MXPA01005242A - Therapeutic product and its use - Google Patents

Abstract

The present invention is based on the discovery that, by employing certain, non-racemic, proportions of the respective enantiomers of tramadol, the most beneficial therapeutic index, in terms of analgesic efficacy and reduction of side effects (e.g. nausea, vomiting, dizziness, constipation, sedation and others) associated with administration of the racemate, may be achieved.

Description

THERAPEUTIC PRODUCT AND ITS BRIEF USE DESCRIPTION OF THE INVENTION The present invention relates to a novel, non-racemic form of tramadol, and its use in analgesia. Tramadol (cis-2-dimethylaminomethyl-1- (3-methoxy-phenyl) -1-cyclohexanol) is a chiral drug substance that is used as a high potency analgesic agent. Although tramadol is currently marketed as the racemate alone, there has been considerable interest in the physiological properties associated with its individual enantiomers, mainly 15, 2S- (-) -tramadol and 1R, 2R- (+) - tramadol, the latter being subsequently shown (1).

In particular, the analgesic efficiency and safety of the racemate and the individual enantiomers have been investigated in a randomized double-blind study with gynecological patients using intravenous analgesia controlled by the patient; see S. Grond et al. , Pain (1995) 62 (3): 313-320. Although (+) - tramadol appeared to be more potent to produce analgesia, it also produced more nausea and vomiting. Since the racemate has more efficiency than (-) - tramadol and no more side effects than (+) - tramadol, it was concluded that the racemate had more clinical utility. In another study it was shown that there is complementary and synergistic antinociceptive interaction between the individual enantiomers of tramadol; see R.B. Raffa et al, J. Pharmacol. Exp. Ther. (1993) 267 (1): 331-340. The enantiomers have different potencies at the opioid receptors, and to inhibit the re-acceptance of serotonin and the re-acceptance of noradrenaline. Therefore, it seems that both enantiomers of tramadol contribute to the analgesic effect. The present invention is based on the discovery that, by employing certain non-racemic proportions of the respective enantiomers of tramadol, the most beneficial therapeutic index can be achieved, in terms of analgesic efficiency and reduction of side effects (eg, nausea, vomiting, vertigo, constipation, sedation and others) associated with racemate administration. According to a first aspect of the present invention a product comprising a non-racemic mixture of the simple enantiomers of tramadol as a preparation (equipment) combined for simultaneous, separate or sequential use in the treatment or prevention of pain. According to a second aspect of the present invention, a non-racemic mixture of the simple enantiomers of tramadol is used in the manufacture of a medicament for the treatment or prevention of pain, and is particularly useful for the treatment of patients prone to side effects. typically associated with the administration of racemic tramadol. The medication is, however, useful for treating other types of patients, as described below. According to a third aspect of the claimed invention, a product comprises a non-racemic mixture of the simple enantiomers of tramadol and a pharmaceutically acceptable carrier. In the context of the present application, when reference is made to a non-racemic mixture of tramadol, it is intended to include enantiomerically pure (-) - tramadol (-) - tramadol, or enantiomeric excesses relative to (-) - tramadol close to the enantiomeric purity . Typically, the non-racemic mixture for use in the present invention comprises at least 60% by weight of (-) - tramadol. While enantiomerically pure (-) - tramadol may be useful for achieving analgesia, it is preferred that (-) - tramadol be formulated with at least some (-) - tramadol, since the optimal balance between both enantiomers is achieved. analgesic efficiency and safety. Particularly preferred weight ratios of the enantiomers are in the range of 10-40: 90-60 (+) - tramadol: (-) - tramadol (+ :-), the most preferred ratios are in the range of 20 -40: 80-60 (+ :-), and the most preferred relationships are in the range of 30-40: 70-60 (+ :-). These preferred non-racemic mixtures are particularly useful for the treatment of patients who are prone to side effects typically associated with the administration of racemic tramadol. A couple of examples of such secondary examples are given above. Other secondary examples typically observed in the administration of racemic tramadol include blurred vision, lethargy, drowsiness, hallucinations, respiratory depression and euphoria. The present invention, however, is particularly useful for treating those patients prone to nausea and vomiting. This is because, as explained in the following Example, it is believed that (-) -tramadol modulates the emetic properties of (+) - tramadol, thereby reducing the total emetic capacity of racemic tramadol. This effect can be exploited for maximum benefit by using different release profiles for the different enantiomers, as described below. The present invention is also believed to be particularly suitable for the treatment of patients exhibiting abnormal CYP2D6 liver enzyme activity. The CYP2D6 gene encoding sparteine oxygenase is highly polymorphic, and an ever-increasing number of mutations are identified. The wild type gene is CYP2D6 * 1A. Anyone who does not have the wild type gene can be categorized as having abnormal enzymatic activity. The precise nature of any particular mutation determines the degree to which a patient exhibits abnormal enzymatic activity. Thus, by applying simple laboratory genetic analysis techniques it is possible to determine the approximate proportion at which (+) - tramadol will be metabolized by a particular patient, and therefore how fast and effective the analgesia will be. In accordance with the present invention it is contemplated that patients phenotypically or genotypically -diagnosed as extensive metabolizers of racemic tramadol will benefit particularly from the administration of non-racemic tramadol, since they are especially disposed to side effects such as nausea and vomiting. In addition, the administration regimen can be designed to suit any individual patient once their CYP2D6 genotype is known. Other non-racemic proportions of the two enantiomers of tramadol are also useful for the treatment or prevention of pain, depending on the cause of the pain and / or the patient to be treated. For example, mixtures comprising a high proportion of (-) - tramadol can be used, for example, related in weight in the range of 0-10: 100-90 (+ :-), with patients particularly prone to side effects associated with tramadol. racemic Another option is to employ a more equal balance of the two enantiomers, with the more effective (+) - enantiomer in excess, for example weight ratios in the range of 60-80: 40-20 (+ :-), typically 60- 70: 40-30 (+ :-). Such relationships may be useful for treating patients particularly not prone to side effects associated with racemic tramadol, or wherein the analgesic efficiency is of primary importance. The administration of (-) - tramadol before or to a faster portion of (+) - tramadol would, however, still be beneficial in reducing side effects. In the context of the present Application, all weight ratios cited should be construed as including a tolerance of, say, + 5% by weight. The present invention is also believed to be particularly useful for the treatment of pain and / or other effects associated with migraine. For this purpose, a further aspect of the present invention is the use of a non-racemic mixture of the simple enantiomers of tramadol in the manufacture of a medicament for the prevention or treatment of migraine. The amount of non-racemic tramadol administered to any particular patient will depend on the patient and the conditions for which the non-racemic tramadol is administered, or on whether the non-racemic tramadol is for use in prophylaxis or therapy. Suitable amounts for administration are easily derivable by the skilled person. The different enantiomers of tramadol can be administered simultaneously, separately or sequentially. They can be formulated for immediate or controlled release, or a combination of the two, or for release at different rates, or at different times. Preferred modes of administration of (-) - tramadol release before or at a faster rate than (+) - tramadol, so as to optimize the effect of (-) - tramadol on the emetic properties of (+) -tramadol. Although, situations can be contemplated, where the inverse is required, it is desirable to administer (+) - tramadol before or at a faster rate than (-) - tramadol. A particularly preferred mode of administration is with (-) - tramadol in immediate release form and (+) - tramadol in controlled release form, employing a combination of immediate and controlled release technologies, as described in WO-A-9840053 , the contents of which are incorporated herein by reference. It is contemplated that a dosage form of this type may be particularly beneficial for achieving rapid analgesia without the concomitant side effects associated with the administration of racemic tramadol. A number of different types of dosage form can be contemplated for the non-racemic mixtures of the present invention, for administration by a variety of routes, eg, oral, rectal, transdermal, nasal, ophthalmic, pormonary and injectable (subcutaneous or intravenous). ). Suitable dosage forms include, for example, tablets, suppositories, capsules, for example containing multiparticles, patches, polymeric implants, aerosols, liposomes or microparticles for injection, and any other conventional dosage form. Particularly preferred dosage forms are described in O-A-9840053. Of the dosage forms described in that document, a bilayer tablet is particularly preferred, which includes (-) - tramadol for immediate release in one layer and (+) - tramadol for controlled release in another layer. The results on which the present invention is based are reported in the following Example. Example The objective was identified in the optimal range of enantiomeric relationships capable of providing the most beneficial therapeutic index, in terms of analgesic efficiency and reduction of nausea and vomiting associated with racemic tramadol.

