WO1997026889A1

WO1997026889A1 - Method and composition for the potentiation of anti-inflammatory drugs

Info

Publication number: WO1997026889A1
Application number: PCT/AU1997/000035
Authority: WO
Inventors: Brian Andrew Hills
Original assignee: The University Of New England
Priority date: 1996-01-22
Filing date: 1997-01-22
Publication date: 1997-07-31
Also published as: AUPN766496A0

Abstract

Method of enhancing or potentiating anti-inflammatory and/or analgesic action of a non-steroidal anti-inflammatory drug (NSAID) in a human or another mammalian animal comprising administering to the human or another mammalian animal the NSAID in association with one or more phospholipids in the form of lamellar bodies; and an enhanced or potentiated anti-inflammatory and/or analgesic NSAID composition comprising a NSAID in association with one or more phospholipids in the form of lamellar bodies.

Description

Method and composition for the potentiation of anti-inflammatory drugs

Technical Field

The present invention relates to methods and compositions for the potentiation of anti-inflammatory drugs. In particular, the invention relates to the potentiation of the anti-inflammatory and/or analgesic activity of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Background Art

Aspirin and other NSAIDs are widely used as analgesics and/or anti- inflammatory compounds. They include among their number some of the most widely used therapeutic substances known. Unfortunately, all of these compounds, to a greater or lesser extent, cause erosion of the gastro-intestinal tract resulting in the development of internal bleeding and/or ulcers. The relatively aggressive action of NSAIDs was recently reviewed in an editorial in Lancet (April 1994). This side effect of NSAIDs is of particular concern as large quantities of them are prescribed as analgesics for those suffering from arthritis and other rheumatic diseases. These patients typically require the administration of these compounds regularly over long periods. It is also known (Whitehouse, 1984) that arthritis induced in rats sensitises the gastric mucosa to insult by aspirin and other NSAIDs.

It would be advantageous to administer NSAIDs at lower doses as presently required and still obtain the desired analgesic and/or anti- inflammatory effect. Administering lower doses may also lessen the adverse effects of these drugs. Furthermore, lower doses may result in the production of cheaper forms of the medicaments as less active ingredient would be required to produce the product.

The present inventor has previously disclosed (Australian Patent No 628320) that gastro-intestinal ulcers due to acid insult may be prevented, cured and/or soothed by the internal administration to a patient of an effective amount of a composition containing a dispersion of ripe banana in milk. This previous invention was predicated upon the finding of lamellar bodies of phospholipids in bananas.

It is believed that these surface-active phospholipids induce or stabilise a replacement layer of phospholipid on the mucosa of the gastro- intestinal tract and thereby relieves the symptoms of gastro-intestinal ulcers which are caused by the breakdown of the naturally occurring phospholipid layer.

It has now been found by the present inventor that, surprisingly, the phospholipid material potentiates the action of NSAIDs. The present invention is directed to this further finding relating to the combined action of phospholipids and NSAIDs. Disclosure of Invention

In a first aspect, the present invention consists in a method of enhancing or potentiating anti-inflammatory and/or analgesic action of a non- steroidal anti-inflammatory drug (NSAID) in a human or another mammalian animal comprising administering to the human or another mammalian animal the NSAID in association with one or more phospholipids.

In a second aspect, the present invention consists in an enhanced or potentiated anti-inflammatory and/or analgesic active non-steroidal anti- inflammatory drug (NSAID) composition comprising a NSAID and one or more phospholipids.

