CN113069415B - Insoluble drug nanosuspension and preparation method thereof - Google Patents
Insoluble drug nanosuspension and preparation method thereof Download PDFInfo
- Publication number
- CN113069415B CN113069415B CN202110382909.8A CN202110382909A CN113069415B CN 113069415 B CN113069415 B CN 113069415B CN 202110382909 A CN202110382909 A CN 202110382909A CN 113069415 B CN113069415 B CN 113069415B
- Authority
- CN
- China
- Prior art keywords
- stabilizer
- drug
- water
- nanosuspension
- cosolvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
- A61K47/30—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
Abstract
The invention relates to the technical field of medicines, in particular to a slightly soluble medicine nano suspension and a preparation method thereof. The method comprises the following steps: (1) dissolving an insoluble drug in a cosolvent to obtain a drug-cosolvent solution; (2) dissolving a stabilizer in water to obtain an aqueous solution containing the stabilizer; (3) adding the drug-cosolvent solution obtained in the step (1) into the aqueous solution containing the stabilizer obtained in the step (2) under stirring, and after the addition is finished, continuously stirring and shearing to obtain the insoluble drug nanosuspension; wherein the volume ratio of the latent solvent to water is 1 (2-10); the stabilizer is a mixture of a charge stabilizer and a steric stabilizer. The nano suspending agent prepared by the method has the advantages that the particle size of the medicine is within the range of 200-350 nm, the stability is excellent, and the dissolution speed and the degree of the suspending agent are obviously improved compared with those of the bulk drugs.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a slightly soluble medicine nano suspension and a preparation method thereof.
Background
In recent years, with the wide application of combinatorial chemistry and high-throughput screening technologies in drug development, a large number of compounds with large molecular weight and complex structures emerge. According to statistics, 40% of sold drugs are poorly soluble drugs and up to 90% of the drugs under development worldwide. Because of their extremely low solubility in water, these drugs have poor dissolution in the gastrointestinal tract and low oral bioavailability, limiting the development and clinical use of pharmaceutical formulations.
The nano suspension is a novel nano drug delivery system developed aiming at insoluble drugs in recent years, belongs to a submicron colloid dispersion system, and can be used for both water-insoluble drugs and oil and water-insoluble drugs. Compared with the traditional suspension, the nano suspension has the drug particle size of less than 1000nm and exists in a nano state, so that the dissolution rate of the drug can be increased, the bioavailability is improved, and the absorption by a human body is facilitated. In addition, the nano suspension only consists of drugs and a small amount of stabilizing agent, has the advantages of high drug loading, accurate drug dosage and the like, and is one of the hot spots of research in the field of pharmacy at present.
The solvent-antisolvent method is a common method for preparing the nano suspension at present, has strong operability and simple preparation process and is widely applied. The principle of preparing the drug nanosuspension by solvent-antisolvent precipitation depends on the higher solubility of the drug in an organic solvent, then the drug-containing organic solvent is added into the antisolvent (usually water or other aqueous media) to form a supersaturated aqueous phase, and finally the nanoscale drug is precipitated. However, the good solvents adopted by the traditional anti-solvent method for preparing the nano suspension are mostly dichloromethane, methanol, DMSO and other organic solvents, most of the organic solvents have high boiling points and are difficult to remove, the organic solvents are easy to remain after the nano suspension is prepared into a preparation, and most of the organic solvents have certain toxic and side effects and are not beneficial to the environment and human bodies after long-term use.
Therefore, the method has important significance for finding a non-toxic, good thermal stability, recyclable, cheap and easily available green solvent to replace an organic solvent in the traditional anti-solvent method for preparing the insoluble drug nanosuspension.
Disclosure of Invention
The invention aims to solve the problem that the organic solvent residue in the process of preparing the nano suspension by the existing solvent-anti-solvent method in the prior art causes adverse effects on human bodies and the environment, and provides the slightly-soluble drug nano suspension and the preparation method thereof.
In order to achieve the above objects, the present invention provides, in one aspect, a method for preparing a poorly soluble drug nanosuspension, comprising the steps of:
(1) dissolving an insoluble drug in a cosolvent to obtain a drug-cosolvent solution;
(2) dissolving a stabilizer in water to obtain a water solution containing the stabilizer;
(3) adding the drug-cosolvent solution obtained in the step (1) into the aqueous solution containing the stabilizer obtained in the step (2) under stirring, and after the addition is finished, continuously stirring and shearing to obtain the insoluble drug nanosuspension;
wherein the volume ratio of the latent solvent to water is 1 (2-10);
the stabilizer is a mixture of a charge stabilizer and a steric stabilizer.
Preferably, the poorly soluble drug is a polyethylene glycol soluble drug of class II and class iv drugs in the classification system of biopharmaceutics;
preferably, the poorly soluble drug is selected from at least one of apigenin, ibuprofen, perampanel, eslicarbazepine, terbinafine hydrochloride, budesonide, fluticasone propionate, beclomethasone propionate, and dexamethasone.
