WO2010082855A1 - Pharmaceutical compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation - Google Patents
Pharmaceutical compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation Download PDFInfo
- Publication number
- WO2010082855A1 WO2010082855A1 PCT/PL2009/000083 PL2009000083W WO2010082855A1 WO 2010082855 A1 WO2010082855 A1 WO 2010082855A1 PL 2009000083 W PL2009000083 W PL 2009000083W WO 2010082855 A1 WO2010082855 A1 WO 2010082855A1
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- WIPO (PCT)
- Prior art keywords
- ziprasidone
- pharmaceutical composition
- composition according
- active ingredient
- granulate
- Prior art date
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- 229960000607 ziprasidone Drugs 0.000 title claims abstract description 68
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- ZCBZSCBNOOIHFP-UHFFFAOYSA-N ziprasidone hydrochloride hydrate Chemical compound [H+].O.[Cl-].C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 ZCBZSCBNOOIHFP-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960003474 ziprasidone hydrochloride Drugs 0.000 title claims abstract description 23
- 239000012458 free base Substances 0.000 title claims description 21
- 239000002245 particle Substances 0.000 claims abstract description 38
- 239000004480 active ingredient Substances 0.000 claims description 28
- 239000008187 granular material Substances 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 15
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 9
- 229920002125 Sokalan® Polymers 0.000 claims description 9
- 229960000913 crospovidone Drugs 0.000 claims description 9
- 239000012530 fluid Substances 0.000 claims description 9
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 9
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 9
- 239000007884 disintegrant Substances 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 108010019160 Pancreatin Proteins 0.000 claims description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 238000007908 dry granulation Methods 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 238000005469 granulation Methods 0.000 claims description 6
- 230000003179 granulation Effects 0.000 claims description 6
- 229940055695 pancreatin Drugs 0.000 claims description 6
- 239000008055 phosphate buffer solution Substances 0.000 claims description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
- 238000009490 roller compaction Methods 0.000 claims description 5
- 238000005538 encapsulation Methods 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 238000003801 milling Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000008177 pharmaceutical agent Substances 0.000 claims 4
- 239000000314 lubricant Substances 0.000 claims 2
- 238000007873 sieving Methods 0.000 claims 2
- 102000020897 Formins Human genes 0.000 claims 1
- 108091022623 Formins Proteins 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 39
- 229940079593 drug Drugs 0.000 description 20
- 239000003814 drug Substances 0.000 description 19
- 229920000642 polymer Polymers 0.000 description 13
- 239000002775 capsule Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000011835 investigation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000004584 polyacrylic acid Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000005056 compaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229920006037 cross link polymer Polymers 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000000017 hydrogel Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000013583 drug formulation Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000013515 script Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000000194 supercritical-fluid extraction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation
- compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation.
- Ziprasidone free base is a compound with the chemical formula as follows:
- Ziprasidone is typically administered as hydrochloride acid addition salt, hydrochloride or monohydrate of this salt with the chemical formula:
- ziprasidone hydrochloride The method for preparation of ziprasidone hydrochloride was presented in the US patent specification No. US 4 831 031, where also its application as a neuroleptic agent useful inter alia in the treatment of schizophrenia was disclosed.
- Ziprasidone free base and ziprasidone hydrochloride are hereinafter collectively referred to as "ziprasidone" for convenience.
- Ziprasidone belongs to the class Il of Biopharmaceutical Classification System (BCS), which indicates that the active ingredient is poorly soluble in water but highly permeable across biological barriers. Therefore, the factor having a decisive influence on bioavailability of the drugs belonging to this class is their solubility.
- the size of active ingredient crystals is a parameter which helps to control the solubility. The size of active ingredient crystals directly influences its absorption rate into the organism. This is particularly essential for ziprasidone, which is a highly active drug characterized by narrow therapeutic range.
- ziprasidone is administered orally as hydrochloride acid addition salt.
- the drug containing ziprasidone in form of ziprasidone hydrochloride monohydrate is characterized with high permeability through biological barriers but it is poorly soluble in water, what negatively affects its bioavailability.
- the formulation of pharmaceutical compositions containing active ingredients poorly soluble in water is difficult.
- the adequate preparation of pharmaceutical composition allows for increase of drug solubility what results in improvement of bioavailability.
- the use of various methods for preparation of pharmaceutical compositions containing active ingredients poorly soluble in water is known in the pharmaceutical industry It was disclosed in the international patent application No. WO 2006/024944 A that implementation of polymers in the pharmaceutical composition improves solubility of the drugs which are poorly soluble. This effect is achieved as a result of partial coating of the drug particles with polymer that preferably contains hydrophilic and hydrophobic groups.
- the polymer used in this invention was Hydroxypropyl Methylcellulose Acetate Succinate (HMPCAS) which contains low amount of carboxylic acid groups.
- a ziprasidone depot formulation pharmaceutical composition with prolonged action
- the composition contains at least two surfactants, i.e. cetylpiridine chloride, gelatin, casein, phosphatides, etc.
- the pharmaceutical composition contains crystalline ziprasidone free base or crystalline ziprasidone hydrochloride in form of particles of size at most 85 ⁇ m, preferably particles of average size between 5-50 ⁇ m.
- the composition contains known pharmaceutically acceptable excipients, such as carboxymethyl cellulose, pregelatinized starch and others.
- the pharmaceutical composition is in a form of capsules and that is why the granulate volume is an important parameter that determines capsule size and patient comfort of medication administration.
- pharmaceutical compositions were disclosed that contain relatively low amount of active ingredient in the granulate (about 23% according to Example 3 (a)). Thus, a large capsule has to be used for relatively small drug dose. Such solution makes it necessary to use large capsules which can house the proper dosage unit which in turn can be uncomfortable for the patients when taking the drug.
- the purpose of the present invention is to provide new pharmaceutical compositions containing ziprasidone and the method for their preparation.
- the term "adequately crosslinked polymer” refers to the polymer that forms hydrogel in aqueous environment and, while surrounding particles of the active ingredient, creates suitable environment favoring dissolution of ziprasidone.
- ziprasidone in micronized form with the average particle size D[4.3] below 2 ⁇ m is dissolved worse than the larger particles. This observation is surprising as usually particles of a small size due to a larger solvent accessible surface area are more readily dissolved than the larger particles.
- Crospovidone polyvinylpyrrolidine is a substance insoluble in water and is usually used in pharmaceutical compositions as a disintegrant.
- crospovidone of average particle size within the range of 5-10 microns and large specific surface area about 2.0-2.5 m 2 /g was advantageously used (an example of crospovidone of this type is known under the trade name Polyplasdone INF-IO, ISP).
- This polyvinylpyrrolidine has very high capillary activity what results in the increase of amount of water provided to the system, which in turn facilitates increase in substance dissolution rate.
- compression of crospovidone with other ingredients of the pharmaceutical composition they are significantly concentrated and intermolecular interactions are generated.
- sodium carboxymethyl starch with sodium content in the range of 2.8-4.2% was used (it is known under the trade name Ultraamylopectin of type A, JRS Pharma).
- the generally used pharmaceutically acceptable auxiliary substances such as lactose monohydrate (known under the trade name Flowlac-100), microcrystalline cellulose
- the pharmaceutical composition according to the invention contains ziprasidone hydrochloride in the form of micronized particles, wherein average particle size can be characterized by volume weighted mean D[4.3], which is less than 2 ⁇ m or by Sauter diameter D[3.2], which is less than 1 ⁇ m.
- the viscosity of the polymer is within the range 29,400-39,400 cp (viscosity measured for 0.5% w/w aqueous solution at 25°C, according to the European Pharmacopoeia).
- This type of carbopol is available under the trade name Carbopol 974P, Noveon.
- polyacrylic acid forms hydrogel of high viscosity it is preferable to use disintegrant. It is especially preferable to use new compounds belonging to the group of the so-called superdisintegrants.
- sodium carboxymethyl starch with sodium content in the range 2.8-4.2% (known inter alia under the trade name Ultraamylopectin of type A, JRS Pharma) was used.
- the generally used pharmaceutically acceptable excipients such as lactose (known under the trade name Flowlac-100), microcrystalline cellulose (known under the trade name Avicel PHlOl) and magnesium stearate are used besides the carrier for preparation of the pharmaceutical composition according to the invention.
- the pharmaceutical composition according to the invention contains ziprasidone free base in the form of micronized particles, wherein average particle size can be characterized by volume weighted mean D[4.3], which is less than 2 ⁇ m or by Sauter diameter D[3.2], which is less than 1 ⁇ m.
- average particle size expressed by D [4.3] parameter lower than 2 ⁇ m or D [3.2] parameter lower than 1 ⁇ m, measured by means of a method of particles size laser measurement by Malvern, means that the particles size of 90% is lower than 5 ⁇ m.
- the method of investigation of drug pharmaceutical availability was chosen based on the methodology published in the FDA internet service (http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm).
- the method comprises investigation of therapeutic substance release from the drug form with the help of apparatus Il (blade apparatus) with the rotational speed of 75 rpm.
- apparatus Il blade apparatus
- pancreatin As the acceptor fluid 0.05M phosphate buffer solution of pH 7.5 containing 2% of sodium lauryl sulfate and pancreatin was added. The addition of pancreatin reduces the influence of hard gelatin capsule on degradation time and release rate of therapeutic substance. Additionally, in order to avoid floating of the drug onto the acceptor fluid surface capsules were placed in sinkers.
- the investigation of pharmaceutical availability consists of two stages.
- the capsules are macerated for 15 minutes in 700 ml of 0.05M phosphate buffer solution containing 0.5% w/w pancreatin.
- 200 ml of phosphate buffer solution of pH 7.5 and containing 9% w/w of sodium lauryl sulfate is added.
