Patent Application
20110311619
The present invention relates to a novel pharmaceutical composition containing fenofibrate. Fenofibrate, also known as 1-methylethyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoate, is a lipid-regulating agent. It has a molecular weight of 360.83 g/mol and a melting point in the crystalline state between 79° C. and 82° C.
Fenofibrate is recommended in the treatment of adult endogenous hyperlipidemia, hypercholesterolemia and hypertriglyceridemia. A treatment of 300 mg to 400 mg of fenofibrate per day enables a 20% to 25% reduction of cholesterolemia and a 40% to 50% reduction of triglyceridemia to be obtained.
The major fenofibrate metabolite in the plasma is fenofibric acid, which is the active form of fenofibrate. The melting point of fenofibric acid in the crystalline state is between 179° C. and 183° C. The plasma elimination half-life of fenofibric acid is roughly 20 hours. Its maximum plasma concentration is reached, on average, five hours after ingestion of the drug. The mean plasma concentration is roughly 15 μg/ml for a dose of 300 mg fenofibrate per day. This level is stable throughout the treatment.
Fenofibrate is a very slightly water-soluble active ingredient whose absorption in the digestive tract is limited. An increase in its solubility or its rate of solubilization results in better digestive absorption.
Because of this low affinity for water and its hydrophobic nature, fenofibrate is absorbed better after the ingestion of food compared to under conditions of fasting. This phenomenon is called the food effect. It is particularly important when the absorption of fenofibrate taken with a fatty meal is compared to the absorption of fenofibrate under conditions of fasting.
The principal disadvantage of the food effect is that the patient's diet must be monitored during the treatment. Moreover, as fenofibrate is absorbed better with a fatty meal, it is usually taken after a fatty meal, which is incompatible with a treatment for hyperlipidemia, hypercholesterolemia or hypertriglyceridemia.
Various approaches have been explored in order to increase the rate of solubilization of fenofibrate: micronization of the active ingredient, addition of a surfactant, comicronization of fenofibrate with a surfactant and submicronization of fenofibrate.
Patent EP256933 describes fenofibrate granules in which the fenofibrate is micronized in order to increase its bioavailability. The crystalline fenofibrate microparticles are less than 50 μm in size. The binder used is polyvinylpyrrolidone. The document suggests other types of binder, such as methacrylic polymers, cellulose derivatives and polyethylene glycols. The granules described in the examples of EP256933 are obtained by a method using organic solvents.
Patent EP330532 proposes improving the bioavailability of fenofibrate by comicronizing it with a surfactant, such as sodium lauryl sulfate. The comicronizate is then granulated by wet granulation in order to improve the flow capacities of the powder and to facilitate the transformation into gelatin capsules. This comicronization enables a significant increase in bioavailability compared to the use of fenofibrate described in EP256933. The granules described in EP330532 contain polyvinylpyrrolidone as a binder.
This patent teaches that the comicronization of fenofibrate with a solid surfactant significantly improves the bioavailability of the fenofibrate compared to the use of a surfactant, of micronization or of the combination of a surfactant and of micronized fenofibrate.
Patent WO98/31361 proposes improving the bioavailability of the fenofibrate by attaching to a hydrodispersible inert support micronized fenofibrate, a hydrophilic polymer and, optionally, a surfactant. The hydrophilic polymer, identified as polyvinylpyrrolidone, represents at least 20% by weight of the composition described above.
This method makes it possible to increase the rate of dissolution of the fenofibrate, and also its bioavailability. However, the preparation method of that patent is not entirely satisfactory since it requires the use of a considerable amount of PVP and of the other excipients. The example presented in that patent application refers to a composition containing only 17.7% of fenofibrate expressed as a mass ratio. This low mass ratio for fenofibrate leads to a final form which is very large in size, hence a difficulty in administering the desired dose of fenofibrate, or the administration of two tablets.
Application WO2004/041250 relates to fibrate compositions comprising fibrate particles of submicron average size smaller than 2000 nm.
