CN116196274A - Nanometer suspension, freeze-dried powder, preparation method and application - Google Patents

Nanometer suspension, freeze-dried powder, preparation method and application Download PDF

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Publication number
CN116196274A
CN116196274A CN202111456219.9A CN202111456219A CN116196274A CN 116196274 A CN116196274 A CN 116196274A CN 202111456219 A CN202111456219 A CN 202111456219A CN 116196274 A CN116196274 A CN 116196274A
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nifedipine
nanosuspension
stabilizer
freeze
hours
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连王权
周建宏
杨光
韩宇
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Kaihui Pharmaceutical Shanghai Co ltd
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Kaihui Pharmaceutical Shanghai 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses a nanometer suspension, freeze-dried powder, a preparation method and application thereof. The nanosuspension comprises: nifedipine effective medicine 10-200 mg/mL; a stabilizer; and (3) a solvent. In the preparation process of the nano suspension, the raw material medicine can be dissolved without using an organic solvent, and the median particle diameter D50 of the nifedipine effective medicine in the obtained suspension can be below 1000 nanometers and is uniformly distributed in the nano suspension; the appearance of the nano suspension is uniform and the stability is good; the nanometer suspension can be stably stored in an ampoule. The nifedipine nano freeze-dried powder has good stability.

Description

Nanometer suspension, freeze-dried powder, preparation method and application
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to nifedipine nano suspension, freeze-dried powder, a preparation method and application thereof.
Background
Nifedipine is a dihydropyridine calcium ion (Ca) widely applied to treatment of hypertension and coronary heart disease 2+ ) Antagonists, which primarily prevent the influx of calcium ions across the membrane into muscle cells, which in turn cause vascular smooth muscle relaxation, coronary artery dilation, increase blood flow, reduce peripheral vascular resistance, and lower blood pressure. Through years of clinical application, nifedipine has become one of the common medicines for clinically treating hypertension and angina pectoris, and the structural formula is as follows:
Figure BDA0003387777840000011
nifedipine is a nonpolar structure, is a water-insoluble drug, is classified according to a biopharmaceutical classification system, and belongs to a BCS II drug, namely a low-solubility/high-permeability drug. The medicine is orally taken, has obvious liver first pass metabolism effect after being absorbed by gastrointestinal tract, and has low bioavailability.
At present, nifedipine is mainly taken as an oral tablet in the domestic market, and the oral preparation of nifedipine has the advantages of convenient use, more prominent defects, remarkable first pass effect of the liver of the oral preparation, low bioavailability, short half-life in vivo and frequent administration. In addition, the fluctuation of the blood concentration is closely related to the blood pressure reducing effect and the incidence rate of adverse reaction, and particularly, when the common tablet is used, the fluctuation of the blood concentration is large, the blood pressure is easy to drop too fast and too low, and the stable blood concentration and the stable blood pressure reducing effect cannot be maintained for a long time.
Chinese patent document CN1047519C discloses an injection of nifedipine solution type, which consists of nifedipine, polyvinylpyrrolidone, ethanol for injection and water for injection, wherein the concentration of nifedipine is only 0.2-0.5mg/mL, and the concentration of polyvinylpyrrolidone is 0.1-0.2mg/mL.
The existing nifedipine injection has the specification of 0.5mg/mL, is used by intravenous drip, and has the defect of short drug effect in vivo after single administration due to low concentration of active ingredients in the existing injection on the market. At present, no products with the effective medicine concentration of nifedipine higher than 0.5mg/mL are found.
Disclosure of Invention
The invention aims to overcome the defects of obvious liver first pass effect, low bioavailability, short drug effect, high administration frequency and the like of the traditional nifedipine preparation, and provides nifedipine nano suspension, freeze-dried powder and a preparation method and application, wherein the nifedipine nano suspension can avoid the first pass effect, has high bioavailability, long drug effect and stable drug effect.
Since the nanosuspension is a thermodynamically unstable system, the drug nanoparticles have higher surface energy, and particle aggregation and ostwald ripening phenomena easily occur, resulting in an increase in drug particles. Without the action of a suitable stabilizer, it is difficult to prepare stable nanosuspensions, and problems of drug crystal growth or flocculation precipitation also occur easily during storage and transportation thereof, thereby leading to a change in the pharmacodynamic action of the drug in the human body. Therefore, the selection of the stabilizer and the control of its amount are critical in the preparation of nanosuspensions. There is no stabilizer suitable for all medicines in the nanometer suspension of medicines, and different stabilizer types and concentration requirements exist for different medicines, so that the optimization of proper stabilizer types and dosage is the biggest technical difficulty solved by the invention.
The invention provides the following technical scheme to solve the technical problems.
