IT202200021852A1 - Viscous ophthalmic liquid composition comprising natural gums and extracts - Google Patents

Description

DESCRIPTION of the invention entitled:

?Viscous ophthalmic liquid composition comprising natural gums and extracts?

The present invention relates to a viscous liquid ophthalmic composition comprising or, alternatively, consisting of natural gums and extracts, in particular at least one mucilage and at least one hydrocolloid, useful for example as a humectant and/or for carrying active ingredients, which possesses peculiar technological characteristics.

STATE OF THE ART

Ophthalmic formulations are a series of preparations intended for application on the external surface of the eye, i.e. at the level of the cornea and conjunctiva, and in the periocular area. In the first case, in particular, these formulations are generally presented in liquid form with an aqueous base, are called eye drops or eye drops, and are one of the most widely used pharmaceutical forms for the treatment of the eye and/or for the maintenance of its functionality, when used in a preventive phase.

Among the various formulations of eye drops, an important typology is constituted by products with mucoadhesive properties, which allow the solution to be maintained on the ocular surface for a prolonged period of time. In particular, this characteristic is very important in the case of patients who have tired, red eyes or who require a soothing action, since the maintenance of the active substances on the ocular surface is prolonged over time, consequently determining a greater efficacy of the preparation. Among the substances most used to obtain the therapeutic effects mentioned above are some plant extracts.

We cannot exclude that there is a direct correlation between the rheological properties of an aqueous solution, and in particular its viscosity, and the mucoadhesive properties of said aqueous solution. This statement can be confirmed especially in the case in which the substances that are used to increase the viscosity of the solution are made up of polymeric chains, of natural, semi-synthetic or synthetic origin, capable of coordinating water through the formation of hydrogen bonds.

For example, EP0507224 identifies some specific polysaccharides of natural origin (e.g. xanthan gum, carrageenans, gellan gum) to prepare a controlled-release ophthalmic topical composition, dispersing the micronized active ingredient within said polysaccharides which, by gelling, slow down its release; while WO2006068899 describes an ophthalmic composition containing Aloe vera gel as a vehicle for numerous possible active ingredients.

In addition to mucoadhesion, ophthalmic formulations, and eye drops in particular, must possess a further characteristic, necessary to guarantee their safe use: they must be sterile and must maintain sterility throughout their period of use. However, at the moment the solutions on the market still suffer from strong limitations and inconveniences.

? however, it is important to underline the fact that liquid ophthalmic formulations often present, as previously described, a certain degree of viscosity, functional with respect to their capacity to improve the degree of hydration of the eye, as well as to increase the residence time in situ of the formulation itself, and, consequently, of the active ingredients transported in it. This viscosity, therefore necessary from a technological/functional point of view, can however present problems during the terminal filtration phase, mainly due to the difficulty of a viscous solution in passing through the narrow mesh of the filters used in this operation,

Furthermore, the passage of the viscous solution through the narrow mesh of the filter determines the application of a shear stress that can lead to structural modifications of the viscous system, with alteration of the degree of viscosity of the solution itself, thus compromising the functionality of the eye drops during their use.

Even terminal sterilization, however, which involves the use of high temperatures, generally above 120°C, for a period of time normally set at around 15 minutes, presents some critical issues.

First of all, this technique is not suitable for eye drops that contain, in their formulation, also thermolabile substances. Furthermore, it is always necessary to consider the possibility that high temperatures can also favor reactions between the various elements that make up the eye drops themselves.

In response to these problems, one could try to reduce the viscosity of the solution by increasing the temperature, or by increasing the filtration pressure.

However, both of these two attempts have disadvantages related, in the first case, to the temperatures to which some components may be sensitive, and in the second case, to the fact that the filters may clog more quickly or be damaged, with the consequent risk of a lack of sterility of the final product. Furthermore, as previously mentioned, the mechanical stress induced by the passage of the solution through the filters can lead to an alteration of the viscosity of the filtered solution, even more so when working at high pressures.

There is, therefore, still a strong need to have available a viscous ophthalmic aqueous liquid composition, containing gums and plant extracts, which can be easily sterilized, preferably by a filtration process, without the limitations and drawbacks just described.

