Preparation containing mifepristone and preparation method thereof

Abstract

The invention discloses a preparation containing mifepristone and a preparation method thereof. The composition comprises quick-release particles and slow-release particles, mifepristone exists in the sustained-release granules in an amorphous form; the weight ratio of the mifepristone in the quick release particles to the mifepristone in the slow release particles is (0.4-2.2): 1; the quick-release particles comprise 5-15% of mifepristone, 45-95% of a filler, 2-20% of a disintegrating agent, 0-2.0% of a lubricant and 0-8% of an adhesive; the sustained-release particles comprise 4.5 to 15 percent of mifepristone and 85 to 95.5 percent of sustained-release auxiliary materials. The sustained-release granules can be continuously released in the intestinal tract, the active ingredients reach a supersaturated state after being released in the intestinal tract, the solubility of the medicine is improved, the medicine is absorbed at the lower end of the small intestine, the supersaturated state can last for more than 4 hours, sufficient time is provided for absorption of the medicine in the intestinal tract, and the bioavailability is remarkably improved. The sustained-release part is not adhered to the intestines and the stomach, has small irritation to the intestines and the stomach, and has no falling risk.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a mifepristone-containing preparation and a preparation method thereof. BACKGROUND

[0002] Mifepristone is a strong bioactive progesterone receptor antagonist, which is widely used in clinical practice as an early pregnancy termination drug. With the deepening of its understanding, its application has gradually expanded to the field of reproductive health (such as emergency contraception) and the treatment of some gynecological diseases (such as uterine fibroids, endometriosis, etc.), and its application prospect is broad.

[0003] However, its solubility in aqueous medium is low, and it is pH-dependent (solubility is better in acidic environment, and solubility is poor in alkaline and neutral environment). After oral administration of mifepristone preparation, the drug is first dissolved in the acidic environment in the stomach, and as the drug is transferred to the neutral environment in the intestine, the solubility rapidly decreases, resulting in the precipitation of part of the dissolved drug, thereby the bioavailability of the drug is only 30%-50%. Therefore, pharmaceutical researchers have been trying to develop a mifepristone preparation that can improve the bioavailability, so as to further enhance the effect of the drug.

[0004] CN1218665A discloses a high-efficiency mifepristone preparation, its preparation method and use: a solid dispersion preparation made of mifepristone and a certain proportion of ionic or non-ionic surfactant, which improves the bioavailability of the drug through the solubilization of the surfactant. However, due to the dilution effect of gastric juice and intestinal juice, the actual solubilization effect of the surfactant is limited.

[0005] CN1311000A discloses a mifepristone gelatin capsule and its preparation method: a scheme of mixing mifepristone with solvents such as propylene glycol, ethanol, Tween-20, polyethylene glycol-400 and surfactants to prepare a liquid gelatin capsule. Mifepristone is stored in the form of a solution in the pharmaceutical preparation, and when the drug enters the stomach, the gelatin capsule is broken under the action of pepsin, and the drug is rapidly released. However, the drug stays in the stomach for a short time, and the stomach cannot completely absorb the drug. The unabsorbed drug enters the intestine due to the increase in pH value, resulting in a decrease in solubility and precipitation. Therefore, this method does not greatly improve the bioavailability.

[0006] WO2012 / 083801A1 discloses a steroid intrauterine antiprogestin composition and its preparation method and application: a pharmaceutical preparation containing a rapid release system and a slow release adhesion system, the drug contained in the rapid release system is rapidly released in the stomach to take effect, the slow release adhesion system adheres to the gastric mucosa to release slowly and continuously, prolongs the residence time of the drug in the stomach, and releases most of the antiprogestin in the stomach (the first paragraph of the invention content of the patent), thereby improving the bioavailability of the drug. The disadvantage is that: the existing technology, the rapid release system and the slow release adhesion system are released in the stomach, specifically, the slow release part (the slow release particles are crystals, not amorphous) is an adhesion system, its mechanism is to adhere the slow release part to the gastric mucosa for continuous release, and increase the solubility of mifepristone by means of the acidic environment in the stomach. Because the slow release part adheres to the gastric mucosa for a long time, it has a great stimulation to the gastric mucosa, in addition, the food peristalsis has a certain influence on the adhesion system after eating, which may cause the adhesion system to be unstable and easy to fall off, thereby causing unstable curative effect. SUMMARY

[0007] The technical problem to be solved by the present application is to overcome the defects in the prior art that the solubility of mifepristone is affected by pH value, and the drug is precipitated in the intestinal tract, resulting in low bioavailability, or the rapid release system and the slow release adhesion system are released in the stomach, adhere to the gastric mucosa for a long time, have a great stimulation to the gastric mucosa, and the food peristalsis has an influence on the adhesion system after eating, which may cause the adhesion system to be unstable and easy to fall off, thereby causing unstable curative effect. The present application provides a preparation containing mifepristone and a preparation method thereof.

