A compound drug substance, pharmaceutical compositions thereof and uses thereof

Abstract

The present application provides a 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound bulk drug, wherein the particle size D90 of the compound bulk drug is 70-5 μm. The present application also provides a composition comprising the bulk drug and an excipient. The bulk drug or the composition is used in the preparation of a drug for promoting the excretion of uric acid. The bulk drug of the present application can make the pharmaceutical composition comprising the same have better content uniformity and faster dissolution rate.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field. Specifically, it relates to compound active pharmaceutical ingredients, pharmaceutical compositions thereof, and their uses. Background Technology

[0002] Currently, the industry has discovered 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (hereinafter referred to as "dotenorazole"). Compared with existing uric acid excretion-promoting drugs, it has a more precise inhibitory effect on uric acid transporters, reduces interference with other transport proteins, and therefore has fewer side effects. Furthermore, it hardly affects intestinal uric acid excretion or renal tubular uric acid secretion function, avoiding the risk of urinary tract stones or kidney damage caused by excessive promotion of uric acid secretion.

[0003] In clinical studies, dotenoroxetine's AUC in different populations 0-inf The concentrations were 1209.38, 1424.76, 1797.95, and 1832.67 ng hr / mL, respectively, indicating different C values ​​among different population groups. max The values ​​were 93.30, 100.92, 112.07, and 116.15 ng / mL (Reference 1). Preliminary studies by technicians have revealed that, in order to achieve the desired AUC of domperidone in vivo... 0-inf For formulations with a concentration of 1200-1800 ng hr / mL, the corresponding formulation must achieve a cumulative dissolution of more than 60% over 2 hours under the following in vitro dissolution conditions: 900 ml water + paddle motion at 75 rpm, pH 4.5 acetate buffer + paddle motion at 75 rpm, and pH 6.8 phosphate buffer + paddle motion at 40 rpm, in order to be effective in humans.

[0004] The preparation of formulations based on the active pharmaceutical ingredients disclosed in the existing technology (References 2-4) is difficult to meet the above requirements, and the prepared formulations have large batch-to-batch differences in content.

[0005] Therefore, further research is needed on dotenoroxetine raw material and its pharmaceutical compositions.

[0006] Document 1: Nakatani H, Fushimi M, Sasaki T, Okui D, Ohashi T. Clinicalpharmacological study of dotinurad administered to male and female elderly or young subjects. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):8-16. doi: 10.1007 / s10157-019-01836-0. Epub 2019 Dec 30. PMID: 31889230; PMCID: PMC7066278; Reference 2: WO2021117697A1; Reference 3: CN102639518B; Reference 4: CN110914246B. Summary of the Invention

[0007] The present invention aims to solve at least one of the technical problems existing in the prior art.

[0008] In a first aspect of the present invention, a 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound active pharmaceutical ingredient is provided, characterized in that the particle size D90 of the active pharmaceutical ingredient is 70-5 μm.

[0009] In a second aspect of the invention, a pharmaceutical composition is provided comprising the active pharmaceutical ingredient of the compound of the first aspect of the invention, and an excipient; further, the excipient comprises one or more of a filler, a binder, a disintegrant, a lubricant, and a flow aid.

[0010] In a third aspect of the invention, a method for preparing the pharmaceutical composition of the invention is provided, comprising the following steps: (i) The 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound is pulverized to a specific particle size range. (ii) The excipient and the product of step (i) are mixed to form a composition, the mixture is granulated and sieved; (iii) Optionally, the particles obtained in step (ii) are mixed with an excipient other than that described in step (ii).

[0011] In a fourth aspect of the invention, the use of the compound active pharmaceutical ingredient or the pharmaceutical composition of the invention in the preparation of a medicament that promotes the excretion of uric acid is provided.

[0012] Through inventive research, this invention has discovered that the active pharmaceutical ingredient (API) of this invention enables the pharmaceutical composition containing it to have a high degree of content uniformity, thereby reducing the content difference between different tablets and improving medication safety; furthermore, the API of this invention enables the pharmaceutical composition containing it to have a faster dissolution rate, thereby improving drug bioavailability. Attached Figure Description

[0013] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood in conjunction with the following description of the accompanying drawings and embodiments, wherein: Figure 1 The particle size distribution of active pharmaceutical ingredient 1 is shown. Figure 2 The particle size distribution of active pharmaceutical ingredient 2 is shown. Figure 3 The particle size distribution of active pharmaceutical ingredient 3 is shown. Figure 4 The particle size distribution of active pharmaceutical ingredient 4 is shown. Figure 5 The particle size distribution of active pharmaceutical ingredient 7 is shown. Figure 6 The particle size distribution of active pharmaceutical ingredient 8 is shown. Figure 7 The particle size distribution of active pharmaceutical ingredient 9 is shown. Figure 8 The particle size distribution of active pharmaceutical ingredient 10 is shown. Figure 9 The particle size distribution of active pharmaceutical ingredient 11 is shown. Figure 10 The XRD patterns of active pharmaceutical ingredient 1, active pharmaceutical ingredient 9, and active pharmaceutical ingredient 13 and their pre-pulverization XRD patterns are shown. Figure 11 Images of the fluidized bed after drying during the formulation process are shown. Detailed Implementation

[0014] The embodiments of this application are described in detail below. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0015] The endpoints and any values ​​of the ranges disclosed in this application are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this application.

