TR202013443A2 - SEMI SOLID PHARMACEUTICAL COMPOSITIONS USED IN MELASMA TREATMENT - Google Patents
SEMI SOLID PHARMACEUTICAL COMPOSITIONS USED IN MELASMA TREATMENT Download PDFInfo
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- TR202013443A2 TR202013443A2 TR2020/13443A TR202013443A TR202013443A2 TR 202013443 A2 TR202013443 A2 TR 202013443A2 TR 2020/13443 A TR2020/13443 A TR 2020/13443A TR 202013443 A TR202013443 A TR 202013443A TR 202013443 A2 TR202013443 A2 TR 202013443A2
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- cream formulation
- formulation according
- alcohol
- ascorbic acid
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- 206010008570 Chloasma Diseases 0.000 title claims abstract description 11
- 208000003351 Melanosis Diseases 0.000 title claims abstract description 11
- 239000007787 solid Substances 0.000 title description 4
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 238000009472 formulation Methods 0.000 claims abstract description 35
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims abstract description 34
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims abstract description 30
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 29
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000006071 cream Substances 0.000 claims abstract description 24
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims abstract description 21
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960001727 tretinoin Drugs 0.000 claims abstract description 21
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 14
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 14
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 14
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 14
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960000541 cetyl alcohol Drugs 0.000 claims abstract description 13
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 9
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- 239000008117 stearic acid Substances 0.000 claims abstract description 8
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- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 23
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Abstract
Melazma tedavisi için etkin madde olarak ağırlıkça %0.10 Flusinolon Asetonit, ağırlıkça %0.050 Tretinoin ve ağırlıkça %4.0 Hidrokinon içeren stabilitesi iyileştirilmiş ve oda koşulunda saklanabilen bir krem formülasyonu olup; antioksidan olarak askorbik asit, EDTA, bütilhidroksianisol (BHA), butilhidroksîtoluen (BHT), antimikrobik koruyucu olarak benzil alkol, emülgatör olarak setil alkol, stearik asit, Gliseril stearat ve PEG 75 stearat ile Magnezyum aluminyum silikat, sertleştirici olarak Stearil alkol, emoliyan olarak gliserin, çözücü ve taşıyıcı olarak saf su içerir.It is a cream formulation with improved stability containing 0.10% by weight of Fluxinolone Acetonite, 0.050% by weight of Tretinoin and 4.0% by weight of Hydroquinone as the active ingredient for the treatment of melasma and can be stored at room conditions; Ascorbic acid, EDTA, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT) as antioxidant, benzyl alcohol as antimicrobial preservative, cetyl alcohol as emulsifier, stearic acid, Glyceryl stearate and PEG 75 stearate Magnesium aluminum silicate as hardener, emolliear alcohol as hardener contains pure water as solvent and carrier.
Description
TARIFNAME MELAZMA TEDAVISINDE KULLANILAN YARI KATI FARMASÖTIK KOMPOZISYONLAR Teknik Alan Bulus melazma tedavisi için Flusinolon asetonid, Hidrokinon ve Tretinoin içeren bir krem ile ilgilidir. DESCRIPTION SEMI SOLID PHARMACEUTICAL COMPOSITIONS USED IN THE TREATMENT OF MELASMA Technical Area The invention relates to a cream containing Flucinolone acetonide, Hydroquinone and Tretinoin for the treatment of melasma.
Teknigin Durumu Melazma, ciltte bazi bölgelerde melanin pigmentinin çok çalismasi nedeniyle siyah veya kahverengi lekeler seklinde görülen ve günes lekesi olarak bilinen bir cilt hastaligidir. Bu lekelerin nedeni tam olarak bilinmemekle birlikte genetik faktörler, hormon degisiklikleri, ilaç kullanimi, isiga duyarlilik ve uzun süre günese maruz kalmanin melazma ile iliskili oldugu bilinmektedir. State of the Art Melasma is black or brown in some areas of the skin due to the overworking of the melanin pigment. It is a skin disease that appears in the form of spots and is known as sunspot. The exact cause of these stains genetic factors, hormonal changes, drug use, photosensitivity and long-term It is known that exposure to the sun is associated with melasma.
Standart terapi, cildin etkilenen bölgelerinin yoksunlugunu veya agartilmasini, günes koruyucularin kullanimini ve günes isigindan kaçinmayi içerir. Hidrokinon en popüler topikal depigmentasyon ajanidir. oldugundan formülasyonlarinin kimyasal stabilitesi önemlidir. . Tretinoin (Retin-A), melazma için yaygin olarak kullanilan bir baska tedavi ajanidir. Standard therapy includes deprivation or bleaching of affected areas of skin, sunscreen use and avoiding sunlight. Hydroquinone is the most popular topical depigmentation agent. chemical stability of formulations is important. . Tretinoin (Retin-A), common for melasma It is another therapeutic agent used as
Melazma, Flusinolon asetonid (%001), Hidrokinon (%40) ve Tretinoin (%005) kombinasyonunu içeren ürünler ile basarili bir sekilde tedavi edilebilmektedir [3]. TRI-LUMA krem, sirasiyla 0.01%/4%/0.05% fluocinolone acetonide, hydroquinone, ve tretinoin içerir. Formülasyon ve üretim metodu EP1562531 Bl (TR2016/03686) patentinde açiklanmistir. Üretim metodunun özelligi emülgatör ajaninin karisima sonradan ilave edilmesidir. Melasma, containing a combination of Flucinolone acetonide (001), Hydroquinone (40%) and Tretinoin (005%) It can be successfully treated with products [3]. TRI-LUMA cream, 0.01%/4%/0.05% respectively Contains fluocinolone acetonide, hydroquinone, and tretinoin. Formulation and production method EP1562531 B1 (TR2016/03686) patent. The peculiarity of the production method is that the emulsifying agent is mixed is added later.
Etkin Madde Molekül Yapisi Çözünürlük Stabilite Flusinolon HO Hîîîgîgvi Suda ve heptan'da pratik |SIkta stabildir. Asit, asetonit n 2-' ;dr/&ko 3 olarak çözünmez. Aseton ve baz ve oksijene / ' ;Ti/;J " anhidr etanolde çözünür [4] karsi hassastir. Active Ingredient Molecular Structure Solubility Stability Flucinolone HO Hîîîgîgvi Practical in water and heptane |Stable in water. Acid, acetonite is insoluble as n 2-' ;dr/&ko 3. To acetone and base and oxygen / ' ;Ti/;J " is soluble in anhydrous ethanol [4].
Hidrokinon Suda ve etanolde (%96) Isik ve oksijen ile ”OGG” çözünür [5][6] kararir [5]. Hydroquinone In water and ethanol (96%) With light and oxygen “OGG” dissolves [5][6] darkens [5].
Tretinoin mc CH, CH; cn 'o` Suda pratik olarak Isik, sicaklik ve CH. kismen, etanolde (%96) az [4] çözünür [4] Flusinolon asetonid topikal olarak uygulanan sentetik bir kortikosteroiddir. Diger kortikosteroidler gibi flusinolon da antienflamatuvar, antiprüritik ve vazokonstriktör etki gösterir. Krem, pomat, topikal çözelti ve sampuan formunda hazirlanabilir. Tretinoin mc CH, CH; cn 'o` Light, temperature and CH. partly, little in ethanol (96%) [4] soluble [4] Flucinolone acetonide is a topically applied synthetic corticosteroid. Like other corticosteroids Flucinolone also shows anti-inflammatory, antipruritic and vasoconstrictor effects. Cream, ointment, topical solution and can be prepared in the form of shampoo.
Hidrokinon deride depigmentasyon olusturmak için topikal olarak kullanilir. Melanin olusumundaki tirozin-tirozinaz yolaginda bir ya da daha fazla basamagi inhibe eder. Derideki melanositlerin içerigini azaltir. Yapica depigmentasyon yapan güçlü bir ilaçtir. Tedavide genellikle kremleri kullanilir. Hydroquinone is used topically to induce depigmentation of the skin. in the formation of melanin It inhibits one or more steps in the tyrosine-tyrosinase pathway. The content of melanocytes in the skin reduces. Yapica is a powerful depigmenting drug. Creams are generally used in the treatment.
Tretinoin oral veya topikal olarak kullanilan A vitamininin dogal bir türevidir. Topikal tretinoin isiktan etkilenerek zarar görmüs derinin tedavisinde kullanilir. Hafif isiktan etkilenerek zarar gören ciltteki kirisikliklarin benekler halindeki hiper pigmentasyonunun, pürtüklü görünümün ve gevsekligin azaltilmasinda etkilidir. Cildi isiktan etkilenerek zarar görmüs hastalarda topikal tretinoin tedavisine bagli olumlu etkiler çogu zaman tedavinin ilk ayi içinde görülür. Tretinoin is a natural derivative of vitamin A used orally or topically. topical tretinoin light It is used in the treatment of affected and damaged skin. Skin damaged by light exposure speckle hyper-pigmentation of wrinkles, rough appearance and looseness effective in reducing Topical tretinoin therapy in patients whose skin is damaged by light. The associated positive effects are often seen within the first month of treatment.
Bulusun açiklamasi Gelistirilen ürün melasma tedavisi için Flusinolon asetonid, Hidrokinon ve Tretinoin içeren bir krem formülasyonudur. Gelistirilen krem formülasyonu etkin madde olarak agirlikça %0.10 Flusinolon Asetonit, agirlikça %Ü.050 Tretinoin ve agirlikça %40 Hidrokinon içerir. Description of the invention The developed product is a cream containing Flucinolone acetonide, Hydroquinone and Tretinoin for the treatment of melasma. formulation. The developed cream formulation is 0.10% by weight Flucinolone as the active ingredient. Contains Acetonite, Ü.050% by weight Tretinoin and 40% by weight of Hydroquinone.
Yari kati ürün bilesiminde bulunan etkin maddelerin çözünürlükleri birbirinden farklidir. Flusinolon asetonid suda çözünmezken, Tretinoin ve Hidrokinon suda çözünür etkin maddelerdir. Yari kati ve çift fazli emülsiyon seklinde olan (y/s) bitmis ürün içerisinde düsük konsantrasyonda bulunan Tretinoin (%005) ve Flusinolon asetonid (%001) etkin maddelerinin endüstriyel boyutta üretiminde homojen sekilde dagitilabilmesi çok önemlidir. Bu sekilde etkin ve güvenilir bir tedavi saglanabilmektedir. The solubility of the active substances in the semi-solid product composition is different from each other. Flucinolone Tretinoin and Hydroquinone are water-soluble active ingredients while acetonide is insoluble in water. half and double Tretinoin, which is in low concentration in the finished product in the form of a phased emulsion (y/s). (005%) and Flucinolone acetonide (001%) homogeneous in the industrial production of active ingredients It is very important that it can be distributed in a way. In this way, an effective and reliable treatment can be provided.
Gelistirilen üretim prosesi ile her üç maddenin de ürün içerisinde homojen bulunmasi saglanmaktadir. llaveten formülasyonda kullanilan etkin maddelerin Franz difüzyon hizi dogrudan bitmis ürünün etkinligini etkilemektedir. Bu nedenle söz konusu her üç etkin maddenin franz difüzyon hizinin uygun olmasi oldukça önemlidir. With the developed production process, it is ensured that all three substances are found homogeneously in the product. In addition, the Franz diffusion rate of the active ingredients used in the formulation directly affect its effectiveness. For this reason, the franz diffusion rate of all three active substances in question should be appropriate. It is quite important to be.
Bu etken maddeler ile ilgili diger bir sorun ise, birçok etken maddede oldugu gibi, birbirleriyle ve çevresel sartlarin etkisi ile görülen stabilite sorunlaridir. Flusinolon asetonid asit, baz ve oksijene karsi hassas bir etkin maddedir. Hidrokinon, isik ve oksijen etkisiyle bozunmaktadir. Ilaveten Tretinoin isik, sicaklik ve neme çok hassastir. Piyasada etkin maddeleri tek basina içeren ürünlerin tamaminin oda kosulunda saklanabilmesine ragmen, referans kombinasyon ürünün buzdolabinda saklaniyor olmasi [5], etkin maddelerin de birbiriyle geçimsiz olduklarini göstermektedir. Formülasyon içerisine eklenen antioksidan maddelerle bu etkilesim minimum seviyede tutulup, bitmis ürünün oda sicakliginda saklanabilmesi mümkün olmaktadir. Another problem with these active substances is that, as with many active substances, they are related to each other and to the environment. are the stability problems seen with the effect of the conditions. Flucinolone acetonide is sensitive to acid, base and oxygen. is the active ingredient. Hydroquinone degrades under the influence of light and oxygen. In addition, Tretinoin light, temperature and It is very sensitive to moisture. All products containing active substances alone in the market are in room condition. Although the reference combination product is stored in the refrigerator [5], effective shows that the substances are incompatible with each other. Antioxidant added to the formulation This interaction with substances is kept to a minimum and the finished product can be stored at room temperature. is possible.
Sonuç olarak, melazma tedavisinde kullanabilecek, yaklasik 15-25°C oda sicakliginda saklanabilen ve stabilitesi iyilestirilmis yari kati formulasyonlarla ilgili teknik alanda bir yenilik gerekmektedir. As a result, it can be used in the treatment of melasma, stored at approximately 15-25°C room temperature, and An innovation is required in the technical field regarding semisolid formulations with improved stability.
Krem formülasyonlarina giren yardimci maddeler asagida belirtilmistir: Antioksidanlar: Gallik asit, propil gallat, alfa tokoferol, l-tokoferol, sodyum sülfit, sodyum meta- bisülfit, fenil alanin, triptofan, tiogliserol, sistein HCI, astaxanthin, bütilhidroksianisol (BHA), butilhidroksitoluen (BHT), askorbik asit [1] ve kelat yapici etilendiamintetraasetik asit (EDTA). bütilhidroksianisol (BHA)agrIikça % agirlikça %0.0075-O.1 oraninda kullanilabilir. Daha tercih edildigi durumda Askorbik asit agirlikça %0.05-0.30, EDTA agirlikça % agirlikça agirlikça %003 veya 0.02'dir. Excipients included in cream formulations are listed below: Antioxidants: Gallic acid, propyl gallate, alpha tocopherol, l-tocopherol, sodium sulfite, sodium meta- bisulfite, phenyl alanine, tryptophan, thioglycerol, cysteine HCl, astaxanthin, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), ascorbic acid [1] and chelating ethylenediaminetetraacetic acid (EDTA). butylhydroxyanisole (BHA)wt% 0.0075-0.1%wt rate can be used. More preferably, Ascorbic acid 0.05-0.30% by weight, EDTA by weight % by weight 003 % by weight or 0.02.
Gelistirilen formülasyonda askorbik asitin stabilite üzerindeki etkisi son derece belirgin olmus ve diger antioksidanlar ile birlikte Sinerji göstermistir. In the developed formulation, the effect of ascorbic acid on stability was very evident and other showed synergy with antioxidants.
Antimikrobiyal koruyucular: P-hidroksi benzoik asit esterleri, alkil hidroksi benzoatlar, fenoksietanol, fenil etil alkol, metil ve propil hidroksi benzoatlar, benzil alkol [1]. Antimicrobial preservatives: P-hydroxy benzoic acid esters, alkyl hydroxy benzoates, phenoxyethanol, phenyl ethyl alcohol, methyl and propyl hydroxy benzoates, benzyl alcohol [1].
Formülasyonda benzil alkol tercih edilmistir. Benzil alkol agirlikça %0.01-10.0 oraninda kullanilabilir. Benzyl alcohol is preferred in the formulation. Benzyl alcohol can be used at a rate of 0.01-10.0% by weight.
Daha tercih edildigi durumda benzil alkol miktari agirlikça %03 ila %0.5'tir. En tercih edildigi durumda benzil alkol miktari agirlikça %03› veya %0.5'tir. More preferably, the amount of benzyl alcohol is from 03 to 0.5% by weight. In the most preferred the amount of benzyl alcohol is 03% or 0.5% by weight.
Emülgatörler: Anyonik emülgatörler (potasyum laurat, trietanolamin stearat, sodyum lauril sülfat, alkil polioksietilen sülfat, dioktil sodyum sülfosüksinat), katyonik emülgatörler (kuaterner amonyum bilesikleri, setiltrimetilamonyum bromür, Iaurildimetilbenzilamonyum klorür), non-iyonik emülgatörler (polioksietilen yag alkolü eterleri, sorbitan yag asidi esterleri, poloksamerler, Ianolin alkolleri, etoksillenmis lanolin alkolleri, setil alkol, stearik asit ve Gliseril stearat ve PEG 75 stearat), multimoleküler monomoleküller (arap zamki, jelatin, lesitin, kolesterol), ince ögütülmüs kati partiküller (bentonit, hektorit, kaolin, magnezyum hidroksit ve magnezyum alüminyum silikat) [1]. Emulsifiers: Anionic emulsifiers (potassium laurate, triethanolamine stearate, sodium lauryl sulfate, alkyl polyoxyethylene sulfate, dioctyl sodium sulfosuccinate), cationic emulsifiers (quaternary ammonium compounds, cetyltrimethylammonium bromide, Iaurildimethylbenzylammonium chloride), non-ionic emulsifiers (polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, poloxamers, Ianolin alcohols, ethoxylated lanolin alcohols, cetyl alcohol, stearic acid and Glyceryl stearate and PEG 75 stearate), multimolecular monomolecules (gum arabic, gelatin, lecithin, cholesterol), finely ground solid particles (bentonite, hectorite, kaolin, magnesium hydroxide and magnesium aluminum silicate) [1].
