Molecular oxygen and hyaluronic acids for topical-vaginal uses

Abstract

A method for treatment of vaginal disorders may include: administering topically to a subject in need thereof a therapeutically effective amount of molecular oxygen and hyaluronic acid. The molecular oxygen may be in gaseous form. The vaginal disorders may be selected between vaginal dryness and vulvovaginal atrophy.

Claims

1. A method for treatment of vaginal disorders, the method comprising: administering topically to a subject in need thereof a therapeutically effective amount of molecular oxygen and hyaluronic acid; wherein the molecular oxygen is in gaseous form, and wherein the vaginal disorders are selected from the group consisting of vaginal dryness and vulvovaginal atrophy.

2. The method of claim 1, wherein the molecular oxygen has a purity degree greater than or equal to 80% volume per volume (v/v) and less than or equal to 97% (v/v).

3. The method of claim 1, wherein the hyaluronic acid has a molecular weight greater than or equal to 200 kilodaltons (kDa) and less than or equal to 2 megadaltons (MDa).

4. The method of claim 1, wherein the molecular oxygen is administered jointly with the hyaluronic acid.

5. The method of claim 4, wherein the molecular oxygen also is administered prior to the joint administration with the hyaluronic acid.

6. The method of claim 1, wherein the molecular oxygen is administered using a flow rate greater than or equal to 0.1 liters per minute (L/min) and less than or equal to 5 L/min.

7. The method of claim 1, wherein the hyaluronic acid is in a form of a salt of a biologically acceptable alkaline metal.

8. The method of claim 7, wherein the hyaluronic acid is in the form of sodium hyaluronate.

9. The method of claim 8, wherein the sodium hyaluronate is administered at a dosage greater than or equal to 10 milligrams (mg) and less than or equal to 100 mg out of a unit of volume of the molecular oxygen, and wherein a maximum unit of volume of the molecular oxygen is greater than or equal to 1.5 liters (L) and less than or equal to 75 L.

10. The method of claim 8, wherein the sodium hyaluronate is administered together with the molecular oxygen for a time greater than or equal to 5 minutes and less than or equal to 15 minutes.

11. The method of claim 1, wherein the selected vaginal disorder is vaginal dryness.

12. The method of claim 1, wherein the selected vaginal disorder is vulvovaginal atrophy.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Vaginal disorders are typical intimate disorders of female genitalia, which occur at an early age, in adulthood or during maturity.

(2) Vaginal disorders can be identified by a specific clinical picture (bacterial, viral, fungal infections; irritative, allergic or psychosomatic vaginitis) or may show up as one or more symptoms resulting from an imbalance of local and systemic homeostasis (dryness, burning, itching, leucorrhoea, redness, irritation and swelling). For the purposes of the present invention, vaginal disorders are preferably selected between vaginal dryness and vulvovaginal atrophy.

(3) Oxygen has long been used for therapeutic purposes for the treatment of conditions such as decompression syndrome and carbon monoxide poisoning.

(4) Recently, oxygen has started to be used in cosmetics for skin rejuvenation, for the treatment of photo-induced skin aging and for the improvement of skin complexion. Exposure to oxygen therapy of open wounds on pigskin showed an increase in the pO2 of the injured surface tissue. Repeated treatments accelerate the skin's healing, and wounds treated with oxygen show an increase in neoangiogenesis and tissue oxygenation. It is therefore believed that molecular oxygen reactivates microcirculation, thus activating red blood cells and favouring neoangiogenesis (Fries R B, Wallace W A, Roy S, Kuppusamy P, Bergdall V, Gordillo G M, Melvin W S, Sen C K (2005) Dermal excisional wound healing in pigs following treatment with topically pure oxygen, Mutat Res 579: 172-181).

(5) Besides the reparative and regenerative effects (Roth V, Herron M S, et al., Stimulating angiogenesis by hyperbaric oxygen in an isolated tissue construct. Undersea Hyperb Med 2011, 38 (6): 509-514), molecular oxygen stimulates the epidermal turnover, thus improving hydration and tissue elasticity.

(6) The oxygen present in the association object of the present invention advantageously works as a vehicle for hyaluronic acid and at the same time as an “enhancer” of the permeability of hyaluronic acid, thus stimulating local microcirculation as well as tissue regeneration and facilitating protein absorption through vaginal mucosa.

(7) The oxygen contained in the combination of the present invention preferably has a purity comprised between 80% and 97% by volume (v/v).

(8) The purified oxygen can be obtained by techniques known to those skilled in the art, such as by using a compressed air generator, which filters the outdoor air and purifies it from the components it contains in order to increase the oxygen volume percentage out of the total volume of air.

(9) In the preferred embodiment, the purified oxygen is administered simultaneously with hyaluronic acid.

(10) Preferably, sodium hyaluronate is administered together with said purified oxygen for a time ranging from 5 min to 15 min.

(11) Preferably, oxygen is administered even before co-administration with hyaluronic acid, in order to condition the vaginal environment and improve local blood circulation.

(12) Said prior conditioning has a duration preferably comprised between 3 min and 10 min.

