Use of an oleogel containing triterpene for healing wounds

Abstract

An oleogel comprising a non-polar liquid and a powder containing triterpene is provided as an oleogel that may be used for healing wounds.

Claims

1. A method for treating epidermolysis bullosa in a patient in need thereof, comprising topically administering to the patient an oleogel comprising a triterpene fraction, wherein the triterpene fraction comprises betulin.

2. The method of claim 1, wherein the method comprises topically administering the oleogel to an area of wounds caused by epidermolysis bullosa.

3. The method of claim 1, wherein the method comprises topically administering the oleogel to an area of epidermolysis bullosa comprising blisters.

4. The method of claim 1, wherein the triterpene fraction comprises between 1 weight-percent and 20 weight-percent of the oleogel.

5. The method of claim 4, wherein the triterpene fraction comprises between 6 weight-percent and 12 weight-percent of the oleogel.

6. The method of claim 1, wherein the fraction of betulin in the triterpene fraction is greater than 60 weight-percent.

7. The method of claim 1, wherein the fraction of betulin in the triterpene fraction is greater than 80 weight-percent.

8. The method of claim 1, wherein the triterpene fraction further comprises lupeol.

9. The method of claim 8, wherein the joint fraction of betulin and lupeol in the triterpene is greater than 80 weight-percent in the triterpene fraction.

10. The method of claim 8, wherein the joint fraction of betulin and lupeol is greater than 85 weight-percent in the triterpene fraction.

11. The method of claim 1, wherein the oleogel further comprises a nonpolar liquid.

12. The method of claim 11, wherein the nonpolar liquid is a plant, animal, mineral, or synthetic oil.

13. The method of claim 12, wherein the plant oil is a vegetable oil which is selected from one of the following: sunflower oil, olive oil, avocado oil, and almond oil.

14. The method of claim 11, wherein the nonpolar liquid consists of sunflower oil.

15. The method of claim 11, wherein the nonpolar liquid fraction comprises between 80 weight-percent and 99 weight-percent in relation to the total weight of the oleogel, and wherein the triterprene fraction comprises between 1 weight-percent and 20 weight-percent in relation to the total weight of the oleogel.

16. The method of claim 1, wherein the oleogel further comprises betulinic acid, oleanolic acid, and erythrodiol.

17. The method of claim 1, wherein the patient is a human.

18. The method of claim 1, wherein the epidermolysis bullosa is epidermolysis bullosa junctionalis, epidermolysis bullosa simplex, dystrophic epidermolysis bullosa, or epidermolysis bullosa dystrophica inversa.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention is explained hereafter on the basis of examples, in particular with reference to the appended figures.

(2) FIG. 1 illustrates the particle size distribution of an example of a highly dispersed oleogel-forming agent in an oleogel suitable for healing wounds.

(3) FIG. 2 illustrates the wound healing progress in the case of healing wounds according to the “porcine ex-vivo wound model” under the influence of a triterpene-containing oleogel.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

(4) FIG. 1 illustrates the particle size distribution of an example of a highly dispersed oleogel-forming agent in an oleogel suitable for healing wounds. In the example, the particle size is between 0.5 μm and 40 μm; the maximum of the size distribution is between 8 μm and 10 μm. According to gas chromatographic analysis, this powder contains 85 weight-percent betulin, 5 weight-percent betulinic acid, 3% oleanolic acid, 0.7 weight-percent lupeol, and 6.3 weight-percent other triterpene derivatives.

(5) Using this powder as the gel-forming agent, an oleogel was produced, in that the powder was mixed, at 10 weight-percent in relation to the total weight of the oleogel, with sunflower oil. The result was a stable semisolid gel having strongly pronounced thixotropy (oleogel S10). This gel is referred to hereafter as oleogel S10, “S10” indicating a fraction of 10% of the triterpene-containing powder in the oleogel. Additional wound healing substances are not provided in oleogel S10.

