CN109953979A - Cinacalcet pharmaceutical composition and its medical usage - Google Patents

Cinacalcet pharmaceutical composition and its medical usage Download PDF

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Publication number
CN109953979A
CN109953979A CN201811586112.4A CN201811586112A CN109953979A CN 109953979 A CN109953979 A CN 109953979A CN 201811586112 A CN201811586112 A CN 201811586112A CN 109953979 A CN109953979 A CN 109953979A
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pharmaceutical composition
cinacalcet
polyethylene glycol
alcohol
composition described
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Inventor
孙飘扬
王捷
王立坤
赵妍
刘畅
李琳
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • 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
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones

Abstract

This hair provides cinacalcet pharmaceutical composition and its medical usage.Specifically, the present invention provide it is a kind of can injection cinacalcet Pharmaceutical composition, preparation method and its medical usage, cinacalcet pharmaceutical composition provided by the invention has improved chemical stability.

Description

Cinacalcet pharmaceutical composition and its medical usage
Technical field
The present invention relates to field of pharmaceutical preparations, are related to a kind of for the pharmaceutical composition of parenteral administration and its preparation side Method, specially it is a kind of can injection cinacalcet Pharmaceutical composition and preparation method thereof, there is improved chemical stabilization Property.
Background technique
Chronic kidney disease (CKD) is common one of the chronic disease of China, is shown according to epidemiological survey, number of the infected About 1.2 hundred million, account for the 10.8% of population.Secondary hyperparathyroidism (SHPT) is that CKD patient is most common concurrent One of disease is mainly shown as the horizontal raising of parathyroid hormone (PTH) and parathyroid hyperplasia.Have now been found that different kinds of molecules thing Part takes part in the regulation process of PTH, including 1. hypocalcemia and calcium receptor (CaSR) are lowered；2. activated vitamin D and its receptor (VDR) it reduces；3. phosphate retention；4. target organ is to PTH reaction decline etc..
Cinacalcet is the isomery agonist of CaSR, in conjunction with CaSR after pass through allosteric effect and enhance extracellular calcium Effect inhibits PTH secretion and parathyroid cells proliferation, participates in maintaining blood calcium dynamic equilibrium, concrete structure formula is as follows.
Cinacalcet is insoluble in water, and solubility is less than 0.03mg/ml in water, and unstable.With low aqueous solubility Compound usually shows low dissolution rate, and usually shows low bioavilability (Ansel, et al.Pharmaceutical Dosage Forms and Delivery Methods(6th ed.1995),pp.105-108)。 The cinacalcet hydrochloride listed at present is oral tablet, and CN1946382 is Amgen marketed drug Sensipar Formulation patent discloses a kind of cinacalcet hydrochloride oral preparation, including the auxiliary materials such as cinacalcet hydrochloride and microcrystalline cellulose. CN101437490 discloses the emulsion and preparation method of a kind of cinacalcet free alkali, after the emulsion can reduce injection Stimulation, pain, rubescent and swelling.WO2008064202 discloses a kind of cinacalcet sustained-release tablet, which can subtract It is few to generate high local concentrations in gastrointestinal tract, it is possible to reducing the adverse reactions such as Nausea and vomiting.WO2010086129 is disclosed A kind of cinacalcet cyclodextrin inclusion compound and preparation method thereof, the inclusion compound and microcrystalline cellulose, Crospovidone, stearoyl are rich Horse acid sodium redissolves fast speed after being mixed and made into tablet, and solubility is preferable.
The cinacalcet preparation listed at present is oral preparation, and in dialysis patient, intravenous injection can be obvious Improve the compliance of patient, mitigate patient's oral medication burden, reduce gastrointestinal side effect caused by a large amount of oral drugs, It is more particularly suitable administration route.But the drug of poorly water-soluble, precipitation reaction may occur when entering internal for injection, this heavy The concentration of drug would generally be reduced by forming sediment, and lead to drug efficacy delay or reduction, in addition, drug is possible in intravenous precipitating after intravenously administrable Can generate serious pain reaction (Wei G D, In vitro methods to assess drug precipitation, International Journal of Pharmaceutics 393(2010)1–16).Therefore to prepare can injection Cinacalcet needs to find a good solubilizing systems to improve solubility of the API in system, and reduces drug in vivo Precipitation reaction
Summary of the invention
The present invention provides one kind can injection cinacalcet Pharmaceutical composition.By taking suitable pharmaceutic adjuvant, The solubility and stability of cinacalcet are improved, the precipitating that the cinacalcet injection being prepared can be obviously improved drug is anti- It answers.
