NEW CHEMICAL COMPOUND CONTAINING ACTIVE ENANTIOMETER S-(-) KETOROLAC TROMETHAMINE FOR THE TREATMENT OF PAIN

Abstract

The invention relates to a novel chemical compound characterized in that it contains the active enantiomer S-(−) ketorolac tromethamine combined with other pharmaceutically acceptable adjuvants or excipients, said compound being advantageous over other NSAIDs and, in particular, the known active principle ketorolac tromethamine, comprising a single isomer that is pure and has a better therapeutic index, retaining its therapeutic activity by improving its physicochemical properties, such as solubility or stability, which translates into a decrease in the dose administered, reducing direct gastrointestinal side effects and the time required for the development of the desired therapeutic action. The invention is suitable for use as a medication for the treatment of pain of moderate to high intensity and can be administered in any form in the dose range from 0.5 milligrams to 30 milligrams.

Claims

1. A novel chemical compound, characterized in that it contains an active enantiomer, S-(−) ketorolac tromethamine, which is characterized by the following structure and nomenclature: ##STR00003## 2-amino-2-hydroximethyl-1,3 propanediol (1:1) S-(−)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate; S-(−)-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid salt with 2-amino-2-hydroximethyl-1,3-propanediol (1:1).

2. The novel chemical compound as set forth in claim 1, characterized in that it comprises the active enantiomer S-(−) ketorolac tromethamine in combination with a ether pharmaceutically acceptable excipient or adjuvant.

3. The novel chemical compound as set forth in claim 1, characterized in that it comprises a single isomer that is pure and has a better therapeutic index than its predecessor, the active substance having the name ketorolac tromethamine.

4. The novel chemical compound as set forth in claim 1, characterized in that it retains its therapeutic activity improving its physicochemical properties, including as solubility or stability, which results in fewer direct gastrointestinal side effects and less time required for the development of the desired therapeutic action, advantages that are significant when compared with other NSAIDs and in particular with its predecessor, the known active substance ketorolac tromethamine.

5. The novel chemical compound as set forth in claim 1, characterized in that it is used as a medication for the treatment of moderate to severe pain.

6. The novel chemical compound as set forth in claim 5, in combination with a pharmaceutically acceptable excipient.

7. The novel chemical compound as set forth in claim 5, in combination with a pharmaceutically acceptable excipient, formulated for administration in a dose range of 0.5 milligrams to 30 milligrams.

8. A pharmaceutical composition comprising the novel chemical compound as set forth in claim 1 in combination with a pharmaceutically acceptable excipient or adjuvant, wherein the pharmaceutical composition is formulated for oral administration.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is formulated to contain 0.5 milligrams to 30 milligrams of the S-(−) ketorolac tromethamine.

10. A method of treating moderate to severe pain in a subject in need thereof comprising administering to the subject an effective amount of the compound as set forth in claim 1.

11. The method of claim 10 wherein administration of the compound results in fewer direct gastrointestinal side effects and less time required for the development of the desired therapeutic action compared to the administration of racemic ketorolac tromethamine.

12. The method of claim 11 wherein the compound is administered in a does range of 0.5 milligrams to 30 milligrams.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0025] FIG. 1. Antinociceptive efficacy in DRC (oral route)

[0026] FIG. 2. Pharmacological potency of ASA, morphine, rac-ketorolac, and s-ketorolac

[0027] FIG. 3. Maximum effect (Emax) on CT of maximum doses (oral route)

[0028] FIG. 4. Global effect of maximum dose (for 4 hours)

[0029] FIG. 5. Fixed effect 4 hours after administrating maximum dose

[0030] FIG. 6. Effective dose 50 in rats, oral route

[0031] FIG. 7. Lethal dose in 50% of the rat population, oral route

[0032] FIG. 8. Therapeutic index in rats, oral route

DETAILED DESCRIPTION OF THE INVENTION

[0033] The S-(−)-ketorolac tromethamine is a novel chemical compound that is characterized as a non-steroidal anti-inflammatory (NSAID) from the family of the heterocyclic derivatives and is used as an analgesic, antipyretic, and anti-inflammatory drug. Unlike ketorolac tromethamine, this chemical compound is constituted by the enantiomer S(−), which is the most active, 60 times more active than the R (+) form. The consequence of this is that, unlike ketorolac tromethamine, the dose administered can be reduced, thus decreasing the direct gastrointestinal side effects and the time required for the development of the desired therapeutic effect.