The invention provides a nifedipine nanometer suspension, which comprises the following components:
nifedipine effective medicine 10-200 mg/mL;
a stabilizer;
a solvent;
the mass ratio of the nifedipine effective drug to the stabilizer is (12-1): 1, a step of;
the stabilizer is a first stabilizer and/or a second stabilizer (the first stabilizer and the second stabilizer are only used for distinguishing and have no special meaning);
the first stabilizer is one or more of povidone K30 (PVP K30), poloxamer 407 (P407), tween 20 (TW 20), vitamin E polyethylene glycol succinate (TPGS), hypromellose E5 (HPMC E5), hypromellose E15 (HPMC E15), polyvinyl alcohol 0588 (PVA 0588), poloxamer 188 (P188), polyoxyethylene 40 hydrogenated castor oil (RH 40), polyoxyethylene 35 castor oil (RH 35), sodium Dodecyl Sulfate (SDS) and tween 80 (TW 80);
the second stabilizer comprises a component one and a component two (the component one and the component two are used for distinguishing and have no special meaning), the component one is one or more of hypromellose E5 (HPMC E5), hypromellose E15 (HPMC E15), polyvinyl alcohol 0588 (PVA 0588) and povidone K30 (PVP K30), and the component two is one or more of Sodium Dodecyl Sulfate (SDS), tween 80 (TW 80), poloxamer 188 (P188), polyoxyethylene 40 hydrogenated castor oil (RH 40) and polyoxyethylene 35 castor oil (RH 35).
In the invention, the mass ratio of the nifedipine effective drug to the stabilizer is (10-1): 1, for example 8: 1. 7: 1. 6: 1.5: 1. 4: 1. 3: 1. 2:1 or 1:1.
in the present invention, the first stabilizer is preferably one or more of povidone K30 (PVP K30), poloxamer 407 (P407), tween 20 (TW 20) and vitamin E polyethylene glycol succinate (TPGS), more preferably povidone K30 (PVP K30), poloxamer 407 (P407), tween 20 (TW 20) or vitamin E polyethylene glycol succinate (TPGS).
In the present invention, the second stabilizer is preferably one or more of hypromellose E5 (HPMC E5), hypromellose E15 (HPMC E15) and polyvinyl alcohol 0588 (PVA 0588), more preferably hypromellose E5 (HPMC E5), hypromellose E15 (HPMC E15) or polyvinyl alcohol 0588 (PVA 0588).
In the present invention, in the second stabilizer, the second component is preferably one or more of Sodium Dodecyl Sulfate (SDS), tween 80 (TW 80), poloxamer 188 (P188), polyoxyethylene 40 hydrogenated castor oil (RH 40) and polyoxyethylene 35 castor oil (RH 35), more preferably Sodium Dodecyl Sulfate (SDS), tween 80 (TW 80), poloxamer 188 (P188), polyoxyethylene 40 hydrogenated castor oil (RH 40) or polyoxyethylene 35 castor oil (RH 35).
In the present invention, when the stabilizer is a second stabilizer, the mass ratio of the first component to the second component may be (1 to 3): 1, preferably (1-2): 1, for example 1:1. 1.5:1 or 2:1.
in the present invention, the median particle diameter D50 of the nifedipine effective drug is less than 1000nm, preferably 200 to 800nm, more preferably 200 to 400nm, for example 210nm, 230nm, 250nm, 270nm, 290nm, 300nm, 330nm, 350nm, 370nm or 390nm.
In the present invention, the concentration of the nifedipine effective drug is preferably 20 to 100mg/mL, more preferably 30 to 80mg/mL, for example 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL or 70mg/mL.
In the present invention, the concentration of the stabilizer may be 2 to 100mg/mL, preferably 5 to 50mg/mL, more preferably 8 to 45mg/mL, for example 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL or 35mg/mL.
In the present invention, the solvent may be conventional in the art, preferably one or more of purified water, water for injection and physiological saline, more preferably water for injection.
In the present invention, the solvent preferably does not include an organic solvent. The organic solvent generally refers to an alcohol, ether or nitrile organic solvent, such as ethanol, diethyl ether or acetonitrile.
In the present invention, the amount of the solvent may be determined according to actual product requirements. For example, when the required nifedipine concentration is 50mg/mL, 10mL of solvent is required to be added for each 0.5g of nifedipine drug substance.
In the present invention, the nifedipine nanosuspension may preferably further comprise other functional additives than the stabilizer.
The other functional additives may include one or more of pH modifiers, bacteriostats, tonicity modifiers and lyoprotectants.
Wherein, the pH value regulator is conventional in the art, and is preferably one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, hydrochloric acid, acetic acid, sodium acetate, citric acid and sodium citrate.
The bacteriostat may be conventional in the art, and is preferably one or more of phenol, cresol, chlorocresol, benzyl alcohol and chlorobutanol.
The osmolality adjusting agent may be conventional in the art, preferably one or more of sodium chloride, glucose and glycerol.
The lyoprotectant may be conventional in the art, preferably one or more of lactose, mannitol, sucrose and glucose.
The concentration of the pH adjustor is preferably 0 to 10mg/mL, for example 2mg/mL.
The concentration of the bacteriostat is preferably 0 to 5mg/mL, for example 1mg/mL.
The concentration of the osmotic pressure regulator may be 0 to 100mg/10g nifedipine nanosuspension, preferably 1 to 90mg/10g nifedipine nanosuspension, for example 50mg/10g nifedipine nanosuspension, 55.2mg/10g nifedipine nanosuspension, 70mg/10g nifedipine nanosuspension, 80mg/10g nifedipine nanosuspension, 82.6mg/10g nifedipine nanosuspension, 85.7mg/10g nifedipine nanosuspension or 85.2mg/10g nifedipine nanosuspension.
