CN113616592A - Dihydropyridine drug nanosuspension and preparation method thereof - Google Patents
Dihydropyridine drug nanosuspension and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a dihydropyridine drug nanosuspension which is prepared by carrying out nanocrystallization treatment on a dihydropyridine drug and a stabilizer; the dihydropyridine drug comprises any one of nifedipine, nitrendipine, nisoldipine and felodipine; the stabilizer is any one of Soluplus, chitosan, TPGS, polyvidone K30, lecithin and poloxamer 407; and discloses a preparation method of the dihydropyridine drug nanosuspension, which adopts any one or more of a medium grinding method, a high-pressure homogenization method, a solvent precipitation method and a high-pressure homogenization method for combined use. The dihydropyridine drug nanosuspension prepared by the method has the characteristics of high preparation efficiency and high dissolution rate, and can ensure the rapid absorption and stable drug effect of the drug when being used as a preparation intermediate or a drug preparation finished product; the invention has clear mechanism and feasible, stable and reliable process technology, and provides a technical means which is easy for industrialization for the development of the nanometer suspension.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a dihydropyridine drug nanosuspension and a preparation method thereof.
Background
Dihydropyridines drugs belong to common drugs for clinical treatment of diseases such as arrhythmia, hypertension, angina pectoris and the like, and can inhibit the influx of extracellular calcium ions, relax vascular smooth muscles, reduce peripheral vascular resistance and lower blood pressure. Nifedipine, nitrendipine, felodipine and nisoldipine are all classified in dihydropyridine drugs, belong to the biological pharmacy classification system (BCS) II class, and have low solubility and high permeability.
At present, researchers at home and abroad improve the problem of poor solubility of dihydropyridine drugs by using a novel drug preparation method, for example, chinese patent CN109730967A discloses a nifedipine solid dispersion and a preparation method thereof, chinese patent CN110563635B discloses a micronization method of bulk drugs of dihydropyridine antihypertensive drugs, and chinese patent CN102406608A (discloses a solid preparation of nisoldipine liposome, the problem of poor solubility of dihydropyridine drugs should be further solved by a preparation technology to seek better solubility.
Meanwhile, the nano suspension technology is a novel nano technology capable of improving the bioavailability of insoluble drugs, and a stable preparation is prepared from the drugs and a proper stabilizer through a corresponding technology. The nanometer suspension has the advantages of large specific surface area, high saturation solubility, high dissolution speed and the like, and is widely applied to the development and research of insoluble pharmaceutical preparations. The stabilizers used in current pharmaceutical formulations are classified as steric stabilizers or charge stabilizers or a combination of both to achieve a stable state of nanosuspension. However, there is no disclosure of improving the solubility of dihydropyridine drugs using nanosuspension techniques.
Therefore, the problem to be solved by those skilled in the art is how to provide a dihydropyridine drug nanosuspension and a preparation method thereof.
Disclosure of Invention
In view of the above, the invention provides a dihydropyridine drug nanosuspension and a preparation method thereof, which can simultaneously match with a plurality of dihydropyridine drugs and can obviously improve the solubility of the dihydropyridine drugs, thereby improving the bioavailability and reducing the toxic and side effects of the dihydropyridine drugs.
In order to achieve the purpose, the invention adopts the following technical scheme:
a dihydropyridine drug nanosuspension is prepared by carrying out nanocrystallization treatment on a dihydropyridine drug and a stabilizer; the dihydropyridine drug comprises any one of nifedipine, nitrendipine, nisoldipine and felodipine;
the stabilizer is any one of Soluplus, chitosan, TPGS, povidone K30, lecithin and poloxamer 407.
The beneficial effects of the preferred technical scheme are as follows: the stabilizer disclosed by the invention can form stable nanometer suspension with a plurality of dihydropyridine drugs; in the bipyridine medicament nanometer suspension disclosed by the invention, the bipyridine medicaments exist in a form of a primary crystal form.
Preferably, the dihydropyridine drug is any one of nifedipine, nitrendipine, nisoldipine and felodipine; the dihydropyridine drugs have the same 1, 4-dihydropyridine functional group, and the in vitro cumulative dissolution rates of the dihydropyridine drug nanosuspension in dissolution media with pHs of 1.2, 4.5 and 7.4 are respectively improved by 5-7 times, 3-6 times and 2-7 times compared with those of the bulk drugs.
Preferably, the stabilizer is poloxamer 407.
