CN107663158B - Preparation method of oseltamivir carboxylate and atomizing agent thereof - Google Patents
Preparation method of oseltamivir carboxylate and atomizing agent thereof Download PDFInfo
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Abstract
The invention provides a preparation method of oseltamivir carboxylic acid hydrochloride, which comprises the following steps: a. introducing a protecting group A into an amino group on oseltamivir phosphate 1 to obtain a compound 2; b. hydrolyzing the ester group on the compound 2 under the action of strong alkali to obtain a compound 3; c. removing the protecting group A of the compound 3 by using hydrogen chloride to obtain oseltamivir carboxylate 4; the reaction route is as follows:
Description
Technical Field
The invention belongs to the field of medicine synthesis and preparations, particularly relates to preparation of an anti-influenza medicine, and particularly relates to preparation methods of oseltamivir carboxylate and an atomizing agent thereof.
Background
Influenza virus is a virus causing influenza in humans and animals, and taxonomically, influenza virus belongs to the orthomyxoviridae, causes acute upper respiratory infection, and is rapidly transmitted through the air, with periodic pandemics occurring all over the world. Influenza virus nucleoproteins can be classified into three types, A, B and C, according to their antigenicity. Among them, type a and type b are likely to cause a pandemic of influenza, while type c appears in a scattered form and generally does not cause a pandemic.
Influenza virus is a minus-strand RNA virus that is spherical (80-120 nm in diameter) and contains a segmented genome. Influenza a and b viruses contain 8 RNA segments, each of which is encapsulated by a viral nucleoprotein and associated by a polymerase complex. The complex particle formed by nucleoprotein, RNA and polymerase, called ribonucleoprotein particle, is enveloped by a lipid membrane composed of matrix protein M1 and membrane protein M2. Two spike proteins are embedded in the lipid membrane and extend to the viral surface: hemagglutinin and neuraminidase in stick form, respectively. These two types of proteins play an important role in the replication of viruses.
Influenza is a highly contagious disease that is transmitted primarily by human respiratory secretions, typically by droplets from coughing or sneezing. Infection is generally thought to start and spread from the bronchial epithelium of the trachea. Histological studies have shown that influenza virus replication occurs throughout the upper and lower respiratory tract. The onset of influenza disease is closely related to the progression of viral replication.
Although influenza viruses replicate in the respiratory tract, they affect the systemic state. Infection and replication of influenza viruses cause death of host cells, which leads to inflammation of the respiratory tract and rapid immune response, resulting in systemic symptoms including weakness, fever, chills, headache, loss of appetite, muscle soreness and dizziness. These early systemic symptoms are often accompanied by respiratory symptoms such as dry cough, runny nose, sneezing, sore throat. The symptoms of low frequency include productive cough, hoarseness, and pain behind the sternum. Systemic symptoms usually last 3-4 days, however coughing and physical discomfort may last 2 weeks after the fever has subsided. After influenza infection, serious complications such as complicated pneumonia, myocarditis, meningitis and other serious diseases are also easily induced, and even death is caused.
Around every 10-40 years, a global influenza pandemic will occur due to the emergence of new influenza virus antigens. Influenza pandemics may affect 50% of the world population due to little or no immunity against the new virus. There have been hundreds of years reported on global influenza pandemics. Well documented influenza pandemics occurred in 1918 (spanish flu), 1957 (asian flu) and 1968 (hong kong flu) causing 3000, 100 and 80 million deaths, respectively. However, in 2009 outbreaks of H1N1 swine flu spread to over 200 countries and regions worldwide, 20000 people died.
There are two main approaches in controlling influenza: 1) prophylaxis, vaccination or other antiviral prophylactic agents; 2) using antiviral drugs for treatment. The purpose of the latter approach is to alleviate symptoms and shorten the duration of the infection after viral infection, while preventing other complications such as bronchitis and pneumonia.
Vaccination is generally recommended for high risk groups to prevent infections such as the elderly, children, severe chronic patients, people with low immunity and people who may be in close contact with the patient. Because the high variability of influenza viruses increases the difficulty of people in dealing with influenza, people cannot accurately predict the virus subtype that will prevail, and thus cannot pertinently carry out preventive vaccination. On the other hand, antigenic changes that occur every few decades will result in new strains of influenza that have no vaccine at all.
