LT4329B - EXTERNAL USE PRE-FIRE AGENT - Google Patents
EXTERNAL USE PRE-FIRE AGENT Download PDFInfo
- Publication number
- LT4329B LT4329B LT97-100A LT97100A LT4329B LT 4329 B LT4329 B LT 4329B LT 97100 A LT97100 A LT 97100A LT 4329 B LT4329 B LT 4329B
- Authority
- LT
- Lithuania
- Prior art keywords
- nimesulide
- weight
- inflammatory agent
- component
- oil
- Prior art date
Links
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 claims abstract description 67
- 229960000965 nimesulide Drugs 0.000 claims abstract description 66
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 21
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 21
- 239000004480 active ingredient Substances 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 43
- 239000006071 cream Substances 0.000 claims description 38
- 238000002360 preparation method Methods 0.000 claims description 37
- -1 fatty acid ester Chemical class 0.000 claims description 17
- 238000010521 absorption reaction Methods 0.000 claims description 16
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 16
- 239000000194 fatty acid Substances 0.000 claims description 16
- 229930195729 fatty acid Natural products 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 15
- 239000002245 particle Substances 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical group CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 claims description 9
- 229940043276 diisopropanolamine Drugs 0.000 claims description 9
- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 claims description 9
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 claims description 8
- 229960003338 crotamiton Drugs 0.000 claims description 8
- 150000007530 organic bases Chemical group 0.000 claims description 8
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- 239000000463 material Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000002736 nonionic surfactant Substances 0.000 claims description 7
- 239000002674 ointment Substances 0.000 claims description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- 239000010419 fine particle Substances 0.000 claims description 6
- 239000003871 white petrolatum Substances 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 4
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 3
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 2
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- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- LUPNKHXLFSSUGS-UHFFFAOYSA-M sodium;2,2-dichloroacetate Chemical compound [Na+].[O-]C(=O)C(Cl)Cl LUPNKHXLFSSUGS-UHFFFAOYSA-M 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Išradimo sritis ir pramoninis panaudojimas Šis išradimas yra susijęs su priešuždegiminiu agentu, skirtu išoriniam vartojimui, j kurį įeina nimesulidas, kaip veiklusis ingredientas. Konkrečiau, šis išradimas yra susijęs su priešuždegiminiu agentu, skirtu išoriniam vartojimui, į kurį įeina nimesulidas, kaip veiklusis ingredientas, ir pagrindo komponentas, kuriame nimesulidas yra įterptas į pagrindo komponentą disperguotoje būsenoje, o taip pat ir su šio agento pagaminimo būdu.FIELD OF THE INVENTION AND INDUSTRIAL USE The present invention relates to an anti-inflammatory agent for external use, which includes nimesulide as an active ingredient. More particularly, the present invention relates to an anti-inflammatory agent for external use, which includes nimesulide as the active ingredient, and a base component wherein the nimesulide is incorporated into the base component in a dispersed state, and also to a process for the preparation of this agent.
Ankstesnis technikos lygisPrior art
Nesteroidiniai priešuždegiminiai preparatai turi tokį trūkumą, kad vartojant peroraliniu būdu, jie sukelia skrandžio ir žarnų trakto sutrikimus. Norint išvengti šio trūkumo, buvo atlikti įvairūs tyrimai, bandant sukurti priešuždegiminį agentą išoriniam vartojimui, ir klinikiniam naudojimui buvo pateikti keli prekybiniai produktai. Tačiau iki šiol sukurtas išorinio vartojimo priešuždegiminis agentas turi nepakankamą klinikinį poveikį net ir tuo atveju, kai jis yra veiksmingas pagrindiniuose testuose.Non-steroidal anti-inflammatory drugs have the disadvantage that they cause gastrointestinal disorders when administered orally. To overcome this drawback, various studies have been conducted in an attempt to develop an anti-inflammatory agent for external use, and several commercial products have been made available for clinical use. However, the exogenous anti-inflammatory agent developed so far has insufficient clinical effects even when effective in major tests.
Nimesulidą (4-nitro-2-fenoksimetansulfonanilidą), kuris yra vienas iš nesteroidinių priešuždegiminių agentų, pirmą kartą susintetino Riker Co. Jungtinėse Valstijose ir po to jį, kaip peroralinio vartojimo preparatą, ištobulino Europoje Helsinn Co. Šveicarijoje. Kadangi jis yra skirtingas nuo įprasti} rūgštinių priešuždegiminių agentų, yra žinoma, kad nimesulidas selektyviai inhibuoja PGE2 (C0X2), ir jis yra naujo tipo farmacinis agentas, kuris, kaip galima tikėtis, bus efektingas klinikiniam naudojimui.Nimesulide (4-nitro-2-phenoxymethanesulfonanilide), one of the non-steroidal anti-inflammatory agents, was first synthesized by Riker Co. In the United States and thereafter it was refined as an oral preparation in Europe by Helsinn Co. In Switzerland. Because it is different from common acidic anti-inflammatory agents, nimesulide is known to selectively inhibit PGE2 (C0X2) and is a novel type of pharmaceutical agent that is expected to be effective in clinical use.
Nagrinėjant ankstesnį, su nimesulidu susijusį technikos lygį, reikia pacituoti US patentą Nr. 3480597, aprašantį medžiagą, ir gavimo būdą aprašančius patentus: ekspertų patikrintą Japonijos patento publikaciją (Kokoku) Sho-58-35989, ekspertų patikrintą Japonijos patento publikaciją (Kokoku) Sho58-50984 ir ekspertų patikrintą Japonijos patento publikaciją (Kokoku) Sho-5944311. Tačiau šiuose literatūros šaltiniuose nėra aprašymų arba darbinių pavyzdžių, susijusių su konkrečiais farmaciniais preparatais, nors juose minimos dozuotos formos, tokios kaip kapsulės, kremai, geliai, dangalai ir pan.In the prior art relating to nimesulide, reference is made to U.S. Pat. Patent Nos. 3480597, describing the material, and the patents describing the process thereof: Expert Examined Japanese Patent Publication (Kokoku) Sho-58-35989, Expert Inspected Japanese Patent Publication (Kokoku) Sho58-50984, and Expert Inspected Japanese Patent Publication (Kokoku) Sho-5944311. However, these references do not include descriptions or working examples of particular pharmaceuticals, although they do refer to dosage forms such as capsules, creams, gels, coatings, and the like.
Be to, kaip literatūros šaltinis gali būti pacituota atvira Japonijos patento paraiška (Kohyo) Hei-6-502842, paremta paraiška tarptautiniam patentui, susijusi su nimesulido farmaciniu preparatu. Šis patentas yra skirtas nimesulido inkliuzijos junginio su ciklodekstrinu pagaminimui, kad būtų gaunamas vandenyje tirpus nimesulidas, norint padidinti tirpumą vandenyje ir tuo pačiu padidinti nimesulido absorbciją iš skrandžio ir žarnų trakto. Todėl šio išradimo objektas nėra išorinis vartojimas. Taigi, nėra žinoma jokio literatūros šaltinio, kuriame būtų aiškiai aprašomas nimesulido, kaip išorinio vartojimo preparato, panaudojimas, ir nežinoma atvejo, susijusio su tikru išoriniu nimesulido panaudojimu konkrečioje dozuotoje formoje.In addition, an open Japanese patent application (Kohyo) Hei-6-502842 based on an international patent application relating to a pharmaceutical preparation of nimesulide may be cited as a source of literature. This patent is for the preparation of a nimesulide inclusion compound with cyclodextrin to produce a water-soluble nimesulide to increase water solubility while increasing the absorption of nimesulide from the gastrointestinal tract. Therefore, the present invention is not intended for external use. Thus, there is no literature available that explicitly describes the use of nimesulide as a topical preparation, nor is there any case regarding the actual external use of nimesulide in a particular dosage form.
Nors nimesulidas turi farmakologinį poveikį lygų arba netgi didesnį nei indometacinas, kuris laikomas labai stipriai veikiančiu priešuždegiminiu agentu, vis tik yra keletas neišspręstų problemų, susijusių su jo, kaip išorinio preparato, topiniu vartojimu. Šios problemos yra: 1) nimesulidas yra blogai tirpus ir nelengvai ištirpinamas vandenyje ir įvairiuose organiniuose tirpikliuose; 2) norint ištirpinti nimesulidą, reikia pridėti labai gerai soliubilizuojančio tirpiklio, kuris sukelia problemas, tokias kaip odos suerzinimas, odos sutrūkinėjimas, niežėjimas ir staigus uždegimas; 3) net ir ištirpinus nimesulidą, gauti farmaciniai preparatai labai pageltonuoja ir jų išvaizda labai pablogėja; 4) naudojami farmaciniai prepatatai sutepa drabužius, kurie liečiasi su preparatu.Although nimesulide has a pharmacological effect equal to or even greater than indomethacin, which is considered a very potent anti-inflammatory agent, there are still some unresolved problems with its topical use as an external agent. These problems are: 1) Nimesulide is poorly soluble and not readily soluble in water and various organic solvents; 2) To dissolve nimesulide, it is necessary to add a very solubilizing solvent which causes problems such as skin irritation, skin cracking, itching and sudden inflammation; 3) even after dissolution of the nimesulide, the resulting pharmaceuticals are very yellow and greatly impaired in appearance; 4) pharmaceutical formulations used lubricate clothing in contact with the preparation.
Taigi susidaro padėtis, kad atsisakoma bandyti panaudoti nimesulidą, kaip išorinį preparatą.This results in a refusal to attempt to use nimesulide as an external preparation.
Problemos, kurias turi išspręsti išradimasProblems to be solved by the invention
Šio išradimo tikslas yra gauti išorinio panaudojimo priešuždegiminį agentą, turintį nimesulido, topiniam vartojimui, kuris yra nimesulido išorinis preparatas, rodantis puikią absorbciją ir neturintį problemų, susijusių su spalvos atsiradimu bei nekenksmingumu odai.It is an object of the present invention to provide a topical application of an anti-inflammatory agent containing nimesulide for topical use which is an external preparation of nimesulide which exhibits excellent absorption and has no problem with color development and harmlessness to the skin.
Šių problemų sprendimo būdaiSolutions to these problems
Atlikę plačius tyrimus, nagrinėdami aukščiau aprašytus nimesulido, kaip išorinio preparato, trūkumus, išradėjai atrado, kad visi aukščiau aprašyti trūkumai išnyksta, kai nimesulidas disperguotoje formoje sumaišomas su pagrindo komponentu, ir pateikė šį išradimą. Tai yra, kai nimesulidas įmaišomas disperguotoje formoje į pagrindo komponentą, jis turi stebėtinai gerą farmakologinį poveikį, lygų arba netgi geresnį nei farmacinio preparato, kuriame nimesulidas yra įmaišytas ištirpintoje formoje, poveikis. Be to, gali būti sumažintas soliubilizuojančio agento kiekis ir todėl pagerinamas nekenksmingumas odai. Dar daugiau, buvo nustatyta, kad neatsiranda farmacinio preparato spalvos pasikeitimo, skirtingai nuo pilnai ištirpinto tipo farmacinių preparatų. Tai yra, gali būti išspręstos visos aukščiau aprašytos išorinio vartojimo preparato problemos.After extensive studies of the above described drawbacks of nimesulide as an external preparation, the present inventors have discovered that all of the above drawbacks disappear when the nimesulide is dispersed in a dispersed form with the base component and has provided the present invention. That is, when nimesulide is incorporated in a dispersed form into a base component, it has a surprisingly good pharmacological effect, equal to or even better than that of a pharmaceutical preparation in which nimesulide is mixed in a dissolved form. In addition, the amount of solubilizing agent may be reduced and thus improved skin harmlessness. Moreover, unlike fully reconstituted pharmaceutical formulations, no discoloration of the pharmaceutical formulation was found. That is, all the above external preparation preparation problems can be solved.
Konkrečiau, šio išradimo tikslas yra pasiekiamas, įmaišant nimesulidą, kaip veiklųjį ingredientą, disperguotoje formoje į pagrindo komponentą, kuris apima alyvos tipo medžiagą, nejoninį paviršiaus aktyvų agentą, bazinę medžiagą, vandenį ir/arba absorbciją didinančią medžiagą. Tiksliau, 0,1-5 masės% nimesulido, kaip veikliosios medžiagos, smulkių dalelių pavidalu disperguojama ir įmaišoma į pagrindo komponentą, kuriame yra dar ir hidrofilinio polimero arba baltojo vazelino, pagaminant išorinio vartojimo preparatą, tokį kaip kremas arba tepalas.More specifically, the object of the present invention is achieved by incorporating nimesulide as the active ingredient in dispersed form into a base component comprising an oil-like substance, a non-ionic surfactant, a base substance, water and / or an absorption enhancer. In particular, 0.1 to 5% by weight of nimesulide as an active ingredient is dispersed in the form of fine particles and incorporated into a base component further comprising a hydrophilic polymer or white petroleum jelly to form a topical preparation such as a cream or ointment.
Nimesulidas, kaip veiklusis ingredientas, pagrindo komponente gali būti naudojamas bet kokioje formoje, kokioje jį galima pagaminti smulkių dalelių pavidalu. Disperguojamų dalelių sumalimo lengvumo ir kainos požiūriu, tinkamas nimesulido dalelių skersmuo yra 0,01 pm arba daugiau. Antra vertus, transderminės absorbcijos ir aplikacijos pojūčio (grubumo pojūtis) požiūriu, tinkamesni skersmenys yra 75 pm arba mažesni, t.y. tokio dydžio dalelės, kurios praeina per 200-akučių sietą, geriau nuo 0,5 iki 50 pm, o geriausia nuo 1 ik 30 pm.Nimesulide, as an active ingredient, can be used in the base component in any form in which it can be prepared in the form of fine particles. In terms of the ease and cost of grinding of the dispersible particles, a suitable particle diameter of nimesulide is 0.01 µm or more. On the other hand, in terms of transdermal absorption and application sensation (sense of roughness), preferred diameters are 75 µm or less, i.e. particles of a size passing through a 200-mesh sieve are preferably 0.5 to 50 µm, and preferably 1 to 30 µm.
Šio išradimo išorinio vartojimo priešuždegiminis agentas gali būti pagamintas tokiu būdu. Pavyzdžiui, kremo pavidalo agentas gaminamas, pridedant ir maišant karštai išlydytos alyvos tipo komponentų fazę ir vandeninę fazę, kurioje ištirpinti vandenyje tirpūs komponentai; pridedant nimesulidą smulkių dalelių pavidalu; ir toliau maišant ir šaldant. Tepalas pagaminamas, pridedant nimesulidą smulkių dalelių pavidalu į karštai išlydytus alyvos tipo komponentus maišant ir šaldant, ir po to vėl maišant ir šaldant.The anti-inflammatory agent for external use of the present invention may be prepared as follows. For example, a cream-like agent is prepared by adding and mixing a hot melt oil-type component phase and an aqueous phase in which the water-soluble components are dissolved; adding nimesulide in the form of fine particles; and further stirring and freezing. The ointment is made by adding nimesulide in the form of fine particles to the hot-melted oil-like components under stirring and refrigeration, and then again under stirring and refrigeration.
Pageidautina kontroliuoti farmacinio preparato pH, kad jis būti) nuo 4 iki 8, geriau nuo 5 iki 7, odos erzinimo ir transderminės absorbcijos požiūriu.It is desirable to control the pH of the pharmaceutical preparation to be from 4 to 8, preferably from 5 to 7, in terms of skin irritation and transdermal absorption.
Šio išradimo priešuždegiminio išorinio vartojimo preparato pagaminimui naudojamo pagrindo pavyzdžiai apima taip vadinamą gelinį kremą, kuriame yra hidrofilinis polimeras, alyvos tipo medžiaga, nejoninis paviršiaus aktyvusis agentas, bazinė medžiaga ir vanduo; susigeriantį kremą, pagaminamą iš aukštesniojo alkoholio, angliavandenilio, riebalų rūgšties esterio, polihidroksilinio alkoholio, bazės, antiseptiko, vandens ir pan.; hidrofilinį tepalą arba absorbuojamo tepalo kremą pagal The Japanese Pharmacopeia, pagaminamą iš baltojo vazelino, paviršiaus aktyviosios medžiagos, aukštesniojo alkoholio, angliavandenilio, riebalų rūgšties esterio, polihidroksilinio alkoholio, antiseptiko, vandens ir pan.; ir FAPG pagrindą, kuriame yra aukštesnysis alkoholis, polihidroksilinis alkoholis ir pan. Kaip kremo pavidalo agento receptas, tinkamiausias transderminės absorbcijos požiūriu, yra farmacinis preparatas, gaunamas pridedant 0,1-5 masės.% nimesulido į taip vadinamą gelio kremo pagrindą, kuriame yra 0,2-3 masės.% hidrofilinio polimero, 2-20 masės.% alyvos tipo medžiagos, 0,5-7 masės% nejoninio paviršiaus aktyviojo agento, 0,015 masės% bazinės medžiagos ir 50-90 masės% vandens. Kaip tepalo pavidalo preparato receptas labiausiai tinkamas yra farmacinis preparatas, gaunamas pridedant 0,1-5 masės% nimesulido į vazelino tepalą, turintį 35-80 masės% baltojo vazelino, 2-20 masės% alyvos tipo medžiagos ir 0,5-7 masės% nejoninio paviršiaus aktyviojo agento.Examples of the base used in the preparation of the anti-inflammatory topical formulation of the present invention include a so-called gel cream comprising a hydrophilic polymer, an oil-like substance, a non-ionic surfactant, a base and water; absorbent cream made from higher alcohol, hydrocarbon, fatty acid ester, polyhydric alcohol, base, antiseptic, water, etc .; a hydrophilic ointment or absorbent ointment cream according to The Japanese Pharmacopeia made from white petroleum jelly, surfactant, higher alcohol, hydrocarbon, fatty acid ester, polyhydric alcohol, antiseptic, water, etc .; and an FAPG base containing higher alcohol, polyhydroxyl alcohol, and the like. As a cream formulation, the most suitable formulation for transdermal absorption is a pharmaceutical preparation obtained by adding 0.1 to 5% by weight of nimesulide to a so-called gel cream base containing from 0.2 to 3% by weight of a hydrophilic polymer, 2 to 20% by weight. .% oil-type material, 0.5-7% w / w non-ionic surfactant, 0.015% w / w base and 50-90% w / w water. The most suitable formulation for the preparation of an ointment is a pharmaceutical preparation obtained by adding 0.1-5% by weight of nimesulide to a petroleum jelly containing 35-80% by weight of white petroleum jelly, 2-20% by weight of an oil-like substance and 0.5-7% by weight. nonionic surfactant.
Dabar šio išradimo pagrindiniai komponentai aprašomi smulkiau.The main components of the present invention are now described in more detail.
Hidrofilinio polimero pavyzdžiais yra karboksivinilo polimerai (CARBOPOL 940, 941, kuriuos gamina B.F. Goodrich Chemical Co., HIBISWAKO 104,105, kuriuos gamina Wako Pure Chemical Industries, Ltd., ir pan.), hidroksipropilceliuliozė (HPC-L, HPC-M, kurią gamina Nippon Soda Co., Ltd., ir pan.), polioksietileno-polioksipropileno blokinis kopolimeras (Lutrol F68, kurj gamina BASF Co., ir pan.). Šie hidrofiliniai polimerai gali būti naudojami vieni arba kaip dviejų arba daugiau polimerų mišinys; klampumo ir lipnumo požiūriu geriau, kai jų kiekiai yra 0,2-3 masės%, o geriausia 0,5-2 masės%.Examples of hydrophilic polymer include carboxyvinyl polymers (CARBOPOL 940, 941 manufactured by BF Goodrich Chemical Co., HIBISWAKO 104,105 manufactured by Wako Pure Chemical Industries, Ltd., etc.), hydroxypropyl cellulose (HPC-L, HPC-M manufactured by HPC-L, HPC-M). Nippon Soda Co., Ltd., etc.), a polyoxyethylene-polyoxypropylene block copolymer (Lutrol F68 manufactured by BASF Co., etc.). These hydrophilic polymers can be used alone or as a mixture of two or more polymers; viscosity and stickiness are preferably present in amounts of 0.2 to 3% by weight, preferably 0.5 to 2% by weight.
Alyvos tipo medžiagos pavyzdžiais yra riebalų rūgščių esteriai, tokie kaip diizopropiladipatas, diizopropilsebacatas, dietilsebacatas, vidutinio ilgio riebalų rūgščių trigliceridai, vidutinio ilgio riebalų rūgščių propilenglikoliai, izopropilo miristatas ir pan.; riebalų rūgštys, tokios kaip stearino rūgštis, oleino rūgštis, miristino rūgšis ir pan.; aukštesnieji alkoholiai, tokie kaip cetanolis, stearilo alkoholis, cetostearilo alkoholis, oleino alkoholis, behenilo alkoholis ir pan.; angliavandeniliai, tokie kaip baltasis vazelinas, skystas parafinas, skvalanas ir pan.; augaliniai aliejai ir riebalai, tokie kaip alyvų aliejus, hohobos aliejus, ricinos aliejus ir pan.; ir kitos alyvos tipo medžiagos, tokios kaip krotamitonas, benzilo alkoholis ir panašios. Kremo pavidalo preparatų atveju kremo pasiskleidimo, transderminės absorbcijos, lipnumo, blizgesio ir preparatų nestabilumo (t.y. skysčių atsiskyrimo) požiūriu, alyvos tipo medžiagos kiekis mišinyje turi būti 2-20 masės%, geriau 5-15 masės%. Tepalo pavidalo preparatų atveju, alyvos tipo medžiagos kiekis mišinyje yra 2-20 masės%, geriau 3-7 masės%.Examples of oil-type material include fatty acid esters such as diisopropyl adipate, diisopropyl sebacate, diethyl sebacate, medium-length fatty acid triglycerides, medium-length fatty acid propylene glycols, isopropyl myristate, and the like; fatty acids such as stearic acid, oleic acid, myristic acid, etc .; higher alcohols such as cetanol, stearyl alcohol, cetostearyl alcohol, oleic alcohol, behenyl alcohol and the like; hydrocarbons such as white petroleum jelly, liquid paraffin, squalane, etc .; vegetable oils and fats such as olive oil, hohoba oil, castor oil, etc .; and other oil-like substances such as crotamitone, benzyl alcohol, and the like. In the case of cream formulations, the oil-like substance in the mixture should be present in an amount of 2-20% by weight, preferably 5-15% by weight, in terms of cream dispersion, transdermal absorption, tackiness, gloss and instability of the preparations (i.e. liquid separation). In the case of oily preparations, the oil-like substance is present in an amount of 2-20% by weight, preferably 3-7% by weight.
Paviršiaus aktyviojo agento pavyzdžiais yra riebalų rūgščių sorbitano esteriai, tokie kaip sorbitano monostearatas, sorbitano seskvistearatas ir pan.; riebalų rūgščių glicerolio esteriai, tokie kaip glicerolio monostearatas, diglicerolio monooleatas ir pan.; riebalų rūgščių polioksietilensorbitano esteriai, tokie kaip polioksietilen(20)sorbitano monostearatas, polioksietilen(20)sorbitano monooleatas ir pan.; riebalų rūgščių polietilenglikolio esteriai, tokie kaip polioksietileno(lO) monostearatas, polioksietileno(lO) monolauratas ir pan.; polioksietilenalkilo eteriai, tokie kaip polioksietileno(9) laurilo eteris, polioksietileno(23) cetilo eteris ir pan.; polioksietilenalkilfenilo eteriai, tokie kaip polioksietileno(lO) nonilfenilo eteris, polioksietileno(lO) oktilfenilo eteris ir pan.; ir polioksietileno hidrintas ricinos aliejus, toks kaip polioksietileno(lO) hidrintas ricinos aliejus, polioksietileno(60) hidrintas ricinos aliejus ir pan. Šie paviršiaus aktyvieji agentai gali būti naudojami vieni arba kaip dviejų arba daugiau agentų mišinys, kurių kiekis yra 0,5-7 masės%, geriau 1-5 masės%.Examples of the surfactant include sorbitan esters of fatty acids such as sorbitan monostearate, sorbitan sesquistearate and the like; glycerol esters of fatty acids such as glycerol monostearate, diglycerol monooleate and the like; polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, and the like; polyethylene glycol esters of fatty acids such as polyoxyethylene (10) monostearate, polyoxyethylene (10) monolaurate and the like; polyoxyethylene alkyl ethers such as polyoxyethylene (9) lauryl ether, polyoxyethylene (23) cetyl ether and the like; polyoxyethylene alkyl 10 phenyl ethers such as polyoxyethylene (10) nonylphenyl ether, polyoxyethylene (10) octylphenyl ether and the like; and polyoxyethylene hydrogenated castor oil such as polyoxyethylene (10) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil and the like. These surfactants can be used alone or as a mixture of two or more agents in an amount of 0.5-7% by weight, preferably 1-5% by weight.
Bazinės medžiagos pavyzdžiais yra neorganinės arba organinės bazės, tokios kaip kalio hidroksidas, natrio hidroksidas, trietanolaminas, diizopropanolaminas, monoetanolaminas ir pan.; transderminės absorbcijos požiūriu tinkamesnės yra organinės bazės. Bazinės medžiagos kiekis mišinyje yra 0,01-5 masės%, geriau 0,1-2 masės%.Examples of the base include inorganic or organic bases such as potassium hydroxide, sodium hydroxide, triethanolamine, diisopropanolamine, monoethanolamine and the like; organic bases are more suitable for transdermal absorption. The amount of base substance in the mixture is 0.01-5% by weight, preferably 0.1-2% by weight.
Be to, norint padidinti transderminę nimesulido absorbciją, j aukščiau aprašytus farmacinius preparatus galima pridėti absorbciją stiprinančių medžiagų, priklausomai nuo farmacinės receptūros tipo. Absorbciją stiprinančių medžiagų pavyzdžiais yra organinės bazės, krotamitonas, vidutinio ilgio riebalų rūgščių esteriai, 1-mentolis, benzilo alkoholis ir pan. Organinė bazė palengvina nimesulido išsilaisvinimą iš pagrindo, kadangi ji padaro nimesulidą tirpiu vandenyje, sudarydama druską su nimesulidu. Organinės bazės pavyzdžiais yra diizopropanolaminas, megluminas, trietanolaminas ir l-(2hidroksietil)pirolidinas; labiausiai tinkamos yra diizopropanolaminas ir l-(2hidroksietil)pirolidinas. Absorbciją stiprinančios medžiagos kiekis mišinyje yra 0,1-20 masės%, geriau 0,2-10 masės%, kuri yra viena arba kaip dviejų arba daugiau medžiagų mišinys.In addition, absorption enhancers may be added to the pharmaceutical formulations described above to increase transdermal nimesulide absorption, depending on the type of pharmaceutical formulation. Examples of absorption enhancers are organic bases, crotamitone, medium length esters of fatty acids, 1-menthol, benzyl alcohol and the like. The organic base facilitates the release of nimesulide from the base as it makes the nimesulide water soluble by forming a salt with nimesulide. Examples of the organic base include diisopropanolamine, Meglumine, triethanolamine and 1- (2-hydroxyethyl) pyrrolidine; most preferred are diisopropanolamine and l- (2-hydroxyethyl) pyrrolidine. The absorbent is present in an amount of from 0.1 to 20% by weight, preferably 0.2 to 10% by weight, which is either alone or as a mixture of two or more substances.
Aukščiau aprašyta bazinė medžiaga ir organinė bazė, kaip absorbciją stiprinanti medžiaga, veikia ir kaip preparato pH kontroliuojantis agentas. Tai yra, kai farmacinio preparato pH yra per mažas (pvz., 3 arba mažiau), didelis rūgštingumas erzina odą. Kai pH yra per didelis (pvz., 9 arba daugiau), sumažėja medicininio preparato transderminė absorbcija, labai erzinama oda ir farmacinis preparatas įgauna geltoną spalvą. Tokiu būdu, farmacinio preparato pH kontroliuojamas geriausiai 4-8 ribose, pridedant aukščiau aprašytos bazinės medžiagos arba absorbciją stiprinančios medžiagos reikiamą kiekį.The above-described basic material and the organic base also act as a pH-controlling agent for the preparation as an absorption enhancer. That is, when the pH of the pharmaceutical is too low (e.g. 3 or less), high acidity irritates the skin. When the pH is too high (e.g. 9 or more), the transdermal absorption of the medicinal product is reduced, the skin is severely irritated and the pharmaceutical product becomes yellow. In this way, the pH of the pharmaceutical preparation is preferably controlled within the range of 4-8 by adding the necessary amount of the above-described base material or absorption enhancer.
Apart aukščiau aprašytų komponentų, galima pridėti ir sumaišyti gyvulinių aliejų ir riebalų, vaškų, angliavandenilių, antiseptikų, drėkinančių medžiagų ir pan. Gyvulinių aliejų ir riebalų pavyzdžiais yra jautienos lajus, kiaulienos lajus, arklienos aliejus ir pan. Vaškų pavyzdžiais yra smulkiakristalinis vaškas, kalnų vaškas, bičių vaškas ir pan. Angliavandenilių pavyzdžiais yra parafinas, cerezinas ir pan. Antiseptikų pavyzdžiais yra metilparabenas, propilparabenas, butilparabenas ir pan. Drėkinančių medžiagų pavyzdžiais yra polihidroksiliniai alkoholiai, tokie kaip glicerolis, 1,3-butilenglikolis, propilenglikolis, dipropilenglikolis ir pan. Šių priedų kiekiai mišinyje gali būti tokie, kokie paprastai yra naudojami kremų ir tepalų receptūrose.In addition to the components described above, animal oils and fats, waxes, hydrocarbons, antiseptics, moisturizers and the like can be added and blended. Examples of animal oils and fats include beef tallow, pork tallow, horse oil and so on. Examples of waxes include fine crystal wax, mountain wax, beeswax and the like. Examples of hydrocarbons include paraffin, ceresine and the like. Examples of antiseptics include methylparaben, propylparaben, butylparaben and the like. Examples of wetting agents include polyhydric alcohols such as glycerol, 1,3-butylene glycol, propylene glycol, dipropylene glycol and the like. The amounts of these additives in the mixture may be those normally used in formulations of creams and ointments.
PAVYZDŽIAIEXAMPLES
Šis išradimas smulkiau pailiustruojamas toliau duodamais pavyzdžiais.The invention is further illustrated by the following examples.
pavyzdysexample
100 (3), (4), (5), (6) ir (8) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (7) komponentą apie 90 % (10) komponento, ir mišinys maišomas, kad susidaryti} emulsija. (2) komponentas laipsniškai dedamas 50 °C temperatūroje, ir mišinys kruopščiai maišomas. Po to, laipsniškai dedamas (1) komponentas ir disperguojamas maišant. Po to pridedamas tirpalas, pagamintas ištirpinant (9) komponentą likusiame (10) komponente, ir mišinys maišomas tol, kol jis pasidaro homogeninis. Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.Components 100 (3), (4), (5), (6) and (8) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added by dissolving component (7) in about 90% of component (10), and the mixture is stirred to form an emulsion. (2) The component is gradually added at 50 ° C and the mixture is stirred thoroughly. The component (1) is then gradually added and dispersed with stirring. A solution prepared by dissolving component (9) in the remaining component (10) is then added and the mixture is stirred until homogeneous. This results in an anti-inflammatory cream-containing preparation containing nimesulide.
pavyzdysexample
Komponentas masės% (1) Nimesulidas (dalelių skersmuo: 20-40 pm) 3 (2) Karboksivinilo polimeras 1 (3) Diizopropilsebacatas 5 (4) Izopropilmiristatas 10 (5) Krotamitonas 3 (6) Polioksietilen(20)sorbitano monostearatas 5 (7) Metilparabenas 0,1 (8) Propilparabenas 0,1 (9) Diizopropanolaminas 0,5 (10) Grynas vanduo_72,3Component by weight (1) Nimesulide (particle diameter: 20-40 µm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl sebacate 5 (4) Isopropyl myristate 10 (5) Crotamiton 3 (6) Polyoxyethylene (20) Sorbitan monostearate 5 (7) ) Methylparaben 0,1 (8) Propylparaben 0,1 (9) Diisopropanolamine 0,5 (10) Pure water_72,3
100 (3), (4), (5), (6) ir (8) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (7) komponentą apie 90 % (10) komponento, ir mišinys maišomas, kad susidarytų emulsija. (2) komponentas laipsniškai dedamas 50 °C temperatūroje, ir mišinys kruopščiai maišomas. Po to, laipsniškai dedamas (1) komponentas ir disperguojamas maišant. Po to pridedamas tirpalas, pagamintas ištirpinant (9) komponentą likusiame (10) komponente, ir mišinys maišomas tol, kol jis pasidaro homogeninis. Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.Components 100 (3), (4), (5), (6) and (8) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added by dissolving component (7) in about 90% of component (10), and the mixture is stirred to form an emulsion. (2) The component is gradually added at 50 ° C and the mixture is stirred thoroughly. The component (1) is then gradually added and dispersed with stirring. A solution prepared by dissolving component (9) in the remaining component (10) is then added and the mixture is stirred until homogeneous. This results in an anti-inflammatory cream-containing preparation containing nimesulide.
pavyzdysexample
Komponentas masės% (1) Nimesulidas (dalelių skersmuo: 5-20 pm) (2) Karboksivinilo polimeras (3) Dietilsebacatas (4) Vidutinio ilgio riebalų rūgšties trigliceridas (5) Krotamitonas (6) Polioksietilen(20)sorbitano monostearatas (7) Metilparabenas (8) Propilparabenas (9) l-(2-Hidroksietil)pirolidinas (10) Grynas vanduoComponent by weight (1) Nimesulide (particle diameter: 5 to 20 pm) (2) Carboxyvinyl polymer (3) Diethyl sebacate (4) Medium length triglyceride of fatty acid (5) Crotamiton (6) Polyoxyethylene (20) Sorbitan monostearate (7) Methylparaben (8) Propylparaben (9) 1- (2-Hydroxyethyl) pyrrolidine (10) Pure water
JJ
0,10.1
0,10.1
0,50.5
74,374.3
100 (3), (4), (5), (6) ir (8) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (7) komponentą apie 90 % (10) komponento, ir mišinys maišomas, kad susidarytų emulsija. (2) komponentas laipsniškai dedamas 50 °C temperatūroje, ir mišinys kruopščiai maišomas. Po to, laipsniškai dedamas (1) komponentas ir disperguojamas maišant. Po to pridedamas tirpalas, pagamintas ištirpinant (9) komponentą likusiame (10) komponente, ir mišinys maišomas tol, kol jis pasidaro homogeninis. Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.Components 100 (3), (4), (5), (6) and (8) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added by dissolving component (7) in about 90% of component (10), and the mixture is stirred to form an emulsion. (2) The component is gradually added at 50 ° C and the mixture is stirred thoroughly. The component (1) is then gradually added and dispersed with stirring. A solution prepared by dissolving component (9) in the remaining component (10) is then added and the mixture is stirred until homogeneous. This results in an anti-inflammatory cream-containing preparation containing nimesulide.
pavyzdysexample
Komponentas masės% (1) Nimesulidas (dalelių skersmuo: 5-20 pm) 5 (2) Karboksivinilo polimeras 1 (3) Dietilsebacatas 5 (4) Vidutinio ilgio riebalų rūgšties trigliceridas 8 (5) Krotamitonas 3 (6) Polioksietilen(20)sorbitano monostearatas 5 (7) Metilparabenas 0,1 (8) Propilparabenas 0,1 (9) l-(2-Hidroksietil)pirolidinas 0,5 (10) Grynas vanduo 72,3 ϊόο (3), (4), (5), (6) ir (8) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (7) komponentą apie 90 % (10) komponento, ir mišinys maišomas, kad susidarytų emulsija. (2) komponentas laipsniškai dedamas 50 °C temperatūroje, ir mišinys kruopščiai maišomas. Po to, laipsniškai dedamas (1) komponentas ir disperguojamas maišant. Po to pridedamas tirpalas, pagamintas ištirpinant (9) komponentą likusiame (10) komponente, ir mišinys maišomas tol, kol jis pasidaro homogeninis. Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.Component% by weight (1) Nimesulide (particle diameter: 5-20 pm) 5 (2) Carboxyvinyl polymer 1 (3) Diethyl sebacate 5 (4) Medium length triglyceride of fatty acid 8 (5) Crotamiton 3 (6) Polyoxyethylene (20) Sorbitan monostearate 5 (7) Methylparaben 0,1 (8) Propylparaben 0,1 (9) 1- (2-Hydroxyethyl) pyrrolidine 0.5 (10) Pure water 72.3% (3), (4), (5) Components (6) and (8) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added by dissolving component (7) in about 90% of component (10), and the mixture is stirred to form an emulsion. (2) The component is gradually added at 50 ° C and the mixture is stirred thoroughly. The component (1) is then gradually added and dispersed with stirring. A solution prepared by dissolving component (9) in the remaining component (10) is then added and the mixture is stirred until homogeneous. This results in an anti-inflammatory cream-containing preparation containing nimesulide.
pavyzdysexample
Komponentas masės% (1) Nimesulidas (dalelių skersmuo: 0,5-10 ųm) 3 (2) Karboksivinilo polimeras 1 (3) Diizopropiladipatas 5 (4) Izopropilmiristatas 10 (5) 1-Mentolis . 2 (6) Polioksietilen(20)sorbitano monostearatas 5 (7) Metilparabenas 0,1 (8) Propilparabenas 0,1 (9) Diizopropanolaminas 0,5 (10) Grynas vanduo_73,3Component by weight (1) Nimesulide (particle diameter: 0.5-10 µm) 3 (2) Carboxyvinyl polymer 1 (3) Diisopropyl adipate 5 (4) Isopropyl myristate 10 (5) 1-Menthol. 2 (6) Polyoxyethylene (20) Sorbitan monostearate 5 (7) Methylparaben 0,1 (8) Propylparaben 0,1 (9) Diisopropanolamine 0,5 (10) Pure water_73,3
100 (3), (4), (5), (6) ir (8) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (7) komponentą apie 90 % (10) komponento, ir mišinys maišomas, kad susidarytų emulsija. (2) komponentas laipsniškai dedamas 50 °C temperatūroje, ir mišinys kruopščiai maišomas. Po to, laipsniškai dedamas (1) komponentas ir disperguojamas maišant. Po to pridedamas tirpalas, pagamintas ištirpinant (9) komponentą likusiame (10) komponente, ir mišinys maišomas tol, kol jis pasidaro homogeninis. Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.Components 100 (3), (4), (5), (6) and (8) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added by dissolving component (7) in about 90% of component (10), and the mixture is stirred to form an emulsion. (2) The component is gradually added at 50 ° C and the mixture is stirred thoroughly. The component (1) is then gradually added and dispersed with stirring. A solution prepared by dissolving component (9) in the remaining component (10) is then added and the mixture is stirred until homogeneous. This results in an anti-inflammatory cream-containing preparation containing nimesulide.
pavyzdysexample
Komponentas (1) Nimesulidas (dalelių skersmuo: 5-20 ųm) (2) Stearino rūgštis (3) Diizopropiladipatas (4) Cetanolis (5) Vidutinio ilgio riebalų rūgšties trigliceridas (6) Polioksietilen(23)cetilo eteris (7) Sorbitano monostearatas (8) 1,3-butilenglikolis (9) Diizopropanolaminas (10) Natrio benzoatas (11) Grynas vanduo masės%Component (1) Nimesulide (particle diameter: 5-20 µm) (2) Stearic acid (3) Diisopropyl adipate (4) Cethanol (5) Medium length triglyceride of fatty acid (6) Polyoxyethylene (23) Cetyl ether (7) Sorbitan monostearate ( 8) 1,3-Butylene glycol (9) Diisopropanolamine (10) Sodium benzoate (11) Pure water by weight
0,5 o0.5 o
J oYeah
JJ
0,10.1
69,469.4
100 (2), (3), (4), (5), (6) ir (7) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (8), (9) ir (10) komponentus (11) komponente, ir mišinys maišomas, kad susidarytų emulsija. (1) komponentas laipsniškai dedamas 50 °C arba žemesnėje temperatūroje, ir mišinys maišomas tol, kol jis pasidaro homogeninis.Components 100 (2), (3), (4), (5), (6) and (7) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added by dissolving components (8), (9) and (10) in component (11), and the mixture is stirred to form an emulsion. The component (1) is gradually added at a temperature of 50 ° C or lower and the mixture is stirred until homogenous.
Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.This results in an anti-inflammatory cream-containing preparation containing nimesulide.
pavyzdysexample
Komponentas masės% (1) Nimesulidas (dalelių skersmuo: 0,5-0 pm) 3 (2) Krotamitonas 3 (3) Dietilsebacatas 5 (4) Mikrokristalinis vaškas 10 (5) Vidutinio ilgio riebalų rūgšties trigliceridas 7 (6) Riebalų rūgšties polietilenglikolio esteris 10 (7) Behenilo alkoholis 4 (8) Diizopropanolaminas 0,2 (9) Dipropilenglikolis 7 (10) Propilenglikolio monostearatas 7 (11) Baltasis vazelinas_43,8Component by weight (1) Nimesulide (particle diameter: 0.5-0 pm) 3 (2) Crotamiton 3 (3) Diethyl sebacate 5 (4) Microcrystalline wax 10 (5) Medium length triglyceride of fatty acid 7 (6) Polyethylene glycol of fatty acid ester 10 (7) Behenyl alcohol 4 (8) Diisopropanolamine 0.2 (9) Dipropylene glycol 7 (10) Propylene glycol monostearate 7 (11) White Vaseline_43.8
100 (2), (3), (4), (5), (6), (7), (8), (9), (10) ir (11) komponentai išlydomi šildant 80 °C temperatūroje. (1) komponentas laipsniškai dedamas 50 °C temperatūroje ir disperguojamas maišant. Taip gaunamas priešuždegiminis tepalo pavidalo preparatas, turintis nimesulido.Components 100 (2), (3), (4), (5), (6), (7), (8), (9), (10) and (11) are melted by heating at 80 ° C. Component (1) is gradually added at 50 ° C and dispersed with stirring. This produces an anti-inflammatory ointment containing nimesulide.
pavyzdys (Dispersinio tipo kremo preparatas, kurio veikliojo ingrediento dalelių skersmuo yra 75-180 pm)Example (A dispersion type cream formulation with a particle diameter of 75-180 µm as an active ingredient)
Komponentas masės% (1) Nimesulidas (dalelių skersmuo: 75-180 pm) (2) Karboksivinilo polimeras (3) Izopropilmiristatas (4) Polioksietilen(20)sorbitano monostearatas (5) Metilparabenas (6) Propilparabenas (7) Propilenglikolis (8) Dietanolaminas (9) Grynas vanduoComponent by weight (1) Nimesulide (particle diameter: 75-180 µm) (2) Carboxyvinyl polymer (3) Isopropyl myristate (4) Polyoxyethylene (20) Sorbitan monostearate (5) Methylparaben (6) Propylparaben (7) Propylene glycol (8) Diethanolamine (9) Pure water
0,10.1
0,10.1
0,50.5
72,372.3
100 (3), (4) ir (6) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (6) ir (7) komponentus apie 90 % (9) komponento, ir mišinys maišomas, kad susidarytų emulsija. (2) komponentas laipsniškai dedamas 50 °C temperatūroje, ir mišinys kruopščiai maišomas. Po to, laipsniškai dedamas (1) komponentas ir disperguojamas maišant. Po to pridedamas tirpalas, pagamintas ištirpinant (8) komponentą likusiame (9) komponente, ir mišinys maišomas tol, kol jis pasidaro homogeninis. Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.Components 100 (3), (4) and (6) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added by dissolving components (6) and (7) in about 90% of component (9) and the mixture is stirred to form an emulsion. (2) The component is gradually added at 50 ° C and the mixture is stirred thoroughly. The component (1) is then gradually added and dispersed with stirring. A solution prepared by dissolving component (8) in the remaining component (9) is added and the mixture is stirred until homogenous. This results in an anti-inflammatory cream-containing preparation containing nimesulide.
Standartinis pavyzdys (Kremo pavidalo preparatas, kuriame veiklusis ingredientas yra ištirpęs)Standard Example (Cream preparation containing the active ingredient dissolved)
Komponentas masės% (1) Nimesulidas 3 (2) Karboksivinilo polimeras 1 (3) Izopropilmiristatas 15 (4) Polioksietilen(20)sorbitano monostearatas 5 (5) Metilparabenas 0,1 (6) Propilparabenas 0,1 (7) 1,3-Butilenglikolis 3 (8) Dietanolaminas 6 (9) Grynas vanduo_66,8 ioo“ (3), (4) ir (6) komponentai išlydomi šildant 75 °C temperatūroje. Šioje temperatūroje pridedamas atskirai pagamintas tirpalas, ištirpinant (5) ir (7) komponentus apie 90 % (9) komponento, ir mišinys maišomas, kad susidarytų emulsija. (2) komponentas laipsniškai dedamas 50 °C temperatūroje, ir mišinys kruopščiai maišomas, kad ištirptų (2) komponentas. Po to, laipsniškai dedamas (1) komponentas ir maišoma. Po to pridedamas tirpalas, pagamintas ištirpinant (8) komponentą likusiame (9) komponente, ir mišinys maišomas tol, kol jis pasidaro homogeninis. Taip gaunamas priešuždegiminis kremo pavidalo preparatas, turintis nimesulido.Component by weight (1) Nimesulide 3 (2) Carboxyvinyl polymer 1 (3) Isopropyl myristate 15 (4) Polyoxyethylene (20) Sorbitan monostearate 5 (5) Methylparaben 0,1 (6) Propylparaben 0,1 (7) 1,3- Butylene Glycol 3 (8) Diethanolamine 6 (9) Pure Water_66.8 ioo The components of (3), (4) and (6) are melted by heating at 75 ° C. At this temperature, a separately prepared solution is added, dissolving components (5) and (7) in about 90% of component (9), and the mixture is stirred to form an emulsion. The component (2) is gradually added at 50 ° C, and the mixture is stirred thoroughly to dissolve the component (2). Thereafter, component (1) is gradually added and stirred. A solution prepared by dissolving component (8) in the remaining component (9) is added and the mixture is stirred until homogenous. This results in an anti-inflammatory cream-containing preparation containing nimesulide.
išbandymo pavyzdys: Karagenino sukeltos žiurkės kojos edemos slopinimo testasTest Example: Test for inhibition of carrageenan-induced rat leg edema
Kremo tipo preparatų, aprašytų 1, 2, 5, 7 ir 8 pavyzdžiuose bei standartiniame pavyzdyje, o taip pat ir prekybinio indometacino turinčio kremo tipo preparato priešuždegiminis aktyvumas buvo tirtas remiantis karagenino sukeltos žiurkės kojos edemos slopinimu.The anti-inflammatory activity of the cream-type formulations described in Examples 1, 2, 5, 7 and 8 as well as the standard indomethacin-containing cream-type formulation was tested based on the suppression of carrageenan-induced rat foot edema.
MetodikaMethodology
Tiriamoji medžiaga buvo uždėta ant Wister žiurkių patinėlių, sveriančių 132-150 g, dešiniosios kojos pado ir dešiniosios kojos padas buvo fiksuotas, padengiant jį vyniojimo plėvele. Uždėjus vaistą, gyvuliukai buvo surakinti plastikiniais kaklo varžtais ir patalpinti į atskirus narvus, norint išvengti vaisto prarijimo. Praėjus 4 valandoms po vaisto uždėjimo, vaistas buvo pilnai pašalintas, panaudojant sugeriančią medvilnę, kurioje buvo šiek tiek šilto vandens. Tuoj pat po to, po kojos pado oda suleista fiziologinio tirpalo (0,1 ml), kuriame buvo 1 % karagenino. Po 3 valandų matuotas kojos tūris ir išskaičiuotas pabrinkimo vystymosi santykis, išeinant iš kojos tūrio prieš proflogistinės medžiagos suleidimą.The test substance was applied to Wister rat males weighing 132-150 g, the right foot pad and the right foot pad fixed with a wrap wrap. After application, the animals were secured with plastic neck screws and placed in separate cages to prevent ingestion. 4 hours after application, the drug was completely removed using absorbent cotton containing some warm water. Immediately thereafter, saline (0.1 ml) containing 1% carrageenan was injected subcutaneously into the skin of the foot. After 3 hours, foot volume was measured and the swelling development ratio was calculated before leaving foot volume prior to injection of proflogistic material.
Bandymo rezultatai parodyti 1 lentelėje.The test results are shown in Table 1.
lentelėtable
Iš 1 lentelės rezultatų matyti, kad 1, 2, 5, 7 ir 8 pavyzdžių farmaciniai preparatai rodo didesnį priešuždegiminį poveikį, lyginant su prekybiniu indometacino kremo tipo preparatu; šis poveikis yra lygus arba netgi didesnis už standartinio pavyzdžio, kuriame nimesulidas yra ištirpintoje formoje, poveikį.The results of Table 1 show that the pharmaceutical formulations of Examples 1, 2, 5, 7 and 8 show a greater anti-inflammatory effect compared to the commercially available indomethacin cream formulation; this effect is equal to or even greater than that of the standard sample in which the nimesulide is in dissolved form.
išbandymo pavyzdys: Nusispaivinimo testastest example: Drain test
Buvo pagaminti ir paskleisti ant medvilninio audinio šio išradimo kremo pavidalo preparatai ir standartinis pavyzdys, ir stebimas jų nusispalvinimo laipsnis. Rezultatai parodyti 2 lentelėje.Formulations of the present invention in the form of a cream and a standard sample have been made and spread on the cotton fabric, and their degree of coloration is monitored. The results are shown in Table 2.
lentelėtable
Kaip matyti iš 2 lentelės, audinys buvo spalvotas standartinio pavyzdžio kremo preparato, kuriame nimesulidas yra ištirpintoje būsenoje, atveju, o 1 ir 2 pavyzdžio kremo preparatai beveik nerodė nusispalvinimo.As shown in Table 2, the tissue was colored in the standard sample cream formulation in which the nimesulide is in the reconstituted state, while the sample formulations 1 and 2 showed almost no coloration.
Išradimo preparatu poveikisEffect of the Invention
Šio išradimo priešuždegiminis išorinio vartojimo agentas, kuriame nimesulidas yra įmaišytas disperguotoje būsenoje, turi farmakologinį poveikį lygų arba netgi didesnį, nei ištirpinto tipo preparato poveikis, neerzina odos, yra nekenksmingas ir netepa odos ir drabužių, nes jis yra nespalvotas. Iš to seka, kad šis išradimas yra ypatingai naudingas, kaip agentas dermatologijos srityje, gydant egzemą, dermatitą ir pan., ir kaip priešuždegiminis išorinio vartojimo preparatas ortozės srityje, gydant chronišką sąnarių reumatizmą, osteoartritą, pečių sąnarių periartritą, peritendinitą, malagiją ir tumentiją, bei skausmus po sužeidimo.The anti-inflammatory external use agent of the present invention, wherein nimesulide is in a dispersed state, has a pharmacological action equal to or even greater than that of the reconstituted formulation, is non-irritating, non-irritating, and does not stain the skin and clothing. It follows that the present invention is particularly useful as an agent in the field of dermatology for the treatment of eczema, dermatitis, etc., and as an anti-inflammatory agent for external use in the field of orthosis for the treatment of chronic joint rheumatism, osteoarthritis, shoulder arthritis, peritendinitis and pain after injury.