PURPOSES OF THE INVENTION

The object of the present invention is to provide a viscous, water-based liquid ophthalmic composition comprising or, alternatively, consisting of plant gums and extracts, said composition being easily sterilizable through a filtration process.

Another object of the invention is the use of said sterilized viscous liquid ophthalmic composition with aqueous base within ophthalmic pharmaceutical formulations, said composition maintaining its viscosity characteristics unchanged.

A further purpose of the invention is the use of said viscous liquid ophthalmic composition with an aqueous base, and/or of the pharmaceutical formulations comprising it, in the treatment and/or prevention of eye diseases and/or as artificial tears to be used, for example, to counteract the symptoms of dry eyes, ensuring the sterility and stability of said composition.

Another object of the present invention is the use of said viscous liquid ophthalmic composition with an aqueous base, and/or of the pharmaceutical formulations comprising it, to convey specific active ingredients useful in the treatment and/or prevention of eye diseases, always maintaining the sterility and stability of said composition and of said specific active ingredients conveyed therein.

These and other purposes are achieved by the present invention which will be described in detail below, without in any way wishing to limit its scope.

DESCRIPTION OF THE INVENTION

The present invention relates to a viscous liquid ophthalmic composition with an aqueous base comprising or, alternatively, consisting of at least one mucilage and at least one hydrocolloid.

Preferably, said composition is characterized in that said at least one mucilage is present in an amount of from 0.01 to 10% w/w of the total weight of the composition, preferably in an amount of from 0.2 to 1% w/w of the total weight of the composition. Preferably, said composition is characterized in that said at least one hydrocolloid is present in an amount of from 0.01% to 10% w/w of the total weight of the composition, preferably in an amount of from 0.2% to 1% w/w of the total weight of the composition. Preferably, said composition is characterized in that said at least one mucilage and said at least one hydrocolloid are in a ratio [mucilage:hydrocolloid] in a range of from 10:1 to 1:2 to each other, preferably in a range of from 5:1 to 3:1.

Preferably, said composition is characterized in that said composition has a dynamic viscosity of between 1.01 and 1.60 mPas, at a temperature of 25?C?2?C, and an external pressure of 1 atmosphere.

Preferably, said composition is characterized in that said at least one mucilage is selected from the group comprising or, alternatively, consisting of aloe mucilage, marshmallow mucilage, lime mucilage, marigold mucilage, psyllium mucilage or mixtures thereof.

Preferably, said composition is characterized in that said at least one hydrocolloid is selected from the group comprising or, alternatively, consisting of xanthan gum, guar gum, karaya gum, carob gum, gum arabic, gum ghetti, starch, konjac gum, glucomannan, alginic acid or its sodium, potassium or magnesium salts, cellulose derivatives, chitosan, sodium hyaluronate or mixtures thereof.

Preferably, said composition is characterized in that the hydrocolloid/mucilage pair is selected from the group comprising or, alternatively, consisting of xanthan gum/mallow mucilage, guar gum/marshmallow mucilage, sodium alginate/aloe mucilage, hydroxypropyl methylcellulose/linseed mucilage and karaya gum/lime mucilage, mallow mucilage/sodium hyaluronate.

Preferably, said composition is for use in the treatment and/or prevention of eye diseases and/or as eye drops or artificial tears to be used, preferably to counteract the symptoms of dry eye.

The present invention relates to an ophthalmic pharmaceutical formulation comprising the composition as reported above and, optionally, at least one active ingredient and/or excipient for pharmaceutical use.

The Applicant is not aware of any documents that analyze or exploit particular interactions between the different types of mucilages and/or hydrocolloids, to obtain advantages in the preparation processes of the formulations and compositions which are the object of the present invention.

The Applicant has found it useful to adopt, during the production phases, a whole series of measures to avoid as much as possible the contamination of the composition, which is however subjected, as a final step, to a sterilizing treatment.

The most commonly used techniques to carry out this treatment are basically two:

- sterilizing filtration of the liquid formulation in controlled contamination environments; and

- the terminal sterilization of the product once divided into the final containers.

