TR2023019879A2 - ORAL THIN FILM FORMULATIONS CONTAINING COLCHISINE AND FEBUXOSTAT NANOCRYSTALS TOGETHER - Google Patents
ORAL THIN FILM FORMULATIONS CONTAINING COLCHISINE AND FEBUXOSTAT NANOCRYSTALS TOGETHERInfo
- Publication number
- TR2023019879A2 TR2023019879A2 TR2023/019879 TR2023019879A2 TR 2023019879 A2 TR2023019879 A2 TR 2023019879A2 TR 2023/019879 TR2023/019879 TR 2023/019879 TR 2023019879 A2 TR2023019879 A2 TR 2023019879A2
- Authority
- TR
- Turkey
- Prior art keywords
- sodium
- formulation
- feature
- accordance
- febuxostat
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 49
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title claims description 39
- 229960005101 febuxostat Drugs 0.000 title claims description 39
- 239000002159 nanocrystal Substances 0.000 title claims description 17
- 239000010409 thin film Substances 0.000 title claims description 14
- 238000009472 formulation Methods 0.000 claims abstract description 46
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 claims abstract description 29
- 230000000694 effects Effects 0.000 claims abstract description 20
- 229960001338 colchicine Drugs 0.000 claims abstract description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- 239000002552 dosage form Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 23
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 15
- 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 14
- 229930195725 Mannitol Natural products 0.000 claims description 14
- 239000000594 mannitol Substances 0.000 claims description 14
- 235000010355 mannitol Nutrition 0.000 claims description 14
- 239000001814 pectin Substances 0.000 claims description 14
- 235000010987 pectin Nutrition 0.000 claims description 14
- 229920001277 pectin Polymers 0.000 claims description 14
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 13
- 235000010413 sodium alginate Nutrition 0.000 claims description 13
- 239000000661 sodium alginate Substances 0.000 claims description 13
- 229940005550 sodium alginate Drugs 0.000 claims description 12
- 235000011187 glycerol Nutrition 0.000 claims description 11
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 11
- 235000010234 sodium benzoate Nutrition 0.000 claims description 11
- 239000004299 sodium benzoate Substances 0.000 claims description 11
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims description 11
- 235000012141 vanillin Nutrition 0.000 claims description 11
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims description 11
- 239000008109 sodium starch glycolate Substances 0.000 claims description 10
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 10
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 10
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 10
- 239000012498 ultrapure water Substances 0.000 claims description 10
- 235000015165 citric acid Nutrition 0.000 claims description 9
- 239000013543 active substance Substances 0.000 claims description 8
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 8
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 8
- 229920000053 polysorbate 80 Polymers 0.000 claims description 8
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 235000015424 sodium Nutrition 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 7
- 239000010408 film Substances 0.000 claims description 7
- 229920000609 methyl cellulose Polymers 0.000 claims description 7
- 235000010981 methylcellulose Nutrition 0.000 claims description 7
- 239000001923 methylcellulose Substances 0.000 claims description 7
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 7
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 7
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 6
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 6
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- 229940044519 poloxamer 188 Drugs 0.000 claims description 6
- 229920001993 poloxamer 188 Polymers 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 229920002774 Maltodextrin Polymers 0.000 claims description 5
- 239000005913 Maltodextrin Substances 0.000 claims description 5
- 239000004373 Pullulan Substances 0.000 claims description 5
- 229920001218 Pullulan Polymers 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229940035034 maltodextrin Drugs 0.000 claims description 5
- 229960004063 propylene glycol Drugs 0.000 claims description 5
- 235000019423 pullulan Nutrition 0.000 claims description 5
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 claims description 4
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 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 4
- -1 PuIIuIan Polymers 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- 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 3
- 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 3
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims description 3
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 3
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- WEEGYLXZBRQIMU-UHFFFAOYSA-N 1,8-cineole Natural products C1CC2CCC1(C)OC2(C)C WEEGYLXZBRQIMU-UHFFFAOYSA-N 0.000 claims description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 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
- WEEGYLXZBRQIMU-WAAGHKOSSA-N Eucalyptol Chemical compound C1C[C@H]2CC[C@]1(C)OC2(C)C WEEGYLXZBRQIMU-WAAGHKOSSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
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- 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
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims description 2
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Abstract
Bu buluş, gut hastalığında ağrının ve inflamasyonun hızlı ve etkili bir şekilde tedavisinin gerçekleştirilmesinin yanı sıra yaşam konforlarını artırmaya yönelik geliştirilen, gut tedavisinde etkin bir şekilde kullanılmak üzere Kolşisin?i ve Febuksoksat?ın etkilerini sinerjistik olarak bir arada içeren, ağızda hızlı dağılan/çözünen ince filmler/stripler formülasyonları ile ilgilidir.This invention is a thin drug that is developed to provide rapid and effective treatment of pain and inflammation in gout as well as to increase life comfort, synergistically containing the effects of Colchicine and Febuxoxate for effective use in the treatment of gout, and quickly dispersing/dissolving in the mouth. It relates to films/strips formulations.
Description
TARIFNAME KOLSISIN iLE FEBUKSOSTAT NANOKRISTALLERINI BIR ARADA IÇEREN Teknik Alan Bu bulus, gut hastaliginda agrinin ve inflamasyonun hizli ve etkili bir sekilde tedavisinin gerçeklestirilmesinin yani sira yasam konforlarini artirmaya yönelik gelistirilen, gut tedavisinde etkin bir sekilde kullanilmak üzere Kolsisin”i ve Febuksoksat”in etkilerini sinerjistik olarak bir arada içeren, agizda hizli dagilan/çözünen ince filmler/stripler formülasyonlari ile ilgilidir. DESCRIPTION CONTAINING COLSISINE AND FEBUXOSTAT NANOCRYSTALS TOGETHER Technical Field This invention quickly and effectively relieves pain and inflammation in gout. aiming to increase the comfort of life as well as providing treatment Colchicine was developed to be used effectively in the treatment of gout and It is a rapid oral preparation that synergistically combines the effects of febuxoxate. It is related to dispersible/dispersible thin films/strips formulations.
Teknigin Bilinen Durumu Gut, monosodyum ürat kristallerinin hiperürisemi varliginda sinovyal eklemlerde ve diger dokularda birikmesiyle karakterize edilen otoinflamatuvar bir hastaliktir. Known Status of the Technique Gout, monosodium urate crystals in the synovial joints in the presence of hyperuricemia It is an autoinflammatory disease characterized by accumulation in tissues and other tissues.
Akut gut artrit alevlenmeleri, etkilenen eklemde hizli baslayan siddetli agri, sislik, sicaklik, eritem ve azalmis hareket ile karakterizedir. Kronik gut ise uzun süreli eklem iltihabi ile gelisen kemik erozyonlari ve kikirdak hasari olusumu ile karakterizedir. Acute gouty arthritis flares, rapid onset of severe pain in the affected joint, swelling, It is characterized by warmth, erythema and decreased movement. Chronic gout is long-term Bone erosions and cartilage damage that develop with arthritis is characterized.
Teknigin bilinen durumunda; gut tedavisinde iki strateji bulunmaktadir: J Ilk olarak nonsteroidal antiinflamatuvar ilaçlar (NSAII), kortikosteroidler, Kolsisin gibi oral tedaviler veya interlökin-1 inhibitörleri ile tedavi gelmektedir. In the known state of the technique; There are two strategies for treating gout: J Firstly, nonsteroidal anti-inflammatory drugs (NSAII), corticosteroids, Oral treatments such as colcisin or treatment with interleukin-1 inhibitors are available.
J Ikinci ve en önemli strateji ise ürati potansiyel olarak düsürmeye yönelik tedavilerdir. J The second and most important strategy is to potentially lower urate. are treatments.
