CA1206882A - Use of cholecalciferol derivatives - Google Patents
Use of cholecalciferol derivativesInfo
- Publication number
- CA1206882A CA1206882A CA000421298A CA421298A CA1206882A CA 1206882 A CA1206882 A CA 1206882A CA 000421298 A CA000421298 A CA 000421298A CA 421298 A CA421298 A CA 421298A CA 1206882 A CA1206882 A CA 1206882A
- Authority
- CA
- Canada
- Prior art keywords
- epimer
- alpha
- treatment
- dihydroxycholecalciferol
- trihydroxycholecalciferol
- 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
Links
- 150000003704 vitamin D3 derivatives Chemical class 0.000 title 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 claims abstract description 9
- 210000002966 serum Anatomy 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 230000035945 sensitivity Effects 0.000 claims abstract 2
- 206010020590 Hypercalciuria Diseases 0.000 claims description 3
- 201000000306 sarcoidosis Diseases 0.000 claims description 3
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 2
- 206010029148 Nephrolithiasis Diseases 0.000 claims description 2
- 230000000148 hypercalcaemia Effects 0.000 claims description 2
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000012876 carrier material Substances 0.000 claims 1
- 201000000173 nephrocalcinosis Diseases 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 239000003981 vehicle Substances 0.000 description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 210000002303 tibia Anatomy 0.000 description 6
- 241001673526 Lydia Species 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 229960002061 ergocalciferol Drugs 0.000 description 3
- 210000004349 growth plate Anatomy 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000011653 vitamin D2 Substances 0.000 description 3
- 235000009434 Actinidia chinensis Nutrition 0.000 description 2
- 244000298697 Actinidia deliciosa Species 0.000 description 2
- 235000009436 Actinidia deliciosa Nutrition 0.000 description 2
- HZZDXVXOETXUEY-UHFFFAOYSA-N CC.[Na].[Na] Chemical class CC.[Na].[Na] HZZDXVXOETXUEY-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 239000004368 Modified starch Substances 0.000 description 2
- 239000008118 PEG 6000 Substances 0.000 description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000018678 bone mineralization Effects 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- -1 carrier Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000007887 hard shell capsule Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 1
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 description 1
- 235000021318 Calcifediol Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol 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)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- JMGZBMRVDHKMKB-UHFFFAOYSA-L disodium;2-sulfobutanedioate Chemical compound [Na+].[Na+].OS(=O)(=O)C(C([O-])=O)CC([O-])=O JMGZBMRVDHKMKB-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000005470 impregnation Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Nutrition Science (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT
The use of the C-25 R- or S-epimer of 1.alpha.,25,26-trihydroxycholecalciferol for the treatment of disease states characterized by higher than normal serum levels of endogenously produced 1.alpha.,25-dihydroxycholecalciferol or characterized by conditions where there is an increased sensitivity to 1.alpha.,25-dihydroxycholecalciferol, as well as corresponding pharmaceutical preparations.
The use of the C-25 R- or S-epimer of 1.alpha.,25,26-trihydroxycholecalciferol for the treatment of disease states characterized by higher than normal serum levels of endogenously produced 1.alpha.,25-dihydroxycholecalciferol or characterized by conditions where there is an increased sensitivity to 1.alpha.,25-dihydroxycholecalciferol, as well as corresponding pharmaceutical preparations.
Description
- ~Z~3681~Z
The invention is based on the finding of novel whoosh logical properties of the C-25 R- and S-epimers of lug-trihydroxycholecalciferol, hereinafter denominated the R-and S-epimers. Specifically it has been found that the R- or S-epimer lower higher than normal levels of endogenously 10 produced la,25-dihydroxycholecalciferol.
Accordingly, the invention relates to the R- or S-epimer as an agent for the treatment of disease states characterized by higher than normal serum levels of endow 15 venously produced la,25-dihydroxycholecalciferol or kirk-terraced by conditions where there is an increased sunsuit-viny to la,25-dihydroxycholecalciferol. The invention also relates to the use of the R- or S-epimer for the alone-mentioned treatment, as well as to pharmaceutical compost-20 lions on the basis of the R- or S-epimer for this treatment and to a corresponding method of treatment comprising the administration of the R- or S epimer.
