Stables compositions of microgranules of gastro-protected omeprazole and process for their preparation

dV0 93/25204 PCT / FR93 / 00582 1 Stable compositions of micro ~ ra ~ nules of omeprazole ~ astro-proteués and their process for obtaining The present invention relates to a galenic formulation of omepr azole in the form of gastro-protected microgranules having stability over time compatible with pharmaceutical requirements as well as the manufacturing process of said microgranules.

Omeprazole or 5-methoxy- 2- [[(4-methoxy -3,5-dimethyl -2pyridinyl) methyl] sulfinyl] -1H-benzimidazole, an anti-ulcer substance reducing gastrointestinal acid secretion, is well known and has been described in particular in Swedish Patent No. 78 04231 (Aktiebolaget H ~ ssle Fack).

T1 is also known that omeprazole has a very low solubility in water, but that it is on the other hand very soluble in alkaline solutions and that it degrades very quickly in an acidic medium.

Its degradation half-life is ten minutes in aqueous solutions of pH less than 4, eighteen hours to one. pH equal to 6.5 and about 300 days for a pH of 11.

When omeprazole is used orally, it is therefore essential to gastro-protect the galenic form of the active ingredient (capsules, tablets or powder) so as to avoid any contact thereof in an acidic medium at the level gastric while achieving rapid dissolution in the intestinal environment, the level at which omeprazole must be absorbed, i.e., as soon as the ambient pH becomes greater than 6.8.

The in vitro dissolution characteristics of an oral formulation of omeprazole as well as the bioavailability results achieved in humans using these oral formaalations, consisting of protected granules were described in the Journal of Scandinavian Gastro-enterology ( 1985; 20 (suppl.

108): 113-120, Pilb: ran A.

Cederberg (;).

However, it was found that the conventional enteric granules did not exhibit sufficient stability over time to be used in a satisfactory pharmaceutical form (capsules or tablets of microgranules), since a degradation of the active principle is rapidly observed when they are placed under normal conditions of use (ambient temperature of 25 ° C, humidity between 40 and 75%), with the appearance of WO 93/25204 PCT / FR93 / 00582 2 harmful degradation products, as described for example in Acta Chemica Scandinavia 43 (1989) 536-548 (Arase BR, ~ NDSTROM & AL.).

To overcome these drawbacks, it has in particular been proposed (EP-A0 247 983 Hl ~ SSLE AG), to mix in a mass of cellulose coating derivatives and disintegrants an adequate amount of omeprazole and an alkaline sodium salt. , potassium, magnesium, calcium or alkaline ammonium salts, so as to obtain by extrusion a core whose composition is buffered and has an alkaline pH between 7 and 12.

The microgranules thus produced are then conventionally gastro-protected and meet the dissolution and gastro-resistance standards defined for optimal use of the product by the oral route, that is to say a dissolution greater than 76 ~ 1o after 30 minutes in an aqueous medium with a pH equal to 6.8 and a gastro-resistance greater than 85% after 2 hours in a medium with a pH equal to 1.2.

However, this type of embodiment has several significant drawbacks, both from a technical and economic point of view.

First of all, this makes it necessary to prepare combinations of products and mixtures, with risks of overall toxicity and instability during the manufacturing process.

In addition, it is necessary to use a specific type of expensive device adding to the high cost of the active principle, which tends to increase the price of the finished product too much for massive use worldwide the daily treatment cost linked to the use of such a product being much higher than that obtained by using a treatment of the bismuth salt and metronidazole or macrolide type acting as an antacid and destructive agents of Helicobacter pylori (agent responsible for the majority of gastrointestinal ulcerations).

The object of the invention overcomes these drawbacks.

It relates to a new stable formulation of gastro-protected microgranules of omeprazole and the process making it possible to obtain them, under advantageous economic conditions.

According to the invention, the omeprazole is used in the form of a powder diluted in a substantially equal amount of mannitol so as to ~ obtain a homogeneous and stable suspension and so as to ensure better uniformity of the omeprazole content during application on neutral grains consisting of a mixture of sugar and starch.

WO 93/25204 - PCT / FR93 / 00582 3 The present invention therefore relates to a stable formulation of omeprazole microgranules characterized in that they comprise a neutral core consisting of sugar and starch coated with an active layer comprising a dilution of omeprazole in mannitol in substantially equal amounts.

