Pharmaceutical composition and preparation method thereof

Abstract

The invention provides a pharmaceutical composition containing an active component, a filler, an adhesive and hydrogenated castor oil and a preparation method of the pharmaceutical composition, the active component comprises cis-(+)-5-[(2-dimethylamino) ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2, 3-dihydro-1, 5-benzothiaza # imgabs0 #-4 (5H)-one hydrochloride, and the filler, the adhesive and the hydrogenated castor oil are used for preparing the pharmaceutical composition. The weight ratio of the filler to (the adhesive and the hydrogenated castor oil) is 3.5: 1-4.5: 1. The pharmaceutical composition disclosed by the invention is good in process compressibility, excellent in hardness and tablet weight stability and stable and reliable in quality, and the dissolution of the medicine meets the specification.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a pharmaceutical preparation comprising cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-keto hydrochloride pharmaceutical composition and preparation method thereof. Background Art

[0002] Diltiazem It is a calcium channel blocker that inhibits the entry of calcium ions into vascular smooth muscle cells and myocardial cells, thereby reducing myocardial oxygen consumption, dilating coronary arteries and peripheral blood vessels, lowering blood pressure, and reducing cardiac load. The compound has two chiral centers and can produce four chiral isomers. Compound cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketohydrochloride is also called diltiazem hydrochloride Compounds with clinical uses are widely used in the treatment of heart disease, angina pectoris, etc.

[0003] CN108524459A discloses a diltiazem Tablets and preparation methods thereof, compared with the traditional static cooling method, this method can simplify the subsequent process through vacuum loading, and the product stability and quality are higher. However, the patent does not provide diltiazem Regarding the quality and stability of the tablets, the tablets prepared in this application according to its disclosed prescription process do not meet the requirements in terms of hardness and tablet weight stability.

[0004] Other existing technologies all add a variety of excipients, and the ingredients are relatively complex. Therefore, it is necessary to continue to study diltiazem The preparation prescription process is aimed at obtaining a preparation product with good process compressibility, excellent quality and fewer types of pharmaceutical excipients. Summary of the invention

[0005] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a technical solution to the above problem.

[0006] According to a first aspect of the present invention, a pharmaceutical composition comprising an active ingredient, a filler, a binder and hydrogenated castor oil is provided, wherein the active ingredient comprises cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketone hydrochloride; the weight ratio of the filler: (binder + hydrogenated castor oil) is in the range of 3.5:1-4.5:1.

[0007] According to a second aspect of the present invention, there is provided a method for preparing the pharmaceutical composition of the present invention, comprising the following steps:

[0008] Granulation: The active ingredient, filler, hydrogenated castor oil and binder are mixed and granulated; the weight ratio of the filler: (binder + hydrogenated castor oil) ranges from 3.5:1 to 4.5:1;

[0009] Mixing: mixing the granules obtained by granulation with a lubricant to obtain mixed granules;

[0010] Tableting: The mixed granules are compressed into tablets.

[0011] The pharmaceutical composition of the present invention comprises an active ingredient, a filler, hydrogenated castor oil and a binder. In the present invention, the active ingredient comprises cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketone hydrochloride; and the weight ratio of filler: (binder + hydrogenated castor oil) is in the range of 3.5:1-4.5:1. The pharmaceutical composition has good process compressibility, excellent hardness and tablet weight stability, stable and reliable quality, and drug dissolution meets regulations.

[0012] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0014] Figure 1 The compound of the present invention is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -X-ray powder diffraction pattern of 4(5H)-keto hydrochloride. The horizontal axis is 2θ (°) and the vertical axis is intensity (counts);

[0015] Figure 2 The compound of the present invention is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of -4(5H)-keto hydrochloride. DETAILED DESCRIPTION

[0016] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0017] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0018] The endpoints and any values ​​of the ranges disclosed in this article 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 each range, the endpoint values ​​of each range and the individual point values, and the 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 article.

[0019] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0020] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0021] Pharmaceutical composition

[0022] The present invention provides a pharmaceutical composition comprising an active ingredient, a filler, a binder and hydrogenated castor oil, wherein the active ingredient comprises cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketone hydrochloride; the weight ratio of the filler: (binder + hydrogenated castor oil) is in the range of 3.5:1-4.5:1.

[0023] In a specific embodiment, the weight ratio of filler: (binder + hydrogenated castor oil) of the present invention is selected from any one of 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1 or a range between any two of the values.

