Losartan potassium pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention discloses a losartan potassium pharmaceutical composition as well as a preparation method and application thereof. The losartan potassium pharmaceutical composition comprises a eutectic compound formed by losartan potassium and arginine and polyethylene glycol with the molecular weight of 4000. Through the synergistic effect of a co-crystallization technology and specific auxiliary materials, the solubility and stability of losartan potassium are remarkably improved, and the dissolution rate of losartan potassium in a hydrochloric acid medium with the pH value of 1.2 for 15 min reaches up to 85% or above and is far superior to that of commercially available common tablets. Animal experiments show that the relative bioavailability of the pharmaceutical composition can reach more than 200% of that of a commercially available reference preparation, so that low-dose efficient treatment is realized, and adverse reactions are reduced. The composition has excellent stability under high-temperature and high-humidity conditions, is suitable for preparing medicines for treating primary hypertension and related cardiovascular diseases, and has important clinical value.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a losartan potassium pharmaceutical composition, its preparation method, and its application. Background Technology

[0002] Hypertension is one of the most common cardiovascular diseases worldwide and a significant risk factor for damage to target organs such as the heart, brain, and kidneys. Angiotensin II receptor blockers (ARBs) have become first-line drugs for the clinical treatment of hypertension due to their good tolerability and proven efficacy.

[0003] Losartan potassium, the first marketed ARB drug, effectively inhibits vasoconstriction and aldosterone release by selectively blocking the binding of angiotensin II to AT1 receptors, thereby lowering blood pressure and protecting target organs such as the heart, brain, and kidneys. In addition, it is also used to treat patients with chronic heart failure who are intolerant to angiotensin-converting enzyme (ACE) inhibitors.

[0004] However, losartan potassium has significant limitations in clinical application, severely restricting its efficacy and patient experience. Firstly, its absolute oral bioavailability is low (approximately 33%), primarily because after absorption in the gastrointestinal tract, it undergoes first-pass metabolism in the liver, with up to 67% of the drug being inactivated and unable to enter systemic circulation to exert its effect. This pharmacokinetic characteristic means that patients often need to take higher doses to achieve the desired antihypertensive effect. This not only increases the cost of medication for patients but also raises the risk of adverse reactions such as headache, dizziness, and hyperkalemia due to higher drug exposure.

[0005] Secondly, the dissolution behavior and in vivo absorption of existing commercially available losartan potassium tablets may be affected by various factors such as formulation process and excipients, which may lead to fluctuations in efficacy between different individuals or different batches, affecting the stability and controllability of treatment.

[0006] Furthermore, some patients may experience a range of adverse reactions during use, including but not limited to allergic reactions (such as angioedema), gastrointestinal discomfort (such as vomiting, abnormal liver function), hematologic abnormalities (such as anemia, thrombocytopenia), and musculoskeletal system reactions (such as myalgia, arthralgia). These potential safety risks are closely related to the drug's exposure level and metabolic processes in the body.

[0007] Therefore, developing a novel formulation that can significantly improve the bioavailability of losartan potassium has become an urgent technical problem to be solved in this field. By improving bioavailability, the clinical dosage can be significantly reduced while maintaining the same therapeutic effect. This not only effectively reduces the incidence of the aforementioned adverse reactions and improves medication safety, but also reduces treatment costs for patients and improves medication adherence, which has significant clinical and social value.

[0008] Currently, although there are attempts to optimize treatment by changing dosage forms (such as sustained-release formulations) or preparing combination formulations, there is still a lack of technical solutions that can fundamentally solve the core problem of losartan potassium's strong first-pass effect and low bioavailability. Therefore, there is an urgent need for a new technical approach to modify the physicochemical properties of losartan potassium at the molecular level in order to overcome the bottlenecks in its current clinical applications. Summary of the Invention

[0009] To address the shortcomings of existing technologies, this invention provides a losartan potassium pharmaceutical composition, its preparation method, and its application. By forming a cocrystal with losartan potassium and arginine and compounding it with a specific polyethylene glycol 4000, a significant improvement in dissolution rate and bioavailability (bioavailability can reach more than 200% of commercially available drugs) and a significant enhancement in physical stability are synergistically achieved. This enables better efficacy with lower doses and reduces adverse reactions.

[0010] This invention is achieved through the following technical solution:

[0011] A losartan potassium pharmaceutical composition comprising a cocrystal complex formed by losartan potassium and a cocrystal precursor molecule, and compounded with polyethylene glycol; wherein the cocrystal precursor molecule is arginine; and the polyethylene glycol has a molecular weight of 4000.

[0012] Preferably, the mass ratio of losartan potassium, eutectic precursor molecule, and polyethylene glycol is 1:(0.4~1):(1~2).

[0013] Preferably, the dissolution rate of the pharmaceutical composition within 15 minutes in media with pH 1.2, 4.5, and 6.8 is not less than 85%.

[0014] Preferably, the pharmaceutical composition has a relative bioavailability of not less than 200% relative to commercially available losartan potassium tablets.

[0015] Preferably, after 3 months of accelerated testing at 40°C and 75% relative humidity, the pharmaceutical composition showed no recrystallization and no significant change in dissolution behavior.

[0016] Preferably, the pharmaceutical composition further includes pharmaceutically acceptable excipients.

[0017] Preferably, the pharmaceutically acceptable excipients include fillers, disintegrants, binders, and lubricants;

[0018] The filler is one or a mixture of two or more of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch;

[0019] The disintegrant is one or a mixture of two or more of the following: crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch.

[0020] The adhesive is one or a mixture of two of hydroxypropyl methylcellulose and povidone;

[0021] The lubricant is one or a mixture of two of magnesium stearate and sodium stearate fumarate.

[0022] Preferably, the pharmaceutical composition is a solid oral dosage form, more preferably a tablet.

[0023] The preparation method of the above-mentioned losartan potassium pharmaceutical composition includes the following steps:

[0024] Step 1) Dissolve losartan potassium and arginine co-crystal precursor molecules together in a solvent to form a solution;

[0025] Step 2) Dissolve polyethylene glycol in the solution obtained in Step 1) to combine the co-crystal complex formed by losartan potassium and arginine co-crystal precursor molecules with polyethylene glycol to obtain a mixture;

[0026] Step 3) Remove the solvent from the mixture obtained in Step 2) to obtain the final product.

[0027] The above-mentioned losartan potassium pharmaceutical composition is used in the preparation of a drug for treating essential hypertension.

[0028] The beneficial effects of this invention are as follows:

[0029] (1) This invention forms a losartan potassium-arginine cocrystal and combines it with polyethylene glycol 4000 of a specific molecular weight, which synergistically disrupts the original stable crystalline structure of losartan potassium, causing it to be highly dispersed in an amorphous or microcrystalline state. In vitro dissolution experiments have shown that the dissolution rate of this compound can reach more than 85% within 15 minutes in hydrochloric acid medium at pH 1.2, while the dissolution rate of the active pharmaceutical ingredient and commercially available ordinary tablets under the same conditions is only about 5%. This rapid dissolution characteristic ensures that the drug can quickly reach a high concentration in the gastrointestinal tract, providing a fundamental guarantee for subsequent efficient absorption.

[0030] (2) This invention fundamentally solves the core problem of low bioavailability (approximately 33%) of losartan potassium due to severe first-pass effect. Animal pharmacokinetic studies (using rats as an example) show that the relative bioavailability of the tablets of this invention compared to the commercially available reference formulation can be increased by more than 200%. This means that at the same dosage, more active drug enters the systemic circulation to exert its therapeutic effect. Therefore, it is expected that a lower dose can be used in clinical practice to achieve the same or even better antihypertensive effect as the original drug, thereby significantly reducing the economic burden on patients and reducing the risk of adverse reactions such as headache and hyperkalemia caused by high-dose exposure.

