HU230900B1 - New granulating process and the granulates prepared by this - Google Patents

Description

OH GRANULATION PROCESS AND THIS GRANULATE

SERVICE INVENTION

EGB Pharmaceuticals

Publicly M & A Hearing Company Limited. Budapest

Internal Priority Claims P 09 00408

Internal Priority: Dawn: 2 (Jun 0 & s 2S.

FeltáláMkc '

Dr. Zoltán Tölgyesi 35% daddy Dr. Zsigmood Zsolt 20% Maglód Dr. György IJjfahssy 20% Budapest LevenOszné Huszár Magdefea 10% Budapest Dr. TnnfeaLNagy Peter 10% Budapest Monika Agyages 5% Sajöszeoipéto

Filed on: January 25, 2010

SUMMARY OF THE INVENTION The present invention relates to a high-grade gmrmmatmn produced by this process for the production of a granulate containing thousands of milligrams of kernel material in microcrystalline form on an industrial scale, and a cereal bowl made with such a grapefruit. The GMMs prepared according to the process of the present invention contain the active ingredient in a unitary form and are advantageously useful in the field of pharmaceutical delivery. késritményekben.

Ezezzyme is a selective cholesterol: absorption inhibitor which, in combination with an OMG ^ CoA mductase: inhibitor (statin), has been shown to improve nutritional control when administered to patients with primary ischemic erosive familial and non-familial hyperpholesterolemia when used alone.

Echinacea is a white crystalline powder with regard to its chemical properties, insoluble in deep water and in digestive juices, but soluble in organic solvents. The Bío & Mfoia Classification! According to the BCS system, ezetimibe is a Class 11 active ingredient, in which the litter is highly dependent on the solubility of the active ingredient. For therapeutic effect, despite the water solubility of the active ingredient, adequate bioavailability must be achieved. Appropriate:

many solubility-increasing procedures have become known

EP1799648. European Patent Application: Ezetimibe is prepared as an amorphous form of a polymeric adsorbent or an amorphous dl spermate in solid form.

No. WG200W63766. International Patent Application No. 5,102,125 discloses a composition comprising amidorphous ezedmib solid dispersion and at least one solubility enhancing polymer. In one embodiment, ezetimibe and the enhancer polymer are dissolved together in a common solvent: either in a solvent mixture, and the solution is supplemented or spray-dried. Alternatively, the ezetimibe can be melted in the melt of the solubility-enhancing polymer and then spray-melted. it is dissolved in a solvent pellet in which the polymer is less soluble in a less volatile solvent, so that the polymer is precipitated earlier when the solution is evaporated or spray-dried.

© bP 1849459. European Patent Application EP-A-00004 discloses a pharmaceutical composition in which: ezetimibe is ground together with at least one hydrophilic excipient, e.g.

with saccharide or with polysaccharide, starch, eltoelatinate starch After milling, ezetimibe has a grain size d »0.5} of less than 25 µm.

WO 2007/011349. In their International Patent Application, their active ingredient has a poorly soluble content, e.g. ezetimlb's biohazoaxaxes increase the intimacy of its hormone material to a pharmaceutically acceptable eukorml. Ex a intimate contact may be achieved by dissolving the sugar and granulating the active ingredient therein.

No. 1'S 200 "0275052. US álmuekbeli discloses a pharmaceutical composition which ensure adequate solubility in ezeümib particle size d (90) is smaller than 25 _(m.

WO 2008'101723. International Patent Application No. 5,102,125 discloses a drug physiologic composition in which the ezetimpho is uniformly distributed in amorphous form in a hydrofluoric polymer.

The WC32ÖO9 / _O77573: no. international patent application is such; discloses a suspension in which ezetimibe is micromachined: it has a very small particle size and a high surface area of ezetimibe in the form of micromers. During the preparation of the suspension, the; ezetimibe is taken up in solution and then precipitated with antisobnms, the precipitate is recovered, dried and then re-suspended and. The suspension thus formed is homogenized.

The prior art methods of the present invention include the use of ezetimibe d ' is achieved by feeding the ezetinrib to the wf state or by applying a micromix. These processes have several disadvantages and difficulties.

