WO2009044423A1 - Ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid - Google Patents
Ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid Download PDFInfo
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- WO2009044423A1 WO2009044423A1 PCT/IT2008/000626 IT2008000626W WO2009044423A1 WO 2009044423 A1 WO2009044423 A1 WO 2009044423A1 IT 2008000626 W IT2008000626 W IT 2008000626W WO 2009044423 A1 WO2009044423 A1 WO 2009044423A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention concerns ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid. More particularly, the invention concerns ophthalmic solutions indicated for use as tear substitutes, containing a combination of hyaluronic acid and a polysaccharide known as TSP (Tamarindus indica Seed Polisaccharide) which are able, when administered together in a combination, to act synergistically in stimulating the return to normality in the conjunctival mucosa affected by the dry eye syndrome, thus inducing a remarkable improvement in the number and morphology of the conjunctival microvilli.
- TSP Tin indica Seed Polisaccharide
- the eye surface is maintained constantly humid by the presence of the pre-corneal tear film, which is an organised liquid structure coating the conjunctiva and the exposed surface of the eyeball. It is fundamentally important that the structure is quantitatively and qualitatively suitable in order to obtain proper cleansing and protection.
- the tear film contains substances with high bactericide power as lysozyme and antibodies, which protect the eyes from the attack of many antigens.
- the tears which are the result of a series of solutions excreted by different glands in the conjunctival sac, are arranged in layers over the corneal and conjunctival surface by the eyelids movements, thereby making up a complex three-layered structure, comprising:
- an internal layer of mucus consisting of a mixture of glycoproteins (mucin) produced by specialised cells (i.e. the conjunctival goblet cells) which are present in the conjunctival epithelium - said layer is adsorbed on the cornea, thus transforming the corneal epithelium in a hydrophilic surface: if mucin is lacking the epithelial cells are hydrophobic and cannot be hy- drated by the tears;
- a thick intermediate aqueous layer secreted by the main and accessory lachrymal glands consisting essentially of water, electrolytes, proteins, enzymes and mucin; this layer is spread over the said hydrophilic surface, and has the function of providing atmospheric oxygen to the corneal epithelium, of exerting an antibacterial activity and of washing away any de- bris;
- a thin external lipid layer secreted by sebaceus tarsal palpebral glands or Meibomian glands, having the following functions: retarding the underlying water layer evaporation, increasing the surface tension to stabilize the film avoiding its escape on the skin and lubricating the eyelids.
- the eyelids movement squeezes the mucus out of the conjunctival cells and introduces it into the fornixes, and from there it is uniformly distributed on the whole corneal surface by the blinking movements of the eyes.
- the three-layers structure described above constitutes a complex physiological system, having the main functions of protecting the eye surface, maintaining the hydration, the lubrication and the clearness of the corneal surface, and of cooperating in producing a correct vision.
- the perfect equilibrium and continuous renovation of the said physiological system is a necessary condition for it to be able to carry out said functions.
- a constant but not excessive water evapo- ration from the tear fluid must take place, so as to keep the osmolarity thereof to the physiological level of about 300 m ⁇ sm/l, and the tear film must be continuously redistributed on the corneal surface as a result of the blinking.
- the lipids of the exter- nal layer are arranged into a double phase: a polar phase, adjacent to the intermediate layer, and a thicker phase at the interface with the air.
- the aqueous phase shows instead fixed ionic concentrations: mainly sodium, potassium, calcium, magnesium, zinc, chlorine and bicarbonate are important for maintaining the tears osmolarity.
- the integrity of the internal mucin layer represents one of the essential elements of the maintenance of the tear film stability.
- mucin enhances the wettability of the corneal surface, allows the aqueous film to keep adhering to the exposed surface in a continuous and homogeneous way, thus safeguarding its stability, and increases the viscosity of the lachrymal fluid, preventing it from flowing away too rapidly from the conjunctival sac.
- mucin when mucin is absent or insufficient the cornea becomes non- wettable and, as a consequence of the unbalance between electrolytes and glycoproteins present, the tear film becomes unstable and subject to breaking, with formation of dry areas.