In pharmaceutical composition of the invention, cinacalcet includes cinacalcet free alkali and its pharmaceutically acceptable salt and molten Object is closed in agent.Preferably, cinacalcet indicates cinacalcet hydrochloride.
The present invention provides a kind of injection cinacalcet pharmaceutical compositions, comprising cinacalcet or its officinal salt, and At least there are also a kind of carrier, the carrier is selected from ethyl alcohol, propylene glycol, the tert-butyl alcohol, polyethylene glycol, dimethyl acetamide, glycerol, benzene Methanol, n-methyl-2-pyrrolidone, Emulsifier EL-60, Crodaret, lauryl sodium sulfate, diformazan Base sulfoxide, diethylene glycol monoethyl ether, polysorbate, poloxamer, povidone, polyethylene glycol hydroxystearate, poly- second two Alcohol cetostearyl alcohol ether；Preferred alcohol, propylene glycol, the tert-butyl alcohol, polyethylene glycol, dimethyl acetamide, glycerol, benzyl alcohol, N- first Base -2-Pyrrolidone, Emulsifier EL-60, polyoxyl 40 hydrogenated castor oil, lauryl sodium sulfate, dimethyl sulfoxide, Diethylene glycol monoethyl ether, polysorbate 20, polyoxyethylene sorbitan monoleate, PLURONICS F87,30 POVIDONE K 30 BP/USP 12,30 POVIDONE K 30 BP/USP 17, poly- second two 15 hydroxy stearic acid ester of alcohol, polyethylene glycol cetostearyl alcohol ether 12, polyethylene glycol cetostearyl alcohol ether 20；Most preferably polysorbate 20, polyoxyethylene sorbitan monoleate, Solutol HS 15, polyoxyl 40 hydrogenated castor oil, Emulsifier EL-60,12 It is one or more in sodium alkyl sulfate.
" carrier " of the present invention is to can be improved the liquid such as the solubilizer, cosolvent, cosolvent of cinacalcet solubility Body preparation often uses additives.
In pharmaceutical composition of the invention, the concentration of cinacalcet or its officinal salt is 0.01-100mg/mL, preferably 0.1-10mg/mL, can be 0.1mg/mL, 0.11mg/mL, 0.12mg/mL, 0.13mg/mL, 0.14mg/mL, 0.15mg/mL, 0.16mg/mL、0.17mg/mL、0.18mg/mL、0.19mg/mL、0.2mg/mL、0.21mg/mL、0.22mg/mL、0.23mg/ mL、0.24mg/mL、0.25mg/mL、0.26mg/mL、0.27mg/mL、0.28mg/mL、0.29mg/mL、0.3mg/mL、 0.31mg/mL、0.32mg/mL、0.33mg/mL、0.34mg/mL、0.35mg/mL、0.36mg/mL、0.37mg/mL、0.38mg/ mL、0.39mg/mL、0.4mg/mL、0.41mg/mL、0.42mg/mL、0.43mg/mL、0.44mg/mL、0.45mg/mL、 0.46mg/mL、0.47mg/mL、0.48mg/mL、0.49mg/mL、0.5mg/mL、0.51mg/mL、0.52mg/mL、0.53mg/ mL、0.54mg/mL、0.55mg/mL、0.56mg/mL、0.57mg/mL、0.58mg/mL、0.59mg/mL、0.6mg/mL、 0.61mg/mL、0.62mg/mL、0.63mg/mL、0.64mg/mL、0.65mg/mL、0.66mg/mL、0.67mg/mL、0.68mg/ mL、0.69mg/mL、0.7mg/mL、0.71mg/mL、0.72mg/mL、0.73mg/mL、0.74mg/mL、0.75mg/mL、 0.76mg/mL、0.77mg/mL、0.78mg/mL、0.79mg/mL、0.8mg/mL、0.81mg/mL、0.82mg/mL、0.83mg/ mL、0.84mg/mL、0.85mg/mL、0.86mg/mL、0.87mg/mL、0.88mg/mL、0.89mg/mL、0.9mg/mL、 0.91mg/mL、0.92mg/mL、0.93mg/mL、0.94mg/mL、0.95mg/mL、0.96mg/mL、0.97mg/mL、0.98mg/ mL、0.99mg/mL、1mg/mL、1.5mg/mL、2mg/mL、2.5mg/mL、3mg/mL、3.5mg/mL、4mg/mL、4.5mg/mL、 5mg/mL、5.5mg/mL、6mg/mL、6.5mg/mL、7mg/mL、7.5mg/mL、8mg/mL、8.5mg/mL、9mg/mL、9.5mg/ mL、10mg/mL。
In pharmaceutical composition of the invention, ethyl alcohol, propylene glycol, the tert-butyl alcohol, polyethylene glycol, diethylene glycol monoethyl ether, two Methylacetamide, glycerol, benzyl alcohol, n-methyl-2-pyrrolidone proportion are 1%-90%v/v, preferably 1%-50%w/ V, can for 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 35.5%, 36%, 36.5%, 37%, 37.5%, 38%, 38.5%, 39%, 39.5%, 40%, 41.5%, 41%, 41.5%, 42%, 42.5%, 43%, 43.5%, 44%, 44.5%, 45%, 45.5%, 46%, 46.5%, 47%, 47.5%, 48%, 48.5%, 49%, 49.5%, 50%v/v.
