Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the invention concerns a novel, solid state form of a pharmacologically active benzenesulfonamide derivative, a process for its preparation and pharmaceutical compositions containing it.
• a number of benzenesulfonamide derivatives such as 4-[5-(4-Methylphenyl)-3- trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (also known as celecoxib) are known for therapeutic and prophylactic use based at least in part on their activity as selective inhibitors of the cyclooxygenase-2 (COX-2) enzyme. This enzyme is involved in the in vivo synthesis of prostaglandins which are mediators of various painful inflammatory conditions.
• COX-2 cyclooxygenase-2
• Benzenesulfonamide derivatives such as celecoxib are used as the active pharmaceutical agents in pharmaceutical compositions for the treatment and/or prevention of disorders or diseases of animals (including humans) mediated at least in part by the cyclooxygenase-2 prostaglandin synthesis enzyme.
• Solid state biopharmaceutical property of a pharmaceutical compound is its rate of dissolution in aqueous fluid.
• the solid state form of a compound may also affect its behavior on compaction and its storage stability.
• Important related solid state physical properties include the solid state stability, filterability, compressibility and flowability of the milled powder sample.
• Form III celecoxib also tends to form elongate needles which may fuse into a monolithic mass during compression in a tableting die. This process can also occur when Form III celecoxib is mixed with other substances, leading to the separation and agglomeration of celecoxib crystals during the preparation of pharmaceutical compositions resulting in an unevenly blended composition containing undesirably large aggregates of celecoxib. Consequently, it is difficult to prepare a pharmaceutical composition with the required consistent and uniform blend of active ingredient and excipients. In addition, the low bulk density of form Nil celecoxib makes it difficult to process the small quantities required during formulation of the pharmaceutical compositions.
• celecoxib Form N has advantages over Form III in respect of handling, formulation and/or administration of the celecoxib active ingredient as a pharmaceutical. Unlike the previously obtained celecoxib Form I, the Form N is surprisingly stable and does not readily transform to the thermodynamically more stable Form III celecoxib except under extreme conditions.
• celecoxib Form III As a result, it is especially suitable for processing and formulation for therapeutic or prophylactic use. In addition as stated earlier, it has improved properties in relation to celecoxib Form III, such as a higher intrinsic dissolution rate of about 11 ⁇ g/min. cm 2 compared with 8 ⁇ g/min. cm 2 for Form III.
• the present invention provides a novel solid-state crystalline form of celecoxib substantially free of the amorphous form of celecoxib which is designated as celecoxib Form N,
• This crystalline form may be characterised, for example, by its X- ray powder diffraction (XRPD) pattern, infra-red or Raman spectra, differential scanning calorimetry (DSC) thermogram, and thermogravimetric analysis (TGA).
• XRPD X- ray powder diffraction
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• the present invention also includes a process for the manufacture of celecoxib Form N and pharmaceutical formulations containing celecoxib Form N.
• Figure 1 is a representative XRPD pattern of celecoxib Form N.
• Figure 2 is a representative near IR spectrum of celecoxib Form N.
• Figure 3 is a representative Raman spectrum of celecoxib Form N.
• Figure 4 is a comparison of a representative XRPD pattern of celecoxib Form N with the same sample after one week at 50 0 C and 80% relative humidity.
• Figure 5 is a representative DVS isotherm plot of celecoxib Form N.
• Figure 6 is a comparison of a representative XRPD pattern of an 80:20 w/w mixture of celecoxib Form N and amorphous celecoxib with a scanned XRPD pattern for celecoxib Form I published as Figure 1a in European patent 1150960, US patent application publication US 2004/0087640 and the equivalent PCT International patent application WO 01/42222.
• Figure 7 is a representative XRPD pattern of celecoxib Form N plotted on the same
• Figure 8 shows representative XRPD patterns of an 80:20 mixture by weight of celecoxib Form N and amorphous celecoxib plotted in A as d spacings at different times maintained at ambient temperature and relative humidity (RH) of 25 0 C and 60%.
• RH ambient temperature and relative humidity
• Figure 9 shows the XRPD patterns of figure 8 on a larger scale. The presence of peaks characteristic of celecoxib Form III is again indicated with arrows.
• celecoxib Form N that is a celecoxib polymorph having the following characteristic X-ray powder diffraction (XRPD) peaks (designated as d values) at about: 16.0+0.2 A, 15.3 ⁇ 0.2 A, 12.3+0.2 A, and 10.6+0.2 A and which is substantially amorphous free.
• XRPD characteristic X-ray powder diffraction
• substantially amorphous free denotes a polymorphic form of celecoxib that contains less than about 5% by weight of an amorphous form oi celecoxib and, particularly, less than about 2.5% by weight and, preferably, less than about 1 % of an amorphous form of celecoxib.
• samples of celecoxib Form N which are substantially amorphous free show no significant content of celecoxib Form III by XRPD analysis after being stored at 25°C and 60% relative humidity for prolonged periods of at least 2 months. This is based on the fact that amorphous celecoxib decomposes readily to the thermodynamically stable celecoxib Form III which unlike the amorphous form has distinctive XRPD peaks.
• Celecoxib Form N of the present invention also has the following additional characteristic XRPD peaks (designated as d values): 8.0 ⁇ 0.2 A, 6.5 ⁇ 0.1 A , 5.4 +0.1 A.
• An illustrative XRPD pattern for celecoxib Form N according to the invention is shown in Figure 1 , measured using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer.
• An illustrative near infrared (NIR) spectrum for celecoxib Form N according to the invention is shown in Figure 2, measured using a Bruker NIR Multi Purpose Analyser (MPA) with He-Ne laser as a light source.
• MPA Bruker NIR Multi Purpose Analyser
• the spectra were obtained using a reflection fibre-optical solid probe, with the probe tip in close contact with the samples. The measurements were carried out in triplicate over the range 4000 cm “1 - 12000 cm “1 , with a resolution of 8 cm “1 . The spectra were averaged over 32 scans.
• FIG. 3 An illustrative Raman spectrum for celecoxib Form N according to the present invention is shown in Figure 3.
• Celecoxib Form N has characteristic Raman absorption peaks at 3152, and 3140 cm “1 with additional characteristic Raman absorption peaks at 620, 1200, 970, 800, 498, and 245 cm “1 .
• Fourier transform (FT) Raman spectra were obtained using a Bruker Equinox 55 spectrophotometer with a Bruker FT-Raman module 106/S. Radiation of 1064 nm from an Nd: YAG laser was used for excitation. The resolution was set at 4 cm "1 with the laser power at the sample set at 50 mW.
• FT Fourier transform
• the amorphous forms of many active substances often suffer from significant problems with solid state stability, for example at above ambient temperature and under conditions of high humidity. Thus, they may readily transform into other crystalline forms of that substance or into various mixtures of crystalline and amorphous phases of that substance.
• the celecoxib Form N of the present invention is stable, as evidenced by the lack of any phase transformation into any other crystalline or amorphous form of celecoxib when stored for one week under non-ambient stress condition of 50 0 C and 80% relative humidity (RH).
• a non-ambient XRPD experiment was performed using CuK ⁇ i radiation on a powder sample of celecoxib Form N using a PANalytical X'Pert PRO powder diffractometer.
• the sample was held one week at 50 0 C and 80 % RH in an Anton Pa temperature humidity chamber (THC).
• THC Temperature Control Unit 100
• RH Generator Software RH 200 from VTI Corporation controlled the relative humidity.
• Celecoxib Form N of the present invention is also non-hygroscopic as is demonstrated in Figure 5 which shows an illustrative Dynamic Vapour Sorption (DVS isotherm plot for celecoxib Form N.
• DVS Dynamic Vapour Sorption
• a representative sample of celecoxib Form N was analyzed using a DVS-1 gravimetric sorption analyzer (Surface Measurement System, U.K.). Measurements were preformed at 25°C on a sample size of approximately 20 mg. The uptake and loss of vapor was gravimetrically measured using Cahn D200 recording ultra- microbalance.
• the relative humidity was increased in 10 steps from 0-90% relative humidity. It can be seen from Figure 5 shows that celecoxib Form N adsorbed only 0.023% water.
• Hygroscopicity is defined in European Pharmacopoeia Technical Guide (1999, p. 86), based on the static method, after storage at 25 0 C for 24 hours at 80% relative humidity.
• slightly hygroscopic means that the increase in mass due to absorption of water by a compound is equal to or greater than 0.2 % m/m but less than 2 % m/m.
• Hygroscopic means that the increase in mass due to absorption of water by a compound is equal to or greater than 2% m/m but less than 15 % m/m
• Very hygroscopic means that the increase in mass due to absorption of water is equa to or greater than 15 % m/m.
• the celecoxib Form N of the present invention is essentially non-hygroscopic.
• Celecoxib Form N can be prepared from any form of celecoxib, including amorphous and/or crystalline forms, and solvated and/or desolvated forms thereof.
• a typical process for preparing celecoxib Form N according to the invention comprises heating the celecoxib to a suitable temperature (i.e., a melting temperature) to form a melt, and then (ii) cooling the melt in a controlled manner.
• the starting celecoxib may, for example, be crystalline celecoxib Form III produced as described in US patent application publication no.
• Suitable solvents of diluents include those which do not interact with the celecoxib to form solvates, complexes or the like and which have a boiling point greater than about 170, for example, hydrocarbons such as decane, tetradecane and tetrahydronaphthalene, of which n-decane is particularly preferred.
• the cooling step can typically be carried out over a time period of from about 1 hour to about 10 hours, preferably from about 2 hours to about 5 hours, and more preferably over a period of about 3 hours.
• the temperature at which the process is carried out is typically in the range of from about 160 0 C to about 170 0 C, for example from about 162 0 C to about 165 0 C, and preferably from about 162.5 0 C to about 163.5 0 C.
• the solid state purity of the resultant celecoxib Form N in respect of any other amorphic or polymorphic form of celecoxib is typically greater than about 95% by weight and, more particularly, is greater than about 97.5 % by weight.
• a pharmaceutical composition or other dosage form comprising celecoxib Form N together with one or more pharmaceutically acceptable excipients for use in the treatment or prevention of those diseases and medical conditions where treatment with a cyclooxygenase-2 (COX-2) inhibitor is desirable.
• celecoxib Form N or a pharmaceutical composition thereof according to the present invention can be employed in the treatment or prevention of diseases and medical conditions including, but not limited to, osteoarthritis, rheumatoid arthritis, familial adenomatous polyposis, and the relief of pain associated with inflammatory conditions.
• Celecoxib Form N may be used in the preparation of rapid, controlled, and sustained release pharmaceutical formulations, suitable for oral, rectal, parenteral, transdermal, buccal, nasal, sublingual, subcutaneous or intravenous administration.
• the formulations are preferably administered orally, for example in the form of rapid or controlled release tablets, microparticles, mini tablets, capsules and oral solutions or suspensions, or powders for the preparation thereof.
• formulations of the present invention may optionally include various standard pharmaceutically acceptable excipients well known in the pharmaceutical art, such as binders, fillers, diluents, buffers, lubricants, glidants, disintegrants, perfumes, sweeteners, surfactants and coatings.
• excipients may serve multiple roles in the formulations, for example they may act as both binders and disintegrants.
• Suitable disintegrants include, but are not limited to, starch, pre- gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and cross-linked polyvinylpyrrolidone.
• binders include, but are not limited to, acacia, cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium- aluminum silicate, polyethylene glycol and bentonite.
• acacia cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose
• gelatin glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium- aluminum si
• suitable fillers and diluents include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium phosphate, calcium carbonate and calcium sulfate.
• Suitable lubricants useful in the formulations of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silicon dioxide.
• suitable perfumes include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits and combinations thereof.
• suitable dyes include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.
• Conventional pharmaceutically acceptable coatings may typically be used to facilitate swallowing, modify the release properties, improve the appearance, and/or mask the taste of formulations according to the invention.
• coatings include, but are not limited to hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate copolymers.
• sweeteners include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.
• buffers include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.
• suitable surfactants include, but are not limited to, sodium lauryl sulfate and polysorbates.
• the celecoxib Form N according to the invention is also suitable for inclusion in conventional formulations intended for administration by intravenous or intraperitonea means.
• Dispersions can also be prepared in a liquid carrier or intermediate, such as glycerin, liquid polyethylene glycols, triacetin oils, and mixtures thereof. To improve storage stability, such preparations may also contain a preservative to prevent the growth of microorganisms.
• the celecoxib Form N according to the invention may also be used for the preparation of conventional formulations adapted for local or topical administration.
• Such formulations typically contain other pharmaceutically acceptable excipients, such as polymers, oils, liquid carriers, surfactants, buffers, preservatives, stabilizers, antioxidants, moisturizers, emollients, colorants and perfumes well known in the art.
• compositions of the invention may also contain one or more other pharmaceutical active ingredients well known in the art for use in the treatment or prevention of diseases and medical conditions including, but not limited to, osteoarthritis, rheumatoid arthritis, familial adenomatous polyposis, and for the relief of pain associated with inflammatory conditions.
• an opiate or non-opiate analgesic may be also be present in a composition of the invention.