[0031] (3) In this invention, polyethylene glycol 4000 with a specific molecular weight not only acts as a solubilizer but also serves as an effective crystallization inhibitor. It can stably maintain the drug in an amorphous state and prevent it from recrystallizing during storage. Accelerated stability tests show that after being placed under harsh conditions of 40°C and 75% relative humidity for 3 months, the compound showed no recrystallization and no significant change in dissolution behavior, demonstrating superior physical stability compared to traditional formulations. This ensures that the product maintains stable quality and consistent efficacy throughout its shelf life.

[0032] (4) This invention alters the physical form of the drug by forming a eutectic complex. Simultaneously, the specially selected PEG4000 polyethylene glycol can form a protective film on the surface of the gastrointestinal mucosa. This dual effect reduces the direct irritation of losartan potassium raw material to the gastrointestinal tract, and is expected to reduce the incidence of adverse gastrointestinal reactions such as vomiting and diarrhea, providing patients with a more comfortable and better-tolerated treatment experience.

[0033] (5) This invention is not a simple mixing of excipients, but rather an organic combination of "eutectic technology" and "stabilization and dispersion technology of specific carriers". The two produce a significant synergistic effect: eutectic technology creates conditions for solubilization and improved absorption, while polyethylene glycol 4000 ensures the long-term stability of this high-energy state during production and storage. The final result is a leap in bioavailability (over 200%) and excellent stability, achieving unexpectedly superior technical effects. Attached Figure Description

[0034] Figure 1 The XRD pattern of the sample from Comparative Example 1 in Test Example 1;

[0035] Figure 2 The XRD pattern of the sample from Example 1 in Test Example 1;

[0036] Figure 3 The XRD pattern of the sample from Example 2 in Test Example 1;

[0037] Figure 4 For comparison of the in vitro dissolution curves in the hydrochloric acid medium at pH 1.2 in Test Example 3;

[0038] Figure 5 For comparison of the in vitro dissolution curves of the acetate medium at pH 4.5 in Test Example 3;

[0039] Figure 6 For comparison of in vitro dissolution curves in the phosphate medium at pH 6.8 in Test Example 3. Detailed Implementation

[0040] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0041] Unless otherwise specified, the technical means used in the following embodiments are all conventional means well known to those skilled in the art, and the experimental methods without specific conditions are all conventional methods in the art.

[0042] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0043] The experimental animals used in the following examples were SD rats, which were purchased from Shanghai Slack Laboratory Animal Co., Ltd.

[0044] A method for preparing losartan potassium tablets, the specific steps of which are as follows:

[0045] (1) Preparation of raw materials and auxiliary materials

[0046] Losartan potassium: purity ≥99.5%, meeting the requirements of the Chinese Pharmacopoeia or relevant standards.

[0047] Arginine: Purity ≥ 99.5%, meeting the requirements of the Chinese Pharmacopoeia or relevant standards.

[0048] Polyethylene glycol: Polyethylene glycol 4000 was selected, which meets pharmaceutical standards.

[0049] Filler: Select one or more of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch, which meet pharmaceutical standards.

[0050] Disintegrant: One or a mixture of two or more of the following are selected: crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch, which meet pharmaceutical standards.

[0051] Adhesive: Select one or a mixture of two of hydroxypropyl methylcellulose and povidone, which meet pharmaceutical standards.

[0052] Lubricant: Select one or a mixture of two of magnesium stearate and sodium fumarate stearate, which meet pharmaceutical standards.

[0053] (2) Solvent selection

[0054] Choose a suitable solvent, such as ethanol, water, or an aqueous solution of ethanol. Dissolve losartan potassium and arginine separately in an appropriate amount of solvent to prepare solutions of a certain concentration.

[0055] (3) Polyethylene glycol compounding and drying with specific molecular weight

[0056] 1) Dissolve polyethylene glycol 4000 in a solution, and dry the mixture in a vacuum drying oven at a temperature of 40-50°C for 6-8 hours to obtain a solid powder of polyethylene glycol 4000 co-crystallized with losartan potassium and arginine.

[0057] 2) Alternatively, the mixture can be spray-dried to obtain a solid powder of the compound.

[0058] 3) Alternatively, dissolve polyethylene glycol 4000 in the solution, and granulate the mixture in a fluidized bed using the filler as a substrate. The inlet air temperature is 50~70℃ and the material temperature is 30~50℃ to obtain the compound particles.

[0059] (4) Tablet preparation

[0060] 1) Tablets were prepared using a solid powder of polyethylene glycol 4000 co-crystallized with losartan potassium and arginine.

[0061] ①Auxiliary material mixing: The compound solid powder, filler and disintegrant are mixed evenly in a high-speed mixer to form a premix.

[0062] ② Granulation: Dissolve the binder in an appropriate amount of water to prepare a binder solution. Add the premix to a wet granulator, slowly add the binder solution, and simultaneously stir and granulate until uniform wet granules with moderate hardness are formed.

[0063] ③ Drying: Transfer the wet granules to a low-temperature drying oven and dry them at a temperature of 40~50℃ until the moisture content of the granules is controlled between 2% and 4%.

[0064] ④ Granulation: The dried granules are granulated by passing them through a vibrating screen to remove oversized or undersized granules and obtain uniform granules.

[0065] ⑤ General mixing: Add the granulated particles and lubricant to the three-dimensional mixer and mix them evenly to ensure that all components are evenly distributed.

[0066] ⑥ Tableting: The mixed granules are compressed into tablets using a tableting machine, and the tablet hardness, weight variation and other indicators are controlled to meet the requirements of the Chinese Pharmacopoeia.

[0067] 2) Tablets were prepared using a compound of polyethylene glycol 4000 granules co-crystallized from losartan potassium and arginine.

[0068] ①Auxiliary material mixing: Add the compound particles, binder and disintegrant to the three-dimensional mixer and mix evenly.

[0069] ② General mixing: Add the lubricant to the three-dimensional mixer and mix.

[0070] ③ Tableting: The mixed granules are compressed into tablets using a tableting machine, and the tablet hardness, weight variation and other indicators are controlled to meet the requirements of the Chinese Pharmacopoeia.

[0071] Example 1

[0072] A method for preparing losartan potassium tablets, the specific steps of which are as follows:

[0073] (1) Formula composition

[0074] Losartan potassium 50 g, arginine 20 g, polyethylene glycol 4000 50 g, lactose 100 g, microcrystalline cellulose 10 g, low-substituted hydroxypropyl cellulose 12 g, hydroxypropyl methylcellulose 6 g, magnesium stearate 2 g.

[0075] (2) Preparation process

[0076] ① Add losartan potassium and arginine to an appropriate amount of purified water and stir at 40°C for 2 hours to form a complex solution.

[0077] ② Add polyethylene glycol 4000 to the composite solution and stir to dissolve. Dry the mixture in a vacuum drying oven at a temperature of 40-50℃ for 6-8 hours to obtain a solid powder of polyethylene glycol 4000 co-crystallized with losartan potassium and arginine.

[0078] ③ Mix the compound solid powder, lactose, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose in a wet granulator for 15 minutes until uniformly mixed to form a premix.

[0079] ④ Dissolve hydroxypropyl methylcellulose in an appropriate amount of aqueous ethanol solution to prepare an adhesive solution.

[0080] ⑤ Slowly add the binder solution into the wet granulator, stir and granulate for 2 minutes to form wet granules.

[0081] ⑥ Transfer the wet granules to a low-temperature drying oven at 45°C and dry for 2.5 hours until the moisture content is 3%.

[0082] ⑦ The dried granules are granulated by passing them through a 24-mesh vibrating screen.

[0083] ⑧ Add the granulated particles and magnesium stearate to a three-dimensional mixer and mix for 3 min.

[0084] ⑨ Use a tablet press to compress the total mixture of granules into tablets containing 50 mg of losartan potassium per tablet.

[0085] Example 2

[0086] A method for preparing losartan potassium tablets, the specific steps of which are as follows:

[0087] (1) Formula composition

[0088] Losartan potassium 50 g, arginine 50 g, polyethylene glycol 4000 100 g, microcrystalline cellulose 110 g, croscarmellose sodium 10 g, povidone 6 g, sodium fumarate stearate 4 g.

[0089] (2) Preparation process

[0090] ① Add losartan potassium and arginine to an appropriate amount of purified water and stir at 38°C for 1.8 h to form a complex solution. Then add polyethylene glycol 4000 and stir to dissolve.

[0091] ② The mixture is granulated in a fluidized bed using microcrystalline cellulose as a substrate. The inlet air temperature is 50~70℃ and the material temperature is 30~50℃ to obtain compound granules.

[0092] ③ Add the compound particles, povidone, and croscarmellose sodium to a three-dimensional mixer and mix for 15 minutes until homogeneous.

[0093] ④ Add sodium fumarate stearate to the three-dimensional mixer and mix for 3 minutes.

[0094] ⑤ Use a tablet press to compress the mixed granules into tablets containing 50 mg of losartan potassium per tablet.

[0095] Comparative Example 1

[0096] The commercially available original formulation, losartan tablets (specification: 50 mg, batch number: T030146).

[0097] Comparative Example 2

[0098] A method for preparing losartan potassium tablets, the specific steps of which are as follows:

[0099] (1) Formulation composition (without polyethylene glycol 4000)

[0100] Losartan potassium 50 g, arginine 20 g, lactose 100 g, microcrystalline cellulose 10 g, low-substituted hydroxypropyl cellulose 12 g, hydroxypropyl methylcellulose 6 g, magnesium stearate 2 g.

[0101] (2) The preparation process is the same as in Example 1.

[0102] Comparative Example 3

[0103] A method for preparing losartan potassium tablets, the specific steps of which are as follows:

[0104] (1) Formulation composition (using polyethylene glycol 6000)

[0105] Losartan potassium 50 g, arginine 20 g, polyethylene glycol 6000 50 g, lactose 100 g, microcrystalline cellulose 10 g, low-substituted hydroxypropyl cellulose 12 g, hydroxypropyl methylcellulose 6 g, magnesium stearate 2 g.

[0106] (2) The preparation process is the same as in Example 1.

[0107] Comparative Example 4

[0108] A method for preparing losartan potassium tablets, the specific steps of which are as follows:

[0109] (1) Formulation composition (using polyethylene glycol 8000)

[0110] Losartan potassium 50 g, arginine 20 g, polyethylene glycol 8000 50 g, lactose 100 g, microcrystalline cellulose 10 g, low-substituted hydroxypropyl cellulose 12 g, hydroxypropyl methylcellulose 6 g, magnesium stearate 2 g.

[0111] (2) The preparation process is the same as in Example 1.

[0112] Test Example 1: X-ray Diffraction (XRD)

[0113] 1. Experimental Design

[0114] The samples were scanned using an XRD instrument and the diffraction patterns were recorded using commercially available original reagent samples (Comparative Example 1) and samples from Examples 1 and 2.

[0115] 2. Test Results

[0116] like Figure 1-3 The XRD patterns of the samples from Comparative Example 1 and Examples 1 and 2 are shown. As can be seen from the figure, the samples from Examples 1 and 2 are both amorphous.

[0117] Test Example 2: Differential Scanning Calorimetry (DSC)

[0118] 1. Experimental Design

[0119] DSC analysis was performed on the losartan potassium, arginine and eutectic samples of Example 2, and the heat flow curves were recorded.

[0120] 2. Test Results

[0121] Table 1 DSC Analysis Results

[0122]

[0123] As shown in Table 1, losartan potassium-arginine eutectic is formed, and the losartan potassium-arginine eutectic in the solid powder of polyethylene glycol 4000 compound is amorphous.

[0124] Test Example 3: In vitro dissolution test

[0125] 1. Experimental Design

[0126] The dissolution behavior of tablets prepared in Examples 1 and 2 and Comparative Examples 1-4 in 900 mL of different pH media (pH 1.2 hydrochloric acid, pH 4.5 acetate, and pH 6.8 acetate) was detected using the paddle method according to the 2025 edition of the Chinese Pharmacopoeia to simulate the gastrointestinal environment. The paddle speed was 50 rpm and the temperature was 37 ± 0.5 °C. Sampling times were 5, 10, 15, 20, 30, 45, 60, 90, and 120 min. Concentrations were determined by HPLC.