In pharmaceutical composition of the invention, Emulsifier EL-60, lauryl sodium sulfate, dimethyl sulfoxide, poly- sorb Ester 20, polyoxyethylene sorbitan monoleate, PLURONICS F87,30 POVIDONE K 30 BP/USP 12,30 POVIDONE K 30 BP/USP 17,40 rilanit special of polyethylene glycol, polyethylene glycol 15 hydroxy stearic acid esters, polyethylene glycol cetostearyl alcohol ether 12, ratio shared by ethylene glycol cetostearyl alcohol ether 20 are 0.01%- 50%w/v, preferably 0.01%-20%w/v, most preferably 0.05%-10%w/v, can for 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6%, 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%, 9.1%, 9.2%, 9.3%, 9.4%, 9.5%, 9.6%, 9.7%, 9.8%, 9.9%, 10%w/v.
In pharmaceutical composition of the invention, pH value is 2.0~12.0, preferably 3.0~9.0, can for 3.0,4.0,4.5, 4.6、4.7、4.8、4.9、5.0、5.1、5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、 6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、9.0。
Pharmaceutical composition of the present invention further comprises novel vitamin D analogues, the novel vitamin D analogues choosing From paricalcitol, Chinese mugwort ground ostelin, Alfacalcidol, cholecalciferol, calcitriol, doxercalciferol, preferably paricalcitol.
Pharmaceutical composition of the present invention, wherein the quality of novel vitamin D analogues be 0.1 μ g-10 μ g, can for 0.1 μ g, 0.2μg、0.3μg、0.4μg、0.5μg、0.6μg、0.7μg、0.8μg、0.9μg、1.0μg、1.1μg、1.2μg、1.3μg、1.4μ g、1.5μg、1.6μg、1.7μg、1.8μg、1.9μg、2.0μg、2.1μg、2.2μg、2.3μg、2.4μg、2.5μg、2.6μg、2.7 μg、2.8μg、2.9μg、3.0μg、3.1μg、3.2μg、3.3μg、3.4μg、3.5μg、3.6μg、3.7μg、3.8μg、3.9μg、 4.0μg、4.1μg、4.2μg、4.3μg、4.4μg、4.5μg、4.6μg、4.7μg、4.8μg、4.9μg、5.0μg、5.1μg、5.2μ g、5.3μg、5.4μg、5.5μg、5.6μg、5.7μg、5.8μg、5.9μg、6.0μg、6.1μg、6.2μg、6.3μg、6.4μg、6.5 μg、6.6μg、6.7μg、6.8μg、6.9μg、7.0μg、7.1μg、7.2μg、7.3μg、7.4μg、7.5μg、7.6μg、7.7μg、 7.8μg、7.9μg、8.0μg、8.1μg、8.2μg、8.3μg、8.4μg、8.5μg、8.6μg、8.7μg、8.8μg、8.9μg、9.0μ g、9.1μg、9.2μg、9.3μg、9.4μg、9.5μg、9.6μg、9.7μg、9.8μg、9.9μg、10μg。
Pharmaceutical composition of the present invention, the wherein ratio of cinacalcet or its officinal salt and novel vitamin D analogues For 2000:1-400000:1, preferably 10000:1-150000:1.
