CN103142478A - Calcitriol emulsion and preparation method thereof - Google Patents
Calcitriol emulsion and preparation method thereof Download PDFInfo
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- CN103142478A CN103142478A CN2013100927681A CN201310092768A CN103142478A CN 103142478 A CN103142478 A CN 103142478A CN 2013100927681 A CN2013100927681 A CN 2013100927681A CN 201310092768 A CN201310092768 A CN 201310092768A CN 103142478 A CN103142478 A CN 103142478A
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Abstract
The invention relates to a calcitriol emulsion and a preparation method thereof. The emulsion is prepared from the following ingredients in percentage by weight: 0.0005% of calcitriol, 0.7-1.2% of meglumine, 12-18% of polyethylene glycol 400, 1.5-2.5% of polyethylene glycol 6000, 0.5-30% of vegetable oil, 4.0% of emulsifying agent, 1.0% of coemulsifier and the balance of water for injection. According to the emulsion, 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 Emulsion 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.Calcitriol Emulsion 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 Emulsion, 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 Emulsion that a kind of active component content is high, medicine stability good, bioavailability is high.This Emulsion is made by the component of following percentage by weight:
Its optimizing prescriptions is:
Further, above-mentioned vegetable oil is selected from one or more in Oleum Camelliae, Oleum Arachidis hypogaeae semen, olive oil, Semen Maydis oil, Oleum Ricini and Oleum Gossypii semen.
Further, mentioned emulsifier is selected from one or more in arabic gum, tragakanta, stearic acid sodium, enuatrol, sodium lauryl sulphate, fatty acid glyceride, poloxamer.
Further, above-mentioned coemulsifier is selected from one or more in methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate, xanthan gum and agar.
The preparation method of this Emulsion is:
1) get the vegetable oil of recipe quantity, add calcitriol, emulsifying agent and the coemulsifier of recipe quantity, stir under 500-1000rpm, make oil phase;
2) get the water for injection of recipe quantity, add the PEG400 of recipe quantity, stir; Continue to add meglumine and the polyethylene glycol 6000 of recipe quantity, stir 15-25min under 45-55 ℃ to all dissolving to get solution;
3) in the same direction with the mixing speed of 500-1000rpm, above-mentioned oil phase is slowly added in gained solution, emulsifying is 2-4 time in the high pressure dispersing emulsification machine, filters fill, 115 ℃ of sterilization 30min, and get final product.
The preparation method of this Emulsion is more preferably:
1) get the vegetable oil of recipe quantity, add calcitriol, emulsifying agent and the coemulsifier of recipe quantity, stir under 800rpm, make oil phase;
2) get the water for injection of recipe quantity, add the PEG400 of recipe quantity, stir; Continue to add meglumine and the polyethylene glycol 6000 of recipe quantity, stir 20min under 50 ℃ to all dissolving to get solution;
3) in the same direction with the mixing speed of 800rpm, above-mentioned oil phase is slowly added in gained solution, emulsifying is 3 times in the high pressure dispersing emulsification machine, filters fill, 115 ℃ of sterilization 30min, 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 Emulsion
Prescription is:
Preparation method is:
1) get the Oleum Ricini of recipe quantity, add calcitriol, arabic gum and the methylcellulose of recipe quantity, stir under 500rpm, make oil phase;
2) get the water for injection of recipe quantity, add the PEG400 of recipe quantity, stir; Continue to add meglumine and the polyethylene glycol 6000 of recipe quantity, stir 15min under 45 ℃ to all dissolving to get solution;
3) in the same direction with the mixing speed of 500rpm, above-mentioned oil phase is slowly added in gained solution, emulsifying is 2 times in the high pressure dispersing emulsification machine, filters fill, 115 ℃ of sterilization 30min, and get final product.
Embodiment 2 calcitriol Emulsions
Prescription is:
Preparation method is:
1) get the Oleum Arachidis hypogaeae semen of recipe quantity, add calcitriol, tragakanta and the hydroxypropyl cellulose of recipe quantity, stir under 1000rpm, make oil phase;
2) get the water for injection of recipe quantity, add the PEG400 of recipe quantity, stir; Continue to add meglumine and the polyethylene glycol 6000 of recipe quantity, stir 25min under 55 ℃ to all dissolving to get solution;
3) in the same direction with the mixing speed of 1000rpm, above-mentioned oil phase is slowly added in gained solution, emulsifying is 4 times in the high pressure dispersing emulsification machine, filters fill, 115 ℃ of sterilization 30min, and get final product.
Embodiment 3 calcitriol Emulsions
Prescription is:
Preparation method is:
1) get the Semen Maydis oil of recipe quantity, add calcitriol, poloxamer and the sodium alginate of recipe quantity, stir under 800rpm, make oil phase;
2) get the water for injection of recipe quantity, add the PEG400 of recipe quantity, stir; Continue to add meglumine and the polyethylene glycol 6000 of recipe quantity, stir 20min under 50 ℃ to all dissolving to get solution;
3) in the same direction with the mixing speed of 800rpm, above-mentioned oil phase is slowly added in gained solution, emulsifying is 3 times in the high pressure dispersing emulsification machine, filters fill, 115 ℃ of sterilization 30min, and get final product.
Comparing embodiment 1 calcitriol Emulsion
Preparation method is with embodiment 3:
Comparing embodiment 2 calcitriol Emulsions
Preparation method is with embodiment 3.
Comparing embodiment 3 calcitriol Emulsions
Preparation method is with embodiment 3.
Stability experiment 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 Emulsion 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 Emulsion of the present invention obviously is better than the comparative example.