[0127] 2. Test Results

[0128] Table 2 Dissolution data in hydrochloric acid medium at pH 1.2

[0129]

[0130] Table 3 Dissolution data in acetate medium at pH 4.5

[0131]

[0132] Table 4. Dissolution data in acetate medium at pH 6.8

[0133]

[0134] The experimental results are shown in Table 2-4 and Figure 4-6 As shown, the compound tablets of the present invention have a dissolution rate of over 85% in various media within 15 minutes, which is significantly faster than commercially available original tablets.

[0135] Test Example 4: In vivo pharmacokinetic study

[0136] 1. Experimental Design

[0137] Thirty healthy SD rats (200-250 g) were randomly divided into a control group and an experimental group, with 15 rats in each group. There were no statistically significant differences in baseline physiological status (body weight, blood pressure, and gastrointestinal absorption function) between the two groups. Each group was given a single oral dose of a commercially available tablet suspension equivalent to 6 mg / kg of losartan potassium (Comparative Example 1, control group) and a tablet suspension prepared according to Example 2 of this invention (experimental group). Blood samples were collected at different time points, and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) was used to ensure high sensitivity and specificity for the detection of losartan potassium and its active metabolites (such as EXP-3174). Pharmacokinetic parameters were calculated.

[0138] 2. Test Results

[0139] (1) Absorption related parameters

[0140] Table 5 Absorption-related parameters

[0141]

[0142] As shown in Table 5, the present invention improves drug solubility, dissolution rate, and gastrointestinal membrane permeability, thus significantly increasing absorption compared to commercially available original formulations. The AUC of the formulation group in Example 2 of the present invention... 0-t (0~24 h) is about 2.4 times that of the commercially available original formulation, with a significant increase in relative bioavailability.

[0143] (2) Distribution-related parameters

[0144] Table 6 Distribution-related parameters

[0145]

[0146] As shown in Table 6, the active pharmaceutical ingredient in both the experimental and control groups is losartan potassium. Its distribution characteristics in vivo (such as tissue affinity and plasma protein binding rate) are mainly determined by the chemical structure of the drug itself. This invention does not directly change the distribution mechanism of losartan potassium, so the differences in distribution-related parameters are small.

[0147] (3) Metabolic and excretion-related parameters

[0148] Table 7. Metabolic and Excretion Related Parameters

[0149]

[0150] As shown in Table 7, losartan potassium is mainly metabolized in the liver (CYP3A4 and CYP2C9 are the main metabolic enzymes), and the metabolite EXP-3174 still has antihypertensive activity; the excretion routes are bile (main) and urine (minor). The present invention has a weak effect on the activity of liver metabolic enzymes in rats, therefore there is no significant difference in metabolic and excretion parameters.

[0151] (4) Results Analysis

[0152] The absorption advantages are clear: the losartan potassium-arginine cocrystal of the present invention can significantly shorten the Te time by improving solubility and dissolution rate. max Improve C max Regarding bioavailability, this addresses the issues of low oral bioavailability and slow absorption of losartan potassium.

[0153] Drug efficacy correlation: The antihypertensive effect of losartan potassium was positively correlated with the blood concentration of losartan potassium (and EXP-3174), with the experimental group showing a higher C-cell concentration. max Earlier peak time may result in a faster onset of blood pressure reduction and a stronger peak blood pressure reduction effect.

[0154] Safety Note: CL and t in the experimental group and the control group 1 / 2 No difference indicates that although the experimental group C max Elevated, but without the risk of drug accumulation.

[0155] Test Example 5: Stability Test

[0156] 1. Experimental Design

[0157] (1) Samples: losartan potassium tablets (100 mg specification, aluminum-plastic blister pack with composite film bag) prepared in Examples 1 and 2, and the commercially available original formulation of Comparative Example 1 (100 mg specification, aluminum-plastic blister pack).

