JPH0371411B2 - - Google Patents
Info
- Publication number
- JPH0371411B2 JPH0371411B2 JP57062868A JP6286882A JPH0371411B2 JP H0371411 B2 JPH0371411 B2 JP H0371411B2 JP 57062868 A JP57062868 A JP 57062868A JP 6286882 A JP6286882 A JP 6286882A JP H0371411 B2 JPH0371411 B2 JP H0371411B2
- Authority
- JP
- Japan
- Prior art keywords
- administration
- substance
- concentration
- administered
- hyperphosphatemia
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- FCKJYANJHNLEEP-XRWYNYHCSA-N (24R)-24,25-dihydroxycalciol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CC[C@@H](O)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C FCKJYANJHNLEEP-XRWYNYHCSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000004046 24R,25-dihydroxy-cholecalciferol Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 7
- 239000011574 phosphorus Substances 0.000 description 7
- 229910052698 phosphorus Inorganic materials 0.000 description 7
- 201000005991 hyperphosphatemia Diseases 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 241000700157 Rattus norvegicus Species 0.000 description 5
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 5
- 229910052782 aluminium Inorganic materials 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 102000055006 Calcitonin Human genes 0.000 description 4
- 108060001064 Calcitonin Proteins 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 4
- 229960004015 calcitonin Drugs 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- -1 triglyceride ester Chemical class 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000000813 peptide hormone Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- LRNVEDCUBISUTC-OWRPZGOZSA-N 24,24-difluoro-25-hydroxyvitamin D3 Chemical compound C1(/[C@@H]2CCC([C@]2(CCC1)C)[C@@H](CCC(F)(F)C(C)(C)O)C)=C\C=C1\C[C@H](O)CCC1=C LRNVEDCUBISUTC-OWRPZGOZSA-N 0.000 description 1
- FCKJYANJHNLEEP-SRLFHJKTSA-N 24,25-dihydroxycholecalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCC(O)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C FCKJYANJHNLEEP-SRLFHJKTSA-N 0.000 description 1
- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 description 1
- RYSMHWILUNYBFW-UHFFFAOYSA-N 4-amino-2-[6-(dimethylamino)purin-9-yl]-5-(hydroxymethyl)oxolan-3-ol Chemical compound C1=NC=2C(N(C)C)=NC=NC=2N1C1OC(CO)C(N)C1O RYSMHWILUNYBFW-UHFFFAOYSA-N 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 206010000599 Acromegaly Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010068975 Bone atrophy Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000000038 Hypoparathyroidism Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000299461 Theobroma cacao Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019688 fish Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000003307 slaughter Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical class C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は24R，25−ジヒドロキシコレカルシフ
エロールを含有する抗高燐血症剤に関する。
近年、高燐血症が問題化しつつある。高燐血症
は、慢性腎不全、副甲状腺機能低下症、末端肥大
症、急性不用骨委縮等の病態において、腎での排
泄機能の低下（再吸収の増加）等により生起す
る。最近、慢性腎不全の長期透析患者が増加の一
途をたどり、それらの患者は高燐血症による異所
性石灰化、代謝性アシドーシス症状等を併発する
ので、透析量を増加する方法、食品中の燐を制限
する方法、アルミゲルを燐のバインダーとして投
与する方法等により血中の燐を制御している。殆
んどの透析患者はアルミゲルを投与する方法が施
されているが、最近の研究では脳にアルミゲルに
起因するアルミニウムが蓄積されていくことが解
明され、アルミゲルを投与する療法が非常に危険
であることが判明してきた。その他の高燐血症の
治療法としては、カルシトニンの投与が試みられ
ている。カルシトニンはペプチドホルモンである
ため投与後２〜３時間程度の間は薬理作用が強力
であるが、作用の持続性が劣り、然も投与時直後
とカルシトニンの効果消失時との体内状態の変動
差が激しく、患者にとつて苛酷な治療法になり易
いものである。さらに、異種動物（ブタ、ウナギ
等）由来のペプチドホルモンの投与は、抗体産生
により連続投与したときの効果が初回投与の場合
よりも低下したり、更にアナフイラキシーなどの
危険性もあり得る。また、カルシトニンは経口投
与では薬効が発現しないので、筋注等で投与する
ため患者の苦痛を伴い、安全な治療薬とは言い難
い。
上述したごとき事実に鑑み、安全な抗高燐血症
剤の開発が待望されてきている。
本発明者等は健康な人間の体内に存在する内因
性のもので安全性の高い物質について鋭意研究し
た結果、24R，25−ジヒドロキシコレカルシフエ
ロール（以下本物質又は24R，25−（OH）2−D3と
略称す）が血清無機燐低下作用を有することの知
見を得て本発明に到達した。
24，25−ジヒドロキシコレカルシフエロール、
本物質及び24S，25−ジヒドロキシコレカルシフ
エロールはいずれも公知物質で次のような構造を
有し、例えばフアルマシア、10：319〜322，1974
に開示されており、それらのうち本物質を本発明
においては有効成分とする。
24，25−（OH）2−D3 24R，25−（OH）2−
D3
24S，25−（OH）2−D3
本物質の生理活性については、発見者のH.F.
DeLucaが24，24−ジフルオロ−25−ヒドロキシ
ビタミンD3と25−ヒドロキシビタミンD3を比較
した実験よりビタミンＤ欠のクル病の治ゆや長骨
の正常な成長過程には、24R，25−（OH）2−D3が
必須でないと報告していたり（Endocrinol，108
(6)2067〜2071（1981），Calif.Tissue Int.33 489〜
497（1981））、また、Ａ，W.Normanらは卵の孵
化には、24R，25−（OH）2−D3が必須である
（Science，201 835〜837（1978））と報告している
等、不活性型であるとか活性型であるとか、
24R，25−（OH）2−D3の作用については現在でも
不明な点が多い。
本発明者らは、片腎及び残りの片腎の2/3を摘
出して腎機能を低下させた5/6腎摘ウイスター系
ラツトに高燐血症状態を発現せしめ、次いで高燐
血症状態にある5/6腎摘ラツトに24R，25−（OH）
2−D3を投与することにより血清中の無機燐濃度
が有意に低下することを知見した。また、シグマ
社製のプロマシン−アミノヌクレオサイド
（Puromycin−Aminonucleoside；以下ANと略
称する）の投与により高燐血症状態を発現せしめ
たウイスター系ラツトに24R，25−（OH）2−D3を
投与することにより血清中の無機燐濃度が有意に
低下することを知見した。
本発明の抗高燐血症剤は活性成分として上記の
物質を含有し、下記に示すごとき種々の製剤形態
で用いられる。本発明の抗高燐血症剤は経口的、
非経口的経路又は直腸経路で投与され得るが、経
口投与が好ましい。
本物質を有効成分とする製剤は錠剤、散剤、顆
粒剤、坐剤、カプセル剤、アルコール溶液剤、油
性溶液剤、水性懸濁液剤などの投与形態で用いら
れる。また油性溶媒としては、中級脂肪酸のトリ
グリセライドエステル、コーン油、綿実油、落花
生油、魚肝油、油状エステルなどが用いられる。
またカカオ油、グリセリン等も好ましい。その他
の成分として乳糖、でんぷん、タルク、ステアリ
ン酸マグネシウム、ソルビン酸、ソルビン酸の
塩、糖又はその誘導体アルコール、生理食塩水、
界面活性剤、酸化防止剤等を本物質と併用し得
る。
本物質は、単位投与形態の中に２×10-5〜10重
量％、好ましくは２×10-4〜１重量％含有し得
る。又、本物質は成人に対し１日当り0.5μｇ〜１
×105μｇ、好ましくは１〜１×104μｇ投与す
る。
次に本物質の急性毒性を調べた結果を記す。
急性毒性：
ICR系雄マウス（体重25±３ｇ）10匹を用いて
本物質をエタノールに溶解し、エタノール濃度が
１％になるように中級脂肪酸のトリグリセライド
エステルに溶解し、経口（p.o.）投与した。投与
量は50mg／Kgであつた。投与後２週間中毒症状に
ついて観察したが10匹とも異常なく生存した。屠
殺後、血液、生化学検査、解剖所見、病理組織学
的検索を行なつたが、１％エタノール含有中級脂
肪酸のトリグリセライドエステルのみを投与した
コントロール群と何らかわるところがなかつた。
したがつて、本物質の経口投与のLD50の値は50
mg／Kg以上であるので、活性型ビタミンD3アナ
ログといわれている1α−（OH）−D3（経口投与の
LD50は１mg／Kg以下である）と比較して本物質
は極めて安全なものといえる。
以下に実施例を例示して本発明の効果を具体的
に説明する。なお、実施例中で使用した24R，25
−（OH）2−D3の24位の光学異性体の構造確認は
Tetrahedron Letters NO.26，p2203〜2206，
1975を参照しておこなつた。
実施例 １
アルゴンをバブリングしながら400W高圧水銀
ランプで72時間照射して反応性のパーオキシドを
消失・除去せしめた中級脂肪酸のトリグリセライ
ドエステル１Kgに24R，25−（OH）2−D3５mgを溶
解し、１カプセル中に24R，25−（OH）2−D3を
0.5μｇ含有するように下記剤皮成分を加温溶解し
軟カプセル製造機を用いて常法により軟カプセル
剤を作成した。
剤皮処方例
ゼラチン 10重量部
グリセリン ２ 〃
防腐剤 0.05 〃
（エチルバラベン）
チタンホワイ 0.2 〃
水 0.2 〃
（最終形態における重量部）
同様にして１カプセル中に1μｇ，2μｇ，4μｇ，
5μｇ，6μｇ，8μｇ又は10μｇ含有するものをそれ
ぞれ作成した。
実施例 ２
24R，25−（OH）2−D310mgをイソプロピルアル
コール10mlに溶解し、次に得られたイソプロピル
アルコール溶液１mlを攪拌しながら蒸留水1000ml
に加えた。得られた水溶液は、イソプロピルアル
コールの濃度が0.1重量％であり、24R，25−
（OH）2−D3の濃度が1μｇ／mlであり、このもの
を経口投与用組成物（以下組成物Ａという）とし
た。同様にして、24R，25−（OH）2−D3の濃度が
0.1μｇ／mlでイソプロピルアルコールの濃度が
0.1重量％である経口投与用組成物（以下組成物
Ｂという）を調製した。
体重200±30gのウイスター系雄ラツトの片腎
を全摘し、さらに残りの片腎を2/3摘出して、5/6
腎摘ラツトを調製した。また、体重200±30gの
ウイスター系雄ラツトを擬似手術したものを対照
とした。手術後１ケ月経過してから、各組成物を
各群ごとに一週間に６回の割合で９週間の間自由
摂取させた。なお、24R，25−（OH）2−D3の投与
量は１週毎に摂水量を測定し、摂水量の平均値か
ら１日当りの平均投与量を求めた。又、所定期間
の９週間を経過後、屠殺して腹部下行大静脈より
採血し、血清中の無機リンの濃度をモリブデナム
ブルー（Molybdenum blue）比色法で測定した。
結果を第１表に示す。
