WO2013058721A1 - Pharmaceutical granules and production method - Google Patents
Pharmaceutical granules and production method Download PDFInfo
- Publication number
- WO2013058721A1 WO2013058721A1 PCT/TR2012/000172 TR2012000172W WO2013058721A1 WO 2013058721 A1 WO2013058721 A1 WO 2013058721A1 TR 2012000172 W TR2012000172 W TR 2012000172W WO 2013058721 A1 WO2013058721 A1 WO 2013058721A1
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- WIPO (PCT)
- Prior art keywords
- granules
- pharmaceutical
- weight
- pharmaceutically acceptable
- range
- Prior art date
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- 150000007513 acids Chemical class 0.000 description 1
- PWACSDKDOHSSQD-IUTFFREVSA-N acrivastine Chemical compound C1=CC(C)=CC=C1C(\C=1N=C(\C=C\C(O)=O)C=CC=1)=C/CN1CCCC1 PWACSDKDOHSSQD-IUTFFREVSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
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- 150000004781 alginic acids Chemical class 0.000 description 1
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- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 230000009285 allergic inflammation Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
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- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229960001705 buclizine Drugs 0.000 description 1
- MOYGZHXDRJNJEP-UHFFFAOYSA-N buclizine Chemical compound C1=CC(C(C)(C)C)=CC=C1CN1CCN(C(C=2C=CC=CC=2)C=2C=CC(Cl)=CC=2)CC1 MOYGZHXDRJNJEP-UHFFFAOYSA-N 0.000 description 1
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- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
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- KKHPNPMTPORSQE-UHFFFAOYSA-N chlorphenoxamine Chemical compound C=1C=C(Cl)C=CC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KKHPNPMTPORSQE-UHFFFAOYSA-N 0.000 description 1
- 229960000876 cinnarizine Drugs 0.000 description 1
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 description 1
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- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 description 1
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- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
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- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 description 1
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- MZDOIJOUFRQXHC-UHFFFAOYSA-N dimenhydrinate Chemical compound O=C1N(C)C(=O)N(C)C2=NC(Cl)=N[C]21.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 MZDOIJOUFRQXHC-UHFFFAOYSA-N 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229960001971 ebastine Drugs 0.000 description 1
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 229940095686 granule product Drugs 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 229960004958 ketotifen Drugs 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 229960001474 meclozine Drugs 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 description 1
- 239000002524 monosodium citrate Substances 0.000 description 1
- 235000018342 monosodium citrate Nutrition 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 229960001951 montelukast sodium Drugs 0.000 description 1
- LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 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
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
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- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
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- 229940083037 simethicone Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 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
- A61K9/1682—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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
-
- 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
Definitions
- the present invention relates to pharmaceutical granules having maximum 1% of moisture content by weight and production method thereof.
- Piperazine derivative of levocetirizine which is the R-enantiomer of cetirizine is a potent and selective HI receptor antagonist.
- Levocetirizine is a new antihistaminic which binds to HI receptors with high affinity, even two times higher as compared to cetirizine.
- Levocetirizine competes with histamine and inhibits histamine from binding to HI receptors. This antagonism blocks the effects of histamine on the gastrointestinal tract, uterus, large blood vessels and bronchial smooth muscle. The blockage of HI receptors suppresses histaminic activities such as oedema, flare and itching.
- levocetirizine enters the central nervous system in little amounts and has little affinity to HI receptors explain its non-sedative nature to some extent.
- Levocetirizine formulations existing in the prior art are in oral solution, oral drop and film tablet forms.
- the production method existing in the prior art related to levocetirizine formulations is wet granulation method which is generally implemented by spraying a granulation solution on the active agent mixture.
- the granulation solution can comprise other excipients such as filling agent, binder in addition to various pharmaceutically acceptable solvents.
- the solvents used in pharmaceutical technology for this purpose are the solvents such as water, deionized water, toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol (for instance ethyl alcohol) and/or alcohol mixtures.
- moisture content of levocetirizine granules produced by wet granulation method was measured by Karl Fischer method (with Metrohm, Karl Fischer reactive, at 25 °C) and the results of the analysis implemented on the samples taken by 5 different production lines are given below; % moisture content was measured according to total granule weight (See Table II).
