CN111743868B - Lyophilized preparation of polymer micelle encapsulating arbidol hydrochloride and preparation method thereof - Google Patents
Lyophilized preparation of polymer micelle encapsulating arbidol hydrochloride and preparation method thereof Download PDFInfo
- Publication number
- CN111743868B CN111743868B CN202010594073.3A CN202010594073A CN111743868B CN 111743868 B CN111743868 B CN 111743868B CN 202010594073 A CN202010594073 A CN 202010594073A CN 111743868 B CN111743868 B CN 111743868B
- Authority
- CN
- China
- Prior art keywords
- polymer
- arbidol hydrochloride
- preparation
- hydrochloride
- pla
- 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
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
- A61K9/14—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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- 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
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Abstract
The invention relates to the technical field of polymer micelles, and provides a freeze-dried preparation of the polymer micelle entrapping the arbidol hydrochloride and a preparation method thereof, wherein the freeze-dried preparation comprises the following components: arbidol hydrochloride: 5-6 parts; block polymer: 50-80 parts; 3-12 parts of a stabilizer; freeze-drying protective agent: 30-40 parts; the stabilizer comprises the following components in a mass ratio of 2-5:1 poloxamer 188 and an organic acid; by adopting the arbidol hydrochloride, the block polymer, the stabilizer and the freeze-drying protective agent, under the specific mixture ratio, the mass ratio of the arbidol hydrochloride to the block polymer to the stabilizer is 2-5:1, the arbidol hydrochloride-encapsulated polymer micelle formed by taking poloxamer 188 and an organic acid as stabilizers can remarkably improve the physical stability of the polymer micelle and the chemical stability of the arbidol hydrochloride in long-term storage, and the substances are not obviously changed when the polymer micelle is placed for 6 months under long-term conditions (25 ℃/RH 60%) and accelerated conditions (40 ℃/75%).
Description
Technical Field
The invention relates to the technical field of polymer micelles, in particular to a freeze-dried preparation of a polymer micelle entrapping arbidol hydrochloride and a preparation method thereof.
Background
Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease caused by influenza virus, which has high prevalence rate, wide epidemics and rapid spread. Influenza epidemics occur in different degrees every year, and only in the twentieth century there have been 5 world-scale pandemics, causing immeasurable losses to people's life and socioeconomic performance.
Arbidol Hydrochloride (AH), chemically 6-bromo-4- (dimethylaminomethyl) -5-hydroxy-1-methyl-2- (phenylthiomethyl) -1H-indole-3-carboxylic acid ethyl ester Hydrochloride monohydrate, is an interferon inducer, an immunopotentiator and an anti-influenza virus drug, and has the following structural formula:
it is a broad-spectrum antiviral drug, can inhibit A, B and C type influenza virus, is the only drug for resisting C type influenza virus, and is used for treating H type influenza virus1N1、H2N2、H3N2、H6N1、H5N1The virus has therapeutic effect, can enter cell nucleus to directly inhibit synthesis of virus DNA and RNA, and simultaneously enhance immunity. The tablet formulation was developed by the Russian chemical pharmaceutical research institute, approved for Russian marketing by the Russian Committee in 1993, and is now licensed for marketing in 28 countries.
Arbidol hydrochloride is easy to dissolve in methanol, slightly soluble in glacial acetic acid, almost insoluble in water, dilute hydrochloric acid and sodium hydroxide, the solubility in water is only 0.024mg/ml (25 ℃), the intravenous injection is limited, the preparation sold on the market at present is mainly tablets, capsules and dry suspensions, the specifications are 100mg and 200mg, and the pharmacokinetics experiments show that the absorption is rapid after the Arbidol hydrochloride tablet is administrated by gastric gavage of rats, the plasma tmax is 20min, and the half-life period is 6.7 h. Because the half-life period of the arbidol hydrochloride is short, in order to achieve the best treatment effect, the common arbidol hydrochloride tablet or capsule needs to be administrated 3-4 times a day, 200mg each time, and inconvenience is brought to patients when the common arbidol hydrochloride tablet or capsule is clinically administrated.
In view of the above problems, there have been many attempts by scholars at home and abroad, including extensive studies on crystal forms and novel formulations of arbidol hydrochloride.
