Modified release ibuprofen dosage form

THE REPUBLIC OF POLAND (12) TRANSLATION OF THE EUROPEAN PATENT (19) PL (11) PL / EP 1793809

<img file="PL1793809T3_D0001.tif" />

Patent Office of the Republic of Poland (96) Date and number of the European patent application:

30.09.2005 05805851.2 (97) The grant of the European patent was announced:

11.07.2012 European Patent Bulletin 2012/28 EP 1793809 B1 (13) T3 (51) Int.CL

A61K 9/20 (2006.01)

A61K 9/22 (2006.01)

A61K 31/00 (2006.01)

A61K 9/14 (2006.01) (54) Title of the invention:

Modified release ibuprofen dosage form (3 °) r,

Priority:

2004-09-30 US 614,932 P

2005-06-10 US 689 631 P

29.09.2005 US 238802 (43) Application announced:

June 13, 2007 in the European Patent Bulletin No. 2007/24 (45) The following was announced about the submission of the translation of the patent:

31.12.2012 News of the Patent Office 2012/12 (73) The right holder of the patent:

SCOLR Pharma, Inc., Bellevue, US (72) Inventor (s):

MICHAEL HITE, Seattle, US

CATHY FEDERICI, Seattle, US

ALAN BRUNELLE, Woodinville, US f2 STEPHEN TURNER, Snoqualmie, US s

W (74) Representative:

thing, pat. Helena Danuta Stefani-lwanow

JAN WIERZCHOŃ &amp; PARTNERS

Τ 'OFFICE OF PATENTS AND ZNAKÓW TOWAROWYCH SP. J.

Q_ iii ul. Żurawia 47/49

J 00-680 Warsaw

ABOUT.

Attention:

Within nine months of the publication of the information on the grant of the European patent, any person may file an objection to the European Patent Office against the European patent granted. The objection must be submitted in the form of a written statement of reasons. It is considered brought only when the opposition fee has been paid (Art. 99 (1) of the Convention on the Grant of European Patents).

14397/12 / P-RO / DS / KM

EP 1 793 809

Modified release ibuprofen dosage form

Background of the invention

Ibuprofen is 2- (4-isobutylphenyl) propionic acid and is a non-steroidal anti-inflammatory compound (NSAID) that is characterized by high levels of anti-inflammatory, analgesic and antipyretic effects necessary for the effective treatment of rheumatoid arthritis and osteoarthritis and other inflammatory conditions. Most ibuprofen dosage forms contain immediate release dosage forms which provide a rapid onset of therapeutic effect followed by a sharp drop in the level of the active ingredient requiring multiple administrations. They do not maintain therapeutic levels from one treatment over an extended period of time. Therefore, multiple administrations at intervals of four to six hours are required.

WO 00/07570 discloses a stable pharmaceutical composition comprising a mixture of (i) an ibuprofen drug; (ii) the drug domperidone; and (iii) a carrier material, characterized in that the carrier material is substantially free of povidone and comprises at least one diluent in combination with at least one release modifying agent. The document states that when a dosage form is exposed to an aqueous medium after injection, the release modifying excipients cause the active ingredient to be released from the solid composition at a desired rate, for example, substantially instantaneously or at a desired controlled rate.

The sustained release formulations do not have an initial burst of the drug and therefore exhibit a significant delay between administration and the achievement of an effective therapeutic blood level. Therefore, there is a need for a solid dosage form, such as a compressed tablet, which provides an initial burst. initial burst) of the released ibuprofen leading to a rapid onset of action which then ensures the sustained release of sufficient ibuprofen to maintain a favorable blood level of ibuprofen for an extended period of 8 or more hours.

The essence of the invention

Accordingly, we provide a solid dosage form for oral administration of ibuprofen comprising a modified release ibuprofen formulation that provides an immediate burst effect and then sustained the release of sufficient ibuprofen to maintain a blood concentration of at least 6.4 pg / ml for an extended period of at least 8 hours after a single dose.

More particularly, the invention relates to a solid dosage form for modified oral administration of ibuprofen comprising:

hydrophilic polymer,

- 2300 to 800 mg of ibuprofen in a solid dosage form evenly dispersed in said polymer;

dissolution aid in said hydrophilic polymer in an amount in the range of 10% to 35% by weight of ibuprofen, said dissolution aid comprising sodium carbonate, glycine, arginine, croscarmellose sodium, or a combination thereof, or a combination of any two such excipients; and an inert formulation excipient dispersed in said hydrophilic polymer in an amount ranging from 15% to 75% by weight of ibuprofen, said formulation excipient including microcrystalline cellulose, silica, magnesium stearate, stearic acid, lactose, pregelatinized starch, calcium phosphate or any combination of of them wherein said hydrophilic polymer comprises a first hydroxypropyl methyl cellulose having a viscosity greater than 100 cps, and a second HPMC with a viscosity of about 100 cps, each at a concentration of 17% to 42% by weight of ibuprofen, wherein at least 20% of ibuprofen is released within 2 hours after exposure to a mixed aqueous medium of a single dosage unit, then ibuprofen is released with a relatively constant a rate for a period of at least 8 hours and in which at least 70% of the ibuprofen is released within a period of not more than 14 hours after such administration or exposure, in which release is determined by means of a stirred aqueous medium, stirring at 50 rpm in a KH2PO4 medium of pH 7.2.

