GB2282758A - Oral morphine-6-glucuronide compositions - Google Patents

Oral morphine-6-glucuronide compositions Download PDF

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Publication number
GB2282758A
GB2282758A GB9317504A GB9317504A GB2282758A GB 2282758 A GB2282758 A GB 2282758A GB 9317504 A GB9317504 A GB 9317504A GB 9317504 A GB9317504 A GB 9317504A GB 2282758 A GB2282758 A GB 2282758A
Authority
GB
United Kingdom
Prior art keywords
morphine
glucuronide
compositions
treatment
pain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
GB9317504A
Other versions
GB9317504D0 (en
Inventor
Ronald Brown Miller
Stewart Thomas Leslie
Derek Allan Prater
Sandra Therese Antoi Malkowska
Kevin John Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Euro Celtique SA
Original Assignee
Euro Celtique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Euro Celtique SA filed Critical Euro Celtique SA
Priority to GB9317504A priority Critical patent/GB2282758A/en
Publication of GB9317504D0 publication Critical patent/GB9317504D0/en
Priority to PCT/GB1994/001808 priority patent/WO1995005831A1/en
Publication of GB2282758A publication Critical patent/GB2282758A/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Abstract

Morphine-6-glucuronide is used as active ingredient in a pharmaceutical composition for the treatment of pain by oral administration e.g. in the form of a capsule or tablet.

Description

PHARMACEUTICAL COMPOSITIONS This invention is concerned with improvements relating to pharmaceutical compositions and, more particularly, is concerned with pharmaceutical compositions containing a morphine derivative as active ingredient.
Morphine is an opioid analgesic widely used in the treatment of pain. Thus, for example, morphine (typically in the form of morphine sulphate) may be orally administered to humans for the treatment of cancer pain. To this end, the active ingredient has been formulated in sustained release form so that a patient need only take the medicament a few times a day, say twice a day.
Morphine-6-glucuronide is a known metabolite of morphine and, itself, has powerful analgesic properties, as least comparable with those of morphine.
It has now been found, in accordance with the present invention, that morphine-6-glucuronide, when orally administered to humans, is absorbed and, unexpectedly, gives rise to appreciable plasma levels of morphine-6-glucuronide, morphine and morphine-3 glucuronide , over extended periods of time, e.g. 48 hours or more. Accordingly we have found that morphine-6-glucuronide is a useful active ingredient for the formulation of pharmaceutical compositions having a prolonged or controlled duration of activity.
Accordingly, therefore, the present invention provides an orally administrable pharmaceutical composition, for the treatment of pain, containing, as active ingredient, morphine-6-glucuronide. In particular, the invention is concerned with such an orally administrable pharmaceutical composition having an effective duration of activity such that it may be administered at relatively extended intervals, e.g. on a once or twice daily basis and, possibly, over a prolonged regimen of treatment, e.g. of one or more weeks, that is for the treatment of chronic pain. The invention is also concerned with the use of morphine-6-glucuronide in the preparation of pharmaceutical compositions for the treatment of pain, especially, as noted above, compositions intended for relatively infrequent administration possibly over a prolonged regimen of treatment.Further, the invention provides a method for the relief of pain using as composition as defined above.
Pharmaceutical compositions in accordance with the invention will basically comprise the active ingredient, morphine-6-glucuronide, together with a pharmaceutical carrier or diluent. The compositions may be in liquid form, e.g. formulated as syrups, solutions or linctuses comprising a solution of morphine-6-glucuronide in an appropriate solvent, such as water, together with optional adjuvants such as flavouring agents, thickening agents, preservatives, etc. Such liquid compositions may optionally be filled into capsules, for example soft or hard gelatin capsules and in this case, of course, the carrier should be one which does not interact with the material of the capsule wall.
The compositions of the invention are, however, more conveniently put up in solid dosage unit form, e.g. as granules, tablets (which may be effervescent), or as sachets capsules containing a powder, granules or pellets containing morphine-6-glucuronide for either immediate or controlled release. Such solid dosage unit forms will generally comprise the morphine-6-glucuronide together with a solid pharmaceutical diluent or excipient such as lactose, starch, microcrystalline cellulose, pregelatinised starch, or calcium phosphate; together with appropriate optional adjuvants such as binders, tablet disintegrants, controlled release agents, glidants and tablet lubricants.
The morphine-6-glucuronide content of a dosage unit form in accordance with the invention depends upon a number of variables including, for example, the total dosage of morphine-6-glucuronide required for any particular patient and the number of dosage units to be administered at any one time. Typically, however dosage unit forms in accordance with the invention will contain from 1 to 1000 mg of morphine-6-glucuronide, typically, for example, 5, 20, 100, or 200 mg of morphine-6glucuronide.
As noted above, morphine-6-glucuronide, when orally administered to humans, gives appreciable plasma levels of morphine-6-glucuronide (and morphine) over an extended period of time. In contrast, morphine sulphate gives rise to appreciable plasma levels of morphine, or the metabolite morphine-6- glucuronide, over a much shorter period. These facts are evidenced by the results of the following trials.
Adult volunteers were given, on separate occasions; (i) 20 mg of morphine-6-glucuronide as an aqueous solution thereof; and, as a control, (ii) 10 mg of morphine sulphate, as an aqueous solution thereof.
The plasma levels of morphine-6-glucuronide and morphine were measured for each individual at various times after administration. The mean values of plasma levels obtained for (a) morphine-6-glucuronide and (b) morphine are shown in Figs. 1 and 2, respectively; the curves labelled Morphine sol. showing the plasma levels obtained by the administration of the morphine solution, and those labelled M-6-G sol. showing the levels obtained by administering the morphine-6-glucuronide solution.
In order that the invention may be well understood the following Examples of pharmaceutical compositions in accordance with the invention are given by way of illustration only.
Examples 1 and 2 - Liquid Formulations (1) (2) 20 mg/5 ml 200 mg/5 ml k w/v k w/v Morphine- 6-glucuronide 0.400 4.00 Hydroxypropylmethyl cellulose 15 cps 3.00 3.00 Nipasept sodium 0.200 0.200 Flavouring 0.050 0.100 Sodium saccharin 0.050 0.100 Phosphate/citrate buffer qs ad pH Purified water to 100 to 100 Examples 3 and 4 - Capsule Formulations (3) (4) mg/capsule mg/capsule Morphine-6-glucuronide 20.0 200 Lactose 125.5 91.0 Polyvidone 3.00 6.00 Collodial anhydrous silica 0.750 1.50 Magnesium stearate 0.750 1.50 TOTAL 150 300 Example 5 and 6 - Tablet Formulation (5) (6) mv/Tablet mg/Tablet Morphine-6-glucuronide 20.0 200 Lactose 115.5 31.0 Microcrystalline cellulose 22.5 45.0 Polyvidone 7.50 15.0 Croscarmellose sodium type A 3.00 6.00 Collodial anhydrous silica 0.750 1.50 Magnesium stearate 0.750 1.50 TOTAL 150.00 300.00

