CN111000829A - Paricalcitol solid oral preparation and preparation method thereof - Google Patents

Paricalcitol solid oral preparation and preparation method thereof Download PDF

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Publication number
CN111000829A
CN111000829A CN201911264658.2A CN201911264658A CN111000829A CN 111000829 A CN111000829 A CN 111000829A CN 201911264658 A CN201911264658 A CN 201911264658A CN 111000829 A CN111000829 A CN 111000829A
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release
controlled
paricalcitol
quick
plasticizer
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刘薇
陈阳生
王明刚
臧云龙
刘晓霞
孙桂玉
王清亭
牛建兴
耿立朵
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CP Pharmaceutical Qingdao Co Ltd
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses paricalcitol controlled-release particles and a preparation method thereof, the paricalcitol controlled-release particles comprise quick-release particle cores and controlled-release coating layers wrapping the quick-release particle cores, the quick-release particle cores comprise paricalcitol, fillers and antioxidants, the controlled-release coating layers comprise controlled-release materials, plasticizers and anti-sticking agents, and the paricalcitol controlled-release particles are obtained by wrapping the quick-release particle cores with the controlled-release coating layers during preparation. The invention solves the problems of single dosage form, poor stability of oral preparations and the like of the paricalcitol on the market, achieves the aims of long acting and increased 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

Paricalcitol solid oral preparation and preparation method thereof
Technical Field
The invention relates to a western medicine preparation technology, in particular to paricalcitol controlled-release particles, and a preparation method of the controlled-release particles, belonging to the technical field of medicines.
Background
Secondary Hyperparathyroidism (SHPT) is caused by the presence of factors that stimulate the parathyroid glands, especially hypocalcemia, magnesium hypofunction and hyperphosphatemia, and the glands proliferate and hypertrophy after stimulation, secrete excessive parathyroid hormone, and compensate and maintain the normocalcium and phosphorus. The disease is mostly seen in vitamin D deficiency, severe renal insufficiency, osteomalacia, pregnancy or lactating women.
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 becomes an important way for clinically treating secondary hyperparathyroidism. However, in clinical application, calcitriol has toxic and side effects of significantly increased blood calcium. In view of the limitations of calcitriol in clinical therapy, a number of vitamin D analogs with low side effects and high selectivity have been developed in succession.
Paricalcitol is a vitamin D analogue developed by yapei corporation, and exerts its corresponding physiological effects by binding to Vitamin D Receptor (VDR) as calcitriol. The medicine can inhibit parathyroid hormone more quickly and durably, has small influence on calcium, phosphorus and calcium-phosphorus deposition, so continuous hypercalcemia is less generated, the curative effect of the medicine in reducing aortic calcification and improving bone is also better than that of calcitriol, and the medicine can reduce the fatality rate, the hospitalization frequency and the hospitalization time of a patient, so that the medicine is an excellent medicine for treating osteoporosis. In 1998, injection preparations of paricalcitol (Zemplar) were marketed in the U.S. for the prevention and treatment of SHPT, which was effective in the prevention and treatment of SHPT in patients with Chronic Kidney Disease (CKD) in stages iii and iv before dialysis and transplantation surgery.
Figure 992594DEST_PATH_IMAGE001
Paricalcitol is a synthetic bioactive vitamin D analog, and has modifications of calcitriol side chain (D2) and A ring (19-nor) of formula C27H44O3The structure is as follows:
the paricalcitol is insoluble in water, soluble in organic solvents, very unstable in chemical properties and sensitive to oxygen. At present, the paricalcitol in the market only has two dosage forms, namely a soft capsule and an injection, the dosage forms are single, and patients have no choice. The injection is inconvenient to administer and limited in use; the soft capsule has poor stability, and is easy to absorb moisture to influence disintegration and content in 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 paricalcitol, the invention develops an oral solid preparation with high stability, convenient taking and simple preparation process.
In order to achieve the purpose, the invention adopts the technical scheme that:
the controlled-release paricalcitol granules consist of a quick-release granule core and a controlled-release coating layer wrapping the quick-release granule core, wherein the quick-release granule core consists of paricalcitol, a filler and an antioxidant, and the controlled-release coating layer consists of a controlled-release material, a plasticizer and an anti-sticking agent, and are characterized in that the controlled-release paricalcitol granules consist of the following components in percentage by weight:
paricalcitol 0.00002%
65 to 75 percent of filling agent
0.02 to 0.04 percent of antioxidant
15 to 25 percent of controlled release material
3 to 10 percent of plasticizer
3-10% of an anti-sticking agent.
Wherein the filler is lactose; the antioxidant is tert-butyl hydroquinone; the controlled-release material is carboxymethyl ethyl cellulose or ethylene acrylic acid copolymer; the plasticizer is triethyl citrate or dimethyl phthalate; the antisticking agent is magnesium stearate.
Wherein the controlled release material is preferably an ethylene acrylic acid copolymer; the plasticizer is preferably triethyl citrate.
Wherein the weight ratio of the ethylene acrylic acid copolymer to the triethyl citrate is preferably 3-5: 1-2; most preferably, the weight ratio of the ethylene acrylic acid copolymer to the triethyl citrate is 4: 1.
the paricalcitol controlled-release granules of the invention can be prepared by the following method:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing paricalcitol, a filler and an antioxidant, and preparing a quick-release particle core of 20-24 meshes by using absolute ethyl alcohol as an adhesive for later use;
(3) dissolving the controlled release material, the plasticizer and the anti-sticking agent by 80 percent ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the quick-release particle core prepared in the step (2), and drying to obtain paricalcitol controlled-release particles;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The paricalcitol controlled-release particles provided by the invention have 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 controlled Release granules of Parricalciferol
A preparation method of paricalcitol controlled-release particles comprises the following steps:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing paricalcitol, a filler and an antioxidant, and preparing a quick-release particle core of 20-24 meshes by using absolute ethyl alcohol as an adhesive for later use;
(3) dissolving the controlled release material, the plasticizer and the anti-sticking agent by 80 percent ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the quick-release particle core prepared in the step (2), and drying to obtain paricalcitol controlled-release particles;
(5) and (6) inspecting, packaging, and warehousing qualified products.
The paricalcitol controlled-release granules are prepared according to the preparation method by using the raw and auxiliary materials in the formula (1000 bags) in the following table 1. Where "/" indicates unused.
Figure 112866DEST_PATH_IMAGE002
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 controlled release granules of paricalcitol obtained in examples 1 to 5 and a reference preparation, paricalcitol soft capsule (trade name: Zemplar), were used as test samples, packaged commercially and placed at a temperature of 40 ℃. + -. 2 ℃ and a relative humidity of 75% + -5% for 6 months. Samples were taken at the end of 1 month, 2 months, 3 months and 6 months during the test period, and the content of the paricalcitol preparation was determined according to the paricalcitol content detection method.
The method for detecting the content of paricalcitol 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 paricalcitol peak.
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 paricalcitol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 min, freezing in a refrigerator at the temperature of-18 ℃ for 30 min, taking out, centrifuging (4000 r/min) for 5 min, 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 paricalcitol control was precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0. mu.g of paricalcitol per 1ml, and the content was measured by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the content determination of the accelerated stability test of paricalcitol are shown in table 2.
Figure 985007DEST_PATH_IMAGE003
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 controlled release granules of paricalcitol obtained in examples 1 to 5 and a reference preparation, paricalcitol soft capsule (trade name: Zemplar), were used as test samples, packaged commercially and placed at a temperature of 25 ℃. + -. 2 ℃ and a relative humidity of 60% + -10% for 24 months. Samples were taken at the end of 0 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months of the test period, and the content of the paricalcitol preparation was determined according to the paricalcitol content detection method.
The method for detecting the content of paricalcitol 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 paricalcitol peak.
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 paricalcitol), placing the test sample into a 10ml centrifuge tube, precisely adding 5ml of methanol, shaking for 2 min, freezing in a refrigerator at the temperature of-18 ℃ for 30 min, taking out, centrifuging (4000 r/min) for 5 min, 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 paricalcitol control was precisely weighed, dissolved in methanol and diluted to a solution containing about 1.0. mu.g of paricalcitol per 1ml, and the content was measured by the same method. Calculating according to the peak area by an external standard method to obtain the product. The results of the content determination of the paricalcitol long-term stability test are shown in table 3.
Figure 430901DEST_PATH_IMAGE004
As can be seen from the results of content measurement of accelerated and long-term stability tests of paricalcitol in tables 2 and 3, the content measurement results of the paricalcitol controlled-release granules of example 1 at accelerated time of 6 months and long time of 24 months are significantly better than those of the paricalcitol soft capsule of the control formulation and examples 2-5, which shows that when ethylene acrylic acid copolymer is used as the controlled-release material and triethyl citrate is used as the plasticizer, the weight ratio of the controlled-release material to the plasticizer is 4: 1, the prepared paricalcitol controlled-release granules have the best stability effect and are superior to the paricalcitol soft capsules on the market.

