HRP960520A2 - Novel therapeutic analgesic pharmaceutical composition for intramuscular administration - Google Patents
Novel therapeutic analgesic pharmaceutical composition for intramuscular administration Download PDFInfo
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- HRP960520A2 HRP960520A2 HRP960520A HRP960520A2 HR P960520 A2 HRP960520 A2 HR P960520A2 HR P960520 A HRP960520 A HR P960520A HR P960520 A2 HRP960520 A2 HR P960520A2
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- nimesulide
- dimethylacetamide
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- ethyl oleate
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- 230000000202 analgesic effect Effects 0.000 title claims description 25
- 230000001225 therapeutic effect Effects 0.000 title claims description 14
- 238000007918 intramuscular administration Methods 0.000 title description 8
- 239000008194 pharmaceutical composition Substances 0.000 title 1
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- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 27
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- 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 description 25
- 229960000965 nimesulide Drugs 0.000 claims description 24
- 238000002347 injection Methods 0.000 claims description 17
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- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 16
- 229940093471 ethyl oleate Drugs 0.000 claims description 16
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 13
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
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- 238000010521 absorption reaction Methods 0.000 claims description 6
- 239000003623 enhancer Substances 0.000 claims description 6
- 238000010255 intramuscular injection Methods 0.000 claims description 5
- 239000007927 intramuscular injection Substances 0.000 claims description 5
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- 229960004217 benzyl alcohol Drugs 0.000 description 7
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
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- 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 description 2
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- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 2
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Description
Prikazani izum se odnosi na novi terapeutski analgetski farmaceutski spoj za davanje injekcijama, koji sadrži Nimeslid koji je N-(4-nitro, 2-fenoksifenil) metansulfonamid, za intramuskularno davanje, kao i na postupak za njegovu izradu. The presented invention relates to a new therapeutic analgesic pharmaceutical compound for injection, containing Nimeslide, which is N-(4-nitro, 2-phenoxyphenyl) methanesulfonamide, for intramuscular administration, as well as to a process for its production.
Poznato stanje tehnike Known state of the art
Primjena Nimesulida putem intramuskularnog davanja kao analgetika nije bila uspješna, budući da je Nimesulid praktično netopljiv u vodi, a njegove formulacije u konvencionalnim uljnim bazama ili u vidu suspenzija dovode do taloženja u mišićnom tkivu što je suprotno glavnom cilju - brzom otklanjanju bolova. The use of Nimesulide through intramuscular administration as an analgesic was not successful, since Nimesulide is practically insoluble in water, and its formulations in conventional oil bases or in the form of suspensions lead to deposition in muscle tissue, which is contrary to the main goal - rapid pain relief.
Istraživanja tržišta i literature ukazuju da nije zabilježen parenteralni dozni oblik Nimesulida. (Drugs, 48 (3) 431-454, 1994.) Market research and literature indicate that no parenteral dosage form of Nimesulide has been recorded. (Drugs, 48 (3) 431-454, 1994.)
Formulacija Nimesulida u vidu injekcija prikazana je u poznatom stanju tehnike (PCT patent br. WO 95/34533), a koristi jednu sol Nimesulida (nimesulid-L-lizin) kompleksiranu s ciklodekstrinima. Maksimalna ostvarena topljivost data je kao 2,4 mh/mL, što nije pogodno za intramuskularne injekcije, budući da zahtijeva vrlo velike obujme da bi se dale terapeutske doze. Objavljena oralna doza Nimesulida je u opsegu od 100 do 400 mg dnevno. Pod pretpostavkom da je intramuskularna doza jednaka polovini oralne doze, trebalo bi se ubrizgati 50 mg lijeka što bi zahtijevalo približno 20 ml otopine opisane u poznatom stanju tehnike, tj. u WO 95/34533. The formulation of Nimesulide in the form of injections is shown in the known state of the art (PCT patent no. WO 95/34533), and uses one salt of Nimesulide (nimesulide-L-lysine) complexed with cyclodextrins. The maximum achieved solubility is given as 2.4 mh/mL, which is not suitable for intramuscular injections, as it requires very large volumes to deliver therapeutic doses. The published oral dose of Nimesulide is in the range of 100 to 400 mg per day. Assuming that the intramuscular dose is equal to half of the oral dose, 50 mg of the drug should be injected, which would require approximately 20 ml of the solution described in the prior art, ie in WO 95/34533.
Mi u prikazanom izumu dajemo formulaciju Nimesulida u vidu intramuskularne injekcije koja obuhvaća molekulu osnovnog lijeka u pogodnoj bazi, a u koncentraciji od 50 mg/ml. Sa tom se formulacijom mogu pogodno davati terapeutski djelotvorne doze Nimesulfida. Osim toga, prikazani izum daje mogućnost ubrizgavanja 0,5 ml do 3,0 ml 50 mg/ml otopine, a prema zahtjevima doziranja. In the presented invention, we provide the formulation of Nimesulide in the form of intramuscular injection, which includes the molecule of the basic drug in a suitable base, and in a concentration of 50 mg/ml. With this formulation, therapeutically effective doses of Nimesulfide can be conveniently administered. In addition, the present invention provides the possibility of injecting 0.5 ml to 3.0 ml of a 50 mg/ml solution, according to dosage requirements.
Prikazani izum koristi tehniku topljenja za postizanje tako velikih koncentracija Nimesulida, a da pri tome ne koristi soli lijeka ili sredstva za kompleksiranje, kao što je spomenuto za poznata rješenja. The presented invention uses a melting technique to achieve such high concentrations of Nimesulide, without using drug salts or complexing agents, as mentioned for known solutions.
Cilj je prikazanog izuma ostvariti novi terapeutski analgetski spoj za davanje u vidu injekcija koja sadrži Nimesulid za intramuskularno davanje, od koga će Nimesulid biti brzo apsorbiran i razveden u tjelesnim fluidima. The aim of the presented invention is to realize a new therapeutic analgesic compound for administration in the form of injections containing Nimesulide for intramuscular administration, from which Nimesulide will be quickly absorbed and dissolved in body fluids.
Sljedeći je cilj izuma ostvariti postupak za pripremanje novog terapeutskog analgetskog spoja za davanje u vidu injekcija, koja sadrži Nimesulid, prema prikazanom izumu, namijenjene za intramuskularno davanje. The next goal of the invention is to realize a procedure for preparing a new therapeutic analgesic compound for administration in the form of injections, which contains Nimesulide, according to the presented invention, intended for intramuscular administration.
Kratak pregled izuma Brief overview of the invention
Prikazani izum ostvaruje novu terapeutsku analgetsku kompoziciju za davanje u vidu injekcija za intramuskularno davanje, koja kompozicija sadrži: The presented invention realizes a new therapeutic analgesic composition for administration in the form of injections for intramuscular administration, which composition contains:
1. Nimesulid 2,5% do 10% mas./zapr. 1. Nimesulide 2.5% to 10% wt./vol.
2. Nosač/baza pojačivača parenteralne apsorpcije 90% do 97,5% mas./zapr. 2. Carrier/base of parenteral absorption enhancer 90% to 97.5% w/v.
Nosač/baza pojačivača parenteralne apsorpcije sadrži: The parenteral absorption enhancer carrier/base contains:
1. Dimetilacetamid 5% do 12% mas./zapr. 1. Dimethylacetamide 5% to 12% wt./vol.
2. Benzil benzoat 20% do 50% mas./zapr. 2. Benzyl benzoate 20% to 50% by weight.
3. Benzil alkohol 0% do 10% mas./zapr. 3. Benzyl alcohol 0% to 10% wt./vol.
4. Etil oleat 30% do 65% mas./zapr. 4. Ethyl oleate 30% to 65% wt./vol.
Prema jednom preporučljivom izvođenju prikazanog izuma, nova terapeutska analgetska kompozicija za davanje injekcijama sadrži: According to one recommended embodiment of the presented invention, the new therapeutic analgesic composition for administration by injection contains:
1. Nimesulid 5% mas./zapr. 1. Nimesulide 5% wt./vol.
2. Dimetilacetamid 10% mas./zapr. 2. Dimethylacetamide 10% wt./vol.
3. Benzil benzoat 40% mas./zapr. 3. Benzyl benzoate 40% wt./pr.
4. Benzil alkohol 2% mas./tapr. 4. Benzyl alcohol 2% wt./tap.
5. Etil oleat 30% do 65% mas./zapr. 5. Ethyl oleate 30% to 65% wt./vol.
Detaljan opis izuma Detailed description of the invention
Prikazani izum ostvaruje novi terapeutski analgetski spoj za davanje u vidu injekcija za intramuskularno davanje, koji spoj sadrži: The presented invention realizes a new therapeutic analgesic compound for administration in the form of injections for intramuscular administration, which compound contains:
1. Nimesulid 2,5% do 10% mas./zapr. 1. Nimesulide 2.5% to 10% wt./vol.
2. Nosač/baza pojačivača parenteralne apsorpcije 90% do 97,5% mas./zapr. 2. Carrier/base of parenteral absorption enhancer 90% to 97.5% w/v.
Nosač/baza pojačivača parenteralne apsorpcije sadrži: The parenteral absorption enhancer carrier/base contains:
1. Dimetilacetamid 5% do 12% mas./zapr. 1. Dimethylacetamide 5% to 12% wt./vol.
2. Benzil benzoat 20% do 50% mas./zapr. 2. Benzyl benzoate 20% to 50% by weight.
3. Benzil alkohol 0% do 10% mas./zapr. 3. Benzyl alcohol 0% to 10% wt./vol.
4. Etil oleat 30% do 65% mas./zapr. 4. Ethyl oleate 30% to 65% wt./vol.
Prema jednom preporučljivom izvođenju prikazanog izuma, novi terapeutski analgetski spoj za davanje injekcijama sadrži: According to one preferred embodiment of the presented invention, the new therapeutic analgesic compound for administration by injection contains:
1. Nimesulid 5% mas./zapr. 1. Nimesulide 5% wt./vol.
2. Dimetilacetamid 10% mas./zapr. 2. Dimethylacetamide 10% wt./vol.
3. Benzil benzoat 40% mas./zapr. 3. Benzyl benzoate 40% wt./pr.
4. Benzil alkohol 2% mas./zapr. 4. Benzyl alcohol 2% wt./vol.
5. Etil oleat 30% do 65% mas./zapr. 5. Ethyl oleate 30% to 65% wt./vol.
Prema jednom drugom preporučljivom izvođenju prikazanog izuma, benzil benzoat je dijelom zamijenjen sa 5% do 10% mas./zapr. Cremofors (polioksietilen glikolisano ricinusovo ulje) EL-om. According to another preferred embodiment of the present invention, benzyl benzoate is partially replaced by 5% to 10% w/v. Cremofors (polyoxyethylene glycol castor oil) by EL.
Prema drugom preporučljivom izvođenju prikazanog izuma, neki konvencionalno poznat anti-oksidator kao što je askorbil palmitat, butil hidroksi anisol, butil hidroksi toluol, propil galat i a-tokoferol, dodaje se spomenutom analgetskom spoju za ubrizgavanje. According to another preferred embodiment of the present invention, some conventionally known anti-oxidant such as ascorbyl palmitate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate and α-tocopherol is added to said analgesic compound for injection.
Prikazani izum također osigurava postupak za pripremanje novog terapeutskog analgetskog spoja za ubrizgavanje, prema prikazanom izumu, koji postupak obuhvaća sljedeće stupnjeve: The presented invention also provides a process for preparing a new therapeutic analgesic compound for injection, according to the presented invention, which process comprises the following steps:
(a) 5% do 12% mas./zapr. dimetilacetamida i 30% do 50% mas./zapr. benzil benzoata miješaju se posudi opremljenoj miješalicom malom brzinom (1000-1500 min-1) i toj se smjesi doda 4% do 7% mas./zapr. Nimesulida i miješa dok ne bude potpuno otopljen. (a) 5% to 12% w/v. of dimethylacetamide and 30% to 50% wt./vol. of benzyl benzoate are mixed in a container equipped with a mixer at low speed (1000-1500 min-1) and 4% to 7% wt./vol. is added to this mixture. Nimesulide and stir until completely dissolved.
(b) 0% do 10% mas./zapr. benzil alkohola i dio od 20% do 65% mas./zapr. etil oleata miješa se u posudi s miješalicom. (b) 0% to 10% w/v. benzyl alcohol and a portion from 20% to 65% by weight. of ethyl oleate is mixed in a mixing bowl.
(c) Smjesa dobivena u stupnju (a) dodaje se smjesi dobivenoj u stupnju (b) uz lagano miješanje, a zapremina dobivene smjese dopuni se do 100 ml preostalom količinom etil oleata, što daje željeni analgetski spoj za ubrizgavanje. (c) The mixture obtained in step (a) is added to the mixture obtained in step (b) with gentle mixing, and the volume of the obtained mixture is made up to 100 ml with the remaining amount of ethyl oleate, which gives the desired analgesic injectable compound.
Prema jednom preporučljivom izvođenju postupka prema prikazanom izumu, u stupnju (a) ovog postupka miješa se 10% mas./zapr. dimetilacetamida i 40% mas./zapr. benzil benzoata i tome se dodaje 5% mas./zapr. Nimesulida. U stupnju (b) ovog postupka miješa se 2% mas./zapr. benzil alkohola i dio od 30% do 65% mas./zapr. etil oleata. According to one recommended implementation of the process according to the presented invention, in step (a) of this process, 10% wt./vol. dimethylacetamide and 40% wt./vol. benzyl benzoate and 5% by weight is added to it. Nimesulide. In step (b) of this procedure, 2% wt./vol. benzyl alcohol and a portion from 30% to 65% wt./vol. ethyl oleate.
Poželjno je da se stupanj (c) ovog postupka izvodi uz kontinuirano ispiranje azotom, a dobivena gotova otopina se propušta kroz 0,22 μ najlonski membranski filtar. It is preferable that step (c) of this procedure is carried out with continuous nitrogen flushing, and the resulting finished solution is passed through a 0.22 μ nylon membrane filter.
Prema jednom drugom preporučljivom izvođenju prikazanog izuma, u tijeku pripremanja analgetskog spoja za ubrizgavanje dodaje se jedan konvencionalan anti-oksidator kao što je askorbil palmitat, butil hidroksi anisol, butil hidroksi toluol, propil galat i a-tokoferol. According to another recommended embodiment of the presented invention, a conventional antioxidant such as ascorbyl palmitate, butyl hydroxy anisole, butyl hydroxy toluene, propyl gallate and α-tocopherol is added during the preparation of the analgesic compound for injection.
Izum će biti opisan s pozivom na sljedeće primjere pripremanja analgetskog spoja za ubrizgavanje. The invention will be described with reference to the following examples of the preparation of an analgesic compound for injection.
Primjer I Examples
(a) Miješati 10 g dimetilacetamida i 40 g benzil benzoata u posudi s miješalicom malom brzinom (1000-1200 min-1) na temperaturi između 25° i 30°C. Dodati 5 g Nimesulida u malim inkrementima i miješati dok se potpuno ne otopi. (a) Mix 10 g of dimethylacetamide and 40 g of benzyl benzoate in a mixing bowl at low speed (1000-1200 min-1) at a temperature between 25° and 30°C. Add 5 g of Nimesulide in small increments and mix until completely dissolved.
(b) Miješati 10 g Cremofor EL i jednu količinu etil oleata u posudi sa miješalicom, a na sobnoj temperaturi. (b) Mix 10 g of Cremofor EL and one amount of ethyl oleate in a container with a mixer, at room temperature.
(c) Dodati smjesu dobivenu u stupnju (a) smjesi dobivenoj u stupnju (b) uz lagano miješanje u trajanju od oko 30 min. Dopuniti zapreminu do 100 ml etil oleatom i filtrirati kroz 0,22 μ najlonski membranski filtar da bi se ista sterilizirala. (c) Add the mixture obtained in step (a) to the mixture obtained in step (b) with gentle mixing for about 30 min. Make up to 100 ml with ethyl oleate and filter through a 0.22 μ nylon membrane filter to sterilize it.
Primjer II Example II
(a) Miješati 20 g dimetilacetamida i 76 g benzil benzoata u posudi s miješalicom malom brzinom, a na temperaturi između 25° i 30°C. Dodati dobivenoj mješavini 10 g Nimesulida u malim inkrementima i miješati dok se potpuno ne otopi. (a) Mix 20 g of dimethylacetamide and 76 g of benzyl benzoate in a mixing bowl at low speed and at a temperature between 25° and 30°C. Add 10 g of Nimesulide to the resulting mixture in small increments and mix until it is completely dissolved.
