CN102188419A - Single preparations containing fenofibrate and atorvastatin - Google Patents
Single preparations containing fenofibrate and atorvastatin Download PDFInfo
- Publication number
- CN102188419A CN102188419A CN2010101234855A CN201010123485A CN102188419A CN 102188419 A CN102188419 A CN 102188419A CN 2010101234855 A CN2010101234855 A CN 2010101234855A CN 201010123485 A CN201010123485 A CN 201010123485A CN 102188419 A CN102188419 A CN 102188419A
- Authority
- CN
- China
- Prior art keywords
- atorvastatin
- fenofibrate
- single preparation
- hydroxide
- carrier material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides single preparations containing fenofibrate and atorvastatin, comprising fenofibrate particles, atorvastatin enteric particles and pharmaceutically applicable excipients. In the fenofibrate particles, the fenofibrate exists in a highly dispersed form in a carrier material stably. The atorvastatin enteric particles comprise atorvastatin and a stabilizer, wherein the stabilizer is selected from calcium carbonate, calcium hydroxide, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate and sodium hydroxide. The preparations provided by the invention further contain excipients for improving the liquidity and compressibility, comprising a filler, a disintegrant, a lubricant, an adhesive and a flow aid.
Description
Technical field
The invention belongs to field of biological pharmacy, be specifically related to a kind of Pharmaceutical composition that comprises fenofibrate and atorvastatin, it is specially a kind of single preparation, as tablet or capsule.
Background technology
During the clinical treatment hyperlipemia, fibrate and statins are often united use.The two forms complementary effect in the pharmacological action of blood fat reducing, obvious as fibrate triglyceride reducing and increase HDL-C aspect effect, and statins has very positive effect aspect reduction DLD-C and the raising HDL-C.
Fenofibrate has the clinical advantage above the special class of shellfish family other drug as effective lipid regulating agent.Fenofibrate (Fenofibrate) chemical name is 2-(4-(4-chlorobenzene formacyl) phenoxy group)-2 Methylpropionic acid isopropyl ester.Fenofibrate is a kind of prodrug, and the effect through esterase is metabolized to fenofibrate acid rapidly and plays effect for reducing blood fat in vivo, has tangible reduction serum total cholesterol, the effect of total triglyceride and high density lipoprotein increasing.In disclosed 54mg of FDA and 160mg fenofibrate tablet (trade name Tricor) prescription, comprise colloidal silica, crospovidone, lactose monohydrate, lecithin, microcrystalline Cellulose, polyvinyl alcohol, polyvidone, sodium laurylsulfate, sodium stearyl fumarate, Pulvis Talci, titanium dioxide and xanthan gum.And at FDA in the 48mg and the tablet of 145mg of approval in 2004, comprise hypromellose (3cps), docusate sodium, sucrose, sodium laurylsulfate, lactose, silicified microcrystalline cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, Pulvis Talci, soybean phospholipid and xanthan gum.In open source literature, many improvement that relate to fenofibrate stripping or absorption are arranged.Disclose fenofibrate and the common micronization of surfactant as U.S. Pat 4895726 and US5880148, U.S. Pat 6074670 and US6277405 disclose micronized fenofibrate, and it has been coated on the water-solubility carrier that contains optional surfactant.U.S. Pat 6814977 discloses fenofibrate has been dissolved in the medium chain triglycerides of fatty acid, U.S. Pat 6719999 discloses fenofibrate has been dissolved in different third sorbitol anhydride of glycerol, propylene glycol or dimethyl, and U.S. Pat 5827536 discloses fenofibrate is dissolved in the TC.In open source literature, mention particular formulations and the Emulsion and the suspensoid of micronized fenofibrate and particular polymers or surfactant additive.U.S. Patent Application Publication 20040087656 discloses particle diameter less than 2000nm, fenofibrate with bioavailability of improvement.The medicine that U.S. Patent Application Publication 20030224059 discloses the microgranule of active pharmaceutical ingredient and comprised same substance go forward one by one carrier and preparation method.U.S. Patent Application Publication 20040198646 discloses the compositions of the menthol solutions that comprises medicine, especially for the relatively poor medicine of dissolubility in water, and the method for preparing said composition.
