Patent Application
20240269127
The present invention specifically relates to a quinoline compound sustained-release tablet and a preparation method therefor, and belongs to the pharmaceutical field.
Quinoline compounds are the inhibitors of urate anion transporter 1 (URAT1), which are self-developed by Hinova Pharmaceuticals Inc., possessing independent intellectual property rights (currently, 8 invention patents have been applied), and used for the treatment of hyperuricemia and gout. The active ingredients of quinoline compound sustained-release tablets are quinoline compounds, having a structure represented by formula I:
Application number: CN201611109936.3, invention name: Quinoline compounds, preparation method thereof, and use thereof as urate transporter inhibitor drug.
According to the PK test results of the drug in rats (
The object of the present invention is to provide a quinoline compound sustained-release tablet and a preparation method therefor. In the present invention, the concept of sustained-release formulations is used in the development of the compound preparations, with the development goal of administrating once a day, effectively reducing Cmax while maintaining AUC unchanged. The determined formulation is fully released within 12-20 h, improves drug compliance, reduces the incidence of adverse reactions, and increases drug stability.
The present invention provides a quinoline compound sustained-release tablet, which contains the following raw and auxiliary materials in parts by weight:
Further, the filler is lactose and/or microcrystalline cellulose, and preferably, the filler is composed of lactose and microcrystalline cellulose at a mass ratio of 10-30:2-10; the sustained-release material is hydroxypropyl methylcellulose; the lubricant includes but is not limited to magnesium stearate, sodium fumarate, glyceryl behenate, and/or stearic acid.
More further, said lactose includes but is not limited to lactose monohydrate, anhydrous lactose, and/or lactose with different particle sizes; said microcrystalline cellulose includes but is not limited to microcrystalline cellulose PH101, PH102, PH301, and/or PH302; said hydroxypropyl methylcellulose includes but is not limited to hydroxypropyl methylcellulose K4M, K100LV, and/or K750; and said lubricant is magnesium stearate.
More further, the sustained-release tablet comprises the following raw and auxiliary materials in parts by weight:
Further, the quinoline compound is a compound as represented by formula I, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof;
wherein:
More further, the quinoline compound is 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid and/or an optical isomer, a solvate, a pharmaceutically acceptable salt, and a prodrug thereof; the structure of said 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid is as follows:
More further, the quinoline compound is crystalline form I, crystalline form II and/or a sodium salt crystalline form of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid. The X-ray powder diffraction pattern is generally obtained when the compound or its salt is irradiated with a Cu-Kα light source.
More further, there are characteristic peaks where diffraction angles 2θ are 6.5±0.2°, 13.6±0.2°, 14.1±0.2°, 17.7±0.2°, 21.8±0.2°, 22.0±0.2°, 22.8±0.2°, 23.2±0.2°, 24.3±0.2°, 26.8±0.2°, and 27.4±0.2° in the X-ray powder diffraction pattern of the crystalline form I of 2-[4-(6-bromoquinolyl)thio]-2-ethylbutyric acid.
More further, the relative intensity of the characteristic peak is:
More further, there are characteristic peaks where diffraction angles 2θ are 7.9±0.2°, 9.5±0.2°, 15.9±0.2°, 18.2±0.2°, 19.1±0.2°, 23.9±0.2°, and 26.1±0.2° in the X-ray powder diffraction pattern of the crystalline form II of 2-[4-(6-bromoquinolyl)thio]-2-ethylbutyric acid.
More further, the relative intensity of the characteristic peak is:
More further, there are characteristic peaks where diffraction angles 2θ are 6.1±0.2°, 10.5±0.2°, 12.0±0.2°, 14.1±0.2°, 15.9±0.2°, 18.0±0.2°, 21.7±0.2°, 27.6±0.2°, 32.0±0.2°, 33.8±0.2°, and 36.4±0.2° in the X-ray powder diffraction pattern of the sodium salt crystalline form of 2-[4-(6-bromoquinolyl)thio]-2-ethylbutyric acid.
