IT202100016577A1 - Association of hyaluronic acid and oxygen for use in the treatment of symptoms and/or disorders associated with Lichen sclerosus - Google Patents

Description

TITLE: ?Association of hyaluronic acid and oxygen for use in the treatment of symptoms and/or disorders associated with Lichen sclerosus?

DESCRIPTION

FIELD OF THE INVENTION

The field of the present invention relates to an association of molecular oxygen and hyaluronic acid for use in the treatment of anogenital symptoms/disorders.

STATE OF ART

Lichen sclerosus? a chronic inflammatory dermatitis with a predilection for the anogenital area which, in some cases, can be severely affected (labia minora atrophy, phimosis, introital stenosis, etc.). ? a pathology that predominantly affects women (woman/man ratio 6 to 1). Specifically, most cases are diagnosed in postmenopausal women, but can affect women and men of any age. Lichen sclerosus? usually an itchy condition, although it can also be asymptomatic.

The pathology of Lichen sclerosus ? characterized by symptoms such as burning and itching that can afflict women in their daily lives. These symptoms can lead to dyspareunia and injury, both caused by scratching and frailty. of the fabrics. In the advanced stages there is a radical change in the anatomy of the genitals: disappearance of the clitoris, incorporated in fibrosis, disappearance of the labia minora and majora, reduction of the vulvar introitus up to the impossibility of to have sexual intercourse and in extreme cases not even to undergo a gynecological examination. Furthermore, fibrosis can involve the peri-urethral region with dislocation of the urethra and cause the so-called vaginal urination. What are the fabrics? sclerotic patients undergo ulceration causing intense pain and burning. Lichen sclerosus in women? considered a rare pathology (1.7% of gynecological patients) due to the low incidence, but ? also an underestimated pathology why? hidden or unrecognized: patients, in fact, sometimes consider the symptoms of Lichen sclerosus related to menopause.

In men, it can occur a phimosis or fusion of the foreskin on the coronal sulcus. Who? affected perceives a progressive discomfort.

Hyaluronic acid? a natural polysaccharide which constitutes a fundamental part of the extracellular matrix of the skin and cartilage, has remarkable properties adhesive, moisturizing and reparative of mucous membranes and skin. The use of hyaluronic acid for topical use? been used with positive results in the oral treatment of Lichen planus, suggesting that even non-pharmacological active ingredients can have a significant effect in reducing the symptoms of this type of chronic dermatosis.

As far as dermatological pathologies are concerned, topical oxygen therapy? effective in the treatment of psoriasis cos? such as atopic dermatitis and acne [7] given the capabilities? regenerating and anti-inflammatory properties of oxygen in this therapeutic area.

The association of high concentration oxygen and hyaluronic acid shows a certain therapeutic efficacy in the treatment of vulvovaginal atrophy as well as as described in European patent application No. 3645016.

Problem of the prior art

The treatment of Lichen sclerosus, aimed at reducing the disabling symptoms, is mainly carried out with topical corticosteroids. However, their prolonged use can induce drug resistance phenomena and cause important side effects, such as aggravation of atrophy (Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006 Jan;54(1) :1-15; quiz 16-8. doi: 10.1016/j.jaad.2005.01.010. PMID: 16384751). Furthermore, cortisones have no effect on the repair of the scars of the disease.

To overcome the problem linked to the prolonged use of corticosteroids, often even for life, ? desirable to consider new approaches aimed at reducing symptoms.

SUMMARY OF THE INVENTION

Object of the present invention ? an association of molecular oxygen and hyaluronic acid or its salts for use in the treatment of symptoms and/or disorders associated with genital and/or anal Lichen sclerosus.

Further object of the present invention ? a kit for use in the treatment of symptoms and/or disorders from (or associated with) genital Lichen sclerosus.