Specifically included among the above mentioned disease 25 states are hypercalcemia, sarcoidosis, hypercalciuria, nephrolithiasis and nephrQcalcinosis.
As indicated above, the R- and S-epimer lower the serum level of la,25-dihydroxycholecalciferol. Additionally, 30 both the R- and S-epimers promote bone mineralization in vitamin deficient animals, but only the R-epimer promotes bone mineralization in disodium ethanes 1-hydroxy-1,1 diphosphonate-blocked animals.
The foregoing activities can be demonstrated in the following tests:
Mé/3.1.83 ~''~
,. .
Swiss (a) Anti-rachitogenic activity in chicks White Leghorn chicks are placed on a vitamin Defoe client diet containing 1% calcium and 0.7% phosphorus, and are housed under ultraviolet-fre2 lighting. The test come pounds are dissolved in propylene glycol and administered orally for 21 consecutive days to the chicks which are one to two days of age at the start of treatment. Controls are treated with vehicle alone. Chicks are autopsies on the day after the last treatment day and the tibia ash weight is determined Nine to ten chicks are used for each treatment group and for the control group. The mean tibia ash weights expressed in my are given in Table I. The results show that the R- and S-epimers possess similar antirachitogenic activity.
Tale I
Mean tibia ash weight (my) 20 Dose (mg/chick/day) S-epimer R-epimer 0 112.1+6.2 124.9~2.8 122.6+ 4.1 100 159.4+4.4 157.5+ 5.3 25300 187.0+8.7 207.8+ 7.8 1000 210.4+7.8 213.3+10.0 (b) Intestinal gala us absorption in chicks White Leghorn chicks are placed on the vitamin D-deficient diet and are housed under ultraviolet-free lighting for 21 days. A single oral dose of 1 mug of test compound dissolved in propylene glycol is administered. At various tires after dosing, 2 Sue of kiwi (chloride) is 35 given orally, and serum radioactivity is measured 45 minutes after administration of the isotope. Vehicle-treated con-trots are included at each time period. Ten chicks are used in each treatment and control group. The results given in ~L~0~38Z
Table II show that the the S- and R-epimers possess similar intestinal kiwi absorption activity.
table II
Treatment Time (hours) Serum Cay (cpm/0.2 ml) Vehicle, 0.2 ml 3 1338~ 51 S-Epimer 1977+122 10 R-Epimer 2077+174 Vehicle, I ml 6 1345+ 89 S-Epimer 2067+128 R-Epimer 1992+212 I
(c) Prevention of EHDP-induced mineralization block in rats Charles River male rats are treated for 10 consecutive days with disodium ethanes 1-hydroxy-1,1-diphosphonate (EHDP).
20 The compound is given subcutaneously on each treatment day at a dose of 2 mg/0.2 ml/rat in distilled water. The test compounds are administered orally, dissolved in propylene glycol, on each treatment day. Rats are autopsies on the day after the last treatment day and the tibias are pro-25 cussed by silver impregnation of the bone salts. Epiphysealplate widths are measured with a microscope. activity is based upon dose dependent narrowing of the widened opt-fuzzily plate induced by EHDP. Ten rats are used in each treatment group. Positive (EHDP alone) and negative (vehicle alone) control groups of ten rats each, are inkwell-dyed in each experiment. The results given in Table III
indicate that the R-epimer caused calcification of the tibia epiphyseal plate in EHDP-blocked rats while the S-epimer did not.
~206~8Z
Table III
Dose Mean tibia epiphyseal plate width (mcg/rat/day) (micron) EHDP + EHDP EHDP +
_ S-epimer alone R-epimer 0 1190+42 1162+36 611+51 .