Patent document CN102413829A discloses a lyophilized preparation of abidopol hydrochloride-entrapped nano-micelle, the size of the nano-micelle is 8-25nm, the nano-micelle comprises 20-43 wt% of phosphatidylcholine, 55-78 wt% of maltose and 2-8 wt% of abidopol hydrochloride, the particle size of the phosphatidylcholine micelle can be almost unchanged after being stably placed for 7 days, however, the inventor finds in further research that, although the physical stability of the abidopol hydrochloride can be improved to a certain extent by the method, in the long-term (25 ℃/RH 60%) and accelerated (40 ℃/75%) stability investigation, related substances of the micelle are increased faster, so that the effective period of the drug is too short to be applied in clinic.
Therefore, it is necessary to research an abidol hydrochloride nano micelle system, which can solve the problem of physical stability of the abidol hydrochloride micelle and the problem of chemical stability of the abidol hydrochloride micelle during long-term storage.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defect that the physical stability and the long-term storage chemical stability of the arbidol hydrochloride micelle are poor in the prior art, so that the arbidol hydrochloride-entrapped polymeric micelle and the preparation method thereof are provided.
The invention provides a freeze-dried preparation of polymer micelle loaded with arbidol hydrochloride, which comprises the following raw materials in parts by weight:
the stabilizer comprises poloxamer 188 and organic acid in a mass ratio of 2-5: 1.
Further, the organic acid is at least one of citric acid, tartaric acid, malic acid and fumaric acid; citric acid is preferred.
Further, the lyoprotectant is selected from at least one of mannitol, lactose and sucrose.
Further, the block polymer comprises mPEG-PLA, wherein the weight average molecular weight of mPEG in the mPEG-PLA is 1000-2000, and the weight average molecular weight of PLA is 5000-10000. Wherein mPEG is methoxy polyethylene glycol, and PLA is polylactic acid.
Further, the block polymer also comprises polyethylene glycol 1000 vitamin E succinate, and the mass ratio of the mPEG-PLA to the polyethylene glycol 1000 vitamin E succinate is 3-5: 1.
The invention also provides a preparation method of the lyophilized preparation of the polymer micelle entrapping the arbidol hydrochloride, which comprises the following steps:
dissolving the block polymer, the arbidol hydrochloride and the stabilizer in an organic solvent, removing the organic solvent by rotary evaporation to form a polymer drug organic membrane, adding water to dissolve the polymer drug organic membrane, adding a freeze-drying protective agent, and freeze-drying to obtain the compound.
Further, the organic solvent is at least one of methanol, acetone and ethanol; preferably a mixed solvent of methanol and acetone.
Further, the mass of the block polymer and the volume of the organic solvent are 5 to 8 g: 400 and 600 ml.
Further, the ratio of the mass of the block polymer to the volume of water is 5 to 8 g: 10-50 ml.
The arbidol hydrochloride aerosol also comprises a propellant.
The technical scheme of the invention has the following advantages:
1. the lyophilized preparation of the polymer micelle entrapping the arbidol hydrochloride provided by the invention adopts the arbidol hydrochloride, the block polymer, the stabilizer and the lyophilization protectant according to the mass ratio of 2-5:1, the arbidol hydrochloride-encapsulated polymer micelle formed by taking poloxamer 188 and an organic acid as stabilizers can remarkably improve the physical stability of the polymer micelle and the chemical stability of the arbidol hydrochloride in long-term storage, and the substances are not obviously changed when the polymer micelle is placed for 1 month under long-term conditions (25 ℃/RH 60%) and accelerated conditions (40 ℃/75%).
2. The lyophilized preparation of the polymer micelle entrapping the arbidol hydrochloride provided by the invention can further improve the physical stability of the polymer micelle by preferably adopting citric acid as a stabilizer.
3. According to the lyophilized preparation of the arbidol hydrochloride-entrapped polymer micelle, the block polymer also comprises polyethylene glycol 1000 vitamin E succinate, the physical stability of the polymer micelle can be further improved by adopting the mass ratio of 3-5:1 between mPEG-PLA and polyethylene glycol 1000 vitamin E succinate, the occurrence of the condition that the arbidol hydrochloride leaks out of the polymer micelle is improved, and the chemical stability of the arbidol hydrochloride is improved.
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
Example 1
The embodiment provides a lyophilized preparation of a polymer micelle encapsulating arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 4g mPEG1000-PLA50001g polyethylene glycol 1000 vitamin E succinate0.5g of abidol hydrochloride, 0.8g of poloxamer 188, 0.4g of citric acid and 4g of mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG1000-PLA5000Mixing polyethylene glycol 1000 vitamin E succinate, arbidol hydrochloride and poloxamer 188, adding a mixed solvent (prepared by mixing 200ml of methanol and 300ml of acetone) for dissolving, adding citric acid, uniformly mixing, performing rotary evaporation at 45 ℃ to remove the organic solvent to obtain a polymer drug organic membrane, performing vacuum drying overnight, and removing the residual organic solvent.
