Compound antihypertensive drug and preparation method thereof

Abstract

The invention discloses a telmisartan and hydrochlorothiazide compound tablet which is characterized in that the telmisartan and hydrochlorothiazide compound tablet comprises a double-layer tablet A and a double-layer tablet B, and the layer A is prepared from telmisartan lipidosome, a diluent and a lubricant; and the layer B is prepared from hydrochlorothiazide, a diluent, a disintegrating agent, a lubricant and an antioxidant. The telmisartan liposome comprises lipid and telmisartan, the dosage ratio of the lipid to the telmisartan is (0.5-2.3): 1, the lipid comprises phospholipid and cholesterol, and in the lipid, the content of the cholesterol accounts for 20%-60% of the total amount of the lipid. The telmisartan liposome comprises lipid, telmisartan and a PH buffer solution, and the PH of the PH buffer solution is 5-7. According to the telmisartan and hydrochlorothiazide compound tablet prepared by the invention, the telmisartan dissolution is good, and the tablet is safe and stable.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, specifically relating to a telmisartan-hydrochlorothiazide compound tablet. Background Technology

[0002] Telmisartan-hydrochlorothiazide combination tablets are a combination antihypertensive drug, mainly composed of telmisartan and hydrochlorothiazide. Telmisartan is an angiotensin II receptor antagonist that selectively binds to angiotensin II receptors, blocking the action of angiotensin II, thereby dilating blood vessels and lowering blood pressure. Hydrochlorothiazide is a thiazide diuretic that lowers blood pressure by reducing blood volume through sodium excretion. The two components exert their antihypertensive effects through different mechanisms and have a synergistic effect, enhancing the antihypertensive efficacy.

[0003] Telmisartan usually exists in the form of free acid and has very poor water solubility in the physiological pH range of the gastrointestinal tract, between pH 1 and pH 7. To improve its water solubility, alkaline reagents such as sodium hydroxide and meglumine need to be added during formulation preparation. However, after adding alkaline reagents, telmisartan particles become alkaline, and hydrochlorothiazide is easily degraded when it comes into contact with alkaline substances, resulting in increased impurities, reduced content, and affecting drug quality.

[0004] In CN102512423A, at least one of the telmisartan granules and hydrochlorothiazide granules is coated with a water-soluble polymer before being compressed into tablets. The resulting telmisartan-hydrochlorothiazide compound tablets have good stability, but this also introduces more excipients. Long-term use may have adverse effects on the patient's health. Therefore, how to produce a safe, stable, and well-dissolved telmisartan-hydrochlorothiazide compound tablet remains to be solved. Summary of the Invention

[0005] This application provides a telmisartan-hydrochlorothiazide combination tablet, in which telmisartan dissolves well and is safe and stable.

[0006] This application provides a telmisartan-hydrochlorothiazide combination tablet comprising two bilayer tablets, A and B, wherein layer A is made of telmisartan liposomes, diluent, and lubricant; and layer B is made of hydrochlorothiazide, diluent, disintegrant, lubricant, and antioxidant.

[0007] Preferably, the telmisartan liposome comprises lipids and telmisartan, with a lipid-to-telmisartan ratio of 0.5 to 2.3:1.

[0008] Preferably, the lipids comprise phospholipids and cholesterol, wherein the cholesterol content accounts for 20%-60% of the total lipids.

[0009] Preferably, the telmisartan liposome comprises lipids, telmisartan, and a pH buffer, wherein the pH of the pH buffer is 5-7.

[0010] Preferably, the pH buffer can be any one or a combination of acetate, succinate, gluconate, histidine, citrate, carbonate, PBS, and HEPES.

[0011] Preferably, the phospholipid can be one or more of dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), disqualoylphosphatidylcholine (DEPC), dilauroylphosphatidylcholine (DLPC), and dimyristoylphosphatidylcholine (DMPC).

[0012] This application also provides a method for preparing telmisartan-hydrochlorothiazide compound tablets, comprising:

[0013] 1) Preparation of telmisartan liposomes: The particle sizes of telmisartan liposomes were d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm;

[0014] 2) Preparation of telmisartan layer particles: Telmisartan liposomes, diluent, lubricant are mixed, stirred, dried, and granulated;

[0015] 3) Preparation of hydrochlorothiazide layer particles: weighing, premixing, granulation, drying, and sizing;

[0016] 4) Tableting: Telmisartan intermediate particles and hydrochlorothiazide intermediate particles are compressed into double-layer tablets.