- the inventors have found that the fact that moisture content of the granules produced by wet granulation method is more than 1% by weight causes degradation of the formulations independent from storage conditions.
- the inventors have found an improved formulation and production method in order to obtain stable levocetirizine granules as a solution for this problem.
- the present invention discloses pharmaceutical granule formulations having a maximum granule moisture content of 1% and comprising levocetirizine as the active agent.
- Moisture content of the granule formulations of the present invention is maximum 1% by weight, preferably in the range of 0.1% to 1% by weight.
- the term "levocetirizine” used throughout the text refers to levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof.
- Levocetirizine used in the formulations of the present invention is preferably its dihydrochloride salt, polymorphically is in its crystalline form.
- the granule formulations according to the present invention comprise levocetirizine dihydrochloride in the range of 0.1 to 10% by weight, preferably in the range of 0.1% to 5% by weight.
- the present invention discloses pharmaceutical granules comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.
- the present invention discloses pharmaceutical granules having a maximum moisture content of 1% in proportion to total granule weight, comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.
- the present invention discloses pharmaceutical granules having moisture content in the range of 0.1 to 1% in proportion to total granule weight, comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.
- the present invention discloses use of these granules in production of a dosage form suitable for oral use.
- Oral dosage forms of the present invention can be solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet; modified, fast, slow, controlled, prolonged release tablets; orodispersible tablet, mini tablet, microtablet, pellet, as well as multiple dosage forms comprising one or more of these dosage forms or liquid dosage forms such as suspension dosage forms.
- excipients that can be used in the granule formulations according to the present invention can be selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, sweeteners, flavouring agents, taste masking agents, diluents, binders, glidants, wetting agents, effervescent acid-base couple, anti-adhesive agents, solvents, sweeteners or combinations thereof.
- the disintegrants that can be comprised in the present invention can be selected from highly dispersive polymers, for instance cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicone dioxide, alginic acid, sodium alginate, corn starch.
- highly dispersive polymers for instance cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicone dioxide, alginic acid, sodium alginate, corn starch.
- the anti-adhesive agents that can be comprised in the present invention are used in order to prevent the mixture comprising active agent from forming rough surfaces by adhering to device and machine surfaces during the process.
- Substances which can be used for this purpose can comprise one or more components selected from the following group comprising talc, colloidal silicon dioxide, magnesium stearate and corn starch.
- the formulations according to the present invention comprise at least one pharmaceutically acceptable binder of minimum 1% by weight, preferably in the range of 1 to 10% by weight, more preferably in the range of 1 to 5% by weight.
- the preferred binder is sorbitol.
- the lubricants that can be comprised in the present invention can comprise one or more components selected from the group comprising highly metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.
- highly metallic stearates such as magnesium
- the diluents that can be comprised in the present invention can comprise one or more components selected from the group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, directly compressible lactose, lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates and/or derivatives thereof.
- alkali metal carbonates cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, directly compressible lactose, lactose, maltose, mannitol, simethicone, sorbitol, starch,
- the sweetening agents that can be used in the formulations of the present invention can comprise one or more components selected from the group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, acesulphame, maltose, saccharin and/or pharmaceutically acceptable salts or combinations thereof.
- the solvents that can be comprised in the present invention can comprise one or more components selected from the group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol and/or alcohol mixtures.
- the film coating agent according to the present invention is composed of the following components and/or combinations thereof such as lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol.
- lactose hydroxypropyl methylcellulose
- triacetin titanium dioxide
- polyvinyl alcohol polyvinyl alcohol
- talc polyvinyl alcohol
- lecithin polyethylene glycol
- the type and amount of the filling agent and effervescent acid-base comprised in the formulations have a role in stability of the end product.
- the effervescent acids that can be comprised in the formulations prepared in the scope of the present invention can be citric acid, monosodium citrate, tartaric acid, fumaric acid, malic acid and/or pharmaceutically acceptable salts, hydrates, anhydrates thereof or preferably a combination thereof.
- Effervescent base can be sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.
- the particularly preferred effervescent acid-base couple is sodium hydrogen carbonate and citric acid wherein the weight ratio of citric acid: sodium hydrogen carbonate is minimum 1, preferably in the range of 1 to 2.
