CN104800156A - Alfacalcidol solution and preparation method thereof - Google Patents
Alfacalcidol solution and preparation method thereof Download PDFInfo
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- CN104800156A CN104800156A CN201510191547.9A CN201510191547A CN104800156A CN 104800156 A CN104800156 A CN 104800156A CN 201510191547 A CN201510191547 A CN 201510191547A CN 104800156 A CN104800156 A CN 104800156A
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Abstract
The invention relates to an alfacalcidol solution and a preparation method thereof. The solution is prepared from the following ingredients by weight percent: 0.0005 percent of alfacalcidol, 0.9-1.2 percent of polyvinylpyrrolidone K30, 27-30 percent of hydroxypropyl methylcellulose water solution, 12-14 percent of lauryl sodium sulfate, 0.2 percent of an antioxygen, 0.5 percent of a corrigent, and the balance of distilled water. Compared with the prior art, the content of alfacalcidol in the solution is remarkably increased; the medicine dose is reduced; the stability of alfacalcidol for light and air is improved; the bioavailability of alfacalcidol is remarkably improved as well.
Description
Technical field
The present invention relates to pharmaceutical technology sectors, be specifically related to a kind of alfacalcidol solution and preparation method thereof.
Background technology
Alfacalcidol (Alfacalcidol), its chemistry by name 9,10-open loop gallbladder steroid-5Z, 7E, 10 (19)-triolefin-1 α, 3 β-glycol.Work the balanced action regulating calcium, phosphorus in vivo, and the absorption at intestinal of calcium and phosphorus can be increased, reduce parathyroid hormone level in blood plasma, and improve postmenopausal women and use hormone medicine to cause osteoporosis.Be applicable to rickets, osteomalacia that osteoporosis and a variety of causes cause.This product has to be impelled intestinal absorption calcium and regulates the effect such as inorganic salt transhipment in sclerotin.Have the patient of obvious renal insufficiency, particularly need chronic hemodialysis person, endogenous calcitriol composition reduces significantly, even almost stops synthesis, thus causes renal osteodystrophy.Alfacalcidol is changed into 1-25-(OH)2-D3 rapidly at liver, and the latter is the metabolite of vitamin D3, plays the effect regulating calcium and phosphate metabolism.Because this conversion process is very rapid, thus the clinical effect of alfacalcidol and 1-25-(OH)2-D3 basically identical.Its Main Function is by 1-25-(OH)2-D3 level in blood circulation in raising body, thus increases calcium, phosphatic intestinal absorption, promotes bone mineralising, reduces parathormone level, reduce bone calcium simultaneously and disappear molten.Oral this product can make intestinal normal absorption calcium, thus can correct low blood calcium, alleviates the pain of bone and muscle, makes the blood plasma alkali phosphatase that increased reduce or become normal, reduces the serum parathyroid concentration that increased and makes it to be tending towards normal, thus promoting sclerotin mineralising.This product also has the effect accelerating skeleton collagen maturation.Also find its propagation to cell in recent years, differentiation and have important effect to immune system, abroad started to be applied to clinical as a kind of new immunomodulating hormone.Physiological disposition: oral absorption is rapid, and plasma drug level peak time is urinate calcium level after 3-6h, 7h can increase, and biological respinse is relevant with dosage, and plasma half-life is 3.5-6h.Drain by bile and urine after metabolism.These product are mainly used in the renal osteodystrophy of osteoporosis, Patients with Chronic Renal Failure, particularly need the patient of chronic hemodialysis, Post operation be spontaneous and false parathyroid gland machine goes down, vitamin D3 dependency rickets and hypophosphatemia vitamin D-resistant rickets, be also used for the treatment of the treating for skin disease such as psoriasis in recent years.
At present, the primary formulation form of alfacalcidol is soft capsule and soft gelatin capsule; Dosage form is more dull, and alfacalcidol is to light and air-sensitive, lower for ordinary organic solvents dissolubility, and the stability of soft capsule and soft gelatin capsule is bad, and active constituent content is extremely low, and bioavailability is low.Alfacalcidol solution is not reported 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 surprisingly finds, when preparing alfacalcidol solution, third methylcellulose aqueous solution and sodium lauryl sulphate in the PVP K30 added in appropriate amount, hydroxyl, the content of active component alfacalcidol in preparation, stability and bioavailability can be significantly improved, have unforeseeable technique effect, the Clinical practice for medicine is significant.
