Soluble pharmaceutical compositions containing salts of disubstituted 1,2,4-triazine compounds

Abstract

Disclosed is a pharmaceutical composition comprising a salt of a compound having formula (I) and one or more excipients, wherein the pharmaceutical composition avoids inducing disproportionation of the salt of the compound. TIFF2024525954000024.tif34120

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 223,711, filed July 20, 2021, the entire contents of which are incorporated herein by reference.

[0002] Throughout this application, various publications are referenced, including those referenced within parentheses. The disclosures of all publications mentioned throughout this application are incorporated by reference into this application to provide further description of the art to which this invention pertains and features in the art that may be used in the present invention.

[0003] The present invention is directed, inter alia, to pharmaceutical compositions and manufacturing methods for producing such pharmaceutical compositions. [Background technology]

[0004] U.S. Patent No. 10,029,993 and U.S. Patent No. 10,329,263, the entire disclosures of which are incorporated herein by reference in their entireties, describe CYP11β2 beta-hydroxylase inhibitors. To facilitate administration of such inhibitors to human subjects, formulations with good oral absorption characteristics are needed. Summary of the Invention

[0005] Provided herein is a compound of the formula: [ka] and one or more excipients, wherein the pharmaceutical composition avoids inducing disproportionation of the salt of the compound.

[0006] Provided herein is a compound of the formula: [ka] and one or more excipients, wherein the pharmaceutical composition has a solubility profile such that in an in vitro solubility test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in a dissolution medium of water at 37° C., greater than 70% of the compound dissolves within 15 minutes.

[0007] These and other embodiments and aspects of the present disclosure are provided in detail herein. [Brief description of the drawings]

[0008] [Figure 1] Powder X-ray diffraction peaks detected from MLS-101 after storage with a metal salt (croscarmellose Na) for 3 days (storage conditions: 60°C / 75% RH). [Diagram 2] Solubility test of API (left) and X-ray diffraction of API (right). [Diagram 3] Dissolution test results of 10% API capsules under various conditions. [Figure 4] Dissolution test results of tablet formulations after storage in open and closed containers at 25°C and 40°C / 75% RH. [Diagram 5] XRPD diffractograms of DC Lot 1 final blend and uncoated tablets. [Figure 6] XRPD diffractograms of the final blend and uncoated tablets of DC Lot 4. [Figure 7] XRPD diffractograms of DC Lot 5 final blend and uncoated tablets. [Figure 8] XRPD diffractograms of various steps in the process for producing HSWG for Lot 6. [Figure 9] XRPD diffractograms of the final blend, uncoated tablets, and film-coated tablets of Lot 11. [Figure 10] XRPD diffractograms of the final blend, uncoated tablets, and film-coated tablets of Lot 13. [Figure 11]XRPD diffractograms of the final blend, uncoated tablets, and film-coated tablets of Lot 15. [Figure 12] XRPD diffractograms of the final blend, uncoated tablets (Trials #1 and #2), and film-coated tablets (Trial #2) of Lot 17. [Figure 13] XRPD diffractograms of the final blend, uncoated tablets (Trials #1, #2, and #3), and film-coated tablets (Trial #2) of Lot 18. [Figure 14] Summary of analytical data for prototype formulations. [Figure 15] Dissolution profiles of 12.5 mg, 25 mg, and 100 mg tablet prototypes in 0.1 HCl. [Figure 16] Summary of analytical data for prototype formulations. [Figure 17] Dissolution profile of the 12.5 mg tablet prototype in water. [Figure 18] Dissolution profile of 12.5 mg tablet prototype in 0.1 N HCl. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Pharmaceutical Compositions Provided herein is a compound of the formula: [ka] and one or more excipients, wherein the pharmaceutical composition avoids inducing disproportionation of the salt of the compound.

[0010] Also provided herein is a compound of the formula: [ka] and one or more excipients, wherein the pharmaceutical composition has a solubility profile such that, in in vitro solubility testing of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in a dissolution medium of water at 37° C., greater than 70%, greater than 75%, greater than 80%, or greater than 85% of the compound dissolves within 15 minutes. In embodiments, the pharmaceutical composition has a solubility profile such that, in in vitro solubility testing of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in a dissolution medium of water at 37° C., greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95% of the compound dissolves within 30 minutes.

[0011] In embodiments, the salt is an anion salt. In embodiments, the salt is a halogen anion salt. In embodiments, the salt is an HBr salt. In embodiments, the salt is a salt other than an HBr salt. In embodiments, the salt is a halogen anion salt other than an HBr salt.

[0012] In an embodiment, the pharmaceutical composition does not include any of croscarmellose sodium and magnesium stearate. In an embodiment, the pharmaceutical composition does not include any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate. In an embodiment, the pharmaceutical composition does not include any of dicalcium phosphate, croscarmellose sodium, magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and dibasic calcium phosphate. In an embodiment, the pharmaceutical composition does not include magnesium or sodium salts. In an embodiment, the pharmaceutical composition does not include calcium, magnesium, or sodium salts. In an embodiment, the pharmaceutical composition does not include magnesium or sodium. In an embodiment, the pharmaceutical composition does not include calcium, magnesium, or sodium. In an embodiment, the pharmaceutical composition does not include metal salts.

[0013] In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of croscarmellose sodium and magnesium stearate. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of dicalcium phosphate, croscarmellose sodium, magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous calcium hydrogen phosphate. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of magnesium or sodium salts. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of calcium, magnesium, or sodium salts. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of magnesium or sodium. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of calcium, magnesium, or sodium. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of calcium, magnesium, or sodium. In an embodiment where the salt is an HBr salt, the pharmaceutical composition does not include any of metal salts.