Of the two, sterilizing filtration has been adopted here because it has been found to be more useful, as it ensures that the composition remains unchanged in relation to the possible negative action determined by the use of high temperatures in terminal sterilization techniques. Sterilizing filtration is performed here using filters having a size of approximately 0.10 microns to approximately 1 micron, preferably approximately 0.20 microns to approximately 0.80 microns, even more preferably approximately 0.30 microns to approximately 0.50 microns, for example approximately 0.22 microns or approximately 0.45 microns.

A ?rheological modifier? is a substance that is able to modify the flow properties of a liquid, including its viscosity. There are some types of plant-based compounds that can boast this ability.

In this regard, the authoritative text by Jean Bruneton (Pharmacognosie 3<a >ed., TEC Editore, Paris, France) on pages 36-38, which are here considered incorporated by reference, attributes to polysaccharides of vegetal origin the characteristic of gelling aqueous solutions and, therefore, said polysaccharides can fall into the category of rheological modifiers. Again according to Bruneton, an alternative classification of vegetal polysaccharides has also been suggested, based on their botanical origin, which divides them into 3 classes (page 38; Monographies):

- polysaccharides originating from microorganisms and fungi;

- polysaccharides originating from algae;

- polysaccharides that originate from higher plants.

See also Aspinall, G.O. The Polysaccharides, vol. 1, (1982), vol.2 (1983), vol. 3 (1985), Academic Press, New York; Aspinall, G.O. (1987). Chemical Modification and Selective Fragmentation of Polysaccharides, Acc. Chem. Res., 20, 114-120; Doublier, J. -L. (1993). Rh?ologie des polyosides en milieu aqueux: solutions, gels et m?langes, IAA, 111 (01-02), 22-28.

A similar, but more complex, classification method is proposed and followed by Marcello Nicoletti (Botanica Farmaceutica, 2007 ed., Edises, Naples, Italy, which is here considered incorporated by reference). In particular, the origin of polysaccharides is better specified and the further processing that said polysaccharides may undergo is also taken into account.

According to the method proposed by Nicoletti (see, in the chapter Glycides, pages 52-64, which are considered fully incorporated here for ready reference), the following categories 1-5 are therefore recognised:

1. hydrocolloids (or gums) exuding from the plant: examples of these are gum arabic, gum tragacanth, gum karaja, gum ghatti;

2. hydrocolloids (or gums) present in the seeds of vegetables: examples include starch, guar gum, carob gum, tamarind gum, konjac gum, glucomannan, flax, psyllium and plantain polysaccharides;

3. algal hydrocolloids: they are extracted from the thallus of red and brown algae from which polysaccharides such as agar-agar, carrageenans and alginates are obtained (alginic acid and its sodium, potassium, calcium and magnesium salts);

4. hydrocolloids (or mucilages) present in leaves, flowers and roots: examples of these are aloe, marshmallow, mallow, calendula, lime;

5. hydrocolloids present in other various parts of plants, in particular in the cell walls, examples of which are cellulose, hemicellulose, extensin and pectin. Celluloses, in particular, can be subject to subsequent processing to obtain semi-synthetic derivatives such as, for example, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylpropylmethylcellulose, carboxymethylcellulose and its salts.

Finally, a further class of hydrocolloids can be mentioned, consisting of a series of substances of animal, biotechnological or fermentative origin, with a very heterogeneous chemical structure (category 6). These substances too, thanks to their behaviour in solution, can be used as rheological modifiers. Among them, we can mention derivatives obtained by extraction from animal parts or by biotechnological means (such as hyaluronic acid), derivatives from the exoskeleton of crustaceans (such as chitosan) and derivatives from bacterial fermentation (such as xanthan gum).

The Applicant, after a long and in-depth research and development activity, has selected particular mucilages and hydrocolloids to give the compositions which are the object of the present invention.

An embodiment of the present invention is directed to a viscous liquid ophthalmic composition of aqueous base comprising or, alternatively, consisting of at least one mucilage, or a hydrocolloid obtained from leaves, roots or seeds of plants belonging to category 4 of the preceding list, and at least one hydrocolloid, belonging to categories 1-3, 5 and/or 6 as previously described, according to the Nicoletti method. Preferably, said at least one mucilage or hydrocolloid (category 4; Nicoletti) obtained from leaves, flowers and roots is selected from the group comprising or, alternatively, consisting of (non-limiting list, but only exemplifying): aloe, marshmallow, mallow, calendula, psyllium and lime and/or mixtures thereof.

