Medicament for the treatment of viral skin and tumour diseases

Abstract

The invention relates to a medicament containing a compound of general formula (I), where R.sub.1=independently, a straight or branched, saturated, singly- or multiply-unsaturated, optionally substituted C.sub.11-C.sub.21 alkyl, alkylene or alkinyl group, preferably a C.sub.11-C.sub.15 alkyl, alkylene or alkinyl group, particularly a C.sub.11-C.sub.13 alkyl, alkylene or alkinyl group, most preferably a C.sub.13 alkyl group, R.sub.2=independently, a straight or branched C.sub.1-C.sub.8 alkyl, alkylene or alkinyl group, preferably a C.sub.1-C.sub.6 alkyl, alkylene or alkinyl group, in particular a C.sub.2-C.sub.4 alkyl, alkylene or alkinyl group, most preferably a C.sub.3 alkyl group, a —[CH.sub.2—(CH.sub.2)m-O].sub.nH group with n=1 to 10, preferably n=1 to 5, to m=1 to 5, preferably m=1 to 3, a —CH.sub.2—[CH—(OH)].sub.p[CH.sub.2—R.sub.3]- group, where R.sub.3=independently H or OH, p=1 to 7, preferably p=1 to 4, a pentose group or a hexose group, as therapeutically active agent, alone or in combination with one or several further pharmaceutical agents as a combination preparation for the treatment of viral skin diseases and/or tumor diseases, in particular caused by human papilloma virus (HPV) and/or herpes viruses and a topically acting medicament formulation and the use thereof.

Claims

1. A pharmaceutical composition comprising: (i) a compound having the formula
A-B  (I), wherein A is a radical having the formula ##STR00005## and wherein B is a radical having the formula —O—R.sub.2 (III), and wherein R.sub.1 is, independent of each other, an unbranched or branched, saturated, singly or multiply unsaturated, optionally substituted C.sub.13-C.sub.21 alkyl, alkylene, or alkynyl radical, and R.sub.2 is, independent of each other, an unbranched or branched C.sub.1-C.sub.8 alkyl, alkylene, or alkynyl radical; and (ii) a mixture of catechols comprising 2-20% (w/w) of (−)-epicatechol, 2-20% (w/w) of (−)-epicatechol gallate, 1-25% (w/w) of (−)-epigallocatechol, 40-75% (w/w) of (−) -epigallocatechol gallate, 0.05-5% (w/w) of (−)-gallocatechol, and 0.5-20% (w/w) of (−)-gallocatechol gallate; and wherein the pharmaceutical comprises at least 5-50% (w/w) of the compound of formula (I).

2. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises 1-30% (w/w) of said mixture of catechols and at least 10-50% (w/w) of said compound of formula (I).

3. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition comprises 2-20% (w/w) of said mixture of catechols.

4. The pharmaceutical composition of claim 3, wherein said pharmaceutical composition comprises 15-18% (w/w) of said mixture of catechols.

5. The pharmaceutical composition of claim 2, wherein said pharmaceutical composition comprises at least 25-50% (w/w) of said compound of formula (I).

6. The pharmaceutical composition of claim 5, wherein said pharmaceutical composition comprises at least 35-50% (w/w) of said compound of formula (I).

7. The pharmaceutical composition of claim 1, wherein said mixture of catechols comprises 5-7% (w/w) of said (−)-epicatechol gallate.

8. The pharmaceutical composition of claim 1, wherein said mixture of catechols comprises 0.1-0.6% (w/w) of said (−)-gallocatechol.

9. The pharmaceutical composition of claim 1, wherein said mixture of catechols comprises 1-5% (w/w) of said (−)-gallocatechol gallate.

10. The pharmaceutical composition of claim 1, wherein said mixture of catechols comprises 10.8% (w/w) of (−)-epicatechol, 6.5% (w/w) of (−)-epicatechol gallate, 9.2% (w/w) of (−)-epigallocatechol, 54.8% (w/w) of (−)-epigallocatechol gallate, and/or 4.0% (w/w) of (−)-gallocatechol gallate.

11. The pharmaceutical composition of claim 1, wherein said pharmaceutical composition comprises at least 10-50% (w/w) of said compound of formula (I).

12. The pharmaceutical composition of claim 11, wherein said pharmaceutical composition comprises at least 25-50% (w/w) of said compound of formula (I).

13. The pharmaceutical composition of claim 12, wherein said pharmaceutical composition comprises at least 35-50% (w/w) of said compound of formula (I).

14. The pharmaceutical composition of claim 1, wherein said catechols are isolated from a tea extract.

15. The pharmaceutical composition of claim 1, wherein one or more additional pharmaceutical compound(s) is/are administered simultaneously or separately.