[0014] In one embodiment where the salt is other than the HBr salt, the pharmaceutical composition may include a metal salt, may include calcium, magnesium, or sodium, may include a calcium salt, a magnesium salt, or a sodium salt, may include dicalcium phosphate, croscarmellose sodium, and magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous calcium hydrogen phosphate. In an alternative embodiment where the salt is other than the HBr salt, the pharmaceutical composition does not include any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous calcium hydrogen phosphate, does not include a calcium salt, a magnesium salt, or a sodium salt, does not include calcium, magnesium, or sodium, or does not include a metal salt.

[0015] In embodiments, the salt of the compound is in a solid form. In embodiments, the salt of the compound is in a crystalline form. In embodiments, the salt of the compound is in an amorphous form. In embodiments, the pharmaceutical composition comprises a mixture of crystalline and amorphous forms of the salt of the compound.

[0016] In embodiments, the pharmaceutical composition comprises one or more pharma- ceutically acceptable excipients selected from the group consisting of microcrystalline cellulose, lactose, mannitol, polyvinylpyrrolidone, colloidal silicone dioxide, pregelatinized starch, low-substituted hydroxypropyl cellulose, talc, glyceryl dibehenate, and stearic acid.

[0017] In an embodiment, the pharmaceutical composition comprises microcrystalline cellulose 102, mannitol 400DC, pregelatinized starch, and glyceryl dibehenate.

[0018] In embodiments, the composition comprises from about 0.5 milligrams to about 500 milligrams of the compound. In embodiments, the pharmaceutical composition comprises from about 5 milligrams to about 150 milligrams of the compound. In embodiments, the composition comprises from about 12.5 milligrams to about 100 milligrams of the compound. In embodiments, the pharmaceutical composition comprises 12.5 milligrams, about 25 milligrams, about 50 milligrams, or about 100 milligrams of the compound.

[0019] In embodiments, the pharmaceutical composition comprises: a) about 30% by weight to about 60% by weight of lactose, mannitol, or a combination thereof; b) about 25% to about 50% by weight of microcrystalline cellulose; c) about 1% to about 10% by weight of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; d) about 1% to about 10% by weight of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.

[0020] In an embodiment of the pharmaceutical composition, the compound is more water soluble than the same compound in an equivalent pharmaceutical composition containing a calcium salt, a sodium salt, or a magnesium salt. In an embodiment of the pharmaceutical composition, the compound is more water soluble than the same compound in an equivalent pharmaceutical composition containing a sodium salt or a magnesium salt. In an embodiment of the pharmaceutical composition, the pharmaceutical composition has a solubility profile such that in an in vitro dissolution test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in a dissolution medium of water at 37° C., more than 70%, more than 75%, more than 80%, or more than 70% of the compound dissolves within 15 minutes. In an embodiment, the pharmaceutical composition has a solubility profile such that in an in vitro dissolution test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in a dissolution medium of water at 37° C., more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the compound dissolves within 30 minutes.

[0021] In embodiments, the pharmaceutical composition comprises: a) When stored at 25°C + / - 2°C and 60% relative humidity (RH) + / - 5% for 6 or 12 months. b) When stored at 30℃±2℃ and 65%RH±5%RH for 6 or 12 months. c) stored at 30°C + / - 2°C and 75% RH + / - 5% RH for 6 or 12 months; and / or d) Avoid disproportionation of more than 1% of salt when stored at 40°C + / - 2°C and 75% RH + / - 5% RH for 6 months.

[0022] In embodiments, the pharmaceutical composition comprises: a) When stored at 25°C + / - 2°C and 60% relative humidity (RH) + / - 5% for 6 or 12 months. b) When stored at 30℃±2℃ and 65%RH±5%RH for 6 or 12 months. c) stored at 30°C + / - 2°C and 75% RH + / - 5% RH for 6 or 12 months; and / or d) Avoid disproportionation of more than 5% of salt when stored at 40°C + / - 2°C and 75% RH + / - 5% RH for 6 months.

[0023] In embodiments, the pharmaceutical composition comprises: a) When stored at 25°C + / - 2°C and 60% relative humidity (RH) + / - 5% for 6 or 12 months. b) When stored at 30℃±2℃ and 65%RH±5%RH for 6 or 12 months. c) stored at 30°C + / - 2°C and 75% RH + / - 5% RH for 6 or 12 months; and / or d) Avoid disproportionation of more than 10% of the salt when stored at 40°C + / - 2°C and 75% RH + / - 5% RH for 6 months.

[0024] In embodiments, the storage conditions are in a closed container. In embodiments, the storage conditions are in an open container.

[0025] In embodiments, after storage under any of the aforementioned conditions, the pharmaceutical composition has a solubility profile such that, in in vitro solubility testing of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in water dissolution medium at 37° C., greater than 70%, greater than 75%, greater than 80%, or greater than 85% of the compound dissolves within 15 minutes. In embodiments, after storage under any of the aforementioned conditions, the pharmaceutical composition has a solubility profile such that, in in vitro solubility testing of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in water dissolution medium at 37° C., greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, or greater than 95% of the compound dissolves within 30 minutes.

[0026] In an embodiment, the pharmaceutical composition comprises about 5 milligrams to about 20 milligrams of the compound, preferably about 10 milligrams to about 15 milligrams of the compound, or more preferably about 12.5 milligrams of the compound. a) about 1% by weight to about 8% by weight of a compound; b) about 50% to about 60% by weight of lactose, mannitol, or a combination thereof; c) about 25% to about 40% by weight of microcrystalline cellulose; d) about 1% to about 10% by weight of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; e) about 1% to about 10% by weight of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.

[0027] In an embodiment, the pharmaceutical composition comprises about 15 milligrams to about 35 milligrams of the compound, preferably about 20 milligrams to about 30 milligrams of the compound, or more preferably about 25 milligrams of the compound. a) about 5% by weight to about 15% by weight of a compound; b) about 30% by weight to about 50% by weight of mannitol; c) about 30% by weight to about 50% by weight of microcrystalline cellulose; d) about 1% to about 10% by weight of pregelatinized starch; e) about 1% to about 5% by weight of glyceryl dibehenate, colloidal silicone dioxide, or a combination thereof.

[0028] In an embodiment, the pharmaceutical composition comprises about 80 milligrams to about 120 grams of the compound, preferably about 95 milligrams to about 105 milligrams of the compound, or more preferably about 100 milligrams of the compound. a) about 30% by weight to about 40% by weight of a compound; b) about 20% by weight to about 30% by weight of mannitol; c) about 20% by weight to about 40% by weight of microcrystalline cellulose; d) about 1% to about 10% by weight of pregelatinized starch; e) about 1% to about 5% by weight of glyceryl dibehenate, colloidal silicone dioxide, or a combination thereof.

[0029] In any of the above pharmaceutical compositions, the pharmaceutical composition comprises 3% to 8% by weight of stearic acid, preferably about 5% by weight of stearic acid.

[0030] tablet In an embodiment, the pharmaceutical composition is a tablet. In an embodiment, the tablet comprises a coating. In an embodiment, the coating comprises hydroxypropyl methylcellulose, polyvinyl alcohol, or a combination thereof.

[0031] Manufacturing methods for producing pharmaceutical compositions Provided herein is a compound of the formula: [ka] and one or more excipients, wherein the pharmaceutical composition avoids inducing disproportionation of the salt of the compound, and / or the pharmaceutical composition has a solubility profile such that, in an in vitro solubility test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in a dissolution medium of water at 37° C., more than 70%, more than 75%, more than 80%, or more than 85% of the compound dissolves within 15 minutes; a) Formula: [ka] and b) mixing the salt with one or more excipients, thereby producing a pharmaceutical composition.

[0032] In one embodiment, the pharmaceutical composition has a solubility profile such that in an in vitro solubility test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in a dissolution medium of water at 37° C., greater than 70%, greater than 75%, greater than 80%, or greater than 85% of the compound dissolves within 30 minutes.

[0033] In one embodiment, the salt is an anion salt. In one embodiment, the salt is a halogen anion salt. In one embodiment, the salt is an HBr salt.

[0034] In an embodiment of the above method of manufacture, step b) comprises: i) blending the salt with one or more excipients; ii) roller compaction of the product of step i); and iii) grinding the product of step ii).

[0035] In an embodiment, the one or more excipients of step i) comprise stearic acid, more preferably about 5% by weight stearic acid.In an embodiment, step b) further comprises blending the product of step iii) with one or more additional excipients, preferably the one or more additional excipients comprise stearic acid.

[0036] In one embodiment, the method further comprises tableting the pharmaceutical composition to produce a tablet core, hi one embodiment, the method further comprises film coating the tablet core.

[0037] In one embodiment of the method of manufacture, the one or more excipients do not include any of croscarmellose sodium and magnesium stearate. In one embodiment of the method of manufacture, the one or more excipients do not include any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate. In one embodiment of the method of manufacture, the one or more excipients do not include any of dicalcium phosphate, croscarmellose sodium, magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and calcium hydrogen phosphate anhydrous. In one embodiment of the method of manufacture, the one or more excipients do not include magnesium or sodium salts. In one embodiment of the method of manufacture, the one or more excipients do not include calcium, magnesium, or sodium salts. In one embodiment of the method of manufacture, the one or more excipients do not include magnesium or sodium. In one embodiment of the method of manufacture, the one or more excipients do not include calcium, magnesium, or sodium. In one embodiment of the method of manufacture, the one or more excipients do not include metal salts.

[0038] In one embodiment of the method of manufacture, the salt of the compound is in solid form. In an embodiment, the salt of the compound is in crystalline form. In an embodiment, the salt of the compound is in amorphous form. In an embodiment of the method of manufacture, the pharmaceutical composition comprises a mixture of crystalline and amorphous forms of the salt of the compound.

[0039] In one embodiment of the method of manufacture, the one or more excipients are selected from the group consisting of microcrystalline cellulose, lactose, mannitol, polyvinylpyrrolidone, colloidal silicone dioxide, pregelatinized starch, low-substituted hydroxypropyl cellulose, talc, glyceryl dibehenate, and stearic acid.

[0040] In one embodiment of the method of manufacture, the one or more excipients include microcrystalline cellulose 102, mannitol 400DC, pregelatinized starch, and glyceryl dibehenate.

[0041] In one embodiment of the method of manufacture, the pharmaceutical composition comprises: a) about 30% by weight to about 60% by weight of lactose, mannitol, or a combination thereof; b) about 25% to about 50% by weight of microcrystalline cellulose; c) about 1% to about 10% by weight of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; d) about 1% to about 10% by weight of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.

[0042] In an embodiment of the method of manufacture, the pharmaceutical composition has the following characteristics: a) 20% to 30% by weight of microcrystalline cellulose; b) 20% to 30% by weight of D-mannitol, and c) 3% to 8% by weight of stearic acid.

[0043] Methods and compositions for use Also provided herein is a method of treating hypertension and / or reducing blood pressure in a hypertensive subject, comprising administering to the hypertensive subject any of the compositions described herein.

[0044] Also provided herein is a method for inhibiting CYP11β2 beta-hydroxylase in a subject, the method comprising administering to the subject any of the compositions described herein.

[0045] Also provided herein is any of the compositions described herein for use in treating hypertension and / or reducing blood pressure in a hypertensive subject.

[0046] Also provided herein is any of the compositions described herein for use in inhibiting CYP11β2 beta-hydroxylase in a subject.

[0047] definition Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0048] In the discussion, unless otherwise stated, adjectives such as "substantially" and "about" modifying a condition or relationship feature of one or more features of an embodiment of the invention are understood to mean that the condition or feature is defined within an acceptable range of tolerance for the operation of the embodiment for its intended use. Unless otherwise indicated, the word "or" in this specification and claims is considered to be an inclusive "or" and not an exclusive or, indicating at least one, and any combination, of the items it conjugates.

