Patent Description:
Hand-foot-and-mouth disease (HFMD) is a global infectious disease caused by enterovirus. The main pathogenic viruses include enterovirus <NUM> (EV71), Coxsachie A16 (CoxA16) and other enteroviruses, where EV71 is the most harmful. The hand-foot-and-mouth disease is more common in infants and children, especially children under <NUM> years old, but less common in adults. However, patients with immunodeficiency may also be infected. At onset, blisters on hands, feet and mouth are the typical features. In addition, the disease is accompanied by symptoms such as fever, headache, sore throat and rash, etc. In severe cases, myocarditis, pulmonary edema, aseptic meningitis and even fatal pulmonary embolism or massive hemorrhage may occur. Individual severe children's conditions develop rapidly and the mortality rate is high.

The compound has been disclosed at least in two prior art documents [<CIT> and <CIT>]. Both of the documents have disclosed the structure and use of the compound to treat hand foot mouth disease caused by enterovirus <NUM> and the preparation method thereof.

Specifically, the last chemical structure in the ninth page of the <CIT> is the structure of the compound and its Embodiment 75F (<NUM> pages) discloses the preparation method and nuclear magnetic hydrogen spectrum of the compound. The last chemical structure of para [<NUM>] discloses the structure of the compound, and the preparation method and nuclear magnetic hydrogen spectrum of the compound are disclosed in [<NUM>] - [<NUM>] paras of <CIT>.

<CIT> discloses a salt form and crystal form of a compound <NUM>, preparation method thereof and intermediate:
<CHM>.

<CIT> discloses a novel anti-enterovirus <NUM> (EV71) <NUM>, <NUM>, <NUM>-thiadiazolidine-<NUM>,<NUM>-dioxide derivative or a pharmaceutically acceptable salt thereof, and specifically, a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:
<CHM>.

<CIT> discloses a novel anti-enterovirus <NUM> (EV71) <NUM>,<NUM>,<NUM>-thiadiazolidine-<NUM>,<NUM>-dioxide derivative or a pharmaceutically acceptable salt thereof, and specifically, a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:
<CHM>.

An objective of the present invention is to provide a pharmaceutical composition with high stability and rapid dissolution and suitable for treating child hand-foot-and-mouth disease, and a preparation method thereof. Specifically, the pharmaceutical composition provided by the present invention includes:.

Further, the suspending agent may further include one or more of carboxymethylcellulose sodium, carrageenan or crospovidone (CL-M).

Specifically, the pharmaceutically acceptable salt includes hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, fumarate, maleate, tartrate or trifluoroacetate.

Optionally, the povidone is povidone K30 or povidone K90.

Further, the content of the suspending agent povidone K90 is <NUM> to <NUM>%.

Further, the content of the suspending agent crospovidone (CL-M) is <NUM>% to <NUM>% of a total weight of the composition, preferably, <NUM> to <NUM>%.

Further,the solubilizer preferably accounts for <NUM> to <NUM>% of a total weight of the pharmaceutical composition.

Preferably, the diluent includes mannitol and sorbitol; and the weight ratio of the mannitol to the sorbitol is <NUM>:<NUM>~ <NUM>:<NUM>.

Further, the auxiliary materials further include essence; the essence includes one or more of orange essence, strawberry essence and banana essence; and the essence preferably accounts for ≤ <NUM>% of a total weight of the pharmaceutical composition, preferably, <NUM>% to <NUM>%.

Further, the specific weight of each bag of active ingredient may be <NUM> to <NUM>, preferably, <NUM> to <NUM>, more preferably, <NUM> to <NUM>, most preferably, <NUM>.

Further, the diluent may account for <NUM>% to <NUM>% of a total weight of the pharmaceutical composition.

Preferably, the pharmaceutical composition provided by the present invention includes: <NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol and <NUM> parts to <NUM> parts of povidone K30 or povidone K90.

Further, the pharmaceutical composition may further include: <NUM> parts of poloxamer <NUM>.

Further, the pharmaceutical composition may further include: <NUM> parts of crospovidone (CL-M).

