GB2403405A

GB2403405A - Topical composition for the treatment of joint damage or pain

Info

Publication number: GB2403405A
Application number: GB0312474A
Authority: GB
Inventors: David Wilkie
Original assignee: HEALTH PERCEPTION
Current assignee: HEALTH PERCEPTION
Priority date: 2003-06-02
Filing date: 2003-06-02
Publication date: 2005-01-05
Also published as: GB0312474D0

Abstract

A composition comprising glucosamine, a pain relief agent and an anti-rheumatic agent is described. The composition is useful the treatment of joint pain or damage. The preferred application of the composition is as a topical application such as a gel, lotion or patch. The preferred embodiment comprises N-acetyl glucosamine, ethanol and horse chestnut extract.

Description

TOPICAL COMPOSITION

This invention relates to a topical composition. More particularly the present invention relates to a topical composition for the maintenance of joints.

The joints of the body are prone to damage through injury, poor diet, wear or as part of the ageing process. Damage of this type can be in the bones themselves or be in the cartilage associated with bones or simply within the joint. It is known that dietary supplements can be used to ensure that the body has an adequate supply of the necessary materials for the maintenance of healthy joints and thus alleviate or prevent damage to the joints. Generally, known dietary supplements are taken orally so that they have systemic effect and are able to be supplied by the blood circulation to any joint in the body.

Other problems associated with joints include rheumatism, rheumatic pain and joint pain in general. It would be most useful to be able to provide a combination of dietary supplement and pain relief in a single dose formulation.

A traditional remedy for rheumatism and rheumatic pain is the administration of horse chestnut extracts; generally extracts from the fruit such as tinctures, emulsions, tonics or infusions are used for this purpose and are generally given orally. However, horse chestnut has a very bitter taste and this renders it unpalatable for oral administration without pre-processing of the nut to remove the bitter taste.

It is therefore an object of the present invention to provide a composition for the relief of joint pain or damage which is not taken orally.

Accordingly, the present invention provides a composition comprising glucosamine, a pain relief agent and an anti-rheumatic agent.

Preferably, the composition is in the form of a lotion, cream, gel, unguent, ointment, or other formulation suitable for topical administration. Ideally, the topical formulation is applied to a patch for prolonged topical application.

Additionally, the presence of the patch overcomes the disadvantage of inadvertent removal of the composition.

Preferably, the pain relief agent is a mint derivative such as menthol.

Advantageously, the use of menthol had the further beneficial effect that it is antiseptic and that it improves the uptake of the glucosamine by improving its absorption across the skin.

The pain relief agent is preferably present a concentration of between 0. 01 and 5% by weight. Where the pain relief agent is menthol, it is preferred that the menthol is present at a concentration of between 0.01 and 1.0% by weight, and ideally at 0.5% by weight.

Preferably, the anti-rheumatic agent is a herbal or other plant extract. In the most preferred embodiment the extract is a horse chestnut (Aesculus hippocastanum) extract. The preferred concentration of the anti- rheumatic agent is of between 0.01 and 1.0% by weight. Where the anti- rheumatic agent is horse chestnut, the preferred concentration is of between 0.05 and 0.15% by À a.

weight and ideally is 0.1% by weight. . .

The glucosamine is preferably present at a concentration of up to 5% by weight. In the most preferred embodiment the glucosamine is present at a, concentration of 2% by weight. À it.

Standard gel formulations based on carboxymethyl cellulose, poloxomers and carbopol were investigated with respect to their ability to form a stable gel system with appropriate theological properties following the incorporation of glucosamine.

The giucosamine was found to form unstable gel systems due to interactions with the gel forming excipients. Irreversible Maillard reactions caused 'browning' of the formulation and the acid-base interaction resulted in marked thinning of the gel. Further studies were therefore undertaken using N-acetylglucosamine which should have improved transdermal penetration due to its increased lipophilicity. The final formulation is detailed in Table 1.

Table 1. Final formulation of N-acetylglucosamine gel together with a rationale behind the inclusion of each constituent.