- the term "dry eye” is commonly used to refer to the ophthalmic conditions resulting from the reduction or the instability of the tear film - characterised form a subjective point of view, by a series of annoying symptoms comprising burning sensation, foreign body sensation, photophobia and blurred vision, heavy ocular feeling, easy irritation due to wind, smoke and dusts and visual- disturbances - while the typical alterations of the corneal surface occurring in this connection are generally referred to by the term “keratoconjunctivitis sicca". In such situations a degeneration of the conjunctival cells occurs, resulting in increased desquamation, loss of the cell surface microplicae, breaking of the epithelial cells membrane and reduction of the number of mucin-producing goblet cells.
- the corneal and conjunctival epithelial cells appear to be suffering and with a reduced number of microvilli, until their com- plete disappearance.
- the reduction of the number of microvilli is with a good approximation proportional to the affection severity and to the seriousness of the symptomatology.
- This anatomo-pathological situation is accompanied, in various degrees, by an infiltration of inflammatory cells at the level of the conjunctival cells. (Cennamo G. L., Del Prete A., Forte R., Cafiero G-, Del Prete S., Marasco D., Impression cytology with scanning electron microscopy: a new method in the study of conjunctival microvilli, Eye (2007), 1-6).
- the dry eye syndrome lacking a protective effect of the tear film, predisposes to other pathological conditions such as actinic, bacterial, viral and allergic keratoconjunctivitis.
- mucus is characterised by crystallizing in a fern pattern when made to evaporate at room temperature from an aqueous solution.
- the ferning phenomenon which is believed to result from the interaction of the electrolytes with the high molecular weight glycoproteins of mucus, is evidenced after a short time from the collection of tear mucus from the lower fornix of the conjunctiva.
- a dense ferning for instance, is considered to be the expression of a perfect equilibrium between mucin and electrolytes, while the partial presence or the absence of tear ferning, which is detected in eyes affected by keratoconjunc- tivitis sicca, denotes a quantitative lack of tear mucus or a qualitative alteration of the glycoproteins or of their environment (i.e., pH, hydration, electrolytic equilibrium).
- Keratoconjunctivitis sicca is normally treated with liquid ophthalmic preparations generally known as "artificial tears", to be instilled in drops in order to replace or supplement the natural tear production.
- said preparations have only a moistening effect, as they consist of physiological saline solutions, neutral and isotonic with the lachrymal film, based on sodium chloride only or on balanced mixtures of various electrolytes.
- compositions for use as artificial tears having non- newtonian rheologic behaviour are those containing carboxyvinyl polymers such as Carbopol ® , the cellulose esters, such as methylcellulose and the alcoholic derivatives thereof, (e.g. hydroxypropylcellulose and hydroxypropyl- methylcellulose) and hyaluronic acid.
- Carbopol ® the cellulose esters, such as methylcellulose and the alcoholic derivatives thereof, (e.g. hydroxypropylcellulose and hydroxypropyl- methylcellulose) and hyaluronic acid.
- the latter is a polysaccharide of natural origin present in many tissues and fluids, both human and animal, and largely employed in ophthalmic preparations, owing to the marked pseudoplastic behaviour of its aqueous solutions, and because of its good capacity to link both with water and the epithelial cell wall.
- a natural polysaccharide polymer that may be considered enclosed in the cited category is the polysaccharide obtained from seeds of the tamarind tree, the Tanarindus indica, an evergreen plant that may reach 15 m of height and that produces legume fruit and that is widespread in India, in Africa and the whole the Far East where it is cultivated primarily for food production.
- the fruit contains big seeds having an high percentage of polysaccharides, which have the function to accumulate and preserve vital energetic substances.
- the seed which was considered originally a by-product, has found various applications, once ground to the powder form (known as "tamarind gum” or “tamarind kernel powder”).
- tamarind gum or "tamarind kernel powder”
- the most important of such applications are in textile industry and in paper industry, where tamarind gum is employed respectively as sizing agent, and in food industry, where it is used as thickening, gelling, stabilising and binding agent in any kind of products, as do other polysaccharide products such as alginates, pectines, guar gum or locust bean gum.
- Raw tamarind kernel powder which is commercially available as such, contains from 65 to 73% by weight of polysaccharide, from 15 to 23% of protein material, from 3 to 8% of fats and oil and from 2 to 4% of ashes, besides minor amounts of crude fibre, tannins and other impurities.
