FR2792528A1 - KETOPROFENE MICROGRANULES, PREPARATION METHOD AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Abstract

The subject of the present invention is microgranules of prolonged release ketoprofen each consisting of an active core containing ketoprofen coated with a polymeric layer allowing the prolonged release of the active principle and containing Eudragit (R) RL and of Eudragit (R) RS in a substantially equal mass proportion.

Description

The present invention relates to a new galenical formulation of

  extended release ketoprofen for daily oral administration in the form

of microgranules.

  It also extends to their preparation process and to the compositions

pharmaceuticals containing them.

  o10 Ketoprofen, or 2- (3-benzoyl-phenyl) -propionic acid, is well known as an analgesic and anti-inflammatory drug. It was described in the patent

US-3,641,127.

  Ketoprofen has been shown in clinical studies to have analgesic activity at a plasma concentration above about 1

  15 microgram / ml (D'Arienzo et al., Drugs Exptl. Clin. Res., X (12), 863-866, 1984).

  Document EP-A-403 383 describes sustained-release granules which each comprise a core comprising ketoprofen and microcrystalline cellulose and a coating comprising a water-soluble cellulose derivative and a non-water-soluble cellulose derivative. The mass proportion of ketoprofen is between 60 to 80%, it is preferably equal to 75%. The granule cores are obtained by extrusion-spheronization and their coating is carried out in a fluidized air bed using a solution of the two cellulose derivatives in the

MeOH / CH2CI2 mixture.

  The Applicant has demonstrated that the granules described in EP-A-403 383 have a release profile such that the plasma peak is of the order of 3.5 micrograms / ml at 8 hours after an oral administration of a capsule containing 250 mg of ketoprofen. In addition, the plasma concentration is only higher than the analgesic concentration for approximately 16 hours, so that two doses

daily are necessary.

  Furthermore, the granules described in EP-A-403 383 have the

  disadvantage of being obtained by a process which uses organic solvents.

  Document EP-A-361 910 describes one of the dispersible granules prepared by adsorption of a pulverulent active principle of particle size less than 100 microns, on a powdery excipient of particle size between 250 and 500 microns. The active ingredient can be ketoprofen and the excipient can be lactose. The particles obtained are mixed with a solid excipient at room temperature which has a low melting point, for example stearic acid or a derivative of polyethylene glycol. The mixture is heated until this excipient melts, and cooled to resolidify this same excipient once fixed on the particles of active principle. The granules described in EP-A-361 910 contain contents in principle

  active in the order of 25%, and appear limited to these low contents.

  Document EP-A-204 596 describes granules of sustained-release ketoprofen obtained by extrusion of a mixture of ketoprofen, of one or more erodible polymers, of at least two lipid excipients, one of which has the property of gelling the polymer or polymers and the other has lubricating properties. The polymer is, for example, ethylcellulose, an acrylate or a vinylpyrrolidone / vinyl acetate copolymer. Lipid excipients are

  fatty acids or vegetable oils.

  The granules described in EP-A-204 596 have disadvantageously

  extremely variable release profiles from one formulation to another.

  Document EP-A-667,148 describes tablets consisting of an active principle core coated with a cationic polymer and then with an anionic polymer. The cationic polymer is soluble at a pH less than or equal to 6, for example an aminoalkyl methacrylate copolymer. The anionic polymer is soluble at a pH greater than or equal to 5.5. The anionic polymer can be chosen from a methacrylic acid / methacrylate L copolymer (Eudragit L), a copolymer

  methacrylic acid / methacrylate S (Eudragit S), hydroxypropylmethylcellulose.

  The document EP-A-667 148 describes in particular a tablet (example 1 of the document EP-A-667 148) consisting of: - a core, containing 24% by weight of ketoprofen and lactose, coated - a layer containing a methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer and talc, itself coated - with a layer containing a methacrylic acid / methacrylate S copolymer

and talc.

  The bioavailability study of this formulation (FIG. 2 of document EP-A-667,148) shows that the plasma concentration of ketoprofen is almost zero for the 13 hours following the administration of the tablet containing 50 mg of ketoprofen and then increases linearly until at 1.5 pg / ml

for the next 3 hours.

