Fenofibrate nano eutectic composition and preparation method thereof

Abstract

The invention relates to a fenofibrate nano eutectic composition and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The fenofibrate nano eutectic composition is composed of fenofibrate, a eutectic forming agent, a stabilizer, a filler, a flow aid and a lubricant. The specific method comprises the following steps: forming a fenofibrate eutectic from fenofibrate and a eutectic forming agent, and performing nanocrystallization through a medium grinding method so as to improve the solubility and the dissolution rate of an indissolvable bulk drug; forming a nano suspension from the nano-crystallized eutectic, a stabilizer and water, and freeze-drying to obtain stable nano eutectic particles; and uniformly mixing with other auxiliary materials, and filling into capsules or pressing into tablets. Compared with an original drug, the dissolution rate and bioavailability of the tablet are increased.

Description

TECHNICAL FIELD

[0001] The present application relates to a fenofibrate nanoscale eutectic composition and a preparation method, belonging to the technical field of pharmaceutical preparations. BACKGROUND

[0002] Fenofibrate is suitable for treating primary hypertriglyceridemia and hypercholesterolemia with cardiovascular disease risk. For patients who have not improved through diet and exercise, especially individuals with diabetes, obesity or family history, fenofibrate is often the choice of treatment.

[0003] Fenofibrate belongs to BCS II drugs, with poor solubility and low bioavailability. To improve its solubility and bioavailability, inclusion compounds (CN107469091A), solid dispersions (CN106727338A), self-microemulsifying formulations (CN118304260A), nanofor mulations (CN111759810A) and other related preparation technologies have been developed and applied, and certain effects have been achieved. Although there are obvious differences in composition and preparation method, maintaining the relative stability of the drug and preventing aggregation and precipitation is one of the common problems faced by the development of the above formulations.

[0004] Pharmaceutical co-crystals are crystals formed by combining a drug with a pharmaceutically acceptable molecule through hydrogen bonds, π-π stacking or van der Waals forces, etc. non-covalent bonds in the same lattice, which can effectively improve the stability and bioavailability of the drug. The applicant found through a large number of experiments that some amino acids containing amide structures can form relatively stable co-crystals with fenofibrate. To further improve the solubility and dissolution rate of the co-crystals, the co-crystals are nano-processed in the present application, and to overcome the tendency of co-crystal particles to aggregate after particle size reduction, an appropriate amount of crystallization inhibitor (stabilizer) is added during the nano-processing of the co-crystals to maintain the stability of the nanoscale co-crystal system. SUMMARY

[0005] Co-crystals and nanotechnology have been partially applied in the development of poorly soluble drugs, but the solubilization effect of both alone is limited for some drugs, especially large-sized drugs, and the technical barriers for their combined application are high, and there are fewer reports. To maximize the solubilization potential, the present application uses fenofibrate as a model drug, combines co-crystals with nanotechnology, and through a series of prescription process explorations, a relatively stable fenofibrate nanoscale eutectic composition is obtained, which greatly improves the bioavailability of the product.

[0006] The application is realized by the following technical scheme: a fenofibrate nanoscale eutectic composition, characterized by comprising the following components by weight: 48% of fenofibrate raw material, 17%-20% of eutectic forming agent, 1%-5% of surface stabilizer, 7%-13% of suspension stabilizer, 16%-21% of filling agent, 1% of flow aid and 1% of lubricant, wherein the ratio of the stoichiometric number of fenofibrate and the eutectic forming agent is 1:1.

[0007] The eutectic forming agent is asparagine (Asn) or glutamine (Gln).

[0008] The surface stabilizer is sodium dodecyl sulfate or sodium dioctyl sulfosuccinate.

[0009] The suspension stabilizer is maltodextrin or sorbitol.

[0010] The filling agent is lactose or pregelatinized starch.

[0011] The flow aid is micro-powder silica gel or talc powder.

[0012] The lubricant is magnesium stearate or sodium stearyl fumarate.