Vehicle controls (no EHDP) 376+13 (d) Effects on the serum levels of Lydia and ODE
The effect of subcutaneous administration of the S-and R-epimers on serum levels of la,25-dihydroxycholecal-ciferol and 25-hydroxycholecalciferol (Lydia and ODE) was determined according to known methods (Archives ox Biochemistry and Biophysics, Vol. 201, No. 1, 1980, Z77-285). The results are shown in Table IV. The effect was initially shown in a 7 day experiment and later in a 28 day treatment study which demonstrated that the reduction of Lydia levels was sustained. The ability 25 to control endogenous production of Lydia is glint-gaily useful in the treatment of among other disease states, sarcoidosis and hypercalciuria~
Table IV
Daily treatment No. of No. of Serum levels of daysratsla~25(0H)2D3 ODE
~pg/ml) (ng/ml) Vehicle, 0.2 ml- 7 1899.6+0.5 37.6+1.9 35 S-Epimer 1 mug 127.9+2.8 32~0+1.7 R-Epimer l mug 1214.0+4.1 36.0+1.8 , .~, :
)6~38;2 Vehicle, 0.2 ml pa 10 3~.8+7.3 64.2+4.3 S-Epimer 1 mug 108.0+2.3 40.6+3.4 R-Epimer 1 mug 108.2+1.7 34.7+4.2 The R- and S-epimers may be administered in dosages that are in the range of 0.5 to 500 micrograms per day. They are preferably administered orally, but can also be ad mini-stored subcutaneously, intramuscularly, intravenously or intraperitoneally, for instance in form of tablets, cap-10 sulks or elixirs or oral administration; or in sterile solutions or suspensions for parenteral administration.
About 0.5 to 500 micrograms of the R- or S-epimer is compounded with pharmaceutically acceptable adjutants, such as a vehicle, carrier, excipient, binder, preservative, 15 stabilizer and/or flavor in a unit dosage form.
Illustrative of the adjutants which may be incorporated into tablets or capsules are a binder, such as corn starch or gelatin; an excipient, such as dicalcium phosphate; a 20 disintegrating agent, such as corn or potato starch or alginic acid; a lubricant, such as magnesium Stewart; a sweetening agent, such as sucrose; a flavoring agent, such as peppermint. Other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
25 For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as sweetening agent, methyl and propel parabens as preservatives, a dye and a flavoring, such as orange flavor.
Sterile compositions for injection can be formulated according Jo conventional pharmaceutical practice by dozily-vying or suspending the active substance in a vehicle, such as water for injection, a naturally-occurring vegetable oil, such as sesame oil, or a synthetic fatty vehicle, such as 35 ethyl owlet. Buffers, preservatives and antioxidant can also be incorporated.
lZ~68~3~
Example 1 Tablet Formulation mg/tablet 1. The R- or S-epimer of la,25,26-trihydroxychole-calciferol 0. 025 0 .100 0 . 5
The invention is based on the finding of novel whoosh logical properties of the C-25 R- and S-epimers of lug-trihydroxycholecalciferol, hereinafter denominated the R-and S-epimers. Specifically it has been found that the R- or S-epimer lower higher than normal levels of endogenously 10 produced la,25-dihydroxycholecalciferol.
Accordingly, the invention relates to the R- or S-epimer as an agent for the treatment of disease states characterized by higher than normal serum levels of endow 15 venously produced la,25-dihydroxycholecalciferol or kirk-terraced by conditions where there is an increased sunsuit-viny to la,25-dihydroxycholecalciferol. The invention also relates to the use of the R- or S-epimer for the alone-mentioned treatment, as well as to pharmaceutical compost-20 lions on the basis of the R- or S-epimer for this treatment and to a corresponding method of treatment comprising the administration of the R- or S epimer.
Specifically included among the above mentioned disease 25 states are hypercalcemia, sarcoidosis, hypercalciuria, nephrolithiasis and nephrQcalcinosis.
As indicated above, the R- and S-epimer lower the serum level of la,25-dihydroxycholecalciferol. Additionally, 30 both the R- and S-epimers promote bone mineralization in vitamin deficient animals, but only the R-epimer promotes bone mineralization in disodium ethanes 1-hydroxy-1,1 diphosphonate-blocked animals.
The foregoing activities can be demonstrated in the following tests:
Mé/3.1.83 ~''~
,. .