[0008] The present application is a gel preparation containing rapid release particles and slow release particles, wherein the active ingredient contained in the rapid release particles exists in the form of crystals, and the active ingredient contained in the slow release particles exists in the amorphous form. When the human body takes the drug, the rapid release particles can be rapidly released in the acidic environment in the stomach to immediately reach the effective concentration, and are absorbed in the duodenum and the upper part of the small intestine, while the slow release particles can be continuously released in the intestinal tract. Because the active ingredient mifepristone contained therein exists in the amorphous form, it can reach a supersaturated state after being released in the intestinal tract, thereby improving the solubility of the drug and being absorbed in the lower part of the small intestine. Moreover, this supersaturated state can be maintained for more than 4 hours under the action of the slow release material, thereby providing sufficient time for the absorption of the drug in the intestinal tract and further significantly improving the bioavailability. The slow release part of the present application does not adhere to the gastrointestinal tract, has little stimulation to the gastrointestinal tract, and has no risk of falling off.

[0009] The technical problem to be solved by the present application is solved by the following technical scheme.

[0010] The present application provides a mifepristone-containing preparation, which comprises immediate-release granules and sustained-release granules; the immediate-release granules comprise the following components: 5-15% mifepristone, 45-95% filler, 2-20% disintegrant, 0-2.0% lubricant and 0-8% binder; the above percentages are the weight percentages of each component relative to the total weight of the immediate-release granules;

[0011] The sustained-release granules comprise the following components: 4.5-15% mifepristone and 85-95.5% sustained-release auxiliary material; the above percentages are the weight percentages of each component relative to the total weight of the sustained-release granules.

[0012] In the sustained-release granules, the mifepristone is in an amorphous form; the weight ratio of the mifepristone in the immediate-release granules to the mifepristone in the sustained-release granules is (0.4-2.2): 1.

[0013] In the present application, the mifepristone in the immediate-release granules is preferably in a crystalline form.

[0014] In the present application, the immediate-release granules can be prepared by dry granulation or wet granulation.

[0015] In the present application, the weight ratio of the mifepristone in the immediate-release granules to the mifepristone in the sustained-release granules is preferably (0.5-2.1): 1, more preferably (0.8-2.0): 1, for example 1:1, 1.4: 1, 1.6:1, 1.8:1 or 2.0: 1.

[0016] In the present application, the amount of mifepristone in the immediate-release granules is preferably 6-14%, more preferably 7-13.33%, for example 8%, 9%, 10% or 12%.

[0017] In the present application, the filler in the immediate-release granules can be any kind of filler commonly used in the art, and is preferably selected from one or more of lactose, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, calcium carbonate, powdered cellulose and corn starch, more preferably a mixture of lactose and microcrystalline cellulose.

[0018] When the filler contains lactose, the amount of lactose is preferably 40-80%, more preferably 44-78%, for example 56.17%, 59.5%, 62%, 68%, 70%, 75% or 76%, the above percentages being the weight percentages relative to the total weight of the immediate-release granules.

[0019] When the filler contains microcrystalline cellulose, the amount of microcrystalline cellulose is preferably 5-22%, more preferably 6-21%, for example 8%, 10%, 15%, 18% or 20%, the above percentages being the weight percentages relative to the total weight of the immediate-release granules.

[0020] In the present invention, the amount of the filler in the immediate-release granules is preferably 50% to 85%, for example, 55%, 60%, 66.17%, 69.5%, 80% or 82%.

[0021] In the present invention, in the rapid-release granules, the disintegrant can be conventional in the art, preferably one or more of pregelatinized starch, potato starch, dextrin, croscarmellose sodium, sodium starch glycolate and cross-linked polyvinylpyrrolidone, such as pregelatinized starch and / or croscarmellose sodium.

[0022] The pregelatinized starch, the potato starch or the dextrin is usually used in a dry granulation process and can function as a disintegrant or a binder.

[0023] Wherein, the cross-linked sodium carboxymethyl cellulose, the sodium starch glycolate or the cross-linked polyvinylpyrrolidone is usually used in a wet granulation process.

[0024] In the present invention, in the rapid-release granules, when the disintegrant contains pregelatinized starch, the amount of pregelatinized starch is preferably 10-20%, for example 15% or 20%, and the above percentages are weight percentages relative to the total amount of the rapid-release granules;

[0025] In the present invention, in the rapid-release granules, when the disintegrant contains croscarmellose sodium, the amount of croscarmellose sodium is preferably 2-10%, for example 3% or 4%, and the above percentages are weight percentages relative to the total amount of the rapid-release granules.

[0026] In the present invention, the amount of the disintegrant in the rapid-release granules is preferably 4% to 20%, for example, 4%, 8%, 10%, 15%, 18% or 20%.

[0027] In the present invention, the lubricant in the immediate-release granules can be a lubricant conventionally added in dry granulation, which is used to prevent the roller from sticking during the dry granulation process. The lubricant can be magnesium stearate.

