EP2490674A2 - Melt-granulated cinacalcet - Google Patents
Melt-granulated cinacalcetInfo
- Publication number
- EP2490674A2 EP2490674A2 EP10776083A EP10776083A EP2490674A2 EP 2490674 A2 EP2490674 A2 EP 2490674A2 EP 10776083 A EP10776083 A EP 10776083A EP 10776083 A EP10776083 A EP 10776083A EP 2490674 A2 EP2490674 A2 EP 2490674A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- cinacalcet
- weight
- matrix former
- tablets
- dosage form
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- VDHAWDNDOKGFTD-MRXNPFEDSA-N cinacalcet Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 VDHAWDNDOKGFTD-MRXNPFEDSA-N 0.000 title claims abstract description 67
- 229960003315 cinacalcet Drugs 0.000 title claims abstract description 61
- 239000011159 matrix material Substances 0.000 claims abstract description 47
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- 150000003839 salts Chemical class 0.000 claims abstract description 21
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- 235000012054 meals Nutrition 0.000 claims abstract description 9
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- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 10
- 238000002844 melting Methods 0.000 claims description 10
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- 239000008187 granular material Substances 0.000 claims description 8
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- QANQWUQOEJZMLL-PKLMIRHRSA-N cinacalcet hydrochloride Chemical compound Cl.N([C@H](C)C=1C2=CC=CC=C2C=CC=1)CCCC1=CC=CC(C(F)(F)F)=C1 QANQWUQOEJZMLL-PKLMIRHRSA-N 0.000 description 8
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- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
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- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 201000003913 parathyroid carcinoma Diseases 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 208000017954 parathyroid gland carcinoma Diseases 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000005029 sieve analysis Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
- A61P5/20—Drugs for disorders of the endocrine system of the parathyroid hormones for decreasing, blocking or antagonising the activity of PTH
Definitions
- the invention relates to an intermediate obtainable by co-melt processing of (i) crystalline cinacalcet or a pharmaceutically acceptable salt thereof, with (ii) a matrix former and tablets containing the intermediates of the invention.
- the invention further relates to a process for the preparation of the tablets according to the invention.
- the invention relates to the use of a matrix former and a wicking agent for the preparation of cinacalcet formulations, which can preferably be administered independently of the meals.
- the calcimimetic cinacalcet is used to treat secondary hyperparathyroidism as a result of chronic renal insufficiency.
- the substance is approved for the treatment of hypercalcaemia in patients with parathyroid carcinoma.
- Synthesis and effect of cinacalcet are described in EP 1 203 761 Bl.
- Patients with chronic kidney disease often develop parathyroid hyperfunction (secondary hyperparathyroidism) due to their underlying disease.
- Inadequate kidneys excrete less phosphate with the urine and produce less active vitamin D3, which is necessary for the maintenance of a physiological calcium ion blood level. When the calcium ion level drops, parathyroid hormone is increasingly released in the parathyroid glands.
- parathyroid overproduction causes calcium ions to be mobilized from the bones and make the bones more fragile.
- Cinacalcet binds to the calcium-sensitive receptors on the surface of the parathyroid cells. This increases the sensitivity of the receptor to extracellular calcium ions and a higher calcium level in the blood than actually simulated. As a result, the parathyroid hormone secretion decreases, so less calcium is released from the bone.
- Cinacalcet is also available by spray-drying in amorphous form, see WO 2008/000422 Al.
- active ingredients in amorphous form often show disadvantageous properties in terms of storage stability.
- WO 2008/064202 describes sustained-release cinacalcet-containing compositions. Delayed release dosage forms are commonly used for specific applications. However, immediate release dosage forms are desirable for a variety of applications.
- the tablets contain cinacalcet in micronized form with an active ingredient content of about 18%.
- the film-coated tablets should be taken with or shortly after a meal, as the bioavailability increases with food intake by 50 to 80 percent and then is acceptable.
- micronization results in an agent with undesirably low flowability.
- micronized drug is more difficult to compress and occasionally there is uneven drug distribution within the pharmaceutical formulation to be compressed. Due to the large increase in surface area during micronization, the oxidation sensitivity of the active substance also increases.
- Object of the present invention was therefore to overcome the disadvantages mentioned above. It is intended to provide the active ingredient in a form which has good flowability and good compression. Furthermore, a uniform distribution of the active ingredient should be ensured. Micronization of the active ingredient should be avoided. Furthermore, the active ingredient should be provided in a form which ensures good solubility with good storage stability at the same time. Even after 2-year storage (or 3-month storage under stress conditions), a correspondingly good solubility should be achievable. It should be possible to administer it independently of the meals. The term "administration independent of the meals" means that the patient can take the medicine with meals, but does not necessarily have to take with meals.
- a Solubility of greater than 3 mg / ml in particular 10 mg / ml can be achieved.
- a storage stability of 12 months at 40 ° C and 75% humidity is to be achieved.
- the impurities should be after such storage ⁇ 2 wt .-%, in particular ⁇ 1 wt .-%.
- the objects of the present invention have been achieved by an intermediate obtainable by melt processing, preferably melt granulation or melt extrusion, cinacalcet and matrix former, and by using the intermediate to produce immediate release tablets.
- the invention thus relates to an intermediate obtainable by melt processing
- the term “cinacalcet” (i) encompasses both the “free base” described above and pharmaceutically acceptable salts thereof. This may be one or more salts, which may also be present in a mixture.
- salt is meant herein that the amine group of the cinacalcet has been protonated to form a positively charged nitrogen atom associated with a corresponding counter anion.
- the salts used are preferably acid addition salts.
- suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, lactates, butyrates, propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates.
- the pharmaceutically acceptable salt is more preferably cinacalcet hydrochloride. Also most preferably, the pharmaceutically acceptable salt is cinacalcetate carbonate. With particular preference, the pharmaceutically acceptable salt is cinacalcet methanesulfonate.
- the cinacalcet (i) used, preferably the cinacalcet hydrochloride used, is usually crystalline material. Preferably, it was not micronized. Cinacalcet hydrochloride in polymorphic form I is preferably used. The polymorphic form I is disclosed, for example, in WO 2007/62147.
- non-micronized Cinacalcet in the context of this invention refers to particulate Cinacalcet, which generally has an average particle diameter (D50) of 20 to 280 ⁇ , preferably 60 to 250 ⁇ , more preferably from 65 to 200 ⁇ , even more preferably from 70 to 125 ⁇ , and in particular from 75 to 1 10 ⁇ .
- D50 average particle diameter
- average particle diameter in the context of this invention refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry. In particular, a Mastersizer 2000 from Malvern Instruments was used for the determination. All measurement conditions are selected as described on pages 9 and 10 of WO 2005/034928 ie wet measurement, 1750 rpm, Span ® 85 as dispersants, evaluation according to the Fraunhofer method.
- the average particle diameter also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, then 50% by volume of the particles have a larger diameter than the D50 value.
- the D10 value is defined as the particle diameter at which 10% by volume of the particles have a smaller diameter than the diameter which corresponds to the D10 value.
- the D90 value is defined as the particle diameter at which 90% by volume of the particles have a smaller diameter than the diameter corresponding to the D90 value.
- the non-micronized Cinacalcet also has usually D10 values of 1 to 50 ⁇ , more preferably from 1 to 30 ⁇ , and in particular from 2 to 25 ⁇ . Furthermore, the non-micronized cinacalcet usually has D90 values of from 200 to 800 / im, more preferably from 250 to 700 microns, and especially from 300 to 50 microns.
- Crystalline cinacalcet is usually in the form of needles. Characterization by means of volume-median particle diameter may not be sufficiently specific. It has been found that a more exact characterization of advantageously usable Cinacalcet, especially Cinacalcet hydrochloride, can be done by the description of the specific surface.
- the specific surface area is determined in the context of this invention according to the gas adsorption method, in particular by means of the BET method.
- the cinacalcet (i) used in particular the cinacalcet hydrochloride, has a water content of from 0.01 to 0.20% by weight, more preferably from 0.02 to 0, 10% by weight.
- the residual water content is determined by the Karl Fischer method using a coulometer at 160 ° C.
- a Metrohm 831 KF Coulometer with a titration cell without a diaphragm is preferably used.
- a sample of 20 mg cinacalcet is analyzed.
- the "matrix former" (ii) is generally a material which, when heated above the melting point, in particular in a melt granulation or melt extrusion process, is deformable and able to embed particulate cinacalcet, ie a matrix for particulate cinacalcet.
- the matrix former thus preferably has a thermoplastic behavior, ie it is a thermoplastic matrix former.
- the matrix former is also a substance that is able to attach to the cinacalcet or salts thereof (chemically or physically) during the extrusion process and to increase the hydrophilicity of the surface.
- the matrix former (ii) may be hydrophilic polymers, in particular hydrophilic thermoplastic polymers. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, amino, carboxy, sulfonate.
- the hydrophilic polymer usable for the preparation of the intermediate preferably has a weight-average molecular weight of 1,000 to 150,000 g / mol, more preferably 2,000 to 90,000 g / mol, especially 3,000 to 75,000 g / mol. In the context of this application, the weight average molecular weight preferably determined by gel permeation chromatography.
- the polymers used as matrix formers exhibit substantially no emulsifying action. That is, the matrix former used should preferably not have a combination of hydrophilic and hydrophobic groups (especially hydrophobic fatty acid groups). Furthermore, it is preferred that the intermediate according to the invention does not contain polymers which have a weight-average molecular weight of more than 150,000 g / mol. Such polymers usually undesirably affect the dissolution properties.
- the resulting solution preferably exhibits a viscosity of 0.1 to 8 mPa / s, more preferably 0.5 to 7 mPa / s, in particular from 1 to 6 mPa / s, measured at 25 ° C and according to Ph. Eur., 6th edition, chapter 2.2.10.
- the hydrophilic polymer used as the matrix former has a glass transition temperature ( Tg ) or a melting point of 25 ° C to 200 ° C, more preferably 40 ° C to 170 ° C.
- the glass transition temperature is the temperature at which the hydrophilic polymer becomes brittle upon cooling and softens when heated. This means that hydrophilic polymers soften at temperatures above the glass transition temperature (T g ) and become plastically deformable without breaking.
- the glass transition temperature or the melting point are determined with a Mettler-Toledo ® DSC1, wherein a heating rate of 10 ° C per minute and a cooling rate of 15 ° C per minute are employed. The method of determination is based essentially on Ph.Eur. 6.1, chapter 2.2.34.
- the matrix former (ii) also comprises solid, non-polymeric compounds which preferably have polar side groups.
- the intermediate of the invention may comprise, for example, the following hydrophilic polymers as matrix formers: polysaccharides, such as hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ® VA64, BASF), polyalkylene glycols , such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ® , BASF) and mixtures of the polymers mentioned.
- hydrophilic polymers as matrix formers: polysaccharides, such as hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polyme
- HPMC hydroxypropylmethylcellulose
- HPMC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPC hydroxypropylmethylcellulose
- HPMC hydroxypropylmethylcellulose
- HPMC hydroxypropylmethylcellulose
- HPMC hydroxypropylmethylcellulose
- HPC Hydroxypropylcellulose
- polyvinylpyrrolidone preferably having a weight-average molecular weight of 10,000 to 60,000 g / mol, in particular 12,000 to 40,000 g / mol
- copolymer of vinylpyrrolidone and vinyl acetate in particular with a Weight-average molecular weight of 40,000 to 75,000 g / mol
- Particularly preferred matrix formers (ii) are co-block polymers of polyethylene glycol and polypropylene glycol, i.
- Polyoxyethylene polyoxypropylene block polymers Preferably, these have a weight-average molecular weight of from 1,000 to 20,000 g / mol, more preferably from 1,500 to 12,500 g / mol, in particular from 5,000 to 10,000 g / mol.
- These block polymers are preferably obtainable by condensation of propylene oxide with propylene glycol and subsequent condensation of the resulting polymer with ethylene oxide. That is, preferably, the ethylene oxide is present as an "end block".
- the block polymers have a weight ratio of propylene oxide to ethylene oxide of from 50:50 to 95: 5, more preferably from 70:30 to 90:10.
- the block polymers preferably have a viscosity at 25 ° C. of from 200 to 2000 mPas, more preferably from 500 to 1500 mPas, in particular from 800 to 1200 mPas.
- the intermediate according to the invention contains cinacalcet or a pharmaceutically acceptable salt thereof, preferably in non-micronized form, and matrix former, wherein the weight ratio of active ingredient (i) to matrix former (ii) is 5: 1 to 1: 5, more preferably 3: 1 to 1: 3, more preferably 2: 1 to 1: 2, in particular about 1: 1.
- the type and amount of the matrix former be selected such that at least 50% of the surface area of the resulting intermediate particles is covered with matrix former, more preferably at least 60% of the surface area, particularly preferably at least 80% of the surface, in particular at least 95% of the surface.
- cinacalcet (i) and matrix former (ii) are "melt processed” together.
- the melt processing is carried out as a melt extrusion or more preferably as a melt granulation.
- Melt processing may further include, as described below, further pharmaceutical excipients, such as e.g. Disintegrants and wicking agents are buried. If disintegrants and wicking agents (quasi intragranular) are contained in the intermediate (a) according to the invention, they are referred to as components (iii-int) or (iv-int) in the context of this application.
- disintegrants and wicking agents in the oral dosage form according to the invention (as component (ß)) are included, they are referred to in the context of this application as components (iii-ex), or (iv-ex).
- the oral dosage form according to the invention preferably in the form of a tablet, preferably with immediate release, may contain:
- Melt processing can be carried out in conventional melt processing equipment as described below.
- the melting conditions are usually chosen so that cinacalcet remains in a crystalline state.
- the intermediate according to the invention is used in the preparation of an oral dosage form.
- the oral dosage form is, for example, capsules, powders or granules for filling into sachets or tablets.
- the Production of tablets is preferred here.
- the intermediate according to the invention is particularly preferably used for the production of an immediate release tablet (known in English as "immediate release tablet").
- the invention therefore relates to an oral dosage form, in particular an immediate release tablet containing
- auxiliaries ( ⁇ ) known to the person skilled in the art, in particular those described in the European Pharmacopoeia.
- auxiliaries ( ⁇ ) used are disintegrants, release agents, fillers, additives to improve the powder flowability, lubricants, wetting agents, and / or lubricants.
- the ratio of active ingredient to auxiliaries is preferably selected so that the resulting formulations
- the tablet according to the invention contains 1 to 40 wt .-%, 5 to 35 wt .-%, more preferably 10 to 30 wt .-%, particularly preferably 15 to 25 wt .-% disintegrant (iii), based on the total weight of the formulation.
- disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after introduction into water.
- Suitable disintegrants are, for example, organic disintegrants such as carrageenan, celluloses and cellulose derivatives: croscarmellose, starches and starch derivatives: sodium carboxymethyl starch, polysaccharides: soy polysaccharides, alginates and crospovidone.
- inorganic disintegrants such as bentonites can be used.
- alkaline disintegrants can be used.
- alkaline disintegrating agents are meant disintegrating agents when dissolved in water produce a pH of more than 7.0. Mixtures of the aforementioned disintegrants may also be used.
- Crospovidone and / or croscarmellose are particularly preferably used as disintegrating agents, in particular in the abovementioned amounts.
- the tablet according to the invention contains 0 to 35 wt .-%, 1 to 30 wt .-%, more preferably 5 to 25 wt .-%, particularly preferably 10 to 20 wt .-% wicking agent (iv), based on the total weight of the formulation.
- a wicking agent is an agent capable of drawing a biological fluid (preferably water) into a solid (preferably into the intermediates (i), preferably by physisorption).
- Physiosorption is defined as a form of adsorption in which the liquid molecules can adhere to the surface of the wicking agent, preferably by means of van der Waals bonding between the surface of the wicking agent and the adsorbed liquid molecule (preferably water).
