Nasal ointment

Abstract

The present invention relates to a nasal ointment comprising hyaluronic acid, dexpanthenol and an aloe vera extract. The present invention also relates to the use of hyaluronic acid, dexpanthenol and an aloe vera extract for manufacturing an agent used in various medical procedures. The invention also relates to a method for the preparation of said nasal ointment.

Description

[0001] Nasal ointment

[0002] technical field

[0003] The present invention relates to a nasal ointment comprising hyaluronic acid, dexpanthenol, and an aloe vera extract. The present invention also relates to the use of hyaluronic acid, dexpanthenol, and an aloe vera extract to manufacture an agent used in various medical procedures. The invention further relates to a method for preparing said nasal ointment.

[0004] Previous art

[0005] A variety of products have been described for their beneficial effects on the nasal mucosa, particularly for promoting nasal mucosal healing. The review by Jegedevswari Selvarajah et al., Int J Mol Sci. 2020 Jan; 21(2): 480, discusses therapies available for treating nasal mucosal wounds. Among others, nebulized sodium hyaluronate is mentioned as a way to accelerate recovery after endonasal surgery.

[0006] Some ointments are also known to promote hydration of the nasal mucosa, such as Bepanthen® ointment, which contains dexpanthenol. In addition, various aloe vera gels are available, and the cooling and moisturizing effects of extracts from this plant have been documented.

[0007] However, despite this knowledge, there remains a need to provide effective solutions to promote the healing of nasal wounds, resulting in particular from endonasal surgery, and to reduce or treat dryness and inflammation of the nasal mucosa, particularly in subjects suffering from conditions that promote these symptoms, such as various types of chronic and acute rhinitis, as well as diseases such as cystic fibrosis or primary ciliary dyskinesia.

[0008] It is particularly useful to provide solutions with properties that promote patient comfort, and in particular to avoid the application of strongly odorous products to the nasal mucosa. Products intended for internal use in the nasal cavities and with an odor perceptible to the patient can indeed be bothersome, notably by interfering with the perception of environmental odors and food aromas. Therefore, it would be desirable to provide an effective product with a neutral odor. Summary of the invention

[0009] The first aspect of the invention consists of a nasal ointment comprising hyaluronic acid, dexpanthenol and an aloe vera extract.

[0010] The second aspect of the invention consists of the use of hyaluronic acid, dexpanthenol and an aloe vera extract to manufacture an agent used in a medical process intended for the regeneration and / or healing of the nasal mucosa.

[0011] The third aspect of the invention consists of the use of hyaluronic acid, dexpanthenol and an aloe vera extract to manufacture an agent used in a medical procedure intended to prevent, reduce and / or treat dryness of the nasal mucosa.

[0012] The fourth aspect of the invention consists of the use of hyaluronic acid, dexpanthenol and an aloe vera extract to manufacture an agent used in a medical procedure intended to reduce or treat inflammation of the nasal mucosa.

[0013] The fifth aspect of the invention consists of a method for manufacturing a nasal ointment comprising mixing hyaluronic acid, dexpanthenol and an aloe vera extract with water and an excipient.

[0014] Detailed description of the invention

[0015] The nasal ointment of the present invention combines three active ingredients: hyaluronic acid, dexpanthenol, and an aloe vera extract. These three active ingredients have synergistic effects that give the ointment unique properties for the purpose of

[0016] the regeneration and / or healing of the nasal mucosa;

[0017] the prevention, reduction and / or treatment of dryness of the nasal mucosa; and the treatment or reduction of inflammation of the nasal mucosa.

[0018] The ointment of the present invention preferably has a neutral odor, so as to avoid patient discomfort and / or irritation of the mucous membranes. Thus, the nasal ointment is preferably free of perfumes, aromas, essential oils, or any other ingredient whose odor is perceptible upon administration of the ointment into the nasal passages. The present active ingredients advantageously have a neutral odor at effective concentrations.

[0019] In a preferred aspect of the invention, the ointment consists of hyaluronic acid, dexpanthenol, an aloe vera extract, an excipient, and water.

