CN116350592A - Setitol nanocrystalline and preparation method and application thereof - Google Patents

Setitol nanocrystalline and preparation method and application thereof Download PDF

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CN116350592A
CN116350592A CN202310288406.3A CN202310288406A CN116350592A CN 116350592 A CN116350592 A CN 116350592A CN 202310288406 A CN202310288406 A CN 202310288406A CN 116350592 A CN116350592 A CN 116350592A
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alcohol
settop
nanocrystalline
stabilizer
freeze
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葛月宾
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South Central Minzu University
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South Central University for Nationalities
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K47/26—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
    • A61K47/36—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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 provides a setitoyl alcohol nanocrystalline and a preparation method and application thereof. The prepared settop alcohol nanocrystalline can be rapidly dissolved in an aqueous medium, the in-vivo bioavailability is obviously improved, and the prepared settop alcohol nanocrystalline has small particle size, narrow distribution, good stability, small stabilizer dosage, safety and effectiveness, is 4.04 times higher than the blood concentration of a commercial dry suspension, can relatively reduce daily dose, and ensures patient compliance through pretreatment of low-speed shearing and homogenization of low pressure; in addition, the solidification is carried out through freeze drying, so that the settop alcohol nanocrystalline is more stable, the storage and the transportation are facilitated, and the obtained nanocrystalline freeze-dried powder is fast in redissolution and can keep the original particle size and dispersibility; the preparation method provided by the invention has the advantages of simple process and controllable process, and is easy for process amplification and industrial production.

Description

Setitol nanocrystalline and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a setitoyl alcohol nanocrystal and a preparation method and application thereof.
Background
The Staventol (STP) is a poorly water-soluble drug (solubility is about 49.2 mug/mL), is used for treating severe myoclonus epilepsy of infants with Dravet syndrome, is currently marketed in foreign countries in the form of capsules and dry suspensions (250 mg,500mg of two specifications), is administered 2-3 times per day, and the recommended maximum total dose is 3000 mg/day, and the blood concentration reaches the peak value (4-22 mug/mL) 2-3 hours after a single administration, and is generally required to be taken along with meals to achieve the optimal effect. The Stave (STP) belongs to BCSII medicines with low water solubility and high permeability, is slowly and incompletely dissolved in the gastrointestinal tract, has poor stability in an acidic environment, has higher daily oral dosage due to the limitation of oral absorption, and severely limits further clinical application, so that a preparation technology is needed to increase the solubility and improve the dissolution rate, promote the absorption of the stave in vivo, and is prepared into the stave preparation with quick dissolution, high bioavailability and good stability.
The currently used nano-crystallization preparation methods can be classified into a "Bottom-up" method and a "Top-down" method. The Bottom-up method refers to a preparation method in which nanocrystals are built from a molecular form of a drug; the top-down method refers to that nano crystals are crushed from larger particles to obtain nano basic drug particles. The preparation of the Bottom-up method comprises solvent evaporation method, precipitation method, spray drying method, supercritical antisolvent method, freeze drying method, etc. The Top-down method is based on mechanical pulverization, and comprises a ball milling method, a high-pressure homogenizing method, a micro-jet high-pressure homogenizing method and the like.
To date, no nanoscale settop alcohol preparation is marketed at home and abroad. Therefore, the novel preparation of the settop alcohol, which is safe and effective and convenient to use, is designed to have important clinical value.
Disclosure of Invention
The invention aims at providing a setitoyl alcohol nanocrystalline as well as a preparation method and application thereof, aiming at the defects in the prior art.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the first object of the invention is to provide a settop alcohol nanocrystalline which comprises, by mass, 20-50 parts of settop alcohol, 3-10 parts of a first stabilizer, 20-40 parts of a second stabilizer and 1-10 parts of a lyoprotectant, wherein the first stabilizer comprises one or more of a surfactant and a polymer; the second stabilizer is cellulose; the freeze-drying protective agent is any one of sucrose, lactose, glucose and mannose.
Further, the surfactant is selected from any one of sodium dodecyl sulfate, cetyltrimethylammonium bromide, poloxamer, tyloxapol, carbomer 974P, lecithin and tween; the polymer is selected from any one of hypromellose, povidone, polyvinylpyrrolidone, polyvinyl alcohol and acacia.
