A nanocrystalline pharmaceutical composition comprising rosuvastatin calcium

Abstract

The application provides a nanocrystal drug composition containing rosuvastatin calcium, which contains the following components in parts by weight: 100 parts of rosuvastatin calcium, 20-150 parts of a stabilizer and 200-2000 parts of a pharmaceutically acceptable carrier; the stabilizer is composed of a steric hindrance stabilizer and an electrostatic stabilizer, and the weight ratio of the two is 1:0.5 to 1:2; in the nanocrystal drug composition, the average particle size of rosuvastatin calcium is distributed between 200 nm and 800 nm, and the polydispersity index (PDI) is less than 0.2; by using a specific stabilizer combination and a preparation process, the application prepares rosuvastatin calcium into a nanocrystal with an average particle size of 200 nm-800 nm, significantly improves the solubility and dissolution rate of the drug, and the nanocrystal drug composition exhibits excellent physical stability and chemical stability under accelerated test conditions, overcomes the problems that rosuvastatin calcium is unstable to light, moisture and heat and the bioavailability of existing preparations is limited, and has significant clinical application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a nanocrystalline pharmaceutical composition containing rosuvastatin calcium. Background Technology

[0002] Rosuvastatin calcium is a selective HMG-CoA reductase inhibitor, mainly used to treat hypercholesterolemia and mixed dyslipidemia. As a statin drug, it has significant efficacy and is known as a "super statin".

[0003] However, rosuvastatin calcium belongs to the Biopharmaceutical Classification System (BCS) Class II drugs, which are characterized by low solubility and high permeability. Its low solubility in water leads to a limited dissolution rate after oral administration, which in turn affects bioavailability.

[0004] In addition, the calcium structure of rosuvastatin contains a dihydroxyheptenic acid side chain, which is highly susceptible to degradation by light, heat, moisture and pH, generating lactone products or oxidation products.

[0005] While existing conventional tablets or capsules have improved dissolution to some extent through micronization technology, the increased surface area and surface energy of the powder after micronization make it prone to aggregation, leading to a decrease in the physical stability of the formulation (such as uneven content and decreased dissolution). At the same time, the increased powder fineness also increases the contact area between the drug and the external environment, exacerbating chemical instability and leading to an increase in related substances (impurities), which affects drug safety.

[0006] Nanocrystallization technology is an effective means to solve the solubility problem of poorly soluble drugs. By reducing the drug particle size to the nanoscale, the specific surface area is significantly increased, which can greatly improve the dissolution rate and saturated solubility. However, nanocrystals are in a thermodynamically unstable state and are prone to Ostwald ripening or particle aggregation, resulting in an increase in particle size. Moreover, the chemical instability of rosuvastatin calcium itself is more prominent in the nanoscale state. Therefore, a nanocrystallized drug composition containing rosuvastatin calcium is proposed. Summary of the Invention

[0007] In view of this, embodiments of the present invention provide a nanocrystalline pharmaceutical composition containing rosuvastatin calcium to solve or alleviate the technical problems existing in the prior art, and at least provide a beneficial alternative.

[0008] The technical solution of this invention is implemented as follows: a nanocrystalline pharmaceutical composition containing rosuvastatin calcium, which, by weight, comprises the following components: 100 parts of rosuvastatin calcium, 20-150 parts of stabilizer, and 200-2000 parts of pharmaceutically acceptable carrier; The stabilizer is composed of a steric hindrance stabilizer and an electrostatic stabilizer, with a weight ratio of 1:0.5 to 1:2. In the nanocrystalline pharmaceutical composition, the average particle size of rosuvastatin calcium is distributed between 200 nm and 800 nm, and the polydispersity index (PDI) is less than 0.2.

[0009] In some embodiments, the steric hindrance stabilizer is selected from one or more of povidone K30, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, poloxamer 188, and poloxamer 407. The electrostatic stabilizer is selected from one or more of sodium dodecyl sulfate, sodium cholate, and sodium deoxycholate.

[0010] In some embodiments, the stabilizer consists of hydroxypropyl methylcellulose E5 and sodium dodecyl sulfate in a weight ratio of 1:1.

[0011] In some embodiments, the pharmaceutically acceptable carrier includes fillers, disintegrants, lubricants, and flow aids; The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch, and the weight part is 100-1000 parts; The disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose, and the weight part is 20-200 parts; The lubricant is selected from one or more of magnesium stearate, stearic acid, and talc, and the weight ratio is 1-20 parts; the flow aid is selected from one or more of colloidal silica and micronized silica, and the weight ratio is 1-10 parts.

