CN105769767A - Etofibrate self-emulsifying preparation and preparation method thereof - Google Patents

Etofibrate self-emulsifying preparation and preparation method thereof Download PDF

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Publication number
CN105769767A
CN105769767A CN201610225179.XA CN201610225179A CN105769767A CN 105769767 A CN105769767 A CN 105769767A CN 201610225179 A CN201610225179 A CN 201610225179A CN 105769767 A CN105769767 A CN 105769767A
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China
Prior art keywords
etofibrate
self
preparation
parts
emulsifying
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刘小平
张信平
李小菲
周刚
郭杰
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Wuhan University of Technology WUT
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Wuhan University of Technology WUT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Dispersion Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses an etofibrate self-emulsifying preparation and a preparation method thereof. The etofibrate self-emulsifying preparation comprises, by weight, 0.1-10 parts of etofibrate, 15-50 parts of an oil phase, 25-60 parts of emulgator and 10-35 parts of co-emulsifier. The preparation method includes the following steps that the etofibrate is dissolved in the co-emulsifier at the temperature of 37 DEG C, then the oil phase and the emulgator are sequentially added and stirred to be uniform, and the etofibrate self-emulsifying preparation is obtained. By means of the etofibrate self-emulsifying preparation and the preparation method thereof, the etofibrate can be transferred to the absorption portion rapidly and uniformly, adverse stimulation to gastrointestinal tracts of the etofibrate is reduced, the etofibrate self-emulsifying preparation exists in tiny emulsion droplets which can be rapidly discharged out of the stomach, and medicine is widely distributed in the whole gastrointestinal tracts, so that stimulation caused by long-time contact between a great quantity of medicine with the gastric walls is reduced.