The dosage form releases ibuprofen at a rate sufficient to initially deliver an effective amount of ibuprofen within about 2.0 hours after administration. The dosage form then sequentially delivers the remaining amount of ibuprofen at a relatively constant rate sufficient to maintain the level of ibuprofen over the predetermined delivery time for at least 8 hours.

As used herein, the relative rate constant refers to the substantially linear relationship shown in the examples after the first burst (up to about 2 hours) between the percentage released and the elapsed time.

Brief description of the drawings

Figure 1: In-vitro dissolution of example 1

Figure 2: In-vitro dissolution of example 2

Figure 3: In-vitro dissolution of example 3

Figure 4: In-vitro dissolution of example 4

Figure 5: In-vitro dissolution of example 5

Figure 6: In-vitro dissolution of example 6

Figure 7: In-vitro dissolution of example 7

Figure 8: In-vitro dissolution of example 8

Figure 9: In-vitro dissolution of example 9

Figure 10: In-vitro dissolution of example 10

Figure 11: In-vitro dissolution of example 11

Figure 12: In-vitro dissolution of example 12

Figure 13: In-vitro dissolution of example 13

Figure 14: In-vitro dissolution of example 14

Figure 15: In-vitro dissolution of example 15

Figure 16: In-vitro dissolution of example 16

Figure 17: In-vitro dissolution of examples 17 and 18

Figure 18: In-vitro dissolution of BRUFEN RETARD, an extended release form of ibuprofen commercially available in Europe.

Figure 19: In vivo data from the comparison of the present invention with Mortin®

Detailed description of the invention

The present invention is further illustrated and described with reference to the following disclosure, examples, and discussion below. In the examples and discussions that follow, the use of specific polymers, electrolytes, excipients, fillers and tabletting excipients is provided by way of example only! it is not intended to limit the scope of the present invention. While the invention is illustrated and described herein with reference to specific embodiments of the invention, the invention is not intended to be limited to the details given. On the contrary, various modifications may be made in detail within the scope and range of the equivalents of the claims and without departing from the invention.

The content of ibuprofen in the dosage form is between 300 mg and 800 mg per dosage unit, preferably about 300, 400 or 600 mg per dosage unit form. In addition, the use of ibuprofen prodrugs such as ibuprofenlizine and ibuprofen-arginine is contemplated. If a smaller dosage form is desired, a single dose of ibuprofen can be split into multiple, for example two to three, dosage units, such as tablets, which can be administered at substantially the same time. The dosage form may contain from about 25% to about 75% by weight of ibuprofen.

When used in the dosage form, these hydrophilic polymer gels dissolve slowly in the acidic aqueous medium, which allows ibuprofen to diffuse out of the gel in the stomach and digestive tract. Hydroxypropyl methylcellulose (HPMC) is available in forms that have a variety of viscosity indexes. Generally, these polymers, or combinations thereof, may be present in the dosage form alone or in combination in an amount or concentration ranging from 10% to 70% by weight of the ibuprofen present in the formulation, e.g. 15% to 50% or 15% to 33%. depending on the release schedule that is necessary to be achieved with a particular dosage form.

One hydrophilic polymer useful in the present invention is HPMC K4M. It is a non-ionic swellable hydrophilic polymer manufactured by The Dow Chemical Company under the trade name Methocel. HPMC K4M is also referred to as HPMC K4MP, wherein P refers to premium cellulose ether intended for controlled release preparations. 4 briefly suggests that the polymer has a nominal viscosity (2% in water) of 4000. The percentage of methoxy and hydroxypropyl groups is 19-24 and 7-12, respectively. In its physical form, HPMC K4M is a free flowing, off-white powder with a particle size restriction of 90% &lt;100 mesh sieve. A more comprehensive list of HPMCs includes K100LVP, K15MP, K100MP, E4MP, and E10MP CR with nominal viscosities of 100, 15,000, 100,000, 4,000, and 10,000 respectively.

Solid dosage forms also include at least one formulation excipients such as one or more fillers, a diluent, or a compression aid. These are excipients that assist in the preparation or manufacture of the dosage form and for the tableted solid dosage form tabletting aids such as microcrystalline cellulose (MCC) such as MCC 105 (particle size about 20 µm), MCC 200 (particle size about 180 pm) and MCC 302 (particle size about 90 pm), silicified microcrystalline cellulose (MCC related to S1O2), such as Prosolv90 (particle size approx. 90 µm) and Prosolv 50 (particle size approx. 50 µm) lactose such as spray dried lactose (Lactopress®), calcium phosphate, silica or pregelatinized starch and combinations thereof are incorporated into the formulation at or at a concentration in the range of about 15% to about 75% by weight of the ibuprofen present in the dosage form. It is contemplated that, if desired, different microcrystalline cellulose particle sizes may be used, for example two different particle sizes each being present in distinct amounts ranging from 17% to 33% by weight of the ibuprofen present in the dosage form. In one embodiment, the silica may be preblended with ibuprofen or the silica and / or excipients of the MCC formulation may be preblended with the ibuprofen.

In addition to the formulation excipients, the dosage form also comprises at least one dissolution aid. Such excipients, which typically include a pore former, a lubricant, or a disintegrant which aid in dissolution of the dosage form. Such dissolution aids are present in the dosage form in an amount or concentration ranging from about 10% to about 35% by weight of the ibuprofen, for example, 10% to about 15%. The excipient is suitably selected from sodium carbonate, glycine, arginine, and croscarmellose sodium, or a combination thereof, or a combination of any two of such dissolution excipients.