Preferably, in the step (1), the latent solvent is polyethylene glycol with a relative molecular mass in the range of 200-600.
Preferably, the weight ratio of the charge stabilizer to the water is 0.1-0.3%; the weight ratio of the three-dimensional stabilizer to water is 0.1-0.3%;
further preferably, the weight ratio of the charge stabilizer to the steric stabilizer is 1 (1-3).
Preferably, the charge stabilizer is sodium dodecyl sulfate or sodium dodecyl sulfate, and the steric stabilizer is poloxamer or povidone K30.
Preferably, the ratio of the weight of the poorly soluble drug to the volume of water is 0.0002 to 0.06 g/mL.
Preferably, in the step (3), the adding speed of the drug-cosolvent solution is 20-80 mL/min.
Preferably, in the step (3), the stirring speed is 300-1100 r/min.
Preferably, in the step (3), the shearing time is 5-20 min.
The invention provides the slightly soluble drug nanosuspension prepared by the method, wherein the particle size of the drug in the slightly soluble drug nanosuspension is 200-350 nm.
Compared with the prior preparation technology of the insoluble drug nanosuspension, the invention has the following advantages:
1. the invention adopts a latent solvent method to prepare the nano suspension, which not only can improve the solubility of the medicine and further improve the medicine-loading rate, but also can lead the latent solvent to be capable of being used as a stabilizing agent to exist in a nano suspension system, thus leading the prepared nano suspension to have higher physical stability. Meanwhile, the polyethylene glycol used in the invention is a green solvent which is nontoxic, good in thermal stability, recyclable, low in price and easy to obtain, and not only can eliminate the dependence of the traditional anti-solvent method on an organic solvent, but also can avoid the adverse effects on human bodies and the environment caused by using the organic solvent.
2. The invention combines the use of a charge stabilizer (electrostatic effect) and a steric stabilizer (steric hindrance effect), so that the nanosuspension has excellent stability.
3. Compared with the bulk drugs, the nanosuspension prepared by the invention has the in-vitro release degrees of the buffers with the pH values of 1.0, 4.5 and 6.8, the cumulative release degree of the nanosuspension reaches more than 60 percent at each pH value for 60min, and the cumulative release degree of the bulk drugs is only 29.08 percent at the maximum at the pH value of 4.5 for 60 min.
4. Compared with bulk drugs, the nano suspension prepared by the invention has the advantages that the Cmax in rats is increased by 3.8 times and the AUC in rats is increased 0-t The product is increased by 1.6 times compared with original medicine, and is absolutely freshThe bioavailability is increased by 1.6 times compared with the original medicine, and the medicine has faster and better effect.
5. In the invention, the solidification operation such as freeze-drying is not needed, the cost can be reduced, and the large-scale production operation is reasonable.
Drawings
FIG. 1 is a graph comparing the dissolution curves of apigenin and apigenin nanosuspension in test example 3;
figure 2 is a comparison of the time-dependent plasma levels of the two groups of gavage administrations in test example 4.
Detailed Description
The following detailed description of embodiments of the invention refers to the accompanying drawings. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
In one aspect, the present invention provides a process for preparing a poorly soluble drug nanosuspension, comprising the steps of:
(1) dissolving an insoluble drug in a cosolvent to obtain a drug-cosolvent solution;
(2) dissolving a stabilizer in water to obtain a water solution containing the stabilizer;
(3) adding the drug-cosolvent solution obtained in the step (1) into the aqueous solution containing the stabilizer obtained in the step (2) under stirring, and after the addition is finished, continuously stirring and shearing to obtain the insoluble drug nanosuspension;
wherein the volume ratio of the latent solvent to water is 1 (2-10);
the stabilizer is a mixture of a charge stabilizer and a steric stabilizer.
In the present invention, the poorly soluble drug may be a polyethylene glycol-soluble drug among class II and class iv drugs in the biopharmaceutical classification system.
In a preferred embodiment, the poorly soluble drug is selected from at least one of apigenin, ibuprofen, perampanel, eslicarbazepine, terbinafine hydrochloride, budesonide, fluticasone propionate, beclomethasone propionate, and dexamethasone.
Further preferably, the poorly soluble drug is selected from apigenin, ibuprofen, perampanel, eslicarbazepine, terbinafine hydrochloride, budesonide, fluticasone propionate, beclomethasone propionate or dexamethasone.
In a preferred embodiment, in the step (1), the cosolvent is polyethylene glycol having a relative molecular mass in the range of 200 to 600. In particular, the polyethylene glycol may have a relative molecular mass of 200, 300, 400, 500 or 600.
In the present invention, the nanosuspension preparation is carried out using a cosolvent method. The latent solvent method is based on a solvent-antisolvent method, and a method for preparing the nano suspension by replacing the traditional organic solvent with a green and environment-friendly cosolvent with high solubility and good stability for the medicine is found. The latent solvent is used, so that the drug solubility can be improved, the drug loading rate can be further improved, and the latent solvent can be used as a stabilizer to exist in a nano suspension system, so that the prepared nano suspension has higher physical stability. Meanwhile, the polyethylene glycol used in the invention is a green solvent which is nontoxic, good in thermal stability, recyclable, cheap and easy to obtain, and can eliminate the dependence of the traditional anti-solvent method on an organic solvent and avoid the adverse effects on human bodies and the environment caused by the use of the organic solvent.
In a preferred embodiment, the water is pure water.
Preferably, the weight ratio of the charge stabilizer to the water is 0.1-0.3%; the weight ratio of the three-dimensional stabilizer to water is 0.1-0.3%;
further preferably, the weight ratio of the charge stabilizer to the steric stabilizer is 1 (1-3). Most preferably 1:2. Specifically, the weight ratio may be 1:1, 1:1.5, 1:2, 1:2.5, or 1: 3.
In the invention, the specific surface area of the drug is increased after the drug is prepared into the nano suspension, which inevitably causes the free energy and the surface energy of the Gibbs to be increased sharply, thereby causing the nano suspension to be a thermodynamically unstable system. In order to reduce the energy of the system, the drug particles spontaneously aggregate to reduce the specific surface area, so that a series of unstable physical phenomena such as agglomeration, growth, sedimentation, crystal form change and the like occur. According to the DLVO theory and the steric stability theory, the stabilizer can be effectively adsorbed on the surfaces of the drug particles due to the electrostatic effect or the steric hindrance effect of the stabilizer, so that the occurrence of drug particle agglomeration is reduced. The type and amount of stabilizer will directly affect the average particle size, homogeneity and stability of the nanosuspension. Therefore, when the combined stabilizer is used, namely the charge stabilizer (electrostatic effect) and the steric stabilizer (steric effect) in the weight ratio of 1 (1-3) are used at the same time, the particle size of the nano suspension is 200-350 nm, and the stability is good.
In a preferred embodiment, the charge stabilizer is sodium dodecyl sulfate or sodium dodecyl sulfate and the steric stabilizer is poloxamer or povidone K30.
In a preferred embodiment, the stabilizer is lauryl sulfuric acid and sodium povidone K30, and the weight ratio of sodium lauryl sulfate to water is 0.1% and the weight ratio of povidone K30 to water is 0.2%.
In a preferred embodiment, the volume ratio of the latent solvent to water is 1 (2-10). Specifically, the volume ratio of the latent solvent to water may be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1: 10.
In the invention, polyethylene glycol is used as a cosolvent, and the volume ratio of the polyethylene glycol to an antisolvent (water) is controlled, so that the polyethylene glycol and the antisolvent form a certain volume difference, which is favorable for precipitation and crystallization of a medicament, but when the ratio is continuously increased, the drug loading rate of the system is too low, which is not favorable for the exertion of the drug effect of a preparation, so that the ratio of the cosolvent to the antisolvent is controlled to be 1: 2-1: 10.
In a preferred embodiment, in the step (3), the addition rate of the drug-cosolvent solution is 20 to 80 mL/min. Specifically, the addition rate may be 20mL/min, 25mL/min, 30mL/min, 35mL/min, 40mL/min, 45mL/min, 50mL/min, 55mL/min, 60mL/min, 65mL/min, 70mL/min, 75mL/min, or 80 mL/min.
In a preferred embodiment, in the step (3), the stirring speed is 300 to 1100 r/min. Specifically, the stirring speed can be r/min, 400r/min, 500r/min, 600r/min, 700r/min, 800r/min, 900r/min, 1000r/min or 1100 r/min.
In a preferred embodiment, in the step (3), the shearing time is 5 to 20 min. Specifically, the shearing time is 5min, 6min, 7min, 8min, 9min, 10min, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min, 19min or 20 min.
In the preferred embodiment, the ratio of the weight of the poorly soluble drug to the volume of water in the production process is 0.0002 to 0.06 (g/mL).
In the invention, polyethylene glycol is used as a cosolvent, and the volume ratio of the polyethylene glycol to an antisolvent (water) is controlled to be 1 (2-10), so that a certain volume difference is formed between the polyethylene glycol and the antisolvent to facilitate the precipitation and crystallization of a drug, and the synergistic effect of a charge stabilizer and a steric stabilizer is adopted to further prevent the phenomena of aggregation, growth and the like of the drug.
In the invention, the particle size of the medicament in the slightly soluble medicament nano suspension prepared by the method is 200-350 nm.
The present invention will be described in detail below by way of examples, but the scope of the present invention is not limited thereto.
