HK1080391B - Pharmaceutical composition comprising fenofibrate and process for its preparation - Google Patents

Description

The present invention relates to a new pharmaceutical composition containing fenofibrate.

Fenofibrate is recommended for the treatment of hyperlipidemia, hypercholesterolemia and endogenous adult hypertriglyceridemia. 300 to 400 mg of fenofibrate daily reduces cholesterol by 20 to 25% and triglyceridemia by 40 to 50%.

The major plasma metabolite of fenofibrate is fenofibric acid. The plasma elimination half-life of fenofibric acid is about 20 hours. Its maximum plasma concentration is reached on average five hours after ingestion of the drug. The average plasma concentration is about 15 micrograms/ml for a 300 mg daily dose of fenofibrate. This level is stable throughout treatment.

Phenofibrate is a very poorly water-soluble active substance with limited absorption in the digestive tract, and increased solubility or rate of solubilization leads to better digestive absorption.

Various routes have been explored to increase the solubilization rate of the phenofibrate: micronisation of the active substance, addition of a surfactant, and co-micronisation of the phenofibrate with a surfactant.

The patent EP 256 933 describes phenofibrate granules in which the phenofibrate is micronized to increase its bioavailability. The crystalline phenofibrate microparticles are less than 50 μm in size. The binder used is polyvinylpyrrolidone. The paper suggests other types of binder such as methacrylic polymers, cellulose derivatives, and glycolylated polethylenes. The granules described in the examples of EP 256 933 are obtained by a process using organic solvents.

Patent EP 330 532 proposes to improve the bioavailability of fenofibrate by co-micronising it with a surfactant, such as sodium lauryl sulfate. The co-micronised is then wet granulated to improve the flow capacities of the powder and facilitate capsulization. This co-micronisation results in a significant increase in bioavailability compared to the use of fenofibrate described in EP 256 933. The granules described in EP 330 532 contain polyvinylpyrrolidone as a binder.

This patent shows that co-micronisation of the phenofibrate with a solid surfactant significantly improves the bioavailability of the phenofibrate compared to the use of a surfactant, micronisation or combination of a surfactant and the micronised phenofibrate.

The patent WO 98/31361 proposes to improve the bioavailability of fenofibrate by attaching to an inert medium which is hydrodispersible to the micronized fenofibrate a hydrophilic polymer and possibly a surfactant.

This process increases the rate of dissolution of fenofibrate and its bioavailability. However, the patented preparation process is not entirely satisfactory as it requires the use of a large amount of PVP and other excipients. The example in this patent application is a composition containing only 17.7% of fenofibrate expressed in mass ratio. This low ratio of fenofibrate to mass ratio results in a very large final form which makes it difficult to administer the desired dose of fenofibrate, or two tablets.

It has been found in the present invention that incorporation of a cellulosic derivative used as a solubilisation binder and adjuvant in a composition containing micronized phenofibrate and a surfactant results in a higher bioavailability than a composition containing a co-micronized phenofibrate and surfactant.

The present invention therefore concerns a pharmaceutical composition containing micronized fenofibrate, a surfactant of hydroxypropylmethylcellulose as a binder and solubilisation adjuvant, characterised by a mass ratio of fenofibrate to hydroxypropylmethylcellulose of 5/1 to 15/1.

The composition of the invention is best presented in powdered or granular capsules, preferably in the form of granules, which may be prepared by mounting on neutral microgranules, by spraying an aqueous suspension containing the surfactant, solubilised hydroxypropylmethylcellulose and the micronized phenofibrate in suspension, or by wet powder granulation, whereby the constituents, including the micronized phenofibrate, the surfactant and the cellulosic derivative, are granulated by wet granulation using an aqueous, dried and calibrated granulation solution.

The pharmaceutical composition according to the present invention has a high proportion of fenofibrate, so it can be presented in a smaller formulation than the earlier art formulas, which makes this composition according to the invention easily administered.

