CN102885792A - Oral solid rapid release preparation of cinacalcet hydrochloride - Google Patents
Oral solid rapid release preparation of cinacalcet hydrochloride Download PDFInfo
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- CN102885792A CN102885792A CN201210385915XA CN201210385915A CN102885792A CN 102885792 A CN102885792 A CN 102885792A CN 201210385915X A CN201210385915X A CN 201210385915XA CN 201210385915 A CN201210385915 A CN 201210385915A CN 102885792 A CN102885792 A CN 102885792A
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- cinacalcet hydrochloride
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Abstract
The invention discloses an oral solid rapid release preparation of cinacalcet hydrochloride. The oral solid rapid release preparation comprises cinacalcet hydrochloride and medicinal auxiliary materials, wherein the average particle diameter of cinacalcet hydrochloride is 5-15 mum; the cinacalcet hydrochloride is needlelike crystalized fine particles; the medicinal auxiliary materials include a filling agent, a bonding agent, a disintegrating agent and a lubricating agent; and the preparation is in the form of a tablet. The oral solid rapid release preparation has the beneficial effects that: the average particle diameter of cinacalcet hydrochloride is defined, so that the dissolution rate and dissolution amount of cinacalcet are increased, a preparation process is simple and safe, the quality is controllable, and cost is low; and the oral solid rapid release preparation is suitable for industrial production.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to a kind of immediate release oral solid dosage form of cinacalcet hydrochloride.
Background technology
Cinacalcet hydrochloride (Cinacalcet Hydrochloride) chemistry (R)-N-[1-(1-naphthyl) by name]-3-[3-(trifluoromethyl) phenyl-propane-1-amine hydrochlorate, its structural formula is:
Cinacalcet hydrochloride is a kind of Sensipar, it is white or off-white color nonhygroscopic solid powder, there is a kind of stable crystal formation to exist in the room temperature situation, it is slightly soluble in water, rapidly dissolvable in methanol and 95% ethanol, dissolubility has the pH value dependency, in alkaline pH, dissolubility is less than 0.001mg/mL, but it has higher permeability.
This medicine obtains FDA (Food and Drug Adminstration) (FDA) approval on March 8th, 2004 at present, go on the market with trade name Sensipar, advance (Amgen Inc) by biotech company-An, this product is used for the treatment of the Secondary cases hyperthyroidism of chronic nephropathy dialysis patient and is used for the treatment of parathyroid carcinoma patient's calcium level rising symptom, and this medicine can be used separately or share with the pure and mild phosphate binders of vitamin D.
This medicine can be combined by the calcium-sensing receptor in parathyroid gland, reduce the secretion of parathyroid hormone, and then cause the reduction of serum calcium and calcium phosphate product level, usually, constitutional hyperparathyroidism patient can observe initial therapeutic response in 2 hours after taking second dose of this medicine, observing this medicine peak time of lasting therapeutic response in 4～6 weeks after the treatment beginning is 2～6 hours; When this medicine and high fat diet take together, can cause blood drug level and area under the drug-time curve to raise; The white combination rate of this medicated egg is 93%～97%, and distribution volume reaches 1000 liters; Cytochrome P450 3A4,2D6 are all relevant with this medicine metabolism with 1A2.Metabolite is mainly by urine and defecate, and eliminating the half-life is 40 hours.
The open CN1946382A of Chinese patent discloses a kind of cinacalcet hydrochloride compositions with specific stripping behavior, selected silicon dioxide as fluidizer in the said composition, this product is easy to be scattered in air, healthy unfavorable for the workman, and require the D of cinacalcet hydrochloride microgranule in this patent
50Be less than or equal to 50 μ m, this particle size range is wider, can not well control dissolution rate and the stripping quantity of cinacalcet hydrochloride in this scope.
The open CN101522173A of Chinese patent is the patent of Israel Te Wa company, this patent is mainly disclosed to be the solid composite that cinacalcet and other polymer form, main purpose is still to have faster dissolution rate greater than 100um keeping API to have under the condition of greater particle size, and then improves its bioavailability.Carrier mainly is polymer, comprises polyvidone, poloxamer and Polyethylene Glycol etc., and has provided the amount ranges of API, but the method operation is comparatively loaded down with trivial details, is difficult for satisfying industrialization production requirements.
The open CN102198108A of Chinese patent discloses tablet or capsule; stipulated concrete supplementary product kind PEG-6000; mannitol; MCC; polyvinylpolypyrrolidone; pregelatinized Starch and magnesium stearate etc.; stipulated amount ranges; dry granulation; the stripping feature of said preparation; 5-10min stripping 40-80%; 15-20min stripping 80-90%; 30-45min stripping 90-100%; has similar drug release behavior to commercial preparation Sensipar; this patent has mainly been protected a kind of compositions; being characterized as of said composition: comprise main cinacalcet hydrochloride, contain in addition polyethylene glycol 6000; mannitol; microcrystalline Cellulose; polyvinylpolypyrrolidone; part pre-paying starch and magnesium stearate, the wherein independent dry granulation of polyethylene glycol 6000 and mannitol and API; be used for improving the dissolution rate of cinacalcet, this operation is also comparatively complicated.
