Patent Application
20230000853
The present invention relates to a phamaceutical composition comprising nitroxoline, a nitroxoline tablet, a method for preparing the same, and a use thereof
Nitroxoline, the chemical name of which is 5-nitro-8-hydroxyquinoline, was developed as an oral antibiotic drug in the 1960s. It was mainly used for urinary system infections, and had a safe history of use before being replaced due to discovery and use of new antibiotics.
In recent years, new studies have found that nitroxoline can simultaneously inhibit the methionine aminopeptidase MetAP2 and the silence information regulator 2-related enzyme SIRT1 in vascular endothelial cells, and exert a synergistic inhibitory effect on tumor angiogenesis, as well as an inhibitory effect on the proliferation of tumor cells. Therefore, nitroxoline can be developed to treat tumors including bladder cancer.
As discussed above, nitroxoline can be used for various clinical indications, such as urinary tract infection and bladder cancer. When oral administration is applied to treat diseases, different clinical indications have different requirements for drug dissolution rate. For example, the treatment of urinary tract infection involves a short-term administration that requires the drug to take effect as soon as possible, so a relatively fast drug dissolution rate is ideal to better achieve an effective anti-infective effect; while the treatment of bladder cancer involves a long-term administration that requires a narrow variation range of blood drug concentration, so a relatively moderate drug dissolution rate is ideal.
At present, there is no pharmaceutical composition containing nitroxoline with a moderate dissolution rate in the prior art. Therefore, the development of pharmaceutical composition containing nitroxoline with a moderate dissolution rate is an urgent technical problem to be solved at present.
The technical problem to be solved by the present invention is to provide a phamaceutical composition containing nitroxoline, a nitroxoline tablet, a method for preparing the same, and a use thereof, so as to overcome the defect that there is no pharmaceutical composition containing nitroxoline with a moderate dissolution rate in the prior art.
The inventors found in the research that nitroxoline has low solubility and slow dissolution in 0.1 mol/L hydrochloric acid, water and phosphate buffer (pH 6.8) at 37° C., and the properties of nitroxoline itself will have an adverse effect on obtaining a pharmaceutical composition containing nitroxoline with a moderate dissolution rate. After extensive research, the inventors found that pharmaceutical compositions containing nitroxoline with different dissolution rates can be obtained by controlling the particle size of active pharmaceutical ingredient (API). After further research, the inventors found that nitroxoline tablets with a moderate dissolution rate (the dissolution rate within 60 min is more than 75%) can be prepared when the particle size D90 of nitroxoline is 10 to 100 μm. In addition, the resulting nitroxoline tablets have uniform content, narrow variation range in hardness, and good fluidity and compressibility.
The present invention solves the above technical problem through the following technical solutions:
The present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutically acceptable carrier, the active pharmaceutical ingredient is nitroxoline or a pharmaceutically acceptable salt thereof, and the particle size D90 of the active pharmaceutical ingredient is 10 to 100 μm.
In some preferred embodiments, the active pharmaceutical ingredient is nitroxoline.
In some preferred embodiments, the pharmaceutically acceptable salt of nitroxoline is a base addition salt formed by nitroxoline and an inorganic base or an organic base, an acid addition salt formed by nitroxoline and an inorganic acid or an organic acid, or a salt formed by nitroxoline and an alkaline or acidic amino acid, and preferably nitroxoline hydrochloride or lysine salt. The inorganic base is sodium hydroxide and/or sodium phosphate, the organic base is triethylamine and/or diethylamine, the inorganic acid is hydrochloric acid and/or phosphoric acid, the organic acid is tartaric acid and/or citric acid, the alkaline amino acid is lysine, and the acidic amino acid is glutamic acid.
In some preferred embodiments, the particle size D90 of the active pharmaceutical ingredient is 10 to 70 μm, preferably 40 to 70 μm, for example 12.61 μm, 42.55 μm, 43.29 μm, 70.58 μm or 99.31 μm.