- a wicking agent does so with or without swelling.
- a non-swelling wick that attracts water will eventually have a volume that essentially consists of the volume of the wick and the amount of water that attracts it.
- a swelling wicking agent will have a volume consisting essentially of the volume of the wicking agent, the amount of water it attracts, and an additional volume caused by steric and molecular forces.
- the wicking agent (iv) preferably causes the formation of channels or pores in the intermediate according to the invention or in the tablet according to the invention. This facilitates the penetration of the water molecules into the intermediates, in particular by physisorption. Therefore, the function of the wick means is to transport water to the surfaces within the intermediates to thereby create channels in or a network on an enlarged surface.
- wicking agents used are: microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, kaolin, titanium dioxide, fumed silica, aluminum, niacinamide, m-pyrol, bentonite, magnesium aluminum silicate, polyester, polyethylene, or mixtures thereof.
- the wicking agents of the pharmaceutical composition of the present invention contain cellulose and cellulose derivatives such as, for example, silified microcrystalline cellulose, colloidal silica, and mixtures thereof.
- the preferably used silified microcrystalline cellulose is commercially available under the trade name Prosolv ® and has a silica content of 1 to 3 wt .-%, preferably from 2 wt .-% to.
- the oral dosage form according to the invention may further contain fillers (v).
- Fillers are generally to be understood as meaning substances which serve for the formation of the tablet body in the case of tablets with small amounts of active ingredient (eg less than 60% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.
- Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, chitin, cellulose and derivatives thereof, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin and / or dextrose, hydrogenated vegetable oil.
- sugar alcohols and / or disaccharides such as mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof can be used.
- sugar alcohols here also includes monosaccharides.
- Fillers are usually used in an amount of from 1 to 80% by weight, more preferably from 5 to 50% by weight, especially from 20 to 40% by weight, based on the total weight of the formulation.
- the tablet of the present invention may further contain additives for improving powder flowability.
- An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ®. Preference is given to using silica having a specific surface area of from 50 to 400 m 2 / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition, Sept. 2, 1966.
- Additives for improving the powder flowability are usually added in an amount of 0.1 to 5% by weight, e.g. 1, 5 to 4 wt .-%, based on the total weight of the formulation used.
- Lubricants can be used.
- Lubricants are generally used to reduce sliding friction.
- the sliding friction is to be reduced, which consists during tabletting on the one hand between the up in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall.
- Suitable lubricants are for example stearic acid, adipic acid, sodium stearyl fumarate is (Pruv ®) and / or magnesium stearate.
- Lubricants are usually used in an amount of 0, 1 to 5 wt .-%, preferably 1, 0 to 3 wt .-%, based on the total weight of the formulation.
- release agents can be used.
- release agents are usually understood substances which reduce the agglomeration in the core bed. Examples are talc, silica gel, polyethylene glycol (preferably with 2,000 to 10,000 g / mol weight-average molecular weight) and / or glycerol monostearate.
- the unambiguous delimitation is therefore preferably based on the fiction that a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient.
- a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient.
- sorbitol is not additionally used as a matrix former.
- microcrystalline cellulose - if used as a wicking agent - not additionally used as a filler (although microcrystalline cellulose also produces a filling effect).
- the tablet according to the invention (based on the total weight of the tablet core) contains the following constituents:
- Tablet (based on the total weight of the tablet core) the following constituents: more than 40 to 60% by weight of cinacalcet (i)
- the tablets according to the invention preferably contain no polymers which lead to a delayed release.
- the tablets according to the invention contain no polymers having a molecular weight of more than 150,000 g / mol.
- the invention further provides a process for the preparation of the tablets according to the invention, comprising the steps
- melt processing preferably melt extrusion or, in particular, melt granulation, to an intermediate
- step (d) compression of the resulting intermediates (preferably the granules resulting from step (c)) into tablets, if appropriate with the addition of further pharmaceutical auxiliaries;
- step (a) of the process cinacalcet, preferably crystalline Cinacalcet or its pharmaceutically acceptable salts with (ii) a matrix former and optionally further - described above - pharmaceutical excipients (ß) are provided and preferably mixed.
- the matrix former preferably does not comprise a polymer having a weight-average molecular weight of more than 150,000 g / mol.
- pharmaceutical auxiliaries which are added in step (a) (and / or also in step (d)) of the process according to the invention.
- the mixing can be done in conventional mixers.
- a Turbula ® T 10B (Bachofen AG, Switzerland) is suitable.
- the mixing time is usually 1 minute to 1 hour, preferably 5 minutes to 20 minutes.
- step (a) in step (a)
- step (b) of the process of the invention the mixture of step (a) is melt-processed into the intermediate material of the invention, i. preferably melt-extruded or melt-granulated.
- Clnacalcet (i) is processed with the - preferably thermoplastic - matrix former (ii) in such a way that cinacalcet is embedded in the matrix material.
- the melting conditions are selected so that the matrix former is melted or fused, but the active ingredient remains in a solid state.
- cinacalcet in crystalline form in particular clacalcet hydrochloride in crystalline form I
- the melting conditions are preferably chosen such that the active ingredient is retained in crystalline form, in particular crystalline form I.
- the temperature selected in the melt processing is 10 ° C below to 10 ° C above the melting point of the matrix former, preferably with the proviso that the selected temperature is at least 10 ° C below the melting temperature of the Cinacalcets used.
- the melt processing may preferably be carried out as melt granulation or as melt extrusion.
- a melt granulation takes place.
- the fusion in this case runs preferably above an intensive mixer with heated jacket unit, for example a Diosna ® -6 PI can be used advantageously.
- a melt extrusion takes place.
- This is a continuous process (batch-independent), the premixing and granulation not being sequential in time, but in one production step.
- a preferred process for preparing the melt extrudate, the melt extrusion through a twin-screw extruder (for example, Leistritz ® micro 18) is.
- Advantage here is the setting of a temperature gradient, depending on the selected matrix former which significantly reduces the residence time of the cinacalcet under high temperatures.
- the temperature gradient is usually between 80 and 190 ° C. and is preferably chosen so that the cinacalcet is still present in crystalline form after processing.
- step (c) of the process according to the invention the extrudate is granulated.
- the granulation can be done before, during or after cooling. Granulation preferably already takes place in the context of melt processing.
- steps (b) and (c) can also be understood as a method step.
- the granulation conditions are selected so that the resulting particles (granules) have a weight average particle size (D50) of from 75 to 600 / ⁇ m, more preferably from 120 to 500 ⁇ , more preferably from 150 to 400 ⁇ , in particular from 200 to 350 ⁇ ..
- the weight-average particle size is determined by sieve analysis (using a Retsch ® AS 2000, amplitude 1, 5 sec, interval 10 min., Sample weight 15.8 g).
- the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.3 to 0.85 g / ml, more preferably 0.4 to 0.8 g / ml, especially 0.5 to 0.7 g / ml exhibit.
- the Hausner factor is usually in the range of 1, 02 to 1, 3, more preferably from 1, 03 to 1, 25 and in particular from 1, 04 to 1, 15.
- "Hausner factor” is the ratio of tamped density understood to bulk density. Bulk density and tamped density are determined according to USP 24, Test 616 "Bulk Density and Tapped Density".
- step (d) of the process according to the invention the granules obtained in step (c) are compressed into tablets, ie compression into tablets takes place.
- the compression can be done with tableting machines known in the art, such as eccentric presses or concentric presses.
- a pressing force of from 2 to 40 kN, preferably from 2.5 to 35 kN is usually used.
- the press fats ® 102i (Fette GmbH, Germany).
- eccentric presses usually a pressing force of 1 to 20 kN, preferably from 2.5 to 10 kN, applied.
- the Korsch ® EK0 is used.
- Process step (d) is preferably carried out in the absence of solvents, in particular organic solvents, i. as dry compression.
- step (d) of the process according to the invention it is possible to add to the intermediates from step (b) or (c) pharmaceutical auxiliaries ( ⁇ ).
- suitable auxiliaries ⁇
- the invention is not only the inventive method, but also the tablets produced by this method.
- the tablets produced by the process according to the invention may be tablets which are swallowed whole (unfiltered or preferably film-coated). It can also be chewable tablets or disperse tablets.
- Disperse tablets is here understood to mean a tablet for the production of an aqueous suspension for oral use.
- step (e) of the method according to the invention it is preferred that they be coated with a film layer in step (e) of the method according to the invention.
- the above-mentioned ratios of active ingredient to excipient relate to the unpainted tablet.
- macromolecular substances are used for the coating, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac.
- HPMC in particular HPMC having a weight-average molecular weight of from 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH 3 groups of from 1.2 to 2.0.
- the layer thickness of the coating is preferably 1 to 100 ⁇ . more preferably 2 to 80 ⁇ .
- the tabletting conditions are preferably chosen so that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.05 to 0.2 mm / mg.
- the resulting tablets preferably have a hardness of from 70 to 200 N, particularly preferably from 100 to 150 N, in particular if the tablet weight is more than 200 mg. If the tablet weight is 200 mg or less, the resulting tablets preferably have a hardness of from 30 to 100 N, more preferably from 40 to 70 N, on. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8. In addition, the resulting tablets preferably have a friability of less than 3%, particularly preferably less than 1%, in particular less than 0.8%. The friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.
- the tablets according to the invention usually have a "content uniformity" of 95 to 105% of the average content, preferably 98 to 102%, in particular 99 to 101% of the average content.
- the "Content Uniformity” is according to Ph. Eur.6.0, Section 2.9.6. certainly.
- the release profile of the tablets according to the invention usually has a released content of at least 30%, preferably at least 50%, according to the USP method (paddle, 900 ml of 0.1 N HCl, pH 1, 2, 37 ° C., 75 rpm) after 10 minutes. especially at least 70%. If these parameters are met, the tablets are considered as immediate release tablets.
- the above information on hardness, friability, content uniformity and release profile in this case relate preferably to the uninfiltrated tablet.
- the granules resulting in step (c) of the process according to the invention may also be processed into a particulate dosage form, optionally by adding further pharmaceutical auxiliaries, for example by filling into capsules or in sachets.
- the invention thus relates to an oral dosage form containing cinacalcet, matrix former and disintegrants for the treatment of hyperparathyroidism, the administration taking place independently of the meals.
- disintegrants are used in an amount of 10 to 30% by weight, based on the total weight of the oral administration form.
- a polyoxyethylene polyoxypropylene block polymer is used for this purpose as a matrix former, in particular as described in more detail above.
- the content of cinacalcet is from 20 to 60% by weight, in particular from 40 to 60% by weight.
- Polyoxyethylene polyoxypropylene block polymer (Mw ca. 8350): 30.0 mg
- Crospovidone 28.0 mg film:
- Example 1 The in vitro solubility behavior of (non-film) tablets according to Example 1 and Comparative Example 1 was determined according to USP (paddle, 900 ml 0, 1 N HCl, pH 1, 2, 37 ° C, 75 rpm) before and after storage (40 ° C , 75% relative humidity).
- HPLC method of tablets according to Example 1 before and after storage (40 ° C., 75% relative atmospheric humidity).
Abstract
The invention relates to an intermediate, which can be obtained by means of melt-extruding (i) cinacalcet or a pharmaceutically acceptable salt thereof, comprising (ii) a matrix former and oral forms of administration, in particular tablets containing the intermediates according to the invention. The invention further relates to a method for producing the tablets according to the invention. Finally, the invention relates to the use of a matrix former and a wicking agent for producing cinacalcet formulations, which preferably can be administered independently of meals.
Description
Schmelzgranuliertes Cinacalcet Melt granulated cinacalcet
Die Erfindung betrifft ein Intermediat, erhältlich durch gemeinsame Schmelzverarbeitung von (i) kristallinem Cinacalcet oder eines pharmazeutisch verträglichen Salzes davon, mit (ii) einem Matrixformer sowie Tabletten enthaltend die erfindungsgemäßen Intermediate. Die Erfindung betrifft ferner ein Verfahren zur Herstellung der erfindungsgemäßen Tabletten. Schließlich betrifft die Erfindung die Verwendung eines Matrixformers und eines Dochtmittels zur Herstellung von Cinacalcet-Formulierungen, die vorzugsweise unabhängig von den Mahlzeiten verabreicht werden können. The invention relates to an intermediate obtainable by co-melt processing of (i) crystalline cinacalcet or a pharmaceutically acceptable salt thereof, with (ii) a matrix former and tablets containing the intermediates of the invention. The invention further relates to a process for the preparation of the tablets according to the invention. Finally, the invention relates to the use of a matrix former and a wicking agent for the preparation of cinacalcet formulations, which can preferably be administered independently of the meals.
N-[(lR)- l-(l-naphthyl)ethyl]-3- [3-(trifluormethyl)phenyl]propan- 1-amin ist unter dem INN-Namen "Cinacalcet" bekannt und weist folgende Strukturformel auf: N - [(1R) -1- (1-naphthyl) ethyl] -3- [3- (trifluoromethyl) phenyl] propane-1-amine is known by the INN name "cinacalcet" and has the following structural formula:
Das Calcimimetikum Cinacalcet dient zur Behandlung des sekundären Hyperparathyreoidismus infolge einer chronischen Niereninsuffizienz. Zudem ist die Substanz zur Behandlung der Hypercalcämie bei Patienten mit Nebenschilddrüsenkarzinom zugelassen. Synthese und Wirkung von Cinacalcet sind in EP 1 203 761 Bl beschrieben. Patienten mit einer chronischen Nierenerkrankung bekommen infolge ihrer Grunderkrankung häufig eine Nebenschilddrüsen-Überfunktion (sekundärer Hyperparathyreoidismus). Insuffiziente Nieren scheiden mit dem Urin weniger Phosphat aus und bilden weniger aktives Vitamin D3, das für die Aufrechterhaltung eines physiologischen Calciumionen-Blutspiegels notwendig ist. Wenn der Calciumionenspiegel sinkt, wird in den Nebenschilddrüsen vermehrt Parathormon ausgeschüttet. Die Parathormon-Überproduktion bewirkt wiederum, dass Calciumionen aus den Knochen mobilisiert wird und die Knochen brüchiger werden. Cinacalcet bindet an die calciumempfindlichen Rezeptoren an der Oberfläche der Nebenschilddrüsenzellen. Dadurch wird die Empfindlichkeit des Rezeptors gegenüber extrazellulären Calciumionen gesteigert und ein höherer Calciumspiegel im Blut als
tatsächlich vorhanden simuliert. Als Folge sinkt die Parathormon-Sekretion, damit wird weniger Calcium aus dem Knochen freigesetzt. The calcimimetic cinacalcet is used to treat secondary hyperparathyroidism as a result of chronic renal insufficiency. In addition, the substance is approved for the treatment of hypercalcaemia in patients with parathyroid carcinoma. Synthesis and effect of cinacalcet are described in EP 1 203 761 Bl. Patients with chronic kidney disease often develop parathyroid hyperfunction (secondary hyperparathyroidism) due to their underlying disease. Inadequate kidneys excrete less phosphate with the urine and produce less active vitamin D3, which is necessary for the maintenance of a physiological calcium ion blood level. When the calcium ion level drops, parathyroid hormone is increasingly released in the parathyroid glands. In turn, parathyroid overproduction causes calcium ions to be mobilized from the bones and make the bones more fragile. Cinacalcet binds to the calcium-sensitive receptors on the surface of the parathyroid cells. This increases the sensitivity of the receptor to extracellular calcium ions and a higher calcium level in the blood than actually simulated. As a result, the parathyroid hormone secretion decreases, so less calcium is released from the bone.