More further, the relative intensity of the characteristic peak is:
The present invention also provides a method for preparation of the sustained-release tablet mentioned above, and the preparation of crystalline form I of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid comprises the following steps:
The present invention also provides a method for preparation of the sustained-release tablet mentioned above, and the preparation of crystalline form II of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid comprises the following steps:
The present invention also provides a method for preparation of the sustained-release tablet mentioned above, and the preparation of said sodium salt crystalline form of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid comprises the following steps:
The present invention also provides a method for preparation of the quinoline compound sustained-release tablet mentioned above, which is prepared using wet granulation, dry granulation, direct powder compression or membrane controlled-release techniques, and preferably wet granulation.
Further, the wet granulation comprises the following steps:
More further, in step b, ⅓ of the pre-determined amount of lactose in the formula is placed in a wet granulator, stirred for 5 min, and then ⅓ of the pre-determined amount of lactose and ½ of the pre-determined amount of quinoline compound are added and stirred for 5 min. Finally, the remaining amounts of lactose and quinoline compounds are added, and stirred for 5 min. Then, microcrystalline cellulose and hydroxypropyl methylcellulose are added and stirred for 10 min.
More further, in step c, the granulation process involves passing through a 20-mesh sieve, the drying is carried out at 60° C., and the sorting is performed with a 20-mesh sieve; and/or, in step d, the tablet is coated at a weight gain of 2-4%.
The present invention also provides a crystalline form of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid, which is crystalline form I of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid, and there are characteristic peaks where diffraction angles 2θ are 6.5±0.2°, 13.6±0.2°, 14.1±0.2°, 17.7±0.2°, 21.8±0.2°, 22.0-0.2°, 22.8-0.2°, 23.2=0.2°, 24.3=0.2°, 26.8=0.2°, and 27.4±0.2° in the X-ray powder diffraction pattern thereof.
Further, the relative intensity of the characteristic peaks is:
The present invention also provides a crystalline form of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid, which is crystalline form II of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid, and there are characteristic peaks where diffraction angles 2θ are 7.9±0.2°, 9.5±0.2°, 15.9±0.2°, 18.2±0.2°, 19.1±0.2°, 23.9±0.2°, and 26.1±0.2° in the X-ray powder diffraction pattern thereof.
Further, the relative intensity of the characteristic peaks is:
The present invention also provides a crystalline form of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid, which is the sodium salt crystalline form of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid, and there are characteristic peaks where diffraction angles are 6.1±0.2°, 10.5±0.2°, 12.0±0.2°, 14.1±0.2°, 15.9±0.2°, 18.0±0.2°, 21.7±0.2°, 27.6±0.2°, 32.0±0.2°, 33.8±0.2°, and 36.4±0.2° in the X-ray powder diffraction pattern thereof.
Further, the relative intensity of the characteristic peaks is:
Another aspect provides a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned crystalline Form 1, crystalline Form 1, or their respective pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the sodium salt crystalline form of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid as defined above.
The present invention has the following advantages:
Obviously, based on the above content of the present invention, according to the common technical knowledge and the conventional means in the field, other various modifications, alternations, or changes can further be made, without department from the above basic technical spirits.
With reference to the following specific examples, the above content of the present invention is further illustrated. But it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples. The techniques realized based on the above content of the present invention are all within the scope of the present invention.
Various embodiments of this patent document provide crystalline forms of a quinoline compound, dosage forms the quinoline compound, methods of preparation thereof, and method of treating diseases with the dosage form.
Although the following contents may refer to or exemplify a specific embodiment of a dosage form, they are not limited to the specified ranges of the dosage form. In view of practicality and economy considerations, a person skilled in the art can make various modifications to, e.g., the amount of active ingredient and the dosage regimen of the dosage form for treating diseases or disorders.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the field of the present invention. In case of conflict, the definitions provided in the application prevail.
The term “a”, “an” or “the” as used herein means “one or more” or “at least one”. That is, reference to any element or composition of the present invention by “a”, “an” or “the” does not exclude the possibility of the presence of a plurality of the elements and compositions. The term “extended release” or “ER” as used herein refers to extended release of an active pharmaceutical ingredient over an extended period of time, which is longer than about 2 hours, preferably longer than about 4 hours, more preferably longer than about 8 hours, more preferably longer than about 12 hours, more preferably longer than about 16 hours, or up to longer than about 24 hours.