[0020] The term "constituted" is used here to define a closed list of ingredients, excluding any other component, as opposed to the terms "comprising" and "includes," which denote an open list of ingredients and allow for the presence of optional additional ingredients. Aloe vera extract has

[0021] Aloe vera extract has a refreshing, soothing, softening, moisturizing, and regenerating effect. It calms overheating and skin reactivity, and helps the skin and mucous membranes to repair themselves. It contains numerous components such as vitamins A, C, E, B1, B2, B3, B4, B6, B9 (folic acid), and B12, many minerals, enzymes (bradykinase, lipase, peroxydase, tyrosinase, etc.), seven of the eight essential amino acids, fatty acids (linoleic acid), saponins, salicylic acid, and sterols, which give it its regenerating, anti-inflammatory, soothing, and moisturizing properties.

[0022] Aloe vera extract is obtained from aloe vera leaves and is referenced as CAS NO.: 8001-97-6. ​​Aloe vera extracts can be obtained from various suppliers such as Hânseler AG (Herisau, Switzerland).

[0023] Aloe vera extract is preferably in gel form.

[0024] Aloe vera extract is preferably present in a concentration of 1 to 10% by mass, relative to the total mass of the nasal ointment, preferably in a concentration of 2 to 9%, preferably 3 to 8%, preferably 4 to 7%, preferably 4.5 to 6%, preferably 5% by mass relative to the total mass of the nasal ointment.

[0025] Dexpanthenol

[0026] Dexpanthenol is a precursor of pantothenic acid, or vitamin B5. Pantothenic acid, in turn, is the precursor of coenzyme A, a substance found in every cell and playing a key role in energy metabolism. Specifically, it promotes the development, function, and repair of epithelial and endothelial tissues.

[0027] Pantothenic acid is therefore involved in the formation and regeneration of skin and mucous membranes, thus contributing to wound healing. As a precursor, dexpanthenol plays a key role in this mechanism.

[0028] Like all B complex vitamins, pantothenic acid is water-soluble, non-toxic and very well tolerated, even at very high doses, and is found throughout the body.

[0029] Dexpanthenol is referenced as CAS NO.: 81-13-0 and is available from many suppliers.

[0030] Dexpanthenol is preferably present in a concentration of 0.5 to 5% by mass, relative to the total mass of the nasal ointment, preferably in a concentration of 0.6 to 4%, preferably 0.7 to 3%, preferably 0.8 to 2%, preferably 0.9 to 1.5%, preferably 1% by mass relative to the total mass of the nasal ointment.

[0031] Hyaluronic acid

[0032] Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan (GAG) naturally distributed throughout the human body. Hyaluronic acid is the main component of the extracellular matrix. It is found in large quantities in the skin, where it is produced by fibroblasts and keratinocytes. One of its primary functions is to retain water within the intercellular matrix of connective tissue. This water-retention capacity contributes significantly to skin elasticity. Hyaluronic acid acts as a water pump, maintaining elasticity by serving as a water reservoir. Hyaluronic acid is also involved in tissue repair.

[0033] In normal human skin, hyaluronic acid exists as a medium molecular weight polymer (600-1000 kDa). The physiological degradation of hyaluronic acid in the skin is produced by internalization by keratinocytes and by fragmentation by hyaluronidases.

[0034] A local deficiency in hyaluronic acid leads to insufficient regeneration of connective tissue fibrils, a low rate of vascular tissue regeneration, decreased phagocytic activity of histiocytes, and reduced fibroblast proliferation. Furthermore, in the event of tissue injury, the administration of exogenous hyaluronic acid provides anti-inflammatory activity and stimulates the formation of granulation tissue, thereby accelerating the healing process and epithelialization of lesions.

[0035] High molecular weight hyaluronic acid has been used for many years as a natural moisturizer in the cosmetics industry. However, the use of very low molecular weight hyaluronic acid, such as HyaCare® 50 (origin: Evonik), with a molecular weight of 50 kDa, has demonstrated superior penetration into the skin and mucous membranes compared to medium molecular weights. It is also possible to use hyaluronic acid with an even lower molecular weight, such as Hyalo Oligo® (origin: Kewpie Corp., Japan), with a molecular weight of 7 kDa.

