WO2011050944A1 - Formulations contenant du célécoxib - Google Patents

Formulations contenant du célécoxib Download PDF

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Publication number
WO2011050944A1
WO2011050944A1 PCT/EP2010/006538 EP2010006538W WO2011050944A1 WO 2011050944 A1 WO2011050944 A1 WO 2011050944A1 EP 2010006538 W EP2010006538 W EP 2010006538W WO 2011050944 A1 WO2011050944 A1 WO 2011050944A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
composition
lactose
solubiliser
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PCT/EP2010/006538
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English (en)
Inventor
Parshwakumar V. Kalyankar
Ganesh V. Gat
Jawed Hussain
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Ratiopharm Gmbh
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Publication of WO2011050944A1 publication Critical patent/WO2011050944A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles

Definitions

  • the present invention relates to pharmaceutical compositions comprising celecoxib or a pharmaceutically acceptable salt thereof, a process for the preparation of said pharmaceutical composition, an oral deliverable dose unit comprising said composition, a process for the production of granules or capsules comprising said composition, the use of said composition for lactose intolerant patients and finally a lactose-free oral deliverable dose unit.
  • Celecoxib and salts thereof are reported to be a selective inhibitor of cyclooxygenase-2 (COX-2) with no inhibition of cyclooxygenase- 1 (COX- 1 ) at therapeutic doses.
  • the compound has been approved within the EU as a non-steroid anti-inflammatory drug for the symptomatic relief in osteoarthrosis and rheumatoid arthritis, but it is also a potential candidate for many other diseases.
  • celecoxib is hydrophobic and practically insoluble in aqueous buffers at physiological pH ranges. Therefore, a suitable formulation is needed to transfer the drug into the gastrointestinal tract. Usually the particles are milled or micronised to a particle size of less than 10 ⁇ to make the compounds more accessible.
  • the patent WO 00/32189 discloses celecoxib compositions and states that the particles preferably have a size of about 5 to 7 ⁇ .. For this reason, the celecoxib particles have to been micronized using a pin mill in an elaborate process prior to being mixed with the other components of the formulation.
  • micronisation entails a number of drawbacks.
  • the micronisation of a pharmaceutically active compound often results in a low flowability or pourability of the product formulation.
  • the enlargement of the outer surface area due to micronisation increases the susceptibility of the substance towards oxidation. Therefore, a micronised agent is more likely to degrade over time.
  • the number and severity of the side effects caused by the composition are reduced to a minimum, especially taking specific population intolerances towards any of the substances contained therein into account.
  • the content mass variation of capsules with the composition should conform with the low acceptance values established in the art or be superior in this respect.
  • Content stability is generally a desirable attribute for the present formulations.
  • the formulation should exhibit a good bioavailability, especially with regard to the bioequivalence of established formulations containing celecoxib on the market.
  • a pharmaceutical composition comprising celecoxib or a pharmaceutically acceptable salt thereof, wherein the composition further comprises:
  • particle size distribution D90 of the composition particles is preferably 30 ⁇ or greater.
  • the above celecoxib composition thus comprises the additional excipients: a filler, disintegrant and a solubiliser.
  • a filler due to the nature of pharmaceutical excipients, it cannot be excluded that a certain compound meets the functional requirements of more than one of the above mentioned excipient classes.
  • the same pharmaceutical compound can only be subsumed as one of the functional excipient classes presented above. For example, if dicalcium phosphate dihydrate is described as a filler, it cannot additionally classify as a solubiliser or as a disintegrant. Therefore, the composition of the invention must comprise at least three unique additional excipients besides the active ingredient.
  • a filler is every compound that participates in the formation of granules when concentrations of the active pharmaceutical ingredients about 85 wt.% or lower are present.
  • Fillers are used to top up the volume for an appropriate oral deliverable dose.
  • Fillers are usually relatively chemically inert, but they can have a significant effect on the bioavailability of the active ingredient. They can influence the solubility of the active ingredient and enable a powder of an insoluble compound to break up more readily on capsule shell disintegration.
  • Typical state of the art formulations employ lactose as a filler.
  • Preferred fillers of the invention are calciumphosphate, saccharose, calciumcarbonate, calciumsilicate, magnesiumcarbonate, magnesiumoxide, maltodextrine, calcium- sulfate, dextrate, dextrine, dextrose, hydrogenated vegetable oil and/or cellulose derivatives.
  • a pharmaceutical composition according to the invention may comprise an inorganic salt as a filler.
