CN113811309B - Polymer formulation for treating viral infections, preparation method and use - Google Patents
Polymer formulation for treating viral infections, preparation method and use Download PDFInfo
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Abstract
A preparation method and application of a polymer containing a Ruidexivir compound or a pharmaceutically acceptable salt thereof. The problem of water solubility of the adefovir dipivoxil compound or pharmaceutically acceptable salt thereof can be solved without sulfobutyl-beta-cyclodextrin Sodium (SBECD) and any acid-base regulator, the solubility of the adefovir can be greatly improved, and the formed particles have better lung aggregation effect and lower toxic and side effects; can be used for treating infection caused by trachomaceae virus, coronaviridae virus, filoviridae virus, flaviviridae virus or paramyxoviridae virus, lassa virus, hooning virus, severe Acute Respiratory Syndrome (SARS), and 2019 novel coronavirus (SARS-CoV-2), middle East Respiratory Syndrome (MERS), ebola virus, marburg virus, zika or respiratory syncytial virus.
Description
Technical Field
The present invention relates to the field of pharmaceutical formulations, in particular to polymer compositions containing Remdesivir (GS-5734) or derivatives thereof for the treatment of human diseases caused by various viral infections.
Background
Remdesivir (GS-5734), also known as rendesavir, formula C 27 H 35 N 6 O 8 P, the structural formula is shown in figure 1; is a nucleoside analogue with broad-spectrum antiviral activity, can be identified by RNA-dependent RNA polymerase (RdRp), penetrates into the synthesis of viral genome, prevents the formation of phosphodiester bonds, further terminates the synthesis of RNA chain, and inhibits viral replication. In addition to competing with Adenosine Triphosphate (ATP) for RdRp, adefovir can inhibit the correct riboexonuclease, block viral replication, and thus inhibit viral activity. Adefovir as a monophosphate prodrug can significantly increase the potency of the parent nucleoside by delivering monophosphate into the cell and effectively bypassing the rate limiting first phosphorylation step. The phenol and amino acid ester in the structure mask the negative charge of the monophosphate group, so that the monophosphate group can conveniently and passively permeate into cells. The cytolactonase (such as carboxylesterase-1 and cathepsin A) breaks down the ester into a carboxyl structure, then continues to break down into nucleoside monophosphates, and finally is phosphorylated to nucleoside triphosphates to exert antiviral effects. Phase I and phase II clinical trials of Ruidexivir for the treatment of ebola virus infection have been completed without significant adverse effects; adefovir in CN103052631B and CN105443098B can treat respiratory syncytial virus infection and parainfluenza virus infection; in CN107073005a adefovir can treat filoviridae virus infections; in CN108348526a adefovir can treat lassa virus and hooning virus infections; in HAE fineIn cells, the EC50 value of adefovir for SARS-CoV and MERS-CoV is 74nM, and in delayed brain tumor cells, the EC50 value for murine hepatitis virus is 30nM; despite the lack of animal and clinical trial data for covd-19, phase iii clinical trials of covd-19 therapy have been entered in view of the powerful potential of adefovir for the treatment of covd-19.
However, because of the poor solubility of adefovir, the solubility in water is about 0.03mg/ml, and the chemistry is unstable, solutions between pH about 4-5 are most stable, and at pH 4 or below, the solubility increases, as also demonstrated in US patent 20190083525. And the ryposi is dissolved in an aqueous solution containing an organic solvent, and can be rapidly reduced along with the reduction of the proportion of the organic solvent or the solubilizer in the mixed solution, so that the ryposi is extremely easy to precipitate in the dilution process, and the safety problem is caused. According to the description of US20190083525 and the research of US, a large amount of Tween 80 or PEG300 is needed for dissolving the Ruidexivir, the composition viscosity is high, a sterile production process is adopted, the filtration is difficult, a terminal sterilization process can cause the problem of sample stability, the clinical application can cause the precipitation of the Ruidexivir crystals if diluted by 10 times or 100 times, the long-term standing is unstable, the problems of hemolysis, hypersensitivity and the like can be caused in vivo, and the problems are that the Tween 80 is not selected as a solubilizer by a Jiider company, and the sulfobutyl betacyclodextrin is selected.
According to US patent 20190083525 and related literature reports, a freeze-dried formulation of adefovir contains the following inactive ingredients in addition to the active ingredients: water for injection, sodium sulfobutyl-beta-cyclodextrin (SBECD), the pH of the formulation is adjusted to 3.0 to 4.0 using hydrochloric acid and/or sodium hydroxide, and then lyophilized. The Rede xi Wei Neng attacks the RdRP target based on Denison MR in the article "Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease" published by mBio, which makes the virus difficult to replicate and difficult to cleave by the nucleic acid error correction enzyme ExoN, and the Rede xi has the capability of forcibly interfering with the virus and increasing the concentration of the Rede xi Wei Xie drug, which can further resist the drug resistance of the virus.
However, limited to the maximum tolerated dose, clinical trial (NCT 04257657) adefovir clinical dosing regimen is: 200mg was intravenously administered on the first day, followed by 100mg once daily, completed within thirty minutes, and continued for 9 to 13 days depending on the viral load. Following intravenous administration, sufficient Remdesivir is delivered into the cells to metabolise active GS-443902 (FIG. 2) to ensure proper blood levels in the body.