[0049] The terms "a" and "an," as used above and elsewhere in this specification, should be understood to refer to "one or more" of the listed components. It will be apparent to one of ordinary skill in the art that the use of the singular includes the plural, unless specifically stated otherwise. Thus, the terms "a," "an," and "at least one" are used interchangeably in this application.

[0050] For the purpose of a better understanding of the present teachings, and without limiting the scope of the teachings in any manner, unless otherwise indicated, all numbers expressing quantities, percentages or proportions, and other numerical values ​​used in the present application and claims are understood to be modified in all instances by the term "about". Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending on the desired properties to be obtained. At the very least, each numerical parameter should be construed in light of the reported significant digits and by applying ordinary rounding techniques.

[0051] In the specification and claims of this application, the verbs "comprise," "include," and "have," and their conjugations, are used to indicate that the object or objects of the verb are not necessarily a complete recitation of the components, elements, or parts of the subject or objects of the verb. Other terms used herein are meant to be defined by their well-known meanings in the art.

[0052] As used herein, "ALDSI" and "MLS-101" refer to the hydrobromide (HBr) salt of a disubstituted 1,2,4-triazine compound represented by formula (A). [ka]

[0053] The weights and / or strengths of "ALDSI," "MLS-101," and "compounds" of the present invention refer to the weight of the free base in the HBr salt, not the weight of the HBr salt.

[0054] The compounds of formula (A) and pharma- ceutically acceptable salts thereof can be made, for example, by the processes described in U.S. Pat. No. 10,029,993 and European Publication No. 3549935, the disclosures of which are incorporated herein by reference in their entireties.

[0055] The present invention relates to the surprising discovery that MLS-101 undergoes disproportionation when combined with pharmaceutical excipients containing metal salts, particularly calcium, magnesium, and sodium salts. Thus, each pharmaceutical composition of the present invention is "free" of excipients containing metal salts (particularly "free" of calcium, magnesium, or sodium salts) in order to avoid disproportionation of MLS-101 and maintain its water solubility. Those skilled in the art will understand that if a pharmaceutical composition contains such a trace amount of a metal salt, it is within the scope of the present invention if such a trace amount does not cause disproportionation above the acceptable threshold limit. Thus, the use of the term "free" encompasses an amount of metal salt that is sufficiently low so as not to cause disproportionation above the acceptable threshold limit. As used herein, 10% disproportionation is the acceptable threshold limit for disproportionation. In some embodiments, a lower threshold for disproportionation may be preferred. For example, in embodiments of the present invention, the composition avoids disproportionation of more than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0056] The pharmaceutical composition of the present invention may contain a "therapeutically effective amount" or a "prophylactically effective amount" of the compound of the present invention. A "therapeutically effective amount" refers to an amount effective at the dosage and for the period of time necessary to achieve the desired therapeutic result. The therapeutically effective amount of a compound may vary depending on factors such as the disease state, age, sex, and weight of the individual. A therapeutically effective amount is also one in which any toxic or harmful effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective at the dosage and for the period of time necessary to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects before or at an early stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0057] Overview With regard to the foregoing embodiments, it is contemplated that each embodiment disclosed herein is applicable to each of the other disclosed embodiments.

[0058] As used herein, all headings are for organizational purposes only and are not intended to limit the disclosure in any manner. The contents of any individual section may be equally applicable to all sections. All combinations of the various elements disclosed herein are within the scope of the invention.

[0059] Additional objects, advantages, and novel features of the present invention will become apparent to one of ordinary skill in the art upon examination of the following examples, which are not intended to be limiting. Additionally, each of the various embodiments and aspects of the present invention as described hereinabove and as claimed in the claims section below finds experimental support in the following examples.

[0060] It is understood that certain features of the invention that are described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination, or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not considered essential features of those embodiments, unless the embodiment would not operate without those elements.

[0061] In order to facilitate a more complete understanding of the present invention, examples are provided below. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the present invention is not limited to the specific embodiments disclosed in these examples, which are for illustrative purposes only. EXAMPLES

[0062] Example 1 Risk assessment of salt disproportionation The peaks derived from ALDSI were detected after storage of ALDSI containing a metal salt (croscarmellose Na) for 3 days (storage conditions: 60°C / 75% RH).

[0063] As shown in FIG. 1, ALDSI is highly prone to disproportionation in the presence of metal salts.

[0064] Research into salt disproportionation and strategies to reduce the risk of disproportionation Following the discovery of salt disproportionation in ALDSI in the presence of metal salts, we sought strategies to reduce the disproportionation risk.

[0065] Summary of results: The risk of salt disproportionation can be reduced by appropriate selection of excipients.

[0066] Examination of the influence of possible factors on salt disproportionation Temperature and Humidity Sample: API (ALDSI)

[0067] Storage conditions: In an open container, 25°C / 60%RH, 40°C / 75%RH, and 60°C / 75%RH (relative humidity)

[0068] Sampling times: 3 days and 1 week

[0069] ALDSI Solubility Test Test method: JP Apparatus for Paddle Method (Apparatus2)

[0070] Rotation speed: 50 rpm for 0 to 30 minutes, and 250 rpm for 30 minutes.

[0071] Dissolution medium: JP Second Fluid for solubility testing (a mixture of phosphate buffer (pH 6.8) and water (1:1) as described in the Japanese Pharmacopoeia).

[0072] result ALDSI did not show any retardation of dissolution or the appearance of new peaks in the XRPD (see FIG. 2).

[0073] conclusion In the absence of excipients, the risk of salt disproportionation due to temperature and humidity is minimal.

[0074] Pharmaceutical Manufacturing Methods Compression Effects The API alone was compressed at 300, 600, and 900 kilograms of force (i.e., approximately 2942, 5884, and 8826 Newtons, respectively) to assess solubility. a) There was no difference in solubility between the samples. b) When the sample was stored at 60°C / 75% RH (for 3 days or 1 week), there was no change in solubility over time.

[0075] Conclusions: Compression has a minimal effect on the risk of salt disproportionation.

[0076] Impact of Wet Granulation The API alone was mixed with a large, medium, and small amount of water to evaluate its solubility. a) There was no difference in solubility between the samples.

[0077] Conclusion: Wet granulation conditions have minimal impact on the risk of salt disproportionation.

[0078] Effect of grinding conditions The API alone was ground for 1, 3, 20, and 30 minutes to assess solubility. a) There was no difference in solubility between the samples. b) When the sample was stored at 60°C / 75% RH (for 3 days or 1 week), there was no change in solubility over time.

[0079] Conclusion: Grinding may have a minimal effect on the risk of salt disproportionation.

[0080] Disproportionation due to commonly used excipients Formulation conditions API and excipients in a 1:1 (w / w) ratio

[0081] Mix in a mortar (without applying pressure for about 10 minutes)

[0082] Storage conditions 60℃ / 75%RH, 1 week in an open container

[0083] test X-ray diffraction (XRD)

[0084] Residue after solubility test: a) Water solubility is significantly reduced after salt disproportionation, so samples with no residue were considered to have undergone no disproportionation. ALDSI free base is yellow, so yellow residue was considered to represent salt disproportionation. White residue was considered to be insoluble excipients and no salt disproportionation as ALDSI free base.

[0085] result A potential risk of salt disproportionation due to interactions with metal salts was presented. [Table 1]

[0086] Stability study of 10% API capsules I Formulation of 10% API capsules Excipients were selected that did not contain metal salts.

[0087] Formulation Method D-Mannitol and Talc were mixed and sieved. API was added to the sieved mixture, blended, sieved and filled into HPMC capsules. [Table 2]

[0088] Stability study of 10% API capsules II FIG. 3 shows the results of dissolution testing of 10% API capsules under various conditions. [Table 3]

[0089] conclusion There was no risk of delayed dissolution or increased related substances in the three formulations tested. The 10% API capsules formulated with excipients that are not considered to cause disproportionation may be a pharmaceutical formulation with a low risk of salt disproportionation.

[0090] Tablet (Formulation) Research I formulation In order to design a formulation that can avoid the risk of salt disproportionation, low-substituted hydroxypropylcellulose (L-HPC) and three lubricants were selected, which were deemed to have no risk of salt disproportionation ("disproportionation due to commonly used excipients") based on the results of the study presented above.

[0091] Formulation Method The API granules, disintegrant, and lubricant were mixed in a polyethylene bag. The mixture was then subjected to tableting (900 kilograms of force, i.e., approximately 8826 Newtons) after checking the pressure dependency. [Table 4]

[0092] Tablet studies II (stability test results) Solubility test results Solubility after storage for one month in open and closed containers at 40°C / 75% RH, closed at 25°C: No change from the initial value for any formulation.

[0093] Reason for decreased solubility after storage at 60°C: The tablets were stored at a temperature close to the melting point of the individual lubricants, causing the lubricants in the tablets to dissolve.

[0094] FIG. 4 shows the solubility test results.

[0095] Purity Test Results All formulations showed no change from the initial values ​​under all storage conditions tested. [Table 5]

[0096] Example 2 Introduction This example documents the formulation development of 12.5, 25, and 100 mg MLS-101 film-coated tablet dosage forms with immediate release characteristics.

[0097] The physicochemical properties of MLS-101 have been previously evaluated and no significant problems have been identified, suggesting that the compound can be formulated by either direct compression or granulation (dry and wet) manufacturing methods.

[0098] The information provided from formulation development activities and laboratory analysis of the different formulations evaluated will determine more promising approaches for identifying drug products for which manufacturing processes can be developed.

[0099] the purpose To develop an immediate release oral solid dosage form (OSD) of MLS-101 using the following different approaches: a) Direct Compression (DC), b) Roller compaction (RC), c) high shear wet granulation (HSWG);

[0100] To evaluate the stability of the developed dosage form.

[0101] material The materials used in this study are listed in Table 6. All materials were stored at room temperature (RT). [Table 6]

[0102] method Crystal state evaluation X-Ray Powder Diffraction - USP <941> The crystalline state of the samples at different preparation steps was studied by X-ray powder diffraction (XRPD) using a Bruker X-ray diffractometer model D2 Phaser (Karlsruhe, Germany) with Cu Kα radiation (λ = 1.54184 Å) in increments of 0.01°2θ (scan rate of 3°2θ / min) with a step time of 0.2 s, over the range of 3-56°2θ, 0.6 mm divergence slit, 1.0 mm scattering plate, and 3.0 mm acceptance window, where applicable. Samples were analyzed using a low volume sample holder, keeping the samples under a constant rotation speed of 15 rpm during the analysis.

[0103] Formulation Development Approach Table 7 presents the compositions of direct compression (DC) formulation lots 1, 2A, 2C, 3A-5, roller compaction (RC) lot 2B, and high shear wet granulation (HSWG) lot 6. Table 8 presents placebo blend lots 7-10 (corresponding to active lots 1, 4-6). Table 8 also contains the compositions of "new" (discussed below) DC formulation prototype lots 11, 13, and 15, which do not contain metal ion-containing excipients, as well as the respective placebo lots 12, 14, and 16, respectively, and additional lots 17-19.

[0104] It was discovered that MLS-101 is susceptible to salt disproportionation in the presence of excipients containing metal salts. Therefore, to reduce the salt disproportionation risk, we proposed additional "new" DC lots 11, 13, 15, 17, 18, and 19 (Table 8) that do not contain excipients such as dicalcium phosphate, croscarmellose sodium, and magnesium stearate.

[0105] 100 mg FB tablets Lot 19 were prepared according to Lot 18, substituting SMCC for MCC and increasing the lubricant to 3%.