Cinacalcet ist durch Sprühtrocknung auch in amorpher Form erhältlich, siehe WO 2008/000422 AI . Wirkstoffe in amorpher Form zeigen jedoch häufig nachteilige Eigenschaften im Hinblick auf die Lagerstabilität. Cinacalcet is also available by spray-drying in amorphous form, see WO 2008/000422 Al. However, active ingredients in amorphous form often show disadvantageous properties in terms of storage stability.
Die WO 2008/064202 beschreibt Cinacalcet-haltige Zusammensetzungen mit verzögerter Freisetzung. Darreichungsformen mit verzögerter Freisetzung werden üblicherweise für spezielle Anwendungen verwendet. Für eine Vielzahl von Anwendungen sind jedoch Darreichungsformen mit sofortiger Freisetzung wünschenswert. WO 2008/064202 describes sustained-release cinacalcet-containing compositions. Delayed release dosage forms are commonly used for specific applications. However, immediate release dosage forms are desirable for a variety of applications.
Die derzeitig vermarkteten Filmtabletten sind Tabletten mit sofortiger Freisetzung (= Immediate-Release Tabletten) und in WO 2005/034928 beschrieben. Die Tabletten enthalten Cinacalcet in mikronisierter Form mit einem Wirkstoffanteil von ungefähr 18 %. Dabei sollten die Filmtabletten mit oder kurz nach einer Mahlzeit eingenommen werden, da sich die Bioverfügbarkeit bei gleichzeitiger Nahrungsaufnahme um 50 bis 80 Prozent erhöht und erst dann akzeptabel ist. The currently marketed film-coated tablets are immediate-release tablets (= immediate-release tablets) and described in WO 2005/034928. The tablets contain cinacalcet in micronized form with an active ingredient content of about 18%. The film-coated tablets should be taken with or shortly after a meal, as the bioavailability increases with food intake by 50 to 80 percent and then is acceptable.
Mit der Mikronisierung von Cinacalcet gehen jedoch einige Nachteile einher. Zunächst resultiert die Mikronisierung in einem Wirkstoff mit unerwünscht niedriger Fließfähigkeit. Ferner ist der mikronisierte Wirkstoff schwieriger zu verpressen und gelegentlich kommt es zu ungleichmäßiger Wirkstoffverteilung innerhalb der zu verpressenden pharmazeutischen Formulierung. Durch die starke Vergrößerung der Oberfläche während der Mikronisierung nimmt zudem die Oxidationsempfindlichkeit des Wirkstoffs zu. However, there are some disadvantages associated with the micronization of cinacalcet. First, micronization results in an agent with undesirably low flowability. Furthermore, the micronized drug is more difficult to compress and occasionally there is uneven drug distribution within the pharmaceutical formulation to be compressed. Due to the large increase in surface area during micronization, the oxidation sensitivity of the active substance also increases.
Aufgabe der vorliegenden Erfindung war es daher, die vorstehend genannten Nachteile zu überwinden. Es soll der Wirkstoff in einer Form bereitgestellt werden, die eine gute Fließfähigkeit aufweist und eine gute Verpressung ermöglicht. Ferner soll eine gleichmäßige Verteilung des Wirkstoffs gewährleistet sein. Eine Mikronisierung des Wirkstoffs soll vermieden werden. Weiterhin soll der Wirkstoff in einer Form bereitgestellt werden, die gute Löslichkeit bei zeitgleich guter Lagerstabilität gewährleistet. Auch nach 2 -jähriger Lagerung (bzw. 3-monatiger Lagerung unter Stressbedingungen) soll eine entsprechend gute Löslichkeit erzielbar sein. Es soll eine Verabreichung unabhängig von den Mahlzeiten ermöglicht werden. Unter dem Begriff "Verabreichung unabhängig von den Mahlzeiten" ist zu verstehen, dass der Patient das Arzneimittel zu den Mahlzeiten einnehmen kann, aber nicht zwingend zu den Mahlzeiten einnehmen muss. Insbesondere soll eine
Löslichkeit von größer 3 mg/ml, insbesondere von 10 mg/ml erreicht werden. Ferner soll eine Lagerstabilität von 12 Monaten bei 40 °C und 75 % Luftfeuchte erzielt werden. Die Verunreinigungen sollen nach derartiger Lagerung < 2 Gew.-%, insbesondere < 1 Gew.-% sein. Ferner soll es möglich sein, Cinacalcet-Tabletten sowohl mit rascher Zerfallszeit als auch mit vorteilhafter Härte bereit zu stellen. Object of the present invention was therefore to overcome the disadvantages mentioned above. It is intended to provide the active ingredient in a form which has good flowability and good compression. Furthermore, a uniform distribution of the active ingredient should be ensured. Micronization of the active ingredient should be avoided. Furthermore, the active ingredient should be provided in a form which ensures good solubility with good storage stability at the same time. Even after 2-year storage (or 3-month storage under stress conditions), a correspondingly good solubility should be achievable. It should be possible to administer it independently of the meals. The term "administration independent of the meals" means that the patient can take the medicine with meals, but does not necessarily have to take with meals. In particular, should a Solubility of greater than 3 mg / ml, in particular 10 mg / ml can be achieved. Furthermore, a storage stability of 12 months at 40 ° C and 75% humidity is to be achieved. The impurities should be after such storage <2 wt .-%, in particular <1 wt .-%. Furthermore, it should be possible to provide cinacalcet tablets both with rapid disintegration time and with advantageous hardness.
Alle vorstehend genannten vorteilhaften Eigenschaften sollen zudem bei hohem Wirkstoffanteil (z.B. bei Wirkstoffgehalten von 20 %, 30 %, 40 % und/oder 50 %) erzielbar sein. Insbesondere sollen die vorstehend genannten Eigenschaften zudem bei hohem Wirkstoffanteil und zugleich hoher "Content Uniformity" erzielbar sein. All of the advantageous properties mentioned above should also be achievable with a high proportion of active ingredient (for example at active substance contents of 20%, 30%, 40% and / or 50%). In particular, the aforementioned properties should also be achievable with a high proportion of active ingredient and at the same time high "content uniformity".
Die Aufgaben der vorliegenden Erfindung konnten insbesondere durch ein Intermediat gelöst werden, das durch Schmelzverarbeitung, bevorzugt Schmelzgranulation oder Schmelzextrusion, von Cinacalcet und Matrixformer erhältlich ist, sowie durch Verwendung des Intermediats zur Herstellung von Tabletten mit sofortiger Freisetzung. In particular, the objects of the present invention have been achieved by an intermediate obtainable by melt processing, preferably melt granulation or melt extrusion, cinacalcet and matrix former, and by using the intermediate to produce immediate release tablets.
Gegenstand der Erfindung ist somit ein Intermediat, erhältlich durch Schmelzverarbeitung von The invention thus relates to an intermediate obtainable by melt processing
(i) Cinacalcet oder eines pharmazeutisch verträglichen Salzes (i) Cinacalcet or a pharmaceutically acceptable salt
davon, mit of it, with
(ii) einem Matrixformer. (ii) a matrix former.
Grundsätzlich umfasst im Rahmen dieser Anmeldung der Begriff "Cinacalcet" (i) sowohl die vorstehend dargestellte "freie Base" als auch pharmazeutisch verträgliche Salze davon. Hierbei kann es sich um ein oder mehrere Salze handeln, die auch im Gemisch vorliegen können. Unter "Salz" wird hierbei verstanden, dass die Amingruppe des Cinacalcets protoniert wurde, wobei sich ein positiv geladenes Stickstoffatom bildet, das mit einem entsprechenden Gegenanion assoziiert ist. Basically, in the context of this application, the term "cinacalcet" (i) encompasses both the "free base" described above and pharmaceutically acceptable salts thereof. This may be one or more salts, which may also be present in a mixture. By "salt" is meant herein that the amine group of the cinacalcet has been protonated to form a positively charged nitrogen atom associated with a corresponding counter anion.
Bevorzugt werden als Salze Säureadditionssalze verwendet. Beispiele für geeignete Salze sind Hydrochloride, Carbonate, Hydrogencarbonate, Acetate, Lactate, Butyrate, Propionate, Sulfate, Methansulfonate, Citrate, Tartrate, Nitrate, Sulfonate, Oxalate und /oder Succinate. The salts used are preferably acid addition salts. Examples of suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, lactates, butyrates, propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates.
Besonders bevorzugt handelt es sich im Falle von Cinacalcet bei dem pharmazeutisch verträglichen Salz um Cinacalcet-Hydrochlorid. Ebenfalls besonders bevorzugt handelt es sich bei dem pharmazeutisch verträglichen Salz um Cinacalcet-Carbonat. Weiterhin besonders bevorzugt handelt es sich bei dem pharmazeutisch verträglichen Salz um Cinacalcet-Methansulfonat.
Bei dem verwendeten Cinacalcet (i), bevorzugt bei dem verwendeten Cinacalcet- Hydrochlorid, handelt es sich üblicherweise um kristallines Material. Bevorzugt wurde es nicht mikronisiert. Bevorzugt wird Cinacalcet-Hydrochlorid in polymorpher Form I verwendet. Die polymorphe Form I ist z.B. in WO 2007/62147 offenbart. In the case of cinacalcet, the pharmaceutically acceptable salt is more preferably cinacalcet hydrochloride. Also most preferably, the pharmaceutically acceptable salt is cinacalcetate carbonate. With particular preference, the pharmaceutically acceptable salt is cinacalcet methanesulfonate. The cinacalcet (i) used, preferably the cinacalcet hydrochloride used, is usually crystalline material. Preferably, it was not micronized. Cinacalcet hydrochloride in polymorphic form I is preferably used. The polymorphic form I is disclosed, for example, in WO 2007/62147.
Der Begriff "nicht mikronisiertes Cinacalcet" bezieht sich im Rahmen dieser Erfindung auf partikuläres Cinacalcet, das im allgemeinen einen mittleren Teilchendurchmesser (D50) von 20 bis 280 μπι, bevorzugt 60 bis 250 μτα, mehr bevorzugt von 65 bis 200 μιη, noch mehr bevorzugt von 70 bis 125 μν , und insbesondere von 75 bis 1 10 μπι aufweist. The term "non-micronized Cinacalcet" in the context of this invention refers to particulate Cinacalcet, which generally has an average particle diameter (D50) of 20 to 280 μπι, preferably 60 to 250 μτα, more preferably from 65 to 200 μιη, even more preferably from 70 to 125 μν, and in particular from 75 to 1 10 μπι.
Der Ausdruck "mittlerer Teilchendurchmesser" bezieht sich im Rahmen dieser Erfindung auf den D50-Wert des volumenmittleren Teilchendurchmessers, der mittels Laserdiffraktometrie bestimmt wurde. Insbesondere wurde zur Bestimmung ein Mastersizer 2000 von Malvern Instruments verwendet. Alle Messbedingungen werden wie auf Seiten 9 und 10 von WO 2005/034928 beschrieben gewählt, d.h. Nassmessung, 1750 rpm, Span® 85 als Dispergiermittel, Auswertung gemäß der Fraunhofer Methode. Der mittlere Teilchendurchmesser, der auch als D50-Wert der integralen Volumenverteilung bezeichnet wird, wird im Rahmen dieser Erfindung als der Teilchendurchmesser definiert, bei dem 50 Volumen-% der Teilchen einen kleineren Durchmesser haben als der Durchmesser, der dem D50-Wert entspricht. Ebenso haben dann 50 Volumen-% der Teilchen einen größeren Durchmesser als der D50-Wert. Analog wird als D10-Wert der Teilchendurchmesser definiert, bei dem 10 Volumen-% der Teilchen einen kleineren Durchmesser haben als der Durchmesser, der dem D10- Wert entspricht. Ebenso wird als D90-Wert der Teilchendurchmesser definiert, bei dem 90 Volumen-% der Teilchen einen kleineren Durchmesser haben als der Durchmesser, der dem D90-Wert entspricht. The term "average particle diameter" in the context of this invention refers to the D50 value of the volume-average particle diameter, which was determined by means of laser diffractometry. In particular, a Mastersizer 2000 from Malvern Instruments was used for the determination. All measurement conditions are selected as described on pages 9 and 10 of WO 2005/034928 ie wet measurement, 1750 rpm, Span ® 85 as dispersants, evaluation according to the Fraunhofer method. The average particle diameter, also referred to as the D50 value of the integral volume distribution, is defined in the context of this invention as the particle diameter at which 50% by volume of the particles have a smaller diameter than the diameter corresponding to the D50 value. Likewise, then 50% by volume of the particles have a larger diameter than the D50 value. Analogously, the D10 value is defined as the particle diameter at which 10% by volume of the particles have a smaller diameter than the diameter which corresponds to the D10 value. Similarly, the D90 value is defined as the particle diameter at which 90% by volume of the particles have a smaller diameter than the diameter corresponding to the D90 value.
Das nicht mikronisierte Cinacalcet weist ferner üblicherweise D10-Werte von 1 bis 50 μτη, mehr bevorzugt von 1 bis 30 μπι, und insbesondere von 2 bis 25 μτη auf. Weiterhin weist das nicht mikronisierte Cinacalcet üblicherweise D90-Werte von 200 bis 800 /im, mehr bevorzugt von 250 bis 700 μτη, und insbesondere von 300 bis öOO ^m auf. The non-micronized Cinacalcet also has usually D10 values of 1 to 50 μτη, more preferably from 1 to 30 μπι, and in particular from 2 to 25 μτη. Furthermore, the non-micronized cinacalcet usually has D90 values of from 200 to 800 / im, more preferably from 250 to 700 microns, and especially from 300 to 50 microns.
Kristallines Cinacalcet liegt üblicherweise in Form von Nadeln vor Charakterisierung mittels volumenmittlerem Teilchendurchmesser ist gegebenenfalls nicht spezifisch genug.
Es hat sich gezeigt, dass eine exaktere Charakterisierung von vorteilhaft verwendbarem Cinacalcet, insbesondere Cinacalcet- Hydrochlorid, durch die Beschreibung der spezifischen Oberfläche erfolgen kann. In einer bevorzugten Ausführungsform wird (i) kristallines Cinacalcet oder ein pharmazeutisch verträgliches Salz davon mit einer spezifischen Oberfläche von 0,01 bis 12 m2/g, mehr bevorzugt von 0, 1 bis 8 m2/g, Insbesondere von 0, 1 bis 7 m /g, eingesetzt. Die spezifische Oberfläche wird im Rahmen dieser Erfindung gemäß Gasadsorptionsmethode, insbesondere mittels BET-Methode, bestimmt. Crystalline cinacalcet is usually in the form of needles. Characterization by means of volume-median particle diameter may not be sufficiently specific. It has been found that a more exact characterization of advantageously usable Cinacalcet, especially Cinacalcet hydrochloride, can be done by the description of the specific surface. In a preferred embodiment, (i) crystalline cinacalcet or a pharmaceutically acceptable salt thereof having a specific surface area of from 0.01 to 12 m 2 / g, more preferably from 0.1 to 8 m 2 / g, especially from 0.1 to 7 m / g, used. The specific surface area is determined in the context of this invention according to the gas adsorption method, in particular by means of the BET method.
In einer bevorzugten Ausführungsform weist das verwendete Cinacalcet (i), insbesondere das Cinacalcet-Hydrochlorid, einen Wassergehalt von 0,01 bis 0,20 Gew.-%, mehr bevorzugt von 0,02 bis 0, 10 Gew.-%, auf. Der Restwassergehalt wird nach der Karl Fischer Methode bestimmt, wobei ein Coulometer bei 160 °C verwendet wird. Bevorzugt wird ein Metrohm 831 KF Coulometer mit einer Titrierzelle ohne Diaphragma verwendet. Üblicherweise wird eine Probe von 20 mg Cinacalcet analysiert. In a preferred embodiment, the cinacalcet (i) used, in particular the cinacalcet hydrochloride, has a water content of from 0.01 to 0.20% by weight, more preferably from 0.02 to 0, 10% by weight. The residual water content is determined by the Karl Fischer method using a coulometer at 160 ° C. A Metrohm 831 KF Coulometer with a titration cell without a diaphragm is preferably used. Usually a sample of 20 mg cinacalcet is analyzed.