Kolsisin, antiinflamauar ve analjezik ilaçlar arasinda yer almakla birlikte akut gutun sebep oldugu alevlenmelerin giderilmesinde endikedir. Ayni zamanda inflamasyonu baskiladigi da bilinmektedir. Ürat düsürücü tedaviler arasinda ksantin oksidaz inhibitörlerinin kullanimi da bulunmaktadir. Ksantin oksidaz inhibitörü olan Febuksostat, ürat birikiminin meydana geldigi gut hastaligi görülen eriskinlerde hiperüriseminin tedavisi için onaylanmistir. Ürat düsürücü ilaçlari alan hastalar alevlenmeleri önlemek için ayni anda NSAII'Ier, Kolsisin veya düsük doz kortikosteroidlerle birlikte tedaviler önerilmektedir. Febuksostat ve Kolsisin'in oral yoldan gut tedavilerinde günümüzde bir arada kullanimi tedavinin etkinligi açisindan önem kazanmistir. Kombine tedaviler daha iyi etki, daha az toksisite, daha etkin tedavi ve daha az ilaç direnci gelistirme potansiyeli olusturmaktadir. Ancak bu tedaviler daha çok kati dozaj sekilleri ile olmakla birlikte özellikle geriatrik ve pediatrik hastalar bu ilaçlari çignemekte veya yutmakta güçlük çekmektedirler. Ayrica bogulma korkusu yasayan disfajik (yutma güçlügü çeken) hastalar da bu kati dozaj formlarini almakta isteksizdirler. Although colchicine is among the anti-inflammatory and analgesic drugs, it is It is indicated for the relief of exacerbations caused by gout. At the same time It is also known to suppress inflammation. Among urate-lowering treatments There is also the use of xanthine oxidase inhibitors. xanthine oxidase Febuxostat, an inhibitor, is used for gout disease in which urate accumulation occurs. It is approved for the treatment of hyperuricemia in adults. Urate lowering Patients taking medications concurrently with NSAIDs, Colcisin to prevent exacerbations or combined treatments with low-dose corticosteroids are recommended. febuxostat and Colchisin are used together in oral gout treatments today. has gained importance in terms of the effectiveness of the treatment. Combined treatments have better effect, less toxicity, more effective treatment and less potential for developing drug resistance It constitutes. However, these treatments are mostly administered with strict dosage forms. However, especially geriatric and pediatric patients chew or consume these drugs. They have difficulty swallowing. Also dysphagic with fear of choking Patients (with difficulty swallowing) are also reluctant to take these solid dosage forms.
Bu ihtiyaci karsilamak için ilaç endüstrisi artik yenilikçi dozaj sekilleri tasarlama yönünde arastirmalarini hizlandirmistir. Bu dozaj sekillerinden birisi de agizda hizli dagilan/çözülen ince filmlerdir (OTF). OTF”ler su gereksinimi olmadan kullanilabilmeleri ve dil üzerine konulduklarinda kalinti birakmadan çözülüp dagilabilmeleri yönüyle hasta uyuncunu artiran dozaj sekilleri olarak günümüzde popülerligini artirmaktadir. Suda çözünürlügü olmayan ilaçlarin çözünürlügünü artirma stratejilerinden biri olan boyut küçültme teknikleri ilaçlarin biyoyararlanimini artirma yönünde büyük katki saglamaktadir. Bu stratejilerden biri de nanoteknolojinin kullanildigi nanokristallerdir. Özellikle suda çözünürlügü olmayan ilaçlarin boyutlarinin küçültülmesiyle birlikte artmis yüzey alani sayesinde biyoyararlanim da artirilmaktadir. To meet this need, the pharmaceutical industry is now designing innovative dosage forms. He accelerated his research in this direction. One of these dosage forms is oral administration. They are rapidly dispersing/dissolving thin films (OTF). OTFs without water requirement They can be used and dissolve without leaving any residue when placed on the tongue. Nowadays, they are dosage forms that increase patient compliance due to their ability to disperse. is increasing its popularity. The solubility of drugs that are not water-soluble Size reduction techniques, one of the strategies to increase the It makes a great contribution to increasing bioavailability. Of these strategies One of them is nanocrystals using nanotechnology. Particularly water solubility Increased surface area with decreasing size of non-drug drugs Thanks to this, bioavailability is also increased.
Gut hastaligi, yasam ve beslenme tarzi ile iliskili çesitli klinik tablolarla ortaya çikabilen bir hastaliktir. Ayni zamanda monosodyum ürat kristallerinin hiperürisemi varliginda sinovyal eklemlerde ve diger dokularda birikmesiyle karakterize edilen inflamatuar artropatidir. Hiperürisemiden kaynakli eklemlerde olusan ürik asit kristallerinin yigilmasiyla meydan gelen eklemlerde agri, kizariklik ve sislik belirtileri ile karakterizedir. Ürik asit kristalleri düsük sicakliklarda daha hizli çökelir, bu nedenle ayak parmaklari, el parmaklari, eller, ayaklar, dirsekler ve kulaklar gut alevlenmelerinin görüldügü ve yumusak dokularda (gut tofüs) ürik asit kristallerinin biriktigi bölgelerdir. Ürik asit kristalleri ayrica idrar yollarinda da birikme gösterebilir. Ürik asidin yaklasik üçte ikisi böbreklerde ve üçte biri bagirsaklardan atilir. Gout disease manifests itself with various clinical manifestations related to lifestyle and nutrition. It is a disease that can occur. At the same time, monosodium urate crystals It accumulates in synovial joints and other tissues in the presence of hyperuricemia. It is characterized by inflammatory arthropathy. In joints caused by hyperuricemia Pain and redness in the joints caused by the accumulation of uric acid crystals and is characterized by symptoms of fog. Uric acid crystals precipitate faster at lower temperatures, so foot fingers, fingers, hands, feet, elbows and ears for gout flares is seen and uric acid crystals accumulate in soft tissues (gouty tophi) regions. Uric acid crystals may also accumulate in the urinary tract. About two-thirds of uric acid is excreted in the kidneys and one-third in the intestines.
Normal fizyolojik pH'da, ürik asit iyonize ürat formunda dolasmaktadir. Gut, dokularda asemtomatik birikintiler, akut gut, kritik dönemler ve kronik gut olmak üzere 4 evreye ayrilir. Akut gut, yetiskin popülasyonda sik görülen bir inflamatuar artrittir. Akut gut artrit alevlenmeleri, etkilenen eklemde hizli baslayan siddetli agri, sislik, sicaklik, eritem ve azalmis hareket ile karakterizedir. Agri birincil belirti olmasina ragmen, akut gut artritinin etkili tedavisi hem agriyi hem de altta yatan iltihabi hedeflemelidir. Akut gut tedavisi dinlenme, buz uygulamasi ve oral NSAII, düsük doz Kolsisin veya kortikosteroidler ile yönetilebilir. At normal physiological pH, uric acid circulates in the form of ionized urate. Gout, asymptomatic deposits in tissues, acute gout, critical periods and chronic gout It is divided into 4 phases. Acute gout is a common inflammatory disease in the adult population. It is arthritis. Acute gouty arthritis flares, rapid onset of severe arthritis in the affected joint It is characterized by pain, swelling, warmth, erythema and decreased movement. Pain is the primary symptom Although effective treatment of acute gouty arthritis treats both the pain and the underlying should target inflammation. Treatment of acute gout is rest, ice application, and oral NSAIDs. It can be managed with low dose Colchicin or corticosteroids.
Gut ataklari arasindaki asemptomatik dönem kritik dönemdir. Bu dönem, aylar hatta yillar sürebilir. Ancak tedavisiz hastalarda ataklar daha sik, daha uzun ve daha siddetli olma egilimindedir. Kronik gut, istirahatte veya hareket halindeyken eklem agrisina yol açan uzun süreli eklem iltihabi ile karakterizedir. Kronik gut, kronik sinovit, kemik erozyonlari ve kikirdak hasari ile kendini gösterir. The asymptomatic period between gout attacks is the critical period. This period, months It may even take years. However, in untreated patients, attacks are more frequent, longer and It tends to be more severe. Chronic gout, at rest or while moving It is characterized by long-term joint inflammation leading to joint pain. chronic gout, Chronic synovitis manifests itself with bone erosions and cartilage damage.
Hiperürisemi devam ederse, monosodyum ürat kristal birikintileri ayrica, kronik gut aitriti veya kronik gut olarak adlandirilan, eklem yapilarinda hasara yol açabilen kronik inflamatuar yanitlari indükler. Gut hastaliginin yüksek insidansi ve mevcut tedavi yöntemlerinin zorluklari göz önüne alindiginda, hastalara uzun süreli ilaç kullaniminin neden oldugu agir ekonomik yükü ve siddetli fiziksel ve ruhsal agrilari azaltmak için yeni etkili ve güvenli gut tedavisi ilaçlari veya yeni tedaviler bulmak gerekmektedir. If hyperuricemia persists, monosodium urate crystal deposits may also form in chronic It causes damage to joint structures, called gout arthritis or chronic gout. It induces chronic inflammatory responses that can High incidence of gout and Considering the difficulties of current treatment methods, patients the heavy economic burden and severe physical and mental health problems caused by long-term drug use new effective and safe gout treatment drugs to reduce mental pain or new Treatments need to be found.
Gut tedavisi iki stratejiyi kapsar. Ilk olarak inflamatuar artritin NSAII, kortikosteroidler, Kolsisin veya interlökin-1 inhibitörleri ile tedavisidir. Ikinci ve en önemli strateji, ürat seviyesini 0,36 mmol/L (6 mg/dL) seviyesine düsürmektir. Gout treatment involves two strategies. First, inflammatory arthritis is caused by NSAII, Treatment with corticosteroids, colcisin or interleukin-1 inhibitors. second and most The important strategy is to reduce the urate level to 0.36 mmol/L (6 mg/dL).