  • this inorganic salt is dicalcium phosphate dihydrate or Calipharm D.
  • Dicalcium phosphate dihydrate is insoluble in water, non-hygroscopic, but still hydrophilic. Surprisingly, this behaviour contributes to a high storage stability of the composition. This is in contrast to e.g. lactose, which is readily soluble in water.
  • lactose has the limitation that some people - about 75% of the world population - have a more or less severe intolerance towards this compound and would therefore find drugs without this compound more agreeable on digestion. Therefore, a pharmaceutical composition comprising dicalcium phosphate dihydrate will not only enhance the storage stability of the resulting product, but will offer an adequate treatment, which is suitable for lactose intolerant people.
  • the pharmaceutical composition according to the present object may not comprise lactose or a lactose derivative. This can be achieved by employing a filler, which does not comprise lactose or one of its derivatives.
  • lactose has disadvantages, when used in a pharmaceutical composition. Apart from the widespread incidence of lactose intolerance in many human groups, it can more easily disintegrate than other substances, especially dicalcium phosphate dihydrate.
  • the filler is contained in an amount of 0 to 30 wt.% , more preferably 1 to 20 wt.% and most preferably 2 to 15 wt.% based on the total content of the composition.
  • the pharmaceutical composition of this invention further comprises a disintegrant, or a combination of more than one disintegrant compound.
  • a disintegrant is generally every compound that accelerates the disintegration of the orally deliverable dose unit - preferably a capsule or tablet - on contact with water.
  • Suitable disintegrants are polacrilin potassium, corn starch, microcrystalline cellulose, starch, pre-agglutinated starch, sodium carboxymethyl starch, sodium carboxymethyl cellulose, croscarmellose sodium and/or cross-linked polyvinylpyrrolidone (crospovidone).
  • crospovidone cross-linked polyvinylpyrrolidone
  • so-called "superdisintegrants” are used. These include croscarmellose and more preferably crospovidone.
  • the disintegrant is an intragranular crospovidone such as Polyplasdone XL 10.
  • Crospovidone is cross-linked polyvinylpyrrolidone and therefore has similar chemical structural units as linear polyvinylpyrrolidone (PVP). It is very hydrophilic, but on the other hand still insoluble in water. In addition, crospovidone has the advantage over croscarmellose that it does not change the viscosity of a solution and hardly swills.
  • Crospovidone is a "superdisintegrant", in which the solubility is decreased by cross- linking. This compound is extraordinary suitable for water- insoluble pharmaceutically active ingredients.
  • the pharmaceutical composition further comprises one or more solubilisers.
  • the term “solubiliser” means any organic excipient, which modifies the solubility and dissolution of the active pharmaceutical ingredient.
  • the solubiliser has binding properties.
  • the solubiliser is capable of reducing the dissolution time of a pharmaceutical composition by 5 %, more preferably by 20 % as compared to the same pharmaceutical composition comprising calcium hydrogen phosphate instead of the solubiliser.
  • the solubilisers are selected, for example, from the group of known inorganic or organic excipients.
  • excipients preferably include polymers, low molecular weight oligomers, natural products and surfactants.
  • the solubiliser is a water-soluble compound, having a water solubility of more than 10 mg/1, more preferably of more than 20 mg/1, still more preferably of more than 50 mg/1 at a temperature of 25 °C.
  • the solubility of the solubiliser might be e.g. up to 1 ,000 mg/1 or up to 300 mg/ml at a temperature of 25 °C.
  • the water- solubility is determined according to the column elution method of the Dangerous Substances Directive (67/548/EEC), Annex V, chapter A6.
  • the solubiliser is a hydrophilic polymer, preferably having the above mentioned water- solubility.
  • hydrophilic polymer encompasses polymers comprising polar groups.
  • polar groups are hydroxy, amino, carboxy, carbonyl, ether, ester and sulfonate groups. Hydroxy or sulfonate groups are particularly preferred.
  • the hydrophilic polymer usually has a weight average molecular weight, ranging from 1 000 to 1 200 000 g/mol, preferably from 2 500 to 900 000 g/mol, particularly from 3 000 to 50 000 or 600 000 to 800 000 g/mol. Most preferred is a weight average molecular weight of between 35 000 to 45 000 g/mol or 650 000 to 750 000 g/mol.
  • the molecular weights of the polymers are measured by gel permeation chromatography (GPC).
  • a 2 % w/w solution of the hydrophilic polymer in pure water at 25 °C preferably has a viscosity of from 0.5 to 20.0 mPa-s, more preferably from 1.0 to 6.0 mPa s; particularly preferred is from 1.0 to 1.4 mPa s or 3 to 5.0 mPa-s.
