Pharmaceutical compositions

The present invention relates to a pharmaceutical composition comprising a nitrate vasodilator and a compound of formula I: ##STR1##

DESCRIPTION
 The present invention relates to the use of nitrate vasodilators,
 particularly glyceryl trinitrate, capsaicin and capsaicin like compounds
 as analgesics.
 The analgesic properties of topical chilli pepper preparations have been
 known for sometime. For example, in 1850 the use of such preparations in
 the treatment of chilblains (Turnbull A., Dublin Med. Press 1850; 95-6.)
 was reported. It seems that this analgesic effect can be attributed to the
 capsaicin-containing fraction of the chilli pepper and that this effect
 is, at least in part, mediated by the ability of capsaicin to reversibly
 deplete unmyelinated C fibre afferent neurones of sensory neuropeptides,
 in particular, neuropeptide Substance P (SP) (Rains and Bryson, Drugs and
 Ageing 1995; 7:317-28; Fitzgerald M., Pain 1983; 15: 109-30.). As
 Substance P has an important role in central transmission of nociceptive
 or "pain" signals, its repeated depletion from afferent neurones as a
 consequence of the repeated application of capsaicin results in a
 "desensitisation" to pain. Isolated capsaicin has the chemical formula:
 N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide.
 An analgesic effect with topical application of capsaicin has been
 demonstrated in conditions as diverse as post mastectomy pain syndrome
 (Watson and Evans, Pain 1992; 51: 375-79.), painful diabetic neuropathy
 Tandan et al., Diabetes Care 1992; 15: 8-13.; The Capsaicin Study Group,
 Arch Intern Med 1991: 151: 2225-9), post-herpetic neuralgia (Watson et
 al., Pain 1988, 33: 333-40; Watson et al., Clin. Ther. 1993, 15: 510-26;
 Bernstein et al., J. Am Acad Dermatol 1989, 21: 265-70.) and pain in
 Guillian-Barre syndrome (Morganlander et al, Annals of Neurology 1990,
 29:199). Capsaicin has also been used in the treatment of osteoarthritis
 (Deal et al., Clin Ther 1991, 13: 383-95; McCarthy and McCarty, J.
 Rheumatol 1992, 19: 604-7; Altman et al., Seminars in Arthritis and
 Rheumatism 1994, 23: 25-33.). The symptoms of osteoarthritis include the
 destruction of joint architecture and are almost a natural accompaniment
 of advancing age. Thus, the therapeutic aim in treating this condition is
 largely to palliate symptoms and to maximise quality of life. Patients
 suffering from conditions such as osteoarthritis, for which the use of a
 topical preparation of capsaicin is known to have an effect, generally,
 will have tried the first line of treatment "over the counter"
 preparations and will then have progressed to the use of codeine based
 drugs and anti-inflammatories. However, these available therapeutic agents
 are limited by side effects such as gastric bleeding with non-steroidal
 anti-inflammatory agents (Blower et al., Aliment Pharmacol Ther 1997; 11:
 283-91.) and analgesic tolerance with codeine based preparations. It is
 probable, therefore, that capsaicin will have been used in situations
 where conventional analgesia has either failed to have an effect or has
 created side effects. It, therefore, would be undesirable for an agent
 kept in reserve for such a situation to itself be prone to cause side
 effects which may necessitate termination of treatment prior to a point
 where analgesia is apparent.
 Unfortunately, topical application of capsaicin, especially initially, is
 associated with burning discomfort at the application site and this
 prominent side effect compromises the efficacy of the treatment. The
 Capsaicin Study Group reported that 87 of 138 patients in their study
 suffered burning discomfort after application of 0.075% capsaicin, while
 Watson and colleagues (Clinical Therapeutics, 1993, 15:510-26) reported
 that 9 of 33 patients in their study suffered burning after application of
 0.025% capsaicin. This discomfort has lead to patients dropping out of at
 least one study (Watson et al. Pain 1988; 33: 333-40). The failure of
 patient drug compliance makes the full potential of this agent to give
 pain relief hard to gauge.