Further, the cellulose is any one of methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, cellulose acetate, hydroxypropylmethyl cellulose and microcrystalline cellulose.
Further, the particle size of the settop alcohol nanocrystalline is 100 nm-500 nm.
The second object of the invention is to provide a preparation method of the settop alcohol nanocrystalline, which comprises the following specific steps:
step S1, preparation of setiton alcohol nanometer coarse suspension
Metering a first stabilizer and a second stabilizer, and dissolving the first stabilizer and the second stabilizer in water by ultrasonic to obtain a water phase; taking the bulk drug of the settop alcohol according to the metering, and dissolving the bulk drug in an organic solvent to obtain an organic phase; at a certain stirring speed and temperature, injecting an organic phase into a water phase at a preset speed according to a preset proportion, and uniformly stirring to obtain a settop alcohol nanometer crude suspension; the mass concentration of the first stabilizer in the water phase is 0.03 mg/mL-0.1 mg/mL, and the mass concentration of the second stabilizer is 0.2 mg/mL-0.4 mg/mL; the mass concentration of the stave in the organic phase is 2.5 mg/mL-12.5 mg/mL;
step S2, preparation of setiton alcohol nanocrystalline
And adding a freeze-drying protective agent into the settop alcohol nano crude suspension, homogenizing under high pressure, and freeze-drying and solidifying to obtain powdery settop alcohol nano crystals.
Further, the organic solvent is one or more of methanol, ethanol, acetone, isopropanol, acetonitrile, DMSO, DMF and ethyl acetate.
In step S1, the ultrasonic dissolution power of the stabilizer is 200-450 w, the volume ratio of the water phase to the organic phase is 100 (4-8), the injection speed of the organic phase is 2-10 mL/min, the stirring speed is 200-1000 r/min, and the temperature is 0-50 ℃.
In step S2, the power of high-pressure homogenization is 800bar to 1200bar, and the number of homogenization cycles of high-pressure homogenization is 6 to 30 weeks.
In step S2, the pre-freezing temperature of freeze drying is-20-80 ℃ and the pre-freezing time is 6-24 hours.
The third purpose of the invention is to provide an antiepileptic pharmaceutical composition which is prepared by adopting the settop alcohol nanocrystalline.
Antiepileptic drugs refer to compositions comprising settop alcohol nanocrystals and at least one pharmaceutically and pharmacologically compatible component selected from the group consisting of: fillers, solvents, diluents, carriers, excipients, distribution and reception agents, delivery agents such as preservatives, stabilizers, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, thickening agents, sweeteners, flavoring agents, fragrances, antibacterial agents, fungicides, lubricants and prolonged delivery control agents, the choice and ratio of which depend on the nature and route of administration and the dosage. Examples of suitable suspending agents are ethoxylated isostearyl alcohols, polyoxyethylene, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid, and the like can be used to provide protection against microorganisms. Antiepileptic drugs may also include isotonic agents, for example, sugars, sodium chloride, and the like. The sustained action of the composition can be achieved using agents that slow the absorption of the active ingredient, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery agents include water, ethanol, polyols and mixtures thereof, natural oils (such as olive oil) and organic esters for injection (such as ethyl oleate). Examples of fillers are lactose, milk candy, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of disintegrants and partitioning agents are starch, alginic acid and salts and silicates thereof. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc and high molecular weight polyethylene glycols. Pharmaceutical compositions for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous and topical or rectal administration of an active ingredient, alone or in combination with another active compound, can be administered to animals and humans in standard administration forms as a mixture with conventional pharmaceutical carriers. Suitable standard administration forms include oral forms such as tablets, capsules, pills, powders, granules, chewing gums and oral solutions or suspensions; sublingual and buccal administration forms; an aerosol; an implant; topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, or intraocular forms; and rectal administration forms.
