Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/485—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention is directed to, inter alia , pharmaceutical compositions and processes for producing such pharmaceutical compositions.
• compositions comprising a salt of a compound having the formula:
• compositions comprising a salt of a compound having the formula:
• Figure 1 Powder x-ray diffraction peaks detected from MLS-101 after 3 days of storage with a metal salt (croscarmellose Na) (storage conditions: 60°C/75% RH).
• a metal salt croscarmellose Na
• Figure 2 Dissolution Test of API (left) and X-Ray Diffraction of API (right).
• Figure 3 Results of a dissolution test of the 10% API capsules under various conditions.
• Figure 4 Results of a dissolution test of tablet formulations after storage at 25°C in closed, 40°C/75% RH in open and closed containers.
• Figure 5 XRPD diffractograms of final blend and uncoated tablet for DC lot 1.
• Figure 6 XRPD diffractograms of final blend and uncoated tablet for DC lot 4.
• Figure 7 XRPD diffractograms of final blend and uncoated tablet for DC lot 5.
• Figure 8 XRPD diffractograms of at various steps of HSWG manufacturing process for lot 6.
• Figure 9 XRPD diffractograms of lot 11 final blend, uncoated tablet, and film coated tablet.
• Figure 10 XRPD diffractograms of lot 13 final blend, uncoated tablet, and film coated tablet.
• Figure 11 XRPD diffractograms of lot 15 final blend, uncoated tablet, and film coated tablet.
• Figure 12 XRPD diffractograms of lot 17 final blend, uncoated tablet (Trials #1 & #2), and film coated tablet (Trials #2).
• Figure 13 XRPD diffractograms of lot 18 final blend, uncoated tablet (Trials #l/#2 & #3), and film coated tablet (Trials #2).
• Figure 14 Summary of analytical data for prototype formulations.
• Figure 15 Dissolution profile of 12.5 mg, 25 mg, and 100 mg tablet prototypes in 0.1 HC1.
• Figure 16 Summary of analytical data for prototype formulations.
• Figure 17 Dissolution profile of 12.5 mg tablet prototypes in water.
• Figure 18 Dissolution profile of 12.5 mg tablet prototypes in 0. IN HC1.
• compositions comprising a salt of a compound having the formula:
• compositions comprising a salt of a compound having the formula:
• the pharmaceutical composition has a dissolution profile such that more than 70%, more than 75%, more than 80%, or more than 85% of the compound is dissolved in 15 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C.
• the pharmaceutical composition has a dissolution profile such that more than 70% more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the compound is dissolved in 30 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C.
• 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.
• the pharmaceutical composition does not comprise any of croscarmellose sodium, and magnesium stearate. In embodiments, the pharmaceutical composition does not comprise any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate. In embodiments, the pharmaceutical composition does not comprise any of dicalcium phosphate, croscarmellose sodium, magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous dibasic calcium phosphate. In embodiments, the pharmaceutical composition does not comprise a magnesium salt or a sodium salt. In embodiments, the pharmaceutical composition does not comprise a calcium salt, a magnesium or a sodium salt. In embodiments, the pharmaceutical composition does not comprise magnesium or sodium. In embodiments, the pharmaceutical composition does not comprise calcium, magnesium or sodium. In embodiments, the pharmaceutical composition does not comprise a metal salt.
• the pharmaceutical composition does not comprise any of croscarmellose sodium, and magnesium stearate. In embodiments where the salt is an HBr salt, the pharmaceutical composition does not comprise any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate. In embodiments where the salt is an HBr salt, the pharmaceutical composition does not comprise any of dicalcium phosphate, croscarmellose sodium, magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous dibasic calcium phosphate. In embodiments where the salt is an HBr salt, the pharmaceutical composition does not comprise a magnesium salt or a sodium salt.
• the pharmaceutical composition does not comprise a calcium salt, a magnesium or a sodium salt. In embodiments where the salt is an HBr salt, the pharmaceutical composition does not comprise magnesium or sodium. In embodiments where the salt is an HBr salt, the pharmaceutical composition does not comprise calcium, magnesium or sodium. In embodiments where the salt is an HBr salt, the pharmaceutical composition does not comprise a metal salt.
