NOVEL COMPOSITION

Abstract

A composition comprising a pharmaceutically active ingredient, a solubilising agent and a thixotropic agent.

Claims

1. A composition comprising a pharmaceutically active ingredient, a solubilising agent and a thixotropic agent.

2. The composition as claimed in claim 1, wherein the composition is in the form of a solution.

3. The composition as claimed in claim 1, wherein the composition is in the form of a sprayable composition.

4. The composition as claimed in claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of NSAIDs and pharmaceutically acceptable salts thereof.

5. The composition as claimed in claim 4, wherein the NSAID is selected from the group consisting of flurbiprofen, ketoprofen or diclofenac.

6. The composition as claimed in claim 4, wherein the NSAID is flurbiprofen.

7. The composition as claimed in claim 1, wherein the composition comprises from 1% to about 5% NSAID by weight of the composition.

8-10. (canceled)

11. The composition as claimed in claim 1, wherein the viscosity of the composition returns to its initial viscosity within 30 seconds following withdrawal of the shearing force.

12-14. (canceled)

15. The composition as claimed in claim 1, wherein the thixotropic agent is selected from combinations of one or more celluloses and one or more alkali metal carboxyalkylcelluloses and is present in an amount of about 1.5 to about 5 w/w %.

16. The composition as claimed in claim 15, wherein the combination of cellulose and alkali metal carboxyalkylcellulose is microcrystalline cellulose and sodium carboxymethylcellulose.

17-18. (canceled)

19. The composition as claimed in claim 1, wherein the solubilising agent is present in the composition in an amount of 3-10 w/w %.

20. (canceled)

21. The composition as claimed in claim 1, wherein the solubilising agent is selected from the group consisting of one or more cyclodextrins.

22-25. (canceled)

26. The composition as claimed in claim 1, wherein the composition further comprises one or more stabilisers present at an amount of 0.05-5% w/w.

27. The composition has claimed in claim 26 wherein the one or more stabilisers is selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose and xanthan gum.

28-31. (canceled)

32. The composition as claimed in claim 1, wherein the pH of the composition is from 6.0-8.0.

33-42. (canceled)

43. A composition comprising: 1-5% an NSAID; 1-5% a combination of a cellulose and an alkali metal carboxyalkylcellulose; 1-15% one or more cyclodextrins; 0.1-10% one or more pH adjusters; 0.1-15% one or more buffers; and 0.05-5% one or more stabilisers.

44-45. (canceled)

46. The composition as claimed in claim 44, wherein the composition comprises: 1-2% Flurbiprofen; 2-4% a combination of a cellulose and an alkali metal carboxyalkylcellulose; 5-7% one or more cyclodextrins; 0.1-5% one or more pH adjusters; 2-4% one or more buffers; and 0.1-3% one or more stabilisers.

47-51. (canceled)

52. The composition as claimed in claim 43, wherein the comprises: 1-2% Flurbiprofen; 2-4% A combination of microcrystalline cellulose and sodium carboxymethylcellulose; 5-7% A combination of beta-cyclodextrin and hydroxypropyl beta cyclodextrin; 0.1-5% Sodium hydroxide; 1-10% Disodium hydrogen phosphate; 0.1-5% Citric acid monohydrate; and 0.1-0.3% Xanthan gum.

53. A thixotropic composition comprising an active pharmaceutical ingredient having a low shear viscosity of 30-80 Pascal seconds (Pa.Math.s) and high shear viscosity of 0.01-5 Pascals seconds (Pa.Math.s).

54-100. (canceled)

101. The composition as claimed in claim 53, wherein the composition is in the form of a solution comprising: 1-5% by weight of flurbiprofen or pharmaceutically acceptable salt thereof, 5-7% by weight of a solubilising agent selected from cyclodextrins or combinations thereof; 1.5-5% by weight of a thixotropic agent selected from combinations of one or more celluloses and one or more alkali metal carboxyalkylcelluloses; 0.1-1% by weight of one or more stabilisers selected from ethyl cellulose, hydroxypropyl methyl cellulose and xanthan gum; 1-5% by weight of one or more buffers selected from citric acid, disodium hydrogen phosphate, sodium hydrogen phosphate and combinations thereof; and 0.1-1% by weight of one or more pH adjusters, wherein the composition has a low shear viscosity of 50-60 Pascal seconds (Pa.Math.s) and high shear viscosity of 0.1-1 Pascals seconds (Pa.Math.s), and wherein the composition has a yield point of 1-30 Pa.

102-155. (canceled)

Description

[0241] The present invention will now be described in more detail with reference to the following Examples and Figures in which:

[0242] FIG. 1 illustrates the retention profile for example compositions of the present invention, a lozenge and a control composition when the model is at 45°.