Examples of mucilages are:

- Aloe vera gel powder 200:1; Aloe vera (L.) Burm.f. (Aloe barbadensis Mill.); CAS No.: 85507-69-3 / 94349-62-9; EINECS/ELINCS: 287-390-8 / 305-181-2 (spontaneous cultivation of ripe leaves which are dried by spray dryer to give a powder); Relative density: 300-600 g/l; Hygroscopic powder, pH 3.5-5; excipient: maltodextrin.

- Althaea 30% aqueous dry extract; Althaea officinalis L.; ALTHAEA OFFICINALIS root extract; CAS No.: 73049-65-7; EINECS/ELINCS: 277-254-6. Extraction solvent: water Type of preparation: dry extract, where 90% passes through 300 microns and 98% passes through 200 microns. Althaea (root) 27-33% polysaccharides dry extract (e.g.) excipient maltodextrin, hygroscopic powder, pH 3.5-5.5.

- Malva 25-30% polysaccharides dry extract; Malva sylvestris L.; CAS No.: 84082-57-5; EC No.: 282-003-9; hygroscopic powder, pH 4-6. Extraction solvent: water. Excipient: maltodextrin. Not less than 90% passes through 300 microns, relative density: 400-700 g/l.

Preferably, said hydrocolloid (categories 1-3, 5 and/or 6; Nicoletti) is chosen from the group comprising or, alternatively, consisting of (non-exhaustive list, but only for illustrative purposes):

- gum arabic, gum tragacanth, gum karaja, gum ghatti (gum ghatti is the amorphous and translucent exudate of Anogeissus latifolia, a large tree of the Combretaceae family);

- starch, guar gum, carob gum, tamarind gum, konjac gum, glucomannan, flax, psyllium and plantain polysaccharides;

- extracts from the thallus of red and brown algae from which polysaccharides such as agar-agar, carrageenans and alginates (alginic acid and its sodium, potassium, calcium and magnesium salts) are obtained;

- cellulose, hemicellulose, extensin and pectin; celluloses can give, through subsequent processing, semi-synthetic derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylpropylmethylcellulose, carboxymethylcellulose and its salts;

- derivatives obtained by extraction from animal parts such as hyaluronic acid, derivatives from the exoskeleton of crustaceans such as chitosan and derivatives from bacterial fermentation such as xanthan gum.

An example of guar gum could be a guar gum having Minimum 5,000 cps / 200 mesh CAS No.: 9000-30-0; EC No.: 232-536-0; pH 5.5-7. Viscosity: (RVT, 1%, 25?C, 20 rpm, 24 hours) min. 5000 mPas. Particle distribution: minimum 90% passes through 200 mesh.

According to the invention, the term ?viscous? is used to indicate a degree of viscosity of a solution greater than that of water at a pressure of 1 atmosphere and a temperature of 25?C?2?C, in particular, a dynamic viscosity value greater than 1.01 mPa?s, at a temperature of 25?C?2?C.

According to the present invention, the term ?mucilage? refers to one of the compounds of category 4 as previously described, i.e. a hydrocolloid present in the leaves, flowers and roots of certain plants, such as, for example but not limited to, Aloe vera (leaves), Althaea officinalis (root), Malva sylvestris (leaves), Calendula officinalis (flowers), Tilia tomentosa (leaves and flowers).

Still in relation to the genera, it is common knowledge to the expert technician in the field that the substances of therapeutic and health interest can be found in different parts of the plant and this situation depends on the plant under examination. Therefore, the expert technician in the field will be able to conveniently choose, on the basis of the state of the art, and of the common general knowledge, the part of the plant of interest to be subjected to extraction.

Said mucilages can be obtained, starting from the plant that contains them, using all the techniques and equipment known to the expert in the field and present in the state of the art. Commonly, the production process includes an extraction of said mucilages from the chosen plant using a solvent; generally said solvent is water.