At present, the freeze-dried preparation of the adefovir cyclodextrin reported by Jiled is not reported by other dosage forms, and although the existing dosage forms solve the problem of water solubility of the adefovir and are used for clinic, the existing adefovir Wei Jixing still has the following problems: (1) Sodium sulfobutyl- β -cyclodextrin is excreted in the kidneys mainly by glomerular filtration, and is generally safe in vivo, but creatinine clearance <50mL/min, or prolonged multi-dose administration can cause histopathological changes in tubular vacuolation, even alveolar foci, liver necrosis and tubular blockage. (2) Rede Wei Liaoxiao is dose dependent, and the phagocytic efficiency and rate of monocytes should be improved to better increase the steady state PBMC level of GS-443902; (3) The CT image of pathological features of the COVID-19 shows that most of COVID-19 patients have pathological changes in the lung and the focus is irregular. The lung lesions of the mild patients are mainly ground glass density shadows; the severe patient lung lesions are mainly marked by ground glass density shadows and diffuse solid shadows, are mostly marked by cord shadows, are partly marked by double lung lesions, and are rarely marked by white lung. Through lung biopsy, pathological changes occur in the lungs of a patient, including: (1) protein exudates are present in the lungs; (2) a large number of immune cells exist in the air cavity; (3) fibrin is visible in the lungs; (4) alveolar epithelial cell proliferation, and COVID-19 has a severe damage to the lung; in addition, the COVID-19 has influence on the liver, spleen and kidney, so that the concentration of focus parts of the medicine should be increased as much as possible, thereby improving the curative effect.
Disclosure of Invention
Based on the above problems, the present inventors have made various attempts to screen a plurality of carriers and preparation processes, develop a polymer powder injection form containing adefovir (Remdesivir, GS-5734) or its derivatives, solve the problems of water solubility, physical and chemical stability of adefovir without sulfobutyl-beta-cyclodextrin Sodium (SBECD) and any acid-base regulator, and importantly, after the polymer powder injection is reconstituted, the polymer powder injection can self-assemble into particles with the size of 10-100nm, which is favorable for passive drug aggregation in the lung, improves the maximum tolerance dose of adefovir, improves the concentration of focal sites, improves the uptake of PBMC, improves the curative effect, and has no problem of accumulation of sulfobutyl-beta-cyclodextrin sodium kidney after long-term administration.
In one aspect, the present invention provides a polymer composition loaded with adefovir (Remdesivir, GS-5734) or a derivative thereof, the composition being made from adefovir or a derivative thereof and an amphiphilic block polymer, wherein the weight ratio (in parts by weight) of adefovir or a derivative thereof to the amphiphilic block polymer is: 1 part of Ruidexivir or a derivative thereof and 4-33 parts of amphiphilic block polymer.
According to some embodiments of the invention, wherein the amphiphilic block polymer is a polymer carrier comprising a biodegradable hydrophilic block and a hydrophobic block, the hydrophilic component (the hydrophilic component from which the polymer carrier is made) is polyethylene glycol or methoxypolyethylene glycol or α -carboxy- ω -hydroxypolyethylene glycol, and the hydrophobic component (the hydrophobic component from which the polymer carrier is made) is selected from the group consisting of: polylactic acid, poly (epsilon-lactone), polyglutamic acid or derivatives or mixtures thereof.
According to some embodiments of the invention, wherein the amphiphilic block polymer is ase:Sub>A type ase:Sub>A-B, A-B-ase:Sub>A or B-ase:Sub>A-B block copolymer.
According to some embodiments of the invention, the hydrophilic and hydrophobic components have weight average molecular weights of 1500-12000 daltons and 1000-10000 daltons, respectively.
The amphiphilic block polymer can be prepared according to the conventional method. The following is an illustration of some of the polymers:
the polymer methoxy polyethylene glycol-poly (D, L-lactic acid) (MPEG-PDLLA) with different block ratios can be obtained by the following synthesis process: adding D, L-lactide, MPEG-OH (molecular weight range is optionally 1500-12000) and stannous octoate (0.01% -0.8% w/w) into a three-neck flask according to a preset mass ratio, reacting for 6-50 hours in an oil bath at 130-150 ℃ under the conditions of mechanical stirring and nitrogen protection, then raising the temperature to 150-180 ℃ and vacuumizing the reaction system. After twenty minutes, terminating the reaction, after the temperature of the reaction system is reduced to room temperature, dissolving the polymer with absolute ethyl alcohol, then pouring the polymer into cold diethyl ether for precipitation, filtering the precipitation, placing the precipitation in a fume hood to volatilize the solvent until the polymer is solidified, and finally drying the polymer in vacuum for later use.
The polymer methoxy polyethylene glycol-polycaprolactone (MPEG-PCL) with different block ratios can be obtained by the following synthesis process: caprolactone, MPEG-OH (molecular weight range is 1500-12000) and stannous octoate (0.01% -0.8% w/w) are added into a three-neck flask according to a preset mass ratio, and are reacted for 6-50 hours in an oil bath at 130-150 ℃ under the conditions of mechanical stirring and nitrogen protection, then the temperature is raised to 150-180 ℃, and the reaction system is vacuumized. After twenty minutes, terminating the reaction, after the temperature of the reaction system is reduced to room temperature, dissolving the polymer with absolute ethyl alcohol, then pouring the polymer into cold diethyl ether for precipitation, filtering the precipitation, placing the precipitation in a fume hood to volatilize the solvent until the polymer is solidified, and finally drying the polymer in vacuum for later use.