Table 2 long-term stable experiment assay result (%)
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 (7)
1. a calcitriol Emulsion, is characterized in that, made by the component of following percentage by weight:
2. calcitriol Emulsion according to claim 1, is characterized in that, made by the component of following percentage by weight:
3. calcitriol Emulsion according to claim 1 and 2, is characterized in that, described vegetable oil is selected from one or more in Oleum Camelliae, Oleum Arachidis hypogaeae semen, olive oil, Semen Maydis oil, Oleum Ricini and Oleum Gossypii semen.
4. calcitriol Emulsion according to claim 1 and 2, is characterized in that, described emulsifying agent is selected from one or more in arabic gum, tragakanta, stearic acid sodium, enuatrol, sodium lauryl sulphate, fatty acid glyceride, poloxamer.
5. calcitriol Emulsion according to claim 1 and 2, is characterized in that, described coemulsifier is selected from one or more in methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium alginate, xanthan gum and agar.
6. the preparation method of the described calcitriol Emulsion of claim 1-5, is characterized in that, the method comprises the steps:
1) get the vegetable oil of recipe quantity, add calcitriol, emulsifying agent and the coemulsifier of recipe quantity, stir under 500-1000rpm, make oil phase;
2) get the water for injection of recipe quantity, add the PEG400 of recipe quantity, stir; Continue to add meglumine and the polyethylene glycol 6000 of recipe quantity, stir 15-25min under 45-55 ℃ to all dissolving to get solution;
3) in the same direction with the mixing speed of 500-1000rpm, above-mentioned oil phase is slowly added in gained solution, emulsifying is 2-4 time in the high pressure dispersing emulsification machine, filters fill, 115 ℃ of sterilization 30min, and get final product.
7. the preparation method of calcitriol Emulsion claimed in claim 6, is characterized in that, the method comprises the steps:
1) get the vegetable oil of recipe quantity, add calcitriol, emulsifying agent and the coemulsifier of recipe quantity, stir under 800rpm, make oil phase;
2) get the water for injection of recipe quantity, add the PEG400 of recipe quantity, stir; Continue to add meglumine and the polyethylene glycol 6000 of recipe quantity, stir 20min under 50 ℃ to all dissolving to get solution;
3) in the same direction with the mixing speed of 800rpm, above-mentioned oil phase is slowly added in gained solution, emulsifying is 3 times in the high pressure dispersing emulsification machine, filters fill, 115 ℃ of sterilization 30min, and get final product.
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| CN201310092768.1A CN103142478B (en) | 2013-03-21 | 2013-03-21 | Calcitriol emulsion and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104800155A (en) * | 2015-04-22 | 2015-07-29 | 青岛正大海尔制药有限公司 | Alfacalcidol injection and preparation method thereof |
| WO2015119183A1 (en) * | 2014-02-05 | 2015-08-13 | 協和発酵キリン株式会社 | Liquid drug containing active vitamin d3 or derivative thereof |
| CN108030767A (en) * | 2017-12-29 | 2018-05-15 | 河南泰丰生物科技有限公司 | A kind of Calcijex and preparation method thereof |
| CN108969527A (en) * | 2017-05-31 | 2018-12-11 | 上海通用药业股份有限公司 | A kind of pharmaceutical preparation and its preparation method and application |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5952317A (en) * | 1995-09-21 | 1999-09-14 | Wisconsin Alumni Research Foundation | Calcitriol derivatives and their uses |
| US20050053653A1 (en) * | 2003-09-05 | 2005-03-10 | Argaw Kidane | Osmotic delivery of therapeutic compounds by solubility enhancement |
| CN1732009A (en) * | 2002-11-06 | 2006-02-08 | 诺瓦西股份有限公司 | Methods of using vitamin d compounds in the treatment of myelodysplastic syndromes |
| 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 |
-
2013
- 2013-03-21 CN CN201310092768.1A patent/CN103142478B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5952317A (en) * | 1995-09-21 | 1999-09-14 | Wisconsin Alumni Research Foundation | Calcitriol derivatives and their uses |
| CN1732009A (en) * | 2002-11-06 | 2006-02-08 | 诺瓦西股份有限公司 | Methods of using vitamin d compounds in the treatment of myelodysplastic syndromes |
| US20050053653A1 (en) * | 2003-09-05 | 2005-03-10 | Argaw Kidane | Osmotic delivery of therapeutic compounds by solubility enhancement |
| 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015119183A1 (en) * | 2014-02-05 | 2015-08-13 | 協和発酵キリン株式会社 | Liquid drug containing active vitamin d3 or derivative thereof |
| JPWO2015119183A1 (en) * | 2014-02-05 | 2017-03-23 | 協和発酵キリン株式会社 | Liquid preparation containing active vitamin D3 or a derivative thereof |
| CN104800155A (en) * | 2015-04-22 | 2015-07-29 | 青岛正大海尔制药有限公司 | Alfacalcidol injection and preparation method thereof |
| CN108969527A (en) * | 2017-05-31 | 2018-12-11 | 上海通用药业股份有限公司 | A kind of pharmaceutical preparation and its preparation method and application |
| CN108030767A (en) * | 2017-12-29 | 2018-05-15 | 河南泰丰生物科技有限公司 | A kind of Calcijex and preparation method thereof |
| CN108030767B (en) * | 2017-12-29 | 2020-07-24 | 河南泰丰生物科技有限公司 | Calcitriol injection and preparation method thereof |
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| CN103142478B (en) | 2014-10-01 |
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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. |