- the polysaccharide fraction of tamarind gum (tamarind seed polysaccharide, in the following also referred to as TSP) has found a valid use as active component of tear substitutes and as carrier for topical ophthalmic sustained release drugs as described, in particular, in the European Patent EP 0892636 (Farmigea) and in the corresponding US patent N. 6,056,950, the contents of which is incorporated herein by reference.
- TSP tamarind seed polysaccharide
- mucomimetic properties that the polysaccharide fraction of tamarind gum appears to have it must be evidenced the "feming" ability previ- ously described. Therefore, similarly to the hyaluronic acid, said polysaccharide fraction is able to give, by evaporation, crystalline products having morphology quite similar to that of crystallized tear mucus.
- an object of the present invention is to define a pharmacologic treatment for the dry eye syndrome therapy wherein the tear substitute is not only able to remain for a long time on the ocular surface and to self-integrate with the surface of the epithelia, exerting a protective role over them, but also is able to help the restoration of their integrity, particularly to help a rapid return to normality in the conjunctival mucosa, overall in respect of the number and of the morphology of the microvilli.
- tamarind seed polysaccharide consists of a main chain of glucopyranosyl units bound to each other through (1 ⁇ 4) linkages, with short side chains consisting of xylopyrano- syl units attached to the main chain through (1 ⁇ 6) linkages.
- Said xylopyrano- syl units are single, or they may be bound, in turn, to single galactopyranosyl units through a (1 ⁇ 2) linkage. It was also reported the further presence of arabinofuranosyl units. Therefore, the structure of the tamarind seed polysaccharide (TSP) may be represented as follows
- the procedure for the extraction, filtration and purification of the polymer from the starting raw material requires a high technological specialization in order to maintain unchanged the functional characteristics, also in view of the high molecular weight, which ranges, in a correctly purified product, from 600,000 to 750,000 Da.
- the hyaluronic acid is chemically definable as an unbranched glyco- saminoglycan, consisting of alternate units of D-glucuronic acid (GIcUA) and N-acetyl-D-glucosamine (GIcNAc), which structure may be represented by the following formula:
- the average molecular weight of the hyaluronic acid used in ophthalmology (in the form of the corresponding sodium salt) for artificial tear solutions is normally comprised between 700,000 and 1 million Da.
- the present invention specifically provides an ophthalmic preparation for use as tear substitute containing, in combination, from 0.05 to 2% by weight of tamarind seed polysaccharide and from 0.05 to 1% by weight of hyaluronic acid in aqueous solution.
- tamarind seed polysaccharide (Tamarindus indica Seed Polysaccharide o TSP, sometimes also generically referred to with the term “xyloglucan ”) as used in the present application, means any polysaccharide- enriched fraction obtainable from tamarind gum (i.e. tamarind kernel powder), the latter being the raw product currently available on the market.
- a partially purified polysaccharide fraction of tamarind gum is sold, for instance, by Dai- nippon Pharmaceutical Co. LTD of Osaka, Japan, under the trade name GIy- loid ® .
- the concerned polysaccharide fraction is preferably further purified to give a practically pure tamarind seed polysaccharide.
- hyaluronic acid means the previously described polysaccharide (generally also referred to as “glyco- saminoglycan”), in particular in the salt form commonly used for the formulation of artificial tears, i.e. sodium hyaluronate.
- the ophthalmic preparation according to the invention contains, in combination in aqueous solution, from 0.1 to 1% by weight of tamarind seed polysaccharide and from 0.1 to 0.5% by weight of hyaluronic acid.
- the weight concentrations in the ophthalmic preparation according to the invention are comprised between 0.1 and 1 % of tamarind seed polysaccharide and between 0.1 and 0.5% by weight of hyaluronic acid.
- An embodiment which has been specifically studied in the experimental work provided below, and which provides superior clinical performances regarding the ability of the two active agents to cooperate in restoring the normality of the conjunctival epithelium, contains, in aqueous solution, 0.2% by weight of tamarind seed polysaccharide and 0.4% by weight of hyaluronic acid.
- the tamarind seed polysaccharide used in the preparations of the invention has a molecular weight comprised in the range from 450,000 Da to 750,000 Da (preferably 600,000-750,000 Da), and the hyaluronic acid has molecular weight comprised in the range from 600,000 Da to 1 ,000,000 Da (preferably 700,000-1 ,000,000 Da).
