Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-14
2001-03-20
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S810000
Reexamination Certificate
active
06204271
ABSTRACT:
BACKGROUND OF THE INVENTION
Opioid analgesics such as e.g. morphine are the most powerful analgesic drugs. The pain relieving activity of opioid analgesics includes a depressive effect on the central nervous system. The analgesic activity of opioid analgesics such as morphine and deltorphin II can be mediated via different opioid receptors, for example via receptors &mgr;-opioid and &dgr;-opioid receptors. Opioid analgesics are invaluable for the treatment of severe acute or chronic pain as, for example, may occur in bone degenerative diseases and cancer conditions. They are easy to administer and they provide effective pain relief in most patients. Due to the excellent overall tolerability of opioids the doses of morphine and other strong opioids can be increased to relatively high levels. Yet, in particular upon long term use, there is a development of unacceptable side effects.
These side effects include the development of physical dependence and tolerance, sedation, respiratory depression, hypotension, increase in cerebrospinal fluid pressure, nausea, vomiting and constipation. In some patients, particularly in the chronically ill, the opioid side effects make it impossible to continuously administer sufficiently high dosages to adequately control pain over the needed period of time. There are also some pain conditions that do not sufficiently respond to opioid pain treatment alone. Therefore, there is a constant need for improved opioid containing analgesic combinations with increased analgesic activity which comprise opioid and non-opioid analgesically active agents and which offer the possibility of reducing the opioid dose needed for efficient pain relief and thereby also reducing the opioid side effects that might result from the otherwise required higher dosages.
It is therefore an object of the present invention to provide an opioid containing analgesic composition having high analgesic potency and a reduced propensity for causing undesirable side effects.
It is also an object of the invention to provide a non-opioid substance with analgesic effects showing synergy with the analgesic activity of the opioid, and to provide analgesic compositions comprising an opioid analgesic agent, in particular morphine, and such a synergistically effective non-opioid analgesic agent which allows to reduce the amount of the opioid necessary to achieve effective pain treatment.
It is further an object of the invention to provide a method for producing opioid induced analgesia in larger mammals, in particularly in humans, whereby undesirable side effects of acute and chronic administration of strong opioids are reduced.
SUMMARY OF THE INVENTION
The present invention is directed to producing analgesia in larger mammals, in particular in humans, by co-administering synergistically effective amounts of (1) 4-chloro-5-[(4,5-dihydro-1H-imidazol-2-yl)-amino]-6-methoxy-2-methylpyrimidine (generic name: moxonidine) of formula I,
or its physiologically compatible acid-addition salts; and (2) of an opioid analgesic agent. The present invention further pertains to analgesic pharmaceutical compositions comprising synergestically effective amounts of moxonidine or its physiologically compatible acid addition salts and an opioid analgesic agent.
DETAILED DESCRIPTION OF THE INVENTION
According to the invention there is provided a pharmaceutical analgesic composition comprising synergistically effective amounts of (1) moxonidine or pharmaceutically acceptable salts thereof and of (2) an opioid analgesic agent or a pharmaceutically acceptable derivative or salt thereof. In such a combination the opioid agent or a pharmaceutically acceptable derivative or salt thereof can be administered in a low-analgesic dose, or even in a per se sub-analgesic dose. The composition may contain both, moxonidine and the opioid agent, together in one dosage form or each in a separate dosage form.
Moxonidine and its pharmacologically acceptable salts used in accordance with the invention are within the scope of the 5-[(2-imidazolin-2-yl)-amino]-pyrimidine derivatives with blood pressure lowering properties described in the published German Patent Application No. 28 49 537, and are known from this patent application. Pharmaceutical preparations containing moxonidine are commercially available as antihypertensive medications under the trade name Physiotens®. The compounds can be manufactured in a known manner essentially in accordance with the processes described in the aforementioned published German Patent Application or in a manner similar to these processes. Moxonidine is known to be an imidazoline/&agr;
2
-adrenergic (I
1
/&agr;
2
-AR) receptor agonist.
Salts with inorganic acids, such as hydrohalic acids, or with organic acids, for example lower aliphatic monocarboxylic or dicarboxylic acids such as acetic acid, fumaric acid or tartaric acid or aromatic carboxylic acids such as salicylic acid are suitable as physiologically compatible acid-addition salts of moxonidine.
It has now been found that moxonidine has an analgesic activity, which synergizes with the analgesic activity of opioids, in particular opioids such as morphine or deltorphin II, when moxonidine and such an opioid analgesic are co-administered for the treatment of pain. This co-administration results in a greater-than-additive effect (i.e., synergy).
The opioid agonist with opioid receptor activity used in the present invention may be selected from morphine and compounds structurally related to morphine, or functionally related to morphine such as deltorphin II, or pharmaceutically acceptable derivatives or salts thereof. Further examples of clinically opioid analgesics are e.g. fentanyl and remifentanil. Most preferably used is morphine. Suitable pharmaceutically acceptable salts of opioids include hydrochlorides, hydrobromides, hydroiodides, sulphates, bisulphates, nitrates, citrates, tartrates, bitartrates, phosphates, malates, maleates, fumarates, succinates, acetates, terephthalates, pamoates and pectinates. Preferably, the pharmaceutically acceptable salt of morphine is a hydrochloride, a sulphate or a tartrate.
The dosages of opioid compounds to be administered for the relief of pain naturally vary depending on the type and severeness of the condition to be treated, as well as on the type of the opioid compound and of the route of administration used. For example, dosages of 10 to 20 mg of morphine per single unit dosage form are common for liquid analgesic formulations. According to the invention, by administering a combination of an opioid with moxonidine, equal pain relieving effects may be achieved with dosages that are substantially reduced as compared to the dosages needed when the opioid is administered alone. Depending on the amount of moxonidine added, dosages may be reduced down to {fraction (1/30)}, suitably down to ⅙ to {fraction (1/10)}. In order to provide a synergistic interaction according to the present invention, the quantitative ratio of moxonidine to the opioid is particularly chosen such that the weight-to-weight ratio of moxonidine to the opioid is such that the effective doses for each of the two compounds range from 25% to 75% (ED
25
to ED
75
); in other words, the ratio of doses for 25% to 75% effect of each compound, when administered alone, may be used to set the ratio of moxonidine to the opioid to be administered in an individual dosage form. Preferably, the quantitative ratio of moxonidine to the opioid is chosen such that the contribution of analgesic efficacy from each, moxonidine and the opioid, is approximately in the same order (40-60%:60-40%), and in particular equal. For example, when equi-effective analgesic amounts of moxonidine and morphine are used in combination, an enhancement of the analgesic potency of morphine of up to about 6-fold of the theoretically expected additive potency is observed, and for moxonidine, respectively, an enhancement of up to about the 9-fold potency of the theoretically expected (additive) potency is found.
According to the invention analgesia is
Fairbanks Carolyn A.
Kitto Kelley F.
Stone Laura S.
Wilcox George L.
Evenson, McKeown, Edwards & Lenahan P.L.L.C.
Kulkosky Peter F.
Solvay Pharmaceuticals GmbH
LandOfFree
Analgesic composition and method for using same does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Analgesic composition and method for using same, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Analgesic composition and method for using same will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2461743