In some preferred embodiments, the particle size Ds( )of the active pharmaceutical ingredient is 4 to 50 μm, preferably 4 to 40 μm or 4 to 35 μm, more preferably 10 to 40 pm, for example 4.58 μm, 10.88 μm, 11.02 μm, 14.95 μm or 33.60 μm.
In some preferred embodiments, the particle size D90 of the active pharmaceutical ingredient is 0 to 10 μm, and is not 0, preferably 0.1 to 6 μm or 2 to 10 μm, and more preferably 2 to 6 μm, for example 0.12 μm, 3.44 μm, 3.67 μm, 3.99 μm or 5.66 μm.
In some preferred embodiments, the active pharmaceutical ingredient is present in an amount of 20 to 65 parts by weight or 20 to 60 parts by weight, preferably 25 to 60 parts by weight, more preferably 40 to 61 parts by weight, and further more preferably 56 to 61 parts by weight, for example 56.3 parts by weight, 60.1 parts by weight, 60.2 parts by weight or 60.4 parts by weight per 100 parts by weight of the pharmaceutical composition.
In some preferred embodiments, the carrier comprises a filler. The filler is preferably one or more of starch, pregelatinized starch, partially pregelatinized starch, lactose, sucrose, mannitol, sorbitol, hydrous calcium phosphate, anhydrous calcium phosphate and microcrystalline cellulose, and more preferably one or more of starch, lactose and microcrystalline cellulose. The filler is preferably present in an amount of 30 to 300 parts by weight, more preferably 50 to 100 parts by weight, further more preferably 30 to 90 parts by weight, and still further more preferably 30 to 75 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the carrier comprises a binder. The binder is preferably one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and starch, more preferably one or more of polyvinylpyrrolidone, hydroxypropyl methylcellulose and starch, and further more preferably polyvinylpyrrolidone and/or starch. The binder is preferably present in an amount of 0 to 100 parts by weight, and not 0, more preferably 2 to 50 parts by weight, and further more preferably 30 to 50 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the carrier comprises a disintegrant. The disintegrant is preferably one or more of low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and crospovidone, more preferably low-substituted hydroxypropyl cellulose and/or crospovidone, and further more preferably low-substituted hydroxypropyl cellulose. The disintegrant is preferably present in an amount of 0 to 100 parts by weight, and not 0, more preferably 1 to 25 parts by weight or 5 to 25 parts by weight, further more preferably 1 to 10 parts by weight, 2 to 10 parts by weight or 5 to 10 parts by weight, and still further more preferably 5 to 6 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the carrier comprises a lubricant. The lubricant is preferably one or more of magnesium stearate, sodium stearyl fumarate and sodium dodecyl sulfate, and more preferably sodium stearyl fumarate and/or sodium dodecyl sulfate. The lubricant is preferably present in an amount of 0.25 to 20 parts by weight, more preferably 0.5 to 5 parts by weight, and further more preferably 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the carrier comprises a glidant. The glidant is preferably one or more of silica, talc and sodium dodecyl sulfate, more preferably silica and/or sodium dodecyl sulfate, and further more preferably sodium dodecyl sulfate. The glidant is preferably present in an amount of 0 to 20 parts by weight, and not 0, more preferably 0.5 to 10 parts by weight, and further more preferably 4 to 10 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the carrier comprises a filler and a binder, wherein the filler and the binder are present in a total amount of 30 to 300 parts by weight, preferably 32 to 280 parts by weight, more preferably 32 to 140 parts by weight, and further more preferably 56.5 to 70 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the carrier comprises a lubricant and a glidant, wherein the lubricant and the glidant are present in a total amount of 1 to 10 parts by weight, preferably 1 to 15 parts by weight, more preferably 2.5 to 10 parts by weight, and further more preferably 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the pharmaceutical composition also comprises a coating agent.