[0028] In the present invention, the amount of the lubricant in the immediate-release granules is preferably 0.2% to 2.0%, for example, 0.5%, 0.83% or 1%.

[0029] In the present invention, the binder in the immediate-release granules can be a binder conventionally added in wet granulation. The binder is preferably selected from one or more of povidone K30, povidone K25, povidone K90, hypromellose and hydroxypropyl cellulose, such as povidone K30.

[0030] In the present invention, the amount of the binder in the rapid-release granules is preferably 2% to 8%, for example, 4%.

[0031] In the present application, the sustained-release granules are preferably prepared by hot melt extrusion.

[0032] In the present application, the amount of mifepristone in the sustained-release granules is preferably 6-14%, more preferably 7-13.33%, for example 4.83%, 7.25%, 9%, 10% or 12%.

[0033] In the present application, the sustained-release granules, the sustained-release auxiliary materials are preferably selected from one or more of hydroxypropyl methyl cellulose, copovidone, hydroxypropyl methyl succinate acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyoxyethylene and polyvinyl alcohol, more preferably a mixture of hydroxypropyl methyl cellulose and copovidone.

[0034] When the sustained-release auxiliary materials contain hydroxypropyl methyl cellulose, the amount of hydroxypropyl methyl cellulose is preferably 20-50%, more preferably 25-50%, for example 28.99%, 30%, 40%, 46.38%, 47.58% or 50%, the above percentages being weight percentages relative to the total amount of the sustained-release granules.

[0035] When the sustained-release auxiliary materials contain copovidone, the amount of copovidone is preferably 40-70%, more preferably 43-65%, for example 46.38%, 47.58%, 50% or 63.77%, the above percentages being weight percentages relative to the total amount of the sustained-release granules.

[0036] In the present application, the amount of the sustained-release auxiliary materials in the sustained-release granules is preferably 88-95.5%, for example 89%, 90%, 92.75%, 94% or 95.17%.

[0037] In the present application, the form of the mifepristone-containing preparation is not limited, for example, it can be a capsule or a tablet.

[0038] The present application also provides a preparation method of the mifepristone-containing preparation, which comprises the following steps:

[0039] S1 the raw and auxiliary materials of the immediate-release granules are granulated by dry granulation or wet granulation to prepare the immediate-release granules;

[0040] S2 the raw and auxiliary materials of the sustained-release granules are prepared by hot melt extrusion to prepare the sustained-release granules.

[0041] The particle size of the mifepristone raw material for preparing the immediate-release granules in S1 or the mifepristone raw material for preparing the sustained-release granules in S2 is preferably D90≤10μm. Generally, the mifepristone raw material is micronized to a particle size of D90≤10μm using an air jet mill.

[0042] In the immediate-release granules of S1, the particle size of mifepristone is D90≤10μm.

[0043] In S2, the mifepristone in the sustained-release granules is in an amorphous state after hot melting and is dispersed in the auxiliary materials.

[0044] In S1, the raw and auxiliary materials of the immediate-release granules are generally mixed uniformly and then granulated by using a dry granulator.

[0045] In a preferred embodiment, the preparation method of the immediate-release granules can comprise the following steps: a) pre-mixing the raw and auxiliary materials except the binder in a wet granulator, adding a slurry containing the binder, and stirring and shearing to obtain wet granules; and b) transferring the wet granules to a fluidized bed for heating and drying to obtain dry granules. The solvent of the slurry containing the binder is generally water, and the concentration can be 20%.

[0046] In S1, the dry granulation or the wet granulation is generally sized by using a Φ1.5 mm screen.

[0047] In S2, the hot melt extrusion is generally performed in a conventional extruder. The extruder generally has 8 zones, and zones 1-3 are generally heating zones and can be operated according to the conventional operation in the art. Zones 4-8 are melting zones, and the temperature of the melting zone generally refers to the temperature of the hot melt extrusion.

[0048] In S2, the temperature of the hot melt extrusion is preferably 165-195°C, more preferably 170-190°C, for example, 175°C, 180°C or 185°C.

[0049] In S2, the extrudate obtained by the hot melt extrusion is generally cut into granules.

[0050] In S2, the average particle size D50 of the sustained-release granules is preferably 0.3-0.6 mm.

[0051] In the present application, the immediate-release granules and the sustained-release granules are generally mixed to obtain the mifepristone-containing preparation.

[0052] When the mifepristone-containing preparation is a capsule, the immediate-release granules, the sustained-release granules and an additional portion of magnesium stearate are generally mixed and then filled into the capsule.

[0053] The amount of the additional portion of magnesium stearate can be conventional in the art, for example, can be 25 g / 10,000 capsules.

[0054] On the basis of the common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, thereby obtaining various preferred examples of the present application.

[0055] The reagents and raw materials used in the present application are commercially available.

