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
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)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Nutrition Science (AREA)
- Endocrinology (AREA)
- Reproductive Health (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) | DE3363334D1 (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 |
| DK157244C (en) * | 1984-02-08 | 1990-04-23 | Hoffmann La Roche | CALCIFEROLD DERIVATIVES, THESE DERIVATIVES FOR USE AS PHARMACEUTICAL ACTIVE SUBSTANCES, THESE DERIVATIVES FOR USE AS ANTIPROLIFERATIVE AND DIFFERENTIENT-INACTIVE ACTIVE SUBSTANCES, AND MEDICINAL CONTAINERS |
| JPS6391323A (en) * | 1986-10-03 | 1988-04-22 | Kureha Chem Ind Co Ltd | Antiurinary calculosis agent |
| DE3765250D1 (en) * | 1987-10-30 | 1990-10-31 | Kureha Chemical Ind Co Ltd | USE OF 24,25-DIHYDROXYCHOLECALCIFEROL FOR THE TREATMENT OF URINAL STONES. |
| 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 JP JP58019894A patent/JPS58148822A/en active Granted
- 1983-02-10 IL IL67881A patent/IL67881A0/en unknown
- 1983-02-10 ZA ZA83923A patent/ZA83923B/en unknown
- 1983-02-10 NZ NZ203251A patent/NZ203251A/en unknown
- 1983-02-10 CA CA000421298A patent/CA1206882A/en not_active Expired
- 1983-02-11 IE IE285/83A patent/IE54722B1/en unknown
- 1983-02-11 AU AU11340/83A patent/AU560066B2/en not_active Ceased
- 1983-02-11 PH PH28503A patent/PH17993A/en unknown
- 1983-02-11 BE BE0/210100A patent/BE895884A/en not_active IP Right Cessation
- 1983-02-11 IT IT19545/83A patent/IT1173654B/en active
- 1983-02-11 EP EP83101341A patent/EP0086476B1/en not_active Expired
- 1983-02-11 DE DE8383101341T patent/DE3363334D1/en not_active Expired
- 1983-02-11 DE DE19833304819 patent/DE3304819A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| IL67881A0 (en) | 1983-06-15 |
| IT8319545A0 (en) | 1983-02-11 |
| EP0086476B1 (en) | 1986-05-07 |
| DE3304819A1 (en) | 1983-08-25 |
| NZ203251A (en) | 1986-04-11 |
| DE3363334D1 (en) | 1986-06-12 |
| JPH0474332B2 (en) | 1992-11-26 |
| AU560066B2 (en) | 1987-03-26 |
| JPS58148822A (en) | 1983-09-05 |
| AU1134083A (en) | 1983-08-18 |
| EP0086476A2 (en) | 1983-08-24 |
| IT1173654B (en) | 1987-06-24 |
| IE830285L (en) | 1983-08-12 |
| PH17993A (en) | 1985-02-28 |
| BE895884A (en) | 1983-08-11 |
| ZA83923B (en) | 1983-11-30 |
| IE54722B1 (en) | 1990-01-17 |
| EP0086476A3 (en) | 1983-11-09 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |