WO1995005831A1 - Pharmaceutical compositions containing morphine-6-glucuronide for the treatment of pain - Google Patents
Pharmaceutical compositions containing morphine-6-glucuronide for the treatment of pain Download PDFInfo
- Publication number
- WO1995005831A1 WO1995005831A1 PCT/GB1994/001808 GB9401808W WO9505831A1 WO 1995005831 A1 WO1995005831 A1 WO 1995005831A1 GB 9401808 W GB9401808 W GB 9401808W WO 9505831 A1 WO9505831 A1 WO 9505831A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- morphine
- glucuronide
- treatment
- pain
- pharmaceutical compositions
- 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.)
- Ceased
Links
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
Definitions
- morphine-6-glucuronide when orally administered to humans, gives appreciable plasma levels of morphine-6-glucuronide (and morphine) over an extended period of time.
- morphine sulphate gives rise to appreciable plasma levels of morphine, or the metabolite morphine-6- glucuronide, over a much shorter period.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Morphine-6-glucuronide is used as active ingredient in a pharmaceutical composition for the treatment of pain.
Description
PHARMACEUTICAL COMPOSITIONS CONTAINING M0RPHINE-6-GLUCUR0NIDE FOR THE TREATMENT OF PAIN
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-S-glucuronide, typically, for example, 5, 20, 100, or 200 mg of morphine-6- glucuronide.
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, l 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 % w/v % w/v
Morphine-6-glucuronide 0.400 4.00
Hydroxypropylmethyl cellulose 15 cps 3 3..0000 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) mα/Tablet ma/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
1. An orally administrable pharmaceutical composition for the treatment of pain containing morphine-6- glucuronide as active agent.
2. A pharmaceutical composition as claimed in claim 1 in dosage unit form.
3. The use of morphine-6-glucuronide in the preparation of a pharmaceutical composition for the treatment of pain.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9317504A GB2282758A (en) | 1993-08-23 | 1993-08-23 | Oral morphine-6-glucuronide compositions |
| GB9317504.0 | 1993-08-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1995005831A1 true WO1995005831A1 (en) | 1995-03-02 |
Family
ID=10740892
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1994/001808 Ceased WO1995005831A1 (en) | 1993-08-23 | 1994-08-18 | Pharmaceutical compositions containing morphine-6-glucuronide for the treatment of pain |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2282758A (en) |
| WO (1) | WO1995005831A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995020966A1 (en) * | 1994-02-07 | 1995-08-10 | Lts Lohmann Therapie-Systeme Gmbh | Pharmaceutical composition for systemic transdermal administration containing the active agent morphine-6-glucuronide |
| WO1997021416A3 (en) * | 1995-11-29 | 1997-09-12 | Farmhispania | Glycoconjugates of opiated substances |
| WO2008043962A1 (en) | 2006-10-12 | 2008-04-17 | Neorphys | Novel morphine derivatives |
| US8258298B2 (en) | 2008-12-10 | 2012-09-04 | Sanofi | Synthesis of morphine-6-glucuronide or one of the derivatives thereof |
| US8440634B2 (en) | 2008-12-11 | 2013-05-14 | Sanofi | Bicyclic derivatives of morphine-6-glucuronide, preparation method thereof and use of same in therapeutics |
| US8461122B2 (en) | 2008-12-10 | 2013-06-11 | Sanofi | Derivatives of morphine-6-glucuronide, preparation method thereof and use of same in therapeutics |
| CN107028968A (en) * | 2016-02-03 | 2017-08-11 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition containing glucuronic acid morphine or its officinal salt |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9901257D0 (en) * | 1999-04-09 | 1999-04-09 | Hel Ab | Treatment of pain after joint surgery |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3602370A1 (en) * | 1986-01-27 | 1987-08-06 | Chrubasik Sigrun | Use of analgesics by inhalation |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9202464D0 (en) * | 1992-02-05 | 1992-03-18 | Danbiosyst Uk | Composition for nasal administration |
-
1993
- 1993-08-23 GB GB9317504A patent/GB2282758A/en not_active Withdrawn
-
1994
- 1994-08-18 WO PCT/GB1994/001808 patent/WO1995005831A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3602370A1 (en) * | 1986-01-27 | 1987-08-06 | Chrubasik Sigrun | Use of analgesics by inhalation |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| "Analgesic activity of morphine-6-glucuronide", THE LANCET, 1988, pages 828 - 9 * |
| "Further evidence that morphine-6-beta-glucuronide is a more potent opioid agonist than morphine", J.PHARMACOL.EXP.THER., vol. 261, no. 1, 1992, pages 25 - 31 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995020966A1 (en) * | 1994-02-07 | 1995-08-10 | Lts Lohmann Therapie-Systeme Gmbh | Pharmaceutical composition for systemic transdermal administration containing the active agent morphine-6-glucuronide |
| WO1997021416A3 (en) * | 1995-11-29 | 1997-09-12 | Farmhispania | Glycoconjugates of opiated substances |
| WO2008043962A1 (en) | 2006-10-12 | 2008-04-17 | Neorphys | Novel morphine derivatives |
| US8158764B2 (en) | 2006-10-12 | 2012-04-17 | Neorphys | Morphine derivatives |
| US8258298B2 (en) | 2008-12-10 | 2012-09-04 | Sanofi | Synthesis of morphine-6-glucuronide or one of the derivatives thereof |
| US8461122B2 (en) | 2008-12-10 | 2013-06-11 | Sanofi | Derivatives of morphine-6-glucuronide, preparation method thereof and use of same in therapeutics |
| US8440634B2 (en) | 2008-12-11 | 2013-05-14 | Sanofi | Bicyclic derivatives of morphine-6-glucuronide, preparation method thereof and use of same in therapeutics |
| CN107028968A (en) * | 2016-02-03 | 2017-08-11 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition containing glucuronic acid morphine or its officinal salt |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9317504D0 (en) | 1993-10-06 |
| GB2282758A (en) | 1995-04-19 |
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