Example 1
Preparation of apigenin nano suspension
1.6g of apigenin raw material medicine is taken and put into 20ml of polyethylene glycol 400(PEG-400), and the mixture is dissolved completely by boiling water bath ultrasound; 160mg of Sodium Dodecyl Sulfate (SDS) and 320mg of polyvinylpyrrolidone K30(PVP-K30) were taken as stabilizers and dissolved in 160ml of pure water to be sufficiently swelled. Adding the apigenin-PEG 400 solution into water containing a stabilizer by a peristaltic pump under the condition of continuous stirring, wherein the injection speed is 20ml/min, the stirring speed is 420r/min, and after the solution is completely dripped, continuously stirring and shearing for 15min to obtain the apigenin nano suspension.
Example 2
Preparation of ibuprofen nanosuspension
4g of ibuprofen raw material medicine is taken to be put into 20ml of polyethylene glycol 600(PEG-600), and the ibuprofen raw material medicine is dissolved completely by boiling water bath ultrasound; 200mg of Sodium Dodecyl Sulfate (SDS) and 400mg of polyvinylpyrrolidone K30(PVP-K30) were taken as stabilizers and dissolved in 200ml of pure water to be sufficiently swelled. And under the condition of continuous stirring, adding the ibuprofen-PEG 600 solution into water containing a stabilizer through a peristaltic pump, wherein the injection speed is 20ml/min, the stirring speed is 800r/min, and after the solution is completely dripped, continuously stirring and shearing for 10min to obtain the ibuprofen nano suspension.
Example 3
Preparation of Perampanel nanosuspension
Taking 0.08g of Perampanel raw material medicine into 20ml of polyethylene glycol 300(PEG-300), and carrying out ultrasonic treatment in a boiling water bath to completely dissolve the Perampanel raw material medicine; 160mg of Sodium Dodecyl Sulfate (SDS) and 320mg of polyvinylpyrrolidone K30(PVP-K30) were taken as stabilizers and dissolved in 160ml of pure water to be sufficiently swelled. Adding the perampanel-PEG 300 solution into water containing a stabilizer by a peristaltic pump under the condition of continuous stirring, wherein the injection speed is 40ml/min, the stirring speed is 420r/min, and after the solution is completely dripped, continuously stirring and shearing for 20min to obtain the perampanel nano suspension.
Example 4
Preparation of eslicarbazepine nanosuspension
4.0g of eslicarbazepine bulk drug is taken to be put into 20ml of polyethylene glycol 200(PEG-200), and the mixture is subjected to ultrasonic treatment in boiling water bath to be completely dissolved; 80mg of Sodium Dodecyl Sulfate (SDS) and 160mg of polyvinylpyrrolidone K30(PVP-K30) were taken as stabilizers, and dissolved in 80ml of pure water to be sufficiently swelled. Under the condition of continuous stirring, adding the eslicarbazepine-PEG 200 solution into water containing a stabilizer by a peristaltic pump, wherein the injection speed is 20ml/min, the stirring speed is 1000r/min, and after the solution is completely dripped, continuously stirring and shearing for 10min to obtain the eslicarbazepine nano suspension.
Example 5
Preparation of terbinafine hydrochloride nano suspension
1.2g of terbinafine hydrochloride raw material medicine is taken to be put in 20ml of polyethylene glycol 400(PEG-400), and the terbinafine hydrochloride raw material medicine is dissolved completely by boiling water bath ultrasound; 120mg of Sodium Dodecyl Sulfate (SDS) and 120mg of polyvinylpyrrolidone K30(PVP-K30) were taken as stabilizers, and dissolved in 120ml of pure water to be sufficiently swelled. Under the condition of continuous stirring, adding the terbinafine hydrochloride-PEG 400 solution into water containing a stabilizer by a peristaltic pump, wherein the injection speed is 20ml/min, the stirring speed is 420r/min, and after the solution is completely dripped, continuously stirring and shearing for 5min to obtain the terbinafine hydrochloride nano suspension.
Example 6
Preparation of budesonide nanosuspensions
Taking 0.75g of budesonide bulk drug into 30ml of polyethylene glycol 400(PEG-400), and carrying out ultrasonic treatment in a boiling water bath to completely dissolve the budesonide bulk drug; 150mg of Sodium Dodecyl Sulfate (SDS) and 300mg of polyvinylpyrrolidone K30(PVP-K30) were taken as stabilizers and dissolved in 150ml of pure water to be sufficiently swelled. Under the condition of continuous stirring, adding the budesonide-PEG 400 solution into water containing a stabilizer by a peristaltic pump, wherein the injection speed is 20ml/min, the stirring speed is 420r/min, and after the solution is completely dripped, continuously stirring and shearing for 15min to obtain the budesonide nano suspension.