The amount of fenofibrate is equal to or greater than 60% by weight, preferably 70% by weight, preferably even more than 75% by weight, of the composition.

In the present invention, the phenofibrate is not co-micronized with a surfactant, but is instead micronized alone and then combined with a surfactant and the binding cellulose derivative, a solubilization adjuvant.

The surfactant is chosen from solid or liquid surfactants at room temperature, e.g. sodium lauryl sulphate, Polysorbate® 80 or Montane® 20, preferably sodium lauryl sulphate.

The surfactant is between 1 and 10%, preferably between 3 and 5% by weight of fenofibrate.

The binding cellulosic derivative is between 2 and 15%, preferably between 5 and 12% by weight of the composition.

Hydroxypropylmethylcellulose with an apparent viscosity of 2.4 to 18 mPa (cP) and even more preferably 2.4 to 3.6 mPa (cP) is preferred, such as Pharmacoat 603®.

The average particle size of fenofibrate is less than 15 μm, preferably 10 μm, preferably even less than 8 μm.

The invention may also contain at least one excipient such as diluents such as lactose, foaming agents such as Dimethicone® and Simethicone®, lubricants such as talc.

The pharmaceutical composition of the invention is advantageously granular in an amount equivalent to a dose of fenofibrate between 50 and 300 mg, preferably 200 mg.

The present invention also relates to a process for preparing the powder or granules of the composition described above, which does not use any organic solvent.

The first variant is that the granules are prepared by mounting them on neutral microgranules.

Neutral microgranules have a particle size of between 200 and 1000 microns, preferably between 400 and 600 microns.

The installation is carried out in a drag-dredging turbine, a perforated turbine or a fluidised air bed, preferably a fluidised air bed.

The mounting on neutral microgranules is by spraying an aqueous suspension containing the surfactant, the solubilised binding hydroxypropylmethylcellulose and the micronized phenobarbital in suspension.

The second variant is that the granules are obtained by wet powder granulation, which makes it possible to densify the powders and improve their flow properties, and also to preserve homogeneity by avoiding the unmixing of the various constituents.

The micronized phenofibrate, surfactant, hydroxypropylmethylcellulose and possibly other excipients are mixed, granulated, dried and then calibrated.

In a particular method of application, the phenofibrate and the other excipients are mixed in a planetary mixer. The wetting solution is brought directly into the mixture. The moistened mass obtained is granulated with an oscillating granulator and then dried in the oven. The granules are obtained after passing through an oscillating caliper. Figure 1 represents the in vivo release profile of sample 1C formulation and a prior art formulation in fasting subjects.Figure 2 represents the in vivo release profile of sample 1C formulation and a prior art formulation in newly fed subjects.Figure 3 represents the in vivo release profile of sample 2B formulation and a prior art formulation in fasting subjects.Figure 4 represents the in vivo release profile of comparative sample 3 formulation and a prior art formulation in newly fed subjects.

The invention is illustrated by the following examples.

Example 1: Granules The following information is provided for the purpose of this Regulation:

The microgranules are obtained by spraying an aqueous suspension on neutral nuclei. - What?

Fénofibrate micronisé	64,5
Microgranules neutres	21
HPMC (Pharmacoat 603®)	11,2
Polysorbate® 80	3,3
Teneur en fénofibrate	645 mg/g

The in vitro dissolution is determined by a continuous flow cell method with a flow rate of 8 ml/min of sodium lauryl sulphate at 0,1 N. The percentage of product dissolved over time compared to a previous state of the art formulation, Lipanthyl 200 M, is given in the following table.

Temps (min)	15	30
Exemple 1 A (% dissous)	73	95
Lipanthyl 200M (% dissous)	47,3	64,7

Formulation 1A is more rapidly dissolved than Lipanthyl 200M.

1B) Microgranules (X FEN 1935)

The average particle size of the fenofibrate is 6,9 ± 0,7 microns.

The microgranules are obtained by spraying an aqueous suspension on neutral nuclei.