By diluted powder is meant according to the invention a mixture of an omeprazole powder ~ a mannitol powder, sodium lauryl sulfate and carboxy methyl starch:

Preferably, the mixed powders have a substantially equal particle size, less than 100 microns.

The term “substantially equal amounts” means an omeprazole powder I mannitol powder weight ratio close to 1, that is to say between 0.9 and 1.2.

The neutral cores consisting of sugar and starch in proportions by weight close to 4 parts to 1 part of omeprazole powder, have an average diameter of between 0.7 mm and 0.9 mm.

The layer of active principle, or active layer applied to the neutral grains will preferably have a thickness of between 100 and 300 μm approximately (0.1 and 0.3 mm):

To ensure good stability of the active principle during storage of the microgranules according to the invention, the moisture content of the active layer is less than 1%, preferably less than 0.5%.

In addition, the microgranule according to the in ~~ ention advantageously comprises a complementary protective layer of the active layer consisting of mannitol and a binding agent, in order to permanently isolate the core on which is applied the omeprazole of the layer external coating intended to ensure gastroprotection of the active nuclei.

Preferably, the binding agent is hydroxypropylmethylcellulose (HPMC), while the enteric layer comprises hydroxypropylmethyl cellulose phthalate (HPMCP) or ammonium copolymers of methacrylic acid and talc.

To meet the in vitro dissolution criteria for omeprazole microgranules that at least 75% of the omeprazole must be dissolved after 30 minutes when placing the microgranules in an aqueous medium with a pH of 6.8 and at a temperature of 37 ° C ,, is added to the mixture WO 93/25204 ~ ~ PCT / FR93 / OOS82 4 initial omeprazole and mannitol about 10% of carboxy-methyl-ami ~ on (EXPLOTAB ~ marketed by the MENDELL company) in order to obtain ~ I. complete disaggregation granules at a pH of 6.8, as well as about 5% ion surfactant such as sodium lauryl sulfate which improves ~ the solubilisatson of omeprazole in the intestinal environment.

I In addition, as binder solutions are used to apply the active layer to the neutral grains and then the additional protection of manni ~ Iol, high viscosity solutions of the order of 15 centipoise (15.10-3 Ps) of hydroxypropylmethylcellulose (HPMC ) (P ~ COA ~ marketed ~ ar the company SHINETSU) used in solution in a mixture of at least 8% ethanol and at most 20% water, for example a mixture of 10 parts of at for 90 parts of ethanol at 95 ° and in small quantities in order to Iimiter ~ as much as possible the solvent and water content of the granules throughout the manufacture of the active granules.

Finally, according to one embodiment of the stabilized omeprazole granules according to the invention, the enteric coating of the microgranes consists of hydroxypropylmethylcellulose phthalate (HPMCP) (HP 5 ~ 4 R, * sold by the company SHIN -ETSU) in 7.5% solution in ~ an 80-20 mixture by mass of acetone and 95 ° ethanol, is applied in external bends after pre-assembly of the active microgranules of omeprazole and mannitol by spraying '' a 33% sucrose syrup, in a water / ethanol mixture of 44/56 by mass, this sugar syrup having a total sucrose weight of approximately 25% relative to the amount of gastro-resistant coating.

This outer layer may include talcum lubricant.

Throughout the duration of the various application and coating phases, the temperature of the granules is maintained between 32 ° C and 38 ° ~ and between each phase, drying is carried out at a temperature between 35 ° C and 40 ° C so that the contents of solvents and water are minimal, the final content being less than 1% for water and 2000 ppm for ethanol.

Other features and advantages of the invention appear ~ lt in the light of the examples below.

Example 1: Process for the preparation of Microgranules of Omépra ~ ZOle * Trademark VVO 93/25204 PCT / FR93 / 00582 .6 dosed at 8.9: 1% by weight.

All the quantities mentioned are expressed in kg of dry mass for a final quantity equal to 237.80 kg of microgranules having a content of 84.1 mg of omeprazole per gram of microgranules.

