TR201602566A1 - PULMONARY THERAPEUTIC FORMULATIONS - Google Patents
PULMONARY THERAPEUTIC FORMULATIONS Download PDFInfo
- Publication number
- TR201602566A1 TR201602566A1 TR2016/02566A TR201602566A TR201602566A1 TR 201602566 A1 TR201602566 A1 TR 201602566A1 TR 2016/02566 A TR2016/02566 A TR 2016/02566A TR 201602566 A TR201602566 A TR 201602566A TR 201602566 A1 TR201602566 A1 TR 201602566A1
- Authority
- TR
- Turkey
- Prior art keywords
- pharmaceutical composition
- feature
- specified
- pharmaceutically acceptable
- sorbitan
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 28
- 230000002685 pulmonary effect Effects 0.000 title claims description 14
- 230000001225 therapeutic effect Effects 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 37
- 208000006673 asthma Diseases 0.000 claims abstract description 20
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 13
- 206010006451 bronchitis Diseases 0.000 claims abstract description 12
- 206010014561 Emphysema Diseases 0.000 claims abstract description 9
- 239000003862 glucocorticoid Substances 0.000 claims abstract description 9
- 206010006458 Bronchitis chronic Diseases 0.000 claims abstract description 7
- 208000007451 chronic bronchitis Diseases 0.000 claims abstract description 7
- 238000009097 single-agent therapy Methods 0.000 claims abstract description 7
- 201000009961 allergic asthma Diseases 0.000 claims abstract description 6
- 230000001684 chronic effect Effects 0.000 claims abstract description 6
- 208000019693 Lung disease Diseases 0.000 claims abstract description 5
- 208000009079 Bronchial Spasm Diseases 0.000 claims abstract description 4
- 208000014181 Bronchial disease Diseases 0.000 claims abstract description 4
- 206010006482 Bronchospasm Diseases 0.000 claims abstract description 4
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 26
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- 239000000725 suspension Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 15
- 229960002714 fluticasone Drugs 0.000 claims description 14
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 14
- 238000009472 formulation Methods 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 239000004480 active ingredient Substances 0.000 claims description 11
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 10
- VBJGJHBYWREJQD-UHFFFAOYSA-M sodium;dihydrogen phosphate;dihydrate Chemical compound O.O.[Na+].OP(O)([O-])=O VBJGJHBYWREJQD-UHFFFAOYSA-M 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 241000475481 Nebula Species 0.000 claims description 9
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 9
- 229940068977 polysorbate 20 Drugs 0.000 claims description 9
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 claims description 8
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- 229920000056 polyoxyethylene ether Polymers 0.000 claims description 8
- 229940035044 sorbitan monolaurate Drugs 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- 229960000289 fluticasone propionate Drugs 0.000 claims description 7
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 claims description 7
- 239000003002 pH adjusting agent Substances 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
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- 239000000594 mannitol Substances 0.000 claims description 5
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- 239000004094 surface-active agent Substances 0.000 claims description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
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- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
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- -1 hybritose Chemical compound 0.000 claims description 4
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- 230000000069 prophylactic effect Effects 0.000 claims description 4
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 3
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
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- 230000001932 seasonal effect Effects 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- HJRDNARELSKHEF-CLFAGFIQSA-N 2-[2-[(z)-octadec-9-enoyl]oxyethoxy]ethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCOCCOC(=O)CCCCCCC\C=C/CCCCCCCC HJRDNARELSKHEF-CLFAGFIQSA-N 0.000 claims description 2
- 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 claims description 2
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 claims description 2
- 239000004147 Sorbitan trioleate Substances 0.000 claims description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- 229940075564 anhydrous dibasic sodium phosphate Drugs 0.000 claims description 2
- 229940092705 beclomethasone Drugs 0.000 claims description 2
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
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- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 2
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- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
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- 229960001664 mometasone Drugs 0.000 claims description 2
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 claims description 2
- GIPDEPRRXIBGNF-KTKRTIGZSA-N oxolan-2-ylmethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC1CCCO1 GIPDEPRRXIBGNF-KTKRTIGZSA-N 0.000 claims description 2
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- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
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- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 claims description 2
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- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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Abstract
Mevcut buluş; erişkin veya pediyatrik hastalarda astım, mevsimsel veya pereniyel allerjik rinit ve allerjik rinit ile birlikte olan astım (allerjik astım, bronşiyal astım), kronik ve akut bronşit, Kronik Obstruktif Akciğer Hastalığı (KOAH), amfizem, bronkospazm gibi akciğer hastalıklarının profilaktik, semptomatik veya terapötik tedavisinde kullanılmak üzere glukokortikoid grubunda yer alan uygun etken maddenin ve/veya farmasötik olarak kabul edilebilir türevlerinin monoterapi olarak tek başına kullanıldığı farmasötik bileşim/ler ile ilgilidir.The present invention includes; asthma (allergic asthma, bronchial asthma), chronic and acute bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, bronchospasm and pulmonary diseases in adult or pediatric patients The present invention relates to a pharmaceutical composition (s) in which the active agent and / or pharmaceutically acceptable derivatives thereof suitable for use in the glucocorticoid group are used as monotherapy alone.
Description
TARIFNAME: PULMONER YOLLA UYGULANAN TERAPÖTIK FORMÜLASYONLAR BULUSUN ILGILI OLDUGU ALAN Mevcut bulus; eriskin veya pediyatrik hastalarda astim, mevsimsel veya pereniyel allerjik rinit ve allerjik rinit ile birlikte olan astim (allerjik astim, bronsiyal astim), kronik ve akut bronsit, Kronik Obstruktif Akciger Hastaligi (KOAH), amfizem, bronkospazm gibi akciger hastaliklarinin profilaktik, semptomatik veya terapötik tedavisinde kullanilinak üzere glukokortikoid grubunda yer alan uygun etken maddenin ve/veya farmasötik olarak kabul edilebilir türevlerinin monoterapi olarak tek basina kullanildigi farmasötik bilesim/ler ile Mevcut bulus; uygun etken maddenin flutikazon, S-(floroinetil)60i,90t-difloro-l lß-hidroksi- ve/veya farmasötik olarak kabul edilebilir türevleri oldugu ve uygun farmasötik formlarda etken madde olarak kullanildigi farmasötik bilesim/ler ile ilgilidir. DESCRIPTION: THERAPEUTIC FORMULATIONS APPLIED BY PULMONARY WAY FIELD OF THE INVENTION The present invention; in adult or pediatric patients with asthma, seasonal or perennial allergic asthma with rhinitis and allergic rhinitis (allergic asthma, bronchial asthma), chronic and acute lung such as bronchitis, Chronic Obstructive Pulmonary Disease (COPD), emphysema, bronchospasm for use in the prophylactic, symptomatic or therapeutic treatment of The appropriate active ingredient in the glucocorticoid group and/or pharmaceutical acceptance Pharmaceutical composition(s) in which its derivatives are used alone as monotherapy The present invention; suitable active ingredient is fluticasone, S-(fluoroinethyl)60i,90t-difluoro-1lß-hydroxy- and/or pharmaceutically acceptable derivatives and in suitable pharmaceutical forms relates to the pharmaceutical composition(s) in which it is used as an active ingredient.
