Sartan pharmaceutical composition and preparation method thereof

Abstract

The invention provides a sartan pharmaceutical composition suitable for dry granulation and high-speed production tabletting and a preparation method of the sartan pharmaceutical composition, and belongs to the technical field of pharmaceutical preparations. The composition provided by the invention comprises active ingredients, sublimable substances and pharmaceutically acceptable auxiliary materials. The specific preparation method comprises the following steps: mixing the sartan active component, the sublimable substance and the pharmaceutically acceptable auxiliary materials except the lubricant, and carrying out dry granulation; then carrying out high-temperature convection drying treatment on the obtained medicine-containing particles; and finally, mixing the treated medicine-containing particles with a lubricant, and tabletting. According to the composition disclosed by the invention, crystal form transformation of bulk drugs does not occur in a dry granulation process, a porous structure formed in a high-temperature convection drying process is beneficial to improvement of compressibility of the materials, related substances are good in stability, and the composition is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a sartan drug composition and a preparation method thereof. Background Art

[0002] Sartan drugs are a common type of antihypertensive drugs, belonging to angiotensin II receptor antagonists (ARBs). By inhibiting the action of angiotensin II on the body, they indirectly play the role of reducing blood pressure.

[0003] Sartan drugs generally have polymorphism, and the crystal forms that are beneficial to drug dissolution are mostly in a metastable state. When the raw materials of this metastable state are subjected to high pressure or shear force during the preparation process of the preparation, they are prone to crystal transformation or degradation, which will affect the quality of the drug to a certain extent, and then affect its bioavailability and efficacy.

[0004] Patent CN1044088C proposed a preparation method of candesartan cilexetil tablets. By adding a low-melting-point oily compound with lubricating and buffering effects (such as polyethylene glycol 6000 in the examples), the crystal transformation phenomenon of candesartan cilexetil during the production process was reduced. However, the low-melting-point oily compound is prone to heat melting when subjected to long-term high-speed extrusion. At this time, the viscosity increases, which will increase the risk of sticking during the tabletting process.

[0005] Patent WO2009157711A1 disclosed a method for preparing gastroretentive porous tablets. First, drug-containing granules are prepared by a wet granulation method or a direct powder compression process, and then mixed with a sublimable substance and other excipients for tabletting, and finally the final tablets are obtained after drying. Patent CN1318021C disclosed a rapidly disintegrating tablet. After mixing the active ingredient, the sublimable substance and the excipients for tabletting, the tablets are dried to obtain a porous structure. The above patent technologies all have their limitations. They can only be applied to the porous tablet dosage forms described in their patents, and the research on the application of dry granulation technology is not mentioned in the examples, and they cannot be directly applied to the preparation development of sartan active ingredients that are highly sensitive to pressure in this application.

[0006] Patent CN115040482B disclosed a method for stabilizing active ingredients. By optimizing the liposome preparation technology, the active ingredient irbesartan was encapsulated to avoid the problem of easy degradation of irbesartan. However, the liposome technology has high requirements, many operation steps, relatively high costs for the required excipients and equipment, and the liposome encapsulation rate is low, and problems such as drug leakage may occur during long-term storage.

[0007] Currently, the conventional granulation techniques for sartan drugs mostly involve wet granulation, and a few use direct powder compression. During wet granulation, the active pharmaceutical ingredient needs to be exposed to a humid and hot environment, which easily leads to an increase in related substances and a decrease in stability. In contrast, direct powder compression has high requirements for the powder properties (such as angle of repose, compressibility, etc.) of the equipment and raw and auxiliary materials, and quality risks such as material stratification and uneven content are likely to occur. If dry granulation is used, the strong extrusion of the roller will damage the metastable crystal structure of sartan drugs, resulting in an increase in related substances. In addition, the secondary compressibility of the granules after dry granulation is poor, and problems such as capping or lamination are likely to occur.

[0008] To improve the secondary compressibility of the material after dry granulation, some plasticizing excipients are usually added externally (such as Patent CN102961355A, etc.). However, this method has limited effect on improving compressibility and high requirements for the properties of the excipients, undoubtedly increasing a large amount of economic costs.

[0009] Patent CN101557871A turns the powder into granules through low compaction force and then applies an air flow to carry away the fine particles, thus obtaining granules with good fluidity and compressibility. However, this method requires expensive special equipment, has a low yield, and causes a large amount of material loss, unable to meet the requirements of commercial production.

[0010] In summary, it is necessary to develop a sartan drug composition and its preparation method that can meet the requirements of dry granulation and high-speed tableting, have good stability during dry roller compaction, tableting, and subsequent storage, and at the same time have low production costs and are suitable for industrial production. Summary of the Invention

[0011] The object of the present invention is to provide a sartan drug composition and its preparation method applicable to dry granulation and high-speed production tableting, in which the active ingredient in the obtained preparation is stable and the related substances can be effectively controlled.

[0012] One inventive point of the present invention lies in disclosing a sartan drug composition, which includes a sartan active ingredient, a sublimable substance, and a pharmaceutically acceptable excipient, wherein the sartan active ingredient is selected from at least one of losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, olmesartan, and azilsartan.

[0013] Further preferably, the sartan active ingredient is selected from candesartan, telmisartan, olmesartan, and azilsartan. These active ingredients are more unstable, and the beneficial effects of the present invention are more significant.

[0014] Specifically, the sartan active ingredient can be the active ingredient itself or an active ingredient precursor.

[0015] Preferably, the sublimable substance is selected from adamantane.

[0016] Adamantane has the characteristics of high melting point, high stability, easy sublimation and good lubricity. At present, no researchers have been found to apply it to the development of sartan drug compositions. In the present invention, the sublimable substance adamantane is used as a key component. After repeated experiments and a large amount of research, the applicant unexpectedly found that the drug composition containing adamantane can be stored stably for a long time, meeting the requirements of the storage period. Even for the related substances of the accelerated stored drugs, they can be consistent with the original research product, and even better than the original research product.

[0017] Preferably, the pharmaceutically acceptable excipients include fillers, glidants, binders, disintegrants, and lubricants. Among them, the filler is selected from at least one of microcrystalline cellulose, pregelatinized starch, mannitol, lactose, sucrose, and calcium hydrogen phosphate; the glidant is selected from at least one of colloidal silicon dioxide and talc powder; the binder is selected from at least one of hydroxypropyl cellulose and hydroxypropyl methylcellulose; the disintegrant is selected from at least one of croscarmellose sodium and crospovidone; and the lubricant is preferably magnesium stearate.

[0018] Preferably, the proportion of the sartan active ingredient is 2%-18%, the proportion of the sublimable substance is 11%-43%, and the proportion of the pharmaceutically acceptable excipients is 46%-86%, where the proportions are all percentages by weight of the total feed amount.

[0019] More preferably, in the pharmaceutically acceptable excipients, the proportion of the filler is 38%-75%, the proportion of the glidant is 1%-3%, the proportion of the binder is 0.5%-1.5%, the proportion of the disintegrant is 3%-7%, and the proportion of the lubricant is 0.5%-1%, where the proportions are all percentages by weight of the total feed amount.

[0020] Another inventive point of the present invention is to provide a preparation method of a sartan drug composition, which includes the following steps: (1) Mix the sartan active ingredient, the sublimable substance and the pharmaceutically acceptable excipients other than the lubricant, and then perform dry roller compaction granulation; (2) Perform high-temperature convection treatment on the obtained drug-containing granules to obtain dry granules; (3) Mix the obtained dry granules with the lubricant and then press them into tablets.

[0021] Preferably, the feeding speed of the dry granulation is 10-20 rpm, the speed of the pressing wheel is 8-16 rpm, the gap of the pressing wheel is 0.5-1.5 mm, and the aperture of the screening mesh for sizing is 1.2 mm.

[0022] Preferably, the temperature of the high-temperature convection treatment is 45-55 °C, the air volume is 15-25 CFM, and the treatment time is 8-16 h.

[0023] Preferably, the content of the sublimable substance in the dry granules is not more than 0.5%.

[0024] Specifically, the tablets may also be coated.

[0025] Advantages of the present invention: (1) The sublimable substance used in the present invention plays a lubricating and protective role in the dry granulation process, effectively preventing the material from sticking to the rollers and the crystal structure of the active substance from being damaged, thereby controlling the growth of related substances.

[0026] (2) The present invention performs high-temperature convection treatment on the drug-containing granules obtained after dry granulation. The porous structure formed after removing the sublimable substance greatly improves the secondary compressibility of the material, and at the same time effectively avoids the over-lubricating effect brought by the sublimable substance. Therefore, during the tableting process, tablets with high hardness can be pressed without using a large pressure, effectively protecting the active ingredients.

[0027] (3) It meets the requirements of dry granulation and high-speed production tableting of sartan drugs. The overall process is simple, with high production efficiency and cost advantages. Specific embodiments

[0028] The present invention will be described below through specific examples, but the present invention is not limited thereto.

[0029] The experimental methods used in the following examples are all conventional methods unless otherwise specified; the reagents, materials, etc. used in the following examples can all be obtained from commercial channels unless otherwise specified.

[0030] Examples 1 - 3:

[0031]

[0032] Preparation method: S1 Sieving: Crush adamantane and lactose respectively and pass through a 40-mesh sieve.

[0033] S2 Mixing: Place the active ingredient and all other excipients except magnesium stearate in a mixer, rotate at 15 rpm for 10 min.

[0034] S3 Dry roll compaction (strong extrusion 1): Place the material obtained in S2 in a dry granulator, set the feeding speed of dry granulation to 10 - 20 rpm, the pressure roller speed to 8 - 16 rpm, the pressure roller gap to 0.5 - 1.5 mm, and the aperture of the sizing screen to 1.2 mm.

[0035] S4 Convective drying: Screen the granules prepared in S3, collect the granules and place them in a fluidized bed for high-temperature convection treatment, set the temperature to 45 - 55 °C, the air volume to 15 - 25 CFM, and the treatment time to 8 - 16 h until the adamantane content is not more than 0.5%.

[0036] S5 Tabletting (Powerful Extrusion 2): Mix the granules collected in S4 with magnesium stearate and then tablet.

[0037] Examples 4 - 7:

[0038] Preparation Method: S1: Crush adamantane, lactose, and / or mannitol separately and sieve through a 40 - mesh sieve.

[0039] S2 - S5: The same methods as S2 - S5 in Examples 1 - 3.

[0040] Comparative Examples 1 - 3:

[0041] Note: In the comparative component item, in Comparative Example 1, menthol with sublimability but without lubricity is used; in Comparative Example 2, borneol, a sub - optimal substance with sublimability and lubricity, is used; in Comparative Example 3, polyethylene glycol 6000 with lubricity but without sublimability is used.

[0042] Preparation Method: S1: Crush the comparative component and lactose separately and sieve through a 40 - mesh sieve.

[0043] S2 - S5: The same methods as S2 - S5 in Examples 1 - 3. Test Example: Investigation on the Stability of Related Substances

[0044] Aluminum - plastic package the samples of Examples 1 - 7 and Comparative Examples 1 - 3. At the same time, take appropriate amounts of the reference preparations of candesartan cilexetil tablets, olmesartan medoxomil tablets, and azilsartan tablets with the same packaging, place them at 40°C for 30 days under high - temperature conditions, and regularly sample for detection.

[0045] Chromatographic conditions for related substances of candesartan cilexetil tablets: Use octadecylsilane - bonded silica gel as the filler (Waters Symmetry C18, 4.6 mm × 100 mm, 3.5 μm, or a chromatographic column with equivalent efficiency); use acetonitrile - water - trifluoroacetic acid (10:90:0.1) as mobile phase A and acetonitrile - water - trifluoroacetic acid (90:10:0.1) as mobile phase B, and perform gradient elution according to the following table; the flow rate is 1.0 mL per minute; the column temperature is 25°C; the detection wavelength is 254 nm; the injection volume is 10 μL.

[0046]

[0047] Chromatographic conditions for related substances of olmesartan medoxomil tablets: Use octadecylsilane chemically bonded silica gel as the filler; use acetonitrile - 0.015mol / L potassium dihydrogen phosphate solution (pH 3.5) (adjust the pH to 3.5 with 0.015mol / L phosphoric acid solution) (20:80) as mobile phase A, and acetonitrile - 0.015mol / L potassium dihydrogen phosphate solution (pH 3.5) (79:21) as mobile phase B, and perform gradient elution according to the following table; the detection wavelength is 250nm; the injection temperature is 4°C.

[0048]

[0049] Chromatographic conditions for related substances of azilsartan tablets: Use octadecylsilane chemically bonded silica gel as the filler (CAPCELL PAK C18 MGⅡ, 4.6mm×150mm, 3μm or a chromatographic column with equivalent performance); use phosphate buffer solution (weigh 1.36g of potassium dihydrogen phosphate, dissolve in 1000mL of water, adjust the pH value to 3.0 with phosphoric acid) - acetonitrile (75:25) as mobile phase A, and acetonitrile as mobile phase B, and perform linear gradient elution according to the following table; the flow rate is 1.5ml per minute; the column temperature is 35°C; the detection wavelength is 250nm; the injection volume is 5µL.

[0050]

[0051] The specific test results are as follows:

[0052] As can be seen from Table 1, the total impurity content of Examples 1 - 7 is better than that of the corresponding reference preparations; in Comparative Example 1, menthol was used, and the active pharmaceutical ingredient could not be effectively protected during the dry granulation process, and the increase in related substances was significantly faster than that of the reference preparation and corresponding Examples 1, 4, and 5; in Comparative Example 2, borneol was used, and the protective effect on the active pharmaceutical ingredient was not as good as that of adamantane, and the total impurity content was higher than that of the corresponding reference preparation and Example 2; in Comparative Example 3, polyethylene glycol 6000 was used, and the total impurity content was higher than that of the corresponding reference preparation and Examples 3, 6, and 7. At the same time, the excessive pressure and sticking phenomenon shown by Comparative Example 3 in Test Example 3 cannot be ignored.

Claims

1. A sartan pharmaceutical composition, characterized in that The sartan pharmaceutical composition is prepared from a sartan active ingredient, a sublimable substance and a pharmaceutically acceptable excipient, wherein the sartan active ingredient is selected from at least one of losartan, valsartan, irbesartan, candesartan, telmisartan, olmesartan and azilsartan, and the sublimable substance is adamantane. The method for preparing the sartan pharmaceutical composition is characterized by comprising the following steps: (1) Mixing the sartan active ingredient, the sublimable substance and the pharmaceutically acceptable excipients other than the lubricant and then performing dry roller granulation; (2) subjecting the drug-containing particles obtained in the previous step to high-temperature convection treatment to obtain dry particles; (3) The dried granules obtained in the previous step are mixed with a lubricant and pressed into tablets.

2. The sartan pharmaceutical composition according to claim 1, characterized in that: Pharmaceutically acceptable excipients include fillers, glidants, binders, disintegrants, and lubricants.

3. The pharmaceutical composition according to claim 2, characterized in that The filler is selected from at least one of microcrystalline cellulose, pregelatinized starch, mannitol, lactose, sucrose or calcium hydrogen phosphate, the glidant is selected from at least one of colloidal silicon dioxide and talc, the binder is selected from at least one of hydroxypropyl cellulose and hypromellose, the disintegrant is selected from at least one of cross-linked carboxymethyl cellulose sodium and cross-linked polyvinylpyrrolidone, and the lubricant is preferably magnesium stearate.

4. The sartan pharmaceutical composition according to claim 1, characterized in that Sartan active ingredients account for 2%-18%, sublimable substances account for 11%-43%, and pharmaceutically acceptable excipients account for 46%-86%, where all percentages are percentages of the total weight of the materials.

5. The pharmaceutical composition according to claim 2, characterized in that Fillers account for 38%-75%, glidants account for 1%-3%, binders account for 0.5%-1.5%, disintegrants account for 3%-7%, and lubricants account for 0.5%-1%, where the percentages are all percentages of the total weight of the materials.

6. The method for preparing the sartan pharmaceutical composition according to claim 1, characterized in that The high temperature convection treatment temperature is 45-55℃, the air volume is 15-25CFM, and the treatment time is 8-16h.

7. The method for preparing the sartan pharmaceutical composition according to claim 1, characterized in that The content of sublimable substances in the dry particles is not more than 0.5%.

8. The sartan pharmaceutical composition according to claim 1, characterized in that The composition may also be coated.

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