Two studies were carried out to determine the analgesic and emesis efficiency of tramadol and its enantiomers in the rat and the ferret, respectively. The comparison of the data obtained in these studies allowed the determination of a range of optimal enantiomeric relationships for these species. Pharmacokinetic / pharmacodynamic modeling made it possible to extrapolate these data to humans. Analgesic Efficiency Rating Tramadol and its pure enantiomers were examined for their analgesic efficiency in the rat using the Randall-Selitto test (Arch. "Int. Pharmacodyn. (1957) 111: 409-419) in the rat. to measure the effect of tramadol and its enantiomers on yeast-induced analgesia, with the perception of pain assessed by an increase in paw pressure increase using an analgesimeter.For comparative purposes the effects of the active metabolites of tramadol enantiomers , O-demethyltramadol were also tested, different amounts of each of the test substances were orally administered to the rats, using a constant dose volume of 10 ml / kg. Immediately after administration, 0.1 ml of a suspension was injected. 20% w / v Brewer's yeast in saline subcutaneously within the plantar surface of the right paw of each rat to induce hyper -algesia.The left leg was injected similarly with 0.1 ml of saline, as a control. Tolerated pressure measurements of the left (non-inflamed) and right (inflamed) legs were taken 30 minutes after administration of the test substance. The observed results are illustrated in the Figure 1, for the inflamed leg and Figure 2, for the non-inflamed leg, as a percentage increase in pain tolerance with various doses of the test substance. In both Figures, T = tramadol and Ml = 0-demethyltramadol. Assessment of Nausea Tramadol and its pure enantiomers were examined for their effects of nausea on the ferret. For comparative purposes the effects of the active metabolite of (+) - tramadol, (+) - O-demethyltramadol ((+) - Ml), were also tested. Orally dosed ferrets were observed for a period of 4 hours for signs of nausea and vomiting. Any ferret that experienced nausea or vomiting during the 4-hour period was considered a reactant, that is, presenting as nausea. The results are illustrated in Figure 3; T and Ml represent tramadol and O-demethyltramadol, as in Figures 1 and 2. As expected, (+) - Ml is highly emetic.

