HK1131051B - Pharmaceutical composition of phenofibrate with high bioavailability and method for preparing same - Google Patents

Description

The present invention relates to a new pharmaceutical composition with a high bioavailability by higher solubility and its preparation process. The present invention relates in particular to a pharmaceutical composition for oral administration containing an active substance of low aqueous solubility.

Many active substances have the disadvantage of low solubility in water, thus a low solubility profile and therefore low bioavailability in the body after oral administration, and the therapeutic dose to be administered should therefore be increased to avoid this disadvantage, in particular with many lipid-lowering active substances such as those belonging to the fibrate family.

Fenofibrate is a well-known lipid-lowering agent in the fibrate family, marketed in various dosages (100 and 300 mg, e.g. Secalip®), but in a form leading to low bioavailability of the active substance, because of its low water solubility, fenofibrate is poorly absorbed in the digestive tract and therefore has incomplete, irregular and often variable bioavailability from one individual to another.

To improve the solubility profile and bioavailability of fenofibrate and thus reduce the dose to be administered, it would be useful to increase its solubility so that it can reach a level close to 100%.

In addition, for the comfort of the patient, it is advantageous to seek a galenic form that requires only one dose per day and that allows the same effect as that obtained with multiple doses.

A process to improve the bioavailability of fenofibrate is described in patent EP-A-0 330 532. This patent describes the effect of co-micronizing fenofibrate with a surfactant, e.g. sodium lauryl sulfate to improve the solubility of fenofibrate and thus increase its bioavailability. This patent shows that co-micronizing fenofibrate with a solid surfactant can improve the bioavailability of fenofibrate significantly more than the improvement obtained either by adding a surfactant, either by micronizing only fenofibrate or by mixing the fenofibrate and microfibrate separately.

This process according to patent EP-A-0 330 532 leads to a new galenic form where the active substance, co-micronised with a solid surfactant, has an improved phenofibrate dissolution and thus increased bioavailability, which allows, with equal efficacy, a decrease in the daily dose of the drug: 67 mg and 200 mg instead of 100 mg and 300 mg respectively.

However, the preparation process according to this patent is not entirely satisfactory in that it does not lead to complete bioavailability of the active substance and has several disadvantages.

There is therefore a need to improve the bioavailability of fenofibrate to reach, in very short times, a level close to 100% (or in any case above the following limits: 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes in a medium consisting of 1200 ml of water with 2% Polysorbate 80 or 1000 ml of water with sodium lauryl sulphate 0,025 molar, with a pallet rotation rate of 75 t/min), even when low surfactant solvent media are used.

The applicant has shown in a surprising way that it is possible to solve this problem by a new process of preparing a pharmaceutical composition by spraying a suspension of the active substance on an inert water-soluble medium.

The use of polymer such as polyvinylpyrrolidone for the manufacture of tablets is already known, at concentrations of 0.5 to 5% by weight, up to 10% by weight. In this case, polyvinylpyrrolidone is used as a binder. Similarly, the use of polymer such as hydroxymethylpropylmethylcellulose as a binder for granulation is known. Thus, EP-A-0 519 144 describes pellets of a poorly soluble substance, omeprazole, which are obtained by dispersion or suspension of the active substance in a solution containing the said polymer in an inert granulator in a fluidized bed. However, as long as the polymer (HPMC) is still used and only binding granulation, the use of the active substance in the solution is not permitted.The final active substance and polymer content of the final coated pellet is only about 1% by weight of the final coated pellet, and the size of the inert pellets in this document is quite large, which in the case of fenofibrate would lead to a final volume of the formulation which is too large for easy oral administration.

Err1:Expecting ',' delimiter: line 1 column 141 (char 140)

The document WO-A-96 01621 also describes a delayed-effect composition, comprising an inert core (silica in all examples) coated with a layer containing the active substance mixed with a hydrophilic polymer, the active substance/polymer weight ratio being between 10/1 and 1/2 and the active substance/inert core weight ratio being between 5/1 and 1/2, with an external layer to confer the delayed effect. These compositions can be compressed. The hydrophilic polymer may be polyvinylpyrrolidone. The document also describes a process for preparing this composition; for example, in a fluid granulator, a dispersion of the active substance in an inert polymer solution is pulverized. This document only deals with the technical problem of delayed compression, since the delayed effect is not a problem for the compression of the layers.