[0012] In some embodiments, the composition is in the form of tablets, capsules, or granules.

[0013] A method for preparing a nanocrystalline pharmaceutical composition containing rosuvastatin calcium as described above includes the following steps: S1. Disperse the stabilizer in an appropriate amount of water for injection, stir to dissolve, and obtain an aqueous solution of the stabilizer; S2. Disperse rosuvastatin calcium in the above-mentioned stabilizer aqueous solution and pre-disperse it using a high-shear homogenizer to obtain an initial suspension. S3. The initial suspension is subjected to cyclic homogenization using a high-pressure homogenizer. The homogenization pressure and number of cycles are controlled until the particle size meets the requirements, thus obtaining rosuvastatin calcium nanocrystal suspension. S4. The nanocrystalline suspension obtained in S3 is mixed with a pharmaceutically acceptable carrier, and then dried, sieved, granulated, tableted, or filled to obtain the final product.

[0014] In some embodiments, steric hindrance stabilizers adsorb onto the surface of drug particles to form a polymer chain barrier, preventing particles from approaching each other; electrostatic stabilizers impart surface charges to the particles, preventing aggregation through electrostatic repulsion. The two work synergistically to construct a dense protective layer, effectively maintaining the physical morphology of the nanocrystals and blocking particle aggregation, while also forming a protective film on the drug surface to isolate it from moisture and oxygen, thereby significantly improving the chemical stability of the drug.

[0015] In some embodiments, Filler: selected from one or more of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch, in parts by weight of 100-1000, preferably a combination of microcrystalline cellulose and lactose, which has good flowability and compressibility and is suitable for adsorption granulation of nanocrystalline suspensions; Disintegrant: Selected from one or more of croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose, in parts by weight of 20-200 parts, preferably croscarmellose, which has strong capillary action, can quickly absorb water and swell, and accelerate the disintegration and dissolution of nanocrystalline particles. Lubricant: Selected from one or more of magnesium stearate, stearic acid, and talc, in parts by weight of 1-20.

[0016] Flow aid: Selected from one or more of colloidal silica and micronized silica, in parts by weight of 1-10. Micronized silica not only improves flowability, but its porous structure also helps to adsorb nanocrystalline suspensions and prevent drugs from migrating on the particle surface.

[0017] The embodiments of the present invention have the following advantages due to the adoption of the above technical solutions: This invention utilizes a specific combination of stabilizers and a specific preparation process to prepare rosuvastatin calcium into nanocrystals with an average particle size between 200 nm and 800 nm, significantly improving the drug's solubility and dissolution rate. This nanocrystal drug composition exhibits excellent physical and chemical stability under accelerated testing conditions, overcoming the problems of rosuvastatin calcium's instability in the face of light, moisture, and heat, as well as the limited bioavailability of existing formulations, and has significant clinical application value.

[0018] The above overview is for illustrative purposes only and is not intended to be limiting in any way. Detailed Implementation

[0019] In the following description, only certain exemplary embodiments are briefly described. As those skilled in the art will recognize, the described embodiments can be modified in various ways without departing from the spirit or scope of the invention.

[0020] It is important to note that terms such as "first," "second," "symmetric," "array," "set in," and "set with" are used only to distinguish between descriptive and positional descriptions and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Therefore, features specified with terms such as "first" or "symmetric" may explicitly or implicitly include one or more of that feature; similarly, when the quantity of certain features is not limited by words such as "two" or "three," it should be noted that such features also explicitly or implicitly include one or more features.

[0021] In this invention, unless otherwise explicitly specified and limited, terms such as “installation,” “connection,” and “fixation” should be interpreted broadly; for example, they can be fixed connections, detachable connections, or integral moldings; they can be mechanical connections, direct connections, welding, or indirect connections through an intermediate medium; they can be internal connections between two components or the interaction between two components.

[0022] This invention provides a nanocrystalline pharmaceutical composition containing rosuvastatin calcium, which comprises the following components in parts by weight: 100 parts of rosuvastatin calcium, 20-150 parts of stabilizer, and 200-2000 parts of pharmaceutically acceptable carrier; The stabilizer consists of a steric hindrance stabilizer and an electrostatic stabilizer, with a weight ratio of 1:0.5 to 1:2. In the nanocrystalline pharmaceutical composition, the average particle size distribution of rosuvastatin calcium is between 200 nm and 800 nm, and the polydispersity index (PDI) is less than 0.2.

