WO2006022536A1

WO2006022536A1 - New medical use of the meldonium

Info

Publication number: WO2006022536A1
Application number: PCT/LV2005/000010
Authority: WO
Inventors: Ivars Kalvins; Anatolijs Birmans
Original assignee: Joint Stock Company 'grindeks'
Priority date: 2004-08-24
Filing date: 2005-08-23
Publication date: 2006-03-02
Also published as: LV13450B

Abstract

Second medical use of Meldonium is disclosed for treating of skin and subcutaneous tissue lesions and treatment of skin irritation as well as topical compositions containing Meldonium. Topical pharmaceutical compositions of Meldonium were shown to substantially improve the healing of wounds, prevent skin irritation of allergic and other origin. Thus said compositions are useful for treating and prevention of skin and subcutaneous tissue lesions and skin irritation of various origin.

Description

NEW MEDICAL USE OF THE MELDONIUM

TECHNICAL FIELD

The invention relates to second medical use of 3-(2,2,2-trimethylhydrazinium)propionate for treatment of tissue lesions and associated skin irritation and compositions therefore.

BACKGROUND OF THE INVENTION

The healing of tissue lesions is a rather complicated process, usually involving an associated skin irritation, and its facilitation as a rule is a demanding task. Usually healing is facilitated by various pharmaceutical compositions, mostly providing for aseptic conditions of wound. Various ointments, gels, creams etc. containing antibacterial agents (antibiotics, silver etc.) are used for this purpose. These compositions shorten the healing time of infected wounds but do not affect or even impede the healing of non-infected wounds. Another deficiency (weak point) of such agents and their compositions is their toxicity since the topical/local application on large areas leads to absorption of large quantities of antibiotics through the impaired body surface. The tissue lesion is typically surrounded by inflamed area which is not healed by antibacterial preparations.

Topical preparations are known for facilitation of wound healing based on stimulating certain metabolic processes. These preparations comprise active agents, such as 6-methyluracil, 6-hydroxymethyluracil (pentoxyl), and dexpanthenol (INN) (+2,4-dihydroxy-N-(3- hydroxypropyl)-3,3-dimethylbutyramide) or solcoseryl . The action of dexpanthenol is based on formation of panthothenic acid in the body, which facilitates mitosis of cells and increases the strength of collagen fibres, thus stimulating the healing of wounds. The shortcoming of this agent is its low solubility in physiological fluids, therefore the benefit from dexpanthenol is questionable in cases where a profusion of exudates is present (DE 531260). The same shortcoming relates to derivatives of uracil, where the topical formulations use non-aqueous vehicle. The impediment of exudate escape by water-insoluble ointments or other topical formulations favour the growth of microbial flora in the wound. Besides that the uracil derivatives bring about dyspeptic disorders. In order to at least partially overcome said problems technologically complex formulations are proposed which combine water-insoluble agents with cyclodextrine and/or cellulose derivatives to provide water-dispersible forms that can be mixed with water soluble vehicles for ointments or gels (RU 2155586 C 2, RU 2149007 Cl). Such approach considerably complicates the technological process of manufacturing local/topical formulations and causes considerable problems in standardization and securing stability thereof.

The known Solcoseril ointment, produced from deproteinized calf serum, is a potential source of risk due to possible infection with Kreuzfeld- Jacob disease.

Therefor the aim of this invention was to provide for an agent to treat tissue lesions characterized by low toxicity and good water-solubility, safety at use on large tissue lesion/skin/wound areas, preventing irritation of allergic or other origin, and last but not least, characterized by easily preparable and stable formulations, compatible with different components of ointment vehicles, antibacterial agents and other components of wound-healing therapy.

This aim was surprisingly solved by using as the active agent the known substance Meldonium.

Meldonium as dihydrate is well-known substance that regulates carnitine and gamma- butyrobetaine balance in the body thus influencing the beta-oxydation rate of fatty acids (Dambrova M., Liepinsh K, Kalvinsh I. Mildronate: cardioprotective action through carnitine- lowering effect.. Review. // Trends Cardiovasc.Med. - 2002. - Vol. 12, N.6. - P. 275-279.Rupp K, Zarain-Herzberg A, Maisch B. The use of partial Fatty Acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure // Herz, 2002. - Vol. 27, N.7. - P. 621-636. Mildronate, Met-88. Drugs Fut. 2001, 26(1), p.82).

Due to these properties meldonium (marketed as MILDRONATS ^®, MILDRONATE^® and MHJlβPOHAT^®") is widely used as anti-ischemic and stress-protective agent in therapy of various cardiovascular impairments and other pathologies, involving tissue ischemia (R.S.Karρov, O.A.Koshelskaya, A.V.Vrublevsky, A.A.Sokolov, A.T.Teplyakov, I.Skarda, V.Dzerve, D.Klintsare, A.Vitols, I.Kalvinsh, L.Matveyeva, D.Urbane. Clinical efficacy and safety of Mildronate in patients with ischemic heart disease and chronic heart failure. Kardiologiya, 2000 , Vol.6, P.69-74.). Since the molecule of Meldonium contains trimethylammonium group it can be expected that this substance will have low skin-absorbatioπ rate.

We have surprisingly found out that Meldonium, when applied topically, significantly stimulated the healing of tissue lesions as well as attenuated skin irritation of allergic or other origin such as neurodermal rash or skin lesions.

DETAILED DESCRIPTION OF THE INVENTION

Our discovery that topical pharmaceutical compositions of Meldonium stimulate the healing processes of tissue lesions and do not cause, but quite contrary, alleviate skin irritation of allergic or other origin, is surprising, since it can not be explained by the action of Meldonium on cardiovascular system which is based on lowering the tissue carnitine level.

We have discovered that Meldonium in forms of ointment, creme, gel, emulsion, lotion, foam aerosol or solution stimulates the healing process of tissue lesions what was demonstrated experimentally and definable by the following wound characteristics specific for progress in tissue lesions healing:

-diminishing of the absolute size of wound,

-shortening of the wound-healing time,

-daily diminishing of the wound area,

-increase of the regeneration index,

-increase of regeneration regression index,

-complete wound healing time,

-connective tissue maturation process.

Thus we have successfully demonstrated that topical compositions of Meldonium significantly increase the healing rate of tissue lesions and normalize the healing process by improving the maturation of connective tissue and improving the externals of the healed tissue lesions.

It is especially true for healing of complicated tissue lesions, i.e., caused by chemical bums, thermal burns, burns of mixed origin, deep wounds etc.

Meldonium can be applied as various pharmaceutical compositions. The weight concentration of Meldonium in said compositions ranges from 0.5 to 40%, preferably from 10 to 12% of the weight of an ointment, creme, gel, emulsion, oil, liniment, milk, lotion, foam aerosol or solution base, made of suitable and pharmaceutically acceptable ingredients. The compositions are adjusted to have their pH in the range of 4 to 8.

If required for said compositions can be augmented by other components, such as enzymes, dermatological agents, insect repellents, flavourings, colorants and/or aromatic oils. Examples

The following pharmaceutical composition (hereinafter "PC") illustrates but in no way limits the invention:

Table 1

The effect of Meldonium gel on ulcer healing of the tissue lesions. Experiments were performed on 80 male Wistar rats (body weight 185 - 210 g). The animals were kept in concordance with GLP and received normalized standard fodder (Mackta J. Inspecting the Process: A Collaborative Approach to Improving Animal Care, Lab. Animal 2000, 29, 10, 32-34).

Aseptic tissue lesion was initiated by subcutaneous injection under light ether narcosis of 0.5 ml 9% acetic acid solution in the right foreshoulder. At the same time a dose of 300 mg/kg of 6% dextran was injected into the abdominal cavity, which promoted the inflammation process by histamine liberation.

The development of ulcer at the injection site started on the 2 or 3 day. On the 4 day almost all animals had developed an ulcer. 50 animals with similarly developed ulcers were selected. The ulcers were surrounded by local irritation area.

