Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1994-07-12
1997-05-13
Venkat, Jyothsna
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424489, 424499, A61K 950
Patent
active
056290110
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a composition for nasal administration and more particularly to a composition for the nasal administration of the polar metabolites of opioid analgesics.
Opioid analgesics have a useful role in pain relief, particularly for patients in the terminal stages of cancer. Morphine is a widely used agent and can be administered via injection as an oral controlled release formulation or by suppository. Morphine has also been given via the nasal route and morphine snuff was described in the last century.
The intranasal administration of opiates has been discussed by Ralley (Can. J. Anaesth. 36, 5 491.493 (1989) who suggested that morphine could be given by this route. The route was relatively free of side effects normally associated with opioids but a possible disadvantage was the short duration of sedation which lasted only up to 60 minutes.
Nasal administration of morphine is discussed in EP 205282 where a sustained release effect is achieved through the use of a cellulosic derivative that adheres to the mucosa. A solid unit dosage form is described.
WO 8203768 describes a system for nasal drug delivery comprising morphine or its analogues having at least one phenolic hydroxy group with a non toxic nasal carrier. Ointments, gel solution or suspension salts of morphine are preferably used in the sustained release products.
It is well known that the therapeutic use of morphine gives rise to various side effects, including constipation and respiratory depression. Recently it has been disclosed that some of the metabolites of morphine, namely morphine-6-glucuronide and morphine-6-sulphate may be several times more active than the parent drug and is less likely to have the unwanted side effects (Pasternak et al (1987) Life Sciences 41, 2845; Hanna et al. (1991) Brit. J. Anaes. 66, 103; Brown et al (1985) J Pharm. Sci. 74,821). They may also have a longer biological half-life. The use of morphine-6-glucuronide as a drug substance in its own right has been discussed in the pharmaceutical and medical literature (Osborne et al (1988) Lancet April 6 p.828). Similarly, morphine-6-sulphate has been described in the literature as an analgesic agent (Brown et al Supra). However, the major problem facing delivery of these agents and polar metabolites of this and other opioid analgesics by methods other than injection, is the high water solubility of the compounds. It is unlikely that the materials will be well absorbed across mucosal surfaces, for example from the gastrointestinal tract. It is possible that the glucuronides would be absorbed from the colon but this would only occur after the glucuronide was converted back to the parent compound by the action of the reducing conditions within the large bowel created by the microbial flora in that region. The polar nature of the compounds also means that they are likely to be poorly transported across normal mucosal surfaces such as the nasal, buccal, vaginal and rectal mucosae. However, we have now found, surprisingly, that the absorption of such polar metabolites across the nasal mucosa can be greatly increased by combination with an absorption promoting agent.
Thus the present invention provides a composition for nasal administration comprising a polar metabolite of an opioid analgesic and an absorption promoting agent. A preferred metabolite is a glucuronide, especially morphine-6-glucuronide, however glucuronides of other opioid analgesics such as codeine, levorphanol, hydromorphone, oxymorphone, nalbuphine, buprenorphine, nalorphine, hydrocodone, oxycodone and butorphanol are also suitable. A further preferred metabolite is a sulphate, especially morphine-6-sulphate but again sulphates of other opioid analgesics such as those mentioned above are also suitable.
Opioid analgesics are metabolised in the body to a variety of compounds that are more polar than morphine itself, and this is what we mean by the term metabolite as used herein. The polar nature of a compound can be determined by measuring its partition coefficient between an aqueous buffer a
REFERENCES:
patent: 5362498 (1994-11-01), Aiache
Brown et al., "Analgesic Potencies of Morphine-3-and 6-Sulfates . . ., " J. Pharm. Sci, vol. 74, No. 8, Aug. 1985, pp. 821-824.
Osbourne et al., "Analgesic Activity of Morphine-6-Glucuronide," Lancet, Apr. 6, 1988, p. 828.
Houdi et al., "Potent Central Activity of Morphine . . . ," Pharm. Res. 9, 5-103 (1992).
Hanna et al, "Disposition of Morphine-6-. . . ," British J. Anaesthesia, 66:pp. 103-107; (1991).
Rally, "Intranasal Opiates . . . ," Can. J. Anaesth., vol. 36, No. 5, pp. 491-493 (1989).
Pasternak et al, "Morphine-6-Glucuronide . . . ," Life Sciences, vol. 41, No. 2845 (1987).
Danbiosyst UK Limited
Venkat Jyothsna
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