Pharmaceutical compositions containing oxcarbazepine and methods of making the same

Abstract

The present invention provides a pharmaceutical composition containing ostarabax and a preparation method thereof. Specifically, the pharmaceutical composition includes a pharmaceutical active ingredient, a filler, a binder, a disintegrant, and an alkalizing agent; the pharmaceutical active ingredient is ostarabax or a pharmaceutically acceptable salt thereof; the BET specific surface area of the pharmaceutical active ingredient is 5 m 2 / g - 30 m 2 / g; and the pharmaceutical composition does not include sodium carbonate. The composition of the present invention has excellent dissolution characteristics and avoids gastrointestinal side effects caused by sodium carbonate.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more specifically to a pharmaceutical composition containing oxaragone and a method for preparing the same. Background Technology

[0002] Elagolix Sodium is an oral GnRH antagonist co-developed by Abbvie and Neurocrine Biosciences. It works by inhibiting the pituitary gonadotropin-releasing hormone receptor, thereby reducing circulating levels of sex hormones. As a novel GnRH antagonist, ellagox has shown good efficacy in treating uterine fibroids and endometriosis, and possesses significant market potential.

[0003] Oxalgolin sodium tablets tend to form gels when taken orally, affecting drug dissolution from the formulation and absorption in the body. Furthermore, oxagolin sodium exhibits poor stability within the formulation and has a short shelf life.

[0004] CN111698992A discloses a composition for oxagorlin sodium that uses an anti-gelling agent (alkalizing agent) to address the problems associated with oxagorlin sodium tablets. In this patent application, sodium carbonate is added to the formulation as both an anti-gelling agent and a stabilizer, and a dry or wet granulation process is used. In this patented technology, 104 mg of sodium carbonate is added to the formulation of a 200 mg tablet. After oral administration, the sodium carbonate in the tablet reacts with stomach acid to neutralize it, producing a large amount of carbon dioxide, which may lead to bloating and indigestion.

[0005] CN113384581A discloses a composition of oxaragoline sodium, wherein the stabilizer is selected from magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, and meglumine. However, the dissolution curves of its formulations 1 and 2 are quite different from those of the original formulation (the actual similarity factor F2 is calculated to be less than 50).

[0006] WO2021180862A1 discloses a pharmaceutical composition containing oxagorli or a pharmaceutically acceptable salt thereof, which achieves faster release of the active pharmaceutical ingredient by adding a superdisintegrant, but it only provides dissolution curve data in 0.1N hydrochloric acid medium, and the dissolution in other pH media cannot be consistent with the original formulation.

[0007] Therefore, it is necessary to provide compositions / formulations of oxagorli that have low gastrointestinal irritation and good dissolution properties. Summary of the Invention

[0008] The purpose of this invention is to provide a pharmaceutical composition comprising oxagorli or a pharmaceutically acceptable salt thereof, and a method for preparing the same. The pharmaceutical composition of this invention achieves reproducible dissolution characteristics in different dissolution media by controlling the specific surface area of ​​the active pharmaceutical ingredient, and avoids the gastrointestinal side effects caused by sodium carbonate.

[0009] In a first aspect, the present invention provides a pharmaceutical composition comprising:

[0010] Active pharmaceutical ingredients, fillers, binders, disintegrants, and alkalizing agents;

[0011] The active pharmaceutical ingredient is oxaragone or a pharmaceutically acceptable salt thereof;

[0012] The BET specific surface area of ​​the active pharmaceutical ingredient is 5m². 2 / g–30m 2 / g; and

[0013] The pharmaceutical composition does not include sodium carbonate.

[0014] In another preferred embodiment, the pharmaceutically acceptable salt is oxaragoline sodium.

[0015] In another preferred embodiment, the active pharmaceutical ingredient is an amorphous substance.

[0016] In another preferred embodiment, the BET specific surface area of ​​the active pharmaceutical ingredient is 5 m². 2 / g–25m 2 / g, more preferably 5.7m 2 / g–23.5m 2 / g.

[0017] In another preferred embodiment, the pharmaceutical composition comprises the following components:

[0018] The active pharmaceutical ingredient is 100-300 parts by weight; preferably 180-220 parts by weight.

[0019] The filler is 100-300 parts by weight; preferably 200-240 parts by weight.

[0020] The adhesive is 3-30 parts by weight; preferably 4-8 parts by weight.

[0021] The disintegrant is 20-150 parts by weight; preferably 70-100 parts by weight; and

[0022] The alkalizing agent is 20-170 parts by weight; preferably 40-70 parts by weight.

[0023] In another preferred embodiment, the pharmaceutical composition does not include carbonates and bicarbonates.

