WO2016041036A1 - Pharmaceutical composition containing an analgesic agent and an antispasmosdic agent - Google Patents

Pharmaceutical composition containing an analgesic agent and an antispasmosdic agent Download PDF

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Publication number
WO2016041036A1
WO2016041036A1 PCT/BR2015/000146 BR2015000146W WO2016041036A1 WO 2016041036 A1 WO2016041036 A1 WO 2016041036A1 BR 2015000146 W BR2015000146 W BR 2015000146W WO 2016041036 A1 WO2016041036 A1 WO 2016041036A1
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agent
antiespasmodic
analgesic
analgesic agent
pharmaceutical combination
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PCT/BR2015/000146
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French (fr)
Portuguese (pt)
Inventor
Jaime ABRAMOWICZ
Fernando Rafael De Souza
Carlos Antonio Martins
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Diffucap Chemobras Química E Farmacéutical Ltda
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Priority claimed from BR102014023319A external-priority patent/BR102014023319A2/en
Application filed by Diffucap Chemobras Química E Farmacéutical Ltda filed Critical Diffucap Chemobras Química E Farmacéutical Ltda
Priority to US15/512,110 priority Critical patent/US20170281596A1/en
Priority to EP15842123.0A priority patent/EP3195864A4/en
Priority to RU2017111270A priority patent/RU2017111270A/en
Publication of WO2016041036A1 publication Critical patent/WO2016041036A1/en

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction

Definitions

  • Combinations of antispasmodics and analgesics are known in the market for the treatment of gastrointestinal, biliary tract and genitouriary tract pain. These preparations combine the action of an antispasmodic with various analgesics such as Paracetamol, Dipyrone and Ibuprofen, and there is no history of a combination of an antispasmodic with Tromethamine Ketorolac as an analgesic agent.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition containing an analgesic agent and an antispasmodic agent is disclosed, with ketorolac tromethamine as the analgesic agent, which is physically isolated from the antispasmodic agent, the antispasmodic agent which is combined with the analgesic agent, ketorolac tromethamine, being hyoscine, pargeverine, tolterodine, mebeverine or papaverine. Both the analgesic agent, ketorolac tromethamine, and the antispasmodic agent are combined in a separate, immediate release form. The analgesic agent, ketorolac tromethamine, can also be found in the present combination in a separate, immediate release form, while the antispasmodic agent in the combination is likewise in a separate form, but having a programmed release. The proportion by weight of the active ingredient, ketorolac tromethamine, ranges from 2.5% to 20%, and the proportion by weight of the active antispasmodic ingredient ranges from 2.5% to 20%.

Description

"COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMODICO"  "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT"
CAMPO DE APLICAÇÃO APPLICATION FIELD
O presente pedido de patente de invenção refere-se a uma nova combinação farmacêutica composta por um analgésico, o Cetorolaco de Trometamina (ácido carboxílico-5- Benzoíl-2, 3-diidro-lH-pirrolizina-l, 2-amino-2-hidroximetil- 1, 3-propanodiol) e um antiespasmódico do tipo Hioscina, ou outras como a Pargeverina, Tolterodina, Mebeverina e a Papaverina.  The present patent application relates to a novel pharmaceutical combination comprising an analgesic, Ketorolac of Tromethamine (5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,2-amino-2-carboxylic acid). hydroxymethyl-1,3-propanediol) and a hyoscine-type antispasmodic, or others such as Pargeverine, Tolterodine, Mebeverine and Papaverine.
Este pedido de patente de invenção tem como característica, apresentada em um tipo preferido de realização, grânulos de cada princípio ativo separado a fim de evitar a incompatibilidade por contato entre o agente analgésico e os agentes espasmódicos que formam o presente pedido de patente de invenção inovadora, cuja combinação está descrita e reivindicada na presente patente.  This patent application features, in a preferred embodiment, granules of each separate active ingredient in order to avoid contact incompatibility between the analgesic agent and the spasmodic agents forming the present inventive patent application. , the combination of which is described and claimed in the present patent.
O Cetorolaco de Trometamina é um anti- inflamatório não esteroide, com ação analgésica, anti- inflamatória e antipirética, cujo mecanismo de ação está relacionado còm sua capacidade de inibir a síntese de prostaglandinas e um efeito analgésico periférico.  Tromethamine Ketorolac is a non-steroidal anti-inflammatory, analgesic, anti-inflammatory and antipyretic agent whose mechanism of action is related to its ability to inhibit prostaglandin synthesis and a peripheral analgesic effect.
A título de exemplo, a Hioscina é um alcalóide sintetizado por determinadas plantas, que produz um efeito anticolinérgico, exercendo uma ação antiespasmódica sobre o músculo liso do trato gastrointestinal, biliar e geniturinário.  By way of example, hyoscine is a plant-synthesized alkaloid which produces an anticholinergic effect, exerting an antispasmodic action on the smooth muscle of the gastrointestinal, biliary and genitourinary tract.
Enquanto a Pargeverina e a Tolterodina são agentes antiespasmódicos que inibem, competitivamente, a atividade dos receptores muscarinicos localizados, principalmente, no músculo liso de alguns órgãos e glândulas. While Pargeverine and Tolterodine are antispasmodic agents that competitively inhibit the activity of muscarinic receptors located mainly in the smooth muscle of some organs and glands.
Com respeito à ebeverina e à Papaverina, possuem ação direta sobre a musculatura lisa do trato gastrointestinal e atuam aliviando o espasmo com o efeito consequente de relaxamento do músculo liso.  With respect to ebeverine and papaverine, they have direct action on the smooth muscles of the gastrointestinal tract and act to relieve spasm with the consequent effect of smooth muscle relaxation.
HISTÓRICO HISTORIC
0 Cetorolaco é conhecido desde o ano de 0 Cetorolaco has been known since the year
1978, a partir das patentes:' 1978 from patents: '
Belga N° 856.681 e Norte-Americana N° Belgian No. 856,681 and North American No.
4.089.969, que são mencionadas como .técnica anterior da presente atividade inventiva no âmbito da farmacologia. No. 4,089,969, which are mentioned as prior art of the present inventive activity in the field of pharmacology.
Ambas as patentes pertencem à Syntex e definem o Cetorolaco em sua preparação e sua ação anti- inflamatória e analgésica. 0 Cetorolaco é um inibidor da síntese de prostaglandinas com efeito analgésico periférico, do qual não foi demonstrado nenhum efeito sobre os receptores opioides.  Both patents belong to Syntex and define Ketorolac in its preparation and its anti-inflammatory and analgesic action. Ketorolac is a prostaglandin synthesis inhibitor with peripheral analgesic effect, of which no effect on opioid receptors has been demonstrated.
É absorvido com rapidez assim que acontece a administração oral e intramuscular, com um pico de concentração plasmática entre 1 e 2 horas e sua vida média varia entre 4 e 8 horas. 99% do Cetorolaco se une às proteínas plasmáticas e é administrado a cada 6 horas, o patamar da concentração plasmática é alcançado às 24 horas, o que pode requerer uma dosagem de carga de modo a encurtar o período para alcançar um importante efeito analgésico. A principal via de eliminação do Cetorolaco e seus metabólitos (para- hidroxilados e conjugados) é a urinária (92%), excretando-se o restante pelas fezes. A dosagem usual diária varia de 40 mg a 80 mg, administrando-se em várias ingestões diárias e sendo a dosagem máxima de 90 mg/dia. It is rapidly absorbed as soon as oral and intramuscular administration occurs, with a peak plasma concentration between 1 and 2 hours and its average life ranging between 4 and 8 hours. 99% of Ketorolac binds to plasma proteins and is administered every 6 hours, the plasma concentration plateau being reached at 24 hours, which may require a loading dosage to shorten the period to achieve an important analgesic effect. The main route of elimination of Ketorolac and its metabolites (para- hydroxylates and conjugates) is urinary (92%), the remainder being excreted in faeces. The usual daily dosage ranges from 40 mg to 80 mg, administered in several daily intakes and the maximum dosage being 90 mg / day.
A fórmula química da Hioscina {C17H21NO4} difere da atropina somente porque possui uma ligação de oxigénio entre os átomos de carbono 6 e 7, o qual lhe confere a possibilidade de penetrar a barreira hematoencefálica , mesmo que o N-Butilbromuro derivado, utilizado neste pedido de patente de invenção, não a atravesse.  The chemical formula of hyoscine {C17H21NO4} differs from atropine only in that it has an oxygen bond between carbon atoms 6 and 7, which gives it the ability to penetrate the blood-brain barrier, even though the derivative N-Butylbromuro used in this application patent, do not cross it.
São conhecidas no mercado combinações de antiespasmódicos com analgésicos, para o tratamento de dores espasmódicas gastrointestinais, das vias biliares e do trato genituririário . Estas preparações combinam a ação de um antiespasmódico com diversos analgésicos como Paracetamol, Dipirona e Ibuprofeno, não havendo nenhum antecedente com respeito a uma combinação de um antiespasmódico com Cetorolaco de Trometamina como agente analgésico.  Combinations of antispasmodics and analgesics are known in the market for the treatment of gastrointestinal, biliary tract and genitouriary tract pain. These preparations combine the action of an antispasmodic with various analgesics such as Paracetamol, Dipyrone and Ibuprofen, and there is no history of a combination of an antispasmodic with Tromethamine Ketorolac as an analgesic agent.
Foi comprovado que existe uma importante interação entre os analgésicos e os antiespasmódicos nas referidas preparações, que provoca um alto grau de neutralização dos efeitos dos princípios ativos entre si, que vão de 40% a 90%, provocando a consequente diminuição de suas concentrações plasmáticas.  It has been shown that there is an important interaction between analgesics and antispasmodics in these preparations, which causes a high degree of neutralization of the effects of the active principles among themselves, ranging from 40% to 90%, causing the consequent decrease of their plasma concentrations.
Com base na bibliografia existente, a interação mais importante entre o Cetorolaco de Trometamina e um antiespasmódico, é verificada na combinação com a Hioscina, razão pela qual o presente pedido de patente de invenção foi projetado na forma preferida de realização, em diferentes grânulos para cada principio ativo separado, evitando o contato e a interação dos mesmos na preparação. Based on existing literature, the most important interaction between Tromethamine Ketorolac and an antispasmodic is found in combination with Hyoscine, which is why the present patent application was designed in the preferred embodiment, in different granules for each separate active ingredient, avoiding contact and interaction in preparation.
OBJETO PRINCIPAL MAIN OBJECT
Para as finalidades especificadas, o presente . pedido de patente de invenção refere-se a uma nova combinação farmacêutica que compreende em sua formação grânulos de liberação programada contendo o analgésico Cetorolaco de Trometamina {ácido carboxilico-5- Benzoil-2, 3-diidro-lH-pirrolizina-l, 2-amino-2-hidroximetil- 1, 3-propanodiol) e um agente antiespasmodico tal como a Hioscina, a Pargeverina, a Tolterodina, a Mebeverina e a Papaverina.  For the specified purposes, the present. Patent Application relates to a novel pharmaceutical combination comprising in its formation programmed release granules containing the Tromethamine Ketorolac painkiller (5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,2-carboxylic acid amino-2-hydroxymethyl-1,3-propanediol) and an antispasmodic agent such as Hyoscine, Pargeverine, Tolterodine, Mebeverine and Papaverine.
A composição desta nova combinação farmacêutica foi projetada com a finalidade de evitar a interação dos princípios ativos na preparação, assim como in vivo, uma vez ingerida a preparação.  The composition of this new pharmaceutical combination was designed to avoid the interaction of the active ingredients in the preparation as well as in vivo once the preparation is ingested.
Isto é conseguido em virtude do tipo de microgrânulos para conter cada principio ativo. Assim, os microgrânulos contendo o agente analgésico Cetorolaco de Trometamina são elaborados para que se comportem como de ação imediata, de modo a alcançar rapidamente altas concentrações plasmáticas do analgésico, enquanto que os microgrânulos contendo o agente antiespasmodico (Hioscina, Pargeverina, Tolterodina, Mebeverina, Papaverina, entre outros) são elaborados para que se comportem como de açâo programada, conseguindo a sua liberação gradual no organismo, em tempos e âmbitos distintos do analgésico. DESCRIÇÃO This is achieved by virtue of the type of microgranules to contain each active ingredient. Thus, microgranules containing the Tromethamine Ketorolac analgesic agent are designed to behave as immediate acting to rapidly achieve high plasma concentrations of the analgesic, while microgranules containing the antispasmodic agent (Hioscin, Pargeverine, Tolterodine, Mebeverine, Papaverina, among others) are designed to behave as programmed action, achieving its gradual release in the organism, in different times and areas of the analgesic. DESCRIPTION
A seguir, será demonstrado, a título ilustrativo não limitante, como o presente pedido de patente de invenção pode ser colocada em prática.  In the following, it will be shown by way of non-limiting illustration how the present patent application can be put into practice.
Os grânulos que contêm o princípio ativo Cetorolaco de Trometamina , são projetados para que sejam de liberação imediata, elaborando-se com núcleos compostos de açúcar e amido, os quais são incorporados ao princípio ativo mícronizado, através de polímeros ligantes.  The granules containing the active ingredient Ketorolac of Tromethamine are designed to be immediate release, made up of nuclei composed of sugar and starch, which are incorporated into the micronised active principle through binder polymers.
Os grânulos que contêm o princípio ativo antiespasmódico (Hioscina, Pargeverina, Tolterodina, Mebeverina, Papaverina, entre outros) , são projetados para que tenham liberação programada, para o qual se agrega aos microgrânulos, polímeros de revestimento de maneira tal, para conseguir o perfil de liberação adequado.  The granules containing the antispasmodic active ingredient (Hioscin, Pargeverine, Tolterodine, Mebeverine, Papaverine, among others) are designed to have timed release, to which microgranules are added as coating polymers to achieve the profile. proper release
