CN112843013A

CN112843013A - Composition for treating hepatitis C and preparation method thereof

Info

Publication number: CN112843013A
Application number: CN202011358626.1A
Authority: CN
Inventors: 欧金来; 郭朕; 谢洪明; 张英俊
Original assignee: Yichang Hec Changjiang Pharmaceutical Co ltd
Current assignee: Yichang Hec Changjiang Pharmaceutical Co ltd
Priority date: 2019-11-28
Filing date: 2020-11-27
Publication date: 2021-05-28

Abstract

The invention provides a composition for treating hepatitis C and a preparation method thereof. The composition comprises a compound shown in a formula (I) or a formula (II) or a pharmaceutically acceptable salt thereof, or a compound shown in a formula (III) or (IV) as an active ingredient. The composition or capsule can be used for treating viral hepatitis C, and has the advantages of simple preparation process, high safety, good stability, and rapid dissolution.

Description

Composition for treating hepatitis C and preparation method thereof

Technical Field

The invention relates to the field of pharmacy, in particular to a composition for treating hepatitis C and a preparation method thereof.

Background

Viral Hepatitis type C is a global infectious disease caused by Hepatitis C Virus (HCV), mainly spreading with blood, blood products and body fluids, 55-85% of patients progress to chronic Hepatitis after acute infection with HCV, about 5-15% progress to cirrhosis after 20 years of infection, the annual incidence rate of decompensation of cirrhosis is 3-4%, 2-4% of cirrhosis patients progress to liver cancer (HCC) every year, HCV has serious harm to the health and life of patients, and CHC patients have hidden symptoms, the diagnosis rate and antiviral treatment rate of HCV infection are low, and there are many hidden infection sources in the population, which has become a serious social and public health problem.

Data updated by the World Health Organization (WHO)2016, month 4, show a global chronic HCV infection rate of about 1.1% and an infected person of about 1 million. With the increasing public health and health consciousness and the increasing popularization of basic knowledge of hepatitis c, the detection rate of patients and the proportion of people willing to receive treatment are increasing, and therefore, the people needing treatment and the clinical requirements are expected to be larger and larger.

HCV includes at least 6 genotypes and multiple subtypes, with genotype 1 being reported most common worldwide in 2014, followed by genotypes 3, 2 and 4. In china, genotypes 1b and 2a are more common, with genotype 1b predominant (56.8%), followed by genotypes 2 (24.1%) and 3 (9.1%), with no genotype 4 and 5 found, and relatively few genotype 6 (6.3%).

Therefore, the development of more and more effective drugs for treating viral hepatitis C as soon as possible is a goal of continuous efforts of drug developers.

The prior art CN105693700B provides compounds (I), (II) and their pharmaceutically acceptable salts, which have better biological properties, but the prior art research is still in earlier preclinical research, and in order to help the development of clinical research, further research on the properties of the drugs is needed to find the drug salt form and the drug dosage form suitable for human administration.

Disclosure of Invention

The inventors of the present application have developed a pharmaceutical preparation containing a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient by experiments on the basis of the development of a novel drug (a compound represented by formula (I) or formula (II)). In the development process, the inventor finds that the composition comprising the compound shown in the formula (I) or the formula (II) or the pharmaceutically acceptable salt thereof and the auxiliary material is easy to mix uniformly, and the prepared composition has good dissolution rate, wide disintegrating agent adaptability, wide filling agent adaptability and wide compound proportion adaptability, and is particularly suitable for capsule preparations. Meanwhile, the preparation process of the capsule preparation is simple, and the production steps are few, so that the production cost of the new medicine can be greatly reduced, and the development progress of the new medicine is accelerated.

Based on this, in a first aspect of the invention, a composition is presented. According to an embodiment of the present invention, the composition comprises a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient,

the composition provided by the embodiment of the invention can effectively treat the viral hepatitis C and has high safety.

According to an embodiment of the present invention, the above composition may further comprise at least one of the following additional technical features:

according to an embodiment of the invention, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

According to an embodiment of the present invention, the inorganic acid salt or the organic acid salt is a mono-salt or a di-salt.

According to an embodiment of the present invention, the inorganic acid salt is selected from a hydrohalic acid salt, a halogen series oxygen-containing inorganic acid salt, a carbon series oxygen-containing inorganic acid salt, a nitrogen series oxygen-containing inorganic acid salt, a boron series oxygen-containing inorganic acid salt, a silicon series oxygen-containing inorganic acid salt, a phosphorus series oxygen-containing inorganic acid salt or a sulfur series inorganic acid salt; the organic acid salt is selected from carboxylate, sulfonate, sulfinate or thiocarboxylate.

According to a further embodiment of the invention, the inorganic acid salt is selected from the group consisting of hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate or metaphosphate; the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dioleate, dodecylsulfate, ethylsulfonate, glycerophosphate, heptanoate, glucolate, ethylsulfonate, glycerophosphate, heptanoate, glucolate, ethylsulfonate, glucarate, hydroxyacetate, hydroxymethanesulfonate, malate, lactate, lactobionate, hydroxynaphtholate, salicylate, galactarate, glucolate, Hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate.