The most commonly consumed NSAID is aspirin and the present invention is particularly effective for this drug. It may, however, be used in connection with other NSAIDs including sodium ibuprofen and sodium naproxen. Other compounds in the NSAID group with which the invention may be useful include indomethacin, paracetamol, sulindac, tenoxicam and piroxicam. It will be appreciated, however, that the present invention may be suitable to enhance or potentiate the anti-inflammatory and/or analgesic activity of other NSAIDs not listed. The phospholipids are preferably in the form of lamellar bodies which are a surface-active form of the phospholipids. It is even more preferred that the phospholipid-lamellar bodies are derived from a naturally occurring material such as bananas. As the phospholipids are preferably naturally occurring, they will therefore vary to some extent in composition. The phospholipids, however, will typically be straight chained and largely saturated. The predominant and most surface-active component will normally be L-α-dipalmitoyl phosphatidyl choline (DPPC). Typically, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol may also be present. Lamellar bodies are biological stores of highly surface-active phospholipids found in animal and plant cells and are described in more detail in B.A. Hills "The Biology of Surfactant" Cambridge University Press 1988 pp 48-51. The most suitable source of lamellar bodies is fruit or vegetables containing such bodies.

In a particularly preferred embodiment of the present invention, the phospholipids are prepared by rapid pureeing bananas in skim milk, flash heating the puree to 180-200°C, and rapid drying the heated puree in a spray dryer to form a spray-dried banana-puree powder with a moisture content of 5% or less. This material is hereinafter referred to as Unebam. It is believed that the active ingredient in this material is the surface-active phospholipids in the bananas which are transformed into denser lamellar bodies by the manufacturing process.

In one preferred form of the present invention, the source of the phospholipids is dispersed in a naturally occurring carrier such as milk, with or without the addition of hydrophobic protein. The hydrophobic protein may be derived advantageously from any naturally occurring source, however, it has been found that eggs are a particularly desirable source. One form of hydrophobic protein particularly suitable for the present invention is derived from eggs in the form of dried egg powder (DEP).

In a further preferred form, DEP is added to Unebam preferably in the proportions of 4 parts Unebam: 3 parts DEP to produce a material hereinafter called Superbam.

The NSAID and the phospholipid material should to be administered simultaneously or so proximately in time that both are physiologically active in the gastro-intestinal tract at substantially the same time. In the latter case, either may be administered first provided that the other is administered while the first is still present and physiologically active in the gastro- intestinal tract. Administration in any of these ways is referred to in this specification as administration of the NSAID and the phospholipid in association. Preferred methods for the administration of the phospholipid and the

NSAID include the following:-

(a) dispensing one or two 20 g sachets of Unebam in 100-200 ml of water in a glass or shaker and using that pleasant flavoured drink to wash down one or two NSAID tablets; (b) Unebam is a good pelleting material and may be substituted for the traditional magnesium stearate in the production of NSAID tablets. A suitable tablet may contain 200 mg aspirin, for example, and 600 mg Unebam; or

(c) a 20 g Unebam sachet dispersed in water may be used to wash down an NSAID tablet in which the pelletising material is also Unebam. An advantage of using Unebam as the pelletising material is that the phospholipid is dispersed through the tablet. This means that the phospholipid is released at the same site as the aspirin or other NSAID is released in the gastro-intestinal tract.

It will be appreciated that as the specific activity varies between NSAIDs, the concentration of the NSAID used in the present invention will depend on the particular NSAID. Furthermore, as the combination of the phospholipids with the NSAID potentiates the activity of the NSAID, doses lower than that presently prescribed may be given.

In order that the present invention may be more clearly understood, preferred forms will be described with reference to the following examples and drawing. Brief Description of Drawings

Figure 1 shows the results for the effect of Superbam on plasma aspirin levels. Modes for Carrying Out the Invention

The present inventor has found that the anti-inflammatory and/or analgesic action of aspirin and other NSAIDs may be potentiated by the administration to a human or another mammalian animal of the aspirin or other NSAID in association with one ore more phospholipids. In another aspect the present invention consists in an anti-inflammatory and/or analgesic composition comprising aspirin or another NSAID and one or more phospholipids.

