CN112076190A - Solid preparation containing insoluble thienopyridine composition and preparation method thereof - Google Patents
Solid preparation containing insoluble thienopyridine composition and preparation method thereof Download PDFInfo
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- CN112076190A CN112076190A CN201910514412.XA CN201910514412A CN112076190A CN 112076190 A CN112076190 A CN 112076190A CN 201910514412 A CN201910514412 A CN 201910514412A CN 112076190 A CN112076190 A CN 112076190A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a solid preparation containing an insoluble thienopyridine composition and a preparation method thereof, and the solid preparation has low impurity content and can be quickly dissolved out. The invention relates to a solid preparation containing a slightly soluble thienopyridine composition, which comprises a compound with a structure shown as a formula I and a compound with a structure shown as a formula II, wherein the mass ratio of the compound with the formula II to the compound with the formula I is less than or equal to 1: 100, respectively;
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a solid preparation containing an insoluble thienopyridine composition and a preparation method thereof.
Background
The structure of the compound is shown as formula I, and the chemical name of the compound is as follows: (S) -2- (2-chlorophenyl) -2- ((S) -2-oxo-2, 6,7,7 a-tetrahydrothieno [3,2-c ] pyridopyridin-5 (4H) -yl) acetic acid methyl ester.
The compound of the formula I is a metabolite of clopidogrel in a human body. Clopidogrel is a first-line medicine for preventing and treating circulatory disturbance diseases of heart, brain and other arteries caused by platelet high aggregation. However, there is significant individual variability in the efficacy of clopidogrel, particularly in asians, namely clopidogrel resistance (CPGR). Recent research shows that the cause of CPGR is caused by the differentiation of CYP enzyme activities in the liver of an individual, and specifically shows that clopidogrel cannot be normally metabolized in the liver of part of patients and cannot generate metabolites with a structure shown in formula I and optical isomers thereof, so that clopidogrel is prevented from being subsequently further metabolized into active ingredients and cannot play an anticoagulation role. Therefore, clopidogrel resistance (CPGR) can be effectively avoided by direct administration of the compound of formula I.
The compound of formula I may also produce an impurity compound as shown in formula II in the preparation process:
other impurities may be generated during the process of preparing the compound of the formula I into the preparation and the storage process of the preparation, and in an exploratory study, the compound of the formula II is accidentally found to have a certain critical value in the composition, and the compound of the formula II and other impurities can generate more impurities when the critical value is exceeded, so that the quality control of the compound of the formula II is very important, and the optimal proportion of the composition is determined through creative research. In addition, the compounds of formula I are very poorly soluble in any solvent, very sparingly soluble in water, slightly soluble in ethanol, poorly soluble in methanol, hardly soluble in toluene and very sparingly soluble in acetone. In the process of rapidly disintegrating and absorbing solid preparations, the rate-limiting step of drug absorption is often the dissolution rate of the drug, and especially for poorly soluble drugs, the slow dissolution rate leads to reduced bioavailability. Therefore, the compound of formula I is prepared into a preparation, and the impurity content and the dissolubility of the compound need to be considered, so that the safety, effectiveness and stability of the medicine are ensured. In the prior art, research reports on a composition preparation which ensures that the compound preparation is dissolved out, impurities are controlled, and the drug property is ensured are not reported, so that how to ensure that the solid preparation of the compound shown in the formula I has low impurity content, can be quickly dissolved out, meets the requirement of medicine, and becomes a problem to be solved by technical personnel in the field.
Disclosure of Invention
The invention aims to provide a solid preparation containing a slightly-soluble thienopyridine composition, which comprises a compound shown in the formula I and an impurity compound shown in the formula II generated in the preparation process of the compound shown in the formula I, wherein the impurity content of the preparation is effectively controlled and the stability is improved by controlling the mass ratio of the compound shown in the formula I to the compound shown in the formula II.