[0024] In another preferred embodiment, the filler is selected from the group consisting of mannitol, pregelatinized starch, or combinations thereof.

[0025] In another preferred embodiment, the adhesive is selected from the group consisting of: povidone, polyethylene glycol, hydroxypropyl cellulose, or combinations thereof.

[0026] In another preferred embodiment, the disintegrant is selected from the group consisting of: crospovidone, pregelatinized starch, cross-linked modified starch, crospovidone, crospovidone carboxymethyl cellulose sodium, or combinations thereof.

[0027] In another preferred embodiment, the alkalizing agent is selected from the group consisting of arginine, sodium phosphate, sodium hydroxide, meglumine, calcium phosphate, magnesium oxide, or combinations thereof; preferably, it is magnesium oxide and one or more selected from arginine, sodium phosphate, sodium hydroxide, meglumine, and calcium phosphate; more preferably, the mass ratio of magnesium oxide to other alkalizing agents is 1:(0.1-0.5), more preferably 1:(0.2-0.4), such as 1:0.25 or 1:3.

[0028] In another preferred embodiment, the weight ratio of the active pharmaceutical ingredient to the filler is 1:(0.8-1.2), more preferably 1:(1-1.1).

[0029] In another preferred embodiment, the weight ratio of the active pharmaceutical ingredient to the binder is 1:(0.02-0.035), more preferably 1:(0.025-0.03).

[0030] In another preferred embodiment, the weight ratio of the active pharmaceutical ingredient to the alkalizing agent is 1:(0.1-0.9); more preferably 1:(0.15-0.6); more preferably 1:(0.2-0.4); and even more preferably 1:(0.24-0.35).

[0031] In another preferred embodiment, the weight ratio of the active pharmaceutical ingredient to the disintegrant is 1:(0.3-0.5), more preferably 1:(0.38-0.48).

[0032] In another preferred embodiment, the alkalizing agent is magnesium oxide and arginine, or magnesium oxide and meglumine.

[0033] In another preferred embodiment, the stability of the pharmaceutical composition meets one or more of the following characteristics:

[0034] (a) The total impurity growth of the pharmaceutical composition after being stored at 40°C and 75% RH for 3 months is ≤0.3%, more preferably ≤0.2%, and most preferably ≤0.15%;

[0035] (b) The growth of impurity F after the pharmaceutical composition is stored at 40°C and 75% RH for 3 months is ≤0.1%, more preferably ≤0.06%;

[0036] (c) The growth of impurity H in the pharmaceutical composition after being stored at 40°C and 75% RH for 3 months is ≤0.10%, more preferably ≤0.05%;

[0037] The increase is the difference between the impurity content after 3 months and the initial content.

[0038] In another preferred embodiment, the pharmaceutical composition further includes components selected from the group consisting of lubricants, flow aids, or combinations thereof.

[0039] In another preferred embodiment, the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, hydrogenated vegetable oil, polyethylene glycol 4000, polyethylene glycol 6000, or combinations thereof, preferably magnesium stearate.

[0040] In another preferred embodiment, the flow aid is selected from the group consisting of colloidal silica, talc, magnesium lauryl sulfate, preferably colloidal silica.

[0041] In another preferred embodiment, the pharmaceutical composition comprises the following components:

[0042] The active pharmaceutical ingredient is 100-300 parts by weight; preferably 180-220 parts by weight.

[0043] The filler is 100-300 parts by weight; preferably 200-240 parts by weight.

[0044] The adhesive is 3-30 parts by weight; preferably 4-8 parts by weight.

[0045] The disintegrant is 20-150 parts by weight; preferably 70-100 parts by weight.

[0046] The alkalizing agent is 20-170 parts by weight; preferably 40-70 parts by weight.

[0047] The lubricant is 3-20 parts by weight; preferably 8-12 parts by weight; and

[0048] The gliding agent is 5-30 parts by weight; preferably 12-18 parts by weight.

[0049] In another preferred embodiment, the pharmaceutical composition is a tablet.

[0050] In this invention, the pharmaceutical composition may further include a coating component.

[0051] A second aspect of the invention provides the use of the pharmaceutical composition as described in the first aspect of the invention in the preparation of a medicament for the prevention and / or treatment of gonadotropin-releasing hormone receptor-mediated diseases.

[0052] In another preferred embodiment, the disease is selected from the group consisting of: uterine fibroids, endometriosis, polycystic ovary syndrome, adenomyosis, or a combination thereof.

[0053] A third aspect of the invention provides the use of a pharmaceutical material comprising oxagorli or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition, said pharmaceutical material having a BET specific surface area of ​​5 m². 2 / g–30m 2 / g, wherein the content of oxaragoli or a pharmaceutically acceptable salt thereof in the pharmaceutical material is above 99.75%.