According to an embodiment of the invention, the pharmaceutically acceptable salt is a phosphate salt, the phosphate salt of the compound of formula (I) has the structure of formula (III), the phosphate salt of the compound of formula (II) has the structure of formula (IV),

in the process of developing the pharmaceutical preparation, the inventor finds that when the pharmaceutically acceptable salt is selected from phosphate, the composition has high solubility, stable dissolution rate and is more suitable for patent medicine, and the discovery can further accelerate the development of new medicines.

According to an embodiment of the invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof is 20% to 45%, or 20% to 42%, or 21% to 39%, or 22% to 38%, or 23% to 37%, or 24% to 36%, 25% to 35%, or 26% to 34%, or 27% to 33%, or 28% to 32%, or 29% to 31%, or 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%, or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% based on the total weight of the composition. The inventor finds that the mass fraction of the compound shown in the formula (I) or the formula (II) or the pharmaceutically acceptable salt thereof in the composition has better fluidity in the range, increases the production feasibility, and can effectively ensure the stability, effectiveness and safety of the effect of the composition in treating the hepatitis C virus.

According to an embodiment of the invention, the composition further comprises a pharmaceutically acceptable adjuvant comprising at least one of a diluent, a disintegrant, a glidant and a lubricant.

According to an embodiment of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose.

According to an embodiment of the invention, the disintegrant comprises one or more of crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate. The inventor finds that the dissolution rate of the composition is better by using one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and carboxymethyl starch sodium as a disintegrating agent.

According to an embodiment of the invention, the glidant is aerosil or talc.

According to an embodiment of the invention, the lubricant is magnesium stearate.

According to the embodiment of the invention, the mass fraction of the microcrystalline cellulose is 15-40% based on the total weight of the composition. The inventor finds that the content of the microcrystalline cellulose is 15-40%, and the dissolution rate of the composition is stable.

According to the embodiment of the invention, the mass fraction of one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 30-50% based on the total weight of the composition. The inventor finds that the composition is fast and stable in dissolution because one or more of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose are 30-50% in mass fraction.

According to the embodiment of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose in a mass ratio of 1: 1-1: 3.

According to an embodiment of the present invention, the mass fraction of the disintegrant is 1% to 12% based on the total weight of the composition. The inventors found that the present composition has a reduced dissolution rate due to an increased content of the disintegrant, and that the composition has a faster and more stable dissolution when the content of the disintegrant is in the range of 1% to 12%.

According to the embodiment of the invention, the mass fraction of the glidant is 0.5-2% based on the total weight of the composition.

According to the embodiment of the invention, the mass fraction of the lubricant is 0.5-5% based on the total weight of the composition; in some embodiments, the lubricant is present in an amount of 0.5% to 2% by weight, based on the total weight of the composition. The inventors have found that, in the present composition, an increase in the content of the lubricant decreases the dissolution rate of the composition, and that the content of the lubricant is within the range described in the present invention, and that the dissolution of the composition is fast and stable.

According to an embodiment of the invention, the composition is in the form of an oral formulation.

According to an embodiment of the invention, the composition is in the form of a solid oral formulation.

According to an embodiment of the invention, the composition is in the form of a capsule, tablet, pellet, powder, sustained release formulation, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhalant or patch.

In a second aspect of the invention, the invention proposes a capsule filled with contents comprising a composition as described previously. The capsule provided by the embodiment of the invention can be used for effectively treating the viral hepatitis C, and has good stability and rapid dissolution.

In a third aspect of the invention, the invention proposes a capsule filled with contents comprising: the mass fraction of the compound shown in the formula (III) or the formula (IV) is 20 to 45 percent based on the total weight of the content, and a diluent, a disintegrant, a glidant and a lubricant.

The capsule provided by the embodiment of the invention can be used for effectively treating the viral hepatitis C, and has the advantages of good stability, rapid dissolution and high safety.

According to an embodiment of the present invention, the capsule may further comprise at least one of the following additional technical features:

according to an embodiment of the present invention, the compound represented by formula (III) or formula (IV) is used in an amount of 20 to 45 parts by weight, the diluent is used in an amount of 50 to 75 parts by weight, the disintegrant is used in an amount of 1 to 12 parts by weight, the glidant is used in an amount of 0.5 to 2 parts by weight, and the lubricant is used in an amount of 0.5 to 5 parts by weight.

According to a particular embodiment of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, lactose.

According to a further embodiment of the invention, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate.

According to yet another embodiment of the invention, the disintegrant is croscarmellose sodium.

According to a further embodiment of the invention, the glidant is aerosil or talc.

According to yet another embodiment of the invention, the lubricant is magnesium stearate.

According to the embodiment of the invention, the microcrystalline cellulose is used in an amount of 15-40 parts by weight. The inventor finds that the dissolution rate of the capsule content is more stable when the microcrystalline cellulose is used in 15-40 parts by weight.

According to an embodiment of the present invention, the one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, and sucrose is used in an amount of 30 to 50 parts by weight. The inventor finds that the composition is dissolved out quickly and more stably when one or more of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose are used in an amount of 30-50 parts by weight.

According to the embodiment of the invention, the mass ratio of the microcrystalline cellulose to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose in the diluent is 1: 1-1: 3.