• the pharmaceutical composition may comprise a metal salt, may comprise calcium, magnesium or sodium, may comprise a calcium salt, a magnesium salt or a sodium salt, and may comprise dicalcium phosphate, croscarmellose sodium, and magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous dibasic calcium phosphate.
• the pharmaceutical composition does not comprise any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous dibasic calcium phosphate, does not comprise a calcium salt, a magnesium salt or a sodium salt, does not comprise calcium, magnesium or sodium, or does not comprise a metal salt.
• the salt of the compound is in solid form. In embodiments, the salt of the compound is in crystalline form. In embodiments the salt of the compound is in amorphous form. In embodiments the pharmaceutical composition comprises a mixture of the salt of the compound in crystalline and amorphous forms.
• the pharmaceutical composition comprises one or more pharmaceutically 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.
• pharmaceutically 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.
• the pharmaceutical composition comprises microcrystalline cellulose 102, mannitol 400DC, pregelatinized starch, and glyceryl dibehenate
• 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 to composition comprises 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.
• the pharmaceutical composition comprises: a) about 30 wt% to about 60 wt% of lactose, mannitol, or a combination thereof; b) about 25 wt% to about 50 wt% of microcrystalline cellulose; c) about 1 wt% to about 10 wt% of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; and d) about 1 wt% to about 10 wt% of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.
• the compound is more soluble in water than the same compound in an equivalent pharmaceutical composition comprising a calcium salt, a sodium salt or magnesium salt. In embodiments of the pharmaceutical composition, the compound is more soluble in water than the same compound in an equivalent pharmaceutical composition comprising a sodium salt or magnesium salt.
• the pharmaceutical composition has a dissolution profile such that more than 70%, more than 75%, more than 80%, or more than 70% of the compound is dissolved in 15 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C.
• the pharmaceutical composition has a dissolution profile such that more than 70% more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the compound is dissolved in 30 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C.
• the pharmaceutical composition avoids disproportionation in excess of 1% of the salt: a) when stored at 25 °C +/- 2°C and 60% relative humidity (RH) +/- 5% RH for 6 or 12 months; b) when stored at 30 °C +/- 2°C and 65% RH +/- 5% RH for 6 or 12 months; c) when stored at 30 °C +/- 2°C and 75% RH +/- 5% RH for 6 or 12 months; and/or d) when stored at 40 °C +/- 2°C and 75% RH +/- 5% RH for 6 months.
• RH relative humidity
• the pharmaceutical composition avoids disproportionation in excess of 5% of the salt: a) when stored at 25 °C +/- 2°C and 60% relative humidity (RH) +/- 5% RH for 6 or 12 months; b) when stored at 30 °C +/- 2°C and 65% RH +/- 5% RH for 6 or 12 months; c) when stored at 30 °C +/- 2°C and 75% RH +/- 5% RH for 6 or 12 months; and/or d) when stored at 40 °C +/- 2°C and 75% RH +/- 5% RH for 6 months.
• RH relative humidity
• the pharmaceutical composition avoids disproportionation in excess of 10% of the salt: a) when stored at 25 °C +/- 2°C and 60% relative humidity (RH) +/- 5% RH for 6 or 12 months; b) when stored at 30 °C +/- 2°C and 65% RH +/- 5% RH for 6 or 12 months; c) when stored at 30 °C +/- 2°C and 75% RH +/- 5% RH for 6 or 12 months; and/or d) when stored at 40 °C +/- 2°C and 75% RH +/- 5% RH for 6 months.
• RH relative humidity
• the aforementioned storage conditions are in a closed container. In embodiments, the aforementioned storage conditions are in an open container.
• the pharmaceutical composition after storage under any of the aforementioned conditions, has a dissolution profile such that more than 70%, more than 75%, more than 80%, or more than 85% of the compound is dissolved in 15 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C.
• the pharmaceutical composition after storage under any of the aforementioned conditions, has a dissolution profile such that more than 70% more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% of the compound is dissolved in 30 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37° C.
• 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.