- the filling agents that can be comprised in the present invention can be selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol or combinations thereof.
- the formulations of the present invention comprise at least one pharmaceutically acceptable filling agent of minimum 5% by weight, preferably in the range of 5 to 15% by weight, more preferably in the range of 8 to 15% by weight.
- the preferred filling agent is maltodextrin.
- the present invention discloses a method developed in order to produce a pharmaceutical granule formulation comprising levocetirizine.
- the method according to the present invention comprises granulating the active agent mixture with the granulation solution comprising minimum 50% of deionised water by weight, drying and sieving the granules obtained.
- the present invention also comprises drying the granules obtained effectively.
- One characteristic feature of the production method of the present invention is that said method is wet granulation method.
- Another characteristic feature of the production method of the present invention is that the solution used in the granulation comprises minimum 50% of water in proportion to total solution weight.
- the solution used in the granulation comprises minimum 50% of water in proportion to total weight of the solution, a pharmaceutically acceptable filling agent and/or a binder.
- the solution used in the granulation comprises water in the range of 50% to 70% in proportion to total weight of the solution, a pharmaceutically acceptable filling agent and/or a binder.
- Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator preferably at a temperature in the range of 20 °C to 60 °C, more preferably at a temperature in the range of 30 °C to 50 °C,
- Levocetirizine granules produced by the production method according to the present invention and stored under specific conditions (at 25 °C and under 60% of relative humidity for 12 weeks) and average impurity values of piperazine derivative of said granules are given below (See Table IV).
- the granules produced according to the present invention can surprisingly remain stable longer than the granules produced by wet granulation method existing in the prior art.
- granulation and granule drying temperatures have an important effect on stability of the end product. It has been found that it is advantageous to have the drying temperature of the granule product is more than 50 °C during granulation process. When very high temperatures are used in order to vaporize the granulation solution used especially after granulation process, additional degradations are observed in the active agent and other excipients.
- the present invention discloses wet granulation of the mixture comprising levocetirizine as the active agent and at least one other excipient in fluid bed granulator at a temperature in the range of 20 °C - 60 °C, more preferably in the range of 30 °C - 50 °C.
- the present invention discloses drying the granules obtained at a drying temperature in the range of 50 °C to 90 °C, preferably in the range of 50 to 70 °C.
- the temperature is generally in the range of 50 °C -90 °C, preferably in the range of 50 °C - 70° C for obtaining a stable levocetirizine granule according to the production method of the present invention.
- the formulations according to the present invention can be combined with a second active agent.
- Nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants can be listed as the second active agent.
- Dosage forms can be taken separately, together or successively as well as taken in a single dosage form combining levocetirizine with the other active agent or agents for combined treatment.
- the antihistaminics that can be used in the formulations of the present invention are selected from a group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, tripleamine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastin, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.
- the leukotriene receptor antagonists that can be used in the formulations of the present invention are selected from a group comprising montelukast, zafirlukast and zileuton or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof, preferably montelukast sodium.
- Example 1 Effervescent levocetirizine dihydrochloride granules a. Active Agent Mixture
- the method to be followed in order to prepare effervescent levocetirizine dihydrochloride granules is preferably as follows:
- the method to be followed for preparation of levocetirizine dihydrochloride granules is preferably as follows:
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Abstract
The present invention relates to pharmaceutical granules having maximum 1% of moisture content by weight and production method thereof.
Description
PHARMACEUTICAL GRANULES AND PRODUCTION METHOD
The present invention relates to pharmaceutical granules having maximum 1% of moisture content by weight and production method thereof.
Background of the Invention Levocetirizine which has the chemical name of 2-[2-[4-[(R)-(4-chlorophenyl)-phenyl- methyl]piperazine-l-yl]ethoxy] acetic acid as shown with the following formula (I) is a nonsedating, long-acting Hl-antihistaminic:
Formula (I) Cetirizine was first disclosed in the patent numbered EP0058146 A 1.
