CN1504187A - Pharmaceutical composition containing fenofibrate with high efficacy for hyperlipemia, its preparation method and use - Google Patents
Pharmaceutical composition containing fenofibrate with high efficacy for hyperlipemia, its preparation method and use Download PDFInfo
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- CN1504187A CN1504187A CNA021535361A CN02153536A CN1504187A CN 1504187 A CN1504187 A CN 1504187A CN A021535361 A CNA021535361 A CN A021535361A CN 02153536 A CN02153536 A CN 02153536A CN 1504187 A CN1504187 A CN 1504187A
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Abstract
The invention relates to a novel pharmaceutical preparation containing fenofirate (chemical name: 2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoicacid-1-methylethylester and process for the preparation, the invention relates to in particular an oral preparation containing fenofirate which can substantially increase the bioavailability of fenofirate and realize slow release for fenofirate.
Description
Invention field
The present invention relates to a kind of fenofibrate (fenofirate that contains; chemical name: 2-(4-(4-chlorobenzene formacyl) phenoxy group)-2 Methylpropionic acid isopropyl ester) new pharmaceutical formulation and preparation method thereof; more specifically say; the present invention relates to contain the oral formulations of fenofibrate, said preparation can significantly improve the bioavailability and the slow release fenofibrate of fenofibrate.
Background technology
Fenofibrate is known blood lipid-lowering medicine, effect with tangible reduction cholesterolemia, triglyceride and high density lipoprotein increasing, be used for the treatment of hypercholesterolemia, hypertriglyceridemia clinically, also can be used to treat simultaneously cardiovascular and cerebrovascular diseases such as atherosclerosis, coronary heart disease.The preparation of fenofibrate is mainly the conventional capsule preparation, and unit dose is the 100mg/ grain, and administering mode is oral, and each one, every day three times.But the bioavailability of finding this preparation in the practice is lower.
European patent EP-A-0330532 patent disclosure be used to improve the method for the bioavailability of fenofibrate.This patent has only been described and has been improved the method for the bioavailability of release type fenofibrate medicament composition at once.This patent has further described fenofibrate and surfactant is total to micronized effect; caused a kind of generation of new dosage form simultaneously; wherein said effective ingredient and solid surfactant are total to the dissolution that micronize has improved fenofibrate, have increased bioavailability of medicament thus.
Chinese patent 98801884.5 has been described a kind of compositions of the fenofibrate of release type at once, and it comprises the inertia water solublity holder that the layer less than fenofibrate, hydrophilic polymer and the dispensable surfactant of 20 μ m sizes covers that has that is comprised the micronize form by one deck at least; This patent provides a kind of novel formulation technology simultaneously.Only improved the bioavailability of fenofibrate by the pharmaceutical composition of this patent preparation.
Though the preparation method of above-cited two Patent publish has all significantly improved the bioavailability of fenofibrate, but its characteristics that discharge at once can cause rising and falling big at the intravital blood drug level of patient after the fenofibrate administration, " peak valley " phenomenon is arranged, and this chronic cardiovascular disease patient that need are taken medicine for a long time is disadvantageous beyond doubt.
Summary of the invention
The objective of the invention is to develop the novel formulation that contains fenofibrate, said preparation simultaneously can make the FENOBRATE slow release significantly improving the fenofibrate bioavailability, thus " peak valley " phenomenon that the fenofibrate of having avoided the preparation that contains fenofibrate in the prior art to occur in use discharges.
The inventor has now found that after deliberation by fenofibrate is carried out micronization, and then mix with suitable inert excipients and can obtain the pharmaceutical preparation that contains fenofibrate that delays to discharge, said preparation can discharge fenofibrate more enduringly when significantly improving the bioavailability of fenofibrate, thereby, reduce medicine frequency, reduce the blood drug level peak valley phenomenon, improve curative effect and the safety of using fenofibrate.
Therefore, the present invention relates to delay release type fenofibrate compositions, it comprises: particle diameter is less than or equal to fenofibrate microgranule and the inert excipients of 5 μ m.
The invention still further relates to preparation and contain the method that delays release of pharmaceutical compositions of fenofibrate, this method comprises:
A. adopt crushing technology to prepare mean diameter and be less than or equal to 5 μ m fenofibrate microgranules;
B. excipient with a) in gained fenofibrate microgranule fully mix;
C. add suitable binding agent, and in High Speed Stirring Machine, make micropill;
D. the micropill of the suitable order number of screening is made capsule preparations.
Detailed Description Of The Invention
The invention provides a kind of compositions or preparation of slow release fenofibrate, it comprises the fenofibrate granule of mean diameter≤5 μ m, and inert excipients.