According to the embodiment of the invention, the mass ratio of the microcrystalline cellulose to the mannitol is 1: 1-1: 3.

According to an embodiment of the invention, the capsule is a single-dose formulation, i.e. the capsule is adapted to be administered to a patient once a day to exert an advantageous pharmacological effect, or a multi-dose formulation, i.e. the capsule is adapted to be administered to a patient several times a day or more to exert an advantageous pharmacological effect.

In a fourth aspect of the invention, the invention proposes a method of preparing a capsule as described above, according to an embodiment of the invention, the method comprising:

(1) premixing a proper amount of a compound shown as a formula (I), a formula (II), a formula (III) or a formula (IV) with a diluent, a disintegrant and a glidant to obtain a first mixture;

(2) subjecting the second mixture to a second mixing treatment with a lubricant so as to obtain a second mixture; and

(3) subjecting the second mixture to a capsule filling process so as to obtain said capsules.

According to the method for preparing the capsule, the powder is adopted to directly fill the capsule, the preparation process is simple, the production procedures are few, energy and time are saved, the equipment and operation costs are reduced, the process adaptability is strong, the continuous and stable production of the dosage form can be realized, and the prepared capsule has good stability and is quickly dissolved out.

According to an embodiment of the invention, the method comprises:

(1) premixing a proper amount of a compound shown as a formula (I), a formula (II), a formula (III) or a formula (IV) with a diluent, a disintegrant and a glidant to obtain a first mixture; the time of the first mixing treatment is 15 min-30 min;

(2) carrying out second mixing treatment on the second mixture and the lubricant so as to obtain a second mixture, wherein the second mixing treatment time is 3-7 min; and

According to an embodiment of the present invention, the method may further include at least one of the following additional technical features:

according to the embodiment of the invention, the compound shown in the formula (I), the formula (II), the formula (III) or the formula (IV), the diluent, the disintegrant, the glidant and the lubricant are sieved by a 60-mesh sieve in advance. Further, the raw material powder for preparing the capsule has uniform size, and the continuous and stable production of the capsule preparation is realized.

According to the embodiment of the invention, the time of the first mixing treatment is 15min to 30min, and the time of the second mixing treatment is 3min to 7 min.

According to the specific embodiment of the present invention, the time of the first mixing process is 20min, and the time of the second mixing process is 5 min.

Detailed Description

Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described herein, as such embodiments may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications and patents referred to herein are incorporated by reference in their entirety.

Where a range of values is provided, it is understood that any intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the stated limits, ranges excluding either or both of those included limits are also included in the invention. Certain ranges are provided herein as values previously recited with the term "about". The term "about" is used herein to provide literal support for the precise numerical value preceding it, as well as numerical values that closely or approximately precede the term. In determining whether a value is near or approximately a specifically stated value, the near or approximately unrecited value may be a value that, in the context in which it is provided, provides substantial equivalence to the specifically stated value. The term "about" or "approximately" refers to an error that is acceptable for a particular value, as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

For these and other pharmaceutically acceptable adjuvants or processes mentioned herein, reference may be made to a large number of documents on this subject, see in particular Handbook of Pharmaceutical Excipients, 3 rd edition, edited by Arthur h.kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstuffe fur Pharmazie, Kosmetik and angrenzene Gebiete, edited by H.P. Fiedler, 4 th edition, Cantor, Aulentorf and earlier versions.

The compositions or formulations provided herein can be administered to a patient alone, or can be co-administered or co-administered with other active agents. The terms "co-administration" and "combination" include the simultaneous or sequential administration of two or more therapeutic agents without a specific time period. In one embodiment, the agents are both present in the cell or in the body of the individual, or both exert a biological or therapeutic effect. In one embodiment, each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in a different composition or unit dosage form. In certain embodiments, the first agent is administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapeutic agent.

By "active ingredient" or "active agent" is meant a substance used in therapy (e.g., human therapy, veterinary therapy), including prophylactic and therapeutic therapies. The active ingredient includes any substance used as a medicament for treating, preventing, delaying, alleviating or ameliorating a disease, condition or disorder.

The term "pharmaceutically acceptable salt" means, which may be an inorganic acid salt or an organic acid salt; in some embodiments, the inorganic or organic acid salt may be a mono-or di-salt. In some embodiments, the inorganic acid salt is selected from a hydrohalic acid salt, a halogen series oxygen-containing inorganic acid salt, a carbon series oxygen-containing inorganic acid salt, a nitrogen series oxygen-containing inorganic acid salt, a boron series oxygen-containing inorganic acid salt, a silicon series oxygen-containing inorganic acid salt, a phosphorus series oxygen-containing inorganic acid salt, or a sulfur series inorganic acid salt; the organic acid salt is selected from carboxylate, sulfonate, sulfinate or thiocarboxylate. In other embodiments, the inorganic acid salt is selected from the group consisting of a hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, or metaphosphate salt. In some embodiments, the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, glycerophosphate, and mixtures thereof, Heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate.

The term "oral formulation" refers to a formulation form which is orally administered and in which a drug absorbs into blood in the gastrointestinal tract, and includes tablets, granules, capsules, oral solutions, and the like.

