Fenofibrate oily formulation, oral drug, and preparation method

Abstract

A fenofibrate oily formulation, an oral drug, and a preparation method. The oily formulation comprises fenofibrate, an oily solvent, and a surfactant. The preparation method for the fenofibrate oily formulation comprises mixing, heating, and uniformly stirring the components to obtain a clear oil solution. The fenofibrate oily formulation improves the oral bioavailability of fenofibrate and enables the oral absorption of fenofibrate to be unaffected by diet.

Description

Fenofibrate oily preparation, oral medicine and preparation method Technical Field

[0001] The present application belongs to the technical field of pharmaceutical preparations, and specifically relates to a fenofibrate oily preparation, an oral drug, and a preparation method. Background Art

[0002] Fenofibrate (isopropyl 2-methyl-2-[4-(4-chlorobenzoyl)phenoxy]propionate) is a third-generation phenoxyacetic acid lipid-regulating drug with pharmacological effects similar to clofibrate. Due to its potent lipid-lowering effects, minimal adverse reactions, and low long-term toxicity, it is a preferred drug for patients seeking to lower blood lipids. Fenofibrate is a prodrug; after oral administration, fenofibrate is hydrolyzed by esterases to produce the metabolite fenofibric acid, which is the active drug.

[0003] Fenofibrate, a Class II drug in the Biopharmaceutics Classification System (BCS), is characterized by poor solubility and is a lipophilic drug. Currently, fenofibrate formulations marketed domestically and internationally are primarily capsules and tablets. Lipingzhi utilizes micronization technology to mix fenofibrate with a small amount of surfactant using an airflow pulverizer to create a mixture with an average particle size of 6-7 μm. However, the oral bioavailability of fenofibrate varies significantly between pre- and post-meal administration of Lipingzhi, requiring patients to take the drug with meals, significantly reducing medication compliance.

[0004] Existing research primarily addresses formulation improvements for commercially available oral fenofibrate formulations, including low oral bioavailability and poor patient compliance. The vast majority of patents for oral fenofibrate formulations address only improvements to fenofibrate's dissolution rate, failing to demonstrate its absorption advantage in animals. Alternatively, they only compare bioavailability under fasting conditions, failing to demonstrate whether the formulation's in vivo absorption is unaffected by food.

[0005] Chinese patent CN202010783154.8, based on the solvent diffusion method and using anionic surfactants as stabilizers, provides a method for preparing a fenofibrate nanosuspension that is simple to operate, low-cost, highly reproducible, and easily scalable for industrial production. The nanosuspension exhibits rapid fenofibrate dissolution and release, and good gastrointestinal transit. However, the patent does not describe the bioavailability of the fenofibrate nanocomposition in animals, failing to demonstrate the advantages of the formulation.

[0006] Chinese patent CN201711151074.5 discloses the preparation of mesoporous carbon with adjustable particle size, as well as the preparation of polymer-modified mesoporous carbon nanoparticles and their use as carriers for poorly soluble drugs to promote oral absorption. The oral bioavailability of fenofibrate-loaded mesoporous carbon nanoparticles is 1.65 times that of commercially available formulations. However, the preparation method is complex, and the brand of the commercially available formulation is not disclosed, nor is it specified whether it should be administered before or after meals.

[0007] Chinese patent CN201611200910.X discloses a fenofibrate solid dispersion with excellent in vitro dissolution and in vivo bioavailability. Chinese patent CN201310578065.X discloses an oil-soluble sustained-release pharmaceutical formulation of fenofibrate, which exhibits good dissolution, high bioavailability, and sustained drug release, making it safer and more reliable. However, the high bioavailability of these two formulations is only demonstrated in the fasting state. In the absence of animal studies under fed conditions, it is not possible to demonstrate that oral absorption of fenofibrate under fed conditions is superior to that of commercially available formulations.

[0008] Chinese patent CN201010219622.5 provides a novel solid fenofibrate composition having at least one of the following advantages: no or minimal use of surfactants, superior characteristics over existing products in terms of, for example, bioavailability, and at least one advantage over liquid preparations (e.g., ease of production control, storage stability, ease of administration, and thermodynamic stability). Similar to patent CN201310578065.X, the exemplary preparation only increases the bioavailability of fenofibrate to 7 times that of fenofibrate under fasting conditions, and a comparison of bioavailability under fed conditions is still lacking.