The treatment of animals with Meldonium was initiated on day 4 by topical application of the gel at the predetermined time twice daily. The treatment was conducted for 25 days. The animals were divided into 5 groups of 10 animals each as follows:

Group I - control group - natural healing of ulcer;

Group II - experimental, ulcer treated with Meldonium gel vehicle;

Group III - experimental, ulcer treated with 10% Meldonium gel;

Group IV - experimental, ulcer treated with 5% Meldonium gel;

Group V - experimental, ulcer treated with 2.5% Meldonium gel;

Every 4^th day the experimental and control group animals were visually inspected to evaluate the healing rate of ulcers - the externals of ulcer, painfulness of ulcer area, formation of crust and separation rate thereof, skin temperature, the presence of any local/topical skin irritation of allergic or other origin. The painfulness was evaluated by slightly touching skin in the ulcer area by wooden pick.

The healing rate (V) of ulcer was calculated according to the following formula:

So - S t

V= 100 x

So

where So is the ulcer size before treatment (mm²); St is the ulcer size on the day of measurement (mm²). The regeneration course was characterized by increased epithelization which was characterized by two indices: regeneration index (R_koef) and regeneration regression (R_rCg) index:

So

Rkoef S t;

regeneration index in experiment;

Rreg regeneration index in controls

After 12 days 3 animals of each group were decapitated under light ether narcosis and. a piece of skin from the ulcer area removed surgically.

The ulcer healing process for all groups was evaluated at day 24. Research data show that various agents, ointments, gels etc. can provide for better healing conditions of ulcers, while the healing itself is rather difficult to stimulate (Wounds and wound infection /Edit. Kuzina Mi., Kostyuchenok B.M./ «Medicina», 1990, 532 p.).

There was a significant difference in ulcer healing rate between the control and experimental groups, treated with Meldonium gel. Pharmaceutical compositions, containing various amount of Meldonium significantly increased the healing rate of tissue lesion (Tables 2 and 3).

Table 2 The effect of Meldonium gel on experimental skin ulcer reparative process

*P<0.05

During experiment the healing of ulcers in groups I and II was encumbered by areas of skin irritation surrounding the ulcers of allergic and other origin, while in experimental groups the irritation areas were observed in 3, 2 or zero cases, accordingly, in groups V, IV and III. If the irritated area was treated with 10% Meldonium gel, the irritation disappeared within 1-2 days. Table 3

Morphological examination of skin specimens after 24 day long treatment of experimental ulcers with Meldonium gel

*P<0.05

Note:

+ - morphological feature of low intensity; ++ - medium intensity;+++ - high intensity;

0- feature not present

The animals in experimental groups compared to controls had a less pronounced painfulness of ulcer area which was characterized by a calmer reaction to touching of skin in ulcer area and lower skin sensitivity.

The results of morphological examination of skin specimens obtained after the day 24 arc presented in Table 3. The morphological evidence significant differences between the experimental groups in the proceess of maturation of the newly-formed connective tissue. For groups I and II (control or gel vehicle) under the multilayered squamous epithelium the newly- formed connective tissue is rich with new cells - polyblasts and fibroblasts, while there are very few fibrocites in the matured cells. In the treatment groups a spectacular maturing of connective tissue is observed, in the hystological sections of the newly-formed cells fibrocites are predominant, especially in group III (10% Meldonium gel). All groups, except the group treated with 10% Meldonium gel, display slight oedema.

Thus we have discovered that Meldonium in topical pharmaceutical compositions stimulates improved tissue lesion/wound healing process (including ulcers) comparing with control group and group treated with gel vehicle.

The results obtained in the experiment also showed that topical use of Meldonium not toxic.

Meldonium can be used in pharmaceutical compositions developed both on lipid-soluble and water-soluble base. The water soluble compositions proved to be more advantageous for treating tissue lesions. Good therapeutic effect was obtained also by foam formulations. We have discovered that Meldonium can be efficiently used also in solid compositions which swell and form gel after absorbing the exudates. Such compositions are, e.g., carboxymethylcelluiose products - dressing, powder, wound dressing materials. Particularly advantageous are materials absorbable in biological media, for example, those used for producing absorbable surgical sutures.

