WO1993014773A1

WO1993014773A1 - Pharmaceutic composition and its use

Info

Publication number: WO1993014773A1
Application number: PCT/SE1993/000033
Authority: WO
Inventors: Rune SÖREMARK
Original assignee: Individual
Current assignee: Individual
Priority date: 1992-01-24
Filing date: 1993-01-21
Publication date: 1993-08-05
Anticipated expiration: 1994-07-24
Also published as: AU3465393A; SE9200199D0; SE9200199L

Abstract

The present invention relates to a pharmaceutical composition, e.g. an ointment, a cream or a paste, which can be used to treat superficial skin and mucous membrane affections. The composition is a mixture, which comprises, in percent by weight: 5-60% ZnO; 10-70% of one or several of the substances, which belong to one or several of the groups disaccharides, monosaccharides and glycosides; and 3-30% vitamin E; the rest being mainly only pharmaceutically acceptable vehicles.

Description

Pharmaceutic Composition and Its Use.

The present invention relates to a pharmaceutical composi¬ tion, e.g. an ointment, a cream or a paste, which can be used to treat superficial skin and mucous membrane affec¬ tions. The invention also relates to the use of this compo- sition to produce a pharmaceutical preparation designed to treat such superficial affections. This preparation may be used to treat human beings as well as animals.

BACKGROUND ART It has been known for a long time, that zinc oxide has a po¬ sitive effect on the healing of sores. In vitro-examinations have shown, that zinc oxide has a beneficial antimicrobial effect, is astringent and locally protective as well as an¬ tiphlogistic and antipruritic. Zinc oxide is used today in various ointments, pastes and creams in order to treat skin lesions. SE 451 669 relates to the use of zinc oxide in dressings in order to clean sores and stimulate their hea¬ ling, the zinc oxide in the dressing being bound by means of a tissue-compatible polymer.

It has also been reported, that certain types of sugar, i.a. saccharose, ^ci₂ ^H ₂₂°_ll ' ^^{as a} P^osi^'ti^ve effect on sore hea^¬ ling. Much research is needed regarding the underlying cau¬ ses, but it is true that sugar is able to bind bacteria and virus. An environment with a low water activity in the sore is obtained, which can stop or reduce the bacterial growth. Adding sugar to an infected sore probably gives the bateria an osmotic shock. Also, it has been found, that sufficient amounts of sugar block the lecithins of the microorganisms and consequently prevent the microorganisms from being bound by the receptors of the cellular surface. Thus, a su¬ gar ointment is used successfully against acute mediasti- nitis subsequent to heart surgery operations, against se¬ vere burns etc. In addition to disaccharides such as sacc- harose, meltose and cellobiose, all of which have the mole¬ cular formula C-₂ H„₂ 0,. , probably also monosaccharides such as hexoses, e.g. glucose, fructose or galactose, all of which have the structural formula C6H-1.206_r and certain glycosides are active.

It is also known that vitamin E is an excellent antioxidant and is able to contribute to the stability of the cell memb¬ ranes by protecting the polyunsaturated fatty acids in the lipids of the membrane against attacks by free radicals.

BRIEF DISCLOSURE OF THE INVENTION Thus, the active effect of zinc oxide on certain skin and mucous membrane affections has been thoroughly documented and terapeutic effects of certain types of sugar on sore treatment have been reported. Also, the effect of vitaminE as an antioxidant is known per se. However, these substan- ces apparently have not been utilized in an optimal way for the treatment of superficial skin and mucous membrane affec¬ tions. For the treatment of e.g. skin-fold dermatitis (an¬ gular cheititis, cheititis, intertrigo) , bed sore and ac¬ ne vulgaris there is a need of agents, which are cosmeti- cally acceptable and at the same time more active than those which are available today. Also, for the treatment of other superficial sores such as bed sores and burns there is a need of improved preparations. In the veterina¬ ry field there is a need of improved preparations designed for the treament of various skin lesions, e.g. sores which are slow in healing, skin-fold dermatitis and blisters (dogs, horses) as well as greasy heels on horses.

The purpose of the invention is to meet these needs, which can be done by means of a pharmaceutical composition, which consists of a mixture, which comprises zinc oxide (ZnO) , one or several of the substances, which belong to any ofthe groups disaccharides, monosaccharides and glycosides as well as vitamin E in effective amounts in a pharmaceutically and cosmetically acceptable vehicle, which gives the mix¬ ture the consistency of an ointment, cream or paste, Also, the mixture can and ought to include at least one or seve- ral of the substances zinc sulphate (ZnSO.) , vitamin A and boric acid (H.,BO-,) .

