Compositions Comprising Chemokine Receptor Pathway Inhibitors - Patent application

Abstract

A composition comprising: i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof (particularly, repagermanium or propagermanium); ii. a diluent having a concentration of 30% w / w to 70% w / w; iii. a binder having a concentration of 2% w / w to 5% w / w; iv. a disintegrant having a concentration of 2% w / w to 8% w / w; and v. a lubricant having a concentration of 0.05% w / w to 5% w / w; and a method of treatment using said composition. Preferably, said composition comprises 2.5% w / w to 65% w / w of said CCR2 pathway inhibitor.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to compositions comprising and methods of using chemokine receptor pathway inhibitors. [Background technology]

[0002] (Background technology) Chemokine receptor 2 (CCR2) pathway inhibitor-based treatments for diseases such as renal and respiratory diseases are known.

[0003] Repagermanium or propagermanium can be used as a CCR2 pathway inhibitor. However, propagermanium was approved in Japan in the 1990s to treat hepatitis B, but it has not been approved elsewhere and is classified as a New Chemical Entity (NCE). Repagermanium and propagermanium have been previously described in the literature as polymeric compounds. Its drug substance 3-[(2-carboxyethyl-oxogermyl)oxy-oxogermyl]propanoic acid exhibits polymorphism and can exist in various solid forms. However, the inventors have not observed any pharmacological effect of polymerization of Repagermanium during the manufacture or testing of this drug substance.

[0004] Polymorphs of 3-[(2-carboxyethyl-oxogermyl)oxy-oxogermyl]propanoic acid include repagermanium, propagermanium, proxigermanium, Ge-132, germanium sesquioxide, 2-carboxyethylgerma sesquioxane, SK-818, bis(2-carboxyethylgermanium) sesquioxide.

[0005] The two most highly characterized solid forms, propagermanium and repagermanium, share a common core structure (Mizuno et al., 2015). These two drug substances have distinct International Nonproprietary Names (INNs), the INN for propagermanium being INN#6260 and the INN for repagermanium being INN#6259. They are composed of distinct packings of the monomer molecule 3-[(2-carboxyethyl-oxogermyl)oxy-oxogermyl]propanoic acid, with varying structural units coordinated by H-bonds. X-ray diffraction reveals that propagermanium has a polymeric ladder-like structure of interlocking eight-membered rings composed of Ge-O bonds, which is clearly distinct from the infinite sheet structure in repagermanium. In solid form, propagermanium and repagermanium are distinct; however, in solution, as their structural units are dissolved, they are identical. Summary of the Invention [Means for solving the problem]

[0006] The present inventors have surprisingly discovered a novel composition for the delivery of CCR2 blockers, which overcomes some or all of the shortcomings of the prior art, or at least provides a commercial alternative. The above discussion is intended only to facilitate understanding of the present invention. The above discussion should not be construed in any way as limiting the scope or applicability of the following description of the invention, nor should the above discussion be construed as an admission that any of the information discussed was within the common general knowledge of one of ordinary skill in the art as of the priority date.

[0007] (Summary of the invention) The present invention relates to i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w The present invention provides a composition comprising:

[0008] Preferably, the composition comprises 2.5% w / w to 65% w / w of the CCR2 pathway inhibitor. Preferably, the CCR2 pathway inhibitor is a direct antagonist of CCR2. More preferably, the CCR2 pathway inhibitor is repagermanium or propagermanium or a pharmaceutically acceptable salt thereof.

[0009] Preferably, the diluent is silicified microcrystalline cellulose (SMCC). Preferably, the composition comprises 30% w / w to 70% w / w SMCC.

[0010] Preferably, the binder is hypromellose (HPMC). Preferably, the composition comprises 2% w / w to 5% w / w of HPMC.

[0011] Preferably, the disintegrant is sodium starch glycolate. Preferably, the composition comprises 2% w / w to 8% w / w sodium starch glycolate.

[0012] Preferably, the lubricant is magnesium stearate. Preferably, the composition contains 0.05% w / w to 5% w / w of magnesium stearate.

[0013] The present invention further provides a method for the treatment, amelioration or prevention of a condition or disease, the method comprising the step of administering to a subject a therapeutically effective amount of a) a composition comprising: i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w Includes.

[0014] Preferably, the method involves administering between 10 mg / day and 500 mg / day of the CCR2 pathway inhibitor provided in a single dose or multiple doses.

[0015] Preferably, the condition or disease to be treated, alleviated or prevented is selected from a renal disease, a cardiovascular disease, an eye disease, an oncological disease, or a pulmonary disease.

[0016] In the manufacture of a medicament for the treatment, amelioration or prevention of a condition or disease, i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w Use of.

[0017] 2. Use of a composition for the treatment, amelioration or prevention of a condition or disease, the composition comprising: i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w. Including, use.

[0018] 1. A kit for the treatment, amelioration or prevention of a condition or disease, comprising: a) i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w A composition comprising: b) Instructions for use and Including the kit. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Description of the Invention Detailed Description of the Invention Pharmaceutical Composition The present invention provides compositions for the delivery of a chemokine receptor 2 (CCR2) pathway inhibitor; preferably, the CCR2 pathway inhibitor is repagermanium or propagermanium.

[0020] Many problems can occur when powders containing active agents flow through equipment such as bins, chutes, and hoppers of tablet presses. If the powder is cohesive, "arches" or "ratholes" can form, resulting in irregular flow or flow cessation. Furthermore, if the arches or ratholes spontaneously collapse, spills or uncontrolled discharge can occur.

[0021] For blends of small particle size active agents with other excipients, interparticle adhesion can significantly reduce the flowability of the powder by increasing interparticle friction. Poor flow can cause insufficient mixing of the blend (content non-uniformity) and ratholing or arching in the hopper of the tablet press (segregation problems), affecting both product quality and operation.

[0022] No flow: No flow from bins / hoppers is a common and significant solids handling problem, especially when dealing with fine / milled active agents and high activity loading mixtures. In production, it can cause problems such as starving downstream equipment, production delays, and the need for frequent operator intervention to restart flow. No flow can be due to either arching (sometimes called "bridging" or "plugging") or rathole formation (also called "piping").

[0023] Arching: Can occur in bins where powder exits through a central outlet, but once the powder just above the central outlet moves through that outlet, an additional dome or arch of powder remains over the gap left by the powder that has already flowed out. Arching is affected by the bin / hopper shape and the size of the outlet. This problem occurs when the material has sufficient cohesive strength. Generally, powder discharge stops once the flow channel just above the central outlet is empty. However, an unsupported arch or dome of powder over the gap can collapse, resulting in intermittent flow and possibly heavy spills or uncontrolled discharge.

[0024] Rathole formation: can occur in bins when the powder exits through the central outlet, but the powder at the bin walls remains stagnant, leaving an empty hole (rathole) through the powder starting from the central outlet. Rathole formation is influenced by the shape of the bin / hopper and the size of the outlet through which the powder is fed. Similar to the arching problem, this problem occurs when the powder has sufficient cohesive strength. Generally, powder discharge stops once the flow channel around the central outlet is empty. However, there can be further slippage of stagnant powder near the walls, resulting in intermittent flow and possibly bulk spills or uncontrolled discharge.

[0025] Examples of CCR2 pathway inhibitors (e.g., repagermanium and propagermanium) tend to aggregate, resulting in the formation of rat holes and / or arches. Without being bound by any theory, this appears to be due to static accumulation during the manufacture of therapeutic compositions that contain CCR2 pathway inhibitors.

[0026] To avoid ratholes and arches during the manufacture of a CCR2 pathway inhibitor (e.g., repagermanium or propagermanium) dosage form, a diluent that prevents the CCR2 pathway inhibitor from forming ratholes and arches is required in the dosage form.

[0027] (Diluent) Diluents act as inert fillers in pharmaceutical dosage forms to increase mass, improve content uniformity, and allow accurate dosing of active agents. Diluents may also provide better encapsulation and tableting properties (e.g., improved cohesion or promotion of ingredient flow).

[0028] Natural diluents include starch; hydrolyzed starch; partially pregelatinized starch; simple carbohydrates such as mannitol, lactose, dextrin, glucose, sucrose, sorbitol; polysaccharides such as cellulose, chitin. Certain inorganic salts are also optionally used as diluents, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are Fast-Flo® and STA-Rx 1500®.

[0029] The present invention has discovered that problems associated with poor component flow during the manufacture of dosage forms containing CCR2 pathway inhibitors can be overcome by the addition of an appropriate diluent.

[0030] Preferably, the diluent is present in the composition at a concentration of 30% w / w to 70% w / w, 35% w / w to 65% w / w, 40% w / w to 60% w / w, 45% w / w to 60% w / w or 50% w / w to 60% w / w. For example, the composition may contain 55% w / w of diluent.

[0031] The diluent may be selected from the list including microcrystalline cellulose (MCC), colloidal silicon dioxide (CSD) or silicified microcrystalline cellulose (SMCC).

[0032] MCC is a polymer composed of glucose units linked by 1-4 β-glycosidic bonds. Microcrystalline cellulose is a commonly used excipient in the pharmaceutical industry. It has excellent compression properties and is used in solid dosage forms (e.g., tablets and capsules). Both hard but rapidly dissolving tablets and capsules can be formed.

[0033] CSD is also known as silicon dioxide and has the chemical formula SiO2. It has many uses in capsule and tablet manufacturing: as a diluent, anti-caking agent, adsorbent, disintegrant, or flow agent that allows powders to flow freely when capsules and tablets are processed. CSD appears to be biologically inert.

[0034] SMCC is a synergistic physical intimate blend of microcrystalline cellulose (MCC) and colloidal silicon dioxide (CSD), and the silicon dioxide is located on the surface of the microcrystalline cellulose. An example of a suitable SMCC is PROSOLV® SMCC90LM. It has improved compression properties compared to conventional microcrystalline cellulose in both wet granulation and direct compression. Silicified microcrystalline cellulose appears to have beneficial properties for use in powder-filled capsule formulation. The properties of SMCC are advantageous when used in combination with CCR2 pathway inhibitors (e.g., repagermanium or propagermanium).

[0035] Preferably, the SMCC is present in the composition at a concentration of 30% w / w to 70% w / w, 35% w / w to 65% w / w, 40% w / w to 60% w / w, 45% w / w to 60% w / w or 50% w / w to 60% w / w. For example, the composition may contain 55% w / w of diluent.

[0036] Thus, the composition of the present invention comprises: i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent which is SMCC in a concentration of 30% w / w to 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w may include.

[0037] Preferably, the diluent (eg, SMCC) has an average particle size of 10 μm to 500 μm, more preferably 20 μm to 300 μm, as determined by laser diffraction. For example, the diluent may have an average particle size of 90 μm.

[0038] Preferably, the diluent (e.g., SMCC) has a low water content. Preferably, the water content is less than 20%, less than 15%, or more preferably less than 10%. In one example, the water content may be less than 6%, less than 5%, less than 4%, less than 3%, or less than 2%.

[0039] therefore, i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w A composition is provided comprising:

[0040] The present invention relates to i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof, which is a direct antagonist of CCR2; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w The present invention provides a composition comprising:

[0041] In a preferred embodiment, the chemokine receptor pathway inhibitor is (i) an antagonist of a chemokine receptor or a non-chemokine receptor component of a chemokine receptor pathway; (ii) an inverse agonist of a chemokine receptor or a non-chemokine receptor component of a chemokine receptor pathway; (iii) a negative allosteric modulator of a chemokine receptor or a non-chemokine receptor component of a chemokine receptor pathway. is selected from the group consisting of:

[0042] Thus, the present invention provides i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof, which inhibits a component of the CCR2 pathway other than the chemokine receptor; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w The present invention provides a composition comprising:

[0043] More specific examples of chemokine receptor pathway inhibitors that target components of the chemokine receptor pathway other than the chemokine receptor would be agents that block pathways associated with MCP-1-induced migration, monocyte activation and chemotactic migration. Such agents that can be targeted include the function of cellular structures involved in chemotaxis (e.g., microfilaments, microtubules, and intermediate filaments), as well as surface proteins (e.g., glycosylphosphatidylinositol (GPI)-anchored proteins, more particularly CD55, CD59, and CD16).

[0044] In a preferred embodiment, the chemokine receptor pathway inhibitor is a chemokine receptor antagonist.Known chemokine receptor antagonists include RS504393, RS102895 (Sigma-Aldrich); MLN-1202 (Millennium Pharmaceuticals); INCB3344, INCB3284 and INCB8696 (Incyte Pharmaceuticals); MK-0812 (Merck); CCX140, CCX872-B [CCX-872] (ChemoCentryx), PF-4136309, PF-04178903, PF-04634817 (Pfizer); BMS-741672 (Bristol-Myers Squibb); Cenicriviroc (Allergan). In a preferred embodiment, the chemokine receptor pathway inhibitor is selected from the group including RS504393, RS102895, MLN-1202, INCB8696, MK-0812, CCX140, PF-4136309, BMS-741672.

[0045] In a preferred embodiment, the CCR2 pathway inhibitor is an antagonist of chemokine receptor 2, such as propagermanium, repagermanium, or CCX 140. Propagermanium, repagermanium, and CCX 140 tend to aggregate, resulting in the production of rat holes and / or arches.

[0046] Preferably, the chemokine receptor pathway inhibitor is propagermanium or repagermanium. The INN of propagermanium is INN#6260, and the INN of repagermanium is INN#6259. Propagermanium has been used as an active agent against chronic hepatitis and has been shown to specifically inhibit the in vitro chemotactic migration of monocytes by MCP-1 through a mechanism that appears to involve glycosylphosphatidylinositol (GPI)-anchored proteins (e.g., CD55, CD59 and CD16) (Yokochi, S. (2001) Journal of Interferon and Cytokine Research, 21:389-398). Further names for propagermanium and / or repagermanium include 3-[(2-carboxyethyl-oxogermyl)oxy-oxogermyl]propanoic acid, proxigermanium, Ge-132, bis(2-carboxyethylgermanium)sesquioxide (CEGS), 2-carboxyethylgermasesquioxane, SK-818, organogermanium, germanium sesquioxide, 3,3'-(1,3-dioxo-1,3-digermanoxanediyl)bispropionic acid, 3-oxygermyl propionic acid polymer, and poly-trans-(2-carboxyethyl)germasesquioxane.

[0047] therefore, i. Repagermanium or Propagermanium or a pharmaceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w A composition is provided comprising:

[0048] In a preferred embodiment, the chemokine receptor pathway inhibitor inhibits in vitro chemotactic migration of monocytes induced by MCP-1. In another preferred embodiment, the chemokine receptor pathway inhibitor inhibits in vitro chemotactic migration of monocytes induced by MCP-1 through a mechanism that requires glycosylphosphatidylinositol (GPI)-anchored proteins (e.g., CD55, CD59, and CD16). In another preferred embodiment, the chemokine receptor pathway inhibitor stabilizes the complexes CCR2 / CD55 and / or CCR2 / CD59 and / or CCR2 / CD16. The chemokine receptor pathway inhibitor can be a peptide, a polypeptide, or a small molecule chemical. For example, the chemokine receptor pathway inhibitor can be a protein, a binding protein, or an antibody.

[0049] The chemokine receptor pathway inhibitor may inhibit MCP-1-induced migration and activation and chemotactic migration of monocytes through targeting one or more glycosylphosphatidylinositol (GPI)-anchored proteins selected from the group including CD55, CD59 and CD16. The chemokine receptor pathway inhibitor may modify the complexes CCR2 / CD55 and / or CCR2 / CD59 and / or CCR2 / CD16.

[0050] Although propagermanium is a chemokine receptor pathway inhibitor, it does not inhibit MCP-1 binding, appears to target glycosylphosphatidylinositol (GPI)-anchored proteins (e.g., CD55, CD59, and CD16), and inhibits MCP-1-induced in vitro chemotactic migration of monocytes (Yokochi (2001); Yamada (2004) The Journal of Immunology, 172:3869-3875).

[0051] The compositions of the present invention may contain a range of excipients, both those listed below and others.

[0052] (Binding Agent) Binders, compression aids and granulating agents bind the tablet ingredients together to give them form and mechanical strength.

[0053] Materials used as binders include those derived from natural products (e.g., gum arabic, tragacanth, starch and gelatin). Other binders include methylcellulose (MC), ethylcellulose (EC) and carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP; povidone) and hydroxypropylmethylcellulose (HPMC; hypromellose). Some commercially available binders are Emdex®, Avicell® and Emcompress®.

[0054] Suitable binders for use in the compositions of the present invention include hypromellose (HPMC) and povidone (PVP). Hypromellose is a partially O-methylated O-(2-hydroxypropylated) cellulose.

[0055] Preferably, the concentration of the binder in the composition of the present invention is 2% w / w to 5% w / w, 2.5% w / w to 5% w / w, 3% w / w to 5% w / w, 3.5% w / w to 5% w / w. For example, the concentration of the binder may be 4% w / w. An example of a suitable binder may be 4% w / w hypromellose (HPMC).

[0056] (Disintegrant) Disintegrants aid in dispersion of the tablet in the gastrointestinal tract, release the active agent, and increase the surface area for dissolution.

[0057] Materials used as disintegrants include, but are not limited to, starch (including Explotab®, a commercial disintegrant based on starch). Sodium starch glycolate, Amberlite™, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite are also contemplated. Another form of disintegrant is the insoluble cation exchange resin. Powdered gums are also optionally used as disintegrants and binders, including powdered gums such as agar, karaya or tragacanth. Alginic acid and its sodium salt and crospovidone are also useful as disintegrants.

[0058] Suitable disintegrants for use in the composition of the present invention include sodium starch glycolate and crospovidone.Sodium starch glycolate is the sodium salt of carboxymethyl ether of starch or the sodium salt of cross-linked carboxymethyl ether of starch.Disintegration occurs by the rapid uptake of water, followed by rapid and extensive swelling.The effectiveness of many disintegrants is affected by the presence of hydrophobic excipients (e.g., lubricants), but the disintegrant efficiency of sodium starch glycolate is not impaired.

[0059] Preferably, the concentration of the disintegrant in the composition of the present invention is 2% w / w to 8% w / w, 2% w / w to 7% w / w, 3% w / w to 6% w / w, or 4% w / w to 6% w / w. For example, the concentration of the disintegrant can be 5% w / w. An example of a suitable disintegrant can be sodium starch glycolate at 5% w / w.

[0060] (lubricant / flow agent) In terms of powder flow, lubricants can improve the flow of mixtures by reducing interparticle friction, aiding unit operations. Lubricants can slow down disintegration and dissolution. Glidants improve powder flow during tablet manufacture by reducing interparticle friction and adhesion, and aid rearrangement during compression. They can also be used as anti-caking agents. The properties of glidants and lubricants are somewhat different, but some compounds, such as starch and talc, can be used for both purposes.

[0061] Stearic acid and its salts, such as magnesium stearate and calcium stearate, are the most frequently used lubricants in the pharmaceutical industry. However, other lubricants, such as polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes, can be used. Exemplary soluble lubricants, such as talc, starch, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, polyethylene glycols of various molecular weights, and Carbowax® 4000 and Carbowax® 6000, can also be used. Flow agents can include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0062] Suitable lubricants for use in the compositions of the present invention include magnesium stearate and sodium stearyl fumarate. Magnesium stearate produces a less dense or dense (fluffy) final product, which is easier to fill into capsules. In one example, the lubricant is not sodium stearyl fumarate. Magnesium stearate is a non-uniform ratio of magnesium stearate (C 36 H 70 MgO4) and magnesium palmitate (C 32 H 62 It is a compound of magnesium containing a mixture of solid organic acids, primarily consisting of magnesium oxide (MgO4).

[0063] Preferably, the concentration of the lubricant in the composition of the present invention is 0.05% w / w to 5% w / w, 0.5% w / w to 5% w / w, 1% w / w to 5% w / w, 2% w / w to 5% w / w, 3% w / w to 5% w / w, or 4% w / w to 5% w / w. For example, the concentration of the lubricant may be 5% w / w. An example of a suitable lubricant may be magnesium stearate at 5% w / w. Table 1: Excipients in exemplary compositions of the present invention [Table 1]

[0064] The CCR2 pathway inhibitor can be a pharmaceutically acceptable salt of the active agent. Pharmaceutically and veterinarily acceptable salts include salts that retain the biological effectiveness and properties of the disclosed compounds, which are not biologically or otherwise undesirable. In many cases, the compounds disclosed herein can form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto. Acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt and magnesium salt. Salts derived from organic bases include primary, secondary, and tertiary amines such as, by way of example only, alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkyl amines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkyl amines, disubstituted cycloalkyl amines, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines These include, but are not limited to, salts of amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocyclic amines, bicyclic heterocyclic amines, tricyclic heterocyclic amines, mixed diamines and triamines in which at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, etc. Also included are amines in which the two or three substituents together with the amino nitrogen form a heterocyclic or heteroaryl group.

[0065] Pharmaceutically and veterinarily acceptable acid addition salts can be prepared from inorganic and organic acids. Inorganic acids which may be used include, by way of example only, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids which may be used include, by way of example only, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0066] The pharmaceutical or veterinary acceptable salts of the compounds useful in the present disclosure can be synthesized from parent compounds (which contain basic or acidic moieties) by conventional chemical methods.In general, such salts can be prepared by reacting the free acid or free base forms of these compounds with stoichiometric amounts of appropriate base or acid in water or organic solvent or in the mixture of the two; generally, non-aqueous media (such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred.A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa. (1985), page 1418 (the disclosure of which is hereby incorporated by reference).Examples of such acceptable salts are iodide, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, gamma-hydroxybutyrate, beta-hydroxybutyrate, butyne-l,4-dioate, hexyne-l,4-dioate, hexyne-1,6-dioate, caproate, caprylate, chloride, cinnamate, citrate, decanoate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate. , mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, hydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, hydrogen sulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, propanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartrate, and the like. Table 2: Exemplary compositions of the present invention [Table 2]

[0067] (Method of treatment) The present invention further provides a method for the treatment, amelioration or prevention of a condition or disease, the method comprising the step of administering to a subject a therapeutically effective amount of a) a composition comprising: i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w Includes.

[0068] The subject to be treated is preferably a mammal, including a human mammal.

[0069] The CCR2 pathway inhibitor may be administered alone as a single treatment.

[0070] The CCR2 pathway inhibitor can be a pharma- ceutically acceptable salt of the CCR2 pathway inhibitor.

[0071] (Condition or Disease) In general, a range of conditions that are chemokine-associated may be treated by the methods of the present invention, including conditions associated with increased or decreased chemokine production and / or increased or decreased cellular responsiveness to chemokines. Chemokine-associated conditions should also be understood to mean conditions in which chemokine receptors exhibit abnormal characteristics, are targets of particular pathogens, or are targets for pharmacological intervention.

[0072] The chemokine-associated condition is an inflammatory condition, or a condition resulting from or associated with inflammation. The condition or disease to be treated or prevented may be selected from a renal disease, a cardiovascular disease, an eye disease, an oncological disease, or a pulmonary disease.

[0073] (kidney disease) Preferably, the condition or disease to be treated or prevented is renal disease.The renal disease can be selected from the following list: focal segmental glomerulosclerosis (FSGS; including idiopathic (primary) FSGS, secondary FSGS, hereditary FSGS and any other cause of FSGS), fibrotic disorder in kidney, immunoglobulin A nephropathy (IgAN), Alport syndrome, chronic kidney disease (including chronic kidney disease caused by diabetic nephropathy), renal failure (diabetic and non-diabetic), and renal failure condition (including diabetic nephropathy, glomerulonephritis, scleroderma, glomerulosclerosis, proteinuria of primary kidney disease and renal vascular hypertension).

[0074] (Circulatory disease) Preferably, the condition or disease to be treated or prevented is a cardiovascular disease. The cardiovascular disease can be heart disease, more preferably coronary artery disease (preferably selected from the list including arteriosclerosis, pulmonary hypertension, ischemic heart disease, cardiomyopathy, and inflammatory heart disease). The cardiovascular disease can be chronic heart failure, hypertension, congestive heart failure, left ventricular dysfunction, hypertrophic cardiomyopathy, diabetic cardiomyopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, myocardial infarction and its sequelae, atherosclerosis, angina, heart failure, angina, primary hypertension and pulmonary hypertension, vascular disorders.

[0075] (eye disease) Preferably, the condition or disease to be treated or prevented is an ocular disease, such as ocular inflammatory and fibrotic diseases (including anterior and posterior fibrotic diseases, including macular degeneration), ocular vascular diseases, and fibrovascular scarring and gliosis-related diseases, and ischemic diseases (including diabetic retinopathy).

[0076] (oncological disease) Preferably, the condition or disease to be treated or prevented is oncological disease.For example, solid tumor (including but not limited to carcinoma, sarcoma and undifferentiated tumor), lymphoma, blastoma, glioma, melanoma, germ cell tumor and hybrid tumor (e.g., carcinosarcoma).The treatment can also include the adjunctive or combined treatment of the present invention with one or more antitumor treatments (including but not limited to surgery, radiation therapy, hormone therapy, chemotherapy, immune-mediated therapy, cell-based therapy and oncolytic virus therapy).

[0077] (Lung disease) Preferably, the condition or disease to be treated or prevented is a pulmonary (lung) disease. The pulmonary disease may be an infectious or non-infectious inflammatory lung disease (preferably selected from the list including: community-acquired pneumonia, chronic obstructive pulmonary disease, asthma, bronchiectasis, bronchiolitis, bronchitis, emphysema, pleurisy). Preferably, the CCR2 pathway inhibitor is for use in the treatment, alleviation or prevention of acute respiratory distress syndrome (ARDS). ARDS is a type of respiratory failure characterized by the rapid development of widespread inflammation in the lungs.

[0078] The most common cause of ARDS is primary pneumonia, which can be bacterial, viral or fungal. The second most common cause of lung injury is severe sepsis, which can be associated with pneumonia or non-pulmonary infectious causes (e.g., peritonitis). Other important primary causes of ARDS include aspiration of gastric contents; hemorrhage and shock after major trauma; and some other less common causes (e.g., severe acute pancreatitis, transfusion-related lung injury, and drug reactions).

[0079] Recent studies have also found that ARDS can be found in subjects with infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and thus, that ARDS may be associated with infection with SARS-CoV-2.

[0080] Further diseases to be treated or prevented include secondary aldosteronism, primary pulmonary hyperaldosteronism and secondary pulmonary hyperaldosteronism, insulin resistance, migraine, Raynaud's disease, luminal hyperplasia, cognitive impairment, Alzheimer's disease, stroke, hyperkalemia, preeclampsia, sarcoidosis, ischemia and reperfusion injury, atherogenesis, and rheumatoid arthritis.

[0081] The term "prevention" includes administration of the composition of the present invention to a subject who has symptoms indicating that he / she is at risk of developing the above-mentioned renal disease, cardiovascular disease, oncological disease, eye disease or lung disease, but may not be diagnosed with the renal disease, cardiovascular disease, eye disease or lung disease at the time of treatment.For example, the subject may have a severe persistent cough and / or low oxygen level, but may not be diagnosed with ARDS.The subject may have elevated blood creatine or elevated urinary protein, but may not yet be diagnosed with renal disease.

[0082] The term "alleviation" includes administering the composition of the present invention to subjects with renal disease, cardiovascular disease, oncological disease, eye disease or lung disease, who are at risk of developing post-disease state.For example, the disease can be ARDS, and the post-ARDS state can be fibrosis and persistent inflammation.The post-ARDS state can be caused by ARDS itself, or can be caused by the use of a ventilator during the acute phase of ARDS.

[0083] In one embodiment, the chemokine receptor pathway inhibitor inhibits or partially inhibits proteins other than chemokine receptors, and more preferably, the pathway inhibitor is an agent that blocks MCP-1-induced migration and activation and chemotactic migration of monocytes through targeting glycosylphosphatidylinositol (GPI)-anchored proteins (e.g., CD55, CD59 and CD16).Most preferably, the chemokine receptor pathway inhibitor is propagermanium or repagermanium.

[0084] (Measurement of Inhibition) The phrase "chemokine receptor 2 pathway inhibitor" is intended to include any compound or agent that inhibits or partially inhibits any one of the pathways associated with chemokine receptor 2.

[0085] As used herein, the term "inhibit" refers to a decrease below the limit of detection when compared to a reference. The phrase includes blocking, slowing, or impeding an action to prevent an undesirable outcome.

[0086] As used herein, the term "partially inhibit" refers to some decrease within the limits of detection when compared to a reference. The phrase includes blocking, slowing, or impeding an action to prevent an undesirable outcome.

[0087] Inhibition or partial inhibition of the CCR2 pathway by a CCR2 pathway inhibitor can be measured using in vitro methods provided herein, including, but not limited to, biochemical or cellular assays for assessment of in vitro chemotactic migration of CCR2-expressing neutrophils and other cells as known in the art, as well as measurement of inositol phosphate production, extracellular-regulated kinase (ERK) phosphorylation, cAMP production, actin recruitment, protein phosphorylation, nucleoprotein localization, gene transcription, label-free techniques (e.g., using impedance, light refraction, or charge redistribution), G-protein coupling using proximity reporter systems or other approaches, β-arrestin recruitment or β-arrestin-mediated signaling, transcription factor-based reporter systems, visualization by microscopy using fluorescent labels, use of antibodies to assess cellular localization of the receptor (e.g., enzyme-linked immunosorbent assay), and fluorescence-activated cell sorting.

[0088] Inhibition or partial inhibition of the CCR2 pathway by CCR2 pathway inhibitors can be measured using in vivo methods provided herein, including measuring the cellular and chemokine content of lung exudates, measuring lung function (including the physical volume of lung function) using spirometry-based tests, or measuring lung function output as measured by measuring blood gases or other biochemical measures, and These include, but are not limited to, measuring improvements in functional benefit (including survival or clinical benefit measured by quantitative methods (e.g., walking tests) or qualitative methods (e.g., patient-reported outcome assessments)). Inhibition or partial inhibition may be indicated by qualitative improvement in lung structure as measured by one or more of the above endpoints.

[0089] The inhibition or partial inhibition can be measured using in vivo methods presented herein, including, but not limited to, serial measurements of renal function performed by measuring plasma creatinine and plasma urea (e.g., by autoanalyzer); measurement of proteinuria, measurement of albuminuria (e.g., by radioimmunoassay); and GFR (single shot isotope techniques); evaluation of endpoints (e.g., renal and / or cardiac and / or ocular structures) for evaluation of glomerular and cardiac hypertrophy, glomerulosclerosis and / or fibrosis and / or podocyte changes (e.g., by light microscopy (LM)); and / or immunohistochemistry to measure the degree of matrix deposition and modulation of profibrotic growth factors and their activity; evaluation of systolic blood pressure, modulation of insulin fasting plasma glucose, modulation of hemoglobin A1c; and molecular biology techniques to evaluate renal and cardiac and ocular structures according to conventional assays as known in the art. Inhibition or partial inhibition may be indicated by qualitative improvement in renal and / or cardiac and / or ocular structures as measured by one or more of the above endpoints.

[0090] The term "component" as used herein in the context of the pharmaceutical composition of the invention means a chemokine receptor pathway inhibitor.

[0091] Dosage forms and compositions Dosage forms provided by the present invention may include a vial, cartridge, container, tablet, or capsule containing a pharmaceutical composition of the present invention together with administration instructions for administering the dosage form to a subject for the treatment, amelioration, or prevention of disease.

[0092] The composition of the present invention can be administered by injection in various embodiments, or can be prepared for oral, pulmonary, nasal or any other administration form.Preferably, the composition is administered, for example, orally, intravenously, subcutaneously, intramuscularly, intraorbitally, ophthalmically, intracerebroventricularly, intracranially, intracapsularly, intraspinally, intracisternally, intraperitoneally, bucally, rectally, vaginally, intranasally or by aerosol administration.Preferably, the composition of the present invention is delivered by oral, inhalation or topical route.

[0093] The mode of administration is, in one embodiment, at least appropriate for the form in which the composition is prepared. The mode of administration for the most effective response can be empirically determined, and the following administration means are provided as examples and in no way limit the method of delivery of the compositions of the present invention. All of the compositions provided are commonly used in the pharmaceutical industry and are generally known to appropriately qualified physicians.

[0094] Preferably, the CCR2 pathway inhibitor is provided at a dose of 10 mg / day to 500 mg / day provided in a single dose or multiple doses. Most preferably, the CCR2 pathway inhibitor is provided at a dose of 25 mg / day to 250 mg / day provided in a single dose or multiple doses. Preferably, the adult dose is 100 mg / day to 250 mg / day. Preferably, the pediatric dose is 25 mg / day to 125 mg / day.

[0095] However, it will be understood that the specific dose level for any particular subject will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, number of doses administered, route of administration, rate of excretion, drug combination, and the severity of the particular condition or disease being treated.

[0096] (Excipients) In certain embodiments, the medicament of the present invention may contain pharmaceutically acceptable non-toxic excipients and carriers.As used herein, "pharmaceutical carrier" refers to a pharmaceutically acceptable solvent, suspending agent, excipient or medium for delivering compound to a subject.The carrier may be liquid or solid, and is selected with the planned mode of administration in mind.

[0097] Solid oral dosage forms, including tablets, capsules, pills, troches or lozenges, cachets or pellets, are contemplated for use herein. Solid dosage forms are generally described in Martin, Remington's Pharmaceutical Sciences, 18th Edition (1990, Mack Publishing Co., Easton, PA, 18042), Chapter 89, which is incorporated herein by reference. A description of possible solid dosage forms for the active agent is given by Marshall, Modern Pharmaceutics (Chapter 10, Banker and Rhodes, eds. (1979)). In general, the composition comprises the compound (or a chemically modified form thereof) described as part of the present invention and an inactive ingredient that allows protection against the stomach environment and release of the bioactive agent in the intestine.

[0098] Alternatively, the oral dosage form of the present invention may be a liquid, suspension, or other suitable dosage form. Such liquid oral dosage form may be delivered directly into the feeding tube (nasogastric tube) of a patient who is in a coma and / or on a ventilator and unable to swallow tablets, etc. For example, the oral dosage form may be a capsule containing a powder or small pellets, which may be dispensed from the capsule into the feeding tube, or may be dissolved in liquid and dispensed into the feeding tube. Alternatively, the oral dosage form may be a powder or small pellets (optionally provided in a capsule) that may be dissolved in liquid, for example, for administration to children and the elderly who are unable to swallow tablets or capsules. For example, the oral dosage form containing the CCR2 pathway inhibitor may be a powder or small pellets dissolved in a beverage (e.g., water, apple juice or orange juice) or food (e.g., applesauce). It is preferred that the solubilization medium is neutral or acidic in pH.

[0099] For pills, lozenges, molded tablets or molded tablets, moistening techniques are contemplated. Coatings or mixtures of coatings may also be used on tablets that are not intended for protection against the stomach. These include sugar coatings, or coatings that make the tablet easier to swallow.

[0100] An exemplary capsule consists of a hard shell (e.g., gelatin) for delivery of dry active agent (i.e., powder); for liquid forms, a soft gelatin shell may be used. The composition may be delivered in a capsule. Preferably, the capsule is a gelatin capsule or a vegetarian capsule (e.g., VCaps® or Vcaps®plus). The capsule may be size 4 to size 0. The capsule may contain the composition in powder, granule, or pellet form.

[0101] For the CCR2 pathway inhibitors of the present invention, the location of release can be the stomach, the small intestine (duodenum, jejunum, or ileum), or the large intestine.Those skilled in the art have available compositions that do not dissolve in the stomach but release their material in the duodenum or other parts of the intestine.In one embodiment, the release avoids the harmful effects of the stomach environment, either by protecting the composition or by releasing the compound after the stomach environment (e.g., in the intestine).

[0102] To ensure complete gastric resistance, coatings impermeable to at least pH 5.0 are used. Examples of the most common inactive ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac. These coatings can be used as mixed films.

[0103] The present invention further provides a sustained release oral dosage form comprising a therapeutically effective pharmaceutical composition according to the present invention and a release retarding agent. Preferably, such sustained release oral dosage form is a tablet or pill, or small granules or pellets.

[0104] As used herein, the term "sustained release" refers to the gradual but constant or sustained release of active agent content over a relatively long period of time after oral ingestion. The release can continue from after the pharmaceutical composition passes through the stomach until after the pharmaceutical composition reaches the intestine. The phrase "sustained release" can also refer to delayed release, in which the release of the active agent does not begin immediately after the pharmaceutical composition reaches the stomach, but is rather delayed for a period of time (e.g., until the pharmaceutical composition reaches the intestine). Once intestine is reached, then an increase in pH can trigger the release of active agent from the pharmaceutical composition.

[0105] The term "release retardant" as used herein means a substance that reduces the release rate of active agent from pharmaceutical composition when taken orally.The release retardant can be polymeric or non-polymeric.The release retardant can be used according to any one of several sustained release systems, including, for example, diffusion system, dissolution system and / or osmotic system.

[0106] The release retardant can be an enteric coating or a semipermeable membrane. In one embodiment of the present invention, the release retardant is a water-soluble and / or water-swellable and / or water-insoluble polymer. In particular, the water-soluble polymer is selected from the group including ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or polyvinyl alcohol (PVA). In another embodiment of the present invention, the release retardant is a non-polymeric release retardant (e.g., hydrogenated castor oil or carnauba wax). The release retardant can be a mixture of a water-soluble polymer and a non-polymeric release retardant. One example of such a coating is a mixture of a water-soluble polymer, PVA (e.g., Opadry®), and a non-polymeric release retardant, carnauba wax.

[0107] The sustained release oral dosage form containing the release retardant can be a tablet or pill, or small granules or pellets.

[0108] Colorants and flavoring agents can be included as needed. For example, the compounds can be formulated (e.g., by liposome or microsphere encapsulation) and then further included in an edible product (e.g., a refrigerated beverage containing colorants and flavoring agents).

[0109] To aid in dissolving active agents in aqueous environments, surfactants may be added as wetting agents in certain embodiments.Surfactants may include, for example, anionic surfactants such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.Cationic surfactants may be used as needed, and may include benzalkonium chloride or benzethonium chloride.The list of possible nonionic surfactants that may be included as surfactants in the composition is lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 50 and polyoxyethylene hydrogenated castor oil 60, glycerol monostearate, polysorbate 40, polysorbate 60, polysorbate 65 and polysorbate 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose.When used, these surfactants may be present in the composition of the compound either alone or as a mixture of various ratios.

[0110] Additives that may enhance uptake of the compounds are, for example, the fatty acids oleic acid, linoleic acid, and linolenic acid.

[0111] Controlled release compositions may be desirable. These compositions are also contemplated. In certain embodiments, the compound may be incorporated into an inert matrix (i.e., gums) that allows release by either diffusion or reaching the membrane. In some embodiments, slowly degenerating matrices may also be incorporated into the composition. Another form of controlled release of the active agent is based on the Oros Therapeutic Agent System (Alza Corp.), that is, the drug is encapsulated in a semipermeable membrane that allows water to enter through a single small hole due to osmotic action and push the drug out. Some enteric coatings also have a delayed release effect.

[0112] In other embodiments, a mixture of materials can be used to provide a film coating, which can be carried out, for example, in a pan coater or fluidized bed, or by compression coating.

[0113] (Administration Schedule) It is recognized that in certain embodiments, the compositions of the present invention can be given as a single dose schedule, or preferably, a multiple dose schedule.A multiple dose schedule is a schedule in which the main delivery period can involve 1 to 10 separate administrations, and then other administrations are given at subsequent time intervals as necessary to maintain or enhance the treatment.The administration regimen is also determined, at least in part, by the individual's needs and the physician's judgment.

[0114] The present invention thus provides a tablet comprising a pharmaceutical composition of the present invention; a capsule comprising a pharmaceutical composition of the present invention; an injectable suspension comprising a pharmaceutical composition of the present invention; and a composition for pulmonary delivery comprising a pharmaceutical composition of the present invention.

[0115] (use) The present invention also relates to the use of a compound according to the invention in the manufacture of a medicament for the treatment, amelioration or prevention of a condition or disease, i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w Provide for the use of.

[0116] The present invention also provides a use of the composition for the treatment, amelioration or prevention of a condition or disease, the composition comprising: i. at least one chemokine receptor 2 (CCR2) pathway inhibitor, or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w Includes.

[0117] Preferably, the composition comprises 2.5% w / w to 65% w / w of the CCR2 pathway inhibitor. Preferably, the CCR2 pathway inhibitor is a direct antagonist of CCR2. More preferably, the CCR2 pathway inhibitor is repagermanium or propagermanium or a pharmaceutically acceptable salt thereof.

[0118] Preferably, the diluent is silicified microcrystalline cellulose (SMCC). Preferably, the composition comprises 30% w / w to 70% w / w SMCC.

[0119] Preferably, the binder is hypromellose (HPMC). Preferably, the composition comprises 2% w / w to 5% w / w of HPMC.

[0120] Preferably, the disintegrant is sodium starch glycolate. Preferably, the composition comprises 2% w / w to 8% w / w sodium starch glycolate.

[0121] Preferably, the lubricant is magnesium stearate. Preferably, the composition contains 0.05% w / w to 5% w / w of magnesium stearate.

[0122] (kit) The present invention also provides a kit for the treatment, amelioration or prevention of a condition or disease, the kit comprising: a) i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. A diluent with a concentration between 30% w / w and 70% w / w; iii. A binder at a concentration of 2% w / w to 5% w / w; iv. A disintegrant at a concentration of 2% w / w to 8% w / w; and v. Lubricant with a concentration of 0.05% w / w to 5% w / w A composition comprising: b) Instructions for use and Includes.

[0123] The contents of the kit may be in a lyophilized state and the kit may further comprise a suitable solvent for reconstitution of the lyophilized components. The individual components of the kit may be packaged in separate containers and associated with such containers may be a notice in a format prescribed by a governmental agency regulating the manufacture, use or safety of pharmaceuticals or biological products, the notice indicating approval by the agency of manufacture, use or safety for human administration.

[0124] When the components of the kit are provided in one or more liquid solutions, the liquid solution can be an aqueous solution (e.g., a sterile aqueous solution). For in vivo use, the expression construct can be formulated into a pharma-ceutically acceptable injectable composition. In this case, the container means itself can be an inhaler, syringe, pipette, eye dropper, or other such similar device from which the composition can be applied to the affected area of ​​an animal (e.g., lungs), injected into an animal, or even applied and mixed with other components of the kit.

[0125] The components of the kit can also be provided in dry or lyophilized form. When a reagent or component is provided as a dry form, reconstitution is generally by the addition of a suitable solvent. It is envisioned that the solvent can also be provided in another container means. Regardless of the number or type of the container, the kit of the present invention can also include or be packaged with an instrument that assists in the injection / administration or placement of the final combination composition in the animal's body. Such an instrument can be an inhaler, a syringe, a pipette, forceps, a measuring spoon, an eye dropper, or any such medically approved delivery vehicle.

[0126] (principle) All publications cited herein, including patents and patent applications, whether supra or infra, are hereby incorporated by reference in their entirety. However, the publications mentioned herein are cited for the purpose of describing and disclosing the protocols, reagents and vectors reported therein that may be used in connection with the present invention. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

[0127] As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly indicates otherwise. Thus, for example, reference to "a protein" includes a plurality of such proteins, reference to "an analyte" is a reference to one or more analytes, etc.

[0128] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although any materials and methods similar or equivalent to those described herein can be used to practice and test the present invention, the preferred materials and methods are described herein.

[0129] The invention described herein may include one or more ranges of values ​​(e.g., size, concentration, etc.). A range of values ​​is understood to include all values ​​within that range, including the values ​​defining the range and adjacent values ​​within that range that give the same or substantially the same results as the values ​​immediately adjacent to the values ​​defining the boundaries for the range.

[0130] Throughout this specification, unless otherwise required by context, the word "comprise" or variations thereof (e.g., "comprises" or "comprising") are understood to mean the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers. EXAMPLES

[0131] (Example) Example 1 - Exemplary Compositions Exemplary formulations that may be used in the treatment of disease conditions include the following: Table 3: Exemplary Repagermanium Compositions for Long-Term Use [Table 3] Table 4: Repagermanium Capsule Composition [Table 4] Table 5: Repagermanium Capsule Composition [Table 5] Table 6: Exemplary Repagermanium Compositions for Acute Use [Table 6] Table 7: Exemplary Propagermanium Compositions for Long-Term Use [Table 7] Table 8: Propagermanium Capsule Composition [Table 8] Table 9: Propagermanium Capsule Composition [Table 9] Table 10: Exemplary Propagermanium Compositions for Acute Use [Table 10]

[0132] Example 2 - Safety in Use Study An in-use safety study was conducted to determine reconstitution and dosage information for administration of Repagermanium IR capsules via a nasogastric feeding tube.

[0133] The objectives of this study were to: 1. To determine the stability of Repagermanium pharmaceutical compositions once reconstituted in water for administration by gastric tube; 2. To determine whether there was any residual Repagermanium remaining in the medical pot after the initial 15 mL solution was removed; and 3. To determine whether further flushing of the nasogastric tube is required to deliver an accurate dose of Repagermanium. Reagents and Materials DMX-200 capsules Repagermanium Standard: Bis(2-carboxyethylgermanium(IV) sesquioxide Lactose Monohydrate Fast Flo Magnesium stearate sterile water Enfit® Oral Syringe - 35mL Monoject™ (by Covidien™) Tube Type 1: Nasogastric Feeding Tube - Kangaroo™ (by Covidien™) 8884720841 E 8Fr / CH (2.7mm) x 47" (109cm) Tube Type 2: Nasogastric Feeding Tube - Kangaroo™ (by Covidien™) 8884721237 E 12Fr / CH (4.0mm) x 43 in (109cm)

[0134] (Reconstitution in medical pot) There were a total of six experiments, each performed in duplicate (except for the trace test). Table 11: Reconstitution in medical pot [Table 11] Table 12: Assay results for reconstitution in medical pot (15 ml water) [Table 12-1]

[0135] Results from this study showed that the drug was both chemically and microbiologically stable when reconstituted in 15 mL of water for up to 3 hours, but even after one 15 mL rinse, the total measured dose was less than the expected level of ≥90% Repagermanium.The study also showed that the reconstituted drug did not block, interact with, or adhere to nasogastric tubes with a diameter of 2.7 mm and nasogastric tubes with a diameter of 4.0 mm.

[0136] Example 3 - Follow-up study of stability during use The objectives of this study were to: 1. To determine an appropriate HPLC sample preparation method for measuring repagermanium reconstituted in medical pot. 2. Determine if the Repagermanium requires a larger amount of water to reconstitute (2 x 15 ml rinses / washes).

[0137] Each experiment was performed in duplicate. During the HPLC analysis of the samples, control samples (standards) were analyzed in parallel. Table 12: Reconstitution of Repagermanium Capsules [Table 12-2]

[0138] (Summary of results) The appearance of the solution was recorded as "an opaque white suspension containing undissolved particles." The appearance of the nasogastric tube was recorded as "unchanged after administration."

[0139] The pH results were within the acceptable range of pH 2 to pH 6.

[0140] The microbial load for each experiment was <10 cfu / g TAMC and TYMC and did not change from 0 to 180 min. Table 13: Assay results for reconstitution in medical pot (15 ml water) followed by two 15 ml rinses. [Table 13]

[0141] Results from the second study confirmed the conclusion from the first study that there was a loss of drug during transport for analysis by HPLC. Improved sample preparation for HPLC analysis confirmed that reconstitution of the drug in 15 mL of water followed by a minimum of two 15 mL washes was sufficient to deliver ≥ 90% of the Repagermanium when reconstituted in the medical pot.

[0142] These two studies showed that Repagermanium could be reconstituted in a medical pot with 15 mL of water and administered via a nasogastric tube. Rinsing the medical pot twice with 15 mL of water is necessary to deliver the proper dose. When Repagermanium is reconstituted in a medical pot with 15 mL of water and left on the bench, it remains chemically and microbiologically stable for up to 180 minutes.

[0143] Example 4 - Sustained release Repagermanium tablets The objective is to develop a stable tablet formulation that contains Repagermanium as the active agent and releases it over 8 hours. Trials were carried out to obtain tablets that could pass the friability limit and needed to be as small as possible to be aesthetically pleasing. The preferred manufacturing process is a dry blend direct compression process. Table 15: Composition of coated sustained release Repagermanium tablets [Table 15]

[0144] The tablet core is a round tablet containing 30 mg of Repagermanium and having a diameter of 10.3 mm with a break-bar. The final tablet is film-coated in white.

[0145] The physical properties of the tablets were tested. Table 16: Physical properties of tablets [Table 16]

[0146] The release profile of the tablets was tested in 500 ml purified water. Table 17: Release profile of tablets [Table 17]

[0147] Example 5 - Sustained release propagermanium tablets The objective is to develop a stable propagermanium tablet formulation that provides sustained release over 8 hours. The tablets are as small as possible to pass the friability limit and be aesthetically pleasing. The preferred manufacturing process is a dry blend direct compression process. Table 18: Composition of coated sustained release Repagermanium tablets [Table 18]

[0148] The film-coated, white, round tablets, 10.3 mm in diameter, have a core containing 30 mg of propagermanium and have a break-bar.

Claims

1. i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. a diluent with a concentration of 30% w / w to 70% w / w; iii. a binder at a concentration of 2% w / w to 5% w / w; iv. a disintegrant at a concentration of 2% w / w to 8% w / w; and v. A lubricant at a concentration of 0.05% w / w to 5% w / w A composition comprising:

2. The composition of claim 1 , wherein the CCR2 pathway inhibitor is a direct antagonist of CCR2.

3. 2. The composition of claim 1, wherein the CCR2 pathway inhibitor is repagermanium or propagermanium or a pharma- ceutically acceptable salt thereof.

4. 10. The composition of claim 1, wherein the CCR2 pathway inhibitor is provided at a concentration of 2.5% to 65% w / w.

5. The composition of claim 1 , wherein the diluent is silicified microcrystalline cellulose (SMCC).

6. The composition of claim 1 , wherein the binder is hypromellose (HPMC).

7. The composition of claim 1 , wherein the disintegrant is sodium starch glycolate.

8. The composition of claim 1 , wherein the lubricant is magnesium stearate.

9. 1. A method for the treatment, amelioration or prevention of a condition or disease, comprising: administering a therapeutically effective amount of a) composition to said subject. wherein the composition comprises i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. a diluent with a concentration of 30% w / w to 70% w / w; iii. a binder at a concentration of 2% w / w to 5% w / w; iv. a disintegrant at a concentration of 2% w / w to 8% w / w; and v. A lubricant at a concentration of 0.05% w / w to 5% w / w A method comprising:

10. In the manufacture of a medicament for the treatment, amelioration or prevention of a condition or disease, i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. a diluent with a concentration of 30% w / w to 70% w / w; iii. a binder at a concentration of 2% w / w to 5% w / w; iv. a disintegrant at a concentration of 2% w / w to 8% w / w; and v. A lubricant at a concentration of 0.05% w / w to 5% w / w Use of.

11. 2. Use of a composition for the treatment, amelioration or prevention of a condition or disease, said composition comprising: i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. a diluent with a concentration of 30% w / w to 70% w / w; iii. a binder at a concentration of 2% w / w to 5% w / w; iv. a disintegrant at a concentration of 2% w / w to 8% w / w; and v. A lubricant at a concentration of 0.05% w / w to 5% w / w Including, use.

12. 1. A kit for the treatment, amelioration or prevention of a condition or disease, comprising: a) i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. a diluent with a concentration of 30% w / w to 70% w / w; iii. a binder at a concentration of 2% w / w to 5% w / w; iv. a disintegrant at a concentration of 2% w / w to 8% w / w; and v. A lubricant at a concentration of 0.05% w / w to 5% w / w A composition comprising: b) Instructions for use; Including the kit.

13. 13. The method according to claim 9, the use according to claim 10 or 11 or the kit according to claim 12, wherein the condition or disease to be treated, alleviated or prevented is selected from a renal disease, a cardiovascular disease, an eye disease, an oncological disease or a pulmonary disease.

14. i. the kidney disease is focal segmental glomerulosclerosis (FSGS) or chronic kidney disease caused by diabetic nephropathy; ii. The pulmonary disease is acute respiratory distress syndrome (ARDS); 14. The method, use or kit according to claim 13.

15. 13. The method of claim 9, the use of claim 10 or 11, or the kit of claim 12, wherein the CCR2 pathway inhibitor is provided at 10 mg / day to 500 mg / day provided in a single dose or in multiple doses.

16. 13. The method of claim 9, the use of claim 10 or 11, or the kit of claim 12, wherein the CCR2 pathway inhibitor is a direct antagonist of CCR2.

17. 13. The method of claim 9, the use of claim 10 or 11, or the kit of claim 12, wherein the CCR2 pathway inhibitor is repagermanium or propagermanium or a pharma- ceutically acceptable salt thereof.

18. The method of claim 9, the use of claim 10 or 11, or the kit of claim 12, wherein the CCR2 pathway inhibitor is provided at a concentration of 2.5% w / w to 65% w / w.

19. The method according to claim 9, the use according to claim 10 or 11 or the kit according to claim 12, wherein the diluent is silicified microcrystalline cellulose (SMCC).

20. 13. The method according to claim 9, the use according to claim 10 or 11 or the kit according to claim 12, wherein the binder is hypromellose (HPMC).

21. 13. The method according to claim 9, the use according to claim 10 or 11 or the kit according to claim 12, wherein the disintegrant is sodium starch glycolate.

22. 13. The method according to claim 9, the use according to claim 10 or 11 or the kit according to claim 12, wherein the lubricant is magnesium stearate.

23. i. at least one chemokine receptor 2 (CCR2) pathway inhibitor or a pharma- ceutically acceptable salt thereof; ii. a diluent which is silicified microcrystalline cellulose (SMCC) at a concentration of 30% w / w to 70% w / w; iii. A binder which is hypromellose (HPMC) at a concentration of 2% w / w to 5% w / w; iv. a disintegrant which is sodium starch glycolate in a concentration of 2% w / w to 8% w / w; and v. A lubricant which is magnesium stearate at a concentration of 0.05% w / w to 5% w / w A composition comprising:

24. The composition of claim 1 for oral capsule delivery.

25. The composition of claim 1 for nasogastric delivery.

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