In addition to ibuprofen, many active ingredients are contemplated and may be present in the present dosage form. Combinations of ibuprofen with active substances such as caffeine, psuedoephedrine, aspirin, phenylephrine or sympathomimetics, analgesics such as hydrocodone, and antihistamines are within the scope of the invention.

Advantageous in vitro properties that lead to acceptable in vivo efficacy are considered to be 20% or greater release within 2.0 hours after oral administration or contact with an aqueous medium, followed by more gradual release over several hours, leading to a release of at least 70 % release 8 or 12 hours after administration or contact with the aquatic environment. The in vitro release assay method uses a mixed aqueous environment, such as mixing at 50 rpm, in a KH2PO4 environment of pH 7.2; or substitute methods using different pH media such as 0.1N HCl or SGF @ pH 1.2 for initial (30 min-2 hour period) or using alternative hydrodynamic conditions such as 100 to 150 rpm for 1 -2 hours).

The accepted range for minimum in vivo efficacy is from about 6.4 pg / ml to about 10 pg / ml of mean blood concentration of ibuprofen.

Examples

The formulations of the invention are illustrated by the following examples. The use of specific polymers, electrolytes, excipients, fillers and compression aids is not intended to limit the present invention, but is exemplary only.

A fixed dose including the modified release formulation of the present invention was obtained and tested for both in vitro release and in vivo blood levels as described in Examples 1-20 below. In an in vivo study, the dissolution rates of the subject dosage form were compared against two commercially available tablets, one providing an immediate release formulation of 200 mg ibuprofen and the other providing an immediate release 600 mg ibuprofen formulation. The solid dosage form including the modified release formulation of the present invention showed an initial burst similar to the immediate release of the tablets and a slower, more controlled release of ibuprofen over an eight hour period as best seen in Figure 19.

Unless otherwise stated, all in vitro releases were assessed on a Type II dissolution apparatus in 900 ml of KH2PO4, pH 7.2, at a paddle speed of 50rpm.

Example 1

In one embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K15M and HPMC K100LV), glycine, and sodium carbonate in which the concentration of HPMC K15M was 18% by weight of ibuprofen, the concentration of HPMC K100LV was 17% by weight of ibuprofen, the concentration of glycine was 2.5% by weight of ibuprofen. ibuprofen, and the sodium carbonate concentration was 17% by weight of ibuprofen in the monolithic compressed tablet. The specific preparations are as follows: ___________ ____________________________________

<td>Example la</td><td>mg</td><td>Example Ib</td><td>mg</td>

<td>Ibuprofen 90 grade</td><td> 600</td><td>Ibuprofen 90 grade</td><td> 600</td>

<td>HPMC KI5M</td><td> 110</td><td>HPMC KI5M</td><td> 125</td>

<td>HPMCK100LY</td><td> 100</td><td>HPMCK100LY</td><td> 100</td>

<td>MCC PHI02</td><td> 100</td><td>MCC PHI02</td><td> 100</td>

<td>On₂WHAT₃, anhydrous</td><td> 150</td><td>On₂WHAT₃, anhydrous</td><td> 150</td>

<td>Glycine</td><td> 15</td><td>Glycine</td><td> 15</td>

<td>Colloidal silica, Syloid ^ ΛΛ</td><td> 20</td><td>Colloidal silica, Syloid ^ ΛΛ</td><td> 20</td>

<td>Mg stearate</td><td> 10</td><td>Mg stearate</td><td> 10</td>

<td>Together</td><td> 1105</td><td>Together:</td><td> 1120</td>

The ingredients were passed through a 30-mesh sieve and mixed with the remaining formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional compression techniques.

As shown in Fig. 1, the results of this example demonstrate that the invention provides an in vitro release profile that includes a burst effect followed by a sustained release of residual material leading to more than 90% release in about 12 hours. This formulation thus overcomes one of the major problems, for many ibuprofen formulations, which show significantly less than complete release over an extended period of time.

Example 2

In another embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K100M and HPMC K100LV), sodium carbonate, flow agents and tabletting aids in which the concentration of HPMC K100M was 17% by weight of ibuprofen, the concentration of HPMC K100LV was 17% by weight of ibuprofen and the concentration of ibuprofen was 17% by weight. sodium carbonate was 25% by weight of ibuprofen in the compressed monolithic tablet. The specific formulation is as follows:

<td>Example 2</td><td>mg</td>

<td>Ibuprofen</td><td> 600</td>

<td>HPMC K100M</td><td> 100</td>

<td>HPMCK100LV</td><td> 100</td>

<td>On₂WHAT₃, anhydrous</td><td> 150</td>

<td>MCC PHI02</td><td> 150</td>

<td>Colloidal Silica, Syloid 244</td><td> 20</td>

<td>Mg stearate</td><td> 10</td>

<td>Together:</td><td> 1130</td>

The ingredients of the preparation were mixed in a V-blender. The resulting powder is compressed into tablets using conventional technology. This example uses a combination of medium to high viscosity HPMC and low viscosity HPMC.

As shown in Fig. 2, the results of this example demonstrate an in vitro release profile including a burst effect followed by a sustained release of residual material. The burst effect releases 20% of the ibuprofen within 2 hours, and the release of approximately 90% of the available ibuprofen within 12 to 14 hours.