[0016] In this application, the terms "comprising" or "including" are open-ended expressions, meaning they include the content specified in this application but do not exclude other aspects.

[0017] In this application, the term "active drug substance" refers to the active pharmaceutical ingredient (API) used in the production of various formulations. It is the active ingredient (also known as the active component) in the formulation, prepared by chemical synthesis or biotechnology, and is a substance used as a medicine in the form of powder, crystals, etc., but which cannot be directly taken by the subject.

[0018] In this application, the term "excipient" refers to an excipient that does not cause significant irritation to an organism and does not impair the biological activity and properties of the given active ingredient (such as the active pharmaceutical ingredient described in this invention).

[0019] In this application, the term "particle size D90" refers to the particle size corresponding to 90% of the cumulative particle size distribution of a sample. Specifically, "particle size D90 of 70–5 μm" means that 90% of the particles have a particle size less than or equal to a specific value within the range of 70–5 μm. The term "particle size D50" refers to the particle size corresponding to 50% of the cumulative particle size distribution of a sample. Specifically, "D50 of 40–5 μm" means that 50% of the particles have a particle size less than or equal to a specific value within the range of 40–5 μm.

[0020] In this application, the particle size distribution, also known as the "SPAN value", refers to the value obtained by (particle size D90-D10) / D50, and the magnitude of the value represents the width or narrowness of the particle size distribution.

[0021] In this application, the term "relative standard deviation" or "RSD" refers to a measure of the accuracy of each measurement of uniformity of mixture or content, i.e., how much each individual value deviates from the total.

[0022] The present invention provides a 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound active pharmaceutical ingredient, characterized in that the particle size D90 of the active pharmaceutical ingredient is 70-5 μm.

[0023] According to embodiments of the present invention, the particle size D90 of the compound active pharmaceutical ingredient is 50–5 μm, preferably 36–5 μm, and more preferably 36–10 μm. Specifically, the particle size D90 of the compound active pharmaceutical ingredient is any one value or a range between any two values ​​selected from 50 μm, 45 μm, 40 μm, 36 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, or 5 μm.

[0024] According to embodiments of the present invention, the SPAN value of the compound active pharmaceutical ingredient is 0 to 7, preferably 1 to 6. Specifically, the SPAN value of the compound active pharmaceutical ingredient is any one or a range between any two values ​​from 1, 1.5, 2, 2.5, 2.8, 3, 3.5, 4.0, 4.2, 4.5, 4.8, 5, 5.5, 6, 6.5 or 7.

[0025] According to embodiments of the present invention, the particle size D90 of the compound active pharmaceutical ingredient is 36–5 μm, and the SPAN value is 1–7; preferably, the SPAN value is 1–6, and more preferably, the SPAN value is 1–5.

[0026] According to embodiments of the present invention, the particle size D90 of the compound active pharmaceutical ingredient is 36–10 μm, and the SPAN value is 1–7; preferably, the SPAN value is 1–6, and more preferably, the SPAN value is 1–5.

[0027] According to embodiments of the present invention, the particle size D50 of the compound active pharmaceutical ingredient is 20–1 μm, preferably 20–3 μm. Specifically, the particle size D50 of the compound active pharmaceutical ingredient is any one value or a range between any two values ​​selected from 20 μm, 19 μm, 18 μm, 17 μm, 16 μm, 15 μm, 14 μm, 13 μm, 12 μm, 11 μm, 10 μm, 9 μm, 8 μm, 7 μm, 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm.

[0028] According to embodiments of the present invention, the particle size D90 of the compound active pharmaceutical ingredient is 36–5 μm, and the particle size D50 of the compound active pharmaceutical ingredient is 20–1 μm. Preferably, the particle size D90 of the compound active pharmaceutical ingredient is 36–10 μm, and the particle size D50 of the compound active pharmaceutical ingredient is 20–3 μm.

[0029] According to an embodiment of the present invention, the compound active pharmaceutical ingredient has a crystal form of crystal form II, which has characteristic peaks at least at 15.0, 18.0, 22.6, 23.6 and 23.9 degrees in the diffraction angle (2θ) of powder X-ray diffraction.

[0030] According to an embodiment of the present invention, the crystal form of the compound active pharmaceutical ingredient is crystal form II, which has characteristic peaks at least at 10.6, 14.5, 16.8, 21.0, 27.3 and 29.4 degrees in the diffraction angle (2θ) of powder X-ray diffraction.

[0031] On the other hand, the present invention provides a composition, characterized in that the composition comprises a compound active pharmaceutical ingredient and an excipient as described in the first aspect.

[0032] According to embodiments of the present invention, the excipient includes one or more of fillers, binders, disintegrants, lubricants, and flow aids.

[0033] According to embodiments of the present invention, the excipient does not include solubilizers or surfactants.

[0034] According to an embodiment of the present invention, the filler is selected from one or more of sugar alcohols, cellulose derivatives and lactose hydrates; the cellulose derivative is microcrystalline cellulose, and the lactose hydrate is lactose monohydrate.

[0035] According to an embodiment of the present invention, the filler is selected from sugar alcohols, preferably D-mannitol.

[0036] According to an embodiment of the present invention, the disintegrant is selected from one or more of carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, crystalline cellulose, sodium carboxymethyl starch, corn starch, and talc; preferably, the disintegrant is carboxymethyl cellulose.

[0037] According to an embodiment of the present invention, the adhesive is selected from one or more of low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, partially pregelatinized starch, and pregelatinized starch; preferably, the adhesive is hydroxypropyl methylcellulose.