- one or more tonicity adjusting agents should be added, so as to give the solution a correct value of osmolarity.
- any one of the products currently employed in the art as tonicity agents may be used, such as, for instance, sodium chloride, potassium chloride, mannitol, dextrose, boric acid, sorbitol or propylene glycol.
- ingredients which may be included in the formulation, in accor- dance with the known art are acids or bases as pH adjusting agents, as well as buffers, such as, e.g., the phosphate buffer (monobasic sodium phosphate and dibasic sodium phosphate), or acetate buffer (acetate - acetic acid system).
- buffers such as, e.g., the phosphate buffer (monobasic sodium phosphate and dibasic sodium phosphate), or acetate buffer (acetate - acetic acid system).
- buffers that may be used are the borate, citrate, bicarbonate and trizma (tri-hydroxymethyl-aminomethane) buffers.
- the composition may also comprise preservatives and antimicrobial agents, such as benzalkonium chloride, sodium merthiolate or thimerosal, methyl-, ethyl- and propyl paraben, chlorobutanol, phenilmercurium nitrate or acetate, phenilethilyc alcohol, clorexidine acetate or gluconate, as well as chelating agents such as the edetates or EDTA.
- preservatives and antimicrobial agents such as benzalkonium chloride, sodium merthiolate or thimerosal, methyl-, ethyl- and propyl paraben, chlorobutanol, phenilmercurium nitrate or acetate, phenilethilyc alcohol, clorexidine acetate or gluconate, as well as chelating agents such as the edetates or EDTA.
- the present invention concerns the use of a combination of tamarind seed polysaccharide and of hyaluronic acid in aqueous solution for the production of a preparation for the treatment of dry eye syndrome.
- said tear substitute or preparation preferably comprises from 0.05 to 2% by weight of tamarind seed polysaccharide and from 0.05 to 1% by weight of hyaluronic acid, and more preferably it comprises from 0.1 to 1 % by weight of tamarind seed polysaccharide and from 0.1 to 0.5% by weight of hyaluronic acid.
- the tamarind seed polysaccharide of the proposed preparation for the use described below suitably has a molecular weight comprised from 600,000 Da to 750,000 Da, while the molecular weight of hyaluronic acid is preferably comprised from 700,000 Da to 1 ,000,000 Da.
- the present invention is also disclosed by the following non-limiting examples, according to some specific embodiments thereof, which illustrate examples of formulations based on xyloglucan and hyaluronic acid employed as tears substitutes, having a protective and re-epithelizing activity, according to what is experimentally ascertained and reported in the experimental statement that follows.
- the product is prepared by the following steps: TSP and HA are weighted into a suitable glass vessel; 90% of the available water is added with a light stirring until complete dissolution of the product;
- Example 2 The mannitol amount is added, keeping stirring, and the mixture is left under stirring until complete dissolution of the product; Deionised water is added up to the final weight (100%); monobasic sodium and dibasic sodium phosphate are added to reach desired pH; the solution so obtained is sterilised in autoclave or, in alternative, sterilised by filtration with a 0.22 micron filter.
- Example 2 The mannitol amount is added, keeping stirring, and the mixture is left under stirring until complete dissolution of the product; Deionised water is added up to the final weight (100%); monobasic sodium and dibasic sodium phosphate are added to reach desired pH; the solution so obtained is sterilised in autoclave or, in alternative, sterilised by filtration with a 0.22 micron filter.
- Example 2 Example 2
- the product is prepared in the same way as in the example 1.