The M2 inhibitors amantadine and rimantadine were discovered in the 60 s of the 20 th century and were marketed for the treatment of influenza starting in the 80 s. Both drugs are primary amines substituted with a 10-carbon three-membered ring. The M2 ion channel plays an important role in uncoating and replicating viruses after they enter host cells. Both drugs exert antiviral effects by inhibiting the M2 ion channel. Since the M2 protein is only expressed in influenza a, the M2 inhibitor has no therapeutic effect on influenza b. These two drugs cause relatively significant gastrointestinal adverse reactions. Amantadine also has adverse effects on the central nervous system. Recent studies have found that influenza virus strains have developed resistance to such drugs in the clinic, limiting the use of such drugs in influenza therapy.
Neuraminidase is a glycoside hydrolase, which is expressed in both influenza a and b viruses. After the mature influenza virus is separated from the host cell in a budding mode, hemagglutinin on the surface of the virus is in contact with the host cell membrane through a sialic acid receptor, neuraminidase is needed to hydrolyze the sialic acid, the final contact between the virus and the host cell is cut off, and the virus can be smoothly released from the host cell and then infects the next host cell. Meanwhile, the amino acid sequence of the active site of the neuraminidase is highly conserved, and mutation is not easy to generate, so that drug resistance is caused. This makes neuraminidase an ideal target for drug action, and inhibition of neuraminidase can prevent viral spread to surrounding cells. Currently, the neuraminidase inhibitors commonly used on the market are zanamivir and oseltamivir (trade name tamiflu). In which tamiflu is listed as a reserve drug by governments of various countries for the treatment of influenza virus.
Influenza viruses attack the respiratory system of the human body, mainly distributed in lung tissue. The tamiflu serving as a precursor medicine has no antiviral curative effect, and can act only after being taken orally through being metabolized and hydrolyzed by the liver into an active metabolite, namely oseltamivir carboxylate. However, oseltamivir carboxylate cannot form effective enrichment in the lung, and only less than 10% of the drug is distributed in the lung, so that a higher dose is needed to play an antiviral effect, but more side effects such as dizziness, diarrhea, nausea, vomiting, adverse reactions of the central nervous system and the like can be caused.
Disclosure of Invention
In view of the technical defects in the prior art, according to one aspect of the present invention, there is provided a method for preparing oseltamivir carboxylic acid hydrochloride, comprising the following steps:
a. introducing a protecting group A into an amino group on oseltamivir phosphate 1 to obtain a compound 2, wherein the protecting group A is any one of tert-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 2- (4-biphenyl) isopropyloxycarbonyl, 3, 5-dimethoxyphenylisopropyloxycarbonyl, trityl and 2-nitrobenzenethiophenyl;
b. hydrolyzing an ester group on the compound 2 under the action of strong alkali to obtain a compound 3;
c. removing the protecting group A of the compound 3 by using hydrogen chloride to obtain oseltamivir carboxylate 4;
the reaction route is as follows:
preferably, the step a is completed in a mixed system of an organic solvent and an alkali solution, wherein the reaction temperature is 0-60 ℃.
Preferably, the organic solvent in step a is any one or any several of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dichloromethane and tetrahydrofuran, and the alkali solution is any one of an aqueous sodium bicarbonate solution, an aqueous sodium carbonate solution, an aqueous potassium carbonate solution and an aqueous potassium acetate solution.
Preferably, the step b is completed in a mixed system of an organic solvent and a strong base solution, wherein the reaction temperature is 0-60 ℃.
Preferably, the organic solvent in step b is any one or more of dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, dioxane and acetone, and the strong alkali solution is any one of an aqueous potassium hydroxide solution, an aqueous sodium hydroxide solution and an aqueous lithium hydroxide solution.
Preferably, said step c is performed in an organic solvent, said organic solvent being any one or more of dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, isopropyl ether and chloroform.
Preferably, the step a comprises the steps of:
a1. mixing oseltamivir phosphate, sodium bicarbonate, tetrahydrofuran and water, and stirring until the mixture is clear to obtain a first system;
a2. adding a tetrahydrofuran solution of di-tert-butyl dicarbonate into the first system under an ice bath condition of 0-4 ℃, and reacting for at least 10 hours to obtain a first solution;
a3. and after evaporating the organic phase in the first solution to dryness, extracting the first solution by using tert-butyl methyl ether to obtain an organic phase solution, and performing rotary evaporation on the organic phase solution until the organic phase solution is dried to obtain the compound 2.