[0054] In this invention, the pharmaceutically acceptable salt can be any conventionally pharmaceutically acceptable salt in the art. In some embodiments of this invention, the pharmaceutically acceptable salt is a sodium salt. In some embodiments of this invention, the pharmaceutical material has a BET specific surface area of ​​5 m². 2 / g–30m 2 / g of amorphous oxaragoline sodium.

[0055] Preferably, the BET specific surface area of ​​the pharmaceutical material is 5m². 2 / g–25m 2 / g, more preferably 5.7m 2 / g–23.5m 2 / g.

[0056] Preferably, the content of oxagoli or a pharmaceutically acceptable salt thereof in the pharmaceutical material is above 99.85%, for example 99.86%, 99.87%, 99.88%, 99.89%, or 99.90%.

[0057] In some preferred embodiments of the present invention, the pharmaceutical composition does not contain alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, or alkaline earth metal bicarbonates.

[0058] The formulation and preferred conditions of the pharmaceutical composition are as described above.

[0059] A fourth aspect of the present invention provides a method for preparing a pharmaceutical composition as described in the first aspect of the present invention, comprising the following steps:

[0060] (1) Dry granulation of each component of the pharmaceutical composition;

[0061] (2) Compress the tablets.

[0062] In step (1), the dry granulation method and conditions can be conventional methods and conditions in the art. In some embodiments of the present invention, the dry granulation operation is as follows:

[0063] 1) First, mix the active pharmaceutical ingredient, filler, and binder evenly;

[0064] 2) Use a dry granulation machine for dry pressing, followed by sieving and granulation;

[0065] 3) Add the disintegrant and mix thoroughly; and,

[0066] The alkalizing agent is added during the mixing process in step 1) and / or step 3).

[0067] When the pharmaceutical composition includes the lubricant, the lubricant may be added before the dry pressing in step 2) and / or after the mixing in step 3); as is common knowledge in the art, the materials should also be mixed evenly after the lubricant is added.

[0068] When the pharmaceutical composition includes the gliding agent, the gliding agent may be added during the mixing operation in step 3).

[0069] In step (2), the method and conditions for tablet compression can be conventional methods and conditions in the art.

[0070] In another preferred embodiment, each component is further subjected to a sieving step before mixing. Preferably, each component is sieved independently through a 30-60 mesh sieve, or more preferably, a 30-40 mesh sieve.

[0071] In this invention, when the pharmaceutical composition includes a coating component, according to common knowledge in the art, the coating step is performed after tableting in step (2).

[0072] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0073] Through extensive and in-depth research, including numerous screenings and tests, the inventors have provided a pharmaceutical composition containing oxagorli and its preparation method. The inventors unexpectedly discovered that by using oxagorli raw material with a specific surface area, the pharmaceutical composition of this invention can avoid oxagorli gelation without the need for sodium carbonate, thereby obtaining a pharmaceutical formulation with dissolution characteristics consistent with the raw material and good stability. This invention was completed based on this discovery.

[0074] the term

[0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0076] As used herein, the terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “composed of”.

[0077] As used herein, the term “room temperature” or “normal temperature” refers to a temperature of 4–40°C, preferably 25 ± 5°C.

[0078] Pharmaceutical Composition

[0079] In a first aspect, the present invention provides a pharmaceutical composition comprising: an active pharmaceutical ingredient, a filler, a binder, a disintegrant, and an alkalizing agent; wherein the alkalizing agent does not include sodium carbonate.

[0080] The active pharmaceutical ingredient is oxaragone or a pharmaceutically acceptable salt thereof;

[0081] The BET specific surface area of ​​the active pharmaceutical ingredient is 5m². 2 / g–30m 2 / g.

[0082] In this invention, the pharmaceutically acceptable salt can be any conventionally pharmaceutically acceptable salt in the art. In some embodiments of this invention, the pharmaceutically acceptable salt is a sodium salt, and the active pharmaceutical ingredient is oxagorli sodium. In some embodiments of this invention, the active pharmaceutical ingredient is an amorphous form.