Compared with the prior art, the technical scheme provided by the invention has the beneficial effects that:
(1) The prepared settop alcohol nanocrystals can be rapidly dissolved in an aqueous medium, the in-vivo bioavailability is obviously improved, and through the pretreatment of low-speed shearing and the homogenization of low pressure, the prepared settop alcohol nanocrystals are small in particle size, narrow in distribution, good in stability, small in stabilizer consumption, safe and effective, and the area under the curve is increased by 4.04 times compared with the area under the medicine time curve of a commercial dry suspension, so that the daily dose is relatively reduced, and the patient compliance is ensured; in addition, the solidification is carried out through freeze drying, so that the settop alcohol nanocrystalline is more stable, the storage and the transportation are facilitated, and the obtained nanocrystalline freeze-dried powder is fast in redissolution and can keep the original particle size and dispersibility;
(2) The preparation method provided by the invention has the advantages of simple process and controllable process, and is easy for process amplification and industrial production.
Drawings
FIG. 1 is a PXRD pattern of the settop alcohol nanocrystals prepared in example 1;
fig. 2 is an in vitro dissolution graph of the stave nanocrystals, the stave physical mixture, and the stave bulk drug prepared in example 1 in water.
Detailed Description
No particular technique or condition is identified in the present invention, which is performed according to techniques or conditions described in the literature in this field or according to the product specifications. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The reagent information used in this implementation is as follows:
sodium dodecyl sulfate, abbreviated as SDS, CAS number: 151-21-3; cetyl trimethylammonium bromide, abbreviated as CTAB, CAS number: 57-09-0; poloxamer 188, abbreviated as F68, CAS number: 9003-11-6; poloxamer 407, abbreviated as F127, CAS number: 9003-11-6; carbomer 974p, cas number: 9003-01-4; hypromellose, abbreviated HMPC, CAS number: 9004-65-3; povidone, abbreviated PVP, CAS number: 9003-39-8; polyvinylpyrrolidone, abbreviated PVP K30, CAS number: 9003-39-8; tyloxapol, CAS number: 25301-02-4; methylcellulose, abbreviated as MC, CAS number: 9004-67-5; carboxymethyl cellulose, abbreviated CMC, CAS number: 9004-32-4; ethylcellulose, abbreviated EC, CAS number: 9004-57-3; hydroxyethyl cellulose, abbreviated HEC, CAS number: 9004-62-0; hydroxypropyl cellulose, abbreviated as HPC, CAS number: 9004-64-2; cellulose acetate, abbreviated CA, CAs number: 9004-35-7; microcrystalline cellulose, abbreviated as MCC, CAS number: 9004-34-6.
The first stabilizer and the second stabilizer used in the invention are of the grade of pharmaceutical excipients.
A commercially available dry suspension of settop alcohol was purchased from Biocodex.
The performance characterization method for the settop alcohol nanosuspension and the nanomicelle is as follows:
1) Determination of Size, PDI and Zeta
After STP nanocrystalline powder was suspended with water using a malvern laser particle sizer, particle Size (Size), dispersion coefficient (PDI) and Zeta potential values were measured. Experimental conditions: the solute is STP, the refractive index is 1.578, the solvent is water, the refractive index is 1.330, the temperature is 25 ℃, the balancing time is 60s, the parallel measurement is carried out for 3 times, and the average value is obtained.
2) X-ray diffraction method (PXRD)
And uniformly spreading STP nanocrystalline powder, auxiliary materials and powder of a physical mixture in a sample groove respectively, pressing the surface with a glass slide, fixing a sample frame on PXRD, and testing. Measurement conditions: the anode target is a Cu-K alpha target, the tube voltage is 40kV, the tube current is 40mA, the scanning speed is 0.1s/step, the scanning step length is 0.02 DEG for each step, and the scanning range is 4-50 DEG (2 theta).
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the specific embodiments of the present invention will be given with reference to the accompanying drawings.
STP: stave.
PM: the physical mixture of the settop alcohol is that the settop alcohol is mixed with the first stabilizer, the second stabilizer and the freeze-drying protective agent according to a certain proportion.
The instrumentation involved in the examples is described below: freeze dryer (FreeZone) Labconco, high pressure homogenizer (AH-NANO) ATS Industrial systems, inc.
The invention uses an antisolvent method and a high-pressure homogenization method to prepare the settop alcohol nanocrystalline suspension, adopts freeze-drying and solidification of the settop alcohol nanocrystalline suspension to prepare the settop alcohol nanocrystalline, and uses the average particle size of micelle and PDI as evaluation indexes.