The invention provides the alfacalcidol solution that a kind of active component content is high, medicine stability good, bioavailability is high.This solution is made up of the component of following weight percents:
Alfacalcidol 0.0005%
PVP K30 0.9-1.2%
Third methylcellulose aqueous solution 27-30% in hydroxyl
Sodium lauryl sulphate 12-14%
Antioxidant 0.2%
Correctives 0.5%
Distilled water adds to 100%
Its optimizing prescriptions is:
Alfacalcidol 0.0005%
PVP K30 1.1%
Third methylcellulose aqueous solution 28% in hydroxyl
Sodium lauryl sulphate 13%
Antioxidant 0.2%
Correctives 0.5%
Distilled water adds to 100%
Further, above-mentioned antioxidant is selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite and vitamin E.
Further, above-mentioned correctives is selected from one or more in sorbitol, mannitol, sucrose, saccharin sodium, aspartame and stevioside.
The preparation method of this solution is:
1) take the distilled water of recipe quantity 70-80%, the third methylcellulose aqueous solution in the hydroxyl adding recipe quantity, stirs; Continuing the PVP K30 and the sodium lauryl sulphate that add recipe quantity, stirring 15-25min at 45-55 DEG C to all dissolving;
2) being warming up to 60-70 DEG C, under the mixing speed of 500-1000rpm, adding the alfacalcidol of recipe quantity, continuing to stir 20-40min to all dissolving;
3) add distilled water to full dose, and add antioxidant and the correctives of recipe quantity, stirring and dissolving; Check under room temperature, after qualified, stir fill, then label, pack, inspect by random samples, put in storage.
The preparation method of this solution is more preferably:
1) take the distilled water of recipe quantity 75%, the third methylcellulose aqueous solution in the hydroxyl adding recipe quantity, stirs; Continuing the PVP K30 and the sodium lauryl sulphate that add recipe quantity, stirring 20min at 50 DEG C to all dissolving;
2) being warming up to 65 DEG C, under the mixing speed of 800rpm, adding the alfacalcidol of recipe quantity, continuing to stir 30min to all dissolving;
3) add distilled water to full dose, and add antioxidant and the correctives of recipe quantity, stirring and dissolving; Check under room temperature, after qualified, stir fill, then label, pack, inspect by random samples, put in storage.
The invention has the beneficial effects as follows:
1. in said preparation, the content of alfacalcidol significantly increases, and reduces the dose of medicine;
2. in PVP K30, hydroxyl, the third methylcellulose aqueous solution and adding of sodium lauryl sulphate improve the stability of alfacalcidol to light, air, and 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 alfacalcidol solution
Prescription is:
Alfacalcidol 0.5mg
PVP K30 0.9g
Third methylcellulose aqueous solution 27g in hydroxyl
Sodium lauryl sulphate 12g
Sodium sulfite 0.2g
Aspartame 0.5g
Distilled water adds to 100g
Preparation method is:
1) take the distilled water of recipe quantity 80%, the third methylcellulose aqueous solution in the hydroxyl adding recipe quantity, stirs; Continuing the PVP K30 and the sodium lauryl sulphate that add recipe quantity, stirring 25min at 55 DEG C to all dissolving;
2) being warming up to 70 DEG C, under the mixing speed of 1000rpm, adding the alfacalcidol of recipe quantity, continuing to stir 40min to all dissolving;
3) add distilled water to full dose, and add sodium sulfite and the aspartame of recipe quantity, stirring and dissolving; Check under room temperature, after qualified, stir fill, then label, pack, inspect by random samples, put in storage.