[0083] The inventors have discovered that, without using sodium carbonate as a stabilizer, as used in commercially available oxagrolide sodium tablets, and instead using other alkaline substances as anti-gelling agents or stabilizers, it is difficult to prepare a pharmaceutical composition whose dissolution profile is consistent with that of the commercially available formulation in various dissolution media. Through extensive testing of raw materials and excipients, we found that by controlling the specific surface area of ​​the active pharmaceutical ingredient of this invention to 5 m², we can achieve the desired results. 2 / g–30m 2 / g, enabling the dissolution characteristics of the pharmaceutical formulation to meet the following requirements: in various dissolution media at pH 1.2, pH 4.5, and pH 6.8, at 37°C and a paddle speed of 50 rpm, at least about 80% of oxaragozee or its pharmaceutically acceptable salts can be released within 45 minutes. Furthermore, although a correlation between specific surface area and particle size distribution is generally considered to exist, due to the unique physicochemical properties of the active pharmaceutical ingredient of this invention, it is typically an amorphous substance, and therefore there is no direct correlation between its specific surface area and particle size distribution. In this invention, the BET specific surface area refers to the specific surface area determined by conventional BET specific surface area testing methods in the art. It should be understood that, although the BET specific surface area of ​​the active pharmaceutical ingredient in this invention is determined based on the active pharmaceutical ingredient, if the preparation process of the product / composition does not involve steps or operations that increase or decrease the BET specific surface area of ​​the active pharmaceutical ingredient, the BET specific surface area of ​​the active pharmaceutical ingredient in the product / composition is considered equivalent to the BET specific surface area of ​​the active pharmaceutical ingredient.

[0084] In this invention, the BET specific surface area of ​​the active pharmaceutical ingredient is preferably 5 m². 2 / g–25m 2 / g, more preferably 5.7m 2 / g–23.5m 2 / g.

[0085] In this invention, the content of the active pharmaceutical ingredient can be a conventional content in the art, typically 100-400 mg per unit, such as 150 mg, 200 mg, or 300 mg, calculated as oxagli free base. In some preferred embodiments of this invention, the content of the active pharmaceutical ingredient is 20-45 wt% of the pharmaceutical composition, more preferably 25-40 wt%, and even more preferably 30-35 wt%.

[0086] In this invention, the filler may be a filler conventionally used in the art, preferably mannitol and / or pregelatinized starch.

[0087] In this invention, the adhesive may be an adhesive conventionally used in the art, preferably one or more of povidone, polyethylene glycol and hydroxypropyl cellulose.

[0088] In this invention, the disintegrant can be a disintegrant conventionally used in the art, preferably one or more of crospovidone, pregelatinized starch, cross-linked modified starch, crospovidone polyvinylpyrrolidone, and crospovidone carboxymethyl cellulose sodium.

[0089] In this invention, the alkalizing agent can be any alkalizing agent conventionally used in the art, as long as it does not contain sodium carbonate. Preferably, the pharmaceutical composition or alkalizing agent does not contain carbonates and bicarbonates, such as alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, and alkaline earth metal bicarbonates, thus avoiding potential bloating and indigestion. Preferably, the weight ratio of the active pharmaceutical ingredient to the alkalizing agent can be 1:(0.1-0.9); more preferably 1:(0.15-0.6); more preferably 1:(0.2-0.4); and even more preferably 1:(0.24-0.35).

[0090] In some preferred embodiments of the present invention, the alkalizing agent is one or more selected from arginine, sodium phosphate, sodium hydroxide, meglumine, calcium phosphate, and magnesium oxide, more preferably magnesium oxide and one or more selected from arginine, sodium phosphate, sodium hydroxide, meglumine, and calcium phosphate. In some more preferred embodiments of the present invention, the alkalizing agent is magnesium oxide and arginine, or magnesium oxide and meglumine. More preferably, the mass ratio of magnesium oxide to other alkalizing agents (the sum of the weights of one or more) is preferably 1:(0.1-0.5), more preferably 1:(0.2-0.4), such as 1:0.25 or 1:0.3.

[0091] In this invention, the pharmaceutical composition may further include a lubricant. The lubricant may be a lubricant conventionally used in the art, preferably magnesium stearate.

[0092] In this invention, the pharmaceutical composition may further include a flow aid. The flow aid may be a conventionally used flow aid in the art, preferably colloidal silica.

[0093] In some embodiments of the present invention, the pharmaceutical composition comprises the following components:

[0094] The active pharmaceutical ingredient is 100-300 parts by weight; preferably 180-220 parts by weight.

[0095] The filler is 100-300 parts by weight; preferably 200-240 parts by weight.

[0096] The adhesive is 3-30 parts by weight; preferably 4-8 parts by weight.

[0097] The disintegrant is 20-150 parts by weight; preferably 70-100 parts by weight.

[0098] The alkalizing agent is 20-170 parts by weight; preferably 40-70 parts by weight.

[0099] The lubricant is 3-20 parts by weight; preferably 8-12 parts by weight.

[0100] The gliding agent is 5-30 parts by weight; preferably 12-18 parts by weight.