[0009] Many foreign patents have improved the characteristic that the oral bioavailability of fenofibrate varies greatly before and after meals. Although the absorption of the disclosed oral fenofibrate preparations is not affected by food, the oral bioavailability is still low, the preparation process is complex and the equipment requirements are high.

[0010] US Patent No. 07041319 discloses a fenofibrate nanoparticle that is not affected by diet. A US company has produced an oral product related to this patent, Tricor. TMThe preparation of fenofibrate nanoparticles requires high energy, the stability of the active ingredient may be reduced by heating, and due to the high free energy, the particles are prone to form particle agglomerations, and the preparation process is relatively complicated. In addition, the literature "Katarina Bukara et al. In Vivo Performance of Fenofibrate Formulated With Ordered Mesoporous Silica Versus 2-Marketed Formulations: A Comparative Bioavailability Study in Beagle Dogs, Journal of Pharmaceutical Sciences, 2016, 105, 2381-2385" compared this product with Lipingzhi. Beagle dogs were orally administered 48 mg of Tricor in a fasting state. TM The AUC of fenofibric acid was 11.80±1.170ng / mL*h, which was 3.74 times that of Lipingzhi. The oral bioavailability of fenofibrate in this product is still low and there is room for improvement.

[0011] Korean patent WO2022071768 discloses a method for TM A bioequivalent fenofibrate pharmaceutical composition utilizes surfactants and hydrophilic polymers to stabilize the micronized fenofibrate, resulting in improved bioavailability and oral absorption that is unaffected by dietary changes. However, this invention requires micronized fenofibrate, placing high demands on micronization equipment and a complex process.

[0012] In summary, oral fenofibrate drugs with high bioavailability, absorption not affected by diet, simple preparation process and high formulation stability have great market demand and development prospects.

[0013] Summary of the Invention

[0014] The purpose of the present application is to provide a fenofibrate oily preparation, an oral drug and a preparation method. The fenofibrate oily preparation has high oral bioavailability, its absorption is not affected by diet, its preparation is highly stable and its preparation is simple.

[0015] The present application provides a fenofibrate oily preparation, which comprises the following components in the following mass ratios: 0.5% to 20% fenofibrate, 10% to 60% oily solvent, and 15% to 70% surfactant.

[0016] Preferably, the fenofibrate oily preparation comprises the following components in the following mass ratios: 1% to 15% fenofibrate, 20% to 50% oily solvent, and 30% to 70% surfactant.

[0017] Preferably, the fenofibrate oily preparation comprises the following components in the following mass ratios: 3% to 12% fenofibrate, 30% to 50% oily solvent, and 50% to 70% surfactant.

[0018] Preferably, the fenofibrate oily preparation further comprises a co-surfactant in a mass ratio of 0 to 30%.

[0019] Preferably, the oily solvent is selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: soybean oil, rapeseed oil, palm oil, peanut oil, sunflower oil, coconut oil, linseed oil, castor oil, perilla oil, corn oil, monostearin, stearic acid diglyceride, stearic acid triglyceride, monolinoleic acid glyceride, linoleic acid diglyceride, linoleic acid triglyceride, monooleic acid glyceride, oleic acid diglyceride, oleic acid triglyceride, medium chain triglycerides of different chain lengths, long chain monoglycerides, long chain diglycerides, long chain triglycerides, caprylic acid triglyceride, myristic acid triglyceride, isopropyl myristate, oleic acid, linoleic acid, ethyl oleate, ethyl linoleate and palmitic acid.

[0020] Preferably, the surfactant is selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: polyoxyethylene castor oil, hydrogenated polyoxyethylene castor oil, Tween-20, Tween-60, Tween-80, vitamin E-TPGS, caprylic / capric macrogol glycerides, lauroyl polyoxyethylene-32 glyceride, macrogol-32 stearate and stearyl polyoxyethylene glyceride.

[0021] Preferably, the co-surfactant is selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: diethylene glycol monoethyl ether, polyglycerol oleate, PEG400, isopropyl alcohol, propylene glycol laurate, ethanol and 1,2-propylene glycol.

[0022] The present application provides a method for preparing the above-mentioned fenofibrate oily preparation, comprising the following steps: mixing the components, heating and stirring uniformly, and obtaining a clear oil solution as the fenofibrate oily preparation.

[0023] The present application also provides an oral medicine comprising the above-mentioned fenofibrate oily preparation.

[0024] Preferably, the dosage form of the oral drug includes soft capsules, liquid capsules, hard capsules or dripping pills.

