IE54722B1 - Use of cholecalciferol derivatives - Google Patents

Abstract

Die Verwendung des C-25 R- oder S-Epimeren des 1α,25,26-Trihydroxycholecalciferols zur Behandlung von Krankheiten, die durch über dem Normalwert liegende Spiegel von endogen produziertem 1a,25-Dihydroxycholecalciferol im Serum oder durch erhöhte Empfindlichkeit auf 1α-25-Dihydro- xycholecalciferol gekennzeichnet sind, sowie entsprechende pharmazeutische Präparate.

Description

The invention is based on the finding of novel physiological properties of the C-25 R- and S-epimers of la,25,26trihydroxycholecalciferol, hereinafter denominated the Rand S-epimers. Specifically it has been found that the R- or S-epimer lower higher than normal levels of endogenously produced la,25-dihydroxycholecalciferol.

Accordingly, the invention relates to the R- or Sepimer as an agent for the treatment of disease states characterized by higher than normal serum levels of endo10 genously produced la,25-dihydroxycholecalciferol or characterized by conditions where there is an increased sensitivity to la,25-dihydroxycholecalciferol. The invention also relates to the use of the R- or S-epimer for the manufacture of pharmaceutical preparations for the aforementicned treatment, as well as to pharmaceutical ccnpositions on the basis of the R- or S-epimer for this treatment and to a corresponding method of treatment of a non-human host ccnprising the administration of the R- or S-epimer.

Specifically included among the above mentioned disease states are hypercalcemia, sarcoidosis, hypercalciuria, nephrolithiasis and nephrocalcinosis.

As indicated above, the R- and S-epimer lower the serum level of la,25-dihydroxycholecalciferol. Additionally, both the R- and S-epimers promote bone mineralization in vitamin D-deficient animals, but only the R-epimer promotes bone mineralization in disodium ethane 1-hydroxy-1,1diphosphonate-blocked animals.

The foregoing activities can be demonstrated in the following tests: S 4 7 3 L (a) Anti-rachitogenic activity in chicks White Leghorn chicks are placed on a vitamin D-deficient diet containing 1% calcium and 0.7% phosphorus, and are housed under ultraviolet-free lighting. The test compounds 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 autopsied 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 mg are given in Table I. The results show that the R- and S-epimers possess similar antirachitogenic activity.

Table I Dose (mg/chick/day) 100 300 1000 Mean tibia ash weight (mg) S-epimer R-epimer 112.1+6.2 124.9+2.8 122.6+ 4.1 159.4+4.4 157.5+ 5.3 187.0+8.7 207.8+ 7.8 210.4+7.8 213.3+10.0 (b) Intestinal calcium absorption in chicks White Leghorn chicks are placed on the vitamin Ddeficient diet and are housed under ultraviolet-free lighting for 21 days. A single oral dose of 1 meg of test compound dissolved in propylene glycol is administered. At various times after dosing, 2 uCi of 45Ca (chloride) is given orally, and serum radioactivity is measured 45 minutes after administration of the isotope. Vehicle-treated controls are included at each time period. Ten chicks are used in each treatment and control group. The results given in Table II show that the the S- and R-epimers possess similar intestinal Ca absorption activity.

Table II Treatment Time (hours) Vehicle, 0.2 ml 3 S-Epimer R-Epimer Vehicle, 0.2 ml 6 S-Epimer R-Epimer 1338+ 51 1977+122 2077+174 1345+ 89 2067+128 1992+212 (c) Prevention of EHDP-induced mineralization block in rats Charles River male rats are treated for 10 consecutive days with disodium ethane 1-hydroxy-1,1-diphosphonate (EHDP) 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 autopsied on the day after the last treatment day and the tibias are processed by silver impregnation of the bone salts. Epiphyseal plate widths are measured with a microscope. Activity is based upon dose dependent narrowing of the widened epiphyseal 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 included in each experiment. The results given in Table III indicate that the R-epimer caused calcification of the tibial epiphyseal plate in EHDP-blocked rats while the S-epimer did not.

Table III Dose (mcg/rat/day) Mean tibial epiphyseal plate width EHDP + S-epimer (micron) EHDP alone EHDP + R-epimer 0 1190+42 10 1162+36 611+51 Vehicle controls (no EHDP) 376+13 (d) Effects on the serum levels of la, 25(OH)2D3 and 25(OH)D3 The effect of subcutaneous administration of the Sand R-epimers on serum levels of la, 25-dihydroxycholecalciferol and 25-hydroxycholecalciferol (la,25(OH)2D3 and 25(OH)D3) was determined according to known methods (Archives of Biochemistry and Biophysics, Vol. 201, No. 1, 1980, 277-285). 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 la,25(OH)2D3 levels was sustained. The ability to control endogenous production of la,25(OH)2D3 is clinically useful in the treatment of among other disease states, sarcoidosis and hypercalciuria.

Table IV Daily treatment No. of No. Of Serum levels of days rats la.25(OH)nD, 25(OH)Dn ( pg/ml) (ng/ml) Vehicle, 0.2 ml 7 18 99.6+0.5 37.6+1.9 S-Epimer 1 meg 12 7.9+2.8 32.0+1.7 R-Epimer 1 meg 12 14.0+4.1 36.0+1.8 *7 22 Vehicle, 0.2 ml 28 10 32.8+7.3 64.2+4.3 S-Epimer 1 meg 10 8.0+2.3 40.6+3.4 R-Epimer 1 meg 10 8.2+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. are preferably administered oraily, but can also be administered subcutaneously, intramuscularly, intravenously or intraperitoneally, for instance in form of tablets, capsules or elixirs for oral administration; or in sterile solutions or suspensions for parenteral administration.