The coating agent is preferably hydroxypropyl methylcellulose and/or polyvinyl alcohol, and more preferably hydroxypropyl methylcellulose.
The coating agent is preferably present in the pharmaceutical composition in an amount of 3% to 15% by mass, and more preferably 9% to 13% by mass relative to the mass of the uncoated pharmaceutical composition.
In some preferred embodiments, the pharmaceutical composition comprises an active pharmaceutical ingredient and a pharmaceutically acceptable carrier, wherein the active pharmaceutical ingredient is nitroxoline or a pharmaceutically acceptable salt thereof; the particle size D90 of the active pharmaceutical ingredient is 10 to 100 p.m, the particle size Ds( )of the active pharmaceutical ingredient is 4 to 35 p.m, the particle size Dio of the active pharmaceutical ingredient is 0.1 to 6 μm; the active pharmaceutical ingredient is present in an amount of 56 to 61 parts by weight per 100 parts by weight of the pharmaceutical composition;
The present invention also provides a nitroxoline tablet, wherein the nitroxoline tablet is prepared from the aforementioned pharmaceutical composition.
The present invention also provides a method for preparing the nitroxoline tablet, wherein the pharmaceutical composition in the method is the aforementioned pharmaceutical composition, the pharmaceutical composition comprises adjuvant II, the adjuvant II is the aforementioned lubricant and/or the aforementioned glidant, the method comprises the following steps of: subjecting the components in the pharmaceutical composition except adjuvant II to wet granulation, wet milling, drying and dry milling, adding adjuvant II, subjecting the resulting mixture to total mixing, and tableting to obtain the nitroxoline tablet.
In the above method, when the pharmaceutical composition comprises a coating agent, coating is performed after tableting.
The present invention also provides a use of the aforementioned pharmaceutical composition and/or the aforementioned nitroxoline tablet in the preparation of a medicament for treating cancer. For example, the cancer can be bladder cancer.
The present invention also provides a method for treating cancer, wherein the method comprises the following step of: administering to a subject a therapeutically effective amount of the aforementioned pharmaceutical composition and/or the aforementioned nitroxoline tablet.
The present invention also provides a nitroxoline solid tablet composition, comprising an active pharmaceutical ingredient uniformly dispersed therein and a pharmaceutically acceptable carrier, wherein the active pharmaceutical ingredient is nitroxoline or a pharmaceutically acceptable salt thereof, the particle size D90 of the active pharmaceutical ingredient is 10 to 100 μm, preferably 10 to 70 μm, and more preferably 40 to 70 μm.
In some preferred embodiments, the particle size Ds( )of the active pharmaceutical ingredient is 4 to 50 μm, preferably 4 to 40 μm, and more preferably 10 to 40 μm.
In some preferred embodiments, the particle size D90 of the active pharmaceutical ingredient is 0 to 10 μm, and is not 0, preferably 2 to 10 μm, and more preferably 2 to 6 pm.
In some preferred embodiments, the pharmaceutically acceptable salt of nitroxoline is a base addition salt formed by nitroxoline and an inorganic base or an organic base, an acid addition salt formed by nitroxoline and an inorganic acid or an organic acid, or a salt formed by nitroxoline and an alkaline or acidic amino acid, and preferably nitroxoline hydrochloride or lysine salt. The inorganic base is sodium hydroxide and/or sodium phosphate, the organic base is triethylamine and/or diethylamine, the inorganic acid is hydrochloric acid and/or phosphoric acid, the organic acid is tartaric acid and/or citric acid, the alkaline amino acid is lysine, and the acidic amino acid is glutamic acid.
In some preferred embodiments, the active pharmaceutical ingredient is present in an amount of 20 to 60 parts by weight, and preferably 25 to 60 parts by weight per 100 parts by weight of the pharmaceutical composition.