[0038] According to an embodiment of the present invention, the lubricant is selected from one or more of magnesium oxide, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose fatty acid ester, sodium stearoyl fumarate and talc; preferably, the lubricant is magnesium stearate.

[0039] According to embodiments of the present invention, the pharmaceutical composition is a solid dosage form, specifically, the solid dosage form includes tablets, capsules, powders, pills and / or granules.

[0040] According to embodiments of the present invention, in the pharmaceutical composition, the weight percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 5%-0.1%; preferably, the weight percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 2%-0.2%; more preferably, the weight percentage of the active pharmaceutical ingredient in the pharmaceutical composition is 1%-0.5%.

[0041] According to an embodiment of the present invention, in the pharmaceutical composition, the filler accounts for 70%-95% by weight; preferably, the filler accounts for 80%-95% by weight, and more preferably, the filler accounts for 85%-95% by weight.

[0042] According to embodiments of the present invention, in the pharmaceutical composition, the weight percentage of the disintegrant in the pharmaceutical composition is 10%-1%; preferably, the weight percentage of the disintegrant in the pharmaceutical composition is 8%-3%; more preferably, the weight percentage of the disintegrant in the pharmaceutical composition is 5%.

[0043] According to embodiments of the present invention, in the pharmaceutical composition, the adhesive accounts for 1%-5% by weight; preferably, the adhesive accounts for 2%-4% by weight; more preferably, the adhesive accounts for 3% by weight.

[0044] According to embodiments of the present invention, in the pharmaceutical composition, the weight percentage of the lubricant in the pharmaceutical composition is 0.1%-3%, preferably 0.25%-1%; more preferably, the weight percentage of the lubricant in the pharmaceutical composition is 0.5%.

[0045] According to an embodiment of the present invention, the excipient further includes a colorant.

[0046] Specifically, if a colorant is present, the colorant has a weight percentage of 0.02%-0.05% in the pharmaceutical composition, preferably 0.03%.

[0047] Solid dosage forms can be coated with coating agents and may have markings and letters for identification and further markings for separation. Coating is carried out under conditions of adding conventional coating media and film-forming agents (generally referred to as coating materials) familiar to those skilled in the art. Coating can be carried out using, for example, sugar coating matrices, water-soluble film coating matrices, enteric film coating matrices, sustained-release film coating matrices, etc. For sugar coating matrices, sucrose and one or more combinations selected from the following substances can be used: talc, precipitated calcium carbonate, gelatin, gum arabic, amylopectin, carnauba wax, etc. For water-soluble film coating matrices, for example, cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc.; synthetic polymers such as polyvinyl acetal diethylaminoethyl ester, aminoalkyl methyl acrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, etc.; polysaccharides such as amylopectin, etc. For enteric-coated membrane coating matrices, for example, cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate can be used; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], and methacrylic acid copolymer S [Eudragit S (trade name)] can be used; naturally occurring substances such as shellac can also be used; etc. For sustained-release membrane coating matrices, for example, cellulose polymers such as ethyl cellulose and cellulose acetate can be used; acrylic polymers such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trade name)] and ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] can be used; two or more of the above coating matrices can be mixed in a suitable ratio. Furthermore, coating additives can also be used during coating. For coating additives, for example, light masking agents and / or colorants such as titanium dioxide, talc, iron oxide, etc.; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbate, etc.; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid, etc.

[0048] When the solid dosage form is a tablet, the tablet can be prepared by compression or molding. Compressed tablets can also be prepared by compressing an active ingredient in a free-flowing form (e.g., powder or capsule) in a suitable machine, the active ingredient optionally mixed with a binder, lubricant, filler, or disintegrant. Molded tablets can be prepared by molding a mixture of a wetted powdered compound with an inert liquid dispersion medium in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide sustained or controlled release of the active ingredient therein. Tablet formulation is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, NY, 1980.

[0049] When the solid dosage form is a capsule, any conventional encapsulation is suitable, such as using the carriers mentioned above in hard gelatin capsules. When the composition is in the form of soft gelatin capsules, any physiologically acceptable / pharmaceutical excipients commonly used in the preparation of dispersants or suspensions can be considered, and said physiologically acceptable / pharmaceutical excipients are incorporated into the soft gelatin capsules.

[0050] In one specific embodiment, when the pharmaceutical composition of the present invention is a solid dosage form (such as tablets, powders, dry suspensions, granules, or capsules) in unit dose form, each unit dose of the pharmaceutical composition contains 0.1 mg to 10 mg of the active ingredient (i.e., the active pharmaceutical ingredient of the present invention), preferably 0.1 mg to 5 mg, more preferably 0.5 mg to 2 mg; for example, each unit dose of the pharmaceutical composition contains 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg of the active ingredient.

[0051] On the other hand, the present invention provides a method for preparing a pharmaceutical composition. It includes the following steps: (i) The 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound is pulverized to a specific particle size range. (ii) The excipient and the product of step (i) are mixed to form a composition, the mixture is granulated and sieved; (iii) Optionally, the particles obtained in step (ii) are mixed with an excipient other than that described in step (ii).

[0052] In one specific embodiment, in the method for preparing the pharmaceutical composition of the present invention, step (i) is achieved by using an air jet mill or a high-speed mill, or by sieving.

