NZ203251A - Pharmaceutical compositions containing 1alpha,25,26-trihydroxycholecalciferol - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £03251 Priority Date(s): /.Q.<?.;.&> Complete Specification Filed: AQ..pI;<&3 Class: I./.K3 J. ./.$>*? (f T APR 198? Publication Date: - P.O. Journal, No: .../???.?.

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$ LWFEBI98J j 'tf ^ No.: Date: NI£W ZEALAND PATI-NTS ACT, 1953 COMPLETE SPECIFICATION USE OF CHOLECALCIFEROL DERIVATIVES X/We, F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHAFT, 124-184 Grenzacherstrasse, Basle, Switzerland, a Swiss company, hereby declare the invention for which X / we pray that a patent may be granted to uric/as, and the method by which it is to be performed, to be particularly described in and by the following statement: - • - 1 - (followed by la) 2-03251 la - The invention is based on the finding of novel physiological properties of the C-25 R- and S-epimers of la,25, 26-trihydroxycholecalciferol, hereinafter demoninated the R- and 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 pharmaceutical compositions in unit dosage form containing from 0.5 to 500 micrograms of the C-25 R- or S-epimer of la , 25 ,26-trihydroxy-cholecalciferol in combination with a pharmaceutically acceptable inert carrier material, for the treatment of disease states characterized by higher than normal serum levels of endogenously produced la,25-dihydroxycholecalciferol or characterized by conditions where there is an increased sensitivity to la,25-dihydroxycholecalciferol.

Specifically included among the above mentioned disease states are hypercalcemia, sarcoidosis, hypercalciuria, nephrolithiasis and nephrocalcinosis. la , 25,26-trihydroxycholecalciferol may be prepared according to the process in British Patent Specification No. 2 06 0 64 2.

As indicated above, the R- and S-epimers 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-l,1-diphosphonate-blocked animals.

The foregoing activities can be demonstrated in the following tests: Hrto,Vao _ 2 - 2rsi"} sr 1 \j J ,L -J I (a) Anti-rachitoqenic activity in chicks White Leghorn chicks are placed on a vitamin D-defi-cient 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 activi tv.

Table I Mean tibia ash weight (mg) Dose (mq/chick/dav) 0 30 100 300 1000 S-epimer 124.9+2.8 159.4+4.4 187.0+8.7 210.4+7.8 112.1+6.2 R-epimer 122.6+ 4.1 157. 5+ 5.3 207.8+ 7.8 213.3+10.0 (b) Intestinal calcium 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 meg of test compound dissolved in propylene glycol is administered. At 45 various times after dosing, 2 yCi of Ca (chloride) is 35 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 2 032 5 Table II show that the the S- and R-epimers possess similar 45 intestinal Ca absorption activity.

Table II 45 Treatment Time (hours) Serum Ca (cpm/0.2 ml) Vehicle, 0.2 ml 3 1338+ 51 S-Epimer 1977+122 R-Epimer 2077+174 Vehicle, 0.2 ml 6 1345+ 89 S-Epimer 2067+128 R-Epimer 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. 7 nrx 7 ^ L v - nJ i~ J Table III Dose Mean tibial 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 la,25(OH)2D3 and 25(OH)D The effect of subcutaneous administration of the S-and R-epimers on serum levels of la,25-dihydroxycholecalciferol and 25-hydroxycholecalciferol ( la, 25 ( OH) 2^3 an<^ 25(OH)D^) was determined according to known methods 20 (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 {OW) 2^2 levels was sustained. The ability 25 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)qDj 25(OH) (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 mCg 12 14.0+4.1 36.0+1.8 2 032 5 Vehicle, 0 . 2 ml 28 32.8 + 7. 3 64. 2 + 4 . 3 S-Ep ime r 1 meg 8.0+2. 3 40. 6 + 3. 4 R-Epimer 1 meg 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. They are preferably administered orally, 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-epimer 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 dissolving 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. 2 032 5 Example 1 Tablet Formulation mq/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 . Magnesium stearate 2.000 2.000 2.0 Total 200.000 mg 200.000 mg 200.0 mg 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, 25,26-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. 2 0 3 ? 5 1 Example 3 The drug can be dissolved in a pharmaceutically acceptable solvents, such as alcohol, propylene glycol, glyce-5 rine or polyethylene glycol. Surfactants, such as polyethylene 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 10 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 Butvlated hydroxy- anisol I 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 BHA 0.2 0.2 0.2 Ascorbyl palmitate 1.0 1.0 1.0 20325T 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) The R- or S-epimer of la,25,26-trihydroxychole-calciferol 10 peg 400 PEG 4000 BHA Butylated hydroxytoluene ( BHT) Ascorbyl palmitate mg/capsule 0.025 0.1 0.50 100.0 100.0 100.0 300.0 300.0 300.0 0.1 0.1 0.1 0.1 0.1 0.1 1.0 1.0 1.0 Warm a mixture of PEG 400 and PEG 4000. Add BHT, BHA and ascorbyl palmitate. Add the R- or S-epimer of la,25,26-trihydroxycholecalciferol and dissolve under a stream of 20 nitrogen. Fill into hard-shell capsules. 203351

Claims (2)

WHAT WE CLAIM IS:

1. A pharmaceutical composition in a unit dosage form containing from 0.5 to 500 micrograms of the C-25 R- or S-epimer of la,25,26-trihydroxycholecalciferol in combination with a pharmaceutical^ acceptable inert carrier material, for the treatment of disease states characterized by higher than normal serujn levels of endogenously produced la,25-dihydroxycholecalciferol or characterized by conditions where there is an increased sensitivity to la , 25-dihydroxycholecalciferol.

2. A pharmaceutical composition according to claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 3. OATLTJ THiS jffrk DAY OF 1Q*& A . J . P A R K & S O M i;-.5 J{ -C /V.A-NTS FO« THE ICANTS