- Figure 1 shows, in form of histogram, the results of a pilot study on the effectiveness of the composition according to the invention in the treatment of dry eye syndrome, as concerns the evaluation of the conjunctival microvilli, in terms of absolute values;
- Figure 2 shows the results, in the same pilot study, of the evaluation of the conjunctival microvilli, in terms of variation of the basal values
- Figure 3 shows a SEM 750Ox image of a left eye conjunctival epithelium of a female patient of the same pilot study, said patient belonging to the group TSP+HA, before the treatment;
- Figure 4 shows a SEM 750Ox image of a left eye conjunctival epithelium of the same female patient of Figure 3, after 60 days of treatment with TSP+HA;
- Figure 5 shows in form of histogram the results of the same pilot study of Figure 1 , as concerns the evaluation of the effects on the subjective symptomatology, in terms of absolute values;
- Figure 6 shows the results, in the pilot study, of the evaluation of the effects of subjective symptomatology, in terms of basal values
- Figure 7 shows, in form of histogram, the results of the same pilot study of Figure 1 , as concerns the evaluation of the effects on the subjective symptomatology, in terms of absolute values;
- Figure 8 shows the results, in the same pilot study, of the evaluations of the effects of subjective symptomatology, in terms of basal values
- Figure 9 shows, in form of histogram, the results of the same pilot study of Figure 1 , as concerns the evaluation of the effect on the cytology, in terms of absolute values;
- Figure 10 shows the results, in the same pilot study, of the evaluation of the effects on the cytology, in terms of variation in respect of the basal values
- Figure 11 shows, in form of histogram, the results of the same pilot study of Figure 1 , as concerns the total score (combined score) of the previous evaluation, in terms of absolute values
- Figure 12 shows the results, in the same pilot study, of the combined score of the previous evaluations, in terms of variation in respect to the basal values.
- the polysaccharide hydrogels are provided of a very complicated tri- dimensional structure, whitin which water may be incorporated.
- the water content, the type of interaction that occurs between water and the polymer materials, as well as the water distribution internally to the polymer itself have a critic influence on the mechanical properties, the muco-adhesivity and are at the base of the high degree of biocompatibility.
- Commonly three types of water are distinguished in the polysaccharide gel: linked water, intermediate water and free water.
- the Nuclear Magnetic Resonance spectroscopy (NMR) represents one of the most useful techniques for the study of the structure, the mobility and the hydration properties of the polymeric systems.
- the relaxation time T 2 represents the constant time which describes the decay of the transversal magnetization in time, while the relaxation time Ti describes the recovering process of the longitudinal magnetization.
- T 2 measured for the water in the concerned solution, is the relaxation speed rate of the bonded water and — is the relaxation speed rate of the free
- X b and X f are, respectively, the molar fraction of the bonded and free water.
- the number of bonded water molecules may be expressed in the following way, as dependant on the surface S of the polymer, on the thickness K of the bonded water superficial layer and on the total volume of water V (equation 2):
- TSP solutions having variable concentration from 0.1% (w/w) to 1%
- HA solutions having variable concentration from 0.1% (w/w) to 1%
- spectral parameters of the two polymers HA and TSP in the different concentrations and in their mixtures have been also compared.
- the spectral parameters considered are the following:
- DOSY diffusion Ordered SpectrocsopY
- the chemical shift measures of 23 Na and those carried out on the ace- tyl group of hyaluronic acid are aimed at determining wether the interaction between the two polymeric materials involves the polar ionized groups of the hyaluronic acid or its acetyl group.
- the measures carried out on the anomeric protons are aimed at determining which types of TSP units are prevalently involved in the interaction with HA.
- the mother solutions were prepared dissolving solid polymers in D 2 O at the desired concentrations. Two series of solutions were prepared, the first one obtained after stirring at ambient temperature for 12 h and the second one after stirring for 12 h at ambient temperature and stirring under heating at 8O 0 C for about 60 min. The results obtained from the two series of solutions were completely overlapping; therefore in the following discussion no distinc- tion will be made between them.
- NMR studies were carried out on a NMR Varian INOVA 600 14T spectrometer, operating at 600 MHz for 1 H and 158.6 MHz for 23 Na, provided by a 5 mm inverse triple-resonance probe and a 5 mm broadband probe for
- the spectrometer is equipped with a temperature control system of ⁇ 0.1 0 C.
- the selective proton relaxation times spin-spin Ti are those obtained with the standard sequence inversion-recovery (180°- ⁇ -90°-acquisition) for selective application of an impulse of inversion of the desired frequency. 10
- the relaxation times spin-spin T 2 were measured using the sequence
- Carr-Purcell-Meiboom-Gill (CPMG) (90 o - ⁇ -(180°-2 ⁇ ) n ).
- DOSY maps (Diffusion Ordered Spectroscopy) were registered using a relaxation time of 3 s with a number of transients equal to 4. 30 gradients were utilized and the parameters ⁇ e ⁇ were optimized (1 ms and 80 ms, 15 respectively) to obtain a fall up to 10-5% of the initial signal.