According to the present invention, inert excipients mainly comprises excipient and binding agent, lubricant etc., can also contain any excipient that is generally used for drug world.Can be used for excipient of the present invention has for example: microcrystalline Cellulose, lactose, starch, silica sol, glyceride, stearic acid, crosslinked polyvinylpyrrolidone, carboxymethyl starch, hydroxypropyl cellulose, hydroxy methocel, hydroxypropyl emthylcellulose, gelatin etc.Preferred excipient is the Pulvis Talci that accounts for the heavy 30-50% of compositions among the present invention.Binding agent is to account for compositions to weigh 2% HPMC 75% alcoholic solution.
According to the present invention, the preferred 100nm-5 μ of the mean diameter of fenofibrate m in the preparation of the present invention.
Thus, the invention further relates to a kind of novel formulation, it comprises that mean diameter is the fenofibrate granule of 100nm-5 μ m, account for the heavy 30-50% of preparation as the Pulvis Talci of excipient and account for compositions and weigh 2% HPMC75% alcoholic solution as binding agent.
According to the present invention, the active component fenofibrate can be by known method preparation or commercial obtaining in the preparation of the present invention.
In according to the present invention, preparation of the present invention can be capsule form.As be capsule, then before making capsule, form micropill earlier, and the screening of the size of micropill process, suitable order number is the 16-24 order.
The pharmaceutical preparation of the present invention's preparation is particularly suitable for by oral route and gives the effective ingredient fenofibrate.Especially be particularly suitable for suffering from chronic cardiovascular and cerebrovascular disease, need take the patient of medicine (fenofibrate) for a long time.
Further, the preparation method that contains fenofibrate formulations of the present invention comprises that the fenofibrate granule with average grain 100nm-5 μ m mixes the formation micropill with inert material, obtain micropill through 16 orders-24 mesh sieve branch then, the gained micropill incapsulates behind 18 order granulate.
According to the present invention, 100nm-5 μ m fenofibrate of the present invention can obtain by pulverizing fenofibrate, and grinding mode can be variety of way, pulverizes as fluidized bed airflow.
Description of drawings:
Fig. 1-Fig. 6 shows that the minimum effective dose of preparation 1 of the present invention (definition is seen below) reduction plasma triglyceride and T-CHOL is 30mg/kg/ days, and conventional formulation is 80mg/kg/ days.Fig. 7 shows that this preparation 1 demonstrates the bioavailability and the slow release release action of raising.Fig. 1 is the influence of conventional formulation to hyperlipemia rat glyceride.Abscissa is the dosage of conventional formulation, and vertical coordinate is the amount of triglyceride (TG), n=8-15, compared with the control, and * p＜0.05, * * p＜0.01 is changed mutually with hyperlipidemia model, #p＜0.05, ##p＜0.01.
Fig. 2 is the influence of 1 pair of hyperlipemia rat T-CHOL of preparation.Abscissa is the dosage of preparation 1, and vertical coordinate is the amount of T-CHOL, n=8-15, compared with the control, and * p＜0.05, * * p＜0.01 is changed mutually with hyperlipidemia model, #p＜0.05, ##p＜0.01.
Fig. 3 be under the same dose preparation 1 and conventional formulation to the influence of hyperlipemia rat T-CHOL.
Fig. 4 is the influence of conventional formulation to the hyperlipemia rat T-CHOL, n=8-15, compared with the control, and * p＜0.05, * * p＜0.01 is compared with hyperlipidemia model, #p＜0.05, ##p＜0.01.
Fig. 5 is the influence of 1 pair of hyperlipemia rat T-CHOL of preparation.Abscissa is the dosage of preparation 1, and vertical coordinate is the amount of T-CHOL, n=8-15, compared with the control, and * p＜0.05, * * p＜0.01 is compared with hyperlipidemia model, #p＜0.05, ##p＜0.01.
Fig. 6 be under the same dose preparation 1 and conventional formulation to the influence of hyperlipemia rat T-CHOL.
Be conventional formulation,
Be preparation 1, n=8-15, compared with the control, and * p＜0.05, * * p＜0.01 is compared with hyperlipidemia model, #p＜0.05, ##p＜0.01.
Fig. 7 is the pharmaceutical concentration-time curve of preparation 1 and conventional formulation, and abscissa is the time, and vertical coordinate is a blood drug level;
Be preparation 1;
Be conventional formulation.
The preparation of embodiment 1 fenofibrate capsule preparations of the present invention:
Commercially available medicinal fenofibrate raw material 10kg is adopted the fluidized bed airflow crushing technology, regulates grading wheel to 48 hertz, the fenofibrate of mean diameter 100nm-5 μ m.The related parameter that has that fluidized bed airflow is pulverized is that the grading wheel frequency is to 48Hz; Cleaning pressure is at 0.4Mpa; Sealing load is at 0.08Mpa; The gas intake valve is at 0.8Mpa; The catcher back-flushing valve is at 0.6Mpa; Screw feeder is at 150 rev/mins.
