Mixture for use in the topical treatment of oncological hand-foot syndrome, and method for preparing the mixture

Description

Technical field

[0001] The invention relates to a mixture of substances for use in the dermal treatment of a skin disease, in particular an oncological hand-foot syndrome, and to a method for producing the mixture of substances. State of the art

[0002] Oncological hand-foot syndrome (HFS) is a common side effect of various drugs used in cancer therapy; no other causes are currently known.

[0003] Typical painful skin reactions on the hands and feet are responsible for the syndrome's name. The National Cancer Institute (NCI) defines different degrees of severity. Initially, HFS manifests as minimal skin changes such as erythema or swelling and paresthesia (Grade 1). Pain is not present at this stage. Blisters, bleeding, and swelling of the skin, as well as pain that interferes with patients' daily lives, are typical of Grade 2 HFS. In the third and highest grade, severe pain and extensive skin changes impair self-care, specifically the inability to walk or grasp objects.

[0004] Several mechanisms are discussed regarding the etiology of hand-foot syndrome (HFS). The developmental process has not yet been fully elucidated. However, several hypotheses are known. These include the suggestion of a toxic effect of the drugs on epidermal cells of the skin. A connection with good blood circulation due to the high density of capillaries or with increased sweating of the hands and feet is also being discussed.

[0005] The triggering agents comprise a heterogeneous group. Consequently, it is not yet clear whether the oncological hand-foot syndrome is triggered by different mechanisms of action or whether it represents a distinct disease entity exhibiting a similar symptom complex. Generally, the incidence of occurrence increases with increasing dose and duration of therapy. Similarly, combining two substances known to cause this side effect leads to an increase in the frequency and severity of the reaction.

[0006] Treatment for hand-foot syndrome (HFS) is currently limited to managing symptoms. A 10% urea cream is considered standard in medical circles. Topical glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) are also commonly used. This lack of treatment options underscores the importance of preventative measures. However, there are currently no controlled studies on their effectiveness. Patients must be instructed to minimize stress on the skin of their hands and feet during therapy. This includes avoiding pressure, such as from lifting and carrying objects, friction (e.g., from tight clothing or shoes), and exposure to heat. Maintaining the care of the hands and feet with cooling and moisturizing creams is particularly important during treatment.However, if the syndrome occurs, a dose reduction or a break in therapy is unavoidable in severe cases, which delays the treatment of the cancer, may even have to be discontinued, and thus its success may be called into question.

[0007] Document WO 2010 / 057117 A2 discloses a composition for topical application to the skin for use in the treatment of a skin condition, containing 0.6% by mass of niacin and 4% by mass of ibuprofen, as well as benzyl alcohol as an antioxidant. Document WO 00 / 62743 A2 discloses compositions for topical application in the treatment of skin conditions, containing 3.5% by mass of niacinamide, 1.5% by mass of salicylic acid, 0.5% by mass of vitamin E, as well as EDTA as an antioxidant. Document CA 2 637 538 A1 discloses a cream for the treatment of acne, containing ibuprofen, niacinamide, ascorbic acid, and vitamin E. Document WO 2021 / 204223 A1 discloses a pharmaceutical composition containing nicotinamide in gel form for the topical treatment of oncological foot-hand syndrome. Gels with a 5% by mass content of nicotinamide are disclosed.The document XP093137514 (SANTHOSH AKHIL ET AL: "Randomized double-blind, placebo-controlled study of topical diclofenac in the prevention of hand-foot syndrome in patients receiving capecitabine (the D-TORCH study)", TRIALS, Vol. 23, No. 1, 1 December 2022) discloses the use of a one percent topical diclofenac preparation for the treatment of oncological hand-foot syndrome. Technical task

[0008] The object of the invention is to create a simple and safe drug for the effective dermal treatment of a skin disease, in particular an oncological hand-foot syndrome. Technical solution

[0009] The present invention provides a mixture of materials according to claim 1 which solves the technical problem. Advantageous embodiments are the subject of the dependent claims.

[0010] The substance mixture is intended for topical treatment of a skin disease, particularly in humans. The skin disease is an oncological hand-foot syndrome.

[0011] The mixture contains the non-steroidal anti-inflammatory drug ibuprofen with a mass fraction of 3% to 6% of the mixture.

[0012] The mixture contains nicotinamide with a mass fraction of 2% to 6%.

