CN103142547B - Calcitriol enteric capsule and preparation method thereof - Google Patents
Calcitriol enteric capsule and preparation method thereof Download PDFInfo
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- CN103142547B CN103142547B CN201310092574.1A CN201310092574A CN103142547B CN 103142547 B CN103142547 B CN 103142547B CN 201310092574 A CN201310092574 A CN 201310092574A CN 103142547 B CN103142547 B CN 103142547B
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Abstract
The invention relates to a calcitriol enteric capsule and a preparation method thereof. The enteric capsule consists of a core and an enteric coating layer, wherein the enteric coating layer contains an enteric material accounting for 10-20% by weight, and the core 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 enteric 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 enteric coated 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 enteric coated 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 enteric coated 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 enteric coated capsule that a kind of active component content is high, medicine stability good, bioavailability is high.This enteric coated capsule is made up of core core and enteric coat layer, and wherein enteric coat layer comprises the enteric 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% enteric material to enteric 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 enteric material is selected from one or more in CAP, methacrylic acid copolymer, cellulose acetate benzenetricarboxylic acid ester and hydroxypropyl cellulose phthalate ester.
The preparation method of this enteric coated capsule is:
1) take the supplementary material of recipe quantity, cross respectively 80-120 mesh sieve for subsequent use;
2) binding agent and the enteric 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 enteric coated 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 enteric 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 enteric coated capsule
Prescription is:
Core core is made up of the component of following percentage by weight:
It is 10% CAP that enteric 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 CAP 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 enteric coated capsulees
Prescription is:
Core core is made up of the component of following percentage by weight:
It is 20% cellulose acetate benzenetricarboxylic acid ester that enteric 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 cellulose acetate benzenetricarboxylic acid ester 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 enteric coated capsulees
Prescription is:
Core core is made up of the component of following percentage by weight:
It is 15% hydroxypropyl cellulose phthalate ester that enteric 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 hydroxypropyl cellulose phthalate ester 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 enteric coated capsule
Core core is made up of the component of following percentage by weight:
It is 15% hydroxypropyl cellulose phthalate ester that enteric coat layer comprises percentage by weight.
Preparation method is same embodiment 3:
Comparing embodiment 2 calcitriol enteric coated capsulees
Core core is made up of the component of following percentage by weight:
It is 15% hydroxypropyl cellulose phthalate ester that enteric coat layer comprises percentage by weight.
Preparation method is with embodiment 3.
Comparing embodiment 3 calcitriol enteric coated capsulees
Core core is made up of the component of following percentage by weight:
It is 15% hydroxypropyl cellulose phthalate ester that enteric 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 enteric coated 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 enteric coated 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 enteric coated 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 enteric coated capsule gained.As seen from table, the maximum haemoconcentration of the calcitriol of calcitriol enteric coated 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 (7)
1. a calcitriol enteric coated capsule, is characterized in that, this enteric coated capsule is made up of core core and enteric coat layer, and it is 15% enteric material that described enteric coat layer comprises percentage by weight, and described core core is made up of the component of following percentage by weight:
2. calcitriol enteric coated capsule according to claim 1, is characterized in that, described filler is selected from one or more in starch, lactose, dextrin, amylum pregelatinisatum and Icing Sugar.
3. calcitriol enteric coated capsule 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.
4. calcitriol enteric coated capsule 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.
5. calcitriol enteric coated capsule according to claim 1 and 2, is characterized in that, described enteric material is selected from one or more in CAP, methacrylic acid copolymer, cellulose acetate benzenetricarboxylic acid ester and hydroxypropyl cellulose phthalate ester.
6. the preparation method of the calcitriol enteric coated capsule described in one of claim 1-5, 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 and the enteric 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.
7. the preparation method of calcitriol enteric coated capsule 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 and the enteric 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, pack in capsulae vacuus and get final product.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101554372B (en) * | 2009-05-20 | 2011-07-20 | 青岛正大海尔制药有限公司 | Calcitriol dripping pill and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101554372B (en) * | 2009-05-20 | 2011-07-20 | 青岛正大海尔制药有限公司 | Calcitriol dripping pill and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| 朱园园等.骨化三醇联合钙对老年性骨质疏松防治效果的研究.《中国现代医生》.2012,第50卷(第7期),第66－67页. |
| 李季等.骨化三醇软胶囊的稳定性研究.《中国药业》.2009,第18卷(第2期),第22页. |
| 骨化三醇联合钙对老年性骨质疏松防治效果的研究;朱园园等;《中国现代医生》;20120331;第50卷(第7期);第66－67页 * |
| 骨化三醇软胶囊的稳定性研究;李季等;《中国药业》;20091231;第18卷(第2期);第22页 * |
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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. |