Pharmaceutical composition in gel form for controlled release of an active ingredient comprising xyloglucan and alcohol

Abstract

The present invention relates to a gel composition comprising a pharmaceutically active ingredient, the composition comprising xyloglucan in a concentration of 0.1% to 10.0% by weight, based on the total weight of the composition, and a primary alcohol in a concentration of 20.0% to 50.0% by weight, based on the total weight of the composition. The present invention also describes a method for preparing the composition and its use in treating conditions in which controlled release of the active ingredient is beneficial.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a gel composition containing a medicament active ingredient (active pharmaceutical ingredient).

[0002] The composition contains xyloglucan at a concentration of 0.1% to 10.0% by weight together with alcohol at a concentration of 5.0% to 50.0% by weight based on the total weight of the composition.

[0003] The present invention also describes a method for preparing said compositions and their use in the treatment of medical conditions in which controlled release of active ingredients is useful.The compositions may contain one or more pharmacologic or nutraceutical active ingredients, and may be administered by parenteral, subcutaneous, vaginal, buccal, oral, topical or rectal routes.The compositions may be administered by using a suitable medical device. [Background technology]

[0004] technical level WO 2009 / 028764 describes a gel for releasing proteins obtained from a complex of a polymer and a thermoreversible polysaccharide in the presence of a salt with salting-out properties. The resulting formulation is liquid at room temperature and becomes a gel upon injection, from which the protein is released.

[0005] WO 1999 / 059549 describes injectable hydrogels based on alginate esters that contain therapeutic proteins and metal ions.

[0006] US Patent Application Publication No. 2002 / 0019336 (Patent Document 3) describes a composition comprising a mucopolysaccharide, such as chondroitin sulfate or hyaluronate or ester, which is useful for the release of proteins and which results in the formation of a gel as the pH value changes.

[0007] Miyazaki S. et al., J Contr Rel 56, 75, 1998 (Non-Patent Document 1), describe the release of indomethacin from thermoreversible gels obtained with partially enzymatically degraded xyloglucan at a concentration of 1% to 2% by weight in water or phosphate buffer at pH 7.2.

[0008] Kant A. et al., in Pharmacology online 2: 28, 2011, describe the in situ formation of gels that are dependent on changes in temperature, pH, ions and the presence of UV light and can release active ingredients in a controlled manner. The gels can be formed of synthetic or natural polymers and can be administered by oral, ocular, rectal, vaginal or injectable routes. This document reports that when xyloglucan in aqueous solution is partially degraded with β-galactosidase, the resulting product has the property of being a thermoreversible gel, where gel formation occurs upon cooling from high temperature. This phenomenon does not occur with native xyloglucan (undegraded xyloglucan).

[0009] The in situ gel may comprise a mucoadhesive polymer for release of the active ingredient to the mucosa, as described in EP 3173067.

[0010] European Patent No. 1898876 (Patent Document 5) describes a mucoadhesive composition containing an aqueous solution of xyloglucan at a concentration of 0.05% to 5.0% by weight together with glycerol at a concentration of 10.0% to 70.0% by weight, and the mucoadhesive compositions described in this document are liquids, vaginal suppositories (ovules), gels, vaginal washes and sprays. This patent does not describe the formation of an in situ gel.

[0011] Japanese Patent No. 6490134 (Patent Document 6) describes a gel composition comprising an aqueous xyloglucan solution and at least one sugar and / or alcohol. The composition described in this document comprises xyloglucan at a concentration of 0.1% to 15.0% by weight, an alcohol selected from the group consisting of dihydric, trihydric, tetrahydric, pentahydric and hexahydric alcohols at a concentration of 10.0% to 50.0% by weight, and a water-soluble polymer. The composition described in this document refers to a gel composition for cosmetics and food, the purpose of which is to maintain the obtained gel during its storage.

[0012] Todaro S. et al., Chem. in Eng. Trans. 2016; 49:289-294 (Non-Patent Document 3) describe the rheological properties of xyloglucan depolymerized by high-energy irradiation. Fractions of depolymerized xyloglucan were characterized by FT-IR and the formation of gels in the presence of different concentrations of ethanol.