About 0.5 to 500 micrograms of the R- or S-eplmer is compounded with pharmaceutically acceptable adjuvants, such as a vehicle, carrier, excipient, binder, preservative, stabilizer and/or flavor in a unit dosage form.

Illustrative of the adjuvants which may be incorporated into tablets or capsules are a binder, such as corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent, such as corn or potato starch or alginic acid; a lubricant, such as magnesium stearate; 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. 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 propyl parabens as preservatives, a dye and a flavoring, such as orange flavor Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissol ving 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 ethyl oleate. Buffers, preservatives and antioxidants can also be incorporated. 4 7 2 2 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 20.000 20.00 20. 0 4. Modified starch 20.000 20.000 20.0 5. Magnesium stearate 2.000 2.000 2.0 Total 200.000 mg 200.000 mg 200.0 The ingredients 1 to 4 are mixed and if necessary milled. After addition of the magnesium stearate, the mixture is milled and then pressed to tablets.

Example 2 Capsule Formulation mg/capsule 1, The R- or S-epimer of la,25,25-trihydroxychole- calciferol 0.025 0.100 0.500 2. Lactose 159.975 159.90 159.50 3. Modified starch 20.0 20.0 20.0 4. Talc 20.0 20.0 20.0 Total 200 mg 200 mg 200 mg The ingredient 1 is dissolved in alcohol. The ingredients 2 and 3 are mixed and the solution of 1 is spread over the mixture which is then dried overnight. The mixture is screened, then mixed with talc and filled into capsules.

Example 3 The drug can be dissolved in a pharmaceutically acceptable solvents, such as alcohol, propylene glycol, glycerine or polyethylene glycol. Surfactants, such as polyethy5 lene glycol, sorbitan esters, dioctyl 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 growths. Illustrative of capsule formulations are: a) mg/capsule The R- or S-epimer of la,25,26-trihydroxychole- calfiferol 0.025 0.1 0.50 Polyethylene glycol (PEG) 400.0 400.0 400.00 15 Butylated hydroxy- anisol (BHA) 0.2 0.2 0.2 Ascorbyl palmitate 1.0 1.0 1.0 Dissolve BHA and ascorbyl palmitate 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 soft-shell capsules. b) mg/capsule The R- or S-epimer of la,25,26-trihydroxychole- calciferol 0.025 0.1 0.50 PEG 400 (or PEG 6000) 200.0 200.0 200.0 Polyoxyethylene Sorbitan mono- oleate or monostearate (Polysorbate 80 or Polysorbate 60) 200.0 200.0 200.0 30 BHA 0.2 0.2 0.2 Ascorbyl palmitate 1.0 1.0 1.0 Warm the mixture of PEG 6000 and Polysorbate 60. Add to it BHA and ascorbyl palmitate. Add the R- or S-epimer of la,25,26-trihydroxycholecalciferol under an atmosphere of nitrogen. Fill into hard-shell capsules. c) mg/capsule The R- or S-epimer of la,25,26-trihydroxycholecalciferol PEG 400 0.025 100.0 0.1 100.0 0.50 100.0 10 PEG 4000 300.0 300.0 300.0 BHA Butylated hydroxytoluene 0.1 0.1 0.1 (BHT) 0.1 0.1 0.1 Ascorbyl palmitate 1.0 1.0 1.0 15 Warm a mixture of PEG 400 and PEG 4000. Add BHT , BHA and ascorbyl palmitate. Add the R- or S-epimer of la,25,26trihydroxycholecalciferol and dissolve under a stream of nitrogen. Fill into hard-shell capsules.

Claims (5)

1. The c—25 R- or S-epimer of la, 25,26-trihydroxycholecalciferol as an agent for the treatment of disease states characterized by higher than normal serum levels of 5 endogenously produced la,25-dihydroxycholecalciferol or characterized by conditions where there is an increased sensitivity to la,25-dihydroxycholecalciferol.

2. The use of the C-25 R- or S-epimer of la,25,26trihydrcoycholecalciferol for the manufacture of a pharmaceutical 10 preparation for the treatment of disease states characterized by higher than normal serum levels of endogenously produced la, 25dihydrcsycholecalciferol op characterized by conditions where there is an increased sensitivity to la,25-dihydra>ycholecalciferol.

3. Use of the C-25 R- or S-epimer of la, 25, 2615 trihydroxycholecalciferol for the manufacture of a pharmaceutical preparation for the treatment of hypercalcemia, sarcoidosis, hypercalciuria, nephrolithiasis or naphrocalcinosis.

4. A pharmaceutical composition containing the C-25 20 R- or S-epimer of la,25,26-trihydroxycholecalciferol in combination with a pharmaceutical acceptable inert carrier material, for the treatment specified in claim 2 or 3. 5. A pharmaceutical composition according to claim 4, containing from 0.5 to 500 micrograms of the C-25 R- or 25 S-epimer of la,25,26-trihydroxycholecalciferol. 6. Use of an effective amount of the C-25 R- or S-epimer cf la, 25, 26-trihydroxycholecalciferol for the treatment of the diseased states specified in claim 2 or 3. 5 4 7 2 2 7. Use according to claim 2 or 3 of the C-25 R- or Sepimer of la, 25,26-trihydroxycholecalciferol, substantially as hereinbefore described with particular reference to the accompanying Examples.

5. 8. A pharmaceutical composition according to claim 4, substantially as hereinbefore described with particular reference to the accompanying Examples.