[0053] In one specific embodiment, in the method for preparing the pharmaceutical composition of the present invention, step (ii) is achieved by the following operation: The active pharmaceutical ingredient (API) prepared in step (i) of the present invention is sequentially mixed with a filler, a stabilizer, an optional binder, and an optional disintegrant. Specifically, step (ii) is achieved by the following operation: First, the API prepared in step (i) of the present invention and the filler are mixed, and then the disintegrant, an optional binder, and an optional stabilizer are added and mixed. Preferably, step (ii) is achieved by the following operation: First, the API of the present invention and the first filler are mixed, and then the second filler, the disintegrant, an optional binder, and an optional stabilizer are added and mixed. The first filler and the second filler may be the same or different. Preferably, the first filler is lactose hydrate as described in this application, and the second filler is a cellulose derivative as described in this application. Preferably, the mixing is achieved by stirring, preferably by manual stirring or stirring in a mixing device (such as a hopper mixer).

[0054] In one specific embodiment, in the method for preparing the pharmaceutical composition of the present invention, step (iii) is achieved by performing the following operations: wet granulation or dry granulation of the mixture obtained in step (ii), followed by sieving. Specifically, wet granulation or dry granulation can be performed by those skilled in the art according to the formulation requirements. Preferably, wet granulation involves mixing the mixture obtained in step (ii) with water and granulating it using a wet granulator; or dry granulation involves granulating the mixture obtained in step (ii) using a dry granulator. Preferably, sieving is performed using a 10-80 mesh sieve (e.g., a 10-30 mesh sieve).

[0055] In one specific embodiment, in the method for preparing the pharmaceutical composition of the present invention, step (iii) is performed by mixing the particles obtained in step (ii) with a lubricant and optionally a colorant. Preferably, the mixing is performed by stirring, preferably by manual stirring or stirring in a mixing device (such as a hopper mixer).

[0056] In one specific embodiment, the method for preparing the pharmaceutical composition of the present invention further includes the following step: (iv) compressing the mixture obtained in step (iii) into tablets.

[0057] In one specific embodiment, the excipient does not include a solubilizer or surfactant.

[0058] On the other hand, the present invention provides the use of the active pharmaceutical ingredient or pharmaceutical composition of the present invention in the preparation of a drug that promotes the excretion of uric acid.

[0059] In another aspect, the present invention provides the use of the active pharmaceutical ingredient or pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and / or treatment of at least one of gouty tophi, gouty arthritis, or gouty nephropathy as a pathological condition.

[0060] Unless otherwise stated, the various implementation schemes or different preferred schemes described in this article can be combined arbitrarily.

[0061] The present invention is illustrated below by way of examples, but should not be construed as limiting the scope of the invention to the following examples. All technologies implemented based on the above description of the present invention fall within the scope of the present invention. The compounds or reagents used in the following examples are commercially available or prepared using conventional methods known to those skilled in the art; the experimental instruments used are commercially available.

[0062] Specifically, in the formulation examples, API 1 was purchased from Jinan Guoding Pharmaceutical Technology Co., Ltd., lactose monohydrate was purchased from Difuyi Trading (Shanghai) Co., Ltd., D-mannitol was purchased from Roquette Corporation, microcrystalline cellulose was purchased from Asahi Kasei Corporation, hydroxypropyl methylcellulose was purchased from Shin-Etsu Chemical Industry Co., Ltd., carboxymethyl cellulose was purchased from Gotoku Pharmaceutical Co., Ltd., and magnesium stearate was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.

[0063] During the research, the researchers found that dotenorazole, a BCS II drug, has very poor and pH-dependent solubility. Its solubility under different pH conditions is as follows: in hydrochloric acid at pH 1.2, the solvent volume required to dissolve 1g of the drug exceeds 700L; in Britton-Robinson buffer at pH 2, the solvent volume required to dissolve 1g of the drug exceeds 1000L; in water, the solvent volume required to dissolve 1g of the drug is approximately 240L; and in Britton-Robinson buffer at pH 8, the solvent volume required to dissolve 1g of the drug is less than 1L. Using commercially available dotenorazole raw material or dotenorazole raw material prepared according to existing techniques CN102639518B / CN110914246B to prepare formulations, the cumulative dissolution of the formulations under in vitro dissolution conditions of 900ml water + paddle motion at 75rpm, pH 4.5 acetate buffer + paddle motion at 75rpm, and pH 6.8 phosphate buffer + paddle motion at 40rpm was difficult to exceed 60% simultaneously over 2 hours. The inventors conducted extensive research, including optimizing the types of excipients, such as adding solubilizers or surfactants, and optimizing the formulation process, but it was still difficult to obtain dotenoroxetine formulations with satisfactory dissolution. Furthermore, adding solubilizers or surfactants can introduce related substances that reduce the stability of the formulation product.

[0064] Extensive research by the inventors revealed that dotenoradine API possesses high electrostatic properties, leading to easy adsorption during crystallization. Direct crystallization makes it difficult to obtain stable, small-particle-size dotenoradine API. By controlling the D90 of dotenoradine API within a specific range through pulverization, a formulation product meeting dissolution requirements can be obtained without adding a solubilizer. Furthermore, the inventors unexpectedly discovered that the preparation of formulations from partially crystallized APIs suffers from uneven mixing of raw materials and excipients, resulting in inconsistent tablet content. Mechanical pulverization effectively improved the mixing uniformity of the dotenoradine API by controlling the D90 within a certain range, effectively controlling the total dry-mix content uniformity to less than 3%, a further improvement over pharmacopoeia standards. This ensures consistent formulation content and enhances medication safety.