The beneficial effects of the preferred technical scheme are as follows: the poloxamer 407 used in the invention is a polymer synthesized by Polyoxyethylene (PEO) and polyoxypropylene (PPO), during the preparation process, the PEO block and the dihydropyridine functional group are combined by intermolecular hydrogen bonds, and meanwhile, the PPO block provides a hydrophobic cavity for dihydropyridine drugs, thereby providing a basis for the formation and the stability of nanosuspension.
Moreover, the current research on the nanosuspension stabilizer basically uses one stabilizer or combines a plurality of stabilizers to stabilize one drug, but the invention only uses one stabilizer, namely poloxamer 407, to stabilize a plurality of similar drugs, so that the effect of stabilizing one stabilizer on a plurality of drugs is achieved.
Preferably, the mass ratio of the stabilizer to the dihydropyridine drug is 1: 0.1-5, the drug-loading rate of the dihydropyridine drug nanosuspension is 10-40%, the particle size is 100-700 nm, and the zeta potential is-30 mV-20 mV.
The beneficial effects of the preferred technical scheme are as follows: the dihydropyridine drug nanosuspension prepared by the method can achieve the effect of high efficiency and stability by using a small amount of stabilizer. The prepared dihydropyridine drug nanosuspension has the characteristics of high drug loading, uniform particle size and stable space.
The invention also provides a preparation method of the dihydropyridine drug nanosuspension, which comprises the steps of performing energetical simulation and molecular docking on the dihydropyridine drug and the stabilizer by using a computer-aided drug design method, and screening the stabilizer according to the height of the free energy of the bound ligand and the molecular docking site; and (2) combining the stabilizer and the dihydropyridine drug by adopting any one or more of a medium grinding method, a high-pressure homogenization method, a solvent precipitation method and a high-pressure homogenization method to prepare the dihydropyridine drug nano suspension.
The beneficial effects of the preferred technical scheme are as follows: nanosuspensions meeting the requirements can be prepared by a variety of different methods, and the methods can be combined to achieve high efficiency in nanosuspension preparation.
Preferably, the method specifically comprises the following steps:
(1) adding a stabilizer into water, and uniformly stirring to form a stabilizer solution;
(2) adding dihydropyridine drugs into the stabilizer solution, and uniformly stirring to obtain a crude mixed suspension;
(3) and grinding the crude mixed suspension to obtain the dihydropyridine drug nano suspension.
Preferably, the stirring in the step (1) is magnetic stirring, the stirring speed is 400-800r/min, and the stirring time is 15-60 min.
The beneficial effects of the preferred technical scheme are as follows: the stabilizer is fully dissolved in water, and the formed stabilizer solution can be used for preparing dihydropyridine drug nanosuspension subsequently.
Preferably, the stirring in the step (2) is performed by magnetic stirring, the stirring speed is 300-600r/min, and the stirring time is 30-90 min.
The beneficial effects of the preferred technical scheme are as follows: under the action of magnetic stirring, the dihydropyridine drug raw materials are uniformly dispersed in the stabilizer aqueous solution, and the obtained coarse suspension has the characteristics of uniformity and short-term no precipitation.
Preferably, grinding beads are added during the grinding process in the step (3), and the grinding beads are yttrium-stabilized zirconium beads, zirconium silicate grinding beads or polystyrene grinding beads.
The beneficial effects of the preferred technical scheme are as follows: the grinding beads used in the nano grinding have good roundness, smooth surface, excellent toughness and good wear resistance, and are not broken in high-speed operation; can effectively improve the grinding efficiency.
Preferably, the particle size of the grinding beads is 0.3-0.8 mm, the grinding time is 15-60min, the rotation speed of grinding is 1500-4500 rpm, and the grinding temperature is controlled at 10-30 ℃.
The beneficial effects of the preferred technical scheme are as follows: in the grinding process, collision mechanical energy can be converted into molecular potential energy of the nano suspension, so that the particle size of the medicine is reduced, the specific surface area is increased, the polydispersity index of the 4 dihydropyridine medicine nano suspensions is 0.1-0.4, and the absolute value of the Zeta potential is 10-35 mV.
Preferably, the stabilizer is obtained by screening, and the specific screening method comprises the following steps: firstly, calculating the binding free energy of the stabilizer and the medicament by using Material Studio 2017 software; then use
And (3) carrying out molecular docking research by software, and carrying out comprehensive analysis to obtain the stabilizer.