The polymers poly (D, L-lactic acid) -polyethylene glycol-poly (D, L-lactic acid) (PDLLA-PEG-PDLLA) with different block ratios can be obtained by the following synthesis process: adding D, L-lactide, HO-PEG-OH (the molecular weight range is 1500-12000 optionally) and stannous octoate (0.01-0.8% w/w) into a three-neck flask according to a preset mass ratio, reacting for 6-50 hours in an oil bath at 130-150 ℃ under the conditions of mechanical stirring and nitrogen protection, then raising the temperature to 150-180 ℃ and vacuumizing the reaction system. After twenty minutes, terminating the reaction, after the temperature of the reaction system is reduced to room temperature, dissolving the polymer with absolute ethyl alcohol, then pouring the polymer into cold diethyl ether for precipitation, filtering the precipitation, placing the precipitation in a fume hood to volatilize the solvent until the polymer is solidified, and finally drying the polymer in vacuum for later use.
The polymer polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) with different block ratios can be obtained by the following synthesis process: caprolactone, HO-PEG-OH (molecular weight range is 1500-12000 optionally) and stannous octoate (0.01% -0.8% w/w) are added into a three-neck flask according to a preset mass ratio, and are reacted for 6-50 hours in an oil bath at 130-150 ℃ under the conditions of mechanical stirring and nitrogen protection, then the temperature is raised to 150-180 ℃ and the reaction system is vacuumized. After twenty minutes, terminating the reaction, after the temperature of the reaction system is reduced to room temperature, dissolving the polymer with absolute ethyl alcohol, then pouring the polymer into cold diethyl ether for precipitation, filtering the precipitation, placing the precipitation in a fume hood to volatilize the solvent until the polymer is solidified, and finally drying the polymer in vacuum for later use.
The polymer methoxy polyethylene glycol-polyglutamic acid with different block ratios can be obtained by the following synthesis process: mixing aminated polyethylene glycol monomethyl ether (molecular weight range is optional 1500-12000) or aminated polyethylene glycol (molecular weight range is optional 1500-12000) with gamma benzyl-L-glutamate-N-endocarboxylic anhydride under anhydrous condition, adding N, N-dimethylformamide to dissolve, stirring at 0-30 ℃ for reacting for 70-75 hours to obtain a polymer, settling the polymer in diethyl ether, washing and drying the settled polymer to obtain polyethylene glycol monomethyl ether-b-poly (gamma-benzyl-L-glutamate) block copolymer or poly (gamma-benzyl-L-glutamate) -b-polyethylene glycol-b-poly (gamma-benzyl-L-glutamate) block copolymer, and removing benzyl protecting groups from the obtained block copolymer to obtain polyethylene glycol monomethyl ether-poly (L-glutamate) block copolymer or polyethylene glycol-poly (L-glutamate) block copolymer.
According to some embodiments of the invention, the composition is stored as a lyophilized powder.
In another aspect, the invention provides a process for preparing any of the compositions of the invention, which can be prepared by two methods:
(1) Dissolving the adefovir or the derivative thereof and the amphiphilic block polymer in an organic solvent to obtain a clear solution; then removing the organic solvent by spraying or vacuum pumping to obtain a co-dispersion; injecting water for injection into the co-dispersion to dissolve the co-dispersion, and filtering to obtain a solution; adding water solution containing pharmaceutically acceptable supporting agent to obtain solution with required concentration, filtering with 0.22um filter bag, packaging, and lyophilizing to obtain lyophilized composition;
(2) Co-dissolving adefovir or its derivative and polymer or a supporting agent in tertiary butanol or a mixed solvent of tertiary butanol and water to obtain a clear solution; the solution was filtered through a 0.22um filter capsule, sub-packaged, and then lyophilized to make a lyophilized composition.
According to some embodiments of the invention, wherein the lyophilization process comprises: pre-freezing for 2-5 hours at-40 ℃ to-30 ℃, vacuumizing to 0.2 mbar-1.0 mbar, sublimating to-20 ℃ to-5 ℃ for 5-60 hours according to 2-10 ℃/h, heating to 0-30 ℃ according to 2-10 ℃/h, continuously removing water completely, pressing plugs, and sealing.
According to some embodiments of the invention, wherein the pharmaceutically acceptable scaffolding agent is lactose, mannitol, sucrose, xylitol, sorbitol, dextran, sodium chloride, glucose or mixtures thereof.
According to some embodiments of the invention, wherein the pharmaceutically acceptable scaffolding agent is lactose, sucrose, or mannitol or a mixture thereof.
According to some specific embodiments of the invention, the organic solvent is one or more of ethanol, propylene glycol, tert-butanol, acetonitrile, dichloromethane, acetone, trifluoroethanol or hexafluoroisopropanol.
According to some embodiments of the invention, the organic solvent is t-butanol and/or pharmaceutically acceptable ethanol.