The second object of the present invention is to provide a method for producing the solid preparation.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention relates to a solid preparation containing an insoluble thienopyridine composition, which comprises a compound with a structure shown in a formula I and a compound with a structure shown in a formula II:
further, the mass ratio of the compound of formula II to the compound of formula I is less than 1: 100.
further, the mass ratio of the compound of formula II to the compound of formula I is less than 0.5: 100.
further, the particle size distribution range of the composition is as follows: d90 is less than or equal to 150 mu m.
Further, the particle size distribution range of the composition is as follows: d90 is less than or equal to 100 mu m.
Further, the particle size distribution range of the composition is as follows: d90 is less than or equal to 50 mu m.
Further, the composition also comprises any one or more of a release agent, a disintegrating agent and a lubricating agent.
Further, the mass content of the composition is 2-30% by mass of the solid preparation based on 100%.
The mass content of the diluent is 30-96.9%, the mass content of the disintegrating agent is 1-30%, and the mass content of the lubricant is 0.1-10%.
Further, the mass content of the composition is 4-20% by mass of the solid preparation based on 100%.
The mass content of the diluent is 40-80%, the mass content of the disintegrating agent is 2-20%, and the mass content of the lubricant is 0.5-5%.
The diluent comprises one or more of mannitol, microcrystalline cellulose, lactose, starch, pregelatinized starch, sugar powder, dextrin, and inorganic salt.
The disintegrating agent comprises one or more of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl starch sodium and dry starch.
The lubricant comprises one or more of magnesium stearate, sodium stearyl fumarate, pulvis Talci, polyethylene glycol, and hydrogenated vegetable oil.
The solid preparation is an oral solid preparation and comprises tablets, capsules or granules.
The preparation method of the solid preparation comprises the following steps:
step 1, crushing the raw materials of the composition to obtain crushed raw materials;
step 2, uniformly mixing the crushed raw materials and auxiliary materials to prepare a mixture;
and 3, tabletting, granulating or encapsulating the mixture prepared in the step 2.
The compound of formula I of the present invention can be prepared by purification according to the method disclosed in example 2 of patent No. CN 104245707. The compound of formula II is prepared by synthesis.
The invention controls the proportion of the compound II and the compound I by refining the compound I.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively combines the compound of the formula I and the compound of the formula II into a composition, and can achieve the unexpected effects of controlling the impurity content in a solid preparation and improving the stability by controlling the mass ratio of the compound of the formula I and the compound of the formula II.
The invention effectively improves the dissolution rate of the solid preparation by controlling the particle size of the raw material medicine, so that the solid preparation meets the requirements of the preparation. And experiments prove that the solid preparation can still have the dissolution rate of up to 92 percent under the condition of accelerating 6 months. Shows that the invention has good dissolution rate and stability.
The invention has simple preparation process, can adopt powder to directly tablet, has low production cost and is suitable for industrial production.
The specific implementation mode is as follows:
the present invention is further illustrated in detail by the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Single replacement or improvement and the like belong to the technical scheme protected by the invention.
In the examples of the invention, compounds of formula ii: the compounds of the formula I are in each case referred to by mass.
Example 1
This example discloses a process for the preparation of compounds of formula ii:
synthesis of methyl (S) -2- (2-chlorophenyl) -2- (7 a-hydroxy-2-oxo-2, 6,7,7 a-tetrahydrothieno [3,2-c ] pyridin-5 (4H) -yl) acetate
Step 1. synthesis of IM 1:
a35 mL anhydrous THF suspension containing 7.1g sodium hydride was slowly dropped into 586mL anhydrous THF containing 58.6gSM1 at room temperature, and stirred for 30min, and then 70mL anhydrous THF containing 69.2g SM2 was slowly dropped and stirred at room temperature for 12h, and TLC iodine was used to monitor the reaction. After completion of the reaction, 650 g of saturated saline was added, and the mixture was extracted with 1500mL of DCM. The organic layer is coated with Na2SO4Dried and the solvent evaporated under reduced pressure. The residue was purified on a silica gel column to give IM1 as a colorless oil52.3g (yield 62.3%) (PE/EA ═ 20/1 to 5/1). LC-MS (ESI) [ M + H +]+＝286.5(M+H+) Consistent with the structure.
Step 2. synthesis of IM 2:
a suspension of 7.2g sodium hydride in 36mL of extra dry THF was slowly added dropwise to 861mL of extra dry THF containing 86.1g IM1 in an ethanol bath at-45 ℃ and vigorously stirred for 30min, after which the reaction was continued at low temperature for 3h by slowly adding 241mL of THF containing 48.2g liquid bromine, and the reaction was monitored by TLC iodine. After the reaction, the temperature is slowly raised to the room temperature, 30.5g of triethylamine is slowly added, the mixture is stirred for 5 hours at the room temperature, and TLC iodine is used for detecting and controlling the reaction. The solvent was removed by evaporation under reduced pressure. The residue was purified on a silica gel column. 28.3g (yield 32.9%) of a colorless oily liquid was obtained (PE/EA ═ 15/1 to 5/1). LC-MS (ESI) [ M + H +]+＝284.5(M+H+) Consistent with the structure.
Step 3. synthesis of IM 3:
to 203mL of anhydrous THF in which 20.3g of IM2 was dissolved was added 6.03g of NaHS under nitrogen protection at room temperature, and reacted for 12h under nitrogen protection. The reaction was filtered, the solvent removed by evaporation under reduced pressure from the organic phase, and the residue was purified on a basic alumina column to give IM3 as an off-white pasty solid 3.81g (19.6% yield) (DCM/MeOH 15/1 to 8/1). LC-MS (ESI) [ M + H +]+＝272.5(M+H+) Consistent with the structure.
Step 4 Synthesis of racemic IM4
To 73mL of DMDMMC in which 3.64g of IM3 was dissolved was slowly added dropwise 6.7mL of 4M hydrochloric acid in a nitrogen-protected ice bath at 0 ℃ and vigorously stirred for 30min, and the reaction was monitored by TLC iodine. After the reaction is finishedSeparating, mixing organic layer with Na2SO4Dried and the solvent evaporated under reduced pressure. The residue was purified on basic alumina column. This gave 0.61g (26.5% yield) of a pale yellow oily liquid (DCM/MeOH 15/1 to 8/1). LC-MS (ESI) [ M + H +]+＝172.4(M+H+) Consistent with the structure.
Step 5. Synthesis of Compound of formula II
To a solution of 0.57g IM4 in 11.4mL acetonitrile at 50 deg.C under nitrogen, 0.88g SM3 and 0.46g anhydrous potassium carbonate were added and the reaction was stirred for 3 h. The reaction was monitored by TLC UV 254 nm. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was purified on basic alumina column. Obtain light yellow pasty solid 0.52g (yield 44.1%) (PE/EA-10/1-3/1) LC-MS (ESI) [ M + H +]+＝354.9(M+H+)；1H-NMR(400MHz,d6DMSO) 7.62-7.54(m,2H),7.44-7.25(m,2H),6.03(d,1H),4.86(d,1H),4.63(br,1H),3.68(d,3H),3.10(m,1H),3.00(m,1H),2.44-2.36(m,2H),2.00-1.84(m,1H),1.72-1.61(m,1H) is in accordance with the structure.
Example 2: investigation of the different ratios of Compounds of formula II to Compounds of formula I
This example was investigated by adding different proportions of thienopyridine compositions of pure compounds of formula I and formula II to investigate their quality stability. The method specifically comprises the following steps: the same amount of thienopyridine composition and auxiliary materials are adopted, and the proportion of the compound shown in the formula II and the compound shown in the formula I is different, so that the compound shown in the formula II and the compound shown in the formula I are prepared into tablets by the same preparation method. The content of related substances in the tablet is measured in 0 day and 6 months. The prescription composition is calculated according to 1000 tablets, and is shown in table 1:
TABLE 1 prescription composition TABLE 1
The preparation method comprises the following steps:
1. respectively weighing the pure compounds of the formula I and the formula II; after being uniformly mixed, the mixture is crushed to obtain thienopyridine composition powder;
2. weighing auxiliary materials, premixing thienopyridine composition powder with mannitol accounting for 30% of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix;
3. and tabletting the uniformly mixed mixture by using a tabletting machine to obtain the tablet.
The formulation of the raw materials and adjuvants according to the formulation composition of Table 1, the preparation method of this example was adopted to prepare tablets with numbers A1-A10, and each sample was tested for related substances at 0 day, the results are shown in Table 2:
the detection method of related substances comprises the following steps:
taking a proper amount (about 10mg) of the fine powder of the product, putting the fine powder into a10 ml measuring flask, adding acetonitrile to dissolve and dilute the fine powder to a scale, shaking up, filtering, and taking a subsequent filtrate as a test solution; precisely measuring 1.0ml of the test solution, placing the test solution in a 100ml measuring flask, adding acetonitrile to dilute the test solution to a scale, and shaking up the test solution to serve as a control solution. Injecting 10 μ l of the control solution into a liquid chromatograph, adjusting detection sensitivity to make the peak height of the main component chromatographic peak about 20% of the full scale, precisely measuring 10 μ l of each of the test solution and the control solution, injecting into the liquid chromatograph, and recording chromatogram.
TABLE 2, results of day 0 related substance detection
| Numbering | A1 | A2 | A3 | A4 | A5 | A6 | A7 | A8 | A9 | A10 |
| Single impurity (%) | 0.01 | 0.02 | 0.02 | 0.03 | 0.04 | 0.04 | 0.07 | 0.08 | 0.09 | 0.10 |
| Total impurities (%) | 0.08 | 0.09 | 0.10 | 0.11 | 0.12 | 0.12 | 0.22 | 0.24 | 0.28 | 0.36 |
Each sample of tablets numbered A1-A10 was stored at 40 ℃. + -. 2 ℃ and RH 75%. + -. 5% for 6 months, and then tested for the relevant substances, and the results are shown in Table 3:
TABLE 3 accelerated 6 month related substance test results
| Numbering | A1 | A2 | A3 | A4 | A5 | A6 | A7 | A8 | A9 | A10 |
| Single impurity (%) | 0.02 | 0.03 | 0.03 | 0.04 | 0.05 | 0.05 | 0.12 | 0.14 | 0.16 | 0.18 |
| Total impurities (%) | 0.10 | 0.11 | 0.12 | 0.13 | 0.18 | 0.18 | 1.08 | 1.12 | 1.16 | 1.22 |
From the results of the substance tests shown in tables 2 and 3, the stability of the samples of the formulas A1-A6 is better than that of the samples of the formulas A7-A10, i.e., the mass ratio of the compound of the formula II to the compound of the formula I in the composition is less than or equal to 1: 100 hours, the solid preparation has good stability; the mass ratio of the compound of formula II to the compound of formula I is less than or equal to 0.5: at 100 f, the stability of the solid preparation is best. Especially, after the compound is stored for 6 months under the conditions of 40 ℃ plus or minus 2 ℃ and RH 75% + or5%, the stability advantage is more remarkable, which indicates that the compound in the formula II has a certain critical value in the composition, and the compound in the formula II can generate more impurities with other impurities after the critical value is exceeded, so the quality control of the compound in the formula II is very important, and the optimal proportion of the composition is determined through creative research.