Description

Etofibrate self-emulsifiable preparation and preparation method thereof
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to a kind of etofibrate self-emulsifiable preparation and preparation method thereof.
Background technology
Hyperlipidemia is a kind of common disease, be human body lipid metabolism not normal caused by, refer mainly to T-CHOL in serum, triglyceride and low-density lipoprotein white level be too high or hdl level is too low.Hyperlipidemia early stage does not have obvious clinical symptoms, and the infringement of health is invisible, gradually row by it, and is general.Because hyperlipidemia can accelerate atherosclerosis, once artery occlusion, a lot of disease will be caused, such as cardiovascular and cerebrovascular disease, nephropathy, hepatic disease etc..Cardiovascular and cerebrovascular disease is the main cause that middle-aged and elderly people is lethal, is the number one killer threatening human health
Etofibrate is applicable to hyperlipidemia (serious constitutional and Secondary cases hyperlipidemia), arterial pulse is atherosis, cerebrovascular and tail vein obstacle, blood vessel and retinal vasculopathy, prevention of stroke, heart change, myocardial infarction, hypertension, hyperlipidemia obesity, disturbance of blood circulation etc..
Etofibrate molecular formula C18H18ClNO5, molecular weight 363.79, etofibrate is insoluble in water.Etofibrate is a kind of prodrug, resolves into rapidly clofibrate and nicotinic acid after taking in vivo, plays pharmacological action:
Clofibrate can significantly reduce the level of VLDL and triglyceride in Blood of Patients.Can with the rising of LDL when VLDL is down to minimum.Its effect for reducing fat, mainly by activating to protease, makes VLDL and triglyceride in blood be decomposed into fatty acid and glycerol, and rear both are absorbed by fatty tissue, and is synthesized into triglyceride and is stored in fatty tissue.Additionally, clofibrate can also slightly suppress cholesterol in the synthesis of liver, there is more weak cholesterol reducing effect.
Nicotinic acid can reduce the level of VLDL and triglyceride in blood, and decline degree is relevant with blood lipid level before medication.Long-term prescription, also can reduce LDL and cholesterol levels.Its generation reducing liver synthesis VLDL is primary effect, then reduces LDL and generates, and it is relevant that the reduction of VLDL is likely to reduce cAMP content in fat with medicine.CAMP reduces, and makes the triglyceride enzymatic activity of dependence cAMP reduce, and fatty tissue decomposes minimizing, is released into the free fatty in blood and reduces, and liver synthetic glycerine three ester reduces then.Nicotinic acid also can promote cholesterol to discharge through bile, and stops the esterification of cholesterol.Meanwhile, it appropriateness can also improve HDL level in blood, thus has the effect of atherosclerosis and coronary heart disease.
At present, the type of preparation of etofibrate on the market, common are capsule and tablet.Wherein, capsule is more easily accepted by people, but is still the problems such as existence is taken often, dosage is excessive.It is therefore desirable to use new agent technology to design a kind of brand-new dosage form so that it is dosage and frequency ratio ordinary preparation reduce, and can dramatically increase the compliance of patient.
Summary of the invention
Present invention aim at providing a kind of etofibrate novel formulation so that it is dosage and frequency ratio ordinary preparation reduce, and can dramatically increase the compliance of patient.
For reaching above-mentioned purpose, adopt technical scheme as follows:
A kind of etofibrate self-emulsifiable preparation, comprises etofibrate, oil phase, emulsifying agent, co-emulsifier, is calculated by weight as etofibrate 0.1～10 part, oil phase 15～50 parts, emulsifying agent 25～60 parts, co-emulsifier 10～35 parts.
By such scheme, raw materials by weight portion is calculated as etofibrate 5 parts, oil phase 15～25 parts, emulsifying agent 25～35 parts, co-emulsifier 25～35 parts.
By such scheme, described oil phase is oleic acid, ethyl oleate or olive oil.
By such scheme, described emulsifying agent is polyoxyethylene castor oil, Tween-80 or op-10.
By such scheme, described co-emulsifier is dehydrated alcohol, isopropanol or glycerol.
The preparation method of above-mentioned etofibrate self-emulsifiable preparation, comprises the following steps:
Etofibrate is dissolved in co-emulsifier at 37 DEG C, sequentially adds oil phase, emulsifier for mixing is uniformly mixed so as to obtain etofibrate self-emulsifiable preparation.
Etofibrate is insoluble in water, and its formulation dissolution process is the speed limit process absorbed.Mostly there is the problem that bioavailability is low in oral formulations.The present invention, with self-emulsifying drug delivery transmission system for carrier, can improve the dissolution of etofibrate, promotes that it absorbs, and improves oral administration biaavailability.
Self-emulsifying drug delivery transmission system is as a kind of newtype drug transmission system, being suitable for such as etofibrate slightly water-soluble, oral absorption is poor, bioavailability individual variation is big medicine, it increases the absorption of etofibrate mainly through the following aspects: increase dissolubility and the dissolution of etofibrate；Emulsion droplet can increase and gastrointestinal contact area；Some surfactant can promote the gastrointestinal tract epithelial cell permeability to medicine；Some pharmaceutic adjuvant can suppress enterocyte cytochrome p 450 to the catalysis of etofibrate and the P-glycoprotein outer row etc. to medicine.The etofibrate self-emulsifying drug delivery transmission system prepared can contain insoluble drug etofibrate as much as possible, and its dissolubility is 5～15 μ g/ml so that it is dissolubility increases 1000～3000 times.
In self-emulsifiable preparation, etofibrate is present in the little oil droplet that self emulsifying is formed with dissolved state, therefore the process in leaching of insoluble drug etofibrate no longer becomes the rate-limiting step of its body absorption；Matrix material can increase the dissolubility of medicine etofibrate, thus improving its bioavailability；By increasing the lymphatic transport of medicine, reduce first pass effect, improve bioavailability directly or indirectly；Owing to can avoiding illumination in preparation process or can adding antioxidant in system, therefore self-emulsifying drug delivery transmission system can be used for preparing the preparation needing lucifuge or oxidizable medicine.
Relative to prior art, the present invention has the beneficial effect that:
The etofibrate self-emulsifying drug delivery transmission system that the present invention prepares can make insoluble medicine etofibrate dissolubility increase, and under body temperature environment, can spontaneously form O/W type Emulsion after meeting body fluid under gastrointestinal motility.
