WO2012176155A1 - Composición farmacéutica para uso en inflamación y dolor - Google Patents

Composición farmacéutica para uso en inflamación y dolor Download PDF

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Publication number
WO2012176155A1
WO2012176155A1 PCT/IB2012/053157 IB2012053157W WO2012176155A1 WO 2012176155 A1 WO2012176155 A1 WO 2012176155A1 IB 2012053157 W IB2012053157 W IB 2012053157W WO 2012176155 A1 WO2012176155 A1 WO 2012176155A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
agent
composition according
meloxicam
ketorolac
Prior art date
Application number
PCT/IB2012/053157
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English (en)
Spanish (es)
French (fr)
Inventor
María Angélica ARZOLA PANIAGUA
Enrique Raúl GARCÍA SALGADO LÓPEZ
Juan Pablo SENOSIAIN PELÁEZ
Original Assignee
Laboratorios Senosiain S.A. De C.V.
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Publication date
Application filed by Laboratorios Senosiain S.A. De C.V. filed Critical Laboratorios Senosiain S.A. De C.V.
Priority to BR112013033007A priority Critical patent/BR112013033007A2/pt
Priority to ES201390103A priority patent/ES2441917B1/es
Priority to RU2013157013/15A priority patent/RU2604149C2/ru
Publication of WO2012176155A1 publication Critical patent/WO2012176155A1/es

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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
    • A61K31/33—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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates to a combination and pharmaceutical composition and particularly to a combination of an analgesic and an anti-inflammatory selected from ketorolac and meloxicam or piroxicam and pharmaceutically acceptable carriers or excipients; It also refers to a manufacturing process of a pharmaceutical composition and the use of said composition to treat pain and inflammation.
  • Robert Raffa (USA 2005) indicated that the analgesic therapeutic alternatives available to doctors are limited, mainly for the treatment of long-term pain, therefore, it is optimal that the Treatment is also combined to ensure continuous long-term efficacy.
  • drugs can be administered locally or systemically, which will depend on each patient and the doctor's criteria.
  • the local administration is directed specifically to the place where pain occurs quickly and effectively. Few topically applied medications easily penetrate intact skin, absorption depends on the skin and the properties of the pharmaceutical formulation. The absorption of drugs is regulated by the characteristics of the skin and the liposolubility of the drugs.
  • the skin is formed by three main layers of overlapping tissues: the first is superficial (epidermis), the second sub-epidermal, (dermis) and the third deep sub-dermal (hypodermis).
  • the epidermis contains water in addition to fat, it is a hydrolipidic layer.
  • the cutaneous pH varies between 4.2 and 5.9 depending on the body areas, 5.5 being the average.
  • the present invention was designed to have an alkaline pH between 7.0 and 10.
  • Ketorolac is a NSAID derived from carboxylic and pyrrole pyrrole, it is highly soluble in water. It is a powerful and effective analgesic very effective in the treatment of moderate to severe pain. When administered in combination with another active substance, it usually presents stability problems, in laboratory tests it has been shown that its stability decreases significantly in the presence of acidic substances, this makes the formulation of a pharmaceutical composition where ketorolac and other or other coexists coexist active ingredients without affecting the stability of each of them.
  • Ketorolac depending on the condition can be administered from 2. Omg up to 120mg per day. Doses greater than 120mg per day can be toxic.
  • Meloxicam is an NSAID derived from oxicam, it is insoluble in water and its solubility increases with increasing pH. Meloxicam has a good tolerability profile, it is indicated for the treatment of acute and chronic rheumatoid arthritis, osteoarthritis (degenerative joint disease), shoulder and hip periarthritis, among other conditions.
  • Piroxicam depending on the condition can be administered from 0.2mg to 30mg per day. Doses greater than 50mg can be toxic.
  • Piroxicam is a non-steroidal anti-inflammatory, analgesic and antirheumatic agent, it inhibits the synthesis of prostaglandins and their release through the reversible inhibition of the enzyme cyclooxygenase. It reduces the production of toxic superoxide anion by neutrophils and reduces the production of rheumatoid factor; which translates into pain relief in moving joints, reduction in morning stiffness, swelling, less limitation of movement, increased pressure force and decreased time required to walk.
  • Piroxicam is indicated for a variety of conditions characterized by pain and inflammation such as extra-articular rheumatic diseases: fibrositis, scapulo-humeral periarthritis (painful shoulder), periarthritis, tendinitis, tendosynovitis, musculoskeletal, traumatic and sports conditions: bruises, sprains, dislocations , fractures, muscle tears, sprains, sprains or lower back pain.
  • extra-articular rheumatic diseases fibrositis, scapulo-humeral periarthritis (painful shoulder), periarthritis, tendinitis, tendosynovitis, musculoskeletal, traumatic and sports conditions: bruises, sprains, dislocations , fractures, muscle tears, sprains, sprains or lower back pain.
  • Piroxicam depending on the condition can be administered from 2.5mg to 60mg per day. Doses greater than 60mg can be toxic.
  • the combination of the present invention can be administered in systemic or local administration compositions.
  • topical compositions these can be gel, cream, ointment, paste or other.
  • gel composition is preferred because it is a well tolerated and easily washable formulation. With a gel the sensation of freshness is produced since it is not a formulation that generates cold or heat, its topical action is located on the surface of the skin, that is only in the area of application, without the sufferings of adverse effects caused by the administration of systemically absorbed drugs.
  • US Patent 5, 091, 182 presents a pharmaceutical composition of ketorolac of topical application which is presented in the form of a transdermal patch or collapsible aluminum tube.
  • Said composition has a pH stability between 3.8 and 4.6.
  • the collapsible tube formulation includes a chelating agent such as EDTA since the formulation comes into contact with aluminum in addition to an antioxidant such as BHT and a pH adjusting agent such as tromethamine.
  • the present invention in its preferred embodiment, comprises a topical formulation that is presented in a plastic container, lacks a chelating agent such as EDTA, is stable at a different pH and its Physicochemical stability is regulated with triethanolamine.
  • This composition includes two active principles of marked physicochemical incompatibility with each other, which prevents their coexistence at an acidic pH, as in the invention of US Patent 5,091,182.
  • the application WO 2007/010584 A3 refers to a controlled release system of the type of transdermal patch containing a polymeric matrix, an inorganic dispersing agent and an active ingredient that can be an NSAID; Said polymeric system may contain between 30 and 99% by weight of the polymer, between 1 and 70% of the inorganic dispersing agent and between 1 and 50% by weight of the active ingredient. Said composition is designed as a controlled release system that can range from 24 hours to 30 days.
  • the present invention relates, in its preferred embodiment, to a topical pharmaceutical composition without the use of a matrix, containing 1) ketorolac and 2) meloxicam or piroxicam, and is directly applied to the skin, with synergistic anti-inflammatory and analgesic therapeutic action.
  • ketorolac gel with 2g per lOOg.
  • This composition is topical local administration, immediate action against pain, should be applied 3 or 4 times a day.
  • Ketorolac despite being an NSAID, has a very rapid effect, mainly analgesic and with less anti-inflammatory effect, so it acts in a diminished manner against inflammation
  • the present invention resolves this limitation with the inclusion of another active ingredient: meloxicam or piroxicam.
  • meloxicam or piroxicam.
  • the present invention surprisingly demonstrated that the combination of ketorolac and meloxicam or piroxicam is therapeutic and synergistically effective.
  • the combination of the present invention in a preferred embodiment without limiting the use envisages using formulations containing less active ingredient than existing commercial formulations and thereby a reduction of adverse effects.
  • ketorolac a rapid-response NSAID, mainly analgesic against mild to severe pain
  • meloxicam a long-acting and slow-acting NSAID, mainly anti-inflammatory
  • piroxicam NSAIDs immediate anti-inflammatory activity
  • the pharmaceutical composition of the present invention can be administered orally. In another preferred embodiment, the pharmaceutical composition may be presented topically. These formulations make it easier to administer to people who do not want or cannot receive parenteral administration treatment and who suffer from localized lesions and have mild to severe inflammation and / or pain.
  • the topical pharmaceutical composition of the present invention in the preferred embodiment, has an alkaline pH, this is achieved by creating a buffer and stabilizer system with the use of a support vehicle, a cosolvent, a humectant and essentially an agent that dissociates the agent. gelling and stabilizing the formulation at an alkaline pH such as triethanolamine.
  • the formulation of the present invention has the power to completely cross the skin and reach deep tissue. of the skin, carrying its local analgesic and anti-inflammatory therapeutic action quickly and effectively.
  • the topical formulation of the present invention has good tolerance, does not irritate, is stable against environmental factors, with a consistency suitable for its extension on the skin, with pleasant organoleptic characteristics, does not dehydrate, nor degrease the skin, nor does it generate a greasy feeling
  • the present invention is directed to a combination and to a pharmaceutical composition comprising effective amounts of 1) ketorolac and 2) meloxicam or piroxicam.
  • ketorolac can be formulated from 0. 1g to 10g for each 10g of topical composition.
  • ketorolac can be included from lmg to 120mg.
  • meloxicam can be formulated from 0.2g to 5g for each 10g of composition.
  • meloxicam can be included from 2mg to 30mg.
  • piroxicam can be formulated from 0.2g to 20g for each 10g of composition.
  • piroxicam can be included from 2.5mg to 60mg.
  • Figures 1A and IB are graphs showing the temporal course of ketorolac and meloxicam hyperalgesic behavior, respectively, when administered. topically in the model of thermal hyperalgesia in rats sensitized with carrageenan.
  • Figures 2A and 2B are graphs showing the percentage of the Maximum Effect observed for ketorolac and meloxicam, respectively, in the model of thermal hyperalgesia in rats (* p ⁇ 0.5)
  • Figure 3 is a graph showing the temporal course of hyperalgesic behavior (withdrawal threshold) in rats treated topically with increasing doses of the ketorolac-meloxicam combination in proportion (1: 3.2). Each point represents the mean ⁇ e.e. of at least 6 rats.
  • Figure 4 is a graph showing the dose-antihyperalgesic effect curve after the topical application of the combination of ketorolac and meloxicam in the model of thermal hyperalgesia in rats, measured by the response derived as a percentage of the maximum possible antihyperalgesic effect.
  • Each point represents the mean ⁇ e.e. of at least 6 rats (* p ⁇ 0.05 vs control)
  • Figure 5 shows the experimental DE 40 (0.70 ⁇ 0.03 g / 100) and the theoretical DE 50 (1.17 ⁇ 0.22 g / 100), indicating that the combination of ketorolac and meloxicam produced a synergism in the antihyperalgesic effect.
  • Figure 6 is a graph depicting the temporal course of inflammation in rats treated topically with increasing doses of the ketorolac-meloxicam combination in proportion (1: 3.2). Each point represents the mean ⁇ ee of 6 rats.
  • Figure 7 shows the anti-inflammatory dose-effect curve after topical application of the ketorolac-meloxicam combination in the carrageenan edema model in rats, measured by the derived response as a percentage of the maximum possible anti-inflammatory effect. Each point represents the mean ⁇ ee of at least 6 rats (* p ⁇ 0.05 vs control).
  • Figure 8 shows the experimental DEi 5 (0.12 ⁇ 0.09 g / 100) and the theoretical DEi 5 (0.91 ⁇ 0.26 g / 100), indicating that the ketorolac-meloxicam combination produced a synergism in the anti-inflammatory effect in the edema model Carrageenan-induced rats.
  • a pharmaceutical composition comprising effective amounts of 1) ketorolac and 2) meloxicam or piroxicam.
  • ketorolac is an NSAID that presents synergistic interaction with meloxicam or piroxicam, when the combination of both active ingredients is co-administered, for the treatment of pain and inflammation.
  • ketorolac and 2) meloxicam or piroxicam equal analgesic effects are achieved with doses considerably reduced, compared to formulations with equal doses when each active ingredient is administered separately. Any administration route can be used. Topical administration has been proven to be the most effective.
  • the challenge faced by the development of the present invention is to obtain a stable, safe and therapeutic therapeutic pharmaceutical composition that includes drugs that are physicochemically different from each other, such as ketorolac and meloxicam, which have a marked difference in solubility. .
  • Ketorolac due to its physicochemical characteristics shows greater solubility in slightly acidic solutions between a pH range of 5.0 and 6.9. Meloxicam presents greater stability in slightly basic pH in a range between 7.0 and 9.0. These characteristics of the assets hinder the manufacturing process of the pharmaceutical composition since the stability of each of them can be affected. By performing a simple combination of the active ingredients in solution (ketorolac and meloxicam), physical instability and degradation of the active substances are clearly shown.
  • one way of presenting the formulation is in the form of a gel composition, wherein an agent that dissociates the gelling agent is used, this Excipient is triethanolamine, which additionally acts as a pH regulator, thereby creating a microenvironment conducive to the coexistence of the two active principles of physicochemical properties that are different and incompatible with each other and the formulation is physicochemical stable.
  • the present invention in the form of topical formulation, is characterized in that it comprises ketorolac, meloxicam or piroxicam and its pharmaceutically acceptable salts and, at least, an agent that dissociates the gelling agent and that maintains the pH of 7.0 to 10.0 in said composition .
  • an oral formulation is presented where the main challenge is to keep ketorolac and meloxicam or piroxicam physically stable.
  • topical formulation is one of the most accepted for its convenience of administration and ease of transport
  • the present invention can be presented in cream, gel, ointment, paste or other pharmaceutical form of topical administration, of which the gel is preferred .
  • composition of the present invention which contains the active ingredients ketorolac and meloxicam or piroxicam and / or its salts, is described below.
  • pharmaceutically acceptable, additionally pharmaceutically acceptable carriers or excipients are described below.
  • the amounts by weight of the active ingredients, vehicles and / or excipients may be used within the ranges of use mentioned below.
  • the formulation may contain the active ingredients meloxicam or piroxicam and ketorolac or their pharmaceutically acceptable salts thereof.
  • the use of the active substances is not limited to those indicated since the formulation can be presented with another NSAID such as oxicam, diclofenac, triethanolamine salicylate, naproxen, among others.
  • a topical or oral formulation can be manufactured, where the excipients are selected from the following list.
  • Excipients dispersing agent of the type of propylene glycol, polyethylene glycol or derivatives of glycols, liquid paraffin, polymers of vinyl acid (carbopol), among others; agent that dissociates the gelling agent and / or stabilizing agent: ethanolamines such as monoethanolamine, diethanolamine, triethanolamine, or others; Conservatives: parabens, ethylparaben, methylparaben, butylparaben, sodium benzoate, among others; gelling agent or viscous agent: polymers of vinyl acid (carbopol), lutrol, HPC, among others; alcoholic cosolvent: ethyl alcohol, isopropyl alcohol, methanol, among others; wetting agent: glycerin, sorbitol, polyethylene glycol, among others; emulsifying agent: castor oil, cremophor RH40, Novemer, soy lecithin, twens, among others; buffer regulator or modulator: organic
  • the gelling agent or viscous agent fulfills the function of promoting gel formation with the help of the stabilizing agent (also called the agent that dissociates the gelling agent).
  • the gelling agent or viscosifying agent fulfills the function of a viscosifying agent and with the help of the stabilizing agent that stabilizes the formulation.
  • topical formulations of the present invention a formulation in the form of a translucent gel and a cream. . 0