The high free energy of the amorphous state is fossilized, on the one hand, into a prone crystalline form, which results in solubility and thereby renders the bioavailability irreversible and destructive, and, on the other hand, the chemical stability of the amorphous hafoic material; lower. Therefore, special excipients and procedures are usually required to maintain the amorphous state.

Another common technique used to increase the solubility of ezetimibe mini is to significantly increase the free energy of the material, which results in a deterioration of chemical stability and, on the other hand, to clumping, yeast oil loss, and thus environmental load. Furthermore, the micronized active substance usually accumulates edge electrostatic charges and, due to interparticle repulsive forces, favors a low bulk density which is less suitable for further processing.

A. the separation of the therapeutic delay is a suitable solubility and bisacidification; available in crystalline form. even without the need for milanization. In this way, the product produced by & micromanaging can eliminate the increase in tableware energy, the loss of chemical stability, the risk of static buildup of particles, and the prevention of environmental and health hazards. Such a procedure is described in WO2009 / 077573. the process described in the international application, which, while eliminating the above-mentioned drawbacks, is a complicated, multi-step process which is not suitable for the industrial suspension of ezetimibe without microcrystallization; in size. Further, the ezetimibe suspension produced by the meal described in the application; ezetimibe rubbish; it has a very wide range and the distribution of grains is extremely hdemgsmtek bekinthsta

It is an object of the present invention to provide a quick and simple process on an industrial scale that improves the adverse effect and thus the yield of crystalline ezetimibe without the disadvantages of the prior art amorilization and micronization processes described above.

The above object is solved by the process according to the invention.

The present invention is a fast, 3-step process that results in an industrial-scale, homogeneous particle size distribution and barrel particle size range, so as to request ezetimibe without micromachining and damping to a state that provides proper, rapid dissolution and proper bioavailability. The present invention therefore relates to a process for the preparation of a microcrystalline ezetimibe-containing granule e'oa tasaru

(a) ezetimibe is dissolved in solution;

b) precipitating the dissolved ezelimibe in water, optionally containing pharmaceutical excipients, preferably laarylsilfet;

c) spraying the resulting stertzenzene on the surface of pharmaceutical excipients to form granules.

The process of the present invention does not require the extraction, drying of ezetimibe, and the slurry formed by mixing the ojra-suspension, the solvent containing the ezetimibe and the water containing the pharmaceutical excipients can be directly converted into microscale ezetimibe granules.

The present invention is based on the surprising realization that the silver oxide is soaked in a solvent capable of being solubilized in a high machine concentration, then the appropriately selected excipients are precipitated in water under suitably chosen conditions, and the resulting suspension is directly micronized and then spray-dried. A granulate containing azetimilb of Form Ib can be obtained. The granules thus formed, either alone or in the form of a pharmaceutical formulation, e.g. converted into tablets, capsules, to provide an appropriate rate and extent of release. Thus, the process of the present invention does not require: recovering, drying, and resuspending the ezethnib from the suspension. In fact, during the recovery from the suspension and drying, the phenomenon of aggregation often occurs when the predominantly microcrystalline drug sticks to larger aggregates, which impairs the dissolution of the drug and the reproducibility of the drug release.

As used herein, the term "microcrystalline exetimib" typically refers to crystalline ezetimibe of less than 75 µm, preferably less than $ 0 µm, most preferably less than 25 µm.

The stability of the microcrystalline ezedmib granules produced by the process of the present invention is very good, and the degree of contamination does not increase significantly even in eagle storage. The results of the one-year stability tests are shown in Table 1®.

Surprisingly, it has now been found that water is in itself a constituent of the process of the invention. Until WO2009 / 077573. Application examples L and 2, the precipitation at neutral pH used in precipitation used in Examples L and 2 is extremely high and therefore does not comply with pharmaceutical specifications and is therefore not suitable for use in pharmaceutical formulations (cited in Table L applied, no major degradation as described by the inventors of the above application was observed.

Surprisingly, we have found that the microcrystalline ezetimlh formed in the 3-step water treatment of the present invention is well below the allowable limit for long-term storage: no significant increase in the degree of contamination (IdL 1, Table) :.

ú

Ezetimlb for high woodcentrum © Másaerek © Mósaerek. preferably

Aliphatic alcohols having from 1 to 4 carbon atoms, more preferably 2-propanes, elanes, isopropanes, methanol; the number of smokers 1-4: ketones, donut, aeetom and OMSG. Particularly monomeric are these low-ferrous cosol solvents, which can be evaporated with low energy consumption, preferably by bursting and isopruptyl.

Water soluble excipients are known to those skilled in the art. processing agents and agents that increase the stability of the active ingredient.

Solubility enhancers include, but are not limited to, the following:

foam materials such as e.g. sodium lauryl sulphate, triethanolamur lauryl sulphate, soda limeate, sodium cmulsulbt sodium monoctoctyl bis succinate, pMisorbates, water-soluble, hydrophilic polymers, alkobes are saccharides such as syncrose, lakié, mannitol, deMröz, Serbian; polysaccharides such as e.g. Alginic acid, tragacantha, alginates. dextriu, maltodextrin. polyglycolics such as vinethylglycol, propylene glycol;

Auxiliaries for processing into pharmaceutical compositions are those known to those skilled in the art, and without limitation to the present invention include, but are not limited to, hydro® binders such as PW, RPMC, HPC. HMC. The P ¥. gelatin, xanthan gum, guar gum, starch mucilage and pre-gelatin. CMC-Xa

Excipients that increase the chemical stability of the active substance when the medicinal product is different from ezetimibe. labile. It also contains pk oxidation-sensitive active ingredients, without being limited to the present invention, in particular: pH regulators. antioxidants, pL sodium sulfate, ascorbine. butyl-hydroxy-aaizol; buffalo-hydmxi-toluene, chelating agents, e.g. nitric acid, EA

Surprisingly, it has now been found that in the process of the present invention, the ezetimibe is a solvent and a solvent. a non-reactive suspension containing microcrystalline ezetimibe as a result of the rapid mixing of the water-soluble excipients and the excipients ^; will come out. In contrast, 'WO2009 / 077573. in the procedure described in the application: the cough ^: eye-smoker; process several hours, requires and. The resulting suspension tends to aggregate and further steps are required.

In the feed rate method, the two solutions are mixed rapidly with uniform mechanical stirring with vigorous stirring. The mixing is carried out for 5 to 300 seconds, preferably 15120 seconds, most preferably 30 to 60 seconds. The mixing is then continued, if desired, to utilize the resulting suspension suspensively, optionally with further dewatering of the suspension before use.

Surprisingly, it has been found that eze-mofet is dissolved in sorbene, preferably © phenol or isopropsnol;

the fallout itself uses water;

.the. This < RTI ID = 0.0 > < / RTI > water: particle size distribution and particle size distribution of the microscopic crystals of ezetcibe obtained by rapid and uniform mixing (Fig. 5). in the international application, the resulting suspension does not contain agglomerates of the agglomerates, and that the resulting thousands of milligrams meet the pharmaceutical standards.

In our experiments, the typical particle size of the suspension did not exceed 5 µm for d (50) and 17 µm for d (0O). The measurement was performed on a Maivem Mustersizer 20µU after ultrasonic shaking.

The present invention also provides a process for preparing a suspension of the microcrystalline ezetimibe content, characterized by leaving it.

a) placing ezetimibe on a page;

b) precipitating the dissolved ezetimibe in water, optionally containing pharmaceutical excipients, preferably a lauryl sulfate derivative.

Furthermore, the step of applying the suspensions prepared as described above to a solid pharmaceutical excipient or a mixture thereof, followed by evaporation of the solvent, is of fundamental importance in the present invention.

4 suspensions are sprayed onto a fluidized powder bed in which pharmaceutical excipients are suspended, in a manner known to those skilled in the art. In most embodiments, the atomisation is carried out, preferably in a fluidized bed granulator, which evaporates the solvents delivered by spraying using a counterflow hot air, and then dries the gammadium.

The suspension can also be blended onto a slurry in a spray kneading machine known to those skilled in the art, in which pharmaceutical excipients are maintained in intense motion. In this embodiment, the spraying is preferably provided with vacuum drying and, in a particular case, plating with micromolylate. This is done in a so-called vacuum processor, which, by means of vacuum and optionally microwaving excitation, evaporates the solvents supplied by spraying to a cute output and then dries the granulate.