Pharmaceutical composition of the invention can also include other customary adjuvants for injection.These conventional accessory packages Include but be not limited to antibacterial agent, antioxidant, osmotic pressure regulator, stabilizer, buffer, isotonic agent, surfactant etc..
Wherein antibacterial agent can be selected from but not limited to benzalkonium chloride, benzyl alcohol, anesin, metacresol, nipalgin fourth One or more of ester, methylparaben, propylben, phenol and thimerosal.
Antioxidant can selected from but not limited to vitamin C (ascorbic acid), cysteine, thioglycerol, sodium hydrogensulfite, One of sodium pyrosulfite and vitamin E (tocopherol) are a variety of.
Osmotic pressure regulator can be one or more in glucose sugar and sodium chloride.
Stabilizer can selected from but not limited to sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, sodium thiosulfate, thiocarbamide, Vitamin C, butylated hydroxyarisol, dibutylphenol, propylgallate, tocopherol, methionine, half deamination of hydrochloric acid Acid, half deamination of acetyl acid, N- acetyl-DL- methionine, ascorbyl palmitate, ethylenediamine tetra-acetic acid, ethylenediamine tetra-acetic acid One or more of disodium.
Buffer can selected from but not limited to hydrochloric acid, citric acid, tartaric acid, acetic acid, trometamol, glycine, phosphoric acid, partially Phosphoric acid, poly-metaphosphoric acid, carbonic acid, sodium hydroxid, potassium hydroxide, sodium citrate, potassium citrate, sodium bicarbonate, saleratus, carbonic acid Amine, disodium hydrogen phosphate, dipotassium hydrogen phosphate, ethanol amine, diethanol amine, triethanolamine, 1,2- hexamethylene diamine, sodium carbonate, sodium tartrate One or more of potassium, potassium metaphosphate, potassium metapbosphate, sodium metaphosphate.
Surfactant can be selected from but not limited to Solutol HS 15, NaTDC, polyoxyethylene Castor oil 35, polyoxyethylene sorbitan monoleate, PLURONICS F87, dodecyl sodium sulfate it is one or more.
Pharmaceutical composition of the present invention is placed 2 weeks under the conditions of 25 DEG C, the content of largest single impurity less than 0.5%, Preferably smaller than 0.2%；The content of total impurities is less than 1%, and preferably smaller than 0.5%.
Pharmaceutical composition of the present invention is placed 2 weeks under the conditions of 40 DEG C, and the content of largest single impurity is excellent less than 1% Choosing is less than 0.5%；The content of total impurities is less than 5%, and preferably smaller than 2%.
Pharmaceutical composition of the present invention is placed 2 weeks under the conditions of 60 DEG C, and the content of largest single impurity is excellent less than 5% Choosing is less than 1%；The content of total impurities is less than 10%, and preferably smaller than 5%.
Pharmaceutical composition of the present invention can not precipitate or be injected into after dilution in blood not quiet Precipitating in arteries and veins.
The administration route of pharmaceutical composition of the present invention is selected from intravenous injection, subcutaneous injection, intramuscular injection.
The present invention further provides a kind of product or kits, and it includes any stable pharmaceutical composition described herein is housed The container of object.
The present invention further provides a kind of methods for preparing pharmaceutical composition described in any of the above item, including by Xi Naka Plug or its officinal salt are mixed with pharmaceutically acceptable auxiliary material.
The present invention further provides aseptic powderies made of more than one described in any item pharmaceutical compositions.
Aseptic powdery of the present invention, can also contain excipient, and the excipient is selected from sucrose, trehalose, malt Dextrin, dextran, mannitol, sorbierite, glycine, hydroxyethyl starch, polyethylene glycol, it is a kind of in PVPK30, PVPK12 or It is a variety of, preferably trehalose, sucrose, maltodextrin, mannitol, sorbierite, glycine, hydroxyethyl starch, it is a kind of in PVPK12 or It is a variety of.
The present invention further provides a kind of methods for preparing above-mentioned aseptic powdery, including a) by cinacalcet dissolution or its Officinal salt is in the carrier；B) by solution freeze-drying or spray drying or fluidized bed drying.
The method of the present invention for preparing aseptic powdery further includes the steps that excipient is added before the drying.
The present invention still further comprises purposes of the above-described pharmaceutical composition in the drug of preparation treatment disease, institute It states disease and is selected from hyperparathyroidism (HPT), hyperphosphatemia, hypercalcinemia and calcium-phosphorus product raising, wherein parathyroid gland Hyperfunction can be secondary HPT, be also possible to primary HPT.