[0024] In a specific embodiment, the filler of the present invention includes lactose, such as spray-dried lactose, α-lactose, β-lactose, lactose monohydrate, anhydrous lactose; the filler of the present invention also includes sucrose, mannitol, dextrin, maltodextrin, starch or modified starch, and the modified starch includes, for example, potato starch, corn starch, and rice starch.

[0025] In a specific embodiment, the filler of the present invention is selected from one or more of lactose, dextrin, starch, and modified starch. Specifically, the lactose is selected from anhydrous lactose and / or lactose monohydrate.

[0026] In a specific embodiment, the filler is selected from one or more of lactose, dextrin, starch, and modified starch, and the weight percentage of the filler in the pharmaceutical composition is 35%-85%.

[0027] In a specific embodiment, the filler is selected from lactose.

[0028] In a specific embodiment, the weight percentage of the filler of the present invention in the composition is 35%-85%, preferably 45-80%, most preferably 55-75%; the filler is selected from lactose, and the lactose is selected from anhydrous lactose and / or lactose monohydrate.

[0029] In a particular embodiment, the composition of the invention does not include microcrystalline cellulose.

[0030] In one embodiment, the composition of the present invention does not include calcium carbonate.

[0031] In a specific embodiment, the weight percentage of the hydrogenated castor oil of the present invention in the composition is 5-20%, for example, the weight percentage of the hydrogenated castor oil in the composition is selected from any one of 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or a range between any two of the values.

[0032] In a specific embodiment, the binder of the present invention includes sodium carboxymethylcellulose, ethylcellulose, hydroxypropyl methylcellulose, methylcellulose, pectin, polyethylene glycol, povidone, pregelatinized starch, and the like.

[0033] In a specific embodiment, the binder of the present invention is selected from one or more of sodium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, pectin, polyethylene glycol, povidone, and pregelatinized starch.

[0034] In a specific embodiment, the polyethylene glycol can be selected from: one or more of PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, and PEG 10000.

[0035] In a specific embodiment, the weight percentage of the adhesive of the present invention in the composition is 1%-12%. For example, the weight percentage of the adhesive of the present invention in the composition is selected from any one of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, or a range between any two values, preferably 1-10%, and most preferably 1-8%.

[0036] In a specific embodiment, the present invention further comprises a lubricant, which is selected from stearic acid, magnesium stearate, calcium stearate or other metal stearates, talc, wax and glyceride, light mineral oil, glyceryl behenate, colloidal silicon dioxide and the like.

[0037] In a specific embodiment, the weight percentage of the lubricant of the present invention in the composition is 0%-5%. For example, the weight percentage of the lubricant of the present invention in the composition is selected from any one of 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%, or a range between any two values. The weight percentage of the lubricant of the present invention in the composition is preferably 0-3%.

[0038] In a specific embodiment, the composition comprises the following:

[0039] The composition comprises 9% to 30% by weight of active ingredients;

[0040] The composition comprises 35% to 85% by weight of a filler;

[0041] The composition comprises 5% to 20% by weight of hydrogenated castor oil;

[0042] The composition comprises 1% to 12% by weight of a binder; and / or

[0043] The composition comprises 0-3% by weight of a lubricant.

[0044] In a specific embodiment, the composition comprises the following:

[0045] The composition comprises 9% to 30% by weight of active ingredients;

[0046] The composition comprises 35% to 85% by weight of lactose;

[0047] The composition comprises 5% to 20% by weight of hydrogenated castor oil;

[0048] The composition comprises 1% to 12% by weight of polyethylene glycol; and / or

[0049] The composition comprises 0%-3% by weight of magnesium stearate.

[0050] In a specific embodiment, the composition comprises the following:

[0051] The composition comprises 9% to 30% by weight of active ingredients;

[0052] The composition comprises 35% to 85% by weight of a filler;

[0053] The composition comprises 5% to 20% by weight of hydrogenated castor oil;

[0054] The composition comprises 1% to 12% by weight of a binder; and / or

[0055] The composition comprises 0-3% by weight of a lubricant.