In some preferred embodiments, the pharmaceutically acceptable carrier is one or more of filler, disintegrant, binder, glidant, lubricant, colorant, pH adjuster, surfactant, stabilizer and fragrance; and preferably filler, disintegrant, binder, glidant and lubricant.
In some preferred embodiments, the filler is one or more of starch, pregelatinized starch, partially pregelatinized starch, lactose, sucrose, mannitol, sorbitol, hydrous calcium phosphate, anhydrous calcium phosphate and microcrystalline cellulose.
In some preferred embodiments, the filler is present in an amount of 30 to 300 parts by weight, preferably 50 to 100 parts by weight, more preferably 30 to 90 parts by weight, and further more preferably 30 to 75 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and crospovidone.
In some preferred embodiments, the disintegrant is present in an amount of 0 to 100 parts by weight, and not 0, preferably 5 to 25 parts by weight, and more preferably 5 to 10 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and starch.
In some preferred embodiments, the binder is present in an amount of 0 to 100 parts by weight, and not 0, preferably 2 to 50 parts by weight, and more preferably 30 to 50 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate and sodium dodecyl sulfate.
In some preferred embodiments, the lubricant is present in an amount of 0.25 to 20 parts by weight, preferably 1 to 5 parts by weight, and more preferably 2.5 to 4 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the glidant is one or more of silica, talc and sodium dodecyl sulfate.
In some preferred embodiments, the glidant is present in an amount of 0 to 20 parts by weight, and not 0, preferably 0.5 to 10 parts by weight, and more preferably 4 to 10 parts by weight per 100 parts by weight of the active pharmaceutical ingredient.
In some preferred embodiments, the hardness of the tablet is 6 to 20 kg. In some preferred embodiments, the nitroxoline solid tablet composition further comprises a film coating material.
The film coating material can be hydroxypropyl methylcellulose and/or polyvinyl alcohol.
The weight gain of the film coating material is preferably 3% to 15% per 100 parts by weight of the active pharmaceutical ingredient.
The present invention also provides a nitroxoline tablet, comprising:
In the aforementioned nitroxoline tablet, the types of the filler, disintegrant, binder, lubricant and glidant are as defined above.
The present invention also provides a method for preparing the aforementioned nitroxoline solid tablet, comprising the following steps of:
1) pulverizing the nitroxoline raw material and controlling the D90 to be 10 to 100 μm;
2) weighing the pulverized particles obtained in step 1), filler, disintegrant, binder, glidant and lubricant according to the prescription;
3) formulating the binder;
4) mixing the pulverized particles, filler and disintegrant weighed in step 2) with the binder formulated in step 3), and subjecting the resulting mixture to wet granulation, wet milling, drying and dry milling;
5) adding glidant or lubricant to the dry granules obtained in step 4) to obtain the total mixed granules;
6) tableting the total mixed granules obtained in step 5) with a tableting machine;
7) optionally, film-coating the tablet obtained in step 6) with the film coating material to obtain the nitroxoline tablet.
In the aforementioned method, the nitroxoline raw material can be pulverized by a hammer mill, grinding mill or jet mill.
In the aforementioned method, the tableting can be direct tableting, wet granulation tableting or dry granulation tableting.
The present invention also provides a method for controlling the dissolution rate of the nitroxoline solid tablet, comprising the steps of pulverizing the active ingredient nitroxoline and controlling the particle size D90 of nitroxoline to be 10 to 100 p.m to prepare the nitroxoline solid tablet, wherein the cumulative dissolution rate of the nitroxoline solid tablet at 60 min is not less than 75%.
Regarding the terms not defined herein, they have the meanings commonly understood by those skilled in the art. Regarding the terms defined herein, they have the meanings defined in the description.