[0017] Preferably, in the preparation of telmisartan liposomes, telmisartan, lipids and solvent are mixed, then the solvent is removed and then mixed with buffer.

[0018] Preferably, when preparing telmisartan liposomes, the total concentration of the drug in the liposomes is from 1 mg / mL to 50 mg / mL, more preferably 15 mg / mL.

[0019] Beneficial effects:

[0020] This invention involves forming telmisartan into liposomes, which are then combined with hydrochlorothiazide granules to create a telmisartan / hydrochlorothiazide compound tablet. The liposomes encapsulate telmisartan, protecting it from external environmental factors such as light, heat, oxygen, and humidity, thereby improving drug stability and extending shelf life. Simultaneously, liposomes improve drug solubility and permeability, promoting absorption in the gastrointestinal tract or other absorption sites and enhancing bioavailability. This addresses the issue of low telmisartan dissolution in the acidic environment of the stomach, while avoiding the use of alkaline substances, thus preventing any impact on the dissolution of hydrochlorothiazide. Therefore, the telmisartan / hydrochlorothiazide compound tablets prepared by this invention exhibit good dissolution of telmisartan and are safe and stable. Detailed Implementation

[0021] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0022] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0023] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

[0024] This application provides a telmisartan-hydrochlorothiazide combination tablet, comprising a bilayer tablet with two layers, A and B. Layer A is made of telmisartan liposomes, a diluent, and a lubricant; layer B is made of hydrochlorothiazide, a diluent, a disintegrant, a lubricant, and an antioxidant. The diluent may be lactose monohydrate or corn starch; the lubricant may be talc or magnesium stearate; the disintegrant may be microcrystalline cellulose or sodium carboxymethyl starch; and the antioxidant may be iron oxide red.

[0025] Preferably, the telmisartan liposome comprises lipids and telmisartan, and the ratio of lipids to telmisartan is 0.5 to 2.3:1, which can be 0.5:1, 1:1, or 2.3:1.

[0026] Preferably, the lipids comprise phospholipids and cholesterol, wherein the cholesterol content accounts for 20%-60% of the total lipids, and can be 20%, 40%, or 60%.

[0027] Preferably, the telmisartan liposome comprises lipids, telmisartan, and a pH buffer, wherein the pH of the pH buffer is 5-7, and can be 5, 6.5, or 7.

[0028] Preferably, the pH buffer can be any one or a combination of acetate, succinate, gluconate, histidine, citrate, carbonate, PBS, and HEPES.

[0029] Preferably, the phospholipid can be one or more of dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), disqualoylphosphatidylcholine (DEPC), dilauroylphosphatidylcholine (DLPC), and dimyristoylphosphatidylcholine (DMPC).

[0030] This application also provides a method for preparing telmisartan-hydrochlorothiazide compound tablets, comprising:

[0031] 1) Preparation of telmisartan liposomes: The particle sizes of telmisartan liposomes were d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm;

[0032] 2) Preparation of telmisartan layer particles: Telmisartan liposomes, diluent, lubricant are mixed, stirred, dried, and granulated;

[0033] 3) Preparation of hydrochlorothiazide layer particles: weighing, premixing, granulation, drying, and sizing;

[0034] 4) Tableting: Telmisartan intermediate particles and hydrochlorothiazide intermediate particles are compressed into double-layer tablets.

[0035] Preferably, in the preparation of telmisartan liposomes, telmisartan, lipids and solvent are mixed, then the solvent is removed and then mixed with buffer.

[0036] Preferably, when preparing telmisartan liposomes, the total concentration of the drug in the liposomes is from 1 mg / mL to 50 mg / mL, more preferably 15 mg / mL.

[0037] The telmisartan-hydrochlorothiazide compound tablets prepared by this invention exhibit good telmisartan dissolution and are safe and stable.

[0038] The following discussion will be based on specific embodiments:

[0039] Example 1

[0040] Prescription dosage: Telmisartan 8.0g, myristoyl phosphatidylcholine (DMPC) 4.8g, cholesterol 3.2g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0041] 1) Preparation of telmisartan liposomes

[0042] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0043] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0044] 2) Preparation of telmisartan layer particles

[0045] The prescribed amounts of sorbitol and corn starch were added to the above liposomes and mixed for 15 minutes at a stirring speed of 100 rpm and a cutting speed of 300 rpm. The mixture was dried until the moisture content of the material was below 3.0%. Magnesium stearate was added and mixed for 30 seconds. The dried granules were then granulated using a 1.0 mm sieve and a speed of 200.5 Hz to obtain telmisartan intermediate granules.

[0046] 3) Preparation of hydrochlorothiazide layer particles

[0047] Prescription dosage: 11.2.2g lactose monohydrate, 6.4g microcrystalline cellulose, 0.4g sodium carboxymethyl starch, 0.6g corn starch, 1.25g hydrochlorothiazide, 0.033g iron oxide red. Mix the iron oxide red and microcrystalline cellulose through a 60-mesh sieve three times.

[0048] Premix: Add lactose (partial), microcrystalline cellulose-iron oxide red mixture, sodium carboxymethyl starch, corn starch, hydrochlorothiazide, and the remaining lactose (rinse the bag) in sequence. Set the stirring speed to 100 rpm and the cutter speed to 1000 rpm and mix for 300 seconds.

[0049] Granulation: Set the stirring speed to 100 rpm, the cutter speed to 1000 rpm, the atomization pressure to 0.15 MPa, and the peristaltic pump speed to 80 rpm to spray the wetting agent, then granulate for 180 seconds;

[0050] Drying: Preheat and start the fluidized bed, setting the inlet air temperature to 60±10℃, until it feels slightly hot to the touch. After preheating, add the granulated material to the fluidized bed for drying, setting the inlet air temperature to 60±10℃, and dry until the material moisture content is below 3.0%.

[0051] Granulation: The dried granules are granulated using a granulator with a 1.0mm sieve and a rotation speed of 200.5Hz;

[0052] Total mixing: The granulated particles were mixed with magnesium stearate in a hopper mixer at 8 rpm for 8 min to obtain hydrochlorothiazide intermediate particles;

[0053] Intermediate particle and mixing homogeneity test: The content of hydrochlorothiazide intermediate particles and mixing homogeneity test should be performed. The hydrochlorothiazide (C7H8ClN3O4S2) in this product should be 59.38 mg / g to 65.62 mg / g of the labeled amount.

[0054] (4) Tableting

[0055] The telmisartan intermediate particles and hydrochlorothiazide intermediate particles are compressed into a double-layer tablet using a rotary tablet press. The theoretical tablet weight of the telmisartan layer should be 480 mg, the theoretical tablet weight of the hydrochlorothiazide layer should be 200 mg, and the theoretical hardness of the telmisartan-hydrochlorothiazide tablet should be 100-130 N. The resulting telmisartan-hydrochlorothiazide tablet is designated as tablet 1.

[0056] Example 2

[0057] Prescription dosage: Telmisartan 8.0g, DMPC 2.4g, cholesterol 1.6g, histidine buffer 600mL, sorbitol 302.0g, corn starch 157.7g, magnesium stearate 8.0g.

[0058] 1) Preparation of telmisartan liposomes

[0059] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0060] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0061] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 2.

[0062] Example 3

[0063] Prescription dosage: Telmisartan 8.0g, DMPC 11.0g, cholesterol 7.3g, histidine buffer 600mL, sorbitol 302.0g, corn starch 143.4g, magnesium stearate 8.0g.

[0064] 1) Preparation of telmisartan liposomes

[0065] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0066] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0067] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 3.

[0068] Example 4

[0069] Prescription dosage: Telmisartan 8.0g, DMPC 6.4g, cholesterol 1.6g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0070] 1) Preparation of telmisartan liposomes

[0071] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0072] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0073] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, designated as tablet 4.

[0074] Example 5

[0075] Prescription dosage: Telmisartan 8.0g, DMPC 3.2g, cholesterol 4.8g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0076] 1) Preparation of telmisartan liposomes

[0077] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0078] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0079] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 5.

[0080] Example 6

[0081] Prescription dosage: Telmisartan 8.0g, DMPC 4.8g, cholesterol 3.2g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0082] 1) Preparation of telmisartan liposomes

[0083] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 5.0) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0084] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0085] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, designated as tablet 6.

[0086] Example 7

[0087] Prescription dosage: Telmisartan 8.0g, DMPC 4.8g, cholesterol 3.2g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0088] 1) Preparation of telmisartan liposomes

[0089] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 7.0) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0090] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0091] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 7.

[0092] Comparative Example 1

[0093] Prescription dosage: Telmisartan 8.0g, DMPC 1.9g, cholesterol 1.3g, histidine buffer 600mL, sorbitol 302.0g, corn starch 158.5g, magnesium stearate 8.0g.

[0094] 1) Preparation of telmisartan liposomes

[0095] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0096] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0097] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 8.

[0098] Comparative Example 2

[0099] Prescription dosage: Telmisartan 8.0g, DMPC 11.9g, cholesterol 8.0g, histidine buffer 600mL, sorbitol 302.0g, corn starch 141.8g, magnesium stearate 8.0g.

[0100] 1) Preparation of telmisartan liposomes

[0101] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0102] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0103] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 9.

[0104] Comparative Example 3

[0105] Prescription dosage: Telmisartan 8.0g, DMPC 6.8g, cholesterol 1.2g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0106] 1) Preparation of telmisartan liposomes

[0107] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0108] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0109] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 10.

[0110] Comparative Example 4

[0111] Prescription dosage: Telmisartan 8.0g, DMPC 2.4g, cholesterol 5.6g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0112] 1) Preparation of telmisartan liposomes

[0113] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 6.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0114] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0115] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, denoted as tablet 11.

[0116] Comparative Example 5

[0117] Prescription dosage: Telmisartan 8.0g, DMPC 4.8g, cholesterol 3.2g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0118] 1) Preparation of telmisartan liposomes

[0119] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 4.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0120] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0121] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, designated as tablet 12.

[0122] Comparative Example 6

[0123] Prescription dosage: Telmisartan 8.0g, DMPC 4.8g, cholesterol 3.2g, histidine buffer 600mL, sorbitol 302.0g, corn starch 153.8g, magnesium stearate 8.0g.

[0124] 1) Preparation of telmisartan liposomes

[0125] Preparation of the lipid composition: Weigh DMPC, cholesterol, and telmisartan according to the prescribed amounts, and dissolve them in 250 mL of dichloromethane solution. Evaporate the organic solvent in a ventilated environment at 60°C in a water bath to obtain a dry solid mixture. Measure 300 mL of histidine buffer (pH = 7.5) (m / v = 1:1.56) and add it to the dry solid mixture. Shear the mixture in a water bath at 25°C-60°C using an IKA T25 shear press at 5000 rpm for 10-30 min to obtain a viscous paste, which is the lipid composition.

[0126] Preparation of telmisartan liposomes: The shredded lipid composition was diluted with histidine buffer to the set drug concentration (approximately 15 mg / mL) and stirred until homogeneous to obtain liposomes. Cryo-transmission electron microscopy characterization revealed that it contained multiple liposomes. The liposome particle sizes were determined to be d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm.

[0127] All other preparation conditions and steps were the same as in Example 1, and telmisartan hydrochlorothiazide tablets were prepared, designated as tablet 13.

[0128] Table 1 shows the prescription amounts and statistical data of various parameters used in the preparation of telmisartan layered particles in Examples 1-7 and Comparative Examples 1-6. Examples 1-7 and Comparative Examples 1-6 correspond to Examples 1-7 and Comparative Examples 1-6, respectively.

[0129] Table 1. Summary of prescription quantities and parameters used in the preparation of telmisartan layered particles in Examples 1-7 and Comparative Examples 1-6

[0130]

[0131]

[0132] Because telmisartan typically exists as a free acid under normal conditions, it exhibits very poor water solubility within the physiological gastrointestinal pH range of pH 1 to pH 7. To improve its water solubility, this invention first prepares it as liposomes, and then uses the telmisartan / hydrochlorothiazide tablets. The dissolution rate of telmisartan in tablets 1-13 prepared in Examples 1-7 and Comparative Examples 1-6 in 0.1M hydrochloric acid medium was tested. The reference formulation was selected from two batches: Mikasu, 80mg / 12.5mg, C85536 and D04877A. The test results are shown in Table 2.

[0133] Table 2 shows the dissolution rate of telmisartan in 0.1M hydrochloric acid medium for tablets 1-13 and the reference formulation.

[0134]

[0135]

[0136] Table 3 shows the calculated f2 factor results of the dissolution rate of tablets 1-13 in 0.1M hydrochloric acid medium compared to reference formulations C85536 and D04877A. The formula for calculating the dissolution factor f2 is known to be:

[0137] f2=50×lg(1+(∑(R t -T t )^2 / n))

[0138] R t This represents the average cumulative release of the reference formulation at time t.

[0139] T t This represents the average cumulative release of the test formulation at time t.

[0140] n is the number of test points.

[0141] The similarity factor f² is a formula that measures the degree of similarity between two vectors. In comparing drug dissolution profiles, f² is used to assess the similarity between two dissolution profiles.

[0142] Table 3 shows the f2 factor of telmisartan dissolution rate of tablets 1-13 in 0.1M hydrochloric acid medium compared to reference formulations C85536 and D04877A.

[0143]

[0144] Observing Table 3, the following conclusions can be drawn:

[0145] Comparing tablets 1-3 and tablets 8 and 9, it can be seen that the dissolution rate of telmisartan in tablets 1-3 is similar to that of telmisartan in the reference formulation; however, the dissolution rate of telmisartan in tablets 8 and 9 is not similar to that of telmisartan in the reference formulation. Therefore, it can be seen that, under the same conditions, when preparing telmisartan liposomes, the dissolution rate of telmisartan in the prepared telmisartan-hydrochlorothiazide compound tablets is similar to that of telmisartan in the reference formulation when the ratio of lipid to telmisartan is (0.5-2.3):1.

[0146] Comparing tablets 1, 4, and 5 with tablets 10 and 11, it can be seen that the dissolution rate of telmisartan in tablets 1, 4, and 5 is consistent with that in the reference formulation; however, the dissolution rate of telmisartan in tablets 10 and 11 is not similar to that in the reference formulation. Therefore, it can be seen that, under the same conditions, when preparing telmisartan liposomes, if the cholesterol content in the lipids is 20%-60%, the dissolution rate of telmisartan in the prepared telmisartan-hydrochlorothiazide compound tablets is consistent with that in the reference formulation.

[0147] Comparing tablets 1, 6, and 7 with tablets 12 and 13, it can be seen that the dissolution rate of telmisartan in tablets 1, 6, and 7 is consistent with that in the reference formulation; however, the dissolution rate of telmisartan in tablets 12 and 13 is not similar to that in the reference formulation. Therefore, it can be seen that, under the same conditions, when preparing telmisartan liposomes, if the pH of the histidine buffer is 5-7, the dissolution rate of telmisartan in the prepared telmisartan-hydrochlorothiazide combination tablets is consistent with that in the reference formulation.

[0148] The stability of plates 1-13 was tested.

[0149] Take several unprocessed tablets (1-13) and examine them for 3 months at 40℃ and 75% humidity. Detect changes in content and related substances and record the results in Table 4.

[0150] Table 4 shows the content of relevant substances in tablets 1-13 after being stored at 40℃ and 75% humidity for 3 months.

[0151]

[0152]

[0153]

[0154] Observing Table 4, the following conclusions can be drawn:

[0155] Comparing tablets 1-3 and tablets 8 and 9, it can be seen that after being stored at 40℃ and 75% humidity for 3 months, the content of the active substances telmisartan and hydrochlorothiazide in tablets 1-3 changed very little, and the content of related substances, including single impurities and total impurities, also changed little. In contrast, the content of the active substances telmisartan and hydrochlorothiazide, as well as the content of related substances, including single impurities and total impurities, in tablets 8 and 9 changed significantly. Therefore, it can be seen that, under the same conditions, when preparing telmisartan liposomes, the telmisartan-hydrochlorothiazide compound tablets prepared with a lipid-to-telmisartan ratio of (0.5-2.3):1 have stronger stability.

[0156] Comparing tablets 1, 4, and 5 with tablets 10 and 11, it is evident that tablets 1, 4, and 5, after being stored at 40℃ and 75% humidity for 3 months, showed minimal changes in the content of the active substances telmisartan and hydrochlorothiazide, as well as relatively small changes in the content of related substances, including single and total impurities. In contrast, tablets 10 and 11 showed greater changes in the content of the active substances telmisartan and hydrochlorothiazide, and significant changes in the content of related substances, including single and total impurities. Therefore, it is clear that, under the same conditions, when preparing telmisartan liposomes, the telmisartan-hydrochlorothiazide compound tablets prepared with a cholesterol content of 20%-60% in the lipids exhibit stronger stability.

[0157] Comparing tablets 1, 6, and 7 with tablets 12 and 13, it can be seen that after being stored at 40℃ and 75% humidity for 3 months, the content of the active substances telmisartan and hydrochlorothiazide in tablets 1, 6, and 7 showed little change, and the content of related substances, including single impurities and total impurities, also showed relatively small changes. In contrast, the content of the active substances telmisartan and hydrochlorothiazide, as well as the content of related substances, including single impurities and total impurities, in tablets 12 and 13 showed larger changes. Therefore, it can be seen that, under the same conditions, when preparing telmisartan liposomes, the telmisartan-hydrochlorothiazide compound tablets prepared with a histidine buffer pH of 5-7 have stronger stability.

[0158] Comparing tablet 1 with reference formulations C85536 and D04877A, it can be seen that after being stored at 40°C and 75% humidity for 3 months, the content of the active substances telmisartan and hydrochlorothiazide in tablet 1 changed very little, and the content of related substances, including single impurities and total impurities, also changed little. In contrast, the content of the active substances telmisartan and hydrochlorothiazide, as well as the content of related substances, including single impurities and total impurities, in reference formulations C85536 and D04877A changed significantly. Therefore, it is evident that the telmisartan-hydrochlorothiazide compound tablets provided by this invention have stronger stability.

[0159] It is understood that the above embodiments are merely exemplary implementations used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.

Claims

1. A telmisartan / hydrochlorothiazide compound tablet, characterized in that, It consists of two bilayer tablets, A and B. Layer A is made of telmisartan liposomes, diluent, and lubricant; layer B is made of hydrochlorothiazide, diluent, disintegrant, lubricant, and antioxidant.

2. The telmisartan / hydrochlorothiazide compound tablet according to claim 1, characterized in that, The telmisartan liposome comprises lipids and telmisartan, with a lipid-to-telmisartan ratio of 0.5 to 2.3:

1.

3. The telmisartan-hydrochlorothiazide compound tablet according to claim 2, characterized in that, The lipids comprise phospholipids and cholesterol, with cholesterol comprising 20%-60% of the total lipid content.

4. The telmisartan-hydrochlorothiazide compound tablet according to claim 1, characterized in that, The telmisartan liposome contains lipids, telmisartan, and a pH buffer solution, wherein the pH of the pH buffer solution is 5-7.

5. The telmisartan-hydrochlorothiazide compound tablet according to claim 4, characterized in that, The pH buffer solution can be any one or a combination of acetate, succinate, gluconate, histidine, citrate, carbonate, PBS, and HEPES.

6. The telmisartan-hydrochlorothiazide compound tablet according to claim 3, characterized in that, The phospholipid may be one or more of dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), disqualoylphosphatidylcholine (DEPC), dilauroylphosphatidylcholine (DLPC), and dimyristoylphosphatidylcholine (DMPC).

7. The method for preparing telmisartan-hydrochlorothiazide compound tablets according to any one of claims 1-6, characterized in that, include: 1) Preparation of telmisartan liposomes: The particle sizes of telmisartan liposomes were d(0.1) 1.826 μm, d(0.5) 4.551 μm, and d(0.9) 41.549 μm; 2) Preparation of telmisartan layer particles: Telmisartan liposomes, diluent, lubricant are mixed, stirred, dried, and granulated; 3) Preparation of hydrochlorothiazide layer particles: weighing, premixing, granulation, drying, and sizing; 4) Tableting: Telmisartan intermediate particles and hydrochlorothiazide intermediate particles are compressed into double-layer tablets.

8. The method for preparing telmisartan-hydrochlorothiazide compound tablets according to claim 7, characterized in that, In the preparation of the telmisartan liposomes, telmisartan, lipids and solvent are mixed, then the solvent is removed and then mixed with buffer.

9. The method for preparing telmisartan-hydrochlorothiazide compound tablets according to claim 7, characterized in that, When preparing the telmisartan liposomes, the total concentration of the drug in the liposomes is from 1 mg / mL to 50 mg / mL.

10. The method for preparing telmisartan-hydrochlorothiazide compound tablets according to claim 7, characterized in that, When preparing the telmisartan liposomes, the total concentration of the drug in the liposomes is 15 mg / mL.

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