(2) Adding 30ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Example 2
The embodiment provides a lyophilized preparation of a polymer micelle encapsulating arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 4g mPEG1000-PLA50001g of polyethylene glycol 1000 vitamin E succinate, 0.5g of Arbidol hydrochloride, 0.8g of poloxamer 188, 0.4g of malic acid and 4g of mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG1000-PLA5000Mixing polyethylene glycol 1000 vitamin E succinate, arbidol hydrochloride and poloxamer 188, adding mixed solvent (prepared by mixing 200ml of methanol and 300ml of acetone) to dissolve, adding malic acid, mixing uniformly, removing organic solvent by rotary evaporation at 45 ℃ to obtain polymer drug organic membrane, vacuum drying overnight, and removing residual organic solvent.
(2) Adding 30ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Example 3
The embodiment provides a lyophilized preparation of a polymer micelle encapsulating arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 5g mPEG1000-PLA50000.5g of Arbidol hydrochloride0.8g poloxamer 188, 0.4g citric acid and 4g mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG according to the weight1000-PLA5000Mixing Arbidol hydrochloride and poloxamer 188, dissolving in mixed solvent (prepared by mixing 200ml methanol and 300ml acetone), adding citric acid, mixing, rotary evaporating at 45 deg.C to remove organic solvent to obtain polymer medicine organic film, vacuum drying overnight, and removing residual organic solvent.
(2) Adding 30ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Example 4
The embodiment provides a lyophilized preparation of a polymer micelle encapsulating arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 4g mPEG1000-PLA50001g of polyethylene glycol 1000 vitamin E succinate, 0.5g of Arbidol hydrochloride, 0.8g of poloxamer 188, 0.4g of citric acid and 4g of mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG according to the weight1000-PLA5000Mixing polyethylene glycol 1000 vitamin E succinate, arbidol hydrochloride and poloxamer 188, adding 500ml of methanol for dissolving, adding citric acid, uniformly mixing, rotatably evaporating at 45 ℃ to remove the organic solvent to obtain a polymer medicine organic membrane, drying overnight in vacuum, and removing the residual organic solvent.
(2) Adding 30ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Example 5
The embodiment provides a lyophilized preparation of a polymer micelle encapsulating arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 4g mPEG2000-PLA100002g of polyethylene glycol 1000 vitamin E succinate, 0.6g of saltArbidol acid, 0.3g poloxamer 188, 0.06g citric acid and 3g mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG according to the weight2000-PLA10000Mixing polyethylene glycol 1000 vitamin E succinate, arbidol hydrochloride and poloxamer 188, adding a mixed solvent (prepared by mixing 300ml of methanol and 100ml of acetone) for dissolving, adding citric acid, uniformly mixing, performing rotary evaporation at 45 ℃ to remove the organic solvent to obtain a polymer drug organic membrane, performing vacuum drying overnight, and removing the residual organic solvent.
(2) Adding 10ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Comparative example 1
The phospholipid arbidol hydrochloride freeze-dried powder is prepared by adopting the raw material formula and the method disclosed in the specific embodiment part of the patent document CN02413829A, and the specific steps are as follows: 25g of maltose was dissolved in 200ml of water at 45 deg.C (until all was dissolved). To the maltose solution thus obtained were added 625mg of abidol hydrochloride and 6.25g of phospholipids. The mixture was homogenized using a stirrer and its volume increased to 250ml to give a coarse emulsion. The crude emulsion was filtered through a 0.45 μm sterile microporous membrane filter at 800bar through a homogenizer, and the formulation was poured into 10ml vials and lyophilized.
Comparative example 2
The comparative example provides a lyophilized preparation of polymer micelle entrapping arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 4g mPEG1000-PLA50001g of polyethylene glycol 1000 vitamin E succinate, 0.5g of Arbidol hydrochloride, 1.2g of poloxamer 188 and 4g of mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG according to the weight1000-PLA5000Mixing polyethylene glycol 1000 vitamin E succinate, arbidol hydrochloride and poloxamer 188, adding mixed solvent (prepared by mixing 200ml methanol and 300ml acetone), dissolving, and cooling at 45 deg.CThe organic solvent was removed by rotary evaporation to give a polymeric drug organic film, which was dried overnight under vacuum to remove residual organic solvent.