Embodiment 2 alfacalcidol solution
Prescription is:
Alfacalcidol 0.5mg
PVP K30 1.2g
Third methylcellulose aqueous solution 30g in hydroxyl
Sodium lauryl sulphate 14g
Sodium sulfite 0.2g
Sucrose 0.5g
Distilled water adds to 100g
Preparation method is:
1) take the distilled water of recipe quantity 70%, the third methylcellulose aqueous solution in the hydroxyl adding recipe quantity, stirs; Continuing the PVP K30 and the sodium lauryl sulphate that add recipe quantity, stirring 15min at 45 DEG C to all dissolving;
2) being warming up to 60 DEG C, under the mixing speed of 500rpm, adding the alfacalcidol of recipe quantity, continuing to stir 20min to all dissolving;
3) add distilled water to full dose, and add sodium sulfite and the sucrose of recipe quantity, stirring and dissolving; Check under room temperature, after qualified, stir fill, then label, pack, inspect by random samples, put in storage.
Embodiment 3 alfacalcidol solution
Prescription is:
Alfacalcidol 0.5mg
PVP K30 1.1g
Third methylcellulose aqueous solution 28g in hydroxyl
Sodium lauryl sulphate 13g
Sodium pyrosulfite 0.2g
Stevioside 0.5g
Distilled water adds to 100g
Preparation method is:
1) take the distilled water of recipe quantity 75%, the third methylcellulose aqueous solution in the hydroxyl adding recipe quantity, stirs; Continuing the PVP K30 and the sodium lauryl sulphate that add recipe quantity, stirring 20min at 50 DEG C to all dissolving;
2) being warming up to 65 DEG C, under the mixing speed of 800rpm, adding the alfacalcidol of recipe quantity, continuing to stir 30min to all dissolving;
3) add distilled water to full dose, and add sodium pyrosulfite and the stevioside of recipe quantity, stirring and dissolving; Check under room temperature, after qualified, stir fill, then label, pack, inspect by random samples, put in storage.
Comparing embodiment 1 alfacalcidol solution
Alfacalcidol 0.5mg
Third methylcellulose aqueous solution 28g in hydroxyl
Sodium lauryl sulphate 13g
Sodium pyrosulfite 0.2g
Stevioside 0.5g
Distilled water adds to 100g
Preparation method is with embodiment 3.
Comparing embodiment 2 alfacalcidol solution
Alfacalcidol 0.5mg
PVP K30 1.1g
Sodium lauryl sulphate 13g
Sodium pyrosulfite 0.2g
Stevioside 0.5g
Distilled water adds to 100g
Preparation method is with embodiment 3.
Comparing embodiment 3 alfacalcidol solution
Alfacalcidol 0.5mg
PVP K30 1.1g
Third methylcellulose aqueous solution 28g in hydroxyl
Sodium pyrosulfite 0.2g
Stevioside 0.5g
Distilled water adds to 100g
Preparation method is with embodiment 3.
Test example 1 stability experiment and result
(1) accelerated stability test
Intensity of illumination 4500lx, adopted HPLC method to carry out assay in the 0th, 5 and 10 day after timing sampling.
The condition of HPLC is: chromatographic column: ODS-C18 post, take octadecylsilane chemically bonded silica as filler; Mobile phase: acetonitrile-water (75:25); Determined wavelength: 265nm; Flow velocity: 1.0mL/min; Sample size: 50 μ L.Theoretical cam curve presses the calculating of alfacalcidol peak should not be low by 5000, and alfacalcidol peak and the peak-to-peak separating degree of trans alfacalcidol should be greater than 1.0.External standard method is adopted to calculate content.Assay result (percentage ratio of measured amount and labelled amount) sees the following form 1.
Result shows that the stability of active component alfacalcidol in alfacalcidol solution of the present invention is obviously better than comparative example.
Table 1 accelerated stability test assay result (%)
(2) long-term stable experiment
Temperature 25 DEG C, relative humidity are placed 36 months for 60% time, adopt HPLC method to carry out assay respectively at sampling when 0,3,6,12,24 and 36 months.The same accelerated stability test of condition of HPLC.External standard method is adopted to calculate content.Assay result (percentage ratio of measured amount and labelled amount) sees the following form 2.
Result shows that the stability of active component alfacalcidol in alfacalcidol solution of the present invention is obviously better than comparative example.