The term “D90” herein is an expression of particle size, which refers to the particle size corresponding to the cumulative particle size distribution of a sample reaching 90%;
the term “D50” is an expression of particle size, which refers to the particle size corresponding to the cumulative particle size distribution of a sample reaching 50%;
and the term “D10” is an expression of particle size, which refers to the particle size corresponding to the cumulative particle size distribution of a sample reaching 10%. The term “optional” or “optionally” herein means that the event or circumstance described subsequently can, but need not, occur, and such a description includes the situation in which the event or circumstance does or does not occur.
The term “subject” refers to an animal, preferably a mammal. According to specific embodiments, the subject is a mammal including, for example, a camel, donkey, zebra, cow, pig, horse, goat, sheep, cat, dog, rat, rabbit, guinea pig, mouse, primate (for example, human). In some specific embodiments, the subject is a human. In some specific embodiments, the subject is a person who is susceptible to, suspected of suffering from, or has suffered from cancer, such as bladder cancer.
The term “treating” refers to eliminating a disease, stopping disease progression, slowing disease progression, reducing the duration of one or more symptoms associated with a disease, improving or reversing at least one measurable parameter associated with a disease, or increasing the survival rate of a subject suffering from a disease.
The term “effective amount” refers to the amount of active pharmaceutical ingredient that elicits the desired effect in a subject. In specific embodiments, those skilled in the art can determine an effective amount based on consideration of a variety of factors (for example, via clinical trials), the factors include the disease to be treated, the symptoms involved, administration route, the severity of the disease, the body weight of the patient, the immune status of the patient, and other factors known to those of skill in the art. Effective amount can be obtained from the dose-response curve derived from an animal model test system, and can be determined according to the judgment of the practitioner and each patient's circumstances. The interrelationship of dosing between animal and human is described in Freireich et al., 1966, Cancer Chemother Rep 50: 219, and the human body surface area can be approximately determined from the height and body weight of the patient. The effective amount of the active pharmaceutical ingredient of the present invention can vary from 300 mg to 1500 mg/day, and can be administered once a day or several times a day.
The progressive effects of the present invention are that: The pharmaceutical composition of nitroxoline or a salt thereof with specific particle size of the present invention can be prepared into nitroxoline tablets with a moderate dissolution rate (the dissolution rate within 60 min is more than 75%). In addition, the resulting nitroxoline tablets have uniform content, narrow variation range in hardness, and good fluidity and compressibility.
The nitroxoline with specific particle size of the present invention is beneficial to the preparation of pharmaceutical formulation, and can further control the dissolution and absorption of the active pharmaceutical ingredient of the pharmaceutical composition in body. The obtained nitroxoline tablet is rapidly absorbed after oral administration (Tmax=1.5 to 2.5 hours), and has high absorption rate (bioavailability is over 80%).
The present invention is further described below by the examples, but the present invention is not limited to the scope of the examples. The experimental methods without specific conditions in the following examples were carried out according to conventional methods and conditions, or according to the product description. Known reagents, solvents and materials in the examples can be synthesized using or according to methods known in the art, or are commercially available.
I. Experimental reagents:
Nitroxoline: synthesized from the starting material 8-hydroxyquinoline through nitrosation and oxidation in two steps by reference to literatures “Chemistry of Heterocyclic Compounds (New York, N.Y., United States), 41(8), 1027-1030; 2005” and “International Journal of ChemTech Research, 2(1), 209-213; 2010”;
Nitroxoline lysine salt: prepared according to the method provided in the patent document (CN105228984A);
Starch: Liaoning Dongyuan Pharmaceutical Co., Ltd. or Roquette, France;
Pregelatinized starch: Shanghai Colorcon or Asahi Kasei, Japan;
Microcrystalline cellulose: Dupont, USA or Mingtai Chemical Co., Ltd., Taiwan, China;
Hydroxypropyl methylcellulose: Dow, USA or Shin-Etsu, Japan;
Polyvinylpyrrolidone: BASF, Germany or ISP, USA;
Lactose: Foremost Farms or Kerry, USA;
Hydroxypropyl cellulose: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Shin-Etsu, Japan;
Sodium stearyl fumarate: Jiangxi Alpha Hi-tech Pharmaceutical CO., Ltd. or Rettenmaier, Germany;
Low-substituted hydroxypropyl cellulose: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Shin-Etsu, Japan;
Sodium stearyl fumarate: Jiangxi Alpha Hi-tech Pharmaceutical CO., Ltd. or Rettenmaier, Germany;
Sodium dodecyl sulfate: Hunan Jiudian Pharmaceutical Co., Ltd. or BASF, Germany;
Silica: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Evonik, Germany;
Magnesium stearate: Huzhou Zhanwang Pharmaceutical Co., Ltd. or Peter Greven, Germany;
Crospovidone: Chongqing Star-Tech & JRS Specialty Products Co., Ltd. or ISP, USA.