Claims (3)

  1. CLAIMS: 1. An orally administrable pharmaceutical composition for the treatment of pain containing morphine-6- glucuronide as active agent.
  2. 2. A pharmaceutical composition as claimed in claim 1 in dosage unit form.
  3. 3. The use of morphine-6-glucuronide in the preparation of a pharmaceutical composition for the treatment of pain.
GB9317504A 1993-08-23 1993-08-23 Oral morphine-6-glucuronide compositions Withdrawn GB2282758A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB9317504A GB2282758A (en) 1993-08-23 1993-08-23 Oral morphine-6-glucuronide compositions
PCT/GB1994/001808 WO1995005831A1 (en) 1993-08-23 1994-08-18 Pharmaceutical compositions containing morphine-6-glucuronide for the treatment of pain

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB9317504A GB2282758A (en) 1993-08-23 1993-08-23 Oral morphine-6-glucuronide compositions

Publications (2)

Publication Number Publication Date
GB9317504D0 GB9317504D0 (en) 1993-10-06
GB2282758A true GB2282758A (en) 1995-04-19

Family

ID=10740892

Family Applications (1)

Application Number Title Priority Date Filing Date
GB9317504A Withdrawn GB2282758A (en) 1993-08-23 1993-08-23 Oral morphine-6-glucuronide compositions

Country Status (2)

Country Link
GB (1) GB2282758A (en)
WO (1) WO1995005831A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061152A1 (en) * 1999-04-09 2000-10-19 Hel Ab Management of pain after joint surgery

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4403709A1 (en) * 1994-02-07 1995-08-10 Lohmann Therapie Syst Lts Pharmaceutical composition for systemic transdermal administration with the active ingredient morphine-6-glucuronide
CA2211596A1 (en) * 1995-11-29 1997-06-19 Gregori Valencia Parera Glycoconjugates of opiated substances
FR2907121B1 (en) 2006-10-12 2012-05-04 Neorphys NEW MORPHINIC DERIVATIVES
FR2939436B1 (en) 2008-12-10 2010-12-17 Sanofi Aventis SYNTHESIS OF MORPHINE-6-GLUCURONIDE OR ONE OF ITS DERIVATIVES
FR2939437B1 (en) 2008-12-10 2010-12-17 Sanofi Aventis MORPHINE-6-GLUCURONIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2939796B1 (en) 2008-12-11 2010-12-17 Sanofi Aventis BICYCLIC DERIVATIVES OF MORPHINE-6-GLUCURONIDE, THEIR PREPARATION AND THEIR THERAPEUTIC USE
CN107028968B (en) * 2016-02-03 2020-12-04 江苏恒瑞医药股份有限公司 A pharmaceutical composition containing morphine glucuronide or its pharmaceutically acceptable salt

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003051A1 (en) * 1991-08-06 1993-02-18 Salford Ultrafine Chemicals And Research Limited A process for making morphine-6-glucuronide or substituted morphine-6-glucuronide
WO1993015737A1 (en) * 1992-02-05 1993-08-19 Danbiosyst Uk Limited Compositions for nasal administration containing polar metabolites of opioid analgesics

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3602370A1 (en) * 1986-01-27 1987-08-06 Chrubasik Sigrun Use of analgesics by inhalation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993003051A1 (en) * 1991-08-06 1993-02-18 Salford Ultrafine Chemicals And Research Limited A process for making morphine-6-glucuronide or substituted morphine-6-glucuronide
WO1993015737A1 (en) * 1992-02-05 1993-08-19 Danbiosyst Uk Limited Compositions for nasal administration containing polar metabolites of opioid analgesics

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J.Pharmacol.Exp.Ther.(JULY 1992 ) 262 (1),pages 25-31. *
The Lancet,9 April 1988 page 828 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061152A1 (en) * 1999-04-09 2000-10-19 Hel Ab Management of pain after joint surgery

Also Published As

Publication number Publication date
GB9317504D0 (en) 1993-10-06
WO1995005831A1 (en) 1995-03-02

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