CN114632075A - Voriconazole aerosol inhalation and application - Google Patents
Voriconazole aerosol inhalation and application Download PDFInfo
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
Abstract
The invention relates to voriconazole aerosol inhalant which comprises the following raw materials in parts by mass: 8-13 parts of voriconazole-cyclodextrin inclusion compound freeze-dried powder and 100 parts of water for injection; the voriconazole-cyclodextrin inclusion compound freeze-dried powder is obtained by preparing organic weak acid solution of voriconazole, polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate and cyclodextrin water solution into inclusion compound solution, and then carrying out freeze drying. The compound of polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate is used as a solubilizer, so that voriconazole can be successfully solubilized in organic weak acid to complete the inclusion with cyclodextrin, the blood concentration of the voriconazole after the voriconazole is inhaled can be stable after the obtained inclusion compound is prepared into lyophilized powder for redissolution, the adverse reaction of voriconazole caused by high blood concentration is reduced, and the use safety of voriconazole is improved.
Description
Technical Field
The invention relates to the field of antifungal medicines, and in particular relates to voriconazole aerosol inhalation and application.
Background
Voriconazole is a fluconazole derivative, is a triazole antifungal drug, has broad-spectrum antibacterial activity, and has particularly remarkable antibacterial activity on aspergillus. The therapeutic mechanism of voriconazole is to inhibit cytochrome 450 mediated demethylation of 14 α -sterol, and thus inhibit the conversion of lanosterol to ergosterol, the loss of ergosterol destroying the integrity of fungal cells, which in turn leads to apoptosis of fungi. Dosage forms that have been developed include intravenous injection, oral administration. At present, most of clinical application and research is oral medicaments, including tablets, capsules and dry suspensions. In addition, the oral preparation has the defect of difficult swallowing for patients with severe illness, old people, children and the like with weak autonomous ability; in addition, for patients with lung diseases or patients with severe fungal infections, oral preparations have slow onset of action, and injections are not suitable for patients with renal failure. Voriconazole itself is a poorly soluble drug, and solubilization of such poorly soluble drugs by liposomes, microemulsions and clathrates is one direction of research and development. However, the characteristics of poor stability such as polymerization, fusion, hydrolysis, purity reduction and the like of the drugs during long-term storage in the aqueous phase are always the pain points for the research and development of the insoluble drugs. Freeze-drying to obtain freeze-dried powder for storage, and re-dissolving with proper solvent when in use is an effective strategy. But the problems of dispersibility, particle size and pharmacokinetics of the freeze-dried powder need to be solved.
The voriconazole oral administration has certain adverse reactions including abnormal liver function, rash, hypokalemia, vomiting, edema, headache, paralysis, dizziness, hallucinations, insomnia and the like. Researches show that adverse reactions caused by voriconazole, particularly abnormal liver functions, are mainly caused by nonlinear pharmacokinetic characteristics of voriconazole in metabolism of human bodies, so that the adverse reactions can be relieved by reducing dosage due to high initial blood concentration of oral voriconazole, but the treatment effect can be influenced. The transplanted patient needs to take voriconazole frequently to prevent aspergillus infection, and researches show that the adverse reaction proportion of voriconazole taken by the transplanted patient, children receiving cytotoxic chemotherapy or patients with hereditary immunologic function deficiency is obviously increased. It can be seen that high blood levels of voriconazole limit its clinical application due to its non-linear pharmacokinetic properties. How to stabilize the blood concentration of voriconazole in a patient is a problem to be solved for reducing adverse reactions.