[0056] The preparation method of the pharmaceutical composition comprises the following steps:

[0057] The active ingredient, filler, hydrogenated castor oil and binder are mixed and granulated; the granules obtained by granulation are divided into N portions, namely, the first portion of granules, the second portion of granules, ... the Nth portion of granules, where N is greater than or equal to 2;

[0058] a) mixing the first batch of granules with a lubricant to obtain premixed granules 1;

[0059] b) mixing the second batch of granules with the premixed granules 1 to obtain premixed granules 2;

[0060] c) Repeat step b) until the Nth batch of granules is mixed with the premixed granules N-1 obtained from the previous mixing to obtain mixed granules.

[0061] In a specific embodiment, the pharmaceutical composition of the present invention contains about 10 mg-360 mg of active ingredient per dose, for example, 20 mg, or about 30 mg, or about 50 mg, or about 60 mg, or about 90 mg of active ingredient.

[0062] In a specific embodiment, the composition comprises:

[0063] a) 30 mg active ingredient, 100-200 mg lactose, 15-30 mg hydrogenated castor oil, 8-15 mg polyethylene glycol, 1-4 mg magnesium stearate; or

[0064] b) 60 mg active ingredient, 100-300 mg lactose, 15-60 mg hydrogenated castor oil, 8-30 mg polyethylene glycol, 1-8 mg magnesium stearate; or

[0065] c) 90 mg active ingredient, 100-600 mg lactose, 15-90 mg hydrogenated castor oil, 8-45 mg polyethylene glycol, 1-12 mg magnesium stearate.

[0066] In a specific embodiment, the composition of the present invention is a stable pharmaceutical composition.

[0067] In a specific embodiment, the active ingredient is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketohydrochloride uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ values ​​is substantially as follows Figure 1 shown.

[0068] In the present invention, "having substantially Figure 1 The term "substantially" used in the "X-ray powder diffraction pattern shown" means that the exact position of the peak in the accompanying drawing should not be interpreted as an absolute value. Because it is known to those skilled in the art that the 2θ value of the X-ray powder diffraction pattern may produce errors due to different measurement conditions (such as the equipment and instruments used) and different samples (such as samples from different batches), the measurement error of the diffraction angle of the X-ray powder diffraction pattern is 5% or less, and generally, a difference of ±0.2° of a given value is considered appropriate. It should also be understood that the relative intensity of the peak may fluctuate with experimental conditions and sample preparation such as the preferred orientation of particles in the sample. The use of automatic or fixed divergence slits will also affect the calculation of relative intensities. The intensities shown in the XRD curves included here are only exemplary and cannot be used as absolute comparisons, and any crystalline form having a powder diffraction pattern that is substantially the same as those disclosed herein is within the scope of protection of the present invention.

[0069] Method for preparing pharmaceutical composition

[0070] The present invention provides a method for preparing a pharmaceutical composition, wherein the pharmaceutical composition comprises an active ingredient, a filler, hydrogenated castor oil, a binder and a lubricant, and comprises the following steps:

[0071] Granulation: The active ingredient, filler, hydrogenated castor oil and binder are mixed and granulated; the weight ratio of the filler: (binder + hydrogenated castor oil) ranges from 3.5:1 to 4.5:1;

[0072] Mixing: mixing the granules obtained by granulation with a lubricant to obtain mixed granules;

[0073] Tableting: The mixed granules are compressed into tablets.

[0074] In one embodiment, the granulation step is achieved by the following operations: weighing the active ingredient, filler, hydrogenated castor oil, and binder, mixing them to obtain a mixed powder, granulating the mixed powder using a granulator, and cooling the particles to obtain granulated particles. The weight ratio of the filler: (binder + hydrogenated castor oil) is in the range of 3.5:1-4.5:1.

[0075] Specifically, material mixing may also include an operation of crushing the materials, for example, one or more of the active ingredients, fillers, adhesives, hydrogenated castor oil and the like may be crushed and then mixed to obtain a mixed powder.

[0076] Specifically, the granulation operation is to put the mixed drug powder into a granulator for granulation, the granule temperature range is 80-100° C., and granulated granules are obtained after cooling.

[0077] In one embodiment, the mixing step is achieved by the following operation: uniformly mixing the granules obtained by granulation with the lubricant to obtain mixed granules. Specifically, the mixing may include a pre-mixing operation, such as first mixing a portion of the granulated granules with the lubricant, and then sequentially mixing with one or more batches of the remaining granulated granules.