Summary of the invention
The immediate release oral solid dosage form that the purpose of this invention is to provide a kind of cinacalcet hydrochloride limits by the mean diameter to cinacalcet hydrochloride, improves dissolution rate and the stripping quantity of cinacalcet, to overcome now methodical deficiency.
The technical scheme that realizes the object of the invention is as follows:
A kind of immediate release oral solid dosage form of cinacalcet hydrochloride comprises cinacalcet hydrochloride and pharmaceutic adjuvant, the mean diameter D of cinacalcet hydrochloride
50Be 5 μ m ~ 15 μ m; Described cinacalcet hydrochloride is the acicular crystal microgranule.
Described pharmaceutic adjuvant comprises filler, adhesive, disintegrating agent and lubricant.Wherein: described filler is one or more mixture of microcrystalline Cellulose, mannitol, lactose, pregelatinized Starch, sorbitol, described filler preferably microcrystalline cellulose, pregelatinized Starch.Described adhesive is one or more the mixture in polyvidone, starch slurry, hypromellose and the hydroxypropyl cellulose, and described adhesive is preferably polyvidone.Described disintegrating agent is that cross-linked carboxymethyl cellulose is received, one or more the mixture in low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium and the polyvinylpolypyrrolidone; Described disintegrating agent is preferably polyvinylpolypyrrolidone.Described lubricant is one or more the mixture in magnesium stearate, micropowder silica gel, the Pulvis Talci, and described lubricant is preferably magnesium stearate.
The immediate release oral solid dosage form of cinacalcet hydrochloride of the present invention is preferably tablet, the external accumulative total dissolution rate percentage ratio of this tablet in 0.05N hydrochloric acid in 5 minutes, have 50% ~ 60% cinacalcet hydrochloride by preparation in stripping, and 75% ~ 105% cinacalcet hydrochloride is arranged by stripping in the preparation within 30 minutes.
The present invention also provides the preparation method of the immediate release oral solid dosage form of cinacalcet hydrochloride, and the method may further comprise the steps:
A) with the cinacalcet hydrochloride micronization, obtain mean diameter at the microgranule of 5 ~ 15 μ m;
B) the certain density adhesive solution of preparation;
C) with cinacalcet hydrochloride and filler, disintegrating agent mix homogeneously;
D) adhesive is added in the powder of the principal agent of mix homogeneously and excipient, granulate, be dried at a certain temperature moisture and meet the requirements;
E) granulate that sieves adds disintegrating agent, lubricant, measures granule content, selects the punch die tabletting of certain model, obtains cinacalcet hydrochloride sheet finished product.
Beneficial effect of the present invention: the present invention has improved dissolution rate and the stripping quantity of cinacalcet by the restriction to control cinacalcet hydrochloride mean diameter, and not only preparation technology is simple, safety, and quality controllable, cost is low, is fit to suitability for industrialized production.
The specific embodiment
Further specify by the following examples the present invention, but not as restriction of the present invention.
Size is on the impact of the external dissolution of cinacalcet hydrochloride sheet:
The present invention is by carrying out micronization processes with cinacalcet hydrochloride, collected mean diameter between 1 ~ 5 μ m, between 5 ~ 15 μ m and between 15 ~ 50 μ m, the cinacalcet hydrochloride sample of 3 different particle size ranges is prepared the cinacalcet hydrochloride tablet of 3 kinds of different grain size scopes by wet granulation technology.
On this basis, 50% ~ 60% cinacalcet hydrochloride to be arranged by stripping in the preparation in 5 minutes, and it is foundation by stripping in the preparation that 75% ~ 105% cinacalcet hydrochloride was arranged within 30 minutes, and the In Vitro Dissolution behavior that the cinacalcet hydrochloride tablet of three particle size distribution has carried out in the 0.05N hydrochloric acid is investigated.The result shows: when raw material is between 5 ~ 15 μ m, can guarantee that the stripping behavior of preparation meets the requirements; When the raw material granularity scope is between 1 ~ 5 μ m, 60% ~ 70% cinacalcet hydrochloride is arranged by stripping in the preparation in 5 min; When the raw material granularity scope is between 15 ~ 50 μ m, 70% ~ 80% cinacalcet hydrochloride is arranged by stripping in the preparation during 30min.
