MXPA04007041A - Phospholipid bodies and use thereof in the treatment of inflammatory and autoimmune diseases. - Google Patents

Abstract

This invention relates to synthetic and semi-synthetic compositions having biological activity, and to the uses thereof in the treatment and/or prophylaxis of various disorders in mammalian patients. More particularly it relates to preparation and use of synthetic and semi-synthetic bodies, which after introduction into the body of a patient, produce beneficial anti-inflammatory, organ protective and immune regulatory effects. The invention also relates to treatments and compositions for alleviating inflammatory and autoimmune diseases and their symptoms.

Description

ES, FI, FR, GB, GR, HU, 1E, IT, LU, MC, NL, PT, SE, YES, For Mo-letter codes and other abbreviations, refer to the "Guid- ST T OA-PI- arenrfBFrBJrCFrGe eiREArGN ^ - anee-N < es- ^ ode & Abbrexiaiionlappearing.aLthe.b_egin- OQ, GW, ML, MR, NE, SN, TD, TG), none of each regular issue of the PCT Gazette. : - with inlernalional search report BODIES OF INCLUSION OF PHOSPHOLIPIDS AND USE OF THEM IN MEDICAL TREATMENTS BACKGROUND OF THE INVENTION Field of the invention This invention relates to synthetic and semi-synthetic compositions possessing biological activity and to the uses thereof in the treatment and / or prophylaxis of various disorders in mammalian patients. More particularly, it relates to preparations and uses of synthetic and semi-synthetic inclusion bodies which, after their introduction into the body of a patient, produce beneficial anti-inflammatory, protective of organs and immunoregulatory effects. The invention also relates to treatments and compositions for alleviating inflammatory and autoimmune diseases and the symptoms thereof. | " BACKGROUND OF THE INVENTION Professional antigen presenting cells (APCs), including dendritic cells (DO and macrophages (Mph), are cell types that capture and they actively process antigens (Ags), eliminate cellular debris and infectious organisms and dying cells, including the residues of moribund cells. During this process, the APC can stimulate the production of responses dominated either by Thl pro-inflammatory cytokines (IL-12, IL-1, INF- ?, TNF-, etc.); or by Th2 / Th3 regulatory / anti-inflammatory cytokines (such as IL-10, TGF-β, IL-4 etc.); depending on the nature of the antigen (Ag) or the cellular residues found and the level of maturation / activation of the APCs. APC eliminates cellular debris, some of which are derived from the membranes of body cells, some from bacterial and parasitic infections and from commensal organisms, such as intestinal bacteria. As part of these cellular debris will initiate a pro-inflammatory response, part will initiate a protective and anti-inflammatory response. A functioning immune system can distinguish between the antigens of foreign invading organisms (not own) and tissues or debris derived from "own" material, mounting an immune response only for those antigens that are foreign. When the immune system of a patient can not discriminate between own and non-own materials, autoimmune disorders arise.

Summary of the invention This invention is directed to the discovery that inclusion bodies, such as liposomes, beads or . Similar particles, comprising comprising certain reactive chemical groups such as groups of anionic phospholipids, other than serine phosphate and glycerol phosphate will cause. after its administration to a mammalian patient, an anti-inflammatory effect and therefore can be 10 use in the treatment of numerous diseases. These : Inclusion bodies may further comprise as a minor component on the surface of the. same a *: 'inactive constituent and / or a constituent that is active j¾ but through a different mechanism. In a preferred embodiment, the. invention is directed to a composition of a material capable of producing an anti-inflammatory response in vivo in a mammal, wherein said composition comprises inclusion bodies acceptable for pharmaceutical use of a size comprising f * 20 between 20 nanometers (rim) and 500 micrometers (μp?) Approximately, comprising a plurality of reactive chemical groups (hereinafter referred to as "anti-inflating response promoter groups") other than serine phosphate and glycerol phosphate, which interact with receptors on cells of the immune system mammals altering the profile of the cytokines of the immune system that favor an anti-inflammation. The groups promoting anti-inflammatory responses include the active groups of certain anionic phospholipids and of other phospholipids, other than serine phosphate and glycerol phosphate, certain peptides and synthetic mimetics thereof, adapter proteins, lipids, lipoproteins and the like, which they will be described more specifically below. It is believed that the inclusion bodies interact with the immune system of a mammal through said groups, after the administration thereof, producing an anti-inflammatory response in vivo in said mammal. Preferably, the inclusion bodies are essentially free of pharmaceutically active non-lipid entities. Preferably the groups constitute 60% -100% of the active groups on the surface of the inclusion bodies. In some indications, the inclusion bodies can also transport as an minor component on their surface an inactive constituent (such as choline-phosphate) or a constituent that is active through another mechanism, such as serine-phosphate. In another embodiment, this invention is directed to three-dimensional synthetic, semi-synthetic or natural inclusion bodies, also referred to as inclusion bodies acceptable for pharmaceutical use, which have been designed to comprise, as a main component, at least one promoter ligand. of anti-inflammatory responses, wherein said ligand is an anionic phospholipid other than PG or PS, where PG and PS are as defined below.

In yet another embodiment, this invention is directed to three-dimensional synthetic, semi-synthetic or natural inclusion bodies, also referred to as inclusion bodies acceptable for pharmaceutical use herein, having sizes ranging in a range between 20 nm and 50 microns and that have groups that promote anti-inflammatory responses other than glycerol-phosphate and serine-phosphate, on the surface thereof. In another aspect, the invention is directed to a method for the treatment of a disorder mediated by the functioning of T cells comprising administration to a mammalian patient of an effective amount of inclusion bodies acceptable for pharmaceutical use which carry an effective amount of groups promoting anti-inflammatory responses, to inhibit and / or reduce the progression of the disorder mediated by the functioning of T cells. This invention is further directed to a method for the treatment of an inflammatory disorder comprising the administration to a patient of an effective amount of inclusion bodies acceptable for pharmaceutical use that carry an effective amount of anti-inflammatory response promoting groups to inhibit and / or reduce the progress of said inflammatory disorder. Yet another embodiment of this invention is a method for the treatment of an endothelial function disorder comprising administering to a mammalian patient an effective amount of pharmaceutically acceptable inclusion bodies that carry an effective amount of anti-inflammatory response promoter groups. to inhibit and / or reduce the progress of said endothelial function disorder. Another embodiment is a method for the treatment of an immunological disorder characterized by an inadequate expression of cytokines comprising the administration to a mammalian patient of an effective amount of inclusion bodies acceptable for pharmaceutical use which carry an effective amount of anti-inflammatory response promoter groups. -inflammatory to inhibit and / or reduce the progress of said immune disorder. The invention is further directed to a process for the treatment or prophylaxis of a cardiac disorder in mammals, whose presence or susceptibility to it is detectable by observation of a prolonged interval of QT-c in the patient's electrocardiogram., wherein said process comprises administering to a mammalian patient suffering therefrom or being susceptible thereto of a pharmaceutical composition comprising synthetic, semi-synthetic or natural biocompatible inclusion bodies acceptable for pharmaceutical use, also referred to as inclusion bodies acceptable for pharmaceutical use in this document, and an acceptable vehicle for pharmaceutical use, wherein at least a portion of said inclusion bodies has a size that is in the range between 20 nm and 500 μp? approximately, and wherein the surfaces of said inclusion bodies have been modified to transport, as a main component, at least one group promoting anti-inflammatory responses, wherein said group is an anti-inflammatory group other than glycerol-phosphate and serine phosphate . Another embodiment of the invention is a pharmaceutical composition, in a unit dosage form, for administration to a mammalian patient, comprising inclusion bodies acceptable for pharmaceutical use and a vehicle acceptable for pharmaceutical use, wherein at least a portion of the bodies of inclusion have a size in the range between 20 nm and 500 μ? approximately and where the surface of said inclusion bodies comprise anti-inflammatory response promoting groups, wherein said unit dosage comprises between 500 and 2.5 x 1Q9 inclusion bodies approximately, wherein said group is a group promoting anti-inflammatory responses other than glycerol-phosphate and serine-phosphate. A further embodiment of this invention is a pharmaceutical composition comprising synthetic, semi-synthetic or natural biocompatible inclusion bodies acceptable for pharmaceutical use (also referred to as inclusion bodies acceptable for pharmaceutical use herein) and a pharmaceutically acceptable carrier, where at least a portion of said inclusion bodies has a size between 20 nm and 500 μp? approximately and where the surfaces of said inclusion bodies have been modified to comprise, as a main component, at least one group promoting anti-inflammatory responses, wherein said group is a group promoting anti-inflammatory responses other than glycerol-phosphate and serine -phosphate. Optionally, the inclusion bodies described above may further comprise a constituent which is an inactive surfactant group and / or a constituent which is a surfactant group which is active by another mechanism, for example phosphatidylserine. (See, for example, Fadok et al. International Publication WO 01/66785). In another embodiment, this invention is directed to lyophilized or freeze-dried pharmaceutical acceptable inclusion bodies that carry groups of ligands that promote anti-inflammatory responses such as binding groups and sets of elements [kits] comprising lyophilized or dried inclusion bodies. freezing comprising groups that promote anti-inflammatory responses, or groups that can be converted into groups that promote anti-inflammatory responses, and an acceptable vehicle for pharmaceutical use, where said group is a group that promotes anti-inflammatory responses other than glycerol - phosphate and serine-phosphate. In another aspect, this invention is directed to a method for the treatment of a disorder mediated by the operation of T cells comprising administration to a mammalian patient suffering from or at risk of suffering a disorder mediated by the functioning of T cells, an effective amount of a composition comprising pharmaceutically acceptable inclusion bodies that are of a size between about 20 nm and 500 μ? approximately, comprising on the surface thereof a plurality of groups that promote ani-inflammatory responses other than glycerol-phosphate or serine-phosphate or groups that can be converted into said groups that promote ani-j-inflammatory responses, so that after its administration, the advancement of said disorder mediated by the functioning of T cells is inhibited and / or reduced. Still another embodiment of this invention is directed to a method for the treatment of an endothelial function disorder that comprises administering to a mammalian patient, suffering from or at risk of suffering from an endothelial function disorder, from an effective amount of a composition comprising inclusion bodies acceptable for pharmaceutical use which are from a size between about 20 nm and 500 μ ?? approximately, comprising on the surface thereof a plurality of groups promoting anti-inflammatory responses other than glycerol-phosphate or serine-phosphate, or groups that can themselves be converted into said groups promoting anti-inflammatory responses, so that after its administration, the advancement of said disorder mediated by an endothelial function is inhibited and / or reduced. Another embodiment of this invention is directed to a method for the treatment of an immunological disorder in a mammalian patient suffering from or at risk of suffering from an immunological disorder, comprising administering to said mammalian patient an effective amount of a composition comprising inclusion bodies acceptable for pharmaceutical use that are between approximately 20 nm and 500 μp in size? approximately, comprising on the surface thereof a plurality of groups promoting anti-inflammatory responses other than glycerol-phosphate or serine-phosphate, or groups that can themselves be converted into said groups promoting anti-inflammatory responses, such that after its administration, the progress of said immune disorder is inhibited and / or reduced. Another embodiment of this invention is directed to a method for the treatment in a mammalian patient suffering from or at risk of suffering from an inflammatory disorder comprising the administration to said mammalian patient of an effective amount of a composition comprising acceptable inclusion bodies. for pharmaceutical use which are of a size between approximately 20 nm and 500 μp? approximately, comprising on the surface thereof a plurality of groups promoting anti-inflammatory responses other than glycerol-phosphate or serine phosphate, or groups that can themselves be converted into said groups promoting anti-inflammatory responses, such that after its administration, the progress of said inflammatory disorder is inhibited and / or reduced.

Brief description of the figures The attached Figure 1 is a bar graphical presentation of the results obtained in Example 1 which will be described later. Figure 2 is a bar graph presentation of the results obtained according to Example 2 which will be described later. Figure 3 similarly shows the results obtained according to Example 3 which will be described later. Figure 4 similarly shows the results obtained according to Example 4 which will be described later. Figure 5 similarly shows the results obtained according to Example 5 which will be described later.

Description of the preferred embodiments In accordance with the present invention, acceptable inclusion bodies for pharmaceutical use are administered to patients carrying groups of ligands that promote anti-inflammatory responses on the surface thereof. Without taking into account a particular theory, it is believed that these inclusion bodies interact with the patient's immune system thereby obtaining beneficial effects, such as inhibition of pro-inflammatory cytokines in vivo and / or promotion of anti-inflammatory cytokines. The cells that react can be immune cells, such as professional or non-professional antigen presenting cells, endothelial cells, regulatory cells, such as NK-T cells and others. These inclusion bodies acceptable for pharmaceutical use include synthetic, semi-synthetic and natural inclusion bodies whose contours are typically, but not exclusively, spherical, cylindrical, ellipsoid, including oblate and elongated spherical, serpenteate, reniform, etc., and sizes between 20 nm approximately and 500 μt? approximately in diameter, preferably measured by the major axis. Inclusion bodies acceptable for pharmaceutical use have one or more groups promoting anti-inflammatory responses of predetermined characteristics on the outer surface in such a way that, in one embodiment, they can interact with the appropriate receptor (s), other than the exclusive interaction with the PS receptor or the PG receptor, on the antigen-presenting cells in vivo. The structure of these groups can be altered by synthesis and can include all, part or a modified version of the original anti-inflammatory response promoter group. As used herein, the term "PG" is intended to encompass phospholipids that carry a glycerol-phosphate group with a broad range of at least one fatty acid chain, provided that the resulting PG entity can participate as a structural component of a liposome. . Preferably, said PG compounds can be represented by the following Formula I: where R and R1 are independently selected from C, -C24 hydrocarbon chains, saturated or unsaturated, straight chain or containing a limited amount of branches, where at least one chain has between 10 and 24 carbon atoms. Essentially, the lipid chains R and R1 form the structural component of the liposomes, instead of the active component. Accordingly, they can be varied to include two or one of said lipid chains, whether they are the same or different, as long as they comply with said structural function. Preferably, the chains of atoms may be from about 0 to 24 carbon atoms in length, saturated, monounsaturated or polyunsaturated, straight chain or with a limited amount of branches. As examples of saturated lipid chains which are useful may be mentioned laurate (C12), myristate (C14), palmitate (C16), stearate (C18), arachididate (C20), behenate (C22) and lignocerate (C24) for the PG in the present invention. Palmitoleate (C16) and oleate (C18) are examples of suitable monounsaturated lipid chains. Linoleate (C18), linolenate (C18) and ariquidonate (C20) are examples of polyunsaturated lipid chains suitable for use in PG in the liposomes of the present invention. Phospholipids with only one of said lipid chains, which are also useful in the present invention, are known as lysophospholipids. The present invention also encompasses the use of liposomes in which the active component is the dimeric form of PG, ie, iolipin, but there are also other dimers of Formula I that are suitable. Preferably, said dimers are not synthetically crosslinked with a synthetic cross-linking agent, such as maleimide, but are actually cross-linked by elimination of a glycerol unit as described by Lehninger, Biocheznis ry, p. 525 (1970) and as shown in the following reaction: PG cariUoliptn HOC¾ (OH) CH 2 OH where each R and R 1 are, independently, as previously defined. As used herein, the term "MPS" is intended to encompass phosphatidylserine and analogs / derivatives thereof, provided such analogues / derivatives enhance or stimulate the activity of the phosphatidylserine receptor In a preferred embodiment these cardiolipin-promoting groups of anti-inflammatory responses are anionic phospholipids other than glycerol-phosphate or serine phosphate In a more preferred embodiment the anionic phospholipid is phosphatidylinositol Inositol, hexahydroxycyclohexane, constitutes the chemical bond with the phosphate group in the PI of the phosphatidylinositol through one of its hydroxyl groups There are several stereoisomers of inositol, related to the arrangement of the hydroxyl groups relative to the nucleus All of said stereoisomeric forms of PI are comprised within the terms phosphatidylinositol and PI as used herein Phosphatidylinositol analogs with modified active groups, that also In addition, they interact with PI receptors on antigen-presenting cells, or that otherwise result in an anti-inflammatory reaction in the recipient body, are contemplated within the scope of the term phosphatidylinositol. These include, for example, compounds in which one or more of the hydroxyl groups and / or the phosphate group have been derivatized, or which are in the form of a salt. Many such compounds form free hydroxyl groups in vivo, at or after their administration. Natural phosphatidylinositol (PI) is a natural phospholipid smaller than cell membranes. From a chemical point of view, it contains a phosphoinositol group, a glycerol group and a pair of similar but different Ci8-C2o fatty acid chains, so that they can be represented by the following chemical formula II: where R2 represents ariquidonate (C2o, 5, 8, 11, 14) and R3 represents stearate (Cis, saturated). While the above natural PI compound constitutes the most preferred active constituent of the liposomes used in the present invention, variations in the nature and amount of lipid chains are also within the scope thereof. In essence, the lipid chains form the structural component of the liposomes, instead of the active component. Therefore, it is possible to vary them to include two or one of said lipid chains, whether they are the same or different, as long as they comply with the structural function. Preferably, the lipid chains can be from about 10 to about 24 carbon atoms in length, saturated, monounsaturated or polyunsaturated, straight-chain or with a limited amount of branches. As examples of saturated lipid chains which are useful, mention may be made of laurate (C12), myristate (C14), palmitate (C16), stearate (C18), arachididate (C20), behenate (C22) and lignocerate (C24) for the PI in the present invention. Palmitoleate (C16) and oleate (C18) are examples of suitable monounsaturated lipid chains. Linoleate (C18), linolenate (C18) and ariquidonate (C20) are examples of polyunsaturated lipid chains suitable for use in the IP in the liposomes of the present invention. The stereo configuration of the lipid chain is not important and all stereoisomers are included in the present definition. Single-chain lipid phospholipids, also useful in the present invention, are known as lysophospholipids. All such variations are included in the PI definitions. The present invention can also be considered, from another aspect, as the use of a receptor on the cells of the immune system of mammals, for example macrophages, which specifically bind to the phosphate-inositol group. The invention encompasses inclusion bodies comprising ligands and groups that will bind to said receptor and that will consequently produce an anti-inflammatory response. Therefore, the present invention can be defined as inclusion bodies comprising ligands or active groups thereof that compete for the binding or uptake of the inclusion bodies described herein by the antigen-presenting cells that express phosphate-inositol. The art specialist can easily determine if a particular inclusion body is such that it will compete, carrying out very simple test experiments. For example, inclusion bodies can be evaluated with a line of readily available monocytic cells, such as U937 cells. In a first experiment, U937 cells are incubated only with fluorescently labeled PI liposomes and in other experiments U937 cells are incubated in the presence of fluorescently labeled PI liposomes and different amounts of test compound. If the uptake of the fluorescently labeled liposoTuat PIs in the other experiments is reduced compared to that of the first experiment, then the test compound is competing for the specific receptor and constitutes a compound within the scope of the present invention. Also within the scope of the present invention is the use of inclusion bodies containing a mixture of the aforementioned phospholipids having chemically active groups, where this mixture comprises at least 10% r, preferably at least 50% and more preferably 60-90% of the active phospholipids mentioned previously, such as PI. Instead of the minor constituent being an inactive constituent, it can also be active but through another mechanism. Examples of "three-dimensional portions of inclusion bodies" or "inclusion bodies acceptable for pharmaceutical use" include synthetic, semi-synthetic or natural biocompatible rtds, such as liposomes, solid beads, hollow beads, filled beads, particles, granules and microspheres of biocompatible, natural or synthetic materials, such as polyethylene glycol, polyvinylpyrrolidone, polystyrene, poly (methylmethacrylate), etc., polysaccharides such as hydroxyethylated starch, hydroxyethylcellulose, agarose and the like, commonly used in the pharmaceutical industry. The beads can be solid or hollow or they can be filled with a biocompatible material. The term "biocompatible" refers to substances that, in the amount used, are non-toxic or have acceptable toxicity profiles so that their in vivo use is acceptable. Such inclusion bodies may include liposomes formed by lipids, one of which is, for example, phosphatidylinositol (PI). Alternatively, inclusion bodies acceptable for pharmaceutical use can be solid beads, hollow beads, filled beads, particles, granules and microspheres of biocompatible materials, comprising one or more biocompatible materials such as polyethylene glycol, poly (methylmethacrylate), polyvinylpyrrolidone, polystyrene and a wide range of other natural, semi-synthetic and synthetic materials, with groups that promote anti-inflammatory responses other than glyceryl phosphorylglycerol or serine phosphate, as previously indicated, phosphatidylglycerol analogues with Modified active groups, which also interact with the PI receptors on the antigen-presenting cells, through the same receptor pathway as PI or which otherwise result in an anti-inflammatory reaction in the recipient body, are contemplated within the scope of the term phosphatidylglycerol, these include, for example, moieties in which one or more of the hydroxyl groups and / or the phosphate group have been derivatized, or which are in the form of a salt. Many such compounds form free hydroxyl groups in vivo, at the time or after their administration and, therefore, comprise groups convertible to PI. Preferred compositions of material are liposomes, which may consist of various lipids. However, it is preferred that none of the lipids be positively charged. Liposomes, or lipid vesicles, are sealed sacs, in the micron or sub-micron range, whose walls consist of suitable amphiphiles. They usually contain an aqueous medium. In general, the liposomes are composed of phosphatidylcholine (PC), distearoylphosphatidylcholine, phosphatidylinositol, phosphatidic acid, lysophosphatidic acid, lysophosphatidylinositol, lecithin, cephalin, cerebrosides including sphingomyelin and sphingosine. Said liposomes are prepared and treated in such a way that the active polar groups are on the outer side of the liposomal body. Accordingly, in a preferred embodiment of this invention, synthetic or i-synthetic or natural inclusion bodies are provided, which may be exposed or which may be treated or induced to expose, on the surface thereof, the promoter-active groups. anti-inflammatory responses derived from one or several phospholipid ligands. These phospholipids may be phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, lysophosphatidic acid, lysophosphatidylinositol, lysophospholipid, lysophosphatidylethanolamine, sphingosylphosphorylcholine, sphingosine-1-phosphate, ceramides, sphingomyelin and combinations of two or more thereof. Some are active and it is believed that others, for example, phosphatidylcholine, are inactive in most applications, but they provide structure to the liposome.

Liposomes, or lipid vesicles, are sealed sacs, in the micron or submicron range, whose walls (single-layer or multi-layer) comprise suitable amphiphiles. They usually contain an aqueous medium, although for the present invention the interior content is not important and in general is inactive. Accordingly, in a preferred embodiment, the liposomes, as well as other inclusion bodies acceptable for pharmaceutical use, are essentially free of pharmaceutically active non-lipid entities (eg <1%) and more preferably are free of non-lipid entities acceptable for pharmaceutical use. Said liposomes are prepared and treated in such a way that the active groups are presented outwards on the body of the liposome. The phospholipids of the preferred embodiments of this invention then serve as ligands and as structural components of the liposome itself. Thus, a preferred embodiment of this invention provides liposomal inclusion bodies that expose or can be treated or induced to expose, on the surfaces thereof, one or more groups, preferably inositol-phosphate, which will act as linking groups. Phospholipids that are not PS or active PG should comprise between 10% -100% of the liposome, the balance being an inactive constituent, for example phosphatidylcholine, or a constituent acting through a different mechanism, for example phosphatidylserine or mixtures of the same. Inactive constituents, such as PC, are preferred. At least 10% by weight of said liposome is composed of one or more of the phospholipids which are not PS / PG and which have active anti-inflammatory response promoter groups, preferably at least 50%, more preferably between 60-100% and more preferably between 70-90%, with the most preferred embodiment being about 75% by weight of active phospholipids. Preferred phospholipids for use in the present invention are phosphatidylinositol and phosphatidic acid, optionally with a minor portion (up to less than 50% by weight) of another inactive constituent and / or an active constituent but with another mechanism, ie serine phosphate The most preferred active phospholipid for use in the present invention is phosphatidylinositol (PI), even more preferably a liposome consisting of up to about 70-90% PI, brought to equilibrium with inactive phospholipids. Mixtures of liposomes consisting of the various phospholipids mentioned above that have chemically active groups and mixtures of said liposomes with liposomes constituted by liposomes of inactive phospholipids and / or acting by means of a different mechanism can also be used, provided that the total amount of active phospholipids remains above a minimum of about 10% and preferably above 60% in the total mixture. With respect to the non-liposomal inclusion bodies that may be used in the present invention, they may include solid or hollow biocompatible beads of the appropriate size. Synthetic or semi-synthetic non-liposomal biocompatible inclusion bodies can be selected from polyethylene glycol, poly (methylmethacrylate), polyvinylpyrrolidone, polystyrene and a wide range of other natural, semi-synthetic and synthetic materials. Such materials include biodegradable polymers, such as those described by Dunn, et al., U.S. Pat. No. 4,938,763, the content of which is incorporated herein in its entirety by way of reference. Biodegradable polymers are described in the art and include, for example, straight chain polymers such as polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polycarbonates, polyoxycarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly (amino) acids, polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan and copolymers, terpolymers and combinations thereof.

Other biodegradable polymers include, for example, gelatin, collagen, etc. ~ Biodegradable polymers are described in the art and include, for example, straight chain polymers 5 such as polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polycarbonates, polycarbonates, polyoxycarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerate, oxa Polyalkylene, polyalkylene succinates, poly (nalic acid), poly (amino) acids, polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan and copolymers, terpolymers and combinations thereof. Other biodegradable polymers include, for example, 15 gelatin, collagen, etc. Substances suitable for derivatization for the phospholipids. or portions of them, with groups or groups of union, to the three-dimensional inclusion bodies are commercially available 20 for example from Poliseiences Inc., 400 Valley Road, Warrington ?, PA 18976. or from Sigma Aldrich Fine Chemicals. The methods for "u derivatization are known in the ar e. The preferred specific examples of such methods are described in the International Patent Application I -! - PT / CAtV2"/ 139b, Vrisogeii Ireland Limited, which is incorporated herein by reference.It is contemplated that the patient may be a mammal, including, for example, humans and animals. such as cows, horses, pigs, dogs, cats and the like Phospholipids are amphiphilic molecules (ie they are amphiphiles), which means that the compound comprises molecules that have a water-soluble polar group attached to a hydrocarbon chain Water-insoluble aggregates The amphiphiles that contain the matrix layers have polar and apolar polar regions, and amphiphiles can include, in addition to the phosphorus-supplied solutions. In the process of the invention, others, lipids naturs'its used alone with the phospholipid that transpcrr.an to gr.po or in mixtures with others.The amphiphiles constituting the layer or layers of the liposomes can be synthetic compounds that confer structure, inert , such as polyoxyethylene alkyl ethers, polyoxyethylene alkylesters and sucrose di-esters. Methods for preparing liposomes of appropriate appendage are known in the art and do not form the subject of this invention. You can consult numerous textbooks articles er. Literature on this topic, for example, the review "Liposomes as Pharmaceutical Dosage Forms", by Yechezkel Barenhol z and Daan J A. Chrommelin, and the literature cited therein, for example New, RC "Liposomes: A Practical Approach", IRL Press by OxfOrd- University Press (1990). The diameter of the liposomes, as well as the others 5 inclusion bodies acceptable for pharmaceutical use, of the preferred embodiment of this invention comprises between about 20 nm and 500 μt? about, more preferably between about 20 nm and about 1000 nm, preferably between 50 nm 10 approximately and 500 nm approximately and more preferably between approximately 80 nm and approximately 120 nm (preferably measured by the major axis).

Acceptable inclusion bodies for pharmaceutical use can be suspended in an acceptable vehicle 15 for pharmaceutical use, such as physiological sterile saline, sterile water, pyrogen-free water, isotonic saline and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. Preferably, The inclusion bodies acceptable for pharmaceutical use are formed into a liquid suspension in a biocompatible liquid, such as saline buffer, and are administered to the patient by any appropriate route that introduces it into the immune system., such as intravenously, intravenously or, more preferably, intramuscularly or subcutaneously. It is contemplated that addressable inclusion bodies for pharmaceutical use can be dried by freezing or freeze-dried so that they can be subsequently resuspended for administration. This invention is also directed to a set of elements comprising lyophilized or freeze-dried inclusion bodies that carry anti-inflammatory response promoter groups and an acceptable carrier for pharmaceutical use, such as sterile saline physiological solution, sterile water, pyrogen-free water, isotonic saline solution and amorphous phosphate buffer solutions, as well as other compatible non-toxic substances used in pharmaceutical formulations. A preferred way of administering acceptable inclusion bodies for pharmaceutical use to the patient is a series of injections, administered daily, several times a week, weekly or monthly to the patient, over a period ranging from a week to several months. The frequency and duration of the administration varies from one patient to another and according to the condition being treated, its severity and whether the treatment will be prophylactic, therapeutic or curative. The design and the optimization of the same are skills of the professional in charge. Intramuscular injection is preferred, especially the gluteus muscle pathway. One the indications of the invention, comprises the injection, in the gluteus muscle, of an appropriate amount of inclusion bodies on day 1, another injection on day 2, another injection on day 14 and then "booster" injections at monthly intervals, if appropriate. It is postulated that, in many embodiments of the present invention, pharmaceutically acceptable inclusion bodies comprising groups promoting anti-inflammatory responses on the surface thereof are acting as modifiers of the patient's immune system, similarly to the of a vaccine. Accordingly, they are used in the amounts and methods of administration sufficient to provide a localized concentration of inclusion bodies at the site of introduction. The amounts of such inclusion bodies that are suitable for a modification of the immune system may not correlate directly with the body size of the recipient and therefore can be clearly distinguished from drug dosages, which are designed to provide therapeutic levels of active substances. in the bloodstream and the tissues of the patient. Then, the dosages of drugs will probably be much greater than the dosages that modify the immune system. The correlation between the weight of ros-lipoyomas-and-1-a-quantity of liposomes derives from the fact, accepted by those skilled in the art of liposomal formulations, that a two-layered vesicle of 100 nm in diameter contains 81,230 lipid molecules per vesicle, distributed approximately 50:50 between the two layers (see Richard Harrigan - 1992 University of British Columbia, PhD thesis "Transmembrane pH gradients in liposomes (microform): drug-vesicle interactions and proton flux", published by National Library of Canada , Ottawa, Canada (1993); No. Order of University Microfilms UMI00406756; Canadian No. 942042220, ISBN 0315796936). From this it is possible to calculate, for example, that a dose of 5 x 108 vesicles, in the order of the dose used in the specific examples in vivo later in this document, is equivalent to 4.06 x 1013 lipid molecules . Using Avogadro's number for the number of lipid molecules in a gram molecule (mol), 6.023 x 1023, it can be determined that this represents 6.74 x 10"11 moles, which, with a molecular weight of 857 for PI is approximately at 5.78 x 10"8 or 57.8 ng of PI for said dosage. The amount of inclusion bodies acceptable for pharmaceutical use that will be administered varies according to the nature of the mammalian disorder being treated and according to the identity and characteristics of the patient. It is impotant-that-Zta-quantity-effective-z-efe-eu rpes-d -in iws-i ^ Br-acceptable for pharmaceutical use is not toxic to the patient and should not be so great as to overcome the immune system . When an intra-arterial, intravenous, subcutaneous or intramuscular administration of a liquid suspension of inclusion bodies acceptable for pharmaceutical use is used, it is preferred to administer, for each dose, between about 0.1-50 ml of liquid, which contains an amount of inclusion bodies equivalent in general to 10% - 1000% of the amount of leukocytes usually present in an equivalent volume of whole blood. In general, the amount of inclusion bodies administered per time to a human patient is in the range between approximately 500 and approximately 2.5 x 109 (<250 ng inclusion bodies, in the case of liposomes, prorated for density differences in other embodiments of inclusion bodies), more preferably between about 1,000 and about 1,500,000,000, preferably between 10,000 and 100,000,000 and more preferably between about 200,000 and about 2,000,000. Since inclusion bodies acceptable for pharmaceutical use act, in the process of the invention, as modifiers of the immune system, in the nature of a vaccine, the amount of said inclusion bodies can be used in each injection site for each administration. constitute a quantification more significant than the quantity or weight of inclusion bodies per unit of body weight of the patient. For the same reason, it is now considered that the effective amounts or the amount of inclusion bodies for small animals do not translate directly into effective amounts for larger mammals (ie, more than 5 kg) on a weight-ratio basis . The present invention is indicated for use in the prophylaxis and / or treatment of a wide variety of disorders in mammals in which T-cell functioning, inflammation, endothelial dysfunction and inadequate expression of cytokines are compromised. Patients who suffer or are suspected of having such disorders can be selected for treatment. The term "treatment" refers to a reduction in symptoms, such as, for example, a decrease in the severity or in the amount of symptoms of the particular disease or a limitation of the progressive advance of the symptoms. With respect to disorders due to the function of T cells (mediated by T cells), these include ulcers and wounds and autoimmune disorders including, for example, diabetes, scleroderma, psoriasis, rheumatoid T rr rs. The invention is indicated for use with allergic inflammatory reactions, disorders by reactions in organ and cell transplants and microbial infections that cause inflammatory reactions. It is also indicated for use in prophylaxis against oxidative stress and / or ischemic reperfusion injury, poison intake, exposure to toxic chemicals, radiation injuries and exposure to irritating substances transported by air and water, etc., causing a harmful inflammation. It is also indicated for inflammatory, allergic and T cell-mediated disorders of internal organs, such as kidney, liver, heart, etc. With respect to disorders involving inappropriate expression of cytokines for which the present invention is indicated, they include neurodegenerative diseases. Neurodegenerative diseases, including Down syndrome, Alzheimer's disease and Parkinson's disease, are associated with increased levels of certain cytokines, including interleukin-β (IL-1 (S) (see Griffin WST et al. 1989); Mogi M. et al. (nineteen ninety six)). It has also been shown that IL-? ß inhibits long-term potentiation in the hippocampus (Murray, C. A. et al. (1998)). Long-term potentiation in Iripocampo is a form of synaptic plasticity and is generally considered to be an appropriate model for memory and learning (Bliss, T.V.P. et al. (1993)). Then, it is currently believed that an inappropriate expression of cytokines in the brain is compromised in the development and progress of neurodegenerative diseases and neuroinflammatory disorders. Accordingly, the invention is indicated for the treatment and prophylaxis of a wide variety of neuroinflammatory, neurodegenerative and other neurological disorders in mammals, including Down syndrome, Alzheimer's disease, Parkinson's disease, senile dementia, depression, Huntingdon's disease. , peripheral neuropathies, Guillain Barr syndrome, spinal cord diseases, neuropathic diseases of the joints, chronic inflammatory demyelinating disease, neuropathies including mononeuropathy, polyneuropathy, distal symmetrical sensory neuropathy, neuromuscular junction disorders, myasthenia and amyotrophic lateral sclerosis (ALS) ). The treatment and prophylaxis of these neurodegenerative diseases represent a particularly preferred embodiment of the invention, the treatment of Alzheimer's disease, Parkinson's disease and ALS being especially preferred.

With respect to disorders comprising an endbial drosphism, the present invention is indicated for the treatment and prophylaxis of a wide variety of such disorders in mammals including, for example, cardiovascular diseases, such as atherosclerosis, peripheral arterial or arterial occlusive disease. , -congestive heart failure, cerebrovascular disease (stroke), myocardial infarction, angina, hypertension, etc., vasospastic disorders such as Raynaud's disease, cardiac syndrome X, migraine, etc., and lesions that occur as a result of a ischemia (ischemic or reperfusion-ischemic injury). In summary, it can be practically any disorder whose pathology includes the inappropriate functioning of the endothelium. Other indications for the compositions and processes of the present invention include the treatment of patients to accelerate the healing rate of wounds and ulcers and the treatment of patients before a surgical intervention, in order to accelerate the speed of recovery from surgery. , including the speed of healing of injuries and surgical incisions. With respect to "cardiac disorders", the present invention is indicated for the treatment and prophylaxis of a wide variety of such disorders in mammals including any and all-disorders-eiae-iesades-with the heart and include, for example, ventricular arrhythmias (tachycardia or ventricular fibrillation) and sudden death from heart disease. The susceptibility of patients to cardiac disorders, such as arrhythmias and sudden cardiac death is often indicated by prolonged QT-c intervals in the rhythm of the heartbeat. It is considered that the administration of the compositions according to the preferred embodiments of the invention reduces the QT-c intervals in mammalian patients, which would be indicative of a reduced susceptibility to arrhythmias and sudden cardiac death. The invention will now be described, for illustrative purposes, in the following non-limiting examples. EXAMPLES In the examples that will be described later, the following abbreviations have the meaning detailed below. If an abbreviation is not defined, it has the accepted meaning in general. μ = mieroliter μ? = micromolar CHS = contact hypersensitivity DNFB = 2, 4-dinitrofluorobenzene DHS = late type hypersensitivity EtOH = ethanol g = gram Hs = hours IM = intramuscular g = kilogram LPS = lipopolysaccharide mg = milligram mi = milliliter mM = millimolar ms = millisecond ng = nanogram nra = Nanometer nM = Nanomolar PBS = phosphate buffer salt solution, i.na pg = Picogram Example 1 Liposomes with an average diameter of 100 ± 20 nm were prepared according to the standard methods known in the art and the composition thereof was: 100% POPS (l-palmitoyl-2-oleoyl-sn-glycero-3- [phosphate-serine], called phosphatidylserine or PS in the examples and unless otherwise indicated) 100% POPA (l-palmitoyl-2-oleoyl) .l-sn-glycero-3-phosphate, called phosphatidic acid or PA in the examples and unless otherwise indicated) control, without liposomes.

A stock suspension of each liposome composition, containing 4.8 x 10 14 liposomes per ml, was diluted with PBS to obtain an injectable suspension containing 6 x 106 liposomes per ml. Liposomal suspensions were injected into female BALB / c mice (Jackson Laboratories) of 6-8 weeks and weighing 19-23 g, in order to determine the effect on ear swelling in the CHS model in murders. The tests for the CHS model were used for inflammatory reactions mediated by Thl. The animals were assigned to 3 groups, with 5 animals in each. Groups A and B received approximately 3 x 105 of the previously identified liposomes (ie, 100% PS and 100% PA, respectively), in a volume of 50 μ? approximately. Group C was a control group, which did not receive a liposome. Protocol The following experiments were carried out: TABLE 1 On days 1-6, the mice of groups A and B received injections of the respective liposome preparations. The liposomes were injected in a volume of 50 μ? by intramuscular injection (IM), that is to say approximately 300,000 liposomes per injection, with a total administration during the entire test period of approximately 1,800,000 liposomes. The mice in the control group (group C) were not given liposomes, but they were sensitized, stimulated and evaluated in the same way as groups A and B, as will be described below.

Sensitization If day T ~, after the injection of liposomes corresponding to that day, the mice were anesthetized with 0.2 ml of 5 mg / ml pentobarbital sodium by intraperitoneal injection (IP). The skin of the abdomen of the mice was sprayed with 70% EtOH. Then a scalpel blade was used to remove approximately a one-inch diameter patch of hair from the abdomen. The shaved area was then painted with 25 μ? of 2,4-dinitrofluorobenzene (DNFB) 0.5% in a 4: 1 mixture of acetone: olive oil using a pipette tip. Stimulus On day 6 after injection of liposomes, the mice were stimulated with DNFB as follows: 10 μ? of DNFB 0.2% on the dorsal surface of the right ear with a pipette tip and scattering 10 μ? of vehicle on the left ear also with a pipette tip. Results On day 7, 24 hours after the stimulus, each animal was anesthetized with halothane and the thickness of the ear was measured (in μp?) Using a Peacock spring-powered micrometer. The increase in ear swelling was used as a measure of the CHS response. The data obtained were expressed as the difference between the thickness of the right ear treated minus the thickness of the left ear treated with an ehicle. different animals but with similar characteristics. The degree of significance of the data was determined with the two-tailed Student t test. A value P < 0.05. The results are shown graphically in FIG. 1, which is a bar graph of ear swelling expressed in μt ?. The average value of the respective experiments was used to generate the graph. In FIG. 1 it is shown that a significant reduction (xl (T2 mm) in the ear swelling was achieved with the injection of the liposomes according to the present invention The reduction achieved with the liposomes with 100% PA is substantially equivalent to that obtained with the liposomes with 100% PS, previously described as anti-inflammatory. Example 2 Liposomes consisting essentially of 75% L- -phosphatidylinositol (called phosphatidylinositol or PI in the examples unless otherwise indicated) and 25% l-palmito were prepared and evaluated as l-2-oleoyl-sn- glycero-3-phosphocholine or POPC (referred to as phosphatidylcholine or PC in the examples unless otherwise indicated) in the CHS model in mice previously described. Two groups of ten mice were sensitized on day 1. A group of retrievers.; injections on days T ~, 2 ~ ¡3 ~; W,? and ~ 6 ~ cutv liposomes of 75% PI: 25% PC, at a rate of 600,000 vesicles in 50 μ? of suspension for each injection. On day 6 after the injection of liposomes, the mice were stimulated with DNFB spread over the left ear as described in Example 1. The second control group received 50 μ? of PBS according to the same program and stimulated similarly. Ear thickness measurements were made on day 7. The results, in the form of a bar graph, are shown in FIG. 2. The data represented the changes in the average thickness of the ear (xlO-2 mm) +/- the standard error of the mean (EEM). Significant CHS suppression was observed in the mice that had received PI injections, as compared to the PBS control group (p < 0.01). Example 3 Liposomes of the formulation PI 75% and PC 25% and with an average diameter of 100 + 20 nm were compared according to standard methods. Five groups (A-E) of 10 mice were sensitized, injected and stimulated according to the procedure and program described in Example 1. The following amounts of liposomes were administered in a suspension of 50 μ? : Group A 6 x 10 Group B 6 x 10 Group C 6 x 107 Group D 6 x 10s Group E 6 x 105 Group F 6 x 104 The results, along with a PBS control group, are shown as Net Ear Swelling (x 10"2 mra) +/- EEM in the form of a bar graph in FIG 3. A significant reduction was observed depending on the dose in the ear swelling, compared to the control group, with Group C (6 x 107), where p = 0.05, with Group D (6 x 106), where p = 0.01 and more Significantly with Group E, where p <0.001, no significant differences were observed between the other groups and control (Degree of statistical significance calculated with the paired Student's t-test.) Example 4 A stock suspension of liposomes was diluted of 75% of PI with a size of 100 + 20 nm containing 4.8 x 1014 liposomes per ml to obtain an injectable suspension containing 6 x 106 liposomes per ml. Liposomal suspensions were used as injections for mice, in order to determine the effect on ear swelling in the DHS model of murine. As in Example 1, there were n-ra-towers-female-BALB / c-fJaefeson-Lateeratories -) - of-6-8 weeks and with a weight of 19-23 g. The animals were assigned to 2 groups, of 10 animals in each. One group received the injection of liposomes. The other was the control group that received PBS injections. Each test animal received injections of 50 μ? of suspension containing 6 x 105 liposomes. Protocol The mice were sensitized on day 1, stimulated on day 6, stimulated for the second time on day 12 and received injections on days 13, 14, 15, 16, 17 and 18 of the 75% PI liposomes as will be indicated below. . On day 18, after injection of liposomes, mice were stimulated. The liposomes were injected in 50 μ? of volume via injection I, that is 600,000 liposomes per injection, for a total administration over the entire test period of 3,600,000 liposomes. Sensitization and stimulation were carried out as described in Example 1. Ear thickness was measured on day 19. Results The results are shown in the form of a bar graph in FIG. 4 attached. The results are expressed as net ear swelling (x 1CT2 mm). They show that the 75¾T of liposomes are effective in the DHS model on day 19, 24 hours after the third injection that was applied after the third stimulus. Example 5 The U937 line is a monocytic leukemia cell line that can be differentiated into macrophages with the administration of phorbol esters. Treatment with LPS, a component of the cell wall of Gram-negative bacteria, stimulates an inflammatory response in U937 cells, with subsequent sensitization of the expression of numerous inflammatory molecules, including TNFoc. This model provides an experimental system to evaluate anti-inflammatory therapies. The macrophages can be cultured in a culture medium in the presence of a composition suspected of being anti-inflammatory and then the expression of TNFa can be measured. 1iposomes with a size of 100 ± 20 nm were prepared according to the standard methods known in the art and had a composition of 75% phosphatidylinositol (PI), 25% phosphatidylcholine (PC). The concentration of the liposome stock composition was approximately 39.5 mM of lipids and was diluted to obtain the final final concentrations in the assay: phosphatidylinositol (PI) 100 μ? PI 39.8 μ? PI 10 μ? - PI 3.98 μ? PI 1 μ? U937 cells were grown by growth in RP I medium (GIBCO BRL) supplemented with fetal bovine serum (FCS) 10% and penicillin / streptomycin 1% and then cultured at 37 ° C in an atmosphere containing C02 5%. Concentrations of 5 x 10 5 cells were seeded into the cavities of 6-well plates at a rate of 2 ml per well and then differentiated into macrophages by treatment with 150 nM phorbol myristate myristate (PMA) for 2-3 days. The cell medium was then replaced by complete medium once the U937 cells had differentiated into macrophages. The cells were cultured for another 24 h before the addition of the liposomes in order to reduce the PMA-induced gene / protein sensitization. The cells were then incubated with: Saline phosphate buffer (PBS), as a negative control LPS 10 ng / ml, as a positive control LPS 10 ng / ml + PI 100 μ? LPS 10 ng / ml + PI 39.8 μ? LPS 10 ng / ml + PI 10 μ? LPS 10 ng / ml + PI 3.98 μ? LPS 10 ng / ml + PI 1 μ? The cells were incubated as previously described at 37 ° C in 5% C02. After 18 h, the supernatants of each treatment were collected and evaluated for their TNF-a content using the Quantikine standard enzyme-linked immunosorbent assay (ELISA) test set (R & amp; amp;; D systems, Minneapolis, USA). In FIG. 5 shows the amount of TNF-α secreted in picograms per ml. The results demonstrate that U937 cells differentiated into macrophages express very low levels of TNF-α under normal conditions. However, once they were exposed to LPS, they secreted large amounts of TNF-a into the surrounding medium, which is indicative of cellular stress. Incubation of the cells with PI liposomes decreases the secretion of TNF-a in a dose-dependent manner induced by LPS. Example 6 The metabolism of sphingolipids has been shown to be a dynamic process and the metabolites of sphingolipids, including ceramides, sphingosine and sphingosine-1-phosphate, are currently recognized as messengers that fulfill essential functions in the growth, survival and death of cells (Olesnick, J. Clin Invest. 110: 3-8 (2002)). Liposomes consisting essentially of 75% sphingomyelin and 25% are prepared according to standard methods (see, attracted, et al., Cellular and Molecular Biology Letters 5: 483-493 (2000)) and evaluated with the model. CHS of murines. The methodology used was that described in Example 1 and the size corresponded to the liposomes used in the previous examples, ie 100 ± 20 nm.

Claims (15)

51 NOVELTY OF THE INVENTION Having described the ± nv¾rrc ± ón-como-anfceeede-property is claimed as contained in the following CLAIMS;

1. A composition of matter, characterized in that it comprises inclusion bodies that have a plurality of reactive chemical groups that have the ability to interact with the receptors present on the cells of the mammalian immune system to alter the cytokine profile of the immune system in favor of a antiinflammation, wherein said inclusion bodies have a size of about 20-1000 nm, with the proviso that when said groups are all of the same type, said groups are not serine phosphate or glycerol phosphate.

2. The composition of clause 1, characterized in that the inclusion bodies comprise reactive chemical groups selected from the group consisting of phosphate-inositol, phosphate-ethanolamine, phosphatidic acid, lysophosphatidic acid, lysophosphidyl tidylinositol, lysophosphate-ethanolamine, sphingosine-1-phosphate , ceramides, sphingomyelin or combinations thereof.

3. The composition according to clause 2, characterized in that said reactive chemical groups are groups of 52 phosphate-inositol

4. The composition according to clause 2, characterized in that said inclusion bodies are liposomes.

5. The composition according to clause 4, characterized in that said composition is essentially free of non-lipid entities acceptable for pharmaceutical use.

6. The composition according to clause 5, characterized in that said composition is free of non-lipid entities acceptable for pharmaceutical use.

7. The composition according to clause 5 or 6, characterized in that the liposomes comprise phospholipids or glycophospholipids selected from the group consisting of phosphatidylinositol, phosphat idylcholine, phosphatid letanolamine, phosphatidic acid, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, lysophosphatidic acid, lysophosphatidylinositol, lysophosphatidylcholine, lysophosphatidyl anolamine, sphingosylphosphoryl, sphingosine-1-phosphate, ceramides, sphingomyelin or combinations thereof.

8. The composition according to clause 7, characterized in that the liposomes comprise phosphatidylinositol.

9. The composition according to clause 8, characterized in that the liposomes undertake between 60 and 100% of fcsphatidylinositol.

10. Composition according to clause 9, characterized 53 because the liposomes comprise between 60-90% of phosphatidylinositol.

11. The composition according to clause 9 or clause 10, characterized in that the rest of the liposome is phosphatidylcholine.

12. The composition according to clause 11, characterized in that the liposomes have a size ranging from about 80 nm to about 120 nm.

13. The composition according to any of clauses 4 to 12, characterized in that said composition comprises between approximately 10,000 and 2,500,000,000 of said liposomes per administration unit.

14. A method for treating disorders mediated by the functioning of T cells, inflammatory disorders, disorders of endothelial function, an autoimmune disorder characterized by an inadequate expression of cytokines, a cardiac disorder or a neuroinflammatory neurological disorder, characterized in that it comprises the administering to a patient an effective amount of a pharmaceutical composition according to any of clauses 1-13.

15. The method according to clause 14, characterized in that the amount administered of said inclusion bodies comprises less than 30 mg per kg of body weight. of the patient. TS ~. The sturdy suorÜB with ta: riráusrla í4 é 15, characterized in that the quantity administered of said bodies of comprises between approximately 500 and approximately 2.5 x 109 inclusion bodies. 17. The method according to clause 14, clause 15 or clause 16, characterized in that inclusion bodies are essentially free of non-lipid entities acceptable for pharmaceutical use. 18. The method of clause 17, characterized in that the inclusion bodies are free of non-lipid entities acceptable for pharmaceutical use. 19. The use in the manufacture of a medicament of an effective amount of a pharmaceutical composition according to any of clauses 1-13, characterized in that it is for administration to a mammal in the treatment of a disorder mediated by the functioning of T cells. , an inflammatory disorder, a disorder of endothelial function, an autoimmune disorder characterized by an inadequate expression of cytokines, a cardiac disorder or a neuroinflammatory neurological disorder. 20. Use in the treatment of a disorder mediated by T-cell functioning, an inflammatory disorder, a disorder of endothelial function, an autoimmune disorder characterized by an inadequate expression of cytokines, a cardiac disorder or a neuro-inflammatory neuropathic disorder ", which is considered to be the administration to a mammal of an effective amount of a pharmaceutical composition according to any of clauses 1-13.