Formül 1: Ayrica bulus, flutikazon ve/veya fannasötik olarak kabul edilebilir türevlerinin monoterapisinin kullanildigi farmasötik bilesimlerin pulmoner yolla uygulama için uygun olan formülasyonlarini ve profilaktik, semptomatik veya terapötik kullanimlarini da kapsamaktadir. ÖNCEKI TEKNIK (TEKNIGIN BILINEN DURUMU) Kronik Obstruktif Akciger Hastaligi (KOAH), kronik bronsit ve amfizemden meydana gelen solunum yollarinin obstrüksiyonu ile karakterize ilerleyici nefes darligina yol açan kronik bir solunum yollari hastaligidir. Formula 1: In addition, the invention relates to fluticasone and/or pharmaceutically acceptable derivatives. suitable for pulmonary administration of pharmaceutical compositions in which monotherapy is used. formulations and prophylactic, symptomatic or therapeutic uses. covers. PRIOR ART (KNOWN STATE OF THE ART) Chronic Obstructive Pulmonary Disease (COPD) consists of chronic bronchitis and emphysema. leading to progressive dyspnea characterized by obstruction of the incoming airways It is a chronic respiratory disease.
Obstruktif akciger hastaliklari bütün dünyada sik görülmektedir ve mortalitenin en önemli sebeplerinden birisidir. Dünya Saglik Örgütü'nün istatistiklerine göre dünyada 600 milyon KOAH” 11 vardir. Ülkemizde ise 3 milyon kadar KOAH' 11 oldugu tahmin edilmektedir.Obstructive lung diseases are common all over the world and are the most important cause of mortality. is one of the reasons. According to the statistics of the World Health Organization, 600 million There are 11 COPD. It is estimated that there are about 3 million COPD in our country.
Obstrüksiyona sebep olan hastalik her ne olursa olsun tikaniklik asagidaki belirtilmis üç- mekanizinadan biri ile gelmektedir: a) Lumen içindeki patolojik olaylar sebebiyle b) Solunum yollarinin duvarlarinda meydana gelen patolojik olaylar sebebiyle c) Brons etrafindaki patolojik olaylar sebebiyle A tipi kronik obstrüktif akciger hastaliklari (Amfizem tipi) ve B tipi kronik obstrüktif akciger hastaliklari (Bronsit) tipi olmak üzere KOAH 'in baslica iki türü vardir. Regardless of the disease causing the obstruction, the obstruction is in the following three- It comes with one of the mechanisms: a) Due to pathological events in the lumen b) Due to pathological events occurring in the walls of the respiratory tract c) Due to pathological events around the bronchi Type A chronic obstructive pulmonary diseases (Emphysema type) and type B chronic obstructive pulmonary diseases There are two main types of COPD, lung diseases (Bronchitis) type.
Kronik Bronsit, brons cidarlarinda kronik iltihaplanma ve kalinlasmadan kaynaklanip, brons agacinda asiri mukus yapimi ile seyreden bir hastaliktir. Bu hastalikta hava gecitlerinin daralma derecesi nefes alinayi bozacak kadar olabilir ve siklikla öksürük krizleri ile sonuçlanir. Kronik bronsitli hastalarin gösterdigi semptomlar öksürük ve iltihaplanmadan kaynaklanan asiri mukus ekspektorasyonudur. Pratikte asiri ekspektorasyon belirtileri en az iki yil ve iki yilin en az üç ayinda çogu günler ekspektorasyon olmasidir. Kronik bronsit patolojisinde strüktür özelligi baslica büyük bronslarda mukoz glandlarinin hipertrofisi ve küçük hava yollarinda kronik enflamatuar degisikliklerin bulunmasidir. Kronik bronsit daha ciddi ve daha sik solunum enfeksiyonlarina, bronslarin daralma ve tikanmasina. güçlükle nefes almaya veya güçsüzlüge neden olabilir. Chronic Bronchitis is caused by chronic inflammation and thickening of the bronchial walls, It is a disease that progresses with excessive mucus production in the bronchial tree. The weather in this disease The degree of narrowing of the passages can be enough to disrupt breathing and coughing frequently. result in crises. The symptoms of patients with chronic bronchitis are cough and excessive expectoration of mucus from inflammation. excessive in practice most days for at least two years and at least three months of two years is an expectation. In chronic bronchitis pathology, the structural feature is the most important. hypertrophy of mucous glands in the bronchi and chronic inflammatory disease in the small airways the presence of changes. Chronic bronchitis is more serious and more frequent respiratory to infections, narrowing and obstruction of the bronchi. difficulty breathing or can cause weakness.
Amfizem ise; solunum yetmezligine yol açan en yaygin kronik akciger hastaliklarindan biridir. Akcigerlerdeki hava keseciklerinin (alveol) gerilip genislemesiyle beliren bir hastaliktir. Bu genisleme hava, keseciklerini birbirinden ayiran ince duvarlarin yirtilmasina ve dolayisiyla akcigerlerde esneklik kaybina yol açar. Sonuçta akcigerlere hava girisi ve hava keseciklerinde kan gazlari (oksijen-karbon dioksit) dengesi bozulur. Ilerlemis amfizem olgularinda akcigerler genislemis, solmus ve kurumustur. Esneklikleri kalmadigindan bir yastik gibidirler. Gögüs kafesi açildiginda, akcigerler sönmez, çünkü esneklik kaybi nedeniyle içlerinde hava kalir. Amfizemli hastalarda hakim olan semptom, Orta dereceden agir dereceye degisen KOAH tedavisinde farmakolojik olan ve olmayan terapiler kullanilmaktadir. Cazzola ve arkadaslari tarafindan yapilan çalismada (Respiratory Medicine, Vz4, p.8725, 2008) farmakolojik tedavi yöntemleri arasinda antibiyotikler, bronkodilatörler, kortikosteroidler ve mukolitik ajanlar yer almaktadir. If emphysema; one of the most common chronic lung diseases leading to respiratory failure is one. A condition that occurs when the air sacs (alveoli) in the lungs are stretched and enlarged. is a disease. This expansion causes the air to rupture the thin walls that separate the vesicles from each other. and therefore causes loss of flexibility in the lungs. As a result, air entry into the lungs and The balance of blood gases (oxygen-carbon dioxide) in the air sacs is disturbed. Advanced In emphysema cases, the lungs are enlarged, withered, and dried. Their flexibility They are like a pillow because there is no left over. When the chest is opened, the lungs do not deflate, because air remains in them due to loss of elasticity. The predominant symptom in patients with emphysema Pharmacological and non-pharmacological treatment of moderate to severe COPD therapies are used. In the study by Cazzola et al. (Respiratory Medicine, Vz4, p.8725, 2008) among pharmacological treatment methods antibiotics, bronchodilators, corticosteroids and mucolytic agents.
Persistan astimda seçilecek tedavi inhale kortikosteroidlerdir. Klinik çalismalar inhale kortikosteroidin havayolu enflamasyonunu ve asiri yanitliligini anlamli bir sekilde azalttigini, akciger fonksiyonlarini iyilestirdigini, semptom siddetini azalttigini ve akut astim alevlenmelerinin meydana gelmesini etkili bir sekilde önledigini veya azalttigmi göstermistir (Georgitis JW., 1999). Astim tedavisinde tercih edilen kortikosteroid verilis yolu ilacin dogrudan akcigerlere gitmesini saglayan inhalasyondur; ilaç burada lokal olarak etkisini gösterir ve oral veya parenteral verilme ile iliskili sistemik yan etkiler en aza iner. The treatment of choice in persistent asthma is inhaled corticosteroids. clinical studies inhaled significantly reduced airway inflammation and hyperresponsiveness of corticosteroid reduces the severity of symptoms, improves lung functions, reduces the severity of effectively prevent or reduce the occurrence of asthma exacerbations showed (Georgitis JW., 1999). Corticosteroid administration preferred in the treatment of asthma its route is inhalation, which allows the drug to go directly to the lungs; the drug is locally and systemic side effects associated with oral or parenteral administration are minimized.