Example 3: preparation method for controlling ratio of compound II and compound I and refining
Preparing a crude compound shown in formula I according to the method disclosed in CN 104245707 embodiment 2, adding 1.0g of the crude compound shown in formula I into a 50mL eggplant-shaped bottle, adding 30mL of tetrahydrofuran, heating to 60 ℃, stirring and dissolving, basically dissolving, filtering while the solution is hot, placing the filtrate into a 50mL beaker, stirring, slowly cooling to room temperature, stirring overnight for crystallization, and drying to obtain 0.38g of a finished compound, wherein the mass ratio of the compound II to the compound I in the finished product is less than or equal to 0.5: 100, and purification can be repeated to further reduce the mass ratio of the compound of formula ii to the compound of formula I.
The content determination method of the compound shown in the formula II and the compound shown in the formula I is as follows:
amylose-tri (3, 5-xylyl carbamate) is used as a filling agent, n-hexane-isopropanol-absolute ethyl alcohol (90: 4: 6) is used as a mobile phase, the detection wavelength is 220nm, and the column temperature is 30 ℃. The theoretical plate number is not less than 2000 and the separation degree of the compound of formula I and the compound of formula II is not less than 2.0.
Taking a proper amount of the product, adding absolute ethyl alcohol to dissolve the product, and quantitatively diluting the product to prepare a solution containing about 1mg of the product in every 1ml as a test solution;
and taking a compound reference substance (a calibrated compound of the formula I provided by Woodszegaku biological medicine science and technology Limited), precisely weighing, adding acetonitrile into a10 ml volumetric flask, dissolving and diluting to a scale, precisely weighing 1ml, placing into a 100ml volumetric flask, adding absolute ethyl alcohol to dilute to the scale, and shaking up to obtain the compound reference substance solution of the formula I.
And taking a compound reference substance of the formula II (a calibrated compound of the formula II provided by Woodszegaku biological medicine science and technology Limited), precisely weighing, adding acetonitrile into a10 ml volumetric flask, dissolving and diluting to a scale, precisely weighing 1ml, placing into a 100ml volumetric flask, adding absolute ethyl alcohol to dilute to the scale, and shaking up to obtain a compound reference substance solution of the formula I.
According to 0512 of the four-part general regulation of high performance liquid chromatography 'Chinese pharmacopoeia' 2015 edition, 10 mul of each of the test solution and the reference solution is precisely measured and respectively injected into a liquid chromatograph, and the chromatogram is recorded.
Example 4: study on influence of thienopyridine compositions with different particle sizes on dissolution rate of preparation
This example examines the effect of different particle size thienopyridine compositions on the dissolution of the formulation. The thienopyridine compositions with different particle sizes are prepared into preparations, and then the dissolution rate is measured. The formulation of thienopyridine composition formulations of different particle size are shown in table 4:
TABLE 4 formulation composition of thienopyridine composition formulations of different particle size
The preparation method comprises the following steps:
1. the compound of formula I is less than 0.5: 100, crushing the raw materials of the composition for different time to obtain raw materials with different particle sizes.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, mixing the thienopyridine composition and the mannitol, uniformly mixing the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
The formulation of the formulation ingredients and excipients in Table 4 were followed, and tablets Nos. 1 to 6 were prepared according to the preparation method of this example, and the dissolution rates of the respective samples were measured.
The dissolution rate determination method comprises the following steps:
taking a sample, taking 900ml of hydrochloric acid solution with pH of 1.2 as a dissolution medium according to a dissolution and release determination method (Chinese pharmacopoeia, 2015 edition, four parts, general rule 0931 second method), operating according to the method, taking the solution after 30 minutes, filtering, and taking a proper amount of subsequent filtrate; taking a reference substance (a calibrated compound of the formula I provided by Chengdu Schobenck biomedical science and technology Co., Ltd.), precisely weighing, adding acetonitrile into a10 ml volumetric flask, dissolving and diluting to scale, precisely measuring 1ml, placing into a 100ml volumetric flask, adding a dissolution medium, diluting, and preparing into a solution containing about 10 μ g of the compound of the formula I per 1 ml. The two solutions were taken and subjected to ultraviolet-visible spectrophotometry (general rule 0401), and the absorbance was measured at a wavelength of 220nm, respectively, to calculate the amount of elution of each tablet. The limit is 80% of the indicated amount and should be met.
