Background technology
Calcitriol (Calcitriol) is white crystalline powder, to light and air-sensitive.Be slightly soluble in methanol, ethanol, ethyl acetate.Tm is 111-115 DEG C.It is one of most important metabolic activity product of vitamin D3 in human body, has the intestinal absorption of impelling calcium and regulates in sclerotin the effects such as inorganic salt transhipment; Be mainly used in osteoporosis; The renal osteodystrophy of Patients with Chronic Renal Failure, particularly needs the patient of chronic hemodialysis; After operation, spontaneity and false parathyroid gland machine go down; Vitamin D3 dependency rickets and hypophosphatemia vitamin D resistance rickets; The dermatosiss such as psoriasis; And other vitamin D deficiencies.The oral absorption of calcitriol is fast, within 3~6 hours, reaches peak, t1/2 approximately 3~6 hours, and after 7 hours, urinating calcium concentration increases, the sustainable pharmacologically active of single oral dose 3~5 days.
At present, the main dosage form of calcitriol is soft capsule and soft gelatin capsule; Dosage form is more dull, and calcitriol is to light and air-sensitive, and lower for ordinary organic solvents dissolubility, the stability of soft capsule and soft gelatin capsule is bad, and active constituent content is extremely low, and bioavailability is low.Calcitriol powder do not report in the prior art, and reason is that it can not steady in a long-termly exist, and bioavailability is not high.
Summary of the invention
Research worker is surprisingly found, while preparing calcitriol powder, the meglumine, PEG400 and the polyethylene glycol 6000 that add in right amount, can significantly improve content, stability and the bioavailability of calcitriol in preparation, there is unforeseeable technique effect, significant for the clinical use of medicine.
The invention provides the calcitriol powder that a kind of active component content is high, medicine stability good, bioavailability is high.This powder is made up of the component of following percentage by weight:
Its optimizing prescriptions is:
Further, above-mentioned filler is selected from one or more in starch, lactose, dextrin, amylum pregelatinisatum and Icing Sugar.
Further, above-mentioned lubricant is selected from one or more in magnesium stearate, Pulvis Talci and micropowder silica gel.
The preparation method of this powder is:
1) take the supplementary material of recipe quantity, cross respectively 80-120 mesh sieve for subsequent use;
2) calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000 and filler are uniformly mixed by equivalent incremental method, add lubricant mix rear subpackage and get final product.
The preparation method of this powder is more preferably:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
2) calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000 and filler are uniformly mixed by equivalent incremental method, add lubricant mix rear subpackage and get final product.
The invention has the beneficial effects as follows:
1. in said preparation, the content of calcitriol significantly increases, and has reduced the dose of medicine;
2. improved the stability of calcitriol to light, air having added of meglumine, PEG400 and polyethylene glycol 6000, its bioavailability is also significantly improved.
Detailed description of the invention
Below in conjunction with concrete embodiment, technical scheme of the present invention is further described.
Embodiment 1 calcitriol powder
Prescription is:
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 80 mesh sieves for subsequent use;
2) calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000 and starch are uniformly mixed by equivalent incremental method, add magnesium stearate mix rear subpackage and get final product.
Embodiment 2 calcitriol powders
Prescription is:
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
2) calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000 and lactose are uniformly mixed by equivalent incremental method, add Pulvis Talci mix rear subpackage and get final product.
Embodiment 3 calcitriol powders
Prescription is:
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
2) calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000 and dextrin are uniformly mixed by equivalent incremental method, add micropowder silica gel mix rear subpackage and get final product.
Comparing embodiment 1 calcitriol powder
Preparation method is same embodiment 3:
Comparing embodiment 2 calcitriol powders
Preparation method is with embodiment 3.
Comparing embodiment 3 calcitriol powders
Preparation method is with embodiment 3.
Embodiment 4 stability experiments and result
1. accelerated stability test
Intensity of illumination 4500lx, adopted HPLC method to carry out assay in the 0th, 5 and 10 days after timing sampling.
The condition of HPLC is: chromatographic column: ODS-C18 post, taking octadecylsilane chemically bonded silica as filler; Mobile phase: acetonitrile-water (75:25); Detect wavelength: 265nm; Flow velocity: 1.0mL/min; Sample size: 50 μ L.Theoretical cam curve is pressed the calculating of calcitriol peak should be not low by 5000, and calcitriol peak and the peak-to-peak separating degree of trans calcitriol should be greater than 1.0.Adopt external standard method to calculate content.Assay result (percentage ratio of the amount of recording and labelled amount) sees the following form 1.Result shows that the stability of active component calcitriol in calcitriol powder of the present invention is obviously better than comparative example.
Table 1 accelerated stability test assay result (%)
2. long-term stable experiment
25 DEG C of temperature, relative humidity are placed 36 months for 60% time, respectively at 0,3,6,12,24 and 36 months time sampling adopt HPLC method to carry out assay.The same accelerated stability test of condition of HPLC.Adopt external standard method to calculate content.Assay result (percentage ratio of the amount of recording and labelled amount) sees the following form 2.Result shows that the stability of active component calcitriol in calcitriol powder of the present invention is obviously better than comparative example.
Table 2 long-term stable experiment assay result (%)
The comparative test of embodiment 5 bioavailability
4 beasle dogs (being male) are carried out to oral administration, they are filled with respectively to the calcitriol powder (25 DEG C of temperature, relative humidity are placed 12 months for 60% time) with the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example 3, dosage is only (in calcitriol) of 10.0 μ g/, and be 7 days the interval time of each administration.Give after medicine, blood sample collection under different time, and carry out the maximum haemoconcentration (C of calcitriol
max) and bioavailability (AUC
0 → 48) calculating.Acquisition time is 0h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 32h, 48h.
Following table 3 provides the average result that 4 beasle dogs is given to the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example's 3 calcitriol powder gained.As seen from table, the maximum haemoconcentration of the calcitriol of calcitriol powder of the present invention (embodiment 3) and bioavailability are apparently higher than comparative example.
The comparison (10.0 μ g, n=3) of table 3 bioavailability
Should be noted that; the foregoing is only preferred embodiment of the present invention; be not limited to scope of the present invention, every any amendment of having done within the spirit and principles in the present invention, replacement and the improvement etc. being equal to, within all should being included in protection scope of the present invention.