[0078] In one embodiment, the mixing step is achieved by:

[0079] The granules obtained by granulation are divided into N portions, namely the first portion of granules, the second portion of granules, ... the Nth portion of granules, where N≥2;

[0080] a) mixing the first batch of granules with a lubricant to obtain premixed granules 1;

[0081] b) mixing the second batch of granules with the premixed granules 1 to obtain premixed granules 2;

[0082] c) Repeat step b) until the Nth batch of granules is mixed with the premixed granules N-1 obtained from the previous mixing to obtain mixed granules.

[0083] In a specific embodiment, the tableting step is achieved by the following operations: tableting the mixed granules obtained in the mixing step; and / or, the tableting step is performed by a tablet press.

[0084] Unless otherwise stated, the various embodiments or embodiments of different preferred levels described in the present invention can be arbitrarily combined.

[0085] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0086] Example 1: Active ingredient cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine Preparation of -4(5H)-Ketohydrochloride

[0087] (2S,3S)-5-(2-(dimethylamino)ethyl)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one (CAS 42399-40-6; 3 kg) was heated to 90-100°C in 40 L of acetic anhydride and reacted for 1-2 hours. Excess acetic anhydride was distilled off under reduced pressure, and the residue was dissolved in 2-butanone and ethanolic hydrochloric acid solution was added to prepare cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketone hydrochloride crude product, the crude product is recrystallized using 1L methanol, 3.5L anhydrous ethanol and 500mL purified water: heat up and stir to dissolve the system, add 25g activated carbon to the system, filter while hot, slowly cool down to precipitate solid, rinse with anhydrous ethanol, and dry to obtain 2.75kg white solid (purity 99.96%, optical rotation 117.8°).

[0088] Example 2: Crystalline form of active ingredient

[0089] The X-ray powder diffraction data of the samples were collected under ambient conditions using an Aeris X-ray powder diffractometer from Malvern Panalytical, with a scan range of 3.5°-40°, a scan step of 0.02°, a voltage of 40KV, and a current of 15mA. The X-ray tube used a Cu target.

[0090] The model of the differential scanning calorimeter is TA Instruments DSC250. 4-5 mg of the sample was accurately weighed and placed in a perforated DSC aluminum sample pan and heated to the final temperature at a rate of 10°C / min, with a nitrogen purge rate of 50 mL / min in the furnace. The model of the thermogravimetric analyzer is TA Instruments TGA500. 4-5 mg of the sample was placed in a balanced open aluminum sample pan and automatically weighed in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10°C / min, with a nitrogen purge rate of 25 mL / min.

[0091] The crystal diffraction peak positions of the compounds of the present invention are shown in Table 2-1, and the XRPD spectrum is shown in Figure 1 shown.

[0092] Table 2-1 XRPD diffraction peak data of the crystal form of the compound described in the present invention

[0093]

[0094]

[0095]

[0096] Among the above characteristic diffraction peaks, the main characteristic diffraction peaks of the crystal form include 4.35, 8.53, 16.93, 19.55, 29.29; and may also include any one or more of 20.64, 27.65, 29.73, 38.47; the main characteristic peaks may include 4.35, 8.53, 16.93, 19.55, 27.65, 29.29, 38.47; and may also include 4. 35, 8.53, 16.93, 19.55, 20.64, 27.65, 29.29, 29.73, 38.47; may also include any one or more of 10.74, 21.81, 23.32; still may also include any one or more of 12.72, 15.36, 18.22, 21.16, 25.42, 26.04, 27.30, 32.88.

[0097] In addition, the DSC spectrum and TGA spectrum of the crystalline form of the compound of the present invention are as follows Figure 2 DSC shows that the starting point temperature of the phase change of the sample is 213.92℃, and TGA results show that the weight loss is 0.86% before 213.92℃. The sample continues to lose weight during the heating process and has an endothermic peak at a peak value of 216.27℃.

[0098] Example 3: Formulation Study

[0099] 3.1 Preparation of Formulation 1

[0100] According to the prescription composition of Table 3-1, the active ingredient uses the raw material prepared in Example 1 of the present invention, and the preparation 1 is prepared according to the following process.