Preferably, the step b comprises the steps of:
b1. mixing and stirring the compound 2, methanol and an aqueous solution of sodium hydroxide to obtain a second solution;
b2. removing methanol in the second solution by reduced pressure rotary evaporation, and then adding water and tert-butyl methyl ether to wash to obtain an aqueous phase solution;
b3. the pH of the aqueous phase solution was adjusted to acidic using hydrochloric acid until compound 3 precipitated.
Preferably, the step b1 is stirred at 0-60 ℃ for at least one hour, and the step b3 is carried out under ice bath conditions of 0-4 ℃ and the pH value is adjusted to 2.
Preferably, the step c includes the steps of:
c1. introducing hydrogen chloride gas into ethyl acetate to obtain a second system;
c2. adding said compound 3 to said second system and heating to reflux;
c3. and cooling the second system, and reacting until the oseltamivir carboxylate 4 is separated out.
Preferably, the step c1 is performed under the condition of an ice bath at 0-4 ℃, the step c2 is reacted for 0.5-3 hours after the ice bath is removed and the heating is carried out to reflux, and the temperature of the second system in the step c3 is reduced to 20-25 ℃ and the reaction is carried out for at least 10 hours.
Preferably, the reaction time in the step a2 is 10-12 hours, the stirring time in the step b1 is 1-2 hours, and the reaction time in the step c3 is 10-12 hours.
According to another aspect of the present invention, there is provided a method for preparing oseltamivir carboxylate hydrochloride aerosol, wherein the method for preparing oseltamivir carboxylate hydrochloride comprises the following steps:
i. preparing a mixed solution of oseltamivir carboxylic acid hydrochloride and an osmotic pressure regulator, wherein the content of the oseltamivir carboxylic acid hydrochloride is 5-200 mg;
and i, adding a pH buffering agent to adjust the pH value of the mixed solution in the step i to 3.5-8.5 to obtain the oseltamivir carboxylate atomizing agent.
Preferably, the oseltamivir carboxylate atomizing agent contains 0-2% of surfactant in percentage by mass.
Preferably, the oseltamivir carboxylate nebulant is processed into freeze-dried powder or capsules or tablets.
The preparation method of oseltamivir carboxylic acid hydrochloride provided by the invention can directly generate the oseltamivir carboxylic acid salt which is the active ingredient after tamiflu is metabolized in a human body, and in practical application, the oseltamivir carboxylic acid hydrochloride prepared by the invention can be directly administered to the human body. Meanwhile, the oseltamivir carboxylate is directly prepared into an atomizing agent, and the active ingredients are directly conveyed to respiratory tracts and lung tissues through an atomizing device to play a role in resisting influenza viruses, so that the direct stimulation of medicaments on gastrointestinal tracts can be avoided, and a lower dose can be used so as to reduce possible adverse reactions.
Drawings
Fig. 1 shows a nuclear magnetic resonance hydrogen spectrum of oseltamivir carboxylate 4 according to an embodiment of the present invention.
Detailed Description
The invention provides a method for preparing oseltamivir carboxylic acid hydrochloride, which comprises the following specific reaction route:
combining the reaction route, the preparation method of the oseltamivir carboxylic acid hydrochloride comprises the following steps:
firstly, step a is carried out, in organic solvent, oseltamivir phosphate and di-tert-butyl dicarbonate (Boc)2And reacting O under the action of a strong alkali solution at 0-60 ℃ to obtain a compound 2. Those skilled in the art understand that the organic solvent and the alkali solution in this step jointly constitute the reaction system required in this step, and oseltamivir phosphate and di-tert-butyl dicarbonate are reacted in this reaction system. Specifically, the selection of the organic solvent in this step requires consideration of the following factors: firstly, reactants and products can be dissolved; secondly, the reaction can not be participated in by the self; thirdly, the separation from the reactants and products is convenient; and fourthly, being as low or non-toxic as possible, and the organic solvent may be selected from among N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, methylene chloride and tetrahydrofuranAnd when the type of the organic solvent is selected, the purity of the organic solvent should be ensured, and impurities are prevented from being introduced into the system.