In addition, voriconazole itself is a poorly soluble drug and needs to be solubilized to make a formulation that is easily absorbed and utilized by the human body. The cyclodextrin inclusion of the insoluble drug is used for achieving the purpose of solubilization, is an important solubilization means for the insoluble drug, and a plurality of insoluble drug dosage forms based on cyclodextrin inclusion compounds are on the market and are under study at present. Hydroxypropyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin sodium is generally adopted for inclusion, and the inclusion compound has the advantages of low toxicity and low hemolysis. However, when voriconazole is subjected to cyclodextrin inclusion, voriconazole is found to undergo racemization to some extent at a temperature higher than 50 ℃, resulting in a decrease in the therapeutic effect of the drug. However, at temperatures below 30 ℃, the efficiency of the inclusion of voriconazole with cyclodextrin again becomes very poor. Therefore, it is also an urgent problem to solve the balance between the preparation efficiency and the drug efficacy of voriconazole and cyclodextrin inclusion compounds.
CN113975236A discloses a voriconazole dry suspension, but the voriconazole dry suspension needs to be stored at 2-8 ℃, and once the temperature is slightly high, the voriconazole dry suspension may be degraded to generate impurities, which affects the therapeutic effect, or increases the probability of adverse reaction, although the defect of poor stability of the liquid preparation is avoided, the stability, transportation and storage still need to be further improved. The development of a new voriconazole preparation which has quick response and can be safely taken by various patients has important clinical significance and commercial value.
Since fungal infections are a high incidence site of infection in the lung, accounting for more than half of all visceral fungal infections, pulmonary fungal infections are a difficult symptom to diagnose and treat clinically. Pulmonary fungal infection has become a fungal infection disease with a higher mortality rate at present, such as aspergillus pulmonary infection, and the aerosol inhalation can achieve higher blood concentration in the lung more quickly, but the problem of increased adverse reaction rate cannot be overcome. CN11658610A discloses a triazole antifungal drug suspension for an atomizer, which comprises a triazole antifungal drug, a surfactant, an osmotic pressure regulator, a metal complexing agent, a pH regulator and water. CN0112791071A discloses a polymeric micelle loaded voriconazole composition for aerosol inhalation, which adopts an amphiphilic block copolymer, contains a hydrophilic segment and a hydrophobic segment at the same time, and becomes micelles in an aqueous phase, thereby increasing the solubility and stability of voriconazole. However, in order to achieve clinically applicable solubility, the method needs higher polymer micelle for solubilization, has larger difference between the peak value and the valley value of blood concentration, does not achieve the purpose of stable release, and increases the probability of adverse reaction of patients.
Disclosure of Invention
The technical problem to be solved by the voriconazole preparation is how to achieve effective antifungal effect, guarantee the safety of patients and reduce adverse reactions because voriconazole antifungal agents are used for patients with serious fungal infection, or children transplanted with patients and undergoing chemotherapy, patients with immunologic function deficiency and patients with severe lung diseases. In view of the above, the invention provides a voriconazole aerosol inhalation, which is a voriconazole-cyclodextrin inclusion compound prepared by voriconazole and cyclodextrin in the presence of a specific solubilizer, and improves the solubility of voriconazole. The freeze-drying technology is used for preparing the voriconazole-cyclodextrin inclusion compound into a freeze-dried powder form, so that the defect of instability of voriconazole in a water phase is overcome; the active ingredients are inhaled and administered directly to the focus of the lung through the form of the aerosol inhalation, and the aerosol inhalation has very excellent treatment effect on patients with fungal infection in the lung. The dose of the voriconazole is reduced through atomization inhalation, the blood concentration is stable, and the adverse reaction of the voriconazole is reduced.
In order to solve the problems, the invention provides voriconazole aerosol inhalant which comprises the following raw materials in parts by mass: 8-13 parts of voriconazole-cyclodextrin inclusion compound freeze-dried powder and 100 parts of water for injection; the voriconazole-cyclodextrin inclusion compound freeze-dried powder is obtained by preparing organic weak acid solution of voriconazole, polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate and cyclodextrin water solution into inclusion compound solution and then freeze-drying.
Preferably, the voriconazole aerosol inhalant further comprises auxiliary materials such as a pH regulator, an auxiliary flavor and an osmotic pressure regulator. The selection and amounts of these adjuvants are well known in the art. For example, examples of pH adjusters include, but are not limited to, at least one of tartaric acid, malic acid, citric acid, sodium hydroxide, potassium hydroxide; examples of the auxiliary flavor include, but are not limited to, at least one of sorbitol, mannitol, fructose, sucrose, maltose; examples of the osmotic pressure regulator include, but are not limited to, at least one of sodium chloride and potassium chloride.