The invention also provides application of the dihydropyridine drug nanosuspension as a drug preparation intermediate, wherein the drug preparation comprises tablets, injections, granules or freeze-dried powder injections.
The beneficial effects of the preferred technical scheme are as follows: the dihydropyridine drug nanosuspension can be used as an intermediate of various pharmaceutical preparations, can be further processed into tablets, granules and the like, and provides a new idea for the development of dihydropyridine drug preparations.
According to the technical scheme, compared with the prior art, the invention discloses and provides a dihydropyridine drug nanosuspension, a preparation method and application thereof, and the dihydropyridine drug nanosuspension has the following beneficial effects:
(1) the invention mixes 4 dihydropyridine drugs and single stabilizer solution and then carries out nanocrystallization treatment, so that the particle size of the drugs can be reduced to the nanometer level, thereby effectively improving the solubility:
(2) the dihydropyridine drug nanosuspension is prepared by adopting a wet grinding technology, and the stabilizer and the drug are ground together to fully prevent the aggregation of drug particles so as to ensure the stability of the dihydropyridine drug nanosuspension;
(3) the dihydropyridine drug nanosuspension disclosed by the invention has the advantages that the specific surface area is increased, the dissolution rate is remarkably increased, and the adopted stabilizer belongs to a water-soluble carrier, so that the dissolution rate can be increased under the wetting action of the dihydropyridine drug;
(4) the wet grinding technology adopted by the invention has simple process and good reproducibility, and the drug-loading rate of the prepared nano suspension can reach 10-40%;
(5) the melting point peak (DSC) and the characteristic diffraction peak (XRD) of the nifedipine, nitrendipine, nisoldipine and felodipine bulk drugs used in the invention all exist in 4 kinds of nano suspensions, which shows that the physical stability is good, and the method can realize the large-scale production of dihydropyridine drug nano suspensions.
(6) The dihydropyridine drug nanosuspension has high preparation efficiency and high dissolution rate, and can ensure the rapid absorption and stable drug effect when being used as intermediates of dihydropyridine drug tablets, injections, granules and freeze-dried powder injections;
(7) the preparation method disclosed by the invention has feasible, stable and reliable process technology, and provides a technical means which is easy to industrialize for the development of the nanometer suspension.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a simulation of free energy of binding between different stabilizers and drugs using Materials Studio 2017 software, modeled on nifedipine, according to the present invention;
FIG. 2 shows nifedipine as a model of the present invention, used
The software simulates molecular docking between different stabilizers and the drugs and scores;
FIG. 3 is a scanning electron microscope image of nitrendipine bulk drug in the embodiment of the invention;
FIG. 4 is a scanning electron microscope image of nitrendipine nanosuspension freeze-dried powder in the embodiment of the invention;
FIG. 5 is an atomic mechanical microscope image of nitrendipine bulk drug in an embodiment of the present invention;
FIG. 6 is an atomic mechanics microscope image of a nitrendipine nanosuspension freeze-dried powder in an embodiment of the invention;
FIG. 7 is an XRD diagram of nitrendipine bulk drug, poloxamer 407, a physical mixture and nanosuspension freeze-dried powder provided by the invention;
FIG. 8 is a DSC of nifedipine bulk drug, poloxamer 407, physical mixture, nanosuspension freeze-dried powder provided by the invention;
FIG. 9 is an infrared spectrum of the nisoldipine bulk drug, poloxamer 407, the physical mixture and the nanosuspension freeze-dried powder provided by the invention;
fig. 10 is a raman spectrum of felodipine bulk drug, poloxamer 407, a physical mixture, and nanosuspension freeze-dried powder provided by the invention;
FIG. 11 shows a hydrophobic interaction diagram formed between nifedipine and poloxamer 407 (the yellow region is the region where hydrophobic interaction exists) according to the invention using nifedipine as a model;
fig. 12 is a hydrophobic interaction diagram formed between nifedipine and a stabilizer molecule poloxamer 407 according to the present invention, which is modeled as nifedipine (the yellow region is the region where hydrophobic interaction exists, and is different from fig. 11 in that two cavity sites exist between nifedipine and poloxamer 407);
fig. 13 is a graph of intermolecular hydrogen bonds formed between nitrendipine and poloxamer 407 (yellow dashed line is intermolecular hydrogen bonds) in the model of nitrendipine.