Statins is the HMG-CoA reductase inhibitor, and that uses at present comprises lovastatin, fluvastatin, rosuvastatin, pravastatin, atorvastatin and simvastatin.Atorvastatin is synthetic lipid lowerers, and its calcium salt of clinical use or magnesium salt can be crystalline form or amorphous form or crystalline and unbodied mixed form.Atorvastatin calcium be white to the canescence crystalline powder, in pH4 and following water solublity aqueous solution, can not dissolve, atomic molten in water, pH7.4 phosphate buffer and acetonitrile, slightly soluble in ethanol, easily molten in methanol.The oral post-absorption of atorvastatin is rapid, and tmax is 1-2 hour, degree of absorption and the increase in direct ratio of atorvastatin dosage.The absolute bioavailability of atorvastatin is about 14%.
In existing open source literature, the use of uniting of mentioning this two classes medicine is arranged.The fenofibrate in single dosage form and the combination of statins are disclosed as WO2005034908.But known some statins is easy to degraded and/or oxidation when being subjected to disadvantageous physics and/or electrochemical conditions, and the medicine of optimized combination can require each active substance that different release performances is arranged.
Therefore, need provide a kind of single preparation that comprises fenofibrate and statins, it is stable that active component wherein can keep, and obtain ideal bioavailability.
Summary of the invention
The object of the invention provides a kind of single preparation that comprises fenofibrate and statins.
The present invention is achieved through the following technical solutions:
(1) fenofibrate granule
The high degree of dispersion of fenofibrate reaches by certain preparation technique.The present invention preferably adopts suitable solubilization carrier, makes fenofibrate to reach the purpose same with micronized medicine, promptly obtain higher medicine dispersion with the form stable existence of high degree of dispersion in carrier material, increases the stripping of medicine.
Be applicable to that carrier material of the present invention can be divided into water solublity, slightly solubility and enteric solubility three major types, can separately or unite use.Preferentially select following a few class for use: polyethylene glycols, polyvidone class, surfactant-based, the water-soluble cellulose derivative that contains polyoxyethylene groups, organic acid and saccharide and alcohols, these a few class carriers can separately or be united use.
Several schemes that carrier is selected are specifically described below, but are not construed as limiting the invention, and as known to those skilled in the art, carry out simple prescription screening and optimization of preparation, and carrier material and preparation method can be replaced.
Polyethylene glycols (PEG) has good water-solubility, also can be dissolved in multiple organic solvent, medicine is existed with molecularity, and in preparation process, because solvent evaporation, and viscosity increases suddenly, can hinder medicine assembles, the molecular weight of PEG that is used for solid dispersion is generally between 1000-20000, using always has PEG2000, PEG4000, PEG6000, PEG10000, PEG12000, one or more combination among the PEG20000, polyoxyethylene (40) monostearate, stearic acid, or poloxamer class surfactant is normal and the PEG class is united use to regulate the dispersion and the release of medicine.
Polyvidone claims polyvinylpyrrolidone again, acyl (Polyvinylpyrrolidone in the poly-N-vinyl fourth; Povidone; Plasdone; Kollidone; Be called for short PVP).PVP has the stronger brilliant effect that presses down to many medicines, and according to the difference of its molecular weight and the viscosity that shows, specification has PVPk15, PVPk25, PVPk30, PVPk60, PVPk90 etc.With the solid dispersion of PVP as the preparing carriers of medicine, useable solvents method, solvent deposition method or spray drying method.
The water soluble dyes analog derivative also can be used as solubilization carrier.An embodiment is that hydroxypropyl emthylcellulose (HPMC) and polyoxyethylene polyoxypropylene glycol are used as carrier material, the weight ratio of medicine, HPMC, polyoxyethylene polyoxypropylene glycol is 1: 3-5: 0.2-0.5, arrive, HPMC and polyoxyethylene polyoxypropylene glycol are dissolved in the mixture of ethanol/acetone/water, medicine is added wherein, mix homogeneously is sprayed onto the solution that makes on the celphere in the fluid bed, thereby makes the granule of solid dispersion compositions.In this scheme, solvent for use is selected following one or more mixture: methanol, ethanol, isopropyl alcohol, acetone, dichloromethane, water and their mixture.
The saccharide and the alcohols that can be used for preparing solid dispersion have: dextrose, galactose, sucrose, mannitol, sorbitol, xylitol etc.A plurality of hydroxyls are arranged in the molecule of these materials, can generate solid dispersion with medicine with hydrogen bonded.At the medicine among the present invention, preferred mannitol is as main carrier.