(2) Adding 30ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Comparative example 3
The comparative example provides a lyophilized preparation of polymer micelle entrapping arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 4g mPEG1000-PLA50001g of polyethylene glycol 1000 vitamin E succinate, 0.5g of Arbidol hydrochloride, 0.8g of Tween 80, 0.4g of citric acid and 4g of mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG according to the weight1000-PLA5000Mixing polyethylene glycol 1000 vitamin E succinate, arbidol hydrochloride and Tween 80, adding mixed solvent (prepared by mixing 200ml of methanol and 300ml of acetone) to dissolve, adding citric acid, mixing uniformly, removing organic solvent by rotary evaporation at 45 ℃ to obtain polymer drug organic membrane, vacuum drying overnight, and removing residual organic solvent.
(2) Adding 30ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Comparative example 4
The comparative example provides a lyophilized preparation of polymer micelle entrapping arbidol hydrochloride and a preparation method thereof, and the lyophilized preparation comprises the following raw materials: 4g mPEG1000-PLA50001g of polyethylene glycol 1000 vitamin E succinate, 0.5g of abidol hydrochloride, 0.8g of beta-cyclodextrin, 0.4g of citric acid and 4g of mannitol.
The preparation method comprises the following steps:
(1) weighing mPEG according to the weight1000-PLA5000Mixing polyethylene glycol 1000 vitamin E succinate, arbidol hydrochloride and beta-cyclodextrin, dissolving in mixed solvent (prepared by mixing 200ml methanol and 300ml acetone), adding lemonMixing citric acid, rotary evaporating at 45 deg.C to remove organic solvent to obtain polymer drug organic film, vacuum drying overnight, and removing residual organic solvent.
(2) Adding 30ml of water for injection into the polymer membrane, dissolving the polymer membrane, adding mannitol, adjusting pH to 7.0, filtering with 0.22 μm sterile microporous membrane, and lyophilizing.
Experimental example 1 physical stability-encapsulation efficiency
Weighing 1g of the micelle freeze-dried preparation prepared in each group of examples and comparative examples, adding 5ml of physiological saline for redissolving to obtain polymer micelle solution, and determining the encapsulation efficiency and the drug loading rate by adopting a high performance liquid chromatography method respectively after the polymer micelle solution is placed for 7 days at 4 ℃ before and after the polymer micelle solution is placed. The method comprises the following specific steps: adding a certain amount of normal saline into the micelle freeze-dried preparations prepared in the embodiments and the comparative examples for redissolution to obtain a polymer micelle solution, placing the polymer micelle solution for 7 days before and at 4 ℃, respectively taking 1ml of the polymer micelle solution, adding 4ml of methanol, performing ultrasonic treatment for 30min at room temperature, performing vortex breaking for 1min, filtering the solution by using a sterile microporous filter membrane with the diameter of 0.45 mu m, and determining the content of the arbidol hydrochloride by using a high performance liquid chromatography according to references (determining the content of the arbidol hydrochloride and related substances thereof by using high performance liquid chromatography of Guangyfei et al, J. Pharmacology of China, 2007:27 (4): 492) 494.) by using a high performance liquid chromatography, wherein the chromatographic conditions are as follows: alltech Apollo C18(5 μm, 250 mm. times.4.6 mm) column; mobile phase A: acetonitrile, mobile phase B: 0.1% aqueous triethylamine (pH adjusted to 2.0 with phosphoric acid), mobile phase a: mobile phase B was 47.5: 52.7, detection wavelength: 315 nm; the flow rate is 1.0 ml/min; the temperature is 25 ℃, the sample injection amount is 10 mul, and the theoretical plate number is not less than 10000 calculated by Arbidol hydrochloride. The encapsulation efficiency and the rate of change thereof were calculated, i.e., (encapsulation efficiency before leaving-encapsulation efficiency after leaving)/encapsulation efficiency before leaving, and the results are shown in the following table.
TABLE 1 encapsulation efficiency of different micelle carriers for arbidol hydrochloride
As can be seen from the above table, the polymer micelles prepared in examples 1 to 5 of the present invention have good physical stability, and the encapsulation efficiency after being redissolved for 7 days has a rate of change of less than 1%, which is substantially unchanged, while the encapsulation efficiency of comparative examples 1 to 4 has a significantly reduced rate of change of more than 1%, which indicates that the polymer micelles with abidol hydrochloride entrapped therein prepared in comparative examples 1 to 4 have poor physical stability. In addition, compared with examples 2 to 4, the encapsulation efficiency of the polymer micelle can be further improved and the change rate of the encapsulation efficiency can be reduced by the improvement of the block polymer material, the organic acid species and the organic solvent in example 1 of the present invention.