Advantages of the invention

The association according to the invention is particularly advantageous since? it combines the effects of molecular oxygen and hyaluronic acid on the genital and/or anal tissue level in an enhanced and/or synergistic way. There? this means that the molecular oxygen and the hyaluronic acid included in the association according to the invention support, promote and assist each other's action. Thereby, ? Is it possible to achieve an improvement in the symptoms/disorders associated with Lichen sclerosus and, consequently, an improvement in the quality? of life of those affected by this pathology.

Without wishing to be bound by any theory, the Applicant believes that the use of molecular oxygen included in the association of the invention has a powerful regenerative, antibacterial and biostimulating effect. In this sense, the use of molecular oxygen included in the association proves useful in the treatment of symptoms and/or disorders associated with genital and/or anal Lichen sclerosus for the treatment of lesions and symptoms, such as itching and burning .

The Applicant believes that the increase in availability? of oxygen to the tissues favors the increase of the reparative processes and increases the synthesis of collagen allowing a normal hydroxylation of this protein. In fact, with tissue oxygen tensions lower than normal, collagen is not correctly synthesized, slowing down the healing of ulcers and wounds. Furthermore, oxygen induces a neoangiogenic stimulus through the release of factors such as Vascular Endothelial Growth Factor (VEGF) (Sheikh AY, Gibson JJ, Rollins MD, et al. Effect of hyperoxia on vascular endothelial growth factor levels in a wound model Arch. Surg. 2000; 135:1293?1297). This feature? essential for the restoration of the microcirculation in compromised vascular situations, re-establishing a vascular flow in hypoxic areas which guarantees correct tissue regeneration (Tandara, A. & Mustoe, T. Oxygen in Wound Healing?More than a Nutrient. World J. Surg. ( 2004) 28: 294 ).

It is believed that the improvement of vascular flow in the compromised areas contributes to a better availability of hyaluronic acid locally; given its properties? reparative, hyaluronic acid contributes, together with oxygen, to tissue regeneration, reducing the symptoms and/or disorders associated with Lichen, in particular by resolving the lesions; the combination of hyaluronic acid and oxygen improves the local absorption of hyaluronic acid, an active ingredient which contributes to tissue repair and in particular to the genital lesions typical of Lichen sclerosus.

DESCRIPTION OF THE FIGURES

Figure 1 ? Representation of the cannula type delivery device;

Figure 2 ? Representation of the airbrush type dispensing device;

Figure 3 ? Table 1 representing the results relating to the indices analyzed (pain, burning, itching) of the experimental test of Example 1;

Figure 4 ? Table 2 (Example 1) representing the results of presence/absence of vulvar lesions obtained with the experimental test of Example 1.

DETAILED DESCRIPTION OF THE INVENTION

Lichen sclerosus? a complex disease of autoimmune etiology. The association according to the invention ? able to improve the symptoms and/or disorders associated with genital and/or anal Lichen sclerosus.

By symptoms and/or disturbances associated with genital and/or anal Lichen sclerosus it is meant preferably selected from the group consisting of: pain, burning, itching, dyspareunia, lesions, preferably vulvar lesions, of the foreskin or glans, and mixtures of the previous ones.

Association for use

As anticipated, the combination object of the invention comprises molecular oxygen (or gaseous oxygen) and hyaluronic acid or its salts. According to a preferred embodiment, the association ? made up of molecular (or gaseous) oxygen and hyaluronic acid or its salts.

The association according to the invention comprises molecular oxygen (or gaseous oxygen) with a degree of purity ? 90% (v/v), preferably between 90% and 99% (v/v), preferably between 90% and 96% (v/v), preferably between 92% and 95% (v/v), preferably equal to 95% (v/v).

The molecular oxygen included in the association can? be obtained using methodologies known to those skilled in the art; preferably, the molecular oxygen is obtained thanks to an oxygen concentrator, which sucks the external air and concentrates it in the oxygen fraction. The maximum delivery pressure through the oxygen concentrator ? between 50 and 150 kPa, preferably ? 100kPa.

The dosage of molecular oxygen to be administered? preferably between 5 and 90 litres, preferably between 5 and 80 litres, preferably between 5 and 60 L, preferably between 5 and 20 L, preferably between 7 and 70 litres, preferably between 7 and 60 L.

