GB1595351A

GB1595351A - Pharmaceutical compositions containing flavylium compounds

Info

Publication number: GB1595351A
Application number: GB8131/78A
Authority: GB
Original assignee: Inverni Della Beffa SpA
Current assignee: Inverni Della Beffa SpA
Priority date: 1978-03-01
Filing date: 1978-03-01
Publication date: 1981-08-12
Also published as: CH639557A5

Description

(54) PHARMACEUTICAL COMPOSITIONS CONTAINING FLAVYLIUM COMPOUNDS (71) We, INVERNI DELLA BEFFA S.p.A., an Italian Company of Via Ripamonti, 99, Milan, Italy, do hereby declare the invention, for which we pray that a paten. may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to pharmaceutical compositions and processes for their preparation.

Our copending patent application No. 37252/76 (Serial No. 1889294) describes and claims pharmaceutical compositions comprising in admixture with a pharmaceutically acceptable diluent or carrier, an anthocyanidine. Particularly the aforementioned specification describes pharmaceutical compositions containing anthocyanidines which may be obtained by hydrolysis of naturally occurring glycosides known as anthocyanins. Particular examples of these anthocyaninidines are cyanidine, peonidine, delphinidine, petunidine, malvidine and pelargonidiune which may be represented by the following formula:

wherein: R' = R2 = -OH and R3 = H (cyanidine) R' = -OMe, R2 = -OH and R3 = H (peonidine) R' = R2 = R3 = OH (delphinidine) R1 = OMe and R2 = R3 = OH (petunidine) R' = R3 = -OMe and R2 = -OH (malvidine) R2 = -OH and R' = R3 = H (pelargonidine) We have now discovered that a class of flavylium compounds which are structurally related to the aforementioned anthocyanidines also possess valuable pharmacological activity. Particularly, they are endowed with remarkable cicatrising and epithelium-regenerating properties which render them particularly useful in the treatment of cutaneous wounds, torpid sores, and external and internal ulcers. Also the flavylium compounds have been found to possess distinct anti-inflammatory, vaso-protective, hypolipaemic, hypocholesterolaemic and hypoglycaemic activities.

According to the present invention there are provided pharmaceutical compositions comprising a pharmaceutically acceptable diluent or carrier and as active ingredient a flavylium salt having the formula

wherein each Y, which may be the same or different represents -OH or -OR wherein R is an alkyl group containing 1 to 6 carbon atoms, m is 0 or an integer from 1 to 6 and n is 0 or an integer from 1 to 5, the sum of m and n being from 1 to 11 and X is a pharmaceutically acceptable anion, with the proviso that where represents a group of the formula

wherein (a) R = R = -OH and R = H (b) R = -OMe, R = -OH and R = H (c) R = R = R = OH (d) R = -OMe and R = R = OH (e) R = R = -OMe and R = OH or (f) R = OH and R = R = H and

represents a group of formula

wherein each of Y3, Y5 and Y7 represents a moiety Y as defined above, at least one of Y3, Y5 and Y7 is other than -OH.

Particular classes of pharmaceutical compositions according to the invention are those containing salts having the following formulae:

In the above formulae the group

preferably has one of the following structure

Thus a further preferred class of compounds according to the invention are those having the following formulae:

The groups Y in the above formulae are preferably selected from H, OH and OMe.

Thus if the flavylium compounds are represented by the formula A+ - -- B wherein A+ represents the group and B represents

the group A+ is preferably selected from

and the group B is preferably selected from

The flavylium compounds may be associated with any pharmaceutically acceptable anion X-, e.g. chloride, sulphate, phosphate, acetate, hydroxyl etc.

A particularly preferred class of compounds are those in which at least one of the 3, 5 and 7 positions is unsubstituted.

Flavylium salts suitable for incorporation into pharmaceutical compositions according to the invention may be prepared by known procedures, for example by the condensation reactions reported by A. Robertson and R. Robertson, J. Chem. Soc. 1526, 1928; A. Robertson, R. Robinson and J. Sugiura, J. Chem. Soc. 1533, 1928; S. Murakami and R. Robinson, J. Chem. Soc. 1537, 1928; W. Bradley and R.

Robertson J. Chem. Soc. 1541, 1928.

More specifically, flavylium salts of formula I substituted in the 3-position may be prepared by condensing salicylaldehyde or a derivative thereof of formula

with omega-acyloxy-acetophenone or a derivative thereof of formula

wherein Y, m and n are as defined above and Ac is an acyl radical.