Os referidos grânulos apresentam diâmetros de entre 0,2 mm e 1,8 mm, preferencialmente, entre 0,4 mm e 1,5 mm e agregam a estes corantes para diferenciar os que contêm em cada princípio ativo.  Said granules have diameters of between 0.2 mm and 1.8 mm, preferably between 0.4 mm and 1.5 mm, and add to these dyes to differentiate those contained in each active ingredient.
Os solventes utilizados para a preparação dos grânulos substancialmente esféricos podem ser acetona, álcool isopropílico, álcool etílico, clorofórmio, cloreto de metileno, água ou uma mistura respectiva.  The solvents used for preparing the substantially spherical granules may be acetone, isopropyl alcohol, ethyl alcohol, chloroform, methylene chloride, water or a mixture thereof.
Como polímeros ligantes, são utilizados preferencialmente polivinilpirrolidonas, polietilenoglicóis, metilcelulose, sacarose, gelatina, amido e as misturas dos mesmos. Como polímeros de revestimento ou formadores de película, podem ser utilizados diferentes tipos de metilceluloses, hidroxipropilmetilceluloses, ftalatos de hidroxipropilmetilceluloses, polímeros acrílicos (Eudragit L, S, RL, RS ou suas combinações), gomas laca e etilceluloses , combinados em diferentes proporções em soluções acetônicas, alcoólicas, aquosas ou suas misturas. Estas soluções podem ter plastificantes incorporados do tipo dietilftalato, dibutílftalato, polietilenoglicol, trietilcitrato, triacetina, triglicerídeos de ácidos graxos ou outros. Como lubrificante utilíza-se talco. As binder polymers, polyvinylpyrrolidones, polyethylene glycols, methylcellulose, sucrose, gelatin, starch and mixtures thereof are preferably used. As coating polymers or film formers, different types of coatings may be used. methylcelluloses, hydroxypropyl methylcelluloses, hydroxypropyl methylcelluloses phthalates, acrylic polymers (Eudragit L, S, RL, RS or combinations thereof), shellacs and ethylcelluloses, combined in different proportions in acetonic, alcoholic, aqueous solutions or mixtures thereof. These solutions may have incorporated plasticizers such as diethylphthalate, dibutylphthalate, polyethylene glycol, triethylcitrate, triacetin, fatty acid triglycerides or the like. Talc is used as a lubricant.
Fórmula dos grânulos de Cetorolaco de Ketorolac granules formula of
Trometamina . Tromethamine
Figure imgf000007_0001
Figure imgf000007_0001
Composição como modo preferido de realização do conteúdo de cada cápsula com microgrânulos separados, de acordo com o princípio ativo de liberação imediata tanto do analgésico quanto do ántiespasmódico. PRODUTO FINAL Composition as a preferred embodiment of the contents of each capsule with separate microgranules according to the active principle of immediate release of both analgesic and antispasmodic. FINAL PRODUCT
CÁPSULA FÓRMULA FORMULA CAPSULE
CETOROLACO DE TROMETAMINA 2,5 - 20 %TROMETAMINE KETOROLAC 2.5 - 20%
ANTIESPASMÓDICO 2,5 - 20 %ANTIESPASMODIC 2.5 - 20%
POVIDONA (PVP K 30) 1 - 5 %POVIDONA (PVP K 30) 1 - 5%
TALCO BRANCO 5 - 30 o WHITE TALCO 5 - 30 o
o  The
CORANTES (A+V) 0,03 - 0,06 o  COLORINGS (A + V) 0.03 - 0.06 o
"5  "5
NÚCLEOS . 88,97 - 34,94 o,  CORES. 88.97 - 34.94 o,
o  The
100,00 o  100.00 o
Composição como modo preferido de realização do conteúdo de cada capsula com microgrânulos separados, de acordo com o princípio ativo de liberação programada para o caso do antiespasmódico . Composition as a preferred embodiment of the content of each capsule with separate microgranules according to the active principle of scheduled release for the antispasmodic case.
Figure imgf000008_0001
Figure imgf000008_0001
Não há dúvida de que quando o presente pedido de patente de invenção for colocado em prática, modificações poderão ser . introduzidas referentes a determinados detalhes de construção e forma sem que isso implique em afastamento dos . princípios fundamentais que claramente se compravam nas reivindicações apresentadas a seguir: There is no doubt that when the present patent application is implemented, modifications may be made. relating to certain details of construction and shape without entailing distancing from them. fundamental principles that were clearly taken from the following claims:

Claims

REIVINDICAÇÕES
1. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMODICO", caracterizada por o agente analgésico conter Cetorolaco de Trometamina e estar presente na referida composição em uma proporção de entre 5%, e 20% em peso e o principio ativo antiespasmódico encontrar-se em uma proporção de entre 5% e 20% em peso da referida composição.  1. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESTIC AGENT AND ANTIESPASMODIC AGENT", characterized in that the analgesic agent contains Tromethamine Ketorolac and is present in said composition in a proportion of between 5% and 20% by weight and the antispasmodic active ingredient is found. in a proportion of between 5% and 20% by weight of said composition.
2. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o agente analgésico Cetorolaco de Trometamina encontrar-se fisicamente isolado do agente antiespasmódico.  2. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESTIC AGENT AND ANTIESPASMODIC AGENT" according to Claim 1, characterized in that the Ketorolac Tromethamine analgesic agent is physically isolated from the antispasmodic agent.
3. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o principio ativo antiespasmódico em combinação com o agente analgésico Cetorolaco de Trometamina ser Hioscina .  3. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the antispasmodic active ingredient in combination with the Tromethamine Ketorolac analgesic agent is Hioscin.
4. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o principio ativo antiespasmódico em combinação com o agente analgésico Cetorolaco de Trometamina ser Pargeverina.  4. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the antispasmodic active ingredient in combination with the Tromethamine Ketorolac analgesic agent is Pargeverine.
5. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o principio ativo antiespasmódico em combinação com o agente analgésico Cetorolaco de Trometamina ser Tolterodina. 5. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to Claim 1, characterized in that the antispasmodic active ingredient in combination with the Tromethamine Ketorolac analgesic agent is Tolterodine.
6. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE .ANTIESPASMODICO", de acordo com a reivindicação 1, caracterizada por o princípio ativo antiespasmodico em combinação com o ' agente analgésico Cetorolaco de Trometamina ser Mebeverina. 6. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND AN AGENT .ANTIESPASMODICO" according to claim 1, characterized in that the active ingredient in combination with spasmolytic "analgesic agent ketorolac tromethamine be Mebeverine.
7. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMODICO" , de acordo com a reivindicação 1, caracterizada por o princípio ativo antiespasmodico em combinação com o agente analgésico Cetorolaco de Trometamina ser Papaverina.  "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the antispasmodic active ingredient in combination with the Ketorolac analgesic agent of Tromethamine is Papaverine.
8. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMODICO", de acordo com a reivindicação 1, caracterizada por tanto o agente analgésico Cetorolaco de Trometamina quanto. o agente antiespasmodico se encontrarem combinados em forma separada e de liberação imediata.  8. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that both the Ketorolac Tromethamine analgesic agent and. the antispasmodic agent are combined separately and for immediate release.
9. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMODICO", de acordo com a reivindicação 1, caracterizada por o agente analgésico Cetorolaco de Trometamina encontrar-se na presente combinação em forma separada e de liberação imediata, enquanto o agente antiespasmodico combinado apresenta-se em forma igualmente separada, mas de liberação programada.  9. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to Claim 1, characterized in that the Ketorolac Tromethamine analgesic agent is in the present combination in a separate and immediate release form, while the combined antispasmodic agent is present. equally separate but scheduled release.
10. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMODICO", de acordo com a reivindicação 1, caracterizada por, para apresentação em forma de grânulos que contêm os princípios ativos, estes terem diâmetros de entre 0,2 mm e 1,8 mm, preferencialmente entre 0, 4 mm e 1,5 mm. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to Claim 1, characterized in that, in the form of granules containing the active ingredients, they have diameters of between 0.2 mm and 1.8 mm. mm, preferably between 0.4 mm and 1.5 mm.
11. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o polimero ligante utilizado ser polivinilpirrolidonas (PVP K30) .  "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to Claim 1, characterized in that the binder polymer used is polyvinylpyrrolidones (PVP K30).
12. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o polimero ligante utilizado ser polietilenoglicol .  "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the binder polymer used is polyethylene glycol.
13. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM 13. "PHARMACEUTICAL COMBINATION CONTAINING A
AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o polimero ligante utilizado ser metilcelulose . ANALGESIC AGENT AND ANTIESPASMODIC AGENT "according to claim 1, characterized in that the binder polymer used is methylcellulose.
14. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o polimero ligante utilizado ser amido e suas misturas.  "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESTIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the binder polymer used is starch and mixtures thereof.
15. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o polimero de revestimento para a liberação programada do antiespasmódico ser etilcelulose em distintas proporções em soluções acetônicas, alcoólicas, aquosas ou suas misturas.  15. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the coating polymer for the scheduled release of antispasmodic is ethylcellulose in different proportions in acetonic, alcoholic, aqueous solutions or mixtures thereof.
16. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por o polimero de revestimento para a liberação programada do antiespasmódico ser hidroxipropilmetilcelulose em distintas proporções em soluções acetônicas, alcoólicas, aquosas ou suas misturas. 16. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the coating polymer for the scheduled release of the antispasmodic is hydroxypropyl methylcellulose in different proportions in acetonic, alcoholic, aqueous solutions or mixtures thereof.
17. "COMBINAÇÃO FARMACÊUTIC CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por os polímeros de revestimento para a liberação programada do antiespasmódico serem polímeros acrílicos (Eudragit L, S, RL, RS ou suas combinações) em distintas proporções em soluções acetônicas, alcoólicas, aquosas ou suas misturas.  17. "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to Claim 1, characterized in that the antispasmodic programmed release coating polymers are acrylic polymers (Eudragit L, S, RL, RS or combinations thereof) in different proportions in acetonic, alcoholic, aqueous solutions or mixtures thereof.
18. "COMBINAÇÃO FARMACÊUTICA CONTENDO UM AGENTE ANALGÉSICO E UM AGENTE ANTIESPASMÓDICO", de acordo com a reivindicação 1, caracterizada por a presente combinação ter incorporado plastificantes do tipo dos dietilftalatos, dibutilftalatos, polietilenoglicóis , trietilcitratos, triacetina e triglicerídeos de ácidos graxos.  A "PHARMACEUTICAL COMBINATION CONTAINING AN ANALGESIC AGENT AND ANTIESPASMODIC AGENT" according to claim 1, characterized in that the present combination incorporates plasticizers of the type diethylphthalates, dibutylphthalates, polyethylene glycols, triethyl acid and triglyceride triacetin.
PCT/BR2015/000146 2013-09-20 2015-09-17 Pharmaceutical composition containing an analgesic agent and an antispasmosdic agent WO2016041036A1 (en)

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RU2017111270A RU2017111270A (en) 2013-09-20 2015-09-17 PHARMACEUTICAL COMBINATION CONTAINING AN AGENT ANALGETIC AND SPASMOLITIC AGENT

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