[0106] Blending of lots 1-5, 11, 13, 15, and 17-19 was performed using a GlobePharma MaxiBlend4qt V blender model MB-I.

[0107] A Patterson-Kelly BlendMaster 0.5LV blender was used to process the placebo. All placebo excipients (including Opadry) were milled through a 600 μm sieve and blended for 3 minutes. The lubricant was screened through the same sieve and added to the V blender and blended for an additional 2 minutes. [Table 7] [Table 8]

[0108] Analytical Testing The quality attributes of the drug product were evaluated by analytical tests including appearance, content uniformity, assay, related substances, water content, and solubility profile.

[0109] Stability Program The first R&D stability study was conducted on 12.5 mg MLS-101 FCT Lot 1, 25 mg FCT Lot 4, and 100 mg FCT Lots 5 and 6.

[0110] A second R&D stability study was conducted on 12.5 mg MLS-101FCT lots 11, 13, and 15.

[0111] A third R&D stability study was conducted on MLS-101FCT lots 17 and 18, 25 mg and 100 mg, respectively.

[0112] Tablets were packaged in Aclar® blisters at 10 FCT per blister. The blister material was Pentapharm Aclar PA160 / 02 (254 / 15, clear, 160mm width, colour#: 71 / 9400, Klockner lot 0075966400) and the foil was 25μm Aluminium lidding push through (Constancia AL109CSM).

[0113] Also, small single tablets were packaged in 60 cc round, white, opaque, high-density polyethylene (HDPE) bottles (Drug Plastics & Glass Co.) without caps (so-called “open”) to induce worst-case stability conditions.

[0114] Placebo blends were packaged in 60 cc round, white, opaque HDPE bottles (Drug Plastics & Glass Co.) with induction-sealed, child-resistant polypropylene caps (Berry).

[0115] Stability prototypes were incubated under ICH recommended intermediate (30° C. / 65% RH), long-term (25° C. / 60% RH), and accelerated (40° C. / 75% RH) stability conditions. Extra samples were incubated at 5° C. for reference. Blisters and open bottles were placed in the chambers and monitored for 24 hours / 7 days according to the stability protocols presented in Tables 9, 10, and 11. [Table 9] [Table 10] [Table 11]

[0116] Formulation Development Crystal state evaluation results DC Lots 1, 4, and 5 (Figures 5, 6, and 7, respectively), and HSWG Lot 6 (Figure 8) (prepared with excipients containing metal salts) each showed different XRP diffractograms in the final blends (due to the different excipients used in each formulation) and exhibited the expected crystalline characteristic peaks. The XRPDs of the uncoated tablets showed less intensity in all lots compared to those from the respective final blends, but without any other notable changes. In Lot 6, samples from the various manufacturing steps exhibited XRPD patterns similar to that of the final blend.

[0117] The XRPD patterns of new DC lots 11, 13, and 15 (Figures 9, 10, and 11, respectively), prepared without metal salt-containing excipients, also differed from each other. In contrast to the previous lots, the uncoated tablets showed crystalline peaks of higher intensity than those of the respective final blends. No significant changes were observed in the XRPD patterns of the film-coated tablets when compared to the XRPD patterns of the corresponding uncoated tablets.

[0118] For DC Lots 17 and 18 (FIGS. 12 and 13, respectively), which were prepared with the same excipients as Lot 13 but at drug loadings of approximately 9% and 36%, respectively, the XRPD patterns were generally similar to that of Lot 13 for the final blends up to the uncoated tablet Trial #2 samples (medium or high compression forces). However, the XRPD pattern of Lot 18 (prepared at high drug loading) exhibited significantly reduced intensity of the crystalline peaks of the tablets from Trial #3 compressed at maximum compression force. Again, no significant changes were observed in the XRPD patterns of the film-coated tablets compared to those of the corresponding uncoated tablets.

[0119] Analytical Testing Initial analytical results for appearance, assay, degradation products, and solubility of FCT lots 1 and 4-6 can be found in Figures 14 and 15. The drug products exhibited assay consistencies of 97-100% and no more than 0.05% impurities. However, within the first 30 minutes, lots 1, 4, 5, and 6 exhibited low solubility in water with 55, 72, 73, and 86% release, respectively. In comparison, the solubility profiles in 0.1 N HCl showed 96, 94, 90, and 93% release, respectively, for the same lots within the same 30 minutes.

[0120] Further investigations were then conducted using Swedish Orange capsule size "0" lots 1A (capsules filled with API only) and 1B (final non-compressed blend from lot 1). Results showed rapid water solubility with 104% release for capsule lot 1A (containing API only) within 15 minutes compared to a low recovery of approximately 33% for capsule lot 1B (final blend lot 1) within 30 minutes. It was hypothesized that the metal ion-containing excipients used in the prototypes evaluated (i.e., dicalcium phosphate, croscarmellose sodium, and magnesium stearate) may have induced salt disproportionation, thus producing API free base that was less soluble in water. This hypothesis emerged as a potential risk leading to a second round of prototyping as previously described.

[0121] The results of the new formulations without metal ion excipients for appearance, assay, degradation products, solubility, and content uniformity of FCT lots 11, 13, and 15 (all 12.5 mg MLS-101 free base) can be found in Figures 16, 17, and 18. All drug products did not exhibit impurities greater than 0.05%. Lots 11 and 13 exhibited similar assay results. Lot 13 released 98 and 96% in water and 0.1 N HCl, respectively, within 15 minutes, while Lot 11 exhibited more rapid solubility with approximately 87% released in both media within 15 minutes. Lots 11 and 13 had content uniformity results of 98 and 96% LC, respectively. On the other hand, Lot 15, formulated with mannitol, contained API in an amount of 88.5% and therefore Lot 15 presented a poor assay of 88.5% within 15 minutes, a poor solubility profile with 92 and 89% released in water and 0.1 N HCl, respectively, and a poor content uniformity of 89.6% LC.