Example 7
Preparation of fluticasone propionate nanosuspension
Taking 0.0175g of fluticasone propionate bulk drug in 35ml of polyethylene glycol 400(PEG-400), and carrying out ultrasonic treatment in boiling water bath to completely dissolve the fluticasone propionate bulk drug; 70mg of Sodium Dodecyl Sulfate (SDS) and 210mg of polyvinylpyrrolidone K30(PVP-K30) were dissolved in 70ml of pure water as stabilizers and sufficiently swelled. And under the condition of continuous stirring, adding the fluticasone propionate-PEG 400 solution into water containing a stabilizer by a peristaltic pump, injecting the solution at the speed of 30ml/min and stirring at the speed of 600r/min, and after the solution is completely dripped, continuously stirring and shearing for 15min to obtain the fluticasone propionate nano suspension.
Example 8
Preparation of beclomethasone dipropionate nanosuspension
Taking 0.16g beclomethasone dipropionate bulk drug in 40ml polyethylene glycol 400(PEG-400), and carrying out ultrasonic treatment in a boiling water bath to completely dissolve the beclomethasone dipropionate bulk drug; 200mg of Sodium Dodecyl Sulfate (SDS) and 400mg of polyvinylpyrrolidone K30(PVP-K30) were taken as stabilizers and dissolved in 200ml of pure water to be sufficiently swelled. Under the condition of continuous stirring, adding the beclomethasone dipropionate-PEG 400 solution into water containing a stabilizer by a peristaltic pump, wherein the injection speed is 50ml/min, the stirring speed is 750r/min, and after the solution is completely dripped, continuously stirring and shearing for 15min to obtain the beclomethasone dipropionate nano suspension.
Example 9
Preparation of dexamethasone nanosuspension
1.4g of dexamethasone raw material medicine is taken to be arranged in 35ml of polyethylene glycol 400(PEG-400), and the dexamethasone raw material medicine is dissolved completely by boiling water bath ultrasound; in addition, 280mg of Sodium Dodecyl Sulfate (SDS) and 560mg of polyvinylpyrrolidone K30(PVP-K30) were used as stabilizers, and dissolved in 280ml of pure water to sufficiently swell. Under the condition of continuous stirring, adding the dexamethasone-PEG 400 solution into water containing a stabilizing agent by a peristaltic pump, wherein the injection speed is 20ml/min, the stirring speed is 420r/min, and after the solution is completely dripped, continuously stirring and shearing for 20min to obtain the dexamethasone nanosuspension.
Example 10
Preparation of loteprednol etabonate nano suspension
Taking 1.4g of loteprednol etabonate raw material medicine into 35ml of polyethylene glycol 400(PEG-400), and carrying out ultrasonic treatment in a boiling water bath to completely dissolve the loteprednol etabonate raw material medicine; in addition, 280mg of Sodium Dodecyl Sulfate (SDS) and 560mg of polyvinylpyrrolidone K30(PVP-K30) as stabilizers were dissolved in 280ml of pure water and sufficiently swelled. Under the condition of continuous stirring, adding the loteprednol etabonate-PEG 400 solution into water containing a stabilizer by a peristaltic pump, wherein the injection speed is 20ml/min, the stirring speed is 420r/min, and after the solution is completely dripped, continuously stirring and shearing for 15min to obtain the loteprednol etabonate nano suspension.
Example 11
Preparation of difluprednate nanosuspension
Taking 0.1g of difluprednate bulk drug in 25ml of polyethylene glycol 400(PEG-400), and carrying out ultrasonic treatment in a boiling water bath to completely dissolve the difluprednate bulk drug; in addition, 280mg of Sodium Dodecyl Sulfate (SDS) and 560mg of polyvinylpyrrolidone K30(PVP-K30) as stabilizers were dissolved in 200ml of pure water and sufficiently swelled. Under the condition of continuous stirring, the difluprednate-PEG 400 solution is added into water containing a stabilizer through a peristaltic pump, the injection speed is 20ml/min, the stirring speed is 420r/min, and after the solution is completely dripped, the solution is continuously stirred and sheared for 15min to obtain the difluprednate nanosuspension.
Comparative example 1
Preparation of nanosuspensions by traditional solvent-antisolvent process
1.8g of apigenin raw material medicine is taken to be placed in 30ml of dimethyl sulfoxide (DMSO), and the apigenin raw material medicine is dissolved completely through boiling water bath ultrasound; 450mg of polyvinylpyrrolidone K30(PVP-K30) as a stabilizer was dissolved in 240ml of pure water and sufficiently swelled. And under the condition of continuous stirring, adding the organic phase into the water phase through a peristaltic pump, wherein the injection speed is 20ml/min, the stirring speed is 450r/min, and after the solution is completely dripped, continuously stirring and shearing for 15min to obtain the apigenin nano suspension.
Comparative example 2
The preparation was carried out as described in example 2, except that the volume ratio of polyethylene glycol to water was 1:11, i.e. the volume of polyethylene glycol ether was changed to about 18.2ml keeping the volume of water constant.