[0056] The positive progress effect of the present application is that:

[0057] The present application contains mifepristone formulation, which comprises immediate-release granules and sustained-release granules, and the sustained-release granules can be released in the intestinal tract, and after being released in the intestinal tract, the active ingredient mifepristone contained therein can reach a supersaturation state due to the existence of amorphous form, thereby improving the solubility of the drug, and the drug is absorbed at the lower end of the small intestine, and under the action of the sustained-release material, the supersaturation state can last for more than 4 hours, thereby providing sufficient time for the absorption of the drug in the intestinal tract, and further significantly improving the bioavailability. The sustained-release part of the present application does not adhere to the gastrointestinal tract, has little irritation to the gastrointestinal tract, and has no risk of falling off. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 The dissolution curves of the products of Examples 1-5 and Comparative Examples 1-3 in simulated empty stomach juice are shown in Table 1.

[0059] Figure 2 The dissolution curves of the products of Examples 1-5 and Comparative Examples 1-3 in simulated empty stomach juice are shown in Table 1.

[0060] Figure 3 The dissolution curves of the products of Examples 1-5 and Comparative Examples 1-3 in simulated empty stomach juice are shown in Table 1.

[0061] Figure 4 The dissolution curves of the products of Examples 1-5 and Comparative Examples 1-3 in simulated empty stomach juice are shown in Table 1. DETAILED DESCRIPTION

[0062] The present application will be further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples are not specified, and are selected according to conventional methods and conditions, or according to the instructions of the commodity.

[0063] In order to further understand the present application, the present application will be described in detail in conjunction with the examples.

[0064] The raw materials and equipment used in the examples and comparative examples of the present application are shown in the following table.

[0065] Table 1

[0066]

[0067] Examples 1-5

[0068] The capsule formulation containing mifepristone in Examples 1-5 is shown in the following table (in the following examples, the amount of the prescription is 10000 capsules):

[0069] Table 2

[0070]

[0071] In Examples 1-4, the weight ratio of mifepristone in the immediate-release granules to mifepristone in the sustained-release granules is 50:50. In Example 5, the weight ratio of mifepristone in the immediate-release granules to mifepristone in the sustained-release granules is 2:1.

[0072] The preparation method of the mifepristone-containing capsule formulation in Example 1, Examples 4-5 is the same, comprising the following steps:

[0073] Mifepristone pulverization: The mifepristone bulk drug is micronized to a particle size D90≤10 μm using an airflow pulverizer.

[0074] Immediate-release granule preparation: The micronized mifepristone, lactose, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate are mixed uniformly, and then granulated using a dry granulator, and the granules are sized using a Φ1.5 mm screen.

[0075] Sustained-release granule preparation: The micronized mifepristone, hydroxypropyl methyl cellulose, and copovidone are added to a hot melt extruder and hot melt extruded at 180°C (the extruder zones 1-3 are temperature zones, and zones 4-8 are melt zones, with the temperature of the melt zones being 180°C). The extrudate is cut into microparticles, with an average particle size (D50) of 0.3-0.6 mm.

[0076] Mifepristone capsule preparation: The immediate-release granules, the sustained-release granules, and the additional magnesium stearate are mixed and then used to fill capsules.

[0077] The preparation method of the mifepristone-containing capsule formulation in Example 2:

[0078] Mifepristone pulverization: The mifepristone bulk drug is micronized to a particle size D90≤10 μm using an airflow pulverizer.

[0079] Immediate-release granule preparation: a) Povidone K30 is added to purified water and stirred to dissolve to prepare a granulation slurry (concentration of 20%); b) The micronized mifepristone, lactose, microcrystalline cellulose, and croscarmellose sodium are added to a wet granulator, mixed uniformly, and then the prepared granulation slurry is added, and the mixture is stirred and sheared to obtain wet granules; c) The wet granules are transferred to a fluidized bed and heated to dry, to obtain dry granules; d) The dry granules are sized using a Φ1.5 mm screen, to obtain immediate-release granules.

[0080] Sustained-release granule preparation: The micronized mifepristone, hydroxypropyl methyl cellulose, and copovidone are added to a hot melt extruder and hot melt extruded at 180°C (the extruder zones 1-3 are temperature zones, and zones 4-8 are melt zones, with the temperature of the melt zones being 180°C). The extrudate is cut into microparticles.

[0081] Mifepristone capsule preparation: The immediate-release granules, the sustained-release granules, and the additional magnesium stearate are mixed and then used to fill capsules.

[0082] Example 3 Preparation method of capsule formulation containing mifepristone:

[0083] Milling of mifepristone: The mifepristone bulk drug was micronized to a particle size D90≤10 μm using an air jet mill.

[0084] Preparation of immediate-release granules: The micronized mifepristone, lactose, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate were mixed uniformly, and then granulated using a dry granulator, and the granules were sized using a Φ1.5 mm screen.