The present invention relates to an antihyperphosphatemia agent containing 24R,25-dihydroxycholecalciferol. In recent years, hyperphosphatemia has become a problem. Hyperphosphatemia occurs in pathological conditions such as chronic renal failure, hypoparathyroidism, acromegaly, and acute disuse bone atrophy due to a decrease in renal excretory function (increase in reabsorption). Recently, the number of long-term dialysis patients with chronic renal failure has been increasing, and these patients also develop ectopic calcification due to hyperphosphatemia and metabolic acidosis symptoms. Phosphorus in the blood is controlled by methods such as limiting phosphorus in the blood and administering aluminum gel as a phosphorus binder. Most dialysis patients are treated with aluminum gel, but recent research has revealed that aluminum caused by aluminum gel accumulates in the brain, making therapy using aluminum gel extremely dangerous. It has become clear that. As another treatment for hyperphosphatemia, administration of calcitonin has been attempted. Since calcitonin is a peptide hormone, its pharmacological effects are strong for about 2 to 3 hours after administration, but the duration of the action is poor, and there is a difference in the state of the body immediately after administration and when the effect of calcitonin wears off. It is a treatment method that is likely to be harsh for the patient. Furthermore, when administering a peptide hormone derived from a different species of animal (pig, eel, etc.), the efficacy of continuous administration may be lower than that of the first administration due to antibody production, and there may also be a risk of anaphylaxis. Furthermore, since calcitonin does not exhibit any medicinal efficacy when administered orally, it is difficult to say that it is a safe therapeutic agent because it is administered intramuscularly, which causes pain to the patient. In view of the above-mentioned facts, the development of safe antihyperphosphatemic agents has been eagerly awaited. As a result of intensive research into the endogenous and highly safe substance present in the healthy human body, the present inventors found that 24R,25-dihydroxycholecalciferol (hereinafter referred to as this substance or 24R,25-(OH)) The present invention was achieved based on the knowledge that 2 - D3 ) has a serum inorganic phosphorus-lowering effect. 24,25-dihydroxycholecalciferol,
This substance and 24S,25-dihydroxycholecalciferol are both known substances and have the following structures, for example, Pharmacia, 10:319-322, 1974.
Among them, this substance is used as an active ingredient in the present invention. 24,25−(OH) 2 −D 3 24R,25−(OH) 2 −
D3 24S, 25−(OH) 2 −D 3The physiological activity of this substance is reported by the discoverer HF.