The suspension of the suspension on the surface of the suspended or (mtenzfvm mixed excipients) adheres to: ezefemb crystals, and the solute excipients are precipitated, fixed, parallel to the wetting of the mass of the material. The powder was suspended in powder co-diaphragms at the same time as drying, at a capacity that maintains the optimum bed humidity for germline formation. After the spraying is completed, the remaining solvents are removed as necessary to maintain drying. The dry granulate thus obtained is optionally milled over a mesh size or a perforated plate, according to a further purpose.

The pharmaceutical excipients to which the ointment is modified, chewed and then sued are substances that increase the solubility price and release of ezetine rib in the digestive juices (1) and the recovered and filtered granulate for further processing (2). .

(1) According to the present invention, the auxiliary agents which increase the solubility and release of ezeilibibe in the digestive tract are, in particular, hydrophilic soluble soluble auxiliaries which are a. Frequently known to those skilled in the art as hydrophilic fillers and desmegrants. These include, but are not limited to, the following;

saccharides, such as: saeharoz, iia, mammite;

polyssaeharides, casein, alginic acid, tragacanth, algae, starches, starch derivatives:

celluloses and cellulose derivatives such as microcrystalline cellulose, crystalline cellulose, low substitution hydroxypropyl cellulose, carboxylmethyl cellulose crosslinked sodium, potassium salts; and the physico-chemical properties that are preferred for further processing are selected from materials.

Also included is a granulate prepared by the process described above.

The present invention also relates to pharmaceutical compositions containing a therapeutically effective amount of a Ezetimih containing granulate of the present invention and optionally one or more other active ingredients in a Drinkable amount. with one or more excipients that are pharmaceutically acceptable.

While not limiting the invention to other aspects, the present invention may be further elaborated and may include: compressing a batch of ezetimibe-produced batch granules into a tablet, encapsulating it, optionally mixing it with one or more sub-blends or grams of additional homologous material (s). and then compressing the mixture into tablets, encapsulating or directly formulating these mixtures, e.g. sachetbem

Such further processing is; also, when the above-mentioned ezetum-containing granules contain tablets containing additional heat-reducing agent (s), together with one or more powder blends or granules, so that each of the granutotes can be found in the planar layers of the tablet, in the form of a layered or sandwich tablet.

These. Techniques and methods of bleaching require the use of state-of-the-art pharmaceutical excipients and drug manufacturing processes.

For compression into a single or multi-layered tablet, the necessary excipients may be tabletting excipients known to those of ordinary skill in the art, such as fillers, disintegrants, binders, surfactants, labyrinths, amiadhesives, glucants, dyes, stabilizers, e.g. pH regulators, antioxidants, chelating agents, years of the like.

In the case of a capsule, the necessary excipients may be fillers, disintegrants, surfactants, lubricants, anti-adhesives, stabilizers, pH regulators, antioxidants, chelating agents and the like.

If the milligram-tsmalmd gram date and optionally the additional powder or granules of our active ingredient are reduced directly, e.g. -sachet, then the necessary excipients may be upset agents, muscle repair agents, stabilizing agents from pk ppl regulators ;. mitoxidants, chelating agents and the like.

ία

These excipients are, for the most part, homogenized in one or more steps with the above granulated pellets and, optionally, a further powder or granules of the active ingredient which may be included in the formulations containing the ezetine ribe gradates according to the invention. , preferably Stilins. for example lovastim simvastathy pravastatin, fevwatm, atorvsstaun, phavasiatm, rnsuvastatin.

The gift is illustrated by the following examples without coding the night circle only for the examples.