The present invention still further comprises a kind of method prevented or treat disease, and the method includes giving patient effective amounts The pharmaceutical composition comprising cinacalcet；Wherein the disease is selected from hyperparathyroidism (HPT), hyperphosphatemia, height Disease in caalcemia and calcium-phosphorus product raising, wherein hyperparathyroidism can be secondary HPT, be also possible to primary Property HPT.
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments not limit model of the invention It encloses.
Embodiment 1: stability experiment of the cinacalcet hydrochloride under cosolvent system and dilution precipitation experiments 1. test material Material and method:
1.1 experimental materials:
API: cinacalcet hydrochloride solvent: dehydrated alcohol (traditional Chinese medicinesization examination), 1,3-PD (Aladdin, A1706027), N,N-dimethylacetamide (abbreviation DMA, K1516107, Aladdin), glycerol (traditional Chinese medicinesization examination).
Buffer: sodium chloride (traditional Chinese medicinesization examination), potassium chloride (Shanghai Ling Feng), potassium dihydrogen phosphate (traditional Chinese medicinesization examination), phosphoric acid hydrogen Disodium (traditional Chinese medicinesization examination), PH count (S210-K, Mei Tele-support benefit).
1.2 sample preparation methods
1.2.1 it is infused according to 0.2mg/mL, 0.5mg/mL, 1.0mg/mL cinacalcet hydrochloride of 1 compounding high concentration solvent of table Penetrate liquid.
Table 1
1.2.2 it is infused according to 0.2mg/mL, 0.5mg/mL, 1.0mg/mL cinacalcet hydrochloride that table 2 prepares low concentration solvent Penetrate liquid.
Table 2
Solvent title Solvent usage Purify water volume
1%DMA 1.5mL 148.5mL
Glycerol: water (1:29) 5mL 145mL
5% ethyl alcohol 7.5mL 142.5mL
5% propylene glycol 7.5mL 142.5mL
Prepare blank solvent 150mL first, in accordance with table 2 respectively takes 80mL blank solvent to be placed in 100mL beaker after mixing evenly In, 80mg cinacalcet is respectively added respectively and is stirred overnight to get 80mL1mg/mL cinacalcet injection.Take 20mL 1mg/mL Cinacalcet injection is placed in 50mL centrifuge tube, and corresponding blank solvent 20mL is separately added, be uniformly mixed to get 40mL 0.5mg/mL cinacalcet injection.10mL1mg/mL cinacalcet injection is taken to be placed in 50mL centrifuge tube, it is another to be added Corresponding blank solvent 40mL is uniformly mixed to get 50mL 0.2mg/mL cinacalcet injection.Every kind of solvent is matched Making 3 cinacalcet concentration is respectively 0.2mg/mL, 0.5mg/mL, 1.0mg/mL, totally 12 stability samples.
1.2.3 the buffer (simulating blood plasma) of pH 7.4 is prepared
Weigh 16.00491g sodium chloride, 0.40089g potassium chloride, 0.40326g potassium dihydrogen phosphate and 2.20236g phosphoric acid hydrogen Disodium is placed in 100mL purified water, is stirred evenly, and actual pH 7.36 is surveyed.
1.3 stability experiment detection method detection methods are as follows:
Chromatographic column: Agilent Eclipse Plus C18,4.6*150mm, 3.5 μm
Mobile phase A: 0.03M KH2PO4, KOH adjusting pH=6.5
Mobile phase B: acetonitrile
Flow velocity: 1ml/min
Column temperature: 30 DEG C
Sample volume: 30 μ l
Wavelength: 260nm, 220nm
Dilution: mobile phase A: Mobile phase B=80:20
Gradient see the table below 3:
Table 3
Test solution is prepared:
0.2mg/mL sample is undiluted, 0.5mg/mL sample dilutes 2 times and 1.0mg/mL sample dilutes 4 times of sample introductions point Analysis, using area normalization method calculated result.
2. experimental result
2.1 stability experiment results
By the sample prepared according to Tables 1 and 2 place respectively at 25 DEG C, 40 DEG C, 60 DEG C place 0 day, 7 days, 14 days, It is detected after 1 month, 2 months, 3 months, experimental result is shown in Table 4.