[0013] The fenofibrate nanoscale eutectic composition is prepared by medium grinding technology and freeze-drying technology, and specifically includes the following steps: Step 1: fenofibrate and the eutectic forming agent are placed in ethyl acetate, stirred to dissolve, and the solvent is slowly volatilized at room temperature until complete, and then vacuum dried overnight to obtain fenofibrate eutectic crystals; Step 2: the suspension stabilizer and the surface stabilizer are dissolved in purified water to obtain a stabilizer solution; Step 3: the fenofibrate eutectic crystals obtained in step 1 are added to the stabilizer solution obtained in step 2, and are ground by a planetary ball mill for about 0.5 h at a speed of 500 rpm, and then are transferred to a high-pressure homogenizer for homogenization for 0.5 h at a pressure of 50-70 MPa to obtain a fenofibrate nanoscale eutectic suspension; Step 4: the fenofibrate nanoscale eutectic suspension obtained in step 3 is pre-frozen at-50℃ for 5 h, dried in a freeze dryer for 48 h, and then crushed by a universal crusher and sieved to obtain fenofibrate nanoscale eutectic granules; Step 5: the fenofibrate nanoscale eutectic granules obtained in step 4 are placed in a total mixer, and the filling agent, the flow aid and the lubricant are added, mixed at a speed of 10 rpm for 8 min to obtain total mixed granules; Step 6: the total mixed granules obtained in step 5 are placed in a capsule filling machine for filling or compressed into tablets to obtain the fenofibrate nanoscale eutectic composition. Beneficial effects

[0014] (1) Fenofibrate and amino acid form a co-crystal, which greatly improves the inherent solubility of fenofibrate, reduces the solvation potential energy, and further improves the solubility of the nanocrystalline fenofibrate after nanocrystallization, and effectively maintains the system stability of the nanocrystalline co-crystal through appropriate component and process screening.

[0015] (2) Compared with the original drug Lipantyl (capsule specification 200mg, tablet specification 160mg, both of which are bioequivalent), the dosage of the main drug (specification 120mg) of the application is greatly reduced, the cost of the raw material drug is reduced, the bioavailability is obviously improved, and a reference approach is provided for the design and development of large-specification poorly soluble drugs. DETAILED DESCRIPTION The application will be further described below in combination with specific examples. It should be noted that the following examples are preferred examples for preparing capsules, and are not all, and should not be understood as limiting the application in any form.

[0016] Example 1

[0017] Preparation method: Step 1: Fenofibrate and co-crystal forming agent are placed in ethyl acetate, stirred to dissolve, and the solvent is slowly volatilized at room temperature until complete. After vacuum drying overnight, fenofibrate co-crystal is obtained. Step 2: The suspension stabilizer and surface stabilizer are dissolved in purified water to obtain a stabilizer solution. Step 3: The fenofibrate co-crystal obtained in step 1 is added to the stabilizer solution obtained in step 2, and is ground with a planetary ball mill for about 0.5h at a speed of 500rpm. Then it is transferred to a high-pressure homogenizer and homogenized for 0.5h at a pressure of 50-70MPa to obtain a fenofibrate nanocrystalline suspension. Step 4: The fenofibrate nanocrystalline suspension obtained in step 3 is pre-frozen at-50℃ for 5h, dried in a freeze dryer for 48h, and then crushed and sieved by a universal crusher to obtain fenofibrate nanocrystalline particles. Step 5: The fenofibrate nanocrystalline particles obtained in step 4 are placed in a total mixer, and the filler, glidant and lubricant are added at a speed of 10rpm for 8min to obtain total mixed particles. Step 6: The total mixed particles obtained in step 5 are placed in a capsule filling machine for filling to obtain fenofibrate nanocrystalline capsules.

[0018] Example 2

[0019] Preparation method: The preparation method of Example 1 is referred to for preparation.

[0020] Example 3

[0021] Preparation method: refer to the preparation method of Example 1.

[0022] Example 4

[0023] Preparation method: refer to the preparation method of Example 1.

[0024] Comparative Example 1 (no eutectic forming agent)

[0025] Preparation method: Step 1: micronize the fenofibrate bulk drug; Step 2: dissolve the suspension stabilizer and surface stabilizer in purified water to obtain a stabilizer solution; Step 3: add the fenofibrate bulk drug obtained in Step 1 to the stabilizer solution obtained in Step 2, and grind with a planetary ball mill for about 0.5 h at a speed of 500 rpm, and then transfer to a high-pressure homogenizer to homogenize for 0.5 h at a pressure of 50-70 MPa, to obtain a fenofibrate nanosuspension; Step 4: pre-freeze the fenofibrate nanosuspension obtained in Step 3 at -50°C for 5 h, and dry in a freeze dryer for 48 h, and then crush and sieve with a universal crusher to obtain fenofibrate nanoparticles; Step 5: place the fenofibrate nanoparticles obtained in Step 4 in a total mixer, add the filler, glidant and lubricant, mix at a speed of 10 rpm for 8 min, and obtain total mixed granules; Step 6: place the total mixed granules obtained in Step 5 in a capsule filling machine to fill, and obtain fenofibrate capsules.