CONSTITUENT % RATIONALE DEIONISED WATER TO 100 CARBOPOL 940 0.5 GELLING AGENT SODIUM HYDROXIDE PURE 0.2 GEL THICKENING AGENT PROPYLENE GLYCOL 10 HUMECTANT HORSE CHESTNUT EXTRACT 2 ANTT-TNFLAMMATORY ETHANOL B96 10 COOLING AGENT.

PHENONTP 0.5 PRESERVATIVE err "NAG" 1O 'ACTIVE i..

The composition may also include solvents, diluents, vehicles, excipients, , À binders, anti-caking agents, preservatives, buffers, acidifying agents, stabilizers, gelling agents, emulsifiers, humectants, colourings, fragrances, or other a; . commonly used pharmaceutical formulation additives. Additionally, where the. '.

composition is to be used as a patch, the patch is preferably of the conventional type comprising a polypropylene liner with a polyester backing. Optionally, the patch is provided with a conventional adhesive as generally used for patches or other stick-on dressings.

Preferably, the patch is sufficiently large to be the relevant joint of the human or animal body. For example, the patch may be sufficiently large to be applied to and cover the shoulder or small enough to surround only a finger or toe joint. Alternatively, large patches may be cut or trimmed to the relevant size. The patch may also be shaped so as to allow a joint, for example a knee or elbow joint to bend without straining the patch or causing it to tear or to lift from the underlying skin.

In a second aspect, the present invention also provides the use of a composition comprising glucosamine, a pain relief agent and an antirheumatic agent in the preparation of a medicament for the treatment of joint pain or damage.

The pain relief agent and the anti-rheumatic agent are preferably as described above.

The joint damage treatable by the composition of the invention includes, but is not limited to, sports injuries, accidental injuries, rheumatism, rheumatoid arthritis, osteoarthritis, cartilage damage, cartilage wear or necrosis, arthritis, and damage to the synovial region. Any of these conditions, and others may also cause pain which can be relieved by the composition of the invention.

In a third aspect, the present invention also provides a method of treating a damaged or painful joint using the composition of the invention. Preferably the composition is supplied in topical form.

Embodiments of the invention will now be described in more detail, by way Àe of example only, with reference to the appended drawings of which, À,: Figure 1 shows spectra of NAG solutions at varying pH and NAG.

concentrations after 1 week at 50 C: a = 5g NAG in 50mLs; pH7.02, b = 2. 5g,, . NAG in 50mLs; pH7.02, c = 5g NAG in 50mLs; pH 5.75, d = 2.5g NAG in 50mLs; pH 5.75; , Figure 2 is a UV Scan of NAG solution to determine a suitable wavelength a,..'.

of detection; Figure 3 is an HPLC trace to show the efution profile of NAG solution; Figure 4 is a calibration plot of NAG concentration v's peak area; Figure 5 is an HPLC trace to show the elusion profile of NAG gel in water (1 g/L); Figure 6 shows amount of NAG penetrating the skin with time following application of the NAG alone; Figure 7 shows the amount of NAG penetrating the skin from the gel formulation containing either 5% or 10% NAG, and Figure 8 shows the penetration of both the NAG in the presence and the absence of the NAG gel.

EXAMPLE 1

Method of Preparation 1. Split water into three sections.

2. Into portion 1 disperse carbomer, thenaddextract and glycol.

3. Into portion 2 dissolve sodium hydroxide and then neutralise carbomer (final pH5-6).

4. Into portion 3'NAG' and disperse into gel.

5. Dissolve Phenonip in alcohol and disperse in gel.

RHEOLOGICAL STUDIES

Method.. . À.

The theological properties of the NAG gel formulation were compared to A. . those of commercially available Feldene and Ibuleve gels using using a Carri- Med CS Rheometer using 4cm parallel plates in oscillatory mode.

Results....

Table 2 shows the rheological properties of the NAG gel compared to. . Feldene and Ibuleve gel. Although the NAG gel is generally more viscous than the commercial products the theological profiles are very similar (see Appendix A). The higher viscosity of the NAG gel (relative to both Feldene and Ibuleve) will result in enhanced retention of the gel once applied to the skin.

Table 2. The theological properties of 'NAG' compared to the commercially available products Feldene gel and Ibuleve gel.