Similarly, flavylium salts of formula I unsubstituted in the 3-position may be prepared by condensing salicylaldehyde or a derivative thereof of formula 11 defined above with acetophenone or a derivative thereof of formula IV.

wherein Y and n are as defined above. If desired, any hydroxyl groups representing the groups Y which are likely to interfere with the reactions may be protected and subsequently converted to free hydroxyl groups in a manner known per se.

Thus the production of 3-hydroxyflavylium chloride and 7-hydroxyflavylium chloride are depicted in the following schemes:

The above condensation reactions are generally carried out in the presence of a strong mineral acid and the immediate products are the salts of these acids. The salts may be converted to salts of other acids by conventional procedures.

The particular galenic form of the compositions of the invention depends on the intended route of administration and the condition to be treated and such forms may be amorphous or in the form of shaped dosage units. Examples include sterile liquids suitable for parenteral administration, forms suitable for oral administration (e.g. tablets, capsules, solutions or suspensions); forms suitable for insertion into a body cavity (e.g. anal or vaginal suppositories); forms suitable for topical administration (e.g. ointments, creams, gels and aqueous solutions or suspensions) and dentifrices.

In formulating compositions according to the invention, a wide range of excipients may be used, the nature of which will depend, of course, on the intended mode of application of the composition. Examples include preservatives and buffering, thickening, suspending, stabilising, wetting, emulsifying, colouring and flavouring agents and in particular carboxy vinyl polymers, propylene glycol, ethyl alcohol, water, cetylalcohol, saturated vegetable triglycerides, fatty acid esters or propylene glycol, triethanolamine, glycerol, starch, sorbitol, bentonite, carboxymethyl cellulose, laurylsulphate, dicalcium phosphate, powdered silica and lecithin.

Frequently, more than one diluent or carrier is advantageously used.

The compositions of the invention have been found to be particularly useful in the treatment of wounds, gastric and duodenal ulcers, inflammatory conditions of the mouth and throat, pathogenic conditions of the vascular system and disorders caused by impaired lipidic and glycidic metabolism.

This invention also includes a process for producing the compounds defined above which comprises bringing a compound of formula (I) into a form suitable for pharmaceutical administration, for example by admixing the active ingredient with one or more excipients and/or conversion to one of the galenic forms referred to above.

The invention also provides a method of eliciting a cicatrising, epithelium regenerating, anti-inflammatory, vaso-protective, hypolipaemic, hypocholesterolaemic or hypoglycaemic response in a subject, which comprises administering to the subject an effective dose of a flavylium salt of formula I, preferably from 1 to 100 mg/kg and most preferably 5 to 50 mg/kg per day.

The.compositions according to the invention preferably contain at least 0.2% and most preferably at least 0.5% by weight of flavylium salt of formula I. More concentrated compositions are preferred for internal (i.e. enteral or parenteral) administration, particularly those containing at least 1% and more particularly at least 5% by weight of flavylium salt. The compositions may be administered at a daily dosage rate of from 1 to 100 mg/kg, preferably 5 to 50 mg/kg of flavylium salts.

The following Preparations illustrate the production of substituted flavylium compounds of formula I which may be used as active ingredients in the production of pharmaceutical compositions according to the invention.

Preparation I - 4'-Hydroxyflavylium chloride 122 g of Salicylaldehyde and 136 g of 4-hydroxy-acetophenone were dissolved in a four-necked one-litre flask equipped with a mechanical stirrer and containing 400 ml of anhydrous ethyl acetate. Under agitation and at room temperature, a stream of dry hydrochloric acid was passed into the solution in such manner that saturation was completed in the course of one hour. The mixture was left under agitation for 24 hours, during which precipitation of the reaction product began.

Filtration was carried out, the product dried at 400C in the presence of KOH and recrystallisation carried out twice for methanol. There were obtained 179 g of 4' hydroxyflavylium chloride.

Molecular ion of the corresponding quinoline silyl derivative: M/e 293.

Found: C,68.99; H, 4.54; Cl, 12.92.

C1 > H,1CIO2 requires: C,69.64; H, 4.29; Cl, 13.70.

Preparation 2 -- 3,7-Dihydroxyflavylium chloride 79 g of 2,4-dihydroxybenzaldehyde were dissolved at room temperature in 800 ml of anhydrous ethyl acetate and 106 g of omega-acetoxyacetophenone were added to the solution. The reaction mixture was brought to OOC under agitation and gaseous hydrochlorid acid added to saturation. After standing for 24 hours at room temperature, crystallisation of the product began and it was filtered and dried at 40"C in the presence of NaOH. There were obtained 95 g of 3,7 dihydroxyflavylium chloride.