[0065] To further illustrate this application, the following implementation is provided.

[0066] Experimental Example 1 I. Preparation Examples of Active Pharmaceutical Ingredients Raw material drug 1 Purchased from Jinan Guoding Pharmaceutical Technology Co., Ltd.; The particle size distribution of the active pharmaceutical ingredient was tested as follows: Figure 1 As shown.

[0067] Example of preparation of active pharmaceutical ingredient 2 Weigh an appropriate amount of raw material 1, and pulverize it using a high-speed pulverizer at 2000 rpm for 20 seconds to obtain raw material 2. The particle size distribution of the pulverized raw material is then analyzed as follows: Figure 2 As shown.

[0068] Example of preparation of active pharmaceutical ingredient 3 Weigh an appropriate amount of raw material 1, and pulverize it using a high-speed pulverizer at 20,000 rpm for 30 seconds to obtain raw material 3. The particle size distribution of the pulverized raw material is then analyzed as follows: Figure 3 As shown.

[0069] Example of preparation of active pharmaceutical ingredient 4 Weigh an appropriate amount of raw material 1 and continuously pulverize it using a high-speed pulverizer at 20,000 rpm until the particle size no longer decreases, obtaining raw material 4. The final particle size distribution of the pulverized raw material is as follows: Figure 4 As shown.

[0070] Example of preparation of active pharmaceutical ingredient 5 Weigh an appropriate amount of raw material 1 and pulverize it using a GMP01 standard air jet mill at 0.15 MPa and a feed rate of 900 g / h to obtain raw material 5.

[0071] Preparation examples of 6 active pharmaceutical ingredients Weigh an appropriate amount of raw material 1 and pulverize it using a GMP01 standard air jet mill at 0.15 MPa and a feed rate of 1600 g / h to obtain raw material 6.

[0072] Example of preparation of active pharmaceutical ingredient 7 The active pharmaceutical ingredient (API) 7 was obtained by recrystallization from acetone and water using raw materials purchased from Jinan Guoding Pharmaceutical Technology Co., Ltd. The specific recrystallization process was as follows: 6.00 g of dotenorazole was dissolved in 78 ml of acetone at 55°C, filtered, and then 200 ml of water was added dropwise at 250 rpm. After the addition was complete, the mixture was cooled to room temperature to obtain a white solid. The final particle size distribution of the API after recrystallization is shown in the figure. Figure 5 As shown.

[0073] 8 Examples of Preparation of Active Pharmaceutical Ingredients The active pharmaceutical ingredient (API) 8 was obtained by recrystallization from acetone and water using raw materials purchased from Jinan Guoding Pharmaceutical Technology Co., Ltd. The specific recrystallization process was as follows: 6.00 g of dotenorazole was dissolved in 78 ml of acetone at 55°C, filtered, and then 120 ml of water was added dropwise at 200 rpm. After the addition was complete, the mixture was cooled to room temperature to obtain a white solid. The final particle size distribution of the API after recrystallization is shown in the figure. Figure 6 As shown.

[0074] Preparation examples of 9 active pharmaceutical ingredients Following the method described in CN102639518B, crude dotenorazole (D90 > 100 μm) was obtained. A certain amount of crude dotenorazole was added to acetone, heated to dissolve, and then water was added dropwise. The mixture was then cooled to obtain refined dotenorazole. The particle size distribution of the refined dotenorazole was determined to be D10: 6.81 μm, D50: 102 μm, and D90: 221 μm. An appropriate amount of the refined dotenorazole was weighed and pulverized using a GMP01 standard air jet mill at 0.15 MPa and a feed rate of 800 g / h to obtain active pharmaceutical ingredient (API 9). The final particle size distribution of the API is shown below. Figure 7 As shown.

[0075] Preparation examples of 10 active pharmaceutical ingredients Following the method described in CN102639518B, crude dotenorazole (D90 > 100 μm) was obtained. A certain amount of crude dotenorazole was added to acetone, heated to dissolve, and then water was added dropwise. The mixture was then cooled to obtain refined dotenorazole. The particle size distribution of the refined dotenorazole was determined to be D10: 6.81 μm, D50: 102 μm, and D90: 221 μm. An appropriate amount of the refined dotenorazole was weighed and pulverized using a Noze YQ100 standard air jet mill at a pulverizing pressure of 0.45 MPa and a feed rate of 300 g / min to obtain 10 μL of active pharmaceutical ingredient (API). The final particle size distribution of the API is shown below. Figure 8 As shown.

[0076] Example of preparation of active pharmaceutical ingredient 11 Weigh an appropriate amount of raw material 1 and pulverize it using a GMP01 standard air jet mill at 0.15 MPa and a feed rate of 900 g / h to obtain raw material 11. The final particle size distribution of the raw material is as follows. Figure 8 As shown.

[0077] Example of preparation of active pharmaceutical ingredient 12 Weigh an appropriate amount of crude domperidone and add it to 12 ml of N,N-dimethylformamide. Stir to dissolve, then add 120 ml of purified water dropwise at room temperature at a speed of 150 rpm. After the addition is complete, cool to 5-10℃, filter, and dry to obtain an off-white solid. Pulverize using a GMP01 standard air jet mill at 0.175 MPa and a feed rate of 1000 g / h to obtain 12g of active pharmaceutical ingredient.