Example 1
Preparation of settop amyl alcohol nanocrystalline
3 parts of a first stabilizer HPMC, 20 parts of a second stabilizer HPC and 3 parts of a freeze-drying protective agent sucrose are weighed and added into 100mL of pure water, the pure water is placed on a magnetic stirrer and stirred at 200rpm until the pure water is completely dissolved, the pure water and the second stabilizer HPC are respectively dissolved in water under the condition of 250w of ultrasonic power to obtain water phases, 20 parts of STP bulk drug are weighed and dissolved in 8mL of isopropanol, the organic phase is injected into the water phases at the speed of 6mL/min under the condition of 1000r/min of stirring speed and 0 ℃ according to the volume ratio of the organic phase to the water phases of 4:100, crude suspension is obtained, the crude suspension is added into a high-pressure homogenizer (HPH), the high-pressure homogenizing power of the high-pressure homogenizer is 1000bar, the high-pressure homogenizing cycle is carried out for 6 weeks, the settop pentanol nanocrystalline suspension is obtained, the settop pentanol nanocrystalline suspension is placed at room temperature for 24h, pre-frozen for 6h at-80 ℃, and the powdery settop pentanol nanocrystalline is obtained after freeze drying. The particle size of the prepared settop alcohol nanocrystalline is 466.5nm, and the PDI is 0.275.
Characterization results of the settop alcohol nanocrystalline prepared in example 1 are as follows:
as shown in figure 1, STP bulk drug and drug auxiliary physical mixture have diffraction peaks with the same positions and the corresponding numbers, the diffraction peak intensity of STP nanocrystals is weaker, but the positions of the peaks are consistent, which shows that the drug in the nanocrystals appears in a crystalline form, but the intensity of partial diffraction peak of the drug is weakened due to HPMC loading, and the particle size of the drug is also proved to be reduced.
In order to better explore the bioavailability characteristics of the setteamyl alcohol nanocrystalline, in-vitro dissolution investigation and bioavailability evaluation are carried out, and the specific contents are as follows:
(1) In vitro dissolution investigation
The dissolution curve of STP nanocrystals was determined using the cuvette method. Measurement conditions: the dissolution medium is water, the volume of the dissolution medium is 250mL, the revolution is 100rpm/min, and the temperature is 37.0 ℃. STP, physical mixture, and 3 parts of STP nanocrystalline powder samples (corresponding to STP 10 mg) were weighed separately, precisely weighed, and simultaneously put into a dissolution cup. Starting timing when the crude drug contacts the dissolution medium, sampling at 2, 5, 10, 20, 30, 45, 60, 90, 120, 240, 480 and 720min respectively, extracting 5mL each time and timely supplementing 5mL of the dissolution medium, filtering with a 0.45 μm pore-size filter membrane, taking filtrate as a sample, and measuring absorbance at 270nm wavelength by ultraviolet spectrophotometry.
The preparation process of the STP physical mixture comprises the following steps: taking 20 parts of the stave bulk drug, 3 parts of HPMC, 20 parts of HPC and 3 parts of sucrose, and uniformly mixing.
As shown in figure 2, STP is taken as a poorly soluble drug, dissolution is slower, the dissolution curve is obviously accelerated after the nano crystals are prepared, the accumulated dissolution rate is taken as an investigation index, the nano crystals are 32min, the drug auxiliary physical mixture is about 90min, and the raw material drug is about 190min, so that the dissolution behavior of the stave nano crystals in water is shown to be quick dissolution, and the dissolution rate of the stave nano crystals is obviously higher than Yu Si, namely the physical mixture of the stave raw material and the stave.
(2) Bioavailability of the active ingredients
(2.1) dosing regimen and blood sample treatment
The STP nanocrystalline powder is weighed approximately in proper quantity, precisely weighed, and suspension with the concentration of 100mg/mL is prepared by taking 0.5% sodium carboxymethyl cellulose as a dispersion solvent. Adult Wistar rats (body weight 200±10 g) were fed adaptively for one week, fasted for 12h prior to dosing, and the second day was given 0.2mL of STP nanocrystalline suspension by tail vein injection (STP dose 100 mg/kg). After administration, 0.5mL of whole blood was collected from the orbital venous plexus under anesthesia at 0.5,1,1.5,2,3,4,6,8, 10, 12h, and heparin (50 units/mL) was anticoagulated. Immediately centrifuging at 3000r/min for 5min, separating plasma, and preserving at-20deg.C for extraction.
