CN110934840A - Fluorocalcitriol tablet and preparation method thereof - Google Patents
Fluorocalcitriol tablet and preparation method thereof Download PDFInfo
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- CN110934840A CN110934840A CN201911264635.1A CN201911264635A CN110934840A CN 110934840 A CN110934840 A CN 110934840A CN 201911264635 A CN201911264635 A CN 201911264635A CN 110934840 A CN110934840 A CN 110934840A
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- fluorocalcitriol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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Abstract
The invention discloses a fosfomiol controlled-release tablet and a preparation method thereof, the fosfomiol controlled-release tablet consists of a fosfomiol tablet core and a controlled-release coating layer coated outside the tablet core, the tablet core consists of fosfomiol, a filling agent and an antioxidant, the controlled-release coating layer consists of a controlled-release material, a disintegrating agent, a pore-forming agent and an anti-sticking agent, and the preparation method comprises the step of coating the controlled-release coating layer outside the fosfomiol tablet core. The medicine solves the problems of single formulation, poor stability of oral preparations and the like of the existing fluorocalcitriol, achieves the aims of long acting and improving the curative effect, can also reduce the dosage and reduce the side effect when maintaining the same drug effect, has simple preparation process, and ensures that the obtained product has stable quality and is suitable for large-scale production.
Description
Technical Field
The invention relates to a western medicine preparation technology, in particular to a fosfomiol controlled-release tablet, and a preparation method thereof, belonging to the technical field of medicines.
Background
Osteoporosis is a group of bone diseases caused by various reasons, bone tissues have normal calcification, calcium salts and matrixes are in a normal proportion, and metabolic bone lesions are characterized by reduction of the amount of the bone tissues in unit volume. Osteoporosis can occur in different sexes and at any age, but is most common in postmenopausal women and elderly men. Is characterized by pain in the skeleton and susceptibility to fracture. The bioactive form of vitamin D, calcitriol, plays a key role in a series of physiological functions such as calcium balance in vivo, hormone secretion and cell proliferation and differentiation. The supplement of calcitriol and analogs thereof becomes an important way for the clinical treatment of osteoporosis.
Fluorocalcitriol is a synthetic bioactive analog of calcitriol with molecular formula C27H3F6O3The structure is as follows:
the product and calcitriol are compared in the in vitro test to activate the vitamin D-reactive gene of rat osteoblast strain ROB-C26, and the activity of the product and calcitriol on the vitamin D-reactive gene of rat is tested 6h after the addition of vitamin D, 1 α, 25(OH)2-D324 hydroxylase mRNA expression level, the product is found to have 10 times stronger effect than calcitriol, the retention time in cells is longer, and target genes in the cells can be activated durably. Studies on nephrectomized ratsThe result indicates that the product has certain therapeutic effect on secondary hyperparathyroidism and osteodystrophy caused by chronic renal failure, and the dosage of the product is lower than that of calcitriol.
The chemical properties of fluorocalcitriol are very unstable and sensitive to oxygen. At present, the fluorocalcitriol on the market is only one common tablet, the dosage form is single, and patients have no choice. And the common tablet has poor stability, and is easy to absorb moisture to influence disintegration and content after long-term storage, thereby influencing bioavailability and curative effect.
Disclosure of Invention
In order to solve the problems of single dosage form, poor stability and the like of the existing fosfomiol, an oral solid preparation with high stability, convenient taking and simple preparation process is developed.
In order to achieve the purpose, the invention adopts the technical scheme that:
a kind of fluorocalcitriol controlled release tablet, by fluorocalcitriol tablet core and coating the controlled release coating outside the tablet core to make up, the said tablet core is made up of fluorocalcitriol, filler and anti-oxidant, the said controlled release coating is made up of controlled release material, disintegrating agent, pore-forming agent and antisticking agent, characterized by, according to the weight percent:
fluorocalcitriol 0.00003%
40 to 50 percent of filling agent
0.02 to 0.04 percent of antioxidant
30-40% of controlled release material
3 to 8 percent of disintegrating agent
3 to 8 percent of pore-foaming agent
3-8% of an anti-sticking agent.
Wherein the filler is microcrystalline cellulose; the antioxidant is tert-butyl hydroquinone; the controlled release material is methacrylate copolymer or cellulose acetate; the disintegrant is low-substituted hydroxypropyl cellulose; the pore-foaming agent is polyethylene glycol or polyvidone; the antisticking agent is magnesium stearate.