Es hat sich gezeigt, dass ein höherer Wassergehalt die Fließfähigkeit negativ beeinflussen würde und damit bei einem hohen Wirkstoffgehalt [drug load) auch die Gleichförmigkeit des Gehalts (Content Uniformity). Bei dem "Matrixformer" (ii) handelt es sich im Rahmen dieser Erfindung im Allgemeinen um einen Stoff, welcher beim Erwärmen über den Schmelzpunkt, insbesondere bei einem Schmelzgranulations- oder Schmelzextrusionsprozess, verformbar und in der Lage ist, partikuläres Cinacalcet einzubetten, d.h. eine Matrix für partikuläres Cinacalcet zu bilden. Der Matrixformer weist somit bevorzugt ein thermoplastisches Verhalten auf, d.h. es handelt sich um einen thermoplastischen Matrixformer. Der Matrixformer ist zudem ein Stoff, der in Lage ist, sich beim Extrusionsvorgang an Cinacalcet oder Salzen davon (chemisch oder physikalisch) anzulagern und die Hydrophilität der Oberfläche zu erhöhen. Bei dem Matrixformer (ii) kann es sich um hydrophile Polymere, insbesondere um hydrophile thermoplastische Polymere handeln. Darunter sind Polymere zu verstehen, die hydrophile Gruppen aufweisen. Beispiele für geeignete hydrophile Gruppen sind Hydroxy, Amino, Carboxy, Sulfonat. Ferner weist das zur Herstellung des Intermediats verwendbare hydrophile Polymer bevorzugt ein gewichtsmittleres Molekulargewicht von 1.000 bis 150.000 g/mol auf, mehr bevorzugt von 2.000 bis 90.000 g/mol, insbesondere 3.000 bis 75.000 g/mol, auf. Im Rahmen dieser Anmeldung wird das
gewichtsmittlere Molekulargewicht bevorzugt mittels Gel-Permeationschromatographie bestimmt. It has been shown that a higher water content would negatively affect the flowability and thus with a high active ingredient content [drug load] also the uniformity of the content (content uniformity). In the context of this invention, the "matrix former" (ii) is generally a material which, when heated above the melting point, in particular in a melt granulation or melt extrusion process, is deformable and able to embed particulate cinacalcet, ie a matrix for particulate cinacalcet. The matrix former thus preferably has a thermoplastic behavior, ie it is a thermoplastic matrix former. The matrix former is also a substance that is able to attach to the cinacalcet or salts thereof (chemically or physically) during the extrusion process and to increase the hydrophilicity of the surface. The matrix former (ii) may be hydrophilic polymers, in particular hydrophilic thermoplastic polymers. These are polymers which have hydrophilic groups. Examples of suitable hydrophilic groups are hydroxy, amino, carboxy, sulfonate. Further, the hydrophilic polymer usable for the preparation of the intermediate preferably has a weight-average molecular weight of 1,000 to 150,000 g / mol, more preferably 2,000 to 90,000 g / mol, especially 3,000 to 75,000 g / mol. In the context of this application, the weight average molecular weight preferably determined by gel permeation chromatography.
Es ist bevorzugt, dass die als Matrixformer verwendeten Polymere im Wesentlichen keine Emulgatorwirkung zeigen. Das heißt, der verwendete Matrixformer sollte bevorzugt keine Kombination aus hydrophilen und hydrophoben Gruppen (insbesondere hydrophoben Fettsäuregruppen) aufweisen. Ferner ist es bevorzugt, dass das erfindungsgemäße Intermediat keine Polymere enthält, die ein gewichtsmittleres Molekulargewicht von mehr als 150.000 g/mol aufweisen. Derartige Polymere beeinflussen in der Regel die Auflöseeigenschaften in unerwünschter Weise. It is preferred that the polymers used as matrix formers exhibit substantially no emulsifying action. That is, the matrix former used should preferably not have a combination of hydrophilic and hydrophobic groups (especially hydrophobic fatty acid groups). Furthermore, it is preferred that the intermediate according to the invention does not contain polymers which have a weight-average molecular weight of more than 150,000 g / mol. Such polymers usually undesirably affect the dissolution properties.
Wird das als Matrixformer verwendete Polymer in Wasser in einer Menge von 2 Gew.-% gelöst, so zeigt die resultierende Lösung bevorzugt eine Viskosität von 0, 1 bis 8 mPa/s, mehr bevorzugt von 0,5 bis 7 mPa/s, insbesondere von 1 bis 6 mPa/s, gemessen bei 25 °C und gemäß Ph. Eur. , 6. Auflage, Kapitel 2.2.10 bestimmt. If the polymer used as a matrix former is dissolved in water in an amount of 2% by weight, the resulting solution preferably exhibits a viscosity of 0.1 to 8 mPa / s, more preferably 0.5 to 7 mPa / s, in particular from 1 to 6 mPa / s, measured at 25 ° C and according to Ph. Eur., 6th edition, chapter 2.2.10.
Darüber hinaus besitzt das als Matrixformer verwendete hydrophile Polymer eine Glasübergangstemperatur (Tg) oder einen Schmelzpunkt von 25 °C bis 200 °C, mehr bevorzugt von 40 °C bis 170 °C. Die Glasübergangstemperatur ist die Temperatur, bei der das hydrophile Polymer beim Abkühlen spröde und beim Erhitzen weich wird. Dies bedeutet, dass hydrophile Polymere bei Temperaturen über der Glasübergangstemperatur (Tg) weich werden und ohne zu brechen plastisch verformbar werden. Die Glasübergangstemperatur oder der Schmelzpunkt werden mittels eines Mettler-Toledo® DSC1 bestimmt, wobei eine Aufheizrate von 10 °C pro Minute und eine Kühlrate von 15 °C pro Minute angewandt werden. Die Bestimmungsmethode basiert im Wesentlichen auf Ph.Eur. 6.1 , Kapitel 2.2.34. Für die Bestimmung der Tg wird das Polymer zweimal erhitzt (d.h. erhitzt, abgekühlt, erhitzt). Ferner umfasst der Matrixformer (ii) auch feste, nicht-polymere Verbindungen, die bevorzugt polare Seitengruppen aufweisen. Moreover, the hydrophilic polymer used as the matrix former has a glass transition temperature ( Tg ) or a melting point of 25 ° C to 200 ° C, more preferably 40 ° C to 170 ° C. The glass transition temperature is the temperature at which the hydrophilic polymer becomes brittle upon cooling and softens when heated. This means that hydrophilic polymers soften at temperatures above the glass transition temperature (T g ) and become plastically deformable without breaking. The glass transition temperature or the melting point are determined with a Mettler-Toledo ® DSC1, wherein a heating rate of 10 ° C per minute and a cooling rate of 15 ° C per minute are employed. The method of determination is based essentially on Ph.Eur. 6.1, chapter 2.2.34. For the determination of T g , the polymer is heated twice (ie heated, cooled, heated). Furthermore, the matrix former (ii) also comprises solid, non-polymeric compounds which preferably have polar side groups.
Das erfindungsgemäße Intermediat kann beispielsweise folgende hydrophile Polymere als Matrixformer umfassen: Polysaccharide, wie Hydroxypropylmethylcellulose (HPMC), Polyvinylpyrrolidon, Polyvinylalkohol, Polymere der Acrylsäure und deren Salze, Polyacrylamid, Polymethacrylate, Vinylpyrrolidon-Vinylacetat-Copolymere (beispielsweise Kollidon® VA64, BASF), Polyalkylenglykole, wie Polypropylenglykol oder bevorzugt Polyethylenglykol, Co-blockpolymere des Polyethylenglykols, insbesondere Co-blockpolymere aus Polyethylenglykol und Polypropylenglykol (Pluronic®, BASF) sowie Gemische aus den genannten Polymeren.
Bevorzugt verwendet wird als Matrixformer (ii) Hydroxypropylmethylcellulose (HPMC), bevorzugt mit einem gewichtsmittleren Molekulargewicht von 20.000 bis 90.000 g/mol und/oder bevorzugt einem Anteil an Methylgruppen von 10 bis 35 % ; Hydroxypropylcellulose (HPC), bevorzugt mit einem gewichtsmittleren Molekulargewicht von 40.000 bis 100.000 g/mol, Polyvinylpyrrolidon, bevorzugt mit einem gewichtsmittleren Molekulargewicht von 10.000 bis 60.000 g/mol, insbesondere 12.000 bis 40.000 g/mol, Copolymer aus Vinylpyrrolidon und Vinylacetat, insbesondere mit einem gewichtsmittleren Molekulargewicht von 40.000 bis 75.000 g/mol, Polyethylenglykol, insbesondere mit einem gewichtsmittleren Molekulargewicht von 2.000 bis 50.000 g/mol, Polyoxyethylenalkylether und/oder Polyvinylalkohol, bevorzugt mit einem gewichtsmittleren Molekulargewicht von 1.000 bis 50.000 g/mol, werden verwendet. The intermediate of the invention may comprise, for example, the following hydrophilic polymers as matrix formers: polysaccharides, such as hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone, polyvinyl alcohol, polymers of acrylic acid and salts thereof, polyacrylamide, polymethacrylates, vinylpyrrolidone-vinyl acetate copolymers (e.g., Kollidon ® VA64, BASF), polyalkylene glycols , such as polypropylene glycol or preferably polyethylene glycol, co-block polymers of polyethylene glycol, especially co-block polymers of polyethylene glycol and polypropylene glycol (Pluronic ® , BASF) and mixtures of the polymers mentioned. Preference is given to using as matrix former (ii) hydroxypropylmethylcellulose (HPMC), preferably having a weight-average molecular weight of from 20,000 to 90,000 g / mol and / or preferably a proportion of methyl groups of from 10 to 35%; Hydroxypropylcellulose (HPC), preferably having a weight-average molecular weight of 40,000 to 100,000 g / mol, polyvinylpyrrolidone, preferably having a weight-average molecular weight of 10,000 to 60,000 g / mol, in particular 12,000 to 40,000 g / mol, copolymer of vinylpyrrolidone and vinyl acetate, in particular with a Weight-average molecular weight of 40,000 to 75,000 g / mol, polyethylene glycol, especially having a weight-average molecular weight of 2,000 to 50,000 g / mol, polyoxyethylene alkyl ethers and / or polyvinyl alcohol, preferably having a weight-average molecular weight of 1,000 to 50,000 g / mol are used.
Als Matrixformer (ii) besonders bevorzugt verwendet werden Co-Blockpolymere aus Polyethylenglykol und Polypropylenglykol, d.h. Polyoxyethylen Polyoxypropylen- Blockpolymerisate. Bevorzugt weisen diese ein gewichtsmittleres Molekulargewicht von 1.000 bis 20.000 g/mol, mehr bevorzugt von 1.500 bis 12.500 g/mol, insbesondere 5.000 bis 10.000 g/mol, auf. Diese Blockpolymerisate sind bevorzugt erhältlich durch Kondensation von Propylenoxid mit Propylenglykol und nachfolgender Kondensation des entstandenen Polymers mit Ethylenoxid. Das heißt, bevorzugt liegt der Ethylenoxidanteil als "Endblock" vor. Bevorzugt weisen die Blockpolymerisate ein Gewichtsverhältnis von Propylenoxid zu Ethylenoxid von 50 : 50 bis 95 : 5, mehr bevorzugt von 70 : 30 bis 90 : 10, auf. Die Blockpolymerisate weisen bevorzugt eine Viskosität bei 25 °C von 200 bis 2000 mPas, mehr bevorzugt von 500 bis 1500 mPas, insbesondere von 800 bis 1200 mPas, auf. Particularly preferred matrix formers (ii) are co-block polymers of polyethylene glycol and polypropylene glycol, i. Polyoxyethylene polyoxypropylene block polymers. Preferably, these have a weight-average molecular weight of from 1,000 to 20,000 g / mol, more preferably from 1,500 to 12,500 g / mol, in particular from 5,000 to 10,000 g / mol. These block polymers are preferably obtainable by condensation of propylene oxide with propylene glycol and subsequent condensation of the resulting polymer with ethylene oxide. That is, preferably, the ethylene oxide is present as an "end block". Preferably, the block polymers have a weight ratio of propylene oxide to ethylene oxide of from 50:50 to 95: 5, more preferably from 70:30 to 90:10. The block polymers preferably have a viscosity at 25 ° C. of from 200 to 2000 mPas, more preferably from 500 to 1500 mPas, in particular from 800 to 1200 mPas.
Im Rahmen dieser Erfindung können auch Gemische der vorstehend genannten Matrixformer eingesetzt werden. In einer möglichen Ausführungsform wird beispielsweise ein Gemisch aus Polyvinylpyrrolidon und Polyoxyethylen Polyoxypropylen-Blockpolymerisaten eingesetzt. In the context of this invention, it is also possible to use mixtures of the abovementioned matrix formers. In one possible embodiment, for example, a mixture of polyvinylpyrrolidone and polyoxyethylene polyoxypropylene block polymers is used.
In einer bevorzugten Ausführungsform enthält das erfindungsgemäße Intermediat Cinacalcet oder ein pharmazeutisch verträgliches Salz davon, bevorzugt in nicht mikronisierter Form, und Matrixformer, wobei das Gewichtsverhältnis von Wirkstoff (i) zu Matrixformer (ii) 5 : 1 bis 1 : 5, mehr bevorzugt 3 : 1 bis 1 : 3, noch mehr bevorzugt 2 : 1 bis 1 : 2, insbesondere ungefähr 1 : 1 beträgt. In a preferred embodiment, the intermediate according to the invention contains cinacalcet or a pharmaceutically acceptable salt thereof, preferably in non-micronized form, and matrix former, wherein the weight ratio of active ingredient (i) to matrix former (ii) is 5: 1 to 1: 5, more preferably 3: 1 to 1: 3, more preferably 2: 1 to 1: 2, in particular about 1: 1.
Es ist bevorzugt, dass Art und Menge des Matrixformers so gewählt werden, dass mindestens 50 % der Oberfläche der resultierenden Intermediatteilchen mit Matrixformer bedeckt sind, mehr bevorzugt mindestens 60 % der Oberfläche,
besonders bevorzugt mindestens 80 % der Oberfläche, insbesondere mindestens 95 % der Oberfläche. It is preferred that the type and amount of the matrix former be selected such that at least 50% of the surface area of the resulting intermediate particles is covered with matrix former, more preferably at least 60% of the surface area, particularly preferably at least 80% of the surface, in particular at least 95% of the surface.
Im Rahmen dieser Erfindung ist es besonders bevorzugt, dass Cinacalcet (i) und Matrixformer (ii) gemeinsam "schmelzverarbeitet" werden. Bevorzugt wird hierbei die Schmelzverarbeitung als Schmelzextrusion oder mehr bevorzugt als Schmelzgranulation durchgeführt. Der Schmelzverarbeitung können, wie nachstehend beschrieben, ferner noch weitere pharmazeutische Hilfsstoffe, wie z.B. Sprengmittel und Dochtmittel, beigesetzt werden. Sofern Sprengmittel und Dochtmittel (quasi intragranulär) im erfindungsgemäßen Intermediat (a) enthalten sind, werden diese im Rahmen dieser Anmeldung als Komponenten (iii-int) beziehungsweise (iv-int) bezeichnet. Sofern Sprengmittel und Dochtmittel (quasi extragranulär) in der erfindungsgemäßen oralen Darreichungsform (als Komponente (ß)) enthalten sind, werden diese im Rahmen dieser Anmeldung als Komponenten (iii-ex), beziehungsweise (iv-ex), bezeichnet. In the context of this invention it is particularly preferred that cinacalcet (i) and matrix former (ii) are "melt processed" together. Preferably, the melt processing is carried out as a melt extrusion or more preferably as a melt granulation. Melt processing may further include, as described below, further pharmaceutical excipients, such as e.g. Disintegrants and wicking agents are buried. If disintegrants and wicking agents (quasi intragranular) are contained in the intermediate (a) according to the invention, they are referred to as components (iii-int) or (iv-int) in the context of this application. If disintegrants and wicking agents (quasi extragranular) in the oral dosage form according to the invention (as component (ß)) are included, they are referred to in the context of this application as components (iii-ex), or (iv-ex).