- the amount of the dissolved ziprasidone can be determined using any common method, e.g. UV/Vis spectroscopic method, by comparing absorbance of investigated and standard solution in 1 cm layer at the wavelength of 319 nm in relation to acceptor fluid as a reference. It is typical of the pharmaceutical composition according to the invention that if the dosage form is placed in the apparatus Il according to the Ph. Eur. (blade apparatus) containing 0.05M phosphate buffer solution of pH 7.5 as acceptor fluid with 1% sodium lauryl sulfate and with pancreatin, equipped with blades stirring with speed equal to 75 rpm, at least 75% of ziprasidone contained in the dosage form is dissolved within 30 minutes.
- any common method e.g. UV/Vis spectroscopic method
- micronized substance tends to form large compact agglomerates which remain intact during mixing with excipients and during encapsulation. As a result, the granulate is not homogeneous, which negatively affects uniformity of dosage units. Moreover, the substance is not fully accessible for acceptor fluid, which can result in decrease of substance solubility and in limiting the drug bioavailability. Moreover, micronized ziprasidone has high bulk volume, which makes technological processes difficult and it can easily form dust. Additionally, high bulk volume of the granulate containing micronized ziprasidone makes it necessary to use very large capsules that can house the proper dosage unit. This may be uncomfortable for the patients taking the drug.
- roller compaction method for granulate preparation for production of pharmaceutical composition containing micronized ziprasidone causes that bulk volume of the granulate is significantly lowered, flow properties are improved, the phenomenon of dusting and losses due to adhesion of active ingredient to the production devices are eliminated.
- roller compaction technique of micronized ziprasidone with at least one crosslinked polymer as a carrier allows for effective compression of ziprasidone particles and for obtaining granulate of high integration of the active ingredient with the carrier.
- the method for preparation of pharmaceutical composition containing ziprasidone hydrochloride according to the invention is characterized by the following stages: a. the active ingredient (micronized ziprasidone) is subjected to granulation with at least one pharmaceutically acceptable carrier, b. obtained granules are calibrated , c. calibrated granulate is mixed with excipients, d. the granulate is subjected to encapsulation.
- the granulation process is conducted dry with use of roller compaction method.
- the pharmaceutical composition according to the invention obtained in this way is characterized by high concentration of ziprasidone up to 60% w/w of the active ingredient in the granulate. As a result, a smaller capsule size for high doses of the preparation can be used and thus increasing patient's comfort in taking the drug.
- the powder for compaction containing 3.0 kg of substances mentioned in the following tables was prepared in the 20-L bin blender by Zanchetta. Dry granulation process was conducted in the roller compactor by Alexanderwerk WP 150 Pharma. During the process the pressing force of 8 kN/cm 2 and sieve of 1.0 mm diameter were used for milling of the "ribbons" formed. The proportional granulate content was used for doses 20 and 40 mg as well as for 60 and 80 mg.
- the following example illustrates the influence of the polymer type used in the composition on active ingredient release rate.
- composition prepared according to the scheme presented in Fig. 2 Based on the results presented in Fig. 6, it may be concluded that in the pharmaceutical composition only the use of crospovidone as a pharmaceutically acceptable carrier of high capillary activity being able to form loose gel in aqueous environment allows for obtaining the desired release profile.
- the powder for compaction containing 3.0 kg of substances mentioned in the following tables was prepared in the 20-L bin blender, by Zanchetta. Dry granulation process was conducted in the roller compactor by Alexanderwerk WP 150 Pharma. During the process the pressing force of 8 klM/cm 2 and sieve of 1.0 mm diameter were used for milling of the "ribbons" formed. The proportional granulate content was used for doses 20 and 40 mg as well as for 60 and 80 mg.
- the following example illustrates the comparison of ziprasidone release rate from the pharmaceutical composition containing ziprasidone free base and ziprasidone hydrochloride.
- the following example illustrates the influence of compacting process on ziprasidone release rate.
- the following example illustrates the influence of active ingredient particles size on ziprasidone release rate.
- the following example illustrates the influence of granulate particle size on active ingredient release profile from the capsules.
- Fig. 1 Comparison of ziprasidone hydrochloride and ziprasidone free base solubility within the pH range of 1 to 7.5.
- Fig. 2 presents the flow chart of preparation of composition No. 1
- Fig. 3 presents obtained release profiles of the active ingredient
- Fig. 4 presents the flow chart of preparation of composition No. 2
- Fig. 5 presents obtained release profiles of the active ingredient from the composition No. 1 and composition No. 2
- Fig. 6 presents the comparison of release profiles of the active ingredient from composition No. 1 and composition No. 3
- Fig. 7 presents the flow chart of preparation of composition No. 4 and composition
- Fig. 8 presents the comparison of ziprasidone release profiles from compositions No.
- Fig. 9 presents the comparison of ziprasidone release profiles from compositions No.
- Fig. 10 presents the flow chart of preparation of composition No. 7
- Fig. 11 presents the comparison of ziprasidone release profiles from compositions No.