[0034] The S-enantiomers of the derivatives 2-arylpropionic combined with tromethamine salt share all of the benefits of the non-selective COX inhibitors, with easy absorption and fewer side effects than its main compounds, and turn out to be an excellent option for the treatment of moderate to severe pain.

[0035] The chemical structure of the previously known ketorolac racemic salt is as follows:

##STR00001##

[0036] Meanwhile, the chemical structure of the novel chemical compound S-(−)-ketorolac tromethamine that is described in the present invention is as follows:

##STR00002##

[0037] And its nomenclature is: [0038] 2-amino-2-hydroximethyl-1,3 propanediol (1:1) S-(−)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate; [0039] S-(−)-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid salt with 2-amino-2-hydroximethyl-1,3-propanediol (1:1).

[0040] The results of the preclinical trial titled “Pharmacological comparison of the antinociceptive effects of S-(−)-ketorolac with a prototypical analgesic of the opioid group and with a prototypical analgesic of the group of the NSAIDs,” conducted by Dr. Francisco Javier Lopez Munoz and dated Sep. 20, 2017, showed that the analgesics included in this trial had adequate antinociceptive effects in experimental conditions of gouty arthritis-type pain in lab animals: male Wistar rats weighing between 180 and 200 grams. The prototypical analgesic of the opioid group that was compared with S-(−)-ketorolac tromethamine was morphine, and the prototypical analgesic of the group of the NSAIDs was acetylsalicylic acid. In order to determine and compare the antinociceptive effects of these analgesics the preclinical experimental model of PIFIR “pain-induced functional impairment model in the rat” was used. Based on this, it was demonstrated that: (i) with regard to the pharmacological efficacy of the S-(−)-ketorolac tromethamine, it exhibited similar efficacy to that exhibited by rac-ketorolac and to the prototypical opioid analgesic, morphine, but S-(−)-ketorolac tromethamine exhibited much more efficacy than that exhibited by the prototypical NSAID agents such as acetylsalicylic acid, as is demonstrated in the following table:

TABLE-US-00001 DOSE MAXIMUM (mg/kg. EFFICACY RELATIVE ANALGESIC oral route) (ABC: X ± E.E.) EFFICACY rac-ketorolac 10.0 324.6 ± 7.8  1.0 3.2 310.5 ± 13.5 1.0 Morphine 177.8 310.8 ± 8.9  1.0 Acetylsalicylic 562.3 226.6 ± 11.7 0.70 Acid

[0041] Also, see graphic in FIG. 1/8.—The comparison of the antinociceptive efficacy of the 4 analgesics determined in the CDR, and the dose which generates them can be seen. (N.S.=No significant difference and numeric analysis); (ii) with regard to the pharmacological potency, S-(−)-ketorolac tromethamine turned out to be more potent than morphine, the prototypical opioid analgesic, and the NSAID acetylsalicylic acid, when comparing doses needed to generate 50% of the most effective effect generated in experimental conditions. Therefore, S-(−)-ketorolac tromethamine was 3.3 times more potent than rac-ketorolac, 82 times more potent than morphine, and 1037 times more potent than acetylsalicylic acid, as is shown in the following table:

TABLE-US-00002 ED60 (mg/kg, oral route) (with regard RELATIVE POTENCY ANALGESIC to Emax: 324 au) (relative to 5-ketorolac)  0.36 ± 1.0 — rac-Ketorolac  1.19 ± 1.2 −3.3 Morphine 29.35 ± 1.1 −81.5 Acetylsalicylic 373.3 ± 1.7 −1,036.9 Acid