[0122] conclusion The final lubricated blend of DC formulation lot 5, prepared with microcrystalline cellulose and dicalcium phosphate at high drug loading (36.28%), presented the lowest bulk density of 0.38 g / cm3 and showed "fair" flow. The highest bulk density of 0.64 g / cm3 was obtained for DC lot 15, prepared with mannitol 400DC at low drug loading (4.54%) and showed "good" flow. All other DC formulations of lots 1, 4, 11, and 13 (irrespective of drug loading) and HSWG lot 6 presented bulk densities in the range of 0.41 to 0.58 g / cm3 and showed "fair" flow.

[0123] Most formulations produced tablets that met target weight with RSD less than 1.8% (except for Lot 3A, which had an RSD of 3.7%) and embrittlement less than 0.5%. In general, DC formulation tablets compressed at high or medium compression forces did not exhibit capping, lamination, picking, or stickiness, except for Lot 11 (prepared with talc and without colloidal silicon dioxide). Tablets compressed at low compression forces revealed a thin film of powder adhering to the punch or even minor picking when a chrome tipped punch was used.

[0124] The disintegration time (DT) of the DC formulation was less than 2 minutes and that of HSWG Lot 6 was less than 7 minutes. The DT was good, being ≦15 minutes, a generally accepted target for immediate release oral solid dosage forms.

[0125] Initial analytical results for Lots 1, 4-6 revealed potential issues with salt disproportionation. It was hypothesized that the metal ion-containing excipients used in the prototypes evaluated (i.e., dicalcium phosphate, croscarmellose sodium, and magnesium stearate) may have induced salt disproportionation, thus producing API free base that was less soluble in water. This hypothesis was confirmed as a potential risk leading to the second round of prototyping.

[0126] Thus, newer lots 11, 13, and 15, formulated with microcrystalline cellulose and / or mannitol as fillers, crospovidone XL, pregelatinized starch, and low substituted hydroxypropyl cellulose as disintegrants, and talc, glyceryl dibehenate, and stearic acid as lubricants, showed encouraging data for assay, degradation products, and solubility (in both water and 0.1 N HCL). For content uniformity, lots 11 and 13 also showed encouraging data. Specifically, the formulations demonstrated less than 10% disproportionation as demonstrated by the formulation solubility profile and XRPD.

[0127] The results show that DC formulation lot 13 appears promising. Therefore, 25 mg and 100 mg coated tablets are prepared with excipients including microcrystalline cellulose 102, mannitol 400 DC, pregelatinized starch, and glyceryl dibehenate.

Claims

1. A pharmaceutical composition comprising a salt of a compound having the formula: 【Chemical 1】 and one or more excipients, wherein the pharmaceutical composition a) avoids inducing disproportionation of the salt of the compound and / or b) has a solubility profile such that more than 70% of the compound dissolves within 15 minutes in an in vitro solubility test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in an aqueous dissolution medium at 37°C. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the salt is an anionic salt, or preferably a halogen anion salt, or more preferably an HBr salt.

3. The pharmaceutical composition does not contain any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate, calcium carmellose, sodium stearyl fumarate, calcium stearate, and anhydrous calcium hydrogen phosphate, preferably, the pharmaceutical composition does not contain a calcium salt, a magnesium salt, or a sodium salt, more preferably, the pharmaceutical composition does not contain calcium, magnesium, or sodium, even more preferably, the pharmaceutical composition does not contain a metal salt. The pharmaceutical composition according to claim 2.

4. The pharmaceutical composition according to claim 3, wherein the salt of the compound is in a crystalline form.

5. The pharmaceutical composition according to claim 3, wherein the salt of the compound is in an amorphous form.

6. The pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from the group consisting of microcrystalline cellulose, lactose, mannitol, polyvinylpyrrolidone, colloidal silicon dioxide, pregelatinized starch, low-substituted hydroxypropyl cellulose, talc, glyceryl dibehenate, and stearic acid, preferably, the pharmaceutical composition comprises microcrystalline cellulose 102, mannitol 400DC, pregelatinized starch, and glyceryl dibehenate. The pharmaceutical composition according to claim 4.

7. comprising from about 0.5 milligram to about 500 milligrams of the compound, or preferably from about 5 milligrams to about 150 milligrams of the compound, preferably, the pharmaceutical composition a) from about 30 wt% to about 60 or 99 wt% of lactose, mannitol, or a combination thereof, and b) from about 25 wt% to about 50 or 99 wt% of microcrystalline cellulose, c) from about 1 wt% to about 10 wt% of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof, and d) from about 1 wt% to about 10 wt% of talc, glyceryl dibehenate, colloidal silicon dioxide, or a combination of two or more thereof, and comprising The pharmaceutical composition according to claim 4.

8. wherein the compound is more water-soluble than the same compound in an equivalent pharmaceutical composition comprising a calcium salt, a sodium salt, or a magnesium salt, wherein the pharmaceutical composition avoids disproportionation of more than 10% when stored in a closed container at 25 °C and 60% relative humidity for 6 months, preferably, the pharmaceutical composition avoids disproportionation of more than 5% when stored in a closed container at 25 °C and 60% relative humidity for 6 months, or more preferably, the pharmaceutical composition avoids disproportionation of more than 1% of the salt when stored in a closed container at 25 °C and 60% relative humidity for 6 months, after storage in a sealed container at 25 °C and 60% relative humidity for 6 months, the pharmaceutical composition has a solubility profile such that more than 70% of the compound dissolves within 15 minutes in an in vitro solubility test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in an aqueous dissolution medium at 37 °C, The pharmaceutical composition according to claim 7.