[0101] In this invention, according to common knowledge in the art, the pharmaceutical composition is a solid mixture, which may be a raw material composition or a pharmaceutical preparation. In some embodiments of this invention, the pharmaceutical composition is a tablet. In some preferred embodiments of this invention, the pharmaceutical composition is prepared using a dry granulation process.

[0102] In this invention, the pharmaceutical composition may further include a coating component. The coating component may be a conventional coating material in the art, preferably Opadry. The content of the coating component may be selected according to common knowledge in the art, typically 2%-4% of the weight of the pharmaceutical composition, preferably 2.8-3.2%. Furthermore, the pharmaceutical composition of this invention may also contain other pharmaceutically acceptable excipients, such as colorants, flavoring agents, etc.

[0103] Preferably, the content of oxaragone or a pharmaceutically acceptable salt thereof in the pharmaceutical material is preferably above 99.85%, for example 99.86%, 99.87%, 99.88%, 99.89%, or 99.90%.

[0104] Preferably, the particle size distribution of the active pharmaceutical ingredient is D90≤500μm; and / or D50≤260μm; and / or D10≤60μm.

[0105] In some preferred embodiments, the stability of the pharmaceutical composition meets one or more of the following characteristics:

[0106] (a) The total impurity increase of the pharmaceutical composition after being stored at 40°C and 75% RH for 3 months is ≤0.3%, more preferably ≤0.2%, and most preferably ≤0.15%; for example: the initial total impurity is ≤0.15%, and the total impurity after 3 months is ≤0.35%; for another example: the initial total impurity is ≤0.13%, and the total impurity after 3 months is ≤0.27%; for yet another example: the initial total impurity is ≤0.28%, and the total impurity after 3 months is ≤0.37%;

[0107] (b) The growth of impurity F in the pharmaceutical composition after being stored at 40°C and 75% RH for 3 months is ≤0.1%, more preferably ≤0.06%; for example: the initial content of impurity F is 0%, and the content of impurity F after 3 months is ≤0.06%; for another example: the initial content of impurity F is 0.03%, and the content of impurity F after 3 months is ≤0.1%; for yet another example: the initial content of impurity F is ≤0.05%, and the content of impurity F after 3 months is ≤0.12%;

[0108] (c) The growth of impurity H in the pharmaceutical composition after being stored at 40°C and 75% RH for 3 months is ≤0.10%, more preferably ≤0.05%; for example: the initial content of impurity H is 0.05%, and the content of impurity H after 3 months is 0.10%; for another example: the initial content of impurity H is 0.06%, and the content of impurity H after 3 months is 0.09%; for yet another example: the initial content of impurity H is 0.04%, and the content of impurity H after 3 months is 0.08%;

[0109] The increase is the difference between the impurity content after 3 months and the initial content.

[0110] use

[0111] The present invention further provides the use of the above-described pharmaceutical composition in the preparation of medicaments for the prevention and / or treatment of gonadotropin-releasing hormone receptor-mediated diseases.

[0112] In another preferred embodiment, the disease is selected from the group consisting of: uterine fibroids, endometriosis, polycystic ovary syndrome, adenomyosis, or a combination thereof.

[0113] Furthermore, the present invention also provides the use of pharmaceutical materials comprising oxagorli or pharmaceutically acceptable salts thereof in the preparation of pharmaceutical compositions, said pharmaceutical materials having a BET specific surface area of ​​5 m². 2 / g–30m 2 / g, wherein the content of oxaragoli or a pharmaceutically acceptable salt thereof in the pharmaceutical material is above 99.75%.

[0114] In this invention, the pharmaceutically acceptable salt can be any conventionally pharmaceutically acceptable salt in the art. In some embodiments of this invention, the pharmaceutically acceptable salt is a sodium salt. In some embodiments of this invention, the pharmaceutical material has a BET specific surface area of ​​5 m². 2 / g–30m 2 / g of amorphous oxaragoline sodium.

[0115] Preferably, the BET specific surface area of ​​the pharmaceutical material is 5m². 2 / g–25m 2 / g, more preferably 5.7m 2 / g–23.5m 2 / g.

[0116] Preferably, the content of oxagoli or a pharmaceutically acceptable salt thereof in the pharmaceutical material is above 99.85%, for example 99.86%, 99.87%, 99.88%, 99.89%, or 99.90%.

[0117] In some preferred embodiments of the present invention, the pharmaceutical composition does not contain alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, or alkaline earth metal bicarbonates.

[0118] The formulation and preferred conditions of the pharmaceutical composition are as described above.

[0119] Preparation method

[0120] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which includes the following steps:

[0121] (1) Dry granulation of each component of the pharmaceutical composition;

[0122] (2) Compress the tablets.