Wherein the controlled release material is preferably a methacrylate copolymer; the pore-forming agent is preferably polyethylene glycol.
Wherein, the weight ratio of the methacrylate copolymer to the polyethylene glycol is preferably 3-5: 1-2; most preferably, the weight ratio of methacrylate copolymer to polyethylene glycol is 5: 1.
the fosfomiol controlled-release tablet of the invention can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing the fluorocalcitriol, a filling agent and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying and tabletting to obtain a fluorocalcitriol tablet core for later use;
(3) dissolving the controlled release material, the disintegrant, the pore-forming agent and the anti-sticking agent by 80 percent of ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain a calcitriol fluoride controlled-release tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The fosfomiol controlled-release tablet related by the invention has the following beneficial effects:
(1) the product has high quality stability and improves the bioavailability;
(2) the selected auxiliary materials are common, the preparation process is simple, the obtained product has stable quality, and the method is suitable for large-scale production.
Detailed Description
The following further describes the embodiments of the present invention with reference to examples, but these examples are only illustrative and do not limit the scope of the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Examples 1-5 preparation of Fluorocalcitriol controlled-release tablets
A preparation method of a fosfomiol controlled-release tablet comprises the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing the fluorocalcitriol, a filling agent and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying and tabletting to obtain a fluorocalcitriol tablet core for later use;
(3) dissolving the controlled release material, the disintegrant, the pore-forming agent and the anti-sticking agent by 80 percent of ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain a calcitriol fluoride controlled-release tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
According to the raw and auxiliary materials in the prescription (1000 tablets) in the following table 1, the fosfomiol controlled-release tablet is prepared according to the preparation method. Where "/" indicates unused.
Test example 1 accelerated stability test
Accelerated stability tests were performed according to the guidelines of stability of crude drugs and preparations 9001, the general guidelines of the four ministry of the pharmacopoeia of China 2015 edition. The fluorocalcitriol controlled-release tablets obtained in examples 1 to 5 and a comparative formulation, namely, a fluorocalcitriol soft capsule (trade name: Zemplar), were commercially packaged and allowed to stand at a temperature of 40 ℃ C. + -. 2 ℃ C. and a relative humidity of 75% C. + -. 5% for 6 months. Sampling once at the end of 1 month, 2 months, 3 months and 6 months respectively during the test period, and determining the content of the fluorocalcitriol preparation according to a fluorocalcitriol content detection method.
The method for detecting the content of the fluorocalcitriol comprises the following steps:
testing the spectrum condition and the system applicability: octadecylsilane chemically bonded silica is used as a filling agent; chromatographic conditions are as follows: mobile phase: acetonitrile-water (75: 25); detection wavelength: 265 nm; column temperature: 20 ℃; flow rate: 1.0 ml/min; sample introduction amount: 20 mu l of the mixture; the number of theoretical plates should not be less than 5000 in terms of the peak of fluorocalcitriol.
The determination method comprises the following steps: and (4) avoiding light. Precisely weighing a proper amount of a test sample (about 5 mu g of fluorocalcitriol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 minutes, freezing in a refrigerator at the temperature of-18 ℃ for 30 minutes, taking out, centrifuging (4000 r/min) for 5 minutes, taking the supernatant methanol clear liquid as a test sample solution, precisely measuring 50 mu l, injecting into a liquid chromatograph, and recording a chromatogram. An appropriate amount of fluorocalcitriol control is precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0 μ g of fluorocalcitriol per 1ml, and the determination is carried out by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the accelerated stability test for fluorocalcitriol are shown in Table 2.
Test example 2 Long-term stability test
A long-term stability test is carried out according to 9001 guiding principle of stability of raw material medicines and preparations in accordance with the general guidelines of the four ministry of the chapter of the book of Chinese pharmacopoeia 2015. The fluorocalcitriol controlled-release tablets obtained in examples 1 to 5 and a comparative formulation, namely, a fluorocalcitriol soft capsule (trade name: Zemplar), were commercially packaged and allowed to stand at a temperature of 25. + -. 2 ℃ and a relative humidity of 60. + -. 10% for 24 months. Sampling once at the end of 0 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months during the test period, and determining the content of the fluorocalcitriol preparation according to a fluorocalcitriol content detection method.