Astma ve kronik obstrüktif akciger hastaliklarinin tedavisinde bronkodilatör ilaçlar ve antiinflamatuvar amaçla kullanilan kortikosteroidler aerosol veya ince toz seklinde inhalasyonla lokal etki elde etmek üzere uygulanirlar. In the treatment of asthma and chronic obstructive pulmonary diseases, bronchodilator drugs and Corticosteroids used for anti-inflammatory purposes are in aerosol or fine powder form. They are applied to achieve local effect by inhalation.
Endikasyona ve kullanilan ilaca bagli olarak, pulmoner yolla uygulanan ilaçlar lokal veya sistemik etki olustururlar. Gaz veya oda sicakliginda yeterince buharlasan uçucu sivi halindeki lipofilik ilaçlar solunduklari zaman akcigerde alveol membranini asmak suretiyle hizli bir sekilde kan dolasimina geçerler. Alveollerden hizla bir sekilde absorbe edilirler ve etkileri çok çabuk baslayabilir. Bu tipte ilaç vermenin bir avantaji çok ufak miktarda ilacin dogrudan etki yerine (brons ve bronsiyollerin düz kas tabakasi gibi) uygulanmasidir.Depending on the indication and the drug used, the drugs administered by the pulmonary route may be local or produce systemic effects. Gas or volatile liquid that evaporates sufficiently at room temperature When inhaled, lipophilic drugs in the form of a drug are suspended in the lung by transcending the alveolar membrane. they quickly pass into the bloodstream. They are rapidly absorbed from the alveoli and The effects can wear off very quickly. One advantage of giving this type of medication is that a very small amount of medication is it is applied directly to the site of action (such as the smooth muscle layer of the bronchi and bronchioles).
Böylece, istenmeyen sistemik etkiler en aza indirilmis olur. Inhalasyonla uygulanabilen ve solunum havasi içinde alveol bosluklarina ulasabilen ilaçlar için akcigerler en verimli absorpsiyon yerini olustururlar. Thus, undesirable systemic effects are minimized. It can be administered by inhalation and The lungs are the most efficient for drugs that can reach the alveolar spaces in the breathing air. form the absorption site.
Inhalasyon ile tedavi alaninda terapötik moleküllerin soluinaya uygun partikül büyüklügünde olmasi gerekmektedir. Genellikle 10 um°nin üzerindeki partiküllerin büyük çogunlugu orofarenkste depolanmaktadir. 5-10 pm arasi partiküller büyük hava yollarinda dagilmaktadir. Bronsiyal dagilim için partikül büyüklügü 5 umsnin altinda, alveoler dagilim için 3 um°nin altinda olmalidir. Particle suitable for inhalation of therapeutic molecules in the field of inhalation therapy must be in size. Generally, large particles above 10 µm Most of them are stored in the oropharynx. Particles between 5-10 pm in large airways disperses. Particle size for bronchial distribution is below 5 μm, alveolar should be below 3 µm for dispersion.
Inhalasyon suretiyle uygulama 3 sekilde yapilir; o Basinçli aerosol, 0 Kuru toz inhalasyonu, o Nebülizatör ile uygulama. Application by inhalation is done in 3 ways; o Pressurized aerosol, 0 Dry powder inhalation, o Administration with a nebulizer.
Nebülizatör, ses dalgalariyla (ultrasonik nebülizatör) veya basinçli hava (jet nebülizatör) ile sivi haldeki ilaçlari buhar haline getiren ve solunum yoluyla alinabilmesini saglayan bir cihazdir. Nebülizatör ile küçük çocuklarda ölçülü doz inhalere uyum saglayamayan hastalarda ve agir astimi olan hastalarda astim ilaçlarinin etkili bir sekilde uygulanabilmesi mümkündür. Nebülizatör ile kullanilmak üzere hazirlanmis özel ilaç formlari vardir. Nebulizer, with sound waves (ultrasonic nebulizer) or compressed air (jet nebulizer) with a liquid that turns the drugs into vapor and allows them to be taken by breathing. is the device. Inability to adapt to a metered dose inhaler in young children with a nebulizer effective administration of asthma medications in patients with severe asthma. possible. There are special drug forms prepared for use with a nebulizer.
Inhalasyon yoluyla uygulama için hazirlanan farmasötik bilesimler solüsyon veya süspansiyon içeren nebül gibi bir dozaj formunda olabilir. Nebül formundaki farmasötikler çabuk etki göstermesi ve ilk geçis etkisinin asilmasi açisindan tedavide avantajlidir. Bu tip farmasötikler etken madde partiküllerinin sivilastirilmis itici gaz içinde uygun forma Son birkaç yilda nebülizatör tedavisinin birçok formu gelistirilmistir ve bronkodilatör, kortikosteroid ve antibiyotik gibi birçok ilaç nebülizatör ile kullanilmaya baslanmistir. Pharmaceutical compositions prepared for administration by inhalation, solution or It may be in a dosage form, such as a suspension containing nebula. Pharmaceuticals in the form of nebules It is advantageous in the treatment in terms of its rapid effect and the overcoming of the first-pass effect. this type pharmaceuticals, the active substance particles are formed into the appropriate form in the liquefied propellant gas. Many forms of nebulizer therapy have been developed over the last few years, and bronchodilator, Many drugs such as corticosteroids and antibiotics have been used with nebulizers.
Nebülizatörler, tüm dünyada: eriskinlerde ve çocuklarda özellikle solunum sistemi hastaliklarinin acil tedavisinde yaygin olarak kullanilmaktadir. Inhalasyon yoluyla, ilaçlar hedef alana daha iyi ulastirilabilmekte, alinan total doz ve sistemik dagilim minimuma indirilebilmektedir. Nebulizers all over the world: adults and children especially respiratory system It is widely used in the emergency treatment of diseases. By inhalation, drugs it can be reached to the target area better, the total dose taken and systemic distribution are minimized. downloadable.
Nebülizatör tedavisinde amaç, bir ilacin terapötik dozunun solunabilir partiküller seklinde bir aerosol olarak mümkün oldugunca kisa sürede, genellikle 5-10 dakika içinde, akcigerlere ulastirilmasidir. Optimum bir nebülizatör sistem, yüksek ilaç çikisina, kisa bir nebülizasyon süresine sahip olmali, küçük çapta damlaciklar olusturmalidir (Muers MF. ve Tedavi amaciyla: 0 Hava yolu obstrüksiyonu (bronkodilatörler, steroidler) i Anormal sekresyonlar (salin, rhDNaz, asetilsistein) 0 Nefes darligi (opiyatlar) durumlarinda kullanilmaktadir (Muers MF., 1997). The aim of nebulizer therapy is to deliver the therapeutic dose of a drug in the form of respirable particles. as an aerosol as soon as possible, usually within 5-10 minutes, delivery to the lungs. An optimal nebulizer system has a high drug output, a short It should have a nebulization time and form small droplets (Muers MF. For treatment: 0 Airway obstruction (bronchodilators, steroids) i Abnormal secretions (saline, rhDNase, acetylcysteine) 0 It is used in cases of shortness of breath (opiates) (Muers MF., 1997).
Nebülizatör tedavisi inhalerlere; 0 Yüksek dozlarda ilaç gerektiginde, o Astim ve KOAH ataginda oldugu gibi koordine solunumun güç oldugu durumlarda, o Kronik akciger hastaliklarinda inhaler preparatlarin yeterince etkin olmadigi, ilacin akciger periferine yogun bir sekilde dagiliminin gerektigi durumlarda, o Bebeklerde, inhaler, ara odacik ve maskelerin ise yaramadigi durumlarda, o Inhaler ile kullanima uygun olmayan antibiyotik, lignokain gibi bazi ilaçlarin verilmesi gerektiginde tercih edilmelidir. Nebulizer therapy to inhalers; 0 When high doses of medication are required, o In cases where coordinated breathing is difficult, such as in an attack of asthma and COPD, o Inhaled preparations are not effective enough in chronic lung diseases, In cases where intensive distribution to the lung periphery is required, o In babies, when inhalers, intermediate chambers and masks do not work, o Some drugs such as antibiotics, lignocaine, which are not suitable for use with the inhaler should be given when necessary.
Akcigerlerin insan vücudunun özellikle savunmasiz bir organi olmasi ve solunan ilaçlari kullanan birçok hastanin genel saglik sorunlarina sahip olmasindan dolayi pulmoner yolla uygulamaya yönelik farmasötik formülasyonlar steril olmalidir. The fact that the lungs are a particularly vulnerable organ of the human body and inhaled drugs pulmonary route because many patients using it have general health problems. Pharmaceutical formulations for administration must be sterile.
Bir maddenin üzerinde veya içinde bulunan tüm mikroorganizmalardan arindirilma islemine sterilizasyon denir. Bu islem sonucunda sporsuz bakteriler, virüsler, mantarlar gibi tüm mikroorganizmalar ortadan kaldirilir. Sterilizasyon en genel anlamda ortamda yasayan bütün mikroorganizmalar ile mikroorganizma sporlarinin inaktive edilmesi ya da ortamda mikroorganizma bulunma olasiliginin milyonda bir olmasidir. Saglik ve ilaç endüstrisinde üretimi yapilan bir çok ürün steril olmalidir. Özellikle vücuda ve vücut bosluklarina direkt uygulanacak inhaler, oftalmik, nazal, oküler, enjektabl preparasyonlar, transdermal yamalar gibi farmasötik formülasyonlara uygulanir. Elimination of all microorganisms on or in a substance The process is called sterilization. As a result of this process, non-spore bacteria, viruses, fungi All microorganisms such as Sterilization in the most general sense inactivation of all living microorganisms and microorganism spores or The probability of the presence of microorganisms in the environment is one in a million. Health and medicine Many products produced in the industry must be sterile. Especially the body inhaled, ophthalmic, nasal, ocular, injectable preparations to be applied directly to the cavities, applied to pharmaceutical formulations such as transdermal patches.
Kullanilan sterilizasyon yönteminin çok dikkatli seçilmesi gerekir. Kullanilacak yöntem, üründe herhangi bir bozulmaya neden olmayan en etkili yöntem olmalidir.The sterilization method used must be chosen very carefully. The method to be used It should be the most effective method that does not cause any deterioration in the product.
Sterilizasyon teknikleri temel olarak üç bölümde incelenmektedir: l. Fiziksel sterilizasyon yöntemleri - Sicakligin uygulandigi sterilizasyon yöntemleri: 0 Kuru isi sterilizasyonu 0 Yas isi sterilizasyonu o Dondurarak-kurutma (liyofilizasyon) ile sterilizasyon - Sicakligin uygulanmadigi sterilizasyon yöntemleri: o UV isini ile sterilizasyon o Iyonize radyasyon ile sterilizasyon H. Kimyasal sterilizasyon yöntemleri - Gaz sterilizasyonu: i Etilen oksit (EtO) gazi ile sterilizasyon o Hidrojen peroksit gazi ile sterilizasyon o Klor dioksit gazi ile sterilizasyon lll. Aseptik yöntem Kuru isi sterilizasyonu: Kuru isi hem mikroorganizmalarin, hem de pirojenik maddelerin yok edilmesi amaciyla kullanilmaktadir. Kulu isi sterilizasyonu için gerekli olan yüksek sicakliklarda çogu maddenin yapisinda degisiklikler meydana gelir. Toksik olmamalarina ragmen, uzun süre çok yüksek isi gerektirmesi ve Sporlarin kuru isiya daha dirençli olmalarindan dolayi pek tercih edilmezler. Sterilization techniques are basically examined in three parts: l. Physical sterilization methods - Sterilization methods using temperature: 0 Dry heat sterilization 0 Flat heat sterilization o Sterilization by freeze-drying (lyophilization) - Sterilization methods where heat is not applied: o Sterilization with UV light o Sterilization with ionizing radiation H. Chemical sterilization methods - Gas sterilization: i Sterilization with ethylene oxide (EtO) gas o Sterilization with hydrogen peroxide gas o Sterilization with chlorine dioxide gas ll. aseptic method Dry heat sterilization: Dry heat kills both microorganisms and pyrogenic substances. used for destruction. High required for heat sterilization Changes occur in the structure of most substances at temperatures. To be non-toxic Although it requires very high heat for a long time and Spores are more resistant to dry heat. They are not preferred because of their
Yas isi sterilizasyonu: Bu sterilizasyon islemi otoklav adi verilen ve genellikle ceketli olarak imal edilmis basinca dayanikli sterilizasyon odalarinda yapilir. lZlOC'de doygun su buhariyla yapilan sterilizasyon, düsük maliyetli, güvenilir ve degisikliklere izin verebilen bir sterilizasyon yöntemidir. Islem süresi kisa, toksik olmamasina karsin isiya ve neme duyarli malzemelere uygulanamazlar. Dry heat sterilization: This sterilization process is called autoclave and is usually jacketed. It is made in pressure resistant sterilization chambers manufactured as saturated water at lZlOC Sterilization with steam is low cost, reliable and can allow changes. It is a sterilization method. Processing time is short, non-toxic, but resistant to heat and humidity. They cannot be applied to sensitive materials.
Dondurarak-kurutma (Iiyofilizasyon) ile sterilizasyon: Sulu çözelti halindeki katilarm özellikle sicakliga hassas maddelerin bozulmalarini önleyerek kurutulmalari ile sterilizasyonunda uygulanan bir yöntemdir. Liyofilizasyon, basit olarak materyali önce dondurmak, sonra süblimasyon ile su buharini disari çekerek materyali kurutma temeline dayali bir tekniktir. Maliyeti yüksek olmasi, fazla depolama alanina ihtiyaç duyulmasi ve nakledilmesinin zor olmasi gibi dezavantajlari vardir. Sterilization by freeze-drying (lyophilization): Solids in aqueous solution especially with the drying of heat-sensitive materials by preventing their deterioration. It is a method of sterilization. Lyophilization simply removes the material first. freeze, then sublimation to draw out the water vapor to dry the material based technique. Its high cost, the need for more storage space and It has disadvantages such as being difficult to transport.
Kortikosteroidlerin farmasötik formülasyonlari üretim asamasinda sterilize edilmelidir, fakat kortikosteroidlerin bazilari termolabil özelliklere sahiptir, bu nedenle herhangi bir isil isleme tabi tutulmadan sterilizasyonu gerçeklestirilmelidir. Pharmaceutical formulations of corticosteroids must be sterilized during production, but some of the corticosteroids have thermolabile properties, so any heat Sterilization should be carried out without processing.