Taking 0.5ml of plasma sample, adding 1.5ml of organic solvent, centrifuging for 10min under the conditions of vortex for 5min and 3000r/min, sucking out the organic solvent, drying under nitrogen, and repeatedly adding solvent for extraction for 3 times. Drying the mixture, adding 0.1ml of solvent for dissolution, centrifuging, absorbing supernatant, and carrying out HPLC sample injection analysis.
(2.2) HPLC chromatography
The STP concentration of the plasma samples was determined by HPLC. Chromatographic column: kromasil C18 column (10 nm-5 μm,4.6 mm. Times.250 mm) (Hanbon Science Technology Co., ltd.) mobile phase: methanol-acetonitrile-1% acetic acid solution (50:10:40), detection wavelength: 270nm, flow rate: 0.8mL/min, column temperature: room temperature, sample injection amount: 20. Mu.L. The internal standard is xanthone. Under this condition, the chromatographic peak separation diagram is shown in the following figure. As can be seen, the retention times of STP and the internal standard xanthone were 12.115min and 9.138min, respectively, with blank plasma samples not interfering with the assay.
The result shows that the STP nanocrystalline freeze-dried powder administered to the gastrointestinal tract of the rat has higher blood concentration and AUC than the commercial dry suspension 0-t The relative bioavailability is obviously improved by 4.04 times.
Example 2
Preparation of settop amyl alcohol nanocrystalline
Weighing 5 parts of a first stabilizer HPMC, 30 parts of a second stabilizer HPC and 5 parts of a freeze-drying protective agent sucrose, adding into 100mL of pure water, respectively dissolving in water under the condition of 200w of ultrasonic power to obtain a water phase, weighing 30 parts of STP bulk drug, dissolving in 8mL of isopropanol, injecting an organic phase into the water phase at the speed of 2mL/min under the condition of the stirring speed of 600r/min and the temperature of 25 ℃ according to the volume ratio of the organic phase to the water phase of 6:100 to obtain a crude suspension, adding the crude suspension into a high-pressure homogenizer (HPH), homogenizing under the condition of 800bar of the homogenizing power of the high-pressure homogenizer, circulating for 14 weeks under high pressure homogenization to obtain a settop nanocrystalline suspension, standing at room temperature for 24h at-80 ℃ for pre-freezing for 24h, and freeze-drying to obtain powdery settop nanocrystalline. The particle size of the prepared settop alcohol nanocrystalline is 435.7nm, and the PDI is 0.456.
Example 3
Preparation of settop amyl alcohol nanocrystalline
10 parts of a first stabilizer HPMC, 40 parts of a second stabilizer HPC and 10 parts of a freeze-drying protective agent sucrose are weighed and added into 100mL of pure water, the mixture is respectively dissolved in water under the condition of 450w of ultrasonic power to obtain a water phase, 50 parts of STP bulk drug is weighed and dissolved in 4mL of isopropanol, the organic phase is injected into the water phase at the speed of 10mL/min under the condition of the stirring speed of 200r/min and the temperature of 50 ℃ according to the volume ratio of the organic phase to the water phase of 8:100, the crude suspension is obtained, the crude suspension is added into a High Pressure Homogenizer (HPH), after 26 weeks of high pressure homogenizing circulation, the mixture is placed at room temperature for 24h and pre-frozen at 80 ℃ for 12h, and the powdery settop alcohol nanocrystalline is obtained after freeze drying. The particle size of the prepared settop alcohol nanocrystalline is 422.6nm, and the PDI is 0.378.
Example 4
Substantially the same as in example 1, except that: the first stabilizer is SDS, the second stabilizer is MC, and the lyoprotectant is lactose. The particle size of the prepared settop alcohol nanocrystal is 379.2nm, and the PDI is 0.315.
Example 5
Substantially the same as in example 1, except that: the organic solvent is DMSO. The prepared settop pentanol nanocrystalline has the grain diameter of 202.7nm and the PDI of 0.781.