Acacia, Agar, Alamic Acid, Alginic Acid, Aluminum Monostearate, Attapulgite (Activated, Colloidal Homopolymer, Interpolymer, Carboxymethylcellulose (Calcium, Sodium, Enzymatically-Hydrolyzed), Carmellose, Carrageenan, Microcrystalline Cellulose, Microcrystalline Cellulose and Sodium Carboxymethylcellulose, Cetostearyl Alcohol, Chitosan, Corn Syrup (solid), Cyclomethicone, Dextrin, Egg Phospholipids, Ethylcellulose, Gelatin, Gellan Gum, Glyceryl Behenate, Guar Gum, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, Hypromellose, Isomalt, Alpha-Lactalbumin, Kaolin, Magnesium Aluminum Silicate, Maltitol Solution, Maltodextrin, Pectin, Polycarbophil, Polydextrose (Hydrogenated), Polyethylene Oxide, Polysorbate (20, 40, 60, 80), Polyvinyl Alcohol, Potassium Alginate, Povidone, Propylene Glycol, Alginate, Pullulan, Silica, Hydrophobic Colloidal Silicon Dioxide, Colloidal Sodium Alginate, Sorbitan Monolaurate, Sorbitan Monooleate, Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan Sesquioleate, Sorbitan Trioleate, Starch, Corn Starch, Hydroxypropyl Corn Starch, Pregelatinized Hydroxypropyl Corn Starch, Pea Starch, Hydroxypropyl Pea Starch, Pregelatinized Hydroxypropyl Pea Starch, Potato Starch, Hydroxypropyl Potato Starch, Pregelatinized Hydroxypropyl Potato Starch, Tapioca Starch, Wheat Sucrose, Sucrose Palmitate, Tragacanth, Vitamin E Polyethylene Glycol Succinate, Xanthan Gum [2]. Acacia, Agar, Alamic Acid, Alginic Acid, Aluminum Monostearate, Attapulgite (Activated, Colloidal Homopolymer, Interpolymer, Carboxymethylcellulose (Calcium, Sodium, Enzymatically-Hydrolyzed), Carmellose, Carrageenan, Microcrystalline Cellulose, Microcrystalline Cellulose and Sodium Carboxymethylcellulose, Cetostearyl Alcohol, Chitosan, Corn Syrup (solid), Cyclomethicone, Dextrin, Egg Phospholipids, Ethylcellulose, Gelatin, Gellan Gum, Glyceryl Behenate, Guar Gum, Hydroxyethyl Cellulose, Hydroxypropyl Cellulose, Hypromellose, Isomalt, Alpha-Lactalbumin, Kaolin, Magnesium Aluminum Silicate, Maltitol Solution, Maltodextrin, Pectin, Polycarbophil, Polydextrose (Hydrogenated), Polyethylene Oxide, Polysorbate (20, 40, 60, 80), Polyvinyl Alcohol, Potassium Alginate, Povidone, Propylene Glycol, Alginate, Pullulan, Silica, Hydrophobic Colloidal Silicon Dioxide, Colloidal Sodium Alginate, Sorbitan Monolaurate, Sorbitan Monooleate, Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan Sesquioleate, Sorbitan Trioleate, Starch, Corn Starch, Hydroxypropyl Corn Starch, Pregelatinized Hydroxypropyl Corn Starch, Pea Starch, Hydroxypropyl Pea Starch, Pregelatinized Hydroxypropyl Pea Starch, Potato Starch, Hydroxypropyl Potato Starch, Pregelatinized Hydroxypropyl Potato Starch, Tapioca Starch, Wheat Sucrose, Sucrose Palmitate, Tragacanth, Vitamin E Polyethylene Glycol Succinate, Xanthan Gum [2].
Formülasyonda emülgatör olarak setil alkol, stearik asit, Gliseril stearat ve PEG 75 stearat ile Magnezyum aluminyum silikat tercih edilmistir. Formülasyonda setil alkol agirlikça %20-100, stearik aluminyum silikat agirlikça %20-50 oraninda kullanilabilir. Daha tercih edildigi durumda setil alkol 4.0, Magnezyum aluminyum silikat agirlikça %20 oranindadir. En tercih edildigi durumda setil alkol Sertlestiriciler (Stiffening agents): Castor Oil (Hydrogenated), Cetostearyl Alcohol, Cetyl Alcohol, Cetyl Palmitate, Dextrin, Hard Fat, Alpha-Lactalbumin, Paraffin (Synthetic), Rapeseed Oil (Fully Hydrogenated, Superglycerinated Fully Hydrogenated), Sodium Stearate, Stearyl Alcohol, Wax (Cetyl Esters, Emulsifying, Microcrystalline, White, Yellow) [2]. With cetyl alcohol, stearic acid, glyceryl stearate and PEG 75 stearate as emulsifier in the formulation Magnesium aluminum silicate is preferred. Cetyl alcohol in formulation 20-100% by weight, stearic aluminum silicate can be used at a rate of 20-50% by weight. More preferably cetyl alcohol 4.0 is 20% by weight of Magnesium aluminum silicate. Most preferred cetyl alcohol Stiffening agents: Castor Oil (Hydrogenated), Cetostearyl Alcohol, Cetyl Alcohol, Cetyl Palmitate, Dextrin, Hard Fat, Alpha-Lactalbumin, Paraffin (Synthetic), Rapeseed Oil (Fully) Hydrogenated, Superglycerinated Fully Hydrogenated), Sodium Stearate, Stearyl Alcohol, Wax (Cetyl Esters, Emulsifying, Microcrystalline, White, Yellow) [2].
Formülasyonda sertlestirici olarak Stearil alkol tercih edilmistir. Stearil alkol agirlikça % 20-100 oraninda kullanilabilir. Daha tercih edildigi durumda Stearil alkol agirlikça %2.0'dir. Stearyl alcohol was preferred as a hardener in the formulation. Stearyl alcohol 20-100% by weight rate can be used. More preferably, the Stearyl alcohol is 2.0% by weight.
Emoliyanlar: Alkyl (C12-15) Benzoate, Almond Oil, Aluminum Monostearate, Canola Oil, Castor Oil, Cetostearyl Alcohol, Cholesterol, Coconut Oil, Cyclomethicone, Dimethicone, Ethylene Glycol Stearates, hexylene glycol, Glyceryl Monooleate, Glyceryl Monostearate, lsopropyl Isostearate, lsopropyl Myristate, lsopropyl Palmitate, Isostearyl Isostearate, Hydrogenated Lanolin, Lecithin, Mineral Oil (light), Myristyl Alcohol, Octyldodecanol, Oleyl Alcohol, Oleyl Oleate, Petrolatum, Polydecene (Hydrogenated), Propylene Glycol Dilaurate, Propylene Glycol Monolaurate, Safflower Oil, Soybean Oil (Hydrogenated), Sunflower Oil, Wax, Cetyl Esters, Xylitol, Zinc Acetate ve Glycerin Formülasyonda emoliyan olarak gliserin tercih edilmistir. Gliserin agirlikça % 10-300 oraninda kullanilabilir. Daha tercih edildigi durumda gliserin agirlikça %15.0'dir. Emollients: Alkyl (C12-15) Benzoate, Almond Oil, Aluminum Monostearate, Canola Oil, Castor Oil, Cetostearyl Alcohol, Cholesterol, Coconut Oil, Cyclomethicone, Dimethicone, Ethylene Glycol Stearates, hexylene glycol, Glyceryl Monooleate, Glyceryl Monostearate, Isopropyl Isostearate, lsopropyl Myristate, lsopropyl Palmitate, Isostearyl Isostearate, Hydrogenated Lanolin, Lecithin, Mineral Oil (light), Myristyl Alcohol, Octyldodecanol, Oleyl Alcohol, Oleyl Oleate, Petrolatum, Polydecene (Hydrogenated), Propylene Glycol Dilaurate, Propylene Glycol Monolaurate, Safflower Oil, Soybean Oil (Hydrogenated), Sunflower Oil, Wax, Cetyl Esters, Xylitol, Zinc Acetate and Glycerin Glycerin is preferred as emollient in the formulation. 10-300% by weight of glycerin can be used. More preferably, the glycerine is 15.0% by weight.
Formülasyon çözücü ve tasiyici olarak saf su içerir. The formulation contains purified water as solvent and carrier.
Formülasyonun üretim yöntemi asagida belirtilmistir: (Sekil 1). The production method of the formulation is given below: (Figure 1).
Ana kazan içerisine çözünmüs oksijenden arindirilmis saf su alinir ve 75-80“C'ye kadar isitilir. Pure water purified from dissolved oxygen is taken into the main boiler and heated up to 75-80°C.
Ana kazan içerisine sirasiyla Magnezyum Alüminyum Silikat (Mg-AI Silikat), Askorbik asit ve Disodyum Ededat (EDTA) ilave edilerek palet karistirici ile hizli karistirilarak (vorteks) çözünmesi saglanir. Magnesium Aluminum Silicate (Mg-AI Silicate), Ascorbic acid and Disodium are placed in the main boiler, respectively. Ededate (EDTA) is added and it is dissolved by rapid mixing (vortex) with a pallet mixer.
Ayri bir kazana (A-Kazani) sirasiyla Setil Alkol, Stearik Asit, Stearil Alkol, Gliserin, Gliseril stearat & PEG 75 stearat (Gelot 64), Benzil alkol, Bütil hidroksi toluen (BHT), Bütil hidroksi anisol (BHA), Tretinoin ve Flusinolon Asetonit ilave edilir ve karistirilarak tamamen çözünmesi saglanir. Çözünmenin tamamen gerçeklestigi gözlendikten sonra A-Kazani Ana kazan'a palet karistirici ve homojenizatör esliginde eklenir. Palet karistirici ve homojenizatör birlikte olacak sekilde emülsifikasyon gerçeklestirilir. Cetyl Alcohol, Stearic Acid, Stearyl Alcohol, Glycerin, Glyceryl Stearate & PEG, respectively, in a separate boiler (A-Boiler) 75 stearate (Gelot 64), Benzyl alcohol, Butyl hydroxy toluene (BHT), Butyl hydroxy anisole (BHA), Tretinoin and Flucinolone Acetonide is added and it is completely dissolved by mixing. After observing that complete dissolution has taken place, the A-Boiler is added to the main vessel with a pallet mixer and added with the homogenizer. Pallet mixer and homogenizer together emulsification takes place.