Experimental example 2 physical stability-particle diameter
1g of the micelle lyophilized preparation prepared in each of the examples and comparative examples was weighed, and was redissolved in 5ml of physiological saline, and the average particle size was measured before and after standing at 4 ℃ for 7 days by using a malvern particle size analyzer, and the change rate of the average particle size before and after standing, i.e., the change rate (average particle size before standing-average particle size after standing)/the average particle size before standing, was calculated, and the results are shown in the following table.
TABLE 2 physical stability of different micellar vectors to Abidol hydrochloride
As can be seen from the above table, the polymer micelles obtained in examples 1 to 5 of the present invention have good physical stability, and the change in particle size after being redissolved for 7 days is small, which indicates that the morphology of the polymer micelle remains stable, and in addition, compared with examples 2 to 4, example 1 of the present invention can further reduce the rate of change in particle size of the polymer micelle by improving the block polymer material, the type of organic acid, and the organic solvent.
Experimental example 3 chemical stability
The micelles obtained in the respective groups of examples and comparative examples were lyophilizedThe preparation is respectively placed in a long-term condition (25 ℃/RH 60%) and an accelerated condition (40 ℃/RH 75%) for 6 months, and is respectively placed in 0 month, 1 month, 2 months, 3 months and 6 months, and a sample is taken to determine related substances (%) by adopting a high performance liquid chromatography, and the preparation specifically comprises the following steps: adding a certain amount of physiological saline into the micelle freeze-dried preparations prepared in the embodiments and the comparative examples to redissolve to obtain polymer micelle solutions, respectively taking 1ml of the polymer micelle solutions, adding 4ml of methanol, performing ultrasonic treatment for 30min at room temperature, performing vortex breaking for 1min, filtering by using a sterile microfiltration membrane with the diameter of 0.45 mu m, and determining related substances of the arbidol hydrochloride by using a high performance liquid chromatography according to references (the content of the arbidol hydrochloride tablet and related substances thereof is determined by using high performance liquid chromatography of Gangyufei et al, journal of pharmacy in China, 2007:27 (4): 492 and 494.) by using a high performance liquid chromatography, wherein the chromatographic conditions are as follows: a chromatographic column: alltech Apollo C18(5 μm, 250 mm. times.4.6 mm) column; mobile phase A: acetonitrile, mobile phase B: 0.1% aqueous triethylamine (pH adjusted to 2.0 with phosphoric acid), mobile phase a: mobile phase B was 47.5: 52.7, detection wavelength: 315 nm; the flow rate is 1.0 ml/min; the temperature was 25 ℃ and the amount of sample was 10. mu.l, the theoretical plate number was not less than 10000 calculated as Arbidol hydrochloride, and the results are shown in the following table.
TABLE 3 accelerated stability of different micellar vectors to Abidol hydrochloride
TABLE 4 Long-term stability of different micellar vectors to Abidol hydrochloride
As can be seen from the above table, the chemical stability of the polymer micelles obtained in examples 1 to 5 of the present invention was significantly improved compared to comparative examples 1 to 4, and there was no significant change in the related substances in the micelle lyophilized formulations during 6 months of standing under the long-term conditions (25 ℃/RH 60%) and the accelerated conditions (40 ℃/RH 75%). In addition, compared with the examples 2 to 4, the example 1 of the present invention can further reduce the related substances by improving the block polymer material, the organic acid species and the organic solvent, and has the best chemical stability.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (6)
1. A freeze-dried preparation of polymer micelle entrapping arbidol hydrochloride is characterized by comprising the following raw materials in parts by weight:
the stabilizer comprises the following components in a mass ratio of 2-5:1 poloxamer 188 and an organic acid;
the organic acid is citric acid or malic acid;
the freeze-drying protective agent is mannitol;
the block polymer is mPEG-PLA or a composition consisting of mPEG-PLA and polyethylene glycol 1000 vitamin E succinate, wherein the mass ratio of mPEG-PLA to polyethylene glycol 1000 vitamin E succinate in the composition is 2-4: 1;
the mPEG-PLA is selected from mPEG1000-PLA5000Or mPEG2000-PLA10000。
2. A method for preparing the lyophilized preparation of the arbidol hydrochloride-entrapped polymeric micelle of claim 1, comprising the steps of:
dissolving the block polymer, the arbidol hydrochloride and the stabilizer in an organic solvent, removing the organic solvent by rotary evaporation to form a polymer drug organic membrane, adding water to dissolve the polymer drug organic membrane, adding a freeze-drying protective agent, and freeze-drying to obtain the compound.
