Formulations for oral delivery of proteins, peptides, and small molecules with low permeability

Abstract

The present disclosure relates to pharmaceutical formulations intended for oral delivery of therapeutically active synthetic or natural poorly permeable calcitonin gene-related peptide (CGRP) inhibitors or salts / solvates thereof. The pharmaceutical formulations may comprise the synthetic or natural poorly permeable CGRP inhibitor or its salts or solvates in an amount of 0.01-10 wt% of the total formulation weight; a lipophilic phase comprising a triglyceride of a fatty acid in an amount of 50-80 wt% of the total formulation weight; and at least one lipophilic surfactant comprising a partial ester of a polyol and a fatty acid in an amount of about 10-50 wt% of the total formulation weight.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 832,508, filed on April 11, 2019, the entire content of which is incorporated herein by reference.

[0002] The present disclosure relates to formulations for oral delivery of poorly permeable proteins, peptides, and small molecules. More specifically, the present disclosure relates to pharmaceutical formulations intended for oral delivery of any synthetic or natural molecule having therapeutic activity and having poor permeability, or a salt or solvate thereof.

Background Art

[0003] Poorly permeable molecules are compounds with poor absorption through the intestinal membrane. Therefore, these are administered intravenously or subcutaneously. Due to poor absorption through the intestinal membrane, their clinical use is very limited when it is necessary to administer by IV several times a day (for example, insulin for diabetes). These poorly permeable compounds are identified as Class III and Class IV compounds in the BCS classification proposed by, for example, Amidon GL et al., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability (Pharm Res. March 1995; 12(3):413 - 420), which is incorporated herein by reference in its entirety.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

[0005] [Non-Patent Document 1] Amidon GL et al., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability (Pharm Res. March 1995; 12(3):413 - 420) [Non-Patent Document 2] ICH Harmonized Tripartite Guideline ICH Q3B (Impurities in New Drug Products), dated June 2, 2006 [Non-Patent Document 3] FDA Guidance for Industry, ANDAs: Blend Uniformity, dated August 3, 1999 [Non-Patent Document 4] Code of Federal Regulations, Title 9, Part 3, Revised 1991 [Non-Patent Document 5] Guide for the Care and Use of Laboratory Animals (Research Council, 2011) [Non-Patent Document 6] Title 21, Part 38 of the Code of Federal Regulations [Summary of the Invention] [Problems to be Solved by the Invention]

[0006] The present applicants are developing formulations for orally administered low permeability molecules. The molecules can be CGRP inhibitors. These formulations are very beneficial for patients who require administration several times a day. In order to prepare such formulations for oral delivery of low permeability CGRP inhibitors, the present applicants had to overcome at least this low permeability to the intestinal membrane and, for some of these inhibitors, particularly peptides and proteins, overcome the chemical and physical instabilities in the digestive tract, specifically the loss of activity due to the acidic state in the stomach and enzymatic degradation throughout the intestine. Thus, the present applicants have developed a delayed release coated dosage form capable of delivering a low permeability CGRP inhibitor in the intestine with in-situ generation of a penetration enhancer to enhance its bioavailability.

[0007] In U.S. Patent No. 9,259,389, the inventors found that a digestive inverse emulsion can enhance the bioavailability of oligosaccharides. Unexpectedly, the present applicants found that a solution of a lipid additive having a low permeability molecule dispersed as a powder in a formulation enables better results in bioavailability for this particular class of molecules (i.e., compounds of Class III and Class IV of BCS in the classification proposed by Amidon GL et al. (Pharm Res. March 1995; 12(3):413-420)). Specifically, the present applicants found that a formulation without added water can be beneficial for low permeability molecules, specifically proteins and peptide compounds of Class III of BCS. Without being bound by any theory, water is thought to have a tendency to aggregate molecules of this class with low permeability to each other. More specifically, the present applicants found that a higher degree of results in bioavailability was achieved with this particular class of molecules when the formulation containing a solution of a lipid-based additive having a low permeability Class III protein or peptide molecule or salt of BCS dispersed as a powder in the formulation did not contain water. In contrast, the removal of water was detrimental for the saccharides of U.S. Patent No. 9,259,389.

[0008] In addition, when the applicant etc. can disperse the API as a powder that does not need to solubilize the API in water when it is not necessary to solubilize the active pharmaceutical ingredient ("API"), the drug filling amount can be increased. Further, the formulation is essentially more physically stable because the lipid additive can exist in the solution as a single phase. Therefore, it may not be necessary to add a stabilizer such as silicon dioxide to stabilize the phase. In some embodiments, the thickener can be added for the purpose of manufacturing to maintain the homogeneity of the API powder in the suspension during the process. In some embodiments, the thickener can be silicon dioxide. Finally, compared with other formulations found in the literature using additives such as penetration enhancers, the formulations disclosed herein can generally be recognized and used only as safe additives or already commercially available ingredients.

Means for Solving the Problems

[0009] In some embodiments, the pharmaceutical formulation comprises a synthetic or natural low permeability CGRP inhibitor or a salt or solvate thereof in an amount of 0.01 to 20 wt% of the total mass of the formulation; a lipophilic phase comprising a triglyceride of a fatty acid in an amount of 50 to 80 wt% of the total mass of the formulation; and at least one lipophilic surfactant comprising a polyol and a partial ester of a fatty acid in an amount of 10 to 50 wt% of the total mass of the formulation. In some embodiments, the synthetic or natural low permeability CGRP inhibitor or a salt or solvate thereof is a CGRP antibody, a CGRP receptor antibody, an antigen-binding fragment derived from a CGRP antibody or a CGRP receptor antibody, a CGRP injection inhibitory protein, a CGRP biological neutralizing agent, a small molecule CGRP receptor antagonist, a small molecule CGRP inhibitor, or a polypeptide CGRP inhibitor. In some embodiments, the small molecule CGRP receptor antagonist is (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BHV-3500). In some embodiments, the formulation comprises at least one hydrophilic surfactant having a hydrophilic-lipophilic balance (「HLB」) greater than 10 in an amount of 1 to 30 wt% of the total mass of the formulation. In some embodiments, the at least one hydrophilic surfactant is selected from the group consisting of polyoxyethylene(20) monooleate, PEG 8 caprylic / capric glyceride, PEG 6 caprylic / capric glyceride, poly(oxyethylene)(4) lauryl ether, and mixtures thereof. In some embodiments, the triglyceride of the fatty acid is a medium-chain fatty acid. In some embodiments, the lipophilic surfactant comprises a mixture of monoglycerides and diglycerides of medium-chain fatty acids. In some embodiments, the formulation is water-free. In some embodiments, the sustained-release pharmaceutical dosage form comprises any of the above-described formulations, and the sustained-release dosage form is a coated dosage form whose release is pH-dependent. In some embodiments, a method for treating a patient comprises administering to a person in need thereof an effective amount of any of the above-described formulations.

[0010] Additional advantages will be apparent to those skilled in the art from the following detailed description. The examples and descriptions in this specification are to be considered illustrative in nature and not restrictive.

[0011] All publications, including patent documents, scientific papers, and databases, referred to in this application are incorporated by reference in their entirety for all purposes as if each individual publication were incorporated by reference individually to the same extent. If the definitions set forth in this specification are contrary to or inconsistent with the definitions set forth in patents, applications, published applications, and other publications incorporated by reference herein, the definitions set forth in this specification shall control over the definitions incorporated by reference herein.

[0012] These aspects and / or other aspects will become apparent and be more readily understood from the following description of the embodiments, taken in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0014] The present disclosure relates to pharmaceutical formulations intended for oral administration containing synthetic or natural poorly permeable molecules having therapeutic activity, or pharmaceutically acceptable salts or solvates thereof. These formulations can be lipid-based formulations. In addition, these formulations can be in a delayed-release dosage form. In some embodiments, the dosage form can be a delayed-release soft gel capsule, a hard capsule, or a combination thereof. In some embodiments, this delayed-release dosage form can be an enteric-release dosage form.