The following experiments illustrate methods of carrying out the present invention. A series of trials was carried out using the standard model described in detail by Van Arman (1979) for assessing the efficacy of different drugs as anti-inflammatory agents. The purpose of this trial was to test for any synergism between Unebam or Superbam in combination with aspirin or other NSAIDs. According to this model, 0.6 mg of Sodium Carrageenin was injected into the two hind-paws of female Wistar rats of comparable size (±20 g). After one hour, the NSAID or NSAID/Unebam was administered by stomach tube. Control groups consisting of Unebam alone and water alone. After 1, 2 and 3 hours, the thickness of the hind paws was measured using a micrometer gauge. RESULTS

The results of these trials are summarised in Table 1.

TABLE 1

There is an appreciable synergism between Unebam and aspirin at a typical level of 150 mg/ml, producing a significant increase in efficacy from 33% to 52% after 3 hours when aspirin reaches its peak effectiveness, roughly 1 hour after peak blood level. This is a true synergism because Unebam alone, or water, have no significant anti-inflammatory effects.

This synergism allows aspirin to be effective much sooner, reaching 80% after only 1 hour when aspirin alone (at the 150 mg/kg level) has negligible effect.

This synergism renders aspirin effective at a dose of 100 mg/kg at which it is normally ineffective in the rat.

A modest synergism would appear to apply to other NSAIDs, e.g. Sodium Ibuprofen.

These results indicate that, by using aspirin in combination with Unebam, aspirin can be made to act much sooner in affording relief of inflammatory pain and that it can exert the same anti-inflammatory efficacy at an appreciably lower dose of the order of 1/2 to 2/3 of the presently prescribed levels.

Initial studies suggested that Unebam can act in synergism with aspirin and other anti-inflammatory drugs to enhance their anti-inflammatory effect. It was hypothesised that one of the mechanisms involved in this synergism may be the modification of pharmacokinetics of anti-inflammatory drugs by Unebam. That is, aspirin and other anti-inflammatory drugs may appear in the blood plasma more quickly or at higher peak levels when co- administered with Unebam or Superbam. This could have the effect of making anti-inflammatory drugs available more quickly or at higher levels at their site(s) action and thereby making the anti-inflammatory action or pain relief faster or more effective.

In order to test the effectiveness of the present invention, a trial was undertaken using a human subject. For this preliminary investigation a single subject was used for all blood sampling. The subject took each of three treatments on two separate occasions - Superbam only (one 20g sachet in 100 ml of water), aspirin only (2 x 300 mg tablets with 100 ml of water) and aspirin plus Superbam concurrently (at the above doses). The subject fasted for approximately 10 hours prior to taking treatments and 2 ml of venous blood was taken at 0, 15,

45 and 60 minutes after taking treatments. This blood was put into EDTA tubes to prevent clotting and then centrifuged to collect plasma. All plasma samples were frozen until assay of aspirin could be undertaken. A period of one week was allowed between each treatment/sampling in order that veins may heal properly.

Table 2 shows the plasma levels of aspirin for each treatment, the standard error of the mean and the number of observations for each mean (in parenthesis). The results may, however, be most easily interpreted by reference to Figure 1. This shows that co-administration of Superbam with aspirin gives a faster rate of appearance of aspirin in blood plasma and also that the peak plasma levels of aspirin were increased above those observed with aspirin alone. Superbam alone gives no appearance of aspirin in plasma as might be expected as Superbam contains no salicylates, as some plant materials do. This result implies that the efficiency of aspirin in relieving pain, etc, may be improved by co-administration with Superbam.

TABLE 2. Effects of Superbam on appearance of aspirin in blood plasma.

Time after taking Mean plasma aspirin concentration treatment (mg L) + S.E.M. (n) (min) Treatments

Superbam Aspirin Superbam + Aspirin

0 0 0 0

15 0 3.18±0.81 21.44±5.31

(4) (3)

30 0 17.31±2.26 39.12±0.70

(4) (3)

45 0 26.34+0.59 38.6210.59

(3) (3)

60 0 26.34+2.42 35.85

(4) (1) It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

References:

Whitehouse, M.W, Rainsford-Keochli, V. and Rainsford, K.D. (1984). Aspirin gastrotoxicity: protection by various stratagems. In: Advances in Inflammation Research. Ed by Rainsford, K.D. & Velo, G. Vol 6 pp 77-87.