3. The method according to claim 2, wherein the organic solvent is at least one of methanol, acetone, and ethanol.
4. The production method according to claim 2, wherein the organic solvent is a mixed solvent of methanol and acetone.
5. The method according to any one of claims 2 to 4, wherein the mass of the block polymer and the volume of the organic solvent are in the range of 5 to 8 g: 400 and 600 ml.
6. The method according to any one of claims 2 to 4, wherein the ratio of the mass of the block polymer to the volume of water is 5 to 8 g: 10-50 ml.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010594073.3A CN111743868B (en) | 2020-06-24 | 2020-06-24 | Lyophilized preparation of polymer micelle encapsulating arbidol hydrochloride and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010594073.3A CN111743868B (en) | 2020-06-24 | 2020-06-24 | Lyophilized preparation of polymer micelle encapsulating arbidol hydrochloride and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111743868A CN111743868A (en) | 2020-10-09 |
| CN111743868B true CN111743868B (en) | 2021-04-06 |
Family
ID=72677427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010594073.3A Active CN111743868B (en) | 2020-06-24 | 2020-06-24 | Lyophilized preparation of polymer micelle encapsulating arbidol hydrochloride and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111743868B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2411942C2 (en) * | 2009-05-05 | 2011-02-20 | Общество с ограниченной ответственностью "ЭкоБиоФарм" | Pharmaceutic composition including arbidol in composition of phospholipid nanoparticles |
-
2020
- 2020-06-24 CN CN202010594073.3A patent/CN111743868B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111743868A (en) | 2020-10-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20090077074A (en) | Micellar nanoparticles of chemical substances | |
| EP1283725B1 (en) | Solid dispersion system of pranlukast with improved dissolution, and the preparing method thereof | |
| CN116270473B (en) | Co-carried liposome and preparation method thereof | |
| CN113069415B (en) | Insoluble drug nanosuspension and preparation method thereof | |
| EP3777862A1 (en) | Meloxicam composition, preparation and preparation method and use thereof | |
| Kumar et al. | An informative review on solid dispersion | |
| CN111743868B (en) | Lyophilized preparation of polymer micelle encapsulating arbidol hydrochloride and preparation method thereof | |
| CN116350592A (en) | Setitol nanocrystalline and preparation method and application thereof | |
| CN109498733B (en) | Dragon's blood nano suspension and preparation method thereof | |
| CN114886848B (en) | Preparation method of nano micelle composition and prepared nano micelle composition | |
| CN110840850B (en) | Celecoxib freeze-dried orally disintegrating tablet with high bioavailability and preparation method thereof | |
| CN110652496A (en) | Solid dispersion of cryptotanshinone and preparation method and application thereof | |
| CN105534947A (en) | Preparation method of celecoxib nanosuspension capsules | |
| CN102293748B (en) | Oral PEGylated insulin pH-sensitive naonparticle and preparation method thereof | |
| CN112500344B (en) | Crystalline form of roxasistat and preparation method thereof | |
| Xie et al. | High resveratrol-loaded microcapsules with trehalose and OSA starch as the wall materials: Fabrication, characterization, and evaluation | |
| CN103301067B (en) | It is a kind of improve absorbent properties solid dispersions and its preparation | |
| CN111514147A (en) | Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof | |
| Boukhris et al. | NOVEL ORAL FORMULATION OF CYCLOSPORINE-SPRAY-DRIED DISPERSION USING CYCLODEXTRIN COPOLYMERS. | |
| CN110193014B (en) | Laquinimod micelle freeze-dried preparation for injection, preparation method thereof and laquinimod injection | |
| CN114159391B (en) | Cabalatine bitartrate dry suspension and preparation method thereof | |
| CN116850248B (en) | Kekeping capsule and its preparation method | |
| CN115429756B (en) | Albendazole lipid complex as well as preparation method and application thereof | |
| CN113975233B (en) | Preparation method of enteric stable ursodeoxycholic acid nanosuspension | |
| CN110339163B (en) | Cisplatin-polyglutamic acid complex micelle and preparation method thereof |
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 |