Table 4
Conclusion: the stability with the increase injection of injection cinacalcet concentration increases, while with placement temperature Increase injection stability reduce, with 10%DMA, 1%DMA, 20% ethyl alcohol, 5% ethyl alcohol, 5% propylene glycol, glycerol: water (1:29) be solvent preparation 1.0mg/mL cinacalcet injection and with glycerol: water (1:2) be solvent prepare three kinds of concentration Cinacalcet injection place 3 months stability it is preferable.
2.2 dilution precipitation experiments results
The injection 1mL being prepared according to Tables 1 and 2 is taken, pH7.4 buffer is slowly added under stirring, is seen Phenomenon is examined, experimental result is shown in Table 5.
Table 5
Conclusion: 10%DMA, 1%DMA, 20% ethyl alcohol, 5% ethyl alcohol, 40% propylene glycol, 5% propylene glycol, glycerol: water are used (1:2), glycerol: 0.2mg/mL, 0.5mg/mL and 1mg/mL cinacalcet hydrochloride injection that water (1:29) solvent is prepared have Dilute deposited phenomenon.
Embodiment 2: stability experiment of the cinacalcet hydrochloride under solubilizer system and dilution precipitation experiments 1. test material Material and method:
1.1 experimental materials:
API: cinacalcet hydrochloride solvent: polyoxyethylene sorbitan monoleate (traditional Chinese medicinesization examination), polysorbate 20 (upper seawater rock medicine), pool Luo Shamu 188 (abbreviation F68, BASF), lauryl sodium sulfate (abbreviation SDS, traditional Chinese medicinesization examination), Emulsifier EL-60 (commodity NameELP, 52217816K0, BASF), Solutol HS 15 (trade nameHS15, 90641136WO, BASF), polyoxyl 40 hydrogenated castor oil (trade nameRH40,29686668EO, BASF).
Buffer: sodium chloride (traditional Chinese medicinesization examination), potassium chloride (Shanghai Ling Feng), potassium dihydrogen phosphate (traditional Chinese medicinesization examination), phosphoric acid hydrogen Disodium (traditional Chinese medicinesization examination), PH count (S210-K, Mei Tele-support benefit).
1.2 sample preparation methods
1.2.1 according to 0.2mg/mL, 0.5mg/mL, 1.0mg/mL cinacalcet hydrochloride injection of 6 compounding high concentration of table.
Table 6
1.2.2 0.2mg/mL, 0.5mg/mL, 1.0mg/mL cinacalcet hydrochloride injection of low concentration solvent are prepared
80mL blank solvent is respectively taken to be placed in after mixing evenly first, in accordance with the blank solvent 150mL that table 7 prepares low concentration In 100mL beaker, 80mg cinacalcet is respectively added respectively and is stirred overnight to get 80mL1mg/mL cinacalcet injection.It takes 20mL 1mg/mL cinacalcet injection is placed in 50mL centrifuge tube, and corresponding blank solvent 20mL is separately added, mixing Uniformly to get 40mL 0.5mg/mL cinacalcet injection.10mL1mg/mL cinacalcet injection is taken to be placed in 50mL centrifuge tube In, corresponding blank solvent 40mL is separately added, is uniformly mixed to get 50mL 0.2mg/mL cinacalcet injection.Often It is respectively 0.2mg/mL, 0.5mg/mL, 1.0mg/mL that kind of solvent, which prepares 3 cinacalcet concentration, totally 21 stability samples.
Table 7
Solvent title Solvent usage Purify water volume
0.05% polyoxyethylene sorbitan monoleate 75mg 150mL
0.05% polysorbate 20 75mg 150mL
0.05%F68 75mg 150mL
0.5%HS-15 750mg 150mL
0.5%RH40 750mg 150mL
0.5%ELP 750mg 150mL
1.2.3 the buffer (simulating blood plasma) of pH 7.4 is prepared
Weigh 16.00491g sodium chloride, 0.40089g potassium chloride, 0.40326g potassium dihydrogen phosphate and 2.20236g phosphoric acid hydrogen Disodium is placed in 100mL purified water, is stirred evenly, and actual pH 7.36 is surveyed.
1.3 stability experiment detection method detection methods are as follows:
Chromatographic column: Agilent Eclipse Plus C18,4.6*150mm, 3.5 μm
Mobile phase A: 0.03M KH2PO4, KOH adjusting pH=6.5
Mobile phase B: acetonitrile
Flow velocity: 1ml/min
Column temperature: 30 DEG C
Sample volume: 30 μ l
Wavelength: 260nm, 220nm
Dilution: mobile phase A: Mobile phase B=80:20
Gradient see the table below 8:
Table 8
Time (min) Mobile phase A (%) Mobile phase B (%)
0 80 20
10 40 60
24 28 72
25 80 20
30 80 20
Test solution is prepared:
0.2mg/mL sample is undiluted, 0.5mg/mL sample dilutes 2 times and 1.0mg/mL sample dilutes 4 times of sample introductions point Analysis, using area normalization method calculated result.