The results are shown in Table 5.
TABLE 5 dissolution rate measurement results Table
| Numbering | B1 | B2 | B3 | B4 | B5 | B6 |
| Measurement results | 95％ | 90％ | 87％ | 85％ | 70％ | 62％ |
The measurement result is shown in Table 5, and the dissolution rate can reach more than 80% as shown by the dissolution rate detection result, wherein the particle size of the raw material medicament is controlled to be less than or equal to 150 μm D90.
Example 5
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.2: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 28.124 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 6
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.1: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 30.126 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 7
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 42.135 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 8
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the starting material was pulverized to obtain a thienopyridine composition starting material having a D90 ═ 50.126 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 9
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 75.812 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the thienopyridine composition, the mixture of the mannitol, the residual mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 10
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 90.322 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the thienopyridine composition, the mixture of the mannitol, the residual mannitol, the pregelatinized starch and the low-substituted hydroxypropyl cellulose, and then adding the sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 11
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 100.124 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and part of microcrystalline cellulose, uniformly mixing the thienopyridine composition, the mixture of the microcrystalline cellulose, the rest microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 12
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 120.246 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the thienopyridine composition and the mixture of the mannitol, the rest mannitol and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 13
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.4: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 128.145 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and crospovidone, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 14
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 130.214 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 15
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 140.212 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 16
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 149.046 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniformly mixing.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 17
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.006 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and part of lactose, uniformly mixing a mixture of the thienopyridine composition and the lactose, the rest lactose, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 18
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the starting material was pulverized to obtain a thienopyridine composition starting material having a D90 ═ 149.145 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 19
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 149.210 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, dextrin and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 20
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 149.226 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and part of powdered sugar, uniformly mixing the thienopyridine composition, the mixture of the powdered sugar, the rest powdered sugar, starch, dextrin and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 21
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.136 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 22
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.4: 100, pulverizing the composition raw material to obtain a thienopyridine composition raw material with D90 ═ 148.126 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 23
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.312 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the thienopyridine composition, the mannitol mixture, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 24
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 144.214 μm.
2. Weighing raw and auxiliary materials, mixing the thienopyridine composition with mannitol accounting for 30% of the total amount, uniformly mixing the thienopyridine composition with the mixture of the mannitol, the rest mannitol, pregelatinized starch and substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 25
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 145.214 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and part of lactose, uniformly mixing a mixture of the thienopyridine composition and the lactose, the rest of the lactose, microcrystalline cellulose, starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniformly mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 26
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.4: 100, pulverizing the composition raw material to obtain a thienopyridine composition raw material with D90 ═ 146.216 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the thienopyridine composition, the mixture of the mannitol, the residual mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 27
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.1: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.210 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, mixing the thienopyridine composition and the mannitol, uniformly mixing the rest mannitol, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to be uniformly mixed.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 28
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.216 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and part of microcrystalline cellulose, uniformly mixing the thienopyridine composition, the mixture of the microcrystalline cellulose, the rest microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 29
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.164 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the thienopyridine composition and the mixture of the mannitol, the rest mannitol and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 30
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.214 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and crospovidone, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 31
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw materials of the composition were pulverized to obtain a thienopyridine composition raw material having a D90 ═ 148.246 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 32
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 145.216 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 33
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.3: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.146 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniformly mixing.
3. And filling the uniformly mixed materials into capsules by a capsule filling machine.
Example 34
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.2: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.246 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 35
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.4: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 149.851 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, mixing the thienopyridine composition and the mannitol, uniformly mixing the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to be uniformly mixed.