Bunun için ürik asit düsürücü ilaçlar, ürik asit üretimini inhibe eden ilaçlar, ürik asit atilimini artiran ilaçlar ve gut gelisiminde önemli bir faktör olan ürik asit için ayristirici ilaçlar kullanilmaktadir. For this purpose, uric acid lowering drugs, drugs that inhibit uric acid production, uric acid for drugs that increase excretion and uric acid, which is an important factor in the development of gout. Disintegrating drugs are used.
Akut gut tedavisi NSAII'Ierin, Kolsisin veya kortikosteroidlerin hizli kullanimini içerir. Bunlar, erken baslandiginda, örnegin baslangiçtan sonraki ilk 24 saat içinde en etkilidir. Kronik gut tedavisinde ise ürikozürik ilaçlar, böbrekler yoluyla atilan ürik asit miktarini artirarak kan ürik asit düzeylerini düsürmeye çalisirlar. Ürik asit seviyelerinin düsürülmesi, gut alevlenmelerinden kaçinmanin anahtaridir. Allopurinol ve Febuksostat, tekrarlayan gutun önlenmesi için birinci basamak ilaçlardir. Kolsisin ve/veya Probenesid, birinci basamak ilaçlari tolere edemeyen veya birinci basamak ajanlarin etkisiz oldugu hastalar için tercih edilmektedir. Ürat düsürücü ilaçlari alan hastalar alevlenmeleri önlemek için ayni anda NSAII'Ier, Kolsisin veya düsük doz kortikosteroidlerle tedavi edilmelidir. Treatment of acute gout includes rapid use of NSAIDs, Colchicine or corticosteroids. Contains. These occur when started early, for example within the first 24 hours after starting. is the most effective. In the treatment of chronic gout, uricosuric drugs are administered through the kidneys. They try to reduce blood uric acid levels by increasing the amount of uric acid excreted. Lowering uric acid levels, avoiding gout flares is the key. Allopurinol and Febuxostat are the first choice for preventing recurrent gout. are step-by-step drugs. Colchicine and/or Probenecid are first-line medications tolerable. Preferred for patients who cannot undergo treatment or for whom first-line agents are ineffective. is done. Patients taking urate-lowering drugs should take the same precautions to prevent exacerbations. It should be treated immediately with NSAIDs, Colicine or low-dose corticosteroids.
Geleneksel antiinflamauar ve analjezik ilaçlar arasinda Kolsisin, NSAII'Ier ve glukokortikoidler de bulunmaktadir. Traditional anti-inflammatory and analgesic drugs include Colchicine, NSAIDs and Glucocorticoids are also present.
Kolsisin, Colchicum sp. cinsi bitkilerden ekstrakte edilen bir alkaloidtir. Kolsisin'in terapötik kullanimi gut ve ailevi akdeniz atesinde kanitlanmistir. Yüksek sitotoksisitesi nedeniyle dar bir terapötik indekse ve sik toksik reaksiyonlara yol açar. Kolsisin günde iki ila üç kez 0,5 mg dozda etkilidir. Gut profilaksisinde Kolsisin dozu, yetiskinlerde ve 16 yasindan büyük kisilerde günde bir veya iki kez Ürat düsürücü tedaviler, ksantin oksidaz inhibitörlerini, ürikozürik ajanlarini ve rekombinant ürikaz tedavilerini içermektedir. Ürat düsürücü tedavinin amaci, ürik asidin 6.8 mg/dL veya daha düsük bir subsatürasyon konsantrasyonu hedefine ulasilana kadar serum üratini azaltmaktir. Tedavi edilmeyen gut, ilerleyici monosodyum ürat kristal birikimine, eklem erozyonunun gelismesine ve kronik gut artrite yol açabilir. Bu nedenle, ürat düsürücü tedavinin yararlari vardir. Ürik asit (ürat) üretimini inhibe eden ksantin oksidaz inhibitörü ilaçlar arasinda allopurinol, febuksostat ve topiroksostat yer almaktadir. Colchicin, Colchicum sp. It is an alkaloid extracted from plants of the genus. of Kolsisin Its therapeutic use has been proven in gout and familial Mediterranean fever. High It has a narrow therapeutic index due to its cytotoxicity and causes frequent toxic reactions. opens. Colchicine is effective at a dose of 0.5 mg two to three times a day. In gout prophylaxis The dosage of colchicine is once or twice daily for adults and people over 16 years of age. Urate-lowering treatments include xanthine oxidase inhibitors, uricosuric agents, and Includes recombinant uricase treatments. The purpose of urate-lowering therapy is to acid to a subsaturation concentration target of 6.8 mg/dL or less. The aim is to reduce serum urate until it is reached. Untreated gout, progressive monosodium urate crystal deposition, development of joint erosion and chronic Gout can lead to arthritis. Therefore, urate-lowering therapy has benefits. Uric Xanthine oxidase inhibitor drugs that inhibit acid (urate) production include: allopurinol, febuxostat and topiroxostat.
Ksantin oksidaz inhibitörleri, esas olarak gut tedavisi için kullanilmaktadir. Ürik asit olusumunu azaltirlar ve böylece monosodyum ürat kristallerinin olusumunu engellerler. Hiperürisemi, kanda yaygin bir patoloji olan gut hastaligina yol açabilen yüksek ürik asit seviyeleri ile karakterize edilir. Ksantin oksidazin hem oksitlenmis hem de indirgenmis formlarinin pürin olmayan seçici bir inhibitörü olan Febuksostat, gut hastaliginda hiperüriseminin tedavisi için FDA tarafindan onaylanmistir. Xanthine oxidase inhibitors are mainly used to treat gout. Uric They reduce acid formation and thus prevent the formation of monosodium urate crystals. They prevent. Hyperuricemia causes gout, a common blood pathology. It is characterized by high levels of uric acid, which can cause Xanthine oxidazine heme A selective non-purine inhibitor of both oxidized and reduced forms Febuxostat is approved by the FDA for the treatment of hyperuricemia in gout. has been approved.
Febuksostat, ksantin oksidaz enzimin hem indirgenmis hem de oksitlenmis formuyla kararli bir kompleks olusturarak fonksiyonunu inhibe eder. Febuxostat acts on both reduced and oxidized enzymes, xanthine oxidase. It inhibits its function by forming a stable complex with its form.
Febuksostat'in günlük önerilen dozu 40 mg”dir. Febuksostat ürat birikiminin meydana geldigi kosullarda kronik hiperüriseminin tedavisi için kabul görmüstür. The daily recommended dose of febuxostat is 40 mg. Febuxostat prevents urate accumulation. It has been accepted for the treatment of chronic hyperuricemia when it occurs.
Intoleranslar, advers reaksiyonlar nedeniyle Allopurinol kullanamayan gut hastalarinda bir kullanim alani bulmaktadir. Ayni zamanda ilaç-ilaç etkilesimleri durumunda da kulanilabilmektedir. Ek olarak, kronik gutu olan veya çok yüksek serum ürik asit düzeyleri (10 mg/dL'den fazla) olan hastalarda allopurinole kiyasla Febuksostat'in daha yüksek potensinden sabit dozlarda yararlanabilir. Gout who cannot use Allopurinol due to intolerances, adverse reactions It finds a use in patients. Also drug-drug interactions It can also be used in such cases. Additionally, people with chronic gout or very high compared to allopurinol in patients with serum uric acid levels (greater than 10 mg/dL) May benefit from the higher potency of febuxostat in fixed doses.
Oral dozaj sekilleri içerisinde tabletler günümüzde kullanilan en yaygin uygulama sekli olmasina ragmen bazi dezavantajlari hasta uyuncunu zorlastirmaktadir. Among oral dosage forms, tablets are the most widely used today. Although it has a different form, some of its disadvantages make patient compliance difficult.
Bunlar arasinda zayif biyoyararlanim, zayif çözünürlük, sinirli etkinlik gibi özelliklerini sayilabilir. Yeni nesil dozaj sekilleri kullanilarak bu dezavantajlari büyük ölçüde ortadan kaldirilmasi, farmasötik bilesiklerin uygulanabilirliginin artirilmasi ve etkilerinin gelistirilmesi saglanabilir. Bu sayede, sudaki düsük çözünürlük sorunu düzeltilebilir, pH degisiklikleri tolere edilebilir, ilacin salim mekanizmasi kontrol edilebilir. Sonuç olarak kullanilan etkin madde miktari azaltilarak kullanim kolayligi saglanir, görülen yan etkileri azaltilir ve/veya ortadan kaldirilir. Bu sayede hasta uyuncu ve yasam konforu artirilabilir. Bu sistemler arasinda nanoteknoloji kullanilarak nanopartikül hazirlanmasi üzerine oldukça fazla çalisilma bulunmaktadir. These include poor bioavailability, poor solubility, and limited efficacy. features can be listed. These disadvantages are eliminated by using new generation dosage forms. largely eliminated, impairing the applicability of pharmaceutical compounds can be increased and its effects can be improved. In this way, low water solubility problem can be corrected, pH changes can be tolerated, drug release mechanism can be controlled. As a result, the amount of active ingredient used provides ease of use, reduces side effects and/or is eliminated. In this way, patient compliance and life comfort can be increased. This On the preparation of nanoparticles using nanotechnology among systems There is quite a lot of work to be done.
Nanoteknoloji kullanilarak hazirlanan bu sistemlerden nanosüspansiyonlar, suda çözünürlügü az olan etkin maddeler için verilmesi en uygun dozaj formlari haline gelmistir. Yüksek miktarda ilaç içermesi (neredeyse %100) sayesinde birçok avantaj saglamaktadir. Bunlar arasinda yeterli terapötik konsantrasyona ulasmak, hücrelere girecek olan ilaçlarin verimli bir sekilde tasinmasini saglamak ve farmakolojik etkinligi arttirmak sayilabilir. Ayrica nanopartiküller kullanilarak geleneksel dozaj sekilleriyle verildiginde toksisite olusturan ilaçlarin yan etkilerini azaltilabilmektedir. Bu sebeple bulus ile Febuksostat'in suda çözünürlügü düsük olmasi sebebiyle biyoyararliligini artirmak adina nanosüspansiyonlari (nanopartikülleri, nanokristalleri) hazirlanmistir. Nanosuspensions, one of these systems prepared using nanotechnology, are into the most suitable dosage forms for active substances with low solubility. has arrived. Thanks to its high amount of medicine (almost 100%), it is It provides an advantage. Among these, reaching adequate therapeutic concentration, to ensure efficient transport of drugs that will enter the cells and It can be considered as increasing pharmacological effectiveness. Also using nanoparticles Side effects of drugs that cause toxicity when given in traditional dosage forms can be reduced. For this reason, with the invention, Febuxostat has low water solubility. Nanosuspensions are used to increase bioavailability due to (nanoparticles, nanocrystals) have been prepared.
Ilaç uygulama yollarindan oral yol, uygulama kolayligi yaninda hasta uyuncunun yüksek ve kabul edilebilirliginden dolayi en çok kullanilan ilaç uygulama yollarindan birisidir. Ancak, oral uygulama geriatri, pediatri, yatalak, anksiyete ve panik bozuklugu olan hastalarda yutma zorlugu, bogulma, mide bulantisi gibi uyumsuzluklara sebep oldugundan oral yoldan uygulanabilecek alternatif yöntemler gelistirilmeye baslanmistir. Basta yutma zorlugunun üstesinden gelmek için 1970'lerin sonlarina dogru hizli çözünen oral uygulama sistemleri ve agizda dagilan ince film (strip) fikri ortaya çikmistir. tablet/kapsül yutmanin getirdigi psikolojik faktörlerin de ortadan kaldirilmasi önemlidir. Bunun disinda konvansiyonel kati dozaj sekillerinin (tablet, kapsül) su gerektirmeden kullanilabilmesi mümkün degildir. Yolculuk esnasinda ya da suya ulasilamayan durumlarda kullanilamamaktadirlar. Bunun yani sira asil konvansiyonel bu dozaj sekillerinin majör dezavantaji ise ilacin farmakolojik etkilerinin hemen görülememesidir. Mideye ulasip çözünüp/dagilmasi için geçen süre ile farmakolojik etkinin ortaya çikmasi ortalama olarak en erken 30-60 dakikayi bulmaktadir. Farmakolojik etkinin bir an evvel baslanmasi istenen durumlarda ise konvansiyonel tablet ve kapsüller yetersiz kalmaktadir. Among the drug administration methods, the oral route is not only easier to administer but also improves patient compliance. It is the most commonly used drug application due to its high and acceptability. is one of the ways. However, oral administration is used in geriatrics, pediatrics, bedridden, anxiety and Difficulty swallowing, choking, nausea in patients with panic disorder An alternative that can be administered orally is recommended as it causes incompatibilities. methods have begun to be developed. Overcome difficulty in swallowing Towards the end of the 1970s, rapidly dissolving oral delivery systems and The idea of a thin film (strip) that disperses in the mouth has emerged. Elimination of psychological factors caused by swallowing tablets/capsules It is important. Apart from this, conventional solid dosage forms (tablets, capsules) It is not possible to use it without requiring it. While traveling or on the water They cannot be used in inaccessible situations. Besides this, the main The major disadvantage of these conventional dosage forms is that the drug The effects are not immediately visible. It takes time to reach the stomach and be dissolved/dispersed. On average, the earliest time for the pharmacological effect to appear is 30-60 days. minutes. The pharmacological effect is desired to begin as soon as possible In some cases, conventional tablets and capsules are insufficient.
Sonuç olarak eski teknik/yöntemdeki eksiklikler: J Kolsisin ve Febuksostat”in kombine olarak herhangi bir dozaj seklinde ilaç pazarinda olmayisi, J Gelenekesl ilaçlar ile hizli ve etkili bir tedavinin alinamamasi, J Geleneksel ilaçlar ile daha yüksek doz ilaçlarin kullanimina bagli olarak daha sik ve/veya yüksek yan ve/veya toksik etkilerin ortaya çikma olasiligi, J Bu etkin maddeleri ayri ayri konvansiyonel dozaj sekilleri ile kullanmak zorunda olmak, J Febuksostat'in oral aliminda biyoyararlaniminin düsük olmasi ve bu yüzden istenen etkiyi göstermesi için yüksek dozda uygulanmasi gerekliligi, J Gut hastaliginda yasam konforunu artiran yeni nesil kombine ürünlerin olmayisi, J Gut hastalarinda inflamasyonun ve agrinin önlenmesinin yani sira ürik asit birikiminin önlenmesi için tek bir ürünün olmayisi. As a result, the shortcomings of the old technique/method: J Colcisin and Febuxostat should not be used in combination in any dosage form. not being in the market, J Inability to receive fast and effective treatment with traditional medicines, J Due to the use of traditional medicines and higher doses of medicines, the possibility of frequent and/or high side and/or toxic effects, J Using these active ingredients separately with conventional dosage forms have to, J Febuxostat has low bioavailability when taken orally and therefore The need to apply high doses to show the desired effect, J New generation combined products that increase life comfort in gout disease not to be, J Prevention of inflammation and pain as well as uric acid reduction in gout patients There is no single product to prevent accumulation.
J Pediatrik, geriatrik bireyler ile bazi yetiskinler, kati dozaj formlarini yutma veya çignemekte güçlük çekmektedirler. Bu bireylerin bogulma korkusu nedeniyle kati dozaj sekillerini (tablet, kapsül) alma konusunda isteksiz oluslari, J Geleneksel dozaj sekilleri ile kisisellestirilmis ya da daha düsük doz ile tedaviyi saglayamamak, J Iki ilaç etkin maddesini içeren iki ayri ilaci ayri ayri almanin ekonomik dezavantaji, J Suya erisimin olmadigi durumlarda konvansiyonel ilaçlarin kullanilamamasi mevcut yöntem ve/veya teknikteki önemli eksikliklerdendir. J Pediatric, geriatric individuals and some adults may not swallow solid dosage forms. or they have difficulty chewing. These individuals have a fear of drowning Reluctance to take strict dosage forms (tablets, capsules) due to their occurrence, J Personalized with traditional dosage forms or with lower dosage failure to provide treatment, J It is not economical to take two separate drugs containing two active substances separately. disadvantage, J Inability to use conventional drugs when there is no access to water It is one of the important deficiencies in the current method and/or technique.
Bulusun Açiklamasi Bu açiklamada, gut hastaliginda agrinin ve inflamasyonun hizli ve etkili bir sekilde tedavisinin gerçeklestirilmesinin yani sira yasam konforlarini artirmaya yönelik gelistirilen, gut tedavisinde etkin bir sekilde kullanilmak üzere kolsisin ile febuksostat nanokristallerini bir arada içeren oral ince film formülasyonlari hiçbir sinirlayici etki olusturmayacak sekilde açiklanmaktadir. Description of the invention In this explanation, it is a rapid and effective treatment of pain and inflammation in gout. In addition to providing appropriate treatment, it also aims to increase their living comfort. with colchicine, which was developed for effective use in the treatment of gout. Oral thin film formulations containing febuxostat nanocrystals have no It is explained in a way that does not create a limiting effect.
Bulusun yapisal ve karakteristik özellikleri ve tüm avantajlari asagida yazilan açiklama sayesinde daha net olarak anlasilacaktir ve bu nedenle degerlendirmenin de bu açiklama göz önüne alinarak yapilmasi gerekmektedir. The structural and characteristic features and all the advantages of the invention are listed below. will be understood more clearly thanks to the explanation and therefore The evaluation should be made taking this explanation into consideration.
Mevcut bulus; yukarida bahsedilen gereksinimleri karsilayan, tüm dezavantajlari ortadan kaldiran ve ilave bazi avantajlar getiren kolsisin ile febuksostat nanokristallerini bir arada içeren oral ince film formülasyonlari ile ilgilidir. Present invention; meeting the above-mentioned requirements, with all the disadvantages febuxostat with colchicine, which eliminates It is related to oral thin film formulations containing nanocrystals together.
Bulusun öncelikli amaci; oral ince film formunda olmasi sebebiyle daha hizli etki baslangici sunmasinin yani sira gut hastalarinda inflamasyonun ve agrinin önlenmesinin yani sira ürik asit birikiminin önlenmesi için disfajik, geriatrik, yatalak veya mental engelli hastalarin dahi ihtiyaç duyduklari her an ve her ortamda yutma gereksinimi olmadan, suya ihtiyaç duymadan ilaçlarini konforlu bir sekilde kullanabilmelerini saglamak üzere gelistirilmistir. The primary purpose of the invention is; Faster effect due to being in oral thin film form In addition to providing the beginning, it also reduces inflammation and pain in gout patients. To prevent uric acid accumulation as well as dysphagic, geriatric, Even bedridden or mentally disabled patients whenever and wherever they need You can take your medications comfortably without the need for swallowing or water in the environment. It has been developed to enable users to use it in different ways.
Bulusunbir diger amaci iki ilaç etkin maddesini içeren bir arada içermesi ile iki ayri ilaca harcanan maliyetin azaltilmasidir. Another purpose of the invention is to combine two active pharmaceutical ingredients and is to reduce the cost spent on separate drugs.
Yukarida anlatilan amaçlarin yerine getirilmesi için bu bulus, Febuksostat nanokristalleri ve Kolsisin kombinasyonunu içeren oral ince film dozaj formunda formülasyonlari içermektedir. In order to fulfill the purposes described above, this invention uses Febuxostat In oral thin film dosage form containing combination of nanocrystals and Colcisin Contains formulations.
Bulus ile nanoteknoloji kullanilarak suda çözünürlügü olmayan Febuksostat nano boyuta indirilerek daha düsük dozda bu ilacin kullanilabilmesine imkan saglanmistir. Ayni zamanda her iki ilaç etkin maddesinin bu ilaç dozaj formunun getirdigi avantajlar ile absorpsiyonlari ve dolayisiyla biyoyararliliklarinin artirilmasi amaçlanmistir. Hasta uyuncunu kolaylastiracak ve farmakolojik etkileri hizlandiracak yenilikçi bir dozaj formu (OTF) seklinde tasarlanan bu formülasyon prematür ejakülasyon ve erektil disfonksiyon hastalarinin yasam standardini ve konforunu aitiracaktir. With the invention, Febuxostat nano, which is not soluble in water, was produced using nanotechnology. It can be reduced to a smaller size, allowing the use of this drug in lower doses. has been provided. At the same time, both drug substances are present in this drug dosage form. With the advantages it brings, its absorption and therefore bioavailability It is intended to increase. It will facilitate patient compliance and its pharmacological effects This formulation is designed as an innovative dosage form (OTF) that will accelerate the standard of living of premature ejaculation and erectile dysfunction patients and It will increase your comfort.
Dünya ilaç pazarinda kullanimda olan dozaj sekilleri incelendiginde bu iki etkin maddeyi de ayni anda içeren ve hizli bir etki baslangici sunan ilaç dozaj formu ne ülkemiz ve dünya ilaç pazarinda ne de literatür çalismalarinda yer almaktadir. When the dosage forms in use in the world pharmaceutical market are examined, these two effective What is the drug dosage form that simultaneously contains the substance and offers a rapid onset of action? It is not included in our country's and world's pharmaceutical market nor in literature studies.
Birçok farmasötik preparat, tablet, granül, toz ve sivi formda uygulanmaktadir. Many pharmaceutical preparations are administered in tablet, granule, powder and liquid forms.
Genel olarak tablet tasarimi hastalara kesin bir ilaç dozu vermek amaciyla yutulan veya çignenen bir formdadir. Bununla birlikte bazi hasta gruplari, özellikle pediatrik ve geriatrik hastalar, kati dozaj formlarini yutma veya çignemekte güçlük çekmektedirler. Birçok pediatrik ve geriatrik hasta, bogulma korkusu nedeniyle bu kati dozaj sekillerini alma konusunda isteksizdir. In general, tablet design is designed to give patients a precise dose of medication. It is in a form that can be swallowed or chewed. However, some patient groups, especially Pediatric and geriatric patients have difficulty swallowing or chewing solid dosage forms They are suffering. Many pediatric and geriatric patients do this due to fear of suffocation. Reluctant to take rigid dosage forms.
Tabletler tüm oral dozaj formlari içerisinde yüksek doz homojenligi saglayabilen ve en iyi içerik tekdüzeligine sahip dozaj formudur. Ayrica tüm oral dozaj formlarinin içerisinde en uygun üretim maliyetine sahip dozaj formu da tabletlerdir. Ancak çocuk ve yasli popülasyon için uygulanmasi güç olan bu yöntem, oral yoldan kullanilabilecek yeni bir ilaç formuna ihtiyaç oldugunu göstermistir. Tablets can provide high dose homogeneity in all oral dosage forms. and is the dosage form with the best content uniformity. Also all oral dosage Among the forms, the dosage form with the most affordable production cost is also They are tablets. However, this is difficult to apply for children and the elderly population. The method shows that there is a need for a new drug form that can be used orally. has shown.
Teknolojideki son gelismeler tablet ve kapsül gibi kati dozaj formundaki ilaçlari yutmakta zorluk çeken (disfaji) hastalar için yeni nesil “Oral Ince Film” ler (OTF) gibi alternatif dozaj sekilleri gelistirmeye baslamistir. Latest developments in technology have enabled drugs in solid dosage forms such as tablets and capsules. New generation "Oral Thin Films" (OTF) for patients with difficulty swallowing (dysphagia) Alternative dosage forms such as have begun to be developed.
Bugün gelinen noktada pek çok reçeteli ve reçetesiz ürün grubunda özellikle öksürükte, soguk alginliginda, bogaz agrilarinda, erektil disfonksiyon bozukluklarinda, alerjik reaksiyonlarda, astimda, gastrointestinal bozukluklarda, hipertansiyonda, agri tedavilerinde, horlama sikâyetlerinde, uyku problemlerinde, multivitamin kombinasyonlarinda OTF'lerin kullanimlari giderek artmakta ve ilaç endüstrisi tarafindan konvansiyonel ilaçlarin OTF'ye dönüsümleri de devam etmektedir. At this point today, many prescription and non-prescription product groups, especially cough, cold, sore throat, erectile dysfunction disorders, allergic reactions, asthma, gastrointestinal disorders, in hypertension, pain treatments, snoring complaints, sleep problems, The use of OTFs in multivitamin combinations is increasing and Conversion of conventional drugs to OTF by the industry continues. It does.
Bu yeni nesil dozaj formu ile disfaji de denilen yutma güçlügü çeken tüm yas gruplarindaki hastalar için, tablet/kapsül kullanmanin olusturdugu psikolojik faktörlerin de ortadan kaldirilmasi hedeflenmektedir. Bunun yani sira su gerektirmeden kullanilabilmesi ile yolculuk esnasinda ya da suya ulasilamayan durumlarda dahi kolaylikla ilacin kullanimi gerçeklestirilebilmektedir. Asil bu dozaj seklinin sundugu majör avantaj ise ilacin farmakolojik etkilerinin hemen görülmesidir. Gelistirdigimiz formülasyonlarimiz içerisinde Febuksostat'in nanokristallerini ve Kolsisin'l bir arada ince film formülasyonu halinde sunmanin avantaji mümkün olacaktir. Özellikle yanak içi ve dil altindan geçen kilcal damarlar vasitasiyla agizda hizli bir dagililma ya da çözünmeye ugrayan bu dozaj sekli içerisindeki etkin maddelerin kana hizla karismasi ve farmakolojik etkinin hizli bir biçimde baslatilmasi da söz konusu olacaktir. With this new generation dosage form, all ages with difficulty swallowing, also called dysphagia, For patients in the groups, the psychological effects of using tablets/capsules It is also aimed to eliminate these factors. That means water It can be used without needing to be used during travel or when water is not accessible. Even in such situations, the drug can be used easily. This is the main dosage The major advantage offered by the form is that the pharmacological effects of the drug are immediate. is to be seen. Febuxostat is among the formulations we have developed. Presenting nanocrystals and Colsisin together in thin film formulation advantage will be possible. Especially the capillaries passing inside the cheek and under the tongue This substance undergoes rapid dispersion or dissolution in the mouth via veins. rapid mixing of the active substances in the dosage form into the blood and pharmacological There will also be a rapid onset of effect.
Daha düsük doz Febuksostat nanokristalleri ile etkin bir tedavi sunmanin yani sira etkin maddelerden kaynakli yan etkileri azaltmak ve/veya en aza indirmek de mümkün olabilecektir. Gastrointestinal sisteme geçmeden önce agiz içerisnde tamamen çözünmüs ve dagilmis olan bu ilaç formülasyonu ile ilk geçis etkisi ve mide bagirsak sistemindeki absorpsiyondan kaynakli gecikmelerin de önü alinmis olacaktir. Offering an effective treatment with lower doses of Febuxostat nanocrystals, i.e. as well as to reduce and/or minimize side effects caused by active ingredients. may be possible. In the mouth before passing into the gastrointestinal system With this drug formulation that is completely dissolved and dispersed, the first pass effect and Delays due to absorption in the gastrointestinal system are also prevented It will happen.
OTF sistemleri, agiza yerlestirildiginde 1 dakika içinde parçalanan/çözünebilen/dagilabilen; çigneme, yutma ve su gereksinimi duyulmadan kullanilabilen kati dozaj formlardir. OTF'ler, hidrofilik polimerler kullanilarak hazirlanan, dil üstüne veya tabanina yerlestirilerek kullanilan, tükürük ile temasta hizli bir çözünme saglayan birkaç mikron kalinliginda ilaç formülasyonlaridir. Amerikan Ilaç ve Gida Dairesi (FDA) ise OTF'yi, bir veya daha fazla etkin madde içeren, gastrointestinal sisteme geçmeden önce dil üzerine yerlestirilerek tükürük içinde hizlica çözünen/parçalanan esnek ve kirilgan olmayan bir serit ifadeleriyle tanimlanmaktadir. OTF'ler pekçok essiz avantaja sahiptir. OTF systems are delivered within 1 minute when placed in the mouth. degradable/soluble/dispersible; chewing, swallowing and water requirements They are solid dosage forms that can be used invisibly. OTFs, hydrophilic polymers It is prepared using saliva and is placed on or at the base of the tongue. A drug with a thickness of a few microns that provides rapid dissolution upon contact with formulations. The American Food and Drug Administration (FDA) defines OTF as one or more It contains a lot of active ingredients and is applied to the tongue before passing into the gastrointestinal tract. flexible and fragile material that quickly dissolves/disintegrates in saliva after being placed in A non-existent strip is defined by the expressions. OTFs have many unique advantages. has.
Bunlar arasinda: J Pratiktirler, J pH 'ya duyarli ilaçlar için gelistirilmis stabilite sergilerler, J Suya erisimin mümkün olmadigi durumlarda dahi (seyahat gibi) güvenle kullanilabilirler, J Bogulma riski yoktur, J Gelistirilmis stabilite sergilerler, J Uygulamalari kolaydir, J Zihinsel ve uyumsuz hastalara kolay uygulama olanagi saglarlar, J Uygulamadan sonra agizda çok az kalinti birakir veya hiç birakmazlar, J Gastrointestinal sistem atlanmis olur ve böylece ilaçlarin biyoyararlanimi J Düsük dozda ilaç uygulanmasina olanak saglarlar ve böylece yan etki görülmesini azaltirlar, J Sivi dozaj formlarina göre daha dogru dozlama saglarlar, J Agizda hos bir his birakirlar, J Acil müdahale gerektiren durumlarda farmakolojik etkilerin hizli baslamasini J Ilaçlarin emilim oranini ve miktarini artirirlar, J Özellikle hizli çözünürken genis bir yüzey alani saglayarak suda daha az çözünen ilaçlar için gelismis biyoyararlanim saglarlar, J Konusma ve içme gibi normal fonksiyonlari engellemezler, J Gastrointestinal sistemde bozulma riski yüksek olan ilaçlarin uygulanmasini J Genisleyen bir pazara ve ürün çesitliligine sahiptirler, 12-16 ay içinde gelistirilip piyasaya sürülebilirler, J Suda çözünmeyen hidrofobik ilaçlar için uygulanabilir olmasi ve biyoyararlanimlarini artirmasi sayilabilir. Among them: J They are practical, J They exhibit improved stability for pH sensitive drugs, J Safely even in situations where access to water is not possible (such as travelling) can be used, J There is no risk of drowning, J They exhibit improved stability, J Applications are easy, J They provide easy application to mentally ill and incompatible patients, J They leave little or no residue in the mouth after application, J The gastrointestinal tract is bypassed and thus the bioavailability of drugs is reduced. J They enable the administration of low doses of medication and thus prevent side effects. They reduce the visibility of J They provide more accurate dosing than liquid dosage forms, J They leave a pleasant feeling in the mouth, J Rapid onset of pharmacological effects in situations requiring urgent intervention. J They increase the absorption rate and amount of drugs, J It dissolves less in water by providing a large surface area, especially while dissolving quickly. They provide improved bioavailability for soluble drugs, J They do not interfere with normal functions such as speaking and drinking. J Do not administer drugs that have a high risk of disruption in the gastrointestinal tract. J They have an expanding market and product diversity, They can be developed and launched within 12-16 months, J Applicable for water-insoluble hydrophobic drugs and may be considered to increase their bioavailability.
Söz konusu bulus ile mevcut durumdaki eksiklik ve/veya dezavantajlari asabilmek adina, OTF dozaj sekliyle nanopartiküler ilaç tasiyici sitemleri birlestirmek; farmakolojik aktiviteyi hizlandirmak; biyoyararlanimini artirmak; ilacin oral kullaniminda görülen karacigerden ilk geçis etkisini atlayarak istenen etkiyi daha düsük dozda olusturmak; bu sayede, vücutta olusmasi muhtemel yan etkileri önemli ölçüde azaltmak; kullanilan etkin madde miktarini azaltmaya bagli olarak formülasyon maliyetini düsürmek ve hastanin ilaca ulasabilirligini kolaylastirmak getirilen yenilikler arasinda yer almaktadir. The invention in question and its shortcomings and/or disadvantages in the current situation In order to exceed this, nanoparticulate drug delivery systems with OTF dosage form are used. to connect; accelerate pharmacological activity; increase bioavailability; desired effect by bypassing the first pass effect through the liver seen in oral use of the drug. creating the effect at a lower dose; In this way, possible side effects that may occur in the body significantly reduce impacts; Depends on reducing the amount of active ingredient used to reduce the cost of formulation and increase the patient's accessibility to the drug. Making it easier is among the innovations introduced.
Sonuç olarak gut hastaliginda sik kullanilan iki etkin maddeyi tek bir kombine ilaç formu halinde getirmek, farmakolojik etkiyi hizlandirmak, komorbiteli hastlarda gastrointestinal sistemin üzerindeki yükü azaltip yan etkiyi en aza indirmek, iki ilaci ayri ayri almanin ekonomik açidan dezavantajini gidermek, kati dozaj sekillerini yutma güçlügü çeken veya mental problemi olan hastalar için alternatif bir dozaj formu tasarlamak, suya erisimin olmadigi durumlarda dahi güvenle ilaci kullanabilmek ve hepsinden önemlisi gut hastalarinin yasam standardini artiracak yeni bir ilaç tasiyici sistem formülasyonu gelistirmek adina yeni nesil OTF formülasyonlari gelistirilmistir. Böylece Kolsisin ve Febuksostat ilk kez bir arada bir dozaj formu içerisinde formülize edilmistir. As a result, two active substances frequently used in gout are combined into a single combined drug. form, accelerate the pharmacological effect, in patients with comorbidities reducing the burden on the gastrointestinal system and minimizing side effects, two To eliminate the economic disadvantage of taking the drug separately, solid dosage Alternative for patients who have difficulty swallowing or have mental problems Designing a dosage form allows you to administer the drug safely even in situations where there is no access to water. to be able to use it and, most importantly, to increase the standard of living of gout patients. In order to develop a new drug delivery system formulation, new generation OTF formulations have been developed. Thus, Colsisin and Febuxostat together for the first time It is formulated in a dosage form.
Oral ince film formunda olan bulus dilin ucuna veya tabanina yerlestirilir ve tükürük ile 30-60 saniye içerisinde islanir. Bu sekilde, filmde bulunan etkin maddeler serbestleserek lokal ve/veya sistemik absorpsiyon için dagilir ve/veya çözünür. Gelistirilen bulus ile her iki etkin maddeyi de ayni anda içeren ve hizli bir etki baslangici sunan ilaç dozaj formlari hazirlanmistir. The invention, which is in the form of an oral thin film, is placed on the tip or base of the tongue and It gets wet with saliva within 30-60 seconds. In this way, the effective substances are released and distributed for local and/or systemic absorption and/or soluble. With the developed invention, it contains both active substances at the same time and is produced in a rapid way. Drug dosage forms that offer onset of action have been prepared.