[0013] The mixture preferably contains at least one antioxidant active ingredient with a mass fraction of 0.01% to 10% of the mixture. Beneficial effects

[0014] The skin, particularly on the hands and feet, has a large capillary network. This results in high blood flow, and circulating medications and their breakdown products are present in high concentrations, which can cause inflammation. Furthermore, the skin contains a high concentration of keratinocytes, which, due to their high rate of division, are particularly susceptible to most cancer drugs.

[0015] Nonsteroidal anti-inflammatory drugs (NSAIDs) are used for mild to moderate pain and inflammation and are found in many over-the-counter preparations for topical application. These drugs can therefore effectively relieve pain and inflammation associated with skin conditions and are safe to use without systemic side effects.

[0016] Nicotinamide is a substance that occurs naturally in the human body. Studies have investigated its use in the treatment of acne and polymorphic light eruption, both of which are skin conditions. When applied topically, nicotinamide is attributed with anti-inflammatory and antibacterial effects. Furthermore, it is considered photoprotective and antipruritic. In cosmetics, nicotinamide is a common ingredient used to combat dry and blemished skin. Thus, nicotinamide can alleviate inflammation or infection associated with skin conditions and prevent further skin damage caused by itching. Skin inflammation can be particularly effectively treated by combining a non-steroidal anti-inflammatory drug (NSAID) with nicotinamide, as the two substances combat inflammation through complementary mechanisms of action.

[0017] Oxidative stress is a possible cause of skin diseases, for example, caused by medications or their breakdown products, which are excreted through the skin's sweat glands and, upon contact with atmospheric oxygen, form radicals and / or reactive oxygen species that can trigger inflammatory damage. The antioxidant agent can counteract this cause of an inflammatory reaction and thus combat inflammation in a complementary way to non-steroidal anti-inflammatory drugs and nicotinamide. Description of the execution types

[0018] At least one non-steroidal anti-inflammatory drug is ibuprofen. The topical use of ibuprofen is particularly well-researched through placebo-controlled studies. Due to its acidic properties, the drug accumulates in inflamed tissue, thus explaining its anti-inflammatory effects, and causes only minor local side effects.

[0019] Ibuprofen is present in the mixture at a mass fraction of 3% to 6%, preferably 5%. These mass fractions ensure safe and effective treatment of the skin condition.

[0020] Nicotinamide is present in the mixture at a mass fraction of 2% to 6%, preferably 4%. These mass fractions ensure a safe and effective treatment of the skin condition.

[0021] The mixture preferably contains dexpanthenol in a mass fraction of 1% to 10%, more preferably 3% to 7%, and particularly preferably 5%. Dexpanthenol is the alcohol of vitamin B5, pantothenic acid. In the human body, dexpanthenol is converted into pantothenic acid. Pantothenic acid is a component of coenzyme A, which plays a central role in many metabolic processes. The active ingredient promotes epithelialization and thus accelerates wound healing. Dexpanthenol also moisturizes and cools. It is also known to have an itch-relieving and anti-inflammatory effect. Consequently, it is a valuable component of the mixture. The aforementioned mass fractions ensure a safe and effective treatment of the skin condition.Since dexpanthenol, due to different mechanisms of action, also exhibits the anti-inflammatory and itch-relieving effects caused by nicotinamide, these two substances complement each other well to comprehensively treat the skin disease.

[0022] The at least one antioxidant component comprises, or is preferably, vitamin E, in particular tocopherol. The tocopherol is preferably synthetically produced and / or contains all eight stereoisomers of tocopherol (all-rac-tocopherol). Synthetic production guarantees consistent product quality. The use of all stereoisomers eliminates the need for complex separation of the stereoisomers and thus reduces the cost of manufacturing the mixture.

[0023] The tocopherol is preferably present in the mixture at a mass fraction of 0.05% to 0.5%, more preferably 0.1% to 0.4%, and particularly preferably 0.2%.

[0024] Tocopherol possesses antioxidant properties and is used as an additive at a mass fraction of 0.2% for the preservation of lipophilic pharmaceuticals. Higher concentrations lead to pro-oxidative effects and are therefore counterproductive. Recent research confirms a photoprotective effect of vitamin E. Due to these effects, tocopherol at the specified mass fractions is particularly well-suited for the application of the mixture according to the invention. Tocopherol particularly advantageously supports the photoprotective effect of nicotinamide, so that these two substances together prevent photoinduced skin damage.

[0025] The at least one antioxidant active ingredient comprises, or is, for example, ascorbic acid, preferably with a mass fraction of 0.01% to 1% in the mixture, particularly preferably 0.02% to 0.5%. These mass fractions ensure a safe and effective treatment of the skin condition.

