A pharmaceutical composition against influenza virus

Abstract

The present invention provides a dry suspension of a novel anti-influenza drug and a preparation method thereof. The dry suspension containing Compound I provided by the present invention has good stability, high dissolution rate, and good taste, and can not only meet the medication needs of adults, but also be convenient for children and the elderly to use. The preparation method provided by the present invention is simple in operation, suitable for industrial production applications, and the Compound I dry suspension prepared by the method provided by the present invention has good drug uniformity.

Description

Technical Field

[0001] This application belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition for anti-influenza virus, and more particularly to a dry suspension of pyrimidine derivative anti-influenza virus. Background Art

[0002] Influenza virus, namely influenza virus (IFV), is a segmented single-stranded antisense RNA virus that can cause influenza in humans and animals. The pandemic of influenza and human avian influenza has become a social issue of global concern and a major public health problem threatening human health. According to estimates by the World Health Organization, the seasonal epidemic of influenza can cause 3 million to 5 million severe cases and 250,000 to 500,000 deaths globally every year. China is a high-incidence area of influenza and is often the first area hit by influenza. The estimated number of influenza cases in China every year can reach tens of millions. Influenza and human avian influenza not only seriously endanger human health but even threaten life. During a pandemic, it is also easy to cause panic among the population and then affect social stability. The rampant influenza also brings a great economic burden. Only in the United States, the economic loss caused by adult influenza diseases reaches 80 billion US dollars every year, and the total market value of adult influenza drugs is close to 10 billion US dollars.

[0003] Current influenza treatment options include vaccination and treatment with antiviral drugs. Influenza virus has the characteristics of high mutation rate and frequent virus recombination. The existing anti-influenza drugs are becoming increasingly resistant, and the effect of vaccines is often evaded by influenza virus.

[0004] Compound 1 is a small molecule RNA polymerase inhibitor. Preclinical research results show that Compound I has strong in vitro broad-spectrum anti-influenza A virus activity, and its inhibitory ability against various influenza A viruses is significantly better than that of compounds with the same target and the neuraminidase inhibitor oseltamivir. In vivo pharmacodynamic experiments also show better efficacy in protecting animals and reducing the virus titer in the lungs of animals than the reference compounds with the same target and oseltamivir.

[0005]

[0006] CN201780054195.X discloses a class of anti-influenza virus compounds, and also discloses that Compound I shows a positive effect in the in vitro influenza virus replication inhibition test at the cell level with an EC50 of 0.013 nM; in the pharmacodynamic test study in the influenza A virus H1N1 mouse infection model, it shows that the weight loss rate of the protected animals can reach 4.8% and the survival rate can reach 100% on the 9th day.

[0007] However, currently, there is no research on the preparation of Compound 1. Developing a suitable pharmaceutical dosage form of Compound 1 that can effectively improve the stability of the drug, meet the convenience of use for patients, and improve patient compliance is beneficial for Compound 1 to benefit patients earlier and meet the unmet clinical needs. Summary of the Invention

[0008] The object of the present invention is to provide a pharmaceutical composition of Compound I, which is expected to meet the clinical use requirements and provide a new medication option for influenza patients.

[0009] Specifically, the present invention provides a pharmaceutical composition of Compound I, which comprises a therapeutically and / or prophylactically effective amount of Compound I and one or more pharmaceutically acceptable excipients.

[0010] Furthermore, the present invention provides a dry suspension of Compound I, which comprises the following components in weight percentages: active ingredient Compound I 1% - 10%, filler 70% - 90%, flavoring agent 1% - 3%. Preferably, the content of Compound I is 4% - 8%, and more preferably, the content of Compound I is 4% - 6%.

[0011]

[0012] Furthermore, the dry suspension of Compound I further comprises a stabilizer 4% - 7% and / or a light-shielding agent 0.5% - 2.0%. Preferably, the content of the stabilizer is 5% - 7%, and more preferably, the content of the stabilizer is 6% - 7%.

[0013] Furthermore, the stabilizer is sodium dihydrogen citrate, and the light-shielding agent is titanium dioxide.

[0014] Furthermore, the dry suspension further comprises a suspending agent 1% - 2.5%, a sweetening agent 0.1% - 0.3%, and a preservative 0.1% - 0.4%. Preferably, the content of the preservative is 0.2% - 0.3%.

