阅读说明：本技术 含硝羟喹啉前药的药物组合物及其制备方法和应用 (Pharmaceutical composition containing nitroxoline prodrug and preparation method and application thereof ) 是由 陈杰 申帅 吴友斌 刘江华 郭玉申 于 2020-05-29 设计创作，主要内容包括：本发明公开了含硝羟喹啉前药的药物组合物及其制备方法和应用。该药物组合物包含如下重量份数的各组分：100份活性药物成分、22.5-320份填充剂、0-40份崩解剂、0-95份粘合剂和2-30份润滑剂；相对于每100重量份的活性药物成分,所述填充剂、所述崩解剂和所述粘合剂的总用量为54-345重量份；所述活性药物成分为(S)-(5-硝基喹啉-8-基氧基)甲基1-异丙酰基吡咯烷-2-羧酸酯。该药物组合物具有良好的稳定性和溶出性质,并且具有良好的药代动力学特征,可有利地用于药物的制备和临床应用。(The invention discloses a pharmaceutical composition containing a nitroxoline prodrug, and a preparation method and application thereof. The pharmaceutical composition comprises the following components in parts by weight: 100 parts of active pharmaceutical ingredient, 22.5-320 parts of filler, 0-40 parts of disintegrant, 0-95 parts of adhesive and 2-30 parts of lubricant; the total amount of the filler, the disintegrant and the binder is 54 to 345 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the active pharmaceutical ingredient is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate. The pharmaceutical composition has good stability and dissolution property, has good pharmacokinetic characteristics, and can be advantageously used for preparation and clinical application of medicaments.)

1. The pharmaceutical composition containing the nitroxoline prodrug is characterized by comprising the following components, by weight, 100 parts of an active pharmaceutical ingredient, 22.5-320 parts of a filler, 0-40 parts of a disintegrant, 0-95 parts of a binder and 2-30 parts of a lubricant; the total amount of the filler, the disintegrant and the binder is 54 to 345 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the active pharmaceutical ingredient is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate.

2. A pharmaceutical composition of claim 1, wherein the filler is selected from one or more of starch, pregelatinized starch, partially pregelatinized starch, lactose, sucrose, mannitol, sorbitol, hydrated calcium phosphate, anhydrous calcium phosphate, and microcrystalline cellulose; preferably one or more of pregelatinized starch, lactose, sucrose, mannitol, and microcrystalline cellulose; more preferably a mixture of pregelatinized starch, mannitol, and microcrystalline cellulose, wherein the weight ratio of the three is preferably 0.5-2:1:0.5-2, more preferably 0.8-1.3:1:0.8-1.3, still more preferably 1.06-1.07:1: 1.09-1.25;

and/or the filler is used in an amount of 50 to 320 parts by weight, preferably 60 to 300 parts by weight, more preferably 90 to 200 parts by weight, most preferably 90.8 to 93 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient;

and/or, the disintegrant is selected from one or more of low-substituted hydroxypropyl methylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, croscarmellose sodium and crospovidone, preferably one or two of croscarmellose sodium and crospovidone, more preferably crospovidone;

and/or the disintegrant is used in an amount of 15 to 35 parts by weight, preferably 15 to 17 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient;

and/or the binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and starch, preferably from one or more of hydroxypropyl methylcellulose, povidone and starch;

and/or, the binder is used in an amount of 10-50 parts by weight per 100 parts by weight of the active pharmaceutical ingredient;

and/or the total weight of the filler, the disintegrant and the binder is 100-320 parts by weight, preferably 100-120 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient.

3. A pharmaceutical composition containing a nitroxoline prodrug according to claim 1 or 2, wherein the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, high molecular weight polyethylene glycol, sodium stearyl fumarate and sodium dodecyl sulfate, preferably one or two of sodium stearyl fumarate and sodium dodecyl sulfate, more preferably sodium stearyl fumarate;

and/or the lubricant is used in an amount of 2 to 10 parts by weight, preferably 2 to 8 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient.

4. A pharmaceutical composition comprising a nitroxoline prodrug according to any one of claims 1 to 3, wherein the pharmaceutical composition further comprises a coating agent; the ratio of the mass of the coating agent to the mass of the pharmaceutical composition before coating is 1.5-6%, preferably 2-4%;

and/or, the pharmaceutical composition further comprises one or more of a colorant, a pH adjuster, a surfactant, a stabilizer, and a fragrance.