Further, the cyclodextrin is at least one of hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin sodium, preferably sulfobutyl-beta-cyclodextrin sodium. Hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin sodium are beta-cyclodextrin, and are promising raw materials currently used as inclusion compounds. Sulfobutyl-beta-cyclodextrin sodium is preferred in the present invention because of its fewer side effects.
Further, the mass ratio of voriconazole to cyclodextrin is 1: 8-15, preferably, selecting sodium sulfobutyl-beta-cyclodextrin, wherein the mass ratio of voriconazole to sodium sulfobutyl-beta-cyclodextrin is 1: 1-12. The amount of the sulfobutyl-beta-cyclodextrin sodium is large mainly for improving the inclusion rate, but after the mass amount of the sulfobutyl-beta-cyclodextrin sodium is more than 12 times that of the voriconazole, the inclusion rate is not greatly improved, and even the mass ratio of the voriconazole to the sulfobutyl-beta-cyclodextrin sodium is preferably 1: 10-12.
The total mass of the polyoxyethylene hydrogenated castor oil and the pentaerythritol monostearate is 4 to 7 weight percent of the mass of the voriconazole. The excessive dosage of the solubilizer can reduce the content of active ingredients of the medicine and influence the encapsulation rate of the voriconazole; but the dosage of the solubilizer is more than 4wt% of the voriconazole, otherwise the solubilization purpose cannot be effectively achieved.
Preferably, the mass ratio of the polyoxyethylene hydrogenated castor oil to the pentaerythritol monostearate is 3-5: 1-2.
Further, the organic weak acid is at least one selected from acetic acid, oxalic acid, malic acid and tartaric acid, and the pH of the organic weak acid is 2-4.
Voriconazole is almost insoluble in water, and its solubility is only about 0.2mg/mL at pH 3. In the prior art, voriconazole is generally dissolved in hydrochloric acid and is included with cyclodextrin, and then the obtained inclusion compound is adjusted back to pH6-8 by using alkali liquor. However, the inventors have found that this method leads to a high level of impurities, in particular impurity C, in the resulting clathrate. There may be some damage to the active molecular structure with strong acids/bases. The inventors dissolved voriconazole in a weak organic acid for the purpose of reducing impurities, but the solubility of voriconazole in a weak organic acid was still insufficient, and thus the inventors added a solubilizing agent, in order to hopefully solve the problem of insufficient solubility of voriconazole in weak organic acids, the inventors have unexpectedly found that, the compound of polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate is used as a solubilizer, so that the voriconazole can be successfully solubilized in organic weak acid to complete the inclusion with cyclodextrin, the blood concentration of the aerosol inhalant prepared by the obtained inclusion compound into lyophilized powder for redissolution is stable after inhalation, the phenomenon of large difference between peak concentration and valley concentration of blood can not be caused, the adverse reaction of the voriconazole caused by high blood concentration can be reduced, the use safety of the voriconazole is improved, and the voriconazole sustained-release tablet has excellent clinical significance and commercial value.
Further, the voriconazole-cyclodextrin inclusion compound freeze-dried powder is prepared by the preparation method comprising the following steps:
(S1) dissolving voriconazole in weak organic acid solution containing polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate, adding the solution into cyclodextrin water solution, stirring for 2-4h at 20-30 ℃ to prepare solution of the inclusion compound, and adjusting the pH value of the solution to 5-7;
(S2) freeze-drying to obtain the voriconazole-cyclodextrin inclusion compound freeze-dried powder.