Bulus ile gelistirilen formülasyon içerisinde kullanilan tüm yardimci maddeler suda çözünmekte veya dispers olabilmektedir. Febuksostat ise Poloxamer 188 ve Sodyum Lauril Sülfat (SLS) yüzey aktif maddelerin varliginda sahip olacak sekilde nanokristaller halinde formülasyonlarda kullanilmistir. Yani hazirlanan bu OTF”ler dilaltina veya ucuna yerlestirildiginde tükürük ile çok çabuk bir sekilde çözünmektedir. Dolayisiyla hizli bir etki alinabilmesi, suya ihtiyaç duyulmadan ve yutma güçlügü yasanmadan kullanilabilmesi mümkün olmaktadir. All excipients used in the formulation developed with the invention It can be soluble or dispersed in water. Febuxostat is Poloxamer 188 and In the presence of Sodium Lauryl Sulfate (SLS) surfactants It has been used in formulations in the form of nanocrystals. Well When these prepared OTFs are placed under the tongue or at the tip, they are absorbed very quickly by saliva. It dissolves in some way. Therefore, to get a quick effect, water is required. It is possible to use it without being heard or having difficulty swallowing.
Bu sayede hem hizli bir etki baslangici ortaya çikmakta hem de hastanin sikayetleri kisa sürede karsiligini bulmaktadir. Çünkü, dilalti mukozasinin ince membran yapisi ve oldukça fazla kan damarina sahip olmasi sebebiyle permeabilitesi yüksektir. Bu hizli kanlanma sebebiyle çok çabuk bir biyoyararlanim söz konusudur. Mide-bagirsaktan emilim (absorpsiyon) kismi atlandigi için karacigerden ilk geçis etkisi de ortadan kalkmis olmaktadir. Bu hizli biyoyararlanim, ilk geçis etkisinin atlanmasindan ve daha iyi permeabiliteden kaynaklidir. Ayrica emilim için genis yüzey alani ve uygulama kolayligi, sistemik ilaç tasinmasinda oral mukozayi çok etkili ve seçici bir yol yapmaktadir. Bu sayede gut hastalarinda inflamasyonun ve agrinin önlenmesinin yani sira ürik asit birikiminin kisa süre içerisinde önlenmesi, bu ilaçlari kombine halde dil üstüne veya altina koyarak su gerektirmeden kolayca alabilmeleri saglanir. In this way, a rapid onset of effect occurs and the patient's Their complaints are responded to in a short time. Because the sublingual mucosa is thin Due to its membrane structure and having a lot of blood vessels It has high permeability. Due to this rapid blood flow, it occurs very quickly. There is bioavailability. Absorption part from the gastrointestinal tract Since it is skipped, the first pass effect through the liver is eliminated. this is fast bioavailability, bypassing the first pass effect and better permeability It is sourced. In addition, its large surface area for absorption and ease of application provide systemic This makes the oral mucosa a very effective and selective route for drug transport. This In this way, in addition to preventing inflammation and pain in gout patients, To prevent acid accumulation in a short time, use these drugs in combination By placing them on top or bottom, they can be easily removed without requiring water.
Bulusun tercih edilen uygulamasinda gelistirilen formülasyon tercihen Tablo 1 ve Tablo 2'de verilen miktarlara uygun olarak asagida belirtilen en az bir yardimci madde içermektedir: Jelatin, Pullulan, Pektin, Sodyum aljinat, Polimerize reçine, Maltodekstrin, Hidroksi propil metil selüloz (HPMC), HPMC E 15, HPMC E 50, HPMC K100, Hidroksi etil selüloz (HEC), Karboksi metil selüloz (CMC), Sodyum karboksi metil selüloz (NaCMC), Metil selüloz (MC), Agar Agar, Ksantan zamki, Arap zamki, Karnauba mumu, Çapraz bagli akrilik asit polimeri (Carbopol 980, 6000 veya bunlarin kombinasyonunu içeren gruptan seçilen en az bir dogal polimer (daha tercihen NaCMC, Sodyum aljinat ve Pektin kombinasyonu); Jelatin, Pullulan, Pektin, Sodyum aljinat, Polimerize reçine, Maltodekstrin, Hidroksi propil metil selüloz (HPMC), HPMC E 15, HPMC E 50, HPMC K100, Hidroksi etil selüloz (HEC), Karboksi metil selüloz (CMC), Sodyum karboksi metil selüloz (NaCMC), Metil selüloz (MC), Agar Agar, Ksantan zamki, Arap zamki, Karnauba mumu, Çapraz bagli akrilik asit polimeri (Carbopol 980, 6000 veya bunlarin kombinasyonunu içeren gruptan seçilen en az bir dogal polimer (daha tercihen Pullulan, Sodyum aljinat ve Pektin kombinasyonu); Gliserol, Propilen glikol, Sorbitol çözeltisi (% 50, %60 veya %70'lik), PEG 800, PEG 400 PEG 300 veya bunlarin kombinasyonunu içeren gruptan seçilen ve filmin esnekligini saglayan en az bir elastiklestirici (daha tercihen Gliserin veya Propilen glikol kombinasyonu); Sitrik asit, Askorbik asit, Laktik asit veya Tartarik asit içeren bir gruptan seçilen en az bir tükrük salgilatici ajan (daha tercihen Sitrik asit); Izopropil myristat'tan biri ya da bunlarin kombinasyonunu içeren gruptan seçilen ve Febuksostat nanokristallerinin eldesinde kullanilan en az bir yüzey aktif madde (daha tercihen Poloksamer ; 407, Poloksamer 188, Lesitin, Etil oleat veya Izopropil myristat'tan biri ya da bunlarin kombinasyonunu içeren gruptan seçilen ve OTF hazirlamada yüzey aktiflik saglayan en az bir yüzey aktif madde (daha tercihen Tween 80); J Sükroz, Sorbitol, Laktoz, Mannitol, XyIisorb, Maltodekstrin veya bunlarin kombinasyonunu içeren bir gruptan seçilen en az bir tatlandirici ajani (daha tercihen Mannitol); J Korskarmelloz sodyum, Kollidon CL, Ksantan zamki, Krospovidon, Sodyum nisasta glikolat, Hidroksipropil selüloz, Ac-Di-Sol®, Solutab®, Nymce ZSX®, Primellose®, Vivasol®, Polyplasdone®, Explotab®, Primojel®, Satialgine®, Sodyum bikarbonat veya bunlarin kombinasyonunu içeren gruptan seçilen ve filmin hizli parçalanmasini saglayan en az bir süper dagitici (daha tercihen Sodyum nisasta glikolat); J Vanilin, Karamel, Neroli, Ökaliptol, Nane, Portakal, Tarçin veya Çikolata aromasi içeren bir gruptan seçilen en az bir aroma verici ajan (daha tercihen J Sodyum benzoat, potasyum sorbat, propil paraben, metil paraben, sodyum metabisülfit, sodyum sülfit, benzil alkol, klorbütanol veya bunlarin kombinasyonunu içeren gruptan seçilen ve ince filmleri mikroorganizmalardan koruma saglayan en az bir koruyucu (daha tercihen Sodyum benzoat); J Ultra saf su veya aromatik su içermektedir. The formulation developed in the preferred embodiment of the invention is preferably according to Table 1 and At least one assistant listed below, in accordance with the quantities given in Table 2 The item contains: Gelatin, Pullulan, Pectin, Sodium alginate, Polymerized resin, Maltodextrin, Hydroxy propyl methyl cellulose (HPMC), HPMC E 15, HPMC E 50, HPMC K100, Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Agar Agar, Xanthan gum, Arabian gum, Carnauba wax, Cross-linked acrylic acid polymer (Carbopol 980, At least one natural substance selected from the group consisting of 6000 or combinations thereof polymer (more preferably a combination of NaCMC, Sodium alginate and Pectin); Gelatin, Pullulan, Pectin, Sodium alginate, Polymerized resin, Maltodextrin, Hydroxy propyl methyl cellulose (HPMC), HPMC E 15, HPMC E 50, HPMC K100, Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Agar Agar, Xanthan gum, Arabian gum, Carnauba wax, Cross-linked acrylic acid polymer (Carbopol 980, At least one natural substance selected from the group consisting of 6000 or combinations thereof polymer (more preferably a combination of Pullulan, Sodium alginate and Pectin); Glycerol, Propylene glycol, Sorbitol solution (50%, 60% or 70%), PEG 800, PEG 400, PEG 300 or a combination thereof at least one elasticizer (more preferably) selected and ensuring the flexibility of the film Glycerin or Propylene glycol combination); From a group that includes Citric acid, Ascorbic acid, Lactic acid or Tartaric acid at least one selected salivary secreting agent (more preferably Citric acid); From the group consisting of one or a combination of isopropyl myristate at least one surface selected and used to obtain Febuxostat nanocrystals active ingredient (more preferably Poloxamer; or one of 407, Poloxamer 188, Lecithin, Ethyl oleate or Isopropyl myristate selected from the group containing their combination and used in OTF preparation at least one active surfactant (more preferably Tween 80); J Sucrose, Sorbitol, Lactose, Mannitol, XyIisorb, Maltodextrin or their at least one sweetening agent selected from the group consisting of a combination of preferably Mannitol); J Corscarmellose sodium, Kollidon CL, Xanthan gum, Crospovidone, Sodium starch glycolate, Hydroxypropyl cellulose, Ac-Di-Sol®, Solutab®, Nymce ZSX®, Primellose®, Vivasol®, Polyplasdone®, Explotab®, Primojel®, Satialgine®, selected from the group consisting of sodium bicarbonate or a combination thereof; and At least one superdispersant (more preferably) ensures rapid disintegration of the film. sodium starch glycolate); J Vanillin, Caramel, Neroli, Eucalyptol, Mint, Orange, Cinnamon or Chocolate At least one flavoring agent selected from the group consisting of aroma (more preferably J Sodium benzoate, potassium sorbate, propyl paraben, methyl paraben, sodium metabisulfite, sodium sulfite, benzyl alcohol, chlorobutanol or any of these thin films selected from the group containing the combination At least one preservative that provides protection against microorganisms (more preferably Sodium benzoate); J Contains ultrapure water or aromatic water.