5. A pharmaceutical composition containing a nitroxoline prodrug according to any one of claims 1 to 4, wherein the pharmaceutical composition is a solid formulation, preferably a granule, a powder, a capsule or a tablet, more preferably a tablet, further preferably an immediate release tablet.

6. The tablet containing the nitroxoline prodrug is characterized by comprising the following components in parts by weight, namely 100 parts of active pharmaceutical ingredient, 22.5-320 parts of filler, 0-40 parts of disintegrant, 0-95 parts of binder and 2-30 parts of lubricant; the total amount of the filler, the disintegrant and the binder is 54 to 345 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the active pharmaceutical ingredient is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate;

the filler is one or more of pregelatinized starch, lactose, sucrose, mannitol and microcrystalline cellulose; the disintegrant is one or two of croscarmellose sodium and crospovidone; the adhesive is one or more of hydroxypropyl methyl cellulose, povidone and starch; the lubricant is one or two of sodium stearyl fumarate and sodium dodecyl sulfate; wherein, the tablet is preferably a coated tablet, and the ratio of the mass of the coating agent in the coated tablet to the mass of the uncoated plain tablet is 1.5-6%, preferably 2-4%.

7. A tablet containing a nitroxoline prodrug is characterized by comprising the following components in parts by weight: 100 parts of active pharmaceutical ingredient, 22.5-320 parts of filler, 15-17 parts of disintegrant and 2-10 parts of lubricant; the total amount of the filler and the disintegrant is 100-120 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the active pharmaceutical ingredient is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate;

the filler is a mixture of pregelatinized starch, mannitol and microcrystalline cellulose, and the weight ratio of the pregelatinized starch, the mannitol and the microcrystalline cellulose is 0.5-2:1: 0.5-2; the disintegrant is crospovidone; the lubricant is sodium stearyl fumarate;

wherein the filler is preferably used in an amount of 60 to 300 parts by weight, more preferably 90 to 200 parts by weight, most preferably 90.8 to 93 parts by weight;

wherein the weight ratio of the pregelatinized starch, the mannitol and the microcrystalline cellulose in the filler is preferably 0.8-1.3:1:0.8-1.3, more preferably 1.06-1.07:1: 1.09-1.25;

wherein the lubricant is preferably used in an amount of 2 to 8 parts by weight, more preferably 2 to 2.1 parts by weight;

wherein, the amount of the filler is preferably 90.8 to 93 parts by weight; the weight ratio of pregelatinized starch, mannitol and microcrystalline cellulose in the filler is 1.06-1.07:1: 1.09-1.25; the lubricant is used in an amount of 2 to 2.1 parts by weight.

8. The nitroxoline prodrug containing tablet of claim 7, wherein the tablet is free of a binder;

and/or the tablet is a coated tablet, and the ratio of the mass of the coating agent in the coated tablet to the mass of the uncoated plain tablet is 1.5-6%, preferably 2-4%.

9. A method for preparing granules, powders, capsules or tablets, wherein the raw materials used in the preparation method are the pharmaceutical composition containing the nitroxoline prodrug as claimed in any one of claims 1 to 5;

when the finally prepared formulation is a granule formulation,

the preparation method is dry granulation, and comprises the following steps:

s1: mixing the other components except the lubricant to obtain a mixture I;

s2: mixing the mixture I with a lubricant to obtain a mixture I;

alternatively, the first and second electrodes may be,

the preparation contains a binding agent, and the preparation method is wet granulation, and the preparation method comprises the following steps:

s1: mixing the rest components except lubricant and binder with solution containing binder, wet granulating, drying, and dry granulating to obtain dry granule;

s2: mixing the dry particles with a lubricant to obtain the finished product;

alternatively, the first and second electrodes may be,

the preparation does not contain a binder, and the preparation method is wet granulation, and the preparation method comprises the following steps:

s1: mixing the rest components except lubricant with water, wet granulating, drying, and dry granulating to obtain dry granule;

s2: mixing the dry particles with a lubricant to obtain the finished product;

when the finally prepared preparation is a powder, the preparation method comprises the following steps: directly mixing the components to obtain the product;

when the finally prepared preparation is a capsule, the preparation method comprises the following steps: on the basis of the preparation method of the granules, further filling the obtained granules into capsules to obtain the granules;

when the finally prepared preparation is a tablet, the preparation method comprises the following step of further tabletting the obtained granules on the basis of the preparation method of the granules.