[0085] Preparation of sustained-release granules: The micronized mifepristone, hydroxypropyl methyl cellulose and copovidone were added to a hot melt extruder and hot melt extruded at 150°C (the extruder 1-3 zones were temperature zones, and 4-8 were melt zones, with a temperature of 150°C in the melt zones), and the extrudate was cut into microparticles.

[0086] Preparation of mifepristone capsules: The prepared immediate-release granules and sustained-release granules were mixed with magnesium stearate, and then the capsules were filled.

[0087] Comparative Examples 1-3

[0088] The capsule formulations containing mifepristone in Comparative Examples 1-3 are shown in the following table (in the following comparative examples, the prescription amount is 10000 capsules):

[0089] Table 3

[0090]

[0091] Comparative Example 1 (twice the amount of the immediate-release portion of Example 2)

[0092] Preparation method of capsule formulation containing mifepristone:

[0093] Milling of mifepristone: The mifepristone bulk drug was micronized to a particle size D90≤10 μm using an air jet mill.

[0094] Preparation of immediate-release granules: a) Povidone K30 was added to purified water and stirred to dissolve to prepare a granulation slurry (concentration of 20%); b) The micronized mifepristone, lactose, microcrystalline cellulose and croscarmellose sodium were added to a wet granulator, mixed uniformly, and then the prepared granulation slurry was added, and the granules were prepared by stirring and shearing; c) The wet granules were transferred to a fluid bed and dried to obtain dry granules; d) The dry granules were sized using a Φ1.5 mm screen to obtain immediate-release granules.

[0095] Preparation of mifepristone capsules: The prepared immediate-release granules were mixed with additional magnesium stearate, and then the capsules were filled.

[0096] Comparative Example 2 (twice the amount of the sustained-release portion of Example 1)

[0097] Preparation method of capsule preparation containing mifepristone:

[0098] Mifepristone pulverization: The mifepristone raw material was micronized using a jet mill to a particle size of D90 ≤ 10 μm.

[0099] Preparation of sustained-release granules: Micronized mifepristone, hypromellose and copovidone were added to a hot-melt extruder and hot-melt extruded at 180°C (zones 1 to 3 of the extruder were heating zones, zones 4 to 8 were melting zones, and the temperature of the melting zone was 180°C). The extrudate was cut into microparticles.

[0100] Preparation of mifepristone capsules: The immediate-release granules were mixed with an additional portion of magnesium stearate and then filled into capsules.

[0101] Comparative Example 3 (Investigation of the active ingredient ratio in rapid-release granules and sustained-release granules)

[0102] Regarding the prescription description: Compared with Example 1, the prescription amount of mifepristone in the sustained-release part in Comparative Example 3 was reduced by 62.5 g. In order to keep the total weight of the sustained-release part unchanged, the prescription amounts of hypromellose and copovidone were increased by 31.25 g each. Since the prescription amount of the sustained-release material changed slightly (only 3.62%), the impact on the sustained-release part was negligible.

[0103] In Comparative Example 3, the weight ratio of mifepristone in the immediate-release granules to mifepristone in the sustained-release granules was 3:1.

[0104] Preparation method of capsule preparation containing mifepristone:

[0105] Mifepristone pulverization: The mifepristone raw material was micronized using a jet mill to a particle size of D90 ≤ 10 μm.

[0106] Preparation of immediate-release granules: After uniformly mixing micronized mifepristone, lactose, microcrystalline cellulose, pregelatinized starch and magnesium stearate, granulate using a dry granulator and size the granules using a Φ1.5 mm sieve.

[0107] Preparation of sustained-release granules: Micronized mifepristone, hypromellose and copovidone were added to a hot-melt extruder and hot-melt extruded at 180°C (extruder zones 1 to 3 were heating zones, zones 4 to 8 were melting zones, and the temperature of the melting zone was 180°C). The extrudate was cut into microparticles.

[0108] Preparation of mifepristone capsules: The prepared quick-release granules and sustained-release granules are mixed with magnesium stearate and then filled into capsules.

[0109] Effect Example 1 Comparison of Preparation Dissolution Curves

[0110] The dissolution curves of the products of Examples 1-5 and Comparative Examples 1-3 in simulated fasted gastric fluid (FaSSGF) and simulated fasted intestinal fluid (FaSSIF) were determined as follows: 900 ml of FaSSGF and FaSSIF were used as the dissolution medium, and the dissolution curves were determined at 75 rpm by the slurry method (one capsule was placed in each of six dissolution cups, and the dissolution amount was determined at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, and 4 h, and the results at each time point were averaged).

[0111] Figure 1 The results of the dissolution curves of the products of Examples 1-5 and Comparative Examples 1-3 in simulated gastric fluid showed that:

[0112] Comparative Example 1: The dissolution rate of the capsule composed of all immediate-release granules was too fast (more than 85% was dissolved in the first 30 minutes), and when the drug was transferred to the small intestine, a portion of the drug crystallized and precipitated due to the increase in pH, which made it difficult to be absorbed, thereby leading to a decrease in the bioavailability of the drug.