The method for detecting the content of the fluorocalcitriol comprises the following steps:
testing the spectrum condition and the system applicability: octadecylsilane chemically bonded silica is used as a filling agent; chromatographic conditions are as follows: mobile phase: acetonitrile-water (75: 25); detection wavelength: 265 nm; column temperature: 20 ℃; flow rate: 1.0 ml/min; sample introduction amount: 20 mu l of the mixture; the number of theoretical plates should not be less than 5000 in terms of the peak of fluorocalcitriol.
The determination method comprises the following steps: and (4) avoiding light. Precisely weighing a proper amount of a test sample (about 5 mu g of fluorocalcitriol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 minutes, freezing in a refrigerator at the temperature of-18 ℃ for 30 minutes, taking out, centrifuging (4000 r/min) for 5 minutes, taking the supernatant methanol clear liquid as a test sample solution, precisely measuring 50 mu l, injecting into a liquid chromatograph, and recording a chromatogram. An appropriate amount of fluorocalcitriol control is precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0 μ g of fluorocalcitriol per 1ml, and the determination is carried out by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the long-term stability test content measurement of fluorocalcitriol are shown in Table 3.
As can be seen from the results of the accelerated and long-term stability assay of fosfomiol in tables 2 and 3, the results of the content assay of fosfomiol controlled-release tablet in example 1 are significantly better than those of the fosfomiol soft capsule as a control preparation and examples 2 to 5 when accelerated for 6 months and long-term for 24 months, which indicates that when methacrylate copolymer is used as the controlled-release material and polyethylene glycol is used as the pore-forming agent, the weight ratio of the controlled-release material to the pore-forming agent is 5: 1, the prepared fluocalcitriol controlled release tablet has the best stability effect and is superior to the existing fluocalcitriol soft capsules.
Claims (5)
1. A kind of fluorocalcitriol controlled release tablet, by fluorocalcitriol tablet core and coating the controlled release coating outside the tablet core to make up, the said tablet core is made up of fluorocalcitriol, filler and anti-oxidant, the said controlled release coating is made up of controlled release material, disintegrating agent, pore-forming agent and antisticking agent, characterized by, according to the weight percent:
fluorocalcitriol 0.00003%
40 to 50 percent of filling agent
0.02 to 0.04 percent of antioxidant
30-40% of controlled release material
3 to 8 percent of disintegrating agent
3 to 8 percent of pore-foaming agent
3-8% of an anti-sticking agent.
2. The controlled release tablet of fosfomiol according to claim 1, wherein the filler is microcrystalline cellulose; the antioxidant is tert-butyl hydroquinone; the controlled release material is methacrylate copolymer or cellulose acetate; the disintegrant is low-substituted hydroxypropyl cellulose; the pore-foaming agent is polyethylene glycol or polyvidone; the antisticking agent is magnesium stearate.
3. The controlled-release tablet of fosfomiol according to claim 2, wherein the controlled-release material is preferably a methacrylate copolymer; the pore-forming agent is preferably polyethylene glycol.
4. The controlled release tablet of fosfomiol according to claim 3, wherein the weight ratio of methacrylate copolymer to polyethylene glycol is preferably 3 to 5: 1-2; most preferably, the weight ratio of methacrylate copolymer to polyethylene glycol is 5: 1.
5. the controlled-release tablet of fosfomiol according to claim 1, which can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing the fluorocalcitriol, a filling agent and an antioxidant, sieving with a 20-24 mesh sieve by using absolute ethyl alcohol as an adhesive, granulating, drying and tabletting to obtain a fluorocalcitriol tablet core for later use;
(3) dissolving the controlled release material, the disintegrant, the pore-forming agent and the anti-sticking agent by 80 percent of ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the tablet core prepared in the step (2), and drying to obtain a calcitriol fluoride controlled-release tablet;
(5) and (6) inspecting, packaging, and warehousing qualified products.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201911264635.1A CN110934840A (en) | 2019-12-11 | 2019-12-11 | Fluorocalcitriol tablet and preparation method thereof |
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| CN201911264635.1A CN110934840A (en) | 2019-12-11 | 2019-12-11 | Fluorocalcitriol tablet and preparation method thereof |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103142534A (en) * | 2013-03-21 | 2013-06-12 | 青岛正大海尔制药有限公司 | Calcitriol controlled-release tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103142534A (en) * | 2013-03-21 | 2013-06-12 | 青岛正大海尔制药有限公司 | Calcitriol controlled-release tablet and preparation method thereof |
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Application publication date: 20200331 |