Somit kann die erfindungsgemäße orale Darreichungsform, bevorzugt in Form einer Tablette, bevorzugt mit sofortiger Freisetzung, enthalten: Thus, the oral dosage form according to the invention, preferably in the form of a tablet, preferably with immediate release, may contain:
(a) ein Intermediat, umfassend (a) an intermediate comprising
(i) Cinacalcet, (i) Cinacalcet,
(ii) Matrixformer, (ii) matrix former,
(iii-int) Sprengmittel und /oder (iii-int) disintegrants and / or
(iv-int) Dochtmittel; und (iv-int) Wick; and
(ß) pharmazeutische Hilfsstoffe, umfassend (ß) pharmaceutical excipients comprising
(iii-ex) Sprengmittel und/oder (iii-ex) disintegrants and / or
(iv-ex) Dochtmittel. (iv-ex) Wick.
Sofern auf die Gesamtmenge an Sprengmittel oder Dochtmittel (d.h. sowohl extra- als auch intragranulär) Bezug genommen werden soll, wird die Bezeichnung (iii) beziehungsweise (iv) verwendet. Where reference is made to the total amount of disintegrants or wicking agents (i.e., both extra and intragranular), designations (iii) and (iv), respectively, are used.
Die Schmelzverarbeitung kann, wie nachstehend beschrieben, in üblichen Schmelzverarbeitungsvorrichtungen erfolgen. Die Schmelzbedingungen werden bei Einsatz von kristallinem Cinacalcet üblicherweise so gewählt, dass Cinacalcet in kristallinem Zustand verbleibt. Melt processing can be carried out in conventional melt processing equipment as described below. When using crystalline cinacalcet, the melting conditions are usually chosen so that cinacalcet remains in a crystalline state.
Das erfindungsgemäße Intermediat findet bei der Herstellung einer oralen Darreichungsform Verwendung. Bei der oralen Darreichungsform handelt es sich z.B. um Kapseln, Pulver oder Granulat zur Abfüllung in Sachets oder Tabletten. Die
Herstellung von Tabletten ist hierbei bevorzugt. Besonders bevorzugt findet das erfindungsgemäße Intermediat zur Herstellung einer Tablette mit sofortiger Freisetzung (im Englischen als "Immediate-Release Tablet" bekannt) Verwendung. Gegenstand der Erfindung ist daher eine orale Darreichungsform, insbesondere eine Tablette mit sofortiger Freisetzung, enthaltend The intermediate according to the invention is used in the preparation of an oral dosage form. The oral dosage form is, for example, capsules, powders or granules for filling into sachets or tablets. The Production of tablets is preferred here. The intermediate according to the invention is particularly preferably used for the production of an immediate release tablet (known in English as "immediate release tablet"). The invention therefore relates to an oral dosage form, in particular an immediate release tablet containing
(oc) erfindungsgemäßes Intermediat und (oc) Intermediate according to the invention and
(ß) pharmazeutische Hilfsstoffe. (ß) pharmaceutical excipients.
Hierbei handelt es sich um die dem Fachmann bekannten Hilfsstoffe (ß), insbesondere solche, die im Europäischen Arzneibuch beschrieben sind. These are the auxiliaries (β) known to the person skilled in the art, in particular those described in the European Pharmacopoeia.
Beispiele für verwendete Hilfsstoffe (ß) sind Sprengmittel, Trennmittel, Füllstoffe, Zusätze zur Verbesserung der Pulverfließfähigkeit, Gleitmittel, Netzmittel, und/oder Schmiermittel. Examples of auxiliaries (β) used are disintegrants, release agents, fillers, additives to improve the powder flowability, lubricants, wetting agents, and / or lubricants.
Das Verhältnis von Wirkstoff zu Hilfsstoffe wird bevorzugt so gewählt, dass die resultierenden Formulierungen The ratio of active ingredient to auxiliaries is preferably selected so that the resulting formulations
5 bis 60 Gew.-%, mehr bevorzugt 20 bis 45 Gew.-% Cinacalcet, und 5 to 60% by weight, more preferably 20 to 45% by weight of cinacalcet, and
40 bis 95 Gew.-%, mehr bevorzugt 55 bis 80 Gew.-%, pharmazeutisch verträgliche Hilfsstoffe enthalten. Bevorzugt handelt es sich, wie vorstehend erläutert, hierbei um nicht-mikronisiertes, kristallines Cinacalcet. Bei diesen Angaben wird die Menge an Matrixformer, die zur Herstellung des erfindungsgemäßen Intermediats verwendet wurde, als Hilfsstoff gerechnet. Das heißt, die Menge an Wirkstoff bezieht sich auf die Menge an Cinacalcet, die in der fertigen Formulierung enthalten ist. In einer bevorzugten Ausführungsform enthält die erfindungsgemäße Tablette 1 bis 40 Gew.-%, 5 bis 35 Gew.-%, mehr bevorzugt 10 bis 30 Gew.-%, besonders bevorzugt 15 bis 25 Gew.-% Sprengmittel (iii), bezogen auf das Gesamtgewicht der Formulierung. Als Sprengmittel werden im Allgemeinen Stoffe bezeichnet, die den Zerfall einer Darreichungsform, insbesondere einer Tablette, nach Einbringen in Wasser, beschleunigen. Geeignete Sprengmittel sind z.B. organische Sprengmittel wie Carrageenan, Cellulosen und Cellulosederivate: Croscarmellose, Stärken und Stärkederivate: Natriumcarboxymethylstärke, Polysaccharide: Soja-Polysaccharide, Alginate und Crospovidon. Zudem können anorganische Sprengmittel wie Bentonite verwendet werden. Ebenso können alkalische Sprengmittel verwendet werden. Unter alkalischen Sprengmitteln sind Sprengmittel zu verstehen, die beim Lösen in Wasser
einen pH-Wert von mehr als 7,0 erzeugen. Es können auch Gemische der vorstehend genannten Sprengmittel verwendet werden. 40 to 95 wt .-%, more preferably 55 to 80 wt .-%, pharmaceutically acceptable excipients. As explained above, preference is given to non-micronized, crystalline cinacalcet. In this information, the amount of matrix former used to prepare the intermediate of the invention is calculated as an adjuvant. That is, the amount of active ingredient refers to the amount of cinacalcet contained in the finished formulation. In a preferred embodiment, the tablet according to the invention contains 1 to 40 wt .-%, 5 to 35 wt .-%, more preferably 10 to 30 wt .-%, particularly preferably 15 to 25 wt .-% disintegrant (iii), based on the total weight of the formulation. As disintegrants are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after introduction into water. Suitable disintegrants are, for example, organic disintegrants such as carrageenan, celluloses and cellulose derivatives: croscarmellose, starches and starch derivatives: sodium carboxymethyl starch, polysaccharides: soy polysaccharides, alginates and crospovidone. In addition, inorganic disintegrants such as bentonites can be used. Likewise, alkaline disintegrants can be used. By alkaline disintegrating agents are meant disintegrating agents when dissolved in water produce a pH of more than 7.0. Mixtures of the aforementioned disintegrants may also be used.
Besonders bevorzugt wird Crospovidon und/oder Croscarmellose als Sprengmittel, insbesondere in den oben genannten Mengen, verwendet. Crospovidone and / or croscarmellose are particularly preferably used as disintegrating agents, in particular in the abovementioned amounts.
In einer bevorzugten Ausführungsform enthält die erfindungsgemäße Tablette 0 bis 35 Gew.-% , 1 bis 30 Gew.-% , mehr bevorzugt 5 bis 25 Gew.-% , besonders bevorzugt 10 bis 20 Gew.-% Dochtmittel (iv), bezogen auf das Gesamtgewicht der Formulierung. In a preferred embodiment, the tablet according to the invention contains 0 to 35 wt .-%, 1 to 30 wt .-%, more preferably 5 to 25 wt .-%, particularly preferably 10 to 20 wt .-% wicking agent (iv), based on the total weight of the formulation.
Im Allgemeinen ist ein Dochtmittel (iv) ein Mittel mit der Fähigkeit, eine biologische Flüssigkeit (bevorzugt Wasser) in einen Feststoff zu ziehen (bevorzugt in die Intermediate (i), bevorzugt mittels Physisorption). Physisorption wird definiert als Form der Adsorption, bei welcher die Flüssigkeitsmoleküle an die Oberfläche des Dochtmittels anhaften können, bevorzugt mittels van-der-Waals-Bindung zwischen der Oberfläche des Dochtmittels und dem adsorbierten flüssigen Molekül (bevorzugt Wasser). Normalerweise bewirkt ein Dochtmittel dies mit oder ohne Aufquellen. Normalerweise wird ein nicht quellendes Dochtmittel, das Wasser anzieht, letztendlich ein Volumen haben, das im Wesentlichen aus dem Volumen des Dochtmittels und der Wassermenge besteht, das es anzieht. Im Allgemeinen wird ein quellendes Dochtmittel ein Volumen aufweisen, das im Wesentlichen aus dem Volumen des Dochtmittels, der Wassermenge, die es anzieht, und einem zusätzlichen Volumen, verursacht durch sterische und molekulare Kräfte, besteht. Bevorzugt verursacht das Dochtmittel (iv) in dem erfindungsgemäßen Intermediat oder in der erfindungsgemäßen Tablette die Bildung von Kanälen oder Poren. Dies erleichtert das Eindringen der Wassermoleküle in die Intermediate, insbesondere durch Physisorption. Daher besteht die Funktion des Dochtmittels darin, Wasser an die Oberflächen innerhalb der Intermediate zu transportieren, um dadurch Kanäle in oder ein Netzwerk auf einer vergrößerten Oberfläche zu schaffen. In general, a wicking agent (iv) is an agent capable of drawing a biological fluid (preferably water) into a solid (preferably into the intermediates (i), preferably by physisorption). Physiosorption is defined as a form of adsorption in which the liquid molecules can adhere to the surface of the wicking agent, preferably by means of van der Waals bonding between the surface of the wicking agent and the adsorbed liquid molecule (preferably water). Normally, a wicking agent does so with or without swelling. Normally, a non-swelling wick that attracts water will eventually have a volume that essentially consists of the volume of the wick and the amount of water that attracts it. In general, a swelling wicking agent will have a volume consisting essentially of the volume of the wicking agent, the amount of water it attracts, and an additional volume caused by steric and molecular forces. The wicking agent (iv) preferably causes the formation of channels or pores in the intermediate according to the invention or in the tablet according to the invention. This facilitates the penetration of the water molecules into the intermediates, in particular by physisorption. Therefore, the function of the wick means is to transport water to the surfaces within the intermediates to thereby create channels in or a network on an enlarged surface.
Beispiele von verwendeten Dochtmitteln sind: mikrokristalline Cellulose, silifizierte mikrokristalline Cellulose, kolloidales Siliciumdioxid, Kaolin, Titandioxid, pyrogene Kieselsäure, Aluminium, Niacinamid, m-Pyrol, Bentonit, Magnesium-Aluminium- Silicat, Polyester, Polyethylen, oder Mischungen davon. Bevorzugt enthalten die Dochtmittel der pharmazeutischen Zusammensetzung der vorliegenden Erfindung Cellulose und Cellulosederivate, wie z.B. silifizierte mikrokristalline Cellulose, kolloidales Siliciumdioxid, und Mischungen davon. Die bevorzugt verwendete silifizierte mikrokristalline Cellulose ist kommerziell erhältlich unter dem Handelsnamen Prosolv® und weist einen Siliciumdioxidgehalt von 1 bis 3 Gew.-% , bevorzugt von 2 Gew.-% auf.
Die erfindungsgemäße orale Darreichungsform, insbesondere Tablette, kann ferner Füllstoffe (v) enthalten. Unter Füllstoffen sind im Allgemeinen Stoffe zu verstehen, die zur Bildung des Tablettenkörpers bei Tabletten mit geringen Wirkstoffmengen (z.B. kleiner 60 Gew.-%) dienen. Das heißt, Füllstoffe erzeugen durch "Strecken" der Wirkstoffe eine ausreichende Tablettiermasse. Füllstoffe dienen üblicherweise also dazu, eine geeignete Tablettengröße zu erhalten. Examples of wicking agents used are: microcrystalline cellulose, silicified microcrystalline cellulose, colloidal silica, kaolin, titanium dioxide, fumed silica, aluminum, niacinamide, m-pyrol, bentonite, magnesium aluminum silicate, polyester, polyethylene, or mixtures thereof. Preferably, the wicking agents of the pharmaceutical composition of the present invention contain cellulose and cellulose derivatives such as, for example, silified microcrystalline cellulose, colloidal silica, and mixtures thereof. The preferably used silified microcrystalline cellulose is commercially available under the trade name Prosolv ® and has a silica content of 1 to 3 wt .-%, preferably from 2 wt .-% to. The oral dosage form according to the invention, in particular tablet, may further contain fillers (v). Fillers are generally to be understood as meaning substances which serve for the formation of the tablet body in the case of tablets with small amounts of active ingredient (eg less than 60% by weight). That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size.
Beispiele für bevorzugte Füllstoffe sind Lac tose, Lactosederivate, Stärke, Stärkederivate, behandelte Stärke, Chitin, Cellulose und Derivate davon, Calciumphosphat, Saccharose, Calciumcarbonat, Magnesiumcarbonat, Magnesiumoxid, Maltodextrin, Calciumsulfat, Dextrate, Dextrin und/oder Dextrose, hydrogeniertes Pflanzenöl.. Examples of preferred fillers are lactose, lactose derivatives, starch, starch derivatives, treated starch, chitin, cellulose and derivatives thereof, calcium phosphate, sucrose, calcium carbonate, magnesium carbonate, magnesium oxide, maltodextrin, calcium sulfate, dextrates, dextrin and / or dextrose, hydrogenated vegetable oil.
Ebenfalls können als Füllstoffe Zuckeralkohole und /oder Disaccharide wie Mannitol, Sorbitol, Xylitol, Isomalt, Glucose, Fructose, Maltose und Gemische daraus verwendet werden. Der Begriff Zuckeralkohole umfasst hier auch Monosaccharide. Also, as fillers, sugar alcohols and / or disaccharides such as mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof can be used. The term sugar alcohols here also includes monosaccharides.
Füllstoffe werden üblicherweise in einer Menge von 1 bis 80 Gew.-%, mehr bevorzugt von 5 bis 50 Gew.-%, insbesondere von 20 bis 40 Gew.-%, bezogen auf das Gesamtgewicht der Formulierung verwendet. Fillers are usually used in an amount of from 1 to 80% by weight, more preferably from 5 to 50% by weight, especially from 20 to 40% by weight, based on the total weight of the formulation.
Die erfindungsgemäße Tablette kann ferner Zusätze zur Verbesserung der Pulverfließfähigkeit enthalten. Ein Beispiel für einen Zusatz zur Verbesserung der Pulverfließfähigkeit ist disperses Siliciumdioxid, z.B. bekannt unter dem Handelsnamen Aerosil®. Bevorzugt wird Siliciumdioxid mit einer spezifischen Oberfläche von 50 bis 400 m2/g, bestimmt nach Gasadsorption gemäß Ph. Eur., 6. Auflage 2.9.26., verwendet. The tablet of the present invention may further contain additives for improving powder flowability. An example of an additive to improve the powder flowability is dispersed silica, such as known under the trade name Aerosil ®. Preference is given to using silica having a specific surface area of from 50 to 400 m 2 / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition, Sept. 2, 1966.
