Formulation for oral delivery of proteins, peptides and small molecules with poor permeability
The present disclosure is directed to a pharmaceutical formulation intended for oral delivery of synthetic or natural poorly permeable calcitonin gene-related peptide (CGRP) inhibitors or salts/solvates thereof having a therapeutic activity. The pharmaceutical formulation can include a synthetic or natural poorly permeable CGRP inhibitors or salt or solvate thereof in an amount 0.01-10 wt. % of the total weight of the formulation; a lipophilic phase comprising triglycerides of fatty acids in an amount of 50-80 wt. % of the total weight of the formulation; and at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of about 10-50 wt. % of the total weight of the formulation.
1 . An oral pharmaceutical formulation, comprising:
a synthetic or natural poorly permeable calcitonin gene-related peptide (CGRP) inhibitor or salt or solvate thereof in an amount 0.01-20 wt. % of the total weight of the formulation;
a lipophilic phase comprising triglycerides of fatty acids in an amount of 50-80 wt. % of the total weight of the formulation; and
at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of 10-50 wt. % of the total weight of the formulation,
wherein the synthetic or natural poorly permeable 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), wherein the oral pharmaceutical formulation is in a capsule.
2 . The formulation of claim 1 , further comprising at least one hydrophilic surfactant with a hydrophilic lipophilic balance (“HLB”) above 10 in an amount of 1-30 wt. % of the total weight of the formulation.
3 . The formulation of claim 2 , wherein the at least one hydrophilic surfactant is selected from the group consisting of polyoxyethylene (20) monooleate, PEG 8 caprylic/capric glycerides, PEG 6 caprylic/capric glycerides, poly(oxyethylene)(4)Lauryl ether and mixtures thereof.
4 . The formulation of claim 1 , wherein the triglycerides of fatty acids are medium chain fatty acids.
5 . The formulation of claim 1 , wherein the lipophilic surfactant comprises a mixture of mono and diglyceride of medium chain fatty acids.
6 . The formulation of claim 1 , wherein the formulation does not include water.
7 . A delayed release oral pharmaceutical dosage form comprising:
a pharmaceutical formulation comprising:
a synthetic or natural poorly permeable CGRP inhibitor or salt or solvate thereof in an amount 0.01-20 wt. % of the total weight of the formulation;
a lipophilic phase comprising triglycerides of fatty acids in an amount of 50-80 wt. % of the total weight of the formulation; and
at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of 10-50 wt. % of the total weight of the formulation, wherein the delayed release dosage form is a coated dosage form whose release is pH dependent,
wherein the synthetic or natural poorly permeable 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), wherein the dosage form is a capsule.
8 . A method for treating a patient, comprising administering to a person in need thereof an effective amount of an oral pharmaceutical formulation in a capsule, the oral pharmaceutical formulation comprising:
a synthetic or natural poorly permeable CGRP inhibitor or salt or solvate thereof in an amount 0.01-20 wt. % of the total weight of the formulation;
a lipophilic phase comprising triglycerides of fatty acids in an amount of 50-80 wt. % of the total weight of the formulation; and
at least one lipophilic surfactant comprising partial esters of polyol and fatty acids in an amount