[0015] The formulation may comprise (A) a synthetic or natural molecule with low permeability; (B) a lipophilic phase; (C) at least one lipophilic surfactant; and / or (D) at least one hydrophilic surfactant. In some embodiments, the formulation may comprise a chemical and / or physical stabilizer.

[0016] A synthetic or natural molecule with low permeability In some embodiments, the formulation may comprise a synthetic or natural molecule with low permeability, or any pharmaceutically acceptable salt of these molecules with low permeability, in an amount of up to about 1 wt%, about 2 wt%, about 5 wt%, about 10 wt%, about 15 wt%, or about 20 wt% of the total mass of the formulation. In some embodiments, the formulation may comprise a synthetic or natural molecule with low permeability, or any pharmaceutically acceptable salt of these molecules with low permeability, in an amount of about 0.01 - 30 wt%, about 0.1 - 30 wt%, about 0.01 - 20 wt%, about 0.1 - 20 wt%, about 0.1 - 15 wt%, about 0.1 - 10 wt%, about 0.1 - 5 wt%, about 0.1 - 2 wt%, about 0.1 - 1 wt%, about 0.1 - 0.5 wt%, or about 0.5 - 1.5 wt% of the total mass of the formulation.

[0017] Synthetic or natural low permeability molecules, or pharmaceutically acceptable salts thereof, can include any low permeability protein, polypeptide, peptide, or small molecule intended for oral delivery, and the active ingredients according to the present invention include, but are not limited to, insulin, human growth hormone, calcitonin (such as salmon calcitonin), interferons such as α-, β-, or γ-interferon, glucagon, gonadotropin releasing hormone, enkephalin, vaccines, enzymes, hormone analogs, enzyme inhibitors, antibodies, and antibody mimetics. Synthetic or natural low permeability molecules, or pharmaceutically acceptable salts thereof, are identified as Class III and Class IV in the BCS classification in the classification proposed by Amidon GL et al., A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability (Pharm Res. March 1995; 12(3):413-420).

[0018] CGRP inhibitor Synthetic or natural low permeability molecules can be calcitonin gene-related peptide (CGRP) inhibitors. As used herein, the term "CGRP inhibitor" refers to a chemical substance that can be an inhibitor of a CGRP ligand or a CGRP receptor. Thus, the term "CGRP inhibitor" includes CGRP receptor inhibitors. A CGRP inhibitor can be a CGRP inhibitor or a CGRP receptor inhibitor. CGRP (calcitonin gene-related peptide) is a 37-amino acid neuropeptide that belongs to a family of peptides including calcitonin, adrenomedullin, and amylin. Substantial evidence has been collected to show that CGRP is involved in the pathophysiology of migraine. Clinical trials have been conducted to show that CGRP inhibitors are effective in treating migraine.

[0019] A CGRP inhibitor can be a CGRP antibody, a CGRP receptor antibody, an antigen-binding fragment derived from a CGRP antibody or a CGRP receptor antibody, a CGRP injection-inhibiting protein, a CGRP biological neutralizing agent, a small molecule CGRP receptor antagonist, a small molecule CGRP inhibitor, or a polypeptide CGRP inhibitor. In one embodiment, the CGRP inhibitor can be a small molecule CGRP receptor antagonist. The small molecule CGRP receptor antagonist can be (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BHV-3500).

[0020] The CGRP inhibitor can be administered at a dose of about 1 to 1000 mg per day. In another aspect, the CGRP inhibitor is administered at a dose of about 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 250, 300, 400, 500, 750, or 1000 mg per day. The daily dose of the CGRP inhibitor can be in the range between any of the above values.

[0021] Lipophilic phase In some embodiments, the formulation can contain the lipophilic phase in an amount of up to about 50 wt%, about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, or about 80 wt% of the total mass of the formulation. In some embodiments, the formulation can contain the lipophilic phase in an amount of about 50 - 80 wt%, about 55 - 75 wt%, about 60 - 70 wt%, about 62 - 68 wt%, about 64 - 66 wt%, or about 65 wt% of the total mass of the formulation.

[0022] In some embodiments, the lipophilic phase can be a triglyceride of a fatty acid. The triglyceride of a fatty acid can mean any triglyceride of a pharmaceutically and orally acceptable saturated or unsaturated fatty acid. In some embodiments, the triglyceride of a fatty acid has the following formula:

[0023]

Chemical formula

[0024] (wherein, R1, R2, and R3 each independently represent an alkyl or alkenyl group of a parent fatty acid) may have.

[0025] The fatty acid may be saturated or unsaturated. In particular, since unsaturated fatty acids can result in a slower digestion rate and a lower digestibility, the fatty acid can be saturated. Some common saturated fatty acids are shown in Table 1 below.

[0026]

Table 1

[0027] R1, R2, and R3 may represent a straight chain or a branched chain. In some embodiments, R1, R2, and R3 may be a C3-C23 alkyl or alkenyl group, a C5-C13 alkyl or alkenyl group, or a C7-C9 alkyl or alkenyl group. In some embodiments, the fatty acid is a saturated fatty acid and a medium-chain fatty acid. Therefore, the lipophilic phase may be a triglyceride of a long-chain (e.g., soybean oil and fish oil), medium-chain, or short-chain (e.g., glyceryl triacetate) fatty acid. In some embodiments, the triglyceride may be of caprylic acid, capric acid, or a mixture thereof (e.g., commercially available Miglyol 812 (registered trademark), Captex 355 (registered trademark), Estasan (registered trademark), Neobee M5 (registered trademark), Labrafac CC (registered trademark), and Captex 1000 (registered trademark)). In some embodiments, the triglyceride may be a triglyceride of a C6-C12 fatty acid or a C8-C10 fatty acid.

[0028] Lipophilic surfactant In some embodiments, the formulation may include at least one lipophilic surfactant in an amount of up to about 1 wt%, about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% of the total mass of the formulation. In some embodiments, the formulation may include at least one lipophilic surfactant in an amount of about 10-50 wt%, about 15-35 wt%, about 20-30 wt%, about 22-28 wt%, about 24-26 wt%, or about 25 wt% of the total mass of the formulation. If the formulation includes less than about 10 wt% of at least one lipophilic surfactant, dynamic digestion cannot be optimized. If the formulation includes more than 50 wt% of at least one lipophilic surfactant, the amount of the lipophilic phase available for the release of sodium caprylate may not be optimal.

[0029] In some embodiments, at least one lipophilic surfactant can be a partial ester of a polyol and a fatty acid. The partial ester of a polyol and a fatty acid can mean any partial ester obtained by esterification of a pharmaceutically and orally acceptable polyol and a saturated or unsaturated fatty acid. Common saturated fatty acids are shown in Table 1 above. The fatty acid can be a medium-chain fatty acid such as a C6-C12 fatty acid, and in particular can be caprylic acid and / or capric acid. The polyol can be, for example, propylene glycol and glycerol. For example, the partial ester of a polyol and a fatty acid can be a monoester and / or diester of propylene glycol of a fatty acid (e.g., propylene glycol monolaurate sold under the trade name Lauroglycol®, propylene glycol monomyristate sold under the trade name Mirpyl®, or propylene glycol dicaprylate / dicaprate sold under the trade names Captex 200®, Miglyol 840®, or Neobee M-20®), and / or an ester of polyglycerol of a fatty acid (e.g., polyglyceryl oleate sold under the trade names Plurol Oleique® or Drewpol 10.10.10®, or polyglyceryl mixed fatty acids sold under the trade name Caprol ET®).

[0030] At least one lipophilic surfactant can be a partial ester of propylene glycol and a fatty acid (e.g., commercially available Capryol PGMC® and Capmul PG-8®). In some embodiments, at least one lipophilic surfactant can be a mixture of monoglycerides and diglycerides of fatty acids, a mixture of monoglycerides and diglycerides of medium-chain fatty acids, a mixture of monoglycerides and diglycerides of caprylic acid and / or capric acid (e.g., commercially available Capmul MCM and Capmul MCM C8®, Imwitor 988®, Imwitor 742®), or a mixture of monoglycerides and diglycerides of capric acid (e.g., commercially available Capmul MCM C100 or Imwitor 308®).