IBULEVE FELDENE NAG

G (Nm) 151.1 144.7 378 G" (Nm2) ] 8.35 38.28 72.7 (Parsec) 0.7704 1.818 3.29 Key: G' = Stor age Modulus (elasticity); G" = Loss Modulus (viscosity); is' = Viscosity coefficient Accelerated stability studies of the formulation at Creightons Ltd. had indicated a 'browning' of the gel with time. This occurred to a greater extent at higher pH's. It was felt that this may be due to a Maillard type reaction between the carbomer and the NAG after hydrolysis of the acetyl group. The project team were, therefore, concerned that the NAG was not stable in the gel system. Two studies were therefore undertaken at the University of Brighton. The first, reported in this section, investigated the stability of the NAG at different pH's and the second investigated the amount of NAG present in Creightons samples which had been subjected to long term stability.

studies (see section 3). .. À

NAG Discoloration Study. . À ÀÀ À.

The effect of pH and concentration of NAG on the discoloration of NAG À.e À solutions were investigated.

(1)NAG solutions (5g NAG in 50mLs and 2.5g in 50 mLs) were prepared in S0rensen's buffer at both pH 5.75 and 7.02.

To prepare S0rensen's buffer at pH 5.75 4mLs of 0.2M all-sodium hydrogen orthophosphate were added to 46 mLs of 0.2M sodium dihydrogen orthophosphate and diluted to 100mLs. To prepare S0rensen's buffer at pH 7.02 30.5mLs of 0.2M all-sodium hydrogen orthophosphate were added to 19.5mLs of 0.2M sodium dihydrogen orthophosphate and diluted to 100mLs.

The final pH of each of the buffers was checked using a pH electrode.

(2) All four solutions were placed in an incubator at 50 C for 1 week. A 1mL aliquot of each solution was then scanned in the visible spectrum (370 - 700nm) using a spectrophotometer.

It is clear from the scans obtained from each of the samples (Figure 1) that: The solutions prepared in buffer at a pH of 7.02 exhibited greater adsorption at wavelengths approaching 340nm than the equivalent NAG concentrations maintained at pH 5.75.

At both pies the discoloration of the solutions was NAG concentration dependent as shown by the increased adsorption at wavelengths approaching 340nm.

It is clear from these results that the discoloration of Nacetylglucosamine solutions is dependent on both the concentration of NAG and pH of the solution.

It can be concluded therefore, that discoloration of NAG solutions can be minimized by reducing both concentration of NAG and environmental pH. This also suggests that the discoloration is a consequence of the long term instability of the NAG in aqueous solution and is not only caused by an. . . incompatibility between the carbomer and the NAG. À . . HPLC Method for the Detection of N-Acetylglucosamine (NAG) and its use to Test the Stability of NAG Gel Formulations Quantitative HPLC Methods for the Detection of NAG in Aqueous Solution. À.

Method 1. Standard aqueous solutions of NAG (0.1-0.00625 g/l) were prepared with HPLC grade water.

2. Samples (201) were injected onto an alphasil 5C8 HPLC column (25cm x 4.6mm) using the following conditions: (i) Flow Rate = 1 ml/min (ii) Wavelength of detection: 200mm (determined from U.V. scan of NAG solution (Figure 2)) (iii) Mobile Phase: 30% v/v HPLC grade acetonitrile (iv) Pump: Perkin Elmer series 200 IC pump (v) Detector: Sulmadzu SPD-6A UV spectrophotometric detector (vi) Integrator: G R5A Chromatopac (speed 5mm/min) Results Using the conditions outlined above NAG was eluted from the column with a retention time of 2.4 minutes with no interfering peaks present (Figure 3) The conditions described above were used to prepare a calibration plot of NAG concentration against peak area (Table 3).

Table 3. HPLC Peak areas obtained from increasing concentrations of nacetylglucosamine in water.

Concentration (g/l) Peak Area À . À. À À.

0.1 43077 À.: 0.05 21373 I. 0.025 10887 À À . 0.0125 7287 Àe 0.00625 3222 À À:.