Preferably, before the voriconazole is dissolved in the weak organic acid in the step (S1), the voriconazole is pulverized to have a particle size D90 of 50 μm or less; more preferably, voriconazole is first milled to a particle size D90 of below 40 μm, for example to a particle size D90 of 10-30 μm. Methods and apparatus for comminuting to a specified particle size are well known in the art, such as by jet milling. When the voriconazole-cyclodextrin inclusion compound is prepared, the voriconazole-cyclodextrin inclusion compound can be more effectively included. The pH of the solution adjusted to 6 to 8 in step (S1) is adjusted using a weak base such as 5 to 10wt% aqueous sodium carbonate solution.
Further, the freeze drying is that the raw materials are pre-frozen for 3-5h at the temperature of-20 ℃ to-30 ℃ under the normal pressure, the vacuum pumping is carried out, the temperature is kept for 20-30h at the temperature of-2 ℃ to-12 ℃ under the pressure of 5-50Pa, then the temperature is slowly restored to 0 ℃ to 5 ℃, the temperature is kept for 1-2h, the temperature is raised to 25 ℃ to 35 ℃, the temperature is kept for 2-4h, and the freeze drying is completed.
The voriconazole aerosol inhalant comprises the therapeutically active component of voriconazole-cyclodextrin inclusion compound freeze-dried powder, is redissolved with water for injection when in use, and is atomized by an atomizer to be inhaled by patients. The voriconazole-cyclodextrin inclusion compound freeze-dried powder prepared by the invention has good stability, can be used in an acceleration experiment, has basically unchanged purity and obviously-increased impurities, and shows excellent storage stability. When in use, the voriconazole-cyclodextrin inclusion compound freeze-dried powder is redissolved and then is inhaled by a patient through an atomizer. The atomized liquid drops are small and reach lung disease society directly, so the medicine has quick effect, small dosage and high bioavailability. The voriconazole aerosol inhalant has the advantage of clinical compliance for severe patients, old people, children and other patients with weak self-help ability.
The using method of the atomization inhalation preparation is well known in the field, when the atomization inhalation is carried out, the prepared voriconazole-cyclodextrin freeze-dried powder is redissolved by sterile water for injection, atomized into small drops by an atomizer, and inhaled by a human body through an oral cavity, wherein the dosage is 2-3mg/kg calculated by voriconazole each time.
The invention also provides application of the voriconazole aerosol inhalation in preparing antifungal medicaments, in particular application in treating pulmonary fungal infection.
Drawings
Figure 1 is a histopathological picture of rats after inhalation of voriconazole aerosol inhalant of preparation example 1.
Detailed Description
The voriconazole bulk drug is purchased from Sichuan ren' an pharmaceutical industry, and the content is more than 99.9 percent by an HPLC method. Sulfobutyl-beta-cyclodextrin sodium was purchased from sienna de li biochemical ltd. The average degree of substitution was 4.6. In the examples of the present invention, "part" means part by mass unless otherwise specified, and "part" means percentage by mass unless otherwise specified.
And (3) testing the inclusion rate by using an HPLC method, wherein the inclusion rate = voriconazole mass/voriconazole adding amount in the inclusion compound x 100%.
In the atomization simulation test, a laser particle size tester from Newcastle, Germany was used for droplet size, and the delivery rate and total amount delivered were calculated using a Copley Scientific Limited breathing simulator, UK.
Preparation examplePreparation of voriconazole-cyclodextrin inclusion compound freeze-dried powder
Preparation example 1
(S1) dissolving 0.04 part of polyoxyethylene hydrogenated castor oil and 0.01 part of pentaerythritol monostearate in 15 parts of acetic acid aqueous solution with the pH value of 3, uniformly stirring, slowly adding 1 part of voriconazole raw material, and continuously stirring until the voriconazole is completely dissolved. Adding the obtained acetic acid solution of voriconazole into a saturated aqueous solution dissolved with 10 parts of sodium sulfobutyl-beta-cyclodextrin, stirring for 4h at 30 ℃, completely clathrating, adjusting the pH to 6.5 by using 6.5wt% of sodium carbonate aqueous solution, adding activated carbon with the mass of 0.1wt% of the solution, stirring for 0.5h, filtering by using a 0.22 mu m microporous filter membrane to obtain a clear and transparent solution, and using the clear and transparent solution for the next step of freeze drying.