Example 3

In another embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K15M and HPMC K100LV), sodium carbonate, flow agents and tabletting aids in which the concentration of HPMC K100M was 17% by weight of ibuprofen, the concentration of HPMC K100LV was 17% by weight of ibuprofen and the concentration of ibuprofen was 17% by weight. sodium carbonate was 25% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 3</td><td>mg</td>

<td>Ibuprofen</td><td> 600</td>

<td>HPMC KI5M</td><td> 100</td>

<td>HPMCK100LV</td><td> 100</td>

<td>MCC PHI02</td><td> 100</td>

<td>On₂CO3, anhydrous</td><td> 150</td>

<td>Glycine</td><td> 15</td>

<td>Colloidal Silica, Syloid 244</td><td> 20</td>

<td>Mg stearate</td><td> 10</td>

<td>Together:</td><td> 1095</td>

The ingredients of the preparation were mixed in a V-blender. The resulting powder is compressed into tablets using conventional compression techniques. This example uses a combination of medium to high viscosity HPMC and low viscosity HPMC.

As shown in Fig. 3, the results of this example demonstrate an in vitro release profile that includes a burst effect that releases 20% ibuprofen within 2 hours, followed by a sustained release of the remaining material, evidencing release of 100% ibuprofen present at approximately 11 hours. hours and greater than 90% in approximately 8 hours.

Example 4

In another embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K100M and HPMC K100LV), sodium carbonate, flow agents, and tabletting aids in which the concentration of HPMC K100M was 17% by weight of ibuprofen, the concentration of HPMC K100LV was 17% by weight of the ibuprofen, and the sodium carbonate concentration was 25% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 4</td><td>mg</td>

<td>Ibuprofen</td><td> 600</td>

<td>HPMCK100M</td><td> 100</td>

<td>HPMCK100LV</td><td> 100</td>

<td>MCC PHI02</td><td> 100</td>

<td>On₂CO3, anhydrous</td><td> 150</td>

<td>Colloidal Silica, Syloid 244</td><td> 20</td>

<td>Mg stearate</td><td> 10</td>

<td>Together:</td><td> 1080</td>

The ingredients of the preparation were mixed in a V-blender. The resulting powder is compressed into tablets using conventional technology. This example uses a combination of medium to high viscosity HPMC and low viscosity HPMC.

As shown in Fig. 4, the results of this example demonstrate an in vitro release profile that includes a burst effect followed by a sustained release of residual material. 20% of the Ibuprofen was released within 2 hours, followed by a gradual sustained release giving about 95% release after 12 hours.

Example 5 (not according to the invention)

In another embodiment, the formulation included ibuprofen, hydroxypropyl methylcellulose (HPMC K100M), polyethylene oxide (PEO WSRN 301), sodium carbonate, glycine, flow agents and tabletting aids, wherein the concentration of HPMC is 33% by weight of the ibuprofen. The concentration of the glycine is 8 , 25% by weight of ibuprofen and the concentration of sodium carbonate was 25% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 5</td><td>mg</td>

<td>Ibuprofen</td><td> 600</td>

<td>PEO 301</td><td> 50</td>

<td>HPMCK100M</td><td> 100</td>

<td>MCC PHI02</td><td> 100</td>

<td>Na2CO₃, anhydrous</td><td> 150</td>

<td>Glycine</td><td> 20</td>

<td>Colloidal Silica, Syloid 244</td><td> 20</td>

<td>Mg stearate</td><td> 10</td>

<td>Together:</td><td> 1050</td>

The ingredients of the preparation were mixed in a V-blender. The resulting powder is compressed into tablets using conventional compression techniques.

As shown in Fig. 5, the results of this example demonstrate an in vitro release profile that includes a burst effect followed by a sustained release of residual material. For this formulation, 20% of ibuprofen was released within 2 hours, but incomplete release was shown after 12 hours.

Example 6 (not according to the invention)

In another embodiment, the formulation contained ibuprofen, hydroxypropylmethylcellulose (HPMC K15M), potassium carbonate, flowability agents and tabletting aids in which the concentration of HPMC was 33% by weight of ibuprofen, and the concentration of potassium carbonate was 17% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 6</td><td>mg</td>

<td>Ibuorofen 90 grade</td><td> 600</td>

<td>MCCPH 105</td><td> 210</td>

<td>HPMC KI5M Prem</td><td> 190</td>

<td>MCC PH 200</td><td> 100</td>

<td>K? CCh anhydrous</td><td> 100</td>

<td></td><td> 1200</td>

The ingredients of the preparation were mixed in a V-blender. The resulting powder is compressed into tablets using conventional compression techniques.

As shown in Fig. 6, the results of this example demonstrate an in vitro release profile that includes a burst effect followed by a sustained release of residual material. 20% of the Ibuprofen was released in less than 2 hours, and release thereafter

- 10 was held for 15 hours. However, this dosage form showed incomplete release.

Example 7 (not according to the invention)

In the present embodiment, the formulation contained ibuprofen, hydroxypropylmethylcellulose (HPMC K15M), sodium carbonate, microcrystalline cellulose (MCC PH105 and MCC PH200) wherein the HPMC concentration was 33% by weight of ibuprofen, the sodium carbonate concentration was 17% by weight of ibuprofen, the concentration of MCC PH105 was was 33%, and the MCC PH200 concentration was 17% in the compressed monolithic tablet.