[0031] In some embodiments, at least one lipophilic surfactant can be lecithin, such as soybean lecithin, but is not limited to soybean lecithin.

[0032] Hydrophilic surfactant In some embodiments, the formulation can contain at least one hydrophilic surfactant in an amount of up to about 2 wt%, about 5 wt%, about 8 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, or about 30 wt% of the total mass of the formulation. In some embodiments, the formulation can contain at least one hydrophilic surfactant in an amount of about 0 - 30 wt%, about 0 - 15 wt%, about 0 - 10 wt%, about 1 - 30 wt%, about 5 - 15 wt%, about 8 - 12 wt%, about 9 - 11 wt%, or about 10 wt% of the total mass of the formulation. If the amount of at least one hydrophilic surfactant is more than about 30 wt% of the formulation, it may interfere with the amount of the lipophilic phase available for the release of sodium caprylate.

[0033] In some embodiments, at least one hydrophilic surfactant can be any hydrophilic surfactant having a hydrophilic-lipophilic balance ( "HLB") value greater than 10 that is pharmaceutically and orally acceptable. The HLB value is an empirical parameter commonly used by those skilled in the art to characterize the relative hydrophilicity and lipophilicity of nonionic surfactants.

[0034] In some embodiments, at least one hydrophilic surfactant is a phospholipid; a polyoxyethylene sorbitan fatty acid derivative, such as polyoxyethylene (20) monolaurate (sold under the trade name Tween 20 (registered trademark)), polyoxyethylene (20) monooleate (sold under the trade name Tween 80 (registered trademark) and / or Crillet 4 (registered trademark)), or polyoxyethylene (20) monopalmitate (sold under the trade name Montanox 40 (registered trademark)); a castor oil or hydrogenated castor oil ethoxylate with an HLB value greater than 10, such as polyoxyethylene (35) castor oil (sold under the trade name Cremophor EL (registered trademark)), polyoxyethylene (40) hydrogenated castor oil (sold under the trade name Cremophor RH40 (registered trademark)), polyoxyethylene (40) castor oil (sold under the trade name Etocas 40 (registered trademark)), or polyoxyethylene (60) hydrogenated castor oil (sold under the trade name Nikkol HCO-60 (registered trademark)); a fatty acid ethoxylate with an HLB value greater than 10, such as polyoxyethylene (8) stearate (sold under the trade name Myrj 45 (registered trademark)), polyoxyethylene (30) monolaurate (sold under the trade name Tagat L (registered trademark)), polyoxyethylene (20) stearate (sold under the trade name Marlosol 1820 (registered trademark)), or polyoxyethylene (15) oleate (sold under the trade name Marlosol OL15 (registered trademark)); an alcohol ethoxylate with an HLB value greater than 10, such as polyoxyethylene (10) oleyl ether (sold under the trade name Brij 96 (registered trademark)), polyoxyethylene (15) oleyl ether (sold under the trade name Volpo 015 (registered trademark)), polyoxyethylene (30) oleyl ether (sold under the trade name Marlowet OA30 (registered trademark)), or polyoxyethylene (20) C12 - C14 fatty ether (sold under the trade name Marlowet IMA20 (registered trademark)); a polyoxyethylene - polyoxypropylene copolymer and block copolymer with an HLB value greater than 10, such as a product sold under the trade name Syperonic PE L44 (registered trademark) with an HLB value = 16 or a product sold under the trade name Syperonic F127 (registered trademark) with an HLB value = 22;An anionic surfactant, such as sodium lauryl sulfate, sodium oleate or sodium dioctyl sulfosuccinate, or an alkylphenol surfactant with an HLB value greater than 10, such as polyoxyethylene (9-10) nonylphenol (sold under the trade name Triton N-101 (registered trademark)), or polyoxyethylene (9) nonylphenol (sold under the trade name Synperonic NP9 (registered trademark)); vitamin E; D-alpha-tocopheryl polyethylene glycol succinate (TPGS); or PEG 15 hydroxystearate (sold under the trade name Solutol HS15 (registered trademark)) may be used.;

[0035] In some embodiments, at least one hydrophilic surfactant is a polyethoxylated surfactant. In some embodiments, at least one hydrophilic surfactant is selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, and polyoxyethylene esters of fatty acids, such as polyoxyethylene esters of glycerol and fatty acids. In some embodiments, the fatty acid is saturated or unsaturated. Common saturated fatty acids are shown in Table 1 above. In some embodiments, the fatty acid is a medium-chain fatty acid such as a C6-C12 fatty acid (e.g., lauric acid, caprylic acid and / or capric acid).

[0036] In some embodiments, the number of ethylene oxide group units in the surfactant can be from 4 to 20. In some embodiments, at least one hydrophilic surfactant can be selected from the group consisting of polyoxyethylene (20) monooleate (e.g., the commercial product Tween 80 (registered trademark)), PEG 8 caprylic / capric glyceride (e.g., the commercial product Labrasol (registered trademark)), PEG 6 caprylic / capric glyceride (e.g., the commercial product Softigel 767 (registered trademark)), poly(oxyethylene (4) lauryl ether (e.g., the commercial product Brij 30 (registered trademark)), and mixtures thereof.

[0037] Hydrophilic solvent In some embodiments, the formulation may include at least one anhydrous hydrophilic solvent in an amount of up to about 15 wt%, about 10 wt%, about 5 wt%, or about 1 wt% of the total mass of the formulation to assist in solubilizing the API. In some embodiments, the formulation does not include at least one hydrophilic solvent. In some embodiments, at least one hydrophilic solvent is added, for example, to solubilize a thickening agent.

[0038] In some embodiments, at least one hydrophilic solvent can be selected from the group consisting of propylene glycol, PEG 400, diethylene glycol monoethyl ether, glycerol triacetate, ethanol, glycerol, dimethyl isosorbide, N-methyl-2-pyrrolidone, poloxamer, and mixtures thereof.

[0039] Chemical and / or physical stabilizers In some embodiments, the formulation may include at least one chemical and / or physical stabilizer in an amount of up to about 25 wt% of the total mass of the formulation. In some embodiments, the physical stabilizer can be added to maintain the uniformity of the API powder suspension during the process. As described below, the placebo formulation is physically stable when it is a single phase consisting of lipid additives in solution, but a thickening agent is added because the API powder is dispersed to maintain homogeneity as a suspension.

[0040] The chemical and / or physical stabilizer can be any pharmaceutical ingredient that improves the chemical stability of low-permeability molecules in the formulation or improves the physical stability of low-permeability molecular formulations to comply with the requirements of the ICH Harmonized Tripartite Guideline ICH Q3B (Impurities in New Drug Products), current Step 4 version, dated June 2, 2006.