The fenofibrate of above-mentioned pulverizing is fully mixed with the 10kg Pulvis Talci in the pot of granulating, and its ratio is 1: 1.In high-speed stirred was granulated pot, adding accounted for preparation and weighs 2% HPMC75% alcoholic solution system micropill.Collect the micropill between 24 orders-16 order.Then 50-55 ℃ of oven dry, 18 order granulate, it is an amount of to add 0.5% magnesium stearate, surveys content, encapsulated.Every capsules contains the 100mg fenofibrate of mean diameter 100nm-5 μ m.
Obviously, be easy to carry out the large-scale production of fenofibrate formulations of the present invention by above process.
The fenofibrate formulations (being called for short preparation 1 from now on) that contains that embodiment 1 makes compares in blood fat reducing with conventional fenofibrate capsule (being called for short conventional formulation from now on):
Sample: preparation 1
Conventional fenofibrate capsule (being called for short conventional formulation from now on) is available from Xuzhou grace China medicine group
The effect for reducing blood fat of preparation 1 and conventional formulation.
Method: feed the SD rat with high lipid food, cause serum lipids in rats, give preparation 120,30,40mg/kg days and conventional formulation 20,30,40,60,80mg/kg days then respectively.Got hematometry serum total cholesterol (TC), triglyceride (TG) on the 10th day in experiment.The result: under same experimental conditions, the minimum effective dose that micronization fenofibrate capsule reduces plasma triglyceride and T-CHOL is 30mg/kg days, and standardization fenofibrate capsule is 80mg/kg.My god; 2. two kinds of dosage form fenofibrate can make the triglyceride levels of hyperlipemia rat reduce to normally under effective dose, make the total cholesterol level decline 36.69-51.56% of hyperlipemia rat.Conclusion: preparation is better than ordinary preparation.Its concrete outcome is as follows:
Preparation 1 and conventional formulation are to the influence of hyperlipemia rat triglyceride
Gave the hyperlipemia rat conventional formulation every day 20mg/kg days, 30mg/kg days, 40mg/kg days groups all significantly raise than serum triglycerides with the normal diet group, distinguish than no significance with the hyperlipidemia model group.Give 60mg/kg days group serum triglyceride levels and normal diet group and hyperlipidemia model group every day there are no significant difference.And give 80mg/kg days groups every day, and there is not the significance difference with the normal diet group, with high fat diet group ratio, serum triglyceride level significantly reduces, and the results are shown in Figure 1.
Gave the hyperlipemia rat preparation every day 130mg/kg days, 40mg/kg days groups, serum triglyceride level and normal diet group are distinguished than no significance, and with high fat diet group ratio, serum triglyceride level significantly reduces, and the results are shown in Figure 2.
Under the same dose, the hyperlipemia rat serum triglyceride level that gives preparation 1 significantly is lower than the hyperlipemia rat that gives ordinary preparation, and the result sees Fig. 3.
The influence of conventional formulation and 1 pair of hyperlipemia rat T-CHOL of preparation
Gave the hyperlipemia rat conventional formulation every day 20mg/kg days, 30mg/kg days, 40mg/kg days and 60mg/kg days groups all significantly raise than serum total cholesterol with the normal diet group, distinguish than no significance with the hyperlipidemia model group.Give 80mg/kg days groups every day, serum total cholesterol level raises than remarkable with the normal diet group, but significantly is lower than the hyperlipidemia model group, the results are shown in Figure 4.
Give every day the hyperlipemia rat preparation 120mg/kg days groups, with the normal diet group than the remarkable rising of serum total cholesterol level, distinguish than no significance with the hyperlipidemia model group.And gave every day preparation 130mg/kg days and 40mg/kg days group serum triglyceride levels and normal diet group than significantly raising, but significantly be lower than the high fat diet group, see Fig. 5.
Under the same dose, the hyperlipemia rat serum total cholesterol level that gives preparation 1 significantly is lower than the hyperlipemia rat that gives conventional formulation, the results are shown in Figure 6.
Embodiment 3
The comparison of the bioavailability of preparation 1 and conventional formulation
Being determined in the healthy dog body of bioavailability carried out.