II. Experimental Instruments:
Mechanical mill: SF-130, Taizhou Tiantai Pharmacy Machinery Factory;
Jet mill: Mini-AJM, Shenzhen Xinyite Technology Co., Ltd.;
Malvern laser particle size analyzer: MS2000, Malvern;
Tableting machine: Shanghai Tianfan Machinery Factory, TDP-6;
Coating machine: BY-300B water chestnut type, Taizhou Jintai Pharmaceutical Machinery Factory;
High shear wet granulator: G10, Shenzhen Xinyite Technology Co., Ltd.;
Fluidized bed: WBF-3G, Chongqing Enger Granulating & Coating Technology Co., Ltd.;
Oven: DHG-9240A, Shanghai Bluepard Instruments Co., Ltd.
III. Processing Method of Raw Materials
The initial particle size D90 of the raw material nitroxoline or nitroxoline lysine salt was more than 100 μm. The raw material was pulverized with the mechanical mill to obtain the raw material having the particle size I, II, III or V in the following Table 1. The raw material was pulverized with the jet mill to obtain the raw material having the particle size IV in the following Table 1.
IV. Determination Method for Particle Size
Determination was carried out on the Malvern laser particle size analyzer MS2000 by wet method according to the operation requirements of the instrument, the dispersant was an aqueous Tween 80 solution, and the mass fraction of Tween 80 in the aqueous solution was 0.5%. The results are shown in Table 1 below.
Example 1 Preparation Example I of Nitroxoline Tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline raw material (batch I, 200 g), starch (64 g), lactose (60 g), polyvinylpyrrolidone (16 g, formulated into a solution by adding 64 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%).
The dried granules were subjected to dry milling, followed by the addition of sodium stearyl fumarate (5 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 13%. The coated nitroxoline tablets were thus prepared.
Example 2 Preparation example II of nitroxoline tablets The materials were weighed according to the following proportions:
Specifically, nitroxoline raw material (batch II, 200 g), starch (60 g), lactose (50 g), starch (5 g, formulated into 5% starch pulp by adding 95 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the oven (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (8 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 11%. The coated nitroxoline tablets were thus prepared.
Example 3 Preparation Example III of Nitroxoline Tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline raw material (batch III, 200 g), starch (60 g), lactose (50 g), starch (4 g, formulated into 5% starch pulp by adding 76 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed or oven (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (8 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 9%. The coated nitroxoline tablets were thus prepared.
Example 4 Preparation Example IV of Nitroxoline Tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline raw material (batch IV, 200 g), microcrystalline cellulose (60 g), lactose (50 g), starch (3 g, formulated into 5% starch pulp) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (8 g) was, and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 10%. The coated nitroxoline tablets were thus prepared.
Example 5 Preparation Example V of Nitroxoline Tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline lysine salt (batch V, 200 g), microcrystalline cellulose (280 g), lactose (240 g), hydroxypropyl methylcellulose (10 g, formulated into a solution by adding 115 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s ilica (10 g) and magnesium stearate (8 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ10 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (96 g, formulated into a solution by adding 504 g of water), and the weight gain was 8%. The coated nitroxoline tablets were thus prepared.