  • the viscosity is determined according to the European Pharmacopoeia (hereinafter referred to as Ph. Eur.), 6th edition, Chapter 2.2.10.
  • the pharmaceutical composition comprises a solubiliser with a viscosity in a 1 wt.% solution in water at 25°C of between 1.0 to 20 Pa s, preferably between 2- 10 Pa s, particularly preferably between 3-5 Pa s.
  • the viscosity of a 1% solution of the solubiliser in water at 25 °C is between 1.0 to 1.5 Pa s or 3.5 to 5.2 Pa s.
  • a high viscosity of the solubiliser increases the bioavailability of the resulting pharmaceutical composition.
  • the solubiliser therefore has a weight average molecular weight of 50 000 g/mol or more.
  • a good solubilising effect is achieved when a mixture of a higher and a lower viscosity polymer is employed as the solubilising agent.
  • the hydrophilic polymer used as the solubiliser preferably has a glass transition temperature (Tg) or a melting point of 25 °C to 150 °C, more preferably of 40 °C to 100 °C.
  • Tg glass transition temperature
  • the glass transition temperature or the melting point are determined with a Mettler-Toledo ® DSC 1 , wherein a heating rate of 10 °C per minute and a cooling rate of 15 °C per minute is applied. The determination method is based on Ph. Eur. 6.1 , section 2.2.34. For the determination of Tg, the polymer is heated twice (i.e. heated, cooled, and then heated again).
  • solubilisers derivatives of cellulose (hydroxyproplymethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), preferably sodium or calcium salts thereof, microcrystalline cellulose, hydroxyethyl cellulose) or
  • polyvinylpyrrolidone preferably having a weight average molecular weight of 10 000 to 700 000 g/mol
  • copolymers of polyvinylpyrrolidones preferably copolymers comprising vinylpyrrolidone and vinylacetate units (e.g. Povidon VA 64; BASF), preferably having a weight average molecular weight of 40 000 to 70 000 g/mol or
  • polyoxyethylene alkylethers polyethylene glycol, sugar alcohols like isomalt, sorbitol or mannitol, co-blockpolymers of ethylene oxide and propylene oxide (Poloxamer, Pluronic ® ), derivates of methacrylates, polyvinylalcohol, derivates of glycerol, derivates of polyethylene glycols, derivates of dextrins, and derivates of fatty acids, e.g. sodium lauryl sulfate.
  • the above mentioned kinds of hydrophilic polymers fulfill the functional requirements (molecular weight, viscosity, Tg) as illustrated above.
  • at least one of the above- mentioned solubilisers is present.
  • a combination of two or more solubilisers can be employed.
  • polyvinylpyrrolidone and copolymers of polyvinylpyrrolidone, or preferably copolymers comprising vinylpyrrolidone and vinylacetate units are used as the solubiliser.
  • the solubiliser comprises the poly-N-vinylpyrrolidones PVPK 90 and/or PVPK 30, in particularly wherein the weight average molecular weight of the poly-N-vinylpyrrolidones is equal to or higher than 350 000 g/mol, more preferably at least 600 000 g/mol.
  • the poly- N -vinylpyrrolidone PVPK 90 has a molecular weight of 600 000 to 800 000 g/mol, more preferably of about 700 000 g/mol, while the poly-N- vinylpyrrolidone PVPK 30 has a molecular weight of 35 000 to 45 000 g/mol, more preferably of about 40 000 g/mol.
  • Poly-N-vinylpyrrolidones are water soluble, but can also interact with compounds comprising aromatic moieties. Therefore, the interaction with the pharmaceutically active component may occur when the solubilising polymer comprises more hydrophobic features.
  • a longer polymer such as PVPK 90 has a reduced solubility in water, but a higher hydrophobicity, and leads to a better activation of the active ingredient in the powder. Surprisingly, this effect in combination with particles with a relatively higher particle diameter (D90) affords a good bioavailability and storage stability.
  • non-crosslinked polyvinylpyrrolidones are used both as the solubiliser (e.g. as PVPK 30 or PVPK 90) and crosslinked polyvinylpyrrolidones are employed as the disintegrant (e.g. as crospovidone), the number of possibly intolerable chemical compounds is reduced, since both compounds stem from the same basic structural units and chemical similarity.
  • the particle size distribution D90 of the composition particles is preferably 30 ⁇ or greater.
