorus was calculated based on the
urinary phosphorus concentration and the amount of urine. The
urinary phosphorus concentration was measured by an inorganic
phosphorus measurement reagent (P Test Wako). The increased amount
of urinary phosphorus excretion was calculated based on the
obtained difference of urinary phosphorus amount between before
drug administration and 5 days after the drug administration, and
compared with that of the non-administration group (control). As
for rats in each group, 6 rats in each were subjected to the
experiments. The obtained results are shown in FIG. 2. The increase
of urinary phosphorus excretion in the calcium carbonate
administration was significantly suppressed compared with that of
control. Also, although the increase of urinary phosphorus
excretion was significantly suppressed in the Ionac A-365
administration group, the effect was larger than that of the
calcium carbonate administration group.
EXAMPLE 3
Effects on Blood Phosphorus Concentration and Renal Function in
Rats with 5/6 Nephrectomy
[0043] Using male SD rats (aged 9 weeks), the experiments on the
effects for the lowering action of urinary phosphorus amount and
the renal function in the weakly basic anion exchange resin (Ionac
A-365; Sybron Chemicals. Co.) or calcium carbonate were carried out
as follows.
[0044] Namely, 2/3 of the left kidney was removed, after 1 week the
right kidney being totally removed to make rats with 5/6
nephrectomy. After 1 week, a mixed feed administration of calcium
carbonate or Ionac A-365 started. As a powder feed for rat MF
manufactured by Oriental Yeast was used, and the administration
dose was made 0.3 g content in 15 g of the feed. 12 weeks after the
preparation of rats with 5/6 nephrectomy, blood was collected from
the caudal vein, and the blood phosphorus concentration was
measured by an inorganic phosphorus measurement reagent (P Test
Wako). Also, urine was collected for 24 hours before the
nephrectomy and 12 weeks after the nephrectomy, and the urinary
protein concentration being measured by a protein measurement
reagent (Protein Assay Kit, Bio-lad). As for rats in each group, 9
rats in each were subjected to the experiments. The obtained
results are shown in FIG. 3 and FIG. 4. As shown in FIG. 3, in the
calcium carbonate administration group there was no significant
difference in blood phosphorus concentration compared with control.
In the Ionac A-365 administration group a significant lowering of
blood phosphorus concentration was observed. Also, as shown in FIG.
4, although in control the amount of urinary protein excretion
increased remarkably at 12 weeks after preparation of rats with 5/6
nephrectomy and deterioration of kidney function was shown, in the
calcium carbonate administration group, the increase of urinary
protein excretion amount was significantly suppressed compared with
control. Also, in the Ionac A-365 administration group the increase
of urinary protein excretion amount was significantly suppressed,
its action intensity being larger than that of the calcium
carbonate administration group, showing the suppressive effect
against deterioration of kidney function.
EXAMPLE 4
Effects of High Concentration Bile Acid on Phosphoric Acid
Adsorption Specificity
[0045] With an aim to investigate the effects of a high
concentration bile acid on a phosphoric acid adsorption
specificity, the adsorption property of an anion exchange resin for
phosphate ion and glycolic acid was examined. Considering the ion
concentration in intestinal juice prepared were one preparation
having been added with Ionac A-365 1 mg/ml to an aqueous solution
in which NaH.sub.2PO.sub.4 5 mM and glycolic acid 20 mM was
dissolved and another preparation having been added with Renagel 1
mg/ml to an aqueous solution in which NaH.sub.2PO.sub.4 5 mM and
glycolic acid 20 mM was dissolved. Each was adjusted to pH 6.8 by
sodium hydroxide, and stirred at 37.degree. C. for 1 hour. Then,
the resin was removed by an ultrafilter membrane, and the amount of
phosphoric acid which was not adsorbed to the resin was measured by
an inorganic phosphorus measurement reagent (registered trade mark,
P Test Wako; manufactured by Wako Junyaku Kogyo Co.), whereby the
amount of phosphoric acid adsorbed and removed by each anion
exchange resin was calculated based on this measurement value.
Further, the amount of glycolic acid not adsorbed to the resin was
measured by a bile acid measurement reagent (registered trade mark,
Total Bile Acid Test Wako; manufactured by Wako Junyaku Kogyo Co.),
whereby the amount of glycolic acid adsorbed and removed by each
anion exchange resin was calculated based on this measurement
value. The results are shown in FIG. 5 and FIG. 6. In the presence
of bile acid 20 mM Renagel, a control drug (comparative drug),
showed a high bile acid adsorption activity. In contrast to this,
Ionac A-365 maintained a high phosphoric acid adsorption activity
even in the presence of bile acid 20 mM, wherein very little the
bile acid adsorption was observed.
[0046] Industrial Applicability
[0047] It is found out that a weakly basic anion exchange resin
which has been used up to now at the industrial level for the
purpose of decoloring, demineralization or hazardous substance
removal of solvent, a supplied water or a waste water is useful as
a phosphate ion adsorbent. Since this remarkably suppresses blood
phosphorus concentration and urinary phosphorus excretion,
achieving suppression for deterioration of kidney function, it is
effective for prevention and/or treatment of hyperphosphatemia and
useful as a drug.
* * * * *