Further, the pharmaceutical composition may further include: <NUM> parts of strawberry essence.

Specifically, the pharmaceutical composition is a granule prepared from the active ingredient and the auxiliary materials through mixing, granulation, drying, granule arrangement, total mixing and packaging.

The present invention further provides a use of the pharmaceutical composition for treating child hand-foot-and-mouth disease.

The present invention further provides a method for preparing the pharmaceutical composition as described in any one of the above. The method includes:.

According to the present invention, the pharmaceutical composition with rapid dissolution and high stability is finally obtained by screening the types and the dosage ratio of the auxiliary materials; and the pharmaceutical composition is simple in preparation process and more suitable for industrialized mass production.

An active substance (compound A: <NUM>-(<NUM>-aminopyridine-<NUM>-yl)-<NUM>-(<NUM>-((<NUM>-(<NUM>-ethyl-<NUM>-tetrazole-<NUM>-yl)pyridine-<NUM>-yl)-oxy)-<NUM>,<NUM>-amyldimethyl)-<NUM>,<NUM>,<NUM>-thiadiazolidin <NUM>,<NUM>-dioxide hydrochloride) of the present invention can lock viruses by entering a pocket cavity of an EV71 virus nucleocapsid to prevent a viral capsid from decomposing and releasing virus RNA, thereby inhibiting further replication of the virus. The structural formula is as follows:
<CHM>
<CHM>.

To improve the solubility of insoluble medicines, surfactants, acid-base regulators and the like are mostly used in the prior art. According to the present invention, it is found in the preliminary test process that a compound A and an acidic regulator (citric acid or tartaric acid) can realize complete dissolution of the compound A; upon further study, it is found that when the adding amount of the acid is <NUM> to <NUM> that of the compound A, the solubility of the compound A in hot water can be improved. However, the granules obtained in the preliminary study process can solve the problem of solubility, but the stability is insufficient. Therefore, how to improve the solubility of the active substance provided by the present invention and ensure the stability has become a difficult point in a medicine technology.

In view of this, the present invention provides other preparation forms of the pharmaceutical composition suitable for treating child hand-foot-and-mouth disease, thereby solving the problem of the solubility and the stability of the compound by selecting appropriate auxiliary materials.

The present invention is further described below by the following embodiments and test examples. The embodiments and test examples are only used to illustrate the objective, but not to limit the scope of the present invention, which is defined by the appended claims.

In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below with reference to specific embodiments.

The test materials used in the embodiments of the present invention are all conventional test materials in the field, which can be purchased through commercial channels or can be prepared by methods in the prior art.

<NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of carboxymethylcellulose sodium and <NUM> parts of strawberry essence;.

<NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of hydroxypropyl methylcellulose and <NUM> parts of strawberry essence;.

: <NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of povidone K30 and <NUM> parts of strawberry essence;.

<NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of povidone K90 and <NUM> parts of strawberry essence;.

: <NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of povidone K90, <NUM> parts of poloxamer <NUM> and <NUM> parts of strawberry essence;.

<NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of povidone K90, <NUM> parts of poloxamer <NUM> and <NUM> parts of strawberry essence;.

: <NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of povidone K90, <NUM> parts of poloxamer <NUM>, <NUM> parts of crospovidone (CL-M) and <NUM> parts of strawberry essence;.

: <NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of povidone K90, <NUM> part of carboxymethylcellulose sodium and <NUM> parts of strawberry essence; and.

<NUM> part of compound A, <NUM> parts of mannitol, <NUM> parts of sorbitol, <NUM> parts of povidone K90, <NUM> parts of crospovidone (CL-M), <NUM> parts of polysorbate <NUM> and <NUM> parts of strawberry essence.

Comparative example <NUM>: <NUM> part of compound A, <NUM> parts of sucrose, <NUM> parts of tartaric acid and <NUM> parts of strawberry essence.

A preparation process of Comparative Example <NUM>:.

A preparation process of Comparative Example <NUM> is the same as that of Comparative example <NUM>.

