CN103142496A - Calcitriol controlled-release granule and preparation method thereof - Google Patents
Calcitriol controlled-release granule and preparation method thereof Download PDFInfo
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- CN103142496A CN103142496A CN2013100915735A CN201310091573A CN103142496A CN 103142496 A CN103142496 A CN 103142496A CN 2013100915735 A CN2013100915735 A CN 2013100915735A CN 201310091573 A CN201310091573 A CN 201310091573A CN 103142496 A CN103142496 A CN 103142496A
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Abstract
The invention relates to a calcitriol controlled-release granule and a preparation method thereof. The controlled-release granule consists of a core and a controlled-release coating layer, wherein the controlled-release coating layer contains an controlled-release material accounting for 10-20% by weight, and the core is prepared from the following ingredients in percentage by weight: 0.002% of calcitriol, 2.0-4.0% of meglumine, 1.2-1.8% of polyethylene glycol 400, 15-25% of polyethylene glycol 6000, 50.0-70.0% of filler, 5.0-10.0% of disintegrant and an appropriate amount of binder. According to the controlled-release granule, the content of calcitriol is remarkably increased, so that the drug dosage is reduced; and the stability of calcitriol to light and air is improved, and the bioavailability of calcitriol is also remarkably improved.
Description
Technical field
The present invention relates to the pharmaceutical technology field, be specifically related to a kind of calcitriol controlled release granule and preparation method thereof.
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 ℃.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 effect 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, reaches the peak in 3～6 hours, t1/2 approximately 3～6 hours, and the urine calcium concentration increases after 7 hours, 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 lower for the ordinary organic solvents dissolubility to light and air-sensitive, soft capsule and soft gelatin capsule stable bad, and active constituent content is extremely low, and bioavailability is low.The calcitriol controlled release granule does not have 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 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.
Claims (8)
1. a calcitriol controlled release granule, is characterized in that, 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.
2. calcitriol controlled release granule according to claim 1, is characterized in that, it is 15% controlled-release material that described controlled release coat layer comprises percentage by weight, and described 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.
3. calcitriol controlled release granule according to claim 1 and 2, is characterized in that, described filler is selected from one or more in starch, lactose, dextrin, amylum pregelatinisatum and Icing Sugar.
4. calcitriol controlled release granule according to claim 1 and 2, is characterized in that, described 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.
5. calcitriol controlled release granule according to claim 1 and 2, is characterized in that, described binding agent is selected from one or more in starch, pregelatinized Starch, hyprolose, hypromellose and polyvidone.
6. calcitriol controlled release granule according to claim 1 and 2, is characterized in that, described controlled-release material is selected from one or more in methylcellulose, ethyl cellulose and methacrylate copolymer.
7. the preparation method of the described calcitriol controlled release granule of claim 1-6, is characterized in that, the method comprises the steps:
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.
8. the preparation method of calcitriol controlled release granule claimed in claim 7, is characterized in that, the method comprises the steps:
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.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110893178A (en) * | 2019-12-11 | 2020-03-20 | 正大制药（青岛）有限公司 | Fluorocalcitriol solid oral preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101141966A (en) * | 2005-03-23 | 2008-03-12 | 拜奥克塞尔有限公司 | Use of vitamin D compounds to treat endometriosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101141966A (en) * | 2005-03-23 | 2008-03-12 | 拜奥克塞尔有限公司 | Use of vitamin D compounds to treat endometriosis |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110893178A (en) * | 2019-12-11 | 2020-03-20 | 正大制药（青岛）有限公司 | Fluorocalcitriol solid oral preparation and preparation method thereof |
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Address after: 266103 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee after: Zhengda Pharmaceutical (Qingdao) Co., Ltd. Address before: 266103 3601 Tuen Jie Road, Qingdao economic and Technological Development Zone, Shandong Patentee before: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. |
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