The term "solid oral formulation" refers to tablets, dispersible tablets, fast dissolving tablets, orally dispersible tablets, lyophilized units, porous tablets, conventional tablets, coated tablets, uncoated tablets, enteric-coated tablets (gasto-resistant tablets), effervescent tablets, soluble tablets, chewable tablets, oral lyophilisates, powders, oral powders, pills, capsules and/or granules. In some embodiments, the solid oral formulation is a capsule.

The term "diluent" refers to microcrystalline cellulose, lactose monohydrate, lactose, compressible sugars, sugar, dextrose, mannitol, dextrin, maltodextrin, sorbitol, xylitol, sodium chloride, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, kaolin, powdered cellulose, pregelatinized starch, barium sulfate, magnesium trisilicate, aluminum hydroxide, and combinations thereof. In some embodiments, the diluent of the present invention comprises at least microcrystalline cellulose. In other embodiments, the diluent of the present invention comprises microcrystalline cellulose and one or more selected from the group consisting of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose.

The term "disintegrant" disintegrants include, but are not limited to, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, crosslinked polyvinylpyrrolidone (PVP) (e.g., as known and commercially available under the trade name XL from ISP corporation), alginic acid, sodium alginate and guar gum.

The term "glidant" includes, but is not limited to: silicon dioxide, micropowder silica gel, magnesium trisilicate, powdered cellulose, starch and talcum powder. In some embodiments of the invention, the retention aid is aerosil or talc.

The term "lubricant" includes, but is not limited to: mg, Al or Ca stearate, PEG 4000-8000, talc, sodium benzoate, glyceryl mono-fatty acids (e.g.having a molecular weight of from 200 to 800 daltons, such as glyceryl monostearate (e.g.Danisco, UK)), glyceryl dibehenate (e.g.Comritolo 888TM, gattefosse France), glyceryl palmitostearate (e.g.Precirol, gattefosse France), polyethylene glycol (PEG, BASF), hydrogenated cottonseed oil (Lubitab, Edward Mendell Co., Ltd.), castor oil (Cutina HR, Henkel). In some embodiments of the invention, the lubricant is magnesium stearate.

The invention provides a composition which comprises a compound shown as a formula (I) or a formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient,

the composition of the invention can effectively treat the viral hepatitis C and has high safety.

In some embodiments of the invention, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.

In some embodiments of the invention, the inorganic or organic acid salt is a mono-or di-salt.

In some embodiments of the present invention, the inorganic acid salt is selected from a hydrohalic acid salt, a halogen series oxygen-containing inorganic acid salt, a carbon series oxygen-containing inorganic acid salt, a nitrogen series oxygen-containing inorganic acid salt, a boron series oxygen-containing inorganic acid salt, a silicon series oxygen-containing inorganic acid salt, a phosphorus series oxygen-containing inorganic acid salt, or a sulfur series inorganic acid salt.

In some embodiments of the invention, the inorganic acid salt is selected from the group consisting of a hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, or metaphosphate.

In some embodiments of the invention, the organic acid salt is selected from a carboxylate, sulfonate, sulfinate, or thiocarboxylate salt.

In some embodiments of the invention, the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethylsulfonate, dihydrogensulfonate, dihydro, Glycerophosphate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate.

In some embodiments of the invention, the pharmaceutically acceptable salt is a phosphate salt.

In some embodiments of the invention, the pharmaceutically acceptable salt is a diphosphate salt.

In some embodiments of the invention, the phosphate salt of the compound of formula (I) has the structure of formula (III),

in some embodiments of the invention, the phosphate salt of the compound of formula (II) has a structure of formula (IV),

the invention provides a composition which comprises a compound shown as a formula (III) as an active ingredient,

the invention provides a composition which comprises a compound shown as a formula (IV) as an active ingredient,

in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 45%, or 20% to 42%, or 21% to 39%, or 22% to 38%, or 23% to 37%, or 24% to 36%, 25% to 35%, or 26% to 34%, or 27% to 33%, or 28% to 32%, or 29% to 31%, or 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%, or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, based on the total weight of the composition.

In some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 45% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 42% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 21% to 39% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 22% to 38% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 23% to 37% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 24% to 36% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or pharmaceutically acceptable salt thereof in the composition of the present invention is 25% to 35% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 26% to 34% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 27% to 33% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 28% to 32% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 29% to 31% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 25% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or pharmaceutically acceptable salt thereof in the composition of the present invention is 25% to 30% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 30% to 35% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 35% to 40% based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 25%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or pharmaceutically acceptable salt thereof in the composition of the present invention is about 26%; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 27%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the present invention is about 28%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the present invention is about 29%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 30%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the present invention is about 31%; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or pharmaceutically acceptable salt thereof in the composition of the present invention is about 32%; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 33%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 34%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof in the composition of the present invention is about 35%, based on the total weight of the composition.

In some embodiments of the invention, the composition further comprises a pharmaceutically acceptable adjuvant comprising one or more of diluents, disintegrants, glidants, and lubricants.

In some embodiments of the invention, the composition further comprises at least a diluent.

In some embodiments of the invention, the composition further comprises a pharmaceutically acceptable adjuvant consisting of a diluent, a disintegrant, a glidant, and a lubricant.

In some embodiments of the invention, the diluent comprises at least microcrystalline cellulose.