[0023] In this embodiment, specifically, the steric hindrance stabilizer is selected from one or more of the following: povidone K30, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, poloxamer 188, and poloxamer 407. The electrostatic stabilizer is selected from one or more of sodium dodecyl sulfate, sodium cholate, and sodium deoxycholate.

[0024] In this embodiment, specifically, the stabilizer consists of hydroxypropyl methylcellulose E5 and sodium dodecyl sulfate in a weight ratio of 1:1.

[0025] In this embodiment, pharmaceutically acceptable carriers specifically include fillers, disintegrants, lubricants, and flow aids; The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch, in parts by weight of 100-1000. The disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose, in parts by weight of 20-200. The lubricant is selected from one or more of magnesium stearate, stearic acid, and talc, and the weight is 1-20 parts; the flow aid is selected from one or more of colloidal silica and micronized silica, and the weight is 1-10 parts.

[0026] In this embodiment, specifically, the dosage form of the composition is tablets, capsules, or granules.

[0027] A method for preparing a nanocrystalline pharmaceutical composition containing rosuvastatin calcium as described above includes the following steps: S1. Disperse the stabilizer in an appropriate amount of water for injection, stir to dissolve, and obtain an aqueous solution of the stabilizer; S2. Disperse rosuvastatin calcium in the above-mentioned stabilizer aqueous solution and pre-disperse it using a high-shear homogenizer to obtain an initial suspension. S3. The initial suspension is subjected to cyclic homogenization using a high-pressure homogenizer. The homogenization pressure and number of cycles are controlled until the particle size meets the requirements, thus obtaining rosuvastatin calcium nanocrystal suspension. S4. The nanocrystalline suspension obtained in S3 is mixed with a pharmaceutically acceptable carrier, and then dried, sieved, granulated, tableted, or filled to obtain the final product.

[0028] Example 1 In this embodiment, specifically, a nanocrystalline pharmaceutical composition containing rosuvastatin calcium comprises the following components in parts by weight: 100 parts of rosuvastatin calcium, 30 parts of hydroxypropyl methylcellulose E5 (HPMC E5), 30 parts of sodium dodecyl sulfate (SDS), 500 parts of microcrystalline cellulose (MCC PH102), 50 parts of crospovidone, 5 parts of magnesium stearate, and 3 parts of micronized silica.

[0029] In this embodiment, specifically, a method for preparing a nanocrystalline drug composition containing rosuvastatin calcium includes the following steps: S1. Dissolve HPMC E5 and SDS in an appropriate amount of water for injection to prepare a stabilizer solution; S2. Add rosuvastatin calcium and use a high-shear homogenizer to shear at 10,000 rpm for 10 minutes to obtain the initial suspension. S3. The initial suspension is transferred to a high-pressure homogenizer and homogenized 15 times at a pressure of 1500 bar to obtain a nanocrystalline suspension with an average particle size of 350 nm and a PDI of 0.15. S4. Spray dry the nanocrystalline suspension (inlet air temperature 120℃, outlet air temperature 60℃) to obtain nanocrystalline dry powder. Mix the nanocrystalline dry powder with microcrystalline cellulose and cross-linked polyvinylpyrrolidone evenly, dry granulate, add magnesium stearate and micronized silica powder, mix thoroughly, and compress into tablets to obtain the final product. In this embodiment, specifically, Comparative Example 1 (Ordinary micronized tablets) The formulation is the same as in Example 1, except that: no stabilizer is used, and the rosuvastatin calcium raw material is directly micronized (particle size D90 is about 10μm), and then directly mixed with excipients to form granules and tablets.

[0030] Comparative Example 2 (Single Stabilizer) The formulation is the same as in Example 1, except that only 60 parts of HPMC E5 are used as a stabilizer, and SDS is not used.

[0031] Experimental data and stability study 1. Dissolution test The second method (paddle method) of General Chapter 0931 in Part IV of the 2020 edition of the Chinese Pharmacopoeia was adopted. 900 ml of pH 6.8 phosphate buffer was used as the dissolution medium, and the paddle rotation speed was 50 rpm. Samples were taken at 5, 10, 15, and 30 minutes for analysis. The results are shown in the table below: The nanocrystalline formulation of Example 1 of this invention has a significantly faster dissolution rate than ordinary formulations and single stabilizer formulations, demonstrating excellent solubilizing effect.