Zinc oxide has in in vitro-examinations proved to have a satisfactory antimicrobial and antidermatophytic effect. It is also astringent and locally protective, antiphlogistic and antipruritic and ought to be included in the composi¬ tion in a minimum amount of 5 percent by weight, preferab¬ ly at least 15 percent by weight and suitably at least 20 percent by weight in order to obtain the desired effect.

The maximum amount depends on the consistency requirements and is not more than 60 %, preferably not more than 50 %, suitably not more than 45 %. An optimal amount is about 30 or not more than 35 percent by weight.

The composition according to the invention is to include some type of sugar. Saccharose which is a disaccharide with the molecular formula ^cι₂ ^H ₂₂°₁₁ ' ^anc P^arti^cularly glucose, which is a monosaccharide (hexose) with the structural for- ula C_gH.,₂Og have proven to be active. Also, certain glyco¬ sides can be considered as alternatives or supplements to disaccharides and/or monosaccharides. Consequently, in ac¬ cordance with a further way of defining the composition of the present invention one or several of the substances, which belong to any of the groups disaccharides, monosaccha¬ rides and glycosides, are to be included in it in an amount of 10-70 percent by weight, preferably 10-50 percent by weight and suitably 15-45 %. An optimal amount is 15-35 .

Vitamin E is an excellent antioxidant and contributes to the stability of the cell membranes by protecting the poly- unsaturated fatty acids in the lipids of the membrane from attacks by free radicals and oxidation. Vitamin E appears in the composition according to the invention, due to its protective action, to provide a synergistic effect in com¬ bination with zinc oxide and the above-mentioned type(s) of sugar. Consequently, vitamin E ought to be included in a minimum amount of 5 percent by weight and suitably at least 10 percent by weight in order to obtain said effects to the desired extent. The maximum amount may be as high as 30 % and suitably not more than 20 %. An optimal amount is about 15 percent by weight.

A preferred vehicle (carrier) is the so called Essex cream, which is a trade name for a fatty cream, which in addition to the main components vaseline and liquid paraffin includes emulsifiers as well as preservatives and pH value-adj stment agents. Other suitable vehicles are e.g. pure vaseline, Lo- cobase and cod liver oil (the latter mainly for veterinary use) .

The above-mentioned ingredients are unconditional substances in the composition according to the invention. The condi¬ tional substances, which preferably are to be included in the composition, can be added in the following concentra¬ tions: Zinc sulphate, which is astringent and antiphlogistic, can and ought to - dissolved in a small amount of water - al¬ so be used in a minimum amount of 0.5 %, not more than 3 %. An optimal amount is about 1 percent by weight.

Vitamin A is important for the growth and the function of epithelial tissues of the skin and ought to be included in the composition in a minimum amount of 0.01 and mot more than 3 percent by weight, preferably not more than 1 per¬ cent by weight, suitably not more than 0.5 percent byweight. A suitable amount is about 0.2 percent by weight.

Boric acid, which denatures proteins, is astringent and an¬ tiseptic, bacteriostatic and fungistatic, can be added in a minimum amount of 0.5 %. However, it is true that boron compounds may have certain adverse effects, e.g. having an irritating effect on mucous membranes, and consequently, boric acid should not be added in a larger amount than 3 percent by weight. An optimal amount is about 1 percent by weight.

In in vitro-examinations and clinical examinations, which were performed on human beings, dogs and horses and which will be reported below, an ointment was used, which for each 100 g comprises 32 g ZnO, 1 g ZnSO. inwater solution, 25 g glucose, 1 g H.,B0₃, 15 g vitamin E (tokoferoliacetas (al- fa) 20.400 IE), 0.2 g vitamin A (retinolipalmitas 0.34 mil IE) and the rest a pharmaceutically and cosmetically accep¬ table vehicle, more particularly an Essex ointment, which includes about 0.5 % chlorocresol as a preservative.

In vitro-examinations The antimicrobial activity of a cream having the above-men¬ tioned composition against PityrosporumovaleATCC 42132,44031 Candida albicans H 29, Staphylococcus aureus, Streptococ¬ cus haemolytica as well as Propionebacterium acnes were evaluated. DST-agar with added Tween 80 (2 ml/1) as well as glycerine monostearate (2.5 g/1) was used as a test medium for P. ovale. DST-agar without these additives was used for C. albicans, S. aureus, St. haemolytica and Pr. acnes.