In some embodiments of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose. In some embodiments of the invention, the diluent comprises microcrystalline cellulose and mannitol. In some embodiments of the invention, the diluent comprises microcrystalline cellulose and lactose. In some embodiments of the invention, the diluent comprises microcrystalline cellulose and pregelatinized starch.

In some embodiments of the invention, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate. In some embodiments of the invention, the disintegrant is crospovidone; in some embodiments of the invention, the disintegrant is croscarmellose sodium; in some embodiments of the invention, the disintegrant is sodium starch glycolate.

In some embodiments of the invention, the glidant is aerosil or talc. In some embodiments of the invention, the glidant is aerosil.

In some embodiments of the invention, the lubricant is magnesium stearate.

In some embodiments of the present invention, the microcrystalline cellulose is present in an amount of 15 to 40% by weight, based on the total weight of the composition.

In some embodiments of the present invention, the mass fraction of the one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose is 30 to 50% based on the total weight of the composition. In some embodiments of the present invention, the mannitol is present in an amount of 30 to 50% by weight, based on the total weight of the composition. In some embodiments of the present invention, the lactose is present in an amount of 30 to 50% by weight, based on the total weight of the composition. In some embodiments of the present invention, the pregelatinized starch is present in an amount of 30 to 50% by weight, based on the total weight of the composition.

In some embodiments of the present invention, the mass ratio of the microcrystalline cellulose to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, and sucrose in the diluent is 1:1 to 1: 3. In some embodiments of the present invention, the mass ratio of the microcrystalline cellulose to the mannitol in the diluent is 1:1 to 1: 3. In some embodiments of the invention, the mass ratio of the microcrystalline cellulose to the lactose in the diluent is 1: 1-1: 3. In some embodiments of the invention, the mass ratio of microcrystalline cellulose to pregelatinized starch in the diluent is from 1:1 to 1: 3.

In some embodiments of the invention, the mass fraction of the disintegrant is 1% to 12% based on the total weight of the composition. The inventors found that, in the present composition, the dissolution rate of the composition is decreased by increasing the content of the disintegrant, and that the composition is rapidly and stably dissolved when the content of the disintegrant is in the range of 1% to 12%.

In some embodiments of the invention, the glidant is present in an amount of 0.5 to 2 weight percent, based on the total weight of the composition.

In some embodiments of the invention, the lubricant is present in an amount of 0.5% to 5% by weight, based on the total weight of the composition; in some embodiments, the lubricant is present in an amount of 0.5% to 2% by weight, based on the total weight of the composition.

In some embodiments of the invention, the composition is in the form of an oral formulation.

In some embodiments of the invention, the composition is in the form of a solid oral formulation.

In some embodiments of the invention, the composition is in the form of a capsule, tablet, pellet, powder, sustained release formulation, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhalant or patch.

In some embodiments of the invention, compound III, microcrystalline cellulose, mannitol, croscarmellose sodium, sodium lauryl sulfate, aerosil, magnesium stearate are sieved through a 60 mesh sieve; the aperture of the 60-mesh sieve is 0.25 mm. In some embodiments of the invention, the particle size of compound III, microcrystalline cellulose, mannitol, croscarmellose sodium, sodium lauryl sulfate, aerosil, magnesium stearate is less than 0.25 mm.

The invention provides a capsule filled with contents, wherein the contents are the composition.

The invention also proposes a capsule filled with contents comprising: the compound shown as the formula (III) and a diluent, a disintegrant, a glidant and a lubricant, wherein the mass fraction of the compound shown as the formula (III) is 20-45% based on the total weight of contents.

The invention also provides a capsule filled with contents comprising, based on 100 parts by weight of the contents: the compound shown as the formula (IV) and a diluent, a disintegrant, a glidant and a lubricant, wherein the mass fraction of the compound shown as the formula (IV) is 20-45% based on the total weight of the content.

In some embodiments of the invention, the capsule provided by the invention can be used for effectively treating viral hepatitis C, and has good stability, rapid dissolution and high safety.

In some embodiments of the present invention, the capsule provided by the present invention comprises 20 to 45 parts by weight of the compound represented by formula (III), 50 to 75 parts by weight of the diluent, 1 to 12 parts by weight of the disintegrant, 0.5 to 2 parts by weight of the flow promoter, and 0.5 to 5 parts by weight of the lubricant.

In some embodiments of the present invention, the capsule provided by the present invention comprises 20 to 45 parts by weight of the compound represented by formula (IV), 50 to 75 parts by weight of the diluent, 1 to 12 parts by weight of the disintegrant, 0.5 to 2 parts by weight of the flow aid, and 0.5 to 5 parts by weight of the lubricant.

In some embodiments of the invention, the invention provides capsules wherein the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, and starch.

In some embodiments of the invention, the invention provides capsules wherein the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate.

In some embodiments of the invention, the invention provides capsules wherein the disintegrant is croscarmellose sodium.

In some embodiments of the invention, the capsule provided herein wherein the disintegrant is crospovidone.

In some embodiments of the invention, the invention provides a capsule wherein the disintegrant is sodium starch glycolate.

In some embodiments of the invention, the capsule provided herein wherein the glidant is aerosil or talc.