[0015] Preferably, the filler is selected from sorbitol, mannitol, maltitol or fructose; the suspending agent is sodium carboxymethylcellulose or xanthan gum, the preservative is sodium benzoate, the flavoring agent is orange flavor essence, and the sweetening agent is sodium saccharin or aspartame.

[0016] In another more preferred embodiment of the present invention, a dry suspension comprising Compound I is provided, which comprises the following components in weight percentages: Compound I 3 - 8%, sodium dihydrogen citrate 5% - 7%, sodium benzoate 0.1% - 0.3%, sorbitol 80% - 90%, xanthan gum 1% - 2.5%, titanium dioxide 0.5% - 2.0%, orange flavor essence 1% - 3%, sodium saccharin 0.1% - 0.3%.

[0017] Further preferably, the dry suspension containing Compound I comprises the following components in weight percentages: Compound I 4-8%, sodium dihydrogen citrate 6%-7%, sodium benzoate 0.2%-0.3%, sorbitol 75%-90%, xanthan gum 1%-2%, titanium dioxide 1.0%-2.0%, orange flavor essence 1%-2%, sodium saccharin 0.1%-0.2%.

[0018] In another aspect of the present invention, there is also provided a method for preparing the oral suspension containing Compound I, comprising the following steps:

[0019] (1) Pretreatment: The prescription amounts of raw and auxiliary materials are respectively pulverized and then passed through a 80-mesh sieve;

[0020] (2) Preparation of drug-containing granules: The prescription amount of Compound I, 30%-45% (w / w) of a filler, and an optional suspending agent are mixed evenly to obtain drug-containing granules;

[0021] (3) Preparation of blank granules: The remaining amount of the filler, flavoring agent, and optional other auxiliary materials including a light-shielding agent, a stabilizer, and a sweetening agent are mixed evenly to obtain blank granules;

[0022] (4) Dry granulation: The drug-containing granules, blank granules, and preservative are mixed evenly by the equal increment method, dry granulated, and then sieved through an 18-mesh sieve for sizing and sub-packaged to obtain the dry suspension containing Compound I.

[0023] In the present invention, preferably, the particle size D(v,0.9) of Compound I in the oral dry suspension is ≤50 μm, and more preferably the particle size D(v,0.9) is ≤30 μm.

[0024] According to the present invention, the particle size D(v, 0.9) has the following meaning, that is, when D(v, 0.9) = 50 μm, it means that in the entire described particle population, 90% of the particles by volume have a particle size less than or equal to 50 μm.

[0025] Compound I in the pharmaceutical composition of the present invention may exist in the form of a pharmaceutically acceptable salt of Compound I, or a hydrate of Compound I, or may also exist in the form of the free acid of Compound I. The content of Compound I in the pharmaceutical composition refers to the content after being converted into the free acid form of Compound I.

[0026] CN111819177A and CN109790159A disclose the preparation methods of the pharmaceutically acceptable salt, hydrate, and free form of Compound I, which are incorporated into the present invention by reference.

[0027] The oral dry suspension prepared by the method of the present invention has good stability. In the long-term stability test under high temperature and high humidity conditions, it is proved that there are few related impurities. Moreover, the oral dry suspension prepared by the present invention has good appearance, good dissolution behavior after reconstitution, simple production process, convenient adjustment of dosage, and is not only suitable for adults, but especially suitable for children, the elderly and patients with dysphagia. It has high bioavailability and can meet the medication needs and compliance of special groups such as children and the elderly.

[0028] The preparation method provided by the present invention has no adhesion, small loss of raw materials and excipients, which is conducive to improving the operation environment and reducing production costs. Detailed implementation manners

[0029] It should be noted that, without conflict, the embodiments in this application and the features in the embodiments can be combined with each other.

[0030] Example 1: Preparation of an oral dry suspension of Compound I

[0031] The prescription content is as follows:

[0032]

[0033]

[0034] Preparation method: First, the raw materials and excipients in the prescription amount are respectively pulverized and then passed through an 80-mesh sieve for standby; then, Compound I in the prescription amount, 33.36% (w / w) sorbitol and xanthan gum are mixed evenly to obtain drug-containing granules; then, the remaining amount of sorbitol, titanium dioxide, orange flavor essence and saccharin sodium are mixed evenly to obtain blank granules; the drug-containing granules, blank granules and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve; after dry granulation, it is screened through an 18-mesh sieve for sizing and then packed to obtain an oral dry suspension containing Compound I, and the content of Compound I is 3 mg / 100 mg.