Swiss (a) Anti-rachitogenic activity in chicks White Leghorn chicks are placed on a vitamin Defoe client diet containing 1% calcium and 0.7% phosphorus, and are housed under ultraviolet-fre2 lighting. The test come pounds are dissolved in propylene glycol and administered orally for 21 consecutive days to the chicks which are one to two days of age at the start of treatment. Controls are treated with vehicle alone. Chicks are autopsies on the day after the last treatment day and the tibia ash weight is determined Nine to ten chicks are used for each treatment group and for the control group. The mean tibia ash weights expressed in my are given in Table I. The results show that the R- and S-epimers possess similar antirachitogenic activity.
Tale I
Mean tibia ash weight (my) 20 Dose (mg/chick/day) S-epimer R-epimer 0 112.1+6.2 124.9~2.8 122.6+ 4.1 100 159.4+4.4 157.5+ 5.3 25300 187.0+8.7 207.8+ 7.8 1000 210.4+7.8 213.3+10.0 (b) Intestinal gala us absorption in chicks White Leghorn chicks are placed on the vitamin D-deficient diet and are housed under ultraviolet-free lighting for 21 days. A single oral dose of 1 mug of test compound dissolved in propylene glycol is administered. At various tires after dosing, 2 Sue of kiwi (chloride) is 35 given orally, and serum radioactivity is measured 45 minutes after administration of the isotope. Vehicle-treated con-trots are included at each time period. Ten chicks are used in each treatment and control group. The results given in ~L~0~38Z
Table II show that the the S- and R-epimers possess similar intestinal kiwi absorption activity.
table II
Treatment Time (hours) Serum Cay (cpm/0.2 ml) Vehicle, 0.2 ml 3 1338~ 51 S-Epimer 1977+122 10 R-Epimer 2077+174 Vehicle, I ml 6 1345+ 89 S-Epimer 2067+128 R-Epimer 1992+212 I
(c) Prevention of EHDP-induced mineralization block in rats Charles River male rats are treated for 10 consecutive days with disodium ethanes 1-hydroxy-1,1-diphosphonate (EHDP).
20 The compound is given subcutaneously on each treatment day at a dose of 2 mg/0.2 ml/rat in distilled water. The test compounds are administered orally, dissolved in propylene glycol, on each treatment day. Rats are autopsies on the day after the last treatment day and the tibias are pro-25 cussed by silver impregnation of the bone salts. Epiphysealplate widths are measured with a microscope. activity is based upon dose dependent narrowing of the widened opt-fuzzily plate induced by EHDP. Ten rats are used in each treatment group. Positive (EHDP alone) and negative (vehicle alone) control groups of ten rats each, are inkwell-dyed in each experiment. The results given in Table III
indicate that the R-epimer caused calcification of the tibia epiphyseal plate in EHDP-blocked rats while the S-epimer did not.
~206~8Z
Table III
Dose Mean tibia epiphyseal plate width (mcg/rat/day) (micron) EHDP + EHDP EHDP +
_ S-epimer alone R-epimer 0 1190+42 1162+36 611+51 .
Vehicle controls (no EHDP) 376+13 (d) Effects on the serum levels of Lydia and ODE
The effect of subcutaneous administration of the S-and R-epimers on serum levels of la,25-dihydroxycholecal-ciferol and 25-hydroxycholecalciferol (Lydia and ODE) was determined according to known methods (Archives ox Biochemistry and Biophysics, Vol. 201, No. 1, 1980, Z77-285). The results are shown in Table IV. The effect was initially shown in a 7 day experiment and later in a 28 day treatment study which demonstrated that the reduction of Lydia levels was sustained. The ability 25 to control endogenous production of Lydia is glint-gaily useful in the treatment of among other disease states, sarcoidosis and hypercalciuria~
Table IV
Daily treatment No. of No. of Serum levels of daysratsla~25(0H)2D3 ODE
~pg/ml) (ng/ml) Vehicle, 0.2 ml- 7 1899.6+0.5 37.6+1.9 35 S-Epimer 1 mug 127.9+2.8 32~0+1.7 R-Epimer l mug 1214.0+4.1 36.0+1.8 , .~, :
)6~38;2 Vehicle, 0.2 ml pa 10 3~.8+7.3 64.2+4.3 S-Epimer 1 mug 108.0+2.3 40.6+3.4 R-Epimer 1 mug 108.2+1.7 34.7+4.2 The R- and S-epimers may be administered in dosages that are in the range of 0.5 to 500 micrograms per day. They are preferably administered orally, but can also be ad mini-stored subcutaneously, intramuscularly, intravenously or intraperitoneally, for instance in form of tablets, cap-10 sulks or elixirs or oral administration; or in sterile solutions or suspensions for parenteral administration.