- the said difference may be reasonably correlated to the different tendency to self-aggregation of the two polymers: probably TSP has a bigger tendency to self-associate at increasing concentrations in respect of HA and as a consequence of the self-aggregation phenomena an increase of the bonded water fraction in respect of free water occurs.
- the longitudinal relaxation speed R 1 of the acetyl protons of hyaluronic acid was measured in mixtures having a total constant concentration equal to 0.5% and variable TSP/HA ratios.
- the behaviour of the relaxation speed Ri of the acetyl group is particularly interesting in mixtures HA/TSP having total concentration 0.5%, wherein it is observed once more a decrease of the relaxation speed Ri with increasing HA concentration, but with absolute values that are still lower than those measured in the absence of TSP at the same concentration.
- the amount of the reduction produced in the relaxation speed in the acetyl group as a consequence of the presence of TSP became higher at variable ratios from 3:2 to 4:1 ; in this gap the remarkable synergistic effect of the two polymers is confirmed.
- the relaxation speed spin-spin R 2 of the acetyl protons follows the same behaviour, both in the pure polymer and in its mixture with TSP; namely on increasing the HA concentration a decrease of the relaxation parameter is obtained, but the relaxation speeds in the mixture are lower, and the decrease in the mixture in respect of the pure component increases with high TSP/HA ratios.
- the anomeric protons of TSP at 5.06 ppm, 4.85 ppm and 4.45 ppm result to be not overlapped to signals of hyaluronic acid and, as such, they were taken as a base with the aim of obtaining information on the TSP protons involved in the interaction with HA.
- the proton at 4.45 ppm corresponding to the units of Glucose and Galactose behaves in a completely different way with respect to the other protons. In fact, its value is scarcely dependent on the pure component solution concentration. The same changes in a significant way in presence of HA; in particular, differently from the other protons, it undergoes a significant decrease when the HA content increases. This behaviour must be ascribed to the conformational variations induced in TSP as a consequence of the interaction with HA.
- the Schirmer I test involves the introduction of a bibula paper strip, of standard material and size, in the inferior conjunctival fornix, towards the external canthus.
- the strip is left in situ for a predetermined period of time (3 min) and after said period the soaked part is measured, excluding the folded portion.
- the time employed by the tear fluid to ascend and the length in mm of the paper portion soaked by the tears provides the size of the tear secretion.
- the pH evaluation that is carried out by the use of suitable turnsole paper, is an important test to reveal any pathologic changes in the epithelium.
- the normal values of the tears pH in man range between 6.8 and 7.4, while in the rat the said range moves towards higher values (from 7 to 8).
- the tear fluid becomes basic.
- the Ferning test was described in its generalities in the introductive section.
- the corneal examination comprises the marking with sodium fluorescein, after which the corneal surface is examined with fluorescence microscope.
- a maculate marking reveals the presence of dry zones on the ocular surface, symptom of corneal dryness.
- the marking with Lissamine Green instead, allows to reveal the presence of ulcerated or necrotic zones on the ocular surface.
- control group composition according to the invention (0.4% hyaluronic acid + 0.2%
- TSP TSP+HA
- Mix of glycols and hydroxypropyl-guar Systane multidose bottle, Al- con
- the Schirmer I test was carried out after 2, 3, 4, and 5 days, after atropine administration, in both eyes of all the animals, maintaining for 3 min. the bibula paper strips in the external tertium of the conjunctival fornix.
- the pH measurement was carried out the day 0 and the day 5 using the suitable turnsole paper.
- the Ferning test was carried out on samples of tear film from the treated animals with the different formulations at the day 5, mixing 10 ⁇ l of each formulation with 2 ⁇ l of artificial tears.
- the mixture was examined with a microscope, at room temperature (20 ⁇ 1°C).
- the corneal examination was carried out after 3, 4 and 5 days, after administration of atropine. After marking with fluorescein and with Lissamine Green, the corneal surface was observed using a lamp with suitable filters.
- the Schrimer test results did not show any quantitative differences in the tear volume upon treatment of the animals with the composition of the invention and with the other products already available on the market. Also the evaluation of the tear pH did not show any pathological variations either for the product according to the invention or for anyone of the other produts under examination. Neither the corneal examination after marking with fluorescein and with Lissamine Green showed any pathological alterations of the cornea after the treatment with the product according to the invention, analogously to what observed for the other substances available on the market. The ferning tests produced images of the crystallized tears which do not show essential differences between the various treatments under comparison.
