Composition for Promoting Vascular Smooth Muscle Relaxation

Abstract

A composition for topical application to a part of the body comprises a vasodilator, for example glyceryl trinitrate, as active ingredient dissolved in a blend of volatile and non-volatile solvents of different solvating capacities for the vasodilator. The vasoldator is present in the composition at a concentration at or slightly below saturation, whereby evaporation of the volatile solvent in use will maintain the vasodilator at saturated or super-saturated concentrations in the residue, whereby the vasodilator will become saturated or supersaturated in the solvent remaining and, as the active ingredient passes through the skin and is absorbed in the bloodstream, and thus becomes depleted in the residual composition, continuing evaporation of volatile solvent will maintain the active ingredient substantially at saturation or supersaturation level in the residual composition throughout the major part of the absorption phase, thereby maximising absorption levels but at a moderate dosage level.

Description

The invention will now be described with reference to the following experimental details, provided purely by way of example, and with reference to the accompanying drawings, of which:

FIG. 1 is a bargraph showing comparative saturated solubility of GTN in various solvent blends; and

FIG. 2 is a bargraph showing in vitro transport of compositions according to the invention compared with Percutol.

The experiments provided compositions having a nominal concentration of glyceryl trinitrate of a minimum of 1% or 2% based on the total of volatile and non-volatile solvents. The solvents used were water and ethanol as the volatile component and glycerol together with propylene glycol as an optional additive as the non-volatile component. The experiments related to the use of three respective variables, firstly various ratios of 1% glyceryl trinitrate (GTN) in 57.5:42.5 water:ethanol (1.35:1) and 1% GTN in 87.5:12.5 glycerol:propylene glycol (7:1) (QS 1-QS 6); secondly GTN in various ratios of water-ethanol systems and GTN in glycerol alone (QS 7-QS 13); and thirdly GTN in various ratios of different water:ethanol systems with GTN in 95:5 glycerol:propylene glycol (QS 14-QS 18). For each experiment, the concentration of GTN remaining in the residual (non-volatile) solvent and expressed as a multiple of the saturated concentration was estimated, based on volume change and taking account of the saturated concentration in the solvent or solvent blend of the residual phase.

Initially, predicted saturated concentration in the quarternary solvent blends was estimated based on experimental determinations in binary cosolvents, namely ethanol/water at different ratios and glycerol/propylene glycol at different ratios. It was predicted that the saturated concentration of GTN would be 1% in most quaternary blends or 2% in others (QS 8, QS 10, QS 14 and QS 15). FIG. 1 shows experimental data for the saturated solubility of GTN in the various quaternary and tertiary (QS 7-QS 13) blends. As illustrated, good agreement with prediction was shown by QS 1 to QS 6; QS 7 to QS 13 showed higher solubilities than predicted and QS 14 to QS 18 were also higher, albeit not to the same extent as with QS 7 to QS 13.

Table 1 shows the details of each experiment and the estimated residual concentration of GTN expressed as a multiple of the saturated concentration in the residual solvent.

TABLE 1
					Conc. Of
					GTN
					(predicted)
					(%),
				Prop	Approx.
Series	Water	Ethanol	Glycerol	Glycol	*SS
(W-E:G-PG)	(%)	(%)	(%)	(%)	(predicted)
QS 1.	28.75	21.25	43.75	6.25	(1), *2
QS 2.	31.65	23.375	39.375	5.625	(1), *2.2
QS 3.	34.5	25.5	35.5	5.0	(1), *2.5
QS 4.	37.375	27.625	30.625	4.375	(1), *2.86
QS 5.	40.25	29.75	26.25	3.75	(1), *3.33
QS 6.	43.125	31.875	21.875	3.125	(1), *4
QS 7.	15.2	22.8	62	0	(1), *4.24
QS 8.	25.6	38.4	36.0	0	(2), *14.61
QS 9.	19.8	24.2	56.0	0	(1), *4.70
QS 10.	33.3	40.7	26	0	(2), *20.23
QS 11.	27.0	27.0	46	0	(1), *5.72
QS 12.	42.9	35.1	22	0	(1), *11.94
QS 13.	39.55	30.45	30	0	(1), *8.76
QS 14.	21.6	32.4	43.7	2.3	(2), *5.35
QS 15.	29.25	35.75	33.25	1.75	(2), *7.03
QS 16.	15.	15.	66.50	3.50	(1), *1.76
QS 17.	30.25	24.75	41.75	2.25	(1), *2.77
QS 18.	41.125	28.875	28.5	1.5	(1), *4.1
Note that QS 8, 10, 14 and 15 had a predicted 2% GTN concentration whereas the remainder had a 1% concentration.