[0026] A disadvantage of ascorbic acid is that its antioxidant effect is pH-dependent, which in turn depends on the other substances contained in the mixture and can vary at the application site on the skin surface. At least one of the antioxidant agents can include tocopherol and ascorbic acid.

[0027] The mixture contains, for example, menthol, preferably in a mass fraction of 0.1% to 10%, and particularly preferably 0.25% to 5%. Menthol has anti-inflammatory and cooling properties, as well as secondarily analgesic and antipruritic effects, and thus contributes advantageously to the treatment of the skin condition. Furthermore, menthol has a pleasant odor, which increases patient acceptance.

[0028] It contains at least one antioxidant active ingredient, or is, for example, N-Acetylcysteine ​​(NAC), preferably with a mass fraction of 5% to 10% of the mixture. Disadvantages of N-acetylcysteine ​​include possible side effects such as irritation and an unpleasant odor.

[0029] The mixture contains, for example, propolis. Propolis comprises a variety of active ingredients (approximately 150 identified), including flavonoids, phenyl-substituted carboxylic acids, and essential oils. Propolis has astringent, antimicrobial, anti-inflammatory, immunostimulating, and cytostatic properties and can therefore contribute to the treatment of the skin condition in a variety of ways. However, as a natural product, propolis has a variable composition, making it difficult to guarantee consistent product quality and posing an allergenic risk with topical application. Furthermore, the resinous nature of propolis complicates its homogeneous processing within the mixture.

[0030] The mixture preferably contains a carrier substance, which is or comprises a foam, gel, cream, or ointment. Due to the sensitivity of the treated skin, a carrier substance that is easy to apply, quickly absorbed, and / or cooling is particularly suitable. From this perspective, a foam is especially preferred.

[0031] The carrier substance comprises, or preferably is, a non-ionic and / or hydrophilic cream. A cream, particularly a hydrophilic cream, is characterized by being easy to apply and quickly absorbed. A non-ionic cream does not exhibit any ionic interactions with the active ingredients contained in the mixture that could impair their efficacy.

[0032] The carrier substance preferably contains water with a mass fraction of 40% to 80%, more preferably 60% to 70%. A high water content in the carrier substance results in a light texture of the mixture, making it easy to apply and quickly absorbed. Furthermore, the water cools the skin as it evaporates. Water also acts as a natural penetration enhancer, thus improving transdermal drug delivery.

[0033] A method according to the invention serves to produce the mixture according to the invention for the application according to the invention. The method comprises mixing the components of the mixture, wherein the mixture is preferably heated to a temperature of 40 °C to 90 °C, in particular 50 °C to 80 °C, and most preferably 60 °C to 70 °C, during mixing. Heating, which is carried out, for example, in a water bath, ensures that the components mix uniformly, resulting in a homogeneous mixture. A homogeneous mixture ensures a highly reproducible effect when the mixture is used. The mixture must not be heated too much so that the effectiveness of the components is not thermally impaired. Therefore, heating to the aforementioned temperature ranges is optimal for a high and highly reproducible effectiveness of the mixture. Examples

[0034] The mixture consists, for example, of the following substances with the stated mass fractions in the mixture: Ibuprofen 5 % Nicotinamide 4 % Dexpanthenol 5 % all-rac-tocopherol 0,2 % carrier substance to 100%

[0035] The carrier substance is, for example, the non-ionic hydrophilic cream SR "new" (Unguentum emulsificans nonionicum aquosum) according to the New Formulary (NRF). This cream consists of the following substances in the specified mass fractions: Cetylstearyl alcohol 16,8 % Macrogol-20-cetostearyl ether 4,2 % 2-Ethylhexyl laurate 10,0 % Glycerol 85% 5,0 % Potassium sorbate 0,14 % anhydrous citric acid 0,07 % purified water to 100%

[0036] The hydrophilic component of the non-ionic hydrophilic cream SR "new" is 70%. Glycerol 85% is included as a non-volatile, hydrophilic component at five percent by mass. As a humectant, also known as a moisturizer, it contributes to the consistency and nourishing properties of the base. It promotes the regeneration of the skin's stratum corneum. The high aqueous content leads to microbial susceptibility and therefore necessitates the cream's preservation. Potassium sorbate and anhydrous citric acid are added in a 2:1 ratio for this purpose. These are substances considered safe and well-tolerated. The preservation results in a pH value of approximately 4.8. 2-Ethylhexyl Laurate is included as a lipophilic component at ten percent. Chemically, it is a carboxylic acid ester. This substance is responsible for the rapid absorption of the base into the skin.Emulsifiers are added as a further structural component. The "new" version of the non-ionic hydrophilic cream uses cetylstearyl alcohol, a fatty alcohol, and macrogol-20-cetostearyl ether, a hydrophilic ethoxylated cetylstearyl alcohol, as emulsifiers. The mixture is called non-ionic emulsifying cetylstearyl alcohol, "Cetomacrogol wax BP." This is a self-emulsifying complex emulsifier. Cetylstearyl alcohols have a certain allergenic potential, which, however, mainly occurs with occlusive application.