<td>Example 7</td><td>Mg</td>

<td>Ibuprofen 90 grade</td><td> 600</td>

<td>HPMC KI5M Prem</td><td> 190</td>

<td>MCCPH 105</td><td> 210</td>

<td>MCC PH 200</td><td> 100</td>

<td>On₂COs anhydrous</td><td> 100</td>

<td></td><td> 1200</td>

All ingredients were passed through a 30-mesh screen. Ibuprofen and MCC 105 were mixed in a V-blender. The resulting homogeneous pre-blend was granulated with water, dried and successively blended with the remaining formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional compression techniques.

As shown in Fig. 7, this example demonstrates an in vitro release profile involving a burst effect followed by a sustained release of residual material. The burst effect releases 20% of the ibuprofen in less than 2 hours, followed by a relatively constant release over the next 10-12 hours and approximately 90% release after 12 hours.

Example 8

In the embodiment of example 1, the tablet obtained from the formulation was divided into two different parts, and both parts were placed in a dissolution vessel.

<td>Example 8</td><td>mg</td>

<td>Ibuprofen 90 grade</td><td> 600</td>

<td>HPMC KI5M</td><td> 110</td>

<td>HPMCK100LY</td><td> 100</td>

<td>MCC PHI02</td><td> 100</td>

<td>On₂WHAT₃, anhydrous</td><td> 150</td>

<td>Glycine</td><td> 15</td>

<td>Colloidal Silica, Syloid 244</td><td> 20</td>

<td>Mg stearate</td><td> 10</td>

<td>Together:</td><td> 1105</td>

As shown in Fig. 8, the results of this example demonstrate an in vitro release profile that includes a burst effect, followed by a sustained release of residual material even when partitioned after tabletting. In each case, 20% of the ibuprofen was released in less than an hour and substantially all of the ibuprofen was released in about 12 hours.

Example 9 (not according to the invention)

In one embodiment, the formulation contained ibuprofen, hydroxypropyl methylcellulose (HPMC K15M), sodium carbonate, microcrystalline cellulose (MCC PH 302) wherein the HPMC concentration was 33% by weight ibuprofen, the sodium carbonate concentration was 18% by weight ibuprofen, and the concentration of MCC PH 302 was 33% in a compressed monolithic tablet.

<td>Example 9</td><td>mg</td>

<td>Ibuorofen 90 grade</td><td> 300</td>

<td>HPMC KI5M Prem</td><td> 100</td>

<td>MCC PH 302</td><td> 100</td>

<td>Na? CO? Anhydrous</td><td> 50</td>

<td>Glycine</td><td> 7,5</td>

<td>Silica</td><td> 5,5</td>

<td>Together:</td><td> 563</td>

All ingredients were passed through a 30-mesh sieve and mixed in a V-blender. The resulting homogeneous pre-blend was granulated with water, dried and successively blended with the remaining formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 9, the results of this example demonstrate an in vitro release profile including a burst effect followed by a sustained release of residual material. 20% of the Ibuprofen was released within 2 hours, approximately 90% of the release

- 12 is obtained in about 9 hours, then 100% release in less than 16 hours.

Example 10 (not according to the invention)

In another embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), flow agents and tabletting aids wherein the concentration of HPMC K4M was 32% by weight of ibuprofen, and the concentration of arginine was 17% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 10</td><td>mg</td>

<td>Ibuprofen 90 grade</td><td> 600</td>

<td>Silica</td><td> 5,5</td>

<td>MCCPH 105</td><td> 210</td>

<td>HPMC K4M Prem</td><td> 190</td>

<td>Arginine</td><td> 100</td>

<td>Silica</td><td> 5,5</td>

<td>Together:</td><td> 1111</td>

The ingredients of the preparation were mixed in a V-blender. The resulting powder is compressed into tablets using conventional technology. As shown in Fig. 10, the results of this example demonstrate an in vitro release profile including a burst effect followed by a sustained release of residual material. While the burst effect in this formulation produces a slightly delayed achievement of the percent release, this formulation shows over 90% release within 8 hours.

Example 11 (not according to the invention)

In another embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), sodium carbonate, arginine, flow agents and tabletting aids in which the concentration of HPMC K4M was 32% by weight of ibuprofen, the concentration of sodium carbonate was 17% by weight of the ibuprofen, and the concentration was arginine was 17% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 11</td><td>mg</td>

<td>Ibuorofen 90 grade</td><td> 600</td>

<td>Silica</td><td> 5.5</td>

<td>MCCPH 105</td><td> 210</td>

<td>HPMC K4M Prem</td><td> 190</td>

<td>NaiCCL anhydrous</td><td> 100</td>

<td>MCC PH 200</td><td> 100</td>

<td>Arginine</td><td> 100</td>

<td>Silica</td><td> 5.5</td>

<td>Stearic acid</td><td> 12</td>

<td>Together:</td><td> 1323</td>

The ingredients of the preparation were mixed in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 11, the results of this example demonstrate an in vitro release profile that includes a burst effect followed by a sustained release of residual material. The initial release is greater than 20% of the ibuprofen in less than two hours, and about 90% release in 14 hours.