[0101] Granulation: Weigh the raw material drug, polyethylene glycol 6000 (commercially available, purchased from Nanjing Well Pharmaceutical Group Co., Ltd.) and lactose (commercially available, purchased from Megler GmbH & Co. KG, Germany), crush and sieve to obtain fine powders of each raw material with a particle size of 0.074 mm, and then fully mix the fine powders of each raw material with hydrogenated vegetable oil (commercially available, purchased from JRS Pharma LP) for 5 minutes to obtain a mixed drug powder;

[0102] The mixed powder is granulated using a high-speed stirring granulator, wherein the heating temperature of the high-speed stirring granulator is 90° C., the side knife speed is 3000 rpm, and the stirring speed is 250 rpm, and the granule temperature is heated to 85° C.; then the granules are sucked into a fluidized bed granulator by vacuum feeding, all the granules are blown up by normal temperature gas and cooled to 40° C., and sieved to obtain granules with a particle size of 0.8 mm;

[0103] Mixing: The granules were mixed with magnesium stearate (commercially available from Hunan Erkang Pharmaceutical Co., Ltd.) to obtain mixed granules;

[0104] Tableting: tabletting is performed using a high-speed rotary tablet press to obtain the tablets, with a specification of 30 mg / tablet and a total of 500 tablets.

[0105] Table 3-1 Prescription of Preparation 1

[0106]

[0107]

[0108] Preparation 1 has good compressibility, and there is no sticking or powder adhesion during the tableting process.

[0109] 3.2 Formulation 2-Formulation 6

[0110] The present invention further studies the composition of the preparation and investigates the effect of the preparation, including the study of the types of hardened oil and filler in the preparation. According to the prescription composition of Table 3-2, tablets are prepared with reference to the process of Section 3.1. Preparations 2-6 all use the API prepared in the embodiment of the present invention, and the excipients such as polyethylene glycol 6000 and magnesium stearate of Preparations 2-6 are the same as the excipients used in the process of Section 3.1; the hardened oil in Preparation 2 uses hydrogenated vegetable oil (commercially available, purchased from JRS Pharma LP), the hardened oil in Preparation 3 uses hydrogenated palm oil (commercially available, purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.) instead of hydrogenated vegetable oil, and the hardened oil in Preparations 4-6 uses hydrogenated castor oil (commercially available, purchased from BASF (China) Co., Ltd.) instead of hydrogenated vegetable oil. Microcrystalline cellulose (commercially available, purchased from Asahi Kasei Corporation) is used as a filler in Preparation 4 instead of lactose, and calcium carbonate (commercially available, purchased from SUDEEP PHARMA PVT.LTD) is used as a filler in Preparation 5 instead of lactose.

[0111] Table 3-2 Prescription of Preparation 2-6

[0112]

[0113]

[0114] Preparations 2-6 all have good compressibility during the tableting process, without sticking or powder adhesion; however, preparations 4 and 5 have poor tablet surface glossiness, and further studies have found that the addition of microcrystalline cellulose has an adverse effect on the dissolution of the preparations. Therefore, the preparation composition of the present invention does not include microcrystalline cellulose and calcium carbonate.

[0115] Preparations 1-3 and Preparation 6 had complete and smooth surfaces with uniform color. The hardness of the preparations was further tested according to the following method.

[0116] Hardness test: Randomly select 10 tablets from the preparation to be tested and use a hardness tester to test their radial crushing force. The data displayed by the tablet fracture hardness tester is the hardness of the tablet. Record the tablet hardness of each preparation and calculate the average hardness as the hardness of the preparation.

[0117] Table 3-3 Test results of preparations 1-3 and 6:

[0118] Inspection items Control indicators Preparation 1 Preparation 2 Preparation 3 Preparation 6 Characteristics White flakes qualified qualified qualified qualified Appearance One-sided smooth qualified qualified qualified qualified hardness >4kg 3.88 3.91 3.90 qualified

[0119] 3.3 Formulations 7 to 12

[0120] Tablets were prepared according to the prescription composition in Table 3-4 and the process in Section 3.1. Preparations 7-12 all used the API prepared in the examples of the present invention, and the excipients of Preparations 7-12 were the same as those used in Preparation 6.

[0121] Table 3-4 Prescription of Preparation 7-12

[0122]

[0123]

[0124] *The strength of preparation 11 is 60 mg / tablet, and the strength of preparation 12 is 20 mg / tablet.

[0125] Results: Preparations 7-12 had good compressibility during tableting and the tablet surface was smooth.

[0126] 3.4 Preparation quality inspection

[0127] Hardness test: Randomly select 10 tablets from each preparation to be tested, and use a hardness tester to test their radial crushing force. The data displayed by the tablet fracture hardness tester is the hardness of the tablet. Record the tablet hardness of each preparation, and calculate the average hardness. The average hardness is used as the hardness of the preparation to be tested.