New York, Raven.

Van Arman, CG. (1979). Oedema and increased vascular permeability. In: Anti-inflammatory Drugs. Ed. by Vane J.R. & Ferreira, S.M. pp. 75-91. Berlin: Springer Verlag.

Claims

CLAIMS:

1. A method of enhancing or potentiating anti-inflammatory and/or analgesic action of a non-steroidal anti-inflammatory drug (NSAID) in a human or another mammalian animal comprising administering to the human or another mammalian animal the NSAID in association with one or more phospholipids in the form of lamellar bodies.

2. The method according to claim 1 wherein the NSAID is selected from the group consisting of aspirin, sodium ibuprofen, sodium naproxen, indomethacin, paracetamol, sulindac, tenoxicam and piroxicam.

3. The method according to claim 2 wherein the NSAID is aspirin.

4. The method according to any one of claims 1 to 3 wherein the predominant and most surface-active component of the phospholipids is L-α- dipalmitoyl phosphatidyl choline.

5. The method according to claim 4 wherein the phospholipids further include one or more of phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol.

6. The method according to any one of claims 1 to 5 wherein the phospholipids are derived from bananas.

7. The method according to claim 6 wherein the phospholipids are prepared by rapid pureeing bananas in skim milk, flash heating the puree to 180-200°C, and rapid drying the heated puree in a spray dryer to form a spray-dried banana-puree powder with a moisture content of 5% or less.

8. The method according to any one of claims 1 to 7 wherein the phospholipids are dispersed in a naturally occurring carrier being milk with or without the addition of hydrophobic protein.

9. The method according to claim 8 wherein the hydrophobic protein is derived from eggs in the form of dried egg powder.

10. The method according to any one of claims 1 to 9 wherein the NSAID is pelleted or tabletted with the phospholipids.

11. The method according to claim 10 wherein the phospholipids are in the form of a spray-dried banana-puree powder.

12. An enhanced or potentiated anti-inflammatory and/or analgesic active non-steroidal anti-inflammatory drug (NSAID) composition comprising a NSAID and one or more phospholipids in the form of lamellar bodies.

13. The composition according to claim 12 wherein the NSAID is selected from the group consisting of aspirin, sodium ibuprofen, sodium naproxen, indomethacin, paracetamol, sulindac, tenoxicam and piroxicam.

14. The composition according to claim 13 wherein the NSAID is aspirin.

15. The composition according to any one of claims 12 to 14 wherein the predominant and most surface-active component of the phospholipids is L-α- dipalmitoyl phosphatidyl choline.

16. The composition according to claim 15 wherein the phospholipids further include one or more of phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol.

17. The composition according to any one of claims 12 to 16 wherein the phospholipids are derived from bananas.

18. The composition according to claim 17 wherein the phospholipids are prepared by rapid pureeing bananas in skim milk, flash heating the puree to 180-200°C, and rapid drying the heated puree in a spray dryer to form a spray-dried banana-puree powder with a moisture content of 5% or less.

19. The composition according to any one of claims 12 to 18 wherein the phospholipids are dispersed in a naturally occurring carrier being milk with or without the addition of hydrophobic protein.

20. The composition according to claim 19 wherein the hydrophobic protein is derived from eggs in the form of dried egg powder.

21. The composition according to claim 20 comprising four parts spray- dried banana-puree powder and three parts dried egg powder.

22. The composition according to any one of claims 12 to 21 in pellet or tablet form.

23. The composition according to claim 22 wherein the phospholipids are in the form of a spray-dried banana-puree powder.