[0013] Pasta S. et al. in “I materiali biocompatibili per la medicina / Biomaterials for Medicine” 2014 (2014-01-01), Universitas Studiorum, XP055676486, pp. 369-370 (Non-Patent Document 4) describe the formation of a gel when native (undepolymerized) or depolymerized xyloglucan is mixed with Transcutol® in a relative ratio of 4:1, and state that this gel may be useful for tissue engineering for human applications.

[0014] There is an increasing need in the pharmaceutical field to find new pharmaceutical compositions that can release active ingredients in a controlled manner over time, such as to maintain effective plasma concentrations at effective levels and reduce the frequency of dosing over time.

[0015] In view of the above, the object of the present invention is a controlled release (sustained release) pharmaceutical or nutritional composition in gel form, comprising one or more active ingredients. The gel is formed by direct contact of natural polymers, xyloglucan and alcohol. The pharmaceutical gel composition containing the pharmaceutical active ingredient can be obtained by mixing the ingredients before use, in situ or for the preparation of a pharmaceutical product to be stored at room temperature or refrigerated. [Prior art documents] [Patent documents]

[0016] [Patent Document 1] International Publication No. 2009 / 028764 [Patent Document 2] International Publication No. 1999 / 059549 [Patent Document 3] US Patent Application Publication No. 2002 / 0019336 [Patent Document 4] European Patent No. 3173067 [Patent Document 5] European Patent No. 1898876 [Patent Document 6] Patent No. 6490134 [Non-patent literature]

[0017] [Non-Patent Document 1] Miyazaki S. et al., J Contr Rel 56, 75, 1998 [Non-Patent Document 2] Kant A. et al., Pharmacology online 2: 28, 2011 [Non-Patent Document 3] Todaro S. et al. Chem. in Eng. Trans. 2016; 49:289-294 [Non-Patent Document 4] Pasta S. et al., “I materiali biocompatibili per la medicina / Biomaterials for Medicine” 2014 (2014-01-01), Universitas Studiorum, XP055676486, pp. 369-370 Summary of the Invention

[0018] Summary of the Invention The present invention relates to a controlled release composition in gel form containing a medicament active ingredient.

[0019] The composition comprises xyloglucan, a primary alcohol and one or more active ingredients.

[0020] The present invention discloses a controlled release composition in the form of a gel, comprising one or more medicament active ingredients, xyloglucan, and a primary alcohol, the xyloglucan being present in a concentration of 0.1% to 10.0% by weight based on the total weight of the composition. The composition comprises a primary alcohol selected from the group consisting of 2-(2-ethoxyethoxy)ethanol (Transcutol®), ethanol, propanol, butanol, cetyl alcohol, stearyl alcohol, and cetylstearyl alcohol.

[0021] For some purposes, the primary alcohol is 2-(2-ethoxyethoxy)ethanol (Transcutol®).

[0022] The compositions of the present invention may comprise one or more medicament active ingredients selected from the group including anti-inflammatory agents, antifungal agents, antibiotics, mimetic (or mimetic) antibiotics, growth factors, disinfectants, anticancer agents, proteins, peptides, moisturizers, natural ingredients or mixtures thereof.

[0023] In one embodiment, the composition comprises xyloglucan in a concentration of 0.1% to 10.0% by weight, 2-(2-ethoxyethoxy)ethanol in a concentration of 5.0% to 50.0% by weight, based on the total weight of the composition, together with a medicament active ingredient. The composition is useful for releasing the active ingredient having a local and / or systemic effect in a controlled manner.

[0024] The present invention also describes a method for producing a composition consisting of purified xyloglucan prepared in an aqueous solution and a primary alcohol solution (or alcohol liquid), in which the concentration of purified xyloglucan is 0.1% to 10.0% by weight and the concentration of primary alcohol is 5.0% to 50.0% by weight, and the active ingredient can be contained in both solutions depending on its solubility. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Detailed Description of the Invention The present invention describes a controlled release composition in the form of a gel, the gel containing a pharmaceutical active ingredient that is released in a controlled and effective manner.