- Fig. 12 presents the comparison of ziprasidone release profiles from compositions No.
- Fig. 13 presents the comparison of ziprasidone release profiles from compositions No.
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Abstract
A new pharmaceutical compositions are provided containing ziprasidone and the method for their preparation. The pharmaceutical composition according to the invention contains ziprasidone hydrochloride in the form of micronized particles, wherein average particle size can be characterized by volume weighted mean D[4.3], which is less than 2 μm or by Sauter diameter D[3.2], which is less than 1 μm.
Description
Pharmaceutical compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation
The subject matter of the invention are pharmaceutical compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation.
Ziprasidone free base is a compound with the chemical formula as follows:
Ziprasidone is typically administered as hydrochloride acid addition salt, hydrochloride or monohydrate of this salt with the chemical formula:
The method for preparation of ziprasidone hydrochloride was presented in the US patent specification No. US 4 831 031, where also its application as a neuroleptic agent useful inter alia in the treatment of schizophrenia was disclosed. Ziprasidone free base and ziprasidone hydrochloride are hereinafter collectively referred to as "ziprasidone" for convenience.
Ziprasidone belongs to the class Il of Biopharmaceutical Classification System (BCS), which indicates that the active ingredient is poorly soluble in water but highly permeable across biological barriers. Therefore, the factor having a decisive influence on bioavailability of the drugs belonging to this class is their solubility. The size of active ingredient crystals is a parameter which helps to control the solubility. The size of active ingredient crystals directly influences its absorption rate
into the organism. This is particularly essential for ziprasidone, which is a highly active drug characterized by narrow therapeutic range.
As it was disclosed in patent No. PL 196 867 B ziprasidone is administered orally as hydrochloride acid addition salt. The drug containing ziprasidone in form of ziprasidone hydrochloride monohydrate is characterized with high permeability through biological barriers but it is poorly soluble in water, what negatively affects its bioavailability.
The formulation of pharmaceutical compositions containing active ingredients poorly soluble in water is difficult. The adequate preparation of pharmaceutical composition allows for increase of drug solubility what results in improvement of bioavailability. The use of various methods for preparation of pharmaceutical compositions containing active ingredients poorly soluble in water is known in the pharmaceutical industry It was disclosed in the international patent application No. WO 2006/024944 A that implementation of polymers in the pharmaceutical composition improves solubility of the drugs which are poorly soluble. This effect is achieved as a result of partial coating of the drug particles with polymer that preferably contains hydrophilic and hydrophobic groups. The polymer used in this invention was Hydroxypropyl Methylcellulose Acetate Succinate (HMPCAS) which contains low amount of carboxylic acid groups.
In turn, it was disclosed in the international patent application No. WO 2007/027273 A that the use of surface stabilizers such as hydroxypropyl methylcellulose, gelatin or sodium lauryl sulfate in pharmaceutical compositions allows for obtaining composition that in FAST (on an empty stomach) and FED (during or after the meal) studies has comparable pharmacokinetics. The method for preparation of this composition consists in contact of ziprasidone with at least one surface stabilizer in suitable conditions and for suitable time in order to receive ziprasidone particles of size lower than 2,000 nm. Emulsion polymerization processes, precipitation or supercritical extraction provide suitable conditions. The use of technologically advanced methods for preparation of the composition is expensive and may be problematic in the large- scale processes.
The similar solution was presented in the US patent application No. US 2008/0305161 A where a ziprasidone depot formulation (pharmaceutical composition with prolonged action) for intramuscular and hypodermic administration is in the form of nanoparticles. The composition contains at least two surfactants, i.e. cetylpiridine chloride, gelatin, casein, phosphatides, etc.
There are also other methods for improvement of ziprasidone solubility such as use of cyclodextrins in pharmaceutical compositions described in the patent No. PL 189 324 B.
In turn, in the patent No. PL 195 209 B the pharmaceutical composition was disclosed that contains crystalline ziprasidone free base or crystalline ziprasidone hydrochloride in form of particles of size at most 85 μm, preferably particles of average size between 5-50 μm. Apart from ziprasidone the composition contains known pharmaceutically acceptable excipients, such as carboxymethyl cellulose, pregelatinized starch and others. The pharmaceutical composition is in a form of capsules and that is why the granulate volume is an important parameter that determines capsule size and patient comfort of medication administration. In the patent No. PL 195 209 B pharmaceutical compositions were disclosed that contain relatively low amount of active ingredient in the granulate (about 23% according to Example 3 (a)). Thus, a large capsule has to be used for relatively small drug dose. Such solution makes it necessary to use large capsules which can house the proper dosage unit which in turn can be uncomfortable for the patients when taking the drug.
The purpose of the present invention is to provide new pharmaceutical compositions containing ziprasidone and the method for their preparation.
As a result of work on pharmaceutical composition containing ziprasidone it was unexpectedly noticed that the use of ziprasidone in micronized form, adequately crosslinked polymer and disintegrant guarantees development of pharmaceutical composition with desired release profile parameters.
The term "adequately crosslinked polymer" refers to the polymer that forms hydrogel
in aqueous environment and, while surrounding particles of the active ingredient, creates suitable environment favoring dissolution of ziprasidone. During research and development work on optimal drug formulation it was observed that ziprasidone in micronized form with the average particle size D[4.3] below 2 μm is dissolved worse than the larger particles. This observation is surprising as usually particles of a small size due to a larger solvent accessible surface area are more readily dissolved than the larger particles.
Thus, it was necessary to find the excipients which could increase rate of micronized ziprasidone dissolution.
As a result of work on development of pharmaceutical composition containing ziprasidone hydrochloride it was surprisingly found out that crospovidone perfectly meets above-mentioned requirements.
Crospovidone (polyvinylpyrrolidine) is a substance insoluble in water and is usually used in pharmaceutical compositions as a disintegrant.
Because of use of the micronized ziprasidone hydrochloride in the pharmaceutical composition according to the invention, crospovidone of average particle size within the range of 5-10 microns and large specific surface area about 2.0-2.5 m2/g was advantageously used (an example of crospovidone of this type is known under the trade name Polyplasdone INF-IO, ISP). This polyvinylpyrrolidine has very high capillary activity what results in the increase of amount of water provided to the system, which in turn facilitates increase in substance dissolution rate. Moreover, during compression of crospovidone with other ingredients of the pharmaceutical composition they are significantly concentrated and intermolecular interactions are generated. Crospovidone when in contact with water forms a loose gel which surrounds ziprasidone particles and creates a local environment that facilitates dissolution of ziprasidone hydrochloride. Additionally, this phenomenon prevents ziprasidone particles from floating to the surface of acceptor fluid, forming agglomerates or adhering of substance particles to the vessel walls. Elimination of those phenomena increases contact surface area of ziprasidone and acceptor fluid and, as a consequence, the pharmaceutical drug availability is increased.
Because of the tendency of crospovidone to form loose gels in aqueous environment the use of disintegrant is advantageous. It is especially preferable to use modern compounds belonging to the group of the so-called superdisintegrants. In the pharmaceutical composition according to the invention sodium carboxymethyl starch with sodium content in the range of 2.8-4.2% was used (it is known under the trade name Ultraamylopectin of type A, JRS Pharma).
The generally used pharmaceutically acceptable auxiliary substances such as lactose monohydrate (known under the trade name Flowlac-100), microcrystalline cellulose
(known under the trade name Avicel PHlOl) and magnesium stearate are used besides the carrier for preparation of the pharmaceutical composition according to the invention.
The pharmaceutical composition according to the invention contains ziprasidone hydrochloride in the form of micronized particles, wherein average particle size can be characterized by volume weighted mean D[4.3], which is less than 2 μm or by Sauter diameter D[3.2], which is less than 1 μm.
The term "average particle size" expressed by D [4.3] parameter lower than 2 μm or D
[3.2] parameter lower than 1 μm, measured by means of a method of particle size laser measurement by Malvern, means that the particles size of 90% is lower than 5 μm.
During research and development work on optimal drug form a great difference between aqueous solubility of ziprasidone free base and ziprasidone hydrochloride was observed. This phenomenon is compliant with data available on substances of low solubility, whose addition salts are dissolved to a larger extent -Table 1.
Table 1. Comparison of ziprasidone hydrochloride and ziprasidone free base solubility in water at 37°C.
Table 2. Comparison of ziprasidone hydrochloride and ziprasidone free base solubility in the solution containing acetyl groups and phosphate groups and at 37°C.
Physicochemical properties of both substances, i.e. ziprasidone hydrochloride and ziprasidone free base, significantly differ from each other (Table 3). Thus, it is obvious for persons skilled in the art that substances of such different physicochemical properties need quite different approach when developing the optimal pharmaceutical composition.
Table 3. Comparison of physicochemical properties of ziprasidone hydrochloride and ziprasidone free base.
When developing the optimal drug formulation an appropriate excipients was searched for, which could provide suitable amount of acetyl groups, forming the environment facilitating ziprasidone dissolution. It turned out unexpectedly during the investigations that the use of a polymer, polyacrylic acid of specific linear crosslinking, allows for obtaining pharmaceutical composition of the desired release profile. In the pharmaceutical composition according to the invention, polymer, polyacrylic acid (known as carbopol), was advantageously used. The polymer is characterized with high content of acetyl groups originating from residues of the solvent, ethyl acetate (max. residue level of the solvent ethyl acetate is 0.5%), which is used during synthesis of this polymer. The viscosity of the polymer is within the range 29,400-39,400 cp (viscosity measured for 0.5% w/w aqueous solution at 25°C, according to the European Pharmacopoeia). This type of carbopol is available under the trade name Carbopol 974P, Noveon.