[0158] (2) Conditions

[0159] Accelerated testing: 40℃±2℃, 75% RH±5%, for 0, 3, and 6 months;

[0160] (3) Test items: appearance, related substances, dissolution rate, content, crystallization rate.

[0161] 2. Test Results

[0162] Table 8 Accelerated Test Results of Example 1

[0163]

[0164] Table 9 Accelerated Test Results of Example 2

[0165]

[0166] Table 10 Accelerated Test Results of Comparative Example 1

[0167]

[0168] As shown in Tables 8-10, the tablets prepared in Examples 1 and 2, after being stored under accelerated testing conditions for 6 months, showed no significant changes in content, dissolution rate, related substances, and other indicators, with a slight increase in moisture content (4.1% → 4.9%). No changes in crystal form were observed. In Comparative Example 1, after being stored under accelerated testing conditions for 6 months, impurity L (<0.05% → 0.07%), impurity M (0.05% → 0.09%), and total impurities (0.05% → 0.16%) showed an increasing trend, but all remained within the standard limits; other indicators showed no significant changes. After 6 months of accelerated testing, the moisture content of Comparative Example 1 (5.7%) was slightly higher than that of the self-developed formulation of this invention (4.9%). No changes in crystal form were observed in any of the formulations, and the tablets prepared in Examples 1 and 2 did not exhibit crystal transformation.

[0169] The experimental results of this test case show that, under accelerated testing conditions, the tablets prepared in Examples 1 and 2 have slightly better stability than the formulation in Comparative Example 1.

[0170] The embodiments described above are only some, not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. The scope of protection of the present invention is determined by the scope claimed in the claims. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition of losartan potassium, characterized by, The pharmaceutical composition comprises a co-crystal complex of losartan potassium and a co-crystal precursor molecule, and is compounded with polyethylene glycol; the co-crystal precursor molecule is arginine; and the polyethylene glycol has a molecular weight of 4000.

2. The losartan potassium pharmaceutical composition according to claim 1, wherein The mass ratio of the losartan potassium, the co-crystal precursor molecule and the polyethylene glycol is 1: (0.4-1) : (1-2).

3. A losartan potassium pharmaceutical composition according to claim 1 or 2, wherein The pharmaceutical composition has a dissolution rate of no less than 85% in a pH 1.2, 4.5 or 6.8 medium within 15 min.

4. The losartan potassium pharmaceutical composition according to claim 1 or 2, characterized in that, The relative bioavailability of the pharmaceutical composition is no less than 200% relative to that of a commercially available losartan potassium tablet.

5. The losartan potassium pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition has no recrystallization phenomenon and no obvious change in dissolution behavior after 3 months of accelerated testing at 40℃ and 75% relative humidity.

6. The losartan potassium pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

7. A pharmaceutical composition of Losartan Potassium as claimed in claim 6, wherein, The pharmaceutically acceptable excipient comprises a filler, a disintegrant, a binder and a lubricant. The filler is one or a mixture of two or more of lactose, microcrystalline cellulose, mannitol and pregelatinized starch. The disintegrant is one or a mixture of two or more of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch. The binder is one or a mixture of two or more of hypromellose and povidone. The lubricant is one or a mixture of two or more of magnesium stearate and sodium stearyl fumarate.

8. A pharmaceutical composition of Losartan Potassium as claimed in claim 6, wherein, The pharmaceutical composition is a solid oral preparation, preferably a tablet.

9. A process for preparing a pharmaceutical composition of losartan potassium as claimed in any one of claims 1 to 8, characterized in that, The method comprises the following steps: Step 1) dissolving losartan potassium and the arginine co-crystal precursor molecule in a solvent to form a solution; Step 2) dissolving polyethylene glycol in the solution obtained in step 1) to compound the co-crystal complex of losartan potassium and the arginine co-crystal precursor molecule with the polyethylene glycol to obtain a mixture; Step 3) removing the solvent from the mixture obtained in step 2) to obtain the pharmaceutical composition.

10. Use of the losartan potassium pharmaceutical composition according to any one of claims 1-8 in the preparation of a medicament for treating primary hypertension.

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