[0128] Tablet weight test: 20 tablets are randomly taken from the preparations to be tested, the total weight is accurately weighed, and the average tablet weight is obtained. Then, the weight of each tablet is accurately weighed, and each tablet is compared with the average tablet weight. The tablet weight difference %=100%*(single tablet weight-average tablet weight) / average tablet weight is calculated. The present invention controls the tablet weight difference to be no higher than ±5%, and records the number of tablets exceeding the weight difference limit. If there are more than 2 tablets exceeding the weight difference limit; or if there are no more than 2 tablets exceeding the weight difference limit, but one of them exceeds the limit by 1 times, they are all judged as unqualified. Results: The hardness of preparations 6-12 all meet the control index requirements, but the tablets in preparations 7 and 10 are too heavy or too light, and the tablet weight is unstable. The test results are shown in Tables 3-5.

[0129] Table 3-5 Preparation test results

[0130]

[0131]

[0132] 3.5 Tablet quality and stability test

[0133] The dissolution, related substances and accelerated stability of Formulations 6 and 9 were tested.

[0134] Dissolution test: Take tablets from the preparation separately and measure according to the second method of 0931 of the fourth part of the "Chinese Pharmacopoeia" 2020 edition, with 900 ml of water as the dissolution medium, the rotation speed is 75 revolutions per minute, and 10 ml of the dissolution solution is taken for measurement after 30 minutes and 180 minutes respectively, and the dissolution medium of the same temperature and volume is immediately added to the operating container.

[0135] Related substance detection: According to the high performance liquid chromatography method (General Rule 0512) of the Chinese Pharmacopoeia, the test solution is prepared to contain about 1 ml of diltiazem hydrochloride in each ml of ethanol. 1mg solution, filter and take the filtrate. Accurately measure an appropriate amount of the test solution and quantitatively dilute it with ethanol to make a solution containing diltiazem hydrochloride per 1ml. 5μg of solution.

[0136] If there are impurity peaks in the chromatogram of the test solution of the limit preparation, the area of ​​a single impurity peak shall not be greater than the main peak area of ​​the control solution (0.5%), and the sum of the areas of all impurity peaks shall not be greater than twice the main peak area of ​​the control solution (1.0%).

[0137] Accelerated stability test:

[0138] Preparation 6 and Preparation 9 were subjected to accelerated stability tests, with properties, related substances, dissolution, and content as the inspection items. Accelerated tests were carried out in a stability test chamber for 1 month and 3 months, and the inspection standard was the Chinese Pharmacopoeia 2020 edition. Test conditions: temperature: 40℃±2℃, humidity: 75%±5%;

[0139] Table 3-6 Test data of preparation 6 and preparation 9

[0140]

[0141] The composition of the present invention comprising active ingredients, fillers, binders and hydrogenated castor oil has excellent properties such as hardness, tablet weight and dissolution, and the composition has stable properties. Moreover, under the conditions of the accelerated stability test, all the inspection items have no obvious changes, all meet the quality standard requirements, and the preparation of the present invention has good stability.

[0142] In the experiment of studying the effect of the type and / or content changes of the components of the above-mentioned pharmaceutical composition on tableting and preparation, the inventors further explored the effect of the above-mentioned formulation prescription on the parameter changes of different preparation steps, and found that according to the preparation method provided by the present invention, i.e., comprising granulation, mixing, and tableting steps, and the weight ratio of filler: (binder + hydrogenated castor oil) is in the range of 3.5:1-4.5:1, the operating parameters conventionally adjusted by those skilled in the art can prepare preparations with hardness, tablet weight stability and drug dissolution meeting the requirements.

[0143] 3.6 Preparation method mixing steps

[0144] During the preparation scale-up study, the inventors found that for preparations with the same process formula, some batches had a high rate of unqualified tablets and a relatively low tablet qualification rate due to unstable tablet weight, too high or too low hardness, or tablet appearance.

[0145] The inventors have found that this problem is related to the placement of the intermediate materials, especially the placement time of the mixed particles obtained in the granulation step. In actual R&D and production, based on the production plan, the mixed particles are often placed for 3 to 45 days before tableting. If the mixed particles are placed for too long, it is easy to cause a low tablet qualification rate. Furthermore, after in-depth research, the inventors found that adjusting the operation of the mixing step can effectively solve the problem of low tablet qualification rate.