Comparative example 3
The procedure is carried out as described in example 7, except that the volume ratio of polyethylene glycol to water is 1:1, i.e. the volume of polyethylene glycol is changed to 70ml while keeping the volume of water constant.
Comparative example 4
The procedure was followed as described in example 1, except that SDS was not used and PVP-K30 was used in an amount of 480 mg.
Comparative example 5
The procedure was followed as described in example 1, except that PVP-K30 was not used and SDS was used in an amount of 480 mg.
Test example
1. The average particle size and PDI of the products prepared in examples and comparative examples were determined using a laser particle size analyzer; the instrument parameters include: the channel width is 10 mus, the refractive index is 1.333, the laser wavelength is 632.8, and the scattering angle is 90 ℃. The results are shown in Table 1.
TABLE 1
| Numbering | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| Particle size (nm) | 267.4±4.9 | 215.2±2.8 | 252.1±2.4 | 312.4±1.8 | 286.3±2.0 | 301.5±1.5 |
| PDI | 0.068 | 0.076 | 0.062 | 0.075 | 0.072 | 0.081 |
| Numbering | Example 7 | Example 8 | Example 9 | Example 10 | Example 11 | |
| Particle size (nm) | 345.3±1.3 | 291.6±1.7 | 272.3±2.2 | 280.3±1.9 | 279.5±3.1 | |
| PDI | 0.089 | 0.077 | 0.079 | 0.081 | 0.075 | |
| Numbering | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | |
| Particle size (nm) | 536.3±4.7 | 195.4±1.7 | 361.4±1.5 | 536.3±4.7 | 654.0±2.9 | |
| PDI | 0.156 | 0.085 | 0.091 | 0.369 | 0.451 |
As can be seen from Table 1, the nano cosolvent prepared by the method has the drug particle size within the range of 200-350 nm, is smaller than the nano suspension prepared by the traditional method, can directly influence the drug solubility and the dissolution speed, and further influences the clinical curative effect, and can significantly improve the drug solubility and the dissolution rate, so that the bioavailability is improved, and the clinical curative effect is finally improved. Also, as the ratio of the latent solvent to the anti-solvent increases, the particle size of the drug tends to decrease. However, when the ratio is increased, the drug loading of the system is too low to exert the drug effect of the preparation, so that the ratio of the latent solvent to the anti-solvent is controlled to be 1 (2-10).
2. The stability of the nanosuspensions prepared in examples and comparative examples was examined, and the content, particle size and sedimentation volume ratio of the above samples were observed as a function of time under conditions of 25 ℃ and 60% humidity, and the results of the examination are shown in Table 2.
TABLE 2
As can be seen from table 2, when prepared according to the method described in the present application, the nanosuspension obtained had excellent stability without the need for a curing operation as compared with the conventional preparation method.
3. In vitro dissolution determination
The product of example 1 and apigenin raw material were subjected to dissolution measurement according to the second method (Paddle method) of dissolution and Release measurements of 0931, four parts of the Chinese pharmacopoeia 2020 edition. 5mg of apigenin raw material is precisely weighed, 1000mL of phosphate buffer solution with pH1.0, 4.5 and 6.8 is respectively added into 0.2mL of nano suspension, 0.5% Tween-80 (5g) is added and stirred when the temperature of a dissolving medium is kept at 37.0 +/-0.5 ℃, and the rotating speed of a stirring paddle is set to be 50 r/min. Sampling 5mL (simultaneously adding release medium with the same volume) at 5min, 10min, 15min, 25 min, 45 min and 60min respectively, filtering with a 0.22-micrometer microporous membrane, taking 3mL of subsequent filtrate, diluting methanol to a constant volume of 10mL, performing liquid chromatography detection, continuously performing 3 times, recording peak areas, and calculating the cumulative release amount of the apigenin original drug and the nanosuspension at each time by an external standard method.
The dissolution curve of apigenin and apigenin nanosuspension is shown in figure 1, wherein a, b and c are dissolution curves of apigenin original drug under the conditions of pH1.0, 4.5 and 6.8; d, e and f are dissolution curves of the apigenin nanosuspension under the conditions of pH1.0, 4.5 and 6.8.
The results of in vitro release studies are shown in table 3.
TABLE 3
From the results, the accumulative release rate of the apigenin nanosuspension prepared in example 1 in the invention reaches over 60% at each pH value for 60min, the accumulative release rate of the apigenin bulk drug is only 29.08% at the highest value at pH value of 4.5 for 60min, and the dissolution speed and degree of the apigenin nanosuspension are obviously superior to those of the bulk drug. According to the Ostwald-Freundlich equation and the Noyes-Whitney equation, the dissolution rate of the medicine in the nanosuspension is obviously improved, the particle size of the apigenin is reduced, the surface area is increased, and the cumulative release degree is improved.