There are also mucilages on the market, in the form of powders or gels, extracted, purified and ready for use; they too can be directly used for the realization of the present invention.

When referring to a compound belonging to the other classes described according to the Nicoletti classification method (1-3, 5 and/or 6), according to the invention the term "hydrocolloid" will be used. Examples, not limited to, of these hydrocolloids are: xanthan gum, guar gum, karaya gum, carob gum, alginates, semi-synthetic derivatives of cellulose, chitosan, sodium hyaluronate.

Even with regard to this type of compounds, they may be extracted and/or produced starting from the natural starting material according to the techniques and equipment known to those skilled in the art, as well as being purchased and directly used for the realization of the present invention, when commercially available in the desired/necessary degree of purity.

The aqueous ophthalmic composition of the invention has the desired viscosity characteristics that guarantee the adequate degree of mucoadhesion in the treatment of eye diseases.

In particular, the ophthalmic compositions of the present invention have a dynamic viscosity value ranging from 1.01 mPa s to 1.60 mPa s measured for example with a Brookfield viscometer model DV1M from the Brookfield company (United States of America).

Surprisingly, it has been observed that the composition of the invention, which comprises or, alternatively, is constituted by an aqueous solution of at least one mucilage and at least one hydrocolloid, according to the previous definitions, leads to the obtaining of a solution which presents both a certain degree of dynamic viscosity ranging from 1.01 mPas to 1.60 mPas and consequent mucoadhesion, and the possibility of using a filtration process at room temperature for the final sterilization step of the solution.

The sterilizing filtration technique consists, as previously mentioned, in passing the solution to be sterilized through special sterile filters, with pore diameters ranging from approximately 0.10 micron to approximately 1 micron, preferably from approximately 0.20 micron to approximately 0.80 micron, even more preferably from approximately 0.30 micron to approximately 0.50 micron, for example approximately 0.22 micron or approximately 0.45 micron.

The composition of the invention has been shown to be able to pass easily, or at least without too much effort, through the filters normally used for the sterilizing filtration operation; this characteristic is particularly evident when the compositions of the invention are compared with compositions containing components belonging to only one of the two classes, i.e. only a mucilage or only a hydrocolloid (see the Experimental Section that follows).

According to the present invention, said at least one mucilage and said at least one hydrocolloid are present in a concentration adequate with respect to the viscosity of the solution to be obtained. In particular, said at least one mucilage and said at least one hydrocolloid can be present in solution, each, in a concentration range that goes from 0.01% to 10% weight/weight with respect to the total weight of the composition. Preferably, said range is from 0.2% to 1% weight/weight for each component. Even more preferably, said at least one mucilage and said at least one hydrocolloid, are present in a weight ratio [mucilage: hydrocolloid] included in a range from 10:1 to 1:2, preferably in a range from 5:1 to 3:1.

In this document, when it is said that at least one mucilage (or at least one hydrocolloid) is present in a given percentage composition range, it is intended to mean that, whatever the number of mucilages (or hydrocolloids) included in the composition, their total quantity falls within the indicated concentration range, as a single mucilage (or hydrocolloid) or as the sum of the different mucilages (or hydrocolloids).

In a particular aspect, the viscous ophthalmic composition of the present invention can be used to prepare a viscous liquid ophthalmic pharmaceutical formulation by the addition of one or more other pharmaceutically acceptable components.

According to this aspect, therefore, at least one, or more than one or all of the components belonging to the following classes can optionally be added to the composition of the invention:

- active compounds approved for pharmaceutical, cosmetic, medical and/or food use such as, but not limited to, antioxidants, vasoconstrictors, lubricants, moisturizers, emollients, refreshing agents;