UV isini ile sterilizasyon: UV isigi, dalga boyu 328 ile 210 nm arasinda olan isinlardan olusmaktadir. Mikroorganizmalar üzerinde en öldürücü etki, 240 ile 280 nm dalga boylari arasindaki UV isini ile elde edilir. Dalga boyu 253.7 nm olan isin, öldürücü etkinin en fazla görüldügü UV isinidir. Bu nedenle sterilizasyon amaciyla bu lambalar kullanilmaktadir.Sterilization with UV light: UV light is from rays with wavelengths between 328 and 210 nm. is formed. The most lethal effect on microorganisms, wavelengths between 240 and 280 nm It is obtained by UV light between Ray, with a wavelength of 253.7 nm, has the most lethal effect. is the UV light seen. Therefore, these lamps are used for sterilization.
Her mikroorganizmanin UV isinina karsi direncinin farkli olmasi nedeniyle, sterilizasyonun saglanabilmesi için yeterli siddetteki UV isininin yeterli süre verilmesi gerekir. Bakteri sporlarinin UV isinina karsi çok dayanikli olmasi, radyasyon enerjileri ve penetrasyon güçlerinin azligi sebebiyle kullanim alanlari hava, su ve yüzey sterilizasyonu ile sinirlidir. Because each microorganism has different resistance to UV light, Ensuring sufficient time of UV light of sufficient intensity to ensure sterilization must. Bacterial spores are very resistant to UV light, radiation energies and Air, water and surface sterilization are used in areas of use due to their low penetration power. angry with.
Etilen oksit (EtO) gazi ile sterilizasyon: Etilen oksit renksiz, çok hafif kokusu olan havadan biraz daha agir, yanici ve patlayici, toksik bir gazdir. Solunum sistemi üzerine toksik etkili ve karsinojen olmalari sebebiyle farmasötik forinülasyonlarda tercih edilmezler. Sterilization with ethylene oxide (EtO) gas: Ethylene oxide is colorless, with very faint odour. It is a toxic gas, slightly heavier than air, flammable and explosive. On the respiratory system They are preferred in pharmaceutical formulations because they are toxic and carcinogenic. they are not allowed.
Hidrojen peroksit gazi ile sterilizasyon: Oda sicakliginda sivi olan hidrojen peroksit buharlastirildiginda, degisik aletler ve ambalaj malzemeleri için etkili bir yüzey sterilizasyon maddesi olarak kullanilir. Sterilization with hydrogen peroxide gas: Hydrogen peroxide, which is liquid at room temperature when evaporated, it provides an effective surface for various tools and packaging materials. It is used as a sterilizing agent.
Klor dioksit gazi ile sterilizasyon: Bakterisit, virüsit ve sporisit etkilidir. Ozon tabakasina zarar vermez. Vakumda ve düsük derisimde kullanilmasi nedeniyle, etilen oksidin yerine kullanilabilecek bir gaz olarak kabul edilmektedir. Sterilization with chlorine dioxide gas: It is effective as bactericide, virucidal and sporicide. to the ozone layer It does not hurt. As a substitute for ethylene oxide, it is used in a vacuum and on my low skin. It is considered a usable gas.
Aseptik yöntem: Aseptik yöntem, mikroorganizmalarin islem sahasindan uzak tutulmasi durumudur. Aseptik teknikte havadaki olasi inikroorganizmalari öldürmek için UV lambalari veya kimyasal aeresoller kullanilir. Çogunlukla yapilan islem mikroorganizmanin aseptik alana girisini engellemektir. Bu amaçla hava HEPA filtrelerden süzülerek çalisma ortamina verilir. Aseptic method: Aseptic method, keeping microorganisms away from the processing area is the status. UV to kill possible microorganisms in the air in aseptic technique lamps or chemical aerosols are used. Mostly done To prevent the entry of microorganisms into the aseptic area. For this purpose, air is filtered from HEPA filters. filtered and given to the working environment.
Yukarida açiklanan sterilizasyon yöntemlerinin; toksik, mutajenik veya karsinojen olmalari, isi veya neme hassas olmalari, maddelerin yapisinda bozulmalara sebep olmalari gibi dezavantajlari bulunmaktadir. Asagida bahsi geçen diger sterilizasyon yöntemleri bu dezavantajlarin eliminasyonunda etkili bir çözüm saglar. The sterilization methods described above; toxic, mutagenic or carcinogenic being sensitive to heat or humidity, causing deterioration in the structure of materials. has such disadvantages. Other sterilization methods mentioned below are It provides an effective solution in eliminating the disadvantages.
Iyonize radyasyon ile sterilizasyon: Iyonize radyasyon, elektromanyetik radyasyon ve taneciklerden kaynaklanan radyasyon olmak üzere iki grupta incelenir. Bu gruplarda alfa partikülleri, beta partikülleri, X isinlari, gama isinlari ve nötronlar yer almaktadir.Sterilization with ionizing radiation: Ionizing radiation, electromagnetic radiation and It is examined in two groups as radiation originating from particles. alpha in these groups particles, beta particles, X-rays, gamma rays and neutrons.
Elektromanyetik radyasyon gama isinlari ve X isinlarindan kaynaklanmaktadir. Iyonize radyasyonla yapilan sterilizasyonun en önemli özelligi, isi enerjisine gerek duyulmadan malzemelerin ambalajlari içinde sterilize edilebilmesidir. Ilaç ve ilaç hammaddeleri gama radyasyonuna tabi tutuldugunda yapilari bozulabilir, çesitli radikaller ve parçalanma ürünleri gibi impuriteler olusabilir. Bu impuriteler belirli bir sinir içerisinde (%5'ten az olmak kosuluyla) tutulabildigi takdirde bu yöntein etkili olabilir. Bu degerler disinda meydana gelen ürünler ilacin yapisini degistirerek vücutta istenmeyen etkilerin ortaya çikmasina sebep olabilirler. Maliyeti yüksek ve insan sagligi açisindan zararli olabilirler. Electromagnetic radiation originates from gamma rays and X-rays. ionized The most important feature of radiation sterilization is that it does not require heat energy. materials can be sterilized in their packaging. Pharmaceuticals and pharmaceutical raw materials gamma When exposed to radiation, their structure can be degraded, various radicals and fragmentation products such as impurities may occur. These impurities are within a certain nerve (less than 5%). This method can be effective if it can be kept Apart from these values The resulting products change the structure of the drug, resulting in undesirable effects in the body. they may cause it to break. They can be costly and harmful to human health.
Filtrasyon ile sterilizasyon: Sterilizasyon amaciyla yapilan filtrasyon, herhangi bir sividan veya gazdan mikroorganizmalarin uzaklastirilmasi islemidir. Steril filtrasyon tüm mikroorganizmalari tutacak özellikte olmalidir. Bu nedenle kullanilan filtrenin gözenek çapinin mikroorganizmayi geçirrneyecek boyutta olmasi gerekir. Steril filtrasyonda temel olarak membran filtreler, az da olsa porselen veya cam filtreler de kullanilabilir.Sterilization by filtration: Filtration for the purpose of sterilization, any It is the process of removing microorganisms from liquid or gas. sterile filtration all must be capable of retaining microorganisms. Therefore, the pore size of the filter used Its diameter must be of a size that will not allow the microorganism to pass through. Basic in sterile filtration Membrane filters, porcelain or glass filters can also be used.