[0113] Comparative Example 2: The dissolution rate of the capsule composed of all sustained-release granules was too slow (only 21% was dissolved in the first 30 minutes), and the insufficient absorption of the drug in the duodenum and the upper part of the small intestine also led to a decrease in the bioavailability.

[0114] Comparative Example 3 (ratio of immediate-release active ingredient to sustained-release active ingredient 3:1): The dissolution in the first 30 minutes was 71%, which was still relatively high, given that the bioavailability of the mifepristone immediate-release preparation was only 30%-50%.

[0115] Examples 1-4: The dissolution of the capsule composed of immediate-release granules and sustained-release granules in the first 30 minutes was 50%-60%, and this portion of the drug was mainly released from the immediate-release granules in the stomach and absorbed in the duodenum and the upper part of the small intestine, and since the drug concentration was moderate, there was little precipitation, and the remaining sustained-release granules were slowly released in the intestinal tract and were mainly absorbed in the lower part of the small intestine.

[0116] Example 5 (ratio of immediate-release active ingredient to sustained-release active ingredient 2:1): The dissolution in the first 30 minutes was slightly lower than that of Comparative Example 3, and the risk of precipitation in the intestinal tract was reduced.

[0117] Figure 2 The results of the dissolution curves of the products of Examples 1-5 and Comparative Examples 1-3 in simulated fasted intestinal fluid showed that:

[0118] Comparative Example 1: The final dissolution of the capsule composed of all immediate-release granules was relatively low, because the solubility of crystalline mifepristone was limited in the slightly neutral pH environment.

[0119] Comparative Example 2: Since there were no immediate-release granules, the initial dissolution was relatively low, which led to insufficient absorption in the duodenum and the upper part of the small intestine.

[0120] Comparative Example 3 (ratio of immediate release and sustained release active ingredients 75:25): the final dissolution amount is low (29%), and the improvement in bioavailability is not much.

[0121] Examples 1, 2 and 4: from the dissolution data, the dissolution plateau of the capsules containing the sustained release particles is high, and the solubility is significantly improved, because the mifepristone in the sustained release particles exists in an amorphous state, and after release, it reaches a supersaturated state in the intestinal fluid, and the hydroxypropyl methyl cellulose and copovidone can inhibit the crystallization of the supersaturated drug, so that the supersaturated state lasts for more than 4 hours, thereby ensuring the absorption of the drug in the small intestine. The time of the drug passing through the intestinal tract is generally 3-4 hours, which provides sufficient time for the absorption of the drug in the intestinal tract. In Examples 2 and 4, the content of hydroxypropyl methyl cellulose in the sustained release particles is reduced, and the dissolution plateau of the preparation is slightly lower.

[0122] Example 3 (hot melt extrusion temperature 150°C): after the melting temperature is reduced, the dissolution amount is lower than that of Example 1.

[0123] Example 5: compared with Comparative Examples 1 and 3, the 4h dissolution in simulated intestinal fluid is increased, which is beneficial to the improvement of bioavailability.

[0124] The specific dissolution data is shown below:

[0125] Table 4

[0126]

[0127] Table 5

[0128]

[0129] Analysis of each example and comparative example:

[0130] Example 1: the optimal example, the dissolution amount in simulated gastric fluid for 0.5 hours (the residence time of the drug in the stomach is generally not more than 0.5 hours) is 53%, which is mainly due to the rapid release of the immediate release particles, which ensures the absorption of the drug in the duodenum and the upper part of the small intestine. The dissolution amount in simulated intestinal fluid for 4 hours (the residence time of the drug in the intestinal tract is generally 3-4 hours) is 48%, which is higher than that of Comparative Example 1 composed of only immediate release particles. The dissolution amount of Comparative Example 1 in simulated intestinal fluid for 4 hours is only 22%, and does not increase any more, indicating that the solubility of mifepristone in the crystal form has reached saturation. The dissolution amount of the drug containing amorphous sustained release particles is all more than 22%, indicating that the preparation of mifepristone into an amorphous state can make it reach a supersaturated state, and the hydroxypropyl methyl cellulose and copovidone contained in the sustained release particles can inhibit the recrystallization thereof, so that the supersaturated state lasts for more than 4 hours, thereby ensuring the absorption of the drug in the lower part of the small intestine.

[0131] Example 2 and Example 4: On the basis of Example 1, the proportion of hypromellose is reduced from 46% to 29%. After reducing the proportion of hypromellose, the dissolution of the drug in simulated intestinal fluid is reduced.

[0132] Example 3: On the basis of Example 1, the hot melt extrusion temperature is reduced from 180°C to 150°C. After reducing, the dissolution of the drug in simulated intestinal fluid is reduced.

[0133] Example 5: The proportion of mifepristone contained in the immediate-release granules and the sustained-release granules is 67:33. Compared with Comparative Example 3, the dissolution in simulated gastric fluid for 0.5h is reduced, the risk of precipitation is reduced, the dissolution in simulated intestinal fluid for 4h is increased, and the bioavailability is improved.