- buffer systems consisting of organic and inorganic acids approved for pharmaceutical, medical, cosmetic and food use, such as, but not limited to, citric acid and its sodium, potassium and magnesium salts; tartaric acid and its sodium, potassium and magnesium salts; lactic acid and its sodium, potassium and magnesium salts; phosphoric acid and its sodium, potassium and magnesium salts; carbonic acid and its sodium, potassium and magnesium salts; sulphuric acid and its sodium, potassium and magnesium salts; - osmotic pressure regulators approved for pharmaceutical, medical, cosmetic and food use, such as, but not limited to, salts of inorganic acids (e.g. sodium chloride, potassium chloride, magnesium chloride); salts of organic acids (e.g. sodium, potassium and magnesium salts of citric, tartaric, carbonic, lactic, sulphuric, hydrochloric, nitric acids); other organic compounds (e.g. glycerin, sorbitol, mannitol, xylitol, trehalose, polyalcohols, mono and disaccharides);

- preservatives approved for pharmaceutical, cosmetic, food and medical use, such as, but not limited to, methyl paraben, ethyl paraben, propyl paraben, phenyl ethyl alcohol, phenoxyethanol, benzyl alcohol, benzalkonium chloride, chlorhexidine gluconate, chlorhexidine acetate;

- other pharmaceutically accepted excipients such as, for example but not limited to, surfactants, organoleptic correctors, colorants.

According to a preferred aspect of the invention, the pharmaceutical formulation containing the liquid ophthalmic composition of the invention has the composition reported in Table I. Table I: qualitative-quantitative composition of an ophthalmic formulation comprising the composition according to the present invention (the concentration ranges are expressed in % weight/weight with respect to the total weight of the formulation).

Table I

The ophthalmic pharmaceutical formulation comprising the composition of the invention represents a further object of the present invention.

The viscous liquid ophthalmic composition of the invention, and the pharmaceutical formulation comprising it, for its use in eye diseases and/or as eye drops and/or as artificial tears to be used, for example, in the treatment of dry eye symptoms such as pain, itching, burning or foreign body sensation in the eyes, represents a further object of the invention.

The composition of the present invention, and the ophthalmic formulations comprising it, are capable of overcoming the technical problem related to the difficulty of sterilizing viscous ophthalmic solutions by filtration. In particular, as will be demonstrated in the experimental section that follows, said composition, containing at least one mucilage and at least one hydrocolloid as previously classified and defined, can be filtered through filters with pores of appropriate dimensions ranging from 0.10 micron to 1 micron, preferably from 0.20 micron to 0.80 micron, even more preferably from 0.30 micron to 0.50 micron, for example 0.22 micron or 0.45 micron, suitable for sterilizing the filtered solution, despite the presence of rheological modifiers that increase its viscosity, maintaining flow rate and operating pressure values within ranges compatible with processing in industrial plants and without the need to work at high temperatures, above room temperature.

The object of the present invention is a method of preparing solutions which includes the following steps:

- (i) preferably, proceed with the weighing of the raw materials;

- (ii) in a portion of water, approximately 30%-40% of the total, a heating phase is started in the temperature range 30?C-70?C depending on the characteristics of the mucilage and the gum to be dispersed. Preferably, when the set temperature is reached, the mucilage and hydrocolloid are added using a mechanical shovel or a turbine. Preferably, at the end of complete dispersion, a coarse filtration can optionally be carried out in order to eliminate any insoluble residues;

- (iii) in the remaining 60%-70% of the total water, always under stirring, the preservatives, salts, active ingredients and osmotic agent are dissolved in that order. Preferably, the operation generally takes place at room temperature, for example 25?C?2?C, but, optionally, heat can be used to facilitate dissolution; - (iv) at the end of the dissolution of the solution referred to in point (iii), the two solutions are reunited by inserting the solution from point (ii) into the one prepared in point (iii); preferably, once the two solutions have been reunited, sterilizing filtration is carried out.

The Applicant has found it useful to adopt a sterilizing treatment as it ensures the maintenance of the unaltered characteristics of the composition with respect to the possible negative action determined by the use of high temperatures in terminal sterilization techniques. The sterilizing filtration is performed here using filters having a size of from about 0.10 micron to about 1 micron, preferably from about 0.20 micron to about 0.80 micron, even more preferably from about 0.30 micron to about 0.50 micron, for example about 0.22 micron or about 0.45 micron.

The laboratory data, reported in the experimental part that follows for illustrative and non-limiting purposes, clearly demonstrate what has been described.