4. In vivo pharmacokinetic assay
The sample in example 1 and the apigenin raw drug are taken to be orally administered by rats, the pharmacokinetic characteristics of the drug in vivo are examined, and the bioavailability of the apigenin nanosuspension and the apigenin raw drug is compared. Male SD rats were 6, randomly divided into 3 groups: tail vein group, raw material medicine group and example group, each group is 3. The tail vein group adopts tail vein injection administration, and apigenin injection is administered, wherein the dose is 5 mg/kg; the bulk drug group and the nanosuspension group are administrated by intragastric administration, and the oral suspension of apigenin and the sample in example 1 are respectively administrated, and the dosage is 5 mg/kg. Fasting was 12h before the test, free drinking, and 2h after dosing with a uniform diet.
The original medicine group and the nano suspension group are administrated by gastric lavage, and blood samples are collected at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 24 hours after administration; collecting blood samples at 5min after tail vein injection administration and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0 and 24 h; 0.30mL of blood was drawn through the orbital plexus of the posterior venous plexus of the rat at the above set time points, placed in an anticoagulation tube containing heparin, centrifuged at 14000rpm for 5min, and plasma was separated and frozen in a refrigerator at-20 ℃ for use. The plasma concentration of apigenin is measured by adopting a high performance liquid chromatography-mass spectrometry combined method, and pharmacokinetic parameters after administration are calculated by adopting a non-compartmental model of Phoenix 1.3 software (Pharsight company in America).
Absolute bioavailability of
The time-dependent change of the blood concentration in vivo of two groups of intragastric administration is shown in figure 2, wherein the powder-5mg/kg is apigenin raw material medicine group, and the nano-5mg/kg is example group.
The results of the in vivo pharmacokinetic testing are shown in table 4.
TABLE 4
The pharmacokinetic results show that the Cmax of the apigenin nano suspension prepared by the invention in a rat body is increased by 3.8 times compared with the Cmax of a raw pesticide, and the AUC 0-t The total content of F (absolute bioavailability) is increased by 1.6 times compared with the original medicine, and the total content of F (absolute bioavailability) is increased by 1.6 times compared with the original medicine. The results show that the apigenin nano suspension prepared by the invention has more advantages in drug effect exertion than the original drug and has higher bioavailability.
From the test results, the nano suspension prepared by the method has excellent stability with the medicine particle size within the range of 200-350 nm, and the dissolution speed and degree of the suspension are obviously improved compared with those of the bulk drugs, so that the nano suspension has higher bioavailability in rats.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.
Claims (5)
1. A process for preparing a poorly soluble drug nanosuspension, comprising the steps of:
(1) dissolving an insoluble drug in a cosolvent to obtain a drug-cosolvent solution;
(2) dissolving a stabilizer in water to obtain a water solution containing the stabilizer;
(3) adding the drug-cosolvent solution obtained in the step (1) into the aqueous solution containing the stabilizer obtained in the step (2) under stirring, and after the addition is finished, continuously stirring and shearing to obtain the insoluble drug nanosuspension;
wherein the volume ratio of the latent solvent to water is 1 (2-10);
the stabilizer is a mixture of a charge stabilizer and a steric stabilizer;
the insoluble drug is selected from at least one of apigenin, ibuprofen, perampanel, eslicarbazepine, terbinafine hydrochloride, budesonide, fluticasone propionate, beclomethasone propionate and dexamethasone;
in the step (1), the cosolvent is polyethylene glycol with the relative molecular mass of 200-600;
in the step (2), the weight ratio of the charge stabilizer to water is 0.1-0.3%; the weight ratio of the three-dimensional stabilizer to water is 0.1-0.3%; the weight ratio of the charge stabilizer to the steric stabilizer is 1 (1-3);
the weight of the insoluble drug to the volume of water is 0.0002 to 0.06 g/mL;
the charge stabilizer is sodium dodecyl sulfate or sodium dodecyl sulfate, and the steric stabilizer is poloxamer or povidone K30.
2. The process for preparing a poorly soluble drug nanosuspension according to claim 1, wherein in step (3), the addition rate of the drug-cosolvent solution is 20 to 80 mL/min.
3. The process for preparing a poorly soluble pharmaceutical nanosuspension according to claim 1 or 2, wherein in step (3), the stirring speed is 300 to 1100 r/min.
4. The process for preparing a poorly soluble pharmaceutical nanosuspension according to claim 1 or 2, wherein in step (3), the time period for the shearing is 5 to 20 min.