[0026] The compositions of the present invention are obtained by mixing an aqueous solution of xyloglucan (XG) with an alcohol (e.g., a primary alcohol). Pharmaceutical gel compositions containing a pharma- ceutical active ingredient can be obtained by mixing the two components immediately before use, in situ, or for the preparation of pharmaceutical products that are stored at room temperature or refrigerated.

[0027] The pharmaceutical active ingredient contained in the composition can be contained in an aqueous xyloglucan solution or an alcoholic solution (or alcohol liquid) without any restrictions depending on their solubility. The active ingredient can be stored as is, further diluted with an aqueous solution with or without xyloglucan, or can be contained in a gel at the time of administration.

[0028] The gel composition is formed by mixing xyloglucan with a primary alcohol selected from 2-(2-ethoxyethoxy)ethanol, ethanol, propanol, butanol, cetyl alcohol, stearyl alcohol and cetylstearyl alcohol.

[0029] In one preferred embodiment, a gel composition is described that comprises a pharma- ceutical active ingredient and is composed of xyloglucan and 2-(2-ethoxyethoxy)ethanol.

[0030] Xyloglucan is a polysaccharide derived from tamarind seeds, composed of (1-4)-β-D-glucan chains in which (1-6)-α-D-xylose bonds are partially replaced by (1-2)-β-D-galactoxylose. When xyloglucan is partially degraded by β-galactosidase, it forms a thermoreversible gel in water, and the resulting product has the property of gelling under reversible thermal conditions in dilute aqueous solutions. Gel formation is possible when the removal rate of galactose exceeds 35%. Furthermore, the transition temperature is inversely proportional to the polymer concentration and galactose removal. Such behavior does not occur in native xyloglucan (undegraded xyloglucan). Xyloglucan can be obtained by extraction from plants such as pea, soybean, rice, bamboo, and tamarind seeds. The molecular weight of xyloglucan derived from tamarind seeds is about 5,000 to 1,000,000 Da. The polymer is preferably obtained by extraction with an alkaline solution and then further purified by extraction in boiling water, centrifugation and sterile filtration.

[0031] The xyloglucan contained in the composition of the present invention is native xyloglucan that has not been enzymatically decomposed and has been purified according to the purification method described in European Patent No. 1898876, and is contained at a concentration of 0.1% by weight to 10.0% by weight relative to the total weight of the composition.

[0032] A gel composition obtained by mixing an aqueous xyloglucan solution with a primary alcohol selected from 2-(2-ethoxyethoxy)ethanol, ethanol, propanol, butanol, cetyl alcohol, stearyl alcohol and cetylstearyl alcohol, in which the concentration of xyloglucan is 0.1% to 10.0% by weight and the concentration of the primary alcohol is 5.0% to 50.0% by weight, based on the total weight of the composition, releases the active ingredient in a controlled manner.

[0033] In the present invention, the gel composition is obtained by mixing an aqueous xyloglucan solution with a primary alcohol selected from 2-(2-ethoxyethoxy)ethanol, ethanol, propanol, butanol, cetyl alcohol, stearyl alcohol and cetylstearyl alcohol, and the concentration of the xyloglucan is 0.1% by weight to 10.0% by weight and the concentration of the primary alcohol is 20.0% by weight to 50.0% by weight relative to the total weight of the composition.

[0034] A gel composition obtained by mixing an aqueous xyloglucan solution with 2-(2-ethoxyethoxy)ethanol, in which the concentration of xyloglucan is 0.1% to 10.0% by weight and the concentration of 2-(2-ethoxyethoxy)ethanol is 5.0% to 50.0% by weight, based on the total weight of the composition, releases the active ingredient in a controlled manner.

[0035] The composition contains xyloglucan in a concentration of 0.1% by weight to 10.0% by weight based on the total weight of the composition, and contains 2-(2-ethoxyethoxy)ethanol in a concentration of 20.0% by weight to 30.0% by weight based on the total weight of the composition.