In some embodiments of the invention, the invention provides capsules wherein the lubricant is magnesium stearate.

In some embodiments of the present invention, the microcrystalline cellulose is 15 to 40 parts by weight in the capsule provided by the present invention.

In some embodiments of the present invention, the capsule provided by the present invention comprises one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, and sucrose in an amount of 30 to 50 parts by weight.

In some embodiments of the present invention, the capsule provided by the present invention, wherein the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, and sucrose in a mass ratio of 1:1 to 1: 3.

In some embodiments of the invention, the capsule provided by the invention has a mass ratio of the microcrystalline cellulose to the mannitol of 1: 1-1: 3.

In some embodiments of the present invention, the present invention provides a capsule, wherein the capsule is a single-dose formulation or a multi-dose formulation, wherein the single-dose formulation is a capsule suitable for administration to a patient one dose per day to exert a beneficial effect, and the multi-dose formulation is a capsule suitable for administration to a patient one or more doses per day to exert a beneficial effect.

The present invention provides a method of preparing the aforementioned capsule. According to an embodiment of the invention, the method comprises:

(2) subjecting the second mixture to a second mixing treatment with a lubricant so as to obtain a second mixture;

(3) and subjecting the second mixture to a capsule filling process so as to obtain said capsules.

In some embodiments of the invention, as for the method for preparing the capsule, the powder is adopted to directly fill the capsule, the preparation process is simple, the production process is less, the energy and the time are saved, the equipment and the operation cost are reduced, the process adaptability is strong, the continuous and stable production of the dosage form can be realized, and the prepared capsule has good stability and can be dissolved rapidly.

In some embodiments of the present invention, with respect to the method of preparing the capsule, at least one of the following additional technical features may also be further included:

according to the embodiment of the invention, the compound shown in the formula (I), the formula (II), the formula (III) or the formula (IV) and the diluent, the disintegrant, the glidant and the lubricant are sieved by a 60-mesh sieve in advance. Further, raw materials and auxiliary materials for preparing the capsule are uniformly dispersed, and the continuous and stable production of the capsule preparation is realized.

Detailed Description

The following detailed description of the embodiments of the present invention is intended to be illustrative, and not to be construed as limiting the invention.

Example 1

Compound III capsules were prepared according to the following formulation and dissolution was measured.

The preparation method comprises the following steps:

(1) sieving compound III, microcrystalline cellulose, mannitol, croscarmellose sodium, sodium lauryl sulfate, aerosil and magnesium stearate with a 60-mesh sieve for later use;

(2) weighing the sieved compound III, microcrystalline cellulose, mannitol, crosslinked sodium carboxymethyl cellulose or sodium dodecyl sulfate and superfine silica gel powder according to the following formula proportion, and mixing for about 20min to obtain a mixture A;

(3) adding sieved magnesium stearate, mixing for 5min, and making capsule.

Recipe 1-1: compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 44.49, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00; in total: 100.

prescription 1-2: compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 42.49, croscarmellose sodium: 2.00, sodium dodecyl sulfate: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00; in total: 100.

the dissolution rate (table 1) of the capsules with the prescriptions 1-1 and 1-2 is determined by a dissolution rate determination method (second method of 0931 of the general rules of Chinese pharmacopoeia 2015 edition) with 0.1M HCl as a dissolution medium by a basket method at 100rpm, and the acceptable standard of the dissolution rate is more than or equal to 85 percent within 15 min.

TABLE 1

Time/dissolution	1-1	1-2
			15min	97±2.26	30±6.42

The dissolution test result shows that the dissolution rate of the active ingredient of the formula 1-1 in the example 1 is more than 85% in 15min, and the dissolution is rapid. Whereas the dissolution rate of the formulations 1-2 of example 1 for 15min was significantly less than 85%.

Example 2

Compound III capsules were prepared according to the formula shown below and dissolution was measured.

The preparation method comprises the following steps:

(1) sieving compound III, microcrystalline cellulose, mannitol, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, colloidal silicon dioxide and magnesium stearate with 60 mesh sieve;

(2) weighing the sieved compound III, microcrystalline cellulose, mannitol, croscarmellose sodium (or sodium carboxymethyl starch, or crospovidone), and aerosil according to the following formula proportion, and mixing for 20min to obtain mixture B;

(3) adding sieved magnesium stearate, mixing for 5min, and making capsule.

Prescription 2-1:

compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 44.49, crospovidone: 2.00, micro powder silica gel: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 2-2:

compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 44.49, carboxymethyl starch sodium: 2.00, micro powder silica gel: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 2-3:

compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 44.49, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 2-4:

compound III: 29.27, microcrystalline cellulose: 21.24, mannitol: 42.49, croscarmellose sodium: 5.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 2-5:

compound III: 29.27, microcrystalline cellulose: 19.58, mannitol: 39.15, croscarmellose sodium: 10.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

dissolution is determined according to a dissolution method (table 2) by adopting a dissolution determination method (second method of 0931 of the general rules of Chinese pharmacopoeia 2015 edition) and taking 0.1M HCl as a dissolution medium, basket method and 100rpm according to a method for capsules with the prescriptions of 2-1, 2-2, 2-3, 2-4 and 2-5, and the acceptable standard of the dissolution is more than or equal to 85 percent within 15 min.