Example 6 Preparation example VI of nitroxoline tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline (batch I, 100 g), starch (150 g) and lactose (130 g) were weighed respectively, and added together with an appropriate amount of water into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (10 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (64 g, formulated into a solution by adding 336 g of water), and the weight gain was 11%. The coated nitroxoline tablets were thus prepared.
Example 7 Preparation Example VII of Nitroxoline Tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline (batch I, 150 g), starch (45 g), lactose (30 g), starch (3 g, formulated into 5% starch pulp by adding 57 g of water) and low substituted hydroxypropyl cellulose (10 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material e was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (10 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (32 g, formulated into a solution by adding 168 g of water), and the weight gain was 3%. The coated nitroxoline tablets were thus prepared.
Example 8 Preparation Example VIII of Nitroxoline Tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline (batch I, 120 g), starch (60 g), lactose (60 g), starch (2.4 g, formulated into 5% starch pulp by adding 45.6 g of water) and low substituted hydroxypropyl cellulose (30 g) were weighed respectively, and added into the high shear wet granulator for granulation. The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (6 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (40 g, formulated into a solution by adding 210 g of water), and the weight gain was 5%. The coated nitroxoline tablets were thus prepared.
Example 9 Preparation Example IX of Nitroxoline Tablets
The materials were weighed according to the following proportions:
Specifically, nitroxoline (batch I, 130 g), starch (65 g), lactose (65 g), starch (2.5 g, formulated into 5% starch pulp by adding 47.5 g of water) and crospovidone (15.6 g) were weighed respectively, and added into the high shear wet granulator for granulation.
The resulting soft material was subjected to wet milling, and dried with the fluidized bed (the moisture was controlled to 2-5%). The dried granules were subjected to dry milling, followed by the addition of s odium dodecyl sulfate (5.2 g), and mixed for 10 min to obtain the total mixed granules. The total mixed granules were tableted by the tableting machine (φ6.58.5 mm). The resulting tablets were coated by the coating machine with hydroxypropyl methylcellulose as a film coating powder (60 g, formulated into a solution by adding 315 g of water), and the weight gain was 15%. The coated nitroxoline tablets were thus prepared.
Experimental Example 1 Content and Weight Difference Assay of the Nitroxoline Tablets of the Present Invention
The active pharmaceutical ingredient (nitroxoline) content in the nitroxoline tablets was determined according to high performance liquid chromatography (general rule 0512 of volume IV of the Chinese Pharmacopoeia 2015 Edition).
Content % refers to the ratio of the average content to the theoretical amount of the active pharmaceutical ingredient in each tablet.
The tablet weight difference % was calculated as follows: 20 tablets were randomly selected and weighed, and the average value was calculated; each tablet was weighed separately, and the percentage ratio of the difference between the weight of each tablet and the average value to the average value was calculated.
The content and weight difference of the nitroxoline tablets of the present invention are shown in Table 2 below.
Conclusion: All results meet the requirements of Chinese Pharmacopoeia.
Experimental Example 2 Dissolution Rate Test of the Nitroxoline Tablets of the Present Invention
The nitroxoline tablets prepared in Example 1 to 4 were used. The operation was conducted in accordance with the test method of dissolution rate and release rate (general rule 0931 of volume IV of the Chinese Pharmacopoeia 2015 Edition), 1000 mL of 0.1 mol/L hydrochloric acid solution was used as the dissolution medium, the rotation speed was 60 revolutions per minute. At 60 minutes, the solution was taken and filtered through a membrane filter. 2 mL of the resulting filtrate was added into a 10 mL volumetric flask, and diluted with 0.1 mol/L hydrochloric acid solution until the liquid level reached the mark. The resulting solution was shaked well, and used as the test solution. An appropriate amount of nitroxoline reference substance was accurately weighed, dissolved in 0.1 mol/L hydrochloric acid solution, and quantitatively diluted to prepare a solution containing about 10 μg of nitroxoline per milliliter, as the reference substance solution. According to UV-visible spectrophotometry (general rule 0401 of volume IV of the Chinese Pharmacopoeia 2015 Edition) (UV-2700, Shimadzu), the absorbance was measured at a wavelength of 369 nm, and the dissolution rate of each tablet was calculated.