About 0.5 to 500 micrograms of the R- or S-epimer is compounded with pharmaceutically acceptable adjutants, such as a vehicle, carrier, excipient, binder, preservative, 15 stabilizer and/or flavor in a unit dosage form.
Illustrative of the adjutants which may be incorporated into tablets or capsules are a binder, such as corn starch or gelatin; an excipient, such as dicalcium phosphate; a 20 disintegrating agent, such as corn or potato starch or alginic acid; a lubricant, such as magnesium Stewart; a sweetening agent, such as sucrose; a flavoring agent, such as peppermint. Other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.
25 For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as sweetening agent, methyl and propel parabens as preservatives, a dye and a flavoring, such as orange flavor.
Sterile compositions for injection can be formulated according Jo conventional pharmaceutical practice by dozily-vying or suspending the active substance in a vehicle, such as water for injection, a naturally-occurring vegetable oil, such as sesame oil, or a synthetic fatty vehicle, such as 35 ethyl owlet. Buffers, preservatives and antioxidant can also be incorporated.
lZ~68~3~
Example 1 Tablet Formulation mg/tablet 1. The R- or S-epimer of la,25,26-trihydroxychole-calciferol 0. 025 0 .100 0 . 5
2. Lactose 157.975 157.900 157.5
3, Microcrystalline cellulose 20.00 20.0
4. Modified starch 20. 000 20. 0
5. Magnesium Stewart 2. 000 2. 0 Total 200.000 mg200.000 my 200. 0 my The ingredients 1 to 4 are mixed and if necessary milled. After addition of the magnesium Stewart, the mix-lure is milled and then pressed to tablets.
Example 2 ; 20 - Capsule Formulation mg/capsule 1, The R- or S-epimer of 25 la,25,26-trihydroxychole-calci~erol 0.025 0.1000.500 2. Lactose 159. 975 159. 90159 .50 3. Modified starch 20.0 20.0 20.0 4. Talc 20.0 20.0 _20.0 I Tuttle my 200 mg200 my The ingredient 1 is dissolved in alcohol. The inure-dints 2 and 3 are mixed and the solution of 1 is spread over the mixture which is then dried overnight. The mixture 35 is screened, then mixed with talc and filled into capsules.
~LZC36~3~3Z
Example 3 The drug can be dissolved in a pharmaceutically accept -table solvents, such as alcohol, propylene glyco~, glues-fine or polyethylene luckily. Surfactants, such as polyethy-tone glycol, sorbitan esters, ductile sodium sulfosuccinate, polyoxyethylene-polyoxypropylene co-polymer can also be added for solubilization of the drug. A preservative can be added to the formulation for the prevention of microbial 10 growths. Illustrative of capsule formulations are:
a) mg/capsule The R- or S-epimer of la,25,26-trihydroxychole-15 calfiferol oily 0.5Q
Polyethylene glycol (PUG 400.0 400.00 Butylated hydroxy-anisol (BRA) 0.2 0.2 0.2 Acquirable palpitate lo lo lo Dissolve BRA and acquirable palpitate in PEG. Add the R- or S-epimer of la,25,26-trihydroxycholecalciferol and dissolve under an atmosphere of nitrogen. The liquid is filled into social capsules.