2. experimental result
2.1 stability experiment results
To be prepared according to table 6 and table 7 obtained sample place respectively at 25 DEG C, 40 DEG C, 60 DEG C place 0 day, 7 days, 14 days, It is detected after 1 month, 2 months, 3 months, experimental result is shown in Table 9.
Table 9
Conclusion: the stability with the reduction injection of solubilizer dosage increases, while as the increase for placing temperature is infused The stability for penetrating liquid reduces, with 0.05% polyoxyethylene sorbitan monoleate, 0.5% polysorbate 20,0.05% polysorbate 20,0.05% F68,5%HS15,0.5%HS15,0.5%RH40,0.5%SDS are that the cinacalcet injection of solvent preparation is placed 3 months Stability is relatively preferable.
2.2 dilution precipitation experiments results
1mL injection is taken, pH7.4 buffer is slowly added under stirring, observes phenomenon, experimental result is shown in Table 10.
Table 10
Conclusion: with 0.5% polyoxyethylene sorbitan monoleate, 0.5% polysorbate 20,5%HS-15,0.5%HS-15,5%RH40, 0.2mg/mL, 0.5mg/mL and 1mg/mL cinacalcet hydrochloride note that 0.5%RH40,0.5%ELP, 0.5%SDS solvent are prepared Liquid is penetrated without dilution deposited phenomenon.The 0.2mg/mL salt prepared with 0.05% polyoxyethylene sorbitan monoleate and 0.05% polysorbate 20 solvent Sour cinacalcet injection is without dilution deposited phenomenon.

Claims (15)

1. a kind of cinacalcet pharmaceutical composition of injectable, it is characterised in that comprising cinacalcet or its officinal salt, and extremely Few there are also a kind of carriers, and the carrier is selected from ethyl alcohol, propylene glycol, the tert-butyl alcohol, polyethylene glycol, dimethyl acetamide, glycerol, benzene first Alcohol, n-methyl-2-pyrrolidone, Emulsifier EL-60, Crodaret, lauryl sodium sulfate, dimethyl Sulfoxide, diethylene glycol monoethyl ether, polysorbate, poloxamer, povidone, polyethylene glycol hydroxystearate, polyethylene glycol Cetostearyl alcohol ether；Preferred alcohol, propylene glycol, the tert-butyl alcohol, polyethylene glycol, dimethyl acetamide, glycerol, benzyl alcohol, N- methyl- 2-Pyrrolidone, Emulsifier EL-60, polyoxyl 40 hydrogenated castor oil, lauryl sodium sulfate, dimethyl sulfoxide, diethyl Glycol list ethylether, polysorbate 20, polyoxyethylene sorbitan monoleate, PLURONICS F87,30 POVIDONE K 30 BP/USP 12,30 POVIDONE K 30 BP/USP 17, polyethylene glycol 15 Hydroxy stearic acid ester, polyethylene glycol cetostearyl alcohol ether 12, polyethylene glycol cetostearyl alcohol ether 20；Most preferably polysorbate 20, Polyoxyethylene sorbitan monoleate, Solutol HS 15, polyoxyl 40 hydrogenated castor oil, Emulsifier EL-60, dodecane It is one or more in base sodium sulphate.
2. pharmaceutical composition described in claim 1, it is characterised in that the cinacalcet or its officinal salt concentration are 0.01- 100mg/mL, preferably 0.1-10mg/mL.
3. pharmaceutical composition described in claim 1, it is characterised in that the ethyl alcohol, propylene glycol, the tert-butyl alcohol, polyethylene glycol, two Ethylene glycol monomethyl ether, dimethyl acetamide, glycerol, benzyl alcohol, ratio shared by n-methyl-2-pyrrolidone are 1%-90% V/v, preferably 5%-50%v/v.