Sterilizasyon amaciyla 0.2 um gözenek çapina sahip membran filtreler kullanilir. En küçük bakteri ve virüs yaklasik 0.3 um çapinda olduguna göre, bu gözenek çapina sahip bir filtre bütün bakterileri tutacak Özelliktedir. 0.2 mm ortalama bir degerdir. Isi ve neme karsi duyarli farmasötik bilesimlerin sterilizasyonunda tercih edilirler, ayrica maddenin yapisinda isi ya da radyasyondan kaynaklanan herhangi bir bozulmaya sebep olmadiklari ve dolayisiyla insan sagligini tehdit edebilecek toksik veya mutajenik olma gibi unsurlar içermedikleri için oldukça güvenilir bir yöntemdir. Membrane filters with a pore diameter of 0.2 um are used for sterilization. Smallest Since bacteria and virus are about 0.3 µm in diameter, a filter with this pore diameter It has the feature to keep all bacteria. 0.2 mm is an average value. Against heat and humidity They are preferred in the sterilization of sensitive pharmaceutical compositions, as well as the They do not cause any deterioration in their structure caused by heat or radiation. and therefore factors such as being toxic or mutagenic that may threaten human health It is a very reliable method since it does not contain
Inhalasyon yoluyla uygulama için hazirlanan farmasötik bilesimler solüsyon, süspansiyon, kuru toz, kapsül, granül, tablet, mini tablet, pellet gibi bir dozaj formunda olabilir. Pharmaceutical compositions for administration by inhalation include solutions, suspensions, It can be in a dosage form such as dry powder, capsule, granule, tablet, mini tablet, pellet.
Süspansiyonlar için zayif fiziksel ve kimyasal stabilite bir dezavantajdir. Süspansiyonlar uzun bir süre boyunca saklandiginda fiziksel ve kimyasal stabilite eksikligi olabilir.For suspensions, poor physical and chemical stability is a disadvantage. suspensions There may be a lack of physical and chemical stability when stored for a long period of time.
Fiziksel instabilite, genellikle küçük partikül boyutu sonucu olan, partiküllerin daha büyük partiküller olusturmak üzere agregasyonu ve kristal büyümesi ile meydana gelmektedir. Physical instability is the result of larger particles, usually the result of small particle size. It occurs by aggregation and crystal growth to form particles.
Kimyasal instabilite; süspansiyon içerisinde etken maddenin zaman içinde süspansiyon Ortami ile etkilesimi nedeniyle aktivitesinin azalmasidir. Hatta az çözünürlük bile etken maddenin degradasyonunu hizlandirabilir. Kimyasal degradasyon orani; partikül boyutu, gerçek çözünürlügü ve etken maddenin kimyasal yapisina baglidir.Chemical instability; suspension of the active substance in suspension over time It is the decrease in its activity due to its interaction with the environment. Even low resolution is a factor. can accelerate the degradation of the substance. Chemical degradation rate; particle size, it depends on the actual solubility and the chemical structure of the active substance.
BULUSUN AÇIKLAMASI Mevcut bulus; eriskin veya pediyatrik hastalarda astim, mevsimsel veya pereniyel allerjik rinit ve allerjik rinit ile birlikte olan astim (allerjik astim, bronsiyal astim), kronik ve akut bronsit, Kronik Obstruktif Akciger Hastaligi (KOAH), amfizem, bronkospazm gibi akciger hastaliklarinin profilaktik, semptomatik veya terapötik tedavisinde kullanilmak üzere glukokortikoid grubunda yer alan uygun etken maddenin ve/veya farmasötik olarak kabul edilebilir türevlerinin monoterapi olarak tek basina kullanildigi farmasötik bilesim/ler ile Mevcut bulusun bir diger yönü pulmoner yolla uygulamaya yönelik glukokortikoid grubunda yer alan uygun etken maddenin ve/veya farmasötik olarak kabul edilebilir türevlerinin monoterapi olarak tek basina kullanildigi farmasötik bilesim/ler ile ilgilidir. DESCRIPTION OF THE INVENTION The present invention; in adult or pediatric patients with asthma, seasonal or perennial allergic asthma with rhinitis and allergic rhinitis (allergic asthma, bronchial asthma), chronic and acute lung such as bronchitis, Chronic Obstructive Pulmonary Disease (COPD), emphysema, bronchospasm for use in the prophylactic, symptomatic or therapeutic treatment of The appropriate active ingredient in the glucocorticoid group and/or pharmaceutical acceptance Pharmaceutical composition(s) in which its derivatives are used alone as monotherapy Another aspect of the present invention is glucocorticoid for pulmonary administration. of the appropriate active substance and/or pharmaceutically acceptable relates to pharmaceutical composition(s) in which its derivatives are used alone as monotherapy.
Bulusta glukokortikoid grubunda yer alan uygun etken madde, bunlarla sinirli olmamakla birlikte, beklometazon, budesonid, flunisolid, betainetazoii, flutikazon, triamsinolon, mometazon, siklesonid ve/veya farmasötik olarak kabul edilebilir türevlerinin arasindan tercihen Flutikazon propionat olarak seçilir. The appropriate active ingredient in the glucocorticoid group in the invention is, but is not limited to, together, beclomethasone, budesonide, flunisolide, betainetazoii, fluticasone, triamcinolone, among mometasone, ciclesonide and/or pharmaceutically acceptable derivatives preferably Fluticasone propionate is selected.
Bulusta “farmasötik olarak kabul edilebilir türevleri” teriini ile farmasötik olarak kabul edilebilir uygun tuzlar, esterler, solvatlar, hidratlar, kompleksler, polimorflar, enantiyoinerler, önilaçlar, asit adisyon tuzlari, analoglar, izomerler, rasematlar, amidler, enantiyomer tuzlari, bazik tuzlar, konjugeler, tautomerler, anhidratlar, anhidritler, bazlar, asitler, eterler, kristal ve ainorf formlar veya serbest formlarindan bir veya daha fazlasi ifade edilmektedir. In the invention, the term "pharmaceutically acceptable derivatives" is defined as pharmaceutically acceptable. Suitable salts, esters, solvates, hydrates, complexes, polymorphs, enantioiners, prodrugs, acid addition salts, analogs, isomers, racemates, amides, enantiomer salts, basic salts, conjugates, tautomers, anhydrates, anhydrides, bases, one or more of acids, ethers, crystalline and amorphous forms or free forms is expressed.
Farmasötik bilesimler ölçülü doz inhalatör, kuru toz inhalatör veya nebülizasyon gibi inhalasyon yoluyla uygulanabilir. Pharmaceutical compositions such as metered dose inhaler, dry powder inhaler or nebulization It can be administered by inhalation.
Bulusta farinasötik etken maddeleri içeren inhalasyon yoluyla uygulama için hazirlanan farmasötik bilesimler solüsyon veya süspansiyon içeren nebül gibi bir dozaj formunda olabilir. Prepared for administration by inhalation containing pharmaceutical active ingredients in the invention. pharmaceutical compositions in a dosage form, such as a nebula containing a solution or suspension it could be.
Etken madde/ler, beraber ya da ayri ayri olacak sekilde, nebülizatörler ile uygulanmak üzere adapte edildigi zaman, nebülize edilmis sulu süspansiyon, solüsyon veya çözelti halinde, uygun pH veya toniklik ayarlamasi yapilarak veya bu ayarlamalar yapilmadan, tek birim dozluk veya çok dozluk bir araç halinde olabilir.Active ingredient/s to be administered together or separately with nebulizers nebulized aqueous suspension, solution, or solution case, with or without appropriate pH or tonicity adjustment. It may be in the form of a unit dose or multidose vehicle.