In yet another aspect, the invention provides the use of a composition according to any one of the preceding claims in the manufacture of a medicament for the treatment of a disease caused by infection by a variety of viruses in humans, including trachoma, coronaviridae, filoviridae, flaviviridae, paramyxoviridae, ebola, marburg, zika, lassa, hooning or respiratory syncytial virus.
According to some embodiments of the invention, wherein the coronaviridae comprises SARS virus (severe acute respiratory syndrome virus), SARS-CoV-2 virus (2019 novel coronavirus), middle eastern respiratory syndrome virus (MERS virus).
In yet another aspect, the present invention provides a method of treating a disease caused by a viral infection, the method comprising administering to a human infected with the virus a composition according to any one of the present invention; the virus includes trachomaceae virus, coronaviridae virus, filoviridae virus, flaviviridae virus, paramyxoviridae virus, ebola virus, marburg virus, zhai card virus or respiratory syncytial virus.
According to some embodiments of the invention, wherein the coronaviridae comprises SARS virus, SARS-CoV-2 virus, and middle east respiratory syndrome virus.
According to some specific embodiments of the present invention, the technical solution of the present invention is as follows:
the biodegradable polymer carrier is amphiphilic block copolymer, the hydrophilic block component (A) is selected from polyethylene glycol or methoxy polyethylene glycol or alpha-carboxyl-omega-hydroxyl polyethylene glycol, the hydrophobic block component (B) is selected from polylactic acid, poly (epsilon-lactone), polyglutamic acid or a mixture thereof, and the polylactic acid, the poly (epsilon-lactone) and the polyglutamic acid are preferable. The block copolymer is A-B, A-B-A or B-A-B type block copolymer, and the weight average molecular weight of the hydrophilic component and the hydrophobic component is 1500-12000 daltons and 1000-10000 daltons respectively.
A polymer powder injection containing Remdesivir (GS-5734) or its derivatives is prepared by: the block polymer and the Ruidexivir or the derivative thereof are dissolved in an organic solvent such as absolute ethyl alcohol or tertiary butyl alcohol and the like to obtain a clear solution; then removing the organic solvent by spraying or vacuum pumping to obtain a co-dispersion; injecting water for injection into the co-dispersion to dissolve the co-dispersion, filtering, adding a solution prepared in advance for dissolving freeze-drying excipients, uniformly mixing, filtering the solution, sub-packaging, and freeze-drying to obtain the polymer freeze-dried powder injection of the adefovir dipivoxil compound or pharmaceutically acceptable salt thereof. In clinical application, the composition can be diluted and dissolved by adding water for injection or physiological saline or glucose for injection.
The technical scheme of the invention has the following advantages:
(1) The invention solves the water-solubility problem of the Remdesivir (GS-5734) or the derivatives thereof, does not need to adopt carrier auxiliary materials of sodium sulfobutyl-beta-cyclodextrin and pH regulator which are reported in the US20190083525 and related documents in the prior art, and improves the tolerance of patients.
(2) In particular, the pH value of the aqueous solution of the methoxypolyethylene glycol-polylactide polymer and the polyethylene glycol-polyglutamic acid itself is in the range of 2 to 4 according to the carrier material selected, and no acidulant is required to be added.
(3) The prepared adefovir dipivoxil polymer powder injection has higher drug-loading rate, up to 20%, and the highest concentration after redissolution can reach 17mg/ml; meanwhile, the particle size is adjustable and controllable, and the particle size range is 10-100nm; the nano micelle formed after hydration is more easily accumulated in lung organs in blood circulation, is more easily phagocytized by mononuclear cells, and improves the Ruidexi Wei Liaoxiao.
(4) The prepared polymer powder injection of the Remdesivir (GS-5734) or the derivative thereof contains very few carrier auxiliary materials and has no accumulation or toxicity risk caused by long-term use of the auxiliary materials, so that clinical maximum tolerance dose of the Remdesivir can be increased, curative effect is improved, and toxic and side effects are reduced.
Drawings
FIG. 1 shows the structural formula of Remdesivir (RD);
GS-443902 structural formula;
FIG. 3 is a correlation diagram of the RD polymer powder injection prepared in example 1 (wherein A is a photograph of the RD polymer powder injection, and B is a photograph of the RD polymer after reconstitution;
FIG. 4 is a graph showing particle size of the RD polymer powder injection prepared in example 1 after reconstitution; wherein A is a particle size diagram measured after the RD polymer powder injection is redissolved; b is a transmission electron microscope photo measured after the RD polymer powder injection is redissolved;
FIG. 5 is a graph showing the particle size of a conventional Ruidexivir injection (SBECD carrier);
FIG. 6 shows a graph of the RD polymer powder injection prepared in example 1;
fig. 7 tissue concentration profile of adefovir polymer powder for injection in SD rat tissue and plasma (n=6).
Detailed Description
The following describes the technical scheme of the present invention in detail with reference to the drawings and the embodiments, but the protection scope of the present invention includes but is not limited to the same.
1. Diblock polymer: methoxypolyethylene glycol-poly (D, L-lactic acid), abbreviated MPEG-PDLLA, or MPEG-PLA;
monomethoxy polyethylene glycol-poly (epsilon-caprolactone), abbreviated as MePEG-PCL, or MPEG-PCL;
monomethoxy polyethylene glycol-polyglutamic acid.