(S2) pre-freezing the mixed solution of the inclusion compound obtained in the step (S1) for 5h at the temperature of minus 30 ℃, vacuumizing, heating to minus 10 ℃ at 5Pa, preserving heat for 30h, then slowly heating to 5 ℃ at the heating rate of 0.5 ℃/min, preserving heat for 2h, continuously heating to 25 ℃ at the heating rate of 0.5 ℃/min, preserving heat for 3h, and completing freeze drying to obtain white loose powder which is voriconazole-cyclodextrin inclusion compound freeze-dried powder.
Through tests, the inclusion rate of the voriconazole-cyclodextrin inclusion compound freeze-dried powder obtained in the preparation example 1 is 95.3%, and the voriconazole solution concentration reaches 18.5mg/mL in a phosphate buffer solution with pH =7 and a saturated solution at 25 ℃.
The stability test of the freeze-dried powder obtained in preparation example 1 was carried out under the accelerated test conditions: 50 ℃ and 75 RH%. The results are shown in table 1 below:
table 1 voriconazole clathrate freeze-dried powder stability test data
The voriconazole-cyclodextrin freeze-dried powder prepared by the invention has excellent stability, and even if the voriconazole-cyclodextrin freeze-dried powder is stored for three months under an accelerated condition, the content of active ingredients and the content of related substances of the voriconazole-cyclodextrin freeze-dried powder also meet the standard of pharmacopoeia on clinical medication.
Preparation example 2
The other conditions and operations were the same as in preparation example 1 except that the solubilizer in step (S1) was 0.05 parts of polyoxyethylene hydrogenated castor oil, i.e., pentaerythritol monostearate was not added. Through tests, the inclusion rate of the voriconazole-cyclodextrin inclusion compound freeze-dried powder obtained in the preparation example 2 is 96.4%, and the voriconazole solution concentration reaches 18.6mg/mL in a phosphate buffer solution with pH =7 and a saturated solution at 25 ℃.
Preparation example 3
The other conditions and operations were the same as in preparation example 1 except that the solubilizer in step (S1) was 0.05 part of pentaerythritol monostearate, i.e., hydrogenated castor oil without adding polyoxyethylene. Through tests, the inclusion rate of the voriconazole-cyclodextrin inclusion compound freeze-dried powder obtained in the preparation example 3 is 93.2%, and the voriconazole solution concentration reaches 18.0mg/mL in a phosphate buffer solution with pH =7 and a saturated solution at 25 ℃.
Preparation example 4
The other conditions and operations were the same as in preparation example 1 except that in the solubilizing agent in step (S1), polyoxyethylene hydrogenated castor oil was replaced with polyoxyethylene lauryl alcohol ether of equal mass. Through tests, the inclusion rate of the voriconazole-cyclodextrin inclusion compound freeze-dried powder obtained in the preparation example 4 is 95.8%, and the voriconazole solution concentration reaches 18.3mg/mL in a phosphate buffer solution with pH =7 and a saturated solution at 25 ℃.
Preparation example 5
The other conditions and operations were the same as in preparation example 1 except that in the solubilizing agent in step (S1), pentaerythritol monostearate was replaced with tween-80 of equal mass. Through tests, the inclusion rate of the voriconazole-cyclodextrin inclusion compound freeze-dried powder obtained in the preparation example 4 is 95.2%, and the voriconazole solution concentration reaches 18.2mg/mL in a phosphate buffer solution with pH =7 and a saturated solution at 25 ℃.
Preparation example 6
The other conditions and operations were the same as in preparation example 1 except that the solubilizing agent of step (S1) was 0.05 parts of polyoxyethylene hydrogenated castor oil and 0.02 parts of pentaerythritol monostearate. Through tests, the inclusion rate of the voriconazole-cyclodextrin inclusion compound freeze-dried powder obtained in the preparation example 6 is 97.1%, and the voriconazole solution concentration reaches 19.1mg/mL in a phosphate buffer solution with pH =7 and a saturated solution at 25 ℃.