Freeze-drying also is applicable to the preparation of described solubilizing composition.As select for use polyoxyethylene (40) stearate, poloxamer 188, HPMC, PVPk29/32, glucide as the solubilization carrier material, the weight ratio that feeds intake of medicine and carrier material is 1: 5-1: 20, medicine and carrier material are dissolved in the organic solvent (dehydrated alcohol, dichloromethane, 70% ethanol), stir, make dissolving, carry out lyophilization, freeze-drying time is 24-48 hour, take out, cross 80 mesh sieves, promptly get solid dispersion.
As known to those skilled in the art, the preparation solid dispersion carrier be not limited to above-mentioned carrier, as gelatin hydrolysate, surfactant-based also be to be applicable to the present invention program.
Can be used as the intermediate of preparation as the above-mentioned prepared carrier that contains the fenofibrate of high degree of dispersion, add pharmaceutically acceptable carrier and make other solid preparations, as powder, granule, pellet, tablet, capsule, lozenge etc.These pharmaceutically acceptable carriers comprise aforementioned excipient, as can be used as starch and derivant, cellulose derivative, sucrose, mannitol, silicic acid and the calcium hydrogen phosphate of filler; As MC, HPC, gelatin, the PVP of binding agent, the optional self-crosslinking CMC-Na of disintegrating agent, PVPP, L-HPC, lubricant can be selected from magnesium stearate and Pulvis Talci; Correctives can be selected from the stevioside, A Siba is sweet and other essence, but is not limited thereto.
Another technical scheme comprises, the carrier that contains the fenofibrate of high degree of dispersion can be adsorbed in water solublity or water-soluble solid carrier.Water miscible as sucrose, lactose, Sorbitol, water-insoluble such as starch, cellulose, microcrystalline Cellulose or calcium phosphate.The powder of Xing Chenging can be chosen wantonly with the medicated premix of standard and mix like this, flows or other character helping, and can be filled in hard gelatin capsule or its equivalent.In another preferred embodiment, these powder can randomly mix with the drug excipient of standard and prepare and are used for being pressed into tablet or forming the fusing tablet at tablet machine.
The present invention also is adapted to other fibrates, comprises any salt or ester, bezafibrate, binifibrate, clinofibrate, ciprofibrate, chlorine Bei Te, etofibrate, etofylline clofibrate, gemfibrozil, pirifibrate, Ronifibrate and the simfibrate of fenofibric acid, fenofibric acid.
(2) atorvastatin granule
Hydroxy acid form-lactone form the balance and the change kinetics of atorvastatin are that pH highly relies on.Acid catalyzed reaction is reversible, and base catalyzed reactions is actually irreversible.In pH＞6 o'clock, can not detect balancing response and the hydroxy acid form that is highly advantageous to.Therefore, in pharmaceutical composition, set up nearly neutrality or alkalescence environment, can avoid the lactone form of non-activity to occur for atorvastatin, as pH at least greater than 5.
For example, can be with pharmaceutically acceptable inorganic alkaline compound as stabilizing agent.As calcium carbonate, calcium hydroxide, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide, Lithium hydrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide.Its consumption is generally the 5%-60% of pharmaceutical composition, to obtain ideal alkaline environment.When using calcium carbonate, the weight ratio of atorvastatin and calcium carbonate is 1: 1 to 4: 1.
Add other excipient that pharmaceutically are suitable for and be prepared as granule, as can be used as starch and derivant, cellulose derivative, sucrose, mannitol, silicic acid and the calcium hydrogen phosphate of filler; Binding agent comprises arabic gum, alginic acid, agar, calcium carrageenan, sodium carboxymethyl cellulose, microcrystalline Cellulose, dextrin, ethyl cellulose, gelatin, liquid glucose, guar gum, hypromellose, methylcellulose, pectin, PEG, polyvidone, pregelatinized Starch etc., the optional self-crosslinking CMC-Na of disintegrating agent, PVPP, L-HPC, lubricant can be selected from magnesium stearate and Pulvis Talci; Correctives can be selected from the stevioside, A Siba is sweet and other essence, but is not limited thereto.Other adjuvants that can be included in the present composition comprise correctives, coloring agent, odor mask, buffer agent, antiseptic, stabilizing agent, antioxidant, wetting agent, moisture regulator, surfactant etc.