According to a preferred embodiment of the invention, molecular oxygen ? delivered at a flow preferably between 0.5 and 7 L/min, preferably between 1 and 6 L/min, preferably between 1.5 and 4.5 L/min, preferably equal to 3 L/min.

The combination according to the invention preferably comprises low molecular weight hyaluronic acid; preferably, the association according to the invention comprises hyaluronic acid with a molecular weight between 200 kDa and 2 MDa.

According to a preferred embodiment, the hyaluronic acid ? preferably dissolved in an aqueous solution at a concentration preferably between 0.050% and 0.50% by weight, preferably between 0.050% and 0.30% by weight, preferably between 0.10% and 0.25% by weight, preferably equal to 0.20% by weight on the total volume of the aqueous solution.

Preferably, the dosage of hyaluronic acid ? between 10 mg and 120 mg per unit? of dosage. Preferably, the unit? dosage contains a volume of between 5 and 15 ml, preferably equal to 10 ml. According to a preferred embodiment, the hyaluronic acid solution can be contained in a closed container, preferably an ampoule, bottle, vial.

Preferably, the hyaluronic acid? in the form of hyaluronate salt, preferably sodium hyaluronate.

According to a preferred embodiment, the combination of the invention is delivered directly to the level of the genital and/or anal tissue. It should be noted that the combination of the invention is delivered in the form of a vapor (i.e. vaporized or nebulised).

The association according to the invention can? be dispensed preferably in a time ranging from 5 to 15 minutes (extremes inclusive), preferably ranging from 5 to 10 minutes, preferably equal to 15 minutes, preferably equal to 10 minutes, preferably equal to 5 minutes.

Administration protocol

According to a preferred form of the invention, in particular when the association is intended for the treatment of vaginal Lichen sclerosus, the association? delivered following an administration protocol that includes the following phases:

i) delivery of the combination on the external or vulvar tissue,

ii) distribution of the association inside the female genital apparatus or in the cavity? internal vaginal

the association being the one for use which is the object of the invention.

The organs and anatomical structures placed outside are preferably: the mons de Venus, the labia majora, the labia minora, the Bartholin glands and the clitoris; instead, the organs and anatomical structures located inside the female genital system are preferably: the vagina, the uterine cervix, the uterus, the fallopian tubes and the ovaries.

The external application step i) preferably lasts between 7 and 13 minutes, preferably equal to 10 minutes; while, the internal application step ii) preferably lasts between 2 and 8 minutes, preferably equal to 5 minutes.

For the delivery of the association at the genital and/or anal tissue level, external or internal, two types of delivery devices can preferably be used: a cannula or an airbrush. The cannula? preferably intended for intravaginal delivery of oxygen, hyaluronic acid or its salts and/or the combination of the invention; the airbrush ? preferably used for the external delivery of molecular (or gaseous) oxygen, hyaluronic acid or its salts and/or the combination of the invention.

Preferably, the association according to the invention is to be administered on a weekly basis, preferably once a week; in particular, the association? administrable for a period of time ranging from 5 to 40 consecutive days, preferably ranging from 5 to 10 days, preferably equal to 7 days.

Kit for use in the treatment of symptoms and/or genital Lichen sclerosus disorders

Further object of the present invention ? a kit for use in the treatment of symptoms and/or disorders from or associated with genital Lichen sclerosus, comprising:

- hyaluronic acid or its salts;

- instructions for the preparation of a combination comprising molecular oxygen and hyaluronic acid or its salts;

- one or more dispensing devices suitable for the nebulization of a combination comprising molecular oxygen (or gaseous oxygen) and hyaluronic acid or its salts,

the association being the one for use which is the object of the invention.

According to a preferred embodiment, said kit for use in the treatment of symptoms and/or disorders caused by (or associated with) genital Lichen sclerosus also comprises an oxygen concentrator.

According to a further preferred embodiment, the kit for use in the treatment of symptoms and/or disorders caused by (or associated with) genital Lichen sclerosus further comprises a molecular oxygen transport cable.