Example 6
Substantially the same as in example 1, except that: the organic solvent is ethyl acetate. The prepared settop pentanol nanocrystalline has the grain diameter of 432.8nm and PDI of 0.553.
Example 7
Substantially the same as in example 1, except that: the organic solvent is methanol. The particle size of the prepared settop alcohol nanocrystalline is 986.2nm, and the PDI is 0.456.
Example 8
Substantially the same as in example 1, except that: the organic solvent is ethanol. The prepared settop alcohol nanocrystalline has the grain size of 953.9nm and PDI of 0.437.
Example 9
Substantially the same as in example 1, except that: the organic solvent is acetonitrile. The particle size of the prepared settop alcohol nanocrystal is 731.6nm, and the PDI is 0.572.
Example 10
Substantially the same as in example 1, except that the second stabilizer is different, it may be selected from any one of EC, HPC, CA, CMC, HEC and MCC. The prepared settop alcohol nano grain diameter range is 100 nm-500 nm.
In the experimental process, compared with the prior art, the suspension of the stave nanocrystalline is re-dissolved after freeze-drying, and the turbidity value is increased, which indicates that the drug particles are obviously agglomerated, and the freeze-drying process has a certain influence on the stability of the nanocrystalline; the freeze-dried STP nanocrystalline powder was resuspended after 10 days of acceleration (40 ℃ C., RH 75%) and compared with 0d of acceleration after freeze-drying, the turbidity value of the CMC, HEC, MCC sample showed signs of reduced, indicating slightly faster sedimentation of the drug particles, while the turbidity value of the MC, EC, HPC, CA, HPMC sample showed signs of increased, indicating that the drug particles were likely to agglomerate; but in comparison, the turbidity changes of the MC and HPC samples were minimal, indicating more stability.
Comparative example 1
Substantially the same as in example 1, except that the first stabilizer was different, 9 sets of tests were designed, test 1 being cetyltrimethylammonium bromide; test 2 is poloxamer 188; test 3 is polyvinylpyrrolidone; test 4 is tyloxapol; run 5 was acacia; run 6 is carbomer 974P; test 7 is lecithin; test 8 is tween; test 9 is polyvinyl alcohol.
In the experimental process, the addition of HPMC or SDS can better reduce the aggregation of medicine crystals, the particle size of the settop alcohol is small and the particles are uniformly dispersed, and the addition of hexadecyl trimethyl ammonium bromide, poloxamer 188, polyvinylpyrrolidone, tyloxapol, carbomer 974P, lecithin, polyvinyl alcohol and tween all have small amounts of crystal aggregation, wherein the addition of hexadecyl trimethyl ammonium bromide and acacia aggregation is relatively serious, and the crystal size is relatively large.
Comparative example 2
The same as in example 1 except that the mass parts of the bulk drug of the settop alcohol were different, two sets of experiments were designed, 15 parts of the bulk drug of the settop alcohol was weighed in experiment 1, and 55 parts of the bulk drug of the settop alcohol was weighed in experiment 2. Test 1: the particle size of the settop alcohol nanocrystalline is 982.5nm, and the PDI is 0.348; test 2: the particle size of the settop alcohol nanocrystalline is 957.8nm, and the PDI is 0.372.
Comparative example 3
Substantially the same as in example 1, except that the stirring speed and temperature in the preparation of the antisolvent were different, two sets of experiments were designed, test 1 stirring speed was 1200r/min; the temperature of test 2 was 60 ℃. Test 1: the particle size of the settop alcohol nanocrystalline is 1182.3nm, and the PDI is 0.448; test 2: the particle size of the settop alcohol nanocrystalline is 682.1nm, and the PDI is 0.578.
Comparative example 4
Substantially the same as in example 1, except that the conditions of high pressure homogenization were different, two sets of tests were designed, test 1 homogenizing power was 1200bar, and high pressure homogenization was cycled for 4 weeks; test 2 the homogenizing power was 600bar and the high pressure homogenizing cycle was 28 weeks. Test 1 the particle size of the settop alcohol nanocrystalline is 1022.3nm and the PDI is 0.538; test 2: the particle size of the settop alcohol nanocrystalline is 1258.3nm, and the PDI is 0.491.