[0041] In some embodiments, the chemical stabilizer can be a lipophilic surfactant. For example, the chemical stabilizer can be esters of acetic, succinic, lactic, citric, and / or tartaric acid with monoglycerides and / or diglycerides of fatty acids, such as distilled acetylated monoglyceride (sold under the trade name Myvacet 9-45 (registered trademark)), diglyceryl succinate caprylate / caprate (sold under the trade name Miglyol 829 (registered trademark)), mono / di-succinylated monoglyceride (sold under the trade name Myverol SMG (registered trademark)), glyceryl stearate citrate (sold under the trade name Imwitor 370 (registered trademark)), glyceryl monostearate / citrate / lactate (sold under the trade name Imwitor 375 (registered trademark)), or diacetyl tartaric acid ester of monoglyceride (aster) (sold under the trade name Cordatem T22 (registered trademark)); acid ester ethoxylates formed by reacting fatty acids or glycerol esters of fatty acids with an HLB value of less than 10 with ethylene oxide, such as polyoxyethylene (4) laurate (sold under the trade name Crodet 04 (registered trademark)), polyoxyethylene (2) stearate (sold under the trade name Cithrol 2MS (registered trademark)), polyoxyethylene (3) stearate (sold under the trade name Marlosol 183 (registered trademark)), or glyceryl 12 EO dioleate (sold under the trade name Marlowet G12DO (registered trademark)); sorbitan esters of fatty acids, such as sorbitan monolaurate (sold under the trade name Span 20 (registered trademark) or Crill 1 (registered trademark)), or sorbitan monooleate (sold under the trade name Crill 4 (registered trademark)); transesterification reaction products of triglycerides of natural or hardened vegetable oils and polyalkylene polyols with an HLB value of less than 10, such as polyoxyethylated apricot kernal oil (sold under the trade name Labrafil M1944CS (registered trademark)), polyoxyethylated corn oil (sold under the trade name Labrafil M2125CS (registered trademark)), or polyoxyethylated hardened oil (sold under the trade name Gelucire 37 / 06 (registered trademark));Or it can be an alcohol ethoxylate with an HLB value of less than 10, such as polyoxyethylated (3) oleyl ether (sold under the trade name Volpo N3®), polyoxyethylated (2) oleyl ether (sold under the trade name Brij 93®), or polyoxyethylated (4) lauryl ether (sold under the trade name Marlowet LA4®).;

[0042] In some embodiments, the chemical stabilizer can be a buffering agent such as a citrate, phosphate, or acetate buffer, and / or a thickening agent such as a partially hydrogenated oil, hydrogenated oil, or monoester of an unsaturated or saturated fatty acid, a polyvinylpyrrolidone derivative, or polyethylene oxide.

[0043] In some embodiments, the physical stabilizer is silicon dioxide. In some embodiments, the silicon dioxide can be colloidal silicon dioxide. Colloidal silicon dioxide is also known as fumed silicon dioxide, silica fume, or calcined silica. Such silicon dioxide is commercially available under the trademarks Aerosil® (Evonik industries), Cab-O-Sil® (Cabot Corporation), and Wacker HDK® (Wacker-Chemie GmbH).

[0044] In some embodiments, the formulation can include a lipid thickening agent. Examples of lipid thickening agents include, but are not limited to, Akosoft 36, Geleol, Gelucire, Koliwax, hydrogenated oil, or a combination thereof. In some embodiments, the formulation can include the lipid thickening agent in an amount of about 5 - 25 wt%, about 10 - 20 wt%, about 12 - 18 wt%, about 14 - 16 wt%, or about 15 wt% of the total mass of the formulation.

[0045] In some embodiments, the formulation may include povidone. Examples of povidone may include different grades of povidone such as K30 or K90. In some embodiments, the formulation may include povidone in an amount of about 0.5 to 10 wt%, about 1 to 10 wt%, about 2 to 8 wt%, about 4 to 6 wt%, or about 5 wt% of the total mass of the formulation.

[0046] Formulation formation In some embodiments, the formulation may be liquid in the form of a solution. In some embodiments, the formulation is a solution in which a poorly permeable molecule (e.g., API) is suspended as a powder in the formulation. In some embodiments, the formulation may be an anhydrous inverse microemulsion or an anhydrous inverse emulsion. In some embodiments, the formulation is homogeneous. A homogeneous formulation can be used for the manufacture of any single-phase or multiphase formulation that complies with the FDA guidelines for industry dated August 3, 1999, ANDAS: Manufacture of bulk fill formulations in accordance with blend uniformity, and / or the content uniformity test criteria (mass variation evaluation - European Pharmacopoeia, Uniformity of dosage units 2.9.40, USP General Chapter <905>, and Japanese Pharmacopoeia, Uniformity of dosage units except 6.02), and / or can meet the compliance of the assay results of the stable drug substance in the layered samples obtained over the manufacturing process, and can be any single-phase or multiphase formulation.

[0047] The formulations disclosed herein can be prepared according to the following process. The formulations can be a blend of different additives. In some embodiments, the minimum amount of additives can be added first, and the thickening agent can be added as it approaches the end before adding the API. In some embodiments, the formulation is a clear solution, and the API (i.e., a poorly permeable molecule or its salt) is suspended as a powder in the formulation. The API can be pure API crystals that are milled by any method known to those skilled in the art for obtaining solid API, such as micronization, lyophilization, spray drying, or atmospheric spray freeze drying. It can also be a solid API such as a glucoside derivative, a cellulose derivative, or adsorbed to another additive such as any material having mesoporous silica, nanotubes, or adsorption properties, or complexed like a complex with an ion exchange resin, and can also be the API in a mixture with a solid component.

[0048] The formulations disclosed herein can be digestible. Therefore, glycerides can be de-esterified by pancreatic lipase in the GI fluid to 2-monoglycerides and free fatty acids. The formulation can release sodium caprylate, which can act as a penetration enhancer to promote the absorption of the poorly permeable molecules contained in the formulation. Pancreatic lipase in the presence of colipase can catalyze the lipolysis (also referred to as hydrolysis or de-esterification) of emulsified oil to produce fatty acids. The measurement of the rate of fatty acid production and thus the rate of lipolysis can be followed via continuous titration using a pH stat as described in U.S. Patent No. 9,259,389, which is incorporated herein by reference in its entirety. The degree of digestion after 120 minutes in a pancreatin solution containing a pancreatin extract having an activity of approximately 8 tributyrin units (TBU) per mg of dry powder in distilled water at a dose of 250 mg / ml at 37.5 °C + / - 0.5 °C can be such that at least about 1 mmol, about 1.5 mmol, or about 1.7 mmol of total free fatty acids are released from the formulations disclosed herein.

[0049] In some embodiments, the degree of digestion (and hence the rate of digestion) in the CPS model after 120 minutes is such that at least about 0.2 mmol, about 0.4 mmol, about 0.6 mmol, or about 0.7 mmol of C10 fatty acid (i.e., capric acid) is released from the formulations disclosed herein.

[0050] In some embodiments, the formulations disclosed herein are liquid or semi-solid (i.e., having a melting temperature in a range higher than room temperature) and can be orally administered to patients in need thereof using pharmaceutical dosage forms well known to those skilled in the art. Such pharmaceutical dosage forms can be hard or soft gelatin capsules, whether gelatinous or non-gelatinous. Such capsules can include hard gelatin capsules and soft gelatin capsules, as well as combinations thereof (e.g., over-encapsulation of soft gelatin capsules in hard gelatin capsules or non-gelatinous soft and / or hard capsules). The formulations can also be translated into conventional solid dosage forms using techniques well known to those skilled in the art, such as adsorption, hot melt granulation / coating, and / or by means of selected carriers, diluents, additive substances, and / or binders.

[0051] The site of absorption of low permeability molecules can be in the intestine. Therefore, it is advantageous to co-deliver the formulation and the low permeability molecules to the site of absorption and the location where the formulation is digested. In this case, dilution of the formulation within the stomach must be avoided. As a result, in some embodiments, the pharmaceutical dosage form is a delayed release dosage form containing the formulations disclosed herein. Various drug delivery systems can be envisioned by those skilled in the art to obtain a delayed release dosage form. It is possible to obtain a delayed release dosage form with various materials. These materials can be used to obtain a matrix form (e.g., as described in CA2439366) or a coated form. Some delayed release and protection results can be obtained using coated dosage forms.

[0052] The various types of materials that can be used to manufacture delayed-release dosage forms are as follows: polymers that are sensitive to intestinal enzymes such as esterases and lipases (e.g., salol, shellac, lipidic compounds (stearic acid, partial glycerides), carnauba wax, hydrogenated castor oil), or proteases (e.g., keratin, gluten, zein); polymers that are soluble at intestinal pH (this option is the most widely used in the pharmaceutical industry). These polymers can be polysaccharides such as pectin, cellulose, or starch derivatives. For example, cellulose acetophthalate, hydroxypropylmethylcellulose, cellulose acetohemisuccinate, starch, and amylose acetophthalate; vinyl derivatives (e.g., polyvinyl acetate, polyvinyl acetophthalate); acrylic derivatives (e.g., Eudragit L, Eudragit FS30D); or maleic acid copolymers.