The topical Meldonium formulations can be used for treating of skin and external tissue lesion of different origin, including, but not limited to, neurodermal, fungal, thermal, chemical, sweat ulcers, allergic skin lesions, surgical and traumatic wounds, trophic ulcers and other lesions of skin and tissues. In such cases the topical Meldonium composition can be added a suitable antibacterial or antibiotic agent for combating the aerobic and/or anaerobic microbial flora or combinations thereof to improve the healing of infected wounds, like sulfargin, iodine etc. To further improve the therapeutic efficiency of topical Meldonium formulations they can be combined in specific cases with known stimulants of tissue lesion/wound healing, such as methyluracil or panthenol or combinations thereof. Topical Meldonium formulations (0,5%-40%) for treating of tissue lesions and/or irritation of allergic or other origin can be added other active agent (0,001%-15%): non-steroidal anti-inflammation agents, e.g., arylpropionic acid derivatives, including but not limited to, ketoprophene, ibuprophene, naproxene, flurbiprophene, alminoprophene, tiaprophenic acid etc;. steroidal anti-inflammation agents e.g.,- prednisone, prednisolone, methylprednisone, etc; local anaesthetics e.g., lovocaine, lidocaine, aspirin, ibuprofen, novocaine , fenoprofen, ketoprofen, floktafenin, noramidopirin, etc.; enzymatic agents (for refine of the wounds) e.g., heparin, trypsin, papain etc.; imidazole containing anti-fungucide agents e.g., mikonazole, ketoconazole, flukonazole, flucitozine etc.; antibiotics of the beta-lactam group, viz. Penicillin, cephalosporins, carbapenems, carbacephens, monobactams; macrolide antibiotic group: Erythromycin, Azithromycin, Oleandomycin, Josamycin, Spiramycin, and Roxithromycin; tetracycline antibiotic group: Oxytetracyciline, Morphocycline e.a.; aminoglycoside group: Streptomycin, Neomycin, Gentamycin, Kanamycin, Sisomycin, Spiramycin, Trobamycin, e.a.; Chloramphenicol or Levomycetin group: Levomycetin e.a.; cyclic polypeptide or Polymyxin group: Capreomycin e.a.; Lincosamide group: Clindamycin and Lincomycin, e.a.; Rifamycin group: Rifampicin e.a,, glycopeptide group: Vancomycin e.a.; Streptogramine group: Pristinamycin e.a.; sulfonylamide group: e.g., Sulfadiazine; polyene antifungal agents, e.g., Amphotericin B, Nystatin e.a.; antiviral agents taken from the group including Zidovudine, Acyclovir; drugs of Adamantane series, e.g. Rimantadine, Amantadine, and Moroxydine e.g.; natural tissue lesions, anti-inflammatory or anti-infections preparations e.g., , extracts of a shore drugsquill; ripplessedplantain; common licorice; true aloe; fruits of a oat; roots of a marshmallow; fruits of a anise; flowers of a army-worm; flowers of a potmarigolg calendula; flowers of camomile; seeds of a common flax; blades of a beaberry; top of a common yarrow; pinebud; top of a common ladysmantel; blades of a garden sage; spores of a club-moss; seeds of a comfrey; extracls of the natural anaesthetic preparations e.g., stems of a hop, rootstock of a common valerian, blades of a belladonna, blades of a black henbane, birch fungus (black), flowers of camomile, opium, blades of a peppermint, top of a common rue, fruits of a sea buckthorn, top of a celandine, blades of a jimsonweed datura etc.; extracts of the natural anti-microbe and/or anti-parasite preparations e.g., , flowers of a chamisso arnica, top of a commons St. Johnswort, flowers of a common tansy, blades of the eucalyptus, top of a lichen (Island), top and flowers of camomile, yellow coltsfoot, flowers of linden, fruits of a juniper, buds of a pine, top of a common sundew, top of a silverweed cinquefoil; haemostatic drugs: alum, ferrous chloride, multiminerals, tannins, trichloroacetic acid; adrenornimetic vasoconstrictors: Adrenaline and metazolines; the nonnarcotic analgesic drug Antipyrine; vitamins: A, Bl, B2, B3, B5,B6, B8, Bc, BT, B12, C, D, D2, D-3, D-hormone, E, K, Kl, K3, P, P3, P4, PP,U; antihistamine agents, e.g. H₁ blockers of the ethanolamine group, e.g. Clemastine e.a., medicines of the ethylenediamine group, e.g. Mepyramine e.g., medications of the alkylamine group, e.g. Chlorpheniramine e.g., those of the piperazine group, e.g., Meclozine e.g., those of the phenothiazine group, e.g. Promethazine e.g. or H₂ blockers, e.g., Cimetidine, Ranitidine, Nizatidine e.a. ;