- Phase 1 the tests of the Phase 1 showed the absence of negative interactions between the proposed composition and the physiological status of the conjunctiva-cornea, in the same way as other artificial tear formulations already on the market.
- Phase 2 the tests of the Phase 1 showed the absence of negative interactions between the proposed composition and the physiological status of the conjunctiva-cornea, in the same way as other artificial tear formulations already on the market.
- T1 40 min: Anesthesia with 8.5% chloralium hydrate and exposure to a continuous and constant flow of dry air for 1 h.
- T2 100 min: End of the air flow.
- T3 130 min: 1 % Topical atropine T4 (150 min): End of the cycle.
- the test consisted in a controlled randomized open study on three parallel groups, with blind evaluation, without the wash out step, wherein/the products administered as artificial tear were the following: /
- TSP TSP ophthalmic solution
- HA HA ophthalmic solution
- TSP+HA HA ophthalmic solution
- the score variation of the conjunctival microvilli number from the beginning and end of the treatment was deter- • mined.
- the score variation of the subjective symptomatology, of the objective symptomatology, of the conjunctival cytological pattern (scraping), of the composite score (as defined below) and of the toler- ability and safety of the product were determined.
- Microvilli evaluation The effects of the treatment on the microvilli were evaluated with scanner electronic microspy (SEM). For each eye exam- ined repere points using the vascular grid were identified, in order to operate the basal and final withdrawals in the same area. A sample of epithelium was taken, separately for each eye, from the superior temporal bulbar conjunctiva using the "impression cytology" technique.
- the withdrawal was carried out from a minimum of 48 hours to a maximum of 7 days after the ophthalmoscopic exam.
- a conjunctival scraping was carried out for the cytological evaluation.
- Subjective symptomatology This was the first of the parameters evaluated during each visit (basal or final), when the patient was invited to refer the subjective degree of nuisance suffered during the last week for the following ocular symptoms: itching, burning sensation, irritation, lachrymation. Based on the direct information provided by the patient, the physician of the experimentation converted the total intensity of the ocular discomfort over an analogical scale of 4 points (from 1 to 4), wherein the degree 1 represented the symptom absence, the degree 2 a light symptomatology, the degree 3 a moderate symptomatology and the degree 4 represented the most severe symptomatology
- Conjunctival cytology the inflammatory cellular component was taken from the conjunctiva with scraping and without anaesthetic, fixed with May-Grunwald solution (methylene blue eosinate) found on the market.
- the scraping was carried out from 2 and 7 days after the ophthalmoscopic examination, during the same session when the withdrawal of the sample for the microvilli study was scheduled.
- Composite score - it represents the sum of the four parameters de- scribed above and it was evaluated as a surrogated index of a global effectiveness.
- the effects of the treatment on the microvilli photographed with scanner microscopy were determined evaluating with a 4-points scale.
- the three groups were quite homogeneous, the group “TSP” having an average score of 3.0, and the groups “TSP+HA” and “HA”, having an average score of 3.3.
- the dispersion of the data appeared moderate, being the variation coefficient of 26% vs 22% vs 22%, respectively for TSP, TSP+HA, HA.
- Figures 3 and 4 show, using a scanning electron microscope, the development of the microvilli presence on the conjunctival epithe- Hum in a female patient aged 64 treated for 60 days with TSP+HA.
- Figure 3 allows to appreciate a glabrus epithelial surface due to the almost complete absence of microvilli; based on the criteria described before, to this histological frame a score of 4 (maximal reduction of the microvilli presence) had been assigned.
- Figure 4 shows a rich vegetation of microvilli, which allow to assign to this frame a score of 1 , substantially typical of a normal condition.
- the intensity of the subjective symptomatology was determined with analogical scale of 4 points under the form of intensity of the ocular nuisance, as described above.
- the three groups presented relative homogeneity, both from the point of view of the absolute values of the scores (with an average maximum gap of 0.3 points), and as dispersion values measured under the form of variation coefficient (33% vs 12% vs 29%, respectively for TSP, TSP+HA and HA).
