WO2012171364A1 - Oil-soluble pharmaceutical composition - Google Patents

Abstract

An oil-soluble pharmaceutical composition, comprising a content and an outer wrapping material, wherein the content is an oil solution made from an oil-soluble drug and an auxiliary material, the auxiliary material is a non-polar solvent and solubilizer, the non-polar solvent is a vegetable oil, animal oil or polyoxyethylene 40 hydrocastor oil, and the solubilizer is isopropyl myristate and/or ethyl oleate, Tween, polyethylene glycol 400, and polyethylene glycol 600. The composition is in the form of a capsule, which is a highly bioavailable capsule prepared from the oil-soluble drug as a primary drug in conjunction with the solubilizer for enhancing dissolution of the drug.

Description

 Oil-soluble pharmaceutical composition

 The present invention relates to the field of medicine, and in particular to an oil-soluble pharmaceutical composition composition and a preparation method thereof.

Background technique

Fenofibrate (alias benzoyl lipoester, pulverine, rifafi, English name Fenofibrate, chemical formula C _2Q H ₂₁ CI0 ₄ ), white or off-white crystalline powder; odorless, tasteless. It is very soluble in chloroform, soluble in acetone or ether, slightly soluble in ethanol, and almost insoluble in water. The melting point is 78 to 82 °C. It is rapidly metabolized into fenofibrate acid by the action of esterase in the body to lower blood fat, and has obvious effects of lowering serum cholesterol, triglyceride and raising high-density lipoprotein. It has a significant effect on lowering plasma TG and TC, and is suitable for the treatment of hypertriglyceridemia and hypercholesterolemia with few side effects.

 At present, the domestic fenofibrate compositions mainly include: tablets, capsules, capsules, chewable tablets, dispersible tablets, sustained release capsules, micronized granules, sustained release pellets and the like. However, the existing formulation forms have a low dissolution rate and the bioavailability is not very high.

 The oil-soluble pharmaceutical composition according to the present invention is mainly a hormone, a vitamin or the like which mainly dissolves in a vegetable oil or a fatty oil, and is slightly soluble, slightly soluble, and extremely slightly soluble.

 It is well known that most hormonal drugs are insoluble in water or alcohol, and the administration route is relatively limited, mainly by injection. Currently, oral administration has incomplete absorption, and side effects are relatively large, and liver toxicity is large. There is therefore a need to improve on existing oral dosage forms.

Summary of the invention

 SUMMARY OF THE INVENTION The object of the present invention is to provide a novel oil-soluble pharmaceutical composition for the defects in the prior art which have low dissolution rate and low bioavailability in oral drugs.

 A method of preparing the oil-soluble pharmaceutical composition is also provided.

An oil-soluble pharmaceutical composition comprising a content and an outer wrapping material, wherein the content is an oil solution made of an oil-soluble drug and an auxiliary material; the auxiliary material is a non-polar solvent and a solubilizing agent, and the non-polar solvent is Vegetable oil, animal oil or polyoxyethylene 40 hydrogenated castor oil; the solubilizing agent is isopropyl myristate and / or ethyl oleate, Tween, polyethylene glycol 400, polyethylene glycol 600. The vegetable oil is peanut oil, soybean oil, rapeseed oil, corn oil, olive oil, sunflower oil, sesame oil, linseed oil, cottonseed oil, rice bran oil, coconut oil, camellia seed oil, canola oil, pepper One or more of oil, chili oil, etc., the animal oil being one or more of lard, butter, sheep oil, chicken oil, and duck oil.

 The solubilizing agent is isopropyl myristate and/or ethyl oleate, Tween, polyethylene glycol 400, and polyethylene glycol 600.

 The oil-soluble drug is 2 - 70 g, the solubilizing agent is 1 - 210 g, and the vegetable oil is 400 - 1000 g per 1000 coating compositions.

 The oil-soluble drug is fenofibrate, probucol, undecylenic acid, testosterone undecanoate, diethylstilbestrol, hydroxyprogesterone caproate, testosterone propionate, methyltestosterone, phenylpropionate, benzoic acid Alcohol, fluphene thiophene, or vitamin D3.

 The oil-soluble drug 5 g, the solubilizing agent is one or more of isopropyl myristate, ethyl oleate, Tween, polyethylene glycol 400, and polyethylene glycol 600 per 1000 coating compositions. 15 g, vegetable oil 500-900 g.

 The oil-soluble drug 25 g, the solubilizing agent is one or more of isopropyl myristate, ethyl oleate, Tween, polyethylene glycol 400, and polyethylene glycol 600 per 1000 coating compositions. 20g, vegetable oil 500, the oil-soluble drug 50g, the solubilizing agent isopropyl myristate and / or ethyl oleate, Tween, polyethylene glycol 400, polyethylene glycol 600 per 1000 coating composition One or more of 150g, vegetable oil 500-900g.

 The preparation form is soft capsule, liquid capsule, hard capsule or dropping pills.

 The overwrap material contains gelatin, or gelatin with propylene glycol, or gelatin and glycerin.

 The preparation form is an outer coating of the capsule and an enteric coating.