TABLE 2

The experimental results of the prescriptions 2-1 to 2-5 show that the products of the disintegrant selected from croscarmellose sodium, crospovidone and sodium carboxymethyl starch have better dissolution rate, which indicates that the prescription has wide disintegrant adaptability.

Example 3

The preparation method comprises the following steps:

(1) sieving compound III, microcrystalline cellulose, mannitol, lactose, pregelatinized starch, croscarmellose sodium, micropowder silica gel, and magnesium stearate with 60 mesh sieve;

(2) weighing sieved compound III, microcrystalline cellulose, mannitol (or lactose or pregelatinized starch), croscarmellose sodium and aerosil according to the following formula proportion, and mixing for about 20min to obtain mixture C;

(3) adding sieved magnesium stearate, mixing for 5min, and encapsulating.

Prescription 3-1:

compound III: 29.27, microcrystalline cellulose: 22.24, lactose: 44.49, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 3-2:

compound III: 29.27, microcrystalline cellulose: 22.24, pregelatinized starch: 44.49, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 3-3:

compound III: 29.27, microcrystalline cellulose: 33.37, mannitol: 33.36, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 3-4:

compound III: 29.27, microcrystalline cellulose: 16.68, mannitol: 50.05, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

the dissolution rate (table 3) of capsules with prescriptions 3-1, 3-2, 3-3 and 3-4 is determined by a dissolution rate determination method (second method of 0931 of the general rules of Chinese pharmacopoeia 2015 edition) with 0.1M HCl as a dissolution medium by a basket method at 100rpm, and the acceptable standard of the dissolution rate is more than or equal to 85% in 15 min.

TABLE 3

Time/dissolution	3-1	3-2	3-3	3-4
					15min	99±0.84	91±4.12	92±3.76	97±2.26

The experimental results of the prescription 1-1 and the prescriptions 3-1 to 3-4 show that the products obtained by selecting microcrystalline cellulose and mannitol, lactose or pregelatinized starch as fillers have better dissolution rate, which indicates that the prescription has wide filler adaptability.

Example 4

The preparation method comprises the following steps:

(1) sieving compound III, microcrystalline cellulose, mannitol, croscarmellose sodium, aerosil and magnesium stearate with 60 mesh sieve;

(2) weighing the sieved compound III, microcrystalline cellulose, mannitol, cross-linked sodium carboxymethyl cellulose and superfine silica gel powder according to the following formula proportion, and mixing for about 20min to obtain a mixture D;

(3) adding sieved magnesium stearate, mixing for 5min, and encapsulating.

Prescription 4-1:

compound III: 40.97, microcrystalline cellulose: 18.34, mannitol: 36.69, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 4-2:

compound III: 35.12, microcrystalline cellulose: 20.29, mannitol: 40.59, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 4-3:

compound III: 30.73, microcrystalline cellulose: 21.76, mannitol: 43.51, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 4-4:

compound III: 27.32, microcrystalline cellulose: 22.89, mannitol: 45.79, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

prescription 4-5:

compound III: 24.58, microcrystalline cellulose: 23.81, mannitol: 47.61, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.

dissolution is determined by a dissolution determination method (second method of 0931 of the general rules of Chinese pharmacopoeia 2015 edition) according to a method with 0.1M HCl as a dissolution medium and basket method at 100rpm for capsules with formulas 4-1, 4-2, 4-3, 4-4 and 4-5 (Table 4), and the acceptable standard of dissolution is 15min ≥ 85%.

TABLE 4

Time/dissolution	4-1	4-2	4-3	4-4	4-5
						15min	90±1.03	92±3.43	94±0.75	101±6.69	101±4.00

The results of the prescriptions 4-1 to 4-5 and the prescription 1-1 show that the product obtained by using the compound III with the prescription proportion of 24-41% has better dissolution rate, which indicates that the prescription has wide compound proportion adaptability.

Example 5

The preparation method comprises the following steps:

(2) weighing the sieved compound III, microcrystalline cellulose, mannitol, cross-linked sodium carboxymethyl cellulose and superfine silica gel powder according to the following formula proportion, and mixing for about 20min to obtain a mixture E;

(3) the sieved prescribed amount of magnesium stearate was added to mixture E, mixed for about 5min to homogeneity and filled into capsules.

Prescription 5-1:

compound III: 29.27, microcrystalline cellulose: 22.41, mannitol: 44.82, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 0.50, total: 100.

prescription 5-2:

compound III: 29.27, microcrystalline cellulose: 22.08, mannitol: 44.15, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 0.50, total: 100.

prescription 5-3:

compound III: 29.27, microcrystalline cellulose: 20.91, mannitol: 41.82, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 0.50, total: 100.

the dissolution rate (table 5) of capsules with prescriptions of 5-1, 5-2 and 5-3 is determined according to a dissolution rate determination method (second method of 0931 of the general rules of Chinese pharmacopoeia 2015 edition) by taking 0.1M HCl as a dissolution medium and basket method at 100rpm, and the acceptable standard of the dissolution rate is more than or equal to 85 percent within 15 min.

