Summary of the invention
Research worker is unexpected to be found, during preparation calcitriol controlled release granule, the meglumine that adds in right amount, PEG400 and polyethylene glycol 6000, can significantly improve content, stability and the bioavailability of calcitriol in preparation, have unforeseeable technique effect, significant for the clinical use of medicine.
The invention provides the calcitriol controlled release granule that a kind of active component content is high, medicine stability good, bioavailability is high.This controlled release granule is comprised of core core and controlled release coat layer, and wherein the controlled release coat layer comprises the controlled-release material that percentage by weight is 10-20%, and the core core is made by the component of following percentage by weight:
Calcitriol 0.002%
Meglumine 2.0-4.0%
PEG400 1.2-1.8%
Polyethylene glycol 6000 15-25%
Filler 50.0-70.0%
Disintegrating agent 5.0-10.0%
Binding agent is appropriate.
In its optimizing prescriptions, to comprise percentage by weight be 15% controlled-release material to the controlled release coat layer, and the core core is made by the component of following percentage by weight:
Calcitriol 0.002%
Meglumine 3.0%
PEG400 1.5%
Polyethylene glycol 6000 20%
Filler 60.0%
Disintegrating agent 8.0%
Binding agent is appropriate.
Further, above-mentioned filler is selected from one or more in starch, lactose, dextrin, amylum pregelatinisatum and Icing Sugar.
Further, above-mentioned disintegrating agent is selected from one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and sodium alginate.
Further, above-mentioned binding agent is selected from one or more in starch, pregelatinized Starch, hyprolose, hypromellose and polyvidone.
Further, above-mentioned controlled-release material is selected from one or more in methylcellulose, ethyl cellulose and methacrylate copolymer.
The preparation method of this controlled release granule is:
1) take the supplementary material of recipe quantity, cross respectively the 80-120 mesh sieve standby;
2) binding agent and the controlled-release material got after sieving add respectively distilled water, make binder solution and coating solution;
3) calcitriol, meglumine, PEG400, polyethylene glycol 6000, filler and the disintegrating agent after sieving by equivalent incremental method mix homogeneously, adds above-mentioned binder solution to make soft material;
4) granulate with 40 mesh sieves after, dry 30-60min under 50-70 ℃ crosses 20 mesh sieve granulate; Remove fine powder after No. 4 sieve sieves, make the core core;
5) with above-mentioned coating solution, the core core that makes is carried out fluidized bed coating, drying, packing, sealing, packing and get final product.
The preparation method of this controlled release granule is more preferably:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves standby;
2) binding agent and the controlled-release material got after sieving add respectively distilled water, make binder solution and coating solution;
3) calcitriol, meglumine, PEG400, polyethylene glycol 6000, filler and the disintegrating agent after sieving by equivalent incremental method mix homogeneously, adds above-mentioned binder solution to make soft material;
4) granulate with 40 mesh sieves after, dry 45min under 60 ℃ crosses 20 mesh sieve granulate; Remove fine powder after No. 4 sieve sieves, make the core core;
5) with above-mentioned coating solution, the core core that makes is carried out fluidized bed coating, drying, packing, sealing, packing 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.
The specific embodiment
Below in conjunction with concrete embodiment, technical scheme of the present invention is further described.
Embodiment 1 calcitriol controlled release granule
Prescription is:
The core core is made by the component of following percentage by weight:
Calcitriol 6.0mg
Meglumine 6.0g
PEG400 3.6g
Polyethylene glycol 6000 45g
Starch 210g
Carboxymethyl starch sodium 15g
Pregelatinized Starch is appropriate,
It is 10% methylcellulose that the controlled release coat layer comprises percentage by weight.
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 80 mesh sieves standby;
2) pregelatinized Starch and the methylcellulose got after sieving add respectively distilled water, make binder solution and coating solution;
3) calcitriol, meglumine, PEG400, polyethylene glycol 6000, starch and the carboxymethyl starch sodium after sieving by equivalent incremental method mix homogeneously, adds above-mentioned binder solution to make soft material;
4) granulate with 40 mesh sieves after, dry 30min under 50 ℃ crosses 20 mesh sieve granulate; Remove fine powder after No. 4 sieve sieves, make the core core;
5) with above-mentioned coating solution, the core core that makes is carried out fluidized bed coating, drying, packing, sealing, packing and get final product.
Embodiment 2 calcitriol controlled release granules
Prescription is:
The core core is made by the component of following percentage by weight:
Calcitriol 6.0mg
Meglumine 12g
PEG400 5.4g
Polyethylene glycol 6000 75g
Lactose 150g
Low-substituted hydroxypropyl cellulose 30g
Pregelatinized Starch is appropriate,
It is 20% ethyl cellulose that the controlled release coat layer comprises percentage by weight.