The concentration of the lyoprotectant may be 0-100 mg/g nifedipine nanosuspension, preferably 1-90 mg/g nifedipine nanosuspension, for example 25mg/g nifedipine nanosuspension, 40mg/g nifedipine nanosuspension, 50mg/g nifedipine nanosuspension, 60mg/g nifedipine nanosuspension, 70mg/g nifedipine nanosuspension, 80mg/g nifedipine nanosuspension or 85mg/g nifedipine nanosuspension.
In the invention, the nanosuspension can be stored in a sealed ampoule.
The invention also provides a preparation method of the nifedipine nanosuspension, which comprises the following steps: grinding nifedipine premix;
the nifedipine premix comprises nifedipine bulk drugs, the stabilizer and the solvent.
According to common knowledge, the nifedipine bulk drug becomes an effective nifedipine drug in the nifedipine nano-suspension after being ground.
In the present invention, the median particle diameter D50 of the nifedipine drug substance may be 1 to 200 μm, preferably 2 to 100 μm, more preferably 45.3 to 47.9 μm.
In the invention, the mass ratio of the nifedipine bulk drug to the stabilizer is (12-1): 1, more preferably (10 to 1): 1, for example 8: 1. 7: 1. 6: 1.5: 1. 4: 1. 3: 1. 2:1 or 1:1. in the invention, the mass ratio of the nifedipine bulk drug to the stabilizer is the same as that of the nifedipine effective drug in suspension to the stabilizer.
In the present invention, the nifedipine premix may be prepared by methods conventional in the art, typically by homogenization.
Wherein the homogenizing speed is preferably 3000 to 10000rpm, for example 8000rpm.
The homogenizing time is preferably 0 to 10 minutes, for example 1 minute.
The homogenizing apparatus may be conventional in the art, preferably a high-speed homogenizer, such as the IKA company T25 digital display high-speed homogenizer.
In the present invention, the manner and conditions of the grinding may be conventional in the art. The milling equipment may be conventional in the art, preferably a wet media MILL, such as a walbao MILL RL wet ball MILL. The grinding process can be realized by synchronously starting the equipment to circulate cooling water during grinding.
Wherein the grinding speed of the grinding may be 1000 to 6000rpm, preferably 1500 to 4000rpm, more preferably 1200 to 3500rpm, for example 1200rpm or 3000rpm.
The milling time may be from 0.1 to 24 hours, preferably from 0.5 to 20 hours, for example 1, 2, 3, 4, 5, 8, 12, 16 or 18 hours.
In the present invention, the grinding generally employs grinding zirconium beads, and the size of the grinding zirconium beads may be 0.05 to 1mm, for example, 0.3mm.
The volume of the milled zirconium beads can be 1 to 80mL, such as 5mL or 50mL.
The milled zirconium beads may be fine beads within a range of particle sizes, and the amount of milled zirconium beads may be conventional in the art, typically by volume.
In the invention, when the nifedipine nano-suspension contains other functional auxiliary materials except the stabilizing agent, the nifedipine nano-suspension is preferably prepared by mixing the ground product with the other functional auxiliary materials.
The other functional auxiliary materials are as described above.
The invention also provides nifedipine nano freeze-dried powder, which comprises nifedipine effective drugs and the stabilizer.
According to common knowledge in the art, the solvent content in the nifedipine nano freeze-dried powder preparation is generally below 3%.
In the invention, the nifedipine nano freeze-dried powder preferably further comprises a freeze-drying protective agent.
The lyoprotectant may be conventional in the art, preferably one or more of lactose, mannitol, sucrose and glucose.
The dosage of the freeze-drying protective agent can be prepared according to the requirement. For example, in some preferred embodiments of the invention, lactose and mannitol are formulated as lyoprotectants at concentrations of 2.5%, 5% and 7.5%, respectively.
The dose of the lyoprotectant can be 0-100 mg/g nifedipine nanosuspension, preferably 1-90 mg/g nifedipine nanosuspension, for example 25mg/g nifedipine nanosuspension, 40mg/g nifedipine nanosuspension, 50mg/g nifedipine nanosuspension, 60mg/g nifedipine nanosuspension, 70mg/g nifedipine nanosuspension, 80mg/g nifedipine nanosuspension or 85mg/g nifedipine nanosuspension.
In the invention, the nifedipine nano freeze-dried powder can be stored in a penicillin bottle.
The invention also provides a preparation method of the nifedipine nano freeze-dried powder, which comprises the following steps: freeze-drying nifedipine nano suspension as described above.
In the present invention, the operation and conditions of the freeze-drying may be conventional in the art.
Wherein the time of freeze-drying is preferably 12 to 36 hours, for example 24 hours.
The temperature of the freeze-drying is preferably-50 to 30 ℃, for example-50 to 25 ℃.
The degree of vacuum of the freeze-drying is preferably 0 to 20Pa, for example 0 to 10Pa.
The lyophilization apparatus may be conventional in the art, such as a SCIENTZ-50F lyophilizer for new ganoderma lucidum.