10. Use of a pharmaceutical composition comprising a nitroxoline prodrug according to any one of claims 1 to 5 or a tablet comprising a nitroxoline prodrug according to any one of claims 6 to 8 for the preparation of a medicament for the treatment of an infectious disease or cancer; the infectious disease is preferably a urinary tract infection; the cancer is preferably bladder cancer.

Technical Field

The invention relates to a pharmaceutical composition containing a nitroxoline prodrug, a preparation method and application thereof.

Background

Nitroxoline, known by the english name as Nitroxoline and having the chemical name of 5-nitro-8-hydroxyquinoline, was developed as an oral antibiotic drug in the sixties, is mainly used for urinary system infection, has a safer use history, and is later replaced due to the discovery and use of novel antibiotics. In recent years, new researches show that the nitroxoline can simultaneously inhibit methionine aminopeptidase MetAP2 and a sirtuin 2-related enzyme SIRT1 in vascular endothelial cells, play a synergistic inhibition effect on tumor angiogenesis, and simultaneously have an inhibition effect on the proliferation of tumor cells. Thus, nitroxoline has been newly developed for the treatment of tumors including bladder cancer.

The prodrug is a compound obtained by chemically modifying an active drug, and is converted into the original drug by the action of an enzyme in vivo to exert the drug effect. The prodrug is a modification method of the drug, can overcome various adverse characteristics and properties of the drug, and mainly has the advantages of increasing the solubility of the drug, improving the absorption and distribution of the drug, increasing the stability of the drug, reducing toxicity or adverse reactions, prolonging the action time of the drug, eliminating the inappropriate properties of the drug and the like.

In order to prolong the half-life of nitroxoline, a great deal of research has been conducted in patent application publication WO/2020/063824, which discloses a prodrug of nitroxoline, (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate, which is metabolized into nitroxoline to act after entering the body, and which enables the nitroxoline to have an extended half-life in the body for the purpose of reducing the administration frequency.

However, there is no prior art formulation for the above nitroxoline prodrugs.

Disclosure of Invention

The inventor of the invention has intensively researched and developed a new preparation aiming at the nitroxoline prodrug, (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate, and the preparation has good stability and dissolution property, has good pharmacokinetic characteristics, can be favorably used for preparing medicines, and has good clinical application prospect.

Therefore, one of the objects of the present invention is to provide a pharmaceutical composition containing a prodrug of nitroxoline, which comprises the following components in parts by weight: 100 parts of active pharmaceutical ingredient, 22.5-320 parts of filler, 0-40 parts of disintegrant, 0-95 parts of adhesive and 2-30 parts of lubricant; the total amount of the filler, the disintegrant and the binder is 54 to 345 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the active pharmaceutical ingredient is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate.

In the above pharmaceutical composition, the structural formula of the active pharmaceutical ingredient (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate is as follows:

the active pharmaceutical ingredient can be prepared by the preparation method of patent application example 20, publication number WO/2020/063824.

In the above pharmaceutical composition, the filler may be one or more of starch, pregelatinized starch, partially pregelatinized starch, lactose, sucrose, mannitol, sorbitol, hydrated calcium phosphate, anhydrous calcium phosphate and microcrystalline cellulose, preferably one or more of pregelatinized starch, lactose, sucrose, mannitol and microcrystalline cellulose, and more preferably a mixture of pregelatinized starch, mannitol and microcrystalline cellulose. When the filler is a mixture of pregelatinized starch, mannitol, and microcrystalline cellulose, the weight ratio of the three is preferably 0.5-2:1:0.5-2, more preferably 0.8-1.3:1:0.8-1.3, and still more preferably 1.06-1.07:1: 1.09-1.25.

In the above pharmaceutical composition, the filler is used in an amount of preferably 50 to 320 parts by weight, more preferably 60 to 300 parts by weight, for example 100 or 200 parts by weight, even more preferably 90 to 200 parts by weight, most preferably 90.8 to 93 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient.

In the above pharmaceutical composition, the disintegrant may be one or more of low-substituted hydroxypropyl methylcellulose, carboxymethylcellulose calcium, sodium carboxymethyl starch, croscarmellose sodium and crospovidone, preferably one or two of croscarmellose sodium and crospovidone, and more preferably crospovidone.

In the above pharmaceutical composition, the disintegrant is used in an amount of preferably 15 to 35 parts by weight, for example 31.5 parts by weight, more preferably 15 to 17 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient.

In the above pharmaceutical composition, the binder may be one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone and starch, preferably one or more of hydroxypropyl methylcellulose, povidone and starch.