Zusätze zur Verbesserung der Pulverfließfähigkeit werden üblicherweise in einer Menge von 0, 1 bis 5 Gew.-%, z.B. 1 ,5 bis 4 Gew.-%, bezogen auf das Gesamtgewicht der Formulierung verwendet. Additives for improving the powder flowability are usually added in an amount of 0.1 to 5% by weight, e.g. 1, 5 to 4 wt .-%, based on the total weight of the formulation used.
Ferner können Schmiermittel verwendet werden. Schmiermittel dienen im Allgemeinen zur Verringerung der Gleitreibung. Insbesondere soll die Gleitreibung vermindert werden, die beim Tablettieren einerseits zwischen den sich in der Matrizenbohrung auf und ab bewegenden Stempeln und der Matrizenwand sowie andererseits zwischen Tablettensteg und Matrizenwand besteht. Geeignete Schmiermittel stellen z.B. Stearinsäure, Adipinsäure, Natriumstearylfumarat (Pruv®) und/oder Magnesiumstearat dar.
Schmiermittel werden üblicherweise in einer Menge von 0, 1 bis 5 Gew.-%, bevorzugt 1 ,0 bis 3 Gew.-%, bezogen auf das Gesamtgewicht der Formulierung, verwendet. Furthermore, lubricants can be used. Lubricants are generally used to reduce sliding friction. In particular, the sliding friction is to be reduced, which consists during tabletting on the one hand between the up in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall. Suitable lubricants are for example stearic acid, adipic acid, sodium stearyl fumarate is (Pruv ®) and / or magnesium stearate. Lubricants are usually used in an amount of 0, 1 to 5 wt .-%, preferably 1, 0 to 3 wt .-%, based on the total weight of the formulation.
Weiterhin können Trennmittel verwendet werden. Unter Trennmitteln werden üblicherweise Stoffe verstanden, welche die Agglomeration im Kernbett vermindern. Beispiele sind Talkum, Silicagel, Polyethylenglykol (bevorzugt mit 2.000 bis 10.000 g/mol gewichtsmittlerem Molekulargewicht) und/oder Glycerolmonostearat. Furthermore, release agents can be used. By release agents are usually understood substances which reduce the agglomeration in the core bed. Examples are talc, silica gel, polyethylene glycol (preferably with 2,000 to 10,000 g / mol weight-average molecular weight) and / or glycerol monostearate.
Es liegt in der Natur von pharmazeutischen Hilfsstoffen, dass diese teilweise mehrere Funktionen in einer pharmazeutischen Formulierung wahrnehmen. Im Rahmen dieser Erfindung gilt zur unzweideutigen Abgrenzung daher bevorzugt die Fiktion, dass ein Stoff, der als ein bestimmter Hilfsstoff verwendet wird, nicht zeitgleich auch als weiterer pharmazeutischer Hilfsstoff eingesetzt wird. Beispielsweise wird Sorbitol - sofern als Füllstoff eingesetzt - nicht auch zusätzlich als Matrixformer eingesetzt. Ebenfalls wird beispielsweise mikrokristalline Cellulose - sofern als Dochtmittel eingesetzt - nicht auch zusätzlich als Füllstoff eingesetzt (obwohl mikrokristalline Cellulose auch eine Füllwirkung erzeugt). It is in the nature of pharmaceutical excipients that they partially perform multiple functions in a pharmaceutical formulation. For the purposes of this invention, the unambiguous delimitation is therefore preferably based on the fiction that a substance which is used as a specific excipient is not simultaneously used as a further pharmaceutical excipient. For example, if used as a filler, sorbitol is not additionally used as a matrix former. Also, for example, microcrystalline cellulose - if used as a wicking agent - not additionally used as a filler (although microcrystalline cellulose also produces a filling effect).
In einer bevorzugten Ausführungsform enthält die erfindungsgemäße Tablette (bezogen auf das Gesamtgewicht des Tablettenkerns) folgende Bestandteile: In a preferred embodiment, the tablet according to the invention (based on the total weight of the tablet core) contains the following constituents:
15 bis 40 Gew.-% Cinacalcet (i) 15 to 40% by weight of cinacalcet (i)
15 bis 35 Gew.-% Matrixformer (ii) 15 to 35% by weight of matrix former (ii)
5 bis 40 Gew.-%, bevorzugt 15 bis 40 Gew.-% Füllstoff (v) From 5 to 40% by weight, preferably from 15 to 40% by weight of filler (v)
15 bis 35 Gew.-% Sprengmittel (iii), From 15 to 35% by weight of disintegrant (iii),
0 bis 30 Gew.-% Dochtmittel (iv) und 0 to 30 wt .-% wick (iv) and
1 bis 4 Gew.-% Schmiermittel. 1 to 4 wt .-% lubricant.
In einer alternativen bevorzugten Ausführungsform enthält die erfindungsgemäßeIn an alternative preferred embodiment, the inventive
Tablette (bezogen auf das Gesamtgewicht des Tablettenkerns) folgende Bestandteile: mehr als 40 bis 60 Gew.-% Cinacalcet (i) Tablet (based on the total weight of the tablet core) the following constituents: more than 40 to 60% by weight of cinacalcet (i)
15 bis 35 Gew.-% Matrixformer (ii) 15 to 35% by weight of matrix former (ii)
0 bis 10 Gew.-% Füllstoff (v) 0 to 10% by weight of filler (v)
15 bis 35 Gew.-% Sprengmittel (iii), From 15 to 35% by weight of disintegrant (iii),
0 bis 20 Gew.-% Dochtmittel (iv) und 0 to 20 wt .-% wick (iv) and
1 bis 4 Gew.-% Schmiermittel. 1 to 4 wt .-% lubricant.
Die erfindungsgemäßen Tabletten enthalten bevorzugt keine Polymere, welche zu einer verzögerten Freisetzung führen. Insbesondere ist es bevorzugt, dass die erfindungsgemäßen Tabletten keine Polymere enthalten, die ein Molekulargewicht von mehr als 150.000 g/mol aufweisen.
Gegenstand der Erfindung ist ferner ein Verfahren zur Herstellung der erfindungsgemaßen Tabletten, umfassend die Schritte The tablets according to the invention preferably contain no polymers which lead to a delayed release. In particular, it is preferred that the tablets according to the invention contain no polymers having a molecular weight of more than 150,000 g / mol. The invention further provides a process for the preparation of the tablets according to the invention, comprising the steps
(a) Bereitstellung und bevorzugt Vermischen von (i) kristallinem Cinacalcet oder dessen pharmazeutisch verträglichen Salzen mit (ii) einem Matrixformer, sowie gegebenenfalls weiteren pharmazeutischen Hilfsstoffen; (A) providing and preferably mixing (i) crystalline Cinacalcet or its pharmaceutically acceptable salts with (ii) a matrix former, and optionally other pharmaceutical excipients;
(b) Schmelzverarbeitung, bevorzugt Schmelzextrusion oder insbesondere Schmelzgranulation, zu einem Intermediat; (b) melt processing, preferably melt extrusion or, in particular, melt granulation, to an intermediate;
(c) gegebenenfalls Granulierung des Intermediats; (c) optionally, granulation of the intermediate;
(d) Kompression der resultierenden Intermediate (bevorzugt der aus Schritt (c) resultierenden Granulate) zu Tabletten, gegebenenfalls unter Zusatz weiterer pharmazeutischer Hilfsstoffe; und (d) compression of the resulting intermediates (preferably the granules resulting from step (c)) into tablets, if appropriate with the addition of further pharmaceutical auxiliaries; and
(e) gegebenenfalls Befilmung der Tabletten. Grundsätzlich finden alle Erläuterungen, die vorstehend zu bevorzugten Ausführungsformen des erfindungsgemäßen Intermediats ausgeführt wurden, auch auf das erfindungsgemäße Verfahren Anwendung. (e) optionally, filming the tablets. In principle, all explanations which have been carried out above for preferred embodiments of the intermediate according to the invention also apply to the method according to the invention.
In einer bevorzugten Ausführungsform werden in Schritt (a) des erfindungsgemäßen Verfahrens (i) Cinacalcet, bevorzugt kristallines Cinacalcet oder dessen pharmazeutisch verträglichen Salze mit (ii) einem Matrixformer sowie gegebenenfalls weiteren - vorstehend beschriebenen - pharmazeutischen Hilfsstoffen (ß) bereitgestellt und bevorzugt vermischt. In a preferred embodiment, in step (a) of the process (i) cinacalcet, preferably crystalline Cinacalcet or its pharmaceutically acceptable salts with (ii) a matrix former and optionally further - described above - pharmaceutical excipients (ß) are provided and preferably mixed.
Wie vorstehend erwähnt, umfasst der Matrixformer bevorzugt kein Polymer mit einem gewichtsmittleren Molekulargewicht von mehr als 150.000 g/mol. Gleiches gilt für die pharmazeutischen Hilfsstoffe, die in Schritt (a) (und/oder auch in Schritt (d)) des erfindungsgemäßen Verfahrens zugegeben werden. As mentioned above, the matrix former preferably does not comprise a polymer having a weight-average molecular weight of more than 150,000 g / mol. The same applies to the pharmaceutical auxiliaries which are added in step (a) (and / or also in step (d)) of the process according to the invention.
Die Vermischung kann in üblichen Mischern erfolgen. Beispielsweise ist ein Turbula® T 10B (Bachofen AG, Schweiz) geeignet. Die Mischzeit beträgt üblicherweise 1 Minute bis 1 Stunde, bevorzugt 5 Minuten bis 20 Minuten. The mixing can be done in conventional mixers. For example, a Turbula ® T 10B (Bachofen AG, Switzerland) is suitable. The mixing time is usually 1 minute to 1 hour, preferably 5 minutes to 20 minutes.
In einer bevorzugten Ausführungsform werden in Schritt (a) In a preferred embodiment, in step (a)
100 % des eingesetzten Cinacalcet, 100% of the cinacalcet used,
100 % des eingesetzten Matrixformers, 100% of the matrix former used,
gegebenenfalls 20 bis 70 % des eingesetzten Füllstoffs, optionally 20 to 70% of the filler used,
gegebenenfalls 20 bis 70 % des eingesetzten Dochtmittels, und optionally 20 to 70% of the wicking agent used, and
gegebenenfalls 30 bis 70 % des eingesetzten Sprengmittels, und optionally 30 to 70% of the disintegrant used, and
gegebenenfalls 10 bis 40 % des eingesetzten Schmiermittels
vermischt. Die verbleibenden optionalen Mengen an Füllstoff, Sprengmittel und Schmiermittel werden anschließend in Schritt (d) zugegeben. optionally 10 to 40% of the lubricant used mixed. The remaining optional amounts of filler, disintegrant and lubricant are then added in step (d).
In Schritt (b) des erfindungsgemäßen Verfahrens wird das Gemisch aus Schritt (a) zum erfindungsgemäßen Intermedlat schmelzverarbeitet, d.h. bevorzugt schmelzextrudiert oder schmelzgranuliert. Im Rahmen der Schmelzverarbeitung (b) wird Clnacalcet (i) mit dem - bevorzugt thermoplastischen - Matrixformer (ii) so verarbeitet, dass Cinacalcet im Matrixmaterial eingebettet ist. In diesem Zusammenhang ist es bevorzugt, dass die Schmelzbedingungen so gewählt werden, dass der Matrixformer geschmolzen oder angeschmolzen wird, der Wirkstoff aber in festem Zustand verbleibt. Bevorzugt wird Cinacalcet in kristalliner Form (insbesondere Clnacalcet-Hydrochlorid in kristalliner Form I) verwendet und die Schmelzbedingungen bevorzugt so gewählt, dass der Wirkstoff in kristalliner Form, insbesondere kristalliner Form I, erhalten bleibt. In step (b) of the process of the invention, the mixture of step (a) is melt-processed into the intermediate material of the invention, i. preferably melt-extruded or melt-granulated. In the context of melt processing (b), Clnacalcet (i) is processed with the - preferably thermoplastic - matrix former (ii) in such a way that cinacalcet is embedded in the matrix material. In this connection, it is preferable that the melting conditions are selected so that the matrix former is melted or fused, but the active ingredient remains in a solid state. Preference is given to using cinacalcet in crystalline form (in particular clacalcet hydrochloride in crystalline form I) and the melting conditions are preferably chosen such that the active ingredient is retained in crystalline form, in particular crystalline form I.
Bevorzugt liegt die bei der Schmelzverarbeitung gewählte Temperatur 10 °C unter bis 10 °C über des Schmelzpunkts des Matrixformers, bevorzugt mit der Maßgabe, dass die gewählte Temperatur mindestens 10 °C unterhalb der Schmelztemperatur des verwendeten Cinacalcets liegt. Preferably, the temperature selected in the melt processing is 10 ° C below to 10 ° C above the melting point of the matrix former, preferably with the proviso that the selected temperature is at least 10 ° C below the melting temperature of the Cinacalcets used.
Die Schmelzverarbeitung kann bevorzugt als Schmelzgranulation oder als Schmelzextrusion durchgeführt werden. The melt processing may preferably be carried out as melt granulation or as melt extrusion.
In einer bevorzugten Ausführungsform erfolgt eine Schmelzgranulation. Das Schmelzverfahren läuft in diesem Fall bevorzugt über einen Intensivmischer mit beheizbarer Manteleinheit, beispielsweise kann ein Diosna® PI -6 vorteilhaft verwendet werden. Hierbei wird üblicherweise die Mischung aus den Bestandteilen (i) und (ii) ohne Aufheizen des Mantels trocken vorgemischt (= Schritt a) und erst im zweiten Schritt (b) durch Zuschalten des beheizbaren Mantels, bevorzugt unter Rühren, erwärmt. Die Erwärmung wird bevorzugt fortgeführt bis eine Zunahme der Kraftaufnahme zu beobachten ist. Anschließend wird granuliert und abgekühlt. In a preferred embodiment, a melt granulation takes place. The fusion in this case runs preferably above an intensive mixer with heated jacket unit, for example a Diosna ® -6 PI can be used advantageously. In this case, the mixture of constituents (i) and (ii) is usually premixed dry without heating the shell (= step a) and heated only in the second step (b) by switching on the heatable shell, preferably with stirring. The heating is preferably continued until an increase in the power consumption is observed. It is then granulated and cooled.
In einer bevorzugten Ausführungsform erfolgt eine Schmelzextrusion. Hierbei handelt es sich um ein kontinuierliches Verfahren (chargenunabhängig), wobei die Vormischung und Granulierung nicht zeitlich sequentiell erfolgt, sondern in einem Produktionsschritt. Ein bevorzugtes Verfahren zur Herstellung des Schmelzextrudats stellt die Schmelzextrusion über einen Zweischneckenextruder (z.B. Leistritz® micro 18) dar. Vorteil hierbei ist die Einstellung eines Temperaturgradienten, abhängig vom gewählten Matrixformer, der die Verweilzeit des Cinacalcet unter hohen Temperaturen deutlich verringert. Der Temperaturgradient liegt üblicherweise zwischen 80 - 190 °C und wird bevorzugt so gewählt, dass das Cinacalcet nach der Verarbeitung noch kristallin vorliegt.
