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

Abstract

A mixture of substances for use in the topical treatment of an oncological hand-foot syndrome, characterized in that the mixture contains the following substances: a. Ibuprofen or diclofenac with a mass fraction of 0.5% to 10% in the mixture; b. Nicotinamide with a mass fraction of 0.5% to 10% in the mixture and c. Tocopherol and / or ascorbic acid with a mass fraction of 0.01% to 10% in the mixture.

Description

Technical field

[0001] The invention relates to a mixture of substances for use in the topical treatment of an oncological hand-foot syndrome and 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] The publications CN 108078961 A, CN 108096228 A, and JP 2020-045315 A each disclose a mixture of substances for use in the topical treatment of a skin disease, wherein the mixture contains ibuprofen or loxoprofen as a non-steroidal anti-inflammatory drug, nicotinamide, and ascorbic acid or citric acid as an antioxidant. Natalie H. Matthews et al., in their article "Dermatologic Toxicities of Anticancer Therapy" in Abeloff's Clinical Oncology (6th ed. 2020, pp. 621–648, DOI: 10.1016 / B978-0-323-47674-4.00041-4), describe ongoing studies on the preventive treatment of oncological hand-foot syndrome with nicotine patches. Technical task

[0008] The object of the invention is to create a simple and safe drug for the effective topical treatment of 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 at least one non-steroidal anti-inflammatory drug with a mass fraction of 0.5% to 10% of the mixture.

[0012] The mixture contains nicotinamide with a mass fraction of 0.5% to 10%.

[0013] The mixture 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] The drug in question includes at least one non-steroidal anti-inflammatory agent, ibuprofen or diclofenac. 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] The ibuprofen is preferably present in the mixture at a mass fraction of 1% to 8%, more preferably 3% to 6%, and particularly preferably 5%. These mass fractions ensure safe and effective treatment of the skin condition.

[0020] The diclofenac is preferably present in the mixture at a mass fraction of 1% to 8%, more preferably 3% to 6%, and particularly preferably 5%.

[0021] Diclofenac is characterized by an additional antitumor effect, which is advantageous for its use in treating actinic keratosis. Disadvantages of diclofenac include the potential side effects of photosensitization and skin irritation, as well as a shorter shelf life.

[0022] The nicotinamide is preferably present in the mixture at a mass fraction of 0.5% to 10%, more preferably 2% to 6%, and particularly preferably 4%. These mass fractions ensure a safe and effective treatment of the skin condition.

[0023] 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.

[0024] The at least one antioxidant component comprises tocopherol and / or ascorbic acid. The tocopherol is preferably synthetically produced and / or contains all eight stereoisomers of tocopherol (all-rac-tocopherol). Synthetic production guarantees consistent product quality. Using all stereoisomers eliminates the need for complex separation and thus reduces the cost of manufacturing the mixture.

[0025] 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%.

[0026] 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.

[0027] Ascorbic acid is preferably present in the mixture at a mass fraction of 0.01% to 1%, particularly preferably 0.02% to 0.5%. These mass fractions ensure a safe and effective treatment of the skin condition.

[0028] 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.

[0029] The mixture contains, for example, menthol, preferably in a mass fraction of 0.1% to 10%, particularly preferably 0.25% to 5%. Menthol has anti-inflammatory and cooling properties, as well as secondary 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.

[0030] The mixture contains at least one antioxidant active ingredient, such as N-acetylcysteine ​​(NAC), preferably with a mass fraction of 5% to 10%. Disadvantages of N-acetylcysteine ​​include potential side effects such as irritation and an unpleasant odor.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] A method according to the invention serves to produce the mixture 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

[0036] 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%

[0037] 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%

[0038] 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 substance. 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 substance 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.

[0039] 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.

[0040] 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.

[0041] For the stability study, the mixture was produced four times. The difference was the primary packaging. The mixture was filled twice into aluminum tubes and twice into jars. 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 monthly.

[0042] 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.

[0043] 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.

[0044] Another example of a carrier substance is the cooling cream (Unguentum leniens) 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 %

[0045] 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.

[0046] 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%

[0047] 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.

[0048] 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.

Claims

[1] Compound for use in the topical treatment of oncological hand-foot syndrome, characterized by , that the mixture contains the following substances: a. Ibuprofen or diclofenac with a mass fraction of 0.5% to 10% in the mixture; b. Nicotinamide with a mass fraction of 0.5% to 10% in the mixture and c. Tocopherol and / or ascorbic acid with a mass fraction of 0.01% to 10% in the mixture. [2] Mixture for use according to claim 1, wherein the ibuprofen is contained in the mixture in a mass fraction of 1% to 8%, preferably 3% to 6%, particularly preferably 5%. [3] Mixture for use according to one of claims 1 to 2, wherein the nicotinamide is contained in the mixture in a mass fraction of 0.5% to 10%, preferably 2% to 6%, particularly preferably 4%. [4] Mixture for use according to any one of claims 1 to 3, wherein the mixture contains dexpanthenol with a mass fraction of 1% to 10%, preferably 3% to 7%, particularly preferably 5%. [5] Mixture for use according to claim 1, wherein the tocopherol is contained in the mixture in a mass fraction of 0.05% to 0.5%, preferably 0.1% to 0.4%, particularly preferably 0.2%. [6] Mixture for use according to any one of claims 1 to 5, wherein the ascorbic acid is contained in the mixture in a mass fraction of 0.01% to 1%, particularly preferably 0.02% to 0.5%. [7] Mixture for use according to any one of claims 1 to 6, wherein the mixture contains menthol with a mass fraction of 0.1% to 10%, preferably 0.25% to 5%. [8] Mixture for use according to any one of claims 1 to 7, wherein the mixture contains a carrier substance, the carrier substance comprising a foam, a gel, a cream or an ointment. [9] Mixture for use according to any one of claims 1 to 8, wherein the mixture contains a carrier substance, the carrier substance comprising a non-ionic and / or hydrophilic cream. [10] Mixture for use according to any one of claims 1 to 9, wherein the mixture contains a carrier substance, wherein the carrier substance contains water with a mass fraction of the carrier substance of 40% to 80%, preferably of 60% to 70%. [11] Method for producing a mixture of substances for use according to any one of claims 1 to 10, comprising mixing the substances of the mixture, wherein the mixture is preferably heated to a temperature of 40 °C to 90 °C, particularly preferably 50 °C to 80 °C, and most preferably 60 °C to 70 °C during mixing.