[0036] A low molecular weight hyaluronic acid, as described above, is completely soluble in water and can be cold-processed. For the preparation of oil-in-water or water-in-oil emulsions, it must be added to the aqueous phase. Low molecular weight hyaluronic acid exhibits good compatibility with the other ingredients of the present nasal ointment. Therefore, the nasal ointment of the present invention preferably comprises low molecular weight hyaluronic acid.The hyaluronic acid used in the present invention is preferably characterized by a molecular weight less than or equal to 100 kDa, preferably a molecular weight less than or equal to 90 kDa, preferably a molecular weight less than or equal to 80 kDa, preferably a molecular weight less than or equal to 70 kDa, preferably a molecular weight less than or equal to 60 kDa, preferably a molecular weight less than or equal to 50 kDa, preferably a molecular weight of 5 to 50 kDa, preferably of 7 to 50 kDa.

[0037] Hyaluronic acid is preferably present in a concentration of 0.1 to 1% by mass, relative to the total mass of the nasal ointment, preferably in a concentration of 0.2 to 0.9%, preferably 0.3 to 0.8%, preferably 0.4 to 0.7%, preferably 0.45 to 0.6%, preferably 0.5% by mass relative to the total mass of the nasal ointment.

[0038] Excipient

[0039] The nasal ointment of the present invention preferably also comprises an excipient. Various excipients are known for the preparation of ointments suitable for application to the nasal mucous membranes. The present ointment is preferably in the form of an oil-in-water emulsion. The excipient is therefore preferably one with a high water-absorbing capacity. For example, such an excipient comprises one or more components selected from petrolatum, cetyl acid, cetyl alcohol, stearic acid, stearyl alcohol, cetearyl acid (a mixture of cetyl acid and stearic acid), cetearyl alcohol (a mixture of cetyl alcohol and stearyl alcohol), lanolin, lanolin alcohol, and glyceryl monostearate.

[0040] Preferably, the excipient used in the ointment of the present invention comprises petrolatum (CAS NO.: 8009-03-8), lanolin alcohol (CAS NO.: 8027-33-6), cetearyl alcohol (CAS NO.: 67762-27-0), and water. This base is ideal for nasal ointments because its high water absorption capacity allows for the creation of a medium with a high water content and ensures the miscibility of water-soluble active ingredients in the ointment. White and odorless, this excipient does not cause olfactory discomfort. Examples of such excipients include Pionier® MAA and Pionier® MAA Weich, both commercially available from Hansen & Rosenthal GmbH & Co. KG, Hamburg, Germany. Preferably, petrolatum is present at a concentration of at least 50% by mass, relative to the total mass of the excipient. Preferably, lanolin alcohol is present at a concentration of 5 to 10% by mass, relative to the total mass of the excipient.Preferably, cetearyl alcohol is present in a concentration of 0.1 to 1% by mass, relative to the total mass of the excipient.

[0041] Benefits

[0042] As demonstrated in Example 4 below, the ointment of the present invention is effective for:

[0043] to regenerate and / or heal the nasal mucosa,

[0044] to prevent, reduce and / or treat dryness of the nasal mucosa, and

[0045] reduce or treat inflammation of the nasal mucosa.

[0046] Thus, the invention relates to

[0047] the use of hyaluronic acid, dexpanthenol and an aloe vera extract, to manufacture an agent used in a medical procedure intended for the regeneration and / or healing of the nasal mucosa, preferably in a medical procedure intended to reduce the duration of healing of the nasal mucosa, preferably after endonasal surgery.

[0048] the use of hyaluronic acid, dexpanthenol and an aloe vera extract to manufacture an agent used in a medical procedure intended to prevent, reduce and / or treat dryness of the nasal mucosa, and

[0049] the use of hyaluronic acid, dexpanthenol and an aloe vera extract to manufacture an agent used in a medical procedure intended to reduce or treat inflammation of the nasal mucosa.

[0050] Preferably, the invention relates to the use of a mixture of hyaluronic acid, dexpanthenol and aloe vera extract to manufacture an agent used in said medical processes.