 It would, therefore, be desirable to formulate a cream, ointment or the
 like for the topical application of capsaicin such that the burning
 discomfort on application is reduced while the analgesic properties of
 capsaicin are retained. It would be even more desirable if the formulation
 that lead to a reduction in burning discomfort could also provide an
 analgesic effect greater than that obtained by the application of
 capsaicin alone. Glyceryl trinitrate (GTN) has a long pedigree in the
 treatment of angina pectoris for which it is administered lingually,
 sublingually or bucally in the form of chewable tablets. It can also be
 applied to the skin in the form of a transdermal patch applied to the area
 in which ischaemic pain is sensed (normally the chest or arms). The
 predominate effect is rapid vasodilation which may be mediated through the
 action of GTN on cyclic guanidine monophosphate (cGMP) (Feelisch and
 Noack, Eur J. Pharmacol 1987; 139: 19-30.). This allows venous pooling of
 blood with a subsequent reduction in pressure in the ventricles and
 redistribution of blood to ischaemic regions and, hence, relief from the
 ischaemic pain.
 DETAILED DESCRIPTION OF THE INVENTION
 In a first aspect, the present invention provides a pharmaceutical
 composition comprising a nitrate vasodilator and a compound of formula I:
 ##STR2##
 the composition being useful in a medical treatment, preferably as an
 analgesic.
 In preferred embodiments, the composition is formulated for topical
 application at or in the vicinity of a source of pain or discomfort and
 can further comprise a pharmaceutical carrier rendering it suitable for
 topical application to the skin. Such carriers are well known to those
 skilled in the art. Suitable carriers include those employed in Axsain
 cream available from Bioglan Laboratories Ltd. (purified water, sorbitol
 solution, isopropyl mysristate, acetyl alcohol, petrolatum (white), benzyl
 alcohol, glyceryl stearate and PEG-100 stearate (Arlacel 165)) and those
 employed in the GTN ointment, Percutol (Dominion Pharmaceuticals, UK)
 (lanolin, white petrolatum, lactose and water). Preferably, pharmaceutical
 compositions in accordance with the invention are for ameliorating deep
 seated or internal pain which can be of skeletal or muscular origin, or
 emanate from a joint. In preferred embodiments, pharmaceutical
 compositions in accordance with the invention are useful for ameliorating
 pain associated with arthritis, particularly osteoarthritis.
 Where compounds and compositions are said to ameliorate or to be for
 ameliorating pain or discomfort, it is meant that they are effective to
 reduce the intensity of pain, or have an analgesic effect, and, although a
 so described agent is preferably capable of eliminating a particular pain,
 it need not necessarily be capable of so doing. The term pain is used in a
 general sense and to encompass pain levels between the merely
 uncomfortable and the virtually unbearable.
 In preferred embodiments of the invention, the nitrate vasodilator is
 present in an amount sufficient to reduce burning discomfort associated
 with the application of a compound of formula I to the skin. Preferably,
 the nitrate vasodilator is present in an amount sufficient to augment an
 analgesic effect provided by a compound of formula I.
 Preferably, the nitrate vasodilator is glyceryl trinitrate; the preferred
 compound of formula I is capsaicin.
 In preferred embodiments, pharmaceutical compositions in accordance with
 the invention comprise between 0.01 and 0.1%, preferably between 0.015 and
 0.075% and, more preferably, between 0.015 and 0.035% capsaicin and
 between 0.5 and 2.5%, and preferably, between 0.5 and 2% glyceryl
 trinitrate. Such compositions can be in the form of a cream, jelly,
 ointment, gel, lotion, paste or for application by a patch.
 Other conditions treatable with pharmaceutical compositions in accordance
 with the invention include post mastectomy pain syndrome, painful diabetic
 neuropathy and post-herpetic neuralgia.