Mevcut bulusta pulmoner yolla uygulamaya yönelik farmasötik nebül formülasyonu; farmasötik olarak kabul edilebilir uygun etken madde/ler yaninda en az bir yüzey aktif/stabilize edici madde, en az bir pH ayarlayici/tamponlayici ajan, en az bir izotoni ayarlayici ajan ve çözücünün de dahil oldugu gruptan seçilen bir veya daha fazla yardimci madde içerebilen bir bilesimi tanimlar. The pharmaceutical nebula formulation for pulmonary administration in the present invention; at least one surface alongside suitable pharmaceutically acceptable active substance(s) active/stabilizing agent, at least one pH adjusting/buffering agent, at least one isotonia one or more auxiliary agents selected from the group that includes the setting agent and solvent defines a composition that can contain a substance.
Bulusta yüzey aktif/stabilize edici madde olarak; sorbitan trioleat, sorbitan moiiooleat, sorbitan monolaurat; polioksietilen (20) sorbitan monolaurat (polisorbat 20), polioksietilen (20) sorbitan monopalmitat (polisorbat 40), polioksietilen (20) sorbitan monostearat (polisorbat 60), polioksietilen (20) sorbitan monooleat (polisorbat 80) gibi polisorbatlar, polioksietileneter, stearil polioksietileneter, lauril polioksietileneter/oksietilen kopolimerleri, lauril polioksietileneter/oksipropilen kopolimerleri, sentetik lesitin, dietilen glikol dioleat, tetrahidrofurfuril oleat, etil oleat, gliseril inonooleat, polietilen glikol, gliseril monolaurat veya bunlarin karisimlari kullanilabilir. Bulusta tercihen polisorbat 20 ve sorbitan monolaurat kullanilmaktadir. Bulusta kullanilan yüzey aktif/stabilize edici Bulusta pH ayarlayici/tamponlayici ajan olarak; sülfürik asit, sitrik asit, hidroklorik asit, monosodyum fosfat dihidrat, susuz dibazik sodyum fosfat, sodyum klorür, borik asit, sodyum sitrat, sodyum karbonat, monosodyum fosfat dihidrat, dibazik sodyum fosfat anhidrus veya bunlarin karisimlari kullanilabilir. Bulusta tamponlayici olarak tercihen monosodyum fosfat dihidrat ve dibazik sodyum fosfat anhidrus kullanilmaktadir. Bulusta kullanilan pH ayarlayici/tamponlayici ajan miktari %001-10 tercihen %005-2 agirlik/hacim oranindadir. As a surfactant/stabilizing agent in the invention; sorbitan trioleate, sorbitan moiiooleate, sorbitan monolaurate; polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate polysorbates such as (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), polyoxyethyleneether, stearyl polyoxyethyleneether, lauryl polyoxyethyleneether/oxyethylene copolymers, lauryl polyoxyethyleneether/oxypropylene copolymers, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, glyceryl inonooleate, polyethylene glycol, glyceryl monolaurate or mixtures thereof may be used. In the invention preferably polysorbate 20 and sorbitan monolaurate are used. The surfactant/stabilizer used in the invention As a pH adjusting/buffering agent in the invention; sulfuric acid, citric acid, hydrochloric acid, monosodium phosphate dihydrate, anhydrous dibasic sodium phosphate, sodium chloride, boric acid, sodium citrate, sodium carbonate, monosodium phosphate dihydrate, dibasic sodium phosphate anhydrous or their mixtures can be used. Preferably as buffering agent in the invention monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous are used. in the find the amount of pH adjusting/buffering agent used is 001-10%, preferably 005-2% weight/volume ratio.
Bulusta “izotoni ayarlayici ajan” terimi; standart referans madde ile ayni osrnotik basinca sahip maddeleri ifade etmektedir. Tonisite maddesi iyonik (ör., NaCl) veya iyonik olmayan (ör., mannitol) tipte olabilir. Izotoni ayarlayici ajan olarak; sodyum klorür, gliserol, propilen glikol, mannitol, sorbitol, glukoz veya bunlarin karisimlari kullanilabilir. Bulusa göre formülasyonlar yaklasik pH 2-9 tercihen 5-7 arasinda bir pH degerine tamponlanir.The term "isotonia adjusting agent" in the invention; the same osmotic pressure as the standard reference substance denotes substances. Tonicity agent ionic (eg, NaCl) or non-ionic (eg, mannitol) type. As an isotonia adjusting agent; sodium chloride, glycerol, Propylene glycol, mannitol, sorbitol, glucose or mixtures of these can be used. find it According to the formulations, the formulations are buffered to a pH between approximately pH 2-9, preferably 5-7.
Bulusta tercihen sodyum klorür kullanilmaktadir. Bulusta kullanilan izotoni ayarlayici ajan miktari %0.01-5 tercihen %0. 1-3 agirlik/hacim oranindadir. Sodium chloride is preferably used in the invention. Isotonia adjusting agent used in the invention the amount is 0.01-5%, preferably 0%. It has 1-3 weight/volume ratio.
Bulusta çözücü olarak; laktoz, glikoz, rafinoz, melezitoz, laktitol, maltitol, trehaloz, sukroz, mannitol, nisasta, saflastirilmis su, enjeksiyonluk su, fizyolojik serum, sterilize damitilmis su gibi uygun sulu çözeltiler, propilen glikol, polietilen glikol, gliserol veya bunlarin karisimlari kullanilabilir. Bulusta tercihen enjeksiyonluk su kullanilmaktadir. As a solvent in the invention; lactose, glucose, raffinose, hybritose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, purified water, water for injection, physiological saline, sterilized suitable aqueous solutions such as distilled water, propylene glycol, polyethylene glycol, glycerol or mixtures of these can be used. Water for injection is preferably used in the invention.
Mevcut bulustaki Flutikazon ve/veya farmasötik olarak kabul edilebilir türevlerinin tek basina kullanildigi farmasötik bilesimleri için uygun olan forrnülasyonlarina ait doz araligi; ihtiyaçlarina ve uzmanin degerlendirmesine göre ayarlanmaktadir. Only one of the fluticasone and/or pharmaceutically acceptable derivatives of the present invention the dose range of formulations suitable for the pharmaceutical compositions for which it is used; adjusted according to their needs and expert judgment.
Mevcut bulustaki Flutikazon ve/veya farmasötik olarak kabul edilebilir türevlerini içeren farmasötik süspansiyon nebül formülasyonlarina ait partikül büyüklügü dm degeri 0.10um- Bulusta, Flutikazon ve/veya farmasötik olarak kabul edilebilir türevlerini içeren pulmoner yolla uygulamaya yönelik süspansiyon içeren farmasötik nebül formülasyonu asagidakileri içermektedir: - yaklasik %0001-5 agirlik/hacim oraninda Ilutikazon propiyonat - yaklasik %00001-3 agirlik/hacim oraninda bir veya daha fazla en az bir yüzey aktif/stabilize edici madde -yaklasik %001-10 agirlik/hacim oraninda bir veya daha fazla pH ayarlayici/tamponlayici ajan(lari) - yaklasik %0.01-5 agirlik/hacim oraninda bir veya daha fazla izotoni ayarlayici ajan - kafi miktar bir veya daha fazla ve çözücü(leri). containing Fluticasone and/or pharmaceutically acceptable derivatives of the present invention. particle size dm value of pharmaceutical suspension nebule formulations is 0.10um- The invention contains pulmonary fluticasone and/or its pharmaceutically acceptable derivatives. pharmaceutical nebula formulation containing suspension for administration by route includes: - approximately 0001-5% w/v of Iluticasone propionate - one or more at least one surface with a weight/volume ratio of approximately 00001-3% active/stabilizing agent -one or more pH adjusters/buffers at a weight/volume ratio of approximately 001-10% agent(s) - one or more isotonia adjusting agents at a weight/volume ratio of approximately 0.01-5% - sufficient quantity of one or more and solvent(s).