The preset lyophilization procedure of the lyophilization apparatus is preferably as shown in the following table:
stage(s) Temperature (DEG C) Vacuum degree Pa Time h Stage(s) Temperature (DEG C) Vacuum degree Pa Time h
1 -50 0 6 8 0 10 3
2 -40 5 1 9 5 10 2
3 -25 10 2 10 10 10 1
4 -20 10 2 11 15 10 1
5 -15 10 1 12 20 10 1
6 -10 10 2 13 25 10 Constant temperature section
7 -5 10 2 14 / / /
。
The invention also provides nifedipine nano freeze-dried powder prepared by the preparation method of nifedipine nano freeze-dried powder.
The invention also provides an application of the nifedipine nano suspension or the nifedipine nano freeze-dried powder in preparing a medicament for treating hypertension or angina.
The invention also provides a medicine which comprises the nifedipine nano suspension and/or nifedipine nano freeze-dried powder.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
1. in the nano suspension, the median particle diameter D50 of the nifedipine effective drug can be below 1000 nanometers (for example, 200-400 nanometers) and is uniformly distributed in the nano suspension; the appearance of the nano suspension is uniform and the stability is good; the nanometer suspension can be stably stored in an ampoule.
2. The nanometer suspension prepared by the invention can be subjected to freeze drying and solidification treatment, the prepared nifedipine nanometer freeze-dried powder has good stability, and the nanometer freeze-dried powder can be stably stored in a penicillin bottle.
3. The nifedipine nanometer suspension and nifedipine nanometer freeze-dried powder prepared by the invention can avoid the problem of the first pass effect of an oral preparation, and have high bioavailability, the preparation can form a medicine reservoir at an injection position after intramuscular injection, can realize slow release after one-time administration, can enable the drug effect time to reach more than 3 days, and the specific drug effect time can be adjusted by controlling the particle size and single dose of nifedipine nanometer particles. Compared with oral preparation, the inventive composition can reduce administration frequency and improve compliance of patients.
4. The preparation method of the invention can dissolve the crude drug without using organic solvent, thereby avoiding the problem of organic solvent residue in the solvent method.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Nifedipine drug Substances (APIs) used in the following examples were purchased from Shanghai Michelin Biochemical technologies Co., ltd. (lot number: C11619822).
The particle size distribution of nifedipine drug substance was measured using a dry laser particle sizer (model: LA-960, brand: HORIBA) as shown in Table 1 below:
TABLE 1
Air (MPa) Average particle diameter (μm) D50(μm) D90(μm) D10(μm)
0.10 65.77718 47.80328 149.1711 11.9948
0.20 59.03928 45.22132 130.6400 10.7916
0.30 63.40928 46.3960 143.0300 11.4657
In examples 1 to 12, 13 to 22 and comparative examples 1 to 3, the grinding device was a small and simple wet medium grinding device, the wet medium grinding device uses a magnetic stirrer as a power device, uses a 20mL glass bottle as a grinding container, and uses the magnetic stirrer to provide power to drive the grinding zirconium beads in the grinding container so as to perform wet medium grinding on the medicine in the grinding container;
technological parameters: grinding rotation speed is 1200rpm, grinding zirconium bead size: 0.3mm, volume of milled zirconium beads: 5mL, milling time: 18-20 h.
The grinding equipment of the amplification process recipe of examples 23 to 26 adopts a walbao MILL RL wet ball MILL;
technological parameters: grinding speed 3000rpm, grinding zirconium bead size: 0.3mm, volume of milled zirconium beads: 50mL, milling time: 2-3 h.
Examples 1 to 12, comparative examples 1 to 3 (Single stabilizer prescriptions)
In examples 1 to 12 and comparative examples 1 to 3, the operations and conditions were the same except that the types of stabilizers were different. Specifically, the raw material components and the amounts thereof are shown in Table 2 (API concentration: 50mg/mL, stabilizer concentration: 10mg/mL, liquid medicine volume: 10mL, solvent selection: purified water).
TABLE 2
Figure BDA0003387777840000101
Figure BDA0003387777840000111
The preparation method of the nifedipine nanosuspension comprises the following steps:
1) Adding prescribed amounts of stabilizer and purified water to a container to dissolve the stabilizer into a uniform solution;
2) Adding a prescribed amount of nifedipine bulk drug and 5mL of 0.3mm grinding zirconium beads into the solution in the step 1);
3) And (3) adopting small and simple wet medium grinding equipment, starting medium grinding at a speed of 1200rpm, and discharging after grinding for 18 hours to prepare the nifedipine nanometer suspension.
Stability investigation: and (3) measuring the particle size distribution of the nifedipine nanosuspension prepared by different single stabilizers by adopting a wet laser particle sizer (model HORIBA/LA-960), and examining the influence of the different single stabilizers on the stability of the nifedipine nanosuspension.
Particle size distribution data are shown in table 3.
TABLE 3 Table 3
Figure BDA0003387777840000112
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Figure BDA0003387777840000121
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Figure BDA0003387777840000131
Remarks: in Table 3, "D10, D50, D90" are parameters of particle size, meaning the particle size corresponding to the cumulative particle size distribution of the sample reaching 10%, 50%, 90%, respectively;
"H" represents "hour", "d" represents "day", "W" represents "week", all representing units of time;
"/" indicates that the data was not detected.