4. pharmaceutical composition described in claim 1, it is characterised in that the Emulsifier EL-60, lauryl sodium sulfate, Dimethyl sulfoxide, polysorbate 20, polyoxyethylene sorbitan monoleate, PLURONICS F87, Solutol HS 15, polyoxyethylene Ratio shared by 40 rilanit specials is 0.01%-50%w/v, preferably 0.01%-20%w/v, most preferably 0.05%-10%w/ v。
5. the described in any item pharmaceutical compositions of claim 1-4, it is characterised in that the pH value of the composition be 2.0~ 12.0, preferable ph is 3.0~9.0.
6. pharmaceutical composition described in claim 5, it is characterised in that also contain other auxiliary materials, the auxiliary material be selected from antibacterial agent, It is antioxidant, osmotic pressure regulator, stabilizer, buffer, isotonic agent, one or more in surfactant.
7. pharmaceutical composition described in any one of claims 1-6, it is characterised in that novel vitamin D analogues are further comprised, The novel vitamin D analogues are selected from paricalcitol, Chinese mugwort ground ostelin, Alfacalcidol, cholecalciferol, calcitriol, degree bone Change alcohol, preferably paricalcitol.
8. pharmaceutical composition as claimed in claim 7, it is characterised in that the quality of the novel vitamin D analogues is 0.1 μ g-10 μ g。
9. pharmaceutical composition according to any one of claims 8, it is characterised in that cinacalcet or its officinal salt and novel vitamin D analogues Ratio be 2000:1-400000:1, preferably 10000:1-150000:1.
10. the method for preparing pharmaceutical composition described in any one of claims 1-6, it is characterised in that by cinacalcet or its can Pharmaceutical salts and the mixing of pharmaceutically acceptable auxiliary material.
11. a kind of aseptic powdery made of pharmaceutical composition described in any one of claims 1-6.
12. aseptic powdery described in claim 11, it is characterised in that also contain excipient, the excipient is selected from sucrose, sea Algae sugar, maltodextrin, dextran, mannitol, sorbierite, glycine, hydroxyethyl starch, polyethylene glycol, PVPK30, PVPK12 In one or more, preferably trehalose, sucrose, maltodextrin, mannitol, sorbierite, glycine, hydroxyethyl starch, PVPK12 In it is one or more.
13. a kind of method for preparing aseptic powdery described in claim 11, it is characterised in that a) by cinacalcet or its can medicine In the carrier with salt dissolution；B) by solution freeze-drying or spray drying or fluidized bed drying.
14. method described in claim 13, it is characterised in that further include the steps that excipient is added before it is dried.
15. purposes of the pharmaceutical composition of any of claims 1-9 in the drug of preparation treatment disease, the disease Disease is improved selected from hyperparathyroidism, hyperphosphatemia, hypercalcinemia and calcium-phosphorus product, wherein the parathyroid function is high Into can be secondary hyperparathyroidism, it is also possible to Primary hyperparathyroidism.
CN201811586112.4A 2017-12-25 2018-12-25 Cinacalcet pharmaceutical composition and its medical usage Pending CN109953979A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113069419A (en) * 2019-12-17 2021-07-06 南京恒生制药有限公司 Yiwan kasai pharmaceutical composition and preparation method thereof
WO2023236202A1 (en) * 2022-06-10 2023-12-14 Nanjing Haiwei Pharmaceutical Technologies Co., Ltd. Pharmaceutical formulations of cinacalcet, methods of administration, and uses thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008064202A2 (en) * 2006-11-20 2008-05-29 Dr. Reddy's Labortories, Ltd. Modified-release formulations of calcium receptor-active compounds
CN101437490A (en) * 2006-04-20 2009-05-20 安美基公司 Stable emulsion formulations
WO2011146583A2 (en) * 2010-05-19 2011-11-24 Elan Pharma International Limited Nanoparticulate cinacalcet formulations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101437490A (en) * 2006-04-20 2009-05-20 安美基公司 Stable emulsion formulations
WO2008064202A2 (en) * 2006-11-20 2008-05-29 Dr. Reddy's Labortories, Ltd. Modified-release formulations of calcium receptor-active compounds
WO2011146583A2 (en) * 2010-05-19 2011-11-24 Elan Pharma International Limited Nanoparticulate cinacalcet formulations

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113069419A (en) * 2019-12-17 2021-07-06 南京恒生制药有限公司 Yiwan kasai pharmaceutical composition and preparation method thereof
WO2023236202A1 (en) * 2022-06-10 2023-12-14 Nanjing Haiwei Pharmaceutical Technologies Co., Ltd. Pharmaceutical formulations of cinacalcet, methods of administration, and uses thereof

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