The cream according to the invention was added to the DST- medium, with and without additives, concentrations of 40,

20, 10, 5, 2.5, 1 and 0.5 % of the cream in the agar-medium being obtained. Control platesweremade with distilled wa- ter. Plates were inoculated with 10 cells/ml (0.1 ml) of P. ovale. The rest of the microorganisms were inoculated in a concentration of 10 cells/ml (0.1 ml). P. ovale was read after an incubation of 3 days. Pr. acnes was incubated anae- robicly and was read after 2 days. The rest of the bacteria and C. albicans were read after an incubation time of 1 day. The plates incubated at 37 C. The least inhibitory concentration (MIC) was registered for the minimum concent¬ ration of the cream according to the invention, at which a total growth inhibition could be registered. Table 1 shows the MIC-values for various microorganisms. St. haemolytica was the most susceptible organism with a MIC-value of 0.5 %, whereas C. albicans was the most resis¬ tant with a MIC-value of 10 %. The study shows that the cream according to the invention is active in vitro against a plurality of microorganisms , which are found in many skin affections, e.g. those mentioned above and impetigo, acne vulgaris as well as Pityrosporum-related problems, including seborrhoeic dermatitis, pityriasis versicolor and cutaneous candidiasis.

Table 1

Activity in vitro of a cream according to the invention against various microorganisms (MIC = minimum inhibitory concentration of the preparation according to the inven¬ tion)

Microorganisms

P. ovale ATCC 42132 P. ovale ATCC 44031

C. albicans H 29

S. aureus

St. haemolytica

Pr. acnes

Treatment of acne vulgaris

The cream according to the invention as a local treatment- agent for a mild form av acne vulgaris was evaluated. The study was performed at the skin department of a large Swe- dish hospital. Patients having a mild form of acne were se¬ lected. After a washout-period of two weeks the treatment with the cream was started, the cream having the same com¬ position as in the in vitro-examination, in the morning and in the evening in an open procedure. The patients were eva- luated on day 0, day 7, days 14-21 as well as days 35-42 at the skin department. The number of papules and pustules in the face was counted at every visit. 48 patients in allwere treated in this way, 20 men and 28 women, the patients be- ing 15-35 years old. The results are set forth in Table 2 below. The table shows, that this cream according to the i vention has a satisfactory effect on the number of papules and pustules, when a mild acne in treated.

Table 2

Mean values of the number of lesions in the face of treate patients having a mild acne :

papules pustules

Test on dogs

60 dogs in all of different breeds participated in the stu dy, which was performed in an animal hospital. The diagnose were classified into the following 5 groups: Group 1 skin-fold dermatitis;

2 blisters after plaster or dressings;

3 scurs hosp/cracked pads ;

4 sores slow in healing; and

5 other skin lesions.

The cream had the same composition as the cream used to te acne and was applied by the animal owner 1 or 2 times a da after a cleaning of the sore. A control of the results was carried out after a week and in some cases after two weeks in the animal hospital. Due to. a substantial travel dis¬ tance to the hospital the results in a few cases were re¬ ported by the animal owner on the telephone. The evaluatio of the results was .made on a scale of 1-4 and by one and t same person according the following: 4 Very excellent The result visible after one day.

The lesion is healed within one week 3 Excellent The result is visible after 2-3 day

The lesion is healed within 2 weeks Satisfactory The result is obvious, but it takes more than 2 weeks for the lesion to heal.

Not satisfactory No or small improvement after a treatment for 10 days.

The results have been compiled in Table 3.

Table 3

A compilation of the results of tests on dogs:

Diagnosis Number Evaluation 4 3 2 skin-fold dermatitis 11 9 1 1 blisters 6 6 scurs hosp/cracked pads 3 3 sores slow in healing 24 10 5 0 other skin lesions 16 2 1 4

The results show that the cream according to the invention has an excellent healing effect on skin sores on dogs. The preparation also has an excellent adherence to the skinand the sore. When the cream has been used on infected sores be¬ low plaster casts, the cream has after a cleaning of the sore been applied and new plaster cast has then been app¬ lied. During the next plaster cast the sores have been healed. Excellent results have also been obtained for large skin sores. They will heal quickly after the cream has been applied. Various types of skin-fold dermatitis heal without exception very fast. The cream was also tested on 7 dogs, operated on for anal fistula. The cream was applied on the open sore. Since the sores were large, it took in some cases more than 14 days to heal. However, in all those 7 cases a considerably better and quicker healing could be observed with the cream than without. The cream showed less excellent results on scurs hosp, cracked pads and excema on paws. Tests on horses

The same sore cream was used as in the previous examina¬ tions. 94 horses having various skin lesions participated in the study. Among these 55 have had pastern dermatitis, whereas others have had sores ofvarious types.

The cream was applied by a veterinary or a horse owner. The applications were done after a cleaning of the sore 1-2 times every day. During the 2-5 first applications in most cases a light-weight dressing has been applied on top of the cream. During the subsequent applications no sore dres¬ sing has been used, only the cream. The number of applica¬ tions for every treatment, i.e. up to a healing or up to the moment when the treatment has been discontinued (name- ly in those 8 instances when no healing could be observed) , has varied between 4-13 applications.