Enzyme e.g., vobenzym, flagoenzym, different co-enzymes etc.; pharmaceutical products from calcium; karbazochrom; products produced by the bee (-s) e.g., bee glue, propolis etc.;

Pharmaceutical compositions for the production of gel according to this invention are exemplified but not limited to the following: Meldonium gel compositions:

Table 4

If the wound to be treated was infected by microorganisms, sensitive to chloramphenicol, sulfadiazine silver salt, chinifuryl or propolis, the addition of the named antibacterial agents to the topical compositions of Meldonium further increased their efficiency for about 10%. Additional positive effect on healing of wounds with topical Meldonium formulations on day 24 was evidenced for addition of dexpanthenol or methyluracil. In both cases the efficiency of the combined preparations was increased by 7-8% compared to dexpanthenol or methyluracii control groups and for 6-7% compared with results in the plain Meldonium control group. Table 5

Pharmaceutical compositions which besides Meldonium contained some local anesthetic, non-steroidal anti-inflammatory agent or coenzyme increased the efficiency of the Meldonium gels in treating of infected wounds for average of 9%.

The experimental data show that topical pharmaceutical formulations of Meldonium are not toxic.

Meldonium emulsion, creme, solution, oil, ointment, liniment, pasta, gel, lotion, milk, suspension, powder or foam aerosol, as well as compositions including some other active agent, are prepared by generally known methods.

Claims

1. Use the Meldonium for manufacture of topical acting medicaments for treating and/or preventing tissue lesions of skin and subcutaneous tissue.

2. Use the Meldonium for manufacture of topical acting medicaments for treating and/or preventing topical skin irritation.

3. A topical pharmaceutical composition for treating and preventing lesions of skin and subcutaneous tissue and/or topical skin irritation containing as the active ingredient Meldonium together with topically acceptable pharmaceutical excipients.

4. A topical pharmaceutical composition for treating and preventing lesions of skin and subcutaneous tissue and/or topical/local skin irritation containing as the active ingredient Meldonium together with topically acceptable pharmaceutical excipients characterized in that it further contains at least one but no more than three other active agents selected from the group containing natural and synthetic steroid and non-steroid anti-inflammatory agents, analgesics and anaesthetics, antifungal medicines, antibiotics, antivirals, antihistamine drugs, enzyms, co-enzyms, dermatological drugs, medicines for treating tissue lesions, bees' products,

5. The pharmaceutical composition of claim 3 or 4, characterized in that the amount of Meldonium in the composition is between 0.1% and 40% by weight, preferably between 2.5% and 12% by weight.

6. The pharmaceutical composition of claim 3 or 4, characterized in that the excipients are suitable for preparation of therapeutic and/or prophylactic emulsion, creme, solution, oil, ointment, liniment, paste, gel, lotion, milk, suspension, powder, foam aerosol, cotton or dressing material.

7. Composition of claim 3. or 4 characterized in that the pH thereof is between 4 and 8.

8. Composition of claim 4 characterized in that the other active agent is chloramphenicol,

9. Composition of claim 4 characterized in that the other active agent is dexpanthenol,

10. Composition of claim 4 characterized in that the other active agent is mcthyluracil,

11. Composition of claim 4 characterized in that the other active agent is prednisoϊone,

12. Composition of claim 4 characterized in that the other active agent is sulfadiazine silver salt

13. Composition of claim 4 characterized in that the other active agent is lidocaine

14. Composition of claim 4 characterized in that the other active agent is chinifuryi

15. Composition of claim 4 characterized in that the other active agent is propolis

16. Composition of claim 4 characterized in that the other active agent is ketoprolen

17. Composition of claim 3 or 4, characterized in that as the pharmaceutical excipients hydrophilic excipients are used.

18. Composition of claim 3 or 4, characterized in that as the pharmaceutical excipients hydrophobic excipients are used.

19. Composition of claim 3 or 4, characterized in that as the pharmaceutical excipients excipients a combination of hydrophilic and hydrophobic excipients is used.

20. Composition of claim 3. or 4 characterized in that it is emulsion, creme, solution, oil, ointment, liniment, paste, gel, lotion, milk, suspension, powder, foam aerosol, cotton or wound dressing material.