The data from Table 3 can be seen as a calibration plot in Figure 4. It can be seen that a linear relationship with a correlation coefficient of r2 = 0.998.

The reproducibility of injection was assessed by injecting six replicate (Table 4) aliquots of a single solution (0.025g/i) onto the column using the same conditions as before.

Table 4. Data to show the reproducibility of injection of aliquots of NAG in water (0.025g/1) n=6 Concentration 0.025g/1 Peak Area 11113 Mean iSD 11305.83 an-1= 173.13 NAG can be analysed quantitatively and with a high degree of À . reproducibility using the HPLC method described. . QUANTIFICATION OF NAG IN GEL FORMULATION. À..

Methods A NAG gel was prepared at University of Brighton as described in Section À 1. 201 aliquot of 19 gel/L (in HPLC grade water) was injected onto a C8... .

HPLC column using the same conditions as those used for aqueous NAG. . solutions.

Results As in the aqueous solution samples, NAG displayed a retention time of approximately 2.4 mins (Figure 5). Three additional peaks were also present at 7.8, 9.9 and 15.8 minutes. None of these peaks interfered with the NAG peak present at 2.4 minutes.

Determination of the stability of NAG gels under different storage temperatures.

Methods The gels undergoing stability studies at Creightons were examined by HPLC on 17th December 1998 for NAG content. The samples descriptions provided by Creightons are detailed in Table 5.

2011 aliquots of each gel (0.25g/250mis) were analysed as before. A control solution of NAG (0.0252g/250mis) was run alongside the gel formulations.

Results Sample Code Sample Details NAG Present ( /OWIw) LE21/75B NAG gel 45 C 10.41 LE21/75B NAG gel Ambient]0.49 LE21/75B NAG gel 32 C 10.63 LE21/75A NAG gel Fridge (5 C) 10.61 LE21/75A NAG gel 32 C] 0.74 LE21/75A NAG gel Ambient 10.48 LE21/75A NAG gel 45 C 11.20 LE21/75B NAG gel Fridge (5 C) 10.57 Standard Pure NAG 10 À À .

Conclusions 'lo.

Although the gels had undergone some thinning and a change in colour with ageing there appears to be no detectable decrease in NAG within the gels. À'.

N-Acetylglucosamine skin preparation studies. . . To investigate the in vitro penetration of N-acetylglucosamine (NAG) from both aqueous solution (10%) and gels containing 5% and 10% NAG through epidermal membranes.

Method Preparation of NAG Ge/ NAG gels containing 5Or 10% NAG were prepared according to the formulation detailed in section 1 (development of N-acetylglucosamine gel formulations).

Preparation of Epidermal Membrane (1) Fresh, surgically excised samples of human skin were obtained after reduction abdominoplasties. Following the removal of subcutaneous fat the skin was stored at -20 C prior to removal of the epidermal membrane. ]l

(2) The skin was thawed at room temperature for 30 minutes and then immersed in distilled water at 60 C for 30 seconds. The skin was then removed from the water and placed dermal side down on a cork dissection board.

(3) The epidermal membrane was teased off the dermis using forceps and floated out over cold water. The epidermal membrane was then collected onto aluminium foil, excess water allowed to drain, and the membrane stored at 4 C until required. :.'. .

Preparation of Diffusion Cells., In vitro NAG penetration studies were carried out using isolated epidermal membranes mounted in diffusion cells. . ,

(1) The receptor compartment was filled with sterile phosphate buffered.r.-. À - .

saline (pH 7.4) (PBS) and epidermal membranes were placed on the surface..

of the receptor chamber, stratum corneum side uppermost. The epidermis was cut to size allowing a border to be clamped between the ground glass around the edges of the receptor compartment.

(2) The donor compartment was secured to the receptor compartment using springs supported on holders on the outside of the cells. The receptor volume was 12mL and the area of exposed skin was 2.6 cm2.

(3) Six diffusion cells were assembled and placed on a perspex holder mounted on a 15 place stirring plate in a water bath maintained at 32 C.