[0036] The composition contains xyloglucan at a concentration of 1.0% to 5.0% by weight, and 2-(2-ethoxyethoxy)ethanol at a concentration of 20.0% to 50.0% by weight, based on the total weight of the composition.

[0037] The composition contains xyloglucan at a concentration of 1.0% by weight to 5.0% by weight and 2-(2-ethoxyethoxy)ethanol at a concentration of 20.0% by weight to 30.0% by weight, based on the total weight of the composition.

[0038] By varying the amount of xyloglucan and 2-(2-ethoxyethoxy)ethanol in the composition, it is possible to obtain various amounts of gels characterized by different consistencies and capable of adjusting the release of the active ingredient over time. The composition of the present invention can retain a flexible matrix useful for controlled release depending on the active ingredient, the pathology to be treated and the delivery site.

[0039] It has been found that when a primary alcohol, particularly 2-(2-ethoxyethoxy)ethanol, is added to an aqueous xyloglucan solution so that the concentration of the primary alcohol is 5.0% to 50.0% by weight and the weight concentration of the xyloglucan is 0.1% to 10.0%, a gel is formed in less than 20 seconds, preferably 1 to 10 seconds.

[0040] The composition contains xyloglucan at a concentration of 0.1% to 10.0% by weight, preferably 0.5% to 8.0% by weight, more preferably 1.0% to 5.0% by weight, based on the total weight of the composition. A composition containing xyloglucan at a concentration of 0.1% to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol at a concentration of 5.0% to 50.0% by weight is characterized by having a rheological behavior different from the rheological behavior obtained by a composition containing xyloglucan (XG) and a secondary alcohol at the same concentrations.

[0041] A gel composition containing xyloglucan in a concentration of 0.1% to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol in a concentration of 20.0% to 50.0% by weight forms a gel in a weight percentage of more than 50.0% based on the weight of the composition. Furthermore, the amount of gel formed by a composition containing xyloglucan in a concentration of 0.1% to 10.0% and 2-(2-ethoxyethoxy)ethanol in a concentration of 20.0% to 50.0% is greater than the amount obtained from a composition containing xyloglucan and a secondary alcohol, such as propylene glycol, at the same concentration.

[0042] Xyloglucan in an amount less than 0.1% will form some amount of gel, this amount being less than 10.0% by weight of the solution.

[0043] A composition containing xyloglucan in a concentration of 2.0% to 5.0% by weight and 2-(2-ethoxyethoxy)ethanol in a concentration of 20.0% (w / w) to 50.0% (w / w) forms a gel that separates from solution, the gel being greater than 60.0% by weight of the solution.

[0044] In the present invention, the composition may comprise 4% (w / w) xyloglucan and 50% (w / w) 2-(2-ethoxyethoxy)ethanol.

[0045] In the present invention, the composition may contain xyloglucan at a concentration of 2.0% (w / w) to 5.0% (w / w) and 2-(2-ethoxyethoxy)ethanol at a concentration of 20.0% (w / w) to 30.0% (w / w) based on the total weight of the composition.

[0046] A composition containing xyloglucan at a concentration of 1.0% to 5.0% by weight and a secondary alcohol such as propylene glycol at a concentration of 20.0% (w / w) to 50.0% (w / w) forms a gel that separates from solution in an amount of less than 50.0% by weight of the solution, and the gel formation requires a longer time than a composition containing 2-(2-ethoxyethoxy)ethanol.

[0047] A gel composition obtained by mixing 2-(2-ethoxyethoxy)ethanol with an aqueous xyloglucan solution, in which the concentration of 2-(2-ethoxyethoxy)ethanol is 5.0% (w / w) to 50.0% (w / w) and the concentration of xyloglucan is 0.1% (w / w) to 10.0% (w / w), is obtained by mixing them for less than 20 seconds, preferably less than 10 seconds.

[0048] Rheological parameters are useful for defining the characteristics of a liquid or solid: the moduli G' and G" (known as the storage and loss moduli, respectively) are frequency-dependent material functions. G' describes the behavior of a solid and G" describes the behavior of a liquid. G' follows typical elastic behavior and is consistent with deformations, while G" follows typical liquid behavior.

[0049] The compositions of the invention in gel form are characterized by a storage modulus (G') greater than the loss modulus (G").

[0050] A composition containing xyloglucan at a concentration of 0.1% to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol at a concentration of 5.0% to 50.0% by weight is characterized by a decrease in the value of G' as the frequency decreases, a characteristic that is maintained even after 24 hours.

[0051] The composition of the present invention is characterized in that it has a G' value of 2000 Pa to 500 Pa at time T0 when a frequency of 100 radians / second to 0.1 radians / second is applied.

[0052] The composition of the present invention is characterized in that it has a G' value of 3000 Pa to 1000 Pa after 24 hours (T24) when a frequency of 100 radians / second to 0.1 radians / second is applied.

[0053] A composition comprising xyloglucan in a concentration of 0.1% to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol in a concentration of 5.0% (w / w) to 50.0% (w / w) is characterized by a G″ value of 500 Pa to 100 Pa at time zero (T0) when stress is applied at a frequency of 100 rad / s to 0.1 rad / s.

[0054] A composition comprising xyloglucan in a concentration of 0.1% (w / w) to 10.0% (w / w) and 2-(2-ethoxyethoxy)ethanol in a concentration of 5.0% (w / w) to 50.0% (w / w) is characterized in that it has a G" value of 300 Pa to 100 Pa at T24 when a frequency of 100 rad / s to 0.1 rad / s is applied.

[0055] The compositions comprising xyloglucan and a secondary alcohol, such as propylene glycol, in the abovementioned concentrations are characterized by a G' value that is lower than the G" value at T0, and both of these values ​​are lower than the values ​​obtained for the compositions comprising xyloglucan and 2-(2-ethoxyethoxy)ethanol. The gels comprising propylene glycol form in a longer time than the gels comprising 2-(2-ethoxyethoxy)ethanol, and the gels formed are characterized by a weaker formation. This is confirmed by the G' values ​​being lower than the values ​​obtained with 2-(2-ethoxyethoxy)ethanol, both at T0 and after 24 hours.

[0056] A composition containing xyloglucan in a concentration of 0.1% to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol in a concentration of 5.0% to 50.0% by weight is characterized in that at T0, the viscosity value is higher than the viscosity value obtained for a composition containing xyloglucan and propylene glycol in the same concentrations.

[0057] A composition containing xyloglucan at a concentration of 0.1% by weight to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol at a concentration of 5.0% by weight to 50.0% by weight has a 0 to 95 second at time T0. -1When a shear stress is applied at a shear rate of 1×10 10 ~2×10 3 mPa range.

[0058] A composition containing xyloglucan at a concentration of 0.1% by weight to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol at a concentration of 5.0% by weight to 50.0% by weight is subjected to a shear rate of 0 to 95 seconds. -1 When a shear stress is applied, the viscosity value after 24 hours is 3×10 7 ~1×10 3 It is characterized by its viscosity being mPa·s.

[0059] A comparative composition containing xyloglucan and a secondary alcohol such as propylene glycol at the same concentration shows a viscosity value at T0 lower than that obtained with a composition containing 2-(2-ethoxyethoxy)ethanol. The viscosity value of this composition is at least one order of magnitude lower than that of a composition containing 2-(2-ethoxyethoxy)ethanol, even after 24 hours. A composition containing xyloglucan at a concentration of 0.1% to 10.0% by weight and 2-(2-ethoxyethoxy)ethanol at a concentration of 5.0% to 50.0% by weight can contain other alcohols or esters capable of slowing down the release of the active ingredient. Such additives can be, for example, natural or synthetic polymers soluble in water or water-insoluble waxes. These compounds can be adjusted in a weight ratio of 1:50 to 10:1 with respect to the xyloglucan in the aqueous solution.

[0060] When the aqueous xyloglucan solution is mixed with 2-(2-ethoxyethoxy)ethanol, a gel is formed. The two solutions can therefore be stored in suitable containers for use as needed, and prepared by mixing xyloglucan and 2-(2-ethoxyethoxy)ethanol to form a gel at the site of action. The two components can be delivered to the desired site by forming a gel at the site that can release the active component using a system or medical device that contains the two solutions and has two channels or two chambers. Depending on the solubility in water, the active substance can be included in the aqueous xyloglucan solution or in an alcoholic solution (or alcohol liquid) of 2-(2-ethoxyethoxy)ethanol.

[0061] The process for preparing the composition according to the invention comprises the following steps: A step of preparing a purified xyloglucan aqueous solution having a concentration of 0.1% by weight to 10.0% by weight, and a step of adding the obtained xyloglucan solution to a primary alcohol solution (or alcohol liquid) to adjust the concentration of the primary alcohol to a concentration of 5.0% by weight to 50.0% by weight. In the above method, the active ingredient may be contained in both solutions depending on its solubility.

[0062] The solutions may be mixed at the time of use, prior to use, or during preparation of the gel to be stored.

[0063] A gel composition comprising xyloglucan at a concentration of 0.1% to 10.0% by weight, 2-(2-ethoxyethoxy)ethanol at a concentration of 5.0% to 50.0% by weight, and a pharmaceutical or nutritional ingredient, in which these ingredients are quickly incorporated into the gel, is favorable for the stability of these ingredients and avoids possible deterioration problems. A gel composition comprising 0.1% to 10.0% by weight of xyloglucan and 5.0% to 50.0% by weight of 2-(2-ethoxyethoxy)ethanol may comprise one or more pharmaceutical active ingredients selected from the group comprising anti-inflammatory agents, antifungal agents, antibiotics, mimetic (or mimetic) antibiotics, growth factors, disinfectants, anticancer agents, proteins, peptides, moisturizers, and natural ingredients or mixtures thereof.

[0064] Gel compositions are useful for releasing peptides, proteins and other active ingredients that may degrade upon storage when formulated with other excipients.

[0065] Administration can be by enteral (oral, sublingual, rectal), parenteral (subcutaneous, intradermal) or transdermal routes. The compositions can also be administered vaginally, nasally or via the oropharyngeal mucosa.

[0066] For example, the composition may be useful for administering drugs that easily reach affected areas, for example due to inflammation or infection, injury, dehydration. The composition may also comprise recombinant proteins, such as human recombinant interferon (rIFN), rIFNα, rIFNβ and rIFNγ, G-CSF, etc., where the release is in a controlled manner with full recovery of the administered dose. The ability of the composition according to the invention to release active ingredients in a controlled manner was demonstrated by experiments using rIFNα2b as an example of an active ingredient, as described below. The amount of active IFN released by the system was measured after 1, 3, 5, 24 and 48 hours. The measurements showed that after 5 hours, the total amount of IFN released was about 26%, after 24 hours, the total amount of IFN released was about 60%, and after 48 hours, the IFN was completely released. Such release occurring at 24 and 48 hours allows for a consistently effective plasma concentration of the active ingredient to be obtained with fewer doses.

[0067] The invention also provides kits for carrying out the methods described herein, the kits including dosages of the therapeutic agents in suitable packaging. EXAMPLES

[0068] Working Example Example 1: Measurement of xyloglucan gel formation by 2-(2-ethoxyethoxy)ethanol Aqueous xyloglucan solutions were prepared with concentrations of 0.4 wt %, 1.0 wt %, 3.2 wt % and 4.0 wt %.

[0069] Xyloglucan solutions were prepared by mixing the required amount of xyloglucan in water and leaving under stirring until completely dissolved.

[0070] The xyloglucan solution was mixed with 2-(2-ethoxyethoxy)ethanol in a graduated tube at the concentrations shown in the table. Gel formation was observed less than 10 seconds after mixing the two liquids. In addition to visual assessment, the amount of gel was determined after centrifugation of the solution to assess the percentage of gel in the solution.

[0071] The table below shows the relative amounts of the components xyloglucan, water and 2-(2-ethoxyethoxy)ethanol present in the solution and the amount of gel formed after mixing. The percentage of gel formed is given relative to the total amount of solution.