[0123] In step (1), the dry granulation method and conditions can be conventional methods and conditions in the art. In some embodiments of the present invention, the dry granulation operation is as follows:

[0124] 1) First, mix the active pharmaceutical ingredient, filler, and binder evenly;

[0125] 2) Use a dry granulation machine for dry pressing, followed by sieving and granulation;

[0126] 3) Add the disintegrant and mix well.

[0127] When the pharmaceutical composition includes the alkalizing agent, the alkalizing agent may be added during the mixing operation in step 1) and / or step 3).

[0128] When the pharmaceutical composition includes the lubricant, the lubricant may be added before the dry pressing in step 2) and / or after the mixing in step 3); as is common knowledge in the art, the materials should also be mixed evenly after the lubricant is added.

[0129] When the pharmaceutical composition includes the gliding agent, the gliding agent may be added during the mixing operation in step 3).

[0130] In step (2), the method and conditions for tablet compression can be conventional methods and conditions in the art.

[0131] In this invention, when the pharmaceutical composition includes a coating component, according to common knowledge in the art, the coating step is performed after tableting in step (2).

[0132] Compared with the prior art, the present invention has the following main advantages:

[0133] (1) By controlling the physical properties of the active pharmaceutical ingredient, especially its specific surface area, the present invention achieves reproducible dissolution characteristics in different dissolution media.

[0134] (2) The formulations / compositions of the present invention produce fewer impurities and have higher stability during storage.

[0135] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0136] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0137] Equipment used in formulation preparation

[0138] The formulations described in this application can be prepared using any equipment that meets relevant standards, such as granulators and tablet presses. The preparation method can also selectively employ methods commonly used in the art. Preferably, the following equipment and process are used:

[0139] Granulator: Mini-DC dry granulator (manufactured by Shenzhen Xinyite Technology Co., Ltd.); Dry pressing conditions: dry pressing pressure 20KN, feeding speed 100rpm, pressure roller speed 3rpm.

[0140] Tableting machine: ZP10A rotary tableting machine (manufactured by Beijing Guoyao Longli Technology Co., Ltd.)

[0141] Coating machine: Labcoating II coating machine (manufactured by Shenzhen Xinyite Technology Co., Ltd.)

[0142] BET specific surface area tester: Tristar 3000 (USA); Test method: Static volumetric method;

[0143] Particle size distribution (PSD) testing instrument: Malvern 3000.

[0144] In the following examples, all sodium oxaragoline used were amorphous.

[0145] Preparation for the experiment:

[0146] The PSD and BET specific surface area of ​​different batches of oxagorli sodium active pharmaceutical ingredient were tested. The results are shown in the table below.

[0147]

[0148] A comparison of PSD data between batches shows that there is no correlation between the detected particle size PSD value of sodium oxagoguelin and the BET specific surface area.

[0149] Comparative Example 1

[0150] Olagodil sodium tablets, 200mg specification (manufactured by AbbVie Inc., USA). According to the original drug instructions for oxagodil sodium tablets, the formulation of 200mg oxagodil sodium tablets consists of oxagodil sodium, mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone, magnesium stearate, and a film coating (containing polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and iron oxide red).

[0151] Comparative Example 2

[0152] Oxalagolipid sodium tablets were prepared according to the content disclosed in CN201880067969.7.

[0153]

[0154]

[0155] The BET specific surface area of ​​the sodium oxaragoline used was 5.7 m². 2 / g.

[0156] The formulation in the comparative example was prepared according to the following method:

[0157] 1) Sieve sodium oxalate, mannitol, sodium carbonate monohydrate, pregelatinized starch, povidone K30 and added magnesium stearate separately.

[0158] 2) Place the materials that have been sieved in step 1 into a mixing container and mix them evenly to obtain a mixture.

[0159] 3) The mixture from step 2) is dry-pressed using a dry granulation machine.

[0160] 4) Sieve and granulate to obtain a granulated mixture.

[0161] 5) After sieving the added magnesium stearate, add it to the mixture obtained in step 4) and mix well.

[0162] 6) A rotary tablet press is used for tableting.

[0163] 7) Add the film coating premix powder (Opadry II) to pure water to prepare the coating solution.

[0164] 8) Place the uncoated tablets in the coating pan of a high-efficiency coating machine for coating. The coating layer increases the weight by 3.0% relative to the tablet core.