Table 2 long-term stable experiment assay result (%)
The comparative test of test example 2 bioavailability
Oral administration is carried out to 4 beasle dogs (being male), fill with the alfacalcidol solution of the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example 3 (temperature 25 DEG C, relative humidity are placed 12 months for 60% time) respectively to them, dosage is 10.0 μ g/(in alfacalcidol), and the interval time of each administration is 7 days.After giving medicine, blood sample collection under different time, and carry out the maximum haemoconcentration (C of alfacalcidol
max) and bioavailability (AUC
0 → 48) calculating.Acquisition time is 0h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 32h, 48h.
Provide the average result of alfacalcidol solution gained 4 beasle dogs being given to the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example 3.The results are shown in Table 3.
As seen from table, the maximum haemoconcentration of alfacalcidol of alfacalcidol solution 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 done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (6)
1. an alfacalcidol solution, is characterized in that, is made up of the component of following weight percents:
Alfacalcidol 0.0005%
PVP K30 0.9-1.2%
Third methylcellulose aqueous solution 27-30% in hydroxyl
Sodium lauryl sulphate 12-14%
Antioxidant 0.2%
Correctives 0.5%
Distilled water adds to 100%.
2. alfacalcidol solution according to claim 1, is characterized in that, is made up of the component of following weight percents:
Alfacalcidol 0.0005%
PVP K30 1.1%
Third methylcellulose aqueous solution 28% in hydroxyl
Sodium lauryl sulphate 13%
Antioxidant 0.2%
Correctives 0.5%
Distilled water adds to 100%.
3. alfacalcidol solution according to claim 1 and 2, is characterized in that, described antioxidant is selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite and vitamin E.
4. alfacalcidol solution according to claim 1 and 2, is characterized in that, described correctives is selected from one or more in sorbitol, mannitol, sucrose, saccharin sodium, aspartame and stevioside.
5. the preparation method of the alfacalcidol solution described in claim 1-4, it is characterized in that, the method comprises the steps:
1) take the distilled water of recipe quantity 70-80%, the third methylcellulose aqueous solution in the hydroxyl adding recipe quantity, stirs; Continuing the PVP K30 and the sodium lauryl sulphate that add recipe quantity, stirring 15-25min at 45-55 DEG C to all dissolving;
2) being warming up to 60-70 DEG C, under the mixing speed of 500-1000rpm, adding the alfacalcidol of recipe quantity, continuing to stir 20-40min to all dissolving;
3) add distilled water to full dose, and add antioxidant and the correctives of recipe quantity, stirring and dissolving; Check under room temperature, after qualified, stir fill, then label, pack, inspect by random samples, put in storage.
6. the preparation method of alfacalcidol solution according to claim 5, it is characterized in that, the method comprises the steps:
1) take the distilled water of recipe quantity 75%, the third methylcellulose aqueous solution in the hydroxyl adding recipe quantity, stirs; Continuing the PVP K30 and the sodium lauryl sulphate that add recipe quantity, stirring 20min at 50 DEG C to all dissolving;
2) being warming up to 65 DEG C, under the mixing speed of 800rpm, adding the alfacalcidol of recipe quantity, continuing to stir 30min to all dissolving;
3) add distilled water to full dose, and add antioxidant and the correctives of recipe quantity, stirring and dissolving; Check under room temperature, after qualified, stir fill, then label, pack, inspect by random samples, put in storage.
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| CN201510191547.9A CN104800156A (en) | 2015-04-22 | 2015-04-22 | Alfacalcidol solution and preparation method thereof |
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| CN115350151A (en) * | 2022-09-29 | 2022-11-18 | 湖北欣泽霏药业有限公司 | High-stability alfacalcidol liquid oral preparation and preparation method thereof |
| CN115350149A (en) * | 2022-08-30 | 2022-11-18 | 南通华山药业有限公司 | Stable alfacalcidol water-based solution preparation and preparation method thereof |
| CN116077432A (en) * | 2023-02-21 | 2023-05-09 | 正大制药（青岛）有限公司 | Calcitriol oral solution and preparation method thereof |
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| CN115350151A (en) * | 2022-09-29 | 2022-11-18 | 湖北欣泽霏药业有限公司 | High-stability alfacalcidol liquid oral preparation and preparation method thereof |
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Application publication date: 20150729 |