Piperazine derivative of levocetirizine which is the R-enantiomer of cetirizine is a potent and selective HI receptor antagonist. Levocetirizine is a new antihistaminic which binds to HI receptors with high affinity, even two times higher as compared to cetirizine. Levocetirizine competes with histamine and inhibits histamine from binding to HI receptors. This antagonism blocks the effects of histamine on the gastrointestinal tract, uterus, large blood vessels and bronchial smooth muscle. The blockage of HI receptors suppresses histaminic activities such as oedema, flare and itching. The facts that levocetirizine enters the central nervous system in little amounts and has little affinity to HI receptors explain its non-sedative nature to some extent. Levocetirizine has anti-allergic and anti-inflammatory activity. The studies have shown that levocetirizine inhibits a comprehensive series of reactions that induce and disseminate allergic inflammation.
Levocetirizine formulations existing in the prior art are in oral solution, oral drop and film tablet forms.
The production method existing in the prior art related to levocetirizine formulations is wet granulation method which is generally implemented by spraying a granulation solution on the active agent mixture. The granulation solution can comprise other excipients such as filling agent, binder in addition to various pharmaceutically acceptable solvents. The solvents used in pharmaceutical technology for this purpose are the solvents such as water, deionized water, toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol (for instance ethyl alcohol) and/or alcohol mixtures.
However, in degradation studies of levocetirizine granules produced by wet granulation method, the inventors have observed an increase in impurity concentration (impurity A) of piperazine derivative after the product was kept in 60% of relative humidity at 25°C for 12 weeks. (See Table I). Degradation studies were analysed by HPLC device.
Table I. Degradation Study Results
In addition, moisture content of levocetirizine granules produced by wet granulation method was measured by Karl Fischer method (with Metrohm, Karl Fischer reactive, at 25 °C) and the results of the analysis implemented on the samples taken by 5 different production lines are given below; % moisture content was measured according to total granule weight (See Table II).
Average (~) 1.24
Table II. Moisture content results
As a result of the moisture analysis study conducted, it has been found that the average moisture content of levocetirizine granule samples produced in 5 different production lines is 1.24% in proportion to total granule weight.
The inventors have found that the fact that moisture content of the granules produced by wet granulation method is more than 1% by weight causes degradation of the formulations independent from storage conditions.
The studies conducted in the scope of the present invention have shown that this high moisture content is closely associated with the content of the granulation solution used in wet granulation production method and granulation/drying temperature.
However, this problem related to levocetirizine granules was not disclosed in the prior art and therefore a solution offer was not made.
The inventors have found an improved formulation and production method in order to obtain stable levocetirizine granules as a solution for this problem.
In another aspect, the present invention discloses pharmaceutical granule formulations having a maximum granule moisture content of 1% and comprising levocetirizine as the active agent.
Moisture content of the granule formulations of the present invention is maximum 1% by weight, preferably in the range of 0.1% to 1% by weight. The term "levocetirizine" used throughout the text refers to levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof.
Levocetirizine used in the formulations of the present invention is preferably its dihydrochloride salt, polymorphically is in its crystalline form.
The granule formulations according to the present invention comprise levocetirizine dihydrochloride in the range of 0.1 to 10% by weight, preferably in the range of 0.1% to 5% by weight.
In one aspect, the present invention discloses pharmaceutical granules comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.
In another aspect, the present invention discloses pharmaceutical granules having a maximum moisture content of 1% in proportion to total granule weight, comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.
In another aspect, the present invention discloses pharmaceutical granules having moisture content in the range of 0.1 to 1% in proportion to total granule weight, comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof as the active agent and at least one pharmaceutically acceptable excipient.
In another aspect, the present invention discloses use of these granules in production of a dosage form suitable for oral use.
Oral dosage forms of the present invention can be solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet; modified, fast, slow, controlled, prolonged release tablets; orodispersible tablet, mini tablet, microtablet, pellet, as well as multiple dosage forms comprising one or more of these dosage forms or liquid dosage forms such as suspension dosage forms.
The excipients that can be used in the granule formulations according to the present invention can be selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, sweeteners, flavouring agents, taste masking agents, diluents, binders, glidants, wetting agents, effervescent acid-base couple, anti-adhesive agents, solvents, sweeteners or combinations thereof.
The disintegrants that can be comprised in the present invention can be selected from highly dispersive polymers, for instance cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high-molecular-weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, colloidal silicone dioxide, alginic acid, sodium alginate, corn starch.