• the pharmaceutical composition comprises: a) about 1 wt% to about 8 wt% of the compound; b) about 50 wt% to about 60 wt% of lactose, mannitol, or a combination thereof; c) about 25 wt% to about 40 wt% of microcrystalline cellulose; d) about 1 wt% to about 10 wt% of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; and e) about 1 wt% to about 10 wt% of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.
• the pharmaceutical composition comprises from about 15 milligrams to about 35 milligrams of the compound, preferably from about 20 milligrams to about 30 milligrams of the compound, or more preferably about 25 milligrams of the compound.
• the pharmaceutical composition comprises: a) about 5 wt% to about 15 wt% of the compound; b) about 30 wt% to about 50 wt% of mannitol; c) about 30 wt% to about 50 wt% of microcrystalline cellulose; d) about 1 wt% to about 10 wt% of pregelatinized starch; and e) about 1 wt% to about 5 wt% of glyceryl dibehenate, colloidal silicone dioxide, or a combination thereof.
• the pharmaceutical composition comprises from about 80 milligrams to about 120 grams of the compound, preferably from about 95 milligrams to about 105 milligrams of the compound, or more preferably about 100 milligrams of the compound.
• the pharmaceutical composition comprises: a) about 30 wt% to about 40 wt% of the compound; b) about 20 wt% to about 30 wt% of mannitol; c) about 20 wt% to about 40 wt% of microcrystalline cellulose; d) about 1 wt% to about 10 wt% of pregelatinized starch; e) about 1 wt% to about 5 wt% of glyceryl dibehenate, colloidal silicone dioxide, or a combination thereof.
• the pharmaceutical composition comprises between 3 wt% and 8 wt% of stearic acid, preferably about 5 wt% stearic acid.
• the pharmaceutical composition is a tablet.
• the tablet comprises a coating.
• the coating comprises hydroxypropylmethyl cellulose, polyvinyl alcohol, or a combination thereof.
• the pharmaceutical composition has a dissolution profile such that more than 70%, more than 75%, more than 80%, or more than 85% of the compound is dissolved in 30 minutes in an in vitro dissolution test of the pharmaceutical composition using USP Apparatus 2 Paddle Method at 50 rpm in a dissolution medium of water at 37°C.
• the salt is an anion salt. In an embodiment, the salt is a halogen anion salt. In an embodiment, the salt is an HBr salt.
• step b) comprises: i) blending the salt with one or more excipients; and ii) roller compaction of the product of step i); and iii) milling the product of step ii).
• one or more excipients of step i) comprises stearic acid, more preferably about 5 wt% stearic acid.
• step b) further comprises a step of blending the product of step iii) with one or more additional excipients, preferably wherein the one or more additional excipients comprise stearic acid.
• the process further comprises tableting the pharmaceutical composition to produce tablet cores. In an embodiment, the process further comprises film coating the tablet cores.
• the one or more excipients do not comprise any of croscarmellose sodium, and magnesium stearate. In an embodiment of the process, the one or more excipients do not comprise any of dicalcium phosphate, croscarmellose sodium, and magnesium stearate. In an embodiment of the process, the one or more excipients do not comprise any of dicalcium phosphate, croscarmellose sodium, magnesium stearate, carmellose calcium, sodium stearyl fumarate, calcium stearate, and anhydrous dibasic calcium phosphate. In an embodiment of the process, the one or more excipients do not comprise a magnesium salt or a sodium salt.
• the one or more excipients do not comprise a calcium salt, a magnesium salt or a sodium salt. In an embodiment of the process, the one or more excipients do not comprise magnesium or sodium. In an embodiment of the process, the one or more excipients do not comprise calcium, magnesium or sodium. In an embodiment of the process, the one or more excipients do not comprise a metal salt.
• the salt of the compound is in solid form. In embodiments, the salt of the compound is in crystalline form. In embodiments, the salt of the compound is in amorphous form. In embodiments of the process, the pharmaceutical composition comprises a mixture of the salt of the compound in crystalline and amorphous forms.
• 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.
• the one or more excipients comprise microcrystalline cellulose 102, mannitol 400DC, pregelatinized starch, and glyceryl dibehenate.