 In a second aspect, the present invention provides anD analgesic treatment
 comprising sequentially or simultaneously administering a nitrate
 vasodilator and a compound of formula I
 ##STR3##
 to a patient in need of analgesic treatment. The nitrate vasodilator and
 compound of formula I can be topically applied to the skin at or in the
 vicinity of a source of pain. Preferably, the nitrate vasodilator and
 compound of formula I are applied simultaneously in a single preparation
 comprising the nitrate vasodilator, a compound of formula I and a
 pharmaceutically acceptable carrier. Suitable carriers include those
 employed in pharmaceutical compositions in accordance with the first
 aspect of the invention.
 Preferably, the analgesic treatment is to ameliorate deep seated or
 internal pain. The pain can be of skeletal or muscular origin, or emanate
 from a joint. In this last case, the pain can be associated with
 arthritis, particularly osteoarthritis. The pain can also be neuropathic
 pain, particularly post diabetic neuropathy or post-herpetic neuralgia.
 In preferred embodiments of this aspect of the invention, the nitrate
 vasodilator is used in an amount sufficient to reduce burning discomfort
 associated with the application of a compound of formula I. The nitrate
 vasodilator can be used in an amount sufficient to augment an analgesic
 effect provided by the compound of formula I. The preferred nitrate
 vasodilator is glyceryl trinitrate and the preferred compound of formula I
 is capsaicin. The preparation can be a cream, jelly, ointment, gel,
 lotion, paste or for application by a patch.
 In a third aspect, the invention provides a method of ameliorating deep
 seated or internal pain, comprising topically administering a nitrate
 vasodilator to a subject suffering said pain at or in the vicinity of the
 source of said pain. It is preferred that the nitrate vasodilator should
 be applied to the skin and that the treated pain is of skeletal or
 muscular origin, or emanates from a joint. In the latter case, the pain
 can be associated with arthritis, particularly osteoarthritis. In another
 embodiment, the pain can be neuropathic pain, particularly post diabetic
 neuropathy or post-herpetic neuralgia.
 It is preferred that the nitrate vasodilator should be administered in
 association with a pharmaceutically acceptable carrier and, preferably, in
 a cream, jelly, ointment, gel, lotion, paste or for application by a
 patch.
 The preferred nitrate vasodilator is glyceryl trinitrate.
 In a fourth aspect, the present invention provides a use of a nitrate
 vasodilator in the preparation of a medicament for ameliorating deep
 seated or internal pain or discomfort in an individual, wherein the
 medicament is formulated for topical application in the vicinity of the
 source of said pain and the nitrate vasodilator has an ameliorating effect
 upon said pain.
 In a fifth aspect, the present invention provides a use of a nitrate
 vasodilator and a compound of formula I in the preparation of a medicament
 for ameliorating deep seated or internal pain or discomfort in an
 individual, wherein the nitrate vasodilator has an ameliorating effect
 upon said pain. In a preferred embodiment of this last aspect of the
 invention, the medicament is formulated for topical application at or in
 the vicinity of the source of said pain.
 In preferred embodiments of the last two aspects of the invention, the
 compound of formula I has an ameliorating effect upon the treated pain. A
 medicament prepared in accordance with the fourth aspect of the invention
 can be for sequential or simultaneous administration with a compound of
 formula I.
 The preferred compound of formula I is capsaicin and the preferred nitrate
 vasodilator is glyceryl trinitrate. The treated pain is preferably of
 skeletal or muscular origin, or emanates from a joint. In this last case,
 the pain can be associated with arthritis, particularly osteoarthritis. In
 other embodiments, the pain can be neuropathic pain, particularly post
 diabetic neuropathy or post-herpetic neuralgia.
 The medicament can further comprise a pharmaceutically acceptable carrier
 and can be suitable for topical application to the skin. Preferably the
 medicament is a cream, jelly, ointment, gel, lotion, paste or for
 application by a patch. Preferably the medicament comprises between
 between 0.5 and 2.5%, and preferably, between 0.5 and 2% glyceryl
 trinitrate and, when it comprises capsaicin, the medicament can include
 between 0.01 and 0.1%, preferably between 0.015 and 0.075% and, more
 preferably, between 0.015 and 0.035% capsaicin.