As is clear from the data in Table 3, the nanosuspensions prepared in examples 1 to 12 were excellent in stability, wherein examples 1 to 10 were stored at room temperature for 6 weeks, the D50 particle size was not significantly increased, and the D50 particle size was maintained at 1000nm or less all the time, and examples 11 and 12 were also stable at room temperature for 1 week. The suspensions prepared in comparative examples 1 to 3 are difficult to achieve and stabilize the drug particles at the nanoscale, and effective preparation of the nanosuspension cannot be achieved.
Examples 13 to 22 (compounding of two stabilizers)
In examples 13 to 22, the operations and conditions were the same except that the types of stabilizers were different. Specifically, the raw material components and the amounts thereof are shown in Table 4 (API concentration: 50mg/mL, stabilizer concentration: 10mg/mL, liquid medicine volume: 10mL, solvent selection: purified water). The preparation process is the same as in examples 1 to 12 above.
TABLE 4 Table 4
Raw material composition Dosage (g)
Nifedipine bulk drug 0.5
Stabilizing agent 0.1
Purified water 10
Stability investigation: and (3) measuring the particle size distribution of the nifedipine nanosuspension prepared by different compound stabilizers by adopting a wet-process laser particle sizer (model HORIBA/LA-960), and examining the influence of the different compound stabilizers on the stability of the nifedipine nanosuspension.
Particle size distribution data are shown in table 5.
TABLE 5
Figure BDA0003387777840000141
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Figure BDA0003387777840000151
/>
Figure BDA0003387777840000161
Remarks: in Table 5, "D10, D50, D90", "H", "D", "W", "/" represent the same meanings as in Table 3.
As can be seen from the data in Table 5, the particle sizes of the nanosuspensions prepared by all the formulations of the compound stabilizers are not changed significantly within 4 weeks, and the stability is good.
Examples 23 to 26 (Single stabilizer formulation amplification Process)
In examples 23 to 26, the raw material components and the amounts thereof were as shown in Table 6 (API concentration: 50mg/mL, stabilizer concentration: 10mg/mL, drug solution volume: 150mL, solvent selection: purified water).
TABLE 6
Figure BDA0003387777840000162
The preparation method of the nifedipine nanosuspension comprises the following steps:
1) Adding a prescribed amount of nifedipine bulk drug and a stabilizer into prescribed amount of purified water, and homogenizing by using a T25 digital display high-speed homogenizer of IKA company (homogenizing rotation speed 8000rpm, homogenizing time 1 min) to obtain nifedipine premix;
2) Adding the premix in the step 1) into a hopper of a wet medium grinding machine, simultaneously starting circulating cooling water of equipment, circularly grinding for 0.5-5 h, and discharging;
3) Adding NaCl into the liquid medicine obtained in the step 2), and stirring and mixing to obtain the nifedipine nanometer suspension.
The osmotic pressure of the product obtained in step 2) (i.e., the osmotic pressure of the nifedipine nanosuspension without NaCl was named as initial osmotic pressure), the osmotic pressure of the product obtained in step 3) (the osmotic pressure of the nifedipine nanosuspension after NaCl addition was named as post-adjustment osmotic pressure) and the pH data of the products obtained in examples 23 to 26 are shown in Table 7.
TABLE 7
Figure BDA0003387777840000171
As can be seen from the data in Table 7, by adding a proper amount of osmotic pressure regulator, the osmotic pressure of the nano-suspension is obviously improved, and the isotonic requirement of 140-830 mOsmol/kg of injection can be met. And the materials used in examples 23 to 26 are all neutral (the pH value of the prepared nano suspension is 6.4), so that the general requirement that the pH value of the injection is 4 to 9 is met, and the pH adjustment can be carried out without adding a pH value regulator.
Stability investigation: the particle size distribution of the nifedipine nanosuspension obtained in the steps 2) and 3) in examples 23 to 26 is respectively measured by a wet laser particle sizer (model HORIBA/LA-960), and the influence of an osmotic pressure regulator (NaCl) on the stability of the nifedipine nanosuspension is examined.
Particle size distribution data are shown in table 8.
TABLE 8
Figure BDA0003387777840000181
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Figure BDA0003387777840000191
Remarks: in Table 8, "D10, D50, D90", "D", "W", and "/" have the same meanings as those in Table 3.
The data in table 8 shows that the addition of osmolality adjusting agent in the formulation has no significant effect on the stability of the nanosuspension.
Examples 27 to 52 freeze drying and curing treatment
Freeze drying and solidifying operation:
different types and amounts of freeze-drying protective agents or no freeze-drying protective agent are respectively added into the nifedipine nanosuspension obtained in the step 2) of the examples 23-26 (the addition or not of the freeze-drying protective agent, the addition types, the concentration and the use amount are shown in the table 9), and the nifedipine nanosuspension is prepared by stirring and uniformly mixing, and the nifedipine nanosuspension powder (namely the products of the examples 27-52) is obtained after 24 hours of freeze-drying.
Wherein the products of examples 27 to 31 are prepared from the nifedipine nanosuspension obtained in step 2) of example 23, the products of examples 32 to 38 are prepared from the nifedipine nanosuspension obtained in step 2) of example 24, the products of examples 39 to 45 are prepared from the nifedipine nanosuspension obtained in step 2) of example 25, and the products of examples 46 to 52 are prepared from the nifedipine nanosuspension obtained in step 2) of example 26.