The dissolution profile of the nitroxoline tablets prepared in Examples 1 to 4 is shown in
Nitroxoline belongs to BCS class II drugs, which have low solubility and high permeability. Generally, in formulations containing this type of drugs, the smaller the particle size of the drug, the faster the dissolution of the formulation. However, the inventors unexpectedly found that the smaller the particle size of nitroxoline, the slower the dissolution of the formulation. As can be seen from
Experimental Example 3 Hardness test of the nitroxoline tablets of the present invention
The drug was placed into a hardness tester (SY-3, Yellow Sea) according to the operation requirements, and subjected to hardness test. 10 tablets were measured each time, that is, serial numbers 1 to 10. The hardness of the nitroxoline tablets prepared in Examples 1 to 4 is shown in Table 3 below.
It can be seen from the results of hardness test in the table above that the hardness of the products of Examples 1 to 4 is within the expected range, and the variation range of hardness is narrow.
Experimental Example 4 Fluidity test and compressibility test In this experiment, the fluidity of the particles was evaluated by measuring the Carr Index of the mixed particles, and the compressibility of the particles was evaluated by the Hsusner Ratio.
Carr Index refers to the percentage difference between the tap density and the bulk density of the particles. <10% indicates fairly excellent fluidity, 11 to 15% indicates excellent fluidity, 16 to 20% indicates good fluidity, 21 to 25% indicates passable fluidity, 26 to 31% indicates poor fluidity, and above 32% indicates very poor fluidity.
Hsusner Ratio refers to the ratio of the tap density to the bulk density of the particles. 1.00 to 1.11 indicates fairly excellent compressibility, 1.12 to 1.18 indicates excellent compressibility, 1.19 to 1.25 indicates good compressibility, 1.26 to 1.34 indicates passable fluidity, 1.35 to 1.45 indicates poor fluidity, and 1.46 to 1.59 indicates very poor fluidity.
Test method of the bulk density: About 20 g of the granules were weighed, and slowly added into a 100 mL measuring cylinder. The measuring cylinder was initially inclined, and slowly placed upright after the addition, vibration should be avoided during the process. The volume was read, and the bulk density was obtained by dividing the particle weight by the bulk volume.
Test method of the tap density: After the bulk density test, the measuring cylinder was placed on a tapping instrument, and tapped for 500 times. The volume value was read, and the tap density was obtained by dividing the particle weight by the tap volume.
Before tableting, the total mixed granules of Examples 1 to 4 were taken and tested as described above. The resulting Carr Index and Hsusner Ratio are shown in Table 4 below.
It can be seen from Table 4 above that the Carr Indexes of the nitroxoline total mixed particles of the present invention are all less than 25%, indicating that the particles have good fluidity. Moreover, the Hsusner Ratios of the nitroxoline total mixed particles of the present invention are less than 1.25, indicating that the compressibility of the particles is good or better.
In summary, the pharmaceutical composition of nitroxoline or a salt thereof with specific particle size provided in the present invention allows the resulting nitroxoline tablets to have a moderate dissolution rate (the dissolution rate within 60 min is more than 75%), uniform content, narrow variation range in hardness, and good fluidity and compressibility. Moreover, the nitroxoline tablets are not only conducive to the absorption of active pharmaceutical ingredients in the body, but also have a simple preparation process that is suitable for industrial production.
Although the specific embodiments of the present invention are described above, those skilled in the art should understand that those are only for illustration, and the protection scope of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principle and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 201911405993.X | Dec 2019 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2020/141424 | 12/30/2020 | WO |