Hyaluronic acid or its salts? preferably included inside a closed container, such as for example a vial, bottle, vial. The closed container constitutes a? unit? having preferably a volume between 5 and 15 ml, preferably equal to 10 ml; according to this last embodiment, the number of closed containers comprising hyaluronic acid or its salts? equal to both the number of cannulas and the number of molecular oxygen transport cables.

By salt of hyaluronic acid it is preferably meant sodium hyaluronate.

Hyaluronic acid or its salts? preferably in the form of an aqueous solution of hyaluronic acid, preferably in a concentration between 0.050% and 0.30% by weight, preferably between 0.10% and 0.25% by weight, preferably equal to 0.20% by weight based on total volume of the aqueous solution. According to a preferred embodiment, ? It is possible to spray the combination including molecular oxygen and hyaluronic acid directly on the areas affected by the lesions.

According to a preferred embodiment, the kit for use comprises a disposable delivery device, preferably a vaginal cannula. Note that the vaginal cannula constitutes a vaginal delivery device (or applicator).

Disposable dispenser device means a device that ? used for a single time or a single treatment/protocol, after which? thrown away, i.e. not reusable a second time.

With reference to Figure 1, we describe below the cannula device 100, configured for the delivery of the combination according to the invention.

The cannula 100 comprises a hollow container body 100a, which extends between two ends, along a horizontal axis (X-X): one end? proximal 101 and a? extremity? distal 102. L?Extremity? proximal 101 comprises an opening (not shown in Figure 1), arranged on a flat surface in section with respect to the container body of the cannula. Does the opening include anchoring means for connecting the end? proximal 101 to a molecular oxygen carrying cable of an oxygen concentrator.

The container body 100a comprises a cavity internal (not shown in Figure 1), intended to receive the flow of molecular oxygen coming from the molecular oxygen transport cable and possibly an aqueous solution of hyaluronic acid; and a hole 100b which passes through the container body 100a putting the cavity in fluid communication? internal with the external.

The end? distal 102 comprises a head portion 102a, having an ovoid or rounded shape, provided with at least two holes 102b for the nebulization of the association of molecular oxygen and hyaluronic acid or its salts. Preferably, the head portion 102a is integral with the container body 100a.

It should be noted that the head portion 102a is also hollow and in flow communication with the hollow container body 100a of the cannula.

According to a preferred embodiment, the head portion 102a comprises at least two shaped ribs 102c, which project from the outer surface of the head portion 102a, defining depressions 102d where the at least two holes 102b are located. The holes 102b pass through the head portion 102a putting the hollow container body 100a of the cannula and the outside in fluid communication.

Preferably, there are four shaped ribs 102c and they are arranged in a cross on the head portion 102a. The ribs are preferably tapered, widening towards the end? distal 102 and narrowing towards the? Extremity? proximal 101, cos? to give the head portion 102a a shape that is comfortable for intravaginal insertion.

According to a preferred embodiment, the holes 102b are located in pairs (in number equal to 2) on each of the depressions defined by the ribs 102c.

It should be noted that, advantageously, the ribs 102c are so? shaped allow, at the time of use, to move the mucosal tissues away from the external surface of the cannula, facilitating the release of molecular oxygen and/or of the combination comprising molecular oxygen and hyaluronic acid.

Note that the molecular oxygen transport cable ? the cable of an oxygen concentrator. Preferably, the molecular oxygen transport cable ? of material suitable for transporting molecular oxygen (or gaseous oxygen), preferably ? in polymeric material, preferably ? made of polypropylene (PP). The oxygen concentrator? an instrument known in the state of the art and commercially available, configured to suck the outside air and filter it, to obtain air with an oxygen content ? 80%.

Note that a generic oxygen concentrator preferably comprises:

- a compressed air generator or compressor configured to draw in air from the external environment, filter and compress it.