Bilesen Adi Agirlikça kullanilabilir miktar (%) Febuksostat 1,0-20,0 Kolsisin 0,01-5,0 Pektin 1,0-15,0 Sodyum Karboksi Metil Selüloz Sodyum aljinat 1,0-20,0 Sodyum sakarin 1,0-15,0 Gliserin 2,5-20,0 Sodyum nisasta glikolat 0,5-20,0 Sitrik asit 0,1-10,0 Sodyum benzoat 0,5-10,0 Mannitol 0,1-5,0 Ultra saf su veya aromatik su kullanilip buhiarlastirildigi için agirliga etkisi bulunmamaktir Bilesen Adi Agirlikça kullanilabilir miktar (%) Febuksostat 1,0-20,0 Kolsisin 0,01-5,0 Pektin 1,0-15,0 Sodyum aljinat 1,0-20,0 Sodyum sakarin 1,0-15,0 Gliserin 2,5-20,0 Propilen glikol 0,5-20,0 Sodyum nisasta glikolat 2,5-20,0 Sitrik asit 0,5-10,0 Sodyum benzoat 0,1-5,0 Mannitol 5,0-40,0 Ultra saf su veya aromatik su kullanilip buhiarlastirildigi için agirliga etkisi bulunmamaktir Bulusun tercih edilen bir uygulamasinda gelistirilen formülasyon; Febuksostat, Kolsisin, Pektin, Sodyum Karboksi Metil Selüloz (NaCMC), Sodyum aljinat, Sodyum sakarin, Gliserin, Sodyum nisasta glikolat, Tween 80, Sitrik asit, Sodyum benzoat, Mannitol, Vanilin ve Ultra saf su içermektedir. Ingredient Name Usable amount by weight (%) Febuxostat 1.0-20.0 Colcicine 0.01-5.0 Pectin 1.0-15.0 Sodium Carboxy Methyl Cellulose Sodium alginate 1.0-20.0 Sodium saccharin 1.0-15.0 Glycerin 2.5-20.0 Sodium starch glycolate 0.5-20.0 Citric acid 0.1-10.0 Sodium benzoate 0.5-10.0 Mannitol 0.1-5.0 Since ultrapure water or aromatic water is used and evaporated, it weighs has no effect Ingredient Name Usable amount by weight (%) Febuxostat 1.0-20.0 Colcicine 0.01-5.0 Pectin 1.0-15.0 Sodium alginate 1.0-20.0 Sodium saccharin 1.0-15.0 Glycerin 2.5-20.0 Propylene glycol 0.5-20.0 Sodium starch glycolate 2.5-20.0 Citric acid 0.5-10.0 Sodium benzoate 0.1-5.0 Mannitol 5.0-40.0 Since ultrapure water or aromatic water is used and evaporated, it weighs has no effect The formulation developed in a preferred embodiment of the invention; febuxostat, Colchicin, Pectin, Sodium Carboxy Methyl Cellulose (NaCMC), Sodium alginate, Sodium saccharin, Glycerin, Sodium starch glycolate, Tween 80, Citric acid, Sodium Contains benzoate, Mannitol, Vanillin and Ultra pure water.
Bulusun tercih edilen bir uygulamasinda gelistirilen formülasyon; Febuksostat, Kolsisin, Pektin, Pullulan, Sodyum aljinat, Sodyum sakarin, Gliserin, Propilen glikol, Sodyum nisasta glikolat, Tween 80, Sitrik asit, Sodyum benzoat, Mannitol, Vanilin ve Ultra saf su içermektedir. The formulation developed in a preferred embodiment of the invention; febuxostat, Colchicine, Pectin, Pullulan, Sodium alginate, Sodium saccharin, Glycerin, Propylene glycol, Sodium starch glycolate, Tween 80, Citric acid, Sodium benzoate, Mannitol, Contains Vanillin and Ultra pure water.
Bulusun örnek bir uygulamasinda gelistirilen formülasyon su islem adimlari izlenerek hazirlanmaktadir: Febuksostat nanokristalleri için en az 1 mg hassasiyete sahip hassas terazide bir viyal içerisine Poloxamer 188, SLS ve ultra saf su tartilir. Organik faz için ise Febuksostat ve etil alkol tartilir. Çok noktali manyetik karistirici üzerinde 750 rpm hizda su fazi üzerine organik faz 22G enjektör yardimi ile damla damla ilave edilir. Damlatma bitiminde ek olarak 5 dk bu sekilde homojen bir karistirma saglanir. 1 dakika vorteks yapilir (2500 rpm). uygulanir. Organik fazin uzaklastirilmasi amaciyla 45 °C'de 5 dk süreyle vakum altinda buharlastirma islemi uygulanir (bir rotovapor araciligiyla). Elde edilen karisim üzerine yeniden 3 dakika süreyle %60 güç, siklus 2'de sonikasyon uygulanir. Bu esnada Febuksostat nanokristalleri elde edilir. Formulation water treatment steps developed in an exemplary application of the invention It is prepared as follows: For febuxostat nanocrystals, at least 1 mg Poloxamer 188, SLS and ultra in a vial on a precision scale. pure water is weighed. For the organic phase, Febuxostat and ethyl alcohol are weighed. multipoint Organic phase 22G over water phase on magnetic stirrer at 750 rpm It is added drop by drop with the help of a syringe. Additional 5 minutes at the end of dripping In this way, a homogeneous mixing is achieved. Vortex for 1 minute (2500 rpm). is applied. Vacuum at 45 °C for 5 minutes to remove the organic phase. evaporation process is applied under it (through a rotovapor). Obtained sonicate the mixture again for 3 minutes at 60% power, cycle 2. is applied. Meanwhile, Febuxostat nanocrystals are obtained.
OTF'ler için formülasyonu olusturan tüm bilesenler tüm bilesenlerinin en az 1 mg hassasliga sahip hassas bir terazide tartilir; tartilan bilesenlerin tercihen 2-4 saat süreyle 750 rpm'de ultra saf su (tercihen 1 film formülasyonu için 1 mL) içerisinde karistirilmasi; karistirmanin son 5 dakikasinda 20-60°C (tercihen 40°C) sicakliga ayarlanmis bir manyetik karistirici üzerinde 750 rpm”de karistirilmasi, isitilmasi ve etkin maddeler dahil tüm bilesenlerin çözündürülmesi; sicak eriyik hale gelen karisimin her bir film içerisinde esit miktarda Febuksostat nanokristalleri ve Kolsisin içerecek sekilde kaliplara dökülmesi; kaliba dökülen karisimin tercihen 6- 72 saat (tercihen 24 saat) süreyle oda sicakliginda (tercihen 25 °C) kurutulmasi; her bir filmin ayri ayri kilitli posetler içerisinde, nemden, isidan ve isiktan uzak bir sekilde, oda sicakliginda (25 °C) kullanilacagi ana kadar saklanmasi. All components that make up the formulation for OTFs must contain at least 1 mg of all components. weighed on a precision scale; weighed components preferably for 2-4 hours. in ultrapure water (preferably 1 mL for 1 film formulation) at 750 rpm for mixing; During the last 5 minutes of mixing, the temperature is 20-60°C (preferably 40°C). Mixing and heating at 750 rpm on a magnetic stirrer and solubilizing all components, including active ingredients; hot molten equal amounts of Febuxostat nanocrystals and Pouring into molds to contain colchis; The mixture poured into the mold should preferably be 6- Drying at room temperature (preferably 25 °C) for 72 hours (preferably 24 hours); Each film should be stored separately in locked bags, away from moisture, heat and light. Store at room temperature (25 °C) until use.
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2023019879A2 true TR2023019879A2 (en) | 2024-03-21 |
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