Example 12 (not according to the invention)

In another embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), microcrystalline cellulose (MCC 105), sodium carbonate, flow agents, and various tabletting aids, wherein HPMC K4M is present at 32% by weight of ibuprofen, the sodium carbonate concentration was 17 wt.% Ibuprofen, and tabletting aids, either Lactopress (12a), calcium phosphate (12b), or pregelatinized starch (12c), was present at 17% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 12a</td><td>mg</td><td>Example 12b</td><td>mg</td>

<td>Ibuorofen 90 grade</td><td> 600</td><td>Ibuorofen 90 grade</td><td> 600</td>

<td>Silica</td><td> 5.5</td><td>Silica</td><td> 5.5</td>

<td>MCCPH 105</td><td> 210</td><td>MCCPH 105</td><td> 210</td>

<td>HPMC K4M Prem</td><td> 190</td><td>HPMC K4M Prem</td><td> 190</td>

<td>On₂CO3 anhydrous</td><td> 100</td><td>On₂CO3 anhydrous</td><td> 100</td>

<td>Lactopress</td><td> 100</td><td>Calcium phosphate</td><td> 100</td>

<td>Silica</td><td> 5.5</td><td>Silica</td><td> 5.5</td>

<td>Stearic acid</td><td> 12</td><td>Stearic acid</td><td> 12</td>

<td>Together:</td><td> 1223</td><td>Together:</td><td> 1223</td>

<td>Example 12c</td><td>mg</td>

<td>Ibuorofen 90 grade</td><td> 600</td>

<td>Silica</td><td> 5.5</td>

<td>MCCPH 105</td><td> 210</td>

<td>HPMC K4M Prem</td><td> 190</td>

<td>For what₃ anhydrous</td><td> 100</td>

<td>Starch 1500</td><td> 100</td>

<td>Silica</td><td> 5,5</td>

<td>Stearic acid</td><td> 12</td>

<td>Together:</td><td> 1223</td>

All ingredients were passed through a 30-mesh screen. Ibuprofen and MCC 105 were mixed in a V-blender. The resulting homogeneous pre-blend was granulated with water, dried and successively blended with the remaining formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 12, the results of this example demonstrate that the invention provides an in vitro release profile that includes a burst effect, followed by a sustained release of residual material, with little or no change in the release profile if the choice of tabletting aids is changed. The in vitro profile shows greater than 20% release by 2.0 hours, with a constant rate release and at least 70% release by 14 hours.

Example 13 (not according to the invention)

In another embodiment, the formulation contained ibuprofen, hydroxypropylmethylcellulose (HPMC K4M), microcrystalline cellulose (MCC 105), sodium carbonate, flow agents, and various tabletting aids, in which the HPMC K4M concentration was 32% by weight of ibuprofen, the sodium carbonate concentration was 17 % by weight of ibuprofen, and the concentration of croscarmellose sodium was 3% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 13</td><td>mg</td>

<td>Ibuprofen 90 grade</td><td> 600</td>

<td>Silica</td><td> 5.5</td>

<td>MCCPH 105</td><td> 210</td>

<td>HPMC K4M Prem</td><td> 190</td>

<td>On₂COs anhydrous</td><td> 100</td>

<td>MCC PH 200</td><td> 100</td>

<td>Croscarmellose sodium</td><td> 18</td>

<td>Silica</td><td> 5.5</td>

<td>Stearic acid ~ 1%</td><td> 12</td>

<td>Together:</td><td> 1241</td>

All ingredients were passed through a 30-mesh screen. Ibuprofen, silica and MCC 105 were mixed in a V-blender. The resulting homogeneous pre-blend was granulated with water, dried and successively blended with the remaining formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 13, the results of this example demonstrate an in vitro release profile that includes a burst effect followed by a sustained release of residual material. The in vitro profile shows greater than 20% release by 2.0 hours, followed by a relatively constant release rate and at least 80% release by 14 hours.

Example 14 (not according to the invention)

In another embodiment, the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), microcrystalline cellulose (MCC 105), glycine, sodium carbonate, flow agents, and various tabletting aids in which the HPMC K4M concentration was 32% by weight of the ibuprofen, the concentration of sodium carbonate was 17% by weight of ibuprofen, glycine was present at 8% by weight of ibuprofen and the concentration of croscarmellose sodium was 6% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 14</td><td>mg</td>

<td>Ibuorofen 90 grade</td><td> 600</td>

<td>MCCPH 105</td><td> 200</td>

<td>Silica</td><td> 5.5</td>

<td>HPMC K4M Prem</td><td> 190</td>

<td>MCC PH 200</td><td> 100</td>

<td>Glycine</td><td> 50</td>

<td>Croscarmellose sodium</td><td> 35</td>

<td>Silica</td><td> 5.5</td>

<td>Stearic acid ~ 1%</td><td> 12</td>

<td>Together:</td><td> 1198</td>

- 16 All ingredients were passed through a 30-mesh sieve. Ibuprofen, silica and MCC 105 were mixed in a V-blender. The resulting homogeneous pre-blend was granulated with water, dried and successively blended with the remaining formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 14, the results of this example demonstrate that the invention provides an in vitro release profile that includes a burst effect followed by a sustained release of residual material. The in vitro profile shows greater than 20% release by 2.0 hours, with a constant rate release and at least 70% release by 14 hours.

Example 15

In another embodiment, the formulation contained ibuprofen, polyethylene oxide (PEO 301), PEO 60K, glycine, sodium carbonate, flow agents, and various tabletting aids wherein the PEO concentration was 32% by weight of the ibuprofen, the sodium carbonate concentration was 25% by weight. ibuprofen, and the concentration of glycine was 37% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 15</td><td>mg</td>

<td>Ibuprofen</td><td> 400</td>

<td>PEO 301</td><td> 50</td>

<td>PEO 60K</td><td> 75</td>

<td>On₂WHAT₃</td><td> 100</td>

<td>Glycine</td><td> 150</td>

<td>Maltodextrin M-580</td><td> 100</td>

<td>Stearvnowv acid</td><td> 10</td>

<td>Silica</td><td> 10</td>

<td>Together:</td><td> 895</td>

All ingredients were passed through a 30-mesh screen. Ibuprofen was mixed with the formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 15, the results of this example demonstrate that the invention provides an in vitro release profile that includes a burst effect followed by a sustained release of residual material. The in vitro profile shows greater than 20% release by 2.0 hours with a constant rate release and at least 80% release by 8 hours.