The term “immediate release” or “IR” as used herein refers to release of more than or equal to about 80% of an active pharmaceutical ingredient in less than or equal to about 1 hour. Typically, more than or equal to about 85% or more than or equal to about 90% of an active pharmaceutical ingredient in an immediate release dosage form is released in less than or equal to about 1 hour, wherein the dissolution is determined using a USP type 1 dissolution system (Basket Apparatus) at 100 rpm and a temperature of 37±0.5° C. in a dissolution medium of 900 ml phosphate buffer solution at a pH of 6.8.
The term “pharmaceutically acceptable salts” means salts of compounds disclosed herein which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Non-limiting examples of such salts include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Non-limiting examples of acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Non-limiting examples of acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).
The term “subject” refers to a mammal, and can be an animal or a human.
The term “treating” or “treatment” of any disease or condition refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In some embodiments “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In some embodiments, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In some embodiments, “treating” or “treatment” refers to delaying the onset of the disease or disorder, or even preventing the same. “Prophylactic treatment” is to be construed as any mode of treatment that is used to prevent progression of the disease or is used for precautionary purpose for persons at risk of developing the condition.
An aspect of the patent document provides an extended release dosage form, which comprises:
The amount of the active ingredient in the dosage form, in some embodiments, ranges from about 1 to about 100, from about 1 to about 50, from about 1 to about 40, from about 1 to about 25, from about 1 to about 20, or from about 1 to about 10 mg. Nonlimiting examples of the amount of the active ingredient include about 1, about 2, about 5, about 8, about 10, about 15, about 20, about 25, about 30, about 40, about 50 mg, and any range between any two of the aforementioned values.
The dosage form may be in any suitable shape or configuration. Nonlimiting examples include pellets, balls, granules, globules, and tablets.
To achieve a desirable extended release, the active ingredient may be mixed with the extended release excipient, coated by the extended release excipient, or both. In some embodiments, the dosage form is a tablet with an extended release matrix, which is optionally coated with additional extended release excipient. In some embodiments, the dosage form is a tablet with the active ingredient being coasted with a layer of extended release excipient.
In some embodiments, the compound is
In some embodiments, the extended release excipient and its amount are selected that a single dose (administered once a day) of the dosage form at steady state provides a first Cmax ranging from about 50% to about 95%, from about 60% to about 85%, from about 70% to about 80% or from about 60% to about 80% of a second first Cmax from a single dose (administered once a day) of an immediate release dosage form at steady state. Nonlimiting examples of the first Cmax relative to the second Cmax include about 50%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, and any range between any two of the aforementioned values.
In some embodiments, the extended release excipient and its amount are selected so that a single dose of the dosage form at steady state provides a first AUC ranging from about 70% to about 130%, from about 80% to about 120%, from about 90% to about 110% of a second first AUC from a single dose of the immediate release dosage form at steady state. Nonlimiting examples of the first AUC relative to the second AUC include about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, and any range between any two of the aforementioned values.
In some embodiments, the active ingredient and the extended release excipient are in a ratio ranging from about 1:60 to about 1:5, from about 1:50 to about 1:10, from about 1:40 to about 1:20, or from about 1:40 to about 1:15 by weight. Nonlimiting examples of the ratio between the active ingredient and the extended release excipient include about 1:60, about 1:50, about 1:40, about 1:30, about 1:20, about 1:10, and any range between any two of the aforementioned values.
In some embodiments, the extended release excipient comprises HPMC. In some embodiments, the HPMC has a viscosity ranging from about 400 to about 1500, from about 400 to about 1200, from about 500 to about 1200, from about 500 to about 1100, or from about 600 to about 1000 millipascal seconds (mPa's) at room temperature when tested at a 2% concentration in a water solution. Unless otherwise specified, the viscosity of HPMC is tested at 2% concentration in a water solution.
In some embodiments, the extended release excipient comprises a high viscosity HPMC and a low viscosity HPMC. In some embodiments, the high viscosity HPMC has a viscosity ranging from about 2200 to about 6000, from about 2400 to about 5500, from about 2500 to about 5200, from about 2700 to about 5000, or from about 3000 to about 5000 mPa·s. In some embodiments, the low viscosity HPMC has a viscosity ranging from about 400 to about 1500, from about 400 to about 1300, from about 500 to about 1200, from about 500 to about 1000 mPa·s. In some embodiments, the ratio between the high viscosity HPMC and the low viscosity HPMC ranges from about 40:60 to about 60:40, from about 45:55 to about 65:35, from about 45:55 to about 55:45 by weight.