Tested skin lesions as well as the bases for forming the evaluations of the healing result are shown in Table 4. The compilation is based on the data, which have been re¬ ported by the veterinaries.

Table 4

Diagnosed skin lesions on 94 horses, which were treatedwith the cream according to the invention. Evaluation scale:

+++ = the lesion is healed within one week; ++ = the le¬ sion is healed within two weeks; + = the result is obvious, but it takes more than two weeks to heal; - = no or a mi¬ nor improvement after a treatment for two weeks:

Treated cases Healing effect sores, pastern derma- 55 +++ in 42 cases titis, greasy heal, ++ 10 liguid - 3 sores, pastern deram- 13 +++ 6 titis, greasy heal, ++ 5 dry - 2 blisters 6 sores, "large" 5 sores,superficial 8

shuffle sores 6

It is shown in Table 4, that the cream has a desired effect, particularly on greasy heel. No side effects have been reported.

Claims

CLAIMS :

1. Apharmaceutical composition such as an ointment, a cream or a paste, which can be used to treat superficial skin and mucous membrane affections, c h a r a c t e r i z e d in that it is a mixture, which comprises, inpercent byweigh 5-60 % ZnO;

10-70 % of one or several of the substances which belong to any or several of the groups disaccharides, mono- saccharides and glycosides;

3-30 % vitamin E, and the rest being mainly only a pharmaceutically acceptable ve¬ hicle.

2. A composition according to claim 1, c h a r a c t e ¬ r i z e d in that it comprises at least 15, preferably at least 20 and not more than 50 %, preferably not more than 45 % ZnO.

3. A composition according to claim 1, c h a r a c t e ¬ r i z e d in that it comprises 10-50 %, preferably 15-45 %, suitably 15-35 % of one or several of the substances, which belong to any or several of the groups disaccharides, monosaccharides and glycosides.

4. A composition according to claim 3, c h a r a c t e ¬ r i z e d in that it comprises at least 10 % of one or several disaccharides.

5. A composition according to any of claims 1 and 4, c h a r a c t e r i z e d in that said monosaccharides mainly are one or several hexoses in an amount of at least 10 %, preferably glucose.

6. A composition according to claim 5, c h a r a c t e ¬ r i z e d in that it comprises at least 5, preferably at least 10 and not more than 20 % vitamin E.

7. A composition according to any of claims 1-6, c h a ¬ r a c t e r i z e d in that it comprises 0.5-3 % ZnSO., preferably not more than 2 % ZnSO,.

8. A composition according to any of claims 1-7, c h a - r a c t e r i z e d in that it comprises 0.01-3 % vitamin A, preferably not more than 1, suitably not more than 0.5 % vitamin A.

9. A composition according to any of claims 1-8, c h a ¬ r a c t e r i z e d in that it comprises 0.5-3 % H_BO,, suitably not more than 2 % H-.BO,.

10. A composition according to any of claims 1-9, c h a - r a c t e r i z e d in that 100 g of the composition nomi¬ nally comprises about 30 g ZnO, about 1 g ZnSO. inwater so¬ lution, about 25 g glucose, about 1 g H,B0-,, about 15 g vi¬ tamin E (tokoferoliacetas (alfa) ) , about 0.2 g vitamin A

(retinolipalmitas) , the rest being pharmacologically and cosmetically acceptable vehicles.

11. A use of the composition according to any of claims 1-10 in order to produce preparations for treatment of su¬ perficial skin and mucous membrane affections.

12. A use according to claim 11 in order to produce prepa¬ rations for sore treatments, particularly for treatment of skin-fold dermatitis (angular cheilitis, cheilitis, inter- trigo and decubitus) .

13. A use according to claim 11 in order to produce prepa¬ rations for treatment of acne.

14. A use according to claim 11 in order to produce prepa- rations for pretreatment of superficial skin and mucous membrane affections in animals. AMENDED CLAIMS

[received by the International Bureau on 28 June 1993 ((28.06.93); original claim 3 amended; other claims unchanged (1 page )]

1. A pharmaceutical composition such as an ointment, a cream or a paste, which can be used to treat superficial skin and mucous membrane affections, c h a r a c t e r i z e d in that it is a mixture, which comprises, in percent by weight, 5-60 % ZnO;

15-45 % of one or several of the substances which belong to any or several of the groups disaccharides, mono- saccharides and glycosides;

3. A composition according to claim 1, c h a r a c t e ¬ r i z e in that it comprises 15-35 % of one or several of the substances, which belong to any or several of the groups disaccharides, monoaccharides and glycosides.