However, nothing in the state of the art teaches or suggests the present invention.

Thus, the present invention provides an immediate release phenofibrate composition including: (a) an inert water soluble medium coated with at least one layer containing phenofibrate in micronized form with a size of less than 20 μm, a hydrophilic polymer and possibly a surfactant; said hydrophilic polymer representing at least 20% by weight of the weight of element (a); and (b) one or more phases or external layers.

According to one embodiment, a surfactant is present with the fenofibrate and the hydrophilic polymer.

The invention also provides a composition of fenofibrate with a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, as measured according to the European Pharmacopoeia 75 t/min rotary pallet method, in a solution medium consisting of water with 2% by weight of polysorbate 80 or a solution medium consisting of water with 0,025 M of sodium lauryl sulphate.

The invention also concerns a process for preparing a pharmaceutical composition according to the invention, including the steps of: (a) preparation of a phenofibrate suspension in micronized form with a size of less than 20 μm in a solution of hydrophilic polymer and possibly surfactant; (b) application of the suspension of step (a) on an inert water soluble medium; (c) coating of the granules thus obtained by one or more phases or layers.

Step (b) is preferably implemented in a fluidized bed granulator.

The process may include a compression step for the products obtained in step (b) or (c), with or without additional excipients.

The invention also concerns a suspension of phenofibrate in micronized form with a size of less than 20 μm in a solution of hydrophilic polymer and possibly surfactant.

The present invention is described in more detail in the following description, by reference to the drawings annexed thereto, in which: Figure 1 is a graphic representation of a comparative study of the dissolution profile of a composition according to the present invention and that of Lipanthyl® 200 M;Figure 2 is a graphic representation of a comparative study of the dissolution profile of a composition according to the present invention and that of pharmaceutical products available on the German market;

Err1:Expecting ',' delimiter: line 1 column 111 (char 110)

The advantage is that this dimension is less than or equal to 10 μm.

Err1:Expecting ',' delimiter: line 1 column 97 (char 96)

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The preferred hydrophilic polymer is polyvinylpyrrolidone (PVP), e.g. the PVP used in the present invention has a molecular weight of between 10 000 and 100 000, preferably between 20 000 and 55 000.

Err1:Expecting ',' delimiter: line 1 column 52 (char 51)

The preferred surfactant is sodium lauryl sulfate, which can be co-micronized with fenofibrate.

The compositions of the invention may also contain any excipient which is conventionally used in the pharmaceutical field and chemically compatible with the active substance, such as binders, fillers, pigments, disintegrants, lubricants, wetting agents, buffers, etc. Examples of excipients used in the present invention are: microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearic acid, polyvinyl pyrrolidone (AC SOL®), carboxylated polyvinyl pyrrolidone (Explobeidon®, Primoxyl®), hydroxypropyl carboxylate, hydroxypropyl carboxylate, hydroxyethyl fumarate, hydroxypropyl carboxylate, hydroxyethyl carboxylate, etc.

Err1:Expecting ',' delimiter: line 1 column 57 (char 56)

This outer layer includes conventional excipients. A layer with adjuvants for tablet manufacture can also be used. Depending on the method of manufacture, the outer layer includes a disintegrant and, for example, a lubricant; the granules thus coated and mixed can then be easily compressed and disintegrate easily in water.

The compositions according to the present invention generally include, in relation to the total weight of the nonphase or outer layer composition, an inert water-soluble medium representing 10 to 80% by weight, preferably 20 to 50% by weight, fenofibrate representing 5 to 50% by weight, preferably 20 to 45% by weight, hydrophilic polymer representing 20 to 60% by weight, preferably 25 to 45% by weight, surfactant representing 0 to 10% by weight, preferably 0.1 to 3% by weight.