[0243] FIG. 2 illustrates the retention profile for example compositions of the present invention, a lozenge and a control composition when the model is at 30°.

[0244] FIG. 3 illustrates the corresponding area under the curve that was calculated based on the retention profile for each composition.

[0245] FIG. 4 illustrates the effect of shear rate on the viscosity of an example embodiment of the compositions of the present invention and deionised water.

[0246] FIG. 5 illustrates the relative mucoadhesive properties of a composition of the present invention when measured at a low shear rate.

[0247]

TABLE-US-00077 Ingredient Ex 1 (% wt) Ex 2 (wt %) Ex 3 (wt % Ex 4 (wt %) Purified Water 85.080 86.080 86.63782 86.83782 Microcrystalline cellulose 3.115 2.225 2.225 2.047 Carboxymethyl cellulose sodium 0.385 0.275 0.275 0.253 Beta-cyclodextrin 4.08 4.08 3.0440 3.04400 Disodium hydrogen phosphate 3.07 3.07 2.75400 2.75400 Hydroxypropyl Beta Cyclodextrin 2.15 2.15 2.39700 2.39700 Flurbiprofen 1.56 1.56 1.40224 1.40224 Sodium Hydroxide 0.23 0.23 0.22800 0.22800 Citric acid monohydrate 0.11 0.11 0.10000 0.10000 Methyl paraben 0.2 0.2 0.21100 0.21100 Propyl paraben 0.02 0.02 0.04200 0.04200 Sodium Saccharin — — 0.05000 0.05000 Xanthan Gum — — 0.2000 0.2000 Flavour — — 0.43394 0.43394 Total 100.000 100.000 100.000 100.000

[0248] Method of Preparation

[0249] The composition as described in either Example 1 or Example 2 can be prepared in the following way. An aqueous solution of sodium hydroxide is prepared. Separately, an aqueous mixture of flurbiprofen, disodium hydrogen phosphate, hydroxypropyl beta cyclodextrin, beta-cyclodextrin, citric acid, methyl paraben and propyl paraben was also prepared. The aqueous solution of sodium hydroxide was added to the flurbiprofen-containing aqueous mixture with cooling to form a premix solution. In a separate vessel a combination of microcrystalline cellulose and sodium carboxymethylcellulose are added to water. The mixture is homogenised before the premix solution is added while stirring of the homogenised mixture is maintained. The resulting product is now ready to be dispensed into suitable storage containers.

[0250] In Example 3 and Example 4 the xanthan gum is added to the aqueous combination of microcrystalline cellulose and sodium carboxymethylcellulose.

[0251] The retention profile of the embodiments of the compositions of the present invention was examined using apparatus which measures adhesion on mucosal tissue. The model comprises a slope to which is applied a cellulose membrane. The cellulose membrane is hydrated in a mucin-containing aqueous mixture and is used to mimic the surface of the throat. A sample of the thixotropic composition of the present invention is applied to the membrane. The membrane is then continuously washed with artificial saliva for 30 mins. Samples are collected at regular intervals. Each eluted sample was tested to determine how much of the composition was retained on the slope.

[0252] FIG. 1 illustrates the retention of the composition on the slope of the model when at an angle of 45°. This angle was chosen to simulate the application of the composition to an individual when awake. The results are shown in Table 1.

TABLE-US-00078 TABLE 1 Awake Model Formulation A Formulation B Lozenge Example Time (mins) (% retained) (% retained) (% retained) (% retained)  0 100 100 100 100  2 41.1 24.52 67.64 0.27  4 31.7 24.02 34.66 0.16  6 23.06 24.02 1.23 0  8 22.32 24.02 0.17 0 10 22.32 24.02 0.11 0 15 21.25 21.85 0.11 0 20 20.40 21.85 0.11 0 25 20.40 21.85 0.11 0 30 20.40 19.68 0.11 0

[0253] FIG. 2 illustrates the retention of the composition on the slope of the model when at an angle of 30°. This angle was chosen to simulate the application of the composition to an individual when asleep. The results are shown in Table 2.

TABLE-US-00079 TABLE 1 Asleep Model Formulation A Formulation B Lozenge Example Time (mins) (% retained) (% retained) (% retained) (% retained)  0 100 100 100 100  2 54.25 50.73 68.58 1.01  4 42.26 42.71 35.53 0.33  6 41.39 41.93 2.29 0.24  8 41.23 41.79 0.27 0.22 10 41.14 41.28 0.2 0.21 15 41.10 39.40 0.16 0.21 20 35.69 37.02 0.16 0 25 33.97 33.72 0.16 0 30 33.92 33.72 0.16 0

[0254] As can be seen from FIGS. 1 & 2, the compositions are retained on the slope of the model for a significantly longer time than the lozenge. The flurbiprofen in the compositions is therefore able to provide a longer local effect on the surface of the throat as can be seen from the “Area Under The Curve” plot shown in FIG. 3.