[0025] Beneficial effects: The present application provides an oily preparation of fenofibrate, the components of which include fenofibrate, an oily solvent and a surfactant. Based on the characteristic that the bioavailability of existing fenofibrate preparations is greatly increased after a meal, by co-administering fenofibrate with an oily medium, fenofibrate is promoted to bind to chylomicrons and enter the lymphatic absorption, thereby avoiding the first-pass effect of the liver, thereby improving the bioavailability of oral fenofibrate and reducing the effect of food on oral absorption.

[0026] Comparison of the pharmacokinetic experiments in rats and beagles in the examples of the present application confirmed that the preparation described herein improves the oral bioavailability of fenofibrate, and that the oral bioavailability is less affected by diet. By dose conversion, the AUC of fenofibric acid after administration of Liping in the fed rat state was 196.52% of that in the fasted state, indicating a significant change in bioavailability. However, the AUC after administration of the fenofibrate self-emulsifying formulation (FNB-SEDDS) in the fed rat state was 120.64% of that in the fasted state, indicating a smaller degree of improvement in bioavailability. After administration of Liping in the fed beagle state, the AUC of fenofibric acid was 910.97% of that in the fasted state, indicating that the effect of diet on the commercially available fenofibrate formulation Liping is more pronounced as the animal size increases. The AUC of fenofibric acid after administration of FNB-SEDDS in the fed beagle state was 81.03% of that in the fasted state, indicating no significant difference. Two animal models showed that the oily formulation of the present application improved the oral bioavailability of fenofibrate and its absorption was not affected by diet. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG1 is a concentration-time curve of fenofibric acid in rats after oral administration of Lipingzhi and FNB-SEDDS under fasting conditions;

[0028] FIG2 is a concentration-time curve of fenofibric acid after oral administration of Lipingzhi and FNB-SEDDS to rats under fed conditions;

[0029] FIG3 shows the concentration-time curve of fenofibric acid after oral administration of Liping and FNB-SEDDS to beagle dogs under fasting conditions;

[0030] FIG4 shows the concentration-time curves of fenofibric acid after oral administration of Lipingzhi and FNB-SEDDS with meals in beagle dogs. DETAILED DESCRIPTION

[0031] The present application provides a fenofibrate oily preparation, which comprises the following components in the following mass ratios: 0.5% to 20% fenofibrate, 10% to 60% oily solvent, and 15% to 70% surfactant.

[0032] The components of the fenofibrate oily preparation described in the present application include fenofibrate, and the mass content of the fenofibrate is preferably 1% to 15%, more preferably 3% to 12%. The chemical name of the fenofibrate described in the present application is 2-methyl-2-[4-(4-chlorobenzoyl)phenoxy]propionic acid isopropyl ester, and the molecular formula is C 20 H 21 ClO4, the structural formula is shown in Formula I:

[0033] The components of the fenofibrate oily preparation described in the present application include an oily solvent, and the mass percentage of the oily solvent is preferably 20% to 50%, more preferably 30% to 50%. The oily solvent described in the present application is preferably selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: soybean oil, rapeseed oil, palm oil, peanut oil, sunflower oil, coconut oil, linseed oil, castor oil, perilla oil, corn oil, monostearic acid glyceryl, stearic acid diglyceride, stearic acid triglyceride, monolinoleic acid glyceryl, linoleic acid diglyceride, linoleic acid triglyceride, monooleic acid glyceryl, oleic acid diglyceride, oleic acid triglyceride, medium chain (C6-C12) triglycerides of different chain lengths, long chain (C16-C22) monoglycerides, long chain (C16-C22) diglycerides, long chain (C16-C22) triglycerides, caprylic acid triglyceride, myristic acid triglyceride, isopropyl myristate, oleic acid, linoleic acid, ethyl oleate, isopropyl myristate, Ethyl oleate and palmitic acid; more preferably, at least one selected from the following or a commercial mixture containing at least one of the following components: oleic acid, linoleic acid, ethyl oleate, ethyl linoleate, monolinolein, dilinolein, trilinolein, monoolein, diolein, triolein, medium-chain triglycerides of varying chain lengths, long-chain monoglycerides, long-chain diglycerides, long-chain triglycerides, and caprylic triglyceride; most preferably, at least one selected from the following or a commercial mixture containing at least one of the following components: oleic acid, linoleic acid, ethyl oleate, ethyl linoleate, monolinolein, dilinolein, trilinolein, monoolein, diolein, triolein, medium-chain triglycerides of varying chain lengths, and caprylic triglyceride. The oily solvent can improve the dispersibility of the drug in the gastrointestinal tract, thereby improving the oral bioavailability of the drug. In addition, triglycerides in food can promote the absorption of fenofibrate, which has good fat solubility, into the lymphatic system. Therefore, the oral absorption pathway of fenofibrate is affected by food. The oily solvent in the preparation of the present application can also promote the lymphatic absorption of the drug, thereby reducing the effect of food on the oral bioavailability of fenofibrate.