(6) An oleogel having a highly dispersed, triterpene-containing powder as the oleogel-forming agent is suitable as a wound healing agent for the treatment of arbitrary skin wounds of the human body. Such wounds may be wounds which are caused by accidents, e.g., cuts or abrasions or also burn wounds. However, such wounds may also be wounds which are intentionally required for therapeutic purposes, e.g., wounds after a split skin graft removal or wounds after a laser treatment, e.g., a laser treatment for removing tattoos or skin growths. An oleogel having a highly dispersed triterpene-containing powder as the oleogel-forming agent is also suitable as a wound healing agent for the treatment of wounds which are caused by skin diseases, e.g., epidermolysis bullosa.

FIRST EXAMPLE

(7) The wound healing effect of a triterpene-containing oleogel (oleogel S10) was tested on the basis of the “porcine ex-vivo wound model,” which is the subject matter of DE 103 17 400 B4. The epidermis and the upper part of the dermis were removed in a small circular area from skin samples of the pig ear having a diameter of 6 mm. In a first group of 10 samples, 10 μL of oleogel was introduced once for 48 hours into the wounds resulting in this way, in a second group of six samples, 10 μL Vaseline, which was used as a comparative preparation, was applied, and a third group of 10 samples remained untreated as the control group. After 48 hours, the skin samples were fixed and subsequently histologically studied.

(8) The study showed, on the basis of the reepithelialization progress, improved wound healing in the samples treated using the oleogel in comparison to the other samples. The wound healing progress is graphically shown in FIG. 2 in the form of a bar graph. The left bar shows the wound healing progress for Vaseline, the right bar shows that of the control sample, and the middle bar shows that for the oleogel. As is apparent, the treatment using the oleogel results in a more rapid wound healing progress in comparison to both nontreatment and also to treatment using Vaseline.

(9) In addition, the oleogel showed similarly good maintenance of the morphology of the wound edge as in the untreated samples. The number of the proliferative cells in the regenerating epidermis had a tendency to be reduced under the influence of the oleogel in comparison to the untreated sample, but was equal on the wound edge, while the Vaseline had statistically significantly fewer proliferative cells here.

SECOND EXAMPLE

(10) Patient (f), 3 years of age diagnosis: epidermolysis bullosa junctionalis non-Herlitz wound status before treatment: flat, fibrinous coated chronic wound, right thorax no tendency to heal over more than four weeks size: 13.63 cm.sup.2 therapy until now: daily bandage change, wound care with Mepitel and Mepilex transfer; regular Octenisept skin disinfection. secondary diagnoses: MRSA colonization in six locations, no smear test from the treated location iron deficiency anemia alimentary dystrophy chronic pains beginning of therapy 15 July: daily oleogel S10 application, Mepilex transfer wound bandage concomitant therapy: antiseptic baths medication: ibuprofen 3×80 mg, Tavigil (2×5 mL) wound findings on 17 July: size: 9.58 cm.sup.2 (approximately 30% decrease in wound area) flat uncoated wound epithelization on the wound edges and formation of an epithelial bridge

THIRD EXAMPLE

(11) Patient (m), 4 years of age diagnosis: epidermolysis bullosa simplex initial findings: annular proliferating blisters and crusts back and both flanks present since five weeks massive itching therapy until now: Bepanthen, Fucidin, and Mepilex without sustained improvement beginning of therapy on 12 Dec. 2008: treatment using Octisept solution 2× daily oleogel S10; covering the wound with Mepilex transfer; medication: Fenistel drops; Aerius syrup; Excipial and Lipolotio two times daily; 5% Thesit in Unguentum leniens as needed during the day. Findings on 18 Dec. 2008: fewer blisters and crusts itching alleviated follow-up 2 May 2009 with continuation of the oleogel treatment; healing and absence of the itching

FOURTH EXAMPLE

(12) Patient (f), 12 years of age diagnosis: recessive dystrophic epidermolysis bullosa wound status before therapy: left medial malleolus: flat, slightly inflamed, painful (visual analog scale 0-100: VAS 50), exuding (VAS 50) wound; present since 10 Apr. 2009 right knee ventral: flat, slightly inflamed, slightly painful (VAS 15), exuding (VAS 40) wound; present since 13 Apr. 2009 therapy until now: Urgotul; Mepilex lite therapy from 16 Apr. 2009; both wounds: Urgotul, Mepilex lite, daily bandage change left medial malleolus additionally with oleogel S10 wound findings on 22 May 2009: both wounds healed left malleolus (oleogel S10): epithelized (VAS 100); slightly reddened (VAS 8); not painful or itching (VAS 0) right knee (control): epithelized with residual crust (VAS 90); slightly reddened (VAS 8), slightly painful (VAS 10), and itching (VAS 5)