The anti-adhesive agents that can be comprised in the present invention are used in order to prevent the mixture comprising active agent from forming rough surfaces by adhering to device and machine surfaces during the process. Substances which can be used for this
purpose can comprise one or more components selected from the following group comprising talc, colloidal silicon dioxide, magnesium stearate and corn starch.
The binders that can be comprised in the present invention comprise one or more components selected from the group comprising potato, wheat or corn starch; microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropyl methylcellulose, polyvinylpyrrolidone, lactose, guar gam, pectin, gelatine, sodium alginate.
The formulations according to the present invention comprise at least one pharmaceutically acceptable binder of minimum 1% by weight, preferably in the range of 1 to 10% by weight, more preferably in the range of 1 to 5% by weight. The preferred binder is sorbitol. The lubricants that can be comprised in the present invention can comprise one or more components selected from the group comprising highly metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.
The diluents that can be comprised in the present invention can comprise one or more components selected from the group comprising alkali metal carbonates, cellulose derivatives (microcrystalline cellulose, cellulose acetate etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, directly compressible lactose, lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates and/or derivatives thereof.
The sweetening agents that can be used in the formulations of the present invention can comprise one or more components selected from the group comprising aspartame, dextrose, fructose, sucralose, sodium cyclamate, mannitol, acesulphame, maltose, saccharin and/or pharmaceutically acceptable salts or combinations thereof.
The solvents that can be comprised in the present invention can comprise one or more components selected from the group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptane, hexane, acetonitrile, alcohol and/or alcohol mixtures.
The film coating agent according to the present invention is composed of the following components and/or combinations thereof such as lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol.
The inventors have found that components of the formulation have also an important effect on degradation of the end product.
In the case that the product is particularly an effervescent formulation, the type and amount of the filling agent and effervescent acid-base comprised in the formulations have a role in stability of the end product.
The effervescent acids that can be comprised in the formulations prepared in the scope of the present invention can be citric acid, monosodium citrate, tartaric acid, fumaric acid, malic acid and/or pharmaceutically acceptable salts, hydrates, anhydrates thereof or preferably a combination thereof. Effervescent base, on the other hand, can be sodium, potassium and calcium carbonates, bicarbonates and/or sodium glycine carbonate or a combination thereof.
The particularly preferred effervescent acid-base couple is sodium hydrogen carbonate and citric acid wherein the weight ratio of citric acid: sodium hydrogen carbonate is minimum 1, preferably in the range of 1 to 2.
The filling agents that can be comprised in the present invention can be selected from a group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulphate, xylitol and lactitol or combinations thereof.
The formulations of the present invention comprise at least one pharmaceutically acceptable filling agent of minimum 5% by weight, preferably in the range of 5 to 15% by weight, more preferably in the range of 8 to 15% by weight. The preferred filling agent is maltodextrin.
In another aspect, the present invention discloses a method developed in order to produce a pharmaceutical granule formulation comprising levocetirizine.
The method according to the present invention comprises granulating the active agent mixture with the granulation solution comprising minimum 50% of deionised water by weight, drying and sieving the granules obtained.
The present invention also comprises drying the granules obtained effectively.
One characteristic feature of the production method of the present invention is that said method is wet granulation method.
Another characteristic feature of the production method of the present invention is that the solution used in the granulation comprises minimum 50% of water in proportion to total solution weight.
Another characteristic feature of the production method of the present invention is that the solution used in the granulation comprises minimum 50% of water in proportion to total weight of the solution, a pharmaceutically acceptable filling agent and/or a binder.
Another characteristic feature of the production method of the present invention is that the solution used in the granulation comprises water in the range of 50% to 70% in proportion to total weight of the solution, a pharmaceutically acceptable filling agent and/or a binder.