Preparation example 7
The other conditions and operations were the same as in preparation example 1 except that the solubilizer for step (S1) was 0.01 part of polyoxyethylene hydrogenated castor oil and 0.01 part of pentaerythritol monostearate. Through tests, the inclusion rate of the voriconazole-cyclodextrin inclusion compound freeze-dried powder obtained in the preparation example 7 is 76.5%, and the voriconazole solution concentration reaches 16.4mg/mL in a phosphate buffer solution with pH =7 and a saturated solution at 25 ℃.
As can be seen from the preparation examples, when the proportion and the dosage of the solubilizer are changed, the inclusion rate of the inclusion compound is not greatly influenced, and the inclusion can be smoothly completed. However, it should be noted that the amount of the solubilizer is preferably more than 4wt% of the voriconazole, otherwise the inclusion rate is not high and the utilization of voriconazole is not complete.
Example 1Atomization simulation test
10g of the voriconazole clathrate freeze-dried powder obtained in preparation example 1 was redissolved in 100g of sterile water for injection, and the pH was adjusted to 6.5 with tartaric acid to prepare an aerosol inhalant. Taking 6.2mL of reconstituted voriconazole solution, carrying out HPLC test, wherein the reconstituted voriconazole solution contains 100.5mg of voriconazole in total, and carrying out a respiratory simulation test on the reconstituted voriconazole solution by adopting atomizer atomization, wherein the droplet size D50 is 3.12 microns, the delivery rate is 2.54mg/min, the total delivery amount is 50.88mg, and the delivery efficiency is 50.88/100.5= 50.63%. The result shows that about half (50.63%) of the voriconazole active ingredient can enter the lung after the voriconazole freeze-dried powder obtained by the invention is redissolved and passes through an atomizer. After being redissolved, the voriconazole clathrate freeze-dried powder obtained by other preparation methods is also subjected to simulated respiration tests, and the delivery efficiency is found to be close to 46.4-51.4%, which shows that after being redissolved, the voriconazole freeze-dried powder prepared by the invention is in the form of small-sized droplets through an atomizer, is absorbed by a human body, can directly reach the lung, and has the advantage of clinical compliance for patients infected with fungi in the lung or patients with weak autonomous ability such as the elderly and children.
Example 2Respiratory tract irritation test
Animal species: SD rats (6-7 weeks old) with male and female halves
And (3) testing the sample: experimental group inhalation of aqueous solution of lyophilized powder prepared in preparation example 1 (Voriconazole concentration 16.5 mg/mL)
The research method comprises the following steps: 10 SD rats are selected and half of the rats are administrated with female and male, and the administration dose is 20 +/-0.1 mg/rat. Atomizing, sucking and administrating by using an NE-C28 ohm dragon compression type inhaler, taking the SD rat out of the feeding box, and fixing by using a rat fixer; connecting the atomizer nozzle filled with the liquid medicine to the rat fixer, starting the compression atomizer, and carrying out SD rat aerosol inhalation administration. The preparation is administered once daily, once in the morning and afternoon, for 14 days. The administration period and recovery period were observed for animals and for the administration site. All animals are sacrificed 24 hours after the last administration, and the stimulation reaction of the lips, the palate, the tongue, the nose, the pharynx, the larynx, the trachea, the bronchus and the lung of the animals is observed by naked eyes after the animals are dissected, and whether congestion, red swelling and other stimulation reactions exist is observed; the material is taken for pathological histological examination. The final evaluation was performed based on visual observation and histopathological examination results. Histopathological examination results the very mild inflammatory secretions in the nasal cavity of the rat were visualized by histograms (fig. 1, where organ a is nose/palate, organ B is trachea, organ C is left lung and organ D is right lung) on several representative sections, no significant abnormality was seen in the trachea, no significant abnormality was seen in the left lung and very mild foamy macrophage accumulation in the right lung. Research results show that pathological changes such as nasal inflammatory secretion can be seen in all animals of a test sample group, and very light foam-like macrophage aggregation can be seen in the right lung of individual animals, and the degree of pathological changes is very slight, so that the pathological changes are related to an aerosol inhalation administration mode and are unrelated to the test sample. In conclusion, under the test conditions, the SD rat is subjected to aerosol inhalation to give voriconazole aerosol inhalant, and the respiratory system of animals does not have obvious irritant change, so that the safety of the voriconazole aerosol inhalant is verified.