This shows the mean diameter D of cinacalcet hydrochloride
50Be not enough to guarantee that less than 50 μ m it has stable In Vitro Dissolution behavior, so the average particle size range that the present invention limits cinacalcet hydrochloride is D
50Between 5 ~ 15 μ m.
The preparation method of cinacalcet hydrochloride tablet of the present invention adopts wet granulation technology, namely through micronization, sieve, mix, granulate, the technical processs such as drying, granulate, tabletting.
The particle size distribution method:
A) method parameter
B) mensuration process
Take by weighing the 60mg cinacalcet hydrochloride and put the sample dispersion agent of 20mL and prepare sample to be analyzed, described sample dispersion agent makes by with Isopar G the soybean lecithins of 1.5 grams being diluted to 200mL in advance.Described hanging drop is added to the correction that is full of in advance dispersant (Isopar G) in the measuring cell of background, until diopter reaches about 15%.After finishing measurement, with sample cell turned letter and clean up, refill suspension media, and in this repeated sampling program.For characterizing, list especially D
10, D
50And D
90Numerical value.
The stripping assay method
Dissolving device: 2010 editions Chinese Pharmacopoeia appendix C X dissolution method the second methods;
Dissolution medium: 900 ml 0.05mol/L HCl;
Temperature: 37 ± 0.5(℃);
Rotating speed: 50 rpm;
Sample time: 5 min, 10 min, 15 min, 15 min and 45 min;
Sampling method: the 10 not fluid infusion of ml(of taking a sample), with 0.45 μ m membrane filtration, 5 ml, 5 ml subsequent filtrates are connected in the cuvette, therefrom accurately weighed 1 ml, precision adds 0.25 mol/L NaOH(10 g NaOH and is dissolved in the 1000 ml water) 200 μ l, measure after shaking up;
Condition determination: ultraviolet spectrophotometry; Detect wavelength: 223nm; Detection cell: 1cm quartz colorimetric utensil.
The Determination of Content Uniformity method:
Chromatographic column: Kromasil100A 250*4.6mm, 5um;
Mobile phase: ammonium formate saline solution (take by weighing the 1.26g ammonium formate and put in the 1000ml measuring bottle, ammonia is regulated pH to 7.3)-acetonitrile (40:60);
Detect wavelength: 223nm;
Column temperature: 30 ℃;
Sample size: 10 μ l.
The preparation of the immediate release oral solid dosage form of embodiment 1 cinacalcet hydrochloride
Preparation comprises 90mg(that specified particle diameter distributes by the free alkali of cinacalcet hydrochloride) raw material of active component forms
The preparation of the immediate release oral solid dosage form of cinacalcet hydrochloride may further comprise the steps:
(1) with the cinacalcet hydrochloride micronization, claim to join, sieve, obtain mean diameter at the microgranule of 5 ~ 15 μ m, prepare certain density adhesive solution, then with cinacalcet hydrochloride and filler, disintegrating agent mix homogeneously;
(2) adhesive is added in the powder of the principal agent of mix homogeneously and excipient, granulate, granulate is dried at a certain temperature moisture and meets the requirements, and namely obtains dried granulate;
(3) then add disintegrating agent, lubricant, measure granule content, select the punch die tabletting of certain model, get cinacalcet hydrochloride sheet finished product;
(4) then use coating material, carry out coating, obtain finished product.
The particle size range of cinacalcet hydrochloride of the present invention is controlled between 5 μ m ~ 15 μ m.
Embodiment stripping experimental result, shown in seeing the following form:
Cinacalcet hydrochloride stripping percentage rate
The uniformity of dosage units experimental result, cinacalcet hydrochloride uniformity of dosage units shown in seeing Table
Claims (10)
1. the immediate release oral solid dosage form of a cinacalcet hydrochloride comprises cinacalcet hydrochloride and pharmaceutic adjuvant, it is characterized in that: the mean diameter of cinacalcet hydrochloride is 5 μ m ~ 15 μ m.
2. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 1, it is characterized in that: described cinacalcet hydrochloride is the acicular crystal microgranule.
3. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 2, it is characterized in that: dosage form is tablet.
4. the immediate release oral solid dosage form of each described cinacalcet hydrochloride according to claim 1-3, it is characterized in that: described pharmaceutic adjuvant comprises filler, adhesive, disintegrating agent and lubricant.
5. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 4 is characterized in that: described filler is one or more the mixture in microcrystalline Cellulose, pregelatinized Starch, lactose, mannitol and the sorbitol.
6. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 5, it is characterized in that: described filler is microcrystalline Cellulose, pregelatinized Starch.
7. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 4 is characterized in that: described adhesive is one or more the mixture in polyvidone, starch slurry, hypromellose and the hydroxypropyl cellulose.
8. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 7, it is characterized in that: described adhesive is polyvidone.
9. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 4, it is characterized in that: described disintegrating agent is that cross-linked carboxymethyl cellulose is received, one or more the mixture in low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium and the polyvinylpolypyrrolidone, is preferably polyvinylpolypyrrolidone.
10. the immediate release oral solid dosage form of cinacalcet hydrochloride according to claim 4 is characterized in that: described lubricant is one or more the mixture in magnesium stearate, micropowder silica gel, the Pulvis Talci, is preferably magnesium stearate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201210385915XA CN102885792A (en) | 2012-10-12 | 2012-10-12 | Oral solid rapid release preparation of cinacalcet hydrochloride |
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| CN201210385915XA CN102885792A (en) | 2012-10-12 | 2012-10-12 | Oral solid rapid release preparation of cinacalcet hydrochloride |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105213346A (en) * | 2015-11-02 | 2016-01-06 | 北京泰德制药股份有限公司 | A kind of pharmaceutical composition containing cinacalcet hydrochloride and preparation method thereof |
| CN108464972A (en) * | 2018-07-02 | 2018-08-31 | 福州大学 | A kind of anti-pulmonary hypertension oral tablet and preparation method thereof containing Snopori |
| WO2019034981A1 (en) * | 2017-08-16 | 2019-02-21 | Unichem Laboratories Ltd | Pharmaceutical compositions comprising cinacalcet hydrochloride and one or more binders |
| CN109700778A (en) * | 2019-03-04 | 2019-05-03 | 南京恒生制药有限公司 | A kind of cinacalcet hydrochloride quick releasing formulation and preparation method thereof |
| CN111450073A (en) * | 2020-04-29 | 2020-07-28 | 福建海西新药创制有限公司 | Pharmaceutical composition containing cinacalcet hydrochloride and preparation method thereof |
| CN112546010A (en) * | 2020-12-02 | 2021-03-26 | 普莱赛思(天津)生命科技有限公司 | Pharmaceutical composition for treating nephropathy and preparation method thereof |
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| WO2008058236A2 (en) * | 2006-11-08 | 2008-05-15 | Dr. Reddy's Labortories, Ltd. | Methods for preparing cinacalcet hydrochloride |
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| US20090275780A1 (en) * | 2008-05-05 | 2009-11-05 | Medichem, S.A. | Process for controlling the particle size of a 3-(trifluoromethyl)phenyl]-1-aminopropane derivative |
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| WO2005034928A1 (en) * | 2003-09-12 | 2005-04-21 | Amgen Inc. | Rapid dissolution formulation of a calcium receptor-active compound |
| CN101522173A (en) * | 2006-09-01 | 2009-09-02 | 特瓦制药工业有限公司 | Solid composites of a calicum receptor-active compound |
| WO2008058236A2 (en) * | 2006-11-08 | 2008-05-15 | Dr. Reddy's Labortories, Ltd. | Methods for preparing cinacalcet hydrochloride |
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| WO2011146583A2 (en) * | 2010-05-19 | 2011-11-24 | Elan Pharma International Limited | Nanoparticulate cinacalcet formulations |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105213346A (en) * | 2015-11-02 | 2016-01-06 | 北京泰德制药股份有限公司 | A kind of pharmaceutical composition containing cinacalcet hydrochloride and preparation method thereof |
| CN105213346B (en) * | 2015-11-02 | 2019-03-26 | 北京泰德制药股份有限公司 | A kind of pharmaceutical composition and preparation method thereof containing cinacalcet hydrochloride |
| WO2019034981A1 (en) * | 2017-08-16 | 2019-02-21 | Unichem Laboratories Ltd | Pharmaceutical compositions comprising cinacalcet hydrochloride and one or more binders |
| US11331283B2 (en) | 2017-08-16 | 2022-05-17 | Unichem Laboratories Ltd | Pharmaceutical compositions comprising cinacalcet hydrochloride and one or more binders |
| CN108464972A (en) * | 2018-07-02 | 2018-08-31 | 福州大学 | A kind of anti-pulmonary hypertension oral tablet and preparation method thereof containing Snopori |
| CN109700778A (en) * | 2019-03-04 | 2019-05-03 | 南京恒生制药有限公司 | A kind of cinacalcet hydrochloride quick releasing formulation and preparation method thereof |
| CN111450073A (en) * | 2020-04-29 | 2020-07-28 | 福建海西新药创制有限公司 | Pharmaceutical composition containing cinacalcet hydrochloride and preparation method thereof |
| CN112546010A (en) * | 2020-12-02 | 2021-03-26 | 普莱赛思(天津)生命科技有限公司 | Pharmaceutical composition for treating nephropathy and preparation method thereof |
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Application publication date: 20130123 |