Molecular ion of the corresponding quinoline silyl derivative: m/e 381.

Found: C,64.72; H,4.19; Cl, 11.83.

C15H11C1O3 requires: C,65.59; H,4.04; Cl, 12.91.

Preparation 3-- 3-Hydroxyflavylium chloride 88 g of salicylaldehyde were dissolved in 300 ml of anhydrous ethyl acetate together with 132 g of omega-acetoxyacethophenone. The solution was cooled to OOC and saturation with gaseous HCI commenced, which took about one hour. The mixture was then left at 40C for 48 hours and the crystallised solid filtered off, this consisting of 106 g of 3-hydroxyflavylium chloride.

Molecular ion of the corresponding quinoline silyl derivative: m/e 293.

Found: C,68.72; H,4.17; Cl, 12.86.

C,5H"CIO2 requires: C, 69.64; H, 4.29; Cl, 13.70.

Preparation 4-3 ,4'-dihydroxyflavylium chloride 23.2 g of salicylaldehyde and 45 g of omega-acetoxy-4-acetoxy)-acetophenone were dissolved in 300 ml of anhydrous ethyl acetate. The solution was cooled to -5 C, saturated with gaseous hydrochloric acid and left at 40C for 48 hours. 35.1 g of crystallised product constituted by 3,4'-dihydroxyflavylium chloride was filtered off.

Molecular ion of the corresponding quinoline silyl derivative: m/e 381.

Found: C, 63.82; H, 3.97; Cl, 11.84.

C,5H"CIO3 requires: C, 65.59; H, 4.04; Cl, 12.91.

Preparation 5 - 3,5,7-Trihydroxy-3',4' ,5'-trimethoxyflavylium chloride A solution containing 70 g of (2-O-benzoyl-)2,4,6-trihydroxybenzaldehyde and 95 g of (omega-acetoxy)-3,4,5-trimethyoxyacetophenone in 1600 ml of anhydrous ethyl acetate was saturated at room temperature with gaseous HCI. On standing at room temperature, 104 g of product were filtered off after 24 hours and this was redissolved in 5.5 1 of methanol and 680 ml of concentrated aqueous hydrochloric acid added. The mixture was left under reflux for 12 hours. It was then cooled and concentrated under vacuum until crystallisation began. After standing at 40C for 24 hours, filtration was carried out, the product washed with 200 ml of acetone and dried. There were obtained 76 g of the title compound.

Molecular ion of the corresponding quinoline silyl derivative: m/e 559.

Found: C, 55.83; H, 4.32; Cl, 8.96.

C,8H1,CIO7 requires: C, 56.78; H, 4.50; Cl, 9.31.

Preparation 6 -- 3,7,4'-Trihydroxyflavylium chloride 96.6 of 4-hydroxy-omega-acetoxyacetophenone and 65.7 g of 2,4dihydroxybenzaldehyde dissolved in 1 liter of anhydrous ethyl acetate were saturated at room temperature with gaseous HC1. The solution was left under agitation for three hours at room temperature and then at 40C for twelve hours.

The crystallised solid was then filtered off. There were obtained 142 g of 3,7,4'trihydroxyflavylium chloride.

Molecular ion of the corresponding quinoline silyl derivative: m/e 469.

Found: C, 59.73 H, 3.96; Cl, 11.74.

C,5H1104Clrequires: C,61.98; H, 3.81; Cl, 12.20.

Preparation 7-- 3,5,7-trihydroxyflavylium chloride 240 g of (2-O-benzoyl).2,4,6-trihydroxybenzaldehyde and 178 g of omegaacetoxyacetophenone were dissolved in 3 litres of anhydrous ethyl acetate. Under agitation, HCI was bubbled in to saturation. The solution was left to stand for 24 hours and yielded 175 g of crystallised product, which was redissolved in 7 litres of methyl alcohol containing 430 ml of concentrated hydrochloric acid. The solution obtained was refluxed for 20 hours, then concentrated until crystallisation begins and left for 24 hours at 40C. The 3,5,7-trihydroxyfiavylium chloride obtained weighed 98 g.

Molecular ion of the corresponding quinoline silyl derivative: m/e 469.

Found: C, 62.31; H, 3.69; C, 11.91.