 The preparation method of the oil-soluble pharmaceutical composition comprises: weighing the components of the content in proportion, mixing and stirring to obtain an oil solution, and taking an appropriate amount of the oil solution into the capsule by using a transfer mode capsule manufacturing machine. , the soft capsule or the liquid capsule or the hard capsule or the dropping capsule is overcoated with the enteric coating.

 The mixing and stirring were stirred at a temperature of 10-65 ° C, and the mixture was homogenized by ultrasonic assisted dissolution.

Method for determining the content of the above oil-soluble drug (fenofibrate) composition, using octadecylsilane bonding Silica gel is a filler; acetonitrile-water is the mobile phase; the detection wavelength is 286 nm, the volume ratio of acetonitrile to water in the mobile phase is 70:30, and the _P H value is adjusted to 2.5 with phosphoric acid.

 The oil-soluble pharmaceutical composition of the present invention, by a combination of a non-polar solvent and a solubilizing agent, improves the dissolution of the oil-soluble composition and has a good bioavailability. The oil-soluble drug used in the examples of the present invention is fenofibrate, probucol, and fluphenazine.

 The oil-soluble pharmaceutical composition developed by the present invention is an orange-red oval capsule. The orange-colored soft capsule is made of gelatin, glycerin, water plus appropriate amount of titanium dioxide and food coloring; the suspended semi-solid content is uniformly dispersed in the appropriate amount of non-polar by the treated oil-soluble drug substance. The solvent is prepared by adding an appropriate amount of a solubilizing agent, and the color thereof depends on the color of the raw material drug and the non-polar solvent used.

DRAWINGS

Figure 1 Comparison of the dissolution of fenofibrate and commercially available fenofibrate in this example.

detailed description

 The preferred embodiments of the present invention are described in the following, and the preferred embodiments described herein are intended to illustrate and explain the invention.

 Example 1 Fenofibrate micropowder, soybean oil, corn oil, peanut oil, coconut oil, 1000 parts of pharmacologically active fenofibrate, and medicinal adjuvant isopropyl myristate 18g, the rest For soybean oil and/or corn oil, peanut oil, coconut oil 600g, the components are mixed in the above ratio, and continuously stirred at 40-55 ° C to obtain a fenofibrate oil solution, the fenofibrate oil The solution was filled in an average of soft capsules to prepare a fenofibrate capsule of the present invention. In the embodiment, the fenofibrate micropowder has pharmacological activity, is easily soluble in a non-polar solvent, and is insoluble in water; soybean oil, corn oil, peanut oil, and coconut oil are non-polar solvents for dissolving fenofibrate micropowder. Isopropyl myristate can be used as a solubilizer or surfactant to increase the solubility of fenofibrate particles in the above oil solution. The oil-soluble drug 5 g, the solubilizing agent isopropyl myristate 10 g, ethyl oleate 5 g, vegetable oil soybean oil and/or corn oil, peanut oil, coconut oil 500 g per 1000 parts of the formulation composition. The method is the same as above.

 1-3

The oil-soluble drug 25 g, the solubilizing agent isopropyl myristate 15, the Tween 5 g, the vegetable oil soybean oil and/or the corn oil, the peanut oil, and the coconut oil 700 g per 1000 parts of the formulation composition. The method is the same as above. The oil-soluble drug 50g, the solubilizing agent isopropyl myristate 50, the Tween 40g, the polyethylene glycol 400 amount is 60g, the vegetable oil soybean oil and/or corn oil, peanut oil, coconut, per 1000 capsules of the composition. The oil 900 go method is the same as above.

 In each of the above embodiments, at least one of vegetable oils such as soybean oil, corn oil, peanut oil, and coconut oil may be used to dissolve the fenofibrate micropowder, and isopropyl myristate or/and other solubilizing agents may be used. A solubilizer in which the fenofibrate micropowder is dissolved in the above vegetable oil can also be used as a surfactant in the content of the present invention. Example 2:

 Probucol micropowder

 Soybean oil, corn oil, peanut oil, coconut oil

 Isopropyl myristate The basic idea of the invention is to weigh 20 g of pharmacologically active probucol per 1000 tablets of composition, add medicinal excipient isopropyl myristate, 18 g, and the rest are soybean oil, corn oil, peanut oil 600g of coconut oil, the components are mixed according to the above ratio, and continuously stirred at 40-55 ° C to obtain a probucol oil solution, and the probucol oil solution is uniformly filled in a soft capsule to obtain the present invention. Probucol capsules. In the embodiment, the probucol micropowder has pharmacological activity, is easily soluble in a non-polar solvent, and is insoluble in water; soybean oil, corn oil, peanut oil, and coconut oil are non-polar solvents for dissolving probucol micropowder; Isopropyl myristate, soy phospholipid can be used as a solubilizer or surfactant to increase the solubility of probucol particles in the above oil solution.