[0035] Among them, the particle size D(v, 90) of Compound I is 30 μm.

[0036] Example 2: Preparation of an oral dry suspension of Compound I

[0037] Prescription:

[0038]

[0039]

[0040] Preparation method: First, the raw and auxiliary materials in the prescribed amounts are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the compound I in the prescribed amount, 33.40% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain drug-containing granules. Next, the remaining amount of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules. The drug-containing granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve, granulated by dry granulation, sized through an 18-mesh sieve, and filled into packages to obtain a dry suspension containing compound I, with the content of compound I being 5 mg / 100 mg.

[0041] Among them, the particle size D(v, 90) of compound I is 35 μm.

[0042] Example 3. Preparation of an oral dry suspension of compound I

[0043] The prescription content is as follows:

[0044]

[0045]

[0046] Preparation method: First, the raw and auxiliary materials in the prescribed amounts are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the compound I in the prescribed amount, 33.36% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain drug-containing granules. Next, the remaining amount of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules. The drug-containing granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve, granulated by dry granulation, sized through an 18-mesh sieve, and filled into packages to obtain an oral dry suspension containing compound I, with the content of compound I being 3 mg / 100 mg.

[0047] Among them, the particle size D(v, 90) of compound I is 30 μm.

[0048] Example 4. Preparation of an oral dry suspension of compound I

[0049] The prescription is as follows:

[0050]

[0051]

[0052] Preparation method: First, the raw and auxiliary materials in the prescribed amounts are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the compound I in the prescribed amount, 32.54% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain medicated granules. Next, the remaining sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules. The medicated granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve, granulated by dry granulation, sized through an 18-mesh sieve, and filled into packages to obtain an oral dry suspension containing compound I, with the content of compound I being 6 mg / 100 mg.

[0053] Among them, the particle size D(v, 90) of compound I is 35 μm.

[0054] Example 5. Preparation of an oral dry suspension of compound I

[0055] The prescription content is as follows:

[0056]

[0057]

[0058] Preparation method: First, the raw and auxiliary materials in the prescribed amounts are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the compound I in the prescribed amount, 34.29% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain medicated granules. Next, the remaining sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules. The medicated granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve, granulated by dry granulation, sized through an 18-mesh sieve, and filled into packages to obtain an oral dry suspension containing compound I, with the content of compound I being 10 mg / 100 mg.

[0059] Among them, the particle size D(v, 90) of compound I is 29 μm.

[0060] Example 6. Preparation of an oral dry suspension of compound I

[0061] The prescription content is as follows:

[0062]

[0063]

[0064] Preparation method: First, the prescription amounts of the raw and auxiliary materials are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the prescription amount of Compound I, 39.30% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain medicated granules. Next, the remaining amount of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules. The medicated granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve, granulated by dry granulation, sized through an 18-mesh sieve, and filled into packages to obtain an oral dry suspension containing Compound I, with the content of Compound I being 4 mg / 100 mg.

[0065] Among them, the particle size D(v, 90) of Compound I is 28 μm.

[0066] Example 7. Preparation of an oral dry suspension of Compound I monohydrate

[0067] The prescription content is as follows:

[0068]

[0069]

[0070] Preparation method: First, the prescription amounts of the raw and auxiliary materials are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the prescription amount of Compound I monohydrate, 39.30% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain medicated granules. Next, the remaining amount of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules. The medicated granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve, granulated by dry granulation, sized through an 18-mesh sieve, and filled into packages to obtain an oral dry suspension containing Compound I monohydrate.

[0071] Among them, the particle size D(v, 90) of Compound I monohydrate is 40 μm.

[0072] The structure of Compound I monohydrate is as follows:

[0073]

[0074] The shown Compound I monohydrate is prepared by the method disclosed in WO2019170067.

[0075] Example 8. Preparation of an oral dry suspension containing Compound I hydrochloride

[0076] The prescription content is as follows:

[0077]

[0078] Preparation method: First, the prescription amounts of the raw and auxiliary materials are separately pulverized and then passed through an 80-mesh sieve for standby; then the prescription amounts of Compound I hydrochloride, 30.60% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain drug-containing granules; then the remaining amount of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules; the drug-containing granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve; after dry granulation, the granules are sized through an 18-mesh sieve and then filled into packages to obtain an oral dry suspension containing Compound I hydrochloride.