[0051] Preferably, these medical procedures are applied to a subject in need of them, preferably a subject

[0052] having recently undergone endonasal surgery (as part of post-surgical care), suffering from chronic rhinosinusitis with or without allergy,

[0053] suffering from acute rhinosinusitis,

[0054] suffering from chronic crusted and / or atrophic rhinitis,

[0055] suffering from recurrent nosebleeds, suffering from cystic fibrosis, and / or

[0056] affected by primary ciliary dyskinesia (Kartagener).

[0057] In a preferred aspect of the invention, the medical procedure is intended for the regeneration and / or healing of the nasal mucosa, preferably in a medical procedure intended to reduce the duration of healing of the nasal mucosa, preferably after endonasal surgery, in a subject who has recently undergone such surgery.

[0058] In another preferred aspect of the invention, the medical process is intended to prevent, reduce and / or treat dryness of the nasal mucosa in a subject suffering from chronic rhinosinusitis, with or without allergy, crusty and / or atrophic chronic rhinosinusitis and / or recurrent epistaxis.

[0059] In another preferred aspect of the invention, the medical process is intended to prevent, reduce or treat inflammation of the nasal mucosa in a subject suffering from chronic rhinosinusitis, with or without allergy, crusty and / or atrophic chronic rhinosinusitis and / or recurrent epistaxis.

[0060] Preferably, the medical procedure involves the local administration of the agent at the entrance to the nasal cavities. This local administration can advantageously be carried out using a non-abrasive object or a suitable tip attached to the container holding the ointment. Preferably, the ointment, object, or tip is for single use only to ensure more hygienic application. A cotton swab, for example, is a particularly suitable non-abrasive, single-use object for applying the ointment at the entrance to the nasal cavities. The ointment is then placed on the cottony end of the swab, which is then gently inserted into the subject's nostril to apply the ointment inside the nasal cavities, onto the mucous membrane.

[0061] Preferably, the method involves daily administration of the agent, preferably at least twice a day, preferably exactly twice a day, at the entrance to the nasal cavities. Preferably, the method involves administration of the agent for at least one week, preferably for at least two weeks, preferably for at least three weeks, preferably for at least one month, preferably for at least two months, preferably for at least three months. Examples

[0062] Example 1: Nasal ointment according to the invention

[0063] A nasal ointment is formulated as follows:

[0064]

[0065] 1) Hyacare® 50 kDa (Evonik)

[0066] 2) Aloe Vera Gel 1:1 ad us. external (Hânseler)

[0067] 3) Pionier® MAA (Mixture of petroleum jelly, cetearyl alcohol and lanolin alcohol in water, origin: Hansen & Rosenthal GmbH, Hamburg, Germany)

[0068] Example 2: Nasal ointment according to the invention

[0069] A nasal ointment is formulated as follows:

[0070]

[0071] 1) Hyalo Oligo® (Kewpie Corp. Japan)

[0072] 2) Aloe Vera Gel 1:1 ad us. external (Hânseler)

[0073] 3) Pionier® MAA (Mixture of petrolatum, cetearyl alcohol and lanolin alcohol in water, origin: Hansen & Rosenthal GmbH, Hamburg, Germany) Example 3: Process for preparing the ointments of examples 1 and 2

[0074] An ointment according to Example 1 (10 g) was prepared as follows. Hyaluronic acid (0.05 g) was first dissolved in approximately 3 g of water. Separately, dexpanthenol (0.1 g) was mixed with an equal volume of the excipient Pionier® MAA. The remaining excipient was then added gradually. Aloe vera extract was then added to the dexpanthenol and excipient mixture. With stirring, the hyaluronic acid-water solution was then added to the mixture of the other ingredients. The remaining water (40.5 g) was then added.

[0075] Example 2: Clinical evidence of improved nasal function after twice-daily endonasal application

[0076] Summary :

[0077] The tolerability and objective and subjective benefits of endonasal application of Example 1 ointment were evaluated in 337 patients with nasal dysfunction. Significant improvement in symptoms and the clinical appearance of the endonasal mucosa was observed in 76% to 87% of completing patients after 3 months of treatment.

[0078] Materials and methods:

[0079] Evaluation before and 3 months after application 2x / day of the ointment from Example 1 to the entrance of the nasal cavities with a cotton swab.