One characteristic feature of the production method of the present invention is that said method is composed of the following steps:
1. Preparing the active agent mixture,
2. Preparing the granulation solution by mixing minimum 50% of water by weight and a pharmaceutically acceptable binder and/or a filling agent,
3. Wet granulating the mixture obtained in the first step with this granulation solution,
4. Drying and sieving the granules.
Another characteristic feature of the production method of the present invention is that said method is composed of the following steps:
1. Obtaining the active agent mixture by mixing levocetirizine and/or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient,
2. Preparing the granulation solution by mixing minimum 50% of deionised water by weight and a pharmaceutically acceptable binder and/or a filling agent,
3. Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator preferably at a temperature in the range of 20 °C to 60 °C, more preferably at a temperature in the range of 30 °C to 50 °C,
4. Drying and sieving the granules obtained in a fluid bed dryer at a drying temperature in the range of 50 °C to 90 °C, preferably in the range of 50 to 70 °C
5. Sending the dry granules to tablet compression machine for tablet compression.
Moisture content of the granules obtained this way has been measured by Karl Fischer method (Metrohm, Karl Fischer reactive 25 °C) and it has been found that moisture content of said granules is 0.16 on average in proportion to total granule weight (See Table III).
Table III. Moisture content results-II
Levocetirizine granules produced by the production method according to the present invention and stored under specific conditions (at 25 °C and under 60% of relative humidity for 12 weeks) and average impurity values of piperazine derivative of said granules are given below (See Table IV).
Table IV. Degradation Study Results - II
As seen, the granules produced according to the present invention can surprisingly remain stable longer than the granules produced by wet granulation method existing in the prior art.
In the scope of the present invention, it has also been found that granulation and granule drying temperatures have an important effect on stability of the end product. It has been found that it is advantageous to have the drying temperature of the granule product is more than 50 °C during granulation process. When very high temperatures are used in order to vaporize the
granulation solution used especially after granulation process, additional degradations are observed in the active agent and other excipients.
In one aspect, the present invention discloses wet granulation of the mixture comprising levocetirizine as the active agent and at least one other excipient in fluid bed granulator at a temperature in the range of 20 °C - 60 °C, more preferably in the range of 30 °C - 50 °C.
In one aspect, the present invention discloses drying the granules obtained at a drying temperature in the range of 50 °C to 90 °C, preferably in the range of 50 to 70 °C.
The temperature is generally in the range of 50 °C -90 °C, preferably in the range of 50 °C - 70° C for obtaining a stable levocetirizine granule according to the production method of the present invention.
The formulations according to the present invention can be combined with a second active agent. Nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants can be listed as the second active agent.
Dosage forms can be taken separately, together or successively as well as taken in a single dosage form combining levocetirizine with the other active agent or agents for combined treatment.
The antihistaminics that can be used in the formulations of the present invention are selected from a group comprising diphenhydramine, dimenhydrinate, carbinoxamine, chlorphenoxamine, mepyramine, antazoline, tripleamine, dexchlorpheniramine, dexbrompheniramine, pheniramine, buclizine, hydroxyzine, cinnarizine, meclizine, alimemazine, promethazine, cyproheptadine, ebastine, astemizole, acrivastin, loratadine, desloratadine, ketotifen, cetirizine, levocetirizine or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof.
The leukotriene receptor antagonists that can be used in the formulations of the present invention are selected from a group comprising montelukast, zafirlukast and zileuton or pharmaceutically acceptable salts, solvates, derivatives, polymorphs, hydrates or enantiomers thereof, preferably montelukast sodium.
The examples of the formulation of the present invention are given below. These examples are given in order to elucidate the subject of the present invention. Yet the present invention is not limited to these examples.
EXAMPLES
Example 1. Effervescent levocetirizine dihydrochloride granules a. Active Agent Mixture
b. Granulation Solution
The method to be followed in order to prepare effervescent levocetirizine dihydrochloride granules is preferably as follows:
1. Mixing levocetirizine dihydrochloride and sweetener, flavouring agent and at least one pharmaceutically acceptable excipient and preparing active agent mixture by adding an effervescent mixture into this mixture,
2. Preparing the granulation solution by mixing deionised water and binder and filling agent in the amounts given in order to prepare the granulation solution,
3. Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator at 40 °C,
4. Drying the granules obtained in a fluid bed dryer at the drying temperature of 65°C,
5. Sending the dried granules to tablet compression machine for tablet compression.
Example 2. Levocetirizine dihydrochloride granules
a. Active Agent Mixture
The method to be followed for preparation of levocetirizine dihydrochloride granules is preferably as follows:
1. Mixing levocetirizine dihydrochloride, at least one pharmaceutically acceptable diluent and anti-adhesive agent,
2. Granulating the mixture obtained with the granulation solution in the composition given above,
3. Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator (Fluid Bed Dryer) at 45 °C,
4. Drying the granules obtained in a fluid bed dryer at 60 °C,
5. Compressing the dry granules in tablet form.
Claims
1. Pharmaceutical granules comprising levocetirizine or a pharmaceutically acceptable salt, solvate, polymorph or hydrate thereof and at least one pharmaceutically acceptable excipient, characterized in that moisture content of the granules is maximum 1% in proportion to total granule weight.