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 120 mesh sieves standby;
2) pregelatinized Starch and the ethyl cellulose got after sieving add respectively distilled water, make binder solution and coating solution;
3) calcitriol, meglumine, PEG400, polyethylene glycol 6000, lactose and the low-substituted hydroxypropyl cellulose after sieving by equivalent incremental method mix homogeneously, adds above-mentioned binder solution to make soft material;
4) granulate with 40 mesh sieves after, dry 60min under 70 ℃ crosses 20 mesh sieve granulate; Remove fine powder after No. 4 sieve sieves, make the core core;
5) with above-mentioned coating solution, the core core that makes is carried out fluidized bed coating, drying, packing, sealing, packing and get final product.
Embodiment 3 calcitriol controlled release granules
Prescription is:
The core core is made by the component of following percentage by weight:
Calcitriol 6.0mg
Meglumine 9.0g
PEG400 4.5g
Polyethylene glycol 6000 60g
Dextrin 180g
Microcrystalline Cellulose 24.0g
Polyvidone is appropriate,
It is 15% methacrylate copolymer that the controlled release coat layer comprises percentage by weight.
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves standby;
2) polyvidone and the methacrylate copolymer got after sieving add respectively distilled water, make binder solution and coating solution;
3) calcitriol, meglumine, PEG400, polyethylene glycol 6000, dextrin and the microcrystalline Cellulose after sieving by equivalent incremental method mix homogeneously, adds above-mentioned binder solution to make soft material;
4) granulate with 40 mesh sieves after, dry 45min under 60 ℃ crosses 20 mesh sieve granulate; Remove fine powder after No. 4 sieve sieves, make the core core;
5) with above-mentioned coating solution, the core core that makes is carried out fluidized bed coating, drying, packing, sealing, packing and get final product.
Comparing embodiment 1 calcitriol controlled release granule
The core core is made by the component of following percentage by weight:
Calcitriol 6.0mg
PEG400 4.5g
Polyethylene glycol 6000 60g
Dextrin 180g
Microcrystalline Cellulose 24.0g
Polyvidone is appropriate,
It is 15% methacrylate copolymer that the controlled release coat layer comprises percentage by weight.
Preparation method is with embodiment 3:
Comparing embodiment 2 calcitriol controlled release granules
The core core is made by the component of following percentage by weight:
Calcitriol 6.0mg
Meglumine 9.0g
Polyethylene glycol 6000 60g
Dextrin 180g
Microcrystalline Cellulose 24.0g
Polyvidone is appropriate,
It is 15% methacrylate copolymer that the controlled release coat layer comprises percentage by weight.
Preparation method is with embodiment 3.
Comparing embodiment 3 calcitriol controlled release granules
The core core is made by the component of following percentage by weight:
Calcitriol 6.0mg
Meglumine 9.0g
PEG400 4.5g
Dextrin 180g
Microcrystalline Cellulose 24.0g
Polyvidone is appropriate,
It is 15% methacrylate copolymer that the controlled release coat layer comprises percentage by weight.
Preparation method is with embodiment 3.
Embodiment 4 stability experiments and result
1. accelerated stability test
Intensity of illumination 4500lx regularly adopted the HPLC method to carry out assay after sampling in the 0th, 5 and 10 day.
The condition of HPLC is: chromatographic column: the ODS-C18 post, take 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 calcitriol peak calculating and should do not hanged down 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 controlled release granule of the present invention obviously is better than the comparative example.
Table 1 accelerated stability test assay result (%)
2. long-term stable experiment
25 ℃ of temperature, relative humidity were placed 36 months for 60% time, respectively at 0,3,6,12,24 and 36 months the time sampling adopt the HPLC method to carry out assay.The same accelerated stability test of the 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 controlled release granule of the present invention obviously is better than the 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 oral administration, feed respectively the calcitriol controlled release granule with the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example 3 (25 ℃ of temperature, relative humidity were placed 12 months for 60% time) to them, dosage is 10.0 μ g/ only (in calcitriol), and be 7 days the interval time of each administration.After giving 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 the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example's 3 calcitriol controlled release granule gained.As seen from table, the maximum haemoconcentration of the calcitriol of calcitriol controlled release granule of the present invention (embodiment 3) and bioavailability are apparently higher than the comparative example.
The comparison of table 3 bioavailability (10.0 μ g, n=3)
Should be noted that; the above is only preferred embodiment of the present invention; be not limited to scope of the present invention, every any modification of having done within the spirit and principles in the present invention, the replacement that is equal to and improvement etc. are within all should being included in protection scope of the present invention.