In each of the above embodiments, at least one of vegetable oils such as soybean oil, corn oil, peanut oil, and coconut oil may be used to dissolve the probucol micropowder, and isopropyl myristate may be used as the probucol micropowder in the above vegetable oil. The solubilized solubilizing agent can also be used as a surfactant in the context of the present invention. The oil-soluble drug 50g, the solubilizing agent isopropyl myristate 50, the ethyl oleate 20g, the polyethylene glycol 600 amount is 80g, the vegetable oil soybean oil and/or the corn oil, the peanut oil, per 1000 capsules of the composition. , coconut oil 900 g. The method is the same as above. Example 3:

 Fluoride

 Soybean oil, corn oil, peanut oil, coconut oil

 Isopropyl myristate

 The basic idea of the present invention: For every 1000 compositions, weigh 20 g of pharmacologically active fluphene thiophene, add 18 g of medicinal excipient isopropyl myristate, and the rest are soybean oil, corn oil, peanut oil, coconut oil 600 g. The components are mixed according to the above ratio, and continuously stirred at 40-55 ° C to obtain a fluorinated hexahydrostatic oil solution, and the fluorinated hexahydrostatic oil solution is uniformly filled in a soft capsule to obtain the present invention.癸Finphene static capsules. In the embodiment, the fluorinated perphenazine powder has pharmacological activity, is easily soluble in a non-polar solvent, and is insoluble in water; soybean oil, corn oil, peanut oil, and coconut oil are non-polar solvents, and are used for dissolving fluorene. Static micronized; isopropyl myristate can be used as a solubilizing agent or surfactant to increase the solubility of fluorinated perphenazine particles in the above oil solution.

 In each of the above embodiments, at least one of vegetable oils such as soybean oil, corn oil, peanut oil, and coconut oil may be used to dissolve the fluorinated perphenazine fine powder, and isopropyl myristate may be used as the fluorene perphenazine. The solubilizing agent in which the fine powder is dissolved in the above vegetable oil can also be used as a surfactant in the content of the present invention. Example 4:

 Hydroxyprogesterone citrate powder

 Soybean oil, corn oil, peanut oil, coconut oil

 Isopropyl myristate

 The basic idea of the invention: 20 g of pharmacologically active hydroxyprogesterone caproate is added per 1000 tablets of composition, 18 g of medicinal excipient isopropyl myristate is added, and the rest are soybean oil, corn oil, peanut oil and coconut oil 600 g. The components are mixed in the above ratio, and continuously stirred at 40-55 ° C to obtain a hydroxyprogesterone caproic acid solution, and the hydroxyprogesterone hexanoate oil solution is uniformly filled in a soft capsule to obtain the present invention. Hydroxyprogesterone caproate capsules. In the embodiment, the hydroxyprogesterone caproate micropowder has pharmacological activity, is easily soluble in a non-polar solvent, and is insoluble in water; soybean oil, corn oil, peanut oil, and coconut oil are non-polar solvents for dissolving hydroxypredosterine Ketone micropowder; isopropyl myristate can be used as a solubilizer or surfactant for increasing the solubility of hydroxyprogesterone caproate microparticles in the above oil solution.

In each of the above embodiments, at least one of vegetable oils such as soybean oil, corn oil, peanut oil, and coconut oil , can be used to dissolve hydroxyprogesterone caproate micropowder, isopropyl myristate can be used as a solubilizing agent for the dissolution of hydroxyprogesterone caproate powder in the above vegetable oil, and can also be used for the surface activity in the content of the present invention. Agent. It should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, although the present invention has been described in detail with reference to the foregoing embodiments, The technical solutions described in the foregoing embodiments may be modified, or some of the technical features may be equivalently replaced. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and scope of the present invention are intended to be included within the scope of the present invention.

The following experimental examples are exemplified by fenofibrate capsules, but are not limited thereto.

Standard of embodiment

 Identification of fenofibrate capsules made by the present invention:

 (1) Take the appropriate amount of the product (about equivalent to fenofibrate 0.1g), place in the separatory funnel, add 20ml of acetonitrile, shake vigorously, dissolve fenofibrate, discard the oil phase and evaporate. Take the solids and oxygen cylinder combustion method (Chinese Pharmacopoeia 2010 edition two appendix VII C) for organic destruction, with 0.4% sodium hydroxide solution as the absorption liquid, after the combustion is completed, acidify with dilute sulfuric acid, let cool, add silver nitrate The test solution produces a white curd-like precipitate; separation, precipitation and ammonia test solution is dissolved, and after addition of dilute nitric acid, the precipitate is regenerated.

 (2) Take the appropriate amount of the test solution under the content determination, dilute with ethanol to make a solution containing about 10 ug per lml, and measure it by spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A) at a wavelength of 286 nm. There is maximum absorption.

 (3) In the chromatogram recorded under the content determination, the retention time of the main peak in the test solution should be consistent with the retention time of the reference peak.

 Examination of fenofibrate capsules made by the present invention:

 (1) Difference in loading According to the Chinese Pharmacopoeia 2010 edition two appendix I E capsules under the plastic capsule loading method under the difference test, the internal control standard should not exceed ± 6.5%.

 (2) Time limit for disintegration According to the Chinese Pharmacopoeia 2010 edition two appendix X A disintegration time limit inspection method for the soft capsule collapse time limit method test, the time limit for disintegration in artificial gastric juice is within 1 hour.

(3) The microbial limit is checked according to the method specified in the Microbiological Limit Test Method of Appendix XI of the Chinese Pharmacopoeia, 2010, according to the limits of microbial limits in soft capsules: the number of bacteria shall not exceed 1000 per lg; the number of molds and yeasts Do not pass 100 per lg; E. coli and Pseudomonas aeruginosa are not allowed per lg Check out.