  The object of the present invention relates to an oral formulation consisting of microgranules of prolonged-release ketoprofen, which makes it possible to obtain a plasma peak after approximately 4 to 6 hours, a maximum plasma concentration of less than approximately 2.5 μg / ml. and a plasma concentration greater than about 1 pg / ml for at least 14 hours. Such a formulation advantageously makes it possible to avoid the side effects caused by an excessively pronounced plasma peak, to have a faster analgesic effect after administration, and to prolong this same effect in

  time, so a single daily dose is enough.

  This is why the present invention relates to microgranules of sustained release ketoprofen, characterized in that they each consist of an active nucleus containing ketoprofen coated with a layer allowing the sustained release of the active principle and containing l 'Eudragit RL and

  the Eudragit D RS in a substantially equal mass proportion.

  The term “substantially equal mass proportion” means a mass proportion Eudragit RL / Eudragit (RS close to 1/1, that is to say between

/ 60 and 60/40.

  EudragitD RL and EudragitD RS are aqueous dispersions of the poly copolymer (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) respectively in the proportions 1/2 / 0.2 and

1/2 / 0.1.

  The total mass of EudragitO RL and EudragitO RS contained in the coating layer represents between 1 and 10% of the mass of the microgranule, preferably

2 and 5%.

  Advantageously, the layer coating the core contains a plasticizing agent, such as triethyl citrate, and / or a lubricating agent, chosen from

  pharmaceutically acceptable lubricants, such as silica.

  The mass of ketoprofen contained in the active nucleus represents 50 to 80% of the mass of the microgranule, preferably between 65 to 75%, more preferably

70%.

  The active core advantageously consists of a neutral support grain coated with ketoprofen and a binding agent, chosen from binders

  pharmaceutically acceptable, for example a polyacrylate.

  In this embodiment, the neutral support grain represents 10 to 40%

  by weight of the mass of the microgranule, preferably 20 to 25%.

  The present invention also relates to a process for the preparation of

  extended release ketoprofen microgranules presented above.

  The method according to the invention is characterized in that it comprises a step

  coating the active core by spraying an aqueous suspension containing Eudragit RS and Eudragit RL.

  The active core is advantageously obtained by mounting ketoprofen on neutral support grains with an aqueous suspension of a binding agent such as

a polyacrylate.

  According to a preferred embodiment, a first step of the method consists in preparing a so-called mounting suspension consisting of a suspension

  aqueous of a binding agent, such as Eudragit) NE 30D, at 30% by weight.

  The mounting of ketoprofen is carried out in a coating turbine on neutral support grains, by discontinuous spraying of the suspension described

  above alternating with powdering sequences of ketoprofen.

  The microgranules are then sieved and dried at approximately 60 ° C. for

at least 10 hours.

  A second step consists in preparing a coating suspension consisting of an aqueous suspension at 50% by weight of a mixture of Eudragit RL, Eudragit RS), silica and triethyl citrate in the mass proportions

5/5/2/2.

  The microgranules to be coated are then placed in a coating turbine and sprayed continuously with the coating suspension described above. The coated microgranules are then sieved and dried at around 40 ° C.

for 4 to 8 hours.

  The coating can be carried out in several stages according to the desired kinetics.

  The dried microgranules can optionally be lubricated with talc.

  The present invention also relates to any pharmaceutical composition which contains the microgranules described above, capable of being obtained by the process which has just been presented, the mass of the microgranules contained in said composition corresponding to a daily dose of 50 to 300

  mg, preferably about 100 to 200 mg of ketoprofen.

  The single figure presents the comparative results of in vivo dissolution of a formulation according to the invention (Example 2) and of a formulation of the prior art

  described in document EP-A-403 383.

  Curves 1 and 2 represent the evolution over time of the average plasma concentration of ketoprofen, measured in twelve patients, after oral administration to each of them of a size 1 capsule containing 200 mg of ketoprofene respectively in the form of the formulation according to the invention and under the formulation of the prior art described in document EP-A-403 383. The concentration given on the ordinate is expressed in micrograms / mI. The

  time on the abscissa is given in hours.

  The following examples illustrate the invention without limiting its scope.

EXAMPLE 1:

  Preparation of the mounting suspension The suspension is prepared in a stainless steel container. The purified water is poured into the container and then stirred. 30% by weight of Eudragit NE 1.5 30D are incorporated into the water after vigorous shaking of the container.

  Stirring is continued until the suspension is homogeneous.

  Mounting of ketoprofen on neutral support grains Neutral support grains are placed in a turbine

coating in rotation.