(b) Miješati 4 g benzil alkohola i jednu količinu etil oleata u posudi s miješalicom, a na sobnoj temperaturi. (b) Mix 4 g of benzyl alcohol and one amount of ethyl oleate in a mixing bowl at room temperature.
(c) Dodati smjesu dobijenu u stupnju (a) smjesi dobivenoj u stupnju (b) uz lagano miješanje u trajanju od oko 30 min. Dopuniti zapreminu do 200 ml etil oleatom i filtrirati kroz 0,22 μ najlonski membranski filtar da bi se ista sterilizirala. (c) Add the mixture obtained in step (a) to the mixture obtained in step (b) with gentle mixing for about 30 min. Make up to 200 ml with ethyl oleate and filter through a 0.22 μ nylon membrane filter to sterilize it.
Analgetski spoj za ubrizgavanje prema prikazanom izumu, pokazao je na prethodnim ispitivanjima na životinjama i na pretkliničkim ispitivanjima da ima značajno analgetsko djelovanje. Dalje je utvrđeno da je netoksična čak i pri ponovljenim nanošenjima na isto mjesto. Nije primijećena nijedna pojava nekroze tkiva ili nekog drugog sporednog djelovanja. Analgetske doze kreću se u opsegu od 0,16 mg/kg do 8,4 mg/kg. Ovaj je analgetski spoj veoma djelotvoran i korisan za liječenje akutnih bolnih stanja kao što je poslije-operativna trauma, bol povezan sa rakom, sportske povrede i slično. The analgesic compound for injection according to the presented invention has shown in previous tests on animals and in preclinical tests that it has a significant analgesic effect. It was further established that it is non-toxic even with repeated applications to the same place. No occurrence of tissue necrosis or any other side effect was observed. Analgesic doses range from 0.16 mg/kg to 8.4 mg/kg. This analgesic compound is very effective and useful for the treatment of acute pain conditions such as post-operative trauma, cancer-related pain, sports injuries and the like.
Analgetsko djelovanje terapeutskog spoja pripremljenog prema prikazanom izumu, pokazalo se kao ovisno od doze, a ista je prošla ispitivanja na blago akutnu toksičnost i na neočekivanu toksičnost. The analgesic effect of the therapeutic compound prepared according to the presented invention was shown to be dose-dependent, and it passed tests for mild acute toxicity and unexpected toxicity.
Pretklinička toksikološka ispitivanja su pokazala vrijednosti pri LD50 = 129,55, ED50 = 3 mg/kg sa terapeutskim indeksom = 43,13, kod miševa. To pokazuje veliku sigurnost prikazanog izuma. Preclinical toxicology tests showed values at LD50 = 129.55, ED50 = 3 mg/kg with therapeutic index = 43.13, in mice. This shows the great safety of the presented invention.
Terapeutski analgetski spoj za ubrizgavanje prema prikazanom izumu nije obična smjesa, već ima svojstva koja se razlikuju od ukupnog zbroja svojstava njegovih sastojaka, kako je prije ukazano. The therapeutic analgesic compound for injection according to the presented invention is not a simple mixture, but has properties that differ from the total sum of the properties of its ingredients, as previously indicated.
Kako se mogu načiniti brojna izvođenja prikazanog izuma, a da se ne odstupi od njegovog duha i opsega, namjera je da se ovdje prikazan opis izuma smatra samo kao ilustracija i bez bilo kakvog ograničavanja. As numerous embodiments of the disclosed invention may be made without departing from its spirit and scope, it is intended that the description of the invention disclosed herein be considered as illustrative only and without limitation.
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HRP960520 HRP960520A2 (en) | 1996-11-06 | 1996-11-06 | Novel therapeutic analgesic pharmaceutical composition for intramuscular administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HRP960520 HRP960520A2 (en) | 1996-11-06 | 1996-11-06 | Novel therapeutic analgesic pharmaceutical composition for intramuscular administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP960520A2 true HRP960520A2 (en) | 1998-10-31 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP960520 HRP960520A2 (en) | 1996-11-06 | 1996-11-06 | Novel therapeutic analgesic pharmaceutical composition for intramuscular administration |
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| Country | Link |
|---|---|
| HR (1) | HRP960520A2 (en) |
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1996
- 1996-11-06 HR HRP960520 patent/HRP960520A2/en not_active Application Discontinuation
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