CN114569562A - Anti-influenza virus pharmaceutical composition - Google Patents

Abstract

The dry suspension containing the compound I has good stability, high dissolution rate and good taste, can meet the requirement of adult administration, and is convenient for children and old people to use.

Description

Anti-influenza virus pharmaceutical composition

Technical Field

The application belongs to the technical field of pharmaceutical preparations, particularly relates to an anti-influenza-virus pharmaceutical composition, and especially relates to a pyrimidine derivative anti-influenza-virus dry suspension.

Background

Influenza virus, i.e., influenza virus (IFV), is a segmented, single-stranded, antisense RNA virus that can cause influenza in humans and animals. Influenza, the pandemic of human avian influenza, has become a social problem of global concern and a significant public health problem threatening human health. According to the world health organization estimates, seasonal epidemics of influenza each year can result in 300 to 500 million severe cases and 25 to 50 million deaths worldwide. China is a region where flu attacks first in many places and many times, and the number of flu attacks per year is estimated to reach tens of millions of people. The influenza and the human avian influenza seriously harm the human health and even the life, and easily cause the panic of people and further influence the social stability in a pandemic. Influenza also imposes a significant economic burden, with annual adult influenza disease incurring economic losses of up to $ 800 billion per year in the united states alone, with the adult influenza drug market amounting to $ 100 billion in total.

Current influenza treatment options include vaccination and treatment with antiviral drugs. The influenza virus has the characteristics of high mutation rate and more recombination phenomena among viruses, the drug resistance of the existing anti-influenza drugs is gradually serious, and the vaccine effect is frequently escaped by the influenza virus.

Compound 1 is a small molecule RNA polymerase inhibitor. The preclinical research results show that the compound I has strong in-vitro broad-spectrum anti-influenza A virus activity, and the inhibition capacity on various influenza A viruses is obviously superior to that of a homotarget compound and a neuraminidase inhibitor oseltamivir. The in vivo efficacy test also has better efficacy of protecting animals and reducing the virus titer in the lung of animals compared with the same target point reference compound and oseltamivir.

Cn201780054195.x discloses a class of anti-influenza virus compounds, wherein it is also disclosed that compound I exhibits a positive effect in a cell-level inhibition of influenza virus replication assay with an EC50 of 0.013 nM; the pharmacodynamic test study in the influenza A H1N1 mouse infection model shows that the effect of protecting the weight loss rate of 4.8% and the survival rate of 100% of animals can be realized on the 9 th day.

However, no research on the compound 1 preparation is available, and a suitable pharmaceutical formulation of the compound 1, which can effectively improve the stability of the drug, can meet the requirements of patients on convenience in use and patient compliance, is beneficial to the early benefit of the compound 1 to the patients, and meets the clinical unmet requirements.

Disclosure of Invention

The invention aims to provide a pharmaceutical composition of a compound I, which is expected to meet the clinical use requirement and provide a new drug selection for influenza patients.

In particular, the present invention provides a pharmaceutical composition of compound I comprising a therapeutically and/or prophylactically effective amount of compound I, together with one or more pharmaceutically acceptable excipients.

Further, the invention provides a dry suspension of the compound I, which comprises the following components in percentage by weight: 1-10% of active ingredient compound I, 70-90% of filling agent and 1-3% of flavoring agent, preferably, the content of the compound I is 4-8%, more preferably, the content of the compound I is 4-6%,

further, the dry suspension of the compound I also comprises 4-7% of a stabilizer and/or 0.5-2.0% of an opacifier. Preferably, the content of the stabilizer is 5-7%, more preferably, the content of the stabilizer is 6-7%;

further, the stabilizer is sodium dihydrogen citrate, and the opacifier is titanium dioxide.

Further, the dry suspension also comprises 1-2.5% of a suspending agent, 0.1-0.3% of a sweetening agent and 0.1-0.4% of a preservative, and preferably, the content of the preservative is 0.2-0.3%.

Preferably, the bulking agent 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 saccharin sodium or aspartame.

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

Further preferably, the dry suspension containing the compound I comprises the following components in percentage by weight: 4-8% of compound I, 6-7% of sodium dihydrogen citrate, 0.2-0.3% of sodium benzoate, 75-90% of sorbitol, 1-2% of xanthan gum, 1.0-2.0% of titanium dioxide, 1-2% of orange essence and 0.1-0.2% of saccharin sodium.