  • ketorolac and meloxicam An example of a preferred formulation comprising ketorolac and meloxicam is illustrated in Table 3, wherein the amounts by weight of the active ingredients, vehicles and / or excipients can be used within the ranges of use mentioned, without limiting their use.
  • the present invention can also be presented in other topical pharmaceutical forms such as a cream, an ointment or another.
  • Table 4 illustrates examples of formulations comprising meloxicam and ketorolac where the amounts by weight of the active ingredients, vehicles and / or excipients can be used within the ranges of use mentioned without limiting their use.
  • the process for preparing the pharmaceutical composition in cream is characterized in that it comprises the steps of: a) Adjust the pH of water to 8.0 and disperse the gelling or viscosifying agent;
  • the oral composition in the embodiment of the invention relating to the oral composition, it can be produced in tablet, tablet, granulate, dragee, powder or powder to reconstitute a solution or suspension, solutions or suspensions and, where appropriate, compressibility vehicle, diluent binder, antistatic, lubricant, plasticizer, disintegrant and even present the active ingredients in separate compartments.
  • the outer layer it may or may not contain a polymeric cover that gives it protection from both internal and external factors such as humidity, light, among others.
  • the present topical formulation was subjected to a stability study in which the formulation was challenged at various temperature and humidity conditions in order to check the stability of the pharmaceutical composition. Also, the topical formulation was subjected to a preclinical study to prove its effectiveness.
  • Table 7 presents the results of the stability study for a formulation without triethanolamine, which is the agent that dissociates the gelling agent.
  • Table 8 presents the result of the stability study for a formulation containing triethanolamine, an agent that dissociates the gelling agent.
  • the present formulation shows that the microsystem developed with the formulation surprisingly achieves the absorption of meloxicam and ketorolac in addition to ensuring that the ketorolac drug (unstable in acidic medium) remains stable in a basic medium, therefore, there is a formulation Safe, effective and physicochemical stable that offers the presence of fewer adverse effects.
  • KT ketorolac tromethamine or its salts
  • MLX meloxicam
  • meloxicam MLX
  • ketorolac KT
  • isobolographic analysis was carried out. This method is based on comparing the determined doses that are equieffective. From dose-response curves of the individual agents, the respective ED 50 are obtained, that is, the dose necessary to reach 50% of the maximum possible effect. In the present study, because meloxicam had a limited maximum activity (ceiling effect), the necessary doses were used to reach 15% (SD 15 ) of possible anti-inflammatory effect for each drug. Meanwhile, for the antihyperalgesic effect, because both drugs had at least 40% maximum effect, ED 40s were used to construct the isobolograms.
  • the evaluation of the antihyperalgesic and anti-inflammatory effects of the individual and combination drugs was carried out using topical application formulations in the form of a hydrophilic gel.
  • the doses used were similar in all animals and corresponded to 1 g of the gel applied to the plantar surface of the right leg 1 h before the administration of carrageenan.
  • Anti-hyperalgesic and anti-inflammatory dose-effect curves were obtained, and by means of linear regression the values of the effective dose of the drugs administered individually are obtained in accordance with the aforementioned. They were subsequently applied Topical ketorolac and meloxicam combinations in doses corresponding to different dilutions of the ED 40 of each drug, estimated in the thermal hyperalgesia model, and with these doses the anti-inflammatory effect of the combinations was evaluated. A fixed proportions scheme was used, according to table 9.
  • Table 9 Diagram of concentrations used in preclinical study with the combinations of ketorolac and meloxicam.
  • Topical administration of placebo, without administration of carrageenan did not change the natural withdrawal threshold, which on average occurred at 6 seconds.
  • the administration of carrageenan induced a sustained decrease in the withdrawal threshold that reaches a minimum of about 60 minutes after the injection of the proinflammatory agent ( Figure 1 A-B).
  • a dermal irritability study was carried out that demonstrates that the administration of the present invention is neither irritating nor toxic for such study six healthy albino rabbits were used, for intact skin as eroded, the study was performed according to NOM-096-SSA1-1994 , NOM-039-SSA1- 1993 and Pharmacopoeia of the United Mexican States 8th Edition.
  • the topical synergistic pharmaceutical composition of the combination of meloxicam and ketorolac, or its pharmaceutically acceptable salts, is a useful and effective formulation for treating conditions of mild to severe localized skeletal muscle pain.
  • the use of the active substances is not limited to those indicated since the formulation can be presented with or instead of meloxicam or ketorolac other NSAID drugs such as, piroxicam, oxicam, diclofenac, triethanolamine salicylate, naproxen among others.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/IB2012/053157 2011-06-22 2012-06-21 Composición farmacéutica para uso en inflamación y dolor WO2012176155A1 (es)