- the objective symptomatology was measured with a 4 points scale evaluating the degree of affection of the 4 corneal-conjunctival sectors using a slit lamp as described above.
- the three groups presented a small degree of non-homogeneity, not statistically relevant, being the group TSP+HA at an average score of 2.8, higher of 0.3 point than the score of the TSP group and of 0.1 point of the score of the HA group.
- the data dispersion results relatively high for all the three groups, with a variation coefficient of 41% vs 29% vs 34%, respectively for TSP, TSP+HA, HA.
- Table 7 and the attached Figures 9 and 10 show that, after 60 days of treatment both in the TSP group and the HA group, a slight worsening of the cytologic profile was observed. On the contrary, in the group treated with TSP+HA a strong improvement in the cytologic profile was observed, even if not statistically relevant, with a passage of the average score of 2.7 to a value of 1.9, with a percent improvement of 28 9% in respect of the basal value.
- the composite score represents the sum of the four parameters described above (microvilli, subjective symptomatology, objective symptomatology, cytology) and it is a surrogated index of the global effectiveness. Its maximum theoretical value is 16. In spite of the source of possible off- balance between the groups, mainly due to the cytology, after randomization, at the basal value, the two groups were sufficiently homogeneous, as it results from the following Table.
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RU2010117173/15A RU2493855C2 (en) | 2007-10-02 | 2008-10-02 | Ophthalmic compositions of tamarind seed polysaccharide and hyaluronic acid |
US12/681,256 US8455462B2 (en) | 2007-10-02 | 2008-10-02 | Ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid |
MX2010003488A MX2010003488A (en) | 2007-10-02 | 2008-10-02 | Ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid. |
CA2701721A CA2701721C (en) | 2007-10-02 | 2008-10-02 | Ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid |
PL08835989T PL2197456T3 (en) | 2007-10-02 | 2008-10-02 | Ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid |
AT08835989T ATE499106T1 (en) | 2007-10-02 | 2008-10-02 | OPHTHALMIC COMPOSITIONS BASED ON TAMARIND SEED POLYSACCHARIDES AND HYALURONIC ACID |
EP08835989A EP2197456B1 (en) | 2007-10-02 | 2008-10-02 | Ophthalmic compositions based on tamarind seed polysaccharide and hyaluronic acid |
DE602008005173T DE602008005173D1 (en) | 2007-10-02 | 2008-10-02 | OPHTHALMIC COMPOSITIONS BASED ON TAMARINDIC SEED POLYSACCHARIDES AND HYALURONIC ACID |
JP2010527598A JP5542674B2 (en) | 2007-10-02 | 2008-10-02 | Eye drop composition based on tamarind seed polysaccharide and hyaluronic acid |
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EP (1) | EP2197456B1 (en) |
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DE (1) | DE602008005173D1 (en) |
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IT (1) | ITRM20070510A1 (en) |
MX (1) | MX2010003488A (en) |
PL (1) | PL2197456T3 (en) |
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- 2008-10-02 KR KR1020107006416A patent/KR101570966B1/en active IP Right Grant
- 2008-10-02 WO PCT/IT2008/000626 patent/WO2009044423A1/en active Application Filing
- 2008-10-02 JP JP2010527598A patent/JP5542674B2/en active Active
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Also Published As
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RU2493855C2 (en) | 2013-09-27 |
ES2361529T3 (en) | 2011-06-17 |
ATE499106T1 (en) | 2011-03-15 |
KR20100091151A (en) | 2010-08-18 |
PL2197456T3 (en) | 2012-07-31 |
CA2701721C (en) | 2016-02-23 |
RU2010117173A (en) | 2011-11-10 |
EP2197456B1 (en) | 2011-02-23 |
US8455462B2 (en) | 2013-06-04 |
KR101570966B1 (en) | 2015-11-23 |
US20100279981A1 (en) | 2010-11-04 |
JP2010540619A (en) | 2010-12-24 |
DE602008005173D1 (en) | 2011-04-07 |
PT2197456E (en) | 2011-05-18 |
CA2701721A1 (en) | 2009-04-09 |
JP5542674B2 (en) | 2014-07-09 |
MX2010003488A (en) | 2010-08-31 |
EP2197456A1 (en) | 2010-06-23 |
ITRM20070510A1 (en) | 2009-04-03 |
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