In some embodiments, the dosage form further comprises a filler comprising lactose monohydrate and microcrystalline cellulose. In some embodiments, the ratio between lactose monohydrate and microcrystalline cellulose ranges from about 10:1 to about 1:5, from about 10:1 to about 1:2, from about 10:1 to about 1:1, from about 10:1 to about 2:1, from about 10:1 to about 4:1, from about 10:1 to about 5:1, from about 10:1 to about 6:1, from about 10:1 to about 7:1, or from about 9:1 to about 6:1. In some embodiments, microcrystalline cellulose may be in various size ranging from about 30 μm to about 80 μm, from about 40 μm to about 80 μm, from about 40 μm to about 70 μm, from about 40 μm to about 60 μm, from about 45 μm to about 5 μm. Microcrystalline cellulose such as Avicel PH101 can be obtained from commercial sources.
In some embodiments, the dosage form is configured and the extended release excipient and its amount are selected so that when the dissolution profile is determined using a USP type 1 dissolution system (Basket Apparatus) at 100 rpm and a temperature of 37±0.5° C. in a dissolution medium of 900 ml phosphate buffer solution at a pH of 6.8, the active ingredient in the extended release dosage form has one or more or all of the following in vitro dissolution characteristics:
In some embodiments, the dosage form has any one, two, three, four, five, six, seven or eight of the above dissolution characteristics. In some embodiments, the pharmaceutical composition or dosage form provides the dissolution of the active ingredient having the above (a). In some embodiments, the pharmaceutical composition or dosage form provides the dissolution of the active ingredient having the above (a) and (b). In some embodiments, the pharmaceutical composition or dosage form provides the dissolution of the active ingredient having the above (a), (b) and (e). In some embodiments, the pharmaceutical composition or dosage form provides the dissolution of the active ingredient having the above (a), (b), (f) and (i). In some embodiments, the pharmaceutical composition or dosage form provides the dissolution of the active ingredient having the above (a), (b), (f), (g) and (h). In some embodiments, the pharmaceutical composition or dosage form provides the dissolution of the active ingredient having the above (a), (b), (f), (g) and (i). In some embodiments, the pharmaceutical composition or dosage form provides the dissolution of the active ingredient having the above (a), (b), (f), (g), (h), and (i).
Another aspect provides a method of treating a disease in subject, comprising administering to the subject a dosage form disclosed herein. In some embodiments, the disease is selected from gout, gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular diseases, coronary artery disease, Lesch-Nyhan syndrome, Kearns-Sayre Syndrome, nephropathy, kidney stone, renal failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, and sarcoidosis or hypoxanthine-guanine phosphoribosyl transferase deficiency disease. In some embodiments, the dosage form is administer prophylactically.
59.2 kg of anhydrous methanol was added to a tank reactor, and then stirred. The reaction system was heated to reflux, to which was added 1135 g of crude 2-[4-(6-bromoquinolyl)thio]-2-ethylbutyric acid, and then heated to 65-70° C. to dissolve; the resultant solution was filtered to remove insoluble substances, and then the filtrate was transferred to the tank reactor, followed by heating the reaction system to 65-70° C. to dissolve and allowing the solution to become clear. The heating was turned off, and the solution was naturally cooled for crystallization for 20-24 h. The temperature of the reaction system was controlled to be 15-20° C., and the system was stirred for crystallizing for 2 h. The system was filtered and dried to obtain the product crystalline form I of compound 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid as off-white to white crystalline granules;
XRD, DSC, TGA, and PLM spectra of crystalline form I are shown in
About 10 mg of crude 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid was added to 0.7 mL of tetrahydrofuran and 0.4 mL of dichloromethane, and then the solution was allowed to dissolve and become clear, followed by filtering. The filtrate was placed in a fume hood, and evaporated in an open state at room temperature to obtain the product of crystalline form II of 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid;
XRD, DSC, TGA, and PLM spectra of crystalline form II are shown in
About 300 mg of crude 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid was added into 12 mL of water, and then stirred, to which was added 1 mol/L of NaOH aqueous solution dropwise to pH 12. The sample was allowed to precipitate under stirring. After stirring for additional 3 min, the solution was filtered and dried overnight in vacuum, to obtain the sodium salt crystalline form of compound 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid;
XRD, DSC, and TGA spectra of sodium salt crystalline form are shown in
Formula: 5 g of crystalline form I of compound 2-[4-(6-bromoquinolyl)-thio]-2-ethylbutyric acid prepared in Example 1, 226.1 g of lactose monohydrate, 30 g of microcrystalline cellulose PH101, 57 g of hydroxypropyl methylcellulose K4M (HPMC K4M), 60 g of hydroxypropyl methylcellulose K100LV (HPMC K100LV), and 1.9 g of magnesium stearate.