In another aspect of the present invention, there is also provided a method for preparing the oral suspension comprising compound I, comprising the steps of:

(1) pretreatment: respectively crushing the raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve;

(2) preparing medicine-containing particles: uniformly mixing the compound I with the prescription amount, 30-45% (w/w) of a filling agent and an optional suspending agent to obtain medicine-containing particles;

(3) preparing blank particles: uniformly mixing the rest of the filler, the flavoring agent and optional other auxiliary materials including an opacifier, a stabilizer and a sweetening agent to obtain blank particles;

(4) and (3) dry granulation: and uniformly mixing the medicine-containing granules, the blank granules and the preservative according to an equivalent incremental method, granulating by a dry method, sieving by a 18-mesh sieve, grading, and subpackaging to obtain the dry suspension containing the compound I.

In the present invention, preferably, the particle size D (v,0.9) ≦ 50 μm of Compound I in the oral dry suspension, more preferably, particle size D (v,0.9) ≦ 30 μm.

According to the invention, the particle diameter D (v,0.9) has the meaning that when D (v,0.9) ═ 50 μm, it means that in the entire particle population described, 90% of the total volume of the particles have a particle diameter of 50 μm or less.

The compound I in the pharmaceutical composition can exist in the form of a pharmaceutically acceptable salt of the compound I, or a hydrate of the compound I, or exist in the form of a free acid of the compound I, and the content of the compound I in the pharmaceutical composition refers to the content converted into the free acid of the compound I.

CN111819177A and CN109790159A disclose pharmaceutically acceptable salts, hydrates, and free forms of compound I, which are incorporated herein by reference.

The oral dry suspension prepared by the method has good stability, and the research on high temperature and high humidity long-term stability tests proves that related impurities are less, the oral dry suspension prepared by the method has good appearance, good dissolution behavior after redissolution, simple production and convenient adjustment of dosage, is suitable for adults, particularly children, old people and dysphagia patients, has high bioavailability, and can meet the medication requirements and medication compliance of special groups such as children, old people and the like.

The preparation method provided by the invention has no adhesion, and is low in raw material and auxiliary material loss, thereby being beneficial to improving the operation environment and reducing the production cost.

Detailed Description

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict.

Example 1 preparation of oral Dry suspensions of Compound I

The prescription content is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 33.36% (w/w) sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; uniformly mixing the rest of sorbitol, titanium dioxide, orange-flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the oral dry suspension containing the compound I, wherein the content of the compound I is 3mg/100 mg.

Wherein the particle size D (v, 90) ═ 30 μm of compound I.

Example 2 preparation of oral Dry suspensions of Compound I

Prescription:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 33.40% (w/w) of sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the dry suspension containing the compound I, wherein the content of the compound I is 5mg/100 mg.

Wherein the particle size D (v, 90) ═ 35 μm of compound I.

Example 3 preparation of oral Dry suspensions of Compound I

The prescription content is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 33.36% (w/w) sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the oral dry suspension containing the compound I, wherein the content of the compound I is 3mg/100 mg.

Wherein the particle size D (v, 90) ═ 30 μm of compound I.

Example 4 preparation of oral Dry suspensions of Compound I

The prescription is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 32.54% (w/w) sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the oral dry suspension containing the compound I, wherein the content of the compound I is 6mg/100 mg.

Wherein the particle size D (v, 90) of compound I is 35 μm.

Example 5 preparation of oral Dry suspensions of Compound I

The prescription content is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 34.29% (w/w) of sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, grading, and subpackaging to obtain the oral dry suspension containing the compound I, wherein the content of the compound I is 10mg/100 mg.

Wherein the particle size D (v, 90) ═ 29 μm of compound I.

Example 6 preparation of oral Dry suspension of Compound I

The prescription content is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 39.30% (w/w) sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the oral dry suspension containing the compound I, wherein the content of the compound I is 4mg/100 mg.

Wherein the particle size D (v, 90) ═ 28 μm of compound I.

Example 7 preparation of oral Dry suspension of Compound I monohydrate

The prescription content is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 39.30% (w/w) sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (4) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the oral dry suspension containing the compound I monohydrate.