2. Triblock copolymer: poly (D, L-lactic acid) -polyethylene glycol-poly (D, L-lactic acid) (PDLLA-PEG-PDLLA) or PLA-PEG-PLA;
poly (epsilon-caprolactone) -polyethylene glycol-poly (epsilon-caprolactone), abbreviated as PCL-PEG-PCL.
3. Remdesivir (Remdesivir), abbreviated as RD.
Example 1
RD and MPEG are combined 2000 -PDLLA 2000 (prepared according to the preparation method of MPEG-PDLLA in the specification, the average molecular weight of MPEG-OH is 2000, the dosage of D, L-lactide and MPEG-OH are fed according to the ratio of 1:1, stannous octoate is 0.05% (w/w), the mixture is obtained by oil bath reaction for 30 hours at 130 ℃, the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:5660 mg), organic solvent is removed by rotary evaporation, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, 10 mL/bottle of filtrate is filled, and the mixture is quickly frozen to-40 ℃ in a freeze dryer, and the freeze-drying process is as follows: (1) Pre-freezing at-40 ℃ for 3 hours, vacuumizing to 0.2mbar, sublimating to-10 ℃ for 10 hours according to 5 ℃/h, heating to 10 ℃ according to 5 ℃/h for 3 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The character diagram is shown in figure 3, and the particle size after redissolution is shown in figure 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken and added with 10ml of water for injection or 0.9% sodium chlorideDissolving the water for injection or the water for glucose injection by shaking, and directly drawing out for injection after the bubbles are dissipated, or adding the water for injection into 50 ml-250 ml of physiological saline or the water for glucose injection for intravenous infusion. The sample related substances were determined by HPLC, the HPLC determination chromatographic conditions were as follows:
using octadecylsilane chemically bonded silica as filler, using phosphate buffer (2.72 g of potassium dihydrogen phosphate, 1000ml of water are added, stirring and dissolving, and regulating pH value to 4.0 with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B, and performing linear elution according to the following table; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength is 240nm; the sample volume was 20. Mu.l.
Elution gradient: (appropriate adjustment can be made according to the applicability of the system)
As a result, the related substances of the Rede-Sivir prepared by the process are very low, as shown in figure 6.
Example 2
RD and MPEG are combined 2000 -PDLLA 4000 (prepared according to the preparation method of the MPEG-PDLLA in the specification, the average molecular weight of the MPEG-OH is 2000, the dosage of D, L-lactide and the dosage of the MPEG-OH are fed according to the ratio of 2:1, the stannous octoate is 0.05% (w/w), the mixture is obtained by reacting for 24 hours), the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:4000 mg), the organic solvent is removed rapidly, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, the filtrate is filled into 10 mL/bottle, and the mixture is placed in a freeze dryer for rapid freezing to-40 ℃, and the freeze-drying process is carried out according to the following steps: (1) Pre-freezing at-40 ℃ for 4 hours, vacuumizing to 0.5mbar, sublimating to-20 ℃ for 20 hours according to 3 ℃/h, heating to 15 ℃ according to 5 ℃/h for 2 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, after the bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose is added for injectionIn water for injection, the medicine is infused intravenously.
Example 3
RD and MPEG are combined 5000 -PDLLA 2000 (prepared according to the preparation method of MPEG-PDLLA in the specification, the average molecular weight of MPEG-OH is 5000, the dosage of D, L-lactide and MPEG-OH is 1:2.5, the dosage of stannous octoate is 0.06% (w/w), the mixture is reacted for 35 hours, the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:9000 mg), organic solvent is removed rapidly, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, the filtrate is filled into 10 mL/bottle, and the mixture is placed in a freeze dryer for rapid freezing to-35 ℃ according to the following freeze-drying process: (1) Pre-freezing at-35 ℃ for 4 hours, vacuumizing to 0.2mbar, sublimating to-15 ℃ for 15 hours according to 5 ℃/h, heating to 25 ℃ according to 5 ℃/h for 5 hours, completely removing water, pressing, sublimating and drying to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 4
RD and MPEG are combined 2000 -PDLLA 2000 The preparation method is characterized in that (obtained according to the preparation method of the example 1) is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:9000 mg), organic solvent is removed rapidly, then 80mL of water for injection is added for dissolution, 20mL of water solution containing 20mg of mannitol is added, the mixture is uniformly mixed with 0.22um of water solution for compression filtration, the filtrate is filled into 10 mL/bottle, and the mixture is placed into a freeze dryer for rapid freezing to-40 ℃, and the freeze drying process is carried out according to the following steps: (1) Pre-freezing at-40 ℃ for 3 hours, vacuumizing to 0.3mbar, sublimating to-10 ℃ for 15 hours according to 5 ℃/h, heating to 0 ℃ according to 5 ℃/h for 8 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is added with 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection, and is dissolved by shaking, and after bubbles are dissipated, the mixture is directly scooped outInjecting or adding into 50 ml-250 ml physiological saline or glucose injection water, and infusing intravenously.