[0053] Since delayed-release pharmaceutical dosage forms are pH-dependent, polymers that are soluble at intestinal pH can be used. In some embodiments, the delayed-release pharmaceutical dosage form can be an enteric-coated dosage form, more specifically an enteric-coated capsule, particularly an enteric-coated soft gelatin capsule or an enteric-coated hard capsule, and even more specifically an enteric-coated oval soft gelatin capsule, and even more specifically an enteric-coated oval soft gelatin capsule of 7.5 or smaller. In some embodiments, the gelatin capsule has a hardness of 8-12 N, particularly 9.5 N, according to the tests shown below. Smaller dosage forms can be even more convenient for delivering less permeable substances to the intestine. Delayed-release dosage forms with a size of 3 mm or less can pass through the pyloric inlet faster than larger dosage forms and then release less permeable molecules in the intestine faster after absorption by the patient. In this case, the dosage for administration may require a dosage form consisting of several small dosage forms swallowed simultaneously.

[0054] The manufacture of enteric-coated soft gelatin capsule formulations is well known to those skilled in the art as described in U.S. Patent No. 9,259,389, which is hereby incorporated by reference in its entirety.

[0055] The final delayed-release pharmaceutical dosage form can be a unitary structure or multi-particle. This means that it can coat both the final dosage form (hard capsule, soft gel capsule, or other dosage form) and the intermediate product (pellets, granules, etc.). Certain dosage forms can be in multi-particle form (coated pellets filled in a hard capsule, granules, or pellets used to form several small tablets) to minimize variability between individuals. Examples of reversible agents for enteric coatings that may be associated with acrylic derivatives (e.g., Eudragit L) are as follows: glycerol, propylene glycol, sorbitol, sorbitol / sorbitan blend, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, triacetin, acetylated monoglyceride 9-45, polyethylene glycol.

[0056] Therapeutic activity The formulations disclosed herein can have the same therapeutic activity as the poorly permeable molecule or its salt contained therein. Thus, the present disclosure also relates to the enteric pharmaceutical formulations disclosed herein for use as a drug.

[0057] The term "therapeutically effective amount", as used herein, can refer to the amount of an agent necessary to treat, ameliorate, or prevent a targeted disease state or to exhibit a detectable therapeutic or prophylactic effect. Generally, the therapeutically effective amount can be inferred based on data available from parenteral administration of the product in humans.

[0058] The effective dosage of the compounds disclosed in this specification can be confirmed by conventional methods. The specific dosage level required for any particular patient depends on several factors, including the severity of the condition being treated, the patient's general health (i.e., age, weight, and diet), the patient's gender, the time and frequency of administration, and the tolerance / responsiveness to the therapy. However, generally, the daily dosage (whether administered as a single dose or divided doses) is in the range of 1 to 1000 mg per day, most commonly 5 to 200 mg per day. Alternatively, the dosage can be administered per unit body weight, and in this example, typical dosages are 0.01 μg / kg to 50 mg / kg, especially 10 μg / kg to 10 mg / kg, 50 μg / kg to 2 mg / kg.

Example

[0059] Exemplary compositions of the formulations disclosed herein can be found in Table 2 below.

[0060]

Table 2

[0061] The API in the above formulation was a peptide of five amino acids with a molecular weight of approximately 700 g / mol. In the above formulation, Miglyol, Capmul, and triethyl citrate are penetration enhancers, and Tween and Kolliphor EL are surfactants that assist in the movement of digestion and then improve the effects of Miglyol and Capmul. Water, PEG 400, and propylene glycol solubilize the API but have no activity on permeability. The formulation is designed to act on the low permeability of molecules to the intestinal membrane. Chemical and physical instabilities in the digestive tract, as well as the loss of activity due to acidic conditions inside the stomach, can be controlled by coating.

[0062] Formulations 1 to 4 (F1 to F4) were prepared as described in U.S. Patent No. 9,259,389 and used as a comparator to confirm the improved bioavailability provided by the invention disclosed herein.

[0063] Preparation of Formulation 1: First, dissolve the amount of API in water, and then add Tween 80. Stir the resulting mixture to obtain a homogeneous solution. Next, add solutions of Miglyol 812N and Capmul MCM at a predetermined ratio (see Table 2) to the previous mixture. Stir the final emulsion at room temperature until a homogeneous mixture (without phase separation and with the API completely solubilized) is obtained. This formulation should be stabilized with silicon dioxide.

[0064] Preparation of Formulation 2: This formulation includes the inventive formulation. Mix Capmul MCM and Miglyol 812N at the selected ratio together at room temperature. Next, add a predetermined amount of Tween 80 to the solution. Homogenize the resulting mixture while stirring at room temperature. Finally, add the amount of API and stir the final mixture until a homogeneous suspension (without phase separation and with the API well-dispersed in the formulation) is obtained.

[0065] Preparation of Formulation 3: This formulation has a considerably low digestibility and is another solution of the API with another penetration enhancer (triethyl citrate). First, dissolve the amount of API in a solution of PEG400 and propylene glycol, and then add triethyl citrate and Kolliphor EL. Add Capmul MCM last. Stir the resulting mixture at room temperature to obtain a homogeneous solution (without phase separation and with the API completely solubilized).

[0066] Preparation of Formulation 4: Mix Capmul MCM and Miglyol 812N at the selected ratio together at room temperature. Next, sequentially add a predetermined amount of Tween 80 and triethyl citrate to the solution. Homogenize the resulting mixture while stirring at room temperature. Finally, add the amount of API and stir the final mixture until a homogeneous suspension (without phase separation and with the API well-dispersed in the formulation) is obtained.

[0067] Other exemplary vehicles for API delivery can include: Crodamol GMCC-SS / Triethyl Citrate / Kolliphor EI / PEG 400 / Propylene Glycol, Miglyol 812N / Crodamol GMCC-SS / Tween 80, Miglyol 812N / Crodamol GMCC-SS / Triethyl Citrate / Tween 80, Miglyol 812N / Crodamol GMCC-SS / Tween 80 with added water.

[0068] Digestibility of the formulations disclosed herein Regarding the digestibility components (Miglyol 812N and Capmul MCM) ratio, more than 85% of Formulation 1 (reverse emulsion) and Formulation 2 (API in suspension) have high digestibility. After 30 minutes of digestion, Formulation 1 releases 2.3 mmol of fatty acids per gram of formulation, and Formulation 2 releases 2.1 mmol of fatty acids per gram of formulation. After 3 hours, the maximum amount of fatty acids released by Formulation 1 and Formulation 2 is about 2.8 mmol per gram of formulation, and this release amount is the maximum possible release for all four formulations. More than 75% of the fatty acids are released in less than 30 minutes in these two formulations. Formulation 3 (API in solution) without triglyceride (Miglyol 812N) releases the minimum amount of fatty acids: after 3 hours of digestion, 0.6 mmol of fatty acids per gram of formulation. After 30 minutes of digestion, only 0.3 mmol (50%) of fatty acids per gram of formulation are released. Formulation 4 releases an intermediate amount of fatty acids (2.0 mmol of fatty acids per gram of formulation after 3 hours of digestion) compared to the other three, so the level of the digestive component is about 70%. 1.7 mmol of fatty acids are released after 30 minutes, corresponding to about 85% of the release within 30 minutes.

[0069] The following Table 3 shows the bioavailability of a five - amino - acid peptide of about 700 Da. This peptide is not sensitive to enzymatic degradation and was included in the formulations disclosed herein after administration to dogs.

[0070]

Table 3

[0071] A pharmacokinetic study after duodenal administration of the formulation in dogs was carried out using untreated male beagle dogs (6.5 - 10 kg) to determine the bioavailability of poorly permeable molecules when delivered in the formulation according to the present invention. To do this, the formulated preparation was administered by endoscopy under anesthesia.

[0072] The animals were anesthetized using an intramuscular injection of 0.03 mL / kg of Rompun followed by an intramuscular injection of 0.1 mL / kg of Zoletil 100® or any similar drug.