FIG. 14 is a dissolution diagram of a felodipine and nifedipine bulk drug, a physical mixture, and a nanosuspension in accordance with the present invention;
fig. 15 is a dissolution diagram of the nitrendipine and nisoldipine bulk drug, physical mixture and nanosuspension in the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The embodiment of the invention discloses a dihydropyridine drug nanosuspension, which is prepared by carrying out nanocrystallization treatment on a dihydropyridine drug and a stabilizer; the dihydropyridine drug comprises any one of nifedipine, nitrendipine, nisoldipine and felodipine;
the mass ratio of the stabilizer to the dihydropyridine drug is 1: 0.1-5, the drug-loading rate of the dihydropyridine drug nano suspension is 10-40%, the particle size is 100-700 nm, and the zeta potential is-30 mV-20 mV
The stabilizer is one of Soluplus, chitosan, TPGS, polyvidone K30, lecithin and poloxamer 407.
In order to further optimize the technical scheme, the stabilizer is poloxamer 407.
The embodiment of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) adding stabilizer into water, and standing for 15-60min to obtain stabilizer solution;
(2) adding dihydropyridine drug into the stabilizer solution, and magnetically stirring for 30-90min to obtain a crude mixed suspension;
(3) adding the coarse suspension into a grinding chamber of an ultrafine grinding machine, adding grinding beads at the same time, and grinding to obtain dihydropyridine drug nanosuspension;
wherein the grinding beads are yttrium-stabilized zirconium beads, zirconium silicate grinding beads or polystyrene grinding beads, the particle size of the grinding beads is 0.3-0.8 mm, and the volume of the grinding beads is 140 ml; the grinding time is 15-60min, the grinding speed is 1500-4500 rpm, and the grinding temperature is controlled at 10-30 ℃.
In order to further optimize the technical scheme, the dihydropyridine drug nanosuspension is used as a drug preparation intermediate to prepare tablets, injections, granules or freeze-dried powder injections.
In order to further optimize the technical scheme, the superfine grinding machine is a circulating type nanometer grinding machine;
example 1
The embodiment 1 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) adding 0.1g of Soluplus into 50ml of distilled water, and stirring for 30min by a magnetic stirrer at the stirring speed of 600r/min to obtain a stabilizer solution;
(2) adding 0.25g of nitrendipine into the stabilizer solution, and stirring for 60min by using a magnetic stirrer at the stirring speed of 450r/min to obtain a crude mixed suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nitrendipine nano suspension.
Wherein the prepared nitrendipine nano suspension is diluted by 3 times by purified water, and the particle size is 478.6nm and the potential is-28.62 mV.
Example 2
The embodiment 2 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 0.1g of chitosan, adding the chitosan into 50ml of distilled water, and stirring for 30min by a magnetic stirrer at the stirring speed of 600r/min to obtain a stabilizer solution;
(2) adding 0.25g of nitrendipine into the stabilizer solution, and stirring for 60min by using a magnetic stirrer at the stirring speed of 450r/min to obtain a crude mixed suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nitrendipine nano suspension.
Wherein the prepared nitrendipine nanosuspension is diluted by 3 times by purified water, and the measured particle size is 277.1nm, and the potential is-6.55 mV.
Example 3
The embodiment 3 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 0.1g of TPGS, adding into 50ml of distilled water, and stirring for 30min by a magnetic stirrer at the stirring speed of 600r/min to obtain a stabilizer solution;
(2) adding 0.25g of nitrendipine into the stabilizer solution, and stirring for 60min by using a magnetic stirrer at the stirring speed of 450r/min to obtain a crude mixed suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nitrendipine nano suspension.
Wherein the prepared nitrendipine nano suspension is diluted by 3 times by purified water, and the particle size is 392.3nm and the potential is-15.30 mV.
Example 4
The embodiment 4 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing polyvidone K300.1g, adding into 50ml distilled water, and stirring with a magnetic stirrer for 30min at a stirring speed of 600r/min to obtain a stabilizer solution;
(2) adding 0.25g of nitrendipine into the stabilizer solution, and stirring for 60min by using a magnetic stirrer at the stirring speed of 450r/min to obtain a crude mixed suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nitrendipine nano suspension.
Wherein the prepared nitrendipine nano suspension is diluted by 3 times by purified water, and the particle size is 378.8nm and the potential is-18.28 mV.