Claims (14)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/JP1995/002045 WO1996011002A1 (en) | 1994-10-05 | 1995-10-05 | Antiinflammatory agent for external use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LT97100A LT97100A (en) | 1997-12-29 |
| LT4329B true LT4329B (en) | 1998-04-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LT97-100A LT4329B (en) | 1995-10-05 | 1997-06-03 | EXTERNAL USE PRE-FIRE AGENT |
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| Country | Link |
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| BG (1) | BG63328B1 (en) |
| CZ (1) | CZ288398B6 (en) |
| EE (1) | EE03419B1 (en) |
| FI (1) | FI118953B (en) |
| HU (1) | HU224686B1 (en) |
| IS (1) | IS2271B (en) |
| LT (1) | LT4329B (en) |
| LV (1) | LV11966B (en) |
| NO (1) | NO315732B1 (en) |
| NZ (1) | NZ327092A (en) |
| PL (1) | PL183588B1 (en) |
| RO (1) | RO116040B1 (en) |
| RU (1) | RU2157683C2 (en) |
| SI (1) | SI9620016B (en) |
| SK (1) | SK282637B6 (en) |
| TR (1) | TR199700409T1 (en) |
| WO (1) | WO1997012608A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| IT1289973B1 (en) * | 1997-02-25 | 1998-10-19 | Helsinn Healthcare Sa | GELIFIED NIMESULIDE SYSTEMS FOR TOPICAL USE |
| IT1291997B1 (en) * | 1997-05-26 | 1999-01-25 | Schiena Michele Giuseppe Di | TOPICAL-PHARMACEUTICAL-PREPARATIONS-CONTAINING NIMESULIDE |
| IT1308187B1 (en) * | 1999-02-16 | 2001-12-07 | Formenti Farmaceutici Spa | TOPICAL PHARMACEUTICAL COMPOSITIONS BASED ON NONSTEROID ANTI-INFLAMMATORY. |
| RU2424811C2 (en) * | 2009-04-02 | 2011-07-27 | Евгений Петрович Гребенников | Medication for treatment of psoriasis |
| RU2657803C1 (en) * | 2017-03-21 | 2018-06-15 | федеральное государственное бюджетное образовательное учреждение высшего образования "Алтайский государственный университет" | Agent possessing anti-inflammatory and analgesic action |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3480597A (en) | 1967-03-01 | 1969-11-25 | Vasily Vladimirovich Korshak | Method for the production of polyarylates |
| JPS5835989A (en) | 1981-08-28 | 1983-03-02 | Sanyo Electric Co Ltd | Amorphous photo-semiconductor device |
| JPS5850984A (en) | 1981-09-24 | 1983-03-25 | 松下電工株式会社 | Electric razor |
| JPH06502842A (en) | 1990-05-22 | 1994-03-31 | パットファルム ホウルディング ソシエテ アノニム | Nimesulide and cyclodextrin inclusion compound |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR206496A1 (en) * | 1972-07-03 | 1976-07-30 | Riker Laboratories Inc | PROCEDURE FOR THE PREPARATION OF 2-PHENOXY-4-NITRO-ALKYL OR HALOALKYLSULPHONANILIDES |
| JPS60209515A (en) * | 1984-04-03 | 1985-10-22 | Hokuriku Seiyaku Co Ltd | Anti-inflammatory and analgesic cream agent |
| JPH01224328A (en) * | 1988-03-01 | 1989-09-07 | Kao Corp | antipruritic composition |
| JPH05310508A (en) * | 1992-05-13 | 1993-11-22 | Kanebo Ltd | Dermal external preparation composition |
| RU2007997C1 (en) * | 1992-07-08 | 1994-02-28 | Леонидов Николай Борисович | Methyluracil liniment |
| BE1008307A3 (en) * | 1994-06-16 | 1996-04-02 | Europharmaceuticals Sa | Nimesulide soluble salt, aqueous solution containing same, preparation and use. |
-
1996
- 1996-04-01 CZ CZ19971703A patent/CZ288398B6/en not_active IP Right Cessation
- 1996-04-01 SI SI9620016A patent/SI9620016B/en not_active IP Right Cessation
- 1996-04-01 HU HU9901126A patent/HU224686B1/en not_active IP Right Cessation
- 1996-04-01 SK SK704-97A patent/SK282637B6/en not_active IP Right Cessation
- 1996-04-01 WO PCT/JP1996/000849 patent/WO1997012608A1/en not_active Ceased
- 1996-04-01 PL PL96320534A patent/PL183588B1/en not_active IP Right Cessation
- 1996-04-01 EE EE9700123A patent/EE03419B1/en not_active IP Right Cessation
- 1996-04-01 NZ NZ327092A patent/NZ327092A/en unknown
- 1996-04-01 RU RU97111164/14A patent/RU2157683C2/en not_active IP Right Cessation
- 1996-04-01 TR TR97/00409T patent/TR199700409T1/en unknown
- 1996-04-01 RO RO97-01018A patent/RO116040B1/en unknown
-
1997
- 1997-05-29 BG BG101526A patent/BG63328B1/en unknown
- 1997-06-03 LT LT97-100A patent/LT4329B/en not_active IP Right Cessation
- 1997-06-04 IS IS4497A patent/IS2271B/en unknown
- 1997-06-04 LV LVP-97-108A patent/LV11966B/en unknown
- 1997-06-04 NO NO19972537A patent/NO315732B1/en unknown
- 1997-06-04 FI FI972362A patent/FI118953B/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3480597A (en) | 1967-03-01 | 1969-11-25 | Vasily Vladimirovich Korshak | Method for the production of polyarylates |
| JPS5835989A (en) | 1981-08-28 | 1983-03-02 | Sanyo Electric Co Ltd | Amorphous photo-semiconductor device |
| JPS5850984A (en) | 1981-09-24 | 1983-03-25 | 松下電工株式会社 | Electric razor |
| JPH06502842A (en) | 1990-05-22 | 1994-03-31 | パットファルム ホウルディング ソシエテ アノニム | Nimesulide and cyclodextrin inclusion compound |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2157683C2 (en) | 2000-10-20 |
| IS4497A (en) | 1997-06-04 |
| SK282637B6 (en) | 2002-10-08 |
| CZ288398B6 (en) | 2001-06-13 |
| FI972362A0 (en) | 1997-06-04 |
| FI118953B (en) | 2008-05-30 |
| WO1997012608A1 (en) | 1997-04-10 |
| FI972362L (en) | 1997-07-25 |
| NO972537L (en) | 1997-06-04 |
| LT97100A (en) | 1997-12-29 |
| LV11966A (en) | 1998-02-20 |
| EE9700123A (en) | 1997-12-15 |
| CZ170397A3 (en) | 1998-01-14 |
| TR199700409T1 (en) | 1999-08-23 |
| EE03419B1 (en) | 2001-06-15 |
| NZ327092A (en) | 1999-09-29 |
| IS2271B (en) | 2007-07-15 |
| BG101526A (en) | 1998-01-30 |
| NO315732B1 (en) | 2003-10-20 |
| HUP9901126A3 (en) | 2000-08-28 |
| HUP9901126A2 (en) | 1999-08-30 |
| NO972537D0 (en) | 1997-06-04 |
| SI9620016B (en) | 1999-06-30 |
| HU224686B1 (en) | 2005-12-28 |
| PL320534A1 (en) | 1997-10-13 |
| RO116040B1 (en) | 2000-10-30 |
| LV11966B (en) | 1998-04-20 |
| SI9620016A (en) | 1997-12-31 |
| SK70497A3 (en) | 1997-10-08 |
| BG63328B1 (en) | 2001-10-31 |
| PL183588B1 (en) | 2002-06-28 |
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