[0079] Among them, the particle size D(v, 90) of Compound I hydrochloride is 35 μm.

[0080] Among them, the structure of Compound I hydrochloride is shown in the following formula (II-1):

[0081]

[0082] The Compound I hydrochloride is prepared by the method disclosed in WO2019170067.

[0083] Example 9. Preparation of an oral dry suspension containing Compound I sodium salt

[0084] The prescription content is as follows:

[0085]

[0086]

[0087] Preparation method: First, the prescription amounts of the raw and auxiliary materials are separately pulverized and then passed through an 80-mesh sieve for standby; then the prescription amounts of Compound I sodium salt, 44.91% (w / w) sorbitol, and xanthan gum are mixed evenly to obtain drug-containing granules; then the remaining amount of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, and sodium saccharin are mixed evenly to obtain blank granules; the drug-containing granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method, passed through a 60-mesh sieve; after dry granulation, the granules are sized through an 18-mesh sieve and then filled into packages to obtain an oral dry suspension containing Compound I sodium salt.

[0088] Among them, the particle size D(v, 90) of Compound I sodium salt is 32 μm.

[0089] Among them, the structure of Compound I sodium salt is shown in the following formula (III-1):

[0090]

[0091] The Compound I sodium salt is prepared by the method disclosed in WO2019170067.

[0092] Example 10. Preparation of an oral dry suspension of Compound I

[0093] Prescription:

[0094] Ingredients Single dose (mg) Percentage (%) Compound I 25.00 5.00 Sorbitol 418.50 83.70 Xanthan gum 7.5 1.50 Titanium dioxide 7.5 1.50 Sodium dihydrogen citrate 32.5 6.50 Orange flavor 7.25 1.45 Sodium saccharin 0.5 0.10 Sodium benzoate 1.25 0.25 Total 500 100.00

[0095] Preparation method: First, the raw and auxiliary materials in the prescription amount are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the compound I, sorbitol, xanthan gum, titanium dioxide, sodium dihydrogen citrate, orange flavor essence, saccharin sodium, and sodium benzoate in the prescription amount are mixed evenly and passed through a 60-mesh sieve. After dry granulation, the granules are sized through an 18-mesh sieve, packaged, and a dry suspension containing compound I is obtained, with the content of compound I being 5 mg / 100 mg.

[0096] Example 11: Preparation of an oral dry suspension of compound I

[0097] Prescription:

[0098]

[0099]

[0100] Preparation method: First, the raw and auxiliary materials in the prescription amount are separately pulverized and then passed through an 80-mesh sieve for standby. Then, the compound I, 39.4% (w / w) sorbitol, and xanthan gum in the prescription amount are mixed evenly to obtain drug-containing granules. Then, the remaining amount of sorbitol, orange flavor essence, and aspartame are mixed evenly to obtain blank granules. The drug-containing granules, blank granules, and sodium benzoate are mixed evenly by the equal increment method and passed through a 60-mesh sieve. After dry granulation, the granules are sized through an 18-mesh sieve, packaged, and a dry suspension containing compound I is obtained, with the content of compound I being 7 mg / 100 mg.

[0101] Among them, the particle size D(v, 90) of compound I is 31 μm.

[0102] Example 12: Stability study

[0103] Accelerated test conditions: The dry suspensions prepared in Examples 1 to 11 of the present invention are respectively placed under the conditions of a temperature of 40 ± 2 °C and a relative humidity of 75% ± 5% for an accelerated test for 6 months. Samples of the compound I dry suspension at 0, 1, 3, and 6 months are respectively taken for the investigation of related substances and content.

[0104] The investigation results are shown in Table 1 below:

[0105] Table 1. Investigation results of the accelerated test

[0106]

[0107]

[0108] The dry suspensions prepared in Examples 1-7 and 10-11 of the present invention were placed for 10 days under the conditions of a temperature of 60±2°C and a relative humidity of 75%±5%, and the degradation of Compound I impurities was detected by high performance liquid chromatography. The results are shown in Table 2 below:

[0109] Table 2: Changes in total related impurities

[0110]

[0111] The results of the accelerated test showed that the dry suspensions of Compound I or its pharmaceutically acceptable salts prepared by the method of the present invention had good stability. Under the conditions of a temperature of 40±2°C and a relative humidity of 75%±5%, the single impurity content did not exceed 0.1% after being placed for 6 months. The total impurities and content of Compound I changed little, and basically no degradation impurities increased.