COMPOSITION Neutral grains of sugar and starch 80.00 Active layer: Omprazole 20.00 Mannitol 20.00 Carboxymthyl starch (CMA) 4.00 Sodium lauryl sulfate 2.00 Additional protective layer Mannitol 50.00 Sucrose 8.00 HPMC 15 centipoise 3.20 Eastro-resistant layer HPMCP 32.00 Talc 18.60 237.80 The process according to the invention consists in preparing a dilution of 20 kg of omeprazole in 20 kg of mannitc ~ l in the presence of 4 kg of CMA and 2 kg of lauryl sulphate of:> odium, then to bind this dry dilution on 80 kg of grains ~~ {~ neutral sugar and starch whose diameter is between 0.7 and 0.9 mm using a solution of HPMC (l, 6 kg ) at 4% in water (20 parts) and ethanol xr 'at 95 ° (80 parts) in a circular turbine with an inclined flat bottom, then to protect the active grains thus obtained using 50 kg of mannitol applied with the rest of the HPMC solution (i.e. 1.6 kg), then in preassembling the granules thus protected by a sugar syrup (8 kg of sucrose) at 33% consisting of 44 parts of water for 56 parts of ethanol at 95 ° and finally applying the gastroprotective coating due 32 kg of HPMCP in 7.5% solution in a mixture of 80 parts of 95 ° ethanol for 20 parts of acetone.

WO 93/25204 PCT / FR93 / 00582 .m ~~.

6 The granules thus obtained show gastroresistance greater than 85% in a medium of pH 1.2, since after 2 hours at 37 ° C., the quantity of omeprazole not released in this medium is 91.7%.

In an aqueous medium with a pH equal to 6.8, the dissolution of the granules shows after 30 minutes an omeprazole level of 92%, ie an amount greater than 75% which is the minimum acceptable standard.

After 12 and 24 months, the respective gastroresistance values ​​are 92.1% and 92.8% and the solutions at pH 6.8 are 91.4% and 93.8% under the same operating conditions.

In addition, the very light beige color of the microgranules stored in capsules at room temperature and an external humidity of 60% in glass flasks with lid fitted with a desiccant capsule, is kept constant for a period of at least 24 months.

Example 2 Stability Tests The study of the stability of Omeprazole was carried out on 4 lots of gelatin capsules comprising the microgranules according to the invention and a lot of microgranules.

The controlled batches, the storage conditions; the analysis methods as well as the results are presented below.

1. LOTS CONTROLS Omeprazole eélules C458-1-2, C458-1-6, C458-2-3 and C458-2-4 Omeprazole micro ~ ranules UQM 001-3 LOTS TIME DATES MANUFACTURING CONSERVATION (months) C458-1-2 June 1983 36 C458-1-fi February 1984 36 0458-2-3 September 1984 24 C458-2-4 October 1984 ~ 24 UQM 001-3 October 1990 3 WO 93/25204 PCT / FR93 / 00582 2 ~ ~ a ~ ~ 9 7 2. STORAGE CONDITIONS - 25 ° C - Relative humidity 60% - 30 ° C - Relative humidity 30 - 40%, 60% - 37 ° C - Relative humidity 20 - 30%, 90% _ - 50 ° C - Relative humidity 80% - Refrigerator 3. ANALYSIS OF THE SAMPLES a.aélules Sample solution A - For the omeprazole determination, place the contents of 5 capsules in a 250 ml volumetric flask, then introduce 200 ml of metha-ol ammonia solution ( 9515), and stir magnetically for 30 minutes.

Plot using the same solvent.

Filter and dilute 10 ml of filtrate in a 100 ml volumetric flask with 30 ml of dichloromethane and make up to volume using a methanol-ammonia-dichloromethane solution (24/1175).

B - For the determination of degradation products, dissolve: the contents of 2 capsules in 8 ml of methanol-ammonia solution (95 ~ 5), under a steady state for 30 minutes.

Filter and dilute 2.5 ml ~ of the q P ii filtrate to 100 ml in dichloromethane.

Inject immediately.

i Anyareillaae and conditions ii HPLC device equipped with a UV detector

- Precolumn of silica, 7 .mu.m, 15 mm long x 3.2 mm internal diameter (Brownlee or equivalent).

- Lichrosorb Si 60 column, SFcm, 124 mm long x 4 mm internal diameter * (Hibar Merck or equivalent).

- Flow rate: 1 ml / min.

- Reading at 280 nm - injection: 40 / d.

System check Once baseline stability is achieved, the system is checked as follows * Trademark WO 93/25204 PCT / FR93 / 00582 8 2138149 Dissolve 5 mg of standard omeprazole and 5 mg of sulfone corresponding H 168 / 6fi (the structural formula of which is reproduced below) in 100 ml of mobile phase.

Inject 40 µl several times until a retention time constant is obtained (difference between two injections <1 ~ lo).