 (4) Destructive test and related substances belong to the precision weighing fenofibrate reference substance, add acetonitrile dissolved and diluted to make a solution containing img per im|, take lOul into the liquid chromatograph, record the chromatogram, As a non-destructive sample related substance inspection map; another fenofibrate reference substance 3 parts, each about 50mg, placed in three 50ml volumetric flasks, each adding acetonitrile about 45ml to dissolve, in the first sample vial Add 0.45ml of concentrated hydrochloric acid in the middle, shake it, dilute to the mark with acetonitrile, shake well, boil for 1 hour in water bath, cool to room temperature, dilute to the mark with acetonitrile, shake well, measure lOul into liquid chromatograph, record chromatogram As the acid-destroyed sample related material check spectrum; add 3ml of saturated sodium hydroxide solution to the second sample vial, shake, dilute with acetonitrile to the mark, shake well, boil for 1 hour in water bath, cool to room temperature, add acetonitrile Dilute to the mark, shake well, measure lOul into the liquid chromatograph, record the chromatogram as the relevant substance check spectrum of the alkali-damaged sample; add acetonitrile in the third sample vial Dilute to the mark, shake well, heat to boil for 1 h, cool to room temperature, dilute to the mark with acetonitrile, shake well, measure lOul into the liquid chromatograph, record the chromatogram, and check the spectrum of the substance related to the heat-destroyed sample; Destroy the sample in a constant temperature light box (5 ° C, illuminance 4500LX) for 24 hours, remove, put it at room temperature, add acetonitrile to the mark, shake well, measure lOul into the liquid chromatograph, record the chromatogram, as a photo-damage sample Relevant substance inspection map.

 In order to further confirm what kind of impurities were produced after the destruction of fenofibrate, the following tests were carried out.

 Accurately weigh about 50mg of fenofibrate acid, about 50mg of fenofibrate phenol, about 50mg of fenofibrate reference substance, put them into three 50ml volumetric flasks separately, add acetonitrile to dissolve and dilute to the mark, and shake up. 5 ml of the impurity solution was accurately weighed and placed in two 100 ml volumetric flasks, diluted with acetonitrile to the mark, and shaken. Then, 10 ul each was weighed and injected into a liquid chromatograph to record a chromatogram.

 The experimental results show that the product is stable under illumination, heating and acidic conditions, and is easily degraded under alkaline conditions. The degradation product is mainly fenofibrate acid. The current related substance inspection method can effectively detect degradation products with good resolution.

(5) Relevant substances The contents of this product are accurately weighed in an appropriate amount (about 40 mg of fenofibrate), placed in a centrifuge tube and shaken 4 times with acetonitrile (15 ml each for the first 1-3 times, 4th) times 10ml), shaken centrifuged for 15 minutes each time (4500rad / mi _n), and use a dropper acetonitrile was displaced 100ml volumetric flask, dilute extracts were combined, acetonitrile was added to the mark, as the test after 10 minutes Solution (0.4mg/ml); Precisely measure lml, place in a 100ml volumetric flask, dilute to the mark with acetonitrile, shake well, as a control solution (4ug/ml); Another fenofibrate acid, fenofibrate phenol reference substance, accurately weighed, acetonitrile dissolved and quantitatively diluted to make each iml containing img solution, as a reference solution. According to the chromatographic conditions under the content determination, the ΙΟμΙ control solution is injected into the liquid chromatograph to adjust the detection sensitivity so that the peak height of the main component peak is 10%-20% of the full scale. Then accurately measure the 10 μΙ of the test solution, the control solution and the reference solution, respectively, and inject them into the liquid chromatograph, and record the chromatogram to 2 times of the retention time of the main component. If there is two in the test solution, The peak area of the corresponding peak of the main peak shall not be greater than 0.1% of the peak area of the corresponding peak in the reference solution; the sum of the area of the other impurity peaks shall not be greater than 0.5% of the main peak area of the control solution. Content determination

 According to high performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two appendix V D ).

 Mobile phase screening In order to better separate and analyze the relevant substances in this product, the mobile phase with good separation effect was selected, and the following conditions were screened.

 Water-acetonitrile 30:70

 Water-acetonitrile 30:70 (ΡΗ3.0)

 Water-acetonitrile 30:70 (ΡΗ2.5)

 Water one B S Qing 30:70 (ΡΗ3.5)

 Water-methanol 10:90

 Water-methanol 30:70

 Water-methanol 30:70 (ΡΗ2.0)

 Water-methanol 30:70 (ΡΗ2.5)

 Water-methanol 30:70 (ΡΗ3.0)

 Water-methanol 30:70 (ΡΗ3.5)

Among them, water-acetonitrile (30:70) ρΗ2.5 has the best separation effect (the separation of main peak and main impurity peak is more than 3); the peak peak time is moderate (11~14 minutes); the main peak shape is symmetrical (tailing) Factor Τ=1.01). Therefore, water-acetonitrile (30:70) was selected, and _Ρ 2.5 was adjusted to 2.5 with phosphoric acid.

The detection wavelength is selected from the appropriate amount of fenofibrate reference substance, dissolved and diluted with acetonitrile to prepare a solution containing about 12 ug per 1 ml, and determined by spectrophotometry (Chinese Pharmacopoeia 2000 edition two appendix IV A), scanning wavelength 200nm to The ultraviolet absorption curve in the range of 400 nm has a maximum absorption wavelength of 285 nm to 287 nm. Therefore, the detection wavelength is selected to be 286 nm.