[0134] Comparative Example 1: It is composed of immediate-release granules only, and the dissolution in simulated gastric fluid for 0.5h is high (86%). The drug that is not completely absorbed will be transferred to the intestine and will precipitate. The dissolution of the crystalline mifepristone in simulated intestinal fluid for 4h is only 22%, which cannot guarantee the absorption of the drug in the intestine.

[0135] Comparative Example 2: It is composed of sustained-release granules only, and the final dissolution in simulated intestinal fluid is high, but the dissolution in simulated gastric fluid for 0.5h is low, only 21%, which will lead to insufficient absorption of the drug in the duodenum and the upper part of the small intestine.

[0136] Comparative Example 3: The proportion of mifepristone contained in the immediate-release granules and the sustained-release granules is adjusted from 50:50 to 75:25. After adjusting, the dissolution of the drug in simulated gastric fluid for 0.5h is high (71%). Since the bioavailability of the immediate-release preparation of mifepristone is only 30%-50%, this dissolution cannot be completely absorbed by the human body. Compared with Example 1, the dissolution in simulated intestinal fluid is low, and the improvement of the bioavailability is not much. Therefore, the present application controls the ratio of mifepristone contained in the immediate-release granules and the sustained-release granules to be in the range of (0.4-2.2):1.

[0137] Effect Example 2 Stability Test

[0138] Example 1 The mifepristone capsule preparation was subjected to accelerated 3-month (40°C / 75%RH) dissolution stability test. Specifically,

[0139] The mifepristone capsule preparation of Example 1 was placed under accelerated conditions for 3 months (40°C / 75%RH), and samples were taken at 0 months, 1 month and 3 months, respectively. The dissolution curves were tested in simulated gastric fluid and simulated intestinal fluid according to the method of Effect Example 1. The results showed that the dissolution curve did not change significantly, the dissolution stability was good, and the amorphous drug contained therein did not recrystallize.

[0140] Other embodiments of mifepristone capsule formulations were prepared and tested for stability. The results were comparable to the stability results of Example 1.

[0141] Figure 3 The dissolution profile of the mifepristone capsule formulation of Example 1 in simulated gastric fluid after 1 and 3 months of accelerated storage was determined.

[0142] Figure 4 The dissolution profile of the mifepristone capsule formulation of Example 1 in simulated intestinal fluid after 1 and 3 months of accelerated storage was determined.

[0143] The specific data are as follows:

[0144] Table 6

[0145]

[0146] Table 7

[0147]

Claims

1. A preparation containing mifepristone, characterized in that It comprises immediate-release granules and sustained-release granules; the immediate-release granules comprise the following components: 5-15% mifepristone, 45%-95% filler, 2%-20% disintegrant, 0-2.0% lubricant, and 0-8% binder; the above percentages are the weight percentages of each component relative to the total amount of the immediate-release granules; The sustained-release granules comprise the following components: 4.5-15% mifepristone and 85-95.5% sustained-release auxiliary materials, wherein the above percentages are the weight percentages of each component relative to the total amount of the sustained-release granules; In the sustained-release granules, the mifepristone exists in an amorphous form; the weight ratio of the mifepristone in the immediate-release granules to the mifepristone in the sustained-release granules is (0.4-2.2):

1.

2. The preparation containing mifepristone according to claim 1, wherein In the rapid-release granules, the mifepristone exists in a crystalline form; And / or, the weight ratio of mifepristone in the immediate-release granules to mifepristone in the sustained-release granules is (0.5-2.1):1, preferably (0.8-2.0):1, for example, 1:1, 1.4:1, 1.6:1, 1.8:1 or 2.0:

1.

3. The preparation containing mifepristone according to claim 1, wherein It meets one or more of the following conditions: (1) In the rapid-release granules, the amount of mifepristone is 6-14%; (2) In the immediate-release granules, the amount of the filler is 50% to 85%; (3) In the rapid-release granules, the amount of the disintegrant is 4% to 20%; (4) In the immediate-release granules, the amount of the lubricant is 0.2% to 2.0%; (5) In the immediate-release granules, the amount of the binder is 2% to 8%; (6) In the sustained-release granules, the amount of mifepristone is 6-14%; and (7) In the sustained-release granules, the amount of the sustained-release auxiliary material is 88% to 95.5%.

4. The preparation containing mifepristone according to claim 1, wherein It meets one or more of the following conditions: (1) In the immediate-release granules, the amount of mifepristone is 7% to 13.33%, for example, 8%, 9%, 10% or 12%; (2) In the immediate-release granules, the amount of the filler is 55%, 60%, 66.17%, 69.5%, 80% or 82%; (3) In the immediate-release granules, the amount of the disintegrant is 4%, 8%, 10%, 15%, 18% or 20%; (4) In the immediate-release granules, the amount of the lubricant is 0.5%, 0.83% or 1%; (5) In the immediate-release granules, the amount of the binder is 4%; (6) In the sustained-release granules, the amount of mifepristone is 7 to 13.33%, for example, 4.83%, 7.25%, 9%, 10% or 12%; and, (7) In the sustained-release granules, the amount of the sustained-release auxiliary material is 89%, 90%, 92.75%, 94% or 95.17%.