[0255] The results obtained using this model suggest that the composition remains on the mucosal tissue despite the action of gravitational forces as a result of its high viscosity due to its gel like nature at rest resulting from its high molecular weight; and also as a result of hydrogen bonding and ionic attraction between the composition and the surface of the mucosa.

[0256] In addition, a mucoadhesion study was carried out on a composition in accordance with the present invention. The mucin solution is used to replicate/mimic the mucosal surface of the throat/pharyngeal area. The sample for was prepared as follows:

[0257] A mucin solution was made using deionised water and porcine gastric mucin (II). The solution was made to a concentration of 10%, the pH adjusted to 6.2 using 0.5M NaOH solution before being diluted with DI water to a final concentration of 6% before use. 3 g of the prepared mucin solution was mixed with an equal weight of the sample under test, giving a final mucin concentration of 3% (w/w). For control samples, the mucin solutions and samples under investigation were diluted to 50% (w/w) of their initial concentration using deionised water. All samples were prepared in duplicate and allowed to equilibrate overnight at 5° C. before any analysis was conducted.

[0258] The mucoadhesion study testing was performed on a research rheometer (DHR2, TA Instruments) fitted with a 60 mm aluminium plate measuring system set to a gap of 200 μm during analysis. A solvent trap cover was employed to minimise drying of the sample at the exposed edges.

[0259] The mucoadhesion study was carried out to identify rheological changes that indicate synergistic interactions developed between the compositions of the present invention and mucin solutions. The changes were identified and quantified by measuring viscosity at low and high shear rates.

[0260] The example composition was analysed both individually and when mixed with a prepared mucin solution. Quantifying zero shear viscosity (η.sub.o) was the ideal aim for the example composition; it is believed that this zero shear viscosity provides a suitable indicator of the behaviour of the product in situ. This was entered into the following two equations to give the “rheological synergism parameters” Δη.sub.o and Δη.sub.o/η.sub.o.

Δη.sub.o=η.sub.o(mix)−(η.sub.o(sample)+η.sub.o(mucin))

Δη.sub.o/η.sub.o+1, where η.sub.o=η.sub.o(sample)+η.sub.o(mucin)

[0261] Δη.sub.o is the difference between the actual viscosity values of the composition mixed with mucin and the theoretical value; the theoretical value is defined as the sum of the η.sub.o values of the sample and the mucin when analysed individually. Δη.sub.o/η.sub.o+1 describes the relative rheological synergism, this expresses the relative increase in η.sub.o with regards to the sample and mucin alone.

[0262] A value greater than one indicates some interaction with mucin; a value of 2 for example would mean the measured viscosity of the sample mixed with mucin is double what was expected.

[0263] The results for the composition tested are shown in Table 3.

TABLE-US-00080 TABLE 3 η η Mucin η Mix Δη Relative Shear Rate (mPa.s) (mPa.s) (mPa.s) (mPa.s) η Low Shear (1 s.sup.−1) 1257 3.48 16564 15304 13.1 High Shear (100 s.sup.−1) 32.8 3.48 507 471 14.0

[0264] FIG. 5 illustrates the result obtained at low shear rate.

[0265] The composition contains several functional groups capable of forming hydrogen bonds. The presence of these groups promotes a strong interaction with the mucosal surface of the throat allowing the composition to remain on the mucosal tissue of the throat for longer. In addition, as the gel matrix resists being readily washed off by saliva as a result of its structure, the attraction force between the composition and the surface of the mucosa has more time to form. This increase the contact time of active with the throat enhancing topical action and efficacy

[0266] As can be seen from FIG. 4, when a shear force or stress is applied to the compositions of the present invention the viscosity decreases. A higher rate of shear force/stress results in the composition having a lower viscosity. On removal of the shear force/stress the viscosity of the composition returns to its initial viscosity confirming that the compositions exhibit shear-thinning or thixotropic behaviour.

[0267] An advantage of the present invention is that there is provided a composition which has a viscosity that is sufficient to allow it to be retained on the surface of the throat for a sufficient period of time to allow the active contained therein to exhibit a local effect but on application of a shear force can be converted into a sprayable composition that can be applied to the inflamed/infected area on the surface of the throat with a high degree of accuracy.

[0268] Further modifications of the invention can be made without departing from the scope of the invention described herein.