  • particle size relates in this invention to the D-value (e.g. the D90-value) of the volume averaged particle diameter, as determined by laser diffractometry.
  • a Mastersizer 2000 from Malvern Instruments was utilized to measure the particle sizes.
  • a wet-measurement with 60 sec ultrasonic treatment was conducted at 2000 rpm, with a preferred aperture of 4 to 13 % , preferably in a fluid paraffin dispersion.
  • the data analysis was done in accordance with the Fraunhofer model.
  • the average particle diameter - also called DX value (e.g. the D90-value) of the integrated volume distribution - is likewise defined as the particle diameter, when exactly 90 vol % of the particles have at least the diameter indicated and 10 vol % of the particles have a larger diameter than the indicated value.
  • the D I O-value determines the value, where 10 vol % of the particles have the diameter value indicated, while the D50 value gives the median value of the particle diameters.
  • the storage stability of the composition increases, since the larger particles exhibit a lower surface area per volume and are therefore less susceptible to the action of decomposing agents.
  • the particle size distribution D90 of the composition particles is between 32 ⁇ . and 50 ⁇ , preferably between 40 ⁇ and 50 ⁇ , most preferably at least 48 ⁇ . and at most 50 ⁇ .
  • the D90 value is a very sensitive indicator for the particle properties.
  • the size of the particles is too large or too small, negative effects can occur.
  • small particles are hard to achieve and require extensive micronisation processing.
  • too large particles can easily agglomerate and have a negative impact on the powder uniformity and therefore also on the content uniformity of formulation capsules, as well as reducing bioavailability.
  • Positioning the D90 value of the particles at the given ranges strikes a good balance between avoidance of costly micronisation and avoidance of too large particles with reduced bioavailability.
  • the particle size of the dried granules may preferably be such that 90% of the particles (D90 value) have an average diameter of less than 1500 ⁇ , in a more preferred implementation less than 1000 ⁇ , most preferably less than 800 ⁇ or 600 ⁇ . For various applications this size requirement must be met for the final particle granules before being transferred to the capsule.
  • the particles meet the size requirements before a final blending and/or lubrication step followed by optional sifting through a sieve ⁇ e.g. with magnesium stearate) and packaging or direct transferal to the capsules.
  • the pharmaceutical composition comprises celecoxib or a pharmaceutically acceptable salt thereof in an amount of 10.0 to 90.0 wt.%, based on the total weight of the composition.
  • the pharmaceutical composition may preferably comprise one or more additional excipients as for example: a lubricant, a glidant, an anti-sticking agent, a wetting agent and/or a stabilizer (see Table 1 ).
  • additional excipients as for example: a lubricant, a glidant, an anti-sticking agent, a wetting agent and/or a stabilizer (see Table 1 ).
  • a lubricant may be used.
  • Lubricants are generally employed to reduce dynamic friction.
  • the lubricant is preferably a stearate, talcum powder or fatty acid, more preferably, hexanedioic acid or an earth alkali metal stearate, such as magnesium stearate.
  • the lubricant is suitably present in an amount of 0.1 to 3 wt.%, preferably about 0.5 to 1.5 wt.% of the total weight of the composition.
  • the lubricant is applied in a final lubrication step during the powder preparation.
  • the lubricant generally increases the powder flowability.
  • the glidant can for example be colloidal silicon dioxide (e.g. Aerosil ® ).
  • the glidant agent is present in an amount of 0 to 8 wt.% , more preferably at 0.1 to 3 wt.% of the total weight of the composition.
  • the silicon dioxide has a specific surface area of 50 to 400 m 2 /g, measured according to Ph. Eur. , 6th edition, Chapter 2.9.26.
  • the anti-sticking agent is for example talcum and may be present in amounts of 0.05 to 5 wt.%, more preferably in an amount of 0.5 to 3 wt.% of the total weight of the composition.
  • the pharmaceutical composition comprising celecoxib or a pharmaceutically acceptable salt thereof, may preferably comprise specifically the following excipients in the provided amounts.
  • the composition of this invention preferably comprises a filler or diluent usually in an amount of 0.1 to 50 wt.%, more preferred in an amount of 5 to 25 wt.% and especially preferred in an amount of 18 to 22 wt.% each based on total weight of the composition.
  • composition of this invention comprises the disintegrant usually in an amount of 0.1 to 10 wt.%, more preferred in an amount of 1 to 5 wt.% and especially preferred in an amount of 1.5 to 3.5 wt.% each based on total weight of the composition.
  • the amount of solubiliser employed is from 0.1 to 5 wt.%, more preferably from 1.6 to 3.0 wt.% based on total weight of the composition.
  • the amount of surface active agent is 0.1 to 4.9 wt.%, or more preferably 0.8 to 3.2 wt.% based on total weight of the composition, most preferable the surface active agent is sodium dodecyl sulfate.
  • the lubricant is employed in an amount of 0.1 to 3 wt.%, more preferably 0.6 to 1.2 wt.% based on total weight of the composition.
  • the pharmaceutical composition according to the invention usually is provided in a solid form and has a bulk density of from 0.25 to 0.55 g/ml, preferably from 0.3 to 0.4 g/ml.
  • the bulk and tapped density parameters of the composition can be met either before the optional addition of a lubricant in a lubricating process step or at the final stage after lubrication just before packaging or filling of the capsules.
  • the tapped density is preferably from 0.50 to 0.90 g/ml, more preferably from 0.6 to 0.7 g/ml.
  • the bulk density and tapped density are determined according to USP 24, Test 616 "Bulk Density and Tapped Density".
  • the particles of the composition display a Hausner-factor of preferably from 1.5 to 2.3, more preferably from 1.6 to 2.0, most preferably from 1.7 to 1.8 (see table 2).
  • the Hausner-factor is the ratio of tapped density to bulk density. It is a measure of the compressibility of the respective powder. Usually, a high Hausner-factor indicates low flowability leading to weight differences of the tablets /capsules and therefore to a varying content of the active ingredient. This is a crucial factor for pharmaceutical drugs, since the appropriate dosage and thus bioequivalence with standard formulations must be ensured at any time. However, consolidation of the powder also plays a role and surprisingly, although the Hausner-factor is preferably relatively high for the inventive powders, the values achieved for content stability meet the general requirements.
  • compositions with relatively large particles and a high Hausner-factor were achieved, which show a good bioavailability and good bioequivalence with standard formulations.
  • inventive capsules display a high content uniformity and a low mass variation. Typically, these parameters indicate the relative deviation in the amount of content of the capsules.
  • the active ingredient is preferably contained in a relatively high concentration (100 mg or 200 mg)
  • the content uniformity of high dosage units is adequately represented by the mass variation; see also table 2.9.40.- 1 , Ph. Eur. 6.0, page 328.
  • the mass variation or content uniformity is determined according to Ph. Eur. 6.0, chapter 2.9.40 and provided in terms of the acceptance value.
  • the latter parameter is calculated according to table 2.9.40.-2, Ph. Eur. 6.0, and pages 328 and 329.
  • the maximum allowed acceptance value is 15.0 (Ph. Eur. 6.0).
  • the present invention provides acceptance values of 7.0 or lower, as indicated in Table 4.
  • compositions of the invention with a high weight percentage of the active ingredient of at least 50 wt.%, preferably at least 70 wt.%.
  • compositions and formulations display a high storage stability, which is generally higher than for previous formulations.
  • the storage stability is ascertained for at least 12 months at 40 °C and 75% humidity.
  • the incurred deterioration and/or impurities after this time-span are less than 2.5 wt.%.
  • the storage stability after 3 months was also superior.
  • this invention also incorporates a process for the preparation of a pharmaceutical composition as defined in any of the preceding passages.
  • this process involves any or more of the following steps:
  • the filler, disintegrant and optionally the surface active agent are first sifted through a sieve, while the initial celecoxib particles are sifted through a further sieve with a large diameter.
  • a solution containing the solubiliser is prepared.
  • the above sifted particles are mixed in a high shear mixer granulator.
  • step one This is followed by a third step, in which the products of the second step are wet granulated and kneaded together with the solubiliser solution from step one.
  • step three the products of step three are dried and wet milled and dried again and then finally dry mass sifted.
  • the dried composition of the fourth step is preferably blended with a lubricant and transferred to a container, which can be a PE bag.
  • capsules are filled with the powder products of steps four or five.
  • the invention is particularly concerned with the production of an oral dose unit, preferably tablets, granules and /or capsules comprising the pharmaceutical composition as described above.
  • this invention encompasses an orally deliverable dose unit, preferably a capsule, comprising the composition of the invention as described herein.
  • Another embodiment of this invention is a lactose-free orally deliverable dose unit, preferably a capsule, wherein the administration of said dose unit results in a Cmax in which the 90 % confidence interval is within the range of 80 % - 125 % , preferably within the range of 90 % - 1 10 %, compared to the administration of Celebrex ® , with an equivalent amount of active ingredient.