Further, the alkaline solution in step a is any one of aqueous sodium bicarbonate solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution and aqueous potassium acetate solution, and it is understood by those skilled in the art that the addition of the alkaline solution makes the reaction system weakly alkaline, and preferably, the reaction system can ensure the stability of the generated compound 2 by taking saturated aqueous sodium bicarbonate solution as a measure, i.e., the pH value is between 8 and 9.
Further, the reaction in step a can be continuously carried out at 0-60 ℃, and those skilled in the art understand that the reaction temperature is related to the reaction speed, and the lower the reaction temperature, the lower the corresponding reaction speed. Preferably, the temperature can be controlled at a low level, for example, 5 to 15 ℃ in the initial stage, after a certain period of reaction, for example, 1 hour of reaction, the temperature is raised to 35 to 60 ℃ and then the reaction is continued until the reaction is finished.
Further, after the reaction in step a is completed, the compound 2 is dissolved in the reaction system, and then a corresponding extraction step and a drying step are required to obtain the compound 2 in a solid form, and designers in the field understand that to implement the extraction step, the water-soluble organic solvent in step a needs to be firstly distilled off, then the extraction solvent is added to extract the aqueous phase containing the compound 2, and then the organic phase in which the compound 2 is dissolved is dried and rotary-evaporated to obtain the compound 2 in a solid form.
Further, step b is carried out, in an organic solvent, the compound 2 is subjected to hydrolysis reaction at 0-60 ℃ under the action of a strong base solution to obtain a compound 3, wherein the organic solvent and the strong base solution in the step b jointly form a reaction system in the step b. Specifically, the organic solvent in step b functions similarly to that in step a, and the selection principle can be referred to that in step a, for example, the organic solvent in step b can be any one or any more of dimethylsulfoxide, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, dioxane and acetone. More specifically, the strong alkali solution in the step b is used for hydrolyzing an ester group on the compound 2, the strong alkali solution can be any one of a potassium hydroxide aqueous solution, a sodium hydroxide aqueous solution and a lithium hydroxide aqueous solution, the pH value of the strong alkali solution can be controlled within 13-14, and after the reaction is finished, a corresponding extraction washing step and an acidification precipitation step are required to obtain the compound 3 in a solid form. The skilled artisan understands that to implement the extraction wash step, the water soluble organic solvent in step b is first distilled off and the extraction solvent is then added, after which, unlike in step a, the impurities in the aqueous phase containing the sodium salt of compound 3 need to be extracted in step b, after which the solid of compound 3 precipitates out after acidification of the aqueous phase.
Further, step c is performed, and the compound 3 is reacted with hydrogen chloride in an organic solvent to obtain oseltamivir carboxylate 4. It is understood by those skilled in the art that the organic solvent used in step c is solely used as a reaction system, and accordingly, the organic solvent used in step c may be any one or more selected from dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, acetone, diethyl ether, isopropyl ether and chloroform.
Further, it is understood by those skilled in the art that the purpose of step a is to introduce a protecting group into the amine group on oseltamivir phosphate, and in the above examples, t-butyloxycarbonyl (Boc) was selected as the protecting group for the amine group, and as some variations, any of p-methoxybenzyloxycarbonyl, 2- (4-biphenyl) isopropyloxycarbonyl, 3, 5-dimethoxyphenylisopropyloxycarbonyl, trityl, and 2-nitrophenylthio may be selected as the protecting group for the amine group, and these variations may be finally removed by hydrogen chloride, thereby completing the synthesis scheme designed by the present invention.
As a specific embodiment of the invention, the method comprises the following steps:
firstly, step a1 is executed, and oseltamivir phosphate, sodium bicarbonate, tetrahydrofuran and water are mixed and stirred until the mixture is clear, so that a first system is obtained. Specifically, there are various feeding methods, for example, in which oseltamivir phosphate, sodium bicarbonate, tetrahydrofuran, and water are sequentially fed into a reaction flask, and each material is fed at a time; for another example, in a reaction flask, oseltamivir phosphate, sodium bicarbonate, tetrahydrofuran, and water are sequentially charged, and each material is charged in a batch-wise multiple-cycle manner; for example, oseltamivir phosphate, sodium hydrogen carbonate, tetrahydrofuran and water may be added while stirring, but the addition is not in order.