Example 5
RD and MPEG are combined 2000 -PDLLA 2000 (obtained according to the method of example 1) is dissolved in 100mL (water: tert-butanol=3:7) mixed solvent according to a certain mass ratio (1000 mg:9000 mg), uniformly mixed, subjected to 0.22um pressure filtration, and the filtrate is filled into 10 mL/bottle and is quickly frozen to-40 ℃ in a freeze dryer, and the freeze-drying process is carried out according to the following steps: (1) Pre-freezing at-40 ℃ for 3 hours, vacuumizing to 0.2mbar, sublimating to-10 ℃ for 10 hours according to 5 ℃/h, heating to 10 ℃ according to 5 ℃/h for 3 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 6
RD and MPEG are combined 1500 -PDLLA 2000 (prepared according to the preparation method of MPEG-PDLLA in the specification, the average molecular weight of MPEG-OH is 1500, the dosage of D, L-lactide and MPEG-OH are added according to the ratio of 4:3, the dosage of stannous octoate is 0.05% (w/w), the mixture is reacted for 40 hours, the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:9000 mg), organic solvent is removed rapidly, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, the filtrate is filled into 10 mL/bottle, and the mixture is placed into a freeze dryer for rapid freezing to-40 ℃, and the freeze drying process is carried out according to the following steps: (1) Pre-freezing at-40 ℃ for 3 hours, vacuumizing to 0.2mbar, sublimating to-10 ℃ for 10 hours according to 5 ℃/h, heating to 10 ℃ according to 5 ℃/h for 3 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline is addedOr glucose injection water, and is infused intravenously.
Example 7
RD and MPEG are combined 2000 -PDLLA 1750 (prepared according to the preparation method of the MPEG-PDLLA in the specification, the average molecular weight of the MPEG-OH is 2000, the dosage of D, L-lactide and the dosage of the MPEG-OH are fed according to 0.88:1, the dosage of stannous octoate is 0.05% (w/w), the mixture is reacted for 30 hours, the mixture is co-dissolved in 100mL of tertiary butanol according to a certain mass ratio (1000 mg:19000 mg), the mixture is subjected to ultrasonic dissolution and 0.22um pressurized filtration, the filtrate is divided according to the dosage containing 100mgRD, and the filtrate is rapidly frozen to-40 ℃ in a freeze dryer, and the following freeze-drying process is carried out: (1) Pre-freezing at-40 ℃ for 4 hours, vacuumizing to 0.4mbar, sublimating to-15 ℃ for 10 hours according to 5 ℃/h, heating to 15 ℃ according to 5 ℃/h for 4 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 8
RD and MPEG are combined 2000 -PCL 2000 (prepared according to the preparation method of the MPEG-PCL in the specification, wherein the molecular weight of the MPEG-OH is 2000, the dosage of caprolactone and the dosage of MPEG-OH are 1:1, the stannous octoate is 1% (w/w), the mixture is reacted for 72 hours) and is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:5660 mg), organic solvent is quickly removed, 100mL of water for injection is then added for dissolution, 0.22um is pressurized and filtered, 10 mL/bottle of filtrate is filled, and the mixture is quickly frozen to-40 ℃ in a freeze dryer according to the following freeze-drying process: (1) Pre-freezing at-40 ℃ for 3 hours, vacuumizing to 0.2mbar, sublimating to-10 ℃ for 10 hours according to 5 ℃/h, heating to 10 ℃ according to 5 ℃/h for 3 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is added with 10ml of water for injection or 0.9% sodium chloride water for injection or glucoseDissolving with shaking for injection, and directly injecting after bubbles are dissipated, or adding into 50-250 ml physiological saline or glucose injection water for intravenous infusion.
Example 9
RD and MPEG are combined 2000 -PCL 2000 (according to the specification, the MPEG-PCL is prepared by a preparation method of MPEG-PCL, the molecular weight of the MPEG-OH is 2000, the dosage of caprolactone and the MPEG-OH is 1:1, the dosage of stannous octoate is 0.08% (w/w), the stannous octoate is obtained by reacting for 40 hours), the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:19000 mg), organic solvent is quickly removed, then 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, the filtrate is filled into 10 mL/bottle, and the mixture is quickly frozen to-40 ℃ in a freeze dryer, and the freeze drying process is carried out according to the following steps: (1) Pre-freezing at-40 ℃ for 3 hours, vacuumizing to 0.2mbar, sublimating to-10 ℃ for 30 hours according to 5 ℃/h, heating to 10 ℃ for 3 hours according to 5 ℃/h, completely removing water, pressing, sublimating and drying to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 10
RD and PDLLA are combined 2000 -PEG 2000 -PDLLA 2000 (prepared according to the preparation method of PDLLA-PEG-PDLLA in the specification, the molecular weight of HO-PEG-OH is 2000, the dosage of D, L-lactide and HO-PEG-OH are fed according to the ratio of 2:1, the dosage of stannous octoate is 0.06% (w/w), the stannous octoate is obtained by reacting for 40 hours), the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:9000 mg), the organic solvent is removed rapidly, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, 10 mL/bottle of filtrate is filled, and the mixture is frozen rapidly to-40 ℃ in a freeze dryer according to the following freeze-drying process: (1) Pre-freezing at-40deg.C for 4 hr, vacuumizing to 0.2mbar, sublimating to-10deg.C at 5deg.C/hr for 40 hr, heating to 10deg.C at 5deg.C/hr for 5 hr, completely removing water, and tamponading to obtain RD polymer lyophilized powder with particle diameter shown in table1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 11