Wherein the particle size D (v, 90) ═ 40 μm of the monohydrate of compound I.

Wherein the structure of compound I monohydrate is shown below:

the compound I monohydrate is prepared according to the method disclosed in WO 2019170067.

Example 8 preparation of oral Dry suspensions comprising Compound I hydrochloride

The prescription content is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then uniformly mixing the compound I hydrochloride, 30.60% (w/w) sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (4) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the oral dry suspension containing the hydrochloride of the compound I.

Wherein the particle size D (v, 90) ═ 35 μm for the hydrochloride salt of compound I.

Wherein the structure of the hydrochloride of the compound I is shown as the following formula (II-1):

the compound I hydrochloride is prepared according to the method disclosed in WO 2019170067.

Example 9 preparation of oral Dry suspensions comprising sodium salt of Compound I

The prescription content is as follows:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the sodium salt of the compound I, 44.91% (w/w) of sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, titanium dioxide, sodium dihydrogen citrate, orange flavor essence and saccharin sodium to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (4) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the oral dry suspension containing the compound I sodium salt.

Wherein the particle diameter D (v, 90) ═ 32 μm of the sodium salt of compound I.

Wherein the structure of the sodium salt of the compound I is shown as the following formula (III-1):

the sodium salt of the compound I is prepared according to the method disclosed in WO 2019170067.

EXAMPLE 10 preparation of oral Dry suspensions of Compound I

Prescription:

composition (I)	Single dose (mg)	Percent (%)
			Compound I	25.00	5.00
Sorbitol	418.50	83.70
			Xanthan gum	7.5	1.50
Titanium dioxide	7.5	1.50
			Citric acid sodium dihydrogen	32.5	6.50
Orange-flavored essence	7.25	1.45
			Saccharin sodium salt	0.5	0.10
Sodium benzoate	1.25	0.25
			Is totaled	500	100.00

The preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then uniformly mixing the compound I, sorbitol, xanthan gum, titanium dioxide, sodium dihydrogen citrate, orange flavor, saccharin sodium and sodium benzoate according to the prescription amount, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the dry suspension containing the compound I, wherein the content of the compound I is 5mg/100 mg.

Example 11 preparation of oral Dry suspension of Compound I

Prescription:

the preparation method comprises the following steps: firstly, respectively crushing raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials with a 80-mesh sieve for later use; then, uniformly mixing the compound I, 39.4% (w/w) sorbitol and xanthan gum according to the prescription amount to obtain medicine-containing granules; then uniformly mixing the rest of sorbitol, orange flavor essence and aspartame to obtain blank particles; uniformly mixing the medicine-containing granules, the blank granules and sodium benzoate by an equivalent incremental method, and sieving by a 60-mesh sieve; and (3) after dry granulation, sieving with a 18-mesh sieve, granulating, and subpackaging to obtain the dry suspension containing the compound I, wherein the content of the compound I is 7mg/100 mg.

Wherein the particle size D (v, 90) ═ 31 μm of compound I.

Example 12: stability study

Accelerated test conditions: the dry suspensions prepared in the embodiments 1 to 11 of the present invention are respectively placed at a temperature of 40 ± 2 ℃ and a relative humidity of 75% ± 5% for an accelerated test, and are placed for 6 months, and the dry suspension of the compound I is respectively extracted for 0,1,3, and 6 months to investigate related substances and contents.

The results of the examination are shown in table 1 below:

TABLE 1 results of accelerated test investigation

The dry suspensions prepared in examples 1 to 7 and examples 10 to 11 of the present invention were allowed to stand at a temperature of 60 ± 2 ℃ and a relative humidity of 75% ± 5% for 10 days, and the degradation of impurities in compound I was detected by high performance liquid chromatography, with the following results as shown in table 2:

table 2: about the change of total impurities

The accelerated test shows that the dry suspension of the compound I or the pharmaceutically acceptable salt thereof prepared by the method has good stability, the single impurity content does not exceed 0.1% after the dry suspension is placed for 6 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 75% +/-5%, the total impurities and the content of the compound I are slightly changed, and the increase of degradation impurities is basically avoided.