5. The preparation containing mifepristone according to claim 1, wherein It meets one or more of the following conditions: (1) In the rapid-release granules, the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate, calcium carbonate, powdered cellulose, and corn starch; (2) In the rapid-release granules, the disintegrant is selected from one or more of pregelatinized starch, potato starch, dextrin, croscarmellose sodium, sodium starch glycolate, and cross-linked polyvinylpyrrolidone; (3) In the immediate-release granules, the lubricant is magnesium stearate; (4) In the rapid-release granules, the binder is selected from one or more of povidone K30, povidone K25, povidone K90, hypromellose and hydroxypropyl cellulose; and, (5) In the sustained-release granules, the sustained-release excipient is selected from one or more of hydroxypropyl methylcellulose, copovidone, hydroxypropyl methyl acetate succinate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide and polyvinyl alcohol.

6. The preparation containing mifepristone according to claim 1, wherein It meets one or more of the following conditions: (1) In the rapid-release granules, the filler is a mixture of lactose and microcrystalline cellulose; (2) In the rapid-release granules, the disintegrant is selected from pregelatinized starch and / or cross-linked sodium carboxymethyl cellulose; (3) In the rapid-release granules, the binder is povidone K30; and (4) In the sustained-release granules, the sustained-release excipient is a mixture of hypromellose and copovidone.

7. The preparation containing mifepristone according to claim 1, wherein When the filler contains lactose, the amount of lactose used is 40% to 80%, and the above percentages are the weight percentages of each component relative to the total amount of the immediate-release granules; When the filler contains microcrystalline cellulose, the amount of microcrystalline cellulose is 5% to 22%, and the above percentages are weight percentages relative to the total amount of the immediate-release particles; When the disintegrant contains pregelatinized starch, the amount of pregelatinized starch is 10-20%, and the above percentages are weight percentages relative to the total amount of the immediate-release granules; When the disintegrant contains croscarmellose sodium, the amount of croscarmellose sodium is 2 to 10%, and the above percentages are weight percentages relative to the total amount of the immediate-release granules; When the sustained-release excipient contains hypromellose, the amount of hypromellose is 20-50%, and the above percentages are weight percentages relative to the total amount of the sustained-release particles; When the sustained-release auxiliary material contains copovidone, the amount of copovidone used is 40% to 70%, and the above percentages are weight percentages relative to the total amount of the sustained-release particles.

8. The preparation containing mifepristone according to claim 7, wherein When the filler contains lactose, the amount of lactose is 44% to 78%, such as 56.17%, 59.5%, 62%, 68%, 70%, 75% or 76%; When the filler contains microcrystalline cellulose, the amount of microcrystalline cellulose is 6% to 21%, for example, 8%, 10%, 15%, 18% or 20%; When the disintegrant contains pregelatinized starch, the amount of pregelatinized starch is 15% or 20%; When the disintegrant contains croscarmellose sodium, the amount of croscarmellose sodium is 3% or 4%; When the sustained-release excipient contains hypromellose, the amount of hypromellose is 25% to 50%, for example, 28.99%, 30%, 40%, 46.38%, 47.58% or 50%; When the sustained-release excipient contains copovidone, the amount of copovidone is 43% to 65%, for example, 46.38%, 47.58%, 50% or 63.77%.

9. A method for preparing a preparation containing mifepristone according to any one of claims 1 to 8, characterized in that: It includes the following steps: S1 The raw materials and excipients of the immediate-release granules are prepared by dry granulation or wet granulation to obtain the immediate-release granules; S2 The raw materials and auxiliary materials of the sustained-release granules are hot-melt extruded to prepare the sustained-release granules.

10. The preparation method according to claim 9, characterized in that The preparation method satisfies one or more of the following conditions: (1) The particle size D90 of the raw material drug mifepristone used in the preparation of the immediate-release granules described in S1, or the raw material drug mifepristone used in the preparation of the sustained-release granules described in S2 is ≤10 μm; (2) In S1, after the dry granulation or the wet granulation, the granules are sieved with a Φ1.5 mm mesh; (3) In S2, the temperature of the hot melt extrusion is 165°C to 195°C, preferably 170°C to 190°C, for example 175°C, 180°C or 185°C; (4) In S2, the average particle size D50 of the sustained-release particles is 0.3 mm to 0.6 mm; (5) When the preparation containing mifepristone is a capsule, the quick-release granules, the sustained-release granules and an additional portion of magnesium stearate are mixed and then filled into the capsule.

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