[0080] Population :

[0081] n: 337

[0082] 160 women

[0083] 177 men

[0084] Age: 4 to 82 years. Indications for prescribing the nasal ointment in Example 1:

[0085] Post-endonasal surgery care

[0086] - Chronic rhinosinusitis with or without allergy (with or without administration of topical corticosteroids) daily causing a reduction in biological functions and therefore crusting and nosebleeds)

[0087] - Acute rhinosinusitis

[0088] - Chronic crusty and atrophic rhinitis

[0089] - Recurrent nosebleeds.

[0090] - Cystic fibrosis

[0091] - Primary ciliary dyskinesia (Kartagener)

[0092] Results :

[0093] No subjective or objective signs of intolerance or allergy were observed.

[0094] A significant reduction in postoperative healing time was measured in 87% of patients.

[0095] In patients with chronic rhinosinusitis with or without allergy, acute rhinosinusitis, chronic crusted and atrophic rhinitis, recurrent epistaxis, cystic fibrosis, and / or primary ciliary dyskinesia, an improvement in symptoms and clinical signs (dryness of the nasal mucosa, inflammation, crusting) was recorded in 76% of the subjects evaluated. Improvement in symptoms and clinical signs was observed in all these indications.

Claims

Demands 1. A nasal ointment containing hyaluronic acid, dexpanthenol and an aloe vera extract.

2. The nasal ointment according to claim 1, wherein the aloe vera extract is present in gel form.

3. The nasal ointment according to claim 1 or 2, wherein the hyaluronic acid is characterized by a molecular weight less than or equal to 100 kDa.

4. The nasal ointment according to any one of the preceding claims, wherein the ointment is in the form of an oil-in-water emulsion.

5. The nasal ointment according to any one of claims 1 to 4, further comprising an excipient comprising a mixture of petrolatum, cetearyl alcohol and lanolin alcohol.

6. The nasal ointment according to any one of the preceding claims, wherein the aloe vera extract is present in a concentration of 2 to 9% by mass, relative to the total mass of the nasal ointment; Dexpanthenol is present in a concentration of 0.5 to 5% by mass, relative to the total mass of the nasal ointment; and Hyaluronic acid is present in a concentration of 0.1 to 1% by mass relative to the total mass of the nasal ointment.

7. The nasal ointment according to claim 6, where Aloe vera extract is present in a concentration of 4 to 7% by mass, relative to the total mass of the nasal ointment; Dexpanthenol is present in a concentration of 0.8 to 2% by mass, relative to the total mass of the nasal ointment; and Hyaluronic acid is present in a concentration of 0.4 to 0.7% by mass relative to the total mass of the nasal ointment.

8. The nasal ointment according to any one of the preceding claims, wherein said ointment is composed of hyaluronic acid, dexpanthenol, an aloe vera extract, an excipient and water.

9. Use of hyaluronic acid, dexpanthenol and an aloe vera extract to manufacture an agent used in a medical procedure for the regeneration and / or healing of the nasal mucosa.

10. The use according to claim 9, wherein the agent is used in a medical procedure intended for the regeneration and / or healing of the nasal mucosa in a subject who has recently undergone endonasal surgery.

11. Use of hyaluronic acid, dexpanthenol and an aloe vera extract to manufacture an agent used in a medical procedure intended for a. prevent, reduce and / or treat dryness of the nasal mucosa; and / or b. reduce or treat inflammation of the nasal mucosa.

12. The use according to claim 11, wherein the agent is used in a medical procedure intended to a. To prevent, reduce and / or treat dryness of the nasal mucosa; and / or b. To reduce or treat inflammation of the nasal mucosa in a subject with chronic rhinosinusitis with or without allergy, acute rhinosinusitis, chronic crusty and atrophic rhinitis, recurrent epistaxis, cystic fibrosis, and / or primary ciliary dyskinesia.

13. Use according to any one of claims 9 to 12, wherein the agent is administered at least twice daily by application to the entrance of the nasal cavities.

14. Process for the manufacture of a nasal ointment comprising the mixture of hyaluronic acid, dexpanthenol and an aloe vera extract with water and an excipient.

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