  The active ingredient is assembled on the neutrals, by discontinuous spraying of the suspension described above in alternation with sequences of powdering ketoprofen, and sequences of rest. The mass of microgranules obtained is sieved on a mesh opening grid ranging from 0.85 to 1.18 mm. The microgranules are

  then dried in the rotating turbine at 60 ° C for 10 hours.

  Formula after assembly Quantity in% by mass

KETOPROFENE 72.4

NEUTRAL 23.9

EUDRAGIT NE 30 OF 3.6

  Ketoprofen content 724 mg / g Preparation of the coating suspension Proportions of the excipients used EUDRAGIT RL 30D 50.0% of the total mass of the dry extract Eudragit EUDRAGIT RS 30D 50.0% of the total mass of l dry extract Eudragit SILICA 20.0% of the total mass of the dry extract Eudragit TRIETHYL CITRATE 20.0% of the total mass of the dry extract Eudragit PURIFIED WATER 100.0% of the total mass of Eudragit weighed suspension is prepared in a stainless steel container into which the purified water is introduced. Eudragit RS E) is incorporated into the water after vigorous shaking of the container. Stirring is continued until the suspension is homogeneous. Eudragit RL is incorporated after stirring

vigorous of the can containing it.

  The silica and then the triethyl citrate are incorporated in small amounts into the suspension. Stirring is continued until the mixture is homogeneous,

then during the entire coating.

  Coating of the microgranules The microgranules to be coated are placed in a coating turbine. The coating of the microgranules is carried out by spraying

  continues from the suspension described above.

  The mass of microgranules obtained is sieved on a grid

1.18 mm mesh opening.

  The microgranules are then dried in a rotating turbine at a

  temperature of 35 C for 7 hours.

  The coating step is carried out according to this protocol, in several

  successive phases in order to obtain the desired kinetics.

  Formula after coating Quantity in% by mass

KETOPROFENE 70.4

NEUTRAL 23.2

  EUDRAGIT NE 30D 3.5 EUDRAGIT RL 30D 0.9 EUDRAGIT RS 30DE 0.9

SILICA 0.3

TRIETHYL CITRATE 0.3

  Ketoprofen content 714 mg / g of microgranules In vitro dissolution results mg of the microgranules obtained previously are dissolved in 900 ml of water at a determined pH (6.9 or 7.5), with stirring.

  revolutions / minute, with a paddle machine.

  Percentage by mass of in vitro dissolution of the microgranules of Example 1 Time in hours at pH 6.9 at pH 7.5

1 24.3 25.7

2 43.9 46.8

3 59.4 63.1

4 71.3 74.8

80.1 83.3

6 86.4 89.4

7 90.8 93.4

8 93.6 96.1

EXAMPLE 2:

  The mounting of ketoprofen is carried out according to Example 1 The coating suspension is carried out according to Example 1 5. Coating of the ketoprofen microgranules

  The microgranules to be coated are placed in a coating turbine.

  The coating of the microgranules is carried out by continuous spraying of the

suspension described above.

  The mass of microgranules obtained is sieved on an opening grid

1.18 mm mesh.

  The microgranules are then dried in a rotating turbine at a temperature of 35 "C for 7 hours then, after heating has stopped, maintained

  in a turbine (in rotation) for 2 hours.

  The microgranules obtained are then lubricated with talc in order to obtain the

desired kinetics.

  Formula after coating Quantity in% by mass

KETOPROFENE 68.7

NEUTRAL 22.6

EUDRAGIT NE 30D (E) D 3,4

  EUDRAGIT RL 30D 1.6 EUDRAGIT RS 30D (1.6

SILICA 0.6

TRIETHYL CITRATE 0.6

TALC 0.6

  Ketoprofen content 678 mg / g of microgranules 20. In vitro dissolution results The study is carried out under the same conditions as in Example 1 on 200 mg capsules containing the microgranules obtained previously and on a

  formulation of the prior art of the PROFENID LP 200 mg brand.