• compositions of the invention will typically contain about 100-700 mg of celecoxib Form N per unit pharmaceutical composition (for example per tablet), and preferably about 150-450 mg.
• celecoxib Form N differs in some properties such as intrinsic solubility from celecoxib Form III, it will generally be administered in doses similar to those described in the art for the commercially available celecoxib preparations. Such doses will necessarily be varied with the mode of administration, treatment conditions, age and status of the patient or animal receiving treatment.
• Typical doses for use in osteoarthritis are, for example, about 100 to about 200 mg, for rheumatoid arthritis, for example, about 200 to about 400 mg, for acute pain, for example, up to about 400 mg and for familial adenomatous polyposis, for example, up to about 800 mg.
• Examples 1-6 describe the production of celecoxib Form N and Examples 7-9 illustrate its stability at above ambient temperature and elevated relative humidity.
• Further example 10 illustrates the comparable instability under a variety of conditions of an artificial mixture of celecoxib Form N containing 20% by weight of the amorphous form of celecoxib.
• Example 11 describes attempts at repeating the preparation of celecoxib Form I described in US patent publication US 2004/0087640 and equivalent patent applications.
• Example 12 describes the intrinsic dissolution rates of celecoxib Form N and Example 3 describes the preparation of tablet formulations of celecoxib Form N.
• Celecoxib Form III (2.5g) was suspended in 50 ml of n-tetradecane and then heated to about 165 0 C while stirring. The emulsion obtained was stirred at the same temperature for about 15 min and then cooled to about 145 °C. It was then reheated to about 165 °C and then cooled to about 110 0 C. The resultant suspension was separated by filtration and the crystals obtained were dried at 100 0 C under the vacuo for 12 hours to yield celecoxib Form N.
• Celecoxib Form III (5.0 g) was suspended in 50 ml of n-decane and heated to about 165 0 C while stirring. Obtained emulsion was cooled to about 145 0 C , heated again to about 165 0 C and finally cooled to about 110 0 C. Suspension was filetered and obtained crystals were dried at 100 0 C under the vacuo for 12 hours to yield celecoxib Form N.
• Celecoxib Form III (250 mg) was suspended in 30 ml of n-decane and heated to about 120 °C. The suspension was stirred at the same temperature for 3 hours. Undissolved celecoxib was removed by filtration and the filtrate was heated to about 130 0 C and then cooled to 110 0 C while stirring. The solution was then seeded with about 2.5 mg of celecoxib Form N and cooled to room temperature resulting in the isolation of 40 mg of celecoxib Form N.
• Celecoxib Form III (2.5g) was suspended in 50 ml of r?-decane and heated to about 168 0 C while stirring. The emulsion obtained was stirred at 165-168 0 C for 15 minutes and then slowly cooled to about 144 °C. A seed of 0.025 g of celecoxib Form N was added and stirring was continued at about 143 0 C for 35 minutes. The resultant suspension was cooled to 25 0 C and stirred for an additional 1 hour. The precipitate was removed by filtration and dried at 100 0 C in vacuo for 2 hours to yield 2.44 g of celecoxib Form N.
• Celecoxib Form III (80.0 g) was suspended in 3600 ml of /i-decane and heated to about 168 0 C while stirring. The emulsion obtained was stirred at the same temperature for 40 minutes and cooled to about 149 °C. Seed crystals of celecoxib Form N (1.8g) were added and stirring was continued at about 148-150 0 C for 20 min. The resultant suspension was cooled to 25 0 C and stirred for 15 minutes. The precipitated material was separated by filtration and dried at 100 0 C in vacuo for 18 hours yielding 167.6 g of celecoxib Form N.
• Example 6 (a) Celecoxib Form III (4.0g) having an approximate particle size of 30 ⁇ m was homogenously distributed on a Petri dish having a diameter 9 cm. The dish was put in an oven, heated from room temperature to 163 0 C and held at 163 0 C for 1 hour. The heating was stopped and the celecoxib was allowed to cool in the oven for 3 hours. During the cooling period the oven was not opened. A compact film of celecoxib Form N crystallized at the Petri dish surface.
• Celecoxib Form III (4.Og) was homogenously distributed on a Petri dish having a diameter 3 cm. The dish was put in an oven, heated from room temperature to 163 0 C and held at 163 0 C for 1 hour. The heating was stopped and the celecoxib was allowed to cool in the oven for 3 hours. During the cooling period the oven was not opened. A compact film of celecoxib Form N crystallized at the Petri dish surface.