EXPERIMENTAL SECTION

Example 1: Comparative tests of constant pressure filtration

Solutions in water containing variable quantities of mucilage (class 4) and hydrocolloids (classes 1-3, 5 and 6) were prepared.

In particular, five types of aqueous solutions containing the following hydrocolloid/mucilage pairs in different concentrations were prepared:

1. xanthan gum/mallow mucilage;

2. guar gum/marshmallow mucilage;

3. sodium alginate/aloe mucilage;

4. hydroxypropyl methylcellulose/linseed mucilage;

5. Karaya gum/lime mucilage.

The aqueous solutions containing the different percentages of hydrocolloids and/or mucilages were subjected to a sterilizing filtration process, through a Supporex<? >grade ECV filter (Pall Corporation, USA) at constant operating pressure (100 mbar) and the flow rates were determined.

The general preparation method, applicable to all combinations of mucilages and hydrocolloids, which are the object of this invention, is described below.

In detail, the method for preparing the solutions includes the following phases:

1. weighing of raw materials;

2. in a portion of water, approximately 30%-40% of the total, a heating phase is started in the temperature range 30?C-70?C depending on the characteristics of the mucilage and the gum to be dispersed. Once the set temperature is reached, the mucilage and hydrocolloid are added using a mechanical shovel or a turbine. At the end of the dispersion, a coarse filtration can optionally be carried out in order to eliminate any insoluble residues.

3. In the remaining 60%-70% of the total water, always under stirring, the preservatives, salts, active ingredients and osmotic agent are dissolved in order. The operation generally takes place at room temperature, for example 25?C but, optionally, it is possible to use heat to facilitate dissolution.

4. Once the solution from point 3 has been dissolved, the two solutions are reunited by inserting the solution from point 2 into the one prepared in point 3. Once the reunion has taken place, sterilizing filtration is performed.

At the plant level, the flow of the liquid is measured with a flow meter: the one used in our tests is marketed by the company Kobold (Milan, Italy). The preparation described above can be adapted both on a small scale and on an industrial scale using dissolution and filtration devices usually marketed in the industrial sector.

No particular adjustments to the equipment or methods are necessary; the expert technician in the field will be able to adapt the equipment to individual circumstances by making use of the teachings present in the common state of the art.

The measurements are reported in the following tables (II-VI) in relation to the composition of the solution.

Table II: Flow rate values recorded for the xanthan gum/mallow mucilage composition in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table II

Table III: Flow rate values recorded for the guar gum/marshmallow mucilage composition in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table III

Table IV: Flow rate values recorded for the sodium alginate/aloe mucilage composition in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table IV

Table V: Flow rate values recorded for the composition hydroxypropyl methylcellulose (HPMC)/linseed mucilage in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table V

Table VI: Flow rate values recorded for the composition karaya gum/lime mucilage in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table VI

As is evident from the data reported in the tables, the flow rate decreases with increasing quantity of components (and therefore the viscosity of the solution) very markedly in the case of the presence of a single component (i.e. up to values of even just 10 L/min for quantities of hydrocolloid and/or mucilage of 0.8% w/w). When both components are present, this decrease is much less marked and reaches, in the worst case, 14.7 L/min, remaining more often around 16 L/min, even when the overall concentration of rheological modifiers is equal to 1.6% w/w (0.8+0.8).

Identical to the previously described range 1.01 -1.6 mPa? s (dynamic viscosity 1Pas=1,000cP).

Example 2: Comparative filtration tests at constant flow rate

Solutions in water containing variable quantities of mucilage (class 4) and hydrocolloids (classes 1-3, 5 and 6) were prepared.

In particular, five types of aqueous solutions containing the following hydrocolloid/mucilage pairs in different concentrations were prepared:

1. xanthan gum/mallow mucilage;

2. guar gum/marshmallow mucilage;

3. sodium alginate/aloe mucilage;

4. hydroxypropyl methylcellulose/linseed mucilage;

5. Karaya gum/lime mucilage.

The aqueous solutions containing the different percentages of hydrocolloids and/or mucilages were subjected to a sterilizing filtration process, through a Supporex<? >grade ECV filter (Pall Corporation, USA) at a constant flow rate (17 L/min) and the operating pressure was determined.