I
b) capsule The R- or S-epimer of la,25,26-trihydroxychole-calciferol oily 0.50 30 PEG 400 (or PEG 6000) 200.0 200.0 200.0 Polyoxyethylene Sorbitan moo-owlet or menstruate (Polysorbate 80 or Polysorba~e 60) 200.0200.0 200.0 BRA 0.2 0.2 0.2 35 Acquirable palpitate lo lo lo ~1i206~382 Warm the mixture of PEG 6000 and Polysorbate 60. Add to it BRA and acquirable palpitate. Add the R- or S-epimer of la,25,26-trihydroxycholecalciferol under an atmosphere of nitrogen. Fill into hard-shell capsules.
c) The R- or S-epimer of la,25,26~trihydroxychole-calciferol 0.025 0.1 0.50 10 PEG 400 100.0 100.0 100.0 BRA 0.1 0.1 0.1 Butylated hydroxytoluene (BUT) 0.1 0.1 0.1 US Acquirable palMitate1.0 1.0 1.0 Warm a mixture of PEG 400 and PEG 4000. Add BUT, BRA
and acquirable palpitate. Add the R- or S-epimer of lay 25,26-trihydroxycholecalciferol and dissolve under a stream of 20 nitrogen. Fill into hard-shell capsules.
. -
Example 2 ; 20 - Capsule Formulation mg/capsule 1, The R- or S-epimer of 25 la,25,26-trihydroxychole-calci~erol 0.025 0.1000.500 2. Lactose 159. 975 159. 90159 .50 3. Modified starch 20.0 20.0 20.0 4. Talc 20.0 20.0 _20.0 I Tuttle my 200 mg200 my The ingredient 1 is dissolved in alcohol. The inure-dints 2 and 3 are mixed and the solution of 1 is spread over the mixture which is then dried overnight. The mixture 35 is screened, then mixed with talc and filled into capsules.
~LZC36~3~3Z
Example 3 The drug can be dissolved in a pharmaceutically accept -table solvents, such as alcohol, propylene glyco~, glues-fine or polyethylene luckily. Surfactants, such as polyethy-tone glycol, sorbitan esters, ductile sodium sulfosuccinate, polyoxyethylene-polyoxypropylene co-polymer can also be added for solubilization of the drug. A preservative can be added to the formulation for the prevention of microbial 10 growths. Illustrative of capsule formulations are:
a) mg/capsule The R- or S-epimer of la,25,26-trihydroxychole-15 calfiferol oily 0.5Q
Polyethylene glycol (PUG 400.0 400.00 Butylated hydroxy-anisol (BRA) 0.2 0.2 0.2 Acquirable palpitate lo lo lo Dissolve BRA and acquirable palpitate in PEG. Add the R- or S-epimer of la,25,26-trihydroxycholecalciferol and dissolve under an atmosphere of nitrogen. The liquid is filled into social capsules.
I
b) capsule The R- or S-epimer of la,25,26-trihydroxychole-calciferol oily 0.50 30 PEG 400 (or PEG 6000) 200.0 200.0 200.0 Polyoxyethylene Sorbitan moo-owlet or menstruate (Polysorbate 80 or Polysorba~e 60) 200.0200.0 200.0 BRA 0.2 0.2 0.2 35 Acquirable palpitate lo lo lo ~1i206~382 Warm the mixture of PEG 6000 and Polysorbate 60. Add to it BRA and acquirable palpitate. Add the R- or S-epimer of la,25,26-trihydroxycholecalciferol under an atmosphere of nitrogen. Fill into hard-shell capsules.
c) The R- or S-epimer of la,25,26~trihydroxychole-calciferol 0.025 0.1 0.50 10 PEG 400 100.0 100.0 100.0 BRA 0.1 0.1 0.1 Butylated hydroxytoluene (BUT) 0.1 0.1 0.1 US Acquirable palMitate1.0 1.0 1.0 Warm a mixture of PEG 400 and PEG 4000. Add BUT, BRA
and acquirable palpitate. Add the R- or S-epimer of lay 25,26-trihydroxycholecalciferol and dissolve under a stream of 20 nitrogen. Fill into hard-shell capsules.
. -
Claims (2)
1. Pharmaceutical composition containing the C-25 R or S-epimer of 1.alpha.,25,26-trihydroxycholecalciferol in combination with a pharmaceutical acceptable inert carrier material, for the treatment of disease states characterized by higher than normal serum levels of endogenously produced 1.alpha.,25-dihydroxycholecalciferol or characterized by con-ditions where there is an increased sensitivity to 1.alpha.,25-dihydroxycholecalciferol.