RD and PCL 1000 -PEG 2000 -PCL 1000 (prepared according to the preparation method of the specification PCL-PEG-PCL, wherein the molecular weight of HO-PEG-OH is 2000, the dosage of caprolactone and HO-PEG-OH are fed according to a ratio of 1:1, the dosage of stannous octoate is 0.05% (w/w), the mixture is reacted for 50 hours, the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:9000 mg), the organic solvent is rapidly removed, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, the filtrate is filled into 10 mL/bottle, and the mixture is rapidly frozen to-40 ℃ in a freeze dryer according to the following freeze-drying process: (1) Pre-freezing at-40 ℃ for 3 hours, vacuumizing to 0.2mbar, sublimating to-10 ℃ for 10 hours according to 5 ℃/h, heating to 10 ℃ according to 5 ℃/h for 3 hours, completely removing water, pressing, sublimating and drying to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 12
RD and MPEG are combined 5000 -PDLLA 8000 (prepared according to the preparation method of the MPEG-PDLLA in the specification, the molecular weight of the MPEG-OH is 5000, the dosage of D, L-lactide and the dosage of the MPEG-OH are added according to the ratio of 16:1, stannous octoate is 0.06% (w/w), the stannous octoate is obtained by reacting for 60 hours), the mixture is dissolved in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:5660 mg), organic solvent is removed rapidly, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, the filtrate is filled into 10 mL/bottle, and the mixture is placed in a freeze dryer for rapid freezing to-40 ℃, and the freeze-drying process is carried out according to the following steps: (1) Pre-freezing at-40deg.C for 3 hr, and then evacuating to 0.2mbarAnd sublimating to-10 ℃ at 5 ℃/h for 10h, heating to 10 ℃ at 5 ℃/h for 3h, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 13
RD is combined with monomethoxy polyethylene glycol 2000 Polyglutamic acid 2000 (according to the specification, the molecular weight of methoxy polyethylene glycol-polyglutamic acid is 2000, the mass ratio of gamma benzyl-L-glutamate-N-internal carboxylic anhydride to MPEG-NH2 is 1.5:1, the polymer is obtained by stirring and reacting for 120 hours at 25 ℃, then the polymer is obtained by removing benzyl protecting groups) according to a certain mass ratio (1000 mg:5660 mg), the polymer is dissolved in 150mL of absolute ethyl alcohol, organic solvent is removed rapidly, 100mL of water for injection is added for dissolution, 0.22um is pressurized and filtered, filtrate is filled into 10 mL/bottle, and the mixture is placed in a freeze dryer for rapid freezing to-40 ℃, and the freeze drying process is carried out as follows: (1) Pre-freezing at-40 ℃ for 5 hours, vacuumizing to 0.3mbar, sublimating to-15 ℃ for 35 hours according to 5 ℃/h, heating to 10 ℃ according to 5 ℃/h for 3 hours, completely removing water, and pressing to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Example 14
RD is combined with monomethoxy polyethylene glycol 5000 Polyglutamic acid 12000 (prepared according to the preparation method of methoxy polyethylene glycol-polyglutamic acid in the specification, the molecular weight of the aminated polyethylene glycol is 5000, the mass ratio of gamma benzyl-L-glutamate-N-inner carboxylic anhydride to MPEG-NH2 is 3:1, and the temperature is 5℃)Stirring and reacting for 120h to obtain a polymer, removing benzyl protecting groups to obtain the polymer, dissolving the polymer in 150mL of absolute ethyl alcohol according to a certain mass ratio (1000 mg:5660 mg), rapidly removing organic solvent, adding 100mL of water for injection for dissolving, performing 0.22um pressurized filtration, filling filtrate into 10 mL/bottle, and rapidly freezing to-40 ℃ in a freeze dryer, wherein the freeze drying process comprises the following steps: (1) Pre-freezing at-40 ℃ for 4 hours, vacuumizing to 0.2mbar, sublimating to-15 ℃ for 10 hours according to 5 ℃/h, heating to 15 ℃ according to 5 ℃/h for 5 hours, completely removing water, pressing, sublimating and drying to obtain RD polymer freeze-dried powder for later use, wherein the particle size is shown in table 1. The properties are similar to those of FIG. 3, and the particle size after reconstitution is similar to that of FIG. 4. When in use, 1 bottle of RD polymer freeze-dried powder is taken, 10ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added, shaking is carried out for dissolution, and after bubbles are dissipated, the mixture is directly drawn out for injection, or 50ml to 250ml of physiological saline or glucose water for injection is added for intravenous infusion.
Table 1 shows the drug loading parameters of the lyophilized formulations prepared in the different examples.