The assembly is carried out in a Huttlin fluidised air bed (rotoprocess).

The resulting formula is given below. - What?

Fénofibrate micronisé	65,2
Microgranules neutres	20,1
HPMC (Pharmacoat 603®)	11,4
Laurylsulfate de sodium	3,3
Teneur en fénofibrate	652 mg/g

The size of the neutral microgranules is between 400 and 600 μm.

The following information is provided for the purpose of the calculation of the amount of the fine-tuning agent:

Micro granules of the following composition are prepared:

Fénofibrate micronisé	67,1
Microgranules neutres	17,2
Pharmacoat 603® (HPMC)	11,7
Laurylsulfate de sodium	3,3
Emulsion diméthicone 35 %	0,2
Talc	0,5
Teneur en fénofibrate	671 mg/g

In accordance with the procedure described in paragraph 1A).

The resulting microgranules are divided into capsules of size 1, each containing 200 mg of fenofibrate.

In vitro dissolution is determined by a continuous flow cell method with a flow rate of 8 ml/min of sodium lauryl sulphate at 0,1 N. The comparative results with a previous state of the art formulation, Lipanthyl 200M, are presented in the following table. - What?

Temps (min)	15	30
Exemple 1C (% dissous)	76	100
Lipanthyl 200M (% dissous)	47,3	64,7

The 1C formulation is more rapidly dissolving than Lipanthyl 200M.

The granules are stable under these accelerated storage conditions. Dissolution tests in vitro (in continuous flow cells with a flow rate of 8 ml/min of sodium lauryl sulphate at 0,1 N) were performed. The time-dependent percentages of dissolved product for 1, 3 and 6 month stored capsules are given in the following table.

5	25,1	23,0	20,1
15	71,8	65,6	66,5
25	95,7	88,7	91,0
35	104,7	98,7	98,2
45	106,4	100,2	99,1
55	106,7	100,5	99,5
65	106,8	100,6	99,7

The evolution of the active substance content during storage is shown in the following table. - What?

	208,6	192,6	190,8	211,7

Pharmacokinetic study performed in the fasted subject

The in vivo release profile of capsules containing YFEN 01 granules dosed at 200 mg fenofibrate is compared with that of capsules marketed under the brand name Lipanthyl 200M.

This study was conducted in 9 subjects, blood samples were taken at regular intervals and a dose of fenofibric acid was administered.

The results are presented in the following table and Figure 1.

	76	119
(µg.h/ml)
	96	137
(µg.h/ml)
	2,35	4,71
(µg/ml)
	8,0	5,5
(heures)
Ke	0,032	0,028
(1/heure)
Elim ½	26,7	24,9
(heures)
Les abréviations suivantes sont utilisées dans la présente demande :
Ke : constante d'élimination.

The results obtained for Lipanthyl 200 M and for the product in example 1C are shown in Figure 1 by curves 1 and 2 respectively.

These results show that the composition according to the present invention has a higher bioavailability than Lipanthyl 200 M in the fasted subject.

Pharmacokinetic study in the subject after feeding

The in vivo release profile of capsules containing YFEN 01 granules dosed at 200 mg fenofibrate is compared with that of capsules marketed under the brand name Lipanthyl 200 M.

This study involved 18 subjects, blood samples were taken at regular intervals and a dose of fenofibric acid was administered.

The results are presented in the following table and Figure 2. - What?

	244	257
(µg.h/ml)
	255	270
(µg.h/ml)
	12	13
(µg/ml)
	5,5	5,5
(heures)
Ke	0,04	0,04
(1/heure)
Elim ½	19,6	19,3
(heures)

The results obtained for Lipanthyl 200 M and for the product in example 1C are shown in Figure 2 by curves 1 and 2 respectively.

These results show that the composition according to the present invention is bioequivalent to that of Lipanthyl 200M in the subject who has just been fed.