In the above pharmaceutical composition, the binder is preferably used in an amount of 10 to 50 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.

In the above pharmaceutical composition, the total weight parts of the filler, the disintegrant and the binder are preferably 100-320 parts by weight, such as 195 or 290 parts by weight, more preferably 100-120 parts by weight, such as 108 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient.

In the above pharmaceutical composition, the lubricant may be one or more of stearic acid, magnesium stearate, calcium stearate, high molecular weight polyethylene glycol, sodium stearyl fumarate and sodium dodecyl sulfonate, preferably one or two of sodium stearyl fumarate and sodium dodecyl sulfonate, more preferably sodium stearyl fumarate.

In the above pharmaceutical composition, the lubricant is used in an amount of preferably 2 to 10 parts by weight, for example 3.2 or 5 parts by weight, more preferably 2 to 8 parts by weight, and still more preferably 2 to 2.1 parts by weight, per 100 parts by weight of the active pharmaceutical ingredient.

In the above pharmaceutical composition, the pharmaceutical composition may further comprise a coating agent. The type of the coating agent may be a type of coating agent conventionally used in the art, for example, a coating agent under the trade name opadry. The amount of the coating agent may be an amount conventionally used in the art, for example, the ratio of the mass of the coating agent to the mass of the pharmaceutical composition before coating is 1.5% to 6%, preferably 2% to 4%.

In the above pharmaceutical composition, the pharmaceutical composition may further comprise one or more of a coloring agent, a pH adjuster, a surfactant, a stabilizer, and a perfume.

In the above pharmaceutical composition, the pharmaceutical composition may be a dosage form conventional in the art, such as a solid preparation, for example, granules, powder, capsules or tablets, preferably tablets, and further preferably immediate release tablets.

In a preferred embodiment of the present invention, the pharmaceutical composition is a tablet, and the tablet comprises the following components in parts by weight: 100 parts of active pharmaceutical ingredient, 22.5-320 parts of filler, 0-40 parts of disintegrant, 0-95 parts of adhesive and 2-30 parts of lubricant; the total amount of the filler, the disintegrant and the binder is 54 to 345 parts by weight per 100 parts by weight of the active pharmaceutical ingredient; the active pharmaceutical ingredient is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate;

the filler is one or more of pregelatinized starch, lactose, sucrose, mannitol and microcrystalline cellulose; the disintegrant is one or two of croscarmellose sodium and crospovidone; the adhesive is one or more of hydroxypropyl methyl cellulose, povidone and starch; the lubricant is one or two of sodium stearyl fumarate and sodium dodecyl sulfate. Wherein the tablet is preferably a coated tablet and the ratio of the mass of the coating agent in the coated tablet to the mass of the uncoated plain tablet is 1.5% to 6%, preferably 2% to 4% (e.g. 3%).

In a further preferred embodiment of the present invention, the pharmaceutical composition is a tablet, and the tablet comprises the following components in parts by weight: 100 parts of active pharmaceutical ingredient, 22.5-320 parts of filler, 15-17 parts of disintegrant and 2-10 parts of lubricant; the total amount of the filler and the disintegrant is 100-120 parts by weight (e.g., 108 parts) per 100 parts by weight of the active pharmaceutical ingredient; the active pharmaceutical ingredient is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate;

the filler is a mixture of pregelatinized starch, mannitol and microcrystalline cellulose, and the weight ratio of the pregelatinized starch, the mannitol and the microcrystalline cellulose is 0.5-2:1: 0.5-2; the disintegrant is crospovidone; the lubricant is sodium stearyl fumarate.

In the above further preferred embodiment, the filler is used in an amount of preferably 60 to 300 parts by weight, more preferably 90 to 200 parts by weight, most preferably 90.8 to 93 parts by weight.

In a further preferred embodiment described above, the weight ratio of pregelatinized starch, mannitol, and microcrystalline cellulose in the filler is preferably from 0.8 to 1.3:1:0.8 to 1.3, more preferably from 1.06 to 1.07:1:1.09 to 1.25.

In the above-mentioned further preferred embodiment, the lubricant is used in an amount of preferably 2 to 8 parts by weight, more preferably 2 to 2.1 parts by weight.

In the above further preferred embodiment, preferably, the filler is used in an amount of 90.8 to 93 parts by weight; the weight ratio of pregelatinized starch, mannitol and microcrystalline cellulose in the filler is 1.06-1.07:1: 1.09-1.25; the lubricant is used in an amount of 2 to 2.1 parts by weight.