And 3, filling the uniformly mixed materials into bags by using a particle filling machine.
Example 36
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.142 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 37
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 145.218 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 38
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.216 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and part of lactose, uniformly mixing a mixture of the thienopyridine composition and the lactose, the rest lactose, microcrystalline cellulose, starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniformly mixing.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 39
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 142.216 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, mixing the thienopyridine composition and the mannitol, uniformly mixing the rest mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to be uniformly mixed.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 40
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.4: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 144.124 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, mixing the thienopyridine composition and the mannitol, uniformly mixing the rest mannitol, gelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
EXAMPLE 41
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.3: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 144.546 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and part of microcrystalline cellulose, uniformly mixing the thienopyridine composition, the mixture of the microcrystalline cellulose, the rest microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 42
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.214 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, mixing the thienopyridine composition and the mannitol, uniformly mixing the rest mannitol and low-substituted hydroxypropyl cellulose, and then adding sodium stearyl fumarate to uniformly mix.
3. And tabletting the uniformly mixed mixture by using a tabletting machine.
Example 43
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.1: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.216 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and crospovidone, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 44
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.1: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.268 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and croscarmellose sodium, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 45
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.1: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 146.218 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing the mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and sodium carboxymethyl starch, and then adding sodium stearyl fumarate to uniformly mix.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 46
This example discloses the preparation of a solid formulation of a thienopyridine composition of the invention, specifically:
prescription:
the preparation process comprises the following steps:
1. the compound of formula I is less than 0.5: 100, the raw material of the composition was pulverized to obtain a thienopyridine raw material having a D90 ═ 148.216 μm.
2. Weighing raw and auxiliary materials, premixing the thienopyridine composition and mannitol accounting for 30 percent of the total amount, uniformly mixing a mixture of the thienopyridine composition and the mannitol, the rest mannitol, microcrystalline cellulose, pregelatinized starch and low-substituted hydroxypropyl cellulose, and then adding magnesium stearate for uniformly mixing.
3. And filling the uniformly mixed materials into bags by using a particle filling machine.
Example 47
The dissolution rates of the solid preparation samples obtained in examples 3 to 44 were measured at 0 day and at 6 months of acceleration, respectively, and the results are shown in tables 6 and 7.
TABLE 6 table of 0-day dissolution rate test data
| Examples | Example 5 | Example 6 | Example 7 | Example 8 | Example 9 | Example 10 | Example 11 | Example 12 | Example 13 |
| Dissolution (%) | 95 | 92 | 87 | 87 | 86 | 85 | 85 | 85 | 85 |
| Examples | Example 14 | Example 15 | Example 16 | Example 17 | Example 18 | Example 19 | Example 20 | Example 21 | Example 22 |
| Dissolution (%) | 85 | 85 | 85 | 85 | 85 | 86 | 84 | 85 | 85 |
| Examples | Example 23 | Example 24 | Example 25 | Example 26 | Example 27 | Example 28 | Example 29 | Example 30 | Example 31 |
| Dissolution (%) | 85 | 85 | 85 | 85 | 85 | 86 | 84 | 85 | 85 |