Examples

Example 1

Production of granules and tablets of ezetimibe

Composition MlW db tablet:

mgábl. Testing> ^ Ezeíimibe 10.00 200.0 g Briefly K2 5 5.00! ÖO.Ög I iCrosscarnekose -Na {AeDiSoh 10.00 200.0 g I Microcrystalline cellulose 35.30 Oó.O g i D-Manns (Perhrnl 160C) 35.30 [706.0 g i Pa Iaurilsztéfát 4.40 [88.0 g i iEtilaikchol 96% i40Ö [ [Cleaned water | 1500 |

External Thesis:

img / tbl. Measurement k ^r ussearmdí © se -Na (AcDisol) [9.00 180.0 g | k ysztearát il.00 after, og |

Preparation: Ezetimibe is dissolved in 96% ethyl alcohol at 30-40 ° C, and the povidone and sodium isme solution in water. The saline solution is mixed with vigorous mechanical stirring for 30-69 seconds, and the precipitate formed is then shaken, if necessary, on a stalk with a diameter of 0.4 ° C / mm / cm and continuously removed.

In a Glatt GPCG Type 3.1 Hmdissolution Granulation Machine, dip the microcrystalline prodrug, the O-mamate and the cross-linker nMimw and preheat for 5 minutes with a sufficient volume flow of '75 inlet air.

The dewatered suspension is tested on a powdered gorse mixture suspended in a Suidizanization and granulating machine while the dispersion is stirred vigorously with a slurry.

Feeding capacity: 30-50 g / pers, spray pressure: 2.5 bar.

The resulting granulate is then dried with a suitable volume of inlet air of 75-85 [deg.] C. The dry granulate is scaled on a 0.63 mm perforated plate.

AeDiSd (5 minutes homogemate and finally magnesium spherarate (2 rd bom.

The finished homogenate was prepared with a flat srate of 7 m in diameter, weighing 1 IU, 00 mg. compressed into foblets.

During the preparation, the following results are obtained for each of the fcistennas:

- a phonograph microscope calibrated to measure the particle size of a thousand millimeters of condensed bar; When examined, ezstimebs with crystalline state below 10 μίη, typically at a grain size of pm, were seen (Fig. 1).

ezetimibe Ranian spectroscopy and X-ray diffusion into the tablet®; substantially free of amorphous material by spectra; crystalline state® (Figure 2).

For the USP paddle method, Figure 6 is a serimic release! profile, measured.

Example X.

Granules and tablets containing the active ingredient ezetimibe

Composition for 20,000 tablets:

Img / tbl. .... ................ 4 S? ^ cuvette Bzetlmlbe | 1Q, 00; 200.0 g Hidmxi-pnpS-methyl precursor 6 cp {5.00 100.0 g Crossearmellose -Na (AcDiSol) 110.00 1200.0 g Microcrystalline Cellulose 102 135.30 706.0 g D-Manny (Peritol 160C) | 35.30 766.0 g. Na-Lacrylsulfate | 4.40 88, G Ethyl alcohol 96% M00 Purified water J | 300

Exterior ^; phase:

mgftbk {Testing | | 2mssearmellose -Na (AcDiSol) 9.00 | lSO, Og i | RFG stearate 1.00 hö.O e i

Preparation: Ezetribet is prepared in 96% ethyl alcohol®-eMj, hydrodopropylmethyl-ethyl and sodium; um-l; auryl sulphate in water. Beta solution is stirred vigorously at and for 31F60 seconds. under each other! and suspend the resulting suspension, if necessary, through a filter with a diameter of 04 · 0.6 mm. The suspension is stirred continuously until use.

The Zanehetta P1 Vacuum Mixer was immersed in microcrystalline pre-enzyme, groundwater, and emsarmarmo-emptor and at 50 rpm for 5 minutes.

The esomomimetic slurry was agitated in the vacuum sum processor and mixed under vacuum in a vacuum mixer while the suspension was continuously stirred with the intense mixer.

Total dosing address: 2 »ml ml minute, vacuum: 50 mbar, agitator speed: IPOrpm, aperture speed: 700rpm, spout snow: ~ ^ ~ 85 <'.

The respective granules are then compressed either in a vacuum pump or in a fluidized bed dryer. The dry granulate is regranulated on a perforated sheet of about 63 mm in size.

.4. to the granules they were bound to AcDISol (5 edges homogenization) and finally to magnesium stearate (2 edges homogenization).

The finished homogenizumBum is compressed with a flat tool 7 mm in diameter to 110.00 mg core tablets.