• the pharmaceutical composition comprises: a) about 30 wt% to about 60 wt% of lactose, mannitol, or a combination thereof; b) about 25 wt% to about 50 wt% of microcrystalline cellulose; c) about 1 wt% to about 10 wt% of polyvinylpyrrolidone, pregelatinized starch, or a combination thereof; d) about 1 wt% to about 10 wt% of talc, glyceryl dibehenate, colloidal silicone dioxide, or a combination of two or more thereof.
• the pharmaceutical composition comprises one or more or all of the following features: a) between 20 wt% and 30 wt% of microcrystalline cellulose; b) between 20 wt% and 30 wt% of D-Mannitol; and c) between 3 wt% and 8 wt% of stearic acid.
• Also provided herein is a method of treating hypertension and/or reducing blood pressure in a hypertensive subject, the method comprising administering to the hypertensive subject any of the compositions described herein.
• Also provided herein is a method of inhibiting CYP11b2 beta hydroxylase in a subject, the method comprising administering to the subject the composition of any of the compositions described herein.
• compositions described herein for use in treating hypertension and/or reducing blood pressure in a hypertensive subject.
• compositions described herein for use in inhibiting CYP11b2 beta hydroxylase in a subject.
• each of the verbs, “comprise,” “include” and “have” and conjugates thereof, are used to indicate that the object or objects of the verb are not necessarily a complete listing of components, elements or parts of the subject or subjects of the verb.
• Other terms as used herein are meant to be defined by their well-known meanings in the art.
• ADSI and MLS-101 refers to the hydrobromide (HBr) salt of the disubstituted 1, 2, 4-Triazine compound which is represented by Formula (A):
• Weights and/or strengths of “ALDSI”, “MLS-101,” and “the compound” of the invention refer to the weight of the free base in the HBr salt and not the weight of the HBr salt.
• This invention relates to the surprising discovery that MLS-101 undergoes disproportionation when combined with pharmaceutical excipients containing metal salts, in particular calcium salts, magnesium salts and sodium salts. Accordingly, each pharmaceutical composition of the invention “does not comprise” excipients containing metal salts (and in particular “does not comprise” calcium salts, magnesium salts or sodium salts) in order to avoid disproportionation of MLS-101 and preserve its aqueous solubility. A person skilled in the art will appreciate that a pharmaceutical composition would be within the scope of the invention when it contains trace amounts of such metal salts if such trace amounts do not cause disproportionation above an acceptable threshold limit.
• the use of the term “does not comprise” encompasses amounts of metal salts that are low enough so as to not cause disproportionation above an acceptable threshold limit.
• 10% disproportionation is the acceptable threshold limit for disproportionation.
• a lower threshold limit of disproportionation may be preferred.
• the composition avoids disproportionation in excess of 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.
• the pharmaceutical compositions of the invention may include a “therapeutically effective amount” or a “prophylactically effective amount” of a compound of the invention.
• a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
• a therapeutically effective amount of the compound may vary according to 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 detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
• a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
• ALDSI has a high propensity toward disproportionation in the presence of a metal salt. Study of Salt Disproportionation and Strategy to Reduce the Disproportionation Risk
• Test method JP Apparatus for Paddle Method (Apparatus 2)
• Dissolution medium JP Second Fluid for dissolution test (A mixture of phosphate buffer solution (pH 6.8) and water (1:1), as described in the Japanese Pharmacopoeia.)
• API alone was compressed at 300, 600, and 900 kilograms of force (i.e. about 2942, 5884, and 8826 Newtons, respectively) to evaluate dissolution. a) There were no differences in dissolution among samples. b) There were no changes in dissolution over time when samples were stored at 60°C/75% RH (for 3 days or 1 week).
• API alone was kneaded with large, middle, and small amounts of water to evaluate dissolution. a) There were no differences in dissolution among samples.
• API alone was ground for 1, 3, 20, and 30 min to evaluate dissolution. a) There were no differences in dissolution among samples. b) There were no changes in dissolution over time when samples were stored at 60°C/75% RH (for 3 days or 1 week).