[0165] Examples 1-4

[0166]

[0167]

[0168] The pharmaceutical compositions of Examples 1-4 were prepared according to the formulations in the table above, and the preparation methods are as follows:

[0169] 1) Sift the filler, binder, alkalizing agent, flow aid, lubricant, and disintegrant separately;

[0170] 2) Mix the sieved filler, binder, alkalizing agent, flow aid and sodium oxaragoline in a mixer, then add lubricant and continue mixing in the mixer to obtain a mixture;

[0171] 3) The mixture is dry-pressed into granules using a dry granulator and then sieved to form the granules;

[0172] 4) Add disintegrant and glidant and mix well; then add lubricant and continue mixing; 5) Compress the material into tablets and then coat them with the coating component to obtain the final product.

[0173] Example 1

[0174] The dissolution rate of the formulations prepared in each example was determined according to the dissolution and release rate determination method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0931, Method II). The dissolution rate determination method is as follows:

[0175] 900 ml of dissolution medium (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) was measured and placed in different dissolution vessels. After being kept at a constant temperature of 37.0℃±0.5℃, the above preparation was taken and placed into different dissolution vessels containing the dissolution medium. The mixture was stirred at 50 rpm. Timing was started when the preparation came into contact with the dissolution medium. Samples were taken at fixed time intervals, filtered, and the drug concentration in the filtrate was determined by HPLC. The dissolution rate was calculated.

[0176] Following the above method, using 900 mL of pH 1.2 hydrochloric acid solution as the dissolution medium, the dissolution rates of the formulations obtained in Comparative Example 1, Comparative Example 2, and Examples 1-4 were determined, and the results are listed in the table below.

[0177]

[0178] The results above show that the pharmaceutical compositions of Examples 1-4 can achieve satisfactory dissolution in hydrochloric acid solution at pH 1.2.

[0179] Following the above method, using 900 mL of pH 4.5 acetate buffer as the dissolution medium, the dissolution rates of the formulations obtained in Comparative Example 1 and Examples 1-4 were determined, and the results are listed in the table below.

[0180]

[0181] The results above show that the pharmaceutical compositions of Examples 1-4 can achieve satisfactory dissolution in acetate buffer at pH 4.5.

[0182] Following the above method, 900 mL of pH 6.8 phosphate buffer was used as the dissolution medium to determine the dissolution rates of the formulations obtained in Comparative Example 1 and Examples 1-4, respectively. The results are listed in the table below.

[0183]

[0184] The results above show that the pharmaceutical compositions of Examples 1-4 can achieve satisfactory dissolution in phosphate buffer at pH 6.8.

[0185] Example 2

[0186] The formulations obtained in Comparative Examples 2 and Examples 1-4 were packaged in aluminum-plastic composites and subjected to accelerated stability studies at 40°C and 75% RH, respectively, along with Comparative Example 1 (the original packaging of the marketed product, i.e., aluminum-plastic composites). Related substances in the oxagoguelin sodium tablet samples were analyzed at 0 days and 3 months. The levels of related substances in the stability samples were determined by high-performance liquid chromatography (HPLC). An octadecylsilane-bonded silica gel column (Inertsil ODS-3V C18) was used with gradient elution of 10 mM KH₂PO₄ aqueous solution as mobile phase A and acetonitrile as mobile phase B. The flow rate was 1.0 mL / min, the column temperature was 40°C, and the detection wavelength was 274 nm.

[0187] The test was conducted using the method described above, and the results are shown in Table 14.

[0188] The chemical names and structural formulas of impurities F and H are as follows:

[0189] Impurity F:

[0190] Chemical name: (R)-4-({2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-hydroxy-amino)-butyric acid;

[0191] Impurity F;

[0192] Impurity H:

[0193] Chemical name: (R)-3-(2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidin-2,4-dione; hydrogen sulfate;

[0194] Impurity H.

[0195]

[0196] "--" indicates that it was not detected.

[0197] As can be seen, compared with Comparative Examples 1 and 2, Examples 1-4 of the present invention exhibit lower levels of impurities F, H, and total impurities after 3 months of accelerated storage, demonstrating superior stability. Compared with Comparative Example 2, Examples 1-4 of the present invention also show lower impurity growth rates during the 3-month accelerated stability study, indicating better stability.

[0198] Examples 5-8

[0199]

[0200] The pharmaceutical compositions of Examples 5-8 were prepared according to the formulations in the table above, and the preparation methods were the same as those in Example 1.

[0201] Example 3

[0202] The dissolution rates of the pharmaceutical compositions of Examples 5-8 were determined using the same method as in Example 1 (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer), and the results are listed in the table below.

[0203] pH 1.2

[0204]

[0205] pH 4.5

[0206]

[0207] pH 6.8

[0208]

[0209] The results above show that the drug compositions of Examples 5-8 can achieve satisfactory dissolution in various dissolution media and have the same dissolution characteristics as the original formulation.