- a machine body, comprising or equipped with zeolite molecular sieves. The machine body exploits the principle of different absorption of gas molecules to let O2 pass and retain the other gases present in the air, such as nitrogen, argon, helium and hydrogen. The machine body transforms the outside air into 93-95% pure oxygen.

- oxygen transport cable, equipped with anchoring means suitable for hooking a delivery device, said delivery device being preferably chosen between a vaginal cannula and an airbrush.

According to a further embodiment, the kit for use according to the invention comprises a multipurpose (or reusable) dispenser device, preferably an airbrush.

Preferably, the kit for use according to the invention comprises both a single-use delivery device, preferably a vaginal cannula, and a multi-use (or reusable) delivery device, preferably an airbrush.

With reference to Figure 2, a preferred embodiment of an airbrush suitable for the purposes of the invention is described below.

The airbrush 200 comprises a hollow container body 200a, having an upper surface 201 and a lower surface 202; the hollow container body extends between two ends, along a horizontal axis Y-Y: one end? proximal 203 and a? extremity? distal 204.

Does the container body include a cavity? internal, suitable for receiving a pressurized flow of molecular oxygen.

The end? distal 204 ? consisting of a handle for use by a user.

The end? proximal 203 comprises an opening (not shown in Figure 2), arranged on a flat surface in section with respect to the container body 200a of the airbrush, which puts the cavity in fluid communication with the internal with the external. The opening comprises a nozzle 203a for discharging molecular oxygen or the association of molecular oxygen and hyaluronic acid.

Does the airbrush include a conduit 205 in fluid communication with the cavity? internal part of the container body, arranged between the? extremity? proximal 203 and the? extremity? distal 204, and which projects from one of the surfaces of the container body 200a.

The conduit 205 includes anchoring means for connection to a molecular oxygen transport cable of an oxygen concentrator.

The container body 200a further comprises a valve assembly 206 for regulating the flow of molecular oxygen passing through the cavity. inside the container body. The valve assembly 206 includes a lever or knob 206a which adjusts the position of the valve to modulate the flow of oxygen. The lever or the button are preferably located on the upper surface 201 of the airbrush, between the end? distal 204 and proximal 203.

The airbrush comprises a tank 207, arranged on the upper surface 201 of the container body 200a, the tank 207 comprising a concavity inner 207a and a lid 207b. The concavity? internal 207a includes an opening in fluid communication with the cavity? inside of the container body; this concavity? internal 207a, suitable for receiving a liquid, allows this liquid to flow towards the cavity? inside the container body.

At the moment of use, when the duct 205 is anchored to the cable for transporting the molecular oxygen of a pressure generator and the pressure generator is activated, the outflow of the liquid from the tank 207 to the container body 200a of the gun? induced by the formation of a pressure difference between the cavity? inside of the container body and the concavity? tank interior 207a.

The 200 airbrush? preferably in material suitable for withstanding sterilizations (such as autoclaving or similar), preferably ? steel.

The airbrush ? preferably used for delivery / nebulization at the level of the external genitalia.

EXAMPLES

Below, the Applicant gives examples for purely illustrative and non-limiting purposes.

Example 1 ? Experimental test

1.1 Material and methods

Twenty-five (25) women diagnosed with Lichen sclerosus, performed by vulvoscopy and biopsy, underwent a weekly session for 5 weeks which included:

i) a 10-minute vulvar oxygen therapy treatment with nebulization of low molecular weight hyaluronic acid, at a concentration of 0.2% (w/v) by weight on the total volume of aqueous solution (or external application phase), followed by

ii) a vaginal oxygen therapy treatment combined with hyaluronic acid for 5 minutes (or internal application phase).

For treatment? An oxygen therapy device for gynecological use was used which allows the topical administration of oxygen with a high degree of purity up to 93?3% and at a flow rate between 1 and 6 L/min (litres/minute).