The nanonization of fenofibrate makes it possible to further improve its dissolution profile. However, several disadvantages result from this decrease in size. The nanonized particles are not stable and tend to agglomerate. In addition, grinding at roughly nanometer dimensions has a high risk of changing the crystalline form of the active ingredient from a polymorphic form to an amorphous form. However, the amorphous form is less stable than the crystalline form and will evolve into the crystalline form over time with a potential impact on the dissolution behavior in humans.
It was discovered in the context of the present invention that the conditions of wet milling enabling the production of nanonized fenofibrate can be optimized in order to maintain the fenofibrate in crystalline form during grinding and to obtain greater bioavailability and stability while preserving the absence of the food effect.
The present invention thus relates to an aqueous suspension containing fenofibrate and/or fenofibric acid in suspension, a cellulose derivative as a solubilization adjuvant and a surfactant, wherein the fenofibrate and/or the fenofibric acid are in crystalline form with melting points in differential scanning calorimetry (DSC) of 79° C. to 82° C. and 179° C. to 183° C., respectively, and the average particle size (D50) of the fenofibrate and/or the fenofibric acid is less than 250 nm, preferably 180 nm. Differential scanning calorimetry is used to characterize the melting or crystallization points of crystalline solids, or the vitreous transition temperatures of amorphous solids.
Preferably, the aqueous suspension of the invention comprises fenofibrate or fenofibric acid.
Preferably, 90% of the particles (D90) have a size less than 500 nm, preferably 400 nm. The size of the particles is determined by laser diffraction or light scattering particle analysis.
Advantageously, the suspension of the invention further comprises a phospholipid, preferentially soy lecithin.
The addition of a phospholipid to the suspension improves the stability of the suspension. Over time, the suspension sediments. In the absence of phospholipid, its suspension after agitation is difficult or even impossible: the solid phase of the suspension forms a cake that is difficult to disperse. When a phospholipid is added to the suspension, simple agitation makes it possible to suspend the solid phase. The phospholipid also has the advantage of enabling the formation of micelles in water, promoting the availability of the fenofibrate for absorption.
Advantageously, the proportion of phospholipid in the suspension of the invention is between 0.25% and 10%, preferably between 0.3% and 5%, more preferably between 0.5% and 1%, by weight of the suspension.
Advantageously, the total proportion of the fenofibrate and the fenofibric acid in the suspension of the invention is between 10% and 20%, preferably between 12% and 17%, by weight of the suspension.
The binding cellulose derivative represents between 0.1% and 10%, preferably between 1% and 5%, by weight of the composition.
Advantageously, the cellulose derivative is hydroxypropyl methylcellulose (HPMC).
Hydroxypropyl methylcellulose is preferably chosen, the apparent viscosity of which is between 3 mPa·s (cP) and 15 mPa·s (cP), and even more preferably between 3 mPa·s (cP) and 6 mPa·s (cP), such as for example Pharmacoat 603®.
The surfactant is selected from surfactants that are solid or liquid at room temperature, for example sodium lauryl sulfate, Polysorbate 80 or Montane 20, preferably sodium lauryl sulfate.
The ratio of the fenofibrate and/or the fenofibric acid to the HPMC is preferably between 5:1 and 15:1.
The surfactant represents between 0.1% and 3%, preferably between 0.3% and 1%, by weight relative to the weight of the suspension.
The suspension of the invention may also contain at least one excipient such as antifoaming agents, for instance dimethicone and simethicone.
The present invention also relates to a method for preparing the suspension of the invention, comprising the following steps:
This method for preparing the suspension, consisting of adding part of the cellulose derivative before grinding and the remainder after grinding, is advantageous. Indeed, it makes it possible to limit the viscosity of the suspension and to improve the effectiveness of the grinding.
The proportion of cellulose derivative mixed in step (a) advantageously is between 20% and 40%, preferentially roughly 30%, of the quantity of the cellulose derivative in the final suspension.