The Statins granule preferably carries out enteric coating.
(3) comprise the single preparation of fenofibrate and atorvastatin
Comprising (one) fenofibrate granule and the particulate pharmaceutical composition of (two) atorvastatin, can be tablet or capsule form.In unit formulation, the dosage that comprises atorvastatin is 5,10,20,40,80mg, and the dosage that comprises fenofibrate is 145,160mg
Below the invention will be further described by the specific embodiment.The specific embodiment does not constitute any limitation of the invention.
The specific embodiment
The particulate preparation of embodiment 1 fenofibrate
Press following prescription:
Fenofibrate 54g
Poloxamer 188 54g
PEG6000 54g
Preparation: take by weighing fenofibrate, poloxamer and PEG6000 by recipe quantity, it is standby that fenofibrate was pulverized 80 mesh sieves; Poloxamer and PEG6000 were pulverized 40 sieves,, fenofibrate was slowly added, be stirred to the drug powder complete obiteration, and placed fridge to place 24 hours for 4 ℃ fused pastille liquid, and pulverized and promptly get the fenofibrate granule 80-90 ℃ of heating in water bath melting.
The particulate preparation of embodiment 2 atorvastatins
Atorvastatin calcium 40g
Calcium carbonate 40g
Microcrystalline Cellulose 80g
Hypromellose 23g
Preparation: take by weighing Atorvastatin calcium, calcium carbonate, microcrystalline Cellulose, hypromellose by recipe quantity, pulverized 80 mesh sieves, uniform mixing, spray grain in fluid bed top is coated with enteric coating with acrylic resin II number, the atorvastatin granule.
The preparation of the single preparation of embodiment 3 fenofibrate and atorvastatin
Granule mix homogeneously with the foregoing description 1 and 2 obtains adds an amount of magnesium stearate, mix homogeneously, tabletting.
Claims (10)
1. comprise the single preparation of fenofibrate and atorvastatin, it is characterized in that, comprise fenofibrate granule and atorvastatin enteric coated particles, and the excipient that pharmaceutically is suitable for.
2. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 1 is characterized in that, in the fenofibrate granule, fenofibrate is that form stable existence with high degree of dispersion is in carrier material.
3. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 2, it is characterized in that, described carrier material is the water-solubility carrier material, be selected from polyethylene glycols, polyvidone class, contain surfactant-based, water-soluble cellulose derivative, organic acid and the saccharide and the alcohols of polyoxyethylene groups, these a few class carriers can separately or be united use.
4. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 3 is characterized in that, described carrier material is selected among PEG2000, PEG4000, PEG6000, PEG10000, PEG12000, the PEG20000 one or more combination.
5. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 3 is characterized in that, described carrier material is selected from one or more the combination among PVPk15, PVPk25, PVPk30, PVPk60, the PVPk90.
6. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 3 is characterized in that described carrier material is selected from dextrose, galactose, sucrose, mannitol, sorbitol, xylitol etc.
7. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 1 is characterized in that described atorvastatin enteric coated particles comprises atorvastatin and stabilizing agent.
8. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 7, it is characterized in that described stabilizing agent is selected from calcium carbonate, calcium hydroxide, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide, Lithium hydrate, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide.
9. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 7 is characterized in that described stabilizing agent dosage is the 5%-60% of pharmaceutical composition weight; When using calcium carbonate, the weight ratio of atorvastatin and calcium carbonate is 1: 1 to 4: 1.