(4) After an equilibration period of 1 hour, 200,uL of 10% NAG solution (in distilled water) or 5% or 10% NAG gel spiked with 14C labelled NAG (0. 5,uCi) were placed on the epidermal membranes. In a separate experiment the 14C labelled NAG (0.5,uCi) was applied on to the epidermal membranes and 200pL of 10% NAG solution (in distilled water) or 10% NAG gel applied over this.

(5) 0.1mL aliquots of PBS were removed at timed intervals, diluted to 5mL with scintillant and levels of 14C labelled NAG measured using a Rackbeta Scintillation Counter.

The results are shown in Figures 6 to 8.

The data suggests that the NAG penetrates the epidermal membranes.

There is a log-phase of about 10 hours after which the rate of penetration is reasonably constant. The gel appears to retard the penetration to some c.. Àec e

extent but would offer the advantage of providing a sustained release of gel 'a.

Over time into the skin. ^ c À Àe chic . i]

Claims

1. A composition comprising glucosamine, a pain relief agent and an anti rheumatic agent.

2. A composition according to claim 1, in which the composition is in the form of a lotion, cream, gel, unguent, ointment, or other formulation suitable for topical administration.

3. A composition according to claim 1 or claim 2, in which the formulation is topical and the topical formulation is applied to a patch for prolonged topical application.

4. A composition according to any preceding claim, in which the pain relief agent is a mint derivative.

5. A composition according to claim 4, in which the mint derivative is menthol.

6. A composition according to any preceding claim, in which the pain relief agent is present at a concentration of between 0.01 and 5% by weight.

7. A composition according to claim 5, in which the menthol is present at a concentration of between 0.01 and 1.0% by weight.

8. A composition according to claim 5 or claim 6, in which the method is present at 0.5% by weight.

9. A composition according to any preceding claim in which the anti rheumatic agent is a herbal or other plant extract. 1W

10. A composition according to any preceding claim, in which the antirheumatic agent comprises a horse chestnut (Aesculus hippocastanum) extract.

11. A composition according to any preceding claim, in which the concentration of the anti-rheumatic agent is of between 0.01 and 1.0% i by weight.

12. A composition according to claim 10, in which the anti-rheumatic agent is horse chestnut and in which the concentration is of between 0.05 and 0. 15% by weight.

13. A composition according to claim 12, in which the anti-rheumatic agent is horse chestnut and in which the concentration is 0.1% by weight.

14. A composition according to any preceding claim, in which the glucosamine is present at a concentration of up to 5% by weight.

15. A composition according to any one of claims 1 to 13 in which the glucosamine is present at a concentration of 2% by weight.

16. A composition according to any preceding claim, in which the formulation of N-acetylglucosamine gel comprises: Carbopol 940 0.5% Sodium Hydroxide Pure 0.2% Propylene Glycol 10% Horse chestnut Extract 2% Ethanol B96 10% Phenonip 0.5% "NAG" 10% Deionised Water to 100% Is

17. A patch comprising a composition according to any preceding claim.

18. A patch according to claim 17, in which the patch comprises a polypropylene liner with a polyester backing.

19. A patch according to claim 17 or claim 18 in which the patch is provided with a conventional adhesive.

20. A patch according to any one of claims 17 to 19, in which the patch is shaped so as to allow a joint, to bend without straining the patch or causing it to tear or to lift from the underlying skin.

21. The use of a composition comprising glucosamine, a pain relief agent and an anti-rheumatic agent in the preparation of a medicament for the treatment of joint pain or damage.

22. A composition according to any one of claims 1 to 16 for use in the medicament of claim 21.

23. A composition according to claim 21 or 22 for use in the treatment of sports injuries, accidental injuries, rheumatism, rheumatoid arthritis, osteoarthritis, cartilage damage, cartilage wear or necrosis, arthritis, and damage to the synovial region.

24. A composition substantially as herein before described with reference to and as illustrated by Figures 1 to 8 of the accompanying drawings.

25. A patch substantially as herein before described with reference to and as illustrated by Figures 1 to 8 of the accompanying drawings.

26. Use of a composition substantially as herein before described with reference to and as illustrated by Figures 1 to 8 of the accompanying drawings in the preparation of a medicament for the treatment of joint pain or damage.