[0078] Example of preparation of active pharmaceutical ingredient 13 Weigh an appropriate amount of crude domperidone and add it to 12 ml of N,N-dimethylformamide. Stir to dissolve, then add 120 ml of purified water dropwise at room temperature at a speed of 150 rpm. After the addition is complete, cool to 5-10℃, filter, and dry to obtain an off-white solid. Pulverize using a GMP02 type air jet mill at 0.25 MPa and a feed rate of 40 Hz (130 g / min) to obtain raw material 13.

[0079] Example of preparation of active pharmaceutical ingredient 14 Following the recrystallization method of patent CN110914246B, dotenoradine was recrystallized to obtain a product with a D90 greater than 100 μm. However, the formulation prepared from this active pharmaceutical ingredient showed a dissolution rate of less than 60% within 60 minutes under aqueous conditions, failing to meet the efficacy requirements.

[0080] Based on this patent, the crystallization process was optimized and the stirring speed was increased, but it was still impossible to control the D90 of the active pharmaceutical ingredient to be less than 50 μm.

[0081] Table 1. Particle size distribution of the active pharmaceutical ingredient obtained from the preparation example of the active pharmaceutical ingredient. The particle size distribution of the active pharmaceutical ingredient (API) prepared in this embodiment of the invention was determined using a Mastersizer 3000 laser particle size analyzer (Malvern Panalytical, UK). Specifically, approximately 150 mg of the API prepared in this embodiment of the invention (e.g., API 1) was taken, 1 ml of 0.5% sodium dodecyl sulfate was added to wet the sample, followed by 4 ml of water. After sonication for 5 minutes, the sample was added to the sample dispersion unit until the opacity reached 8-20%, at which point measurement began. The dispersion chamber was stirred at 2500 rpm for 10 seconds.

[0082] II-1. Formulation Examples 1-11 The prescription and dosage information for preparations 1-11 are as follows: Preparation methods of formulation examples 1-11: (1) The active pharmaceutical ingredients prepared in Example 1-11 were simply mixed with lactose monohydrate at a ratio of 1:10, and the mixtures were sieved through a 50-mesh sieve and the materials were collected. (2) The mixture obtained in step (1) is dry-mixed with the remaining lactose monohydrate, D-mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose and carboxymethyl cellulose at a speed of 250 rpm and a shear rate of 1000 rpm. At 2-20 min, 5 samples are taken at different time points, 2 samples at each point, and 0.2~0.6 g of each sample. (3) The mixture obtained in step (2) is wet granulated with purified water, passed through a 40-60 mesh sieve, and dried at 60°C until the moisture content is below 1.5%; (4) The particles obtained in step (3) are granulated dry and then mixed evenly with magnesium stearate; (5) Compress the mixture obtained in step (4) into tablets using an 8.0mm round punch with a tablet hardness of 9-12KN to obtain tablets.

[0083] II-2. Formulation Examples 12-14 The prescription and dosage information for formulations 12-14 are as follows: Preparation methods of formulations in Examples 12-14: Following the method described in Formulation Example 1, formulations 12-14 were prepared by sequentially distributing active pharmaceutical ingredients 1-2 and 4.

[0084] II-3. Formulation Examples 15-19 The formulation and dosage information for Formulation Examples 15-18 are as follows: II-4. Formulation Examples 15-19 In Example 15, the active pharmaceutical ingredient (API) used was API 12, while in Examples 16-19, the API used was API 13. The preparation processes for each example are as follows: Formulation Example 15 1. Weigh out the raw materials and excipients according to the prescription amount and set aside.

[0085] 2. Mix dotenoroxetine with some lactose monohydrate and pass through a 40-mesh sieve. Set aside.

[0086] 3. Add the sieved material and other auxiliary materials to the pellet mill in sequence, turn on the stirring at 250 rpm and the cutter at 1000 rpm to mix.

[0087] 4. Add an appropriate amount of purified water for granulation. Granulation speed is 250 rpm and cutter speed is 1000 rpm.

[0088] 5. Place the wet granules into a fluidized bed for drying.

[0089] 6. Sizing the dried granules to a 30-mesh size.

[0090] 7. Mix magnesium stearate with the dried granules.

[0091] 8. Compress tablets according to the theoretical tablet weight of 200mg, and control the main pressure ≤15KN.

[0092] Formulation Example 16 1. Weigh the raw materials and excipients according to the prescription amount. The active pharmaceutical ingredient used is active pharmaceutical ingredient 13, which is ready for use.

[0093] 2. Mix dotenoradine with some anhydrous dicalcium phosphate and pass through a 40-mesh sieve for later use.

[0094] 3. Add the sieved material and other auxiliary materials to the pellet mill in sequence, turn on the stirring at 250 rpm and the cutter at 1000 rpm to mix.

[0095] 4. Add an appropriate amount of purified water for granulation. Granulation speed is 250 rpm and cutter speed is 1000 rpm.

[0096] 5. Place the wet granules into a fluidized bed for drying.

[0097] 6. Sizing the dried granules to a 30-mesh screen. 7. Mix magnesium stearate with the dried granules.

[0098] 8. Compress tablets according to the theoretical tablet weight of 200mg, and control the main pressure ≤15KN.

[0099] Formulation Example 17 1. Weigh out the raw materials and excipients according to the prescription amount and set aside.

[0100] 2. Mix dotenoramide with some lactose and pass through a 40-mesh sieve.