 An advantage of those aspects of the invention which involve the use of a
 nitrate vasodilator alone, is that they can provide an effective topical
 analgesic treatment for deep seated or internal pain such as that
 emanating from a joint, or a muscular or skeletal source, without the
 attendant disadvantages associated with systemic drug treatments or the
 topical use of capsaicin and like compounds alone. Advantages of those
 aspects of the invention involving the combined use of a nitrate
 vasodilator and a compound of formula I include the prevention of the
 burning sensation normally associated with compounds of formula I and a
 more than additive analgesic effect. When topically applied, such combined
 compositions have the further advantage of not causing the side-effects
 associated with many systematically active drugs when administered via an
 oral route.
 A combination of capsaicin and glyceryl trinitrate (GTN) was tested in a
 volunteer study, details of which are set out in Example 1 below. The
 results of this study show that the burning discomfort normally associated
 with capsaicin was reduced in individuals treated with capsaicin in
 combination with GfN when compared to that felt in individuals treated
 with capsaicin alone.
 The results of a study to determine the analgesic effect and effect on
 tolerability of the addition of GTN to capsaicin cream in patients with
 osteoarthritis are described in Example 2 below. These show that both GTN
 and capsaicin are significantly more effective at reducing the pain of
 osteoarthritis when repeatedly applied to the effected joint than a
 placebo and that the combination of both together gives a more than
 additive effect when compared with a placebo. Furthermore, the results
 demonstrate that the discomfort caused by application of capsaicin is
 significantly less when it is used together with GTN and that a greater
 proportion of patients desire to continue using the combination of
 capsaicin and GTN than either alone.
 Thus, analgesic benefit can be derived in patients with osteoarthritis who
 repeatedly apply either capsaicin or GTN creams to a painful joint and
 that the combination of both together is more effective and more tolerable
 than either alone. The significant number of patients who elected to
 continue on their study medication in the combined group is a testimony to
 its efficacy and tolerability. The patient populations studied are not a
 representative spectrum of adult patients with osteoarthritis pain but
 rather those in whom more conventional agents had either not been
 tolerated or had been ineffective. To have demonstrated both a statistical
 and clinical reduction in pain scores in this group indicates that
 medicaments comprising GTN or GTN and capsaicin are useful additions to
 the treatment options for patients with painful osteoarthritis or other
 conditions involving deep seated pain such as neuropathic pain,
 particularly painful diabetic neuropathy and post-herpetic neuralgia. A
 further advantage of the invention is that patients in particular are
 attracted to the notion of applying medication to that area which is
 affected. Despite an apparent medical prejudice against topical
 preparations (Bateman and Kennedy, BMJ 1995; 310: 817-8; Anonymous, Drug
 Ther Bull 1994; 32: 91-5) the experience with topical anti-inflammatory
 agents suggests that patients preferences in this respect are generated
 not only by the apparent reduction in side effects but also by real
 clinical efficacy (Moore et al. BMJ 1998; 316: 333-8). The lack of
 gastrointestinal and renal side effects represent further advantages in an
 often elderly population group.

EXAMPLE 1
 Discomfort Associated with Topical Application of Capsaicin: A Volunteer
 Study
 Forty healthy individuals were recruited on a voluntary basis for
 participation in the study. AR were aware that burning discomfort may
 occur after application of the preparations and that accidental transfer
 of the cream to other sites (e.g. eyes, nose etc.) could be associated
 with discomfort.
 Four preparations were used: A, B, C and D:
 A--Axsain Vehicle
 B--Axsain Cream 0.075%.sup.1 +GTN 2%.sup.2 (to give 0.025% Capsaicin 1.33%
 GTN
 C--Axsain Cream 0.075%.sup.1 +Axsain Vehicle (to give 0.025% Capsaicin)
 D--GTN 2%.sup.2 +Axsain Vehicle (to give 1.33% GTN)

FNT .sup.2 GTN ointment, Percutol, Dominion Pharmaceuticals (UK)
 0.1 ml (measured with a 2 ml syringe) of each cream was applied to a 1
 inch.sup.2 area (measured with a celluloid template) to the dorsum of the
 non-dominant hand proximal to the metacarpal pharyngeal joint on a single
 occasion, within a 1 day interval between application of each cream.