The outer layer or phase, if any, may represent up to 80% by weight of the total weight, preferably up to 50% by weight.

The hydrophilic polymer is preferably present in excess of 25% by weight, relative to the weight of element (a).

The weight ratio of fenofibrate to hydrophilic polymer may be, for example, between 1/10 and 4/1, preferably between 1/2 and 2/1.

When a surfactant is used, the surfactant/hydrophilic polymer weight ratio may be, for example, between 1/500 and 1/10, preferably between 1/100 and 5/100.

The composition according to the present invention is in the form of tablets.

This tablet is the advantageous result of compressing elements (a) (in the form of pellets) with an external phase.

In another embodiment, the composition according to the present invention is in the form of pellets enclosed in a capsule, e.g. gelatin, or in a bag.

The compositions according to the present invention are particularly suitable for oral administration of the active substances.

The composition according to the present invention is prepared by a novel process involving the spraying on the inert nuclei of a micronized suspension of the active substance in a solution of a hydrophilic polymer and possibly surfactant.

When a surfactant is present, the active substance can be co-micronised with the surfactant.

The method according to the invention is to use the principle of the fluidized bed granulation technique but with specific starting products in order to achieve an improved dissolution profile and thus a high bioavailability.

Err1:Expecting ',' delimiter: line 1 column 623 (char 622)

The invention, as indicated, involves the spraying on an inert medium of a suspension of an active substance micronized with a hydrophilic polymer. At the end of the granulation, the granule formed consists of crystals e.g. of lactose, isolated (or possibly agglomerated with each other by the spraying solution), and particles of active substance and PVP glued to the surface of the crystals. The granule could likewise be made up of coated crystals agglomerated with each other, or even of such a newly coated agglomerate.

The compositions of the invention may also be prepared by other processes, e.g. by spraying the solution of micronized active substance on the inert water soluble medium.

The resulting granules may, if desired, be coated with an outer layer or compacted into tablets or forming agglomerates.

The outer layer (s) is (are) applied by conventional coating techniques, such as coating in a tank or fluidised bed.

When the resulting granules (other coated or not) are compacted to form tablets, this step can be carried out by any suitable conventional technique, e.g. on an alternative or rotary compressor.

The important starting product is the active substance suspension. This suspension is prepared by suspending the micronized active substance in a solution, including the hydrophilic polymer and possibly a surfactant in solution in a solvent. If a surfactant is used, it is put into solution (becher + magnetic agitator or blade agitator). Then the hydrophilic polymer (PVP) is dispersed under agitation in the previously obtained solution. Depending on the solubility of the polymer, it dissolves in the solution or forms a gel or a more or less thick suspension.The order of these steps can be reversed. The solvent used can be aqueous or organic (e.g. ethanol). For example, demineralized water is used. The concentration of active substance in the suspension is 1 to 40% by weight, preferably 10 to 25%. The concentration of hydrophilic polymer in the suspension is 5 to 40% by weight, preferably 10 to 25%. The concentration of surfactant in the suspension is 0 to 10% by weight, preferably less than 5%.

The invention also concerns this new suspension.

Without wishing to be bound by a theory, the applicant considers that this new process, by using a suspension of the micronized active substance in a hydrophilic polymer solution, allows a new composition to be obtained in which the active substance is in a non-reagglomerated form.

The following examples illustrate the invention without limiting it.

A composition containing (a) micronized fenofibrate, Plasdone®, Capsulac® and sodium lauryl sulphate is prepared.

The micronized phenofibrate has a particle size of about 5 μm as measured by a Coulter meter.

Plasdone X25® is a polyvinylpyrrolidone PVP ISP and Capsulac 60® (MEGGLE) is a lactose monohydrate with large crystals (particle size between 100 and 400 μm).