Emülsifikasyonun ardindan ana kazan palet tipi karistirici ile kazan sicakligi 35-40°C'ye düsene kadar sogutulur. After emulsification, with the main boiler pallet mixer, until the boiler temperature drops to 35-40°C. it is cooled.
Ardindan yavas karistirma esliginde, Hidrokinon yavas yavas eklenir. Hydroquinone is then added slowly, accompanied by slow mixing.
Hidrokinon eklenmesinin ardindan yavas hizda karistirma islemi palet tipi karistirici ile gerçeklestirilir. After the hydroquinone is added, the slow speed mixing is carried out with a paddle mixer.
Hazirlanan krem tüplere doldurulur. Örnek 1. Formülasvon Örnekleri (%i: Kullanim Amaci Madde Örnek-2 Örnek-3 Flusinolon Asetonit 0.010 0.010 Etkin Madde Tretinoin 0.050 0.050 Hidrokinon 4.000 4.000 Butil hidroksi toluen 0.020 0.020 Antioksidan Butil hidroksi anisol 0.020 0.020 Askorbik asit 0.250 0.000 Selat yapici Disodyum EDTA 0.030 0.030 Ant'm'kmb'ya' Benzil alkol 0.300 0.300 koruyucu Setil alkol 2.000 2.000 Magnezyum aluminyum silikat 2.000 2.000 sert'ESt'r'c' (St'ffen'ng Stearil alkol 2.000 2.000 Çözücü, tasiyici y.m. y.m. The prepared cream is filled into tubes. Example 1. Formulation Examples (%i: Intended Use Item Example-2 Example-3 Flucinolone Acetonide 0.010 0.010 Active Ingredient Tretinoin 0.050 0.050 Hydroquinone 4,000 4,000 Butyl hydroxy toluene 0.020 0.020 Antioxidant Butyl hydroxy anisole 0.020 0.020 Ascorbic acid 0.250 0.000 Selatizer Disodium EDTA 0.030 0.030 Ant'm'kmb'ya' Benzyl alcohol 0.300 0.300 protector Cetyl alcohol 2,000 2,000 Magnesium aluminum silicate 2,000 2,000 sert'ESt'r'c' (St'ffen'ng Stearyl alcohol 2.000 2.000 Solvent, carrier y.m. m.m.
Franz difüzyon testi (sekil 2-4) Referans ürün ve test ürünlerinde (F4852-F4SS7) bulunan Tretinoin, Hidrokinon ve Flusinolon asetonid etken maddesinin çözünme ortaminda difüzyon hizi analizleri yapilmistir. Test ürünlere (F4852-F4857) ait egim degerlerinin referans ürüne ait egim degerlerine oranlari hesaplanmis olup bu oranlar küçükten büyüge olacak sekilde siralanmistir. Hesaplamalar sonucunda F4852 seri numarali test üründen elde üründen elde edilen oranlarin en küçük °eri %79 ile en küçük 29. degeri %96.60, olarak bulunmus difüzyon hizinin referans ürüne ait difüzyon hizina esdeger oldugu tespit edilmistir. (Kaynak: FDA Guidance for Industry Nonsterile Semisolid Dosage Forms (May 1997)). Franz diffusion test (figure 2-4) Tretinoin, Hydroquinone and Flucinolone acetonide found in reference products and test products (F4852-F4SS7) Diffusion rate analyzes were made in the dissolution medium of the active ingredient. To test products (F4852-F4857) The ratios of the slope values of the reference product to the slope values of the reference product have been calculated and these ratios are smaller. it is arranged in a large order. As a result of the calculations, it was obtained from the test product with serial number F4852. The smallest value of the ratios obtained from the product was 79% and the smallest 29th value was 96.60%. It was determined that the diffusion rate was equivalent to the diffusion rate of the reference product. (Source: FDA Guidance for Industry Nonsterile Semisolid Dosage Forms (May 1997)).