5. The poorly soluble drug nanosuspension prepared by the method of any one of claims 1 to 4, wherein the particle size of the drug in the poorly soluble drug nanosuspension is 200 to 350 nm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110382909.8A CN113069415B (en) | 2021-04-09 | 2021-04-09 | Insoluble drug nanosuspension and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110382909.8A CN113069415B (en) | 2021-04-09 | 2021-04-09 | Insoluble drug nanosuspension and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113069415A CN113069415A (en) | 2021-07-06 |
| CN113069415B true CN113069415B (en) | 2022-09-09 |
Family
ID=76615783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110382909.8A Active CN113069415B (en) | 2021-04-09 | 2021-04-09 | Insoluble drug nanosuspension and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113069415B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114652678A (en) * | 2022-04-08 | 2022-06-24 | 宁夏医科大学 | Insoluble drug nano suspension and preparation method thereof |
| CN115531311A (en) * | 2022-10-24 | 2022-12-30 | 上海迦蓝海纳米技术集团有限公司 | Nanometer suspension containing ibuprofen and preparation method thereof |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103588846B (en) * | 2012-08-15 | 2016-08-03 | 重庆华邦制药有限公司 | A kind of preparation method and its usage of fluticasone propionate microgranule |
| CN103637984A (en) * | 2013-12-24 | 2014-03-19 | 宁夏医科大学 | Baicalin nanometer crystal and preparation method thereof |
| US20150352176A1 (en) * | 2014-06-06 | 2015-12-10 | Newport Research, Inc. | Oil-free and fat-free aqueous suspensions of cyclosporin |
| CN104274401A (en) * | 2014-07-25 | 2015-01-14 | 中国医学科学院药用植物研究所 | High drug-loading content nano suspension for camptothecin medicine based on HCPT-PEG (hydroxycamptothecin-polyethylene glycol) and preparation method of high drug-loading content nano suspension |
| PT107846B (en) * | 2014-08-01 | 2019-03-22 | Hovione Farm S A | Production of Amorphous Solid Dispersion Nanoparticles by Controlled Co-Precipitation |
| CN104814926A (en) * | 2015-04-08 | 2015-08-05 | 中国药科大学 | Lurasidone nanosuspension and preparation method thereof |
| CN106137981B (en) * | 2015-04-15 | 2019-10-15 | 中国医学科学院医药生物技术研究所 | A kind of dabigatran etcxilate freeze-drying nano suspension and preparation method thereof |
| CN105147605B (en) * | 2015-06-24 | 2019-04-19 | 中国人民解放军军事医学科学院毒物药物研究所 | Progesterone nano-composition and preparation method thereof |
| CN108567763A (en) * | 2018-06-12 | 2018-09-25 | 广州中医药大学(广州中医药研究院) | A kind of Paeoniflorin nanocrystal and preparation method thereof |
-
2021
- 2021-04-09 CN CN202110382909.8A patent/CN113069415B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113069415A (en) | 2021-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Jacob et al. | Emerging role of nanosuspensions in drug delivery systems | |
| Mohammad et al. | Drug nanocrystals: Fabrication methods and promising therapeutic applications | |
| CN113069415B (en) | Insoluble drug nanosuspension and preparation method thereof | |
| Kanikkannan | Technologies to improve the solubility, dissolution and bioavailability of poorly soluble drugs | |
| Sikarra et al. | Techniques for solubility enhancement of poorly soluble drugs: an overview | |
| JP5439182B2 (en) | Chemical micelle nanoparticles | |
| Yadav et al. | Nanosuspension: A promising drug delivery system | |
| Alshora et al. | Nanotechnology from particle size reduction to enhancing aqueous solubility | |
| WO2006073154A1 (en) | Medicinal composition and process for producing the same | |
| Kumar et al. | An informative review on solid dispersion | |
| TWI392507B (en) | Embedded micellar nanoparticles | |
| CN114796133B (en) | Injection pharmaceutical preparation and preparation method thereof | |
| CN110840850A (en) | Celecoxib freeze-dried orally disintegrating tablet with high bioavailability and preparation method thereof | |
| CN106902357B (en) | Pharmaceutical composition and application thereof, pharmaceutical clathrate, intravenous preparation and preparation method | |
| CN113398094A (en) | Insoluble veterinary drug nanosuspension and preparation method thereof | |
| Nayak et al. | Nanosuspension: Bioavailability enhancing novel approach | |
| CN111743868B (en) | Lyophilized preparation of polymer micelle encapsulating arbidol hydrochloride and preparation method thereof | |
| US20230404981A1 (en) | Pharmaceutically active compound formulations | |
| JP6654702B2 (en) | Oral formulation and production method thereof | |
| Kumar et al. | Solid dispersions: An approach to enhance solubility of poorly soluble drugs | |
| WO2019186444A1 (en) | Oral liquid formulations of abiraterone | |
| CN113440529B (en) | Injectable pharmaceutical composition and preparation method thereof | |
| CN113975232B (en) | Pharmaceutical composition of metronidazole benzoate | |
| CN113975233B (en) | Preparation method of enteric stable ursodeoxycholic acid nanosuspension | |
| Devi et al. | A review on solid dispersions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |