MXPA03012048A

MXPA03012048A - Pharmaceutical composition in capsules comprising a non-steroidal anti-inflammatory and an opiate analgesic for handling pain.

Info

Publication number: MXPA03012048A
Authority: MX
Inventors: Elena Garcia Armenta Ma
Original assignee: Victor Guillermo Alvarez Ochoa
Priority date: 2003-12-19
Filing date: 2003-12-19
Publication date: 2005-06-23

Abstract

The present invention refers to the formulation or combination of two compounds; being one of them a non-steroidal anti-inflammatory known as ketorolaco and the other an opiate analgesic known as tramadol, which are formulated in capsules. The combination of this compounds gives as a result a more analgesic effect, with less dosing and less colateral effects for handling pain.

Description

"PHARMACEUTICAL COMPOSITION IN INJECTABLE SOLUTION COMPRISING AN NON-STEROID ANTI-INFLAMMATORY AND AN OPIACEAL ANALYSIS FOR THE MANAGEMENT OF PAIN" FIELD OF THE INVENTION The present invention refers to the association or combination of a nonsteroidal antiinflammatory agent known as ketorolac and of an opioid analgesic known as tramadol, which are formulated in injectable solution and which are indicated in patients who present with moderate pain to severe of diverse etiology. BACKGROUND OF THE INVENTION There is currently an increase in research on combinations of analgesic agents with the main objective of increasing analgesic efficacy. These studies have presented evidence suggesting that the combined treatment of NSAIDs with another opioid-type analgesic is more effective than a treatment with an analgesic alone. Ketorolac is a pyrrolizine carboxylic acid, structurally related to indomethacin belongs to the group of non-steroidal anti-inflammatories and has been used mainly for its analgesic activity. This compound has been used by different routes of administration such as intramuscular, intravenous and orally, in the short-term management of moderate to severe pain. It has shown anti-inflammatory, analgesic and antipyretic activity, its effects are associated with the inhibition of prostaglandin synthesis and has been used in different pathologies for the relief of pain. Together with the modulated action on opioid receptors at the central level and the role of nitrous oxide in the nociceptive action of ketorolac; These actions could explain its high power and efficacy compared to other drugs in the same group. Ketorolac absorption is almost complete after oral administration and showed high bioavailability in all forms of administration. Tramadol is an analgesic that acts centrally with a dual action mechanism. It has a weak agonist activity in the μ-opioid receptors and, in short, prolongs the activity of neurotransmitters such as norepinephrine (noradrenaline) and serotonin within the descending inhibitory pathway of pain, inhibitory effects of recapture. These two mechanisms act synergistically to produce pain relief. Compared with other opioids, tramadol has a low potential for abuse and development of dependence.

SUMMARY OF THE INVENTION The present invention seeks to obtain a pharmaceutical composition in injectable solution by combining a non-steroidal anti-inflammatory with analgesic activity, such as ketorolac and that of an opioid analgesic such as tramadol, applying a lower dosage, to be administered via intramuscular, intravenous or infusion every 12 hours, avoiding side effects that occur with the independent administration of the compounds and with higher doses such as ketorolac in a dose of 30 g every 8 hours and tramadol with a dose of 100 mg every 12 hours. According to a first aspect of the invention, there is provided a process for the preparation of an injectable solution that allows to obtain as a result of the combination of the aforementioned drugs, achieving the pharmacological action quickly, because in this way The formulation comes directly into the bloodstream, avoiding the first step of absorption at the gastrointestinal tract, since the onset of action is around 10 minutes, while orally the onset of action is around 20 minutes. According to a second aspect of the invention, there is provided an intravenous solution comprising the reference formulation so that it can be used in the immediate postoperative period, where the oral route is restricted and where the postoperative cases have a pervious intravenous route, (catheter with serum).

DETAILED DESCRIPTION OF THE INVENTION In recent years there has been an increase in research on analgesic drug associations, in order to achieve analgesic synergy, with lower doses used to reduce side effects when they are administered independently and at higher doses.

The applicant carried out a clinical study using the combination of ketorolac / tramadol in solution for injection in 100 patients with post-operative pain of traumatology surgery.

A questionnaire was administered to the patients, to assess the effectiveness of the ketorolac / tramadol combination, a Visual Analogue Scale (VAS) was applied to measure the pain intensity, before and after the administration of the combination, it was measured the start time until 30 minutes after administration and at 12 hours and side effects were assessed.

The results were as follows: Table 1: MEASUREMENT OF PAIN BEFORE ADMINISTRATION: NUMBER OF PATIENTS IS 100 SYMPTOMS No. of patients Pain Away 0 Mild 0 Moderate 53 Severe 47 Table 2: MEASUREMENT OF PAIN 30 MINUTES AFTER THE ADMINISTRATION SYMPTOMS No. of patients Pain Away 83 Mild 17 Moderate 0 Severe 0 Table 3: MEASUREMENT OF PAIN 12 HOURS AFTER THE ADMINISTRATION: SYMPTOMS No. of patients Absent Pain 97 Mild 3 Moderate 0 Severe 0 No side effects were reported during and after administration.