TABLE 9
Figure BDA0003387777840000201
Remarks: in table 9, "2.5%, 5%, 7.5%" each refer to the concentration of lyoprotectant (lactose, mannitol), and "/" represents no such example or no such data (i.e., no such experiment was performed).
Lyophilization was performed using a fresh glossy ganoderma SCIENTZ-50F lyophilizer preset lyophilization program, as shown in table 10 below:
table 10
Stage(s) Temperature (DEG C) Vacuum degree Pa Time h Stage(s) Temperature (DEG C) Vacuum degree Pa Time h
1 -50 0 6 8 0 10 3
2 -40 5 1 9 5 10 2
3 -25 10 2 10 10 10 1
4 -20 10 2 11 15 10 1
5 -15 10 1 12 20 10 1
6 -10 10 2 13 25 10 Constant temperature section
7 -5 10 2 14 / / /
Remarks: in table 10 "/" indicates that this section of program setting is not performed.
The osmotic pressure (mOsmol/kg) of the nifedipine nano-freeze-dried powder prepared in examples 27 to 52 is shown in Table 11 below.
TABLE 11
Figure BDA0003387777840000211
Figure BDA0003387777840000221
Remarks: in Table 11 "/" means the same as Table 9.
As can be seen from the data in Table 11, the nifedipine nano freeze-dried powder prepared in the invention can meet the isoosmotic requirement of 140-830 mOsmol/kg of intramuscular injection.
Examples 53 to 78 lyophilized powder reconstitution
And (3) re-dissolving operation: the formulation group without adding the lyoprotectant (i.e. the lyophilized powder prepared in examples 27, 32, 39 and 46) was reconstituted with physiological saline, and the dispersion of the drug particles was accelerated by vortexing for 5min and sonicating for 15min with a vortexing instrument, to obtain reconstituted products of examples 53, 58, 65 and 72.
The other prescription group (namely, the freeze-dried powder prepared by the above examples 28-31, 33-38, 40-45 and 47-52) added with different proportions and types of freeze-drying protective agents is subjected to re-dissolution treatment by purified water according to the proportion of the liquid medicine before solidification (in 150ml of nifedipine nanosuspension, partial nanosuspension is packaged for preparing the freeze-dried powder, under different examples, different types and different doses of protective agents are added to prepare nifedipine nanosuspension with different protective agent concentrations, and then the nifedipine nanosuspension is packaged into a penicillin bottle for freeze-drying solidification, so that the required purified water for re-dissolution is calculated according to the solid content added to the purified water to restore the concentration before freeze-drying, the specific freeze-dried powder and the addition amount of the water are shown in the following table 12), and the re-dissolved products of examples 54-57, 59-64, 66-71 and 73-78 are obtained by vortex for 5min and ultrasonic 15min acceleration of drug particle dispersion.
Wherein the products of examples 54 to 57 are prepared by re-dissolving the nifedipine nano-freeze-dried powder obtained in examples 28 to 31, the products of examples 59 to 64 are prepared by re-dissolving the nifedipine nano-freeze-dried powder obtained in examples 33 to 38, the products of examples 66 to 71 are prepared by re-dissolving the nifedipine nano-freeze-dried powder obtained in examples 40 to 45, and the products of examples 73 to 78 are prepared by re-dissolving the nifedipine nano-freeze-dried powder obtained in examples 47 to 52.
Table 12
Example 53 Example 58 Example 65 Example 72
Adding the freeze-dried powder (g) 0.17 0.12 0.17 0.17
Adding physiological saline (g) 2.83 1.88 2.83 2.83
Example 54 Example 59 Example 66 Example 73
Adding the freeze-dried powder (g) 0.24 0.17 0.24 0.24
Adding purified water (g) 2.76 1.83 2.76 2.77
Example 55 Example 60 Example 67 Example 74
Adding the freeze-dried powder (g) 0.3 0.21 0.3 0.3
Adding purified water (g) 2.70 1.79 2.69 2.72
/ Example 61 Example 68 Example 75
Adding the freeze-dried powder (g) / 0.24 0.38 0.38
Adding purified water (g) / 1.76 2.62 2.63
Example 56 Example 62 Example 69 Example 76
Adding the freeze-dried powder (g) 0.24 0.17 0.24 0.24
Adding purified water (g) 2.76 1.83 2.79 2.76
Example 57 Example 63 Example 70 Example 77
Adding the freeze-dried powder (g) 0.3 0.21 0.3 0.3
Adding purified water (g) 2.70 1.78 2.69 2.68
/ Example 64 Example 71 Example 78
Adding the freeze-dried powder (g) / 0.25 0.38 0.38
Adding purified water (g) / 1.74 2.61 2.63
Remarks: in table 12 "/" means the same as in table 9.
Stability investigation: the particle size distribution of the freeze-dried powders prepared in examples 73 to 75 above after reconstitution was measured by a wet laser particle sizer (model HORIBA/LA-960). The particle size distribution is shown in table 13 below.
