Galenic composition containing opioid antagonists

Details Galenic composition containing opioid antagonists Galenic composition containing opioid antagonists

1999-08-10

2002-07-16

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S489000, C424S464000, C424S474000, C424S458000, C424S468000, C514S282000

Reexamination Certificate

active

06419959

ABSTRACT:

The invention relates to new galenic compositions with opioid antagonistic activity and their use in opioid-induced constipation. In particular, the invention relates to pellet, granulate or microtablet compositions comprising the active ingredients naloxone, N-methylnalaxone or N-methylnaltrexone as the active ingredients with opioid antagonistic activity.
Constipation arising through medication with the use of strongly effective analgesics of the morphine type represents a large problem. It is considered as one of the most frequent side effects and is an undesired concomitant symptom particularly in continual therapy. This problem arises during treatment in approximately 85% of the patients given morphine. In contrast to other side effects caused by for example morphine, this is a chronic phenomenom that does not loose intensity during the course of treatment [Saller R., Hellenbrecht D. “Schmerzen-Therapie in Praxis und Klinik”, 1st Ed. (1991) Marseille Publishers, Munich]. The paralytic effect of opioids on intestine motility has been known for a long time and is also therapeutically used, for example, in the case of diarrheal illnesses [Manara L., Bianchetti A. “The central and peripheral influences of opioids on gastrointestinal propulsion”, Ann. Rev. Pharmacol. Toxicol. 25, 249-273 (1985)]. Although the mode of action of opioids on intestine motility is not yet completely understood, it is seen in connection with the binding of the opioid to opioid receptors in the intestine. Aside from in the brain, these opioid receptors are also to be found at high density in the gastrointestinal tract above all [Manara L., Bianchetti A. “The central and peripheral influences of opioids on gastrointestinal propulsion”, Ann. Rev. Pharmacol. Toxicol. 25, 249-273 (1985)].
In a series of pharmacological experiments, it could be demonstrated that opioids (morphine was mostly chosen as a model substance) have a direct effect on the smooth musculature of the intestine and, thus, muscle tonicity in intestine segments increases. The enhancement of segmental tonicity leads to a significant prolongation of gastrointestinal passage time with simultaneous decrease of the propulsive motility of the intestine [Cameron J. C. “Constipation related to narcotic therapy”, Cancer Nurs. 15, 372-377 (1992)].
The aim of a therapy is to neutralize this peripheral side effect of morphine and related compounds because opioid-induced constipation can be very painful and finally endangers the success of treatment [Glare P., Lickiss J. N. M. “Unrecognized constipation in patients with advanced cancer: a recipe for therapeutic disaster”, J. Pain Symptom Manage. 7, 369-371 (1992)]. A little more than half of the patients who suffer from this side effect can be sufficiently taken care of with customary laxatives and thickening agents. For the rest of the patients, satisfactory treatment possibilities are still lacking.
Since it is assumed in opiod-induced constipation that the true effect proceeds directly and locally over the entire intestine through the occupation of opioid receptors, this effect should be able to be neutralized through the use of opioid antagonists. However, the use of opioid antagonists only makes sense when the antagonistic effect on the intestine is limited and the central pain-relieving effect is not neutralized. Therefore, only a few opioid antagonists such as for example naloxone, N-methylnalaxone or N-methylnaltrexone are considered which have a peripheral effect and not an effect in the CNS under certain conditions.
Naloxone is a pure opioid antagonist which is customarily intravenously applied as an antidote in the case of opioid poisoning. After oral administration, naloxone is quickly and completely resorbed. Since the substance is subject to a very pronounced first-pass metabolism, only small amounts of the unaltered substance are systemically available. The predominant portion of the applied substance is present in the blood in the form of the metabolites naloxone-3-glucuronide, &bgr;-naloxol-3-glucuronide and &bgr;-naloxol which are not effective or only weakly effective [Vollmer K. O. “Pharmakokinetische Grundlagen des Valoron-N-Prinzips”, Fortsch. Med. 106, 593-596 (1988)]. As a result of this pharmakinetic property, naloxone in a suitable dose is an ideal candidate for relief of opioid-induced constipation: in the intestine, it is present as an active substance and can thus neutralize the paralytic effect of the opioid on the gastrointestinal tract and, after reabsorption, it is largely metabolized and rendered ineffective with the first liver passage. Thus, the pain-relieving effect of the opioids is not adversely affected.
In various small clinical trials, it could be demonstrated that opioid constipation could be partially neutralized by the oral administration of naloxone: in two studies on healthy probands, Basilisco et al. examined the influence of loperamide, a peripherally effective opioid used in diarrheal illnesses, on the gastrointestinal passage time. They demonstrated that naloxone when intravenously applied (40 &mgr;g/kg/hr. in 3 hr) [Basilisco G., Bozzani A., Camboni G., Recchia M., Quatrini M., Conte D., Penagini R., Bianchi P. A. “Effect of loperamide and naloxone on mouth-to-caecum transit time evaluated by lactulose hydrogen breath test”, Gut 26, 700-703 (1985)] and after oral administration of relatively high doses of 16 or 32 mg [Basilisco G., Camboni G., Bozzani A., Paravicini M., Bianchi P. A. “Oral naloxone antagonizes loperamide-induced delay of orocecal transit”, Dig. Dis. Sci. 32, 829-832 (1987)] could neutralize the constipating effect of loperamide.
Culpepper-Morgan et al. report a pilot study in which three patients with opioid-induced constipation were treated with orally applied naloxone. After doses of up to 16 mg, two of the three patients responded to the treatment (neutralisation of constipation). With the other patient, constipation could not be neutralized even with a increase in dose of up to 24 mg naloxone (within 3 hours). Plasma level determinations showed that dose-dependent maximal naloxone concentrations up to 7.9 ng/ml were measured. At doses from 14 mg, the non-responder showed clear withdrawal symptoms which points to an antagonization of the central opioid effect [Culpepper-Morgan J. A., Inturrisci C. E., Portenoy R. K., Foley K., Houde R. W., Marsh F., Kreek M. J. “Treatment of opioid-induced constipation with oral naxolone: A pilot study”, Clin. Pharmacol. Ther. 52, 90-95 (1992)].
Sykes report a study with 12 patients who were administered with oral naloxone at different doses. The naloxone dose was oriented on the daily opioid dose. Naloxone was given in doses of 0.5%, 1%, 2%, 5%, 10%, 20%, and 40% with respect to the opioid dose. No effect was determinable up to 10% naloxone dose. A neutralization of constipation was first reported at the very high dose range (20% to 40%) The absolute naloxone doses which were administered could amount to up to 72 mg naloxone [Sykes N. P. “Oral naloxone in opioid-associated constipation”, The Lancet 337, 1475 (1991)].
Robinson et al. report a study on 12 patients with opioid-induced constipation in which naloxone was also orally administered. The maximally administered dose was 12 mg naloxone. An effect on the gastrointestinal motility or withdrawal symptoms was not determinable in any of the treated patients [Robinson B. A., Johansson L., Shaw J. “Oral naloxone in opioid-associated constipation”, The Lancet 338, 581-582 (1991)].
It is striking that in the cited studies, the results turn out very differently and, above all, naloxone is effective when it is applied in high doses. In this dose range, withdrawal symptoms also already arise in individual patients. The active ingredient is released quickly and unmodified in customary, simple compositions (for example, capsules or drops). When using these simple compositions, naloxone is quickly and completely resorbed in the upper part of th

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