- 17 Example 16 (not according to the invention)

In another embodiment, the formulation contained ibuprofen, polyethylene oxide (PEO 301), PEO 60K, glycine, sodium carbonate, flow agents, and various tabletting aids wherein the PEO concentration was 32% by weight of the ibuprofen, the sodium carbonate concentration was 25% by weight. ibuprofen, and the concentration of glycine was 37% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 16</td><td>mg</td>

<td>Ibuprofen</td><td> 400</td>

<td>PEO 301</td><td> 50</td>

<td>PEO 60K</td><td> 50</td>

<td>For what₃</td><td> 100</td>

<td>Glycine</td><td> 100</td>

<td>Maltodextrin M-580</td><td> 100</td>

<td>Stearic acid</td><td> 10</td>

<td>Silica</td><td> 10</td>

<td>Together:</td><td> 820</td>

All ingredients were passed through a 30-mesh screen. Ibuprofen was mixed with the formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 16, the results of this example demonstrate that the invention provides an in vitro release profile that includes a burst effect followed by a sustained release of residual material. The in vitro profile shows greater than 20% release by 2.0 hours, with a constant rate release and at least 90% release by 8 hours.

Example 17 (not according to the invention)

In another embodiment, the formulation comprised ibuprofen, polyethylene oxide (PEO 301), glycine, sodium carbonate, flow agents and various tabletting aids wherein the PEO concentration was 25% by weight of the ibuprofen, the sodium carbonate concentration was 25% by weight of the ibuprofen, and the glycine concentration was 25% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 17</td><td>mg</td>

<td>Ibuprofen</td><td> 400</td>

<td>PEO 301</td><td> 100</td>

<td>For? WHAT?</td><td> 100</td>

<td>Glycine</td><td> 100</td>

<td>Stearic acid</td><td> 10</td>

<td>Together:</td><td> 710</td>

All ingredients were passed through a 30-mesh screen. Ibuprofen was mixed with the formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 17, the results of this example demonstrate that the invention provides an in vitro release profile that includes a burst effect followed by a sustained release of residual material. The in vitro profile shows greater than 20% release by 2.0 hours with a constant rate release and at least 80% release by 8 hours.

Example 18 (not according to the invention)

In another embodiment, the formulation included ibuprofen, polyethylene oxide (PEO 301), glycine, sodium carbonate, croscarmellose sodium, free flowing agents, and various tabletting aids wherein the PEO concentration was 25% by weight of the ibuprofen, the sodium carbonate concentration was 25% by weight. ibuprofen, and the concentration of glycine was 25% by weight of ibuprofen in the compressed monolithic tablet.

<td>Example 18</td><td>mg</td>

<td>Ibuorofen</td><td> 400</td>

<td>PEO 301</td><td> 100</td>

<td>On ^ CO.</td><td> 100</td>

<td>Glycine</td><td> 100</td>

<td>Croscarmellose sodium</td><td> 50</td>

<td>DCP</td><td> 150</td>

<td>Stearic acid</td><td> 10</td>

<td>Together:</td><td> 910</td>

All ingredients were passed through a 30-mesh screen. Ibuprofen was mixed with the formulation ingredients in a V-blender. The resulting powder is compressed into tablets using conventional technology.

As shown in Fig. 17, the results of this example demonstrate that the invention provides an in vitro release profile involving a burst effect followed by a sustained release of residual material. The in vitro profile shows greater than 20% release by 2.0 hours with a constant rate release and at least 90% release by 8 hours.

Comparative in vitro data

BRUFEN RETARD is commercially available in Europe as a sustained release formulation of ibuprofen. BRUFEN RETARD tablets are specially formulated to allow a gradual release of the active substance, resulting in stable levels and an extended duration of action between doses. BRUFEN RETARD is a film-coated tablet with 800 mg of ibuprofen. BRUFEN RETARD is indicated for its analgesic and anti-inflammatory effects in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, and osteoarthritis. BRUFEN RETARD is indicated for the treatment of periarticular rheumatism, including fibromyalgia. BRUFEN RETARD is indicated for periarticular conditions such as frozen shoulder (capsulitis), bursitis, tendonitis, tenosynovitis and back pain. BRUFEN RETARD can also be used for soft tissue injuries such as sprains and strains. BRUFEN RETARD is also indicated for its analgesic effect for the relief of mild to moderate pain such as dysmenorrhea, dental care, post-episiotomy pain and postpartum pain.

Example 19 (Figure 18)

The in vitro release course of BRUFEN RETARD tablets was assessed in a dissolution type II apparatus in 900 ml of KH2PO4, pH 7.2, at a paddle speed of 50rpm.

As shown in Fig. 18, the results of this example demonstrate the in vitro data obtained for BRUFEN RETARD. The figure shows that BRUFEN RETARD is unable to provide an in vitro release profile that includes a burst effect followed by a sustained release of the residual material. BRUFEN RETARD did not release at least 20% ibuprofen before 2.0 hours, with a constant release rate with at least 70% release in 14 hours.