Claims (5)

1. The controlled-release paricalcitol granules consist of a quick-release granule core and a controlled-release coating layer wrapping the quick-release granule core, wherein the quick-release granule core consists of paricalcitol, a filler and an antioxidant, and the controlled-release coating layer consists of a controlled-release material, a plasticizer and an anti-sticking agent, and are characterized in that the controlled-release paricalcitol granules consist of the following components in percentage by weight:
paricalcitol 0.00002%
65 to 75 percent of filling agent
0.02 to 0.04 percent of antioxidant
15 to 25 percent of controlled release material
3 to 10 percent of plasticizer
3-10% of an anti-sticking agent.
2. Paricalcitol controlled release granules according to claim 1, characterized in that the filler is lactose; the antioxidant is tert-butyl hydroquinone; the controlled-release material is carboxymethyl ethyl cellulose or ethylene acrylic acid copolymer; the plasticizer is triethyl citrate or dimethyl phthalate; the antisticking agent is magnesium stearate.
3. Controlled release particles of paricalcitol, according to claim 2, characterized in that the controlled release material is preferably an ethylene acrylic acid copolymer; the plasticizer is preferably triethyl citrate.
4. Controlled release paricalcitol particles according to claim 3, characterized in that the weight ratio of ethylene acrylic acid copolymer to triethyl citrate is preferably 3-5: 1-2; most preferably, the weight ratio of the ethylene acrylic acid copolymer to the triethyl citrate is 4: 1.
5. controlled release paricalcitol particles according to claim 1, which can be prepared by the following process:
(1) weighing raw and auxiliary materials according to the prescription amount;
(2) uniformly mixing paricalcitol, a filler and an antioxidant, and preparing a quick-release particle core of 20-24 meshes by using absolute ethyl alcohol as an adhesive for later use;
(3) dissolving the controlled release material, the plasticizer and the anti-sticking agent by 80 percent ethanol to prepare controlled release coating liquid;
(4) uniformly spraying the prepared controlled-release coating solution on the surface of the quick-release particle core prepared in the step (2), and drying to obtain paricalcitol controlled-release particles;
(5) and (6) inspecting, packaging, and warehousing qualified products.
CN201911264658.2A 2019-12-11 2019-12-11 Paricalcitol solid oral preparation and preparation method thereof Withdrawn CN111000829A (en)

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