10. the single preparation that comprises fenofibrate and atorvastatin as claimed in claim 3, it is characterized in that the described excipient that pharmaceutically is suitable for comprises can further containing to have and improves liquidity and the excipient of compressibility comprises filler, disintegrating agent, lubricant, binding agent, fluidizer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101234855A CN102188419A (en) | 2010-03-12 | 2010-03-12 | Single preparations containing fenofibrate and atorvastatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101234855A CN102188419A (en) | 2010-03-12 | 2010-03-12 | Single preparations containing fenofibrate and atorvastatin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102188419A true CN102188419A (en) | 2011-09-21 |
Family
ID=44597854
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101234855A Pending CN102188419A (en) | 2010-03-12 | 2010-03-12 | Single preparations containing fenofibrate and atorvastatin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102188419A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102424653A (en) * | 2011-12-27 | 2012-04-25 | 海南锦瑞制药股份有限公司 | Fenofibrate compound and atorvastatin calcium fenofibrate pharmaceutical composition thereof |
| CN107998085A (en) * | 2017-11-29 | 2018-05-08 | 乐普制药科技有限公司 | A kind of tablet containing Atorvastatin calcium alkali solid dispersion and preparation method thereof |
| WO2022071787A1 (en) | 2020-09-29 | 2022-04-07 | Laboratorios Silanes S.A. De C.V. | Pharmaceutical combinations of statins and fibrates for the treatment and prevention of hyperlipidaemia and cardiovascular diseases |
-
2010
- 2010-03-12 CN CN2010101234855A patent/CN102188419A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102424653A (en) * | 2011-12-27 | 2012-04-25 | 海南锦瑞制药股份有限公司 | Fenofibrate compound and atorvastatin calcium fenofibrate pharmaceutical composition thereof |
| CN102424653B (en) * | 2011-12-27 | 2014-10-15 | 海南锦瑞制药股份有限公司 | Fenofibrate compound and atorvastatin calcium fenofibrate pharmaceutical composition thereof |
| CN107998085A (en) * | 2017-11-29 | 2018-05-08 | 乐普制药科技有限公司 | A kind of tablet containing Atorvastatin calcium alkali solid dispersion and preparation method thereof |
| WO2022071787A1 (en) | 2020-09-29 | 2022-04-07 | Laboratorios Silanes S.A. De C.V. | Pharmaceutical combinations of statins and fibrates for the treatment and prevention of hyperlipidaemia and cardiovascular diseases |
| EP4180036A4 (en) * | 2020-09-29 | 2024-01-31 | Laboratorios Silanes S A De C V | Pharmaceutical combinations of statins and fibrates for the treatment and prevention of hyperlipidaemia and cardiovascular diseases |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2010201739B2 (en) | A stable pharmaceutical composition comprising a fixed dose combination of fenofibrate and an HMG-CoA reductase inhibitor | |
| US20180325825A1 (en) | Gemcabene combinations for the treatment of cardiovascular disease | |
| JP5677391B2 (en) | Pharmaceutical formulations with excellent light stability | |
| JP5560188B2 (en) | New process for producing water-dispersible dry pharmaceutical product and pharmaceutical composition obtained thereby | |
| JP5322039B2 (en) | Sustained release oral administration of phenylalanine derivatives | |
| PL217835B1 (en) | Pharmaceutical preparation containing atorvastatin calcium salt, process for the production of this preparation and its use for the treatment of hypercholesterolemia and hyperlipidemia | |
| CN101115478A (en) | A stable pharmaceutical composition comprising a fixed dose combination of fenofibrate and an HMG-CoA reductase inhibitor | |
| CN102188419A (en) | Single preparations containing fenofibrate and atorvastatin | |
| EP2575757A1 (en) | Water soluble formulation comprising a combination of amlodipine and a statin | |
| CN101912612A (en) | Dispersible tablet containing fibrate and statin drug and application thereof | |
| ES2342885T3 (en) | STABLE CONTROLLED RELEASE PHARMACEUTICAL COMPOSITIONS CONTAINING PHENOFIBRATE AND PRAVASTATIN. | |
| US8062664B2 (en) | Process for preparing formulations of lipid-regulating drugs | |
| EP4115879A1 (en) | Pharmaceutical composition comprising hmg-coa reductase inhibitors and fenofibrate | |
| EP1404303A1 (en) | Stable pharmaceutical compositions containing pravastatin | |
| CN102188398A (en) | Solid preparation containing highly dispersed fenofibrate | |
| WO2012002921A1 (en) | Multiple dosage forms comprising fenofibrate or fenofibric acid in combination with hmg co a reductase inhibitors such as statins | |
| WO2006008757A2 (en) | Stabilized pharmaceutical compositions of pravastatin | |
| MXPA01012225A (en) | Novel formulations comprising lipid-regulating agents. | |
| TWI361080B (en) | ||
| US20060177512A1 (en) | Process for preparing formulations of lipid-regulating drugs | |
| AU2002314915A1 (en) | Stable pharmaceutical compositions containing pravastatin | |
| AU2002312297A1 (en) | Stable controlled release pharmaceutical compositions containing pravastatin | |
| MXPA06000111A (en) | Process for preparing formulations of lipid-regulating drugs. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110921 |