Example 3Blood concentration test
Animal species: SD rats (6-7 weeks old) with half male and half female.
And (3) testing the sample: experimental group an aqueous solution (concentration 16.5 mg/mL) obtained by reconstituting the lyophilized powder obtained in preparation examples 1-6 was inhaled by nebulization.
The research method comprises the following steps: 36 SD rats were selected and randomly divided into 6 groups of 6 animals each with half of males and females, each rat being given a single voriconazole dose of 35 mg. Atomizing, sucking and administrating by using an NE-C28 ohm dragon compression type inhaler, taking the SD rat out of the feeding box, and fixing by using a rat fixer; connecting the atomizer nozzle filled with the liquid medicine to a rat fixer, starting the compressed atomizer, and carrying out SD rat aerosol inhalation administration. The preparation is administered 2 times daily, once in the morning and afternoon, and continuously for 3 days. On the third day, after the last aerosol inhalation administration, the blood concentration test was performed before the inhalation administration (i.e. 0h) and at 0.5h, 1h, 1.5h, 2h, 3h and 4h after the administration, and the results were averaged and are shown in table 2 below.
TABLE 2 SD rat voriconazole plasma concentrations (μ g/mL, n =6)
As can be seen from the data in Table 2, the polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate are taken as the solubilizing agent for preparing the clathrate compound, so that the solubilizing effect is achieved, although the reason is unknown, the aerosol inhalant which enables the test rat to inhale the lyophilized powder for redissolving is also provided, the blood concentration is relatively stable within 4h, the difference between the peak value and the valley value of the blood concentration is not large within 4h, the phenomenon that the initial blood concentration is overlarge cannot occur, and the safety of voriconazole administration is enhanced. The inventors have now found that this phenomenon occurs when a combination of polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate is used as a solubilizer, and that the initial blood concentration after inhalation is still high when a single solubilizer is used or other solubilizers are replaced. The polyoxyethylene hydrogenated castor oil and the pentaerythritol monostearate have a certain synergistic effect as a solubilizer and act together, so that the blood concentration of the aerosol inhalant is relatively stable after the aerosol inhalant is inhaled.
Claims (10)
1. The voriconazole aerosol inhalant is characterized by comprising the following raw materials in parts by mass: 8-13 parts of voriconazole-cyclodextrin inclusion compound freeze-dried powder and 100 parts of water for injection; the voriconazole-cyclodextrin inclusion compound freeze-dried powder is obtained by preparing organic weak acid solution of voriconazole, polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate and cyclodextrin water solution into inclusion compound solution and then freeze-drying.
2. Voriconazole aerosol inhalant according to claim 1, wherein the cyclodextrin is at least one of hydroxypropyl- β -cyclodextrin, sodium sulfobutyl- β -cyclodextrin.
3. Voriconazole aerosol inhalant according to claim 1, wherein the mass ratio of voriconazole to cyclodextrin is 1: 8-15.
4. Voriconazole aerosol inhalant according to claim 2, wherein the cyclodextrin is sodium sulfobutyl- β -cyclodextrin and the mass ratio of voriconazole and sodium sulfobutyl- β -cyclodextrin is 1: 1-12.
5. Voriconazole aerosol inhalant according to claim 1, wherein the total mass of polyoxyethylene hydrogenated castor oil, pentaerythritol monostearate is 4-7wt% of the mass of voriconazole, and the mass ratio of polyoxyethylene hydrogenated castor oil, pentaerythritol monostearate is 3-5: 1-2.
