CN103142495B - Calcitriol suspension granule and preparation method thereof - Google Patents
Calcitriol suspension granule and preparation method thereof Download PDFInfo
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- CN103142495B CN103142495B CN201310091555.7A CN201310091555A CN103142495B CN 103142495 B CN103142495 B CN 103142495B CN 201310091555 A CN201310091555 A CN 201310091555A CN 103142495 B CN103142495 B CN 103142495B
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Abstract
The invention relates to a calcitriol suspension granule and a preparation method thereof. The suspension granule is prepared from the following ingredients in percentage by weight: 0.0005% 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 suspension 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 pharmaceutical technology field, be specifically related to a kind of calcitriol mix suspension grain 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 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 mix suspension grain 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 mix suspension grain, 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 mix suspension grain that a kind of active component content is high, medicine stability good, bioavailability is high.This mix suspension grain 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 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.
The preparation method of this mix suspension grain is:
1) take the supplementary material of recipe quantity, cross respectively 80-120 mesh sieve for subsequent use;
2) binding agent of getting after sieving adds distilled water, makes binder solution;
3) by the calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;
4) after granulating with 40 mesh sieves, dry 30-60min, crosses 20 mesh sieve granulate at 50-70 DEG C; Remove fine powder after No. 4 sieve sieves, subpackage, sealing, packaging and get final product.
The preparation method of this mix suspension grain is more preferably:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
2) binding agent of getting after sieving adds distilled water, makes binder solution;
3) by the calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;
4) after granulating with 40 mesh sieves, dry 45min, crosses 20 mesh sieve granulate at 60 DEG C, removes fine powder after No. 4 sieve sieves, subpackage, sealing, packaging 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 mix suspension grain
Prescription is:
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 80 mesh sieves for subsequent use;
2) pregelatinized Starch of getting after sieving adds distilled water, makes binder solution;
3) by the calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000, starch and carboxymethyl starch sodium by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;
4) after granulating with 40 mesh sieves, dry 30min, crosses 20 mesh sieve granulate at 50 DEG C, removes fine powder after No. 4 sieve sieves, subpackage, sealing, packaging and get final product.
Embodiment 2 calcitriol mix suspension grains
Prescription is:
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 120 mesh sieves for subsequent use;
2) hyprolose of getting after sieving adds distilled water, makes binder solution;
3) by the calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000, lactose and low-substituted hydroxypropyl cellulose by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;
4) after granulating with 40 mesh sieves, dry 60min, crosses 20 mesh sieve granulate at 70 DEG C, removes fine powder after No. 4 sieve sieves, subpackage, sealing, packaging and get final product.
Embodiment 3 calcitriol mix suspension grains
Prescription is:
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
2) polyvidone of getting after sieving adds distilled water, makes binder solution;
3) by the calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000, dextrin and microcrystalline Cellulose by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;
4) after granulating with 40 mesh sieves, dry 45min, crosses 20 mesh sieve granulate at 60 DEG C, removes fine powder after No. 4 sieve sieves, subpackage, sealing, packaging and get final product.
Comparing embodiment 1 calcitriol mix suspension grain
Preparation method is same embodiment 3:
Comparing embodiment 2 calcitriol mix suspension grains
Preparation method is with embodiment 3.
Comparing embodiment 3 calcitriol mix suspension grains
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 mix suspension grain 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 mix suspension grain 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, feed respectively the calcitriol mix suspension grain with the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example 3 (25 DEG C of temperature, relative humidity are placed 12 months for 60% time) to them, 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 mix suspension grain gained.As seen from table, the maximum haemoconcentration of the calcitriol of calcitriol mix suspension grain 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.
Claims (7)
1. a calcitriol mix suspension grain, is characterized in that, is made up of the component of following percentage by weight:
Calcitriol 0.0005%
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 mix suspension grain according to claim 1, is characterized in that, is made up of the component of following percentage by weight:
Calcitriol 0.0005%
Meglumine 3.0%
PEG400 1.5%
Polyethylene glycol 6000 20%
Filler 60.0%
Disintegrating agent 8.0%
Binding agent is appropriate.
3. calcitriol mix suspension grain 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 mix suspension grain 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 mix suspension grain 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. the preparation method of the calcitriol mix suspension grain described in claim 1-5 any one, is characterized in that, the method comprises the steps:
1) take the supplementary material of recipe quantity, cross respectively 80-120 mesh sieve for subsequent use;
2) binding agent of getting after sieving adds distilled water, makes binder solution;
3) by the calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;
4) after granulating with 40 mesh sieves, dry 30-60min, crosses 20 mesh sieve granulate at 50-70 DEG C; Remove fine powder after No. 4 sieve sieves, subpackage, sealing, packaging and get final product.
7. the preparation method of calcitriol mix suspension grain claimed in claim 6, is characterized in that, the method comprises the steps:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
2) binding agent of getting after sieving adds distilled water, makes binder solution;
3) by the calcitriol after sieving, meglumine, PEG400, polyethylene glycol 6000, filler and disintegrating agent by equivalent incremental method mix homogeneously, add above-mentioned binder solution to make soft material;
4) after granulating with 40 mesh sieves, dry 45min, crosses 20 mesh sieve granulate at 60 DEG C, removes fine powder after No. 4 sieve sieves, subpackage, sealing, packaging and get final product.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5976784A (en) * | 1996-09-20 | 1999-11-02 | Wisconsin Alumni Research Foundation | Calcitriol derivatives and their uses |
| 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 |
| CN101554372A (en) * | 2009-05-20 | 2009-10-14 | 青岛正大海尔制药有限公司 | Calcitriol dripping pill and preparation method thereof |
| CN102038645A (en) * | 2009-10-12 | 2011-05-04 | 杭州赛利药物研究所有限公司 | Desloratadine grain and preparation method thereof |
| CN102973528A (en) * | 2012-11-19 | 2013-03-20 | 中山大学 | Calcitriol solid lipidic dispersion and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7611728B2 (en) * | 2003-09-05 | 2009-11-03 | Supernus Pharmaceuticals, Inc. | Osmotic delivery of therapeutic compounds by solubility enhancement |
| GB0513984D0 (en) * | 2005-07-07 | 2005-08-17 | Teva Pharma | Dosage form |
| FR2909284B1 (en) * | 2006-11-30 | 2012-09-21 | Galderma Sa | NOVEL VASELIN-FREE OINTMENTAL COMPOSITIONS COMPRISING VITAMIN D DERIVATIVE AND POSSIBLY STEROID ANTI-INFLAMMATORY |
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- 2013-03-21 CN CN201310091555.7A patent/CN103142495B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5976784A (en) * | 1996-09-20 | 1999-11-02 | Wisconsin Alumni Research Foundation | Calcitriol derivatives and their uses |
| 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 |
| CN101554372A (en) * | 2009-05-20 | 2009-10-14 | 青岛正大海尔制药有限公司 | Calcitriol dripping pill and preparation method thereof |
| CN102038645A (en) * | 2009-10-12 | 2011-05-04 | 杭州赛利药物研究所有限公司 | Desloratadine grain and preparation method thereof |
| CN102973528A (en) * | 2012-11-19 | 2013-03-20 | 中山大学 | Calcitriol solid lipidic dispersion and preparation method thereof |
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Address after: 266103 Qingdao economic and Technological Development Zone, unity Road, No. 3601, Shandong Applicant after: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. Address before: 266103 Haier Road, Shandong, Qingdao, No. 1 Applicant before: Qingdao Zhengda Haier Pharmaceutical Co., Ltd. |
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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. |