HK1185008B - Topical compositions for preserving or restoring the integrity of mucosae - Google Patents

Description

Topical composition for maintaining or restoring mucosal integrity

Technical Field

The present invention relates to topical compositions containing choline alfoscerate for maintaining and restoring mucosal integrity.

Background

Choline alfoscerate is known as an nootropic substance, i.e., a substance that improves the nutritional effects of brain cells (by activating blood supply and cellular metabolism) and thus improves intellectual functions.

Choline alfoscerate, as disclosed in WO93/19730, has little systemic toxicity and has significant local tolerance and low incidence of skin irritation, eye irritation and skin sensitization.

Its use in injectable and oral compositions for the treatment of alterations in cognitive function and as a possible growth hormone secretagogue is known in the pharmaceutical field.

Its use in dietary supplements for the same purposes as described for the pharmaceutical industry is also known.

In the dermatological and cosmetic field, for example in WO93/19730, the use thereof for moisturizing, softening (emollient), enhancing the elasticity, repairing and volumizing (volume-enhancing) effects on skin and hair is disclosed.

The integrity of the mucosa may be affected by various exogenous and endogenous causes, such as vitamin deficiencies, improper diet, poor health care, bacterial, viral or fungal infections, gut dysbiosis, alterations in the mucosal microbial flora, endocrine imbalances, debilitating illnesses, genetic factors, mechanical, physical, chemical and traumatic factors, radiation, and the like.

There remains a need for new compositions for maintaining and restoring mucosal integrity.

Drawings

Figure 1 shows an experiment performed on solution G7933 (containing 1% HA and 0.3% choline alfoscerate) in which the deformation rate was varied and the stress and viscosity were measured, including the ascending and descending curves.

Figure 2 shows an experiment performed on solution G7934 (containing 1% HA) in which the deformation rate was varied and the stress and viscosity were measured, including the rise and fall curves.

FIG. 3 shows the viscosity of systems formed from equal volumes of mixtures of G7933 and G7934 solutions with different percentages (1%, 2% and 3% w/v) of mucin solution.

Detailed Description

It has been surprisingly found that topical application of choline alfoscerate to the mucosa aids in its cytotrophic effects, thereby maintaining and restoring the integrity of mucosal tissues.

The term "nutritional effect" means the overall nutritional status of an organism or part thereof.

Accordingly, the present invention relates to topical compositions containing choline alfoscerate for maintaining and restoring mucosal integrity.

The mucous membranes are preferably those commonly referred to as external mucous membranes, such as those of the general mouth and oral cavity, the nasal mucosa, the ocular mucosa, the otic mucosa, the male and female genital mucosa and the anal and rectal mucosa.

According to a preferred aspect of the present invention, the topical compositions containing choline alfoscerate are useful, for example, in the prevention and treatment of inflammatory disorders and/or injuries of the oral mucosa and in the prevention and/or treatment of damaged and/or inflamed gums.

Inflammation and damage of the oral mucosa mean, for example, gingivitis, mucositis (oral ulcers, including recurrent oral ulcers), stomatitis, glossitis, and the like. These disorders may have different etiologies; for example, they may have a mechanical, chemical or pathological cause (infection, oral dysbiosis or intestinal dysbiosis).

It has also been found that topical use of choline alfoscerate is useful for maintaining the correct pH of the oral mucosa.

According to another aspect of the invention, the composition is suitable for human or veterinary use.

Choline alfoscerate is an inner salt of L-alpha-glycerophosphorylcholine; it is an ampholyte, highly soluble in water and ethanol, has high chemical and microbiological stability, and has special organoleptic properties in that it is almost tasteless (flavanourless), odourless (odourless) and colorless.

These organoleptic properties facilitate their use in the topical compositions to which the present invention relates, which are particularly useful for the treatment of the oral and buccal mucosa as well as the nasal mucosa.

Choline alfoscerate is commercially available in anhydrous and hydrated forms; since the compound is markedly hygroscopic, the preferred form is the hydrated form.

Commercially available pharmaceutical grade choline alfoscerate hydrate having the following chemical-physical properties may be preferably used to prepare the composition:

appearance: clear high viscosity fluids

The titer is as follows: 98.0-102.0% (based on anhydrous basis)

Water (K.F.): 13.5 to 16.5 percent

Specific optical rotation: 2.40 ° -2.95 ° (based on anhydrous basis)

Solubility (in water, 10% w/v): completely dissolve

pH：5.0-7.0。

The concentration of choline alfoscerate in the topical composition of the invention may be selected according to the type of mucosa to be treated and the type of composition; for example, it may be between 0.001% w/v and 99% w/v.

The concentration of choline alfoscerate is preferably between 0.010% w/v and 50% w/v.

According to another aspect, the topical compositions to which the present invention relates may also comprise additional active ingredients known for mucosal topical treatment, such as those described in Martindale, the completeddrug reference, 34 th edition.