On the subjects treated? a double evaluation was performed: a subjective one by the patients and one by the doctor. The subjective scale was completed using an analog graded card which evaluated pain during sexual intercourse (dyspareunia), itching and burning with a VAS scale from 0 to 10, where 10 represents the intensity maximum and 0 the absence of the disorder, analyzing the symptoms at T0 (before the first treatment session) and at the end of the 5 sessions (T5). ? the presence or absence of lesions was finally evaluated by the doctor.

1.2 Results

Thanks to the qualitative improvement of the tissues, the patients reported a significant improvement in all the indices analyzed (Table 1, Figure 3), with the greatest effect regarding the reduction of pain (VAS T0= 8.0; VAS T5=1 ,4, Wilcoxon signed-rank test P<0.0001), but also with regard to burning (VAS T0= 6.1; VAS T5=2.0, Wilcoxon signed-rank test P<0.0001) and itching ( VAS T0= 6.5; VAS T5=1.1, Wilcoxon signed-rank test P<0.0001).

The fundamental observation for this study? was the evaluation of the presence of vulvar lesions at T0 and at the end of the treatment. All the women who initially had lesions (84%), especially in the fork area, no longer have lesions. presented this problem, demonstrating the complete resolution of the problem (Table 2, Figure 4).

No side effects associated with the treatment were reported by the patients.

Claims (11)

1. Association of molecular oxygen and hyaluronic acid or its salts for use in the treatment of symptoms and/or disorders associated with genital and/or anal Lichen sclerosus. 2. Association for use according to claim 1, wherein the molecular oxygen has a degree of purity ? 90% (v/v). 3. The combination for use according to claim 1 or 2, wherein the dosage of molecular oxygen is between 5 and 90 litres. 4. Combination for use according to any one of claims 1 to 3, wherein the hyaluronic acid has a molecular weight between 200 kDa and 2 MDa. 5. Combination for use according to any one of claims 1 to 4, wherein the dosage of hyaluronic acid is between 10 mg and 120 mg per unit? of dosage. 6. Combination for use according to any one of claims 1 to 5, wherein the hyaluronic acid is dissolved in an aqueous solution at a concentration between 0.05% and 0.5% by weight of the total volume of the aqueous solution. 7. Combination for use according to any one of claims 1 to 6, wherein the hyaluronic acid is in the form of sodium hyaluronate. 8. Combination for use according to any one of claims 1 to 7, wherein the symptoms and/or disorders associated with genital and/or anal Lichen sclerosus ? chosen from the group consisting of: pain, burning, itching, dyspareunia, genital lesions and mixtures of the above. 9. Kit for use in the treatment of symptoms and/or disorders associated with genital Lichen Sclerosus, comprising: - hyaluronic acid or its salts; - instructions for the preparation of a combination comprising molecular oxygen and hyaluronic acid or its salts; - one or more dispensing devices suitable for the nebulization of a combination comprising molecular oxygen (or gaseous oxygen) and hyaluronic acid or its salts, the association being that for use according to any one of claims 1 to 8. 10. Kit for use according to claim 9, wherein the dispensing device is a disposable vaginal cannula and/or an airbrush. The kit for use according to claim 10, wherein the disposable vaginal cannula (100) comprises a hollow container body (100a), which extends between two ends, along a horizontal axis (X-X), an? end? proximal (101), comprising an opening arranged on a flat surface in section with respect to the container body of the cannula, the opening comprising anchoring means for connecting the end? proximal (101) to a molecular oxygen carrying cable of an oxygen concentrator, an? end? distal (102) comprising a head portion (102a) provided with at least two holes (102b) for nebulization of the association of molecular oxygen and hyaluronic acid or its salts, the head portion (102a) being also hollow and in flow communication with the hollow container body (100a) of the cannula, characterized by the fact that does the container body (100a) include a cavity? internal that, when the? extremity? proximal (101) ? anchored to the molecular oxygen transport cable, it allows the flow of gas from the end? proximal (101) at? extremity? distal cavity (102), and a hole (100b) configured for the injection of an aqueous solution of hyaluronic acid or its salts into the flow of molecular oxygen, the hole (100b) putting the cavity in fluid communication? inside of the container body (100a) with the outside.