[0210] Examples 9-12

[0211]

[0212] The pharmaceutical compositions of Examples 9-12 were prepared according to the formulations in the table above, and the preparation methods were the same as those in Example 1.

[0213] Example 4

[0214] The dissolution rates of the pharmaceutical compositions of Examples 9-12 were determined using the same method as in Example 1 (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer), and the results are listed in the table below.

[0215] pH 1.2

[0216]

[0217]

[0218] pH 4.5

[0219]

[0220] pH 6.8

[0221]

[0222] As can be seen from the above results, the pharmaceutical compositions of Examples 9-12 can achieve satisfactory dissolution in various dissolution media and have the same dissolution characteristics as the original formulation.

[0223] Comparative Examples 3-6

[0224]

[0225]

[0226] The pharmaceutical compositions of Comparative Examples 3-6 were prepared using the same method as in Examples 1-4.

[0227] Example 5

[0228] The dissolution rates of the drug compositions in Comparative Examples 3-6 were determined using the same method as in Example 1 (pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer), and the results are listed in the table below.

[0229] pH 1.2

[0230]

[0231] pH 4.5

[0232]

[0233]

[0234] pH 6.8

[0235]

[0236] Compared to Comparative Example 1, the drug compositions of Comparative Examples 3-6 dissolved more slowly in hydrochloric acid solution at pH 1.2, and a tendency for API gelation was observed. Drug gelation reduces the dissolution rate of API in the formulation, thereby reducing drug absorption in vivo.

[0237] The results above show that using BET with a specific surface area of ​​0.8 m² 2 Oxagra sodium at a concentration of / g, without sodium carbonate, cannot achieve satisfactory dissolution in hydrochloric acid solution at pH 1.2. The drug compositions in Comparative Examples 3-6 cannot achieve dissolution profiles consistent with marketed tablets under various dissolution media. However, using a BET specific surface area of ​​5.7m²... 2 / g, 23.5m 2 / g、22.1m 2 Examples 1-12 of / g can achieve satisfactory dissolution in various dissolution media and have the same dissolution characteristics as the original formulation.

[0238] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: The active pharmaceutical ingredient comprises 180-220 parts by weight, filler 200-240 parts by weight, binder 4-8 parts by weight, disintegrant 70-100 parts by weight, alkalizing agent 40-70 parts by weight, lubricant 8-12 parts by weight, and flow aid 12-18 parts by weight. The active pharmaceutical ingredient is oxagorli sodium; and the BET specific surface area of ​​the active pharmaceutical ingredient is 5.7 m². 2 / g -23.5 m 2 / g; The filler is mannitol; The adhesive is polyvinyl ketone K-30; The disintegrant is crospovidone; the lubricant is magnesium stearate; and The flow aid is colloidal silica; The alkalizing agent is magnesium oxide and arginine, or magnesium oxide and meglumine; and the mass ratio of magnesium oxide to other alkalizing agents is 1:(0.2-0.4). Furthermore, the pharmaceutical composition does not include alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates, and alkaline earth metal bicarbonates.

2. The pharmaceutical composition according to claim 1, characterized in that, The active pharmaceutical ingredient is an amorphous substance.

3. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises the following components: The active pharmaceutical ingredient comprises 180-220 parts by weight, filler comprises 200-240 parts by weight, binder comprises 4-8 parts by weight, disintegrant comprises 70-100 parts by weight, alkalizing agent comprises 40-70 parts by weight, lubricant comprises 8-12 parts by weight, flow aid comprises 12-18 parts by weight, and optionally a coating component.

4. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of magnesium oxide to other alkalizing agents is 1:(0.2-0.3).

5. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of the active pharmaceutical ingredient to the filler is 1:(1-1.1); The weight ratio of the active pharmaceutical ingredient to the binder is 1:(0.025-0.03); The weight ratio of the active pharmaceutical ingredient to the disintegrant is 1:(0.38-0.48); and The weight ratio of the active pharmaceutical ingredient to the alkalizing agent is 1:(0.24-0.35).

6. The pharmaceutical composition according to claim 1, characterized in that, The alkalizing agent is magnesium oxide and arginine.

7. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is selected from the following group of formulations: 。 8. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition is in the form of tablets.

9. Use of the pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for the prevention and / or treatment of gonadotropin-releasing hormone receptor-mediated diseases, wherein, The diseases mentioned are selected from the following group: uterine fibroids, endometriosis, polycystic ovary syndrome, adenomyosis, or a combination thereof.

10. The method for preparing the pharmaceutical composition according to claim 1, characterized in that, Includes the following steps: (1) Dry granulation of each component of the pharmaceutical composition; (2) Compress the tablets.

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