 Patients were instructed not to wash the hand for 2 hours and asked to
 rate their burning discomfort after 6 hours on a 0-10 visual analogue
 score (VAS). Patients had been divided into 4 groups of ten and the order
 of application was varied so as to ensure that one agent was not always
 followed by the same preparation.
 10 subjects A - B - C - D
 10 subjects D - C - B - A
 10 subjects C - A - D - B
 10 subjects B - D - A - C
 Neither investigator nor subject was aware of the constituents of the
 applied cream. Non parametric tests were used for VAS results and p&lt;0.05
 considered statistically significant.
 RESULTS
 Results were obtained from all 40 participants. Apart from burning or
 itching at the site of application of the creams no other side effects
 were apparent.

Difference from
 Constituent of VAS: median Capsaicin
 Group cream (range) (Group C)
 A Axsain Vehicle 0 (0-6) P &lt; 0.001
 (placebo)
 B Capsaicin 0.025% + 0 (0-7) P = 0.002
 GTN 1.33%
 C Capsaicin 0.025% 3 (0-7)
 D GTN 1.33% 0 (0-2) P 0.001
 The results of this double blind, placebo trial of 40 volunteers show the
 burning discomfort associated with application of capsaicin cream (0.025%)
 compared to placebo, GTN cream (1.33%) and to the combination of capsaicin
 cream (0.0250%) plus GTN cream 1.33%. Median VAS for burning pain were 0
 for the placebo, GTN and GTN+capsaicin groups and 3 for the capsaicin
 group after single application of each cream at daily intervals. This
 demonstrates that after a single application, the addition of GTIN to
 capsaicin significantly reduces the burning discomfort associated with the
 application of capsaicin alone.
 EXAMPLE 2
 The Effects of Topical Capsaicin and GTN in Patients with Painful
 Osteoarthritis: a Randomised, Double Blind, Placebo Controlled Study
 Subjects: A double blind, randomised, placebo controlled trial of two
 hundred patients with osteoarthritis pain presenting to a District General
 Hospital Pain Clinic. Previous treatment with non-steroidal
 anti-inflammatory agents or simple analgesics was either ineffective or
 complicated by intolerable side effects. Those using nitrate preparations
 and those in whom concomitant medication was expected to change over the
 study period were excluded from the study. Regional research ethics
 committee approval was granted for the study and all patients gave
 informed written consent for participation in the study. Patients were
 randomly allocated to one of four groups (A, B, C, D) in equal numbers
 using a computer generated random number list. These patients received (in
 a double blind fashion):
 Group A 0.025% capsaicin
 Group B placebo (vehicle for the active agents used in the other groups)
 Group C 1.33% GIN (2 parts 2% GTN, 1 part placebo)
 Group D 0.025% capsaicin, 1.33% GIN (1 part 0.075% capsaicin, 2 parts 2%
 GTN)
 All study creams were contained in a coded, but otherwise unlabelled dark
 glass containers (these were prepared by Bioglan Laboratories Ltd). These
 creams were all white in colour and odourless.
 Patients were instructed to apply a volume of study cream equivalent to a
 grain of rice four times daily over a six week period to a single painful
 joint. They were further instructed not to wash that joint for at least 1
 hour after cream application.
 Patients were asked to record their average daily pain scores using a 0-10
 linear visual analogue score ("VAS"; 0=no pain, 10=most amount of pain
 imaginable) and to further record their total daily analgesic consumption
 (number of tablets taken) and the discomfort of cream application using a
 10 cm linear visual analogue score (0=no discomfort, 10=most amount of
 discomfort imaginable).
 Analysis of Variance (ANOVA) and Regression Techniques were used to examine
 for the main effects of the study creams. Cusum analysis of daily means
 was used to provide information on where changes in patients behaviour
 tended to occur, and descriptive statistics of patients allocated to each
 treatment group. Patients desire to continue with treatment was examined
 using logistic regression.