FIFTH EXAMPLE

(13) Patient (m), 57 years of age diagnosis: epidermolysis bullosa dystrophica inversa wound status before therapy on 18 Nov. 2008: flat fibrinous coated wounds size: 9.48 cm.sup.2 scrotal right and left, no healing over more than three months therapy until now: greatly varying ointments and creams, no improvement additional findings: wound colonization with staph. auereus, proteus diabetes mellitus, requires insulin beginning of therapy 18 Nov. 2008: oleogel S10: 2× daily wound dressing Mepilex transfer wound status on 24 Nov. 2008: almost completely healed, flat, fibrinous coated wound size: 0.65 cm.sup.2 follow-up: worsening after cessation of oleogel S10 therapy attempt with Mirfulan cream, no significant improvement therapy attempt with Imlan Creme Pur, only slight improvement after renewed therapy with oleogel S10, healing

(14) The wound treatment using an oleogel, which includes a triterpene-containing powder as the oleogel-forming agent, already causes a usable healing process and a reduction in size of the wounds, and therefore significant abatement, after a few days. In the event of sustained treatment, the oleogel causes complete healing of the wound, in particular also the healing of chronic wounds in which no healing process had previously spontaneously begun. In the wound healing, the oleogel promotes the reepithelialization in particular and may thus be used in particular in the case of wound healing during the reepithelialization phase.

(15) In addition to the outer epithelia mentioned in the examples, the oleogel is also suitable for healing of wounds on inner epithelia (mucosae), e.g., in the nose, stomach, or genital area. The oleogel may be administered orally harmlessly.

(16) The triterpene composition (composition I) explained in connection with FIG. 1 is merely an example of a triterpene composition which has a wound healing effect as a component or as the oleogel-forming agent of an oleogel. The wound healing effect of a triterpene-containing oleogel is, of course, not restricted to an oleogel having such a special triterpene composition. Three further triterpene compositions are specified as examples hereafter, which were used to manufacture oleogels, whose wound healing effect was verified on the basis of the “porcine ex-vivo wound model.” The main components and the particular fraction in weight-percent are specified hereafter for these compositions, which are referred to as compositions

(17) Composition II:

(18) betulin: 86.85 weight-percent

(19) lupeol: 3.94 weight-percent

(20) betulinic acid: 3.52 weight-percent

(21) erythrodiol: 0.77 weight-percent

(22) oleanolic acid: 0.62 weight-percent

(23) Composition III:

(24) betulin: 78.32 weight-percent

(25) lupeol: 7.18 weight-percent

(26) betulinic acid: 3.46 weight-percent

(27) erythrodiol: 0.77 weight-percent

(28) oleanolic acid: 0.63 weight-percent

(29) Composition IV:

(30) betulin: 60.50 weight-percent

(31) lupeol: 25.43 weight-percent

(32) betulinic acid: 1.68 weight-percent

(33) erythrodiol: 1.47 weight-percent

(34) oleanolic acid: 0.48 weight-percent

(35) As the example of composition III, which has a comparatively small betulin fraction, shows in particular, a high betulin fraction does not necessarily have to be provided for good wound healing.

(36) The joint fraction of betulin and lupeol in compositions I-IV is greater than 80 weight-percent in each case, in particular greater than 85 weight-percent. The fraction in which the individual triterpenes are provided is dependent in particular on the plants or plant parts from which the triterpene-containing powder was obtained. However, good wound healing is not dependent on the special composition of the triterpene-containing powder. Rather, oleogels having arbitrary triterpenes as the oleogel-forming agents appear to have good wound healing properties.

(37) In addition to sunflower oil, of course, arbitrary other fats or oils, which are non-toxic for humans or for mammals or which are medically applicable, are also suitable for manufacturing the oleogel.