Preparation method:
The beneficial effects of the present invention were further demonstrated by reference to the following Experimental examples:
Medium: pH 6.8 phosphate buffer Rolling basket method: 100 RPM
The release rates of 3 tablet samples for each formula were tested, and then the average value was calculated. Samples were taken at 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 16 h, 20 h, and 24 h, and subjected to HPLC analysis to obtain the release curve.
The results indicated that the tablets prepared with sustained-release material HPC HXF had no delayed-release effect in a medium at pH 6.8, with a release rate of over 90% after 1 h. The tablets comprising slow-release materials HPMC K4M at a ratio of 30% and 40% released slowly in the medium at pH 6.8, with a release rate of less than 90% after 24 h. The release rate of the tablets comprising 30% and 40% of sustained-release materials HPMC K750 was moderate, with a release rate of over 95% after 16-20 hours.
Medium: pH 6.8 phosphate buffer Rolling basket method: 100 RPM
For each plain or coated tablet, the release rates of 3 tablet samples were tested, and then the average value was calculated. Samples were taken at 1 h, 2 h, 4 h, 16 h, 20 h, and 24 h, and subjected to HPLC analysis to obtain the release curve.
See Table 4 and
According to the data in Table 4 and
According to the formula of batch 17050401, the amounts were increased to 1000 tablets, and then 18071003 batch samples were produced and subjected to PK testing in beagle dogs. The experimental design was as follows:
The experiment was divided into two stages, and 6 beagles were included, with half male and half female. In the first stage, the experimental animals were orally administered the suspension of active ingredients at a single dose of 5 mg/kg, in which the vehicle was 0.5% sodium carboxymethyl cellulose (0.5% CMC-Na) aqueous solution. After a 7-day washout period, in the second stage, the same experimental animals were orally administered 10 quinoline compound sustained-release tablets (specification 5 mg) once. All animals were fasted overnight before administration and resumed feeding approximately 4 h after administration. 75 mL of KCl-HCl buffer was administered via a gastric tube 15 min before administration. Plasma samples of animals were collected prior to administration as well as at 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, and 48 h after administration. The concentration of quinoline compounds in plasma samples was determined by the validated LC-MS/MS method. The in vivo experimental results in beagle dogs administered with 5 mg/kg of suspension and 5 mg of tablets are shown in Table 5 and
The experimental results showed that under the conditions of ensuring similar AUC, the Cmax of sustained-release tablets was significantly reduced by nearly 25%, that could effectively prevent the incidence of adverse reactions caused by excessive plasma concentrations.
Since HPMC K750, used as a sustained-release material in the tablet formulation, was found to account for a large proportion in the scale-up production, the wear resistance of the tablets during coating was insufficient, the yield was low, and the process compliance decreased. Thus, HPMC K750 was substituted with a mixture of HPMC K4M and K100LV, that not only overcame the problems in the preparation process of tablets, but also obtained the same extended-release effect and pharmacokinetic parameters as those of slow-release tablets in which HPMC K750 was used as sustained-release materials. Therefore, stability studies were carried out on tablet formulations using HPMC K4M and K100LV as sustained-release materials in the subsequent experiment.
See Table 6.
The results indicated that the extended-release effects of the tablets using HPMC K4M and K100LV as sustained-release materials are consistent with those using HPMC K750 as sustained-release materials. In both accelerated and long-term experiments, there was no growth trend in the substances related to the sustained-release tablets of the present invention, and the release curve remained stable and unchanged, demonstrating that the product was stable.
This application is a continuation-in-part of International Patent Application No. PCT/CN2021/119132, filed on Sep. 17, 2021, the disclosure of which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/CN2021/119132 | Sep 2021 | WO |
| Child | 18608261 | US |