9. wherein the pharmaceutical composition comprises from about 5 milligrams to about 20 milligrams of the compound, preferably from about 10 milligrams to about 15 milligrams of the compound, or more preferably about 12.5 milligrams of the compound, preferably, the pharmaceutical composition a) from about 1 wt% to about 8 wt% of the compound, and b) from about 50 wt% to about 60 wt% of lactose, mannitol, or a combination thereof, and c) from about 25 wt% to about 40 wt% of microcrystalline cellulose, and d) from about 1 wt% to about 10 wt% of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof, and e) from about 1 wt% to about 10 wt% of talc, glyceryl dibehenate, colloidal silicon dioxide, or a combination of two or more thereof, and comprising more preferably, the pharmaceutical composition comprises from 3 wt% to 8 wt% of stearic acid, preferably about 5 wt% of stearic acid, and comprising The pharmaceutical composition according to claim 8.

10. The pharmaceutical composition comprises from about 15 milligrams to about 35 milligrams of said compound, preferably from about 20 milligrams to about 30 milligrams of said compound, or more preferably about 25 milligrams of said compound, preferably, the pharmaceutical composition a) from about 5% to about 15% by weight of said compound; and b) from about 30% to about 50% by weight of mannitol; and c) from about 30% to about 50% by weight of microcrystalline cellulose; and d) from about 1% to about 10% by weight of pregelatinized starch; and e) from about 1% to about 5% by weight of glyceryl dibehenate, colloidal silicon dioxide, or a combination thereof, and more preferably, the pharmaceutical composition comprises from 3% to 8% by weight of stearic acid, preferably about 5% by weight of stearic acid. The pharmaceutical composition according to claim 8.

11. The pharmaceutical composition comprises from about 80 milligrams to about 120 grams of said compound, preferably from about 95 milligrams to about 105 milligrams of said compound, or more preferably about 100 milligrams of said compound, preferably, the pharmaceutical composition a) from about 30% to about 40% by weight of said compound; and b) from about 20% to about 30% by weight of mannitol; and c) from about 20% to about 40% by weight of microcrystalline cellulose; and d) from about 1% to about 10% by weight of pregelatinized starch; and e) from about 1% to about 5% by weight of glyceryl dibehenate, colloidal silicon dioxide, or a combination thereof, and the pharmaceutical composition comprises from 3% to 8% by weight of stearic acid, preferably about 5% by weight of stearic acid. The pharmaceutical composition according to claim 8.

12. The pharmaceutical composition is a tablet, preferably the tablet comprises a coating, and more preferably the coating comprises hydroxypropyl methylcellulose, polyvinyl alcohol, or a combination thereof. The pharmaceutical composition according to claim 8.

13. A process for preparing a pharmaceutical composition comprising a salt of a compound having the formula: [Chemical Formula 2] and one or more excipients, the pharmaceutical composition avoiding inducing disproportionation of the salt of the compound and / or the pharmaceutical composition having a solubility profile such that more than 70% of the compound dissolves within 15 minutes in an in vitro solubility test of the pharmaceutical composition using the USP Apparatus 2 Paddle method at 50 rpm in an aqueous dissolution medium at 37 °C, a) obtaining a salt of a compound having the formula: 【Chemical Formula 3】 b) mixing said salt with one or more excipients, thereby producing said pharmaceutical composition, and c) optionally, tableting said pharmaceutical composition to produce a tablet core, preferably, further film-coating said tablet core, comprising a manufacturing method. **Claim 14** The manufacturing method according to claim 13, wherein said salt is an anionic salt, or preferably a halogen anion salt, or more preferably an HBr salt. **Claim 15** Step b) comprises i) blending said salt with one or more excipients, ii) roller compressing the product of step i), iii) grinding the product of step ii), preferably, said one or more excipients in step i) comprise stearic acid, more preferably about 5% by weight of stearic acid, more preferably, step b) further comprises blending the product of step iii) with one or more additional excipients, preferably, said one or more additional excipients comprise stearic acid, The manufacturing method according to claim 14. **Claim 16** None of said one or more excipients comprise any of dicalcium phosphate, croscarmellose sodium, magnesium stearate, calcium carmellose, sodium stearyl fumarate, calcium stearate, and anhydrous calcium hydrogen phosphate, preferably, said one or more excipients do not comprise a calcium salt, a magnesium salt, or a sodium salt, more preferably, said one or more excipients do not comprise calcium, magnesium, or sodium, even more preferably, said pharmaceutical composition does not comprise a metal salt, The manufacturing method according to claim 14. **Claim 17** The manufacturing method according to any one of claims 13 to 16, wherein said salt of said compound is in a crystalline form. **Claim 18** The manufacturing method according to any one of claims 13 to 16, wherein said salt of said compound is in an amorphous form. **Claim 19** Said one or more excipients are selected from the group consisting of microcrystalline cellulose, lactose, mannitol, polyvinylpyrrolidone, colloidal silicon dioxide, pregelatinized starch, low-substituted hydroxypropyl cellulose, talc, glyceryl dibehenate, and stearic acid, preferably, said pharmaceutical composition ​ ​ a) from about 30% to about 60% by weight of lactose, mannitol, or a combination thereof (wherein preferably from 20% to 30% by weight of D-mannitol is included, and preferably said D-mannitol is mannitol 400DC), b) from about 25% to about 50% by weight of microcrystalline cellulose, preferably from about 25% to about 50% by weight of microcrystalline cellulose (wherein preferably said microcrystalline cellulose is microcrystalline cellulose 102), c) from about 1% to about 10% by weight of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof, d) from about 1% to about 10% by weight of talc, glyceryl dibehenate, colloidal silicon dioxide, or a combination of two or more thereof, preferably e) from 3% to 8% by weight of stearic acid, more preferably about 5% by weight of stearic acid, comprising, The production method according to any one of claims 13 to 16.

20. The composition according to any one of claims 1 to 12 for use in treating hypertension and / or reducing blood pressure in a subject with hypertension.

21. The composition according to any one of claims 1 to 12 for use in inhibiting CYP11β2 beta hydroxylase in a subject.

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