It may seem surprising for persons skilled in the art of development of technologies of drug form preparation that polymer, polyacrylic acid, was used in order to increase the dissolution rate, as conventionally this polymer is used in slow release formulations because it forms hydrogels which gradually release an active ingredient to the solution. However, in case of ziprasidone free base, during investigations of pharmaceutical availability carbopol, on the one hand, forms hydrophilic matrix surrounding particles of active ingredient and on the other hand, it provides suitable microenvironment containing acetyl groups that facilitate dissolution of the drug.
Because polyacrylic acid forms hydrogel of high viscosity it is preferable to use disintegrant. It is especially preferable to use new compounds belonging to the group of the so-called superdisintegrants. In the pharmaceutical composition according to the invention sodium carboxymethyl starch with sodium content in the range 2.8-4.2% (known inter alia under the trade name Ultraamylopectin of type A, JRS Pharma) was used.
The generally used pharmaceutically acceptable excipients such as lactose (known under the trade name Flowlac-100), microcrystalline cellulose (known under the trade name Avicel PHlOl) and magnesium stearate are used besides the carrier for preparation of the pharmaceutical composition according to the invention. The pharmaceutical composition according to the invention contains ziprasidone free base in the form of micronized particles, wherein average particle size can be characterized by volume weighted mean D[4.3], which is less than 2 μm or by Sauter diameter D[3.2], which is less than 1 μm.
The term "average particle size" expressed by D [4.3] parameter lower than 2 μm or D [3.2] parameter lower than 1 μm, measured by means of a method of particles size laser measurement by Malvern, means that the particles size of 90% is lower than 5 μm.
The method of investigation of drug pharmaceutical availability was chosen based on the methodology published in the FDA internet service (http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm). The method comprises investigation of therapeutic substance release from the drug form with the help of apparatus Il (blade apparatus) with the rotational speed of 75 rpm. As the acceptor fluid 0.05M phosphate buffer solution of pH 7.5 containing 2% of sodium lauryl sulfate and pancreatin was added. The addition of pancreatin reduces the influence of hard gelatin capsule on degradation time and release rate of therapeutic substance. Additionally, in order to avoid floating of the drug onto the acceptor fluid surface capsules were placed in sinkers. The investigation of pharmaceutical availability consists of two stages. During the first stage the capsules are macerated for 15 minutes in 700 ml of 0.05M phosphate buffer solution containing 0.5% w/w pancreatin. In the second stage 200 ml of phosphate buffer solution of pH 7.5 and containing 9% w/w of sodium lauryl sulfate is added.
The amount of the dissolved ziprasidone can be determined using any common method, e.g. UV/Vis spectroscopic method, by comparing absorbance of investigated and standard solution in 1 cm layer at the wavelength of 319 nm in relation to acceptor fluid as a reference.
It is typical of the pharmaceutical composition according to the invention that if the dosage form is placed in the apparatus Il according to the Ph. Eur. (blade apparatus) containing 0.05M phosphate buffer solution of pH 7.5 as acceptor fluid with 1% sodium lauryl sulfate and with pancreatin, equipped with blades stirring with speed equal to 75 rpm, at least 75% of ziprasidone contained in the dosage form is dissolved within 30 minutes.
It is obvious for persons skilled in the art that when developing the optimal technology of drug form preparation specific problems may occur in the case of substances in the form of micronized particles. The micronized substance tends to form large compact agglomerates which remain intact during mixing with excipients and during encapsulation. As a result, the granulate is not homogeneous, which negatively affects uniformity of dosage units. Moreover, the substance is not fully accessible for acceptor fluid, which can result in decrease of substance solubility and in limiting the drug bioavailability. Moreover, micronized ziprasidone has high bulk volume, which makes technological processes difficult and it can easily form dust. Additionally, high bulk volume of the granulate containing micronized ziprasidone makes it necessary to use very large capsules that can house the proper dosage unit. This may be uncomfortable for the patients taking the drug.
Unexpectedly, it was found out that the use of roller compaction method for granulate preparation for production of pharmaceutical composition containing micronized ziprasidone causes that bulk volume of the granulate is significantly lowered, flow properties are improved, the phenomenon of dusting and losses due to adhesion of active ingredient to the production devices are eliminated.
The use of roller compaction technique of micronized ziprasidone with at least one crosslinked polymer as a carrier allows for effective compression of ziprasidone particles and for obtaining granulate of high integration of the active ingredient with the carrier.
The method for preparation of pharmaceutical composition containing ziprasidone hydrochloride according to the invention is characterized by the following stages:
a. the active ingredient (micronized ziprasidone) is subjected to granulation with at least one pharmaceutically acceptable carrier, b. obtained granules are calibrated , c. calibrated granulate is mixed with excipients, d. the granulate is subjected to encapsulation.
Preferably, the granulation process is conducted dry with use of roller compaction method.
The pharmaceutical composition according to the invention obtained in this way is characterized by high concentration of ziprasidone up to 60% w/w of the active ingredient in the granulate. As a result, a smaller capsule size for high doses of the preparation can be used and thus increasing patient's comfort in taking the drug.