Im optionalen Schritt (c) des erfindungsgemäßen Verfahrens wird das Extrudat granuliert. Die Granulierung kann vor, während oder nach dem Abkühlen erfolgen. Bevorzugt erfolgt die Granulierung bereits im Rahmen der Schmelzverarbeitung. So können beispielsweise die Schritte (b) und (c) auch als ein Verfahrensschritt aufgefasst werden. In a preferred embodiment, a melt extrusion takes place. This is a continuous process (batch-independent), the premixing and granulation not being sequential in time, but in one production step. A preferred process for preparing the melt extrudate, the melt extrusion through a twin-screw extruder (for example, Leistritz ® micro 18) is. Advantage here is the setting of a temperature gradient, depending on the selected matrix former which significantly reduces the residence time of the cinacalcet under high temperatures. The temperature gradient is usually between 80 and 190 ° C. and is preferably chosen so that the cinacalcet is still present in crystalline form after processing. In optional step (c) of the process according to the invention, the extrudate is granulated. The granulation can be done before, during or after cooling. Granulation preferably already takes place in the context of melt processing. Thus, for example, steps (b) and (c) can also be understood as a method step.
In einer bevorzugten Ausführungsform werden die Granulierungsbedingungen (im Schritt (b) oder im Schritt (c)} so gewählt, dass die resultierenden Teilchen (Granulate) eine gewichtsmittlere Teilchengröße (D50-Wert) von 75 bis 600 /<m aufweisen, mehr bevorzugt von 120 bis 500 μτη, noch mehr bevorzugt von 150 bis 400 μπι, insbesondere von 200 bis 350 μνα.. Die gewichtsmittlere Teilchengröße wird mittels Siebanalyse bestimmt (unter Verwendung einer Retsch® AS 2000, Amplitude 1 ,5 sec, Intervall 10 min., Probeneinwaage 15,8 g). In a preferred embodiment, the granulation conditions (in step (b) or in step (c) are selected so that the resulting particles (granules) have a weight average particle size (D50) of from 75 to 600 / <m, more preferably from 120 to 500 μτη, more preferably from 150 to 400 μπι, in particular from 200 to 350 μνα .. The weight-average particle size is determined by sieve analysis (using a Retsch ® AS 2000, amplitude 1, 5 sec, interval 10 min., Sample weight 15.8 g).
Weiterhin werden die Granulierbedingungen bevorzugt so gewählt, dass die resultierenden Granulate eine Schüttdichte von 0,3 bis 0,85 g/ml, mehr bevorzugt 0,4 bis 0,8 g/ml, insbesondere 0,5 bis 0,7 g/ml aufweisen. Der Hausner-Faktor liegt üblicherweise im Bereich von 1 ,02 bis 1 ,3, mehr bevorzugt von 1 ,03 bis 1 ,25 und insbesondere von 1 ,04 bis 1 , 15. Unter "Hausner-Faktor" wird hierbei das Verhältnis von Stampfdichte zu Schüttdichte verstanden. Die Bestimmung von Schütt- und Stampfdichte erfolgt gemäß USP 24, Test 616 "Bulk Density and Tapped Density". In Schritt (d) des erfindungsgemäßen Verfahrens werden die in Schritt (c) erhaltenen Granulate zu Tabletten verpresst, d.h. es erfolgt eine Kompression zu Tabletten. Die Kompression kann mit im Stand der Technik bekannten Tablettiermaschinen wie Exzenterpressen oder Rundlaufpressen erfolgen. Im Falle von Rundlaufpressen wird üblicherweise eine Presskraft von 2 bis 40 kN, bevorzugt von 2,5 bis 35 kN, angewandt. Beispielsweise wird die Presse Fette® 102i (Fette GmbH, Deutschland) verwendet. Im Falle von Exzenterpressen wird üblicherweise eine Presskraft von 1 bis 20 kN, bevorzugt von 2,5 bis 10 kN, angewandt. Beispielsweise wird die Korsch® EK0 verwendet. Further, the granulation conditions are preferably selected so that the resulting granules have a bulk density of 0.3 to 0.85 g / ml, more preferably 0.4 to 0.8 g / ml, especially 0.5 to 0.7 g / ml exhibit. The Hausner factor is usually in the range of 1, 02 to 1, 3, more preferably from 1, 03 to 1, 25 and in particular from 1, 04 to 1, 15. In this case, "Hausner factor" is the ratio of tamped density understood to bulk density. Bulk density and tamped density are determined according to USP 24, Test 616 "Bulk Density and Tapped Density". In step (d) of the process according to the invention, the granules obtained in step (c) are compressed into tablets, ie compression into tablets takes place. The compression can be done with tableting machines known in the art, such as eccentric presses or concentric presses. In the case of rotary presses, a pressing force of from 2 to 40 kN, preferably from 2.5 to 35 kN, is usually used. For example, the press fats ® 102i (Fette GmbH, Germany). In the case of eccentric presses usually a pressing force of 1 to 20 kN, preferably from 2.5 to 10 kN, applied. For example, the Korsch ® EK0 is used.
Verfahrensschritt (d) erfolgt bevorzugt in Abwesenheit von Lösungsmitteln, insbesondere organischen Lösungsmitteln, d.h. als Trockenkompression. Process step (d) is preferably carried out in the absence of solvents, in particular organic solvents, i. as dry compression.
In Schritt (d) des erfindungsgemäßen Verfahrens können den Intermediaten aus Schritt (b) oder (c) pharmazeutische Hilfsstoffe (ß) zugegeben werden. Hierbei wird auf die vorstehend ausgeführten Erläuterungen zu geeigneten Hilfsstoffen verwiesen. Gegenstand der Erfindung ist nicht nur das erfindungsgemäße Verfahren, sondern auch die mit diesem Verfahren hergestellten Tabletten.
Bei den durch das erfindungsgemäße Verfahren hergestellten Tabletten kann es sich um Tabletten, die unzerkaut geschluckt werden (unbefilmt oder bevorzugt befilmt), handeln. Ebenfalls kann es sich um Kautabletten oder um Disperstabletten handeln. Unter "Disperstablette" wird hierbei eine Tablette zur Herstellung einer wässrigen Suspension zum Einnehmen verstanden. In step (d) of the process according to the invention, it is possible to add to the intermediates from step (b) or (c) pharmaceutical auxiliaries (β). Reference is made here to the explanations given above on suitable auxiliaries. The invention is not only the inventive method, but also the tablets produced by this method. The tablets produced by the process according to the invention may be tablets which are swallowed whole (unfiltered or preferably film-coated). It can also be chewable tablets or disperse tablets. "Disperstablette" is here understood to mean a tablet for the production of an aqueous suspension for oral use.
Im Falle von Tabletten, die unzerkaut geschluckt werden, ist es bevorzugt, dass diese mit einer Filmschicht im Schritt (e) des erfindungsgemäßen Verfahrens überzogen werden. Die vorstehend genannten Verhältnisse von Wirkstoff zu Hilfsstoff beziehen sich jedoch auf die unlackierte Tablette. Für die Befilmung werden bevorzugt makromolekulare Stoffe verwendet, beispielsweise modifizierte Cellulosen, Polymethacrylate, Polyvinylpyrrolidon, Polyvinylacetatphthalat, Zein und/ oder Schellack. In the case of tablets which are swallowed whole, it is preferred that they be coated with a film layer in step (e) of the method according to the invention. However, the above-mentioned ratios of active ingredient to excipient relate to the unpainted tablet. Preferably, macromolecular substances are used for the coating, for example modified celluloses, polymethacrylates, polyvinylpyrrolidone, polyvinyl acetate phthalate, zein and / or shellac.
Bevorzugt verwendet wird HPMC, insbesondere HPMC mit einem gewichtsmittleren Molekulargewicht von 10.000 bis 150.000 g/mol und/oder einem durchschnittlichen Substitutionsgrad an -OCH3-Gruppen von 1 ,2 bis 2,0. Preference is given to using HPMC, in particular HPMC having a weight-average molecular weight of from 10,000 to 150,000 g / mol and / or an average degree of substitution of -OCH 3 groups of from 1.2 to 2.0.
Die Schichtdicke des Überzugs beträgt bevorzugt 1 bis 100 μνα. mehr bevorzugt 2 bis 80 μτη. The layer thickness of the coating is preferably 1 to 100 μνα. more preferably 2 to 80 μτη.
Die Tablettierbedingungen werden bevorzugt so gewählt, dass die resultierenden Tabletten ein Verhältnis von Tablettenhöhe zu Gewicht von 0,005 bis 0,3 mm/mg, besonders bevorzugt 0,05 bis 0,2 mm/mg aufweisen. The tabletting conditions are preferably chosen so that the resulting tablets have a tablet height to weight ratio of 0.005 to 0.3 mm / mg, more preferably 0.05 to 0.2 mm / mg.
Ferner weisen die resultierenden Tabletten bevorzugt eine Härte von 70 bis 200 N, besonders bevorzugt von 100 bis 150 N auf, insbesondere wenn das Tablettengewicht mehr als 200 mg beträgt. Sofern das Tablettengewicht 200 mg oder weniger beträgt, weisen die resultierenden Tabletten bevorzugt eine Härte von 30 bis 100 N, besonders bevorzugt von 40 bis 70 N, auf. Die Härte wird gemäß Ph.Eur. 6.0, Abschnitt 2.9.8 bestimmt. Zudem zeigen die resultierenden Tabletten bevorzugt eine Friabilität von kleiner 3 % , besonders bevorzugt von kleiner 1 % , insbesondere von kleiner 0,8 % , auf. Die Friabilität wird gemäß Ph.Eur. 6.0, Abschnitt 2.9.7 bestimmt. Furthermore, the resulting tablets preferably have a hardness of from 70 to 200 N, particularly preferably from 100 to 150 N, in particular if the tablet weight is more than 200 mg. If the tablet weight is 200 mg or less, the resulting tablets preferably have a hardness of from 30 to 100 N, more preferably from 40 to 70 N, on. Hardness is calculated according to Ph.Eur. 6.0, section 2.9.8. In addition, the resulting tablets preferably have a friability of less than 3%, particularly preferably less than 1%, in particular less than 0.8%. The friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.
Schließlich weisen die erfindungsgemäßen Tabletten üblicherweise eine "Content Uniformity" von 95 bis 105 % vom durchschnittlichen Gehalt, bevorzugt von 98 bis 102 % , insbesondere von 99 bis 101 % vom durchschnittlichen Gehalt, auf. Die "Content Uniformity" wird gemäß Ph. Eur.6.0, Abschnitt 2.9.6. bestimmt.
Das Freisetzungsprofil der erfindungsgemäßen Tabletten weist gemäß USP-Methode (Paddle, 900 ml 0, 1 N HCl, pH 1 ,2, 37 °C, 75 UpM) nach 10 Minuten üblicherweise einen freigesetzten Gehalt von mindestens 30 % , bevorzugt mindestens 50 % , insbesondere mindestens 70 % auf. Sofern diese Parameter erfüllt sind, werden die Tabletten als Tabletten mit sofortiger Freisetzung betrachtet. Finally, the tablets according to the invention usually have a "content uniformity" of 95 to 105% of the average content, preferably 98 to 102%, in particular 99 to 101% of the average content. The "Content Uniformity" is according to Ph. Eur.6.0, Section 2.9.6. certainly. The release profile of the tablets according to the invention usually has a released content of at least 30%, preferably at least 50%, according to the USP method (paddle, 900 ml of 0.1 N HCl, pH 1, 2, 37 ° C., 75 rpm) after 10 minutes. especially at least 70%. If these parameters are met, the tablets are considered as immediate release tablets.
Die vorstehenden Angaben zu Härte, Friabilität, Content Uniformity und Freisetzungsprofil beziehen sich hierbei bevorzugt auf die unbefilmte Tablette. Alternativ zur Verpressung in Tabletten können die in Schritt (c) des erfindungsgemäßen Verfahrens resultierenden Granulate auch - gegebenenfalls unter Zusetzung weiterer pharmazeutischer Hilfsstoffe - zu einer partikulären Darreichungsform verarbeitet werden, beispielsweise durch Abfüllung in Kapseln oder in Sachets. The above information on hardness, friability, content uniformity and release profile in this case relate preferably to the uninfiltrated tablet. As an alternative to compression in tablets, the granules resulting in step (c) of the process according to the invention may also be processed into a particulate dosage form, optionally by adding further pharmaceutical auxiliaries, for example by filling into capsules or in sachets.
Gegenstand der Erfindung ist somit eine orale Darreichungsform enthaltend Cinacalcet, Matrixformer und Sprengmittel zur Behandlung des Hyperparathyreoidismus, wobei die Verabreichung unabhängig von den Mahlzeiten erfolgt. In einer bevorzugten Ausführungsform wird hierfür Sprengmittel in einer Menge von 10 bis 30 Gew. -% verwendet, bezogen auf das Gesamtgewicht der oralen Darreichungsform. In einer weiteren bevorzugten Ausführungsform wird hierfür ein Polyoxyethylen Polyoxypropylen-Blockpolymerisat als Matrixformer verwendet, insbesondere wie vorstehend näher beschrieben. In einer weiteren bevorzugen Ausführungsform beträgt der Gehalt an Cinacalcet 20 bis 60 Gew.-% , insbesondere 40 bis 60 Gew.-% . The invention thus relates to an oral dosage form containing cinacalcet, matrix former and disintegrants for the treatment of hyperparathyroidism, the administration taking place independently of the meals. In a preferred embodiment, disintegrants are used in an amount of 10 to 30% by weight, based on the total weight of the oral administration form. In a further preferred embodiment, a polyoxyethylene polyoxypropylene block polymer is used for this purpose as a matrix former, in particular as described in more detail above. In a further preferred embodiment, the content of cinacalcet is from 20 to 60% by weight, in particular from 40 to 60% by weight.
Die Erfindung soll anhand der nachfolgenden Beispiele veranschaulicht werden. BEISPIELE The invention will be illustrated by the following examples. EXAMPLES
Beispiel 1 example 1
Kern: Core:
Cinacalcet-Hydrochlorid (D50 101 μτα): 33,0 mg Cinacalcet hydrochloride (D50 101 μτα): 33.0 mg
Polyoxyethylen Polyoxypropylen-Blockpolymerisat (Mw ca. 8350): 30,0 mg Polyoxyethylene polyoxypropylene block polymer (Mw ca. 8350): 30.0 mg
Sorbitol (Füllstoff): 47,0 mg Sorbitol (filler): 47.0 mg
Natriumstearylfumarat: 7,00 mg Sodium stearyl fumarate: 7.00 mg
Crospovidon: 28,0 mg Film: Crospovidone: 28.0 mg film:
Opadry® AMB 6,40 mg
Das Herstellverfahren umfasste folgende Schritte: Opadry® AMB 6.40 mg The manufacturing process involved the following steps:
■ Cinacalcet HCl und Polyoxyethylen Polyoxypropylen-Blockpolymerisat, 20 mg wurden unter vorsichtigem Erwärmen bis zum Schmelzpunkt des Polymers granuliert Cinacalcet HCl and polyoxyethylene polyoxypropylene block polymer, 20 mg, were granulated with gentle heating to the melting point of the polymer
■ die resultierenden Intermediate wurde gesiebt (Maschenweite 0,6 mm) und weitere 10 min gemischt, The resulting intermediates were sieved (0.6 mm mesh) and mixed for a further 10 minutes,
■ das Granulat wurde zusammen mit Crospovidon und Sorbitol 10 min lang gemischt, ■ the granules were mixed together with crospovidone and sorbitol for 10 minutes,
■ Natriumstearylfumarat wurde durch Sieben hinzugefügt (Maschenweite ■ Sodium stearyl fumarate was added by sieving (mesh size
0,3 mm) und weitere 5 min lang gemischt, 0.3 mm) and mixed for a further 5 minutes,
■ die erhaltene Mischung wurde zu Tabletten verpresst (9,7 x 5 r 3,6; 4,5 kN; 42 N), und ■ the resulting mixture was compressed into tablets (9.7 x 5 r 3.6, 4.5 kN, 42 N), and
■ die Tabletten wurden mit einer Opadry® AMB-Lösung überzogen. ■ the tablets ® AMB solution were coated with an Opadry.