0 S .. ~ H, ', ~) ~' ~ '~ t.: ~.

wo H ~ ~ cH ~ H ~ 1o The retention time of omeprazole is 10 minutes and that of sulfone H 168/66 is 8 minutes.

b. microsranules Determination of the omeorazole content of the microeranules The omeprazole content of the microgranules is determined by spectrophotometry in the ultraviolet after separation by high performance liquid chromatography.

Reagents - Acetonitrile for HPLC (e.g. CARLO ER, BA ref. 412409) - dibasic sodium phosphate (Na2HP04) - Monobasic sodium phosphate (NaH2P04, H20) - Distilled water - Reference substance: OMEPRAZOLE Apparatus for liquid chromatography with UV detector (280 nm) * 2 columns in series, in stainless steel : 'precolumn: length 1.5 cm - ~ internal 3.2 mm -' i grain size 7 ~ cm - column: length 12.5 cm - internal 0 4 mm grain size 5 um I WO 93/25204 PCT / FR93 / 00582 9 2138149 * Stationary phase: Lichrosorb RP 18 i * Injection system: for quantities of 20 / cl (for example automatic injector * WISPT712). *, * Integrator: - LCI 100 PERKIN ELMER or WATERS fi45 DA ~ A 6 MODULE Aastro-resistance and dissolution tests i The microgranules are subjected, for 2 hours 30 minutes, to stirring in appropriate media at constant temperature (37 ° C + / - 0.5 ° C) in ~~ n dissolution apparatus. f Ap ~ areilla ~ e The dissoluüon apparatus used is the paddle apparatus described in ~ the European Pharmacopie.

Rotation speed: 100 revolutions / minute Volume used: 500 ml of pH 1.2 medium.

Addition of 400 ml of medium of pH 7.6.

Nfilieux Medium I: Acid resistance medium.

Place in a 1 liter volumetric flask, 2 grams of sodium chloride ~ t 7 ml of concentrated hydrochloric acid (37%).

Make up to volume with purified water.

Shake until dissolved.

The pH of this solution should be 1.2 ± 10.05.

Medium II: Medium of pH 7; 6 (addition) Dibasic sodium phosphate solution (Na2HP04) 0.235 M.

Prepare 1 liter of solution for 2 vases.

4.RESULTS AND CONCLUSIONS The results are summarized in the tables below.

When determining the impurity content, two main impurities are detected on all batches.

In the results tables, they are identified under the names I and I '.