[0034] The fenofibrate oily preparation described in the present application contains a surfactant, and the mass percentage of the surfactant is preferably 30% to 70%, more preferably 50% to 70%. The surfactant described in the present application is preferably selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: polyoxyethylene castor oil, hydrogenated polyoxyethylene castor oil, Tween-20, Tween-60, Tween-80, vitamin E-TPGS, caprylic capric macrogol glycerides, lauroyl polyoxyethylene-32 glyceride, macrogol-32 stearate and stearyl polyoxyethylene glyceride; more preferably selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: polyoxyethylene castor oil, Tween-20, vitamin E-TPGS, caprylic capric macrogol glycerides, lauroyl polyoxyethylene-32 glyceride, macrogol-32 stearate and stearyl polyoxyethylene glyceride; most preferably selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: polyoxyethylene castor oil, Tween-20, vitamin E-TPGS, caprylic capric macrogol glycerides and lauroyl polyoxyethylene-32 glyceride. Surfactants can reduce surface tension and form a monolayer between the oil phase and the water phase, allowing fenofibrate to remain in the gastrointestinal tract in a soluble form, which is beneficial to the absorption of the drug by the intestinal epithelium.

[0035] The components of the fenofibrate oily formulation described herein preferably also include a co-surfactant, with the weight ratio of the co-surfactant preferably being 0-30%, more preferably 0-15%, and most preferably 0-5%. The co-surfactant is preferably selected from at least one of the following or a commercially available mixture containing at least one of the following: diethylene glycol monoethyl ether, polyglycerol oleate, PEG400, isopropyl alcohol, propylene glycol laurate, ethanol, and 1,2-propylene glycol; more preferably selected from at least one of the following or a commercially available mixture containing at least one of the following: diethylene glycol monoethyl ether, polyglycerol oleate, and 1,2-propylene glycol. The co-surfactant can increase the drug loading capacity of the formulation and enhance the dispersion of the drug within the formulation by increasing interfacial fluidity.

[0036] The present application provides a method for preparing the above-mentioned fenofibrate oily preparation, comprising the following steps: mixing the components, heating and stirring uniformly, and obtaining a clear oil solution as the fenofibrate oily preparation.

[0037] The heating mentioned in the present application is preferably heated to 30-80° C., more preferably heated to 30-60° C., and most preferably heated to 35-40° C. The present application stirs uniformly under the heating conditions, and ultrasound at a frequency of 20-100 Hz can be used to assist dissolution during stirring.

[0038] The present application also provides an oral medicine comprising the above-mentioned fenofibrate oily preparation.

[0039] The dosage forms of the oral medication described in this application include soft capsules, liquid capsules, hard capsules or pills, and there is no special limitation on the preparation method of the oral medication of the dosage form. Oral medications that meet the standards can be prepared using conventional technical means in the field.

[0040] To further illustrate the present application, a fenofibrate oily preparation, oral medication and preparation method provided by the present application are described in detail below with reference to the examples, but they should not be construed as limiting the scope of protection of the present application.

[0041] Example 1

[0042] The formula components and weight percentages of fenofibrate oily preparations:

[0043] Fenofibrate 5.0%, ethyl oleate 47.5%, polyoxyethylene castor oil 38.0%, Plurol Oleique CC497 (polyglycerol oleate) 9.5%.

[0044] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 50 mg of fenofibrate, 475 mg of ethyl oleate, 380 mg of polyoxyethylene castor oil, and 95 mg of Plurol Oleique CC497 are weighed into a round-bottom flask, and magnetic stirring is performed at 40° C. for 30 minutes to obtain the fenofibrate oily preparation.

[0045] Example 2

[0046] The formula components and weight percentages of fenofibrate oily preparations:

[0047] Fenofibrate 4.0%, caprylic / capric triglyceride 38.4%, Tween-20 52.8%, 1,2-propylene glycol 4.8%.

[0048] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 40 mg of fenofibrate, 384 mg of caprylic triglyceride, 528 mg of Tween-20, and 48 mg of 1,2-propylene glycol are weighed into a round-bottom flask, and magnetic stirring is performed at 40° C. for 30 min to obtain the fenofibrate oily preparation.

[0049] Example 3

[0050] The formula components and weight percentages of fenofibrate oily preparations:

[0051] Fenofibrate 4.0%, Maisine CC (glyceryl monolinoleate) 19.2%, Tween-80 67.2%, Transcutol HP (diethylene glycol monoethyl ether) 9.6%.

[0052] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 40.0 mg of fenofibrate, 192.0 mg of Maisine CC, 672.0 mg of Tween-80, and 96.0 mg of Transcutol HP are weighed into a round-bottom flask, and the mixture is magnetically stirred at 40° C. for 30 min to obtain the fenofibrate oily preparation.

[0053] Example 4

[0054] The formula components and weight percentages of fenofibrate oily preparations:

[0055] Fenofibrate 6.0%, oleic acid 18.8%, Tween-60 61.1%, vitamin E-TPGS 14.1%.

[0056] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 60.0 mg of fenofibrate, 188.0 mg of oleic acid, 611.0 mg of Tween-60, and 141.0 mg of vitamin E-TPGS are weighed into a round-bottom flask, and magnetic stirring is performed at 40° C. for 30 min to obtain the fenofibrate oily preparation.

[0057] Example 5

[0058] The formula components and weight percentages of fenofibrate oily preparation:

[0059] Fenofibrate 5.0%, ethyl linoleate 28.5%, Tween-20 61.7%, Labrasol (caprylic / capric macrogol glycerides) 4.8%.

[0060] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 50.0 mg of fenofibrate, 285.0 mg of ethyl linoleate, 617.0 mg of Tween-20 and 48.0 mg of Labrasol are weighed into a round-bottom flask, and magnetic stirring is performed at 40° C. for 30 min to obtain the fenofibrate oily preparation.

[0061] Example 6

[0062] The formula components and weight percentages of fenofibrate oily preparation:

[0063] Fenofibrate 5.0%, oleic triglyceride 19.0%, hydrogenated polyoxyethylene castor oil 61.7%, PEG400 14.3%.

[0064] The preparation process of the fenofibrate oily preparation in this embodiment is as follows: 50.0 mg of fenofibrate, 190.0 mg of oleic acid triglyceride, 617.0 mg of hydrogenated polyoxyethylene castor oil and 143.0 mg of PEG400 were weighed into a round-bottom flask, and magnetically stirred at 45°C for 30 min to obtain the fenofibrate oily preparation.

[0065] Example 7

[0066] The formula components and weight percentages of fenofibrate oily preparations:

[0067] Fenofibrate 5.0%, Peceol (glyceryl monooleate) 38.0%, hydrogenated polyoxyethylene castor oil 52.3%, Transcutol HP 4.7%.

[0068] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 50.0 mg of fenofibrate, 380.0 mg of Peceol, 523.0 mg of hydrogenated polyoxyethylene castor oil, and 47.0 mg of Transcutol HP are weighed into a round-bottom flask, and the mixture is magnetically stirred at 40° C. for 30 min to obtain the fenofibrate oily preparation.

[0069] Example 8

[0070] The formula components and weight percentages of fenofibrate oily preparations:

[0071] Fenofibrate 5.0%, Medium Chain Triglycerides 28.5%, Labrasol 66.5%

[0072] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 50.0 mg of fenofibrate, 285.0 mg of medium-chain triglycerides, and 665.0 mg of Labrasol are weighed into a round-bottom flask, and magnetic stirring is performed at 40° C. for 30 minutes to obtain the fenofibrate oily preparation.

[0073] Example 9

[0074] The formula components and weight percentages of fenofibrate oily preparations:

[0075] Fenofibrate 6.0%, Stearic acid triglyceride 14.1%, Oleic acid diglyceride 14.1%, Hydrogenated polyoxyethylene castor oil 61.1%, Transcutol HP 4.7%.

[0076] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 60.0 mg of fenofibrate, 141.0 mg of stearic acid triglyceride, 141.0 mg of oleic acid diglyceride, 611.0 mg of hydrogenated polyoxyethylene castor oil, and 47.0 mg of Transcutol HP are weighed into a round-bottom flask, and ultrasonicated at 50 Hz for 40 min at 45° C. to obtain the fenofibrate oily preparation.

[0077] Example 10

[0078] The formula components and weight percentages of fenofibrate oily preparations:

[0079] Fenofibrate 7.0%, Glyceryl Monooleate 13.95%, Glyceryl Monostearate 13.95%, Tween-20 51.15%, Transcutol HP 13.95%.

[0080] In this example, the fenofibrate oily preparation was prepared as follows: 70.0 mg of fenofibrate, 139.5 mg of glyceryl monooleate, 139.5 mg of glyceryl monostearate, 511.5 mg of hydrogenated polyoxyethylene castor oil, and 139.5 mg of Transcutol HP were weighed into a round-bottom flask and ultrasonicated at 50 Hz for 40 min at 50° C. to obtain the fenofibrate oily preparation.

[0081] Example 11

[0082] The formula components and weight percentages of fenofibrate oily preparations:

[0083] Fenofibrate 7.0%, Linoleic acid diglyceride 13.95%, Stearic acid diglyceride 13.95%, Tween-20 51.15%, Transcutol HP 13.95%.

[0084] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 70.0 mg of fenofibrate, 139.5 mg of linoleic acid diglyceride, 139.5 mg of stearic acid diglyceride, 511.5 mg of hydrogenated polyoxyethylene castor oil, and 139.5 mg of Transcutol HP are weighed into a round-bottom flask, and ultrasonicated at 50 Hz for 40 min at 50° C. to obtain the fenofibrate oily preparation.

[0085] Example 12

[0086] The formula components and weight percentages of fenofibrate oily preparations:

[0087] Fenofibrate 7.0%, Linoleic acid triglyceride 13.95%, Stearic acid triglyceride 13.95%, Tween-20 51.15%, Transcutol HP 13.95%.

[0088] In this embodiment, the preparation process of the fenofibrate oily preparation is as follows: 70.0 mg of fenofibrate, 139.5 mg of linoleic acid triglyceride, 139.5 mg of stearic acid triglyceride, 511.5 mg of hydrogenated polyoxyethylene castor oil, and 139.5 mg of Transcutol HP are weighed into a round-bottom flask, and ultrasonicated at 50 Hz for 40 min at 50° C. to obtain the fenofibrate oily preparation.

[0089] Example 13

[0090] The formula components and weight percentages of fenofibrate oily preparations:

[0091] Fenofibrate 7.0%, Linoleic acid triglyceride 13.95%, Stearic acid triglyceride 13.95%, Tween-20 51.15%, Lauroglycol TM 90(propylene glycol laurate)13.95%.

[0092] The preparation process of the fenofibrate oily preparation in this embodiment is as follows: 70.0 mg of fenofibrate, 139.5 mg of linoleic acid triglyceride, 139.5 mg of stearic acid triglyceride, 511.5 mg of hydrogenated polyoxyethylene castor oil and 139.5 mg of lauroglycol are weighed. TM 90 in a round-bottom flask and ultrasonicated at 50 Hz for 40 min at 50°C to obtain an oily preparation of fenofibrate.

[0093] Example 14

[0094] The formula components and weight percentages of fenofibrate oily preparations:

[0095] Fenofibrate 6.0%, Linoleic triglyceride 28.2%, Tween-20 28.2%, Macrogol-32 stearate 28.2%, Lauroglycol TM 90(propylene glycol laurate) 9.4%.

[0096] The preparation process of the fenofibrate oily preparation in this embodiment is as follows: 70.0 mg of fenofibrate, 282.0 mg of linoleic acid triglyceride, 282.0 mg of Tween-20, 282.0 mg of polyethylene glycol-32 stearate and 94.0 mg of lauroglycol are weighed. TM 90 in a round-bottom flask and ultrasonicated at 50 Hz for 40 min at 50°C to obtain an oily preparation of fenofibrate.

[0097] Example 15

[0098] The formula components and weight percentages of fenofibrate oily preparations:

[0099] Fenofibrate 6.0%, Linoleic acid triglyceride 28.2%, Tween-20 28.2%, Stearoyl polyoxyethylene glyceride 28.2%, Lauroglycol TM 90(propylene glycol laurate) 9.4%.

[0100] The preparation process of the fenofibrate oily preparation in this embodiment is as follows: 70.0 mg of fenofibrate, 282.0 mg of linoleic acid triglyceride, 282.0 mg of Tween-20, 282.0 mg of stearoyl polyoxyethylene glyceride and 94.0 mg of lauroglycol are weighed. TM 90 in a round-bottom flask and ultrasonicated at 55°C and 50 Hz for 40 min to obtain an oily preparation of fenofibrate.