Example 5
The embodiment 5 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 0.1g of lecithin, adding into 50ml of distilled water, and stirring for 30min by a magnetic stirrer at the stirring speed of 600r/min to obtain a stabilizer solution;
(2) adding 0.25g of nitrendipine into the stabilizer solution, and stirring for 60min by using a magnetic stirrer at the stirring speed of 450r/min to obtain a crude mixed suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nitrendipine nano suspension.
Wherein the prepared nitrendipine nanosuspension is diluted by 3 times by purified water, and the particle size is 425.5nm and the potential is-30.96 mV.
Example 6
The embodiment 6 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 4070.1g of poloxamer, adding into 50ml of distilled water, and stirring for 30min by a magnetic stirrer at the stirring speed of 600r/min to obtain a stabilizer solution;
(2) adding 0.25g of nitrendipine into the stabilizer solution, and stirring for 60min by using a magnetic stirrer at the stirring speed of 450r/min to obtain a crude mixed suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nitrendipine nano suspension.
Wherein the prepared nitrendipine nanosuspension is diluted by 3 times by purified water, and the measured particle size is 232.5nm, and the potential is-14.66 mV.
Example 7
The embodiment 7 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 4070.025g of poloxamer, adding into 50ml of distilled water, and stirring for 60min by a magnetic stirrer at the stirring speed of 800r/min to obtain a stabilizer solution;
(2) adding 0.25g of nitrendipine into the stabilizer solution, and stirring for 90min by using a magnetic stirrer at the stirring speed of 600r/min to obtain a crude mixed suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nitrendipine nano suspension.
Wherein the prepared nitrendipine nano suspension is diluted by 3 times by purified water, and the particle size is 610.2nm and the potential is-5.48 mV.
Example 8
The embodiment 8 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 4071.25g of poloxamer, adding into 50ml of distilled water, and stirring for 15min by a magnetic stirrer at the stirring speed of 400r/min to obtain a stabilizer solution;
(2) adding 0.25g of nifedipine into the stabilizer solution, and stirring for 30min by a magnetic stirrer at the stirring speed of 300r/min to obtain a crude suspension;
(3) and adding the crude suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nifedipine nano suspension.
Wherein the particle size of the prepared nifedipine nano suspension is 410.9nm and the potential is-12.14 mV when the nifedipine nano suspension is diluted by 3 times by purified water.
Example 9
The embodiment 9 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 4070.15g of poloxamer, adding into 50ml of distilled water, and stirring for 20min by a magnetic stirrer at the stirring speed of 700r/min to obtain a stabilizer solution;
(2) adding 0.25g of nisoldipine into the stabilizer solution, and stirring for 40min by using a magnetic stirrer at the stirring speed of 550r/min to obtain a crude suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding at the rotating speed of 3000rpm for 30min to obtain the nisoldipine nano suspension.
Wherein the particle size of the prepared nisoldipine nanosuspension is 158.8nm and the potential is-22.46 mV when the nisoldipine nanosuspension is diluted by 3 times by purified water.
Example 10
The embodiment 10 of the invention also discloses a preparation method of the dihydropyridine drug nanosuspension, which comprises the following steps:
(1) weighing 4070.15g of poloxamer, adding into 50ml of distilled water, and stirring for 20min by a magnetic stirrer at the stirring speed of 700r/min to obtain a stabilizer solution;
(2) adding 0.25g of felodipine into the stabilizer solution, and stirring for 40min by using a magnetic stirrer at the stirring speed of 550r/min to obtain a crude suspension;
(3) and adding the coarse suspension into a grinding cavity of a circulating nano grinding machine, adding 140ml of zirconium oxide grinding beads with the particle size of 0.6-0.8mm, and grinding for 45min at the rotating speed of 2500rpm to obtain the felodipine nano suspension.
Wherein the particle size of the prepared felodipine nano-suspension is 179.1nm and the potential is-27.45 mV when the felodipine nano-suspension is diluted by 3 times by purified water.
The stabilizers used in examples 1 to 10 were selected by the following method:
(1) the binding free energy of the stabilizer to the drug was calculated using the Material Studio 2017 software,
firstly, constructing initial three-dimensional structures of different stabilizers and nifedipine by respectively utilizing a constructed polymer module and a three-dimensional atomic module. And performing energy accumulation simulation by using a hybrid calculation module, and optimizing a monomer structure. The setting task is set to "geometry optimization" and "charge using QEq". And ensuring that the head atom and the tail atom are not in contact, checking 'Return local energy frames', setting the frame number to be 50, and changing the updating energy to be 2 seconds. The binding state at the lowest binding free energy (Δ G) will be selected and output for further analysis, with the results shown in fig. 1.