Sta bilite testi Antioksidan içeren Optimum Formülasyon (Örnek-2) ve Antioksidan içermeyen Formülasyona (Örnek-3) Ait &Ay Stabilite Impürite Analizi Sonuçlari asagida gösterilmistir. 40°C/ 30°C/ 25°C/ 2-8°C/ Test Baslangiç __ %75 am .. %65 en __ %60 en .. Buzdolabi 2 3 2 3 2 3 2 3 Flusinolon Asetonid'e Bagli Impüriteler impurite Tretinoin'e Bagli Impüriteler Izotretinoin BDL %03 BDL %0.1 BDL BDL BDL BDL BDL .Herhapg' b" BDL BDL BDL BDL BDL BDL BDL BDL BDL impurite Toplam Impürite BDL %03 BDL %0.1 BDL BDL BDL BDL BDL Herhangi bir %Ü.6 impurite Bulusun avantajlari Esdeger ürünün saklama kosulunun buzdolabinda 2°-8° C arasinda olmasi nedeniyle hem üretim ve dagitim zincirinde, hem de hasta kullanimi esnasinda özel saklama kosulu gerekmektedir. Ürün buzdolabinda saklanmadigi kosulda etkin maddeler bozunmakta ve impüriteler limit disi seviyelere yükselmektedir. Gerçeklestirilen çalismalar sonucu 6 Ay oda kosulunda impüritelerin limit içinde seyrettigi gösterilmistir. Bu sayede gelistirilen ürün oda kosulunda saklanabilmektedir. 24 ay oda kosulunda yapilan stabilite çalismasi sonucu ürünün özel bir kosul gerekmeksizin saklanabildigi gösterilmistir. ilaveten gelistirilen üretim yöntemi ile homojen bir bitmis ürün elde edilmektedir. Gelistirilmis olan formülün franz difüzyon sonuçlarinin referans ürün ile istatistiksel olarak benzer oldugu gösterilmistir. stablity test Optimum Formulation with Antioxidant (Example-2) and Formulation without Antioxidant (Example-3) The results of the &Month Stability & Impurity Analysis are shown below. 40°C/ 30°C/ 25°C/ 2-8°C/ Test Start __ 75% am .. 65% en __ 60% en .. Refrigerator 2 3 2 3 2 3 2 3 Impurities Due to Flucinolone Acetonide impurity Impurities Due to Tretinoin Isotretinoin BDL 03% BDL 0.1% BDL BDL BDL BDL BDL .Herhapg' b" BDL BDL BDL BDL BDL BDL BDL BDL BDL impurity Total Impurity BDL 03% BDL 0.1% BDL BDL BDL BDL BDL Any %Ü.6% impurity Advantages of the invention Since the storage conditions of the equivalent product are between 2°-8°C in the refrigerator, both production and Special storage conditions are required both in the distribution chain and during patient use. Product Active substances decompose and impurities reach out-of-limit levels if not stored in the refrigerator. is rising. As a result of the studies carried out, the impurities were within the limit in room conditions for 6 months. has been shown to watch. In this way, the developed product can be stored under room conditions. 24 months room As a result of the stability study carried out under the condition, the product can be stored without any special conditions. shown. In addition, a homogeneous finished product is obtained with the developed production method. developed It has been shown that the franz diffusion results of the formula are statistically similar to the reference product.
Sekillerin açiklamasi: Sekil 1. Krem formülasyonu üretim prosesi Sekil 2. Test (F4852-F4SS7) ve Referans Ürüne ait Tretinoin Difüzyon Profilleri A: Referans ürün B: Test ürünü Seri No: F4852 C: Test ürünü Seri No: F4857 Sekil 3. Test (F4852-F4SS7) ve Referans Ürüne ait Hidrokinon Difüzyon Profilleri A: Referans ürün B: Test ürünü Seri No: F4852 C: Test ürünü Seri No: F4857 Sekil 4. Test (F4852-F4857) ve Referans Ürüne ait Flusinolon asetonid Difüzyon Profilleri A= Referans ürün B: Test ürünü Seri No: F48$2 C: Test ürünü Seri No: F4857Description of figures: Figure 1. Cream formulation production process Figure 2. Tretinoin Diffusion Profiles of Test (F4852-F4SS7) and Reference Product A: Reference product B: Test product Serial No: F4852 C: Test product Serial No: F4857 Figure 3. Hydroquinone Diffusion Profiles of Test (F4852-F4SS7) and Reference Product A: Reference product B: Test product Serial No: F4852 C: Test product Serial No: F4857 Figure 4. Flucinolone acetonide Diffusion Profiles of Test (F4852-F4857) and Reference Product A= Reference product B: Test product Batch No: F48$2 C: Test product Serial No: F4857
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| PCT/TR2021/050625 WO2022046006A1 (en) | 2020-08-26 | 2021-06-18 | Semisolid pharmaceutical compositions used in treatment of melasma |
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| FR2901134B1 (en) * | 2006-05-19 | 2008-10-03 | Galderma Sa | USE OF A COMPOSITION COMPRISING A COMBINATION OF HYDROQUINONE, FLUOCINOLONE ACETONIDE, AND TRETINOINE FOR THE TREATMENT OF CUTANEOUS SIGNALS OF PHOTOVEMENSIONING |
| US9629785B2 (en) * | 2010-10-21 | 2017-04-25 | Cadila Healthcare Limited | Pharmaceutical compositions comprising nano size droplets of skin whitening agents |
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