| Examples | Example 32 | Example 33 | Example 34 | Example 35 | Example 36 | Example 37 | Example 38 | Example 39 | Example 40 |
| Dissolution (%) | 85 | 85 | 84 | 85 | 85 | 85 | 84 | 84 | 84 |
| Examples | EXAMPLE 41 | Example 42 | Example 43 | Example 44 | Example 45 | Example 46 | / | / | / |
| Dissolution (%) | 85 | 84 | 85 | 85 | 83 | 84 | / | / | / |
TABLE 7 dissolution testing data sheet for 6 months accelerated
| Examples | Example 5 | Example 6 | Example 7 | Example 8 | Example 9 | Example 10 | Example 11 | Example 12 | Example 23 |
| Dissolution (%) | 94 | 92 | 87 | 87 | 86 | 85 | 85 | 85 | 85 |
| Examples | Example 14 | Example 15 | Example 16 | Example 17 | Example 18 | Example 19 | Example 20 | Example 21 | Example 22 |
| Dissolution (%) | 85 | 85 | 85 | 85 | 85 | 86 | 84 | 85 | 85 |
| Examples | Example 23 | Example 24 | Example 25 | Example 26 | Example 27 | Example 28 | Example 29 | Example 30 | Example 31 |
| Dissolution (%) | 85 | 85 | 85 | 85 | 85 | 86 | 84 | 85 | 85 |
| Examples | Example 32 | Example 33 | Example 34 | Example 35 | Example 36 | Example 37 | Example 38 | Example 39 | Example 40 |
| Dissolution (%) | 85 | 85 | 85 | 85 | 85 | 86 | 84 | 85 | 85 |
| Examples | EXAMPLE 41 | Example 42 | Example 43 | Example 44 | Example 45 | Example 46 | / | / | / |
| Dissolution (%) | 85 | 85 | 85 | 85 | 84 | 83 | / | / | / |
As can be seen from tables 6 and 7, the solid formulations of the present invention all showed dissolution rates of 80% or less under the condition of accelerated for 6 months, indicating that the fixed formulations of the present invention had good stability.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.
Claims (10)
1. A solid preparation containing a slightly soluble thienopyridine composition is characterized in that the composition comprises a compound with a structure shown as a formula I and a compound with a structure shown as a formula II
2. The solid formulation according to claim 1, wherein the mass ratio of the compound of formula ii to the compound of formula I is less than 1: 100.
3. the solid formulation according to claim 1, wherein the mass ratio of the compound of formula ii to the compound of formula I is less than 0.5: 100.
4. the solid preparation according to claim 1 to 3, wherein the particle size distribution of the composition is in the range of: d90 is less than or equal to 150 mu m.
5. The solid formulation according to claim 4, wherein the particle size distribution of the composition is in the range of: d90 is less than or equal to 100 mu m.
6. The solid formulation according to claim 4, wherein the particle size distribution of the composition is in the range of: d90 is less than or equal to 50 mu m.
7. The solid preparation according to claim 1, further comprising any one or more of a release agent, a disintegrant, and a lubricant.
8. The solid preparation according to claim 7, wherein the composition is contained in an amount of 2 to 30% by mass based on 100% by mass of the solid preparation.
9. The solid preparation according to claim 7, wherein the composition is contained in an amount of 4 to 20% by mass based on 100% by mass of the solid preparation.
10. The method for preparing a solid preparation according to claim 7, comprising the steps of:
step 1, crushing the raw materials of the composition to obtain crushed raw materials;
step 2, uniformly mixing the crushed raw materials and auxiliary materials to prepare a mixture;
and 3, tabletting, granulating or encapsulating the mixture prepared in the step 2.
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| CN201910514412.XA CN112076190B (en) | 2019-06-14 | 2019-06-14 | Solid preparation containing insoluble thienopyridine composition and preparation method thereof |
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| CN112076190B CN112076190B (en) | 2023-04-07 |
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| CN115518066A (en) * | 2022-06-17 | 2022-12-27 | 成都施贝康生物医药科技有限公司 | Pharmaceutical composition for treating anticoagulation and application |
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| CN108685913A (en) * | 2018-07-31 | 2018-10-23 | 成都施贝康生物医药科技有限公司 | The composition and preparation method and application of oxygen-containing pyrrole Gray optical isomer or its salt |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115518066A (en) * | 2022-06-17 | 2022-12-27 | 成都施贝康生物医药科技有限公司 | Pharmaceutical composition for treating anticoagulation and application |
| WO2023241688A1 (en) * | 2022-06-17 | 2023-12-21 | 成都施贝康生物医药科技有限公司 | Pharmaceutical composition for treating and resisting blood coagulation and use thereof |
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