Further, step a2 is carried out, and after the tetrahydrofuran solution of di-tert-butyl dicarbonate is added into the first system under the ice bath condition of 0-4 ℃, the specific addition mode is a dropwise addition mode, and the reaction is carried out for at least 10 hours after all dropwise additions are finished, so as to obtain a first solution. Preferably, the reaction is carried out for 10 to 12 hours.
Further, step a3 is performed, after the organic phase is evaporated to dryness, the first solution is extracted by using tert-butyl methyl ether to obtain an organic phase solution, and the organic phase solution is rotary evaporated to dryness to obtain the compound 2. Specifically, the tetrahydrofuran in the first solution is first removed by reduced pressure rotary evaporation, after which the extraction step is performed by adding tert-butyl methyl ether to the first solution, and the organic phase is re-extracted, preferably, the extraction steps are performed a plurality of times and the organic phases are combined and dried and then rotary evaporated to complete dryness to obtain the compound 2. The compound 2 is an off-white solid.
Further, step b1 is performed, the compound 2, methanol and aqueous sodium hydroxide solution are mixed and stirred at 0-60 ℃ for at least one hour to obtain a second solution. Specifically, the compound 2 is put into a reaction flask, then methanol is added and stirred, then an aqueous sodium hydroxide solution is added with stirring, preferably, the aqueous sodium hydroxide solution is a 4.5N aqueous sodium hydroxide solution, and after the aqueous sodium hydroxide solution is completely added, stirring is continued for 1 hour to obtain the second solution.
Further, step b2 was carried out to remove methanol from the second solution by rotary evaporation under reduced pressure, followed by addition of water and t-butyl methyl ether to wash to obtain an aqueous phase solution. Specifically, the water of this step acts similarly to the tert-butyl methyl ether of step a3, and accordingly the water added in this step is used to extract the sodium salt of product 3.
Further, step b3 is carried out, and the pH value of the aqueous phase solution is adjusted to 2 by hydrochloric acid under the condition of ice bath at 0-4 ℃ until compound 3 is precipitated. Specifically, since the compound 3 is insoluble in the aqueous phase, accordingly, after adjusting the pH of the aqueous phase solution to acidic, the sodium salt of the compound 3 is converted to the compound 3 and gradually precipitated out from the aqueous phase.
Further, step c1 is performed, and hydrogen chloride gas is introduced into the ethyl acetate under the condition of ice bath at 0-4 ℃ to obtain a second system. Specifically, the hydrogen chloride gas is dried and then introduced into ethyl acetate. The technical personnel understand that the chlorine hydride gas is continuously introduced, and accordingly, the gas circulation device and the drying device can be matched to realize circulation and continuous introduction.
Further, step c2 is performed, the compound 3 is added into the second system, the ice bath is removed and the reaction is performed after heating to reflux for 0.5-3 hours. It is understood by those skilled in the art that the reaction after heating to reflux can ensure the same temperature for each reaction and can make the temperature of the reaction consistent with the temperature of the solvent, so that the reaction is repeatable and is constant and easy to control.
Further, step c3 is executed, the temperature of the second system is reduced to 20-25 ℃ and the reaction lasts for at least 10 hours until the oseltamivir carboxylate 4 is separated out. Specifically, after separating out oseltamivir carboxylate 4, a filtering, washing and drying step is carried out to obtain dry oseltamivir carboxylate 4.
More specifically, the following shows a preparation example of oseltamivir carboxylic acid hydrochloride:
firstly, 372g of oseltamivir phosphate, 381g of sodium bicarbonate, 3600ml of tetrahydrofuran and 900ml of water are put into a reactor, stirred and dissolved clearly, 238g of a tetrahydrofuran solution of di-tert-butyl dicarbonate is dripped under an ice bath at 0-4 ℃, reaction is carried out overnight at 25 ℃, tetrahydrofuran is removed by reduced pressure rotary evaporation, tert-butyl methyl ether is extracted (2L of 2), and organic phases are combined and subjected to reduced pressure rotary evaporation to dryness to obtain a compound 2.