MASS PERCENTAGE OF DISSOLUTION

  Time in capsule 200 mg of example 2 PROFENID 200 mg hours pH 6.9 pH 7.5 pH 6.9

1 14.8 14.3 15.6

2 28.7 27.7 30.3

3 41.7 39.9 43.3

4 53.7 51.2 54.3

64.6 61.7 63.5

6 74.4 71.2 71

7 83 79.7 76.9

8 90 87.9 81.6

  In vivo dissolution results The in vivo release study of the capsules containing 200 mg of the microgranules obtained previously is carried out on twelve patients in parallel to a study carried out under the same conditions, on twelve patients, by administering to them a formulation of the art. described in document EP-A-403 383 and marketed under the brand PROFENID LP 200 mg. The results are

  shown in the figure and in the following table.

  o10 Confidence interval report to Parameter Average Treatment of 90% of the ratio of the average means of 1 and 2 of 1 and 2 AUCUt i 29.7 0.90 0.81 - 0.98 (pg.h.mi ') 2 33.1 AUC1.f I 39 AUCif 1 39 0.98 0.70- 1.26 (pg.h.ml'1) 2 40 Cmax (pg, ml) 2.2 0.54 0.35 - 0, 73

2 4.2

1 6.4

Tmax (h) 55 1.17

2 5.5

I 13.7

t 1/2 (h) 2 10.6 1.30

2 10.6

  Treatment no 1 = 200 mg capsule of Example 2 Treatment no 2 = Profenid LP 200 mg It appears that the two products are bioequivalent but the release profile of the formulation according to the invention is more advantageous than that of Profenid. Indeed, the duration during which the plasma concentration exceeds the analytical concentration is greater, and the plasma peak is divided by one

  s higher factor 2, so side effects are lessened.

  In addition, the duration at the end of which the plasma peak is observed is 4 hours with the microgranules according to the invention against 8 hours with the formulation

of the prior art.

Io EXAMPLE 3:

  The assembly of ketoprofen is carried out as in Example 1.

  The coating suspension is prepared as in Example 1.

  Coating of Ketoprofen Microgranules

  The microgranules to be coated are placed in a coating turbine.

  The coating of the microgranules is carried out by continuous spraying of the

suspension described above.

  The mass of microgranules obtained is screened on a mesh opening grid of 1.00 mm. The microgranules are then dried in a rotating turbine at a temperature of 45 ° C. for 30 minutes then, after heating has stopped,

  kept in turbine (in rotation) for 6 hours.

  The microgranules obtained are then lubricated with talc.

  Formula after coating Quantity in% by mass

KETOPROFENE 69.9

NEUTRAL 30î 23.0

  EUDRAGIT NE 30D 3.5 EUDRAGIT RL 30D 1.0 EUDRAGIT RS 30D 1.0

SILICA 0.4

TRIETHYL CITRATE 0.4

TALC 0.5

  Ketoprofen content 703 mg / g of microgranules In vitro dissolution results The study is carried out under the same conditions as in Example 1 on

  microgranules obtained previously and on a formulation of the prior art.

  Percentage by mass of dissolution Time in hours of the microgranules of Example 3 at pH: 6.9

1 14.3

2 27.6

3 39.6

4 50.4

59.9

6 68.2

7 75.2

8 81.0

Claims (9)

  1. Microgranules of prolonged release ketoprofen, characterized in that they each consist of an active nucleus containing ketoprofen coated with a layer allowing the prolonged release of the active principle and containing Eudragit RL and Eudragit RS in a substantially equal mass proportion. 2. Microgranules according to claim 1, characterized in that the total mass of EudragitO RL and Eudragit RS represents between 1 and 10% of the   mass of the microgranule, preferably between 2 and 5%.   3. Microgranules according to claim 1 or 2, characterized in that the layer coating the core contains a plasticizing agent, such as triethyl citrate,   and / or a lubricating agent, such as silica.   4. Microgranules according to one of the preceding claims,   characterized in that ketoprofen represents 50 to 80% by weight of the   microgranule, preferably between 65 and 75%.   5. Microgranules according to claim 1, characterized in that the core consists of a neutral support grain coated with ketoprofen and an agent binder, for example a polyacrylate.   6. Microgranules according to claim 5, characterized in that the neutral support grain represents 10 to 40% by weight of the mass of the microgranule, preferably 20 to 25%.   7. Method for preparing the microgranules according to one of   Claims 1 to 6, characterized in that it comprises a step of coating the   active core by spraying an aqueous suspension containing Eudragit RS and Eudragit RL.   8. Method according to claim 7, characterized in that the active core is obtained by mounting ketoprofen on neutral support grains with a   aqueous solution of a binding agent such as a polyacrylate.   9. Pharmaceutical composition containing microgranules according to   one of claims 1 to 6 capable of being obtained according to claim 7   or 8, the mass of the microgranules corresponding to a daily dose of 50 to   300 mg, preferably 100 to 200 mg of ketoprofen.