Table 1 lyophilized formulation loading conditions prepared in different examples
Test case
Tissue distribution investigation
1. Medicament: sample (RD-NPs) prepared in example 1 of this invention
2. The experimental process comprises the following steps:
24 SD rats are taken, the weight range is 221.9-238.4 g, 12 hours of illumination is provided every day, and the ambient temperature and the relative humidity of the animal room are detected and recorded and controlled to be 18-26 ℃ and 40-70%. Taking the sample RD-NPs prepared in the example 1 to prepare a solution with the concentration of 10mg/ml, taking 6 samples from each half of the male and female at 0.25h,1h,4h and 24h after the administration according to 5mg/kg through tail veins, taking 0.5ml blood through jugular veins, placing the blood samples in a marked centrifuge tube after the blood samples are collected, and centrifugally separating plasma (centrifugal conditions: 8000 revolutions/min, 6 minutes, 2-8 ℃); after sacrifice, tissues of brain, heart, lung, liver, spleen and kidney were collected rapidly, rinsed with deionized water, blotted with filter paper to dry the water, weighed immediately, minced with scissors and placed in an EP test tube. The EP test tube is placed in a full-automatic homogenizer, physiological saline is added according to the corresponding volume of 5mL/g for homogenization, 0.25mL of tissue homogenization is measured, 50 mu L of internal standard working solution (200 ng/mL of tosituric stock solution) is added, the mixture is uniformly mixed, 750 mu L of diluent (methanol) is added, 5min is mixed at 2000rpm by vortex, centrifugation is carried out at 12000rpm for 10min, the organic layer is transferred into an EP centrifuge tube, nitrogen flow at 40 ℃ is volatilized, the residue is redissolved by 50 mu L of methanol, centrifugation at 16000rpm is carried out, 20 mu L of tissue homogenization is carried out, HPLC analysis is carried out, and quantitative analysis is carried out by adopting an internal standard method.
The experimental results are shown in figure 7:
0.25 hours: lung & kidney & spleen & heart & liver & plasma & brain & gt
1 hour: lung & spleen & kidney & heart & liver & plasma & brain & gt
4 hours: lung & spleen & kidney & heart & liver & plasma & brain & gt
24 hours: spleen, lung, kidney, heart, liver, brain and plasma
In conclusion, the particle size of the micelle is 10nm-100nm, the drug loading rate can reach 1-20%, the encapsulation efficiency is at least 95%, and the stability is excellent. The preferred process treatment can lead the grain diameter to reach 10nm-100nm, is more convenient for clinical application, can realize high concentration and long-time accumulation in lung tissues, achieves the effect of passive targeted drug delivery, and provides a new choice for clinical application of the adefovir dipivoxil drug.
Claims (10)
1. A polymer composition loaded with adefovir, characterized in that: the drug is prepared from adefovir and an amphiphilic block polymer, wherein the weight ratio of the adefovir to the amphiphilic block polymer is as follows: 1 part of Rede-Sivir and 4-5.66 parts of amphiphilic block polymer; the amphiphilic block polymer is a polymer carrier composed of a biodegradable hydrophilic block and a hydrophobic block, wherein the hydrophilic component is polyethylene glycol or methoxy polyethylene glycol, and the hydrophobic component is selected from the group consisting of: polylactic acid; the weight average molecular weight of the hydrophilic component and the hydrophobic component are 1500-12000 daltons and 1000-10000 daltons, respectively.
2. The composition of claim 1, wherein: the amphiphilic block polymer is an A-B, A-B-A or B-A-B block copolymer.
3. The composition of claim 1, wherein: the composition is stored in the form of a lyophilized powder.
4. A method of preparing the composition of any one of claims 1 to 3, characterized in that: the composition can be prepared by two methods:
(1) Dissolving adefovir and the amphiphilic block polymer in an organic solvent to obtain a clear solution; then removing the organic solvent by spraying or vacuum pumping to obtain a co-dispersion; injecting water for injection into the co-dispersion to dissolve the co-dispersion, and filtering to obtain a solution; adding water solution containing pharmaceutically acceptable supporting agent to obtain solution with required concentration, filtering with 0.22um filter bag, packaging, and lyophilizing to obtain lyophilized composition; or alternatively
(2) Co-dissolving adefovir and a polymer or a stent agent in tertiary butanol or a mixed solvent of tertiary butanol and water to obtain a clear solution; the solution was filtered through a 0.22um filter capsule, sub-packaged, and then lyophilized to make a lyophilized composition.
5. The method of manufacturing according to claim 4, wherein: the pharmaceutically acceptable scaffolds are lactose, mannitol, sucrose, xylitol, sorbitol, dextran, sodium chloride, glucose or their mixture.
6. The method of manufacturing according to claim 4, wherein: the pharmaceutically acceptable scaffolding agent is lactose, sucrose, or mannitol or a mixture thereof.
7. The method of manufacturing according to claim 4, wherein: the organic solvent is one or more of ethanol, propylene glycol, tertiary butanol, acetonitrile, dichloromethane, acetone, trifluoroethanol and hexafluoroisopropanol.
8. The method of manufacturing according to claim 4, wherein: the organic solvent is tert-butanol and/or pharmaceutically acceptable ethanol.
9. Use of a composition according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of infection by a human virus, said virus being an arenaviridae virus, coronaviridae virus, filoviridae virus, flaviviridae virus or paramyxoviridae virus.
10. The use according to claim 9, wherein the coronaviridae virus is SARS virus, SARS-CoV-2 virus or middle east respiratory syndrome virus; the filoviridae virus is ebola virus or marburg virus; the flaviviridae virus is Zika virus; the arenaviridae virus is lassa virus or hooning virus; the Paramyxoviridae virus is respiratory syncytial virus.
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