 Chromatographic conditions and system suitability test using octadecylsilane bonded silica as a filler; acetonitrile monohydrate (pH adjusted to 2.5 with phosphoric acid) (70:30) as mobile phase; detection wavelength was 286 nm. The number of theoretical plates should be no less than 2000 according to the fenofibrate peak.

 The content of the difference in the amount of the sample is mixed, and the mixture is evenly mixed. The appropriate amount (about 10 mg of fenofibrate) is accurately weighed, placed in a centrifuge tube, and ultrasonically extracted 4 times with acetonitrile (15 ml each for the first 1-3 times). , 4th 10ml), after each 10 minutes of ultrasound, centrifuge for 15 minutes (4500rad/min), and dispose the acetonitrile solution in a 100ml volumetric flask with a dropper, combine the extracts, dilute with acetonitrile to the mark, shake well, as a supply The sample is dissolved, and the liquid is accurately sucked into the liquid chromatograph, and the chromatogram is recorded. The appropriate amount of the reference substance is accurately weighed, dissolved and diluted with acetonitrile to prepare a solution containing about 0.1 mg per 1 ml, and determined by the same method. According to the external standard method, the peak area is calculated.

 (1) Dissipation of solvent and blank contents Take appropriate amount of blank sample, accurately weigh 120mg, place it in a centrifuge tube, and extract it four times with acetonitrile (15ml for each 1-3 times, 10ml for the fourth time). Centrifuge for 15 minutes (4500 rad/min) after each 10 minutes of sonication, and dispose the acetonitrile solution in a 100 ml volumetric flask with a dropper, combine the extracts, dilute with acetonitrile to the mark, shake well, pipette lOul into the liquid chromatograph, record Chromatography to 30 minutes, except for a small excipient and solvent peak between 3 minutes, no other peaks, indicating that the solvent and blank content (excipients) did not interfere with the determination.

 (2) Linear relationship test accurately weighed fenofibrate reference substance about 50 mg in a 100ml volumetric flask, dissolved in acetonitrile and diluted to the mark, shake well, No. 1 is a blank control (10ml acetonitrile), precision measurement of 1.0, 3.0, 5.0, 7.0, 9.0, 10.0ml, respectively, placed in 6 10ml volumetric flasks of 2-7, except that the 7th volumetric flask is just up to the scale, the other 5 measuring flasks are diluted with acetonitrile to the mark, shake well. As a test solution. Each precision measurement of lOul was sequentially injected into the liquid chromatograph, and the peak area of the chromatogram was recorded. Each sample was injected in parallel twice, and the average value of the peak area was calculated. The linear equation, linear correlation coefficient and squared value were calculated by taking the average of the peak area as the abscissa (X) and the injection quantity (ug) as the ordinate (Y).

(3) Precision test accurately weighed about 20mg of fenofibrate capsule content, placed in a centrifuge tube, and ultrasonically extracted 4 times with acetonitrile (15ml for each 1-3 times, 10ml for the fourth time), each time After 10 minutes of sonication, centrifuge for 15 minutes (4500 rad/min), and dispose the acetonitrile solution in a 100 ml volumetric flask with a dropper. Combine the extracts, dilute to the mark with acetonitrile, shake well, measure lOul into the liquid chromatograph, record the chromatogram. Figure, continuous injection 6 times. (3) The stability test solution is accurately weighed 20mg of fenofibrate capsule content, placed in a centrifuge tube, and ultrasonically extracted 4 times with acetonitrile (15ml for each 1-3 times, 10ml for the 4th time). Centrifuge for 15 minutes (4500 rad/min) after 10 minutes of sonication, and dispose the acetonitrile solution in a 100 ml volumetric flask with a dropper, combine the extracts, dilute to the mark with acetonitrile, shake well, and measure lOul into the liquid chromatograph. The chromatogram was recorded and the injection was repeated once every 2 hours.

 (4) Recovery rate test Weigh accurately the contents of the blank capsules prepared according to the prescription ratio and the current preparation process, each of which is about 30 mg, which are placed in 9 stoppered centrifuge tubes of No. 1-9, respectively. Take 9 parts of fenofibrate reference substance (20mg±20%), place them in the above 9 stoppered centrifuge tubes, stir them well with a glass rod, and extract them 4 times with acetonitrile (1st) -3 times each 15ml, 4th 10ml), after each 10 minutes of ultrasound, centrifuge for 15 minutes (4500rad/min), and dispose the acetonitrile solution in a 100ml volumetric flask with a dropper, combine the extracts, and dilute to the mark with acetonitrile. Shake well, measure lOul into the liquid chromatograph, record the peak area; take another 10 mg of fenofibrate reference, place it in a 100 ml volumetric flask, dissolve it with acetonitrile and dilute to the mark, shake it, and test it in the same way. , Calculate the recovery rate by peak area according to the external standard method.

 (5) Intermediate precision test In order to investigate the influence of random variation factors on precision, different instruments were used to measure the content of fenofibrate capsules at different times. Dissolution

 Artificial gastric juice: Take 16.4ml of dilute hydrochloric acid, add about 800ml of water and 10g of pepsin. Shake well and dilute to 1000ml with water.