Then, compound 2 and 1600ml of methanol were added to the reactor, 1600ml of an aqueous solution containing 290g of sodium hydroxide was added with stirring, the mixture was stirred at 25 ℃ for 1 hour, disappearance of the raw material was detected by TLC, methanol was removed by rotary evaporation under reduced pressure, 1L of water was added, 1L of t-butyl methyl ether was used to extract impurities, pH was adjusted to 2 with concentrated hydrochloric acid in an aqueous phase ice bath, a large amount of white solid was precipitated, and 340g of compound 3 as a white solid was obtained by filtration and drying, and the total yield of the two steps was 97.5%.
And then, introducing dry hydrogen chloride gas into ethyl acetate at the temperature of 0-4 ℃ in an ice bath, then adding the compound 3 obtained in the previous step while stirring, removing the ice bath, heating to reflux, reacting for 1 hour, cooling to 25 ℃, reacting overnight, precipitating a large amount of white solid, performing suction filtration, and drying to obtain 280g of white solid, namely oseltamivir carboxylate 4, wherein the yield is 98.6%.
Specifically, fig. 1 shows the nuclear magnetic resonance hydrogen spectrum of oseltamivir carboxylate 4 obtained by the present preparation example, and as can be seen from fig. 1, the nuclear magnetic resonance hydrogen spectrum of oseltamivir carboxylate 4 obtained1H NMR(400MHz,D2O), 6.77(s,1H),4.23 to 4.26(m,1H),3.94 to 4.00(m,1H),3.44 to 3.50(m,2H),2.82 to 2.88(m,1H),2.38 to 2.45(m,1H),1.98(s,3H),1.33 to 1.46(m,4H),0.72 to 0.80(m, 6H). The compound 4 can be accurately judged to be oseltamivir carboxylic acid hydrochloride from the nuclear magnetic resonance spectrum.
It is understood by those skilled in the art that oseltamivir carboxylate is a very effective inhibitor of influenza virus neuraminidase, and its specific principle is: because the molecular structure of neuraminidase is composed of 4 identical parts, the shape of the neuraminidase is like a Chinese character 'tian', the center of the part is a cavity which is a place for combining sialic acid and hydrolyzing the sialic acid, and the oseltamivir carboxylate can be inserted into the cavity and can be firmly combined with the neuraminidase, so that the sialic acid on cells is blocked outside, and the activity of the neuraminidase can be inhibited. After oseltamivir carboxylate enters the human body, it competitively binds with the active site of influenza virus neuraminidase, and reduces the spread of influenza a or b virus by interfering with the release of the virus from infected host cells. Specifically, oseltamivir carboxylate can reach all target tissues invaded by influenza virus, and is accumulated in lung, trachea, bronchoalveolar lavage fluid, nasal mucosa, middle ear and other parts, but the binding of the oseltamivir carboxylate to human plasma protein is negligible (not more than 3%). In most subjects, the half-life of the oseltamivir carboxylate in the peak plasma concentration is 6-10 hours, the oseltamivir carboxylate is excreted by the kidney, and the clearance rate of the kidney (18.8L/h) exceeds the glomerular filtration rate (7.5L/h), indicating that the route of tubular excretion is also available besides glomerular filtration.
Furthermore, the existing influenza patients can achieve the treatment purpose by orally taking tamiflu, but more than 90% of absorption loss exists before the tamiflu reaches the lung of the action part, the active metabolite oseltamivir carboxylate of the tamiflu is directly prepared by the preparation method provided by the invention, and then the oseltamivir carboxylate can be prepared into inhalation preparations to directly act on the lung, the onset speed is faster than that of the oral administration, and the loss is less, so that the expected effective dosage can be reduced, and the toxic and side effects can be reduced.