(2) Use of
Software for molecular docking studies
The structure and steric aggregation state of different stabilizers were simulated using a PolmerBuilder module. The molecular structures of polymer and nifedipine were treated with Protein conjugation and ligaprep, respectively, to obtain reasonable bond distribution, chiral centers and predominant configurations. The active site was determined by Receptor Grid Gener for molecular docking studies. The Ligand Docking module is used for Docking nifedipine with the binding sites in the grid file, and the software gives Docking scores, and the result is shown in fig. 2.
Effect verification
Firstly, freeze-dried powder of dihydropyridine drug nanosuspension and morphological observation thereof.
The dihydropyridine drug nanosuspension prepared in example 7 is pre-frozen at-80 ℃ for 12h, transferred to a freeze dryer, frozen at-40 ℃ for 8h, and heated to 12 ℃ for sublimation for 4h to obtain the freeze-dried powder of the dihydropyridine drug nanosuspension.
And observing the surface morphology and the surface three-dimensional morphology of the nitrendipine bulk drug, the physical mixture and the nano suspension freeze-dried powder by using a scanning electron microscope and an atomic mechanics microscope, and photographing and recording. The results are shown in FIGS. 3 to 6.
As can be seen from the graphs in FIGS. 3-6, the dihydropyridine drug substance has a large particle size and is seriously agglomerated, and the corresponding nanosuspension is columnar particles with uniform dispersion and uniform particle size.
And II, characterizing the physical and chemical properties of the dihydropyridine drug nanosuspension.
After the dihydropyridine drug nanosuspension freeze-dried powders prepared in examples 7, 8, 9 and 10 were obtained, the physical and chemical characteristics of different raw material drugs, physical mixtures and nanosuspension freeze-dried powders thereof were characterized by DSC, XRD, FTIR and Raman, and at the same time, molecular docking software was used to simulate the docking state, and the results are shown in fig. 7 to 13.
As can be seen from FIGS. 7 to 10, the drug exists in the nanosuspension in the form of primary crystals, and intermolecular hydrogen bonds and hydrophobic forces are formed between the preferable stabilizer poloxamer 407 and the dihydropyridine drug, so that the nanosuspension achieves a stabilizing effect. As can be seen from figures 11-13, stable intermolecular hydrogen bonds and hydrophobic forces can be formed between the stabilizer poloxamer 407 and nifedipine, and the formation mechanism is further proved from a microscopic angle.
And thirdly, determining the dissolution rate of the dihydropyridine drug nanosuspension.
The determination of dissolution is carried out according to the second method (slurry method) of 0931 of the fourth part of the Chinese pharmacopoeia of 2020 edition, 900ml of buffer solutions with pH1.2, 6.8 and 7.4 are respectively used as dissolution media, the temperature is 37 +/-0.5 ℃, and the rotating speed is set according to the requirements of the second part of the Chinese pharmacopoeia on different medicines. The nanosuspension, physical mixture and bulk drug are contacted with the dissolution medium at the beginning of timing, 10ml are sampled at 5, 10, 15, 30, 45, 60, 90 and 120min, 10ml of the same isothermal dissolution medium is supplemented at the same time, the obtained sample is filtered with a 0.45 μm microporous filter membrane, and the absorbance is measured at 237nm, 333nm, 361nm and 238nm using an ultraviolet spectrophotometer. The measured dissolution profiles are shown in FIGS. 14 to 15.
From the results shown in fig. 14 to 15, it can be seen that the dissolution rates of nifedipine, nitrendipine, nisoldipine and felodipine in the solutions with pH values of 1.2, 4.5 and 7.4 are all less than 30% within 120min, but the dissolution rates of the corresponding nanosuspensions are close to 90% within 15min, and the cumulative dissolution rates of the 4 dihydropyridine drug nanosuspensions are increased by 2 to 7 times compared with those of the bulk drugs. Therefore, the dihydropyridine drug is prepared into the nano suspension, and the accumulative dissolution rate and the dissolution rate of the nano suspension are obviously improved
The term abbreviation correspondence table referred to in the present specification and drawings.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other. The device disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the method part for description.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. A dihydropyridine drug nanosuspension is characterized in that the dihydropyridine drug nanosuspension is prepared by carrying out nanocrystallization treatment on a dihydropyridine drug and a stabilizer; the dihydropyridine drug comprises any one of nifedipine, nitrendipine, nisoldipine and felodipine;
the stabilizer is any one of Soluplus, chitosan, TPGS, povidone K30, lecithin and poloxamer 407.