[0073] The test formulation was delivered into the duodenum (at least 4 cm behind the pyloric sphincter) using a plastic syringe fitted with a catheter passing through the central tube of the endoscope, while the animals were lying on their side with the left side down during the endoscopy. The dose of the poorly permeable molecule to be administered was adjusted to the body weight of each dog recorded on the day of administration so that each dog received the same dose per kg of body weight of the animal.

[0074] Before each administration, between each animal, the catheter was rinsed with 5 mL of 0.9% NaCl and at least 20 mL of air. 1 mL blood samples were collected from the jugular vein or the lateral cutaneous vein of unanesthesised animals into sodium citrate tubes at various time points (usually before administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 hours after administration). Plasma was collected after centrifugation of the samples (10 minutes, 3000 g, +4°C) and stored at -20°C until analysis.

[0075] Pharmacokinetic study after intravenous administration In the pharmacokinetics of the poorly permeable molecules studied, it has been investigated after intravenous administration to calculate their pharmacokinetic parameters and bioavailability after oral and duodenal administration.

[0076] The dogs were fasted for 14 hours before each intravenous administration and fed 6 hours after administration (during kinetic measurements). For intravenous administration, low-permeability molecules were administered to the dogs as a single bolus injection into the peripheral vein (saphenous vein or cephalic vein) using a plastic syringe.

[0077] The dose of the low-permeability molecule to be administered was adjusted to the body weight of each dog recorded on the day of administration so that each dog received the same dose per 1 kg of the animal's body weight. 1 mL blood samples were collected from the saphenous vein or cephalic vein of the unanesthetized animals into sodium citrate tubes at various time points (usually, before administration; 0.083, 0.166, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 hours after administration). Plasma samples were prepared as detailed above (centrifugation and storage at -20 °C until further analysis).

Example

[0078] The exemplary compositions of the formulations disclosed herein can be found in Table 4 below.

[0079]

Table 4

[0080] The API was an antibody mimetic. Formulation F5 was equivalent to placebo formulation F2. Formulations F6 - F8 were used to test the increase in drug filling.

[0081] Digestibility of the formulations disclosed herein: In the placebo formulation (F5), the release of free fatty acids was rapid, and more than 85% of the digestible portion of the formulation was digested within less than 30 minutes, releasing free fatty acids (mainly C8 and C10 fatty acids) known to enhance permeability through the intestinal membrane.

[0082] Formulation manufacturing: The placebo formulation is prepared at room temperature by adding three additives together at a predetermined ratio (see Table 4), and mixed with magnetic stirring until a single-phase solution is achieved (i.e., no phase separation after 24 hours without stirring).

[0083] The API selected in Example 2 is a protein of about 12 kDa, more specifically an antibody mimetic. The lyophilized API was ground with a mortar and pestle before adding to the placebo formulation. The selected amount of API corresponding to the formulation to be produced (see Table 4) is slowly added to the placebo solution with continuous stirring. After adding the total amount of API, the resulting mixture is homogenized with stirring for at least 24 hours.

[0084] The following Table 3 shows the bioavailability of the proteins contained in the formulations disclosed herein after addition to rats (formulations 6, 7, and 8) and dogs (formulation 7).

[0085]

Table 5

[0086] Formulations 6, 7, and 8 are administered to rats via direct injection in the duodenal treatment. 250 mg of the formulation was administered per rat (Sprague Dawley rats, n = 4). This corresponds to 25, 50, and 100 mg / kg body weight of the antibody, respectively. Serum samples were collected at t = 0, 3, 8, 24, 24, 72, 120, and 168 hours after administration. The concentration of the antibody in the serum samples was quantified using an antibody-specific sandwich ELISA. The mean AUC, standard deviation, and bioavailability (F%) are described in the above table. These values will be compared with the bioavailability equivalent to zero (API in PBS buffer) without any formulation.

[0087] The dog study was conducted with formulation 7 in 4 untreated male beagle dogs that were fasted. The dogs were fasted 15 - 16 hours prior to dosing, and food was returned approximately 1 hour after dosing. Each dog was dosed with 5 capsules per day for 6 consecutive days. The dose was approximately 10 mg / animal / kg of antibody per day. Serum samples were taken before dosing on days 1, 2, 3, 4, 5, and 6, 2 hours after dosing on days 1, 2, 3, 4, 5, and 6, and 1, 2, 4, 8, 24, 48, 96, and 168 hours after dosing on day 6. The concentration of antibody in the serum was quantified using an antibody - specific sandwich ELISA. The results showed uptake (absorption) of antibody molecules in all 4 animals with some inter - individual variation, as opposed to no absorption when the API was simply dissolved in PBS buffer.

Example

[0088] BHV - 3500 (vazegepant) is a highly affinity (human CGRP K i = 0.023 nM), selective and structurally unique small - molecule CGRP receptor antagonist.

[0089]

Chemical formula

[0090] The chemical name of BHV-3500 is (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide. BHV-3500 is described, for example, in WO 03 / 104236 published on December 18, 2003, and U.S. Patent No. 8,481,546 issued on July 9, 2013, which are hereby incorporated by reference in their entirety. BHV-3500 has low permeability and was selected for the purposes of this study. BHV-3500-d8 is an octadeuterated analog of BHV-3500 and has the following formula II.

[0091]

Chemical formula

[0092] The pharmacokinetics (PK) of BHV-3500 after a single oral capsule of BHV-3500 in dogs was investigated.

[0093] Materials and Methods 1. Experimental Design and Administration For each group, three female beagle dogs were administered BHV-3500 once as shown in Table 6.

[0094]

Table 6

[0095] 2. Blood Sampling After each administration, blood samples (approximately 3 mL from the jugular vein) for determination of the plasma level of BHV-3500 were obtained from each dog at six time points (before administration, 15, 30, and 60 minutes after administration, and 2 and 4 hours after). EDTA was used as an anticoagulant. Plasma samples were frozen at approximately -70 °C until analysis.

[0096] 3. Preparation of Standard Substances, Internal Standard, and Plasma Samples Standard substances for BHV-3500 and BHV-3500-d8 were prepared and stored at room temperature. The standards were used without further purification for the preparation of calibration standards, and quality control (QC) samples for the determination of BHV-3500 concentration in plasma samples were collected during this study.

[0097] For the determination of BHV-3500 in plasma, 50 μL aliquots from each sample were transferred to the appropriate wells of a 96-well plate, to which 10 μL of 50% acetonitrile (ACN) in water was added, followed by the addition of 250 μL of internal standard solution (10 ng / mL of BHV-3500-d8 in ACN). The plate was sealed and shaken for approximately 5 minutes, after which the plate was centrifuged at 4,000 rpm for 10 minutes at 4 ± 4 °C. A portion (100 μL) of the resulting supernatant was transferred to the appropriate wells of another 96-well plate (containing 300 μL of 0.15% formic acid in water). The plate was sealed and its contents were mixed prior to instrumental analysis.

[0098] The newly prepared standard curve of BHV-3500 and QC samples were analyzed together with the study samples. The calibration substance for the instrument was prepared by adding 10 μL of the BHV-3500 stock solution to 50 μL of blank canine plasma. The blank canine plasma was purchased from BioIVT (Hicksville, NY) and stored frozen at -20 °C. The nominal calibration substance concentrations were in the range of 2.00 - 200 ng / mL. The QC samples were prepared at concentrations of 6.00, 50.0, and 150 ng / mL. The calibration substances and QC samples were processed for analysis following the extraction procedure described above.

[0099] 4. Analytical Instrument and Conditions The calibration substances, QC, and study samples were analyzed under the LC-MS / MS instrument conditions detailed in Table 7.

[0100]

Table 7

[0101] The calibration curve was calculated from the linear regression (weight count 1 / x2) of the peak area ratio of the analyte to the internal standard versus the analyte concentration. The concentration of the analyte in the sample was determined using the peak area ratio and the regression parameters of the calibration curve.