In the above further preferred embodiment, the tablet may be free of binder.

In the above further preferred embodiment, the tablet is preferably a coated tablet and the ratio of the mass of the coating agent in the coated tablet to the mass of the uncoated plain tablet is 1.5% to 6%, preferably 2% to 4% (e.g. 3%).

Another object of the present invention is to provide a method for preparing the aforementioned granules, powders, capsules or tablets, which can be prepared by conventional methods in the art.

When the finally prepared formulation is a granule, dry granulation conventional in the art may be employed, and in this case, the preparation method comprises the following steps:

s1: mixing the other components except the lubricant to obtain a mixture I;

s2: and mixing the mixture I with a lubricant to obtain the lubricant.

When the final preparation is a granule, wet granulation which is conventional in the art may also be used, and when the preparation contains a binder, the preparation method comprises the following steps:

s1: mixing the rest components except lubricant and binder with solution containing binder, wet granulating, drying, and dry granulating to obtain dry granule;

s2: mixing the dry particles with a lubricant to obtain the finished product; alternatively, the first and second electrodes may be,

when the preparation does not contain a binder, the preparation method comprises the following steps:

s1: mixing the rest components except lubricant with water, wet granulating, drying, and dry granulating to obtain dry granule;

s2: and mixing the dry particles with a lubricant to obtain the finished product.

When the final preparation is powder, the preparation method comprises the step of directly mixing the components to obtain the final product.

When the finally prepared preparation is a capsule, the preparation method comprises the following step of filling the obtained granules into a capsule on the basis of the preparation method of the granules.

When the finally prepared preparation is a tablet, the preparation method comprises the following steps: on the basis of the preparation method of the granules, the granules are further tabletted to obtain the tablet.

Another object of the present invention is to provide a use of the aforementioned pharmaceutical composition or the aforementioned tablet for preparing a medicament for treating infectious diseases or cancer. The infectious disease may be, for example, a urinary tract infection. The cancer may be, for example, bladder cancer.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the pharmaceutical composition of the present invention has good stability and excellent dissolution properties, and the pharmacokinetic properties thereof are excellent, and can be advantageously used for clinical development and applications.

Drawings

FIG. 1 is a graph showing the dissolution profiles of the immediate release tablets obtained in examples 1 to 8 and the tablet of comparative example 1.

FIG. 2 is a pharmacokinetic profile of immediate release tablets prepared in examples 1, 3, and 7.

Detailed Description

The present invention will be described in more detail with reference to the following examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention. Various other changes and modifications may be made by one skilled in the art within the scope of the invention.

Experimental reagent:

the nitroxoline prodrug is (S) - (5-nitroquinolin-8-yloxy) methyl 1-isopropionylpyrrolidine-2-carboxylate, prepared according to the method disclosed in example 20 of patent application publication No. WO/2020/063824.

Starch: dongyuan Liaoning or Luogett France

Pregelatinized starch: shanghai Kalekang

Microcrystalline cellulose: JRS PHARMA (Ruidenmei)

Hydroxypropyl methylcellulose: dow (Dow chemical) or Japan shines

Lactose: de national Mei medicament

Sodium stearyl fumarate: JRS PHARMA (Ruidenmei)

Sodium dodecyl sulfate: pasf Germany

Cross-linked povidone: JRS PHARMA (Redenumel) or American ISP or Pasteur Germany

Mannitol: french Rogue

Purifying water: taizhou Shengjieda (a kind of holy Jie)

Croscarmellose sodium: dupont USA

Polyvidone: pasf Germany

Coating powder (trade name: opadry): shanghai Kalekang

An experimental instrument:

an electronic balance: constant velocity of Shunhui, FA1004

Dissolution instrument: tianjin Tiandafang, RC8MD

Automatic sampler of dissolution instrument: the natural hair of the large-day-long-day-life RCQ-8C

A tablet press: shanghai Tianfan, TDP-6

A tablet press: shanghai Tianxiang, ZPS008

A dry granulator: nanjing Hongsheng, GK-25

A coating machine: taizhou Jintai, BY-300

A coating machine: zhejiang Xiaolun, BGB-5F

Ultraviolet spectrophotometer: japanese Shimadzu, UV-2700

Liquid chromatograph: shimadzu, LC-20AT

And (3) dog food: beijing Ke Olympic fodder Co Ltd

Hereinafter, coating weight gain refers to the weight of the coating as a percentage of the weight of the plain tablet.

The compositions and amounts of the examples and comparative examples are as follows: