Liquid delivery components

Abstract

To provide an innovation in the field of the delivery of active substances, following chemical and physical progresses of biomaterials especially for in-situ delivery vehicles that are able to provide a prolonged residence time for the active substances.SOLUTION: The invention provides a composition for use as a delivery vehicle comprising at least one thermo-responsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B) in a liquid formulation. The polymer A is preferably a polyoxyethylene-polyoxypropylene block copolymer or a cellulose derivative. The polymer B a polysaccharide. The composition can include an active substance for delivery or can be used as a delivery vehicle for a substance added at the time of administration such as mesenchymal stem cells.SELECTED DRAWING: Figure 12

Description

[Technical Field]

[0001] The present invention provides an innovative combination of biomaterials formulated into a liquid composition for use as a versatile delivery vehicle in many pharmaceutical and non-pharmaceutical fields. The liquid composition comprising the biomaterial combination of the present invention is provided as a delivery vehicle for medical purposes in humans. [Background technology]

[0002] Biomaterials are substances that interact with biological systems for medical purposes - either therapeutic (repairing, augmenting, repairing or replacing tissue function in the body), protective or diagnostic.

[0003] Biomaterials can be obtained from nature or synthesized in the laboratory using a variety of chemical approaches.

[0004] Biocompatibility pertains to the behavior of biomaterials in various environments under various chemical and physical conditions. The term can also describe specific properties of a material without specifying where or how the material will be used. For example, a material may or may not be able to integrate with a particular cell type or tissue. The ambiguity of the term reflects continually evolving insights into whether and how biomaterials interact with the human body and how those interactions determine the clinical success of medical devices and drugs.

[0005] Controlling the delivery of active substances in the human body is important for medical purposes.

[0006] For certain targets, site-specific delivery may be important to achieve the desired medical result. For other specific targets, site-specific delivery and duration of action may represent the only way to achieve a successful outcome and may represent an important aspect of subject or patient compliance. In addition, in many medical applications, it is necessary to obtain sustained release of the active substance over a long period of time to achieve prolonged contact with the application site, and it is important to maintain the concentration of the active substance above the minimum effective concentration (MEC) for a long period of time. The first consequence of this nature is a consequent reduction in administration frequency, which leads to improved patient compliance and makes it more likely that the patient will achieve symptom relief or cure of the disease. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] “Encyclopedia of Pharmaceutical Technology”3rd edition, Informa Healthcare [Non-patent document 2] Sandri et al. “An In Situ Gelling Buccal Spray Containing Platelet Lysate for the Treatment of Oral Mucositis”, Current Drug Discovery Technologies, 2011,8,277-285 Summary of the Invention [Problem to be solved by the invention]

[0008] Following the chemical and physical advances in biomaterials, particularly for in situ delivery vehicles that can provide extended residence times for active agents, there is a need to provide innovations in the field of active agent delivery.

[0009] Additionally, there is a need for delivery vehicles for use at well-defined selected sites or clinical settings, where active agents can be added to the delivery vehicle and administered to a patient for rapid delivery to the target site. [Means for solving the problem]

[0010] The present invention provides a composition for use as a delivery vehicle comprising at least one thermoresponsive polymer (Polymer A) and at least one ion-sensitive polymer (Polymer B) in a liquid formulation.

[0011] Preferably, polymer A is selected from the group including, but not limited to, polyoxyethylene-polyoxypropylene block copolymers, such as poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, poly(ethylene glycol) / poly(lactic-co-glycolic acid) block copolymers (PEG-PLGA), poly(ethylene glycol)-poly(lactic acid)-poly(ethylene glycol) (PEG-PLA-PEG), poly(N-isopropylacrylamide), cellulose derivatives, such as methylcellulose (MC) and hydroxypropylmethylcellulose (HPMC), and mixtures thereof.

[0012] Preferably, polymer B is selected from the group including, but not limited to, carrageenan, gellan gum, pectin, alginate, etc., and mixtures thereof.

[0013] The liquid compositions of the invention disclosed herein may further comprise at least one bioadhesive polymer (polymer C), selected from the group including, but not limited to, chitosan, hyaluronic acid and its salts, cellulose derivatives such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, polyethylene oxide, cyclodextrin, tragacanth, sodium alginate, xanthan gum, gelatin, pectin, and the like, and mixtures thereof.

[0014] The composition may further comprise at least one other excipient, such as an antioxidant, a chelating agent, a preservative and / or an antibacterial agent, a surfactant, a co-surfactant, a lipophilic compound, purified water or water for injection, organic and inorganic salts, a buffering agent with nutritional activity, etc.

[0015] In one embodiment, the composition further comprises at least one active agent for delivery.

[0016] The at least one active ingredient may be selected from the group comprising proteins or peptides, monoclonal antibodies, cytokines, antacids, adrenergic agonists, antiadrenergics, dyes, immunostimulants, steroidal and nonsteroidal anti-inflammatory drugs, antihistamines, nasal antihistamines / decongestants, antidiarrheals, antineoplastic agents, antibacterial agents, antibiotics, antifungals, antihemorrhoidal agents, antiadrenergics, adrenergic agonists, analgesics, bronchodilators, selective alpha-2 antagonists, anticholinergics / spasmodics, peripheral opioid receptor antagonists, laxatives, genitourinary tract agents, cathartics, vaginal agents, vaginal antifungals, vaginal antimicrobials, oral antiseptics or antibiotics, wound healing agents, hemostatic agents, anesthetics, sclerosing agents, or mixtures thereof.

[0017] In yet another embodiment, the composition is formulated to allow for addition of the active agent at the time of administration, particularly immediately.

[0018] The active agent added at the time of administration can be any of those or those described above, and can also be cells and / or cellular material, including cellular components such as microvesicles, genomic material and lysosomes.

[0019] The cells can be ectoderm (including, but not limited to, skin cells and melanocytes); endoderm (including, but not limited to, alveolar cells and pancreatic cells); mesoderm (including, but not limited to, cardiac muscle cells and skeletal muscle cells); or differentiated cells derived from stem cells such as embryonic stem cells, tissue-specific stem cells, mesenchymal stem cells, and induced pluripotent stem cells, preferably mesenchymal stem cells (MSCs).

[0020] As described herein, the present invention provides compositions for use in the delivery of cellular material as disclosed above. As described herein, the present invention provides compositions for use in the delivery of cells, preferably stem cells, more preferably mesenchymal stem cells. The cells can be added to a vehicle composition at the time of administration.

[0021] To preserve functionality and viability, the cells should be added no more than 8 hours, preferably no more than 6 hours, before administration.

[0022] According to one aspect of the invention, the liquid composition is used as a delivery vehicle in humans.

[0023] According to another aspect of the present invention, the liquid composition is used for the diagnosis, prevention, mitigation, treatment and / or reduction of a pathology or disorder affecting the human body.

[0024] A non-limiting detailed description of the invention follows with reference to non-limiting examples and figures.

[0025] The figures relate directly to the examples presented herein and are explained in detail later in this document. [Brief explanation of the drawings]

[0026] [Figure 1] Figure 1 shows the viability of MSCs after 2, 4 and 6 hours of contact with MSC suspension vehicle at 4°C and 37°C. Clear bars: control (medium + MSCs); filled bars: vehicle + MSCs. [Figure 2] FIG. 2 shows the MTT assay of MSCs at different concentrations of MSC suspension vehicle. [Figure 3] Figure 3 shows DAPI staining (20x magnification) of mesenchymal stem cells in a Boyden chamber with different concentrations of MSC suspension vehicle. Top panels (left to right: control, 75%, 80%); bottom panels (left to right: 90%, 95%, 100%). [Figure 4] FIG. 4 shows the migration rate of MSCs in a Boyden chamber with different concentrations of MSC suspension vehicle. [Figure 5] FIG. 5 presents the Fmax values ​​obtained in the presence of mucin and in the absence of biological substrate. [Figure 6] Figure 6(a and b) shows the penetration force and work values, respectively. [Figure 7] FIG. 7 depicts the G' profile showing that gelation occurs after 20 minutes at 37°C. [Figure 8] FIG. 8 shows the elastic modulus values ​​(G') of the vehicle after two-fold dilution. [Figure 9] FIG. 9 shows the improvement in strength of poloxamer (Kolliphor® P407) based gels at physiological temperature range upon addition of gellan gum (GG). [Figure 10] Figure 10 shows the evolution of the wound area over time for all test samples. 10x magnification images of the samples after different time points (t0, t24, t48 and t72) are shown. The black rectangle encloses the wound area. [Figure 11] Figure 11 depicts a comparison of control, reference vehicle (7386)+PL and (7364 / 1)+PL samples after 72 hours. 10x images of the samples after 72 hours are shown. The black rectangle encircles the wound area. [Figure 12]FIG. 12 shows a comparison of the mean number of cells within the wound gap of control, reference vehicle (7386)+PL and (7364 / 1)+PL samples after different time points (t0, t24, t48 and t72). DETAILED DESCRIPTION OF THE INVENTION

[0027] It has been surprisingly found that combinations of specific biomaterials provide new delivery vehicles that are capable of directing at least one active agent to a specific site of action and maintaining the agent at that site for an extended period of time.

[0028] The biomaterial combination of the present invention comprises at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B) in a composition, preferably in liquid form.

[0029] The biomaterial combination of the present invention may further comprise at least one bioadhesive polymer (polymer C).

[0030] In some embodiments, the biomaterial combinations of the present invention are preferably formulated into liquid compositions together with at least one active agent and at least one physiologically acceptable excipient.

[0031] In other embodiments, the biomaterial combinations of the present invention are preferably formulated into structured viscous compositions together with at least one active agent and at least one physiologically acceptable excipient. According to these embodiments, the structured viscous compositions resemble semi-solid vehicles and / or soft gels, retaining a certain range of liquid fluidity while being able to further structure and gel upon contact with biorelevant media at the site of action.

[0032] One subject of the present invention is the combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), as disclosed below.

[0033] Another subject of the present invention is a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), further comprising at least one bioadhesive polymer (polymer C).

[0034] Another object of the present invention is a liquid composition comprising a combination of at least one thermo-responsive polymer (Polymer A) and an ion-sensitive polymer (Polymer B), at least one active agent, and at least one physiologically acceptable excipient, as disclosed below.

[0035] Another object of the present invention is a liquid composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), at least one bioadhesive polymer (polymer C), at least one active substance, and at least one physiologically acceptable excipient, as disclosed below.

[0036] Another object of the present invention is a structured viscous composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), as disclosed below.

[0037] Another object of the present invention is a structured viscous composition comprising a combination of at least one active substance and at least one physiologically acceptable excipient, as disclosed below.

[0038] Another object of the present invention is a structured viscous composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), at least one bioadhesive polymer (polymer C), at least one active agent, and at least one physiologically acceptable excipient, as disclosed below.

[0039] The liquid compositions of the present invention can be solutions, micellar dispersions, suspensions, emulsions, or microemulsions. The solutions and suspensions of the present invention are water-based solutions or water-based suspensions. The emulsions or microemulsions of the present invention are oil-in-water or water-in-oil emulsions or microemulsions. The liquid compositions of the present invention can also be structured viscous compositions or soft gels.

[0040] The liquid compositions of the present invention can be administered orally, buccally, dentally, ophthalmically, rectally, perianal, vaginally, aurally, or nasally, or by injection. The compositions of the present invention can also be administered topically, preferably by direct application or injection.

[0041] The liquid compositions of the present invention can be administered directly into cavities resulting from surgery, disease, or injury.

[0042] Liquid compositions comprising the biomaterial combinations of the present invention can be administered by submucosal, intraperitoneal, intratumoral, subcutaneous, intramuscular, intraarticular, intranasal, intrathecal, epidural, intrastromal injection into the brain or spinal cord, or into the subretinal space. The liquid compositions of the present invention can be in sterile or non-sterile form.

[0043] The liquid compositions of the present invention can be in the form of enemas, syrups, drops, solutions, suspensions, micellar dispersions, emulsions, microemulsions, structured viscous vehicles, structured viscous vehicles in softgels, vaginal douches, irrigation compositions, and liquid compositions in softgel capsules.

[0044] The liquid composition of the present invention can be used as a versatile delivery vehicle in various pharmaceutical and non-pharmaceutical fields. The liquid composition of the present invention is provided as a delivery vehicle for pharmaceutical and / or medical purposes in humans.

[0045] Liquid compositions comprising the biomaterial combinations of the present invention can be used to deliver at least one active agent directly to the gastrointestinal tract, bladder, vagina, eye, ear, nose, and any other tissue or organ where it would be beneficial, by direct application or injection.

[0046] Another subject of the present invention is a liquid composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), as disclosed below, for use as a delivery vehicle.

[0047] Another subject of the present invention is a liquid composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), as disclosed below, for use as a delivery vehicle for pharmaceutical or medical purposes in humans.

[0048] Another subject of the present invention is a liquid composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B) for use in the diagnosis, prevention, mitigation, treatment and / or reduction of a pathology or disorder affecting the human body, as disclosed below.

[0049] Another object of the present invention is a structured viscous composition comprising at least one thermoresponsive polymer (Polymer A) and at least one ion-sensitive polymer (Polymer B), as disclosed below, for use as a delivery vehicle.

[0050] Another object of the present invention is a structured viscous composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B), as disclosed below, for use as a delivery vehicle for pharmaceutical or medical purposes in humans.

[0051] Another subject of the present invention is a structured viscous composition comprising a combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B) for use in the diagnosis, prevention, mitigation, treatment and / or reduction of pathologies or disorders affecting the human body, as disclosed below.

[0052] The combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B) allows for maintaining the grafted vehicle in the target organ or mucosa and for regulating the in situ release of at least one active agent from the liquid or structured viscous composition of the present invention according to a desired profile at a desired site of action and for a desired duration of the active agent at the site of action.

[0053] In fact, an unexpected synergistic effect on structuring and bioadhesion was found when two types of biomaterials were included in the same composition: the combination of at least one thermoresponsive polymer (polymer A) and at least one ion-sensitive polymer (polymer B) unexpectedly enhanced their ability to interact with the human body in tissues or organs. Either type of polymer can independently gel or structure upon contact with a biorelevant medium, such as the extracellular matrix of a mucosa; surprisingly, when combined together, polymer A synergistically enhanced the interaction of polymer B with the biorelevant medium, and vice versa, resulting in an enhanced gelling or structuring ability. This combination thus interacts with the rheology of the system to regulate the release of at least one active substance from the liquid composition of the present invention at the desired site and enhance its persistence and residence time at that site.

[0054] The mechanisms of action of these biomaterials are different: thermoresponsive polymers (polymer A) gel and form structures with biorelevant media when the temperature reaches a suitable range of values, while ion-sensitive polymers (polymer B) form structures with biorelevant media in the presence of appropriate concentrations of specific ions.

[0055] In one embodiment, the first polymer (A), after contact with a biorelevant medium, creates a gelled or structured composition at physiological temperatures (i.e., about 37°C), while simultaneously allowing the interaction of polymer B with the site of action, where the presence of specific starter ions strengthens the interaction with the other environmental medium, resulting in an expansion of the gelling or structuring capacity of the mixture. The combination of the present invention works thanks to the optimal combination of two polymers A and B, which results in a strong synergistic effect between the polymer itself and the polymer with its microenvironment, resulting in an enhanced gelling / structuring of the composition at the site of action.

[0056] Such enhanced gelation is explained by a significant increase in the viscoelastic modulus G'. The transition from a liquid form to a gel or structured composition state enhances the bioadhesion of the composition, as explained by the differential parameter ΔG', followed by enhanced adhesion at the administration site over a suitable time period. The differential parameter ΔG' is calculated as the difference between the G' values ​​observed for the composition at physiological temperature (i.e., approximately 37°C) and room temperature (i.e., approximately 25°C). Surprisingly, it has been discovered that the differential parameter ΔG' remains unchanged upon dilution with water and / or a biorelevant medium (e.g., simulated colonic fluid or artificial saliva). Such enhanced gelation or structuring also contributes to the greater persistence of the liquid composition at the administration / application site. This allows for the availability of versatile liquid vehicle compositions capable of targeting at least one active substance to a desired site of action (in situ) for a desired duration. This unexpected flexibility allows the liquid composition to be used as a vehicle for a variety of applications in both pharmaceutical and non-pharmaceutical fields.

[0057] The combination of polymer A and polymer B provides the composition of the present invention with bioadhesive properties that allow it to adhere and / or bond with target tissue or organ, such as mucosa and / or submucosa, for a suitable period of time.

[0058] Thus, the compositions of the present invention are flexible vehicles that allow for controlled release of active agents, taking into account the desired site of action and the desired duration of action, thanks to their enhanced implantation properties into selected tissues or organs.

[0059] Such vehicles advantageously allow for control of the release profile of the active agent depending on the different diseases to be treated that require such improved properties. Structured vehicles have a greater ability to control the mobility of the dispersed active agent or create a stronger resistance to the diffusion of the solubilized active agent from inside the depot.

[0060] The compositions of the present invention can act as a reservoir or depot.

[0061] According to the invention disclosed herein, the composition comprises at least one thermoresponsive polymer (polymer A) and an ion-sensitive polymer (polymer B).

[0062] In preparing a liquid composition according to the invention disclosed herein, the selection of a suitable thermoresponsive polymer (Polymer A) and its concentration may be such that the final composition is in a liquid state at temperatures below body temperature (i.e., below about 37°C, preferably about 20-25°C) and becomes a gel or structured composition once exposed to body temperature or higher (i.e., above about 37°C).

[0063] In preparing liquid compositions according to the invention disclosed herein, the selection of a suitable ion-sensitive polymer (Polymer B) and its concentration may be adapted to obtain a suitable sol-gel transition or transition to a structured composition in the presence of a particular ion.

[0064] According to the present invention, the ion-sensitive polymer is capable of absorbing monovalent and / or divalent inorganic ions, such as Na + , K. + , Mg 2+ , Ca 2+ , and Zn 2+The polymer may be selected from those capable of binding with high affinity to organic ions, etc. Responsiveness to ionic strength is a typical property of polymers containing ionizable groups. Changes in ionic strength can cause changes in the size of the polymer micelles and the solubility of the polymer.

[0065] Upon administration, the excellent fluidity of the liquid composition according to the invention disclosed herein allows the composition to automatically warm to body temperature (i.e., about 37°C), thus causing the thermoresponsive polymer (polymer A) to transition from a liquid to a gel state (sol-gel transition) or structured state; then, through the interaction of the ion-sensitive polymer (polymer B) with ions present in biorelevant media and / or bioenvironments, the gel or structured composition is further strengthened as illustrated by a significant increase in the viscoelastic modulus G'.

[0066] To better demonstrate the synergistic interaction between the two polymers, the strength enhancement of gels based on at least one thermoresponsive polymer is demonstrated with a combination of polymer A and polymer B in the physiological temperature range (i.e., approximately 37°C). Such enhancement is indicated by a ΔG' value, which is higher for the combination of the two polymers relative to a solution of the thermoresponsive polymer alone, and further enhancement is obtained upon dilution in a biorelevant medium.

[0067] According to this aspect of the invention, the transition from a liquid form to a gel or structured state enhances the bioadhesive properties of the composition, which in turn enhances adhesion to tissue, e.g., mucosal and / or submucosal, for a suitable period of time at the site of administration, as described by the derivative parameter ΔG′, which is calculated as the difference between the G′ values ​​observed at physiological temperature (i.e., about 37° C.) and room temperature (i.e., about 25° C.) for the neat composition and for the composition diluted in a biorelevant medium (simulated colonic fluid or artificial saliva).

[0068] Furthermore, the increased viscoelasticity of the pharmaceutical liquid composition of the present invention slows down the diffusion of at least one active substance, prolonging the therapeutic effect and delaying the delivery of the active substance to the affected area. When administered into the body by injection, the composition of the present invention automatically warms to body temperature (i.e., about 37°C), and therefore, due to the presence of the thermoresponsive polymer, transitions from a liquid to a gel form with a significant increase in viscosity; then, the interaction of the ion-sensitive polymer with ions at the injection site further strengthens the gel or structured composition. This results in the formation of a depot at the injection site with a sustained release profile of at least one active substance.

[0069] When administered, the liquid composition according to this embodiment of the invention can form a thin gel or structured layer that covers the affected area and has a reduced tendency to flow along the wall of the organ, maximizing the contact time between the liquid composition according to this embodiment of the invention and the affected area: as a result, at least one active substance contained therein remains in contact with the cell membrane of the epithelial cells of the mucosa for a longer period of time compared to known compositions.

[0070] According to the invention disclosed herein, the at least one thermoresponsive polymer (polymer A) may be selected from the group including, but not limited to, polyoxyethylene-polyoxypropylene block copolymers, such as poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, poly(oxyethylene glycol) / poly(lactic-co-glycolic acid) block copolymers (PEG-PLGA), poly(ethylene glycol)-poly(lactic acid)-poly(ethylene glycol) (PEG-PLA-PEG), poly(N-isopropylacrylamide), and mixtures thereof.

[0071] Mixtures of any of the above thermoresponsive polymers can be used to form a suitable liquid composition.

[0072] Also, among the thermoresponsive polymers, some cellulose derivatives such as methyl cellulose (MC), hydroxypropyl methyl cellulose (HPMC) and methyl(hydroxyethyl) cellulose may be selected.

[0073] In a preferred embodiment, the thermoresponsive polymer of the liquid composition is poloxamer 188.

[0074] In another preferred embodiment, the thermoresponsive polymer of the liquid composition is poloxamer 407.

[0075] In yet another preferred embodiment, the thermoresponsive polymer comprises some mixture of poloxamer 188 and poloxamer 407.

[0076] In another preferred embodiment, the thermoresponsive polymer of the liquid composition is methylcellulose.

[0077] According to the invention disclosed herein, the amount of the at least one thermoresponsive polymer ranges from about 0.1 wt % to about 30 wt % based on the weight of the liquid composition, more preferably from about 0.2 wt % to about 25 wt % based on the weight of the liquid composition, and even more preferably from about 0.3 wt % to about 25 wt % based on the weight of the liquid composition.

[0078] According to a preferred embodiment, the at least one thermoresponsive polymer is present in an amount of about 0.1 wt %, or about 0.3 wt %, or about 1.0 wt %, or about 5.0 wt %, or about 10.0 wt %, or about 15 wt %, or about 20 wt %, or about 25 wt %, or about 30 wt %, based on the weight of the liquid composition.

[0079] According to the invention disclosed herein, the at least one ion-sensitive polymer (polymer B) may be selected from the group of polysaccharides including, but not limited to, carrageenan, gellan gum, pectin, alginic acid and / or salts thereof. The at least one ion-sensitive polymer may be, for example, sodium alginate.

[0080] According to the invention disclosed herein, the at least one ion-sensitive polymer is contained in an amount ranging from about 0.001% to about 10% by weight, preferably from about 0.005% to about 5% by weight, and more preferably from about 0.01% to about 2.0% by weight, based on the weight of the composition.

[0081] According to a preferred embodiment, the at least one ion-sensitive polymer is present in an amount of about 0.1 wt %, or about 0.2 wt %, or about 0.3 wt %, or about 0.5 wt %, or about 1 wt %, or about 2 wt %, based on the weight of the liquid composition.

[0082] According to the invention disclosed herein, the liquid composition may further comprise at least one surfactant; according to one embodiment, the at least one surfactant is a PEG-fatty acid monoester surfactant, such as PEG-15 hydroxystearate, PEG-30 stearate, PEG-100 monostearate (also known as polyoxyl 100 monostearate), PEG-40 laurate, PEG-40 oleate, etc.; a PEG-fatty acid diester surfactant, such as PEG-32 dioleate, PEG-400 dioleate, etc.; a polyoxyethylene sorbitan fatty acid ester, such as polysorbate 20, polysorbate 60, polysorbate 80, etc.; a polyoxyethylene alkyl ether, such as PEG-20 cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1, etc. 000, etc.; sorbitan fatty acid ester surfactants, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, etc.; propylene glycol esters of fatty acids; polyglycerol esters of fatty acids; polyoxyethylene castor oil derivatives, such as polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, etc.; caprylocapryl polyoxyl-8 glyceride; polyoxylglycerides, such as caprylocaproyl polyoxylglyceride, lauroyl polyoxylglyceride, oleyl polyoxylglyceride, ceteareth 16, ceteareth 20, ceteareth 10, steareth 20, ceteth 20, etc.

[0083] Any combination of the above non-ionic surfactants can be used to form a suitable pharmaceutical liquid composition. In one embodiment, the non-ionic surfactant is polysorbate 80.

[0084] In another embodiment, the nonionic surfactant is sorbitan monostearate. In another embodiment, the nonionic surfactant is polyoxyl 100 monostearate.

[0085] In another embodiment, the nonionic surfactant is polyoxyl-35 castor oil. In a preferred embodiment, the nonionic surfactant is PEG-15 hydroxystearate (also known as polyoxyl-15-hydroxystearate).

[0086] In yet another embodiment, the at least one surfactant may be selected from the group of ionic surfactants including, but not limited to, egg lecithin, phosphatidylcholine, hydrogenated phosphatidylcholine derived from egg lecithin, soybean lecithin, hydrogenated soybean lecithin, glycerophosphocholine, soybean lysolecithin, phospholipids, hydrogenated phospholipids, sodium lauryl sulfate, and the like.

[0087] Mixtures of any of the above ionic surfactants can be used to form suitable pharmaceutical liquid compositions. Suitable non-ionic surfactants are commercially available from Lipoid® under the Lipoid® brand name.

[0088] In one embodiment, the ionic surfactant is egg lecithin. In another embodiment, the ionic surfactant is hydrogenated phosphatidylcholine derived from egg lecithin. In another embodiment, the ionic surfactant is phosphatidylcholine.

[0089] In another embodiment, the ionic surfactant is soy lecithin.

[0090] In yet another embodiment, the ionic surfactant is hydrogenated soy lecithin.

[0091] According to the invention disclosed herein, the at least one surfactant is contained in an amount ranging from about 0.001% by weight to about 15% by weight, preferably from about 0.005% by weight to about 10% by weight, and more preferably from about 0.01% by weight to about 5% by weight, relative to the weight of the liquid composition.

[0092] According to a preferred embodiment, the at least one surfactant is present in an amount of about 0.3 wt. %, or about 0.5 wt. %, or about 1 wt. %, or about 2 wt. %, or about 3 wt. %, or about 4 wt. %, based on the weight of the liquid composition.

[0093] The compositions of the invention disclosed herein may further comprise at least one bioadhesive polymer selected from the group including, but not limited to, chitosan, hyaluronic acid and its salts, cellulose derivatives such as methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, polyethylene oxide, tragacanth, sodium alginate, xanthan gum, gelatin, pectin, and the like.

[0094] Any combination of the above bioadhesive polymers may be used to obtain a suitable liquid pharmaceutical composition according to the present invention.

[0095] In one embodiment, the at least one bioadhesive polymer is chitosan.

[0096] In another embodiment, the at least one bioadhesive polymer is sodium alginate.

[0097] In a preferred embodiment, the at least one bioadhesive polymer is sodium carboxymethylcellulose. In another preferred embodiment, the at least one bioadhesive polymer is hyaluronic acid and / or a salt thereof.

[0098] According to this embodiment, the at least one bioadhesive polymer provides additional synergy with the other components, resulting in an increased level of adhesiveness of the liquid vehicle and improved residence time at the desired site. In an ideal mechanism of action, the bioadhesive polymer improves the implantability of the vehicle into body tissue, while the other polymer reinforces the structure of the gelled layer obtained by spreading the vehicle composition of the present invention on the targeted body surface, acting as a reservoir or depot, or in any case ensuring durability and efficacy.

[0099] This aspect maximizes the effectiveness of the active agent contained in the liquid delivery vehicle.

[0100] According to the present invention, the at least one physiologically acceptable excipient may comprise an aqueous phase having a hydrophilic character and, optionally, an oil phase having a lipophilic character.

[0101] Therefore, the liquid composition can solubilize both hydrophobic (lipophilic) and hydrophilic active substances. In the case of hydrophobic (lipophilic) active substances, the composition and amount of the oil phase can be varied to achieve complete solubilization of the hydrophobic (lipophilic) active substance in the oil phase. In the case of hydrophilic active substances, the amount of the aqueous phase can be varied to achieve complete solubilization of the hydrophilic active substance in the aqueous phase. In the case of hydrophilic active substances, the presence of a water-based solvent, or in the case of hydrophobic (lipophilic) active and hydrophilic active substances, or in the case of hydrophobic (lipophilic) active substances, two phases of different polarity, can allow both hydrophilic and hydrophobic active substances to be formulated in the same pharmaceutical liquid composition in the form of a micellar dispersion, emulsion, microemulsion, or water-based solution of the present invention.

[0102] All these beneficial features allow the liquid compositions of the present invention to solubilize active substances with different polarities.

[0103] In certain embodiments, the liquid compositions of the present invention comprise at least one hydrophobic active agent.

[0104] In other embodiments, the liquid compositions of the present invention comprise at least one hydrophilic active agent.

[0105] In other embodiments, the liquid pharmaceutical compositions of the present invention comprise at least one hydrophobic active agent and at least one hydrophilic active agent.

[0106] Controlled release is achieved by sustained diffusion—through the contribution of bioadhesive forces—of the active agent from the liquid compositions of the present invention into the tissue and / or submucosal / mucosal layers of the gastrointestinal tract.

[0107] Additionally, the increased viscoelasticity of the liquid compositions of the present invention slows the diffusion of at least one active agent, delaying its delivery to the affected area along with prolonging the therapeutic effect.

[0108] Thus, for the liquid pharmaceutical composition according to such an embodiment of the present invention, the reversible thermoresponsive sol-gel transition coupled with the enhanced gelling ability of the mixture due to the presence of polymer B effectively acts in determining the release profile of at least one active substance in response to contact with the target site, allowing it to act for a long period of time at the affected site.

[0109] When administered by injection, the liquid compositions of the present invention form a depot of at least one active agent, ensuring a similar reservoir that results in sustained release, improved local bioavailability (at the site of administration), and prolonged efficacy: controlled release is achieved by slow diffusion of the depot, accompanied by prolonged diffusion of the at least one active agent into the tissue and / or submucosal / mucosal layers.

[0110] This allows for the effective administration of an optimal dose of active agent in a single injection or with fewer injections, avoiding or reducing the need for repeated injections over time.

[0111] When administered orally, vaginally or rectally, the liquid composition of the present invention forms a thin gel layer over the affected area, reducing its tendency to flow along the tissue walls, maximizing the contact time of the liquid composition with the affected area: as a result, at least one active substance contained therein remains in contact with the cell membrane of the epithelial cells of the mucosa for a longer period of time compared to simple pharmaceutical liquid compositions.

[0112] The invention disclosed herein relates to a liquid composition and the same for use as a delivery vehicle in humans, said pharmaceutical liquid composition comprising: (a) at least one thermoresponsive polymer (polymer A); (b) at least one ion-sensitive polymer (polymer B); (c) optionally at least one physiologically acceptable excipient Includes:

[0113] The invention disclosed herein relates to a liquid composition and the same for use as a delivery vehicle in humans, said pharmaceutical liquid composition comprising: (a) at least one thermoresponsive polymer (polymer A); (b) at least one ion-sensitive polymer (polymer B); (c) at least one active substance (d) optionally at least one physiologically acceptable excipient Includes:

[0114] According to the present invention, the at least one active substance may be selected from the group comprising proteins or peptides, monoclonal antibodies, cytokines, antacids, adrenergic agonists, antiadrenergic agents, dyes, immunostimulants, steroidal and non-steroidal anti-inflammatory drugs, antihistamines, nasal antihistamines / decongestants, antidiarrheals, antineoplastic agents, antibacterial agents, antibiotics, antifungals, anti-hemorrhoidal agents, antiadrenergic agents, adrenergic agonists, analgesics, bronchodilators, selective alpha-2 antagonists, anticholinergics / antispasmodics, peripheral opioid receptor antagonists, laxatives, genitourinary tract medications, cathartics, vaginal agents, vaginal antifungals, vaginal antimicrobials, oral antiseptics or antibiotics, wound healing agents, hemostatic agents, anesthetics, sclerosing agents, or mixtures thereof.

[0115] Suitable antacids may be selected from citric acid, sodium citrate, sodium bicarbonate, magnesium carbonate, magnesium oxide, or mixtures thereof. According to one preferred embodiment, the citric acid is citric acid monohydrate.

[0116] According to one preferred embodiment, the sodium citrate is sodium citrate dihydrate.

[0117] Suitable dyes may be selected from vital dyes (or absorbing dyes), non-vital dyes (or contrast agents), and reactive dyes.

[0118] According to the invention disclosed herein, the vital dye (or absorbent dye) may be selected from the group including, but not limited to, Lugol's solution, methylene blue, toluidine blue, crystal violet, and the like.

[0119] In accordance with the invention disclosed herein, the non-vital dye (or contrast agent) may be selected from the group including, but not limited to, indigo carmine, etc. In accordance with the invention disclosed herein, the reactive dye may be selected from the group including, but not limited to, Congo red, phenol red, etc. Mixtures of any of the above dyes may be used to form a suitable liquid composition.

[0120] According to a preferred embodiment, the at least one dye is methylene blue.

[0121] According to another preferred embodiment, the at least one dye is indigo carmine.

[0122] Suitable immunostimulants according to the present invention are selected from saccharomyces cerevisiae, arginine, resveratrol, astragalus membranaceus, echinacea uncaria, interferons, interleukins, colony stimulating factors, and mixtures thereof.

[0123] Suitable antibacterial or antibiotic agents according to the present invention are selected from rifamycin SV, rifaximin, rifampicin, tetracyclines, benzalkonium bromide, aminoglycosides, cephalosporins, penicillins, macrolides, ansamycins, sulfonamides, carbapenems, or mixtures thereof. Suitable topical antibacterial agents according to the present invention are selected from zinc oxide, silver or its salts, silver sulfadiazine, silver oxide, iodine, chlorhexidine, povidone-iodine, and mixtures thereof.

[0124] Suitable hemostatic agents may be selected from epinephrine, norepinephrine, mixtures and / or salts thereof.

[0125] Suitable sclerosing agents can be selected from ethanolamine oleate, sodium morphine 5%, sodium tetradecyl sulfate 1% and 3%, polidocanol 0.5% to 3%, absolute alcohol, hypertonic (50%) glucose solution, mixtures or salts thereof.

[0126] Suitable anesthetics may be selected from lidocaine, bupivacaine, mepivacaine, articaina, benzocaine, tetracaine, pridocaine, mixtures and / or salts thereof.

[0127] Suitable anti-inflammatory drugs are selected from steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, or mixtures thereof.

[0128] The steroidal anti-inflammatory drug according to the present invention is selected from cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, budesonide, triamcinolone, acetonide, betamethasone, beclomethasone, triamcinolone, dexamethasone, mometasone, desonide, fluocinolone, esters, salts thereof or mixtures thereof.

[0129] The non-steroidal anti-inflammatory drug according to the present invention is selected from 5-ASA, ketorolac, indomethacin, piroxicam, ketoprofen, naproxen, ibuprofen, diclofenac, diflunisal, flurbiprofen, tiaprofenic acid, metamizole, nimesulide, salts thereof or mixtures thereof.

[0130] According to a preferred embodiment, the active agent is a steroidal anti-inflammatory drug, more preferably budesonide.

[0131] Suitable antifungal agents according to the present invention are selected from itraconazole, fluconazole, capsofungin, griseofulvin, or mixtures thereof.

[0132] Suitable anti-hemorrhoidal agents according to the present invention are selected from sincatechins, Saccharomyces cerevisiae, hydrocortisone, pramoxine, phenlephione or mixtures thereof.

[0133] Suitable antiadrenergic agents according to the present invention are selected from doxazosin, prazosin, terazosin, or mixtures thereof.

[0134] Suitable adrenergic agonists and beta-adrenergic blockers according to the present invention are selected from epinephrine, norepinephrine, salts thereof or mixtures thereof, and propranolol, sotalol, metoprolol, and mixtures thereof.

[0135] Suitable analgesics according to the present invention are selected from acetaminophen, phenacene, sodium acylate, or mixtures thereof.

[0136] Suitable bronchodilators according to the present invention are selected from albuterol, procaterol, levabuterol, and mixtures thereof.

[0137] Suitable selective alpha 2 antagonists according to the present invention are selected from salbutamol, terbutaline, ephedrine, orciprenaline sulfate, and mixtures thereof.

[0138] Suitable anti-diarrheal agents according to the present invention are selected from loperamide, saccharomyces boulardii, lactobacillus acidophilus, lactobacillus bulgaricus, and mixtures thereof.

[0139] Suitable intestinal anti-inflammatory agents according to the present invention are selected from 5-aminosalicylic acid, olsalazine, sulfasalazine, budenoside, and mixtures thereof.

[0140] Suitable anticholinergic / antispasmodic agents according to the present invention are selected from octylonium bromide, histiamine, atropine, scopolamine, oxybutyin and mixtures thereof.

[0141] Suitable peripheral opioid receptor antagonists according to the present invention are selected from methylnaltrexone, naloxegol, and mixtures thereof.

[0142] Suitable laxatives according to the present invention are selected from magnesium salts (such as citrates, sulfates, phosphates, bicarbonates), senna, bisacodyl, lactulose, polyethylene glycol (PEG), phosphates, docusate, and mixtures thereof.

[0143] Suitable urogenital tract agents according to the present invention are selected from acetohydroxamic acid, phenazopyridine, bethanechol, and mixtures thereof.

[0144] Suitable nasal antihistamines and decongestants according to the present invention are selected from phenylephrine, oxymetazoline, ephedrine, pseudoephedrine, salts thereof and mixtures thereof.

[0145] Suitable laxatives according to the present invention are selected from bisacodyl, sodium picosulfate, PEG, and mixtures thereof.

[0146] Suitable vaginal agents according to the present invention are selected from estradiol, estrogen, conjugated estrogens, other hormones, and mixtures thereof.

[0147] Suitable vaginal antifungal and antibiotic agents according to the present invention are selected from clotrimazole, clindamycin, miconazole, metronidazole, and mixtures thereof.

[0148] Suitable oral disinfectants or antibacterial agents according to the present invention are selected from benzalkonium chloride, cetylpyridinium hydrochloride or tibezonium iodide, and some amino derivatives such as benzylamine and chlorhexidine, as well as salts and derivatives thereof.

[0149] According to a preferred embodiment of the present invention, the suitable active substance is selected from antacids, dyes, immunostimulants, steroidal and non-steroidal anti-inflammatory drugs, antibacterial agents, antibiotics, anti-hemorrhoidal drugs, or mixtures thereof.

[0150] The dosage of the at least one active agent is designed according to a consideration of diagnosis, prevention, mitigation, treatment and / or reduction of a pathology or disorder affecting the human body.

[0151] According to one aspect of the invention, the liquid composition is used as a delivery vehicle in humans.

[0152] According to another aspect of the present invention, the liquid composition is used for the diagnosis, prevention, mitigation, treatment and / or reduction of a pathology or disorder affecting the human body.

[0153] According to another embodiment, the liquid compositions of the present invention are used as delivery vehicles in the gastrointestinal tract, vagina, bladder, nose, ear, or eye.

[0154] According to another aspect, the liquid compositions of the present invention are used in the diagnosis, prevention, mitigation, treatment and / or reduction of pathologies or disorders affecting the gastrointestinal tract, vagina, bladder, nose and eyes.

[0155] According to these embodiments, the gastrointestinal tract refers to the tract between the oropharyngeal tract and the anus. More specifically, the gastrointestinal tract refers to the mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum), large intestine (cecum, colon, sigmoid colon, and rectum), and / or anus.

[0156] According to a preferred embodiment, the gastrointestinal tract refers to the esophagus, stomach or intestines.

[0157] According to another embodiment, the diagnosis, prevention, mitigation, treatment, and / or reduction of pathologies or disorders affecting the gastrointestinal tract is an inflammatory and / or degenerative pathology, preferably selected from inflammatory lesions, dysplasias, neoplasias, and / or complications occurring during or after endoscopic surgery. More particularly, such inflammatory and / or degenerative diseases can be selected from Barrett's esophagus, preneoplasias, neoplasias, tumors, polyps, adenomas, serrated lesions, ulcers, stenosis, strictures, varices, gastroesophageal reflux disease (GERD), esophagitis, hemorrhoids, fistulas, fissures, motility changes, esophageal cancer, esophageal ulcers, esophageal dysplasias, esophageal stenosis, esophageal varices, colonic varices, inflammatory bowel disease, herbatum, hyperacidity, heartburn, stomach discomfort, local anesthesia, and / or colon cancer. According to another preferred embodiment, in the case of inflammatory lesions occurring during or after excision surgery (e.g., resection, polypectomy, EMR, ESD, etc.), the compositions of the present invention are locally injected into the artificial ulcer formed in the tissue and / or surrounding area by the excision surgery by one or more circular or semicircular in situ injections.

[0158] According to yet another preferred embodiment, the inflammatory and / or degenerative disease of the gastrointestinal tract is Barrett's esophagus, esophagitis, esophageal stenosis (stricture) and / or GERD.

[0159] According to another preferred embodiment, the inflammatory and / or degenerative disease of the gastrointestinal tract is hemorrhoids or fistulas.

[0160] According to another aspect, the liquid composition of the present invention is for use in the diagnosis, prevention, alleviation, treatment and / or reduction of a pathology or disorder affecting the vagina or bladder or gastrointestinal tract, which pathology or disorder affecting the vagina or bladder or gastrointestinal tract is, in more general terms, preferably selected from bacterial infection, fungal infection, cancer, hormonal disorder, and inflammation, more preferably vaginitis, vaginal dryness, itching, burning, cystitis, menopause, candidiasis, herpes, and cervical cancer.

[0161] According to another aspect, the liquid composition of the present invention is for use in the diagnosis, prevention, mitigation, treatment and / or reduction of a pathology or disorder affecting the eye or ear, preferably selected from bacterial infection, fungal infection and inflammation, more preferably selected from dry eye, maculopathy, glaucoma and otitis media.

[0162] According to another aspect, the liquid composition of the present invention is for use in the diagnosis, prevention, alleviation, treatment and / or reduction of pathologies or disorders affecting the nose, preferably selected from sinusitis, such as fungal sinusitis, rhinitis, such as chronic atrophic rhinitis, vestibulitis, nasal congestion, histamine reactions and allergic diseases.

[0163] According to one embodiment, the liquid composition of the present invention is administered via the oral route.

[0164] According to another embodiment, the liquid composition of the present invention is administered via the rectal route.

[0165] According to another embodiment, the liquid composition of the present invention is administered via the vaginal route.

[0166] According to another embodiment, the liquid composition of the present invention is administered via the ocular route.

[0167] According to another embodiment, the liquid compositions of the present invention are administered via the nasal route.

[0168] According to another embodiment, the liquid compositions of the present invention are administered via the auricular route.

[0169] According to another embodiment, the liquid compositions of the present invention are administered by injection.

[0170] According to this embodiment, local submucosal injection is performed by injecting a liquid composition, preferably an emulsion or microemulsion, into the pathological tissue, lesion, or surrounding the pathological tissue or lesion in situ by one or more circular or semicircular injections to provide controlled release of the drug to achieve a long-acting response.

[0171] According to the present invention, the number of local injections can vary depending on the type of pathology or disorder.

[0172] In all of these embodiments, the liquid compositions of the present invention can form a depot of the active agent, ensuring a reservoir of the active agent that provides sustained release, improved local bioavailability (at the injection site), and prolonged efficacy.

[0173] Controlled release is achieved by slow erosion of the depot with prolonged diffusion of the drug into the tissue and / or submucosal / mucosal layers. Thus, efficacy is primarily related to the local action of the active substance, thereby reducing or avoiding any systemic side effects.

[0174] According to the invention disclosed herein, one major component of the aqueous phase of the liquid pharmaceutical composition may be water for injection (WFI).

[0175] In some embodiments of the invention disclosed herein, the aqueous phase may contain, in dissolved form, one or more inorganic salts selected from the group including, but not limited to, chlorides, bromides, iodides, phosphates, carbonates, bicarbonates, sulfates, nitrates, and the like.

[0176] In some embodiments, the aqueous phase may contain one or more organic salts in dissolved form, the organic salts being selected from the group including, but not limited to, citrate, maleate, fumarate, acetate, lactate, and the like.

[0177] Mixtures of any of the above inorganic and organic salts may be used to form a suitable liquid composition, generally to buffer the pH of the composition to an appropriate biocompatible range or to achieve the osmolality required by the physiological environment at the site of administration, particularly upon injection.

[0178] In some embodiments, the aqueous phase of the liquid compositions disclosed herein may contain an amount of one or more inorganic and / or organic salts or mixtures thereof to obtain a hypotonic final liquid composition.

[0179] In some embodiments, the aqueous phase of the liquid compositions disclosed herein may contain an amount of one or more inorganic and / or organic salts or mixtures thereof to obtain an isotonic final liquid composition.

[0180] In some embodiments, the aqueous phase of the liquid compositions disclosed herein may contain an amount of one or more inorganic and / or organic salts or mixtures thereof, e.g., to obtain a hypertonic final liquid composition.

[0181] According to the invention disclosed herein, the inorganic and / or organic salt or mixture thereof may be present in an amount ranging from 0% to 5% by weight based on the weight of the aqueous phase, more preferably from 0.1% to 4% by weight based on the weight of the aqueous phase, and even more preferably from 0.4% to 3% by weight based on the weight of the aqueous phase. In a preferred embodiment, the aqueous phase of the liquid composition contains dissolved sodium chloride.

[0182] According to the latter embodiment, sodium chloride is present in an amount ranging from 0% to 5% by weight relative to the weight of the aqueous phase, more preferably from 0.1% to 4% by weight, even more preferably from 0.4% to 3% by weight relative to the weight of the aqueous phase.

[0183] In some embodiments, the aqueous phase of the liquid compositions disclosed herein comprises a buffer.

[0184] In some embodiments, the buffer is a phosphate buffer.

[0185] In some embodiments, the buffer is a citrate buffer. In some embodiments, the buffer is a bicarbonate buffer.

[0186] In a preferred embodiment, the buffer is a phosphate buffer to which one or more inorganic salts that are not capable of buffering pH have been added.

[0187] According to the latter embodiment, the concentrations of phosphate buffer and inorganic salts that cannot buffer pH are such that an aqueous phase is obtained that is phosphate buffered saline (PBS), several compositions and preparation methods of PBS are well known in the art.

[0188] According to the invention disclosed herein, the pH value of the liquid pharmaceutical composition is in the range of about 4.0 to 10.0, more preferably about 4.5 to 8.5, and even more preferably about 5.0 to 8.0.

[0189] According to the present invention, the pH value of the pharmaceutical liquid composition may be adjusted to within a desired range by common techniques well known in the art, such as by adding physiologically acceptable bases and / or acids.

[0190] According to the invention disclosed herein, the oil phase comprises at least one lipophilic compound.

[0191] In some embodiments, the at least one lipophilic compound may be selected from the group of natural oils, including but not limited to almond oil, castor oil, corn oil, cottonseed oil, olive oil, safflower oil, sesame oil, soybean oil, and the like.

[0192] In some embodiments, the at least one lipophilic compound may be selected from the group of fatty acid esters, including but not limited to isopropyl palmitate, isopropyl myristate, ethyl oleate, and the like.

[0193] In some embodiments, the at least one lipophilic compound may be selected from the group of fatty alcohols, including but not limited to myristic alcohol, oleyl alcohol, and the like.

[0194] In some embodiments, the at least one lipophilic compound may be selected from the group of fatty acids including, but not limited to, myristic acid, oleic acid, palmitic acid, and the like.

[0195] In some embodiments, the at least one lipophilic compound may be selected from the group of triglycerides, such as, for example, long-chain and / or medium-chain triglycerides.

[0196] In some embodiments, the at least one lipophilic compound may be selected from the group of diglycerides.

[0197] In some embodiments, the at least one lipophilic compound may be selected from the group of monoglycerides.

[0198] Mixtures of any of the above lipophilic compounds may be used to form a suitable liquid composition.

[0199] In one embodiment, the lipophilic compound of the oil phase is sesame oil.

[0200] In yet another embodiment, the lipophilic compound of the oil phase is ethyl oleate.

[0201] In yet another embodiment, the lipophilic compound of the oil phase is a medium chain triglyceride.

[0202] In a preferred embodiment, the lipophilic compound of the oil phase is soybean oil.

[0203] According to the invention disclosed in this specification, the oil phase of the liquid composition ranges from about 0.001% by weight to about 20% by weight, preferably from about 0.01% by weight to about 15% by weight, and more preferably from about 0.02% by weight to about 10% by weight, relative to the weight of the liquid composition.

[0204] More preferably, the oil phase is present in the compositions of the present invention in an amount of about 0.02% w / w or about 0.05% w / w, or about 0.1% by weight, or about 1.0% by weight, about 3.0% by weight, or about 5.0% by weight, based on the weight of the composition.

[0205] The liquid compositions of the invention disclosed herein may optionally contain at least one co-surfactant. When in the form of an emulsion or microemulsion, it is beneficial to add at least one co-surfactant to the oil phase-surfactant-water phase mixture, since the co-surfactant acts synergistically with the surfactant to stabilize the system and lower the interfacial tension of the dispersed phase droplets of the liquid composition. In preparing a liquid composition in the form of an emulsion or microemulsion according to the invention disclosed herein, at least one co-surfactant can be selected from the group including, but not limited to, short-chain and medium-chain alcohols, such as ethanol, propanol, isopropanol, etc.; glycols, such as propylene glycol, etc.; polyethylene glycols, such as PEG200, PEG300, PEG400, etc.; DMSO; long-chain alcohols, such as cetyl alcohol, myristyl alcohol, oleyl alcohol, etc.; glycerol; short-chain esters, such as ethyl acetate, ethyl lactate, etc.; fatty acid esters, such as ethyl oleate, isopropyl myristate, isopropyl palmitate, etc.; and salts of fatty acids, such as sodium oleate, sodium palmitate, sodium stearate, etc. Mixtures of any of the above co-surfactants can be used to form a suitable liquid composition. In one embodiment, the co-surfactant is propylene glycol. In another embodiment, the co-surfactant is glycerol. In another embodiment, the co-surfactant is sodium oleate. In a preferred embodiment, the co-surfactant is a mixture of glycerol and sodium oleate.

[0206] According to the invention disclosed herein, the at least one co-surfactant is contained in an amount ranging from about 0.00001% by weight to about 3% by weight of the liquid composition, preferably from about 0.00005% by weight to about 0.05% by weight of the liquid composition, and more preferably from about 0.0001% by weight to about 1.5% by weight of the liquid composition.

[0207] The liquid compositions of the invention disclosed herein may further comprise at least one agent characterized as having trophic activity on epithelial cells of the gastrointestinal mucosa.

[0208] Nutrients are substances that can promote cell growth, differentiation, and survival. In this sense, it would be beneficial to incorporate at least one agent that has been proven to have trophic activity on epithelial cells of the gastrointestinal mucosa into the liquid composition of the present invention, since the liquid composition can exert a positive and beneficial effect on wound healing, promoting cell growth and differentiation for rapid closure of surgical wounds and wound healing.

[0209] Furthermore, at least one physiologically acceptable excipient may be added to the liquid composition according to the invention disclosed herein to obtain a final composition with suitable properties and stability. By way of example, the at least one physiologically acceptable excipient may be selected from among antioxidants, chelating agents, preservatives and / or antimicrobial agents.

[0210] Aspects of the present invention relate to liquid compositions as described above, and for use as delivery vehicles in humans.

[0211] An embodiment of the present invention relates to a liquid composition as disclosed above for use in the diagnosis, treatment, mitigation, reduction and / or prevention of a pathology or disorder affecting the human body.

[0212] The delivery vehicle according to the present invention is capable of controlling the release of at least one active ingredient at the site of administration by sustained diffusion of the active ingredient from the liquid composition of the present invention into the tissue and / or submucosal / mucosal layer at the site of administration.

[0213] In one embodiment, at least one active agent is cellular material, including cells or cellular components.

[0214] A particular application of the compositions of the present invention relates to the delivery of cells and cellular components, including, but not limited to, microvesicles, genetic material, and lysosomes. The cells may be ectoderm, including, but not limited to, skin cells and pigment cells; endoderm, including, but not limited to, alveolar cells and pancreatic cells; mesoderm, including, but not limited to, cardiac myocytes and skeletal muscle cells; or differentiated cells derived from stem cells, such as embryonic stem cells, tissue-specific stem cells, mesenchymal stem cells, and induced pluripotent stem cells, preferably mesenchymal stem cells (MSCs). The cells that need to be delivered to an individual patient can be added to the delivery vehicle immediately prior to administration in the clinical setting.

[0215] Mesenchymal stem cells (MSCs) have unique properties that may make them an excellent option for the treatment of many pathologies: unlike other adult stem cells, they appear to escape recognition as non-self by the immune system and possess immunomodulatory properties, which allow them to be considered for use as allogeneic cell therapy products.

[0216] Although the use of mesenchymal stem cells (MSCs) as a clinical therapy is a relatively new avenue of research for the treatment of various diseases, there is a vast and ever-growing number of preclinical and early clinical trials using MSC therapies that demonstrate the great potential of stem cell therapy to promote the repair of damaged tissues.

[0217] The therapeutic effects of MSCs are based on their functional diversity and interaction with host tissues: MSCs have anti-inflammatory, regenerative, and differentiation properties that can improve outcomes in injured tissues and inflammatory processes.

[0218] A key ability of MSCs is to induce a host response in the surrounding tissue, not only through cell-cell interactions but also through the production of secreted bioactive factors, such as small proteins, chemokines, cytokines, and other cellular regulators, which can be applied in various clinical scenarios.

[0219] These factors have the ability to induce angiogenesis or blood vessel growth, become chemotactic, and induce cell recruitment. MSCs also have the ability to differentiate depending on the environment they are in, regenerating tissue or adapting host tissue in a cell-specific manner.

[0220] Mesenchymal stem cells (MSCs) have become one of the most studied stem cells, especially for the treatment of diseased and damaged tissues and organs. MSCs can be easily isolated from many mature tissues by means of minimally invasive approaches. MSCs have the ability to self-renew for many passages and therefore can potentially be expanded to sufficient numbers for tissue and organ regeneration.

[0221] MSCs are capable of self-renewal by division and can differentiate into a variety of tissues, including bone, cartilage, muscle and adipocytes, as well as connective tissue.

[0222] The delivery of MSCs is a key point in cell therapy, and the composition of the delivery material must take into account the biocompatibility of the cells and the characteristics of the host tissue. Various solutions have been proposed for delivering therapeutic cells, and degradable polymer scaffolds or hydrogels made from naturally derived biopolymers are a type of degradable scaffold with key characteristics.

[0223] Cell therapy is considered a novel treatment, and various types of cells are being investigated for neurodegenerative diseases, stroke, spinal cord injury, liver and pancreatic diseases, cardiac diseases, respiratory diseases, graft-versus-host disease, kidney diseases, bone diseases, chronic wounds and inflammatory bowel diseases, and ENT-head and neck surgery.

[0224] Some early studies combined stem cells with adhesives, but the addition of adhesives offered no benefit, and it was later found that the adhesives impaired cell viability. Therefore, in more recent studies, stem cells have simply been injected in suspension with culture medium.

[0225] Thus, there is a need for improved vehicles for cell therapy that deliver cells to target sites and promote persistence, while being biocompatible and fully resorbable within a period of time.

[0226] The present invention provides such an improved vehicle.

[0227] The vehicles described herein can be used to deliver a variety of different cell types, such as bone cells, chondrocytes, epithelial cells, muscle cells, secretory cells, adipocytes, and especially mesenchymal stem cells, to obtain a variety of tissue structures.

[0228] In one embodiment, the cells include cells derived from ectoderm, endoderm and mesoderm, or stem cells such as embryonic stem cells, tissue-specific stem cells, mesenchymal stem cells, induced pluripotent stem cells, preferably mesenchymal stem cells (MSCs).

[0229] The suspensions and cells comprising the delivery vehicles of the present invention can be used to treat a variety of diseases, including neurodegenerative diseases, stroke, spinal cord injury, liver and pancreatic diseases, cardiac diseases, respiratory diseases, graft-versus-host disease, kidney diseases, bone diseases, chronic wounds, inflammatory bowel diseases, ENT head and neck surgery, and the like.

[0230] The site and number of cells transplanted will depend on the individual need and the particular pathology.

[0231] The compositions of the invention may contain cells suspended at a concentration of about 500-50 million cells / ml, and the resulting cell suspension in the compositions of the invention can be injected by systemic routes, such as enteral and parenteral routes, as well as by topical routes.

[0232] The cells mixed with the vehicle should be administered within no more than 8 hours, preferably no more than 6 hours, when maintained at 4°C to 37°C.

[0233] The cell suspension of the composition of the present invention can be injected directly into a specific area via a syringe or specific device, with or without a needle, which should be selected appropriately based on the site of administration / application.

[0234] The cell suspension of the composition of the present invention can be used for intestinal diseases including inflammatory bowel disease, short bowel syndrome and radiation injury.

[0235] In the case of lesions such as anal fistulas and rectovaginal fistulas, a cell suspension of the composition of the invention can be administered into the wall of the fistula and directly into its lumen (channel).

[0236] A cell suspension of the composition of the present invention can be injected directly into areas of the gastrointestinal tract to correct gastroesophageal reflux or into ulcerative lesions in the digestive system.

[0237] Voiding disorders represent a diverse range of urinary system disorders, including stress urinary incontinence, overactive bladder, and vesicoureteral reflux. Thus, in one embodiment, a cell suspension of the composition of the present invention can be injected into the urethral sphincter through a cystoscopic needle for the treatment of these disorders.

[0238] In organs with high regenerative potential, such as the liver and pancreas, cell suspensions of the compositions of the present invention can be administered to specific areas to stimulate and regenerate the organ.

[0239] For example, in liver diseases, the cell suspension of the composition of the present invention can be used to regenerate liver tissue in diseases such as cirrhosis, alcoholic liver disease, alcoholic hepatitis, inflammatory diseases, and the like.

[0240] In the orthopedic setting, cell suspensions of the compositions of the present invention are administered to damaged cartilage such as articular cartilage injuries, meniscus and rotator cuff injuries, tendon injuries such as Achilles tendon or anterior cruciate ligament, and bone lesions throughout the skeleton.

[0241] In cardiovascular repair, a suspension of the composition of the present invention can be administered to a specific area to support and regenerate necrotic tissue.

[0242] Skin wound healing is a complex process requiring interactions between various cell populations; in one embodiment, a cell suspension of the composition of the present invention is applied topically to damaged and / or impaired skin as a mesenchymal component of skin-equivalent composition to regenerate the dermis, or delivered more directly to the wound to regenerate the dermis.

[0243] The cells contained in the delivery vehicle can secrete growth factors to promote hair growth, and a cell suspension of the composition of the present invention can be administered to the scalp to regrow alopecia hair.

[0244] Liquid suspensions of the compositions of the present invention can be used for a range of alveolar bone resorption that occurs following periodontal disease, severe caries, root fracture or tooth loss / extraction due to accidental trauma.

[0245] In ENT and "head and neck" diseases such as ear, nose and throat diseases, maxillofacial surgery, periodontology, conservative dentistry and ophthalmology, cell suspensions in the compositions of the present invention can be used to restore normal structure and function.

[0246] The loss of retinal nerves, their connections, and supporting glia in degenerative eye diseases leads to permanent blindness, mainly because lost photoreceptors and retinal ganglion cells (RGCs) are not replaced and RGC axons cannot regenerate. The use of cells such as stem cells has demonstrated potential as a cell therapy for degenerative eye diseases through replacing lost cells in the eye and / or releasing growth factors into damaged neuropil. In one embodiment, a cell suspension of the composition of the present invention can be injected to provide trophic support to degenerated retinal nerves and stimulate glia to indirectly assist in nerve repair.

[0247] Depending on the preferred application, the composition according to the present invention may comprise at least one thermo-responsive polymer, at least one ion-sensitive polymer, and at least one bioadhesive polymer. In one embodiment, the at least one thermo-responsive polymer may comprise poloxamer 407, the at least one ion-sensitive polymer may comprise sodium alginate, and the at least one bioadhesive polymer may comprise sodium carboxymethylcellulose.

[0248] In one embodiment, the composition comprises poloxamer 407, sodium alginate, and sodium carboxymethylcellulose.

[0249] Optionally, poloxamer 407 may be present in an amount of about 0.1% to about 30% by weight of the liquid composition, optionally in the range of 0.2% to 25%, 0.3% to 25% by weight of the composition, preferably 15% by weight of the composition.

[0250] Optionally, sodium alginate may be present in an amount of about 0.001% to about 10% by weight of the composition, optionally in the range of 0.005% to 5% by weight of the composition, 0.01% to 2.0% by weight of the composition, and preferably in an amount of 0.2% (w / w) by weight of the composition.

[0251] Optionally, sodium carboxymethylcellulose is present in an amount of about 0.001% to about 10% by weight of the composition, optionally in the range of 0.005% to 5% by weight of the composition, 0.01% to 2.0% by weight of the composition, preferably 0.05% to 0.1% by weight of the composition, and more preferably 0.05% (w / w) by weight of the composition.

[0252] Such compositions can be used in treatment methods, and the compositions are formulated so that active substances can be added when the compositions are administered.Depending on the desired application, the active substances that are added when the compositions are administered can optionally comprise microvesicles, genetic material and cellular material such as lysosomes, differentiated cells derived from ectoderm, endoderm or mesoderm, or stem cells such as embryonic stem cells, tissue-specific stem cells, mesenchymal stem cells and induced pluripotent stem cells, and are preferably mesenchymal stem cells (MSCs).Optionally, in one embodiment, the active substances that are added when the compositions are administered comprise human dermal fibroblasts.

[0253] Such compositions may be used as delivery vehicles in humans.

[0254] Such compositions may be used in the diagnosis, prevention, mitigation, treatment and / or reduction of pathologies or disorders affecting the human body.

[0255] definition References herein to "one embodiment," "embodiment," "an aspect," "aspect," and similar phrases indicate that the described embodiment or aspect may include a particular aspect, feature, structure, or characteristic. Furthermore, such phrases may, but do not necessarily, refer to similar embodiments or aspects mentioned elsewhere in this specification. Furthermore, when a particular aspect, feature, structure, or characteristic is described in connection with other embodiments or aspects, it is within the knowledge of one of ordinary skill in the art that other examples or aspects affect or relate to that aspect, feature, structure, or characteristic, whether or not explicitly stated.

[0256] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds. It should further be noted that the claims may be drafted to exclude any optional element. Accordingly, this statement is intended to serve as a predicate for the use of exclusive terminology, such as "solely," "only," or the use of a "negative" limitation in connection with the recitation of claim elements.

[0257] The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated.

[0258] The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") and are considered to provide support for the terms "consist essentially of," "consisting essentially of," and "consist of."

[0259] The term "consist essentially of" should be interpreted as semi-closed term, meaning free from other ingredients that materially affect the basic and novel characteristics of the present invention (and, optionally, physiologically acceptable excipients and / or adjuvants).

[0260] The term "consist of" is to be construed as closed term.

[0261] PEG: polyethylene glycol GG: Gellan gum PLX: Poloxamer HPC: Hydroxypropyl cellulose HPMC: Hydroxypropyl methylcellulose MC: Methylcellulose PBS: phosphate buffered saline BHA: Butylhydroxyanisole WFI: Water for injection MTT:3-(4,5- Dimethylthiazole -2-yl)-2,5-di Phenyl Tetrazolium bromide

[0262] In this specification, unless otherwise indicated, the term "about" is intended to include values, e.g., weight percentages, that approximate the recited ranges that are equivalent in terms of functionality of the individual components, compositions, or embodiments.

[0263] Those skilled in the art will recognize that for all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass all possible subranges and combinations of subranges thereof, as well as the individual values, particularly integer values, making up the ranges. A recited range includes each specific value, integer, decimal, or identity number within the range.

[0264] Those skilled in the art will recognize that when members are grouped in a general manner, such as a Markush group, the invention encompasses not only the entire recited group in general, but also each individual member of the group and all possible subgroups of the subject group. Moreover, for all purposes, the invention encompasses not only the subject group, but also subjects in which one or more group members are absent. Thus, the invention contemplates the explicit exclusion of any or more of the recited group members. Thus, provisos can be applied to any of the disclosed categories or embodiments, whereby any or more of the recited components, species, or embodiments can be excluded from such category or embodiment, e.g., as used in an explicit negative limitation.

[0265] The term "alleviation" refers to a reduction in the symptoms and / or signs of inflammatory and / or degenerative diseases of the gastrointestinal tract.

[0266] The term "reduce" refers to a decrease in the degree of damage caused by inflammatory and / or degenerative diseases of the gastrointestinal tract, or a decrease in the clinical signs or symptoms associated with such damage.

[0267] The term "emulsion" refers to a heterogeneous preparation composed of two immiscible liquids (conventionally described as oil and water), one dispersed uniformly as fine droplets throughout the other. The phase present as small droplets is called the dispersed, dispersed, or internal phase, and the supporting liquid is known as the continuous or external phase. Emulsions are conveniently classified as oil-in-water (o / w) or water-in-oil (w / o) depending on whether the continuous phase is water or oil. Multiple emulsions are prepared from oil and water by re-emulsifying an existing emulsion to yield two dispersed phases and are also of pharmaceutical interest. An oil-in-water-in-oil (o / w / o) multiple emulsion is a w / o emulsion in which the water globules themselves contain dispersed oil globules; in contrast, a water-in-oil-in-water (w / o / w) emulsion is one in which the internal and external aqueous phases are separated by oil. A "microemulsion" is a thermodynamically stable, transparent (or translucent) dispersion of oil and water stabilized by an interfacial film of surfactant molecules. The surfactants may be pure, a mixture, or combined with cosurfactants such as medium-chain alcohols. Microemulsions are easily distinguished from regular emulsions by their transparency, low viscosity, and more fundamental thermodynamic stability, as well as their ability to form spontaneously. However, although the boundary between the size of swollen micelles (approximately 10-140 nm) and the size of fine emulsion droplets (approximately 100-600 nm) is not clearly defined, microemulsions are highly volatile systems; microemulsion droplets can disappear in a fraction of a second while other droplets spontaneously form elsewhere in the system. The above definitions of "emulsion" and "microemulsion" are taken from the "Encyclopedia of Pharmaceutical Technology," 3 rd This is taken from Informa Healthcare, 2010, pp. 111-114, 2010.

[0268] The term "endoscopic mucosal resection" (EMR) refers to an endoscopic technique developed to remove fixed or flat neoplasms confined to the superficial layers (mucosa and submucosa) of the GI tract. The term "endoscopic mucosal dissection" (ESD) refers to an endoscopic technique developed specifically for the removal of larger lesions.

[0269] An "endoscopic injection needle," also known as an "injection needle" or "injection needle catheter" or "endoscopic injection needle catheter," is a device that includes a relatively long catheter, which can be up to approximately 230 cm in length, and in which an internal injection tube with a distal injection needle is slidably disposed. A proximal actuation handle is typically connected to the catheter and the injection tube to move one relative to the other as needed. The needle is usually retractable. Fluid for the injection tube is typically provided by a Luer connector on the handle. An endoscopic injection needle device is typically delivered to the injection site through a working channel. To protect the lumen of the endoscope working channel from damage, the handle of the needle device is manipulated to retract the distal injection needle into the lumen of the catheter before inserting the device into the endoscope. This is important to prevent exposure of the sharp tip of the needle, as the device will be moved through the lumen of the endoscope. Once the distal end of the endoscopic injection needle device is positioned at the injection site, the handle is again manipulated to move the injection needle distally from the lumen of the catheter. When advanced to its most distal position, the exposed portion of the needle is approximately 4-6 mm long.

[0270] "Viscosity" defines the resistance of a liquid or semi-solid to flow. The flow of a liquid or semi-solid is described by its viscosity, or more precisely, by its shear viscosity η. The shear viscosity of a fluid describes the resistance to shear flow when adjacent layers move parallel to each other at different velocities. Common units of viscosity measurement are pascal seconds (Pa s), poise (P), and cP (centipoise).

[0271] "Elastic modulus G" refers to the elastic or storage modulus obtained in a mechanical state. Elastic modulus (also known as modulus of elasticity) is a measure of an object or material's resistance to elastic (i.e., non-permanent) deformation when stress is applied. The elastic modulus of an object is defined as the slope of the stress-strain curve in the elastic deformation region.

[0272] "Cellular material" refers to cells and / or cellular components.

[0273] "Body temperature" refers to the level of heat produced and retained by bodily processes. Heat is generated internally through the metabolism of nutrients and is lost from the body surface through dissipation, convection, and evaporation of sweat. Heat production and loss are regulated and controlled by the hypothalamus and brainstem. A normal adult's body temperature, when measured by mouth, is 37°C, although small variations throughout the day are usually noted.

[0274] "Room temperature" (RT) is generally defined as ambient air temperature, regardless of the environment being used for a given procedure. More specifically, ambient temperature is defined as 20-25°C, since by its nature it may not be in this range. Generally, protocols calling for steps to be performed at RT require that the temperature not fall below 18°C ​​or exceed 27°C.

[0275] As used herein, "under laboratory test conditions" or "in laboratory conditions" or "in laboratory tests" refers to in vitro conditions, e.g., methods, apparatus, and equipment commonly used in laboratory tests to perform physical-chemical characterization of compositions. The term refers to methods, apparatus, and equipment used and performed in a laboratory.

[0276] "Pa·s" Pascal seconds is a unit of viscosity measurement. "P" Poise is a unit of viscosity measurement. "cP" Centipoise is a unit of viscosity measurement.

[0277] The following examples are provided for the purpose of illustrating certain aspects and embodiments of the present invention and are not intended to limit the invention. [Example]

[0278] Example 1 - Microemulsion

[0279] [Table 1]

[0280] In a suitable vessel, polyoxyl 15-hydroxystearate is warmed to 60° C. with stirring until a homogeneous melt is obtained; then, budesonide is added under stirring while maintaining the temperature at 60° C. Next, medium-chain triglyceride and PEG 400 are added with stirring until the budesonide is completely dissolved (Phase A). Pour a portion (4-20%) of the total amount of WFI into phase A (T = 60 °C) while stirring; once a homogeneous mixture is obtained, reduce the temperature to RT; then add ethanol while stirring until a homogeneous mixture is obtained (phase B). Pour the remaining amount of WFI (80-96%) into the main vessel. Next, add Phase B dropwise with vigorous stirring. Next, add Poloxamer 188 with vigorous stirring until the polymer is completely dissolved. At the end of the poloxamer dissolution, add sodium alginate (Phase C) with vigorous stirring until the polymer is completely dissolved. At the end of the addition, sodium hydroxide is added until a pH of 6 is reached and the mixture is stirred until completely dissolved (Phase D). Add WFI to make the mixture to the final volume.Stir the mixture until it becomes homogeneous.The application of this composition is intended to be bioadhesive to the esophagus and gastric mucosa, so as to be active against esophagitis and Barrett's esophagus, and can be easily carried out by drinking a small amount of the composition.Alternatively, the composition can also be administered by injection, such as submucosal injection, or by a catheter inserted into a gastroscope.

[0281] Example 2 Emulsion

[0282] [Table 2]

[0283] In a suitable container, warm the polyoxyl 15-hydroxystearate to 60°C with stirring until a homogeneous melt is obtained; then add the medium-chain triglyceride with stirring. While maintaining the temperature at 60°C, add the budesonide and butylhydroxyanisole (BHA) to the above mixture with stirring. Stir the mixture until the budesonide is completely dissolved (Phase A). Pour a portion (4-20%) of the total amount of WFI into phase A (T = 60 °C) while stirring; once a homogeneous mixture is obtained, reduce the temperature to RT (phase B). Pour the remaining amount of WFI (80-96%) into another container and warm to 60°C. Add Poloxamer 188 under stirring and stir the mixture until the polymer is completely dissolved (T=60°C) (Phase C). Phase B is added dropwise to phase C under vigorous stirring (T=60° C.). At the end of the addition, the temperature is allowed to cool to RT, then the alginic acid and sodium chloride are added and the mixture is stirred until completely dissolved (phase D). The mixture is brought to the final volume by adding WFI. The mixture is kept under stirring until homogeneous. The application of such a composition is intended to bioadhere to the esophageal and gastric mucosa, and can be easily achieved by swallowing a small amount of the composition. Alternatively, the composition can also be administered by injection, such as submucosal injection, or by a catheter inserted into a gastroscope.

[0284] Example 3 - Emulsion

[0285] [Table 3]

[0286] The method for preparing the composition is described below. a) Charge WFI (90% of the total volume) into a suitable vessel equipped with a stirrer; then cool to a temperature in the range of 5°C to 20°C; then add Poloxamer 407 under stirring. Keep stirring the composition until completely dissolved and then warm to room temperature (Phase A). b) Charge approximately 0.02% of the total volume of WFI into a suitable vessel equipped with a stirrer; increase the temperature to 60°C. Add phosphatidylcholine, glycerol and sodium oleate under stirring. Stir until completely homogenous (Phase B). c) In another vessel, budesonide is added to the soybean oil under stirring at 60°C; the mixture is maintained under stirring at 60°C until completely dissolved (Phase C). d) Add phase C to phase B with stirring at 60°C. Maintain the mixture at T=60°C under stirring until a homogeneous emulsion is obtained. Then cool the emulsion to room temperature (phase D). e) Add Phase D to Phase A under stirring. Then add Norepinephrine Hydrochloride and PBS (prepared according to known conventional formulations) under stirring. Maintain the mixture under stirring until homogenous. f) At the end of the addition, add the sodium alginate with vigorous stirring until completely dissolved. Add WFI to bring the mixture to the final weight. Continue stirring the mixture until homogeneous. Application of such compositions, intended for bioadhesion to the esophageal and gastric mucosa, can be easily accomplished by swallowing a small amount of the composition. Alternatively, the composition can also be administered by injection, such as submucosal injection, or via a catheter inserted into a gastroscope.

[0287] Example 4 - Microemulsion

[0288] [Table 4]

[0289] The preparation and administration methods of Example 4 are similar to those of Example 1.

[0290] Example 5 Water-based solution

[0291] [Table 5]

[0292] In a suitable vessel equipped with a stirrer, purified water (95% of the total volume) is charged; then, sodium benzoate is added under stirring. The mixture is kept under stirring until completely dissolved, and then potassium sorbate is added with stirring until completely dissolved. The poloxamer is added to the above mixture with vigorous stirring until completely dissolved. Sodium alginate is then added to the mixture with stirring until a homogeneous mixture is obtained. Pectin is then added to the mixture with stirring until a homogenous mixture is obtained. Sodium carboxymethylcellulose is then added to the above mixture with stirring until a homogeneous mixture is obtained. Sodium citrate and citric acid are then added to the mixture with stirring until a homogeneous mixture is obtained. At the end of the addition, add the sucralose and flavoring with stirring until completely dissolved. The mixture is brought to the final weight by adding purified water. The mixture is kept under stirring until homogeneity is achieved. The application of such a composition is intended to bioadhere to the esophageal and gastric mucosa and can be easily achieved by swallowing a small amount of the composition.

[0293] Example 6 Water-based solution A vehicle intended for application to the esophageal wall via the oral route is prepared.

[0294] [Table 6]

[0295] The manufacturing method and administration method of Example 6 are the same as those of Example 5.

[0296] The liquid composition is then filled into vials containing 10 mL or 20 mL of the composition.

[0297] Prior to administration, a powder mixture consisting of sodium bicarbonate, calcium carbonate, magnesium oxide, and mannitol is loaded into a plug and plunger single-dose shaker system. The cap is turned to drop the powder into the vehicle, and the vial is then shaken vigorously until a homogenous suspension is obtained. Application of such compositions, intended to bioadhere to the esophageal and gastric mucosa, can be easily accomplished by swallowing a small amount of the composition.

[0298] Example 7 Water-based solution

[0299] [Table 7]

[0300] The manufacturing method and administration method of Example 7 are the same as those of Example 5. Application of such compositions, intended for bioadhesion to the esophageal and gastric mucosa, can be easily accomplished by swallowing a small amount of the composition, which should be taken approximately 30 minutes before gastrointestinal endoscopy (esophageal and gastric), to obtain color contrast of the mucosal tissue during gastrointestinal endoscopy.

[0301] Example 8 Water-based solution

[0302] [Table 8]

[0303] Purified water (95% of the total volume) is charged into a suitable vessel equipped with a stirrer; it is then cooled to a temperature ranging from 5°C to 20°C; Poloxamer 407 is then added while stirring. The mixture is kept under stirring until completely dissolved, and then allowed to warm to room temperature. Sodium alginate is added to the above mixture with stirring until a homogeneous mixture is obtained. Sodium carboxymethylcellulose is then added to the above mixture with stirring until a homogeneous mixture is obtained. The mixture is brought to the final weight with purified water and kept under stirring until homogeneity is achieved.

[0304] Application of such compositions can be easily achieved by injecting a ready-to-use suspension of mesenchymal stem cells (MSCs) in a vehicle.

[0305] The MSC suspension vehicle may be applied to urinary incontinence disorders, particularly the structural and functional restoration of the urethral sphincter.

[0306] After suspension, biocompatibility was tested in terms of viability and cytotoxicity, and functionality tests such as migration of MSCs in the vehicle were performed.

[0307] Viability test MSCs were suspended in the vehicle of Example 8 and the viability of the cells was tested.

[0308] Viability tests were performed on 120,000 cells per FACs tube in a total volume of 300 μl of vehicle. Incubations were performed at both 4°C and 37°C, and analysis was performed after 2, 4, and 6 hours. A control was defined as MSCs cultured in complete cell culture medium alone and analyzed under the same conditions as the MSC suspension vehicle.

[0309] Importantly, the 2-6 hour time period simulates the interval over which the suspension may be administered. Alternatively, the temperature establishes the stability / viability of the cells relative to the vehicle if the suspension is maintained at a low temperature, such as 4 °C, or a physiological temperature, such as body temperature (37 °C), prior to administration. The viability test involved adding 1 μg / mL of propidium iodide (PI) immediately before flow cytometry analysis. Dead cells were stained with PI because they have compromised membranes.

[0310] At both 4°C and 37°C, no difference was observed between the viability of cells in media and those resuspended in the MSC suspension vehicle. The viability obtained at 37°C was favorable; indeed, more cells survived in the MSC suspension vehicle compared to the media control. This result predicts what may occur when these cells reach their target site in the body (Figure 1).

[0311] Cytotoxicity Test: To better understand the biocompatibility of the vehicle of Example 8, a cytotoxicity test was performed according to ISO 10993-5. Mesenchymal stem cells suspended in vehicle were subjected to cytotoxicity testing using the MTT assay. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) is metabolically reduced to an insoluble blue-purple formazan in living cells. On day 1, mesenchymal stem cells in the culture medium were removed from the culture flask by enzymatic digestion using Tryple select (Gibco) or the like.

[0312] The cell suspension was centrifuged at 1400 rpm for 10 min to pellet 1 × 10 4 The cells were suspended in complete culture medium at a density of cells / 100 μl. 100 μl of cell suspension was dispensed into wells of a 96-well tissue culture plate and incubated for 24 hours (5% CO , 37° C., >90% humidity).

[0313] After 24 hours of incubation, the culture medium was aspirated from the cells, and 100 μl of medium containing the appropriate concentration of the vehicle to be tested was added per well.

[0314] Five different concentrations of MSC suspension vehicle were tested: 20%, 10%, 5%, 2.5%, and 1.25% in complete culture medium. Cells were incubated for 24 hours (5% CO2, 37°C, >90% humidity). After 24 hours of treatment, the culture medium was removed from the plates, 50 μl of MTT solution was added to each well, and the plates were incubated for 2 hours in a 37°C incubator. The MTT solution was diluted according to the data sheet containing the In Vitro Toxicology Assay, MTT Based Tox-1 (Sigma).

[0315] After the incubation period, the formazan crystals were solubilized by adding 100 μl of MTT solubilization solution (In Vitro Toxicology Assay, MTT Based Tox-1; Sigma).

[0316] After mixing on an orbital shaker to completely dissolve the crystals, the absorbance was measured at a wavelength of 570 nm and background absorbance was measured at 690 nm.

[0317] The materials were not cytotoxic with viability values ​​above 70%, and the viability of the vehicle after 24 hours was always greater than 74%, as shown in Figure 2. This indicates that the MSC suspension vehicle is not cytotoxic to mesenchymal stem cells.

[0318] Cell migration assay: To assess the suitability of the vehicle of Example 8 as a delivery vehicle, cell migration was performed using a Boyden chamber and images were acquired by fluorescence microscopy.

[0319] The cell migration assay chosen for these experiments is the Boyden chamber, which is ideally suited for the quantitative analysis of different migratory responses of cells.

[0320] The classic Boyden chamber system uses a hollow plastic chamber sealed at one end with a porous membrane. To induce a chemotactic response in cells, an attractant is added to the lower compartment of the chamber.

[0321] In a standard Boyden assay, membrane pore sizes are typically 3–12 μm, and we selected a pore size of 8 μm for a 24-well plate because this dimension supports optimal migration of mesenchymal stem cells.

[0322] After preparing a migration chamber (8 μm) in a 24-well plate, 100 μl of serum-free medium was added to the chamber. After removing the serum, approximately 2 × 10 5 The cells were mixed with a solution of medium and different concentrations of MSC suspension vehicle (75%, 80%, 85%, 90%, 95% and 100%) and placed in a migration chamber at 37°C and 5% CO2 for 2 hours. Complete culture medium was added to the control. A volume of culture medium with serum equivalent to 750 μl was added to the lower part of the chamber and incubated at 37° C., 5% CO2 for 24 hours. The medium was removed from the chamber, and the chamber was washed twice with PBS.

[0323] Cells were fixed with formaldehyde (3.7% in PBS) for 15 minutes at room temperature. After two washes with phosphate-buffered saline (PBS), cells were permeabilized with 100% methanol for 30 minutes at room temperature. After removal of the methanol, Giemsa staining or DAPI staining was performed to detect cells trapped on the membrane.

[0324] Figure 3, DAPI staining, demonstrates an important characteristic of the MSC suspension vehicle: indeed, this composition does not inhibit cell functions such as motility, but rather allows cell migration, which is therefore predictive of cell motility when injected into a specific region of the body.

[0325] Furthermore, the data obtained showed that when the vehicle concentration was equal to 100%, approximately 60% of the cells were able to migrate. When the dilution of the MSC suspension vehicle was increased to simulate the dilution of the normal "in vivo" mechanism, the migration values ​​were comparable to the control, at 83% vs. 89% (Figure 4).

[0326] Example 8-2 Water-based Solution (Injectable Cell Therapy)

[0327] [Table 9]

[0328] Exemplary compositions according to the present invention detailed in this example were tested in an in vitro wound healing test - tissue regeneration test.

[0329] Introduction The liquid composition of the present invention can be used as a vehicle in the field of cell therapy to treat skin injuries. Wound healing is a complex and dynamic process that replaces devitalized and lost cellular structures and tissue layers. There are a series of interacting and overlapping phases in which various cellular and matrix components work together to reestablish the integrity of the damaged tissue and replace lost tissue. The stages of wound healing proceed in an organized manner and follow four processes: hemostasis, inflammation, proliferation, and maturation. This sequence of events begins immediately after injury with the activation of platelets, which secrete a pool of growth factors, cytokines, and proteins from the serum into the local environment. Platelets constitute a source of diverse growth factors and proteins involved in tissue regeneration. Many reports have described the effectiveness of platelet lysates as an alternative supplement to fetal bovine serum (FBS) in experimental and clinical cell culture for tissue regeneration.

[0330] An exemplary composition according to the invention detailed in this Example (also referred to as 7364 / 1) was tested in an in vitro wound healing test - tissue regeneration test and compared to different liquid formulations.

[0331] The liquid formulation (also called 7386) used as a reference vehicle for tissue regeneration is the composition described by Sandri et al. (Non-Patent Document 2). The reference vehicle composition is shown below.

[0332] [Table 10]

[0333] A study was conducted to evaluate the potential use of the composition according to the present invention as a vehicle for tissue regeneration. Both composition 7364 / 1 and reference vehicle 7386 were tested in simulated skin lesions containing platelet lysate to investigate their effects on cell growth and cell regeneration capacity. Serum-free complete medium was used as a control.

[0334] In vitro wound healing test Human dermal fibroblasts (HSFs) at passage 5 were used for the in vitro wound healing test. Dulbecco's modified Eagle's medium (DMEM, Sigma Life Science) supplemented with 10% fetal bovine serum (FBS) (EuroClone, Milan, Italy), 200 U / ml penicillin, and 0.2 mg / ml streptomycin (Gibco by life technologies) was used as the growth medium.

[0335] The human platelet lysate (PL) used in this study was produced by the Red Cross in Ulm (Germany) and was obtained from a pool of 16 or fewer healthy donors.

[0336] Cells were maintained at 37°C in an atmosphere of 5% CO at 95% relative humidity.

[0337] In vitro wound healing studies were performed using a Petri μ-Dish (Ibidi, Giardini, Milan, Italy) containing inserts. The inserts were 0.22 cm diameter, separated by a septum with a cell-free gap of 500 μm ± 50 μm width. 2 The growth zone is formed from two chambers.

[0338] This technique involves making a thin linear scratch "wound" (creating a gap) in a confluent monolayer of cells, and then taking images at regular intervals of the cells filling the gap.

[0339] HSFs were diluted to 10% in growth medium. 5 cells / cm 2After 24 hours, the cells reached confluence and the insert was removed, revealing two regions of the cell layer separated by a pre-applied gap.

[0340] A platelet lysate (PL) mixture was prepared by mixing 190 μL of complete medium with 10 μL of platelets. Both formulations, formulation 7364 / 1 of Example 8.2 (Test) and formulation 7386 (Reference Vehicle), which represent compositions within the scope of the present invention, were diluted 1:20 with the PL mixture prepared above.

[0341] The vehicle obtained by transfection of PL was seeded into the wells. Serum-free complete medium was seeded as a control.

[0342] Photomicrographs were taken at predetermined times (t0, 24 hours, 48 ​​hours and 72 hours) to assess cell proliferation in the gap as an indicator of tissue regeneration.

[0343] Images were analyzed using ImageJ software for image analysis (NIH, Bethesda, MD).

[0344] Absolute wound density (AWD) and relative wound density (RWD) were used to measure cell migration by ImageJ software. This software can detect the presence and number of cells within the gap through the gray scale applying the following formula:

[0345] AWD=MGVt-MGVt0 RWD=(MGVt-MGVt0) / (MGV Ctrlt-MGV Ctrlt0)

[0346] MGV = Mean Gray Value t = a set time t0=starting time Ctrl = control (serum-free medium)

[0347] Table 11 shows the experimental results for each time point. Three photographs were collected and analyzed. The mean and standard deviation are reported.

[0348] [Table 11]

[0349] Figure 10 shows the assessment of the wound area of ​​all test samples over time. 10x images of samples after different times (t0, t24, t48 and t72) are shown. The black rectangle encloses the wound area.

[0350] Table 12 shows the RWD of the test formulations relative to the relevant controls.

[0351] [Table 12]

[0352] At time 0, after the insert was removed, a cell-free gap or wound gap was evident in all samples: serum-free medium (control), formulation 7386 with PL (reference vehicle) and formulation 7364 / 1 with PL (composition within the scope of the present invention).

[0353] A decrease in cell-free areas was observed in all samples after 24 hours. Although some intracellular spaces were still evident, some cell bridges were present in both the control and the two tested vehicles. As shown in Table 12, the compositions within the scope of the present invention incorporating PL showed approximately two-fold higher wound regeneration than the control.

[0354] After 48 hours, all tested samples showed an increase in MGV values. The PL-containing composition of the present invention showed a 3-fold higher RWD ratio than the control, and no difference in cell morphology was observed compared to the control condition. Meanwhile, the PL-containing reference vehicle showed a 2-fold increase compared to the control.

[0355] After 72 hours, cells were seen to have completely migrated into the free gap, as shown in FIG. 11, with the exemplary composition of the present invention containing PL resulting in approximately 2.5-fold RWD in the wound gap compared to the control, while the reference vehicle containing PL resulted in 2.2-fold RWD compared to the control.

[0356] Figure 11 shows a comparison of control, reference vehicle (7386) + PL and (7364 / 1) + PL samples after 72 hours. 10x images of the samples after 72 hours are shown. The black rectangle surrounds the wound area.

[0357] Surprisingly, Figure 11 also shows relevant differences between the exemplary compositions of the present invention and the reference formulation in terms of cell morphology and cell number. Morphology is an important parameter for assessing cell health. Surprisingly, it was revealed that the formulations of the present invention containing PL maintained good cell health, while images of the reference vehicle containing PL showed damaged and wrinkled cells. Indeed, cells resuspended in the formulations of the present invention containing PL showed regular cell margins, while cells resuspended in the reference vehicle containing PL showed irregular margins and reduced cytoplasm.

[0358] Furthermore, the cell population was estimated using ImageJ software to obtain the cell number in the wound gap. Figure 12 shows the average cell number in the wound gap of the tested formulations at predetermined times (t0, t24, t48, and t72). The exemplary composition of the present invention containing PL showed a clear increase in the average cell number in the wound gap over time, which was superior to the reference vehicle containing PL at all test times. Furthermore, it showed superiority over the control from 48 hours onwards.

[0359] This study demonstrates that exemplary formulations according to the present invention containing PL exhibit a positive effect on cell migration and proliferation of human fibroblasts for up to 72 hours.

[0360] In particular, due to this effect on cell migration and maintenance of cell morphology, the formulations of the present invention can be used as delivery vehicles for growth factors such as platelet lysate (PL) in wound healing, and also as potential vehicles for cells and cellular material.

[0361] Example 9 Water-based solution

[0362] [Table 13]

[0363] Add purified water (95% of the total volume) to a suitable vessel equipped with a stirrer; then dissolve sodium benzoate and methyl parahydroxybenzoate until completely dissolved; then cool the solution to a temperature ranging from 5°C to 20°C; then add poloxamer 407 while stirring. Keep stirring the mixture until completely dissolved and then warm to room temperature. Infliximab is then added with stirring until completely dissolved. Next, add gellan gum to the above mixture while stirring until a homogenous mixture is obtained. Next, hydroxypropyl cellulose is added to the above mixture with stirring until a homogeneous mixture is obtained. The mixture is brought to a final weight by adding purified water. The mixture is maintained under stirring until homogeneity is achieved. Application of such compositions can be facilitated by rectal administration, such as an enema, of the composition, which is intended to bioadhere to the mucous membranes of the sigmoid colon and / or rectum.

[0364] Example 10 Water-based solution

[0365] [Table 14]

[0366] The preparation method of Example 10 is the same as that of Example 8. Application of such compositions can be facilitated by injection of a suspension of MSCs into the fistula lumen or fistula wall for the treatment of fistulas, including but not limited to anal fistulas or rectovaginal fistulas.

[0367] Example 11 Water-based solution

[0368] [Table 15]

[0369] The preparation method of Example 11 is the same as that of Example 8. Application of such compositions can be facilitated by injection into the fistula lumen or fistula wall for the treatment of fistulas, including but not limited to anal fistulas or rectovaginal fistulas.

[0370] Example 12 Water-based solution

[0371] [Table 16]

[0372] The preparation of Example 12 is similar to that of Example 8. This composition can be applied topically to the emmorroidal plexus in the form of an enema or as a viscous structured composition that becomes bioadhesive when applied to the target mucosal tissue.

[0373] Example 13 Water-based solution

[0374] [Table 17]

[0375] The preparation method of Example 13 is the same as that of Example 8. The composition can be applied topically to the hemorrhoidal plexus in the form of an enema or as a viscous structured composition that becomes bioadhesive when applied to the target mucosal tissue.

[0376] Example 14 A vehicle composed of 0.31% w / w methylcellulose (MC), 0.38% w / w gellan gum (GG), and 0.22% w / w hydroxypropyl cellulose (HPC) is prepared. Such a vehicle is intended to be applied to the mucosa of the distal colon via the rectal route. The following characteristics were considered: 1) The viscosity of the vehicle at room temperature (25°C), a feature for ease of administration; 2) Increased vehicle viscosity upon temperature increase (room temperature to 37° C.) and dilution with simulated colonic fluid (SCF). Such increase is a function of vehicle persistence at the application site after administration. 3) Viscoelastic behavior after administration, which is a function of the protective effect of the vehicle at the application site. The neat vehicle and the vehicle after dilution 5:2 w / w with simulated colonic fluid (SCF) were subjected to increasing shear rates (10–300 S -1 ) SCFs are prepared according to well-known conventional recipes. From the viscosity data, two response variables are measured: 1) 25℃ and 50S -1 Viscosity of neat vehicle at shear rate: 0.093 ± 0.002 Pa·s; 2) 10S -1 Normalized delta viscosity at: 0.7±0.2, calculated by the following formula: Equation 1: Normalized Δ viscosity = (η 37℃,SFC -η 25℃,水 ) / η 25℃,水 where η 37℃,SFC = viscosity of vehicle diluted with SCF (5:2 w / w), 37°C, 10S -1 Measured at shear rate; η 25℃,水 = viscosity of vehicle diluted with water (5:2 w / w), 25°C, 10S -1 The shear rate was measured.

[0377] 10S -1The use of viscosity values ​​measured at 25°C after dilution with water instead of 37°C in the calculation of normalized Δviscosity in makes it possible to point out not only the influence of ions on the viscosity of the samples, but also the effect of thermal gelation (by MC). The vehicles after dilution 5:2 w / w with SCF were subjected to viscoelastic measurements (oscillating tests) at 37°C and mucoadhesiveness evaluation. Such tests provide a measure of the peel force (Fmax) required to separate the vehicle layer from a filter disc immersed in a mucin suspension in SCF. The following variables were measured: 1) Regarding viscoelasticity measurements: Loss tangent (Tan delta): 0.11±0.01, calculated as the ratio of viscous modulus (G'') and elastic modulus (G'). 2) Regarding mucoadhesion measurement: Maximum peel force (Fmax): 1317±102mN; The prepared vehicle is capable of gelling or structuring and exhibits mucoadhesive properties when diluted with simulated colonic fluid at physiological temperature.

[0378] Example 15 A vehicle composed of 14.0% w / w poloxamer 407 (PLX), 0.29% w / w gellan gum (GG), and 0.41% w / w hydroxypropyl cellulose (HPC) is prepared and is intended to be applied to the mucosa of the distal colon via the rectal route.

[0379] Two different dilutions with SCF are investigated: 5:2 and 5:0.65 w / w. The neat vehicle and the vehicle after dilution with distilled water or SCF to 5:2 or 0:65 w / w are subjected to increasing shear rates (10 to 300 S), as described in Example 16. -1 ) and characterized for viscosity at 1000 kJ / min. From the viscosity data, three variables were measured: 1) 25℃, 50s -1 Viscosity of neat vehicle at shear rate: 0.206 ± 0.001 Pa·s; 2) 10s when diluted 5:2 w / w -1 Normalized Δviscosity at (25°C) = 3.1 ± 0.2, and 10s when diluted to 5:0.65 w / w -1 Normalized delta viscosity at (25°C) = 3.1 ± 0.2, calculated according to the following formula: Equation 1: Normalized Δ viscosity = (η 37℃,SFC -η 25℃,水 ) / η 25℃,水 where η 37℃,SFC = viscosity of vehicle diluted with SCF (5:2 or 5:0.65 w / w), 37°C, 10S -1 Measured at shear rate; η 25℃,水 = viscosity of vehicle diluted with water (5:2 or 5:0.65 w / w), 25°C, 10S -1 The shear rate was measured. 3) 10s when diluted 5:2 w / w -1 Normalized Δviscosity at (37°C) = 12.5 ± 0.7, and 10s when diluted to 5:0.65 w / w -1 Normalized Δviscosity at = 1.13 ± 0.06, calculated according to the following formula: Equation 2: Normalized Δ viscosity = (η 37℃,SFC -η 37℃,水 ) / η 37℃,水 where η 37℃,SFC = viscosity of vehicle diluted with SCF (5:2 or 5:0.65 w / w), 37°C, 10S -1 Measured at shear rate; η 37℃,水 = viscosity of vehicle diluted with water (5:2 or 5:0.65 w / w), 37°C, 10S -1 The shear rate was measured.

[0380] Vehicles diluted with SCF according to both weight ratios also exhibit mucoadhesive properties, in fact showing that higher Fmax values ​​were obtained in the presence of mucin than in the absence of biological substrate (blank) (Figure 5).

[0381] Example 16 A vehicle intended for oral application to the esophageal wall is prepared. The vehicle is composed of 1.5% w / w MC, 0.1% w / w sodium alginate (ALG), 2.7% w / w sodium bicarbonate (NaHCO3), and 0.3% w / w magnesium oxide (MgO). MC is prepared by dissolving it in distilled water at a concentration of 3% w / w while stirring at 90°C. The solution is then placed in an ice bath with stirring until completely clear. The MC solution is mixed 1:1 w / w with an aqueous solution of 0.2% w / w ALG and 5.4% w / w NaHCO3. Finally, MgO is added. After 20 minutes of thermostation at 37°C, the vehicle exhibits increased consistency. This increase is evaluated by penetration testing and viscoelasticity measurements. Penetration testing was performed at room temperature and after 20 minutes of thermostation at 37°C. Figure 6 (a and b) show the values ​​of penetration force and work of penetration, respectively. Viscoelastic measurements were performed at 25 °C and 37 °C after 20 minutes of thermostation. The elasticity of the sample, represented by the storage modulus (G'), is measured at increasing frequencies in the range of 0.1 to 10 Hz. Figure 7 shows the G' profile of the vehicle. The results show that gelation of the vehicle occurs after 20 minutes of thermostation at 37 °C. The vehicle performance is investigated after two dilutions: 3:1 w / w with artificial saliva (AS) and 1:1 w / w with HCl 0.2N. Figure 8 shows the elastic modulus (G') of the vehicle after the above two dilutions. The G' values ​​of the vehicle diluted 3:1 w / w with AS and 1:1 with water instead of HCl are used as references to investigate the effect of an acidic environment on the vehicle performance. The obtained results demonstrate that the elasticity of the vehicle, which is functional for its protective effect on the gastrointestinal wall, increases after dilution with HCl.

[0382] Example 17 Two different vehicles: 1) a vehicle containing a 10.3% w / w aqueous solution of poloxamer 407; 2) a vehicle containing a mixture of 10.3% w / w poloxamer 407 and 0.41% w / w gellan gum in purified water; was prepared. Both vehicles were diluted with water or simulated colonic fluid according to a 5:2 w / w ratio and characterized for elastic modulus G'. The values ​​of the differential parameter ΔG', calculated as the difference between the G' values ​​observed at physiological temperatures (36, 38°C) and room temperature (25°C) upon 5:2 w / w dilution with purified water, were calculated and are shown in Table 18. It is surprisingly observed that the presence of the ion-sensitive polymer, GG, produces a significant increase in such parameter, indicating a strengthening of the gel formed. Even more surprisingly, when the same sample is diluted with simulated colonic fluid in a 5:2 w / w ratio, a further increase in gel strength is observed (Figure 9; Table 19).

[0383] Table 18 - Values ​​of the derivative parameter ΔG' calculated for poloxamer solutions (10.3% w / w poloxamer diluted 5:2 w / w with distilled water) and poloxamer / GG mixtures (10.3% w / w poloxamer / 0.41% w / w GG diluted 5:2 w / w with distilled water) (mean ± standard error, n=3) ΔG' 36または38℃ =(G' 36または38℃ -G' 25℃ )

[0384] [Table 18]

[0385] Table 19 - Values ​​of the derivative parameter ΔG' calculated for poloxamer solution (10.3% w / w poloxamer diluted 5:2 w / w in simulated colonic fluid) and poloxamer / GG mixture (10.3% w / w poloxamer / 0.41% w / w GG diluted 5:2 w / w in simulated colonic fluid) (mean ± standard error, n=3) ΔG' 36または38℃ =(G' 36または38℃ -G' 25℃ )

[0386] [Table 19]

[0387] Thus, it is surprising to see that when a thermo-responsive polymer is combined with an ion-sensitive polymer, the elastic modulus G' at 37° C. is significantly increased. This is even more surprising when the combination of the present invention (thermo-responsive + ion-sensitive) is diluted with simulated colonic fluid, which mimics the actual environment of the intestine (940±222 Pa for water alone vs. 4937±1129 Pa for simulated colonic fluid at approximately 37° C. body temperature).

Claims

1. a liquid formulation comprising 0.3-25% (w / w) of at least one thermo-responsive polymer (polymer A), 0.01-2.0% (w / w) of at least one ion-sensitive polymer (polymer B), 0.01-2.0% (w / w) of at least one bioadhesive polymer, and at least one active ingredient for delivery, wherein the at least one active ingredient for delivery is rifamycin SV; the at least one thermoresponsive polymer (polymer A) is selected from the group consisting of polyoxyethylene-polyoxypropylene block copolymers selected from the group consisting of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407, cellulose derivatives selected from the group consisting of methylcellulose (MC) and hydroxypropylmethylcellulose (HPMC), and mixtures thereof; the at least one ion-sensitive polymer (polymer B) is selected from the group consisting of gellan gum, alginic acid, salts of alginic acid, and mixtures thereof; the at least one bioadhesive polymer is sodium carboxymethylcellulose; A composition for use as a delivery vehicle that is in a liquid state at temperatures below 37°C and becomes a gel or structured composition when exposed to temperatures above 37°C.

2. 10. The composition of claim 1, further comprising at least one other excipient, such as an antioxidant, a chelating agent, a preservative and / or an antibacterial agent, a surfactant, a co-surfactant, a lipophilic compound, purified water or water for injection, organic and inorganic salts, a buffering agent with nutritional activity, etc.

3. 3. The composition of claim 1 or 2, wherein the composition is administered by oral, buccal, ocular, rectal, perianal, vaginal, otic, nasal, dental route or injection, preferably the injection route of administration is submucosal, intraperitoneal, intratumoral, subcutaneous, intramuscular, intraarticular, intranasal, perianal, intrathecal, epidural, intraparenchymal injection into the brain or spinal cord, or into the subretinal space.

4. The composition of any one of claims 1 to 3, wherein the composition is formulated into a solution, micellar dispersion, suspension, emulsion or microemulsion.

5. 5. The composition of any one of claims 1 to 4, wherein the composition is in the form of an enema, a syrup, drops, a solution, a suspension, a micellar dispersion, an emulsion, a microemulsion, a structured viscous composition, a vaginal douche, or a liquid in a softgel capsule.

6. A composition according to any one of claims 1 to 5 for use in the diagnosis, prevention, mitigation, treatment and / or reduction of pathologies or disorders affecting the human body.

7. The composition of any one of claims 1 to 6, wherein the at least one thermoresponsive polymer comprises poloxamer 407 and the at least one ion-sensitive polymer comprises sodium alginate.

8. 8. The composition of claim 7, wherein poloxamer 407 is present in an amount of 15% (w / w) relative to the weight of the composition.

9. 9. The composition of claim 7, wherein sodium alginate is present in an amount of 0.01 to 2.0% (w / w) by weight of the composition.

10. 10. The composition of any one of claims 7 to 9, wherein sodium alginate is present in an amount of 0.2% (w / w) relative to the weight of the composition.

11. 11. The composition of any one of claims 7 to 10, wherein the sodium carboxymethylcellulose is present in an amount of 0.05% (w / w) relative to the weight of the composition.

12. A composition according to any one of claims 7 to 11 for use in the diagnosis, prevention, mitigation, treatment and / or reduction of pathologies or disorders affecting the human body.

13. A composition according to any one of claims 7 to 11 for use in the diagnosis, prevention, alleviation, treatment and / or reduction of inflammatory bowel disease.

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