Comparative example <NUM>: <NUM> part of compound A, <NUM> parts of sucrose, <NUM> parts of tartaric acid, <NUM> parts of polysorbate <NUM> and <NUM> parts of strawberry essence.

Granules prepared by the embodiments and the comparative examples were added into hot water to investigate the solubility. The results are shown in Table <NUM>.

According to the investigation results of the solubility, flocculent precipitates are found in Reference Examples <NUM> and <NUM>; suspension milky solutions are found in the examples or comparative examples in which povidone is added; semi-transparent milky solutions dispersed uniformly are found in Example <NUM> and Example <NUM>; the solution in Example <NUM> can be dispersed rapidly and uniformly through shaking after settlement; and polysorbate <NUM> is added in Example <NUM> and the solution is slightly stink, and Example <NUM> is finally preferred in view of the odor.

According to the guide principle of stability test of crude medicines and pharmaceutical preparations in <NPL>, in the present invention, suspension granules in Examples <NUM> and <NUM>, and soluble granules in Comparative Examples <NUM> and <NUM> were investigated by accelerated stability test and long-term stability test (Example <NUM> and Comparative Example <NUM> were merely listed below).

The condition of the accelerated stability test: the pharmaceutical compositions prepared in Example <NUM> and Comparative example <NUM> were respectively packaged according to a composite film for packaging a polyester/aluminum/polyethylene medicine product, and stood for <NUM> months under the temperature of <NUM> and the relative humidity of <NUM>%, sampling was performed in the <NUM>th, <NUM>st, <NUM>rd and <NUM>th months during the test, and inspection was performed according to stability investigation items. The inspection results of the accelerated test of "related substances" are shown in Table <NUM>. The results show that impurities in Comparative example <NUM> are higher than those in Example <NUM>, which indicates that the solubility of the formula in the comparative example meets the requirement, but the stability is insufficient. Similarly, the change of related substances of the suspension granules in Example <NUM> is much smaller than those in Comparative examples <NUM> and <NUM>.

The condition of the long-term stability test: the pharmaceutical compositions prepared in Example <NUM> and Comparative example <NUM> were respectively packaged according to a composite film for packaging a polyester/aluminum/polyethylene medicine product, and stood for <NUM> months under the temperature of <NUM> and the relative humidity of <NUM>%, sampling was performed in the <NUM>th, <NUM>st, <NUM>rd, <NUM>th, <NUM>th, <NUM>th and <NUM>th months during the test, <NUM>-month stability test was completed at present, and inspection was performed according to stability investigation items, where the inspection results of long-term test of "related substances" are shown in Table <NUM>.

According to the stability investigation results of long-term and accelerated tests, Example <NUM> has higher stability compared with Comparative example <NUM>. The related substances of the product may be affected by temperature and humidity, so the product should be stored in a cool place.

Claim 1:
A pharmaceutical composition, wherein the pharmaceutical composition is a granule, and the granule comprises:
an active ingredient, comprising <NUM>-(<NUM>-aminopyridine-<NUM>-yl)-<NUM>-(<NUM>-((<NUM>-(<NUM>-ethyl-<NUM>-tetrazole-<NUM>-yl)pyridine-<NUM>-yl)-oxy)-<NUM>,<NUM>-amyldimethyl)-<NUM>,<NUM>,<NUM>-thiadiazolidin <NUM>,<NUM>-dioxide or pharmaceutically acceptable salt thereof;
the pharmaceutical composition is characterized by further comprising auxiliary materials comprising a diluent, a suspending agent and a solubilizer;
the diluent comprising one or more of sucrose, mannitol, sorbitol and xylitol, the suspending agent comprising povidone, and the solubilizer comprising poloxamer <NUM> and/or polysorbate <NUM>;
wherein, the active ingredient accounts for <NUM>% to <NUM>% of a total weight of the pharmaceutical composition, the diluent accounts for <NUM>% to <NUM>% of the total weight of the pharmaceutical composition, the suspending agent accounts for <NUM>% to <NUM>% of the total weight of the pharmaceutical composition, and the solubilizer accounts for <NUM>% to <NUM>% of a total weight of the pharmaceutical composition.