 167 patients provided results (83.5%). There were no statistically
 significant differences between the treatment groups in term of sex
 distribution or age (Table 1). Natural variability was seen in pain scores
 within 5 days of start of treatment in some groups so it was decided to
 compare the mean pain scores of days 1-4 ("baseline pain scores", i.e.
 pain scores prior to treatment effect) with the final week of treatment.
 Baseline VAS (0-10 scale) for pain were 4.2. One-way analysis of variance
 of baseline pain scores indicated no differences between treatment groups
 (F=0.31 on 3 and 163 degrees of freedom: p&gt;0.05). Neither age, sex or the
 interaction between GTN and capsaicin were found to be statistically
 significant when regression analysis was used. However, baseline level of
 pain of individuals was significantly associated with the ability to
 change (those with high scores initially showed more propensity to
 improve).
 The mean pain scores after 42 days and the results of the regression
 analysis are shown in Table 2. There was a significant reduction in pain
 scores in the GTN group (mean decrease 0.59, p&gt;0.05), the 0.025% capsaicin
 group (mean decrease 0.5, p&lt;0.05) and in the capsaicin and GTN group (mean
 decrease 1.1). The decrease in mean pain score beyond that given by the
 cream vehicle (placebo) alone was 0.28 in the capsaicin group, 0.37 in the
 GTN group but 0.88 in the group treated with both agents. Combining the
 active agents, therefore, provided a greater than additive effect.
 The Kurskal--Wallis One-way Analysis of variance of ranks indicated
 significant differences between treatment groups in terms of discomfort of
 application. (x.sup.2 =24.91 on 3 degrees of freedom; p&lt;0.001). Those
 allocated to the capsaicin group appeared to have worse baseline
 discomfort (Table 3) the score being higher by 2.1 units (p&gt;0.001). GTN
 and the placebo had an equal effect in terms of application discomfort:
 marginal initial discomfort which changed by a coefficient of 0.33 with
 time. As shown in Table 3, the GTN/capsaicin group had the lowest baseline
 discomfort of all at -1.26 (p&lt;0.05).
 Only these baseline discomfort scores were found to be statistically
 significant in regression analysis. Discomfort of application scores fell
 by about a third of their original values over the six week period,
 irrespective of the treatment (see Table 4). However, with the capsaicin
 only group, this fall is from a higher initial level (2.1 units higher)
 than for the other groups. Thus, the addition of GTN to capsaicin reduces
 discomfort both at the onset and throughout treatment.
 One-way Analysis of variance of daily usage (tablets) of analgesic in week
 1 indicated no differences between treatment groups (F=0.60 on 3 and 163
 degrees of freedom; p&gt;0.05). There was a significant reduction in usage of
 analgesics for people treated with GTN, capsaicin and GTN/capsaicin,
 falling from an initial mean of 4 tablets daily by 0.48 in the GTN and
 GTN/capsaicin groups (p&lt;0.01) and 0.28 in the capsaicin group (p&gt;0.05).
 See Table 5.
 Patients' desire to continue with current treatment is shown in Table 6.
 The percentage of patients who wished to continue with treatment was 24.4%
 and 27.5% in the Capsaicin and GTN treatments groups respectively but
 35.7% in the GTN/capsaicin group. The percentage of patients wishing to
 continue the treatment was significantly greater, therefore, in the
 patient group receiving the combination.