Example 2: Powder 2A) Granules (X FEN 1992)

We prepare pellets of the following composition

Fénofibrate micronisé	71
Lactose	21,5
HPMC (Pharmacoat 603®)	5
Laurylsulfate de sodium	2,5

Micronized fenofibrate, HPCM and lactose are mixed using a planetary blender and granulated in the presence of a solution of sodium lauryl sulphate.

The time to precipitation of the granules is 7 s. The ability to settle and the granulometer distribution are shown in the following tables. - What?

V0	204 ml
V10	186 ml
V500	168 ml
V1250	164 ml
V10-V500	22 ml

0,6	8
0,5	9
0,355	12
0,2	30
0,1	23
0	18

The following shall be reported in the table: • Preparation

The micronized phenofibrate is mixed in a PMA (Niro Fielder) blender with lactose and HPCM, then soaked with an aqueous solution of sodium lauryl sulphate.

The granules are then packed into capsules, size 1, dosed at 200 mg of fenofibrate.

The granules are of the following composition. - What?

Fénofibrate micronisé	70
Lactose	21,5
Pharmacoat 603® (HPMC)	5
Laurylsulfate de sodium	3,5
Teneur	700 mg/g

• Properties of the pellets

The time of flow of the granules is 6 s. The ability to settle and the particle size distribution are shown in the following tables. - What?

V0	216 ml
V10	200 ml
V500	172 ml
V1250	170 ml
V10-V500	28 ml

0,6	5
0,5	7
0,355	11
0,2	30
0,1	25
0	22

The in vitro dissolution is determined by a continuous flow cell method with a flow rate of 8 ml/min of sodium lauryl sulphate at 0,1 N. The comparative results with a previous state of the art formulation, Lipanthyl 200 M, are given in the following table. - What?

Temps (min)	15	30
Exemple 2B (% dissous)	82,2	88,5
Lipanthyl 200 M (% dissous)	47,3	64,7

Formulation 2B is more rapidly dissolved than Lipanthyl 200 M.

• Stability tests

Capsules stored at 40°C / 75% relative humidity are stable for 6 months.

Dissolution tests were performed in vitro (in continuous flow cells with a flow rate of 8 ml/min of sodium lauryl sulphate at 0,1 N).

5	54,2	52,9	49,0
15	81,1	75,8	82,2
25	86,4	79,6	87,2
35	88,8	81,6	89,8
45	90,7	82,9	91,5
55	92,1	83,9	92,7
65	93,2	84,7	93,6

The evolution of the active substance content during storage is shown in the following table. - What?

	196,6	190,0	199,8	203,3

Pharmacokinetic study performed in the fasted subject

The in vivo release profile of capsules containing YFEN 002 granules dosed at 200 mg fenofibrate is compared with that of capsules marketed under the brand name Lipanthyl 200 M.

This study was conducted in 9 subjects, blood samples were taken at regular intervals and a dose of fenofibric acid was administered.

The results are presented in the following table and Figure 3.

	76	70
(µg.h/ml)
	96	82
(µg.h/ml)
	2,35	2,8
(µg/ml)
	8,0	5,5
(heures)
Ke	0 ,032	0,033
(1/heure)
Elim ½	26,7	23,1
(heures)

The results obtained for Lipanthyl 200 M and for the product in example 2B are shown in Figure 3 by curves 1 and 2 respectively.

These results show that the composition of sample 2B is bioequivalent to that of Lipanthyl 200 M in the fasted subject.

Comparative example 3: lot ZEF 001

This example illustrates the earlier art.

It combines the micronisation of the phenofibrate with the use of a surfactant and differs from the present invention by the use of a mixture of binding excipients consisting of a cellulosic derivative other than HPCM: Avicel PH 101 and polyvinylpyrrolidone (PVP K30).

It is prepared by extrusion-sferonization.

• Theoretical formula

Fénofibrate micronisé	75,08
Montanox 80®	4,72
Avicel PH 101®	5,02
PVP K 30®	4,12
Explotab®	11,06

• Profile of dissolution in vitro

In vitro dissolution is determined by a continuous flow cell method with a flow rate of 8 ml/min of sodium lauryl sulphate at 0.1 N. The comparative results with Lipanthyl 200 M are given in the following table. - What?