6. Voriconazole aerosol inhalant according to claim 1, wherein the weak organic acid is selected from at least one of acetic acid, oxalic acid, malic acid, tartaric acid, and has a pH of 2-4.
7. The voriconazole aerosol inhalant according to claim 1, wherein the voriconazole-cyclodextrin inclusion complex lyophilized powder is obtained by a preparation method comprising the following steps:
(S1) dissolving voriconazole in weak organic acid solution containing polyoxyethylene hydrogenated castor oil and pentaerythritol monostearate, adding into cyclodextrin water solution, stirring at 20-30 ℃ for 2-4h to prepare solution of the inclusion compound, and adjusting the pH of the solution to 5-7;
(S2) freeze-drying to obtain the voriconazole-cyclodextrin inclusion compound freeze-dried powder.
8. The voriconazole aerosol inhalant according to claim 7, wherein prior to the voriconazole being dissolved in the weak organic acid in step (S1), the voriconazole is pulverized to a particle size D90 of 50 μm or less.
9. The voriconazole aerosol inhalation according to claim 7, wherein the freeze drying is performed by prefreezing at-20 ℃ to-30 ℃ for 3-5h at normal pressure, vacuumizing, keeping the temperature at-2 to-12 ℃ for 20-30h at 5-50Pa, then slowly returning the temperature to 0 to 5 ℃, keeping the temperature for 1-2h, raising the temperature to 25 to 35 ℃, keeping the temperature for 2-4h, and completing the freeze drying.
10. Use of voriconazole aerosol inhalant according to any one of claims 1 to 9 for the preparation of an antifungal medicament.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686136A (en) * | 2005-05-09 | 2005-10-26 | 张文芳 | Vollikongzole preparation and its preparation method |
| WO2007099396A2 (en) * | 2005-06-07 | 2007-09-07 | Foamix Ltd. | Antibiotic kit and composition and uses thereof |
| WO2008075207A2 (en) * | 2006-04-04 | 2008-06-26 | Foamix Ltd. | Anti-infection augmentation foamable compositions and kit and uses thereof |
| CN103126991A (en) * | 2011-11-25 | 2013-06-05 | 北京万生药业有限责任公司 | Voriconazole nano-micro composite powder and preparation method thereof |
| CN103251565A (en) * | 2013-04-09 | 2013-08-21 | 珠海亿邦制药股份有限公司 | Voriconazole freeze-dried powder injection for injection and preparation method thereof |
| CN108187069A (en) * | 2018-03-04 | 2018-06-22 | 珠海亿邦制药股份有限公司 | A kind of voriconazole pharmaceutical composition and its preparation |
| CN110812334A (en) * | 2019-12-03 | 2020-02-21 | 珠海亿邦制药有限责任公司 | Voriconazole pharmaceutical composition for injection and preparation method thereof |
-
2022
- 2022-05-19 CN CN202210541034.6A patent/CN114632075B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686136A (en) * | 2005-05-09 | 2005-10-26 | 张文芳 | Vollikongzole preparation and its preparation method |
| WO2007099396A2 (en) * | 2005-06-07 | 2007-09-07 | Foamix Ltd. | Antibiotic kit and composition and uses thereof |
| WO2008075207A2 (en) * | 2006-04-04 | 2008-06-26 | Foamix Ltd. | Anti-infection augmentation foamable compositions and kit and uses thereof |
| CN103126991A (en) * | 2011-11-25 | 2013-06-05 | 北京万生药业有限责任公司 | Voriconazole nano-micro composite powder and preparation method thereof |
| CN103251565A (en) * | 2013-04-09 | 2013-08-21 | 珠海亿邦制药股份有限公司 | Voriconazole freeze-dried powder injection for injection and preparation method thereof |
| CN108187069A (en) * | 2018-03-04 | 2018-06-22 | 珠海亿邦制药股份有限公司 | A kind of voriconazole pharmaceutical composition and its preparation |
| CN110812334A (en) * | 2019-12-03 | 2020-02-21 | 珠海亿邦制药有限责任公司 | Voriconazole pharmaceutical composition for injection and preparation method thereof |
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