[0037] The non-ionic hydrophilic cream SR "new" has a low occlusive effect, resulting in good patient acceptance. The cream has only a slight penetration depth, which is not a problem due to its site of action, as the active ingredient mixture only needs to work in the upper layers of the skin. This allows the non-steroidal anti-inflammatory drug, especially ibuprofen, to accumulate advantageously in the stratum corneum.

[0038] The stability of the exemplary mixture with the non-ionic hydrophilic cream SR "new" as a carrier substance was tested in a stability study over six months. This study confirmed that the mixture remains stable for at least two months when stored in a cool place.

[0039] For the stability study, the mixture was produced four times. The difference was the primary packaging. The mixture was filled into aluminum tubes twice and into jars twice. The direct comparison was carried out with identical compositions and primary packaging, but at different storage temperatures (refrigerated temperature from 2°C to 8°C or room temperature). The observation period extended over six months. Documentation points started weekly in the first month, then increased to bi-weekly in the second and third months, and finally to monthly.

[0040] The homogeneity of each cream was examined. A homogeneous strand of cream looks the same throughout and shows no water seepage. The presence of palpable crystals and consistency of viscosity were also checked. Increases in viscosity are clearly indicated by more cracked, firmer, or more easily torn strands of ointment and suggest potential incompatibilities. A fresh strand of each cream was visually compared and photographed, and also examined by touch for palpable crystals.

[0041] Preliminary tests have shown good tolerability of the exemplary mixture of substances with the non-ionic hydrophilic cream SR "new" as a carrier substance on healthy skin.

[0042] Another example of a carrier substance is the cooling cream (Unguentum leniensis) according to the German Pharmacopoeia. This cooling cream consists of the following substances in the specified mass fractions: Yellow wax 7 % Cetyl palmitate 8 % refined peanut oil 60 % purified water 25 %

[0043] The cooling cream forms a lipophilic carrier substance and is used for pruritus, xerosis, and subacute dermatitis. It contains no emulsifier, which makes it very well tolerated but not very stable. Because the water is only mechanically encapsulated, phase separation can easily occur. If phase separation occurs during application, water is released and evaporates, resulting in a beneficial cooling effect on the skin. The low stability makes it difficult to incorporate active ingredients into the carrier substance. Since the cooling cream is absorbed very slowly and is highly greasy, patient acceptance is low.

[0044] Another example of a carrier substance is the hydrophobic base cream according to the German Drug Codex (DAC). This hydrophobic base cream consists of the following substances with the specified mass fractions: Triglycerol diisostearate 3,0 % Isopropyl palmitate 2,4 % Hydrophobic base gel DAC 24,6 % Potassium sorbate 0,14 % anhydrous citric acid 0,07 % Magnesium sulfate heptahydrate 0,5 % Glycerol 85% 5,0 % purified water to 100%

[0045] The hydrophobic base cream is advantageously suited for incorporating the other components of the mixture, as it is hydrating and only slightly occlusive. However, its poor spreadability and highly greasy nature are disadvantages for patient acceptance.

[0046] The spreadability of the hydrophobic base cream can be improved, for example, by adding 10% 85% glycerol and optionally 15% refined evening primrose oil. However, this results in a very sticky consistency.

[0047] In a preliminary study, a mixture of substances according to the invention, in the form of a cream consisting of ibuprofen (5% by mass), nicotinamide (4% by mass), and the non-ionic hydrophilic cream SR "neu," was tested on 13 patients. At the beginning of the preliminary study, the patients presented with oncological hand-foot syndrome of varying severity. All patients received drug therapy for tumors with different medications before and during the preliminary study. The patients applied the cream to their hands and feet twice daily for a period of 14 days.