16. The pharmaceutical composition of claim 15, wherein said one or more additional pharmaceutical compound(s) is/are amphiphilic.

17. The pharmaceutical composition of claim 1, further comprising additives and/or auxiliary substances.

18. The pharmaceutical composition of claim 17, wherein said additives and/or auxiliary substances are hydrophobic and are selected from the group consisting of petroleum jelly, wax, oleyl alcohol, propylene glycol monostearate, and propylene glycol monopalmitostearate.

19. A pharmaceutical composition comprising 35% (w/w) of a compound having the formula
A-B  (I), wherein A is a radical having the formula ##STR00006## and wherein B is a radical having the formula —O—R.sub.2 (III), and wherein R.sub.1 is, independent of each other, an unbranched or branched, saturated, singly or multiply unsaturated, optionally substituted C.sub.13-C.sub.21 alkyl, alkylene, or alkynyl radical, and R.sub.2 is, independent of each other, an unbranched or branched C.sub.1-C.sub.8 alkyl, alkylene, or alkynyl radical; and wherein said pharmaceutical composition further comprises 15% (w/w) of a mixture of catechols comprising 2-20% (w/w) of (−)-epicatechol, 2-20% (w/w) of (−)-epicatechol gallate, 1-25% (w/w) of (−)-epigallocatechol, 40-75% (w/w) of (−)-epigallocatechol gallate, 0.05-5% (w/w) of (−)-gallocatechol, and 0.5-20% (w/w) of (−)-gallocatechol gallate, 24.5% (w/w) of petroleum jelly, 20% (w/w) of wax, 5% (w/w) of propylene glycol monostearate or propylene glycol monopalmitostearate, and 0.5% (w/w) of oleyl alcohol.

20. A method of treating a papilloma virus-induced skin disease or papilloma virus-induced benign tumor disease in a patient, said method comprising administering to a patient a pharmaceutical composition of claim 1.

21. The method of claim 20, wherein said papilloma virus-induced skin disease or benign tumor disease is caused by HPV 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19-29, 31, 32, 34, 36-38, 46-50, 56, or 58.

22. The method of claim 20, wherein said papilloma virus-induced skin diseases are warts or genital warts and the papilloma virus-induced benign tumors are of the skin and/or mucosa.

23. The method of claim 22, wherein said papilloma virus-induced benign tumors of the skin and/or mucosa are verrucae plantares, verrucae vulgares, verrucae planae juveniles, epidermodysplasia verruciformis, Condylomata acuminata, Condylomata plana, bowenoid papulosis, papillomas on the larynx and oral mucosa, or focal epithelial hyperplasia.

24. The method of claim 20, wherein said pharmaceutical composition is applied topically.

25. The method of claim 24, wherein said pharmaceutical composition is applied genitally or vaginally.

26. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is isopropyl myristate.

27. The pharmaceutical composition of claim 1, wherein said mixture of catechols comprises 4-15% (w/w) of (−)-epicatechol, 2-20% (w/w) of (−)-epicatechol gallate, 3-15% (w/w) of (−)-epigallocatechol, 40-75% (w/w) of (−)-epigallocatechol gallate, 0.1-1% (w/w) of (−)-gallocatechol, and 1-10% (w/w) of (−)-gallocatechol gallate.

28. The pharmaceutical composition claim 19, wherein said mixture of catechols comprises 1, 4-15% (w/w) of (−)-epicatechol, 2-20% (w/w) of (−)-epicatechol gallate, 3-15% (w/w) of (−)-epigallocatechol, 40-75% (w/w) of (−)-epigallocatechol gallate, 0.1-1% (w/w) of (−)-gallocatechol, and 1-10% (w/w) of (−)-gallocatechol gallate.

Description

EXAMPLES

(1) Clinical Study for Comparing an Ointment and a Cream Containing Isopropyl Myristate

(2) 93 patients (in each case divided equally into men and women) took part in a multicenter clinical study which was carried out at a total of 30 different centers in Germany and Russia. The study was randomized and performed double-blind. The study examined the clinical efficacy of two different formulations of isopropyl myristate (an ointment and a cream) in the treatment of external genital warts.

(3) The formulations which were tested had the following compositions:

(4) Cream 1:

(5) TABLE-US-00001 Substance Quantity (in % w/w) Cera alba 6.996 Monomuls 2.798 Lameform TGI 5.598 Cetiol V 6.996 Isopropyl myristate 13.992 Tocopherol 0.699 Controx KS 0.066 Glycerol 6.996 Disodium EDTA 0.001 Magnesium sulfate 1.399 D-Panthenol 0.699 Purified water 53.678 Red Iron Oxide* 0.025 Yellow Iron Oxide* 0.054 *The dyes were added for matching as regards color.