Sodium lauryl sulphate (7g) is dissolved in water (demineralised water, 1750g) and the micronized phenofibrate (350g) is suspended in the resulting mixture (e.g. using a 300 t/min propeller agitator for 10 minutes, then using an Ultra Turrax agitator at 10 000 t/min for 10 minutes). PVP (350g) is then added under agitation, the agitation (propeller agitator) being continued until the latter is dissolved (30 minutes).

Separately, lactose (400 g) is suspended in a fluidised air bed granulator (Glatt® GPCG1 - Top Spray or equivalent) and brought to a temperature of 40°C.

The suspension of fenofibrate is sprayed on the lactose under the following conditions: spray pressure: 2.1 bar; air flow 70 m3/h; air inlet temperature: 45°C; air outlet temperature: 33°C; product temperature: 34°C; spray time: 3 h.

The resulting granules may be formulated into capsules or formulated into tablets, and any appropriate conventional technique for preparing such galenic formulations may be used.

Err1:Expecting ',' delimiter: line 1 column 392 (char 391)

Reticulated polyvinylpyrrolidone, microcrystalline cellulose, sodium stearyl fumarate and colloidal silica are respectively disintegrating, binding, lubricating and flowing agents.

The tablet can be obtained from an alternative compressor (e.g. Korsch EKO) or a rotary one (e.g. Fette Perfecta 2).

This gives tablets with the following composition, expressed in mg: - point (a): - What?

Fénofibrate micronisé	100,0
PVP	100,0
Lactose	114,3
Laurylsulfate de sodium	2,0

- What? - external phase (or layer): - What?

PVP réticulée	92,7
Cellulose microcristalline	145,7
Stéryl fumarate de sodium	5,8
Silice colloïdale	3,3

Example 2: Dissolution of a composition according to the invention and of a composition according to the previous art. (a) Dissolution medium and protocol for measuring dissolution. A dissolving medium is sought which is discriminating, i.e. two products with very different dissolution profiles in gastric juice will have very different dissolution curves. This is done by using an aqueous medium containing a surfactant, Polysorbate 80 (polyoxyethylene sorbitol monooleate), which is readily available from several suppliers, monographed in pharmacopoeias and easy to implement (water-soluble liquid product). The rotary pallet method (European Pharmacopoeia) is used under the following conditions: volume of medium: 1200 ml; temperature of medium: 37°C; pallet rotation rate: 75 t/min; samples: every 2.5 minutes.

The composition of the invention consists of two tablets of approximately 100 mg fenofibrate, prepared as shown in example 1.

The composition according to the above art is Lipanthyl ® 200 M from Fournier Laboratories, dosed at 200 mg of fenofibrate (corresponding to 200 mg of fenofibrate co-micronised with sodium lauryl sulphate, and containing lactose, pre-gelatinised starch of cross-linked polyvinylpyrrolidone and magnesium stearate, according to the instructions of EP-A-0 330 532).

The results obtained are shown graphically in Figure 1, showing the percentage of dissolution and the observed standard deviation in parentheses.

These results clearly show that the compositions according to the present invention have a significantly higher dissolution profile than the compositions according to the previous art.

These results also clearly show that with the compositions according to the invention, the observed standard deviation is significantly smaller than with the compositions according to the previous art.

A bioavailability study was conducted in healthy volunteers.

The compositions tested are as follows: The first composition according to the previous art: Lipanthyl ® 200 M from Fournier Laboratories, dosed at 200 mg of fenofibrate, identical to the previous example.Second composition according to the previous art: Secalip ® in capsules (300 mg of fenofibrate as 3 capsules at 100 mg).