Tramadol hydrochloride is the trans- (±) -2 - [(dimethylamino) methyl] -l- (3-methoxyphenyl) cyclohexanol, hydrochloride of and can be represented by the formula (I).

The compound of the formula (I) is known for its analgesic pharmacological activity that acts directly on the Central Nervous System and is currently indicated in the treatment of processes that occur with moderate to severe pain. Etorolaco tromethamine is 5-benzoyl-2, 3-dihydro- (±) -lH-pyrrolizin-1-carboxylic acid, combined with 2-amino-2- (hydroxymethyl) -1,3-propanediol and can be represented by the formula (II).

The compound of the formula (II) is an opiate known for its anti-inflammatory, analgesic and antipyretic pharmacological activity and is currently indicated in the treatment of processes that present acute to severe pain. The concentration of the drug in the formulation is in a proportion of 0.0001% to 20.0%, preferably 1.0 to 5.0%, most preferably 2.5% for Tramadol and in a proportion of 0.0001% to 10.0%, preferably from 0.5 to 5.0%, most preferably 1.0% for ketorolac.

The present invention is characterized in that the drugs combined therein can be found as a base or as a physiologically acceptable salt, with Tramadol hydrochloride being preferred for Tramadol and Ketorolac tromethamine in the case of ketorolac. To dissolve the drugs contained in the formulation can be used a series of polar and non-polar solvents such as: water, alcohols, such as ethyl alcohol, isopropyl myristate, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, lecithin, PEG-40 castor oil , butylene glycol, among others, preferably 2-carbon alcohols, such as ethyl alcohol and polar solvents such as water, are used. The final formulation may contain from 1% to 99% w / w of the solvent. In order to reduce pain caused by tissue damage or irritation, an adjuvant agent of isotonicity has been used, such as dextrose, sodium chloride, mannitol, sorbitol or sodium sulfate, with sodium chloride being preferred. The adjuvant agent of isotonicity can be found in a proportion from 0.0001% to 10.0%. The formulation may also contain other components such as: antimicrobial agents such as benzalkonium chloride, benzyl alcohol, chlorobutanol, parabens, thimerosal among others; a buffer system of pH such as phosphates, citrates, carbonates, bicarbonates, acetates, lactates, among others; a chelating or antioxidant agent such as disodium edetate (E.D.T.A.), ascorbic acid, butylhydroxytoluene (BHT), tocopherols, sodium bisulfite or sodium metabisulfite, anesthetic agents such as benzyl alcohol, or stabilizing agents such as creatinine or sodium caprylate. The final formulation should have a pH between 6 and 8, preferably between 6.9 and 7.9. If this pH is not obtained, it should be adjusted with bases or acids, as the case may be; Sodium hydroxide, potassium hydroxide or sodium lactate can be used as bases, with sodium hydroxide preferred. As acids, hydrochloric acid, lactic acid, citric acid are used among others, hydrochloric acid being preferred. It is important to emphasize the importance of the pH in the aforementioned formulation, since a pH between 6 and 8 must be had, because the formulation at a pH lower than 6, causes irritation and pain at the time and place of application ( intramuscular), causing phlebitis (venous inflammation) in the case of intravenous application. The formulations are contained in containers of adequate capacity to contain the formulation and must withstand an internal pressure of 1.5 Kg / cm2 at a temperature of approximately 121 ° C. The containers used can be made of polypropylene or polyethylene plastic. polypropylene, or borosilicate glass (type I glass) or type soda-lima glass type II and III. The containers used in the present invention are made of borosilicate glass type I, from 1 to 10 raL capacity. Since prolonged exposure to light can cause degradation and precipitation of ketorolac tromethamine, it is preferred that the container be amber colored. The preparation of the solution is carried out in the following manner: in a proportion of the water the ketorolac tromethamine is dissolved, the Tramadol hydrochloride is dissolved separately in the solvent or solubilizing agent selected and the isotonicity agent is added in a portion of water, the three solutions are mixed, pH is adjusted and it is brought to capacity. The solution is then filtered through a membrane of a cellulose, nylon or polyamide derivative with a pore size of 0.20 to 0.60 microns, and is then packed in a vial or amber bottle. Optionally the containers can be subjected to terminal sterilization. When administering Tramadol hydrochloride is rapidly absorbed by the body, with a bioability of 65%. Tramadol has a high tissue affinity and protein binding is around 20%. The pharmacological effect is maintained for 2 hours. In humans, Tramadol is mainly metabolized by N- and O-demethylation pathways and conjugation of O-demethylation products with glucuronic acid. Its half-life in plasma is 6 hours. Ketorolac is rapidly absorbed by the body, with a maximum plasma concentration between 2. 2 and 2.4 μg / mL in 50 minutes for the intramuscular route and 5.4 5 minutes for the intravenous route, its therapeutic effect lasts from 4 to 6 hours with a half-life of 3.8 to 6.3. More than 99.0% of ketorolac present in plasma is bound to proteins, ketorolac undergoes a high hepatic metabolization by conjugation with glucuronic acid, eliminating 92% of it through the kidneys. For the treatment of pain in the short term or as an initial dose, the use of 30 to 60 mg of Ketorolac tromethamine is recommended, then maintenance with doses of 10 to 30 mg every 6 hours. In the case of Tramadol hydrochloride it is recommended to 25 to 100 mg as initial dose, and the maintenance dose should be adjusted to the patient without ever exceeding 400 mg daily. The treatment indicated for the present invention is 10 mg of ketorolac tromethamine and 25 mg of tramadol hydrochloride every 12 hours. Thus, the present invention provides a pharmaceutical formulation in injectable solution that provides from 5 to 30 mg of Ketorolac tromethamine and from 10 to 100 mg of Tramadol hydrochloride in doses of 1 to 10 mL per ampule or vial. 25