2. Pharmaceutical composition according to claim 1, containing from 0.5 to 500 micrograms of the C-25 R- or S-epimer of 1.alpha.,25,26-trihydroxycholecalciferol, for the treatment of disease states selected from the group consisting of hypercalcemia, sarcoidosis, hypercalciuria, nephrolithiasis and nephrocalcinosis.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US34838982A | 1982-02-12 | 1982-02-12 | |
US348,389 | 1982-02-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1206882A true CA1206882A (en) | 1986-07-02 |
Family
ID=23367827
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000421298A Expired CA1206882A (en) | 1982-02-12 | 1983-02-10 | Use of cholecalciferol derivatives |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP0086476B1 (en) |
JP (1) | JPS58148822A (en) |
AU (1) | AU560066B2 (en) |
BE (1) | BE895884A (en) |
CA (1) | CA1206882A (en) |
DE (2) | DE3304819A1 (en) |
IE (1) | IE54722B1 (en) |
IL (1) | IL67881A0 (en) |
IT (1) | IT1173654B (en) |
NZ (1) | NZ203251A (en) |
PH (1) | PH17993A (en) |
ZA (1) | ZA83923B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59155309A (en) * | 1983-02-22 | 1984-09-04 | Teijin Ltd | Active type vitamin d3 composition and its preparation |
DE3565401D1 (en) * | 1984-02-08 | 1988-11-10 | Hoffmann La Roche | CALCIFEROL DERIVATIVES |
JPS6391323A (en) * | 1986-10-03 | 1988-04-22 | Kureha Chem Ind Co Ltd | Antiurinary calculosis agent |
EP0313703B1 (en) * | 1987-10-30 | 1990-09-26 | Kureha Kagaku Kogyo Kabushiki Kaisha | Use of 24,25-dihydroxycholecalciferole in the treatment of urinary calculus |
JP2856444B2 (en) * | 1989-07-28 | 1999-02-10 | 呉羽化学工業株式会社 | Vitamin D lower 3 metabolite preparation |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH644100A5 (en) * | 1979-09-14 | 1984-07-13 | Hoffmann La Roche | CHOLECALCIFEROL DERIVATIVES. |
-
1983
- 1983-02-10 NZ NZ203251A patent/NZ203251A/en unknown
- 1983-02-10 ZA ZA83923A patent/ZA83923B/en unknown
- 1983-02-10 IL IL67881A patent/IL67881A0/en unknown
- 1983-02-10 JP JP58019894A patent/JPS58148822A/en active Granted
- 1983-02-10 CA CA000421298A patent/CA1206882A/en not_active Expired
- 1983-02-11 BE BE0/210100A patent/BE895884A/en not_active IP Right Cessation
- 1983-02-11 PH PH28503A patent/PH17993A/en unknown
- 1983-02-11 EP EP83101341A patent/EP0086476B1/en not_active Expired
- 1983-02-11 DE DE19833304819 patent/DE3304819A1/en not_active Withdrawn
- 1983-02-11 IT IT19545/83A patent/IT1173654B/en active
- 1983-02-11 AU AU11340/83A patent/AU560066B2/en not_active Ceased
- 1983-02-11 DE DE8383101341T patent/DE3363334D1/en not_active Expired
- 1983-02-11 IE IE285/83A patent/IE54722B1/en unknown
Also Published As
Publication number | Publication date |
---|---|
IT8319545A0 (en) | 1983-02-11 |
AU1134083A (en) | 1983-08-18 |
DE3363334D1 (en) | 1986-06-12 |
IL67881A0 (en) | 1983-06-15 |
EP0086476B1 (en) | 1986-05-07 |
PH17993A (en) | 1985-02-28 |
AU560066B2 (en) | 1987-03-26 |
EP0086476A2 (en) | 1983-08-24 |
JPH0474332B2 (en) | 1992-11-26 |
DE3304819A1 (en) | 1983-08-25 |
NZ203251A (en) | 1986-04-11 |
IT1173654B (en) | 1987-06-24 |
IE54722B1 (en) | 1990-01-17 |
IE830285L (en) | 1983-08-12 |
BE895884A (en) | 1983-08-11 |
EP0086476A3 (en) | 1983-11-09 |
ZA83923B (en) | 1983-11-30 |
JPS58148822A (en) | 1983-09-05 |
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