TABLE 13
Particle size μm Example 73 Example 74 Example 75
D10 0.158 0.163 0.166
D50 0.288 0.308 0.320
D90 0.677 0.757 0.944
As can be seen from the data in Table 13, mannitol with concentrations of 2.5%, 5% and 7.5% was added to P407 as a lyoprotectant, and the D50 was below 1000nm after reconstitution of the obtained lyophilized powder. Therefore, the nifedipine nano freeze-dried powder prepared by taking poloxamer 407 as a stabilizer and mannitol as a freeze-drying protective agent can be stably re-dissolved into nifedipine nano suspension.
Comparative examples 4 to 7 suction filtration solidification and re-dissolution treatment
And (3) carrying out suction filtration and solidification operation: and (3) respectively taking the nifedipine nano suspension prepared in the step (2) of the examples 23-26), carrying out suction filtration treatment by using a circulating water vacuum pump and a 0.45 micrometer water-based filter membrane, and drying a filter cake after suction filtration in a blast drying oven at 30 ℃ for 16 hours to obtain a nifedipine product (namely the products of comparative examples 4-7) after suction filtration and solidification.
And (3) re-dissolving operation: the suction filtration solidification study was performed using only a small amount of nifedipine nanosuspension prepared in step 2) of examples 23 to 26. (the dosage of the suction-filtered nano suspension does not affect the quality of a filter cake sample obtained by curing and drying, and only a part of the filter cake obtained by curing and drying is taken for re-dissolution test).
Specifically, the above-mentioned nifedipine products after suction filtration and solidification (i.e., the products of comparative examples 4 to 7) were subjected to a re-dissolution treatment with purified water in accordance with the liquid medicine ratio before solidification (the filter cake after weighing a part and drying was re-dissolved by adding purified water in accordance with the prescription ratio, the specific amounts are shown in table 14 below), and the dispersion of the drug particles was accelerated by vortexing for 5min and ultrasonic for 15min with a vortex meter, and the result showed that the filter cake was not dissolved, i.e., could not be re-dissolved to a suspension state after vortexing and ultrasonic, and therefore, it was not necessary to perform particle size measurement either, and therefore, the suction filtration was not suitable for solidification mode.
TABLE 14
Weight of filter cake (g) Adding purified water (g)
Comparative example 4 0.5 10.0
Comparative example 5 0.4 8.0
Comparative example 6 0.3 6.0
Comparative example 7 0.2 4.0

Claims (10)

1. Nifedipine nanosuspension is characterized in that the nifedipine nanosuspension comprises:
nifedipine effective medicine 10-200 mg/mL;
a stabilizer;
a solvent;
the mass ratio of the nifedipine effective drug to the stabilizer is (12-1): 1, a step of;
the stabilizer is a first stabilizer and/or a second stabilizer;
the first stabilizer is one or more of povidone K30, poloxamer 407, tween 20, vitamin E polyethylene glycol succinate, hypromellose E5, hypromellose E15, polyvinyl alcohol 0588, poloxamer 188, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, sodium dodecyl sulfate and tween 80;
the second stabilizer comprises a component one and a component two, wherein the component one is one or more of hypromellose E5, hypromellose E15, polyvinyl alcohol 0588 and povidone K30, and the component two is one or more of sodium dodecyl sulfate, tween 80, poloxamer 188, polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 35 castor oil.
2. The nifedipine nanosuspension according to claim 1,
the mass ratio of the nifedipine effective drug to the stabilizer is (10-1): 1, for example 8: 1. 7: 1. 6: 1.5: 1. 4: 1. 3: 1. 2:1 or 1:1, a step of;
and/or the first stabilizer is one or more of povidone K30, poloxamer 407, tween 20 and vitamin E polyethylene glycol succinate, preferably povidone K30, poloxamer 407, tween 20 or vitamin E polyethylene glycol succinate;
and/or, in the second stabilizer, the component one is one or more of hypromellose E5, hypromellose E15, and polyvinyl alcohol 0588, preferably hypromellose E5, hypromellose E15, or polyvinyl alcohol 0588;
and/or, in the second stabilizer, the component II is one or more of sodium dodecyl sulfate, tween 80, poloxamer 188, polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 35 castor oil, preferably sodium dodecyl sulfate, tween 80, poloxamer 188, polyoxyethylene 40 hydrogenated castor oil or polyoxyethylene 35 castor oil;
when the stabilizer is a second stabilizer, the mass ratio of the first component to the second component is (1-3): 1, preferably (1-2): 1, for example 1:1. 1.5:1 or 2:1, a step of;
and/or the median particle diameter D50 of the nifedipine effective drug is < 1000nm, preferably 200 to 800nm, more preferably 200 to 400nm, for example 210nm, 230nm, 250nm, 270nm, 290nm, 300nm, 330nm, 350nm, 370nm or 390nm;
and/or the concentration of the nifedipine effective drug is 20-100 mg/mL, preferably 30-80 mg/mL, for example 30mg/mL, 40mg/mL, 50mg/mL, 60mg/mL or 70mg/mL;
and/or the concentration of the stabilizer is 2 to 100mg/mL, preferably 5 to 50mg/mL, more preferably 8 to 45mg/mL, for example 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL or 35mg/mL;
and/or the solvent is one or more of purified water, water for injection and physiological saline;
and/or, the solvent does not include an organic solvent;
the nifedipine nanosuspension preferably also comprises other functional additives besides the stabilizing agent.