  • the Cmax value determines the maximal value of the active agent in the blood serum. It indicates the resorptivity of the agent into the blood before being decomposed. This is a critical value for the bioequivalence of a pharmaceutical ingredient. The exchange of medicines can only take place without danger to the patient, when the bioequivalence lies within very strict ranges.
  • this invention comprises a lactose-free oral deliverable dose unit, preferably a capsule, wherein the administration of said dose results in an AUC(0- ⁇ ) value in which the 90 % confidence interval is within the range of 80 % - 125 % , preferably within the range of 90 % - 1 10 %, as compared to the administration of Celebrex ® , with an equivalent amount of active ingredient.
  • the AUC (0- ⁇ ) determines the area under the curve in a bioequivalence comparison of two formulations over the whole time range.
  • composition as described herein or an orally deliverable unit as previously described may be used for the treatment of patients, who are lactose intolerant.
  • about 75% of the human population is more or less intolerant to lactose, due to absence of the enzyme lactase.
  • drugs containing lactose are not recommended.
  • the dose of a single tablet or capsule might not evoke the acute effects typical of lactose intolerance, patients intolerant to lactose always have to be aware of the lactose content of digested foodstuffs or medication in order to prevent the possibility of an accidental overdose. Therefore, these people often require and prefer pharmaceutical medicines without any lactose.
  • step B materials were transferred to a high shear mixer granulator, mixed and granulated with an aqueous solution of Polyvinylpyrrolidone K30 and Polyvinylpyrrolidone K90.
  • step C The wet granules of step C were semidried in a fluid bed dryer, co-milled and finally dried in a fluid bed dryer.
  • step E The dried granules of step D were sifted through sieve no. #30 mesh and lubricated with magnesium stearate.
  • step E The lubricated granules of step E were filled in size 2 hard gelatin capsules by the use of a capsule filling machine

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Abstract

La présente invention porte sur des compositions pharmaceutiques comprenant du célécoxib ou un sel pharmaceutiquement acceptable de celui-ci, sur un procédé pour la préparation de ladite composition pharmaceutique, sur une dose unitaire administrable par voie orale comprenant ladite composition, sur un procédé pour la production de granulés ou de capsules comprenant ladite composition, sur l'utilisation de ladite composition pour des patients souffrant d'intolérance au lactose et enfin sur une dose unitaire administrable par voie orale exempte de lactose.
PCT/EP2010/006538 2009-10-28 2010-10-26 Formulations contenant du célécoxib WO2011050944A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107115313A (zh) * 2017-07-03 2017-09-01 福建省福抗药业股份有限公司 一种塞来昔布组合物及其制备方法
WO2019157560A1 (fr) * 2018-02-16 2019-08-22 Proteobioactives Pty Limited Méthodes et compositions pour le traitement de la douleur et/ou de l'inflammation
CN111803464A (zh) * 2020-06-30 2020-10-23 北京福元医药股份有限公司 一种塞来昔布胶囊制剂

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Publication number Priority date Publication date Assignee Title
EP0731795B1 (fr) 1993-11-30 1999-12-22 G.D. Searle & Co. Benzenesulfonamides de pyrazolyle substitues destines au traitement des inflammations
WO2000032189A1 (fr) 1998-11-30 2000-06-08 G. D. Searle & Co. Compositions a base de celecoxib
WO2006043025A1 (fr) * 2004-10-19 2006-04-27 Reckitt Benckiser Healthcare (Uk) Limited Compositions granulaires comprenant des granules de fusion solidifies d’un inhibiteur selectif de cox-2
WO2007071420A1 (fr) * 2005-12-23 2007-06-28 Lek Pharmaceuticals D.D. Granules a rupture
WO2009063367A1 (fr) * 2007-11-15 2009-05-22 Pfizer Products Inc. Formes galéniques comprenant du célécoxib permettant un soulagement de la douleur à la fois rapide et prolongé

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0731795B1 (fr) 1993-11-30 1999-12-22 G.D. Searle & Co. Benzenesulfonamides de pyrazolyle substitues destines au traitement des inflammations
WO2000032189A1 (fr) 1998-11-30 2000-06-08 G. D. Searle & Co. Compositions a base de celecoxib
WO2006043025A1 (fr) * 2004-10-19 2006-04-27 Reckitt Benckiser Healthcare (Uk) Limited Compositions granulaires comprenant des granules de fusion solidifies d’un inhibiteur selectif de cox-2
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