Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-11-08
2001-10-02
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S282000, C514S284000, C424S649000
Reexamination Certificate
active
06297286
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to new therapeutic uses of tramadol and its structural and/or functional analogues, and to new formulations thereof.
BACKGROUND OF THE INVENTION
Tramadol has the chemical name (+/−)-trans (RR,SS)-2-[(di-methylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol, and which is generally, and erroneously, referred to in literature as the cis(RS,SR) diastereomer, is a centrally acting, binary analgesic that is neither opiate-derived, nor is a non-steroidal, anti-inflammatory drug (NSAID). It is used to control moderate pain in chronic pain settings, such as osteoarthritis and postoperative cases, and acute pain, such as dental pain.
Used in therapy as a racemic mixture, the (+)-enantiomer binds to the &mgr;-opioid receptor, and both enantiomers inhibit 5-hydroxytryptamine (serotonin) and noradrenaline (norepinephrine) reuptake. Tramadol's major active metabolite, O-desmethyltramadol (M1), shows higher affinity for the &mgr;-opioid receptor and has at least twice the analgesic potency of the parent drug.
Despite the fact that tramadol is chemically unrelated to the opioids adverse side-effects associated with administration of tramadol are similar to those of the opioids.
The efficacy and safety of racemic tramadol and its separate enantiomers have been the subject of much study. It has been observed that the (+)-enantiomer has significantly higher analgesic potency than the (−)-enantiomer. It has also been observed that side-effects such as nausea and vomiting are more frequently experienced on administration of the (+)-enantiomer than the (−)-enantiomer. However, the conclusion drawn from these observations, taking into account efficacy and safety, has been to continue use of the racemate; see Pain 1995 September; 62(3):
313--20
and Anaesthetist 1998 May; 47(5):387-94.
SUMMARY OF THE INVENTION
Surprisingly, we have now found that not only are the side-effects caused by administration of (−)-tramadol less severe than those caused by the racemate or (+)-enantiomer, but also that prophylactic or therapeutic administration of (−)-tramadol can prevent or diminish those side-effects and other symptoms typically associated with administration of opioid drugs, or similar symptoms caused by other means. This effect is believed not to be limited to (−)-tramadol, but to extend to the metabolites of (−)-tramadol and to structural and/or functional analogues of (−)-tramadol. By the latter we mean any drug known to operate pharmacologically in a similar manner to (−)-tramadol.
Thus, according to a first aspect of the invention substantially single enantiomer (−)-tramadol, or a metabolite or a structural and/or functional analogue thereof, is used in the manufacture of a medicament for the prevention and/or treatment of one or more symptoms selected from nausea, vomiting, drowsiness, somnolence, dizziness, respiratory depression, blurred vision, hallucinations, constipation and euphoria, or other central nervous system (CNS) side-effects, especially nausea and/or vomiting. In fact, substantially single enantiomer (−)-tramadol is new class of anti-emetic drug which as a broad spectrum of activity like no other currently marketed anti-emetic.
The symptoms to be alleviated may be associated with administration of another drug. Thus, according to a further aspect of the invention, substantially single enantiomer (−)-tramadol, or a metabolite or a structural and/or functional analogue thereof, is formulated with said another drug as a combined preparation (kit) for simultaneous, separate or sequential use, in the treatment or prevention of a condition for which the said another drug is administered.
DETAILED DESCRIPTION OF THE INVENTION
Examples of drugs of the type which may be used to alleviate the above-mentioned symptoms include substantially single enantiomer (−)-tramadol and its structural and functional analogues including aryl cyclohexanol derivatives such as venlafaxine, codeine, pethidine, dextromethorphan and pentazocine, and derivatives thereof. The metabolites of (−)-tramadol are also believed to be of use in the present invention, and such metabolites are described in detail by Shipton, Anaesth. Intensive Care (2000)28:363-374, which is incorporated herein by way of reference. In the following, unless otherwise stated, reference to substantially single enantiomer (−)-tramadol is intended to embrace the metabolites and analogues of that compound.
While the surprising effects upon which the present invention is based may be common to a number of different compounds, substantially single enantiomer (−)-tramadol and substantially single enantiomer (−)-O-desmethyltramadol are the preferred compounds use in the present invention, with substantially single enantiomer (−)-tramadol being the most preferred.
In the context of this Application, by substantially single enantiomer we mean that one enantiomer is present in an enantiomer excess of at least about 70%, preferably at least about 80%, more preferably at least about 90%, and most preferably at least about 95%. Although it will be understood that any form of tramadol which contains sufficient (−)-tramadol may achieve the beneficial results of the present invention.
The symptoms to be alleviated may be caused by a number of different stimuli. For instance, the symptoms may be caused by administration of any of a number of drugs from different groups. Non-limiting examples of these include:
1) Antidepressants, e.g. moclobemide, trazadone, 1-tryptophan, paroxitine, protryptyline, nefazodone, fluvoxamine.
2) Anxiolytics, e.g. buspirone.
3) Antipsychotics, e.g. clozapine, chlorpromazine.
4) Anticonvulsants, e.g. lamotrigine, gabapentin, carbamezepine.
5) Drugs used in the treatment of neurodegenerative disease, such as muscarinic, nicotinic and dopamine agonists typically used in the treatment of Alzheimer's disease and Parkinson's disease. Specific examples include donepezil, interferon, apomorphine, pergolide, levodopa, bromocriptine, amantadine, tolcapone, selegiline.
6) CNS stimulants, e.g. dexamphetamine, methylphenidate.
7) Drugs used in the treatment of migraine, e.g. ergotamine, methysergide, naratriptan, zolmitriptan.
8) Drugs involved in modulating monoamine or opioid activity, e.g. imipramine, reserpine, venlafaxine, lithium salts, citalopram, fluoxetine, morphine.
9) Opioid drugs, e.g. fentanyl, morphine, sufentanil, diamorphine, buprenorphine, dextromoramide, methadone, oxycodone, phenacozine, nefopam, codeine.
10) Alkaloids, such as those used to treat cancer, e.g. cisplatin.
11) Other drugs useful in cancer treatment or therapy.
It is recognised that there may be overlap between some of the above drug groups.
It is generally preferred to administer substantially single enantiomer (−)-tramadol as a protective, prophylactic dose, which becomes effective prior to release into the body of the drug responsible for the undesirable symptoms. It is believed that substantially single enantiomer (−)-tramadol may be administered at least two to three hours prior to the drug responsible for the undesirable symptoms, and still be effective in preventing and/or treating those symptoms. For these purposes it is convenient to formulate a dosage form in which the (−)-tramadol tramadol is provided in immediate release form and the other drug is provided in controlled release form. This is readily achieved using current technology. Under certain circumstances however it may be preferred to administer the drug responsible for causing the undesirable symptoms before the (−)-tramadol, or at a substantially faster release rate, or at a substantially slower release rate. Any of the dosage forms described in WO-A-9840053 would be suitable for use in the present invention, optionally with any of the formulations described in WO-A-0032558.
Alternatively, the symptoms are not side-effects associated with drug administration, but in
Darwin Discovery Ltd.
Reamer James H.
Saliwanchik Lloyd & Saliwanchik
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