Compared with the tablet of etofibrate or capsule, the present invention more quickly, equably by etofibrate can be delivered to absorption site, reduce etofibrate to gastrointestinal pessimal stimulation, it is present in tiny emulsion droplet, emulsion droplet can from stomach rapid deflation, make medicine widely distributed in whole gastrointestinal tract, thus the stimulation reducing high amount of drug and gastrointestinal wall Long contact time and causing.
Preparation is simple, stable in properties, dosage are accurate and taking convenience.
Accompanying drawing explanation
Fig. 1: for etofibrate standard curve；
Fig. 2: the comparison curves of the accumulative releasing degree of etofibrate self-emulsifying soft capsule and etofibrate capsule；
Fig. 3: etofibrate concentration versus time curve in high blood lipid model rat plasma.
Detailed description of the invention
Following example explain technical scheme further, but not as limiting the scope of the invention.
Implement 1:
Its preparation technology: weigh the etofibrate of recipe quantity, the isopropanol adding recipe quantity makes it dissolve 37 DEG C of water-baths, press recipe quantity more successively and add other adjuvants such as oil phase, emulsifying agent and antioxidant, stir, then, with water: gelatin: capsule material prepared by glycerol (4:2:1), melt adhesive temperature is 70 DEG C, adding preservative agent, nipasol consumption is the 0.05% of gelatin weight.About 20 DEG C of glue capsules of room temperature, rubber THICKNESS CONTROL is at about 0.7mm.The soft capsule prepared is placed in rotating cage and turns 8h, come out of steamer, and at 30-40 DEG C, namely drying 8-10h obtains and make soft capsule, obtains etofibrate self-emulsifying soft capsule.Every soft capsule is containing etofibrate 50mg.
Implement 2:
Preparation technology is with example 1.
Implement 3:
Preparation technology is with example 1
Implement 4:
Preparation technology is with example 1
Assay:
Preparation of Chinese medicine content assaying method requires accurate accurate, and the present invention adopts the content of etofibrate in high effective liquid chromatography for measuring soft capsule.
Chromatographic column: DIKMA octadecylsilane chemically bonded silica packed column (150*4.6mm)
Potassium dihydrogen phosphate-the acetonitrile (55:45) of mobile phase: 0.01mol/l, phosphorus acid for adjusting pH is to 4.1
Flow velocity: 1.0ml/min
Column temperature: 37 DEG C
Sample size: 20 μ l
Inspection wavelength: 221nm
Reference substance solution: precision weighs etofibrate standard substance 20.0mg, joins in 100ml volumetric flask, first dissolves with a small amount of methanol, then dissolves with mobile phase and be diluted to scale, is configured to the reference substance solution that concentration is 0.2mg/ml, ultrasonic, filters, standby.
The drafting of standard curve: respectively precision draw reference substance solution 0.25,0.5,1.0,2.5,5.0ml, it is placed in the volumetric flask of 10ml, add mobile phase dissolved dilution to scale, solution is with after the filtering with microporous membrane of 0.45 μm, HPLC mensuration is carried out by above-mentioned chromatographic condition, precision measures each 20uL of above solution and injects chromatograph of liquid, and the peak area result of record spectrogram, etofibrate goes out peak at retention time 9.448min.Then with the concentration C of etofibrate for abscissa, peak area A is vertical coordinate, drawing standard curve, and regression equation is A=0.535C+2.184, r=0.999.Result shows: in 49.48 μ g/ml～1.0152mg/ml concentration range, linearly well.Result is shown in accompanying drawing 1.
Solution allocation: precision weighs a certain amount of etofibrate self-emulsifying soft capsule content (containing etofibrate 50.0mg) from the product of embodiment 1,2,3,4 respectively, join in 10ml measuring bottle, first dissolve with a small amount of methanol, dissolving and be diluted to scale again with mobile phase, filter, precision measures subsequent filtrate 1.0ml, it is placed in 10ml volumetric flask, add mobile phase and be diluted to scale, shake up, as need testing solution.
The assay of etofibrate: respectively from the product of embodiment 1,2,3,4, take four batches of self-control etofibrate self-emulsifying soft capsules, three groups of need testing solutions are prepared according to solution manufacturing method, take appropriate solution, after the filtering with microporous membrane of 0.45 μm, carry out HPLC mensuration by above-mentioned chromatographic condition, record peak area, and calculate the content of etofibrate according to the standard curve drawn.It is shown that etofibrate self-emulsifying soft capsule drug content is all between the 90～110% of labelled amount, meet the requirement of capsule.Result subordinate list 1.
Table 1
Dissolution in vitro contrast test:
Example gained self-emulsifying soft capsule is a, four every part, takes out the content liquid of four soft capsules, adopts HPLC method, according to Chinese Pharmacopoeia dissolution method (2015 editions annex XC the second methods), with 900mL0.lmol L-1Hydrochloric acid solution, the SDS solution of 1% is release medium, rotating speed 100r min-l, temperature 37 ± 0.5 DEG C, by identical for 7 size shape, the bag filter including 2rnL dissolution medium is completely immersed in dissolution medium, balances 12h.Add in dissolution medium.Respectively at 0.5,1,2,6,8,12,24h respectively take out a bag filter, pour out solution in bag, with the drug level in medium in high effective liquid chromatography for measuring bag, calculate cumulative release percentage rate.Seeing shown in accompanying drawing 2, result shows compared with the conventional capsule medicine of etofibrate, and etofibrate self-emulsifying soft capsule dissolution of the present invention increases.Due to the dissolution of the bigger raising of etofibrate self-emulsifying soft capsule medicine etofibrate hard to tolerate of the present invention, the raising of its biological utilisation, and play the effect for reducing fat of etofibrate in a big way, improve efficiency.
Zoopery:
Embodiment gained etofibrate self-emulsifying soft capsule and common etofibrate capsule are carried out animal experiment in vivo.Adopt Self-control method, with the rat of high blood lipid model for laboratory animal, then after giving the commercially available capsule of etofibrate and etofibrate self-emulsifying soft capsule respectively, obtain in rat body etofibrate concentration versus time curve in blood plasma.Result is shown in accompanying drawing 3, test result indicate that the peak time of self-emulsifiable preparation group Chinese medicine reach 2h, and the highest blood drug level increases to some extent, it was shown that etofibrate self-emulsifying soft capsule has faster and better absorption in rat body, reaches to promote the effect of drug absorption.