[0026] Comparative Example 2 (the ratio of the stoichiometric number of fenofibrate to the eutectic forming agent is 2:1)

[0027] Preparation method: refer to the preparation method of Example 1.

[0028] Comparative Example 3 (the ratio of the stoichiometric number of fenofibrate to the eutectic forming agent is 1:2)

[0029] Preparation method: refer to the preparation method of Example 1.

[0030] Comparative Example 4 (fenofibrate eutectic body without nanometerization treatment)

[0031] Preparation method: Step 1: Fenofibrate and co-crystal former were put into ethyl acetate, stirred to dissolve, slowly evaporated the solvent at room temperature until completely, dried in vacuum overnight to obtain fenofibrate co-crystal; Step 2: Suspension stabilizer and surface stabilizer were dissolved in purified water to obtain stabilizer solution; Step 3: Fenofibrate co-crystal obtained in step 1 was added to the stabilizer solution obtained in step 2, ultrasonic dispersion for 15 min to obtain fenofibrate co-crystal suspension; Step 4: The fenofibrate co-crystal suspension obtained in step 3 was pre-frozen at -50℃ for 5h, dried in a freeze dryer for 48h, and then crushed and sieved by a universal crusher to obtain fenofibrate co-crystal granules; Step 5: Fenofibrate co-crystal granules obtained in step 4 were put into a total mixer, and filler, glidant and lubricant were added, mixed at a speed of 10 rpm for 8 min to obtain total mixed granules; Step 6: The total mixed granules obtained in step 5 were filled into a capsule filling machine to obtain fenofibrate co-crystal capsules.

[0032] Comparative Example 5 (the amount of surface stabilizer exceeds the upper limit, and the amount of suspension stabilizer is below the lower limit)

[0033] Preparation method: The preparation method was prepared according to the preparation method of Example 1.

[0034] Comparative Example 6 (the amount of surface stabilizer is below the lower limit, and the amount of suspension stabilizer exceeds the upper limit)

[0035] Preparation method: The preparation method was prepared according to the preparation method of Example 1.

[0036] Test Example 1: Solubility Investigation An excess amount of fenofibrate, fenofibrate-asparagine and fenofibrate-glutamine co-crystals were taken in a conical flask, and purified water was slowly stirred for 12h to maintain the supersaturated state of the solution, and the solubility was determined, and the results were as follows:

[0037] Compared with fenofibrate raw material, the solubility of fenofibrate-asparagine and fenofibrate-glutamine co-crystals was greatly increased, which greatly improved the solubility characteristics of the raw material. It should be noted that the solubility is determined by two independent factors: the strength of the crystal lattice and the solvation of the co-crystal components. To improve the solubility, the crystal lattice energy can be reduced and / or the solvent affinity can be improved. Due to the hydrophobicity of the drug, solvation will play a decisive role in the water solubility of the co-crystal.

[0038] Test Example 2 Dissolution curve observation According to the dissolution and release determination method (Chinese Pharmacopoeia 2025 Edition Volume 4 General Rules 0931), 0.025 mol / L sodium dodecyl sulfate solution 1000 ml was used as the dissolution medium, the paddle method was used, and the rotation speed was 75 revolutions per minute. The cumulative dissolution amounts of the original research preparation-Lipinuo (capsule), the samples of Examples 1-4 and Comparative Examples 1-6 were determined at 5 min, 15 min and 30 min, respectively. The specific results are as follows:

[0039] As can be seen from the above table, the dissolution amount of the original research preparation Lipinuo at 30 min is only about 75%, while the dissolution amounts of the fenofibrate nanoscale eutectic capsules of Examples 1-4 at 30 min are all more than 95%; the dissolution amounts of the samples of Comparative Examples 1-6 at 30 min are higher than that of the original research preparation Lipinuo, but still less than 85%; among them, the prescription of Comparative Example 1 does not add a eutectic forming agent, only the raw material is ground and homogenized, and the effect of improving the dissolution of the preparation is limited; the amount of the eutectic forming agent in the prescription of Comparative Example 2 is small, and the amount of the formed eutectic is insufficient, resulting in a low dissolution amount; the amount of the eutectic forming agent in the prescription of Comparative Example 3 is large, but the dissolution result is not ideal. Combined with the stick rod phenomenon that occurs during the filling of the capsules, it is speculated that the reason is that the amount of the filler is small under the premise of the same filling amount, and the content is not easy to disperse; the eutectic in the preparation process of Comparative Example 4 is not nanoscale, resulting in a low dissolution; the amounts of the surface stabilizer and the suspension stabilizer in the prescriptions of Comparative Examples 5 and 6 are not within the protection range, which affects the dispersion of the nanoscale eutectic and the dissolution of the raw material, and the actual dissolution result is low.

[0040] Test Example 3 Pharmacokinetic evaluation of rats The contents of Lipinuo were taken in an appropriate amount, a small amount of 0.5% PVP aqueous solution was added to prepare a suspension, and the suspension was prepared; the contents of the nanoscale eutectic capsules of Example 1 were taken in an appropriate amount, a small amount of 0.5% PVP aqueous solution was added to prepare a suspension, and the suspension was prepared.

[0041] Sixteen healthy Wister rats, half male and half female, weighing 200-220 g, were randomly divided into two groups, and were given intragastrical administration at a dose of 100 mg / kg. The rats were fasted for 12 h before administration, and 0.5 mL of blood was taken from the orbital cavity of the rats at 0.5, 1, 1.5, 2, 4, 8, 12, 16, 20 and 24 h after administration. The drug concentration in the treated plasma sample was determined, and the specific results are as follows:

[0042] As can be seen from the above table, the main pharmacokinetic parameters AUC and C maxThe AUC and Cmax of nano-eutectic capsule were higher than those of Fenofibrate tablets, which indicated that the design of nano-eutectic capsule was more helpful to the absorption of drug in vivo than that of common capsule, thus improving the bioavailability of Fenofibrate.

Claims

1. A fenofibrate nano-eutectic composition, characterized in that, It comprises the following weight components: 48% fenofibrate active pharmaceutical ingredient, 17%~20% eutectic forming agent, 1%~5% surface stabilizer, 7%~13% suspension stabilizer, 16%~21% filler, 1% flow aid and 1% lubricant, wherein the stoichiometric ratio of fenofibrate active pharmaceutical ingredient to eutectic forming agent is 1:

1.

2. The fenofibrate nano-eutectic composition according to claim 1, characterized in that, The eutectic forming agent is asparagine (Asn) or glutamine (Gln), the surface stabilizer is sodium dodecyl sulfate or sodium dioctyl sulfosuccinate, the suspension stabilizer is maltodextrin or sorbitol, the filler is lactose or pregelatinized starch, the flow aid is micronized silica gel or talc, and the lubricant is magnesium stearate or sodium stearate fumarate.

3. The fenofibrate nano-eutectic composition according to claim 1, characterized in that, Prepared using media milling and freeze-drying techniques, the specific steps include: Step 1: Place fenofibrate and the eutectic forming agent in ethyl acetate, stir to dissolve, slowly evaporate the solvent at room temperature until complete, and vacuum dry overnight to obtain fenofibrate eutectic; Step 2: Dissolve the suspension stabilizer and surface stabilizer in purified water to obtain a stabilizer solution; Step 3: Add the fenofibrate eutectic obtained in Step 1 to the stabilizer solution obtained in Step 2, grind it with a planetary ball mill, and then transfer it to a high-pressure homogenizer for homogenization to obtain a fenofibrate nano-eutectic suspension. Step 4: Place the fenofibrate nano-eutectic suspension obtained in Step 3 into a freeze dryer to dry it, and then pulverize and sieve it with a universal pulverizer to obtain fenofibrate nano-eutectic particles. Step 5: Place the fenofibrate nano-eutectic particles obtained in Step 4 into a mixer, add filler, flow aid and lubricant, and mix to obtain the total mixed particles; Step 6: Place the total mixed particles obtained in Step 5 into a capsule filling machine for filling or compressing into tablets to obtain the fenofibrate nano-eutectic composition.

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