Claims

NOVELTY OF THE INVENTION Having described the invention as above, the content of the following is claimed as property: CLAIMS 1. An injectable solution formulation characterized in that it comprises: (a) Ketorolac tromethamine in a proportion of 0.0001% to 10.0%, ( b) Tramadol hydrochloride in a proportion of 0.0001% to 20.0%, (c) one or more solubilizing agents, (d) an isotonicity adjuvant agent, and / or (e) antimicrobial agents; and / or (f) a pH buffer system; and (g) anesthetic agents and / or stabilizing agents.
2. A formulation according to claim 1, characterized in that the concentration of the drug in the formulation is in a proportion of 0.0001% to 20.0% for tramadol and in a proportion of 0.0001% to 10.0%, for Ketorolac
3. A formulation according to claim 1 and 2, characterized in that the concentration of the drug in the formulation is in a proportionally proportion from 1.0 to 5.0% for Tramadol and from 0.5 to 5.0% for Ketorolac.
4. A formulation according to claim 1 to 3, characterized in that the concentration of the drug in the formulation is in a proportion of 2.5% for the Screening and 1.0% for ketorolac.
5. A formulation according to claim 1 to 4, characterized in that the drugs combined therein can be found as their base or as a physiologically acceptable salt, with Tramadol hydrochloride being preferred for Tramadol and Ketorolac tromethamine in the case of ketorolac.
6. A formulation according to claim 5, characterized in that it contains 1 or more polar and / or non-polar solvents such as: water, alcohols, such as ethyl alcohol, isopropyl myristate, propylene glycol, polyethylene glycol, glycerol, dimethylacetamide, lecithin, PEG-40 castor oil, butylene glycol, among others.
7. A formulation according to claim 5 and 6, characterized in that it contains 1 or more polar and / or non-polar solvents, wherein the final formulation may contain from 1% to 99% w / w of the solvent.
8. A formulation according to claim 6 characterized in the solvent is ethyl alcohol, water or a mixture thereof.
9. A formulation according to claim 6, characterized in that it contains an isotonicity adjuvant agent, wherein the isotonicity adjuvant agent can be in a proportion from 0.0001% to 10.0%.
10. A formulation in accordance with the claim 9, characterized in that the adjuvant agent of isotonicity is selected from dextrose, sodium chloride, mannitol, sorbitol or sodium sulfate.
11. A formulation in accordance with the claim 10, characterized in that the adjuvant agent of isotonicity is sodium chloride.
12. A formulation according to claim 1, characterized in that it may also contain antimicrobial agents that are selected from the group of benzalkonium chloride, benzyl alcohol, chlorobutanol, parabens, thimerosal, among others.
13. A formulation according to claim 12, characterized in that it can contain in addition to antimicrobial agents a buffer system such as phosphates, citrates, carbonates, bicarbonates, acetates, lactates, among others; a chelating or antioxidant agent such as disodium edetate (E.D.T.A.), ascorbic acid, Butylhydroxytoluene (BHT), tocopherols, sodium bisulfite or sodium metabisulfite.
14. A formulation according to claim 12 and 13, characterized in that it may also contain antimicrobial agents, anesthetic agents such as benzyl alcohol, or stabilizing agents such as creatinine or 5 sodium caprylate.
15. A formulation according to all previous claims, characterized in that it has a pH value between 6 and 8.
16. A formulation according to claim 10, characterized in that it has a pH value between 6. 9 and 7.9.
17. A formulation according to claim 1 to 16, characterized in that it is contained in containers that can be made of plastic from 15 polypropylene or polyethylene-polypropylene, or borosilicate glass (type I glass) or type soda-lime glass type II and III.
18. A formulation in accordance with the claim 17, characterized in that the containers used in the present invention are made of type I borosilicate glass, from 1 to 10 mL capacity.
19. A formulation in accordance with the claim 18, characterized in that the formulation is contained in an amber glass container of 5 type II borosilicates.
20. The use of a formulation according to claim 1 to 19, for the treatment of moderate to severe pain caused by various etiologies by administration of 10 mg doses of Ketorolac tromethamine and 25 mg of Tramadol hydrochloride every 12 hours.
21. Use of the pharmaceutical formulation in injectable solution, according to claim 20, which provides from 5 to 30 mg of Ketorolac tromethamine and from 10 to 100 mg of Tramadol hydrochloride in doses of 1 to 10 mL per ampule.