The embodiments described above and features of the embodiments herein may be combined with each other without conflict.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.

Claims (10)

1. The settop alcohol nanocrystalline is characterized by comprising, by mass, 20-50 parts of settop alcohol, 3-10 parts of a first stabilizer, 20-40 parts of a second stabilizer and 1-10 parts of a freeze-drying protective agent, wherein the first stabilizer comprises one or more of a surfactant and a polymer; the second stabilizer is cellulose; the freeze-drying protective agent is any one of sucrose, lactose, glucose and mannose.
2. The settop alcohol nanocrystal of claim 1, wherein the surfactant is selected from any one of sodium dodecyl sulfate, cetyltrimethylammonium bromide, poloxamer, tyloxapol, carbomer 974P, lecithin, tween, and the polymer is selected from any one of hypromellose, povidone, polyvinylpyrrolidone, polyvinyl alcohol, and acacia.
3. The settop alcohol nanocrystal of claim 3, wherein the cellulose is selected from any one of methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, cellulose acetate, hydroxypropylmethyl cellulose, and microcrystalline cellulose.
4. The settop alcohol nanocrystal of claim 1, wherein the settop alcohol nanocrystal has a particle size of 100nm to 500nm.
5. A method for preparing the settop alcohol nanocrystalline according to any one of claims 1-4, characterized in that the settop alcohol nanocrystalline suspension is prepared by adopting an antisolvent method and a high-pressure homogenization method, and then the settop alcohol nanocrystalline suspension is solidified by adopting a freeze-drying technology, and the method specifically comprises the following steps:
step S1, preparation of setiton alcohol nano suspension
Metering a first stabilizer and a second stabilizer, and dissolving the first stabilizer and the second stabilizer in water by ultrasonic to obtain a water phase; taking the bulk drug of the settop alcohol according to the metering, and dissolving the bulk drug in an organic solvent to obtain an organic phase; at a certain stirring speed and temperature, injecting an organic phase into a water phase at a preset speed according to a preset proportion, and uniformly stirring to obtain a settop alcohol nano suspension; the mass concentration of the first stabilizer in the water phase is 0.03 mg/mL-0.1 mg/mL, and the mass concentration of the second stabilizer is 0.2 mg/mL-0.4 mg/mL; the mass concentration of the stave in the organic phase is 2.5 mg/mL-12.5 mg/mL;
step S2, preparation of setiton alcohol nanocrystalline
And adding a freeze-drying protective agent into the settop alcohol nano suspension, homogenizing under high pressure, and freeze-drying and solidifying to obtain powdery settop alcohol nano crystals.
6. The method according to claim 5, wherein the organic solvent is any one of methanol, ethanol, acetone, propylene glycol, isopropanol, acetonitrile, DMSO, DMF, and ethyl acetate.
7. The process according to claim 6, wherein in step S1, the ultrasonic dissolution power of the stabilizer is 200w to 450w, the volume ratio of the aqueous phase to the organic phase is 100 (4 to 8), the injection speed of the organic phase is 2mL/min to 10mL/min, the stirring speed is 200r/min to 1000r/min, and the temperature is 0 to 50 ℃.
8. The method according to claim 7, wherein in the step S2, the power of the high-pressure homogenization is 800bar to 1200bar, and the number of homogenization cycles of the high-pressure homogenization is 6 to 30 weeks.
9. The method according to claim 8, wherein the pre-freezing temperature for the freeze-drying in step S2 is-20 ℃ to-80 ℃ and the pre-freezing time is 6 to 24 hours.
10. An antiepileptic pharmaceutical composition prepared from the setitoyl alcohol nanocrystal according to any one of claims 1-4.
CN202310288406.3A 2023-03-22 2023-03-22 Setitol nanocrystalline and preparation method and application thereof Pending CN116350592A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116930368A (en) * 2023-07-27 2023-10-24 石家庄四药有限公司 Detection method of settop alcohol isomer

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116930368A (en) * 2023-07-27 2023-10-24 石家庄四药有限公司 Detection method of settop alcohol isomer
CN116930368B (en) * 2023-07-27 2024-03-29 石家庄四药有限公司 Detection method of settop alcohol isomer

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