[0042] Also, see graphic in FIG. 2/8.—Shown is the calculation of the ED.sub.50 and a comparison of the antinociceptive potency of the 4 analgesics; (iii) with regard to latency in reaching the Emax in the temporal curve, S-(−)-ketorolac tromethamine exhibited a latency similar to that exhibited by rac-ketorolac, but less than that exhibited by morphine; that is, it reaches its Emax faster than morphine administered orally. However, the acetylsalicylic acid exhibited the least latency in reaching its Emax, even though that Emax was smaller than those exhibited by the other analgesics. See graphic in FIG. 3/8.—This shows the maximum effects exhibited by the highest doses that it is possible to administer of each one of the analgesics by oral route; (iv) With regard to the Emax reached in the temporal curve, S-(−)-ketorolac tromethamine exhibited an Emax similar to that exhibited by rac-ketorolac and morphine, but this Emax was higher than that exhibited by acetylsalicylic acid. See graphic in FIG. 4/8.—Shown are the global antinociceptive effects achieved by the analgesics upon administration of larger doses by oral route; (v) with regard to a fixed effect 4 hours after administration, the effect produced by S-(−)-ketorolac tromethamine was the same as that exhibited for rac-ketorolac and by morphine but higher than that exhibited by acetylsalicylic acid. See graphic in FIG. 5/8.—This shows the antinociceptive effects exhibited after 4 hours of the administration of the analgesics in the higher doses through oral route; (vi) with regard to the effective dose 50, this turned out to be less than the rest of the active substances being studied. See graphic in FIG. 6/8.—Shown are the effective doses 50 (ED.sub.50) that are particular to each analgesic (taking into account its own efficacy) to produce 50% of its own maximum effect obtained in the PIFIR experimental model in rats by oral route; (vii) With regard to lethal dose 50, S-(−)-ketorolac tromethamine exhibited a LD 50 smaller than the acetylsalicylic acid, but larger than the one reported for rac-ketorolac and morphine, as can be seen in the graphic of FIG. 7/8, which shows a lethal dose 50 (LD.sub.50) of each analgesic to produce death in 50% of the rat population upon administration of every one of the analgesics; (viii) due to the small magnitude of the ED 50 and the large magnitude of the LD 50 of S-(−)-ketorolac tromethamine, a very high and favorable therapeutic index was found with regard to the therapeutic index of rac-ketorolac, of morphine, the opioid prototype, and of the acetylsalicylic acid, the NSAID prototype, as is described in the graphic of FIG. 8/8, which shows the therapeutic index of each analgesic administered by oral route in rats.

[0043] As a consequence of the above, it was concluded in that preclinical trial that very adequate characteristics for efficacy, potency, Emax, Emax latency, fixed effects, and toxic effects were established with the therapeutic index for S-(−)-ketorolac tromethamine, the active enantiomer of ketorolac, compared to the racemic mixture of ketorolac with morphine, the opioid prototype, and acetylsalicylic acid, the NSAID prototype.

[0044] The following conclusions were drawn from the results of the cited preclinical trial: The chemical compound S-(−)-ketorolac tromethamine turned out to be an analgesic with very adequate characteristics for efficacy, potency, Cmax, fixed and toxicity effects with the therapeutic index for S-(−)-ketorolac, the active enantiomer of ketorolac, when compared to the racemic mixture of ketorolac tromethamine with morphine, the opioid prototype, and acetylsalicylic acid, the NSAID prototype.

[0045] Now, if we compare the novel chemical compound described in the present invention with ketorolac tromethamine, it can be said that the latter is a potent analgesic but that its most frequent side effects are directly related to the pharmacological actions for this type of drugs. In particular, they produce effects over the gastrointestinal tract and on the renal and hematological function and inhibit platelet aggregation and can incite the formation of gastric ulcers.

[0046] Scientific evidence shows that the risk of developing severe complications involving peptic ulcers (in particular, high digestive hemorrhaging) is considerably higher with the use of ketorolac tromethamine than with other non-steroidal anti-inflammatory drugs, and the increase in the risk can be particularly substantial when it is used outside the conditions of use that are currently authorized. The chemical compound ketorolac tromethamine is a racemic mixture of the enantiomers (−) S and (+) R, the first of which is the one that possesses analgesic activity.

[0047] The intention behind the strategy of reevaluating the racemic drug and segregating the beneficial part of a non-steroidal anti-inflammatory analgesic such as S-(−)-ketorolac was to develop a novel chemical compound with a single isomer that is pure and has a better therapeutic index than the mixture formulated as a racemate of ketorolac tromethamine.

[0048] This novel chemical compound that is protected in the present invention has several substantial advantages over its predecessor, ketorolac tromethamine, since it retains its therapeutic activity while improving its physicochemical properties, such as solubility or stability, which translates into better solubility and less time required to obtain a therapeutic response.

[0049] This novel chemical compound comprises the active enantiomer S-(−) ketorolac tromethamine in combination with pharmaceutically acceptable excipients or adjuvants to be prescribed or administered in any pharmaceutical form to the patient as a medication for the treatment of pain of moderate to high intensity in the dose range from 0.5 milligrams to 30 milligrams.