Testing of each phase product »gives the following results:

- in the suspension, the precipitated millimeter particle size, as measured by a calibrated earth microscope, is less than $ 1, typically pm, to see a crumpled state of this type t3. figure),

ezetimibe is present in the tablet in a crystalline state substantially free of amorphous material based on Raman spectroscopy and MGD spectra (Figure 4).

Example 3

Tablets containing sephimibe and simvastatin

Composition for 1000 tablets;

Ezetimibe and Simvastatin Caraway Snake Diet (10/20: mg- © tablet)

Előálhtas:

Composition for making Ezctimibe Pellet Granules:

Ezetimibe mg'tbL Measurement

10.00 µg 0.01g Hydroxypropylmethylcellulose óz cp 15.00 µg iCrosscarmellose -Na (AcDiSol) h 0.00 i 10.0 a

Microcrystalline cellulose > 35.30 R5 £> · ÍD-Manni (from Feriite 160C) > 35.30 35x3 sec IN atrium lauryl sulat 4.40 14.40 g i Ethyl alcohol 9% Í20g | Cleaned frame

The ezefcmb powdery granulate is prepared in the same manner as in Example 1.

Ingredients for the preparation of granules containing Simsalva:

i img / tbl. IBemérés | Sim Reply {W BHA) 20.00 1 20 g j CítTOmsuv yl, 00 1 COg) ascorbic acid 3.00 | 1.0 g) Microcrystalline cellulose ko, oo 10.0 g | I..aktóz 1105.30 1105.5 g

iCrosspovádone 110.00 I 10.0 g

Pregelatinised starch 20.00 20.0 g 1 Magnesium stearate h, οο i 1.0 g | ILakíóz 28.50 1 28.5 g ___ | saucer _ 2.00 ___ 1 ....... 2, while g;

Simvastatin containing 0.02% butyl-bridge-amzol is citric acid, ascorbic acid, microcrystalline cellulose, lactose. the crosspovidone, the Starch and the Mg stearate are homogenized and pressed into sheets at a pressure of 20-100 bar using a Fitzpatrick compactor, and then with a Btzmill type grinder (1.5mm shear pad, knife-on mode, 1500 rpm fondul) grinders.

Ezetimibe and simvasiatin-containing grammems and AeOiSni (0mg.tbL) and magnesium stearate (2 mg / tbl) are mixed in a barrel mixer and then pressed into a tablet of 310 mg weight using a lime millimeter diameter lenses. The tablet cores are then coated with a film-coating suspension of hydroxy-proline-triethylcellulose or polyvinyl alcohol until known to produce 10 mg of weight.

Examination of each phase product gives the following results:

the precipitate size of ezetimibe precipitated in the suspension, as measured by a calibrated phenolic rescuer, is less than 10 µm, typically 3-6 µm. a crystalline state of celimibe is shown (Fig. 1X)

Numumib content: Ezetimibe Kanta® in gnululate; crystalline essentially free of amorphous material based on spectroscopic and spiff diffusion spectra; (Figure 2 ..).

Claims (5)

claims A process for preparing a microcrystalline ezetimibe-containing granulate comprising the steps of: a) Ezetimibe is dissolved in a solution; b) precipitating the ezetimibe-containing solution by admixing the ezetimibe with an aqueous solution of lauryl sulfonate slag for 5 to 300 seconds; c) spraying the resulting suspension onto granules of pharmaceutical excipients. 2. The process according to claim 1, wherein the ezetimibe is dissolved in a carbonic solvent, preferably a C 1-4 aliphatic alcohol, preferably 2-propanes, ethanol, isopropanol. methanol, most preferably ethanol, isopropyl alcohol; A C 1-4 ketone, preferably acetone; or DMSO. Method according to any one of claims 1 or 2, characterized in that the mixing is carried out in 15 to 120 seconds, preferably 30 to 60 seconds. 4. A process for the preparation of a pharmaceutical composition comprising the steps of 1-3. A process according to any one of claims 1 to 6, wherein the granulate, optionally one or more further active ingredients and optionally one or more pharmaceutical excipients, is formulated into a pharmaceutical composition. The method of claim 4, wherein the further active ingredient is an HMG-CoA inhibitor, preferably a statin, most preferably, simvastatin, atorvastatin or rosuvastatin.