[0102] 5. Pharmacokinetics The plasma BHV-3500 concentration data of individual animals at the specified (nominal) sampling times were analyzed using Phoenix WinNonlin software (version 8.1; Certara, Princeton, NJ) with a non-compartmental model for extravascular administration.

[0103] The elimination rate constant (λz) was calculated by logarithmic linear regression (using the Best Fit Lambda Z Calculation Method option in Phoenix WinNonlin) at the terminal data point if possible from the data, and the plasma elimination half-life (t1 / 2) was calculated as ln(2) / λz. The area under the plasma concentration-time curve from 0 to the concentration at the 4-hour time point (AUC0-4 h) was calculated by the linear-up / log-down trapezoidal rule.

[0104] The nominal dose level was used for PK analysis. The following PK parameters were evaluated (if applicable and possible from the data). · Elimination half-life (t 1 / 2 ) · Time to maximum plasma concentration (T max ) · Maximum plasma concentration (C max ) · Area under the plasma concentration-time curve [from 0 to the 4-hour time point; AUC 0-4時間

[0105] The abbreviations for PK and the units of measurement are presented in Table 8.

[0106]

Table 8

[0107] Result The determination of the BHV-3500 concentration is shown in Table 9 and graphed in FIGS. 1 and 2.

[0108] [Table 9A]

[0109] [Table 9B]

[0110] The PK parameters are shown in Table 10.

[0111] [Table 10A]

[0112] [Table 10B]

[0113] Summary When BHV-3500 was administered to dogs at 20 mg as an oral capsule (Group 1, vehicle-free) without vehicle, plasma levels were below the quantification limit (BQL) at all time points. BHV-3500 was measurable in plasma only when the 20 mg dose was delivered in combination with vehicle 6 and DDM (Groups 2 and 3, respectively) (see FIG. 1). At this 20 mg dose, plasma BHV-3500 was at the BQL at the first 15-minute time point for Groups 2 and 3, and the maximum concentration was seen 2 hours after dosing with mean exposures of 14.2 and 18.9 ng / mL, respectively, which is 956×(22 nM) and 1,282×(29.5 nM) for the human CGRP receptor (K iexceeds the BHV-3500 affinity for human CGRP receptor (K = 0.023 nM). When BHV-3500 was administered orally as a 50 mg capsule to dogs without vehicle (4 groups, no vehicle), plasma levels were measurable at 1 and 2 hours but not at 4 hours, with BQL at 15 and 30 minutes. When the 50 mg dose was delivered in combination with vehicle 6 (5 groups), plasma levels at 1 and 2 hours increased from 3.4× to 6.6× with mean exposures of 11.5 and 40.6 ng / mL, respectively, which were 782× (18 nM) and 2,763× (63.3 nM) by human CGRP receptor (K i exceeds the BHV-3500 affinity for human CGRP receptor (K = 0.023 nM) (see Figure 2). With vehicle 6, measurable plasma levels were found at 4 hours with a mean exposure of 7.97 ng / mL (different from the no-vehicle condition (4 groups) where the plasma level of BHV-3500 was BQL at 4 hours). When the 50 mg dose was delivered in combination with DDM (6 groups), plasma levels at 1 and 2 hours were similar to the no-vehicle condition (4 groups). With DDM at 4 hours (6 groups) (in contrast to the no-vehicle condition where the plasma level at 4 hours was BQL), measurable plasma levels of BHV-3500 were found at 4 hours with a mean exposure of 8.67 ng / mL, which was 590× (13.5 nM) by human CGRP receptor (K i exceeds the BHV-3500 affinity for human CGRP receptor (K = 0.023 nM).

[0114] The summary of the PK results is presented in Table 11 (Table 11).

[0115]

Table 11

[0116] Description of the study protocol: Study title: Single-dose oral capsule study of BHV-3500 in dogs

[0117] Purpose of the study: To determine the pharmacokinetics of the BHV-3500 capsule formulation after single oral and sublingual administrations in dogs.

[0118] Study period: 3 weeks

[0119] Formulation of the test substance: Identification. Identify the test substance as BHV-3500. The test substance is supplied as capsules.

[0120] Risk to personnel. Conventional safety measures used to handle hazardous or potentially hazardous chemicals are followed to ensure the health and safety of personnel handling the test substance.

[0121] Characterization of the test substance. Provide an analytical certificate (or other appropriate document) verifying the identity or purity of the test substance.

[0122] Preparation and analysis of the dosage. Do not perform analysis on the formulation to be administered.

[0123] Storage. Store the BHV-3500 capsules at room temperature.

[0124] Disposition and retention of samples. Document the total amount of the test substance to be dispensed. Retention samples are not required for this period of the study.

[0125] Basis for the selection of the dosage of the test substance. The dosage level of the test substance was selected based on previous PK studies of the test substance.

[0126] Route of administration. Administer the test substance orally (capsules), which is one of the intended routes of administration in humans, and sublingually.

[0127] Disposition of the test substance. When the test is completed, return and discard any remaining test substance.

[0128] Experimental plan: Refer to Table 6 above.

[0129] Test System: Test animals. Three or three female beagle dogs are obtained from Ridglan Farms, Mount Horeb, WI for use in this study. All animals are immunized by the supplier against distemper, adenovirus type 2, parainfluenza, Bordetella, rabies, papillomavirus, and parvovirus. The dogs are approximately 1 year old and weigh approximately 8 - 12 kg at the start of dosing. The same three animals are used for the administration of all test substances.

[0130] Justification. Dogs are a standard species used in non - clinical toxicity studies and are recognized by the US Food and Drug Administration as a large animal (non - rodent) model system for the safety evaluation of drug pharmacokinetics of pharmaceuticals.

[0131] Justification for the number of animals. The number of animals used is the minimum necessary to obtain meaningful data. To the knowledge of the test requester and the test responsible person, the conduct of this test does not result in unnecessary duplication of existing data with respect to the species, test substance, dose, route, and dosing period.

[0132] Housing. Dogs are individually housed in cages equipped with an automatic watering system. The cages are cleaned daily. Dogs are housed in accordance with the standards set forth in the US Department of Agriculture's welfare standards (Code of Federal Regulations, Title 9, Part 3, Revised 1991) and the Guidelines for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, 2011).

[0133] Diet. Certified Canine Diet #2021C (Harlan Teklad, Madison, WI). Approximately 400 g of diet is made available to each dog daily for a minimum of 2 hours. Each lot of diet is analyzed for contaminants to ensure that it is not present at concentrations predicted to interfere with the conduct or purpose of this test. Analytical data from the lots of diet used during the test are retained on file at the test facility. Dogs are fasted prior to dosing. The diet is provided approximately 1 hour after dosing.

[0134] Water. The water from the City of Chicago, which has been roughly filtered, is appropriately provided to all dogs via an automatic water supply system. The water is periodically analyzed for bacterial contamination and chemical composition (e.g., electrolytes, metals, etc.). The water analysis records are retained in files at the testing facility. Contaminants that are predicted to interfere with this test are known not to be present in the water.

[0135] Animal Identification. Each dog is identified by the USDA tattoo number on its right or left ear. Each dog is also assigned a unique number within this test. All cages are identified by the project number, animal number, and gender. The gauge cards are color-coded by group.

[0136] Environmental Management. The temperature and relative humidity in the animal room are manually recorded daily. A 12-hour light-dark cycle (maintained by an automatic timer) is used. The animal rooms are each maintained at a temperature in the range of approximately 20°C to 25°C and a relative humidity in the range of 30% to 70%.

[0137] Methods: Isolation. Animals purchased for this test are held in isolation for at least two weeks prior to the administration of the test substance. Over the isolation period, the animals are observed for evidence of death or near death at least once a day.

[0138] Randomization. After the animals are released from isolation, the animals are randomly assigned to groups. After randomization, each dog undergoes a detailed clinical observation to ensure its suitability as a test animal.