3. The nifedipine nanosuspension according to claim 2, wherein said other functional additives comprise one or more of pH modifiers, bacteriostats, tonicity modifiers and lyoprotectants;
wherein the osmolality adjusting agent is preferably one or more of sodium chloride, glucose and glycerol;
the lyoprotectant is preferably one or more of lactose, mannitol, sucrose and glucose;
the concentration of the osmotic pressure regulator is preferably 0-100 mg/10g of nifedipine nanosuspension, more preferably 1-90 mg/10g of nifedipine nanosuspension, for example 50mg/10g of nifedipine nanosuspension, 55.2mg/10g of nifedipine nanosuspension, 70mg/10g of nifedipine nanosuspension, 80mg/10g of nifedipine nanosuspension, 82.6mg/10g of nifedipine nanosuspension, 85.7mg/10g of nifedipine nanosuspension or 85.2mg/10g of nifedipine nanosuspension;
the concentration of the lyoprotectant is preferably 0-100 mg/g nifedipine nanosuspension, more preferably 1-90 mg/g nifedipine nanosuspension, for example 25mg/g nifedipine nanosuspension, 40mg/g nifedipine nanosuspension, 50mg/g nifedipine nanosuspension, 60mg/g nifedipine nanosuspension, 70mg/g nifedipine nanosuspension, 80mg/g nifedipine nanosuspension or 85mg/g nifedipine nanosuspension.
4. A process for the preparation of nifedipine nanosuspensions according to any one of claims 1 to 3, comprising the steps of: grinding nifedipine premix;
the nifedipine premix comprises nifedipine bulk drugs, the stabilizer and the solvent.
5. The method for preparing nifedipine nanosuspension according to claim 4,
the median particle diameter D50 of the nifedipine bulk drug is 1-200 mu m, preferably 2-100 mu m, more preferably 45.3-47.9 mu m;
and/or, the nifedipine premix is prepared by homogenizing;
wherein the rotational speed of the homogenisation is preferably in the range 3000 to 10000rpm, for example 8000rpm;
the homogenizing time is preferably 0 to 10 minutes, for example 1 minute;
and/or the grinding speed of the grinding is 1000 to 6000rpm, preferably 1500 to 4000rpm, more preferably 1200 to 3500rpm, for example 1200rpm or 3000rpm;
and/or the milling time is 0.1 to 24 hours, preferably 0.5 to 20 hours, for example 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 8 hours, 12 hours, 16 hours or 18 hours;
and/or when the nifedipine nano-suspension contains other functional auxiliary materials except the stabilizing agent, mixing the ground product with the other functional auxiliary materials to prepare the nifedipine nano-suspension.
6. Nifedipine nano freeze-dried powder, which is characterized by comprising the nifedipine effective drug according to any one of claims 1 to 3 and the stabilizer;
the nifedipine nano freeze-dried powder preferably further comprises a freeze-drying protective agent;
wherein the lyoprotectant is preferably one or more of lactose, mannitol, sucrose and glucose;
the dose of the lyoprotectant is preferably 0-100 mg/g of the nifedipine nanosuspension, more preferably 1-90 mg/g of nifedipine nanosuspension, for example 25mg/g of nifedipine nanosuspension, 40mg/g of nifedipine nanosuspension, 50mg/g of nifedipine nanosuspension, 60mg/g of nifedipine nanosuspension, 70mg/g of nifedipine nanosuspension, 80mg/g of nifedipine nanosuspension or 85mg/g of nifedipine nanosuspension.
7. The preparation method of nifedipine nano freeze-dried powder is characterized by comprising the following steps of: freeze-drying the nifedipine nanosuspension according to any one of claims 1 to 3;
wherein the time of freeze drying is preferably 12 to 36 hours, for example 24 hours;
the temperature of the freeze drying is preferably-50 to 30 ℃, for example-50 to 25 ℃;
the degree of vacuum of the freeze-drying is preferably 0 to 20Pa, for example 0 to 10Pa.
8. The nifedipine nano freeze-dried powder prepared by the preparation method of the nifedipine nano freeze-dried powder according to claim 7.
9. Use of a nifedipine nanosuspension according to any one of claims 1 to 3 or a nifedipine nanosuspension powder according to claim 6 or 8 in the manufacture of a medicament for the treatment of hypertension or angina.
10. A medicament comprising the nifedipine nanosuspension according to any one of claims 1 to 3 and/or the nifedipine nanosuspension powder according to claim 6 or 8.
CN202111456219.9A 2021-12-01 2021-12-01 Nanometer suspension, freeze-dried powder, preparation method and application Pending CN116196274A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113616592A (en) * 2021-09-10 2021-11-09 宁夏医科大学 Dihydropyridine drug nanosuspension and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113616592A (en) * 2021-09-10 2021-11-09 宁夏医科大学 Dihydropyridine drug nanosuspension and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
POOJA J PATEL等: "A Quality-by-Design study to develop Nifedipine nanosuspension: Examining the relative impact of formulation variables, wet media milling process parameters, and excipient variability on drug product quality attributes", 《DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY》, vol. 44, no. 12, pages 1942 - 1952 *

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