[0032] 2. Physical stability study (particle size change) The samples were subjected to accelerated testing at a temperature of 40℃±2℃ and a relative humidity of 75%±5%. Samples were taken in 0 months, 1 month, 3 months and 6 months, and the average particle size and PDI were measured after redispersing.

[0033] Example 1 uses a composite stabilizer, and the particle size remains essentially unchanged within 6 months, indicating that the system effectively inhibits the aggregation and Ostwald ripening of nanoparticles and exhibits excellent physical stability.

[0034] 3. Chemical stability study (related substances) The samples were subjected to a strong thermal degradation test in a 60℃ constant temperature chamber and an accelerated test under 40℃ / 75%RH conditions to examine the changes in total impurities.

[0035] A. High-temperature test at 60℃ (10 days): B. Accelerated test at 40℃ / 75%RH (6 months): Under high temperature and high humidity conditions, the impurity growth rate of the nanocrystalline composition in Example 1 was much lower than that of ordinary micronized formulations (Comparative Example 1) and single stabilizer formulations (Comparative Example 2). This indicates that the specific stabilizer combination of the present invention forms a dense protective layer on the surface of the nanocrystals, effectively blocking the invasion of drug molecules by the humid and hot environment, solving the problem that rosuvastatin calcium is more easily degraded in the nano-state, and achieving a dual improvement in physical and chemical stability.

[0036] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any person skilled in the art can easily conceive of various variations or substitutions within the technical scope disclosed in the present invention, and these should all be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A nanocrystalline pharmaceutical composition containing rosuvastatin calcium, characterized in that, The composition comprises the following components in parts by weight: 100 parts of rosuvastatin calcium, 20-150 parts of stabilizer, and 200-2000 parts of pharmaceutically acceptable carrier; The stabilizer is composed of a steric hindrance stabilizer and an electrostatic stabilizer, with a weight ratio of 1:0.5 to 1:

2. In the nanocrystalline pharmaceutical composition, the average particle size of rosuvastatin calcium is distributed between 200 nm and 800 nm, and the polydispersity index (PDI) is less than 0.

2.

2. The nanocrystalline pharmaceutical composition containing rosuvastatin calcium according to claim 1, characterized in that, The steric hindrance stabilizer is selected from one or more of the following: povidone K30, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, poloxamer 188, and poloxamer 407. The electrostatic stabilizer is selected from one or more of sodium dodecyl sulfate, sodium cholate, and sodium deoxycholate.

3. The nanocrystalline pharmaceutical composition containing rosuvastatin calcium according to claim 1, characterized in that, The stabilizer consists of hydroxypropyl methylcellulose E5 and sodium dodecyl sulfate in a weight ratio of 1:

1.

4. The nanocrystalline pharmaceutical composition containing rosuvastatin calcium according to claim 1, characterized in that, Pharmaceutically acceptable carriers include fillers, disintegrants, lubricants, and flow aids; The filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and pregelatinized starch, and the weight part is 100-1000 parts; The disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose, and the weight part is 20-200 parts; The lubricant is selected from one or more of magnesium stearate, stearic acid, and talc, and the weight ratio is 1-20 parts; the flow aid is selected from one or more of colloidal silica and micronized silica, and the weight ratio is 1-10 parts.

5. The nanocrystalline pharmaceutical composition containing rosuvastatin calcium according to claim 1, characterized in that, The composition is available in tablet, capsule, or granule form.

6. A method for preparing a nanocrystalline pharmaceutical composition containing rosuvastatin calcium as described in any one of claims 1-5, characterized in that, Includes the following steps: S1. Disperse the stabilizer in an appropriate amount of water for injection, stir to dissolve, and obtain an aqueous solution of the stabilizer; S2. Disperse rosuvastatin calcium in the above-mentioned stabilizer aqueous solution and pre-disperse it using a high-shear homogenizer to obtain an initial suspension. S3. The initial suspension is subjected to cyclic homogenization using a high-pressure homogenizer. The homogenization pressure and number of cycles are controlled until the particle size meets the requirements, thus obtaining rosuvastatin calcium nanocrystal suspension. S4. The nanocrystalline suspension obtained in S3 is mixed with a pharmaceutically acceptable carrier, and then dried, sieved, granulated, tableted, or filled to obtain the final product.

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