The (-) -tramadol is seen not to be emetic at doses of up to 200 mg / kg. In comparison, (+) - tramadol induces nausea in 75% of ferrets at 50 mg / kg, while the racemate causes nausea in 25% of animals at 100 mg / kg. Although the racemate is a 50:50 mixture of the two enantiomers it is seen that it induces less nausea than would be expected based on its (+) - enantiomer content. This difference can be explained by the ability of (-) -enantiomer to modulate emesis associated with the (+) - enantiomer. Bioassay of plasma samples and liver microsome analysis have shown that tramadol is metabolized similarly in the rat, the ferret and the human. It is therefore possible to compare the data obtained in each of these studies, to reach the optimal range of enantiomeric relationships for these species. In addition, by pharmacokinetic / pharmacodynamic modeling techniques, it is possible to extrapolate the data obtained for humans, to reach the optimal range of enantiomeric ratios for use in the present invention.

Claims (20)

1. CLAIMS 1. A product characterized in that it comprises the simple enantiomers of tramadol in a non-racemic proportion as a combined preparation (equipment) for simultaneous, separate or sequential use in the treatment or prevention of pain.
2. 2. The product in accordance with the claim 1, characterized in that it comprises at least 60% by weight of (-) - tramadol.
3. 3. The product in accordance with the claim 2, characterized in that the simple enantiomers are in a weight ratio of 10-40: 90-60 (+ :-).
4. 4. The product according to claim 2, characterized in that the single enantiomers are in a weight ratio of 20-40: 80-60 (+ :-).
5. 5. The product according to claim 2, characterized in that the single enantiomers are in a weight ratio of 0-20: 100-80 (+ :-).
6. 6. The product according to any of the preceding claims, characterized in that it releases the (-) -enantiomer before the (+) - enantiomer.
7. 7. The product according to any of claims 1 to 5, characterized in that it releases the (-) - enantiomer faster than the (+) - enantiomer.
8. 8. The product according to any of claims 1 to 5, characterized in that the (-) - enantiomer is in immediate release form and the (+) - enantiomer is in controlled release form.
9. 9. The use of a non-racemic mixture as defined in any of claims 1 to 5, characterized in that it is in the manufacture of a medicament for the treatment or prevention of pain.
10. 10. The use according to claim 9, characterized in that the pain is pain associated with migraine.
11. The use according to claim 9, characterized in that it is for the treatment of a patient prone to side effects associated with the administration of racemic tramadol.
12. 12. The use according to claim 11, characterized in that the side effects are selected from nausea, vomiting, vertigo, constipation, sedation, blurred vision, lethargy, drowsiness, hallucinations, respiratory depression and euphoria, especially nausea and vomiting.
13. 13. The use according to claim 9, characterized in that it is for the treatment of a patient exhibiting abnormal liver CYP2D6 enzyme activity.
14. 14. The use of a non-racemic mixture as defined in any of claims 1 to 5, characterized in that it is in the manufacture of a medicament for the treatment or prevention of migraine.
15. 15. The product comprising the simple enantiomers of tramadol in a non-racemic proportion, the ratio being defined in any of claims 2 to 5, characterized in that it is a pharmaceutically acceptable carrier.
16. 16. The product according to claim 15, characterized in that it releases the (-) - enantiomer before the (+) - enantiomer.
17. 17. The product according to claim 15, characterized in that it releases the (-) - enantiomer faster than the (+) - enantiomer.
18. 18. The product according to claim 15, characterized in that the (-) - enantiomer is in the immediate release form and the (+) - enantiomer is in the controlled release form.
19. 19. The product according to any of claims 15 to 18, characterized in that it comprises the two enantiomers in separate portions thereof.
20. 20. The product according to claim 19, characterized in that it is a bilayer tablet comprising (-) - tramadol in a portion thereof, and (+) - tramadol in another separate portion thereof.