DeLuca's experiment comparing 24,24-difluoro-25-hydroxyvitamin D 3 and 25-hydroxyvitamin D 3 revealed that 24R, 25- (OH) 2 −D 3 is reported to be non-essential (Endocrinol, 108
(6)2067～2071(1981), Calif.Tissue Int.33 489～
497 (1981)), and A. W. Norman et al. reported that 24R, 25-(OH) 2 -D 3 is essential for egg hatching (Science, 201 835-837 (1978)). such as being inactive or active,
There are still many unknowns about the effects of 24R, 25-(OH) 2 -D 3 . The present inventors developed a state of hyperphosphatemia in 5/6 nephrectomized Wistar rats in which one kidney and two-thirds of the remaining kidney were removed to reduce renal function. 24R, 25-(OH) in 5/6 nephrectomized rats with
It was found that administration of 2 - D3 significantly reduced the concentration of inorganic phosphorus in serum. In addition, 24R, 25-(OH) 2 -D 3 was administered to Wistar rats that developed hyperphosphatemia by administering Puromycin-Aminonucleoside (hereinafter referred to as AN) manufactured by Sigma. It was found that the concentration of inorganic phosphorus in the serum was significantly reduced by administering the following. The antihyperphosphatemic agent of the present invention contains the above-mentioned substances as active ingredients, and can be used in various formulations as shown below. The antihyperphosphatemic agent of the present invention can be administered orally;
Although administration may be by parenteral or rectal routes, oral administration is preferred. Preparations containing this substance as an active ingredient are used in dosage forms such as tablets, powders, granules, suppositories, capsules, alcoholic solutions, oily solutions, and aqueous suspensions. Further, as the oily solvent, triglyceride esters of intermediate fatty acids, corn oil, cottonseed oil, peanut oil, fish liver oil, oily esters, etc. are used.
Also preferred are cacao oil and glycerin. Other ingredients include lactose, starch, talc, magnesium stearate, sorbic acid, sorbic acid salts, sugar or its derivative alcohol, physiological saline,
Surfactants, antioxidants, etc. may be used in conjunction with this substance. The substance may be contained in a unit dosage form from 2x10 -5 to 10% by weight, preferably from 2x10 -4 to 1% by weight. In addition, this substance is 0.5 μg to 1 μg per day for adults.
×10 5 μg, preferably 1 to 1×10 4 μg. Next, we will describe the results of investigating the acute toxicity of this substance. Acute toxicity: This substance was dissolved in ethanol and triglyceride ester of intermediate fatty acids to give an ethanol concentration of 1%, and administered orally (po) to 10 ICR male mice (body weight 25 ± 3 g). . The dose was 50mg/Kg. The animals were observed for symptoms of toxicity for two weeks after administration, but all 10 animals survived without any abnormalities. After slaughter, blood, biochemical tests, autopsy findings, and histopathological examinations were performed, but there was no difference in any way from the control group to which only triglyceride ester of intermediate fatty acid containing 1% ethanol was administered.
Therefore, the LD 50 value for oral administration of this substance is 50
mg/Kg or more, 1α-(OH)-D 3 ( orally administered
(LD 50 is less than 1 mg/Kg), this substance can be said to be extremely safe. EXAMPLES The effects of the present invention will be specifically explained below with reference to Examples. In addition, 24R and 25 used in the examples
Structure confirmation of the optical isomer at position 24 of −(OH) 2 −D 3 is
Tetrahedron Letters NO.26, p2203-2206,
This was done with reference to 1975. Example 1 5 mg of 24R, 25-(OH) 2 -D 3 was dissolved in 1 kg of triglyceride ester of intermediate fatty acid, which was irradiated with a 400 W high-pressure mercury lamp for 72 hours while bubbling argon to disappear and remove reactive peroxides. , 24R,25−(OH) 2 −D 3 in one capsule
The following shell components were dissolved by heating to contain 0.5 μg, and soft capsules were prepared by a conventional method using a soft capsule making machine. Shell formulation example Gelatin 10 parts by weight Glycerin 2 Preservative 0.05 (Ethylbaraben) Titanium white 0.2 Water 0.2 (Parts by weight in final form) Similarly, 1 μg, 2 μg, 4 μg,
Products containing 5 μg, 6 μg, 8 μg, or 10 μg were prepared. Example 2 10 mg of 24R,25-(OH) 2 -D 3 was dissolved in 10 ml of isopropyl alcohol, and then 1 ml of the obtained isopropyl alcohol solution was added to 1000 ml of distilled water while stirring.
added to. The resulting aqueous solution has an isopropyl alcohol concentration of 0.1% by weight, and is 24R, 25−
The concentration of (OH) 2 -D 3 was 1 μg/ml, and this was used as a composition for oral administration (hereinafter referred to as composition A). Similarly, the concentration of 24R,25−(OH) 2 −D 3 is
The concentration of isopropyl alcohol is 0.1 μg/ml.