This invention is illustrated with the following examples that do not limit the invention in any way:
Example 1
In the below described examples the powder for compaction containing 3.0 kg of substances mentioned in the following tables was prepared in the 20-L bin blender by Zanchetta. Dry granulation process was conducted in the roller compactor by Alexanderwerk WP 150 Pharma. During the process the pressing force of 8 kN/cm2 and sieve of 1.0 mm diameter were used for milling of the "ribbons" formed. The proportional granulate content was used for doses 20 and 40 mg as well as for 60 and 80 mg.
(A) substance of average particle size D[4.3] below 2 μm (D[2,3] below 1 μm)
Example 2.
The following example illustrates influence of compaction process on the active ingredient release rate.
Based on the results presented in Fig. 5, it can be concluded that the use of compacting process for preparation of pharmaceutical composition according to the invention allows for obtaining the desired release profile.
Example 3.
The following example illustrates the influence of the polymer type used in the composition on active ingredient release rate.
* Composition prepared according to the scheme presented in Fig. 2
Based on the results presented in Fig. 6, it may be concluded that in the pharmaceutical composition only the use of crospovidone as a pharmaceutically acceptable carrier of high capillary activity being able to form loose gel in aqueous environment allows for obtaining the desired release profile.
In the below described examples, the powder for compaction containing 3.0 kg of substances mentioned in the following tables was prepared in the 20-L bin blender, by Zanchetta. Dry granulation process was conducted in the roller compactor by Alexanderwerk WP 150 Pharma. During the process the pressing force of 8 klM/cm2 and sieve of 1.0 mm diameter were used for milling of the "ribbons" formed. The proportional granulate content was used for doses 20 and 40 mg as well as for 60 and 80 mg.
Example 4.
The following example illustrates the influence of the polymer type used in the composition according to the invention.
Example 5.
The following example illustrates the comparison of ziprasidone release rate from the pharmaceutical composition containing ziprasidone free base and ziprasidone hydrochloride.
Composition No. 4* Composition No. 6*
Substance name mg / tablet
Ziprasidone free base 40.00 -
* Composition prepared according to the scheme presented in Fig. 7
According to the results presented in Fig. 9, the use of carbopol leads to obtaining the pharmaceutical composition consistent with the desired release profile only for ziprasidone free base.
Example 6.
The following example illustrates the influence of compacting process on ziprasidone release rate.
* Composition prepared according to the scheme presented in Fig. 7 ** Composition prepared according to the scheme presented in Fig. 10
Example 7.
The following example illustrates the influence of active ingredient particles size on ziprasidone release rate.
(B) substance of average particle size D[4.3] about 20 μm
** Composition prepared according to the scheme presented in Fig. 10
Example 8.
The following example illustrates the influence of granulate particle size on active ingredient release profile from the capsules.
** Composition prepared according to the scheme presented in Fig. 9 Composition No. 10 - granulate particle size: D[v,0.9] - 97 μm Composition No. 9 - granulate particle size: D[v,0.9] - 170 μm
The subject matter of the invention is visualized in the figures, in which:
Fig. 1. Comparison of ziprasidone hydrochloride and ziprasidone free base solubility within the pH range of 1 to 7.5.
Fig. 2 presents the flow chart of preparation of composition No. 1
Fig. 3 presents obtained release profiles of the active ingredient
Fig. 4 presents the flow chart of preparation of composition No. 2
Fig. 5 presents obtained release profiles of the active ingredient from the composition No. 1 and composition No. 2
Fig. 6 presents the comparison of release profiles of the active ingredient from composition No. 1 and composition No. 3
Fig. 7 presents the flow chart of preparation of composition No. 4 and composition
No. 5
Fig. 8 presents the comparison of ziprasidone release profiles from compositions No.
4 and composition No. 5
Fig. 9 presents the comparison of ziprasidone release profiles from compositions No.
4 and composition No. 6
Fig. 10 presents the flow chart of preparation of composition No. 7
Fig. 11 presents the comparison of ziprasidone release profiles from compositions No.
4 and composition No. 7
Fig. 12 presents the comparison of ziprasidone release profiles from compositions No.
7 and composition No. 8
Fig. 13 presents the comparison of ziprasidone release profiles from compositions No.
9 and composition No. 10.
Claims
1. The pharmaceutical composition containing ziprasidone as an active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient is ziprasidone in micronized form and pharmaceutically acceptable carrier is a substance of high capillary activity able to form gel in aqueous environment.
2. The pharmaceutical composition according to claim 1 wherein said active ingredient is ziprasidone hydrochloride in micronized form.
3. The pharmaceutical composition according to claim 2 wherein ziprasidone hydrochloride in micronized form has the average particle size D[4.3] below 2 μm (D[2,3] below 1 μm).
4. The pharmaceutical composition according to claim 2 wherein the substance of high capillary activity able to form loose gel in the aqueous environment is crospovidone.