[0048] The following table provides an overview of the preliminary examination: Patient No. Tumor drugs Initial situation Result 1 Irinotecan + Bevacizumab + Panitumumab severe symptoms and limitations in everyday life steady improvement; symptom-free from day 9. 2 nab-paclitaxel + carboplatin + pertuzumab + trastuzumab very severe symptoms and limitations in everyday life Immediate relief from itching and burning; steady improvement; symptom-free on day 14. 3 Capecitabine Skin on thumb split; few limitations in daily life Subjectively significant improvement; one thumb healed on day 5; 4 Capecitabine Cracked skin on fingers; moderate limitations in daily life Subjectively significant improvement; objectively no change in symptoms is discernible. 5 Capecitabine Cracked, irritated cuticles on hands and rough skin on feet; few limitations in daily life symptom-free from day 11 6 Capecitabine Blisters, redness, pain; hardened, painful fingertips with peeling skin; foot problems making walking difficult; feet very red and hard in the area under the toes and on the heel; inflamed toenails Feet and hands quickly became more supple; redness quickly subsided; walking and standing were quickly pain-free; no more pain despite further skin peeling; no renewed inflammation. 7 Capecitabine Minimal redness, pain sensitivity, sensitivity to cold on hands and feet No improvement, severe tingling in feet on day 5, discontinuation on day 6 8 liposomal irinotecan painful ridges on fingers From day 5 onwards, strong tingling in feet, slight improvement on day 13. 9 Capecitabine Skin reddening no discernible effect 10 Capecitabine dry skin, pain, peeling skin on feet Significant improvement after 12 and 14 days 11 Docetaxel Hands: pain, blisters, peeling skin, torn fingernails No more skin peeling after 1 week; no more blisters after 2 weeks, pain only in the fingertips; overall discomfort and limitations fluctuating between moderate and severe. 12 Trastuzumab, Pertuzumab Redness on hands and arms symptom-free after 2 weeks 13 Docetaxel, Epirubicin Feet: Pain, dry skin, thickening on heels and toes Moderate restrictions until day 7; only a few restrictions thereafter.

[0049] In summary, the preliminary study showed that 10 of the 13 patients experienced at least a subjective reduction in the symptoms of oncological hand-foot syndrome through the application of a substance mixture according to the invention in the form of the cream under investigation. In two patients, the application showed no discernible effect. Only in one patient did the application lead to a worsening of their condition. The preliminary study thus supports the positive effect of a substance mixture according to the invention for use in the dermal treatment of a skin disease, in particular oncological hand-foot syndrome.

Claims

1. A mixture of substances for use in the topical treatment of an oncological hand-foot syndrome, a. wherein the mixture of substances contains nicotinamide in a mass fraction of 2 % to 6 % of the mixture of substances, characterised in that b. the mixture of substances contains ibuprofen in a mass fraction of 3 % to 6 % of the mixture of substances.

2. The mixture of substances for use according to claim 1, wherein the ibuprofen is contained in the mixture of substances in a mass fraction of 5 % of the mixture of substances.

3. The mixture of substances for use according to claim 1, wherein the nicotinamide is contained in the mixture of substances in a mass fraction of 4 % of the mixture of substances.

4. The mixture of substances for use according to claim 1, wherein the mixture of substances contains dexpanthenol in a mass fraction of 1 % to 10 % of the mixture of substances.

5. The mixture of substances for use according to claim 1 wherein the mixture of substances comprises an antioxidant agent in a mass fraction of 0.01 % to 10 % of the mixture of substances.

6. The mixture of substances for use according to claim 5, wherein the antioxidant agent comprises vitamin E.

7. The mixture of substances for use according to claim 6, wherein the vitamin E is contained in the mixture of substances in the form of tocopherol in a mass fraction of 0.05 % to 0.5 % of the mixture of substances.

8. The mixture of substances for use according to claim 5, wherein the antioxidant agent comprises ascorbic acid in a mass fraction of 0.01 % to 1 %.of the mixture of substances.

9. The mixture of substances for use according to claim 1, wherein the mixture of substances contains menthol in a mass fraction of 0.1 % to 10 % of the mixture of substances.

10. The mixture of substances for use according to claim 1, wherein the mixture of substances contains a carrier substance, wherein the carrier substance comprises a foam, a gel, a cream or an ointment.

11. The mixture of substances for use according to claim 1, wherein the mixture of substances contains a carrier substance, wherein the carrier substance comprises a non-ionic and / or hydrophilic cream.

12. The mixture of substances for use according to claim 1, wherein the mixture of substances contains a carrier substance, wherein the carrier substance contains water in a mass fraction of 40 % to 80 % of the carrier substance.

13. A method for producing a mixture of substances according to one of claims 1 to 12 for use in the topical treatment of an oncological hand-foot syndrome, the method comprising mixing the substances of the mixture of substances, wherein the mixture of substances is heated to a temperature of 40 °C to 90 °C during mixing.