CN103142554B - Calcitriol controlled-release capsule and preparation method thereof - Google Patents
Calcitriol controlled-release capsule and preparation method thereof Download PDFInfo
- Publication number
- CN103142554B CN103142554B CN201310093241.0A CN201310093241A CN103142554B CN 103142554 B CN103142554 B CN 103142554B CN 201310093241 A CN201310093241 A CN 201310093241A CN 103142554 B CN103142554 B CN 103142554B
- Authority
- CN
- China
- Prior art keywords
- calcitriol
- core
- controlled release
- make
- polyethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a calcitriol controlled-release capsule and a preparation method thereof. The controlled-release capsule 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 capsule, 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 capsule 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 controlled release capsule 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 controlled release capsule, 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 controlled release capsule that a kind of active component content is high, medicine stability good, bioavailability is high.This controlled release capsule is made up of core core and controlled release coat layer, and wherein controlled release coat layer comprises the controlled-release material that percentage by weight is 10-20%, and core core is made up of 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 core core is made up of 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 controlled-release material is selected from one or more in methylcellulose, ethyl cellulose and methacrylate copolymer.
The preparation method of this controlled release capsule is:
1) take the supplementary material of recipe quantity, cross respectively 80-120 mesh sieve for subsequent use;
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, crosses 20 mesh sieve granulate at 50-70 DEG C; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, dry, pack in capsulae vacuus and get final product.
The preparation method of this controlled release capsule is more preferably:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
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, crosses 20 mesh sieve granulate at 60 DEG C; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, dry, pack in capsulae vacuus 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 controlled release capsule
Prescription is:
Core core is made up of 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 for subsequent use;
2) starch 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, crosses 20 mesh sieve granulate at 50 DEG C; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, dry, pack in capsulae vacuus and get final product.
Embodiment 2 calcitriol controlled release capsules
Prescription is:
Core core is made up of the component of following percentage by weight:
It is 20% ethyl cellulose 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 for subsequent use;
2) pregelatinized Starch 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, 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; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, dry, pack in capsulae vacuus and get final product.
Embodiment 3 calcitriol controlled release capsules
Prescription is:
Core core is made up of the component of following percentage by weight:
It is 15% methacrylate copolymer 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 for subsequent use;
2) polyvidone 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, 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; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, pack in capsulae vacuus and get final product.
Comparing embodiment 1 calcitriol controlled release capsule
Core core is made up of the component of following percentage by weight:
It is 15% methacrylate copolymer that controlled release coat layer comprises percentage by weight.
Preparation method is same embodiment 3:
Comparing embodiment 2 calcitriol controlled release capsules
Core core is made up of the component of following percentage by weight:
It is 15% methacrylate copolymer that controlled release coat layer comprises percentage by weight.
Preparation method is with embodiment 3.
Comparing embodiment 3 calcitriol controlled release capsules
Core core is made up of the component of following percentage by weight:
It is 15% methacrylate copolymer 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, 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 controlled release capsule 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 controlled release capsule 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 controlled release capsule 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 controlled release capsule gained.As seen from table, the maximum haemoconcentration of the calcitriol of calcitriol controlled release capsule 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 (3)
1. a calcitriol controlled release capsule, is characterized in that: core core is made up of following component:
Calcitriol 6.0mg
Meglumine 6.0g
PEG400 3.6g
Polyethylene glycol 6000 45g
Starch 210g
Carboxymethyl starch sodium 15g
Starch 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 for subsequent use;
2) starch 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, crosses 20 mesh sieve granulate at 50 DEG C; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, dry, pack in capsulae vacuus and get final product.
2. a calcitriol controlled release capsule, is characterized in that: core core is made up of following component:
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 controlled release coat layer comprises percentage by weight;
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 120 mesh sieves for subsequent use;
2) pregelatinized Starch 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, 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; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, dry, pack in capsulae vacuus and get final product.
3. a calcitriol controlled release capsule, is characterized in that: core core is made up of following component:
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 controlled release coat layer comprises percentage by weight;
Preparation method is:
1) take the supplementary material of recipe quantity, cross respectively 100 mesh sieves for subsequent use;
2) polyvidone 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, 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; Remove fine powder after No. 4 sieve sieves, make core core;
5) with above-mentioned coating solution, the core core making is carried out to fluidized bed coating, pack in capsulae vacuus and get final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310093241.0A CN103142554B (en) | 2013-03-21 | 2013-03-21 | Calcitriol controlled-release capsule and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310093241.0A CN103142554B (en) | 2013-03-21 | 2013-03-21 | Calcitriol controlled-release capsule and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103142554A CN103142554A (en) | 2013-06-12 |
| CN103142554B true CN103142554B (en) | 2014-11-12 |
Family
ID=48541070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310093241.0A Active CN103142554B (en) | 2013-03-21 | 2013-03-21 | Calcitriol controlled-release capsule and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103142554B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109752471A (en) * | 2019-01-07 | 2019-05-14 | 正大制药（青岛）有限公司 | A kind of detection method of calcitriol |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5795882A (en) * | 1992-06-22 | 1998-08-18 | Bone Care International, Inc. | Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations |
| WO2008134512A1 (en) * | 2007-04-25 | 2008-11-06 | Cytochroma Inc. | Oral controlled release compositions comprising vitamin d compound and waxy carrier |
-
2013
- 2013-03-21 CN CN201310093241.0A patent/CN103142554B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN103142554A (en) | 2013-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103142524B (en) | Calcitriol tablet and preparation method thereof | |
| CN103142470A (en) | Calcitriol injection and preparation method thereof | |
| CN103142554B (en) | Calcitriol controlled-release capsule and preparation method thereof | |
| CN103142534B (en) | Calcitriol controlled-release tablet and preparation method thereof | |
| CN103142501B (en) | Calcitriol pellet and preparation method thereof | |
| CN103142478B (en) | Calcitriol emulsion and preparation method thereof | |
| CN103142496B (en) | Calcitriol controlled-release granule and preparation method thereof | |
| CN103142547B (en) | Calcitriol enteric capsule and preparation method thereof | |
| CN103142546B (en) | Calcitriol capsule and preparation method thereof | |
| CN103142536B (en) | Calcitriol enteric tablet and preparation method thereof | |
| CN103142623B (en) | Calcitriol and strontium ranelate suspension granule and preparation method thereof | |
| CN102319225B (en) | Trimetazidine hydrochloride sustained release tablet and preparation method thereof | |
| CN103142498B (en) | Calcitriol enteric granule and preparation method thereof | |
| CN103142486B (en) | Calcitriol powder and preparation method thereof | |
| CN103142495B (en) | Calcitriol suspension granule and preparation method thereof | |
| CN106265556A (en) | A kind of doxercalciferol sheet and preparation method thereof | |
| CN103142644B (en) | Calcitriol and sodium fluoride suspension granule and preparation method thereof | |
| CN103142642B (en) | Calcitriol and calcium carbonate suspension granule and preparation method thereof | |
| CN103585357A (en) | Callicarpa nudiflora slow release pellet, and preparation method and application of slow release pellet | |
| CN104800166A (en) | Alfacalcidol powder and preparation method thereof | |
| CN104739793B (en) | A kind of Alfacalcidol piece and preparation method thereof | |
| CN103142476B (en) | Calcitriol suspension and preparation method thereof | |
| CN103142467B (en) | Calcitriol ointment and preparation method thereof | |
| CN104840480B (en) | Metformin/folic acid/vitamin B12New application of pharmaceutical composition | |
| CN102068431B (en) | Carbazole sulfamide-derived anti-tumor medicine tablets and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
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. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
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. |