5. The pharmaceutical composition according to claim 2 wherein pharmaceutically acceptable carrier is disintegrant belonging to the group of superdisintegrants.
6. The pharmaceutical composition according to claim 5 wherein ultraamylopectin of type A is used as disintegrant.
7. The pharmaceutical agent according to claim 2 wherein in case of placing the dosage form in the apparatus Il according to the Ph. Eur. (paddleapparatus) containing 0.05M phosphate buffer solution of pH 7.5 as acceptor fluid with 1% sodium lauryl sulfate and with pancreatin, equipped with paddlesstirring with speed equal to 75 rpm, at least 75% of ziprasidone contained in the dosage form is dissolved within 30 minutes.
8. The pharmaceutical agent according to claim 2 wherein ziprasidone accounts for max. 60% w/w of the granulate.
9. The method for preparation of pharmaceutical composition containing ziprasidone hydrochloride as an active ingredient wherein said method consists of the following stages:
28 a. the active ingredient (micronized ziprasidone) is subjected to granulation with at least one pharmaceutically acceptable carrier, b. obtained granules arecalibrated , c. normalized granulate is mixed with theexcipients, d. the granulate is subjected to encapsulation.
10. The method according to claim 9 wherein the granulation process is dry granulation process (dry blending).
11. The method according to claim 10 wherein roller compaction is used as dry granulation method.
12. The method according to claim 9 wherein obtained granules are calibrated by milling - sieving.
13. The method according to claim 9 wherein the excipent used is lubricant, preferably magnesium stearate.
14. The pharmaceutical composition according to claim 1 wherein ziprasidone free base in micronized form is used as an active ingredient.
15. The pharmaceutical composition according to claim 14 wherein ziprasidone free base in micronized form has average particle size D[4.3] below 2 μm (D[2,3] below 1 μm).
16. The pharmaceutical composition according to claim 14 wherein the substance of high capillary activity is able to form gel in aqueous environment and contains suitable amount of acetyl groups.
17. The pharmaceutical composition according to claim 16 wherein the substance containing the suitable amount of acetyl groups is carbopol.
18. The pharmaceutical composition according to claim 14 wherein the pharmaceutically acceptable carrier used is disintegrant belonging to the group of superdisintegrants.
19. The pharmaceutical composition according to claim 18 wherein the disintegrant used is ultraamylopectin of type A.
20. The pharmaceutical agent according to claim 14 wherein in case of placing the dosage form in the apparatus Il according to the Ph. Eur. (paddle apparatus)
29 containing 0.05M phosphate buffer solution of pH 7.5 as acceptor fluid with 1% sodium lauryl sulfate and with pancreatin, equipped with paddles stirring with speed equal to 75 rpm, at least 75% of ziprasidone contained in the dosage form is dissolved within 30 minutes.
21. The pharmaceutical agent according to claim 14 wherein ziprasidone accounts for min. 40% w/w of the granulate.
22. The method for preparation of pharmaceutical composition containing ziprasidone free base as an active ingredient wherein said method consists of the following stages: a. the active ingredient (ziprasidone free base) is subjected to granulation with at least one pharmaceutically acceptable carrier, b. obtained granules arecalibrated, c. calibrated granulate is mixed with theescipients , d. the granulate is subjected to encapsulation.
23. The method according to claim 22 wherein the granulation process is dry granulation process.
24. The method according to claim 23 wherein roller compaction is used as dry granulation method.
25. The method according to claim 22 wherein obtained granules are calibrated by milling - sieving.
26. The method according to claim 22 wherein the excipient used is lubricant, preferably magnesium stearate.
30
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PLP.387050 | 2009-01-15 | ||
| PL387050A PL387050A1 (en) | 2009-01-15 | 2009-01-15 | Pharmaceutical containing the ziprasidone, method of its manufacturing and application |
| PLP.388223 | 2009-06-09 | ||
| PL388222A PL388222A1 (en) | 2009-06-09 | 2009-06-09 | Pharmaceutical composition of ziprasidone hydrochloride and method for production thereof |
| PL388223A PL388223A1 (en) | 2009-06-09 | 2009-06-09 | Pharmaceutical composition of ziprasidone base and method for production thereof |
| PLP.388222 | 2009-06-09 |
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| Publication Number | Publication Date |
|---|---|
| WO2010082855A1 true WO2010082855A1 (en) | 2010-07-22 |
Family
ID=42111896
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/PL2009/000083 WO2010082855A1 (en) | 2009-01-15 | 2009-08-27 | Pharmaceutical compositions comprising ziprasidone free base or ziprasidone hydrochloride and the method for their preparation |
Country Status (1)
| Country | Link |
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| WO (1) | WO2010082855A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011148253A2 (en) | 2010-05-25 | 2011-12-01 | Aurobindo Pharma Limited | Solid dosage forms of antipsychotics |
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| WO2009109844A1 (en) * | 2008-03-07 | 2009-09-11 | Pfizer Inc. | Methods, dosage forms, and kits for administering ziprasidone without food |
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