[0139] Administration. One to two groups of animals receive a single oral capsule dose of BHV-3500 at 20 mg / dog. Four to six groups of animals receive a single oral (capsule) dose of BHV-3500 at a dose of 50 mg / dog. Each group is followed by a washout period of at least 48 hours before the next group is administered.

[0140] Observation of Near - death / Death. Before the start of administration, animals are observed for evidence of death or near - death at least once a day. At the start of administration and throughout the remainder of the observation period, all surviving test animals are observed for evidence of death or near - death at least twice a day to evaluate their general health. Record any abnormal clinical signs. Separate near - death / death checks by at least 4 hours.

[0141] Near - death animals. During the near - death / death observation, any animal determined to have a low probability of survival until the next designated observation period is excluded from the test, weighed, euthanized, and necropsied if the responsible veterinarian and the test supervisor agree. These animals are recorded in the test notes as being euthanized at death. Dead animals are immediately excluded for necropsy and the death is recorded in the test notes.

[0142] Injured or diseased animals. Animals in the test are treated for any disease or injury according to standard veterinary practices. Make a complete record of the environment and placement of any affected animals in the test notes. Isolate any animal that poses a potential infectious threat to other tests.

[0143] Clinical observations. Clinical observations are made approximately 1 hour after each dose administration.

[0144] Body weight management. Animals are weighed before each administration.

[0145] Food intake measurement. The food intake of individual animals is not measured in this test.

[0146] Plasma drug levels. Blood samples (approximately 3 mL collected from the jugular vein) for determination of the plasma level of BHV - 3500 are obtained from each dog at 6 time points (before dosing, 15, 30, and 60 minutes after each dose, 2 and 4 hours after). EDTA is used as the anticoagulant. Plasma samples are frozen at approximately - 70 °C until analyzed at the test center for the concentration of BHV - 3500. Pharmacokinetic modeling includes AUC, t 1 / 2 、T max 、and C max including.

[0147] Necropsy. This is a test without a terminal. The dog is returned for isolation after the last blood sampling.

[0148] Data Notes. All raw data generated at the test center are maintained in loose-leaf notes. The paper data maintained in the loose-leaf notes need not be limited but include the following. · Copy of the original protocol, signed, along with any amendment and / or deviation examples; · Receiving records of animals; · Breeding records of animals; · Test substance data; · Blood sampling data; · TK data Data electronically obtained using ToxData® (e.g., dose administration, daily moribund / death and environmental data, clinical observations, body weight, etc.) are maintained in the database of the computer system, and an electronic copy of the file ToxData®.htm is also backed up on a CD-ROM, and the disk is maintained with the raw data.

[0149] Change in Plan. Changes in the protocol may also proceed with the test in the form of protocol amendments. Changes in the protocol shall not be made without the specific written consent of the test requester.

[0150] Regulatory Standards and Compliance. Due to the nature of the indicators of this test, the test is not conducted in accordance with the Good Laboratory Practice (GLP) regulations described in the U.S. FDA (Title 21 of the Code of Federal Regulations, Part 38). The test is conducted in accordance with the standard operating procedures of the test center.

[0151] Report. A draft report is prepared and submitted to the test requester for review. The information in the report need not be limited but includes the following. · Copy of the approved protocol, including any amendment and / or deviation examples · Species and strains of animals used · Clinical observation data · Body weight data · Plasma drug level data · Pharmacokinetic data

[0152] Submit the final report to the test requester in accordance with the review by the test requester of the draft report.

[0153] Data retention. All raw data generated as a result of this test and copies of the final report from this test shall be stored at the test center for a period of one year from the date of completion of this test. The test requester shall be responsible for all costs associated with the continued storage of the stored materials at the test center repository or the transportation of these materials to another storage facility. The test center QAU shall maintain a complete record of the location of all stored materials.

[0154] Personnel. The resumes of all personnel at the test centers involved in the conduct of this test shall be filed at the test centers.

[0155] Protocol approval. This protocol shall comply with the specific documents of the test requester.

[0156] Definitions Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or specialized terms used in this specification are intended to have the same meaning as commonly understood by those of ordinary skill in the art to which the claimed subject matter pertains. In some instances, terms with commonly understood meanings are defined in this specification for clarity and / or ease of reference, and including such definitions in this specification is not to be construed as representing a substantial difference from what is generally understood in the art.

[0157] References to a value or parameter "about" in this specification include (and describe) variations that relate to the value or parameter itself. For example, the description "about X" includes the description "X". In addition, a reference to a phrase such as "less than", "more than", "at most", "at least", "less than or equal to", "greater than or equal to", or other similar phrases that follow a sequence of values or parameters means that the phrase is applied to each value or parameter in the sequence of values or parameters. For example, the description that a formulation has at most about 10 wt%, about 15 wt%, or about 20 wt% of a component means that the formulation has at most about 10 wt%, at most about 15 wt%, or at most about 20 wt% of the component.

[0158] As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The term "and / or" as used herein, when referring to related listed items, refers to any and all possible combinations of one or more of the associated listed items and is to be construed as including them. The terms "includes", "including", "comprises", and / or "comprising", when used herein, specify the presence of the stated feature, integer, step, operation, element, component, and / or unit, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, units, and / or groups thereof.

[0159] This application discloses several numerical ranges in this specification. Since the disclosed numerical ranges can be implemented over the disclosed numerical ranges, the disclosed numerical ranges inherently support any range or value within the disclosed numerical range that includes the endpoints, even if no explicit range limitation is recited verbatim in this specification.

[0160] The foregoing is presented to enable a person having ordinary skill in the art to make and use the disclosure, and is provided in the context of particular applications and their requirements. Various modifications to the preferred embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of the disclosure. Thus, the disclosure is not intended to be limited to the embodiments shown, but is to be accorded the widest scope consistent with the principles and features disclosed herein.

Claims

1. A synthetic or natural low-permeability calcitonin gene-related peptide (CGRP) inhibitor or a salt or solvate thereof in an amount of 0.01 to 20 wt% of the total mass of the formulation; A lipophilic phase containing a triglyceride of a fatty acid in an amount of 50 to 80 wt% of the total mass of the formulation; and At least one lipophilic surfactant containing a polyol and a partial ester of a fatty acid in an amount of 10 to 50 wt% of the total mass of the formulation A pharmaceutical formulation containing no water, wherein the synthetic or natural low-permeability CGRP inhibitor is a small molecule CGRP receptor antagonist, and the small molecule CGRP receptor antagonist is (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BHV-3500).

2. The formulation according to claim 1, further comprising at least one hydrophilic surfactant having a hydrophilic-lipophilic balance (HLB) of more than 10 in an amount of 1 to 30 wt% of the total mass of the formulation.

3. The formulation according to claim 2, wherein the at least one hydrophilic surfactant is selected from the group consisting of polyoxyethylene (20) monooleate, PEG 8 caprylic / capric glyceride, PEG 6 caprylic / capric glyceride, poly(oxyethylene)(4) lauryl ether, and mixtures thereof.

4. The formulation according to claim 1, wherein the triglyceride of the fatty acid is a medium-chain fatty acid.

5. The formulation according to claim 1, wherein the lipophilic surfactant contains a mixture of monoglycerides and diglycerides of medium-chain fatty acids.

6. A synthetic or natural low-permeability CGRP inhibitor or a salt or solvate thereof in an amount of 0.01 to 20 wt% of the total mass of the formulation; A lipophilic phase containing a triglyceride of a fatty acid in an amount of 50 to 80 wt% of the total mass of the formulation; and At least one lipophilic surfactant containing a polyol and a partial ester of a fatty acid in an amount of 10 to 50 wt% of the total mass of the formulation A pharmaceutical formulation containing no water, which is a sustained-release pharmaceutical dosage form, wherein the dosage form is coated such that its release is pH-dependent, and The aforementioned synthetic or natural CGRP inhibitor with low permeability is a small molecule CGRP receptor antagonist, and the small molecule CGRP receptor antagonist is (R)-N-(3-(7-methyl-1H-indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamide (BHV-3500), a sustained release pharmaceutical dosage form.

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