A composition for oral administration (hereinafter referred to as composition B) containing 0.1% by weight was prepared. One kidney of a male Wistar rat weighing 200±30g was completely removed, and 2/3 of the remaining kidney was removed.
Nephrectomized rats were prepared. In addition, male Wistar rats weighing 200±30 g that underwent sham surgery were used as controls. One month after the surgery, each group was given ad libitum intake of each composition six times a week for nine weeks. For the dosage of 24R, 25-(OH) 2 -D 3 , water intake was measured every week, and the average daily dosage was determined from the average value of the water intake. After a predetermined period of 9 weeks, the animals were sacrificed, blood was collected from the abdominal descending vena cava, and the concentration of inorganic phosphorus in the serum was measured using a molybdenum blue colorimetric method.
The results are shown in Table 1.
【表】
実施例 ３
９〜10週令のウイスター系雄ラツトに下記の要
領でANを投与した。ANを生理食塩水に溶解し
て濃度15mg／mlの溶液を調製した。得られた溶液
を１日１回15mg／KgのANを５日間にわたり皮下
投与し、５日間のAN投与の後に２週間のAN休
薬期間を設けた。AN投与一休薬のサイクルを計
５回繰返した。４回目のAN投与開始より、８匹
のラツトからなる各群に経口投与組成物を実施例
２と同様に38日間自由摂取させた。所定の38日間
の投与終了後、屠殺し、腹部下行大静脈より採血
し、実施例２と同様にして血清中の無機燐の濃度
を測定した。結果を第２表に示す。[Table] Example 3 AN was administered to male Wistar rats aged 9 to 10 weeks as follows. AN was dissolved in physiological saline to prepare a solution with a concentration of 15 mg/ml. The obtained solution was subcutaneously administered once a day at 15 mg/Kg of AN for 5 days, and after the 5 days of AN administration, a 2 week AN washout period was provided. The cycle of AN administration and rest was repeated 5 times in total. From the start of the fourth AN administration, each group of 8 rats was given the orally administered composition ad libitum for 38 days in the same manner as in Example 2. After the prescribed 38-day administration, the animals were sacrificed, blood was collected from the descending abdominal vena cava, and the concentration of inorganic phosphorus in the serum was measured in the same manner as in Example 2. The results are shown in Table 2.
Claims (1)
ルを有効成分とする抗高燐血症剤。1.An antihyperphosphatemic agent containing 24R,25-dihydroxycholecalciferol as an active ingredient.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6286882A JPS58185519A (en) | 1982-04-15 | 1982-04-15 | Antihyperphosphatemic agent |
| US06/374,702 US4442093A (en) | 1981-05-15 | 1982-05-04 | Method for administering 24,25-dihydroxycholecalciferol to persons suffering from hypercalcemia |
| IT21278/82A IT1190824B (en) | 1981-05-15 | 1982-05-14 | PHARMACEUTICAL COMPOSITION CONTAINING 24.25-DIHYDROXICOLECALCIFEROL AS ACTIVE INGREDIENT |
| BE0/208097A BE893193A (en) | 1981-05-15 | 1982-05-14 | PHARMACEUTICAL COMPOSITION CONTAINING 24-25-DIHYDROXY-CHOLECALCIFEROL AS ACTIVE INGREDIENT |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6286882A JPS58185519A (en) | 1982-04-15 | 1982-04-15 | Antihyperphosphatemic agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58185519A JPS58185519A (en) | 1983-10-29 |
| JPH0371411B2 true JPH0371411B2 (en) | 1991-11-13 |
Family
ID=13212684
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6286882A Granted JPS58185519A (en) | 1981-05-15 | 1982-04-15 | Antihyperphosphatemic agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58185519A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55136229A (en) * | 1979-04-10 | 1980-10-23 | Teijin Ltd | Adjustment of bone metabolism in warm-blooded animal and drug for it |
| JPS55139320A (en) * | 1979-04-16 | 1980-10-31 | Teijin Ltd | Bone metabolism regulator |
-
1982
- 1982-04-15 JP JP6286882A patent/JPS58185519A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55136229A (en) * | 1979-04-10 | 1980-10-23 | Teijin Ltd | Adjustment of bone metabolism in warm-blooded animal and drug for it |
| JPS55139320A (en) * | 1979-04-16 | 1980-10-31 | Teijin Ltd | Bone metabolism regulator |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58185519A (en) | 1983-10-29 |
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