From the above results, it is seen that QS 4, QS 5, QS 6, QS 12, QS 13, QS 15 and QS 18 provide promising results in terms of supersaturation in the residual solvent and are within the requirements for ethanol and glycerol limits, respectively. QS 3, QS 8 and QS 10 are also identified as of interest, although QS 10 has a concentration of ethanol which is higher than considered desirable. The remainder, although showing enhanced levels of supersaturation in the residual solvent, may be unacceptable because of the glycerol levels.

The following Table 2 shows the formulation of compositions using solvent blends QS 6 and QS 13, in percentages by weight.

	TABLE 2
	Ingredient	QS 6.	QS 13.
	GTN (10% on lactose)	10	10
	Water	38.25	35.08
	Ethanol	28.97	27.01
	Glycerol	19.41	26.61
	Propyleneplycol	2.77	—
	Dimethicone 200	—	—
	Carbopol 937P	1.00	1.00
	Triethanolamine	0.20	0.20
	Propylparaben	0.10	0.10

To evaluate skin absorption, the experimental systems QS 6 and QS 13 were compared with Percutol in an experimental model in which diffusion of GTN from the test solvent through a SAMCO Silastic membrane into a buffered phosphate receptor fluid was assessed over a period of one hour. All experimental systems performed appreciably (between twice and three times) better than Percutol as shown in accompanying FIG. 2.

However, such in vitro tests, which are difficult to conduct under finite dose, thin-film conditions, may not be fully predictive of in vitro performance. Thus, compositions according to the present invention have also been evaluated in a Phase 1 clinical trial in comparison with a formulation according to WO99/38506. Results are presented in the following Table 3 for peak systemic levels (C_max), time taken to achieve peak systemic levels (T_max) and plasma half-life (t_1/2).

TABLE 3
	GTN dose	Cmax	Tmax	t1/2
Formulation	(mg)	(pg/ml)	(minutes)	(minutes)
WO99/38506	20.0	949.64	25.94	96.31
Current	1.0	1267.50	14.67	8.53

As can be seen, peak systemic levels for the current formulation, at a dose of 1 mg, are significantly higher than for the lanolin-containing composition at a dose of 20 mg. The shorter time taken to achieve the peak systemic levels is indicative of more rapid GTN absorption, despite the lower dose. The significantly shorter half-life indicates rapid absorption and rapid elimination of GTN. The current formulation is estimated to be approximately 25-fold more effective than the lanolin-containing formulation at delivery through the membrane of the glans penis.

Claims

1. A composition for topical application to a part of the body, the composition comprising a vasodilator as active ingredient dissolved in a blend of volatile and non-volatile solvents of different solvating capacities for the vasodilator.

2. A composition according to claim 1, in which the non-volatile solvent has the lower solvating capacity.

3. A composition according to claim 1, in which the vasodilator comprises glyceryl trinitrate.

4. A composition according to claim 1 in unit-dosage form or applied to a condom and containing a dose of vasodilator up to 5 mg.

5. A composition according to claim 1, in which the volatile solvent component comprises a mixture of water with a low molecular weight alcohol.

6. A composition according to claim 5, in which the alcohol comprises ethanol.

7. A composition according to claim 5, in which the water and volatile solvent are present in a ratio from 0.5:1 to 1.6:1 by weight.

8. A composition according to claim 5, in which the alcohol has a maximum concentration of 40% by weight.

9. A composition according to claim 1, in which the non-volatile solvent is present in a concentration of 40% by weight or less of the total solvent content.

10. A composition according to claim 1, in which the non-volatile solvent comprises a polyhydric alcohol optionally blended with a minor amount of additional solvent.

11. A composition according to claim 10, in which the polyhydric alcohol comprises glycerol and the optional additional solvent comprises a glycol.

12. A composition according to claim 11, in which the glycol comprises propylene glycol and is present at up to 20% of the total non-volatile component.

13. A condom having applied thereto a composition according to claim 1.

14. The use of a vasodilator in the preparation of a composition also containing, as solvent, a blend of volatile and non-volatile solvents of different solvating capacities, for topical application to a part of the body for treatment of a condition susceptible to vascular smooth muscle relaxation.

15. A method for the treatment or amelioration of a condition susceptible to vascular smooth muscle relaxation, the method comprising topical application to an affected body part of a composition according to claim 1 and allowing volatile solvent to evaporate.