The additional active ingredient is preferably mesalazine, licorice and its derivatives, silver and its derivatives, aloe vera (aloevera), allantoin and its derivatives, chlorhexidine and benzalkonium chloride.

Topical compositions in the form of anorectal enemas or rectal enemas containing choline alfoscerate and mesalazine can be advantageously used, for example, for the prevention and treatment of ulcerative colitis and Crohn's disease.

The compositions of the present invention may be formulated in a manner suitable for topical application and may be prepared according to conventional methods well known in the art, for example, as described in Remington, the science and practice of pharmacy, 20 th edition.

Known excipients or carriers may also be added to optimize the specific use of the composition, such as those described in handbook of pharmaceutical excipients, 6 th edition, pharmaceutical press, including, for example, film forming agents.

Examples of preferred formulations of the invention are gels, emulsions (oil-in-water (o/w) or water-in-oil (w/o)), creams, ointments, sprays, powders, lotions, foams (mousses) and mouthwashes.

More preferably, the composition is in the form of an aqueous gel.

The aqueous gel may be prepared from pharmaceutically acceptable polymers capable of absorbing large amounts of water and thus may adhere to mucous membranes (mucoadhesion).

The mucoadhesion of the compositions of the invention ensures a sufficient residence time on the mucosa subjected to leaching by physical and mechanical factors that can reduce the residence time of the active ingredient, for example in the case of the oral mucosa.

According to another aspect of the present invention, the composition may further contain hyaluronic acid or a pharmaceutically acceptable salt thereof as a mucoadhesive polymer.

Hyaluronic acid having a molecular weight of 800.000 to 4,000.000Da or a pharmaceutically acceptable salt thereof may be preferably used.

Even more preferably, the pharmaceutically acceptable salt of hyaluronic acid is a sodium salt.

Hyaluronic acid is widely present in various tissues of the human and animal body; in addition, it can retain up to 1000 times its weight in water and has a high level of viscoelasticity.

It has surprisingly been found that choline alfoscerate significantly improves the mucoadhesion of aqueous gels of hyaluronic acid, exerting the effect of mucoadhesion enhancers of hyaluronic acid, in particular of hyaluronic acid sodium salt, even more in particular of those having a molecular weight between 800.000 and 4,000.000Da, and vice versa.

The specific synergistic effect of these two compounds results in greater therapeutic effect of both choline alfoscerate and hyaluronic acid.

In view of the results obtained with the compositions of the invention, it is considered by way of example and not by way of limitation that the components of the compositions of the invention act through a mutual synergistic mechanism; for example, choline alfoscerate stabilizes hyaluronic acid-containing compositions (e.g. hyaluronic acid-containing compositions in the form of a gel) due to its high level of hygroscopicity, which allows hyaluronic acid to exert its mucoadhesive properties as good as possible and allows choline alfoscerate to be therapeutically more effective.

Furthermore, in aqueous systems, an interaction between the anionic function of hyaluronic acid and the cationic function of choline alfoscerate can occur, which can contribute to further improving the mucosal adhesion of hyaluronic acid and increasing the residence of choline alfoscerate and hyaluronic acid on the mucosa.

The examples given below further illustrate the invention.

The percentages are expressed in parts by weight of the total volume of the composition.

EXAMPLE 1 liquid composition for oral mucosa

EXAMPLE 2 mucoadhesive liquid composition for oral mucosa

EXAMPLE 3 gel composition for treatment of canker sores

EXAMPLE 4 mucoadhesive gel compositions for treatment of oral ulcers

EXAMPLE 5 liquid composition in the form of drops for application to the nasal mucosa

EXAMPLE 6 liquid composition in the form of a mucoadhesive gel for application to the nasal mucosa

EXAMPLE 7 liquid composition for ocular Mucosa

EXAMPLE 8 mucoadhesive liquid composition for application to the ocular mucosa

EXAMPLE 9 liquid composition for application to the ear mucosa

0.100 percent of choline alfoscerate

50.000 percent of glycerin

The purified water is properly added to 100 percent

EXAMPLE 10 mucoadhesive liquid composition for application to the ear mucosa

EXAMPLE 11 liquid composition for application to the vaginal and vulvar mucosa

EXAMPLE 12 mucoadhesive liquid compositions for application to the vaginal and vulvar mucosa

EXAMPLE 13 mucoadhesive gel compositions for application to the vaginal and vulvar mucosa

EXAMPLE 14 mucoadhesive gel composition for application to the mucous membranes of the male genitalia

EXAMPLE 15 mucoadhesive gel compositions for anorectal use

EXAMPLE 16 mucoadhesive gel composition for treatment of inflamed gingiva

EXAMPLE 17 mucoadhesive gel composition for treatment of damaged gingiva

EXAMPLE 18 mucoadhesive compositions in the form of pessaries

EXAMPLE 19 mucoadhesive anorectal enema composition

EXAMPLE 20 rectal enema composition (ulcerative colitis/Crohn's disease)