A: Storage period (months) B: Storage conditions - ° C Relative humidity C: Appearance * Trademark A WO 93/25204 ~~ ~ '~ ~ PCT / FR93 / 00582 Omeprazole capsules lot C458-1-2 5 ABCDEFIP Others%%%' 0 a 6 20.3 <0.5 <0.5 <0.2 i 10 6 25 60 a 5 20.6 <0.5 <0.5 <0.2 i 30 60 a 7 20.1 <0.5 <0.5 <0.2 50 80 c 7 19.4 <0.5 <0.5 <0.3 12 25 60 a 5 20.5 <0.5 <0.5 <0.2 30 60 b 6 20.5 <0.5 <0.5 <0.2 18 25 60 a 6 19.8 <0.5 <0.5 <0.2 30 60 b 6 20.1 <0.5 <0.5 <0.2 24 25 60 a 6 20, 7 <0.5 <0.5 <0.2 30 60 c 7 20.2 <0.5 <0.5 <0.3 30 25 60 a 6 20.3 <0.5 <0.5 <0 , 3 i 36 25 60 b 6 19.9 <0.5 <0.5 <0.3 refrigerator a 6 20.8 <0.5 <0.5 <0.2 a = white, b = colored, compliant, c = colored, non-compliant. ~ WO 93/25204 ~~ C.'T / FR93 / 00582 11 Omeprazole capsules lot C458-1-6 ABCDEFIP ~ 4other ~ lc rlc ~ a 5 19.4 <0.5 <0.5 <0, 2 6 25 60 a 5 19.6 <0.5 <0.5 <0.2 30 60 a 6 19.5 <0.5 <0.5 <0.2 50 80 c 7 18.7 <0, 5 <0.5 <0.4 12 25 d30 a 5 19.2 <0.5 <0.5 <0.2 30 60 b 6 19.3 <0.5 <0.5 <0.2 18 25 60 a 5 19.7 <0.5 <0.5 <0.2 30 ~ 0 b 5 19; 1 <0.5 <0.5 <0.3 24 25 E0 a 6 19.0 <0.5 <0.5 <0.2 30 60 c 6 19.2 <0.5 <0.5 <0.3 30 refrigerator a 6 19.8 <0.5 <0.5 <0.2 25 60 a 5 19.3 <0.5 <0.5 <0.2 36 rfrigrat, ~ ur a 6 19.8 <0.5 <0.5 <0.2 25 fi0 b 5 19.2 <0.5 <0.5 <0.2 a = white, b = colored, compliant, c = colored, not in accordance with WO 93/25204 PCT / FR93 / 00582 12 Omeprazole capsules lot 0458-2-3 ABCDEI ~ Others%% ~ a <5 21.2 <0.5 <0.5 <0.2 6 refrigerator a <5 20.9 <0.5 <0.5 <0.2 25 60 a 5 21.1 <0.5 <0.5 <0.2 12 refrigerator a 5 20.8 <0.5 <0 , 5 <0.2 25 60 a <5 20.7 <0.5 <0.5 <0.2 18 refrigerator a <5 20.6 <0.5 <0.5 <0.2 25 60 a 5 20.4 <0.5 <0.5 <0.2 24 25 60 a 6 20.7 <0.5 <0.5 <0.2 a = white, b = color, compliant, c = color, non-compliant Ompraz ole glules lot C458-2-4 ABCDEIP Others%%% 0 a 6 20.7 <0.5 <0.5 <0.2 6 25 0 a <5 20.8 <0.5 <0.5 <0.2 12 25 60 a 5 20.3 <0.5 <0.5 <0.2 18 25 60 a 6 20.5 <0.5 <0, 5 <0.2 24 refrigerator a 5 20.0 <0.5 <0.5 <0.2 25 60 b 5 20.4 <0.5 <0.5 <0.5 a = white, b = colored , compliant, c = colored, non-compliant. ~ 49 W ~ 93/25204 PCT / FR93 / 00582 13 ~ ineprazole microgranules U ~ M 001-3 A: Storage period (months) B: Condition: storage temperature - ~ C Relative humidity C: Appearance D: Determination of omeprazole (mg / g) E: Gastro resistance test F: Dissolution Test -% ABCDEF 0 a 78.0 95.9 95.0 1 25 55-65 a 80.8 93.9 94.0 30 30-40 a 81.2 94.4 95.0 37 20-40 a 80.4 97.0 97.0 37 90 a 77.6 97.5 100.0 3 25 56-65 a 81.4 91.6 92.0 30 30-40 a 79.1 95.7 96, 0 37 20-40 a 80.2 92.0 93.0 37 90 c 41.9 - a = white, b = colored, compliant, c = colored, non-compliant The capsules have good stability in the refrigerator and at 25 ° C, up to 36 months of storage.

All impurities have a concentration of less than 0.50%.

The content of impurities increases a little more with temperature and humidity, and may be su ~ sante to cause staining of the granules.

Microgranules stored in bulk have good stability for 3 months at room temperature and relative humidity 55-65%, at 30 ° C and relative humidity 30-40% and at 37 ° C and relative humidity 20-30%, and for 1 months at 37 ° C and relative humidity 90%.

WO 93/25204 â'CT / FR93 / 00582 '~. ~ 14 LONG, EE OF VALIDITY In view of the results obtained, the specialty is stable for 36 months, provided that it does not exceed 25 ° C during this period.

STANDARDS 1.

Appearance hard gelatin capsules containing whitish to more or less dark beige granules without foreign particles.

2.

Average weight - about 235 mg ~ 10% 3.

Omeprazole content 18.0 - 22.0 mg / capsule (90 - 1I0%) 4. Resistance in acidic medium 85% 5.

Release at pH 6.8 z75% 6.

Degradation products total content s 2.4% I5 individual contents s 0.5% Of course, (a person skilled in the art will be able to make variations in the embodiments of the microgranules according to the invention, in particular, by using devices coating such as fluidized beds instead of the flat bottom turbines described above, or enrnre using methacrylic polymers as gastroprotective materials (for example EUDRAGIT ~ L 100-55 or L 30 D from the company ROHM & HASS) or other gastro-resistant polymers without going beyond the scope and the scope of the invention.

On the other hand, (the invention is not intended to produce microgranules by the conventional extrusion techniques already described in the prior art, these techniques requiring the use of omeprazole in solution in a mass containing solvents and water, which is avoided thanks to the embodiments of the method described above in order to overcome the consequences of the instability of omeprazole under such conditions.