 Selection of dissolution medium The main drug in this product is fenofibrate which is insoluble in water. It does not meet the leakage condition in water, artificial gastric juice, artificial intestinal juice, 20% ethanol solution and 5% sodium dodecyl sulfate solution. In order to find a solvent that satisfies the leak condition, the following solvents were tested.

 Condition 1 a solution containing 5% sodium dodecylsulfate 20% ethanol;

 Condition 2 a solution containing 5% sodium dodecylsulfate 25% ethanol;

 Condition 3 a solution containing 5% sodium dodecylsulfonate 20% acetonitrile;

 Condition 4 Polysorbate 80-water 40:60

 Condition 5 Polysorbate 80-water 35:65

 Condition 6 Polysorbate 80-water 30:70

Condition 7 Polysorbate 80 - water-ethanol 30:60:10 Condition 8 Polysorbate 80 - water 40:60 (containing 1% pepsin)

 The dissolution condition of the 10th edition Pharmacopoeia is 1.0% sodium dodecyl sulfate solution 1000ml, 120rad/min, 60min.

 The final optimal test conditions were as follows: In vitro dissolution test was carried out by using the Chinese Pharmacopoeia 2010 edition two-part transfer basket method, and the dissolution transmitter was selected to be a concentration of 5% sodium dodecyl sulfate solution at a temperature of 37 ° and a rotation speed of 50 r/min. Release at 5 min, 10 min, 20 min, 30 min, 40 min, 60 min, 120 min.

 The results showed that the release rate reached 85%, which met the requirements of the pharmacopoeia.

 Disintegration test: The enteric preparation of the outer casing of the soft capsule or the hard capsule or the liquid capsule of the present invention is subjected to a disintegration test according to the inspection method for disintegrating the enteric capsule in the Appendix XA of the 2010 edition of the Pharmacopoeia. Taking the preferred embodiment of the non-Boubeite intestinal sol pills, Probucol intestinal sol pills as an example

 The experimental results are shown in Table 7.

稳定性试验

Stability test

 The pellets prepared in the above examples of the present invention were exposed to light at 3,500 LX, and the temperatures were respectively room temperature, 40 ° C and 25 ° C, and the humidity was RH 92.5% and RH 75%, respectively, for 10 days. Then, the sealed pellets of the present invention are compared with the properties, the color of the contents, the fragmentation, the disintegration time limit, the content determination and the chromatographic degradation products, and the comparison results show that the light and different temperature and humidity conditions are obtained. The naked nipples of the present invention are substantially stable in their properties.

 In addition, the capsule of the present invention is sealed and packaged, and is accelerated for six months under the condition of temperature of 40 ° C and humidity of RH 75%, and stored at room temperature for 24 months, and regularly according to the preset quality. The temperature standard was used to observe and measure the sample, and it was found that the traits of the sample were basically stable.

 Bioequivalence experiment

(I) Experimental study on the relative bioavailability of fenofibrate capsules in the preferred embodiment of the present invention: In this study, 8 beagle dogs were used as test subjects, and a double crossover test method was used. Oral administration of 1 fenofibrate capsule (containing fenofibrate 50mg) or 1 commercially available fenofibrate capsule (containing fenofibrate 200mg), high performance liquid chromatography for different time plasma The concentration of the drug in the drug, based on the plasma concentration-time data, the main pharmacokinetic parameters were obtained.

 The calculation results show:

In a preferred embodiment of the invention, the fenofibrate in the fenofibrate capsule has a Tmax of 4.688 ± 3.779 (h) , a Cmax of 21.027 ± 16.766 (ug/ml), and a T1/2 of 7.563 ± 5.093 (h). , AUC ₀ ~ ₂₄ is 115.192 ± 38.192 (ug.h / ml), AUC ₀ is 137.94 ± 64.645 (ug.h / ml).

The Tmax of commercially available fenofibrate capsules was 4.036 ± 2.678 (h), Cmax was 17.323 ± 9.006 (ug/ml), and T1/2 was 9.151 ± 4.853 (h), AUC. ~ ₂₄ is 112.221 ± 57.222 (ug.h/ml), AUC. It is 299.153 ± 367.561 (ug.h/ml ) .

 The specific results are shown in Table 1, Table 2, and Table 3. Table 1 Pharmacokinetic parameters after administration of fenofibrate capsules (A) in a preferred embodiment of the present invention. Pharmacokinetic parameters (Pharmaceutical A)

 AUCt AUCi AUCt AUCi(°o) Cmax Ding max T1 2

1 121 .288 133.364 90.945 14.049 9 7.801

2 134.186 264.303 50.77 10.384 4.5 19.468

3 121 .921 122.347 99.652 27.499 3 2.864

4 138.831 154.719 89.731 24.194 2 6.49

5 55.602 60.93 91.255 8.108 3 7.603

6 154.124 156.206 98.667 13.352 12 4.259

7 55.743 58.851 94.719 11.656 2.5 5.375

8 139.838 152.803 91.515 58.978 1 .5 6.643

Mean 115.192 137.94 88.407 21.027 4.688 7.563

SD 38.192 64.645 15.648 16.766 3.779 5.093

RSD/% 33.2 46.9 17.7 79.7 80.6 67.3 Table 2 Pharmacokinetic parameters after single-dose administration of commercially available fenofibrate capsules (R)