• Figure 1 shows an X-ray powder diffraction (XRPD) pattern for a representative sample of celecoxib Form N obtained by one of Examples 1-6 measured using CuKa radiation on a powder sample collected using a PANalytical X'PertPRO powder diffractometer.
• the pattern has characteristic peak position (expressed in d values) at 16.0 ⁇ 0.2A, 15.3 ⁇ 0.2A, 12.3 ⁇ 0.2A and 10.6 ⁇ 0.2A, and further characteristic peaks at 8.0 ⁇ 0.2A, 6.5 ⁇ 0.1 A , and 5.4 ⁇ 0.1 A.
• Figure 2 shows an illustrative near infrared (NIR) spectrum for a representative sample of celecoxib Form N obtained by one of Examples 1-6 , measured using a Bruker NIR Multi Purpose Analyser (MPA) with He-Ne laser as a light source.
• the spectra were obtained using a reflection fibre-optical solid probe, with the probe tip in close contact with the samples. The measurements were carried out in triplicate over the range 4000 cm “1 - 12000 cm '1 , with a resolution of 8 cm "1 .
• the spectra were averaged over 32 scans.
• Figure 3 shows an illustrative Raman spectrum for celecoxib Form N obtained by one of Examples 1-6, demonstrating characteristic Raman absorption peaks at 3152, and 3140 cm “1 with additional characteristic Raman absorption peaks at 620, 1200, 970, 800, 498, and 245 cm “1 .
• Fourier transform (FT) Raman spectra were obtained using a Bruker Equinox 55 spectrophotometer with a Bruker FT-Raman module 106/S. Radiation of 1064 nm from an Nd: YAG laser was used for excitation. The resolution was set at 4 cm "1 with the laser power at the sample set at 50 mW.
• FT Fourier transform
• a non-ambient XRPD experiment was performed using CuK ⁇ i radiation on a small powder sample of celecoxib Form N obtained by one of Examples 1-6 using a PANalytical X'Pert PRO powder diffractometer.
• the sample was held for one week at 50 0 C and 80 % RH in an Anton Par temperature humidity chamber (THC).
• the temperature of the sample was controlled using a Temperature Control Unit 100 (TCU 100), and the RH Generator Software RH 200 from VTI Corporation controlled the relative humidity.
• TCU 100 Temperature Control Unit 100
• RH Generator Software RH 200 from VTI Corporation controlled the relative humidity.
• no change was observed in the X-Ray powder pattern of the celecoxib Form N sample. This can be seen from Figure 4 and demonstrates the stability of celecoxib Form N at above ambient temperature and under conditions of high relative humidity.
• a representative sample of celecoxib Form N obtained by one of Examples 1-6 was analyzed by Dynamic Vapour Sorption (DVS) methodology using a DVS-1 gravimetric sorption analyzer (obtained from Surface Measurement System, U.K.).
• DVD Dynamic Vapour Sorption
• Working Example 1 A was repeated six times starting with the dimethylacetamide (DMA) celecoxib solvate. In each case a mixture of material having the XRPD pattern for Form I and Form III was obtained. No reflections for the starting DMA celecoxib solvate were seen in the XRPD pattern.
• DMA dimethylacetamide
• IDR intrinsic dissolution rates
• the sample substance (200mg) was first compressed using an infrared punch and die set (0.57 cm 2 ) to 1 tons, 1 min, to ensure minimal porosity and improved compaction.
• the compressed sample disc obtained was fixed to the holder of the rotating disc dissolution apparatus.
• the disc was then rotated at 100 rpm in water (900 ml) pre-adjusted to pH 1.2 by addition of dilute hydrochloric acid and containing 0.5% by weight of sodium laurylsulphate at a temperature of 37 0 C.
• the amount of drug in solution was determined by UV spectrometry analysis at 254 nm at different time point from 5 min to 300 min where the plot of concentration against time is essentially linear.
• Procedure a mixture of microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose and crosscarmellose sodium is blended with celecoxib Form N, then granulated by fluid bed granulation with the addition of aqueous solution of surfactant. The granules are dried in the fluid-bed dryer, sized, and homogenized with the external phase. Tableting blend is then compressed into tablet cores that are subsequently coated with the aqueous suspension for film coating in a semi perforated or perforated coating pan.
• Table 3 The amounts of the active ingredient and excipients for 100 and 200 mg dosage immediate release tablet formulations are shown below in Table 3 below:

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• 2005
  • 2005-07-21 WO PCT/HR2005/000041 patent/WO2006051340A1/en active Application Filing
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