[0072] [Table 1]

[0073] Example 2: Measurement of xyloglucan gel formation by glycol propylene (Comparative Example) Xyloglucan aqueous solutions were prepared at concentrations of 0.4%, 1.0%, 3.2% and 4.0% by weight. The solutions were mixed with propylene glycol at the concentrations shown in the table. Xyloglucan solutions were made by mixing the required amount of xyloglucan in water and mixing until completely dissolved.

[0074] The xyloglucan solution was mixed with propylene glycol in graduated tubes at the concentrations shown in the table. In addition to visual assessment, the amount of gel was determined after centrifugation of the solution to assess the percentage of gel in the solution.

[0075] The table below shows the relative amounts of the components xyloglucan, water and propylene glycol in the solution and the amount of gel formed after mixing. The percentage of gel formed is given relative to the total amount of solution.

[0076] [Table 2]

[0077] Example 3: Determination of coefficients G' and G" for compositions containing xyloglucan-2-(2-ethoxyethoxy)ethanol 40 ml of 3.2% (w / w) concentration xyloglucan aqueous solution was mixed with 10 ml of 2-(2-ethoxyethoxy)ethanol. The solutions were loaded into two syringes and directly extruded (poured) onto the rheometer plate for analysis. G' and G" were measured with an Antoon Paar MCR101 rheometer using a 50 mm flat cone and adjusted to a temperature of 37°C. Measurements of G' and G" were performed at T0 and T24.

[0078] Table 3 shows the values ​​of the moduli G' and G" as the applied stress increases.

[0079] [Table 3]

[0080] Example 4: Measurement of storage modulus (G') and loss modulus (G") of a composition containing xyloglucan and propylene glycol (Comparative Example) This example was carried out in the same manner as in Example 3, and the storage modulus (G') and loss modulus (G") values ​​of the composition obtained by mixing 40 ml of a 3.2% (w / w) aqueous xyloglucan solution with 10 ml of 2-(2-ethoxyethoxy)ethanol were measured.

[0081] Table 4 shows the values ​​of the moduli G' and G" measured at time T0 and after 24 hours (T24).

[0082] [Table 4]

[0083] Example 5: Measurement of viscosity of a composition containing xyloglucan and 2-(2-ethoxyethoxy)ethanol Viscosity values ​​were obtained with an Antoon Paar MCR101 rheometer using a 50 mm flat cone geometry. The measurements were carried out at 37° C. Table 5 reports the viscosity values ​​at T0 and 24 hours for compositions obtained by mixing 40 ml of a 3.2% (w / w) aqueous xyloglucan solution with 10 ml of 2-(2-ethoxyethoxy)ethanol.

[0084] [Table 5]

[0085] Example 6: Measurement of viscosity of a composition containing xyloglucan and propylene glycol (Comparative Example) Viscosity values ​​were obtained with an Antoon Paar MCR101 rheometer using a 50 mm flat cone geometry. The measurements were performed at 37°C.

[0086] Table 6 reports the viscosity values ​​at time T0 and after 24 hours of a composition obtained by mixing 40 ml of a 3.2% (w / w) aqueous xyloglucan solution with 10 ml of propylene glycol.

[0087] [Table 6]

[0088] Example 7: Measurement of the release of recombinant interferon (rIFN α2b) from xyloglucan-2-(2-ethoxyethoxy)ethanol gels 2.6×10 8 A solution containing recombinant IFN α2b in IU / mg was prepared in a 4% by weight xyloglucan solution at pH 7. The unit composition is reported in Table 7.

[0089] [Table 7]

[0090] The concentration of rIFN α2b in the gel is 25,000,000 IU / ml, so there are 20,000,000 IU in the extruded (poured) gel.

[0091] In a double-chamber syringe, 2 ml of a solution containing xyloglucan according to Table 7 was placed in one channel and 0.5 ml of 2-(2-ethoxyethoxy)ethanol was placed in the other channel. Following extrusion from the syringe, a gel was rapidly formed in less than 10 seconds.