Priority Applications (3)

Application Number Priority Date Filing Date Title
BR112013033007A BR112013033007A2 (pt) 2011-06-22 2012-06-21 composição farmacêutica para uso contra inflamação e dor
ES201390103A ES2441917B1 (es) 2011-06-22 2012-06-21 Composición farmacéutica para uso en inflamación y dolor
RU2013157013/15A RU2604149C2 (ru) 2011-06-22 2012-06-21 Фармацевтическая композиция против воспаления и боли и способ ее приготовления (варианты )

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MXMX/A/2011/006758 2011-06-22
MX2011006758A MX357376B (es) 2011-06-22 2011-06-22 Composicion farmaceutica para uso en inflamacion y dolor.

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AR (1) AR086733A1 (ru)
BR (1) BR112013033007A2 (ru)
CL (1) CL2013003671A1 (ru)
CO (1) CO6831987A2 (ru)
CR (1) CR20130687A (ru)
DO (1) DOP2013000309A (ru)
ES (1) ES2441917B1 (ru)
GT (1) GT201300318A (ru)
MX (1) MX357376B (ru)
NI (1) NI201300142A (ru)
PE (1) PE20141530A1 (ru)
RU (1) RU2604149C2 (ru)
WO (1) WO2012176155A1 (ru)

Cited By (1)

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WO2014193210A1 (es) * 2013-05-27 2014-12-04 Farmacêuticos Rayere, S.A. Composición farmacéutica sinergística de dos analgésicos con distinto perfil farmacocinético

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ES2332225T3 (es) * 2004-10-04 2010-01-29 World Trade Import-Export, Wtie A.G. Formulaciones farmaceuticas solidas conteniendo diacereina y meloxicam.
WO2007148950A1 (es) * 2006-06-20 2007-12-27 Farmacéuticos Rayere, S.A. Composición farmacéutica sinergística de ketorolaco y clonixinato de lisina
EP2138174A1 (en) * 2007-04-02 2009-12-30 World Trade Import-Export, WTIE A.G. Pharmaceutical composition in the form of a sublingual tablet consisting of a non-steroidal anti-inflammatory agent and an opiate analgesic for pain management
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WO2014193210A1 (es) * 2013-05-27 2014-12-04 Farmacêuticos Rayere, S.A. Composición farmacéutica sinergística de dos analgésicos con distinto perfil farmacocinético

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BR112013033007A2 (pt) 2017-01-31
ES2441917R1 (es) 2014-02-19
ES2441917A2 (es) 2014-02-06
DOP2013000309A (es) 2014-04-15
MX2011006758A (es) 2013-01-10
CO6831987A2 (es) 2014-01-10
NI201300142A (es) 2015-02-25
MX357376B (es) 2018-07-06
CL2013003671A1 (es) 2014-07-11
AR086733A1 (es) 2014-01-15
RU2013157013A (ru) 2015-07-27
ES2441917B1 (es) 2014-11-25
RU2604149C2 (ru) 2016-12-10
GT201300318A (es) 2015-05-21
CR20130687A (es) 2014-02-21

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