[0101] Example 16

[0102] The formula components and weight percentages of fenofibrate oily preparations:

[0103] Fenofibrate 6.0%, Linoleic acid triglyceride 28.2%, Tween-20 28.2%, Myrcenamine polyoxyethylene-32 glyceride 28.2%, Lauroglycol TM 90(propylene glycol laurate) 9.4%.

[0104] The preparation process of the fenofibrate oily preparation in this embodiment is as follows: 70.0 mg of fenofibrate, 282.0 mg of linoleic acid triglyceride, 282.0 mg of Tween-20, 282.0 mg of hard myrceneamine polyoxyethylene-32 glyceride and 94.0 mg of lauroglycol are weighed. TM 90 in a round-bottom flask and ultrasonicated at 55°C and 50 Hz for 40 min to obtain an oily preparation of fenofibrate.

[0105] Experimental Example 1

[0106] Example 2 Oral bioavailability determination of (FNB-SEDDS) prepared in rats

[0107] Twenty healthy male Sprague-Dawley (SD) rats were divided into four groups. After fasting for 12 h, the SD rats in group 1 and group 2 were gavaged with 25 mg / kg of Lipingzhi and FNB-SEDDS, respectively. Blood was collected from the orbital venous plexus at 0.5, 1, 1.5, 2, 4, 8, 12, and 24 h after anesthesia.

[0108] Feeding SD rats in groups 3 and 4 were gavaged with 16.7 mg / kg of Lipingzhi and FNB-SEDDS. Blood was collected from the orbital venous plexus at 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 hours after anesthesia. Plasma concentrations were measured at different time points, and relative bioavailability was calculated using AUC values ​​according to the relative bioavailability experimental method.

[0109] The results are shown in Figures 1 and 2. Under fasting conditions, the AUC of fenofibric acid in rats after administration of Liping was 249.7±39.7μg / mL*h, and the AUC of FNB-SEDDS was 512.6±103.8μg / mL*h. The oral relative bioavailability of FNB-SEDDS was 205.29% of that of Liping (Figure 1). Under fed conditions, the AUC of fenofibric acid in rats after administration of Liping was 327.80±68.10μg / mL*h, and the AUC of FNB-SEDDS was 413.08±104.14μg / mL*h. The oral relative bioavailability of FNB-SEDDS was 126.02% of that of Liping (Figure 2). The specific pharmacokinetic parameters are shown in Table 1. It can be seen that the formulation FNB-SEDDS of the present application improves the oral bioavailability of fenofibrate.

[0110] Based on dose conversion, the AUC of fenofibric acid in fed rats after Liping administration was 196.52% of that in fasted rats, indicating significant bioavailability variation. However, the AUC of FNB-SEDDS in fed rats was not statistically different from that in fasted rats. This suggests that the oral bioavailability of fenofibrate in FNB-SEDDS is unaffected by diet.

[0111] Table 1 Pharmacokinetic parameters of fenofibric acid in rats after oral administration of Lipingzhi and FNB-SEDDS under fasting / fed conditions

[0112] In Table 1, ***p<0.001 compared with the Lipingzhi-fasting group.

[0113] Experimental Example 2

[0114] Example 3 Oral bioavailability determination of (FNB-SEDDS) prepared in beagle dogs

[0115] Six male beagle dogs were divided into two groups for a four-week crossover study with a one-week washout period. During weeks 1 and 2, the beagle dogs were fasted for 12 hours with or without access to water. One group was fed two FNB-SEDDS enteric-coated capsules (144 mg fenofibrate) and the other group was fed one Lipingzhi tablet (200 mg fenofibrate). During weeks 3 and 4, the beagle dogs were fasted for 12 hours with or without access to water. While fed, one group was fed two FNB-SEDDS enteric-coated capsules (144 mg fenofibrate) and the other group was fed one Lipingzhi tablet (200 mg fenofibrate). Blood samples were collected from the forelimb vein at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours. Fenofibric acid plasma concentrations were measured at different time points, and relative bioavailability was calculated using the area under the curve (AUC) according to the relative bioavailability assay.

[0116] In fasting beagle dogs, the AUC of fenofibric acid after administration of Liping was 6.25 ± 3.39 μg / mL*h, while that after administration of FNB-SEDDS was 63.88 ± 17.20 μg / mL*h. The dose-converted relative bioavailability of fenofibrate in FNB-SEDDS was 1418.93% of that in Liping (Figure 3). In fed beagle dogs, the AUC of fenofibric acid after administration of Liping was 56.96 ± 15.31 μg / mL*h, while that after administration of FNB-SEDDS was 51.76 ± 9.59 μg / mL*h. The dose-converted relative bioavailability of fenofibrate in FNB-SEDDS was 126.21% of that in Liping (Figure 4). Specific pharmacokinetic parameters are shown in Table 2. The beagle dog experimental results showed that the preparation FNB-SEDDS of the present application improved the oral absorption of fenofibrate.