Pharmacokinetic parameters (R drugs)

.;■ .· .. . AUCt AUCi AUCt AUCi(° ₀ ) Cmax Ding max T1/2

1 51 .526 58.105 88.677 28.254 2.5 8.572

2 84.376 101.196 83.379 13.706 7 6.171

3 130.727 243.684 53.646 15.019 2.5 9.862

4 70.769 1178.79E > 6.004 12.35 2.5 1.72

5 145.173 151.162 96.038 16.167 2.5 7.644

6 44.439 100.597 44.176 6.18 1.5 18.368

7 182.562 210.922 86.554 33.566 5 12.602 8 188.197 348.76 53.962 13.345 9 8.267

Mean 1 12.221 299.153 64.054 17.323 4.063 9.151

SD 57.222 367.561 30.435 9.006 2.678 4.853

RSD/% 51 122.9 47.5 52 65.9 53 Table 3 Relative bioavailability calculation of fenofibrate capsules

采用 DAS统计分析软件， 运用双交叉设计方差分析法， 双单侧检验法和（1~2 α ) 置信区间对上述主要药代动力学参数进行统计分析和生物等效性评价， 结果表 明： 被试制剂的平均 Tmax， Cmax、 AUC。~₂₄ 均大于等于对照制剂。 本发明的非 诺贝特胶丸对市售非诺贝特胶丸的平均相对生物利用度 F为 146. 7 ± 109. 4%， 其 生物利用度参数值的 90%可信限为 58. 5% 〜204. 8%。可见两种制剂生物利用度不 等效， 试验制剂 25mg比参比制剂 200mg生物利用度高， 其狗生物利用度是市售 非诺贝特胶丸的 4倍以上。 见图 1.

Statistical analysis and bioequivalence evaluation of the above main pharmacokinetic parameters were performed using DAS statistical analysis software, double-crossover design analysis of variance, double unilateral test and (1~2 α ) confidence interval. The average Tmax, Cmax, AUC of the test preparation. ~ ₂₄ are greater than or equal to the control preparation. The average relative bioavailability F of the fenofibrate capsules of the present invention for commercially available fenofibrate capsules is 144.7 ± 109. 4%, and the 90% confidence limit of the bioavailability parameter value is 58. 5% ~ 204. 8%. It can be seen that the bioavailability of the two preparations is not equivalent. The test preparation 25mg is higher in bioavailability than the reference preparation 200mg, and the dog bioavailability is more than 4 times that of the commercially available fenofibrate capsule. see picture 1.

 (b) Experimental study on the relative bioavailability of the preferred embodiment of Probucol capsules in the present invention:

 In this study, 4 beagle dogs were used as the test subjects, and a single-dose cross-fasting oral administration of 1 probucol capsule (including probucol 50 mg) or 4 commercial probucol tablets (4 tablets) was performed. Containing Probucol 500mg), the concentration of the drug in plasma was determined by high performance liquid chromatography, and the main pharmacokinetic parameters were obtained according to the plasma concentration-time data.

The calculation results show: The preferred embodiment of the present invention, Probucol capsules (50 mg), has a Tmax of 7.5 ± 1 (h), a Cmax of 254.182 ± 358.82 (ug/ml), and a T1/2 of 1.775 ± 0.899 (h), AUC. ~ ₂₄ is 613.094 ± 796.315 (ug.h / ml), AUC ^ is 2027.43 ± 3165.858 (ug.h / ml).

The reference preparation commercially available probucol tablets (500 mg) had a Tmax of 6.75 ± 2.5 (h), a Cmax of 128.443 ± 73.838 (ug/ml), and a T1/2 of 4.685 ± 7.007 (h), AUC. ~ ₂₄ is 321.23 ± 85.995 (ug.h/ml), AUC ₀ is 761.534 ± 876 (ug.h/ml)

 The specific results are shown in Table 4, Table 5, Table 6 Table 4. Pharmacokinetic parameters of a single dose of Probucol capsules (A) in a preferred embodiment of the present invention.

表 5 单剂量给予市售普罗布考片 4*125mg (R)后的药物动力学参数

Table 5 Pharmacokinetic parameters after single dose administration of commercial Probucol 4*125mg (R)

 Pharmacokinetic parameters (R drugs)

 Ft 灵纤疆纤隐隐 AUCt AUCi AUCtAUCi(°o) Cmax 丁 max T1/2

1 426.755 457.193 93.342 231.834 8 1.989

2 340.249 2068.596 16.448 79.598 8 15.162

3 220.666 222.36 99.239 71.229 3 0.848

4 297.252 297.987 99.753 131.11 8 0.742

Mean 321.23 761.534 77.196 128.443 6.75 4.685

SD 85.995 876.854 40.603 73.838 2.5 7.007

RSD/% 26.8 115.1 52.6 57.5 37 149.6 Table 6 Relative Bioavailability Calculation of Probucol Capsules