C15H11O4Cl requires: C, 61.98; H, 3.81; Cm, 12.20.

The following experimental data illustrates the pharmacological properties of representative examples of flavylium salts which may be incorporated into pharmaceutical compositions according to the invention.

( I ) Hyperlipaemia induced by olive oil Hyperlipaemia was induced in rats which had been fested for 16 hours by administering olive oil 3 hours prior to sacrifice, at a dose of 2 ml/hg orally.

The substances under test were administered either intraperitoneally (i.p.) or orally (os) one hour prior to sacrificing the rats in the experiments reported in Tables 1 to 4 and 2 hours prior to sacrificing the rats in the experiments reported in Table 5. The concentrations of non-esterified fatty acids (NEFA) and triglycerides in the blood plasma were determined for the experimental subjects and for control rats to which had been administered 0.9% sodium chloride. The results of these tests are given in the following Tables 1 to 5.

TABLE 1 Effect upon hyperlipaemia induded by olive oil in male Morini rats of mean weight 180g Number Dose of NEFA Triglycerides TREATMENT mg/kg (i.p.) animals Eq/l mg/100 ml A Controls 0.9% NaCl - 6 648.24#66.06 186.90#9.51 0.5 ml/hg B 3,4'-dihydroxyflavylium 25 6 480.15#47.16 52.63#4.58* chloride (-26.0) (-71.8) C 3-hydroxyflavylium 25 6 549.89#47.70 109.16#25.66** chloride (-15.2) (-41.6) D 3,7-dihydroxyflavylium 25 6 523.07#26.86 61.88#9.23* chloride (-20.0) (-66.9) * Significantly different (p < 0.01) from the mean obtained from group A according to Student's "t" test ** Significantly different (p < 0.05)from the mean obtained from group A according to Student's "t" test Note: In parentheses, the percentage difference from the controls.

TABLE 2 Effect upon hyperlipaemia induced by olive oil in male Morini rats of mean weight 170g Dose NEFA Triglycerides TREATMENT mg/kg (os) glEq/l mg/i 00ml A Controls 0.9% NaCI Iml/hg - 914.7#32.0 353.6#29.2 B 5,7-dihydroxyflavylium 100 696.2+24.2* 237.5+20.3* chloride (-23.9) (-32.8) * Significantly different (p < 0.01) from the mean obtained from group A according to Students "t" test.

Note: In parentheses, the percentage difference from the controls.

TABLE 3 Effect upon hyperlipaemia induced by olive oil in male Morini rats of mean weight 170g Dose NEFA Triglycerides TREATMENT mg/kg (i.p.) glEq/l mg/100ml A Controls 0.9% NaCI - 1106.3*32.9 255.6*15.2 0.5 ml/hg B 5.7-dihydroxyflavylium 25 625.5#12.5* 68.2#9.2* chloride (-43.5) (-43.5) * Significantly different (p < 0.01) from the mean obtained from group A according to Students "t" test.

Note: In parentheses, the percentage difference from the controls.

TABLE 4 Effect upon hyperlipaemia induced by olive oil in male Wistar and Morini rats of mean weight 175g Number Dose of NEFA Triglycerides TREATMENT mg/kg (i.p.)- Animals gEq/l mg/100ml A Controls 0.9% NaCI - 9 1064.4+39.6 368.35#41.6 0.5 mg/hg B Trihydroxy trimethoxy 25 25 683.2#13.5* 75.2*20.3* flavylium chloride (-35.8) (-79.6) 644RF * Significantly different (p < 0.01) from the mean obtained from group A according to Student's "t" test.

Note: In parentheses, the percentage difference from the controls.

TABLE 5 Effect upon hyperlipaemia induced by oil in male Wistar and Morini rats of mean weight 175g Dose Number of NEFA Triglycerides TREATMENT mg/kg (os) Animals Eq/l mg/100ml A Controls 0.9% NaCI - 8 1056.5+29.3 312.8+33.6 lml/hg B 5,7-dihydroxy 100 8 775.4+20.7* 123.9+11.1* flavylium chloride (-26.6) (-60.4) 628RF C Trihydroxy trimethoxy 100 9 903.8#30.0* 173.9*17.7*0 flavylium chloride (-14.5) (-44.4) 644RF * Significantly different (p. < 0.05) from the mean obtained from group A according to Student's "t" test. o Significantly different (p < 0.05) from the mean obtained from group B according to Student's "t" test.

Note: In parentheses, the percentage difference from the controls.

