CN103142534B - Calcitriol controlled-release tablet and preparation method thereof - Google Patents
Calcitriol controlled-release tablet and preparation method thereof Download PDFInfo
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- CN103142534B CN103142534B CN201310092640.5A CN201310092640A CN103142534B CN 103142534 B CN103142534 B CN 103142534B CN 201310092640 A CN201310092640 A CN 201310092640A CN 103142534 B CN103142534 B CN 103142534B
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Abstract
The invention relates to a calcitriol controlled-release tablet and a preparation method thereof. The controlled-release tablet consists of a tablet 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 tablet 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, an appropriate amount of binder and an appropriate amount of lubricant. According to the controlled-release tablet, 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 controlled release tablet 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 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 controlled release tablet 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 surprisingly found, while preparing calcitriol controlled release tablet, the meglumine adding in right amount, PEG400 and polyethylene glycol 6000, 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 controlled release tablet that a kind of active component content is high, medicine stability good, bioavailability is high.This controlled release tablet is comprised of label and controlled release coat layer, and wherein controlled release coat layer comprises the controlled-release material that percentage by weight is 10-20%, and label is made by the component of following percentage by weight:
In its optimizing prescriptions, to comprise percentage by weight be 15% controlled-release material to controlled release coat layer, and label is made by the component of following percentage by weight:
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 lubricant is selected from one or more in magnesium stearate, Pulvis Talci and micropowder silica gel.
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 tablet is:
1) take the supplementary material of recipe quantity, cross respectively 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) 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 at 50-70 ℃, crosses 20 mesh sieve granulate, adds lubricant to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
The preparation method of this controlled release tablet 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) 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 at 60 ℃, crosses 20 mesh sieve granulate, adds lubricant to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
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 tablet
The prescription of 1000 is:
Label is made by the component of following percentage by weight:
It is 10% methylcellulose that 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) hyprolose and the methylcellulose got after sieving add respectively distilled water, make binder solution and coating 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 at 50 ℃, crosses 20 mesh sieve granulate, adds magnesium stearate to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
Embodiment 2 calcitriol controlled release tablet
The prescription of 1000 is:
Label is made by the component of following percentage by weight:
It is 20% methacrylate copolymer that 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 methacrylate copolymer got after sieving add respectively distilled water, make binder solution and coating 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 at 70 ℃, crosses 20 mesh sieve granulate, adds Pulvis Talci to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
Embodiment 3 calcitriol controlled release tablet
The prescription of 1000 is:
Label is made by the component of following percentage by weight:
It is 15% ethyl cellulose that 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 ethyl cellulose got after sieving add respectively distilled water, make binder solution and coating 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 at 60 ℃, crosses 20 mesh sieve granulate, adds micropowder silica gel to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
Comparing embodiment 1 calcitriol controlled release tablet (1000)
Label is made by the component of following percentage by weight:
It is 15% ethyl cellulose that controlled release coat layer comprises percentage by weight.
Preparation method is same embodiment 3:
Comparing embodiment 2 calcitriol controlled release tablet (1000)
Label is made by the component of following percentage by weight:
It is 15% ethyl cellulose that controlled release coat layer comprises percentage by weight.
Preparation method is with embodiment 3.
Comparing embodiment 3 calcitriol controlled release tablet (1000)
Label is made by the component of following percentage by weight:
It is 15% ethyl cellulose that 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, 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, 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 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 controlled release tablet of the present invention is obviously better than comparative example.
Table 1 accelerated stability test assay result (%)
2. long-term stable experiment
25 ℃ 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 controlled release tablet 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, to them, feed respectively the calcitriol controlled release tablet with the embodiment of the present invention 3, comparative example 1, comparative example 2, comparative example 3 (25 ℃ of temperature, relative humidity are placed 12 months for 60% time), dosage is 10.0 μ g/ only (in calcitriol), 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 controlled release tablet gained.As seen from table, the maximum haemoconcentration of the calcitriol of calcitriol controlled release tablet of the present invention (embodiment 3) and bioavailability are apparently higher than comparative example.
The comparison of table 3 bioavailability (10.0 μ g, n=3)
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 modification of having done within the spirit and principles in the present invention, the replacement being equal to and improvement etc., within all should being included in protection scope of the present invention.
Claims (3)
1. a calcitriol controlled release tablet, is characterized in that: the prescription of 1000 is:
Label 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
Hyprolose is appropriate
Magnesium stearate is appropriate,
It is 10% methylcellulose that 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) hyprolose and the methylcellulose got after sieving add respectively distilled water, make binder solution and coating 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 at 50 ℃, crosses 20 mesh sieve granulate, adds magnesium stearate to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
2. a calcitriol controlled release tablet, is characterized in that: the prescription of 1000 is:
Label 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
Pulvis Talci is appropriate,
It is 20% methacrylate copolymer that 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 methacrylate copolymer got after sieving add respectively distilled water, make binder solution and coating 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 at 70 ℃, crosses 20 mesh sieve granulate, adds Pulvis Talci to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
3. a calcitriol controlled release tablet, is characterized in that: the prescription of 1000 is:
Label 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
Micropowder silica gel is appropriate,
It is 15% ethyl cellulose that 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 ethyl cellulose got after sieving add respectively distilled water, make binder solution and coating 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 at 60 ℃, crosses 20 mesh sieve granulate, adds micropowder silica gel to mix rear tabletting, makes label;
5) with above-mentioned coating solution, the label making is carried out to fluidized bed coating, be drying to obtain.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310092640.5A CN103142534B (en) | 2013-03-21 | 2013-03-21 | Calcitriol controlled-release tablet and preparation method thereof |
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| CN201310092640.5A CN103142534B (en) | 2013-03-21 | 2013-03-21 | Calcitriol controlled-release tablet and preparation method thereof |
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| CN103142534B true CN103142534B (en) | 2014-11-12 |
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| CN110934840A (en) * | 2019-12-11 | 2020-03-31 | 正大制药（青岛）有限公司 | Fluorocalcitriol tablet and preparation method thereof |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4308264A (en) * | 1981-01-28 | 1981-12-29 | Abbott Laboratories | Stabilized, dilute aqueous preparation of 1α,25-dihydroxycholecalciferol for neonatal administration |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05124966A (en) * | 1991-10-31 | 1993-05-21 | Doujin Iyaku Kako Kk | Calcitriol solid preparation |
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2013
- 2013-03-21 CN CN201310092640.5A patent/CN103142534B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4308264A (en) * | 1981-01-28 | 1981-12-29 | Abbott Laboratories | Stabilized, dilute aqueous preparation of 1α,25-dihydroxycholecalciferol for neonatal administration |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| JP特开平5-124966A 1993.05.21 * |
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