As another embodiment of the present invention, there is also provided a method for preparing an oseltamivir carboxylic acid hydrochloride atomizing agent, comprising the steps of:
firstly, preparing a mixed solution of oseltamivir carboxylic acid hydrochloride and an osmotic pressure regulator, wherein the content of the oseltamivir carboxylic acid hydrochloride is 5-200 mg. The skilled person understands that the mixed solution prepared in the step is an isotonic solution, and specifically, the addition amount of the osmotic pressure regulator can be increased or decreased according to actual conditions, as long as the content of the oseltamivir carboxylic acid hydrochloride dissolved in the osmotic pressure regulator is ensured to be 5-200 mg. More specifically, the higher the content of oseltamivir carboxylic acid hydrochloride, the less the addition of the osmotic pressure regulator. Preferably, the osmotic pressure regulator can be one or more selected from sodium chloride, glucose, sorbitol, glycerol, PEG, propylene glycol, mannitol, and lactose. And then adding a pH buffering agent into the mixed solution to adjust the pH value to 3.5-8.5 to obtain the oseltamivir carboxylate atomizing agent. Specifically, the pH buffer may be any one of phosphoric acid, citric acid, carbonic acid, acetic acid, barbituric acid, borate, citrate, and phosphate (e.g., disodium hydrogen phosphate, sodium dihydrogen phosphate).
In a preferred embodiment, the oseltamivir carboxylate atomizing agent contains 0-2% of surfactant by mass. The surfactant is a physiologically acceptable suitable surfactant, and the following are generally selected as surfactants: sorbitan trioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleoyl polyoxyethylene (2) ether, stearoyl polyoxyethylene (2) ether, lauroyl polyoxyethylene (4) ether, block copolymers of ethylene oxide and propylene oxide, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glycerol monooleate, polyethylene glycol 400, glycerol monolaurate, and the like.
To better illustrate the preparation of the nebulant, three specific formulations are shown below:
the formula I is as follows: 10mg of oseltamivir carboxylate, 14.20mg of disodium hydrogen phosphate, 18.04mg of sodium chloride and 4mg of polyoxyethylene (20) sorbitan monooleate, wherein the components are weighed according to the formula, then water for injection is added into the mixture to reach 2ml, the mixture is uniformly mixed, the mixture is transferred to a cleaned glass ampule, the glass ampule is sealed by melting, and the sterilization is carried out for 12 minutes under the high pressure of steam and at the temperature of 120 ℃.
And a second formula: 40mg of oseltamivir carboxylic acid hydrochloride, 14.20mg of disodium hydrogen phosphate, 18.04mg of sodium chloride and 4mg of polyoxyethylene (20) sorbitan monooleate, wherein the components are weighed according to the formula, then water for injection is added into the mixture to 2ml, the mixture is uniformly mixed, the mixture is transferred to a cleaned glass ampule, the obtained product is sealed by melting, and the obtained product is sterilized for 12 minutes under the high pressure of steam at 120 ℃.
And the formula III: 60mg of oseltamivir carboxylate and 18.04mg of sodium chloride, wherein the above substances are weighed according to the formula, water for injection is added into the mixture to 2ml, the mixture is uniformly mixed, filtered and sterilized by a 0.22um filter membrane, transferred to a cleaned glass ampule, and sealed by melting.
In one variation, the oseltamivir carboxylate nebulant is processed into a lyophilized powder, for example, a specific formulation is: 30mg of oseltamivir carboxylate, 200mg of glucose and 3.6mg of sodium chloride, wherein the components are weighed according to the formula, then water for injection is added to 4ml of the mixture, the mixture is dissolved and stirred uniformly, filtered for sterilization, quantitatively separated and filled, half tamponade is carried out, the mixture is put into a freeze dryer for freeze drying, and full tamponade is carried out after the freeze drying is finished. Before clinical use, 4.0ml of water for injection is added, and the mixture is shaken for 5 to 10 seconds until the mixture is dissolved for later use.
In one variation, the oseltamivir carboxylate nebulant is formulated as a capsule or tablet, for example, a specific formulation: 5-60 mg of oseltamivir carboxylate, 80-100 mg of mannitol, 20-40 mg of lactose and 3.6mg of sodium chloride, wherein the materials are weighed according to a formula, uniformly mixed by a three-dimensional mixer or a V-shaped mixer, and quantitatively subpackaged into capsules or tablets with a dosage specification of 100-200 mg are pressed by a tablet press. Before clinical use, 4.0ml of water for injection is added into one tablet, or 4.0ml of water for injection is added into one capsule after the content is poured out, and the capsule is shaken for 5 to 10 seconds until the content is dissolved for later use.