• Residues after dissolution test a) Samples without residues were considered not to undergo disproportionation as the water solubility markedly decreases after salt disproportionation. Yellow residues were considered to represent salt disproportionation as ALDSI free base is yellow in color. White residues were considered an insoluble excipients and no salt disproportionation as ALDSI free base. Results
• D-Mannitol and talc were mixed and sieved.
• the API was added to the sieved mixture, blended, sieved, and filled in HPMC capsules.
• Figure 3 shows the results of a dissolution test of the 10% API capsules under various conditions.
• 10% API capsules formulated with excipients considered not to cause disproportionation may be a pharmaceutical formulation with a low risk of salt di sproporti onati on .
• API granules, a disintegrant, and lubricants were mixed in a polyethylene bag. After confirming pressure dependency, the mixture was subjected to sequential tableting (900 kilogram of force, i.e. about 8826 Newtons). Table 4: Formulations
• Figure 4 shows the dissolution test results.
• This example documents the formulation development of 12.5, 25, and 100 mg MLS-101 film coated tablet dosage form with immediate release characteristics.
• XRPD X-Ray Powder Diffraction
• Table 7 presents the composition of direct compression (DC) formulations lots 1, 2 A, 2C, 3 A-5; roller compaction (RC) lot 2B; and high shear wet granulation (HSWG) lot 6.
• Table 8 presents the Placebo blends lots 7-10 (corresponding to the active lots 1, 4-6).
• Table 8 also contain the composition of ‘new’ (explanations below) DC formulations prototypes without excipients containing metallic ions lots 11, 13, and 15 with their respective Placebo lots 12, 14, and 16, respectively, and additional lots 17 to 19.
• MLS-101 was discovered to be susceptible to salt disproportionation in the presence of excipients containing metallic salts.
• additional ‘new’ DC lots 11, 13, 15, 17, 18, and 19 (Table 8) without excipients such as dicalcium phosphate, croscarmellose sodium, and magnesium stearate were proposed to reduce the salt disproportionation risk.
• the 100 mg FB tablet lot 19 was prepared as per lot 18 with MCC replaced by SMCC and with increased lubricant at 3%.
• Placebos were processed using a Patterson-Kelly BlendMaster 0.5 L V-blender. All placebo excipients (including Opadry) were de-lumped over a 600 pm sieve and blended for 3 min. The lubricant that was screened over the same sieve, added to the V-blender, and mixed for an additional 2 min.
• Table 7 Composition of Different Formulations ofMLS-101 Tablet Lots 1 to 6
• Table 8 Composition of Different Formulations ofMLS-101 Tablet Lots 7 to 19
• the quality attributes of the drug product were assessed by analytical testing including appearance, content uniformity, assay, related substances, water content, and dissolution profile.
• the first R&D stability study was performed on 12.5 mg MLS-101 FCT lot 1, 25 mg FCT lot 4, and 100 mg FCT lots 5 and 6.
• the tablets were packaged in Aclar® blister with 10 FCT per blister.
• the blister material Pentapharm Aclar PA 160/02 (254/15, Clear, 160 mm width, Color #: 71/9400, Klockner lot 0075966400) and the foil was a 25 pm Aluminium lidding push through (Constancia AL109CSM.
• a small portion of the tablets were also 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.
• HDPE high- density polyethylene
• Placebo blends were packaged in 60 cc round white opaque HDPE bottles (Drug Plastics & Glass Co.) with induction sealed child resistant polypropylene caps (Berry).
• Table 10 Stability protocol for MLS-101 12 5 mg FCT lots 11. 13. 15. and matching Placebo blends.
• Table 11 Stability protocol for MLS-101 25 mg FCT lot 17 and 100 mg FCT lot 18
• Lot 15 prepared with Mannitol contains API in an amount of 88.5%, therefore, Lot 15 presented a low assay of 88.5%, lower dissolution profiles with 92 and 89% released in water and 0.1N HC1, respectively, within 15 minutes and, low content uniformity of 89.6% LC.

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• 2022
  • 2022-07-20 CN CN202280051082.5A patent/CN117957213A/zh active Pending
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