[0112] Long-term test: The dry suspensions of Compound I or its pharmaceutically acceptable salts prepared in Examples 2-3 and 10-11 of the present invention were placed for long-term testing under the conditions of 25±2°C and a humidity of 60%±10%. The dry suspensions of Compound I or its pharmaceutically acceptable salts were respectively sampled at 0, 3, 6, 9, and 12 months for the investigation of related substances, content, and dissolution rate. The investigation results are shown in Table 3.

[0113] Table 3: Investigation results of long-term test

[0114]

[0115]

[0116] From the investigation results of the long-term stability test, it can be seen that the dry suspension of Compound I provided by the present invention has good stability at room temperature, and the content and related substances basically do not change after being placed for 12 months.

[0117] Dissolution study of Example 13

[0118] Using pH 1.0 as the dissolution medium and a rotation speed of 25 rpm, the dissolution curves of the dry suspensions prepared in Examples 1-11 were measured. The results are shown in Table 4.

[0119] Table 4 Dissolution percentage

[0120]

[0121]

[0122] From the above results, it can be seen that the dissolution rate of the dry suspension of Compound I prepared by the method of the present invention exceeds 75% within 3 minutes, and the dissolution rate can reach 100% within 30 minutes, showing good dissolution effect.

[0123] Inspired by the above-described ideal embodiments of the present application, through the above description, relevant staff can completely make various changes and modifications without departing from the technical idea of this application. The technical scope of this application is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A dry suspension of Compound I, characterized in that, Comprising the following components in weight percentages: active ingredient Compound I 1% - 10%, filler 70% - 90%, flavoring agent 1% - 3%, stabilizer 4% - 7%, light-shielding agent 0.5% - 2.0%, suspending agent 1% - 2.5%, sweetening agent 0.1% - 0.3%, preservative 0.1% - 0.4%. The stabilizer is sodium dihydrogen citrate, the light-shielding agent is titanium dioxide, and the filler is selected from sorbitol. The suspending agent is xanthan gum. The flavoring agent is orange flavor essence. The sweetening agent is sodium saccharin or aspartame. The preservative is sodium benzoate. The particle size D(v,0.9) of Compound 1 or its pharmaceutically acceptable salt in the dry suspension is ≤50 μm. The preparation method of the dry suspension comprises the following steps: (1) Pretreatment: Crushing the prescription amounts of the raw and auxiliary materials respectively and then passing through a 80-mesh sieve. (2) Preparing the drug-containing granules: Mixing evenly Compound I in the prescription amount, 30% - 45% (w / w) of the filler, and the suspending agent to obtain the drug-containing granules. (3) Preparing the blank granules: Mixing evenly the remaining amount of the filler, flavoring agent, light-shielding agent, stabilizer, and sweetening agent to obtain the blank granules. (4) Dry granulation: Mixing evenly the drug-containing granules, blank granules, and preservative by the equal increment method, performing dry granulation, screening through an 18-mesh sieve for sizing, and packaging to obtain the dry suspension containing Compound I.

2. The dry suspension according to claim 1, characterized in that, The dry suspension comprises the following components in weight percentages: Compound I 3 - 8%, sodium dihydrogen citrate 5% - 7%, sodium benzoate 0.1% - 0.3%, sorbitol 80% - 90%, xanthan gum 1% - 2.5%, titanium dioxide 0.5% - 2.0%, orange flavor essence 1% - 3%, sodium saccharin 0.1% - 0.3%.

3. The dry suspension according to claim 1, characterized in that, Comprising the following components in weight percentages: Compound I 4% - 8%, sodium dihydrogen citrate 6% - 7%, sodium benzoate 0.2% - 0.3%, sorbitol 75% - 90%, xanthan gum 1% - 2%, titanium dioxide 1.0% - 2.0%, orange flavor essence 1% - 2%, sodium saccharin 0.1% - 0.2%.

4. The dry suspension according to any one of claims 1 to 3, characterized in that, The particle size D(v,0.9) of Compound 1 or its pharmaceutically acceptable salt in the dry suspension is ≤30 μm.

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