Claims (6)

1. an etofibrate self-emulsifiable preparation, it is characterised in that comprise etofibrate, oil phase, emulsifying agent, co-emulsifier, is calculated by weight as etofibrate 0.1～10 part, oil phase 15～50 parts, emulsifying agent 25～60 parts, co-emulsifier 10～35 parts.
2. etofibrate self-emulsifiable preparation as claimed in claim 1, it is characterised in that raw materials by weight portion is calculated as etofibrate 5 parts, oil phase 15～25 parts, emulsifying agent 25～35 parts, co-emulsifier 25～35 parts.
3. etofibrate self-emulsifiable preparation as claimed in claim 1, it is characterised in that described oil phase is oleic acid, ethyl oleate or olive oil.
4. etofibrate self-emulsifiable preparation as claimed in claim 1, it is characterised in that described emulsifying agent is polyoxyethylene castor oil, Tween-80 or op-10.
5. etofibrate self-emulsifiable preparation as claimed in claim 1, it is characterised in that described co-emulsifier is dehydrated alcohol, isopropanol or glycerol.
6. the preparation method of etofibrate self-emulsifiable preparation described in claim 1, it is characterised in that comprise the following steps:
Etofibrate is dissolved in co-emulsifier at 37 DEG C, sequentially adds oil phase, emulsifier for mixing is uniformly mixed so as to obtain etofibrate self-emulsifiable preparation.
CN201610225179.XA 2016-04-12 2016-04-12 Etofibrate self-emulsifying preparation and preparation method thereof Pending CN105769767A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0168360A2 (en) * 1984-06-29 1986-01-15 Roberto Valducci Process for preparing etofibrate or similar compounds containing sustained release microgranules and products thus obtained
CN101484138A (en) * 2006-03-07 2009-07-15 诺瓦瓦克斯有限公司 Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same
CN101711738A (en) * 2008-10-08 2010-05-26 中国人民解放军军事医学科学院毒物药物研究所 Oral pharmaceutical composition of Fenofibrate
CN101961324A (en) * 2010-09-10 2011-02-02 武汉药谷生物工程有限公司 Prescription and preparation method of etofbrate release capsules
CN103315953A (en) * 2012-03-20 2013-09-25 胡容峰 Fenofibrate self-microemulsifying preparation and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0168360A2 (en) * 1984-06-29 1986-01-15 Roberto Valducci Process for preparing etofibrate or similar compounds containing sustained release microgranules and products thus obtained
CN101484138A (en) * 2006-03-07 2009-07-15 诺瓦瓦克斯有限公司 Nanoemulsions of poorly soluble pharmaceutical active ingredients and methods of making the same
CN101711738A (en) * 2008-10-08 2010-05-26 中国人民解放军军事医学科学院毒物药物研究所 Oral pharmaceutical composition of Fenofibrate
CN101961324A (en) * 2010-09-10 2011-02-02 武汉药谷生物工程有限公司 Prescription and preparation method of etofbrate release capsules
CN103315953A (en) * 2012-03-20 2013-09-25 胡容峰 Fenofibrate self-microemulsifying preparation and preparation method thereof

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Application publication date: 20160720