(6) Ointment 1:

(7) TABLE-US-00002 Substance Quantity (in % w/w) White Petrolatum, USP 34.023 White Wax, NF 25.000 Isopropyl Myristate, NF 35.000 Oleyl Alcohol, NF 0.500 Propylene Glycol 5.000 Monostearate, NF Red Iron Oxide* 0.022 Yellow Iron Oxide* 0.055 Titanium Dioxide, USP* 0.400 *The dyes were added for matching as regards color.

(8) The patients applied the topical study medication three times daily or until the genital warts had completely healed or for a maximum of twelve weeks.

(9) The following data were collected during the study:

(10) Complete Healing (in %)

(11) TABLE-US-00003 Cream 1 Ointment 1 Male 39.1 42.1 Female 35.0 33.3

(12) Partial healing (in %); this corresponds to at least 75% healing based on the total area of the genital warts.

(13) TABLE-US-00004 Cream 1 Ointment 1 Male 43.5 63.2 Female 50.0 52.4

(14) The results of the study show that a surprisingly high degree of complete healing, or partial healing, takes place as compared with the placebo values from similar studies using different formulations, in association with which the spontaneous regression of genital warts is approx. 20% in the case of women and approx. 5% in the case of men (Aldara™ (Imiquimod) Cream, 5% Product Monograph, marketed by 3M Pharmaceuticals, Northridge, Calif., Beutner K R et al. (1998) J Am Acad Dermatol 38, 230-9, Edwards L et al. (1998) Arch Dermatol 134 (1); 25-30).

(15) This therapeutic effect is attributed to the isopropyl myristate, an antiviral effect of which has consequently been demonstrated for the first time.

(16) Clinical Study for Comparing an Ointment and a Cream Containing Isopropyl Myristate and Polyphenon® E

(17) 272 patients (equally divided between men and women in each case) took part in a multicenter clinical study which was carried out at a total of 30 different centers in Germany and Russia. The study was randomized and performed double-blind. The study examined the clinical efficacy of two different formulations of isopropyl myristate and Polyphenon® E (an ointment and a cream), as against the formulations from Example 1 containing isopropyl myristate, in the treatment of external genital warts.

(18) The Polyphenon® E-containing formulations which were tested had the following compositions:

(19) Cream 2:

(20) TABLE-US-00005 Substance Quantity (in % w/w) Polyphenon ® E 10.000 Cera alba 5.263 Monomuls 2.105 Lameform TGI 4.211 Cetiol V 5.263 Isopropyl myristate 10.526 Tocopherol 0.526 Controx KS 0.050 Glycerol 5.263 Disodium EDTA 0.001 Magnesium sulfate 1.053 D-Panthenol 0.526 Purified water 55.213

(21) Ointment 2:

(22) TABLE-US-00006 Substance Quantity (in % w/w) Polyphenon ® E 15.000 White Petrolatum, USP 24.500 White Wax, NF 20.000 Isopropyl Myristate, NF 35.000 Oleyl Alcohol, NF 0.500 Propylene Glycol 5.000 Monostearate, NF

(23) The patients applied the topical study medication three times daily or until the genital warts had completely healed or for a maximum of twelve weeks.

(24) During the study, the following data were collected:

(25) Complete Healing (in %)

(26) TABLE-US-00007 Cream 1 Cream 2 Ointment 1 Ointment 2 Male 39.1 53.9 42.1 61.0 Female 35.0 39.5 33.3 56.8

(27) Partial healing (≧75% in %)

(28) TABLE-US-00008 Cream 1 Cream 2 Ointment 1 Ointment 2 Male 43.5 64.2 63.2 80.5 Female 50.0 47.4 52.4 81.1

(29) Analysis of the study shows that, when comparing ointment 1 and cream 1, on the one hand, and ointment 2 and cream 2, on the other hand, the combination of isopropyl myristate and Polyphenon® E leads to a surprising increase in the efficacy of the pharmaceutical.

(30) If the efficacy of ointment 2 is now compared with that of cream 2, it then becomes evident that ointment 2 is markedly more effective than cream 2. This suggests a synergistic effect between the Polyphenon® E and the isopropyl myristate in the hydrophobic ointment.

(31) As a result of this synergistic effect, the individual active compounds in the formulation can, in order to achieve the same effect, be employed in substantially smaller quantities than the corresponding individual components. Consequently, the use of this synergistic formulation has advantages not only with regard to the effect but also with regard to the cost of preparing this formulation, something which in turn can have a positive effect on the cost of treating the patient.