TABLE 5

Time/dissolution	5-1	5-2	5-3
				15min	100±0.82	101±1.63	99±2.00

The results of the prescriptions 5-1 to 5-3 and the prescription 1-1 show that the products prepared with the lubricant magnesium stearate in the proportion of 0.5-5% have better dissolution rate, which indicates that the prescription has wide adaptability of the lubricant proportion.

Example 6

In order to further verify the stability of the capsule, the capsule samples are prepared according to the prescription 2-3, and are placed for 6 months under the conditions of 40 ℃ and 75% of relative humidity according to the guiding principle of 9001 raw material drug and preparation stability test of the national drug code 2015, the samples are sampled for detecting the properties, dissolution rate, related substances and content in 1,2, 3 and 6 months, the dissolution condition is 0.1M HCl as a dissolution medium, and the basket method is carried out at 100 rpm. The test results are shown in table 6, and the results prove that the compound III capsule prepared by the invention has good stability.

TABLE 6

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Moreover, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient,

2. the composition of claim 1, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;

optionally, the inorganic or organic acid salt is a mono-or di-salt;

optionally, the inorganic acid salt is selected from hydrogen halide acid salt, halogen series oxygen-containing inorganic acid salt, carbon series oxygen-containing inorganic acid salt, nitrogen series oxygen-containing inorganic acid salt, boron series oxygen-containing inorganic acid salt, silicon series oxygen-containing inorganic acid salt, phosphorus series oxygen-containing inorganic acid salt or sulfur series inorganic acid salt;

the organic acid salt is selected from carboxylate, sulfonate, sulfinate or thiocarboxylate;

optionally, the inorganic acid salt is selected from the group consisting of a hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, or metaphosphate;

the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, embonate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethylsulfonate, glycerophosphate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, succinate, methanesulfonate, ethanesulfonate, mesylate, isovalerate, and isovalerate, Laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate.

3. The composition of any one of claims 1-2, wherein the pharmaceutically acceptable salt is a phosphate salt, wherein the phosphate salt of the compound of formula (I) has a structure of formula (III), wherein the phosphate salt of the compound of formula (II) has a structure of formula (IV),

4. the composition according to any one of claims 1 to 3, wherein the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof is 20% to 45%, or 20% to 42%, or 21% to 39%, or 22% to 38%, or 23% to 37%, or 24% to 36%, 25% to 35%, or 26% to 34%, or 27% to 33%, or 28% to 32%, or 29% to 31%, or 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%, or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, based on the total weight of the composition.

5. The composition of any one of claims 1-4, further comprising a pharmaceutically acceptable adjuvant comprising at least one of a diluent, a disintegrant, a glidant, and a lubricant;

optionally, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose;

optionally, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate;

optionally, the glidant is aerosil or talc;

optionally, the lubricant is magnesium stearate.

6. The composition according to claim 5, wherein the mass fraction of the microcrystalline cellulose is 15-40% based on the total weight of the composition;

optionally, the mass fraction of one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 30-50% based on the total weight of the composition;

optionally, the mass ratio of the microcrystalline cellulose to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 1: 1-1: 3;

optionally, the mass fraction of the disintegrant is 1-12% based on the total weight of the composition;

optionally, the mass fraction of the glidant is 0.5-2% based on the total weight of the composition;

optionally, the lubricant is present in an amount of 0.5 to 5% by weight, based on the total weight of the composition.

7. The composition according to any one of claims 1 to 6, wherein the composition is in the form of an oral formulation;

optionally, the composition is in the form of a solid oral formulation;

optionally, the composition is in the form of a capsule, tablet, pellet, powder, sustained release formulation, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhalant or patch.

8. A capsule filled with contents, characterized in that the contents comprise a composition according to any one of claims 1 to 6.

9. A capsule filled with contents, characterized in that the contents comprise: the compound shown in the formula (III) or the formula (IV) and a diluent, a disintegrant, a glidant and a lubricant, wherein the mass part of the compound shown in the formula (III) or the formula (IV) is 20-45% based on the total weight of the content.

10. The capsule according to claim 9, wherein the compound of formula (III) or formula (IV) is used in an amount of 20 to 45 parts by weight, the diluent is used in an amount of 50 to 75 parts by weight, the disintegrant is used in an amount of 1 to 12 parts by weight, the glidant is used in an amount of 0.5 to 2 parts by weight, and the lubricant is used in an amount of 0.5 to 5 parts by weight.

11. The capsule according to claim 9 or 10, wherein the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose;

optionally, the glidant is aerosil;

optionally, the lubricant is magnesium stearate;

optionally, the microcrystalline cellulose is used in an amount of 15-40 parts by weight;

optionally, the amount of one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 30-50 parts by weight;

optionally, the mass ratio of the microcrystalline cellulose in the diluent to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 1: 1-1: 3.

12. The capsule according to claim 8 or 9, wherein the capsule is a single dose formulation or a multi dose formulation.

13. A method of making a capsule comprising:

(1) premixing the compound shown in the formula (I), or the formula (II), or the formula (III), or the formula (IV) with a diluent, a disintegrant and a glidant to obtain a first mixture, wherein the time of the first mixing treatment is 15-30 min;

(2) subjecting the first mixture and a lubricant to a second mixing treatment to obtain a second mixture, wherein the second mixing treatment time is 3-7 min optionally;