[0101] 3. Add the sieved material and other auxiliary materials to the pellet mill in sequence, turn on the stirring at 250 rpm and the cutter at 1000 rpm to mix.

[0102] 4. Add 10% purified water for granulation at a granulation speed of 250 rpm and a cutter speed of 1000 rpm.

[0103] 5. Place the wet granules into a fluidized bed for drying.

[0104] 6. Sizing the dried granules to a 30-mesh screen. 7. Mix magnesium stearate with the dried granules.

[0105] 8. Compress tablets according to the theoretical tablet weight of 200mg, and control the main pressure ≤15KN.

[0106] Formulation Example 18 1. Weigh out the raw materials and excipients according to the prescription amount and set aside.

[0107] 2. Mix dotenoramide with some lactose and pass through a 40-mesh sieve.

[0108] 3. Add the sieved material and other auxiliary materials to the pellet mill in sequence, turn on the stirring at 250 rpm and the cutter at 1000 rpm to mix.

[0109] 4. Add 10% purified water for granulation at a granulation speed of 250 rpm and a cutter speed of 1000 rpm.

[0110] 5. Place the wet granules into a fluidized bed for drying.

[0111] 6. Sizing the dried granules to a 30-mesh screen. 7. Mix magnesium stearate with the dried granules.

[0112] 8. Compress tablets according to the theoretical tablet weight of 200mg, and control the main pressure ≤15KN.

[0113] Formulation Example 19 1. Weigh out the raw materials and excipients according to the prescription amount and set aside.

[0114] 2. Mix dotenoramide with some lactose and pass through a 40-mesh sieve.

[0115] 3. Add the sieved material and other auxiliary materials to the pellet mill in sequence, turn on the stirring at 250 rpm and the cutter at 1000 rpm to mix.

[0116] 4. Add 10% purified water for granulation at a granulation speed of 250 rpm and a cutter speed of 1000 rpm.

[0117] 5. Place the wet granules into a fluidized bed for drying.

[0118] 6. Sizing the dried granules to a 30-mesh screen. 7. Mix sodium stearate fumarate with the dried granules.

[0119] 8. Compress tablets according to the theoretical tablet weight of 200mg, and control the main pressure ≤15KN.

[0120] III. Example of Effect 1. Uniformity test Experimental methods: The overall mixing uniformity and dry mixing uniformity of the tablets, as well as the tablet content during the compression process, were all tested.

[0121] Overall homogeneity testing: Before tableting, 10 samples representing the upper, middle, and lower layers of the final mixture from each batch are taken. The content of the active ingredient in these samples is analyzed by HPLC. The content of the active ingredient in each sample is compared to obtain the average homogeneity of each batch. The standard deviation and relative standard deviation are obtained using the following formulas: In the above formula, s represents the standard deviation; RSD represents the relative standard deviation; Xi, X2, X3...Xn are the values ​​of individual test samples, expressed as the percentage of the labeled drug content in each sample; X (the horizontal line above) is the average value of the test samples, expressed as the percentage of the labeled drug content in each sample; and n is the number of test samples.

[0122] Dry Mix Uniformity Test: During the formulation preparation process, before adding the wetting agent, the mixture obtained in step (1) was dry-mixed with the remaining lactose monohydrate, D-mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose, and carboxymethyl cellulose at a speed of 250 rpm and a shear rate of 1000 rpm. Samples were taken at 5 min or 10 min at different time points, with 2 samples at each point and 0.2–0.6 g per sample. The content of the active ingredient in the samples was analyzed by HPLC, and the content of the active ingredient in each sample was compared. The standard deviation and relative standard deviation were calculated as above.

[0123] Content detection of tablets during tableting: During the preparation of the formulation, 2-5 tablets are randomly selected every 5 minutes during tableting, and the content of active ingredients in each tablet is detected by HPLC analysis. The average content of tablets in the same time period is calculated, and the changes in tablet content before, during and after tableting are compared.

[0124] The specific test results are shown in Table 2-3.

[0125] Table 2. Dry Mix Uniformity Data of Formulation Table 3 Content during tableting process Crystal form detection: The crystal form of the active pharmaceutical ingredient in this embodiment of the invention was determined using an X-ray powder diffractometer (model Ultimal V). Specifically, a copper target was used in the X-ray tube, with a step size of 2θ = 0.01. ° The voltage is 40kV, the current is 40mA, and the scanning range angle is 8.0~40°. ° The scan rate is 10 °The rotational sample tray was used at a speed of 30 rpm with slits of DHL: 10 mm, DS: 1 degree, SS: 8 mm, RS: open. The sample to be tested was placed in the center of the sample holder groove and compacted with a glass plate before measurement. All active pharmaceutical ingredients (APIs) exhibited the same crystal form, with no change in crystal form before and after pulverization. Representatively, the XRD patterns of APIs 1, 9, and 13 before pulverization are shown below. Figure 10 As shown in the figure, all active pharmaceutical ingredients use the same crystal form as disclosed in patent CN110914246B, type II crystallization.