(2) Hyperlipaemia induced by Triton WR 1339 Hyperlipaemia was induced by intravenous administration of 225 mg/kg of Triton WR 1339 in male Sprague-Dawley and C. River rats of mean weight 200 g 8 hours prior to sacrifice. ("TRITON" is a Registered Trade Mark).

The substances under test were injected intraperitonally twice: the first administration immediately after the Triton and the second 4 hours later.

The results of the tests are given in the following Table 6.

TABLE 6 Effect upon hyperlipaemia induced by Triton WR 1339 Dose mg/kg Number of NEFA Triglycerides TREATMENT twice daily Animals Eq/l mg/100 ml A Controls 0.9% NaCl - 12 650.5*29.6 170.0*4.9 0.5 ml/hg B 5,7-dihydroxyflavylium 50 12 480.3+33.4* 163.8+5.5 chloride 628 RF (-26.2) (-3.6) C Trihydroxy trimethoxy 50 12 437.7+33.8* 141.7+3.7*b flavylium chloride (-32.7) (-16.6) 644 RF * Significantly different (p < 0.05) from the mean obtained from group A according to Students "t" test. b Significantly different (p + 0.05) from the mean obtained from group B according to Student's "t" test.

Note: In parentheses, the percentage difference from the controls.

Pharmaceutical compositions according to the invention may be prepared in accordance with the following formulations: Freeze-dried injectable solution 3,4'-dihydroxyflavylium chloride 15 mg Excipients (mannite, sodium chloride, sodium ethylene diamino tetraacetate, thiourea) q.s. to 125 mg Solvent: double-distilled water (pyrogen-free) 3 ml Capsules 3-hydroxyflavylium chloride 50 mg Excipients (mannite, citric acid, sodium chloride, thiourea, sodium ethylene diamino tetraacetate, lactose, methyl cellulose, magnesium stearate) q.s. to 200 mg Capsules 3,4'-dihydroxyflavylium chloride l00 mg Excipients (mannite, citric acid, sodium chloride, thiourea, sodium ethylene diamino tetraacetate, lactos, methyl cellulose, magnesium stearate) q.s. to 250 mg Tablets 3,4'-dihydroxyflavylium chloride 25 mg Excipients (maize starch, lactose, citric acid, magnesium stearate, thiourea, sugar, talc, gum arabic, magnesium carbonate) q.s. to 200 mg Freeze-dried injectable solution 3,7-dihydroxyflavylium chloride 25 mg Excipients (mannite, sodium chloride, sodium ethylene diamino tetraacetate, thiourea) q.s. to 125 mg Solvent: double-distilled water (pyrogen-free) 3 ml Ointment 3,5,7-trihydroxy-3 '4'5'-trimethoxyflavylium chloride 0.25 g Excipients (cetyl alcohol, saturated vegetable triglycerides, esters of polyethylene glycol 2000 with fatty acids C,2-C14, Tween 80 ("TWEEN" is a Registered Trade Mark), para-oxy benzoates, sorbitol, carboxy vinyl polymer, sodium sulphite, triethanolamine, lecithin, purified water, lactic acid) q.s. to 100 g Dentifrice gel 3 ,5,7-trihydroxy-3'4'5 '-trimethoxyflavylium chloride 0,125 g Excipients (carboxyvinyl polymer, sorbitol, propylene glycol, sodium sulphite, ethyl alcohol, para-oxy benzoates, sodium lauryl sulphate) q.s. to l00 g

Claims

WHAT WE CLAIM IS: l. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and as active ingredient a flavylium salt having the formula

wherein each Y, which may be the same or different represents -OH or -OR wherein R is an alkyl group containing 1 to 6 carbon atoms, m is 0 or an integer from l to 6 and n is 0 or an integer from l to 5, the sum of m and n being from 1 to 11 and X- is a pharmaceutically acceptable anion, with the proviso that where

represents a group of the formula

wherein (a) R' = Rt =~OH and R3= H (b) R = -OMe, R = -OH and R = H (c) R = R = R = OH (d) R = -OMe and R = R = OH (e) R = R = -OMe and R = OH or (f) R = OH and R = R = H and