2. The dihydropyridine drug nanosuspension according to claim 1, wherein the dihydropyridine drug is any one of nifedipine, nitrendipine, nisoldipine, felodipine; the dihydropyridine drugs have the same 1, 4-dihydropyridine functional group, and the in vitro cumulative dissolution rates of the dihydropyridine drug nanosuspension in dissolution media with pHs of 1.2, 4.5 and 7.4 are respectively improved by 5-7 times, 3-6 times and 2-7 times compared with those of the bulk drugs.
3. The dihydropyridine drug nanosuspension according to claim 1, wherein the stabilizer is poloxamer 407, poloxamer 407 is a polymer synthesized from polyoxyethylene and polyoxypropylene, polyoxyethylene blocks and dihydropyridine functional groups are bonded by intermolecular hydrogen bonding during preparation, and the polyoxypropylene blocks provide hydrophobic cavities for the dihydropyridine drug, thereby providing a basis for formation and stabilization of the nanosuspension.
4. The dihydropyridine drug nanosuspension according to any one of claims 1 to 3, wherein the mass ratio of the stabilizer to the dihydropyridine drug is 1:0.1 to 5, the drug-loading rate of the dihydropyridine drug nanosuspension is 10 to 40%, the particle size is 100 to 700nm, and the zeta potential is-30 mV to 20 mV.
5. The method for preparing the dihydropyridine drug nanosuspension according to any one of claims 1 to 4, wherein the dihydropyridine drug and the stabilizer are subjected to energetical simulation and molecular docking by using a computer-aided drug design method, and the stabilizer is screened according to the height of the free energy of the bound ligand and the molecular docking site; and (2) combining the stabilizer and the dihydropyridine drug by adopting any one or more of a medium grinding method, a high-pressure homogenization method, a solvent precipitation method and a high-pressure homogenization method to prepare the dihydropyridine drug nano suspension.
6. The method for preparing a dihydropyridine drug nanosuspension as claimed in claim 5, which comprises the following steps:
(1) adding a stabilizer into water, and uniformly stirring to form a stabilizer solution;
(2) adding dihydropyridine drugs into the stabilizer solution, and uniformly stirring to obtain a crude mixed suspension;
(3) and grinding the crude mixed suspension to obtain the dihydropyridine drug nano suspension.
7. The method for preparing dihydropyridine drug nanosuspension as claimed in claim 6, wherein the magnetic stirring is adopted in the step (1), the stirring speed is 400-800r/min, and the stirring time is 15-60 min; in the step (2), magnetic stirring is adopted for stirring, the stirring speed is 300-600r/min, and the stirring time is 30-90 min.
8. The process for the preparation of a dihydropyridine pharmaceutical nanosuspension according to claim 6, wherein grinding beads are added during the grinding in step (3), said grinding beads being yttrium stabilized zirconium beads, zirconium silicate grinding beads or polystyrene grinding beads; the particle size of the grinding beads is 0.3-0.8 mm, the grinding time is 15-60min, the grinding speed is 1500-4500 rpm, and the grinding temperature is controlled at 10-30 ℃.
9. The application of the dihydropyridine drug nanosuspension as claimed in any one of claims 1 to 4 as an intermediate of a pharmaceutical preparation, wherein the pharmaceutical preparation comprises tablets, injections, granules or lyophilized injections.
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| CN107837231A (en) * | 2017-11-02 | 2018-03-27 | 中国药科大学 | A kind of Nimodipime nanometer method and its dry suspensoid agent |
| CN110711176A (en) * | 2019-11-26 | 2020-01-21 | 宁夏医科大学 | Cilnidipine nanosuspension and preparation method thereof |
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| CN107837231A (en) * | 2017-11-02 | 2018-03-27 | 中国药科大学 | A kind of Nimodipime nanometer method and its dry suspensoid agent |
| CN110711176A (en) * | 2019-11-26 | 2020-01-21 | 宁夏医科大学 | Cilnidipine nanosuspension and preparation method thereof |
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| CN116196274A (en) * | 2021-12-01 | 2023-06-02 | 凯惠药业(上海)有限公司 | Nanometer suspension, freeze-dried powder, preparation method and application |
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Application publication date: 20211109 |