Step (a) can be broken down into a step of addition of the cellulose derivative and agitation until complete dissolution, a step of addition of the surfactant and agitation until complete dissolution, and, optionally, a step of addition of the phospholipid and agitation until complete dispersion. These steps can occur in any order. Preferentially, the cellulose derivative is added before the surfactant.
Grinding is carried out in the presence of beads. They are preferentially made of polymer, advantageously of polystyrene or zirconium and/or yttrium oxide. Their diameter is between 0.1 mm and 0.8 mm, preferentially between 0.2 mm and 0.6 mm.
The chamber of the mill is filled to at least 70% capacity with beads, preferentially at least 80% capacity. The temperature of the product during grinding is maintained below 35° C., preferentially 30° C. Advantageously, the particle size distribution is measured using laser diffraction or light scattering each hour and grinding is stopped when the diameter decreases no further.
The suspension preparation method of the invention can comprise one or more steps of addition of antifoaming agent, advantageously dimethicone and/or simethicone. These steps can occur before or after grinding. Preferentially, at least one step of addition of antifoaming agent is carried out before grinding to limit or to avoid the formation of foam during grinding.
The present invention also relates to a method for preparing microgranules or granules of fenofibrate and/or fenofibric acid comprising one or more layers of the suspension of the invention, advantageously two layers.
Preferably, the microgranules or granules of the invention comprise fenofibrate or fenofibric acid.
Microgranules are spherical supports on which a suspension of active ingredient can be sprayed. They can be of any chemical nature and preferentially contain sugar and starch, cellulose, or magnesium aluminosilicate.
Granules are particles of more or less irregular shape obtained by the spraying of an active ingredient on an excipient in a more or less fine powder state or by a wet granulation method.
According to a first variant, the microgranules or granules of fenofibrate and/or fenofibric acid of the invention are prepared by one or more assemblies, advantageously two, of the suspension of the invention on neutrals.
Neutral microgranules have a particle size between 200 microns and 1000 microns, preferably between 400 microns and 600 microns.
The assembly is carried out in a sugar-coating pan, in a perforated coating pan or in a fluidized bed, preferably in a fluidized bed.
The assembly on neutral microgranules can be carried out by spraying an aqueous suspension of the invention.
The microgranules of the invention assembled on neutrals are particularly suited to the preparation of capsules. The microgranules of the invention assembled on neutrals advantageously comprise an overcoating step after the assembly steps, and preferentially a lubrication step after the overcoating step.
The layer of overcoating preferentially consists of a cellulose derivative, advantageously of HPMC. The proportion of overcoating cellulose derivative in the overcoating composition is at least 3%.
The preferred lubricant is talc.
According to a second variant, the granules of fenofibrate and/or fenofibric acid of the invention are prepared by assembly on granules of excipient.
Suitable excipients comprise sugars, preferentially lactose, and microcrystalline cellulose, for example Avicel PH200.
The excipients used are preferentially excipients known to those persons skilled in the art to have good properties of compression, namely excipients used to prepare granules intended to be compressed.
The second variant of the preparation of granules of fenofibrate and/or fenofibric acid of the invention is thus particularly suited to the preparation of granules intended for the preparation of tablets.
Another object of the invention relates to microgranules or granules of fenofibrate and/or fenofibric acid which can be obtained by the method for preparing microgranules or granules of fenofibrate and/or fenofibric acid of the invention.
The microgranules or granules of fenofibrate and/or fenofibric acid of the invention advantageously comprise between 1% and 10%, preferably between 3% and 6%, by weight of phospholipid.
The microgranules or granules of fenofibrate and/or fenofibric acid of the invention advantageously comprise more than 60% by weight of fenofibrate.
The microgranules or granules of fenofibrate and/or fenofibric acid of the invention advantageously comprise between 1% and 10%, preferably between 3% and 5%, by weight of surfactant.
The microgranules or granules of fenofibrate and/or fenofibric acid of the invention advantageously comprise between 7% and 20%, preferably between 10% and 15%, by weight of cellulose derivative, advantageously of hydroxypropyl methylcellulose, as a binder and a solubilization adjuvant.
The microgranules or granules of fenofibrate and/or fenofibric acid of the invention advantageously comprise between 0% and 5%, preferably between 1% and 3%, by weight of lubricant.
The microgranules or granules of fenofibrate and/or fenofibric acid of the invention advantageously comprise between 0% and 7%, preferably between 0% and 3%, by weight of antifoaming agent.
The microgranules of fenofibrate and/or fenofibric acid of the invention advantageously comprise, from the interior toward the exterior:
The granules of fenofibrate and/or fenofibric acid advantageously comprise, from the interior toward the exterior:
The invention also relates to a solid dosage pharmaceutical formulation comprising the microgranules or granules of fenofibrate and/or fenofibric acid of the invention.
Preferably, the solid dosage pharmaceutical formulation of the invention comprises the microgranules or granules of fenofibrate or fenofibric acid of the invention.
The pharmaceutical formulation of the invention advantageously comprises the microgranules or granules of fenofibrate of the invention in a quantity equivalent to a dose of fenofibrate between 20 mg and 200 mg, preferably between 110 mg and 145 mg, in a particularly preferred manner between 110 mg and 120 mg or between 30 mg and 40 mg, for example equal to 115 mg, 120 mg, 130 mg or 145 mg.
The pharmaceutical formulation of the invention comprising the microgranules or granules of fenofibrate of the invention advantageously has the following pharmacokinetic parameters:
(a) AUC∞ between 105000 and 180000 ng h/ml, and
(b) Cmax between 6500 and 12000 ng/ml,
with Cmax signifying the maximum plasma concentration expressed in ng/ml, and AUC∞ signifying the area under the curve from 0 to infinity, expressed in ng h/ml.
The pharmaceutical formulation of the invention advantageously comprises the microgranules or granules of fenofibric acid of the invention in a quantity equivalent to a dose of fenofibric acid between 18 mg and 180 mg, preferably equal to 135 mg.
The pharmaceutical formulation of the invention is provided in the form of capsules, of orodispersible tablets or of tablets.
For the gelatin capsule form, the microgranules of fenofibrate and/or fenofibric acid are prepared according to the first variant. The suspension of the invention is layered on neutrals, in one or more layers, and then the microgranules are coated with an external layer of overcoating before their lubrication.
For the tablet form, the granules of fenofibrate and/or fenofibric acid of the invention are prepared according to the second variant. The suspension of the invention is assembled on granules of excipient and then the granules are mixed with compression adjuvants such as disintegrants, diluents, binders and lubricants.
Among disintegrants, cross-linked carboxymethyl cellulose derivatives, polyvinylpyrrolidone derivatives and starch derivatives are preferred.
Diluents include sugars, preferentially lactose, and cellulose derivatives, notably microcrystalline cellulose.
Among lubricants, magnesium stearate and sodium stearyl fumarate are preferred.
The invention also relates to a pharmaceutical formulation of fenofibrate and/or fenofibric acid of the invention for the treatment of hypertriglyceridemia, hypercholesterolemia or hyperlipidemia.
Advantageously, said treatment has the same pharmacokinetic profile of fenofibrate and/or of fenofibric acid whether the patient has consumed a high-fat meal or has fasted.
The invention also relates to the use of the microgranules or granules of the invention for the manufacture of a drug intended for the treatment of hypertriglyceridemia, hypercholesterolemia or hyperlipidemia.
The invention is illustrated in a nonrestrictive way by the following examples.
The formula of the suspension is as follows:
Grinding is carried out in a Netzsch Labstar LS1 wet mill loaded to 88% capacity with 0.3 mm diameter ZrO2 Y2O3 beads. The grinding parameters are presented below.
The average diameter of the fenofibrate after 5 h of grinding is 180 nm. The viscosity of the suspension decreases during the process, which is a sign of the alteration of the chains of the HPMC (see
In this state, the suspension does not have a sufficient binding capacity to be able to be sprayed on the granules to obtain an acceptable content.
Removing part of the HPMC yields a less viscous suspension whose viscosity does not change during milling. The residual HPMC is added after grinding, thus preserving its binding capacity.
1. Formula
The formula of the assembly suspensions and information on the raw materials used are presented in table 1. Three suspensions are successively milled. Part of the HPMC (30%) is introduced before milling. The remaining 70% is added after milling.
2. Particle Size Measurements
The suspensions of fenofibrate were analyzed by measuring particle size after milling.
The results are presented in table 2.
Grinding of the fenofibrate suspension is carried out with a Netzsch Labstar LS1 mill equipped with 0.2 mm diameter ZrO2 Y2O3 beads.
The useful volume of the grinding chamber is 0.57 liters. The grinding chamber was filled to 90% capacity with the beads.
The principal grinding parameters are summarized in table 3.
The suspension of step A is assembled on neutrals.
Two or three successive grindings-assemblies are performed to obtain the desired content. The microgranules obtained are lubricated with talc.
The theoretical formula of the granules is indicated in table 4.
The assembly of the fenofibrate suspension is carried out in a GPCG1 fluidized bed.
Lubrication is carried out in a conventional coating pan with 0.5% talc relative to the mass of the granules produced.
The principal parameters of assembly and drying are summarized in table 5.
The principal analytical results are summarized in table 6.
It can be observed in
The grinding suspensions are prepared in the same way as before: the beads used are 0.2 mm in diameter. The temperature during grinding is maintained below 30° C.
The theoretical formula of the granules is indicated in table 7.
The assembly of the suspension of nanonized fenofibrate is carried out in a GPCG1 fluidized bed.
Lubrication is carried out in a conventional coating pan with 0.5% talc relative to the mass of the granules produced.
The principal parameters of assembly and drying are summarized in table 8.
The characteristics of the granules obtained are presented in table 9.
The two-assembly microgranules are put into #2 capsules (theoretical fenofibrate content: 130 mg).
The two-assembly granules are put into capsules in a content of 130 mg. The content of fenofibrate granules is 475.9 mg/g. The filling mass is thus 273.2 mg of granules per gelatin capsule.
The average mass of the full gelatin capsules is 337.1 mg.
This suspension is ground in a wet mill loaded (80%) with 0.2 mm zirconium oxide beads. Grinding is carried out at low speed (roughly 1500 rpm to 2500 rpm). The temperature of the product is maintained below 35° C.
The suspension is layered on granules of sugar (400-600 μm) in a FBC (GPCG1, Glatt, bottom spray, 1.2 mm), on granules of sucrose (540 μm diameter), on granules of microcrystalline cellulose (Ethispheres 100, Cellets 100, Avicel PH200), or on directly compressible lactose.
Granules of lactose DLC21 are selected for the manufacture of tablets because of their desirable compression and dissolution properties.
The granules containing lactose are compressed with lactose as a diluent, croscarmellose sodium as a disintegrant and magnesium stearate as a lubricant.
The compression parameters are as follows:
1-Comparison of the in vivo release profile of the tablets containing granules with 145 mg of nanonized fenofibrate in fasting subjects (TEST) with that of tablets marketed under the name Lipanthyl® (granules with 145 mg of nanonized fenofibrate) in fasting subjects.
Lipanthyl® is regarded as the reference product.
This study is carried out with 31 subjects. Blood samples are taken at regular time intervals and fenofibric acid is assayed.
The results are presented in tables 19 and 20.
The following abbreviations are used in the present application:
These results show that the composition administered under the “TEST” conditions is bioequivalent to the reference product Lipanthyl® administered to a fasting subject.
The results are represented graphically in
2—Comparison of the in vivo release profile of tablets containing granules with 145 mg of nanonized fenofibrate in fasting subjects (TEST) with that of tablets marketed under the name Lipidil EZ® (granules with 145 mg of nanonized fenofibrate) in fasting subjects.
Lipidil EZ® is regarded as the reference product.
This study is carried out with 19 subjects. Blood samples are taken at regular time intervals and fenofibric acid is assayed.
The results are presented in tables 21 and 22.
These results show that the composition administered under the “TEST” conditions is bioequivalent to the reference product Lipidil EZ® administered to a fasting subject.
The results are represented graphically in
Preparation of the suspension to be milled:
The chamber (1, 1 l) of the HOSOKAWA 90AHM mill is loaded to 80% capacity with 0.36-0.5 mm diameter polystyrene beads. The mill is used in recirculation mode. The grinding power is adjusted to achieve the desired particle size (D50<250 nm).
The system is cooled continuously so that the product temperature does not exceed 45° C.
Grinding efficiency is verified by measurement of the particle size (Malvern Mastersizer 2000HydroS).
The grinding parameters are as follows:
Table 14 presents the quantitative (g) and centesimal (%) formula of the ready-to-spray suspension.
Table 15 presents the centesimal and quantitative formula of the fenofibrate granules.
The manufacturing process consists of:
The assembly is carried out in a fluidized bed to obtain a fenofibrate content of the microgranules greater than 600 mg/g.
The assembly parameters are as follows:
Approximately 1700 g of assembled granules are recovered. They are overcoated with HPMC 606/talc.
The quantitative and centesimal formula of the coating suspension is as follows:
The coating parameters are as follows:
The assembled and overcoated granules are lubricated with 0.5% talc relative to the total mass.
The granules of the step B are put into gelatin capsules in a content of 130 mg.
A. Comparison of the in vivo release profile of capsules containing granules with 130 mg of nanonized fenofibrate and comprising soy lecithin in fasting subjects (Test 1) to that of capsules marketed under the name Antara® (granules with 130 mg of micronized fenofibrate) in subjects having just consumed a low-fat meal.
Antara® is regarded as the reference product.
This study is carried out with 12 subjects. Blood samples are taken at regular time intervals and fenofibric acid is assayed.
The results are presented in table 16.
The following abbreviations are used in the present application:
These results show that the composition administered under the “Test1” conditions is bioequivalent to the reference product Antara® administered in subjects having just consumed a low-fat meal. The reduction in the size of the fenofibrate particles combined with the addition of soy lecithin improved the bioavailability of the product.
B. Comparison of the In vivo Release Profile of Gelatin Capsules Containing the Granules with 130 mg of Nanonized Fenofibrate and Comprising Soy Lecithin in Subjects having just Consumed a Low-fat Meal (Test 2) with that of gelatin Capsules Marketed under the Name Antara® (Granules with 130 mg of Micronized Fenofibrate) in Subjects Having just Consumed a Low-fat Meal.
This study is carried out with 11 and 12 subjects, respectively. Blood samples are taken at regular time intervals and fenofibric acid is assayed.
The results are presented in table 17.
These results show that the composition administered under the “Test2” conditions is bioequivalent to the reference product Antara® administered under the same conditions.
C. Comparison of the In vivo Release Profile of Gelatin Capsules Containing Granules with 130 mg of Nanonized Fenofibrate and Comprising Soy Lecithin in Subjects Having Just Consumed a Low-fat Meal (Test 2) with that of Gelatin Capsules Containing Granules with 130 mg of Nanonized Fenofibrate and Comprising Soy Lecithin in Fasting Subjects (Test 1).
The results are presented in table 18 and
These results show that the composition of gelatin capsules comprising granules of nanonized fenofibrate and soy lecithin is bioequivalent under the two conditions of administration, i.e., fasting and with a low-fat meal.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0859064 | Dec 2008 | FR | national |
This application claims priority to and is a U.S. National Phase Patent Application pursuant to 35 U.S.C. §371 of International Patent Application No. PCT/EP2009/067915, filed on Dec. 24, 2009, and published as WO 2010/081623 on Jul. 22, 2010, which claims priority to French Patent Application No. 0859064, filed on Dec. 24, 2008, the contents of which are incorporated herein by reference in their entireties for all purposes.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP09/67915 | 12/24/2009 | WO | 00 | 9/7/2011 |