 TABLE 1
 Patients characteristics
 Treatment Males Females Mean Age
 Placebo 16 (40%) 24 (60%) 48.4
 Glyceryl Trinitrate 22 (49%) 23 (51%) 48.1
 Capsaicin 23 (58%) 17 (42%) 49.7
 GTN + Capsaicin 17 (41%) 25 (59%) 50.9
 All 78 (47%) 89 (53%) 49.2
 TABLE 2
 Pain changes resulting from treatment
 (Baseline Pain Score = 4.2)
 Mean Pain Reduction in Reduction in pain
 Score after 42 pain score score (VAS)
 Treatment days (VAS) (VAS) compared to placebo
 Placebo 3.98 0.22 0
 Capsaicin 3.70 0.5 0.28
 GTN 3.61 0.59 0.37
 Capsaicin/GT 3.10 1.1 0.88
 N
 TABLE 3
 Application discomfort - Baseline scores versus treatment
 Standard
 Variable VAS Error
 Capsaicin 2.1 0.53
 Capsaicin/ -1.26 0.61
 GTN
 TABLE 4
 Application discomfort - changes resulting from baseline score
 Standard
 Variable Coefficient Error Significance*
 Baseline -0.33 0.07 p &lt; 0.01
 discomfort
 * = One-tail tests on Glyceryl trinitrate and Capsaicin; Two-tail test on
 Baseline pain
 TABLE 5
 Analgesic use - changes from treatment
 (Analgesic use at beginning of treatment = 4 tablets per day)
 Tablets per
 day after Reduction in daily tablet
 Variable treatment consumption
 Capsaicin 3.72 -0.28
 GTN 3.52 -0.48
 Capsaicin/GTN 3.52 -0.48
 TABLE 6
 Patients` desire to continue with current treatment
 Patients wishing to Patients not wishing to
 Treatment Group continue continue
 Placebo 3 37
 Glyceryl Trinitrate 11 34
 Capsaicin 11 29
 Glyceryl Trinitrate/ 15 27
 Capsaicin
 EXAMPLE 3
 A composition of capsaicin and GTN for topical application is formulated
 from the following ingredients:

Ingredient % w/w
 Capsaicin 0.025
 Glyceryl Trinitrate (GTN) 1.33
 Lanolin 26.7
 White Soft Paraffin 20.3
 Lactose 12.0
 Sorbitol solution 70% 8.3
 Cetyl alcohol 2.7
 Isopropyl myristate 0.85
 Glyceryl stearate 0.85
 PEG 100 stearate 0.85
 Benzyl alcohol 0.3
 Water 25.795
 The lanolin, white soft paraffin, isopropyl myristate, glyceryl stearate
 and PEG 100 stearate are heated and mixed together to produce a
 homogeneous mixture. A capsaicin/cetyl alcohol mix is then added and the
 bulk mixed.
 Separately, an aqueous phase is prepared by heating and mixing the water,
 sorbitol solution and benzyl alcohol.
 The oil phase is then homogenised with the aqueous phase, and the glyceryl
 trinitrate/lactose mix added with continued mixing as the product is
 allowed to cool.
 EXAMPLE 4
 A composition of GTN for topical application is formulated from the
 following ingredients:

Ingredient % w/w
 Glyceryl Trinitrate 2.0
 Lanolin 40.0
 White soft paraffin 30.0
 Lactose 18.0
 Water 10.0
 The lanolin and white soft paraffin are heated and mixed together to
 produce a homogeneous mixture. The oil phase is then homogenised with the
 water, and the glyceryl trinitrate/lactose mix added with continued mixing
 as the product is allowed to cool.
 EXAMPLE 5
 A composition of capsaicin for topical application is formulated from the
 following ingredients:

Ingredient % w/w
 Capsaicin 0.025
 Lanolin 26.7
 White Soft Paraffin 20.3
 Sorbitol solution 70% 8.3
 Cetyl alcohol 2.7
 Isopropyl myristate 0.85
 Glyceryl stearate 0.85
 PEG 100 stearate 0.85
 Benzyl alcohol 0.3
 Water 39.125
 The lanolin, white soft paraffin, isopropyl myristate, glyceryl stearate
 and PEG 100 stearate are heated and mixed together to produce a
 homogeneous mixture. A capsaicin/cetyl alcohol mix is then added and the
 bulk mixed.
 Separately, an aqueous phase is prepared by heating and mixing the water,
 sorbitol solution and benzyl alcohol.
 The oil phase is then homogenised with the water phase with continued
 mixing as the product is allowed to cool.