And (3) long-term test: the dry suspensions of the compound I or the pharmaceutically acceptable salts thereof prepared in the embodiments 2 to 3 and 10 to 11 of the present invention were placed at 25 ± 2 ℃ and 60% ± 10% humidity for long-term test, and the dry suspensions of the compound I or the pharmaceutically acceptable salts thereof were extracted for 0,3,6,9 and 12 months respectively to investigate the substances, contents and dissolution rates, and the investigation results are shown in table 3.

Table 3: long term test investigation results

According to the long-term stability test investigation result, the compound I dry suspension provided by the invention has good stability when being placed at room temperature, and the content and related substances of the compound I dry suspension are basically unchanged after being placed for 12 months.

Example 13 dissolution Studies

The dry suspensions prepared in examples 1 to 11 were subjected to measurement of dissolution curves using pH1.0 as a dissolution medium at a rotation speed of 25 rpm. The results are shown in Table 4.

TABLE 4 percent dissolution

From the results, the dissolution rate of the compound I dry suspension prepared by the method is 75% within 3min, the dissolution rate within 30min can reach 100%, and the compound I dry suspension has a good dissolution effect.

In light of the foregoing description of the preferred embodiments according to the present application, it is to be understood that various changes and modifications may be made without departing from the spirit and scope of the invention. The technical scope of the present application is not limited to the content of the specification, and must be determined according to the scope of the claims.

Claims (10)

1. A dry suspension of compound I, comprising the following components in percentage by weight: 1-10% of active ingredient compound I, 70-90% of filling agent, 1-3% of flavoring agent,

2. the dry suspension of claim 1, further comprising 4% to 7% stabilizer and/or 0.5% to 2.0% opacifier.

3. The dry suspension of claim 1, wherein the stabilizer is sodium dihydrogen citrate and the opacifier is titanium dioxide.

4. The dry suspension of any one of claims 1 to 3, further comprising 1% to 2.5% of a suspending agent, 0.1% to 0.3% of a sweetener, and 0.1% to 0.4% of a preservative.

5. The dry suspension of claim 4, wherein the bulking agent is selected from the group consisting of sorbitol, mannitol, maltitol, or fructose; the suspending agent is sodium carboxymethylcellulose or xanthan gum, the opacifier is titanium dioxide, the flavoring agent is orange flavor, the sweetening agent is saccharin sodium or aspartame, and the preservative is sodium benzoate.

6. The dry suspension of claim 1, wherein the dry suspension comprises the following components in weight percent: 3-8% of compound I, 5-7% of sodium dihydrogen citrate, 0.1-0.3% of sodium benzoate, 80-90% of sorbitol, 1-2.5% of xanthan gum, 0.5-2.0% of titanium dioxide, 1-3% of orange essence and 0.1-0.3% of saccharin sodium.

7. The dry suspension of claim 1, comprising the following components in weight percent: 4-8% of compound I), 6-7% of sodium dihydrogen citrate, 0.2-0.3% of sodium benzoate, 75-90% of sorbitol, 1-2% of xanthan gum, 1.0-2.0% of titanium dioxide, 1-2% of orange essence and 0.1-0.2% of saccharin sodium.

8. The dry suspension of claim 7, wherein the particle size D (v,0.9) of Compound 1 or a pharmaceutically acceptable salt thereof in the dry suspension is 50 μm or less.

9. The dry suspension of claim 7, wherein the particle size D (v,0.9) of Compound 1 or a pharmaceutically acceptable salt thereof in the dry suspension is 30 μm or less.

10. A method for preparing the dry suspension as claimed in any one of claims 1 to 9, which comprises the following steps:

(1) pretreatment: respectively crushing the raw and auxiliary materials according to the prescription amount, and sieving the crushed raw and auxiliary materials by a 80-mesh sieve;

(2) preparing medicine-containing particles: uniformly mixing the compound I with the prescription amount, 30-45% (w/w) of a filling agent and an optional suspending agent to obtain medicine-containing particles;

(3) preparing blank particles: uniformly mixing the rest of the filler, the flavoring agent, the optional opacifier, the stabilizer and the sweetener to obtain blank particles;

(4) and (3) dry granulation: and uniformly mixing the medicine-containing granules, the blank granules and the preservative according to an equivalent incremental method, granulating by a dry method, sieving by a 18-mesh sieve, grading, and subpackaging to obtain the dry suspension containing the compound I.