[0126] Experimental conclusion: As shown in Table 2, as indicated by the test results of API 8, when the particle size of dotenoradine API is relatively large, with a D90 of 171 μm, the dry mixing uniformity of the resulting mixture of raw materials and excipients is 2.8% at 5 min and 9.0% at 10 min. This means that as the mixing time increases, the raw materials and excipients undergo significant stratification, and the mixing uniformity is greater than 5%, which fails to meet the pharmacopoeia requirements. When the particle size D90 of dotenoradine API is 55.8 μm, the dry powder obtained by mixing dotenoradine API and the main excipients has a mixing uniformity of less than 0.90% at 5 min and a dry mixing content uniformity of 3.4% at 10 min. There is a slight increase after 10 min, but both are below 5%, which can effectively ensure the mixing uniformity of the dry powder obtained by mixing dotenoradine API and the main excipients, effectively improve the content uniformity of the prepared tablets, and improve the safety of drug use. Further reducing the D90 of dotenoradine API and mixing the raw materials and excipients resulted in a dry mixing uniformity of less than 3% within 5 min and 10 min, further improving the mixing uniformity of dotenoradine API and major excipients, and significantly improving drug safety.

[0127] As can be seen from the test results of formulation 10 in Table 3, when the particle size D90 of dotenoradine API is less than 5 μm, although the dry mixing uniformity of the mixture of dotenoradine API and main excipients meets the requirements, the content of the tablets prepared during the tableting process varies greatly at different tableting time points. The content of the formulation is 98.9% in the first stage of tableting, 103.0% in the middle stage, and 106.1% in the last stage, with a content change of more than 7%. The reason for the large content change during tableting is speculated to be that when the particle size D90 of dotenoradine API is less than 5 μm, its surface static electricity increases sharply. In the first stage of tableting, some dotenoradine API is adsorbed onto the equipment, resulting in a lower content in the first stage. In the middle and later stages of tableting, the adsorption becomes saturated, resulting in a higher content in the last stage. Furthermore, the researchers found obvious wall adhesion during the fluidized bed drying process of the formulation. Figure 11 As shown.

[0128] Correspondingly, when the particle size D90 of dotenoxam active pharmaceutical ingredient is greater than 10 μm, the static electricity of the active pharmaceutical ingredient is low, the adsorption during tableting is small, and the content of the tablets changes little at different tableting time periods, effectively improving the content uniformity of the final tablets and further improving the safety of the drug.

[0129] 2. In vitro dissolution test The experimental method is as follows: A paddle method was used with a rotation speed of 75 rpm and 900 ml of dissolution medium. Dissolution curves of the formulation of this invention were determined in 900 ml of water, pH 4.5 acetate buffer, pH 5.5 acetate buffer, and pH 6.8 phosphate buffer, respectively. Appropriate amounts of the dissolution solution were collected at 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min, filtered, and the filtrate was used as the test solution. The in vitro dissolution rate was determined, and the results are shown in Tables 4-7.

[0130] Table 4. Dissolution data under aqueous media conditions Table 5 Dissolution data under pH 4.5 acetate buffer conditions Table 6. Dissolution data under pH 6.8 phosphate buffer solution conditions Table 7 Dissolution data under pH 5.5 buffer solution conditions Experimental conclusion: As can be seen from the data in Table 4-6 above, when the D90 of the active pharmaceutical ingredient is 55 μm, the prepared formulation only dissolves by 54% in aqueous medium after 2 hours, resulting in a corresponding in vivo AUC of the formulation. 0-inf The particle size is too small to achieve effective solubility. When the particle size D90 is between 10 μm and 36 μm, the tablets prepared under different dissolution conditions show a cumulative dissolution of more than 60% over 2 hours. Moreover, it can be seen that dissolution increases as the particle size decreases. However, when D90 is further reduced to 5 μm, the dissolution of the formulation does not increase further but instead slows down. The reason for this is that when the D90 of the active pharmaceutical ingredient is 5 μm, the active pharmaceutical ingredient agglomerates severely, causing some of the active pharmaceutical ingredient to fail to disperse effectively during the formulation preparation process, thus forming large aggregates and resulting in slower dissolution of the formulation.

[0131] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to specific features, structures, materials, or characteristics described in connection with that embodiment or example, which are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0132] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A composition, characterized in that, The composition comprises a 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound active pharmaceutical ingredient and an excipient, wherein the particle size D90 of the active pharmaceutical ingredient is 36–10 μm.

2. The composition according to claim 1, characterized in that, The excipients include one or more of fillers, binders, disintegrants, lubricants, and flow aids.

3. The composition according to claim 2, characterized in that, The filler is selected from one or more of sugar alcohols, cellulose derivatives and lactose hydrates.

4. The composition according to claim 2, characterized in that, The disintegrant is selected from one or more of carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, crystalline cellulose, sodium carboxymethyl starch, corn starch, and talc.

5. The composition according to claim 2, characterized in that, The adhesive is selected from one or more of low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, partially pregelatinized starch, and pregelatinized starch.

6. The composition according to claim 2, characterized in that, The lubricant is selected from one or more of magnesium oxide, stearic acid, magnesium stearate, aluminum stearate, calcium stearate, sucrose fatty acid ester, sodium stearoyl fumarate, and talc.

7. The composition according to claim 1, characterized in that, The composition is a solid dosage form.

8. The composition according to claim 7, characterized in that, The solid dosage forms include tablets, capsules, powders, pills, and / or granules.

9. A method for preparing the composition according to any one of claims 1-8, characterized in that: It includes the following steps, (i) The 3-(3,5-dichloro-4-hydroxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole compound was pulverized; (ii) The excipient and the product of step (i) are mixed to form a composition, the mixture is granulated and sieved; (iii) Optionally, the particles obtained in step (ii) are mixed with an excipient other than that described in step (ii).

10. Use of the pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for promoting uric acid excretion.

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