Die resultierenden Tabletten zeigten vorteilhafte Löslichkeitseigenschaften, die nach Lagerung über drei Monate (bei 40 °C, 75 % Luftfeuchte) erhalten blieben, siehe Beispiel 2. Vergleichsbeispiel 1 The resulting tablets showed advantageous solubility properties which remained after storage for three months (at 40 ° C, 75% humidity), see Example 2. Comparative Example 1
Zum Vergleich wurde Tabletten gemäß WO 2005/34928 AI (Absatz [0057]), enthaltend 30 mg mikronisiertes Cinacalcet-HCl mittels Feuchtgranulation hergestellt. Das Lösllchkeitsverhalten wurde in Beispiel 2 untersucht. For comparison, tablets according to WO 2005/34928 A1 (paragraph [0057]) containing 30 mg of micronised cinacalcet HCl were produced by wet granulation. The solubility behavior was investigated in Example 2.
Beispiel 2 Example 2
Das in-vitro Lösllchkeitsverhalten von (unbefilmten) Tabletten gemäß Beispiel 1 und Vergleichsbeispiel 1 wurde gemäß USP (Paddle, 900 ml 0, 1 N HCl, pH 1 ,2, 37 °C, 75 rpm) vor und nach Lagerung (40 °C, 75 % rel. Luftfeuchte) untersucht. The in vitro solubility behavior of (non-film) tablets according to Example 1 and Comparative Example 1 was determined according to USP (paddle, 900 ml 0, 1 N HCl, pH 1, 2, 37 ° C, 75 rpm) before and after storage (40 ° C , 75% relative humidity).
Die Messung zeigt, dass die erfindungsgemäßen Tabletten ein sehr gutes Löslichkeitsverhalten, insbesondere nach Lagerung, aufweisen, wobei eine Mikronisierung des Wirkstoffs vermieden werden konnte. Beispiel 3 The measurement shows that the tablets according to the invention have a very good solubility behavior, in particular after storage, it being possible to avoid micronization of the active ingredient. Example 3
Es wurde eine Gehaltsbestimmung sowie eine Messung der Verunreinigung mittelsIt was a content determination as well as a measurement of contamination by
HPLC Methode von Tabletten gemäß Beispiel 1 vor und nach Lagerung (40 °C, 75 % rel. Luftfeuchte) durchgeführt. HPLC method of tablets according to Example 1 before and after storage (40 ° C., 75% relative atmospheric humidity).
HPLC-Parameter: HPLC parameters:
Säule: X-Bridge C 18 150 x 4,6 mm, 3,5 μνα. Column: X-Bridge C 18 150 x 4.6 mm, 3.5 μνα.
Durchfluss: 0,9 ml/min. Flow: 0.9 ml / min.
Säulentemperatur: 60°C Column temperature: 60 ° C
Injektionsvolumen: 2 μΐ Injection volume: 2 μΐ
Elutionsmittel A: 25 mmol/1 KH2P04 * H20 pH 3.00 ± 0,05 Eluent A: 25 mmol / 1 KH 2 P0 4 * H 2 0 pH 3.00 ± 0.05
Elutionsmittel B: Acetonitril Eluent B: acetonitrile
Pumpengradient: Zeit [min] % B Pump gradient: time [min]% B
0 25 0 25
3 25 3 25
22 65 22 65
25 25 25 25
Wellenlänge: 225 nm Wavelength: 225 nm
Proben-Lösungsmittel: Wasser / Acetonitril 50/50 Sample solvent: water / acetonitrile 50/50
Probenkonzentrierung: 450 μg/πü Sample concentration: 450 μg / μl
Die Bestimmung zeigt, dass die erfindungsgemäßen Tabletten eine sehr gute Lagerstabilität aufweisen.
The determination shows that the tablets according to the invention have a very good storage stability.
Claims
1. Intermediat, erhältlich durch Schmelzverarbeitung von 1. Intermediate, obtainable by melt processing of
(i) Cinacalcet oder eines pharmazeutisch verträglichen Salzes davon, mit (i) Cinacalcet or a pharmaceutically acceptable salt thereof, with
(ii) einem Matrixformer. (ii) a matrix former.
2. Intermediat nach Anspruch 1 , wobei kristallines Cinacalcet oder ein pharmazeutisch verträgliches Salz davon, eingesetzt wird. 2. Intermediate according to claim 1, wherein crystalline cinacalcet or a pharmaceutically acceptable salt thereof is used.
3. Intermediat nach Anspruch 2, wobei die Schmelzverarbeitungsbedingungen so gewählt werden, dass Cinacalcet in kristallinem Zustand verbleibt. 3. Intermediate according to claim 2, wherein the melt processing conditions are chosen so that cinacalcet remains in a crystalline state.
4. Intermediat nach einem der Ansprüche 1 bis 3, wobei als Matrixformer hydrophile Polymere mit einem gewichtsmittleren Molekulargewicht von 1.000 g/mol bis 150.000 g/mol eingesetzt werden. 4. Intermediate according to one of claims 1 to 3, wherein as a matrix former hydrophilic polymers having a weight-average molecular weight of 1,000 g / mol to 150,000 g / mol are used.
5. Intermediat nach einem der Ansprüche 1 bis 4, wobei als Matrixformer Polyoxyethylen Polyoxypropylen-Blockpolymerisate, bevorzugt mit einem gewichtsmittleren Molekulargewicht von 1.500 bis 12.500 g/mol verwendet werden. 5. Intermediate according to one of claims 1 to 4, wherein polyoxyethylene polyoxypropylene block polymers, preferably having a weight-average molecular weight of 1,500 to 12,500 g / mol are used as the matrix former.
6. Intermediat nach Anspruch 5, wobei das Gewichtsverhältnis von Komponente (i) zu Komponente (ii) 1 : 5 bis 5 : 1 beträgt. 6. Intermediate according to claim 5, wherein the weight ratio of component (i) to component (ii) is 1: 5 to 5: 1.
7. Intermediat nach einem der Ansprüche 1 bis 6, enthaltend ferner 7. Intermediate according to one of claims 1 to 6, further containing
(iii-int) Sprengmittel und /oder (iii-int) disintegrants and / or
(iv-int) Dochtmittel. (iv-int) Wick.
8. Orale Darreichungsform, bevorzugt in Form einer Tablette, bevorzugt mit sofortiger Freisetzung, enthaltend 8. Oral dosage form, preferably in the form of a tablet, preferably with immediate release, containing
(et) ein Intermediat gemäß einem der Ansprüche 1 bis 7 und (et) an intermediate according to any one of claims 1 to 7 and
(ß) pharmazeutische Hilfsstoffe. (ß) pharmaceutical excipients.
9. Orale Darreichungsform nach Anspruch 8, dadurch gekennzeichnet, dass die Komponente (ß) Sprengmittel (iii-ex) und/oder Dochtmittel (iv-ex) enthält. 9. oral dosage form according to claim 8, characterized in that the component (ß) disintegrants (iii-ex) and / or wicking agent (iv-ex) contains.
10. Orale Darreichungsform nach Anspruch 9, wobei die Gesamtmenge an Sprengmittel (iii-int) + (iii-ex) 10 bis 30 Gew.-%, bezogen auf das Gesamtgewicht der Formulierung, beträgt. The oral dosage form of claim 9, wherein the total amount of disintegrant (iii-int) + (iii-ex) is 10 to 30% by weight, based on the total weight of the formulation.
1 1. Orale Darreichungsform nach einem der Ansprüche 8 bis 10, wobei die Tablette einen Gehalt an Cinacalcet von 40 bis 60 Gew. -% aufweist. 1. The oral dosage form according to claim 8, wherein the tablet has a content of cinacalcet of from 40 to 60% by weight.
12. Verfahren zur Herstellung einer oralen Darreichungsform gemäß einem der Ansprüche 8 bis 1 1 in Form einer Tablette, umfassend die Schritte 12. A process for the preparation of an oral dosage form according to any one of claims 8 to 1 1 in the form of a tablet, comprising the steps
(a) Bereitstellen von (i) Cinacalcet oder dessen pharmazeutisch verträglichen Salzen, mit (ii) einem Matrixformer sowie gegebenenfalls weiteren pharmazeutischen Hilfsstoffen; (a) providing (i) cinacalcet or its pharmaceutically acceptable salts, with (ii) a matrix former and optionally other pharmaceutical excipients;
(b) Schmelzverarbeitung zu einem Intermediat; (b) melt processing into an intermediate;
(c) gegebenenfalls Granulierung des Intermediats; (c) optionally, granulation of the intermediate;
(d) Kompression der resultierenden Intermediate zu Tabletten, gegebenenfalls unter Zusatz weiterer pharmazeutischer Hilfsstoffe; und (d) compression of the resulting intermediates to tablets, optionally with the addition of further pharmaceutical excipients; and
(e) gegebenenfalls Befilmung der Tabletten. (e) optionally, filming the tablets.
13. Verfahren gemäß Anspruch 12, wobei die Schmelzbedingungen in Schritt (b) so gewählt werden, dass Cinacalcet in kristallinem Zustand verbleibt. 13. A method according to claim 12, wherein the melting conditions in step (b) are selected so that cinacalcet remains in a crystalline state.
14. Verfahren gemäß Anspruch 12 oder 13, wobei in Schritt (b) oder (c) Granulate mit einer gewichtsmittleren Teilchengröße von 120 bis 500 μτη hergestellt werden. 14. The method according to claim 12 or 13, wherein in step (b) or (c) granules having a weight-average particle size of 120 to 500 μτη are prepared.
15. Orale Darreichungsform enthaltend Cinacalcet, Matrixformer, Dochtmittel und Sprengmittel zur Anwendung in einer Behandlung des Hyperparathyreoidismus, wobei die Verabreichung unabhängig von den Mahlzeiten erfolgt. 15. An oral dosage form containing cinacalcet, matrix former, wicking agent and disintegrants for use in the treatment of hyperparathyroidism, which is administered independently of the meals.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10776083A EP2490674A2 (en) | 2009-10-21 | 2010-10-19 | Melt-granulated cinacalcet |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09013308A EP2314286A1 (en) | 2009-10-21 | 2009-10-21 | Melt granulated cinacalcet |
| PCT/EP2010/006390 WO2011047837A2 (en) | 2009-10-21 | 2010-10-19 | Melt-granulated cinacalcet |
| EP10776083A EP2490674A2 (en) | 2009-10-21 | 2010-10-19 | Melt-granulated cinacalcet |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2490674A2 true EP2490674A2 (en) | 2012-08-29 |
Family
ID=41650433
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP09013308A Withdrawn EP2314286A1 (en) | 2009-10-21 | 2009-10-21 | Melt granulated cinacalcet |
| EP10776083A Withdrawn EP2490674A2 (en) | 2009-10-21 | 2010-10-19 | Melt-granulated cinacalcet |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP09013308A Withdrawn EP2314286A1 (en) | 2009-10-21 | 2009-10-21 | Melt granulated cinacalcet |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20120270949A1 (en) |
| EP (2) | EP2314286A1 (en) |
| CA (1) | CA2785684A1 (en) |
| EA (1) | EA201270573A1 (en) |
| IL (1) | IL219336A0 (en) |
| WO (1) | WO2011047837A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015136329A1 (en) | 2014-03-14 | 2015-09-17 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical composition of cinacalcet |
| WO2019186516A1 (en) | 2018-03-30 | 2019-10-03 | Ftf Pharma Private Limited | Liquid dosage forms of cinacalcet or salt thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013107503A1 (en) | 2012-01-17 | 2013-07-25 | Zentiva Saglik Urunleri San. Ve Tic. A.S. | Method for producing cinacalcet compositions for direct tableting |
| WO2014029953A1 (en) * | 2012-08-21 | 2014-02-27 | Cipla Limited | Hot melt extruded (hme) pharmaceutical composition of cinacalcet |
| WO2014207691A1 (en) | 2013-06-26 | 2014-12-31 | Jubilant Life Sciences Limited | Disintegrant free composition of cinacalcet |
| CN109700778B (en) * | 2019-03-04 | 2021-08-13 | 南京恒生制药有限公司 | Cinacalcet hydrochloride quick-release preparation and preparation method thereof |
| RU2750761C2 (en) * | 2019-09-17 | 2021-07-02 | Общество с ограниченной ответственностью "АМЕДАРТ" | Cinacalcet hydrochloride tablet core |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE122005000033I2 (en) | 1994-10-21 | 2006-11-23 | Nps Pharma Inc | Calcium receptor active compounds |
| DK2821067T3 (en) | 2003-09-12 | 2017-12-04 | Amgen Inc | Quick solution formulation of cinacalcet |
| US6984403B2 (en) * | 2003-12-04 | 2006-01-10 | Pfizer Inc. | Azithromycin dosage forms with reduced side effects |
| CA2598204C (en) * | 2004-11-09 | 2015-01-13 | Board Of Regents, The University Of Texas System | Stabilized hme composition with small drug particles |
| WO2006082500A1 (en) * | 2005-02-03 | 2006-08-10 | Pfizer Products Inc. | Dosage forms providing controlled and immediate release of cholesteryl ester transfer protein inhibitors and immediate release of hmg-coa reductase inhibitors |
| EP1828098A1 (en) | 2005-11-22 | 2007-09-05 | Teva Pharmaceutical Industries Ltd | Crystal forms of cinacalcet hci and processes for their preparation |
| EP2069285A1 (en) | 2006-06-27 | 2009-06-17 | Sandoz AG | Amorphous form of cinacalcet |
| CN101522173A (en) * | 2006-09-01 | 2009-09-02 | 特瓦制药工业有限公司 | Solid composites of a calicum receptor-active compound |
| WO2008064202A2 (en) | 2006-11-20 | 2008-05-29 | Dr. Reddy's Labortories, Ltd. | Modified-release formulations of calcium receptor-active compounds |
| WO2010034497A2 (en) * | 2008-09-25 | 2010-04-01 | Ratiopharm Gmbh | Compacted cinacalcet |
-
2009
- 2009-10-21 EP EP09013308A patent/EP2314286A1/en not_active Withdrawn
-
2010
- 2010-10-19 EP EP10776083A patent/EP2490674A2/en not_active Withdrawn
- 2010-10-19 US US13/503,048 patent/US20120270949A1/en not_active Abandoned
- 2010-10-19 CA CA2785684A patent/CA2785684A1/en not_active Abandoned
- 2010-10-19 EA EA201270573A patent/EA201270573A1/en unknown
- 2010-10-19 WO PCT/EP2010/006390 patent/WO2011047837A2/en active Application Filing
-
2012
- 2012-04-22 IL IL219336A patent/IL219336A0/en unknown
Non-Patent Citations (1)
| Title |
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| ROYCE A ET AL: "ALTERNATIVE GRANULATION TECHNIQUE: MELT GRANULATION", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, NEW YORK, NY, US, vol. 22, no. 9/10, 1 January 1996 (1996-01-01), pages 917 - 924, XP009059037, ISSN: 0363-9045, DOI: 10.3109/03639049609065921 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015136329A1 (en) | 2014-03-14 | 2015-09-17 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical composition of cinacalcet |
| WO2019186516A1 (en) | 2018-03-30 | 2019-10-03 | Ftf Pharma Private Limited | Liquid dosage forms of cinacalcet or salt thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EA201270573A1 (en) | 2012-11-30 |
| US20120270949A1 (en) | 2012-10-25 |
| CA2785684A1 (en) | 2011-04-28 |
| EP2314286A1 (en) | 2011-04-27 |
| WO2011047837A3 (en) | 2011-11-10 |
| IL219336A0 (en) | 2012-06-28 |
| WO2011047837A2 (en) | 2011-04-28 |
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