采用 DAS统计分析软件，运用双交叉设计方差分析法，双单侧检验法和（1~2 α )置信区间对上述主要药代动力学参数进行统计分析和生物等效性评价， 结果 表明： 被试制剂的平均 Tmax， Cmax、 AUC。~₂₄均远远大于对照制剂。 本发明的 普罗布考胶丸对市售普罗布考片的平均相对生物利用度 F为 187. 7. 7 ± 229. 7%， 其生物利用度参数值的 90%可信限为 30. 1% 〜452. 9%。可见两种制剂生物利用度 不等效， 试验制剂 50mg比参比制剂 500mg生物利用度高， 其狗生物利用度是市 售普罗布考片的 10倍以上。

Statistical analysis and bioequivalence evaluation of the above main pharmacokinetic parameters were performed using DAS statistical analysis software, double crossover design analysis of variance, double unilateral test and (1~2 α ) confidence interval. The results showed that: The average Tmax, Cmax, AUC of the test preparation. ~ ₂₄ are much larger than the control preparation. The average relative bioavailability F of the probucol capsules of the present invention on a commercially available probu sample is 187. 7. 7 ± 229.7%, and the 90% confidence limit of the bioavailability parameter value is 30. 1 % ~ 452. 9%. It can be seen that the bioavailability of the two preparations is not equivalent, the test preparation 50mg is higher than the reference preparation 500mg, and the dog bioavailability is more than 10 times that of the commercially available probu tablets.

Claims

Claim  An oil-soluble pharmaceutical composition comprising a content and an outer wrapping material, the content being an oil solution made of an oil-soluble drug and an auxiliary material; the auxiliary material being a non-polar solvent and a solubilizing agent, the non-polar The solvent is vegetable oil, animal oil or polyoxyethylene 40 hydrogenated castor oil; the solubilizing agent is isopropyl myristate and/or ethyl oleate, Tween, polyethylene glycol 400, polyethylene glycol 600.  2. The oil-soluble pharmaceutical composition according to claim 1, wherein the vegetable oil is peanut oil, soybean oil, rapeseed oil, corn oil, olive oil, sunflower oil, sesame oil, linseed oil, cottonseed oil, rice bran oil, One or more of coconut oil, camellia seed oil, canola oil, pepper oil, and chili oil, the animal oil being one of lard, butter, sheep oil, chicken oil, duck oil or Several.  The oil-soluble pharmaceutical composition according to claim 1, wherein the solubilizing agent is isopropyl myristate and/or ethyl oleate, Tween, polyethylene glycol 400, and polyethylene glycol 600.  The oil-soluble pharmaceutical composition according to claim 1, wherein the oil-soluble drug is 2 - 70 g, the solubilizing agent is 1 - 210 g, and the vegetable oil is 400 - 1000 g per 1000 parts of the composition.  5. The oil-soluble pharmaceutical composition according to claim 1, wherein the oil-soluble drug is fenofibrate, probucol, undecylenic acid, testosterone undecanoate, diethylstilbestrol, hydroxyprogesterone caproate, propionic acid Testosterone, methyltestosterone, norronil phenylpropionate, estradiol benzoate, fluphene thiophene or vitamin D3.  The oil-soluble pharmaceutical composition according to claim 5, wherein the oil-soluble drug is 5 g, and the solubilizing agent is isopropyl myristate, ethyl oleate, Tween, and polyethylene. One or more of diol 400, polyethylene glycol 600, 15 g, vegetable oil 500-900 g.  The oil-soluble pharmaceutical composition according to claim 5, wherein the oil-soluble drug 25 g, the solubilizing agent is isopropyl myristate, ethyl oleate, Tween, polyethylene per 1000 formulation compositions One or more of 20 g of diol 400 and polyethylene glycol 600, 500-900 g of vegetable oil.  The oil-soluble pharmaceutical composition according to claim 5, wherein the oil-soluble drug is 50 g, and the solubilizing agent is isopropyl myristate, ethyl oleate, Tween, and polyethylene. One or more of diol 400 and polyethylene glycol 600 are 150 g, and vegetable oil is 500-900 g.  The oil-soluble pharmaceutical composition according to claim 1, which is in the form of a soft capsule, a liquid capsule, a hard capsule or a dropping pellet. The oil-soluble pharmaceutical composition according to claim 9, wherein the outer wrapping material comprises gelatin, or gelatin and propylene glycol, or gelatin and glycerin. The oil-soluble pharmaceutical composition according to claim 1, which is in the form of a capsule and an enteric coating.  The method for preparing an oil-soluble pharmaceutical composition according to claim 11, comprising: weighing the components of the contents in proportion, mixing and stirring to obtain an oil solution, and preparing the oil solution by using a transfer mode capsule. The machine is filled in a capsule, and the soft capsule or the liquid capsule or the hard capsule or the dropping capsule is overcoated with the enteric coating.  The preparation method according to claim 12, wherein the mixing and stirring are stirred at a temperature of from 10 to 65 ° C, and the mixing is homogenized by ultrasonic assisted dissolution. 14. A method for determining the content of an oil-soluble pharmaceutical composition, wherein the drug is fenofibrate, characterized in that: octadecylsilane-bonded silica gel is used as a filler; acetonitrile-water is a mobile phase; and the detection wavelength is 286 nm. The volume ratio of acetonitrile to water in the mobile phase was 70:30, and the _P H value was adjusted to 2.5 with phosphoric acid.