We report the general methodology reported in the previous point

The measurements are reported in the following tables (VII-XI) in relation to the composition of the solution.

Table VII: pressure values recorded for the xanthan gum/mallow mucilage composition in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table VII

Table VIII: Pressure values recorded for the guar gum/marshmallow mucilage composition in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table VIII

Table IX: pressure values recorded for the sodium alginate/aloe mucilage composition in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table IX

Table X: Pressure values recorded for the composition hydroxypropyl methylcellulose (HPMC)/linseed mucilage in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table X

Table XI: Pressure values recorded for the composition karaya gum/lime mucilage in relation to the quantity of the two components, expressed as a weight/weight percentage of the total composition.

Table XI

As can be seen from the data reported in the tables, also in this case the same trend as in example 1 regarding the flow rate is observed: the pressure increases with the increase in the quantity of the components (and therefore in the viscosity of the solution) in a very marked way in the case of the presence of a single component (i.e. up to values exceeding 160 mbar in the case of quantities of hydrocolloid and/or mucilage of 0.8% w/w). When both components are present, this increase is much less marked and reaches, in the worst case, 136 mbar, remaining more often around 120 mbar, even when the overall concentration of the rheological modifiers is equal to 1.6 % w/w (0.8 0.8).

Identical to previous 1.01 - 1.60 mPas (dynamic viscosity)

Formulational examples comprising the composition according to the present invention

Below are some qualitative/quantitative examples of formulations comprising the composition according to the present invention. The quantities of the different components (active ingredients and functional excipients) are expressed as a weight/weight percentage of the total weight of the composition.

Claims (10)

1. An aqueous-based viscous liquid ophthalmic composition comprising, or alternatively consisting of at least one mucilage and at least one hydrocolloid. 2. The composition according to claim 1, characterized in that said at least one mucilage is present in an amount ranging from 0.01 to 10% w/w of the total weight of the composition, preferably in an amount ranging from 0.2 to 1% w/w of the total weight of the composition. 3. The composition according to claim 1 or 2, characterized in that said at least one hydrocolloid is present in an amount ranging from 0.01% to 10% w/w of the total weight of the composition, preferably in an amount ranging from 0.2% to 1% w/w of the total weight of the composition. 4. The composition according to any of the preceding claims, characterized in that said at least one mucilage and said at least one hydrocolloid are in a mucilage:hydrocolloid ratio in a range of from 10:1 to 1:2 to each other, preferably from 5:1 to 3:1. 5. The composition according to any of the preceding claims, characterized in that said composition has a dynamic viscosity of from 1.01 to 1.60 mPa? s, at a temperature of 25?C?2?C, and an external pressure of 1 atmosphere. 6. The composition according to any of the preceding claims, characterized in that said at least one mucilage is selected from the group comprising or, alternatively, consisting of aloe mucilage, marshmallow mucilage, lime mucilage, marigold mucilage, psyllium mucilage or mixtures thereof. 7. The composition according to any of the preceding claims, characterized in that said at least one hydrocolloid is selected from the group comprising or, alternatively, consisting of xanthan gum, guar gum, karaya gum, carob gum, gum arabic, gum ghetti, starch, konjac gum, glucomannan, alginic acid or its sodium, potassium or magnesium salts, cellulose derivatives, chitosan, sodium hyaluronate or mixtures thereof. 8. The composition according to any of the preceding claims, characterized in that the hydrocolloid/mucilage pair is selected from the group comprising or, alternatively, consisting of xanthan gum/mallow mucilage, guar gum/marshmallow mucilage, sodium alginate/aloe mucilage, hydroxypropyl methylcellulose/linseed mucilage and karaya gum/lime mucilage, mallow mucilage/sodium hyaluronate. 9. The composition according to any of the preceding claims, wherein said composition is for use in the treatment and/or prevention of eye diseases and/or as eye drops or artificial tears to be used, preferably to counteract the symptoms of dry eye. 10. An ophthalmic pharmaceutical formulation comprising the composition according to any of the preceding claims and, optionally, at least one active ingredient and/or excipient for pharmaceutical use.