Bulus esas olarak pulmoner yolla kullanilmak üzere glukokortikoid grubunda yer alan uygun etken maddeyi ve/veya farmasötik olarak kabul edilebilir türevlerinin monoterapisini ve farmasötik olarak kabul edilebilir uygun yardimci maddeleri içeren farmasötik bilesim/lerin hazirlanmasi ile ilgilidir. Bulusun hazirlanan farmasötik bilesimlerinin süspansiyon içeren nebül gibi bir dozaj formunda olmasi temeldir. Böylece flutikazon ve/veya farmasötik olarak kabul edilebilir türevleri kullanilarak hazirlanan süspansiyon içeren nebül dozaj formunun oral ya da parenteral kullanima oranla daha az yan etki, solunum sistemi hastaliklarinin acil tedavisinde süratle etki göstermesi, ilaçlarin hedef alana daha iyi ulastirilabilmesi, hasta tarafindan kullaniminin daha kolay olmasi, alinan total dozun ve sistemik dagilimin minimuma indirilebilmesi, daha yüksek terapötik indeks ile sonuçlanmasi ve böylece yasam kalitesinin artmasi söz konusudur. Ayrica bulusta pH ayarlayici/tamponlayici ajanlar ve izotoni ayarlayici ajanlar kullanilarak, uygun tonisite ve pH ortaminda hazirlanan farmasötik bilesimlerin akcigerlere etkin iletim sekli ile maksimum terapötik yararlanim sagladigi gözlenmistir.The invention is mainly used in the glucocorticoid group for pulmonary use. appropriate active ingredient and/or pharmaceutically acceptable derivatives monotherapy and suitable pharmaceutically acceptable excipients. relates to the preparation of pharmaceutical composition(s). Invention prepared pharmaceutical It is essential that the compositions are in a dosage form, such as a suspension containing nebula. Like this prepared using fluticasone and/or pharmaceutically acceptable derivatives Nebule dosage form containing suspension is less than oral or parenteral use. side effects, rapid effect in the emergency treatment of respiratory system diseases, to reach the target area better, easier to use by the patient, minimizing the total dose taken and systemic distribution, higher therapeutic index resulting in an increase in the quality of life. Moreover using pH adjusting/buffering agents and isotonia adjusting agents in the invention, appropriate Effective delivery method of pharmaceutical compositions prepared in tonicity and pH environment to the lungs It has been observed that it provides maximum therapeutic benefit with
Bulusun özellikleri asagidakilerle sinirli kalmamak üzere örnekler asagida verilmistir: Flutikazon ve/veya farmasötik olarak kabul edilebilir türevlerini içeren pulmoner yolla uygulamaya yönelik süspansiyon içeren farmasötik nebül formülasyonu asagidakileri içermektedir: - yaklasik %0001-5 agirlik/hacim oraninda Ilutikazon propiyonat - yaklasik %00001-3 agirlik/hacim oraninda polisorbat 20 ve sorbitan moiiolaurat - yaklasik %0.01-10 agirlik/hacim oraninda monosodyum fosfat dihidrat ve dibazik sodyum fosfat anhidnis - yaklasik %001-5 agirlik/hacim oraninda sodyum klorür - kafi miktar en jeksiyonluk su Flutikazon ve/Veya farmasötik olarak kabul edilebilir türevlerini içeren pulmoner yolla uygulamaya yönelik süspansiyon içeren farmasötik nebül formülasyonu asagidakileri içermektedir: - yaklasik 0.01-10mg flutikazon propiyonat - yaklasik 0.001-3mg polisorbat 20 ve sorbitan monolaurat - yaklasik 0.1-45mg monosodyum fosfat dihidrat ve dibazik sodyum fosfat anhidrus - yaklasik 1-30mg sodyum klorür - kafi miktar en jeksiyonluk su Uretim prosesi: Flutikazon propiyonat, polisorbat 20, sorbitan monolaurat, sodyum klorür ve enjeksiyonluk su tartilir. Flutikazon propiyonat, polisorbat 20, sorbitan monolaurat, sodyum klorür ve enjeksiyonluk su homojenizatörde karistirilir. Homojenize edilmis konsantre karisim, otoklav sisesine transfer edilir ve sise otoklava alinir. Nemli isi sterilizasyonu (Otoklav) ile kütle (bulk) belirli bir süre 100-1400C araliginda ve uygun basinçta otoklavda sterilize edilir. Otoklavda sterilize edilmis konsantre karisim uygun ögütüeü ekipmanina transfer edilir ve optimize edilen parametreler altinda üretim (ögütme islemi) gerçeklestirilir.Examples of the features of the invention are given below, but not limited to the following: Pulmonary route containing fluticasone and/or its pharmaceutically acceptable derivatives pharmaceutical nebula formulation containing suspension for administration includes: - approximately 0001-5% w/v of Iluticasone propionate - polysorbate 20 and sorbitan moiolaurat at a weight/volume ratio of approximately 00001-3% - approx. 0.01-10% w/v monosodium phosphate dihydrate and dibasic sodium phosphate anhydride - sodium chloride approx. 001-5% w/v - sufficient amount of water for injection Pulmonary route containing fluticasone and/or pharmaceutically acceptable derivatives pharmaceutical nebula formulation containing suspension for administration includes: - about 0.01-10mg fluticasone propionate - about 0.001-3mg of polysorbate 20 and sorbitan monolaurate - approx. 0.1-45mg monosodium phosphate dihydrate and dibasic sodium phosphate anhydrous - about 1-30mg sodium chloride - sufficient amount of water for injection Production process: Fluticasone propionate, polysorbate 20, sorbitan monolaurate, sodium chloride and injectable water is weighed. Fluticasone propionate, polysorbate 20, sorbitan monolaurate, sodium chloride and water for injection is mixed in the homogenizer. Homogenized concentrated mixture, transferred to the autoclave flask and the flask is autoclaved. With moist heat sterilization (Autoclave) the mass (bulk) is sterilized in an autoclave at the appropriate pressure and in the range of 100-1400C for a certain period of time. is done. Transfer the concentrated mixture sterilized in autoclave to suitable grinding equipment. and production (grinding) is carried out under the optimized parameters.
Monosodyuin fosfat dihidrat, dibazik sodyum fosfat anhidrus ve en jeksiyonluk su karistirici ile karistirilir ve tampon çözelti elde edilir. Tampon çözelti uygun mikron araliktaki filtreden geçirilerek sterilize edilir ve süzülen çözelti tampon tankinda toplanir.Monosodium phosphate dihydrate, dibasic sodium phosphate anhydrous and injectable water It is mixed with a mixer and a buffer solution is obtained. Buffer solution suitable micron It is sterilized by passing through the filter in the range and the filtered solution is collected in the buffer tank.
Kullanilan uygun ögütüeü, filtreden geçirilmis olan tampon çözelti ile yikanir ve karistiei altinda uygun miktarda tampon Çözeltisi eklenerek Iinal hacim tamamlama gerçeklestirilir.The appropriate mill used is washed with filtered buffer solution and mixed. Inal volume completion is performed by adding the appropriate amount of buffer solution under it.
Final süspansiyonun pH degeri istenilen pH araliginda olmalidir. Final süspansiyon uygun siselere doldurulur ve siseler uygun saselere doldurularak ambalaj lanir.The pH value of the final suspension should be in the desired pH range. Final suspension fit It is filled in bottles and the bottles are packed in suitable bowls.
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