[0146] The formulation and method of Preparation 6 were used, only the mixing steps were changed, and other conditions were exactly the same. After the obtained mixed granules were placed for 40 days, they were tableted to obtain Preparations 13-14 (batch: 10,000 tablets). The mixing steps and qualified rates are shown in Table 3-7.

[0147] Calculation of tablet qualification rate: Take 150 tablets prepared from preparations 13-14 respectively (sample regularly during the tableting process, 20-30 tablets are sampled each time, and a total of 150 tablets are sampled) to calculate the qualification rate of the preparations. The judgment criteria are: the tablets are qualified if there is no loose tablet or cracked tablet, the tablet surface is smooth, and the hardness and tablet weight meet the requirements.

[0148] Table 3-7 Qualified rate of preparations and tablets in different mixing steps

[0149]

[0150]

[0151] It can be seen from Table 3-7 that after the mixed granules of Preparation 13 and Preparation 14 were placed for 40 days, the tablet qualification rate of Preparation 14 was significantly better than that of Preparation 13.

[0152] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0153] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The invention comprises an active ingredient, a filler, a binder and hydrogenated castor oil, wherein the active ingredient includes cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3-dihydro-1,5-benzothiazepine -4(5H)-ketone hydrochloride; the weight ratio of the filler: (binder + hydrogenated castor oil) is in the range of 3.5:1-4.5:

1.

2. The pharmaceutical composition according to claim 1, characterized in that The filler is selected from one or more of lactose, dextrin, starch, and modified starch, and the weight percentage of the filler in the pharmaceutical composition is 35%-85%.

3. The pharmaceutical composition according to claim 2, characterized in that The filler is selected from lactose.

4. The pharmaceutical composition according to claim 1, characterized in that The composition comprises 9% to 30% by weight of active ingredients; The composition comprises 35% to 85% by weight of a filler; The composition comprises 5% to 20% by weight of hydrogenated castor oil; The composition comprises 1% to 12% by weight of a binder; and / or The composition comprises 0-3% by weight of a lubricant.

5. The pharmaceutical composition according to claim 1, characterized in that The binder is selected from one or more of sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, povidone, and pregelatinized starch, and the weight percentage of the binder in the pharmaceutical composition is 1-12%.

6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises a lubricant, and the weight percentage of the lubricant in the pharmaceutical composition is 0-3%.

7. The pharmaceutical composition according to claim 1, characterized in that The composition comprises 9% to 30% by weight of active ingredients; The composition comprises 35% to 85% by weight of lactose; The composition comprises 5% to 20% by weight of hydrogenated castor oil; The composition comprises 1% to 12% by weight of polyethylene glycol; and / or The composition comprises 0%-3% by weight of magnesium stearate.

8. The composition according to claim 1, characterized in that The composition comprises: a) 30 mg active ingredient, 100-200 mg lactose, 15-30 mg hydrogenated castor oil, 8-15 mg polyethylene glycol, 1-4 mg magnesium stearate; or b) 60 mg active ingredient, 100-300 mg lactose, 15-60 mg hydrogenated castor oil, 8-30 mg polyethylene glycol, 1-8 mg magnesium stearate; or c) 90 mg active ingredient, 100-600 mg lactose, 15-90 mg hydrogenated castor oil, 8-45 mg polyethylene glycol, 1-12 mg magnesium stearate.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The pharmaceutical composition comprises an active ingredient, a filler, hydrogenated castor oil, a binder and a lubricant, and comprises the following steps: Granulation: The active ingredient, filler, hydrogenated castor oil and binder are mixed and granulated; the weight ratio of the filler: (binder + hydrogenated castor oil) ranges from 3.5:1 to 4.5:1; Mixing: mixing the granules obtained by granulation with a lubricant to obtain mixed granules; Tableting: The mixed granules are compressed into tablets.

10. The preparation method according to claim 9, characterized in that: The mixing step comprises: The granules obtained by granulation are divided into N portions, namely the first portion of granules, the second portion of granules, ... the Nth portion of granules, where N≥2; a) mixing the first batch of granules with a lubricant to obtain premixed granules 1; b) mixing the second batch of granules with the premixed granules 1 to obtain premixed granules 2; c) Repeat step b) until the Nth batch of granules is mixed with the premixed granules N-1 obtained from the previous mixing to obtain mixed granules.

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