On the healthy dog of 4 acceptance two kinds of different fenofibrate formulations of same dosage (being preparation, ordinary preparation), study, adopt the cross matching of binary cycle two preparations.Between taking for twice, there is one period clean phase of minimum 7 days.The sample that is used for pharmacokinetic analysis is collected by the following time after each administration.Sample time, two kinds of preparations had nothing in common with each other.Preparation 1 is: 0h, 3h, 5h, 7h, 10h, 11h, 12h, 13h, 15h, 17h, 18h, 19h, 24h.Conventional formulation is: 0h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 12h, 14h, 24h.Measure the content of the active metabolite fenofibrate acid of the fenofibrate in the blood plasma.The result who is obtained provides in following table and figure (Fig7):
| Preparation | Dosage (mg/kg) | ????C max???Ug/ml | ????t max????h | ????t 1/2????h | ???AUC 0-24???Ug*h/ml |
| Preparation 1 | ????13.3 | ????8.01 | ????11 | ????31.6 | ????61.6 |
| Conventional formulation | ????13.3 | ????3.82 | ????4 | ????20.8 | ????16.88 |
C
Max: maximum plasma drug level
t
Max: reach C
MaxTime
t
1/2: drug plasma is eliminated the half-life
AUC
0-24: area under a curve during from the 0-24h medicine
The result clearly illustrates that: by the bioavailability of preparation 1 of the present invention apparently higher than conventional formulation.For the bioavailability that conventional formulation obtained, preparation 1 of the present invention has shown significantly improving of effective ingredient bioavailability.Simultaneously, t
MaxProlong to some extent, show that preparation 1 of the present invention has the feature that delays to discharge.
Claims (9)
1, a kind of fenofibrate compositions, said composition contains fenofibrate and the inert excipients of particle mean size≤5 μ m.
2, the compositions of claim 1, wherein, the mean diameter of fenofibrate is 100nm-5 μ m in the said composition.
3, according to the compositions of claim 1 or 2, wherein inert excipients is selected from excipient and binding agent, lubricant etc., and excipient is selected from: microcrystalline Cellulose, lactose, starch, silica sol, glyceride, stearic acid, crosslinked polyvinylpyrrolidone, carboxymethyl starch, hydroxypropyl cellulose, hydroxy methocel, hydroxypropyl emthylcellulose, gelatin.
4, claim 1 or 2 compositions, wherein inert excipients is a Pulvis Talci, it accounts for the heavy 30-50% of compositions.
5, the compositions of claim 4, wherein inert excipients comprises that also accounting for compositions weighs 2% the 75%HMPC alcoholic solution as binding agent.
6, according to the compositions of aforementioned arbitrary claim, its dosage form is a capsule, and content is the micropill through 16 orders-24 mesh sieve screening gained.
7, preparation contains the method for compositions of the fenofibrate of mean diameter≤5 μ m, and this method comprises:
A. the fenofibrate granule with mean diameter≤5 μ m mixes with inert excipients;
B. add suitable binding agent, and in High Speed Stirring Machine, make micropill;
C. the micropill of the suitable order number of screening is made capsule preparations.
8, the method for claim 6, wherein the fenofibrate granule of the mean diameter described in a≤5 μ m obtains by the conventional fenofibrate of comminution by gas stream.
9, the method for claim 6, wherein suitable order number is the 16-24 order described in the c.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021535361A CN100367947C (en) | 2002-12-04 | 2002-12-04 | Pharmaceutical composition containing fenofibrate with high efficacy for hyperlipemia, its preparation method and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021535361A CN100367947C (en) | 2002-12-04 | 2002-12-04 | Pharmaceutical composition containing fenofibrate with high efficacy for hyperlipemia, its preparation method and use |
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| Publication Number | Publication Date |
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| CN1504187A true CN1504187A (en) | 2004-06-16 |
| CN100367947C CN100367947C (en) | 2008-02-13 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134018B (en) * | 2006-07-18 | 2011-09-07 | 安徽省现代中药研究中心 | Fenofibrate pellet and method for preparing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2602423B1 (en) * | 1986-08-08 | 1989-05-05 | Ethypharm Sa | PROCESS FOR THE PREPARATION OF A FENOFIBRATE-BASED MEDICINAL PRODUCT, OBTAINED BY THIS PROCESS |
| FR2627696B1 (en) * | 1988-02-26 | 1991-09-13 | Fournier Innovation Synergie | NEW GALENIC FORM OF FENOFIBRATE |
| FR2758459B1 (en) * | 1997-01-17 | 1999-05-07 | Pharma Pass | FENOFIBRATE PHARMACEUTICAL COMPOSITION HAVING HIGH BIODAVAILABILITY AND PROCESS FOR PREPARING THE SAME |
| FR2795961B1 (en) * | 1999-07-09 | 2004-05-28 | Ethypharm Lab Prod Ethiques | PHARMACEUTICAL COMPOSITION CONTAINING MICRONIZED FENOFIBRATE, A SURFACTANT AND A BINDING CELLULOSIC DERIVATIVE AND PREPARATION METHOD |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134018B (en) * | 2006-07-18 | 2011-09-07 | 安徽省现代中药研究中心 | Fenofibrate pellet and method for preparing the same |
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