(13) Molecular oxygen is preferably administered at the topical-vaginal level at a flow rate ranging from 0.1 L/min to 5 L/min.

(14) The hyaluronic acid contained in the combination preferably has a molecular weight ranging from 200 kDa to 2 MDa.

(15) In the preferred embodiment, hyaluronic acid is in the form of a biologically acceptable alkaline metal salt, and even more preferably, in the form of sodium hyaluronate.

(16) In order to convey hyaluronic acid by means of oxygen therapy (purified molecular oxygen), said hyaluronic acid is preferably dissolved in an aqueous solution, whose concentration is preferably between 0.05% and 0.3% (w/v) by weight if compared to the water volume.

(17) In the preferred embodiment, sodium hyaluronate is administered at a dosage preferably comprised between 10 mg and 100 mg per unit of volume of purified oxygen, where the maximum volume of administered oxygen is preferably between 1.5 L and 75 L.

(18) The association object of the present patent application can be administered continuously, according to the needs of the patient, and with dosing intervals preferably comprised between 20 and 30 days and even more preferably between 6 and 10 days.

(19) An administration protocol for the association object of the present invention, together with the effectiveness data obtained from the same, is described for illustrative and non-limiting purposes.

Examples

(20) Protocol

(21) The protocol provides four administrations at intervals of 20 to 30 days, each lasting 15 minutes.

(22) The treatment is carried out by using a device known under the trade name Exea X2, which transforms air into 95% pure oxygen.

(23) The Exea X2 device consists of:

(24) Compressor: a compressed air generator with the function of taking in air from the external environment, filtering and compressing it.

(25) Machine body: equipped with zeolite molecular sieves. It exploits the principle of different absorption of gas molecules by different surfaces, allowing O.sub.2 to pass through and retaining the other gases present in the air, such as nitrogen, argon, helium and hydrogen. The machine body transforms the outdoor air into 95% pure oxygen.

(26) Dispenser: consisting of a vaginal cannula, connected to the machine body. The cannula is equipped with outlet holes for the delivery of oxygen and hyaluronic acid, which is inserted through a special injection valve, located in the upper part of the cannula.

(27) The hyaluronic acid is previously dissolved in distilled water so as to form a 0.2% (w/v) solution.

(28) The treatment begins with the introduction, for a period of 5 minutes, of purified oxygen, to condition the vaginal environment.

(29) At the end of the 5 minutes of conditioning, the treatment involves the introduction of the hyaluronic acid solution by injecting it into the appropriate valve of the vaginal cannula, together with the oxygen supply, for a duration of 10 minutes.

(30) Effectiveness Analysis

(31) The aforementioned protocol has been tested on a sample of ten patients, aged between 42 and 60 years. Each of the patients subjected to the protocol has been affected by vaginal atrophy for more than a year and has had a PAP test in the last year.

(32) The protocol provides a follow-up visit after 15 days and after 20 days from the treatment, when data on the effectiveness of the treatment are collected.

(33) The effectiveness evaluation is performed by using a Visual Analogue Scale (VAS) with the following parameters:

(34) Feeling of well-being—Parameter measured by means of a questionnaire to the patient, with an evaluation scale from 1 to 5, where 1 represents “no sensation of well-being” and 5 “maximum sensation of well-being”.

(35) Vaginal burning—Parameter measured by means of a questionnaire to the patient, with an evaluation scale from 1 to 5, where 1 represents “no improvement” and 5 “much improved”.

(36) Fluidity—Parameter measured by means of a questionnaire to the patient, with an evaluation scale from 1 to 5, where 1 represents “none” and 5 “normal”.

(37) pH—Evaluated in quintiles, with the following intervals:

(38) TABLE-US-00001 Vaginal pH goodness (physiological pH ~4.6) No Little Average Good Excellent pH >6 5-6 5 4.7-5 >4.7

(39) Vaginal epithelium—Evaluated as follows:

(40) TABLE-US-00002 Flushed - Bleeding on Bleeding on Not flushed Normal petechiae contact scraping
Results

(41) From the evaluation of effectiveness on ten patients undergoing treatment, the following emerged.

(42) TABLE-US-00003 Feeling of Scoring scale 1 2 3 4 5 well-being Evaluation of patients 0 0 0 1 9 Vaginal Scoring scale 1 2 3 4 5 burning Evaluation of patients 0 0 0 1 9 Fluidity Scoring scale 1 2 3 4 5 Evaluation of patients 0 0 0 1 9 pH Scoring scale >6  5-6 5 4.7-5 >4.7 Evaluation of patients 0 0 0 0 10 Vaginal Scoring scale Flushed - Bleeding on Bleeding on Not flushed Normal epithelium petechiae contact scraping Evaluation of patients 0 0 0 0 10

CONCLUSIONS

(43) The sensation described by the patients is one of immediate well-being.

(44) At follow-up visits after 15 and 20 days, the lubrication effect persisted and all reported that during sexual intercourse they had no more of that pain that had previously prevented a normal couple life.

(45) Only one patient reported a marked improvement, but still had a slight burning sensation. However, the patient wanted to complete the therapy, based on the results achieved up to that point.