As will be appreciated by those skilled in the art, the human respiratory system is a relatively fragile physiological system, and particularly, respiratory diseases are generally on the rise under the influence of atmospheric pollution, smoking, and the like. From the clinical point of view, inhalation drugs are the first choice for treating respiratory diseases. However, when the old, the child or some patients use inhalation drugs, some inhalation drugs such as aerosol or powder spray are not easy to use due to poor adaptability, and the clinical treatment effect is not good. The diameter of the formed medicine fog drops is generally between 0.5-12 um, so that the medicine is favorably directly inhaled into a respiratory tract, the local concentration is relatively high, the administration dosage is relatively small, and the tolerance of a patient is greatly improved compared with an aerosol or a powder aerosol. In the present invention, the first formulation, the second formulation and the third formulation are used as descriptions, and a respiration simulator (USP 35-1601 section) and a NGI impactor (chinese pharmacopoeia 2015 edition-device 3) are used as in vitro evaluation means to simulate and evaluate the percentage of the drug atomized that can be inhaled by human body, and the results are shown in the following table:
| test specimen | Delivery dose% | In vitro deposition Rate (FPF) | Fine particle dose |
| Formulation I | 35.5％ | 48.5％ | 31％ |
| Formulation II | 31.1％ | 52.8％ | 28％ |
| Formulation III | 25.7％ | 57.0％ | 27％ |
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (1)
1. The preparation method of the oseltamivir carboxylic acid hydrochloride atomizing agent is characterized by comprising the following steps of:
(1) putting 372g of oseltamivir phosphate, 381g of sodium bicarbonate, 3600ml of tetrahydrofuran and 900ml of water into a reactor, stirring to dissolve the mixture clearly, dropwise adding 238g of a tetrahydrofuran solution of di-tert-butyl dicarbonate at 0-4 ℃ under an ice bath, reacting overnight at 25 ℃, carrying out reduced pressure rotary evaporation to remove tetrahydrofuran, extracting 2L of tert-butyl methyl ether twice, combining organic phases, and carrying out reduced pressure rotary evaporation to dryness to obtain a compound 2;
(2) adding compound 2 and 1600ml of methanol into a reactor, adding 1600ml of aqueous solution containing 290g of sodium hydroxide under stirring, stirring for 1h at 25 ℃, detecting the disappearance of raw materials by TLC, carrying out reduced pressure rotary evaporation to remove the methanol, adding 1L of water, extracting impurities by 1L of tert-butyl methyl ether, adjusting the pH of an aqueous phase to 2 by using concentrated hydrochloric acid under ice bath, precipitating a large amount of white solid, filtering and drying to obtain 340g of white solid compound 3;
(3) introducing dry hydrogen chloride gas into ethyl acetate at the temperature of 0-4 ℃ in an ice bath, then adding the compound 3 obtained in the previous step under stirring, removing the ice bath, heating to reflux, reacting for 1h, cooling to 25 ℃, reacting overnight, precipitating a large amount of white solid, performing suction filtration, and drying to obtain 280g of white solid, namely oseltamivir carboxylate 4;
the reaction route is as follows:
also comprises the following steps:
the formula I is as follows: 10mg of oseltamivir carboxylate, 14.20mg of disodium hydrogen phosphate, 18.04mg of sodium chloride and 4mg of polyoxyethylene (20) sorbitan monooleate, wherein the components are weighed according to the formula, then water for injection is added into the mixture to reach 2ml, the mixture is uniformly mixed, the mixture is transferred to a cleaned glass ampule, and the glass ampule is sealed by melting, and is sterilized for 12 minutes under the high pressure of steam at 120 ℃;
or the formula II: 40mg of oseltamivir carboxylic acid hydrochloride, 14.20mg of disodium hydrogen phosphate, 18.04mg of sodium chloride and 4mg of polyoxyethylene (20) sorbitan monooleate, wherein the components are weighed according to the formula, then water for injection is added into the mixture to reach 2ml, the mixture is uniformly mixed, the mixture is transferred to a cleaned glass ampule, and the glass ampule is sealed by melting, and is sterilized for 12 minutes under the high pressure of steam and at the temperature of 120 ℃;
or the formula III: 60mg of oseltamivir carboxylate and 18.04mg of sodium chloride, wherein the above substances are weighed according to the formula, water for injection is added into the mixture to 2ml, the mixture is uniformly mixed, filtered and sterilized by a 0.22um filter membrane, transferred to a cleaned glass ampule, and sealed by melting.
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