EXAMPLE 21 rheological measurement of the determination of the viscosity of an aqueous solution of hyaluronic acid

List of samples analyzed:

1. solution B1: 1.0% Hyaluronic Acid (HA), 0.3% choline alfoscerate (Co): g7933

2. Solution B2: 1.0% Hyaluronic Acid (HA): g7934

Instrumentation and equipment

The instrument comprises the following steps: paarphysica, mod. RHEOLAB MCH 1

Geometry: z1DIN double slit (doublegap), sample volume 20ml

Shear rate: 1-150s^-1(logarithmic scale)

Number of dots: 20 (each point lasting 30 seconds)

Temperature: 25 deg.C

The experiment was performed by increasing the shear rate (ascending curve) and decreasing the parameter (descending curve) in a manner to confirm the stability of the solution under stress.

Preparation of samples

The test solution was placed directly in the measuring rotor and left for the time required to thermostatize the sample.

The viscosity of a newtonian fluid is constant, while the viscosity of a non-newtonian fluid is a function of the velocity gradient. In macromolecular systems such as hyaluronic acid, pseudoplastic behavior is often observed, in which the viscosity decreases with increasing velocity gradient; this means that these fluids are highly viscous at low deformation speeds and become fluid at high speeds.

Results

Figure 1 shows an experiment performed on solution G7933 (containing 1% HA and 0.3% choline alfoscerate) in which the deformation rate was varied and the stress and viscosity were measured.

As expected for pseudoplastic fluids, the viscosity of the solution decreases with increasing deformation rate, with a value from about 2.7Pa^.s falls to about 0.3Pa^.s。

The same experiment was performed for solution G7934 (containing 1% HA): the results are shown in FIG. 2.

Unlike the previous solution, the viscosity of the sample increases at low deformation rates and then remains almost constant, or decreases very slowly as γ increases. In addition, the viscosity values are considerably lower than G7934, and no more than 0.1Pa, regardless of the velocity gradient applied^.s。

Thus, the addition of choline alfoscerate modulates the rheological properties of the hyaluronic acid solution, greatly increasing the viscosity of the fluid.

In view of these findings, rheological measurements were again performed with a rotational viscometer to determine the change in viscosity (expressed in pa.s) of a mixture containing both G7934 and G7933 solutions and mucin compared to the sum of the individual contributions of the solutions and mucin. This change (called rheological synergy) is calculated according to the following formula:

delta eta (mixture) - [ eta (solution) + eta (mucin) ]

Since the viscosity values of the solutions are of different orders of magnitude, the data are comparable using a standardized rheological synergy:

where Δ η/η is the normalized rheological synergy.

In the presence of interaction between solution and mucin, the parameter gave a positive value and is an indicator of bioadhesion (S.Rossi, F.Ferrari, M.C.Bonferoni and C.Caramella- "characterization of chitosan hydrochloride-mucin interaction by viscosity and turbidity measurements" -EurJPharmSci.2000; 10(4): 251-7).

The viscosity of the systems formed from mixtures of equal volumes of the two test solutions and different percentages (1%, 2% and 3% w/v) of mucin solution was measured (fig. 3).

As can be seen in the above figures, when the concentration of HA dimer is equal, the addition of choline alfoscerate leads to a proportional increase in the rheological synergy and therefore to an increase in the bioadhesion of the mixture.

Claims (11)

1. A topical composition for maintaining and restoring mucosal integrity comprising 0.3% w/v choline alfoscerate and 1.0% w/v hyaluronic acid or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient or carrier.

2. A topical composition as claimed in claim 1 wherein the hyaluronic acid is in the form of a sodium salt.

3. The topical composition as claimed in claim 1 wherein the hyaluronic acid or pharmaceutically acceptable salt thereof has a molecular weight between 800.000 and 4,000.000 Da.

4. A topical composition as claimed in claim 2 wherein the sodium salt of hyaluronic acid has a molecular weight of between 800.000 and 4,000.000 Da.

5. The topical composition as claimed in any one of claims 1 to 4, which contains at least one further active ingredient selected from mesalazine, licorice, silver, aloe, allantoin, chlorhexidine and benzalkonium chloride.

6. A topical composition as claimed in claim 5 wherein the active ingredient is mesalazine.

7. A topical composition as claimed in any one of claims 1 to 4 which is in the form of an aqueous gel.

8. A topical composition as claimed in any one of claims 1 to 4 for human or veterinary use.

9. Use of a topical composition as claimed in any one of claims 1 to 8 in the manufacture of a medicament for the prevention and treatment of inflammatory disorders and/or damage of the oral mucosa.

10. Use of a topical composition as claimed in any one of claims 1 to 8 in the manufacture of a medicament for the prevention and treatment of damaged and/or inflamed gums.

11. Use of a topical composition as claimed in claim 8 in the manufacture of a medicament for the prevention and treatment of ulcerative colitis and crohn's disease.