[0117] The AUC of fenofibric acid in fed beagle dogs following administration of Liping was 910.97% of that in fasted dogs, indicating that the effects of diet on the commercially available fenofibrate formulation, Liping, become more pronounced with increasing animal size. The AUC of fenofibric acid in fed beagle dogs following administration of FNB-SEDDS was not significantly different from that in fasted dogs. These two animal models demonstrate that the oral formulation of the present application enhances the oral bioavailability of fenofibrate and that absorption is unaffected by diet.

[0118] Table 2 Pharmacokinetic parameters of fenofibric acid after oral administration of Lipingzhi and FNB-SEDDS to beagle dogs under fasting / meal conditions

[0119] Compared with Li Pingzhi-fasting, ** p<0.01, *** p<0.001.

[0120] Although the above embodiment provides a detailed description of the present application, it is only a part of the embodiments of the present application, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the scope of protection of the present application.

Claims

1. A fenofibrate oily preparation, characterized in that: The fenofibrate oily preparation comprises the following components in the following mass ratios: 0.5% to 20% of fenofibrate, 10% to 60% of an oily solvent, 15% to 70% of a surfactant and 0% to 30% of a co-surfactant.

2. The fenofibrate oily preparation according to claim 1, characterized in that: The fenofibrate oily preparation comprises the following components in the following mass ratios: 1% to 15% of fenofibrate, 20% to 50% of an oily solvent, 30% to 70% of a surfactant and 0% to 15% of a co-surfactant.

3. The fenofibrate oily preparation according to claim 1, characterized in that: The fenofibrate oily preparation comprises the following components in the following mass ratios: 3% to 12% of fenofibrate, 30% to 50% of an oily solvent, 50% to 67% of a surfactant and 0% to 5% of a co-surfactant.

4. The fenofibrate oily preparation according to any one of claims 1 to 3, characterized in that The oily solvent is selected from at least one of the following or a mixture containing at least one of the following ingredients: soybean oil, rapeseed oil, palm oil, peanut oil, sunflower oil, coconut oil, linseed oil, castor oil, perilla oil, corn oil, monostearic acid glyceryl, stearic acid diglyceride, stearic acid triglyceride, monolinoleic acid glyceryl, linoleic acid diglyceride, linoleic acid triglyceride, monooleic acid glyceryl, oleic acid diglyceride, oleic acid triglyceride, medium chain triglycerides of different chain lengths, long chain monoglycerides, long chain diglycerides, long chain triglycerides, caprylic acid triglyceride, myristic acid triglyceride, isopropyl myristic acid, oleic acid, linoleic acid, ethyl oleate, ethyl linoleate and palmitic acid.

5. The fenofibrate oily preparation according to any one of claims 1 to 3, characterized in that: The surfactant is selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: polyoxyethylene castor oil, hydrogenated polyoxyethylene castor oil, Tween-20, Tween-60, Tween-80, vitamin E-TPGS, caprylic / capric macrogol glyceride, lauroyl polyoxyethylene (32) glyceride, macrogol-32 stearate and stearyl polyoxyethylene glyceride.

6. The fenofibrate oily preparation according to any one of claims 1 to 3, characterized in that: The co-surfactant is selected from at least one of the following or a commercial mixture containing at least one of the following ingredients: diethylene glycol monoethyl ether, polyglycerol oleate, PEG400, isopropyl alcohol, propylene glycol laurate, ethanol and 1,2-propylene glycol.

7. The method for preparing the fenofibrate oily preparation according to any one of claims 1 to 6, characterized in that: The following steps are involved: The components are mixed, heated and stirred uniformly to obtain a clear oil solution which is the fenofibrate oily preparation.

8. The preparation method according to claim 7, characterized in that: The heating includes heating to 30-80°C.

9. The preparation method according to claim 8, characterized in that: In the above, the stirring is accompanied by ultrasound, and the frequency of the ultrasound is 20 to 100 Hz.

10. An oral medicine comprising the fenofibrate oily preparation according to any one of claims 1 to 6.

11. The oral medicament according to claim 10, characterized in that: The dosage form of the oral drug includes soft capsules, liquid capsules, hard capsules or dripping pills.

Images