represents a group of formula

wherein each of Y3, Y5 and Y7 represents a moiety Y as defined above, at least one of Y3, Y5 and Y7 is other than -OH.
2. A pharmaceutical composition according to Claim 1 wherein said flavylium salt has the formula
3. A pharmaceutical composition according to Claim 1 wherein said flavylium salt has the formula
4. A pharmaceutical composition according to Claim 1 wherein said flavylium salt has the formula
5. A pharmaceutical composition according to Claim 1 wherein said flavylium salt has the formula
6. A pharmaceutical composition according to Claim l wherein said flavylium salt has the formula
7. A pharmaceutical composition according to any one of Claims 1 to 6 in which said flavylium salt has the formula
8. A pharmaceutical composition according to any preceding claim in which said flavylium salt has the formula
9. A pharmaceutical composition according to any preceding claim in which said flavylium salt has the formula
10. A pharmaceutical composition according to any preceding claim wherein each Y is selected from H, -OH and -OMe.
11. A pharmaceutical composition according to any preceding claim in which said flavylium salt has the structure

wherein A+ is selected from
12. A pharmaceutical composition to any preceding claim in which said flavylium salt has the structure

wherein B is selected from
13. A pharmaceutical composition according to Claim 1 in which the active ingredient is a 4'-hydroxyflavylium salt.
14. A pharmaceutical composition according to Claim 1 in which the active ingredient is a 3,7-dihydroxyflavylium salt.
15. A pharmaceutical composition according to Claim 1 in which the active ingredient is a 3-hydroxyflavylium salt.
16. A pharmaceutical composition according to Claim tin which the active ingredient is a 3,4'-dihydroxyflavylium salt.
17. A pharmaceutical composition according to Claim 1 in which the active ingredient is a 3,5,7-trihydroxy-3',4',5'-trimethoxyflavylium salt.
18. A pharmaceutical composition according to Claim 1 in which the active ingredient is a 3,7,4'-trihydroxyflavylium salt.
19. A pharmaceutical composition according to Claim l in which the active ingredient is a 3,5,7-trihydroxyflavylium salt.
20. A pharmaceutical composition according to Claim 1 in which the active ingredient is a 5,7-dihydroxyflavylium salt.
21. A pharmaceutical composition according to any preceding claim wherein X- is selected from chloride, sulphate, phosphate, acetate and hydroxyl ions.
22. A composition according to any preceding claim containing a preservative or a buffering, thickening, suspending, stabilizing, wetting, emulsifying, colouring or flavouring agent.
23. A composition according to any preceding claim containing an excipient selected from carboxy vinyl polymers, propylene glycol, ethyl alcohol, water, cetyl alcohol, saturated vegetable triglycerides, fatty acid esters, propylene glycol, triethanolamine, glycerol, starch, sorbitol, bentonite, carboxymethyl cellulose, laurylsulphate, dicalcium phosphate, powdered silica and lecithin.
24. A composition according to any preceding claim comprising at least two excipients.
25. A composition according to any preceding claim containing more than one flavylium salt of formula I.
26. A composition according to any preceding claim in a form suitable for parenteral administration.
27. A composition according to any one of Claims l to 25 in a form suitable for oral administration.
28. A composition according to any one of Claims 1 to 25 in the form of a suppository.
29. A composition according to any one of Claims 1 to 25 in the form suitable for topical administration.
30. A composition according to any one of Claims l to 25 in the form of a dentifrice.
31. A composition according to any one of Claims 1 to 25 in the form of a
32. A composition according to any preceding claim containing at least 0.2 wt% of said flavylium salt.
33. A composition according to Claim 32 containing from 1 to 50 wt% of said flavylium salt.
34. A composition according to Claim 33 containing at least 5 wt% of said flavylium salt.
35. A method of elliciting a cicatrising, epithelium-regenerating, antiinflammatory, vaso-protective, hypolipaemic, hypocholesterolaemic or hypoglycaemic response in a non-human animal, which comprises administering to the subject an effective dose of a flavylium salt of formula I as defined in any of Claims l to 21.
36. A method according to Claim 35 in which the flavylium salt is administered in the form of a composition as claimed in any one of Claims l to 36.
37. A method according to Claim 35 or Claim 36 in which the flavylium salt is administered as a treatment of wounds, gastric and duodenal ulcers, inflammatory conditions of the mouth and throat, pathogenic conditions of the vascular system or disorders caused by impairment of lipidic or glycidic metabolism.
38. A method according to any one of Claims 35 to 37 in which said effective dose is from l to 100 mg/kg per day of said flavylium salt.
39. A method according to Claim 38 in which said effective daily dose is from 5 to 50 mg/kg per day of said flavylium salt.
40. A composition according to Claim l and substantially as hereinbefore described and exemplified.