[0092] To evaluate the release of IFN, the gels were placed in 2% (w / w) culture medium (MEM), thermostated at 37° C., and evaluated by a biological test for cytopathic effect (CPE).

[0093] [Table 8]

[0094] In vitro release kinetics show that IFN is completely released and 100% recovered between 24 and 48 h.

Claims

1. A controlled release composition in the form of a gel comprising a medicament active ingredient, xyloglucan and 2-(2-ethoxyethoxy)ethanol, wherein the concentration of the xyloglucan is 0.1% (w / w) to 10.0% (w / w) and the concentration of the 2-(2-ethoxyethoxy)ethanol is 20.0% (w / w) to 50.0% (w / w).

2. The composition according to claim 1, wherein the concentration of 2-(2-ethoxyethoxy)ethanol is from 20.0% (w / w) to 30.0% (w / w).

3. The composition according to claim 1, wherein the concentration of the xyloglucan is from 1.0% (w / w) to 5.0% (w / w) and the concentration of the 2-(2-ethoxyethoxy)ethanol is from 20.0% (w / w) to 50.0% (w / w).

4. The composition according to claim 1, wherein the concentration of the xyloglucan is 1.0% (w / w) to 5.0% (w / w) and the concentration of the 2-(2-ethoxyethoxy)ethanol is 20.0% (w / w) to 30.0% (w / w).

5. The composition according to claim 1, wherein the concentration of the xyloglucan is from 2.0% (w / w) to 5.0% (w / w) and the concentration of the 2-(2-ethoxyethoxy)ethanol is from 20.0% (w / w) to 50.0% (w / w).

6. The composition according to claim 1, wherein the concentration of the xyloglucan is from 2.0% (w / w) to 5.0% (w / w) and the concentration of the 2-(2-ethoxyethoxy)ethanol is from 20.0% (w / w) to 30.0% (w / w).

7. 2. The composition of claim 1, comprising 4% (w / w) of said xyloglucan and 50.0% (w / w) of said 2-(2-ethoxyethoxy)ethanol.

8. 8. The composition according to any one of claims 1 to 7, characterized in that when subjected to frequencies from 100 rad / sec to 0.1 rad / sec, it has a storage modulus (G') value of from 2000 Pa to 500 Pa at T0 and from 3000 Pa to 1000 Pa after 24 hours.

9. 0 seconds －１ ~95 seconds －１ When subjected to a shear rate of 1×10 at T0, the viscosity value was 1×10 １０ mPa·s to 2×10 ３ mPa·s and a viscosity value of 3×10 at T24 ７ mPa·s to 1×10 ３ The composition according to any one of claims 1 to 8, characterized in that it has a viscosity of mPa·s.

10. 2. The composition of claim 1, wherein the medicamentous active ingredient is selected from the group consisting of anti-inflammatory agents, antifungal agents, antibiotics, mimetic antibiotics, growth factors, disinfectants, antitumor agents, proteins, peptides, and moisturizers.

11. 2. The composition of claim 1 for administration by enteral, parenteral, transdermal or transmucosal route.

12. The composition according to claim 11, wherein the enteral route of administration is oral, sublingual or rectal administration, the parenteral route of administration is subcutaneous or intradermal administration, and the transdermal or transmucosal route of administration is via the vaginal, nasal or oropharyngeal mucosa.

13. The following steps: (a) preparing an aqueous solution of purified xyloglucan; (b) adding the aqueous xyloglucan solution of step (a) to 2-(2-ethoxyethoxy)ethanol to adjust the concentration of 2-(2-ethoxyethoxy)ethanol to 20.0% (w / w) to 50.0% (w / w) 2. A method for preparing the composition of claim 1, comprising:

14. 14. The method of claim 13, wherein the solutions are mixed at the time of use, prior to use, or during the preparation of the gel to be stored.

15. 10. The composition of claim 1 for use in the treatment of a medical condition in which controlled release of the active ingredient is beneficial.

16. The composition of claim 1 contained in a medical device.

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