2. The pharmaceutical granules according to claim 1, characterized in that moisture content of the granules is in the range of 0.1 to 1% by weight in proportion to total granule weight.
3. The pharmaceutical granules according to claim 1, characterized in that said granules comprise levocetirizine dihydrochloride in the range of 0.1 to 10% by weight.
4. The pharmaceutical granules according to claim 3, characterized in that said granules comprise levocetirizine dihydrochloride in the range of 0.1 to 5% by weight.
5. The pharmaceutical granules according claim 1, characterized in that pharmaceutically acceptable excipients are selected from a group comprising binders, disintegrants, viscosity enhancing components, filling agents, drying agents, lubricants, sweeteners, flavouring agents, taste masking agents, diluents, binders, glidants, wetting agents, effervescent acid-base couple, anti-adhesive agents, solvents, sweeteners or combinations thereof.
6. The pharmaceutical granules according to any preceding claims, characterized in that said granules are used in production of a pharmaceutical dosage form appropriate for oral intake.
7. The pharmaceutical granules according to claim 6, characterized in that said granules are in solid dosage forms such as tablet, film tablet, coated tablet, effervescent tablet, layered tablet, modified, fast, slow, controlled, prolonged release tablets, orodispersible tablet, mini tablet, microtablet, pellet; or in multiple dosage forms comprising one or more of these dosage forms or in liquid dosage forms such as suspension dosage forms.
8. A production method for the pharmaceutical granules according to any preceding claims, characterized in that said production method is composed of the following steps:
a) Preparing the active agent mixture, b) Preparing a granulation solution by mixing minimum 50% of water in by weight and at least one pharmaceutically acceptable binder and/or a filling agent,
c) Wet granulating the mixture obtained in the first step with this granulation solution,
d) Drying and sieving the granules.
9. The production method according to claim 8, characterized in that said method is composed of the steps of:
a) Preparing the active agent mixture by mixing levocetirizine and /or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient,
b) Preparing the granulation solution by mixing minimum 50% of deionised water by weight and a pharmaceutically acceptable binder and/or a filling agent, c) Granulating the active agent mixture obtained in the first step with the granulation solution obtained in the second step in a fluid bed granulator at a temperature in the range of 20 °C to 60 °C,
d) Drying and sieving the granules obtained in a fluid bed dryer at a temperature in the range of 50 °C to 90 °C,
e) Sending the dry granules to tablet compression machine for tablet compression.
10. The method according to claims 8-9, characterized in that granulation solution comprises water in the range of 50 to 70% by weight.
1 1. The method according to claims 8-9, characterized in that the temperature of the fluid bed granulator is preferably in the range of 30 °C - 50 °C.
12. The method according to claims 8-9, characterized in that drying temperature is in the range of 50 to 70 °C.
13. The pharmaceutical granule according to any preceding claims, characterized in that said granule is used in combined form with a second active agent.
14. The pharmaceutical granule formulation according to claim 13, characterized in that the second active agent is selected from a group comprising nasal decongestants, leukotriene receptor antagonists, antihistaminics, antidepressants.
15. The granules according to claim 1, characterized in that said granules are used in production of a drug for treatment of allergic rhinitis, persistent allergic rhinitis, perennial allergic rhinitis and chronic idiopathic urticaria.
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| WO2016140630A1 (en) * | 2015-03-05 | 2016-09-09 | PHARMACTIVE ILAÇ SANAYI VE TlCARET A. Ş. | An effervescent composition comprising levocetirizine and pseudoephedrine |
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| WO2016140630A1 (en) * | 2015-03-05 | 2016-09-09 | PHARMACTIVE ILAÇ SANAYI VE TlCARET A. Ş. | An effervescent composition comprising levocetirizine and pseudoephedrine |
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