The study was conducted in 6 healthy volunteers receiving a single dose of fenofibrate, with a minimum rest period of 6 days between doses. Samples for pharmacokinetic analysis were collected after each administration at the time: 0.5; 1 h; 2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h; 36 h; 48 h; 72 h and 96 h after taking the drug. Plasma fenofibric acid content was measured on each sample. The results obtained are given in Table 1 below. - What? Tableau 1

produit	Dose (mg)	Cmax (µg/ml)	tmax (h)	tl/2 (h)	AUC 0-t (µg.h/ml)	AUC 0-∞ (µg.h/ml)
Invention	200	5,4	6	23	148	162
Secalip® 100	3 x 100	1,1	25	39	53	56
Lipanthyl® 200M	200	1,6	8,3	41	71	92

- What? Cmax: maximum plasma concentration tmax: time required to reach Cmax tl/2: Plasma half-life AUC 0- t: Area under the curve 0 to t AUC 0 - ∞: Area under the curve from 0 to 1'∞

These results clearly show that the compositions of the present invention, with an improved dissolution profile compared to the compositions of the previous art, lead to a significantly higher bioavailability of the active substance than the compositions of the present invention. Example 4 Comparison of the dissolution profile of the compositions of the present invention with that of products currently on the market in Germany On the German market there are immediate-acting or prolonged-acting phenofibrate formulations. As in France, the 100 mg & 300 mg (classical) forms coexist with 67 and 200 mg (enhanced bioavailability) forms, as taught in EP-A-0 3302, 53 These products are: Phenobarbital - Ratiopharm; Ratiopharm - Ulm; Capsules; Composition: Phenobarbital 100 mg; Excipients: Lactose, corn starch, magnesium stearate, dye E 171, gelatin.Durafenat; Durachemistry - Wolfrathausen; Capsules; Composition: Phenobarbital 100 mg; Excipient: Lactose, corn starch, magnesium stearate, dye E 171, gelatin.Normalip; Knoll-Ludwigshaffen; Capsules; Composition: Phenobarbital 200 mg; Excipients: Crospovidone, gelatin, lactose monohydrate, magnesium stearate, corn starch, sodium urphate, dyes E 132 and E 171.

A comparison is made between: The tablet of the invention as prepared in Example 1 (2 x 100 mg);Normalip pro ® (200 mg);Lipanthyl ® 200 M (200 mg) (as in the previous example);Fenofibrate Ratiopharm® (2 x 100 mg);Durafenat ® (2 x 100 mg).

The tests are carried out under the same conditions as in the previous examples.

These results clearly show that the compositions according to the invention have a significantly improved dissolution compared to the compositions according to the previous art.

Claims (14)

1. Fenofibrate composition with a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, as measured in accordance with the rotating blade method at 75 rpm according to the European Pharmacopoeia, in a dissolution medium consisting of 1200 ml of water with 2% by weight of polysorbate 80 or 1000 ml of water with 0.025M of sodium lauryl sulfate.
2. Composition according to claim 1 with a dissolution of at least 18.9% in 5 minutes, at least 67.1 % in 10 minutes, at least 89.7% in 20 minutes and at least 95.9% in 30 minutes.
3. Composition according to claim 1 with a dissolution until 18.9% in 5 minutes, until 67.1 % in 10 minutes, until 89.7% in 20 minutes and until 95.9% in 30 minutes.
4. Composition according to one of claims 1 to 3, in which the dissolution media is consisting of 1200 ml of water with 2% by weight of polysorbate 80.
5. Composition according to one of claims 1 to 4, in which the dissolution values are obtained for a composition comprising 200 mg of fenofibrate.
6. Composition according to one of claims 1 to 5, in tablet form.
7. Composition according to one of claims 1 to 5, in granular form in a capsule.
8. Composition according to one of claims 1 to 7, comprising a daily dosage below 200 mg of fenofibrate.
9. Composition according to one of claims 1 to 8, corresponding to a single intake per day.
10. Composition according to one of claims 1 to 9, in which the fenofibrate is micronized.
11. Composition according to one of claims 1 to 10, comprising a hydrophilic polymer.
12. Composition according to claim 11, in which the hydrophilic polymer is polyvinylpyrrolidone with a molecular weight comprised between 10 000 and 100 000.
13. Composition according to one of claims 10 to 12, in which the hydrophilic polymer represents at least 20% by weight, preferably from 20 to 60% by weight.
14. Composition according to one of claims 10 to 13, in which the weight ratio fenofibrate/hydrophilic polymer is comprised between 1/10 and 4/1, preferably from 1/2 and 2/1.