Example 20 - In Vivo study

In an in vivo study, the serum concentrations of patients taking tablets containing the modified release formulation of the present invention were compared with the serum concentrations of patients taking immediate release ibuprofen tablets (Motrin® IB 200 mg and Motrin® 600 mg). The tablets containing the modified release formulation according to the present invention showed a burst effect. burst), then sustained release and therapeutic concentration over extended periods of time, which the other two immediate release formulations failed to show. The minimum mean concentration of ibuprofen in the blood plasma of the patient was between 8 and 10 pg / ml for Motrin® IB.

The in vivo behavior of the fixed modified release doses Ia and Ib of Example 1 was compared to the in vivo behavior of the immediate release formulation (Motrin®). 10 healthy male volunteers over 18 years of age participated in an open-label study. After an overnight fast for at least ten hours, each patient received either one 600 mg dose of either of the two modified release tablets described above or 200 mg every four hours for 3 doses of Motrin® IB immediate release formulation or one 600 mg Motrin® tablet. 88 blood samples were collected prior to dosing and at specific intervals up to 12 hours after dosing.

The blood samples were stored in an ice bath prior to centrifugation and centrifuged as soon as possible under cooling at 35,000 rpm for seven minutes. The plasma collected from each blood collection tube was divided into equal volumes into pre-chilled labeled polypropylene tubes. The samples were stored in an ice bath and then stored frozen at -25 ° C 10 ° C until assayed. Plasma samples were analyzed by a fully validated HPLC method. The analytes were separated by reverse phase chromatography. Assay evaluation was performed by constructing an eight point calibration curve (excluding zero concentration) covering the range of 0.400 pg / ml to 51.200 pg / m (in human plasma) for ibuprofen. The slope and intersection of the calibration curves were determined by weighted linear regression analysis 1 / conc.²). The results are shown in Figure 19.

Table 1. Summary of the 90% CI

<td>Preparation</td><td colspan="3">Standard: D (1 x 600 mg)</td><td colspan="3">Standard: E (3 x 200 mg)</td>

<td></td><td>Cmax</td><td>AUC () - last</td><td>AUCo- »</td><td>Cmax</td><td>AUC () - last</td><td>AUCo- »</td>

<td>B (Ia)</td><td> 42,4-53,8</td><td> 96,2-115</td><td> 97,0-116</td><td> 67,0-85,0</td><td> 86,9-104</td><td> 86,3-103</td>

<td>C (lb)</td><td> 44,7-57,0</td><td> 96,9-116</td><td> 98,7-119</td><td> 70,7-90,3</td><td> 87,5-105</td><td> 87,7-106</td>

<td>D</td><td> -</td><td> -</td><td> -</td><td> 140-179</td><td> 82,3-99,2</td><td> 80,9-97,7</td>

<td>E.</td><td> 55,9-71,5</td><td> 101-122</td><td> 102-124</td><td> -</td><td> -</td><td> -</td>

D is 3 x 200 mg MOTRIN® IB

E is 1 x 600 mg MOTRIN®

Treatment (B &amp; C) versus Treatment E

-21 Systematic ibuprofen exposure following administration of one 600 mg tablet of ibuprofen Ia or Ib (Treatment B &amp; C) was similar to that achieved with the administration of one 600 mg MOTRIN® tablet in comparison. The peak exposure to ibuprofen from one 600 mg ibuprofen tablet Ia or Ib (Treatment AC) was significantly lower than that from the 600 mg MOTRIN® tablet. The absorption time was modified by comparing one 600 mg tablet of ibuprofen Ia or Ib (B &amp; C treatment) with the median value of T_max 5.0 hours up to 1.5 hours T._max one 600 mg MOTRIN ® tablet.

Treatment (B &amp; C) versus Treatment D.

Systematic ibuprofen exposure following administration of one 600 mg ibuprofen Ia or Ib tablet (Treatments B &amp; C) was similar to that obtained for comparison to administration of three 200 mg MOTRIN® IB tablets. The peak exposure to ibuprofen from one 600 mg ibuprofen tablet Ia or Ib (Treatments B &amp; C) was significantly lower than that of the three MOTRIN® IB 200mg tablets. The absorption time was modified by comparing one 600 mg tablet of ibuprofen Ia or Ib (B &amp; C treatment) with the median value of T_max 5.0 hours up to 1.5 hours T._max three MOTRIN® IB 200mg tablets.

Figure 19 shows the results discussed above. Treatment D shows an initial burst which falls into the valley in four hours and a second tablet is administered. This valley occurs again at eight o'clock. This valley includes the minimum plasma concentration for ibuprofen that should be considered therapeutic. A mean plasma ibuprofen concentration of about 6.4-10 pg / ml is considered the blood concentration of ibuprofen to be clinically effective. Treatment E shows an extreme initial burst of ibuprofen, then a steady decline that falls below the therapeutic threshold in approximately 6 hours.

Treatments B and C have an initial burst of ibuprofen that will reach 6.4 pg / ml in approximately 0.5 to 1 hour and maintain the level until approximately 12 hours. The present invention provides a single dose of ibuprofen that provides an initial burst of ibuprofen. (burst) similar to an immediate release ibuprofen formulation and then provides a mean plasma concentration of ibuprofen above 6.4 pg / ml for approximately 12 hours.

Danuta Stefani-Iwanow

Patent Attorney