Temps (min)	15	30
Exemple 3 (% dissous)	24	40
Lipanthyl 200 M (% dissous)	47,3	64,7

Dissolution is slower than that observed for Lipanthyl 200 M.

Pharmacokinetic study performed in the fasted subject

The in vivo release profile of capsules containing ZEF 001 granules dosed at 200 mg fenofibrate is compared with that of capsules marketed under the brand name Lipanthyl 200 M.

This study is performed in 5 subjects on an empty stomach, receiving a single dose, blood samples are taken at regular intervals and a dose of fenofibric acid is given.

The results are presented in the following table and Figure 4. - What?

	92	47
(µg.h/ml)
	104	53
(µg.h/ml)
	3,5	1,7
(µg/ml)
	5,6	4,6
(heures)
Ke	0,04	0,038
(1/heure)
Elim ½	18,9	20,3
(heures)

The results obtained for Lipanthyl 200 M and for the product in Example 3 are shown in Figure 4 by curves 1 and 2 respectively.

These results show the superior bioavailability of Lipanthyl 200 M compared to this formulation based on previous art.

Example 3 shows that the combination of previous state of the art knowledge (i.e. micronisation or use of surfactants) does not allow a rapid dissolution of the fenofibrate, resulting in low bioavailability compared to Lipanthyl 200 M.

The compositions according to the present invention show faster dissolution than the previously used formula and improved bioavailability.

Claims (11)

1. Pharmaceutical composition containing micronized fenofibrate, a surfactant and hydroxypropylmethylcellulose as binder and solubilization adjuvant, characterized in that the fenofibrate/(hydroxypropylmethylcellulose as binder and solubilization adjuvant) ratio by mass is between 5/1 and 15/1.
2. Composition according to Claim 1, characterized in that the hydroxypropylmethylcellulose has an apparent viscosity of between 2.4 and 18 mPa.s (cP), preferably of between 2.4 and 3.6 mPa.s (cP).
3. Composition according to Claim 1 or 2, characterized in that it contains an amount of fenofibrate of greater than or equal to 60% by weight, preferably greater than or equal to 70% by weight, even more preferably greater than or equal to 75% by weight, relative to the weight of the composition.
4. Composition according to any one of the preceding claims, characterized in that the surfactant is chosen from the group formed by polysorbate® 80, Montane® 20 and sodium lauryl sulphate.
5. Composition according to any one of the preceding claims, characterized in that the surfactant represents between 1% and 10%, preferably between 3% and 5% by weight, relative to the weight of the fenofibrate.
6. Composition according to any one of the preceding claims, characterized in that the hydroxypropylmethylcellulose as binder and solubilization adjuvant represents between 2% and 15%, preferably between 5% and 12% by weight of the composition.
7. Composition according to any one of the preceding claims, characterized in that it contains at least one excipient, such as a diluent, for instance lactose, an antifoam agent, for instance Dimethicone® or Simethicone®, or a lubricant, for instance talc.
8. Composition according to any one of the preceding claims, characterized in that the average size of the fenofibrate particles is less than 15 µm, preferably less than 8 µm.
9. Composition according to any one of the preceding claims, characterized in that it is in the form of powder or granules, optionally contained in gelatin capsules.
10. Process for preparing the composition according to any one of the preceding claims, characterized in that granules are prepared by coating on neutral microgranules, by spraying of an aqueous suspension containing the surfactant, the solubilized hydroxypropylmethylcellulose and the micronized fenofibrate in suspension.
11. Process for preparing the composition according to any one of Claims 1 to 9, characterized in that granules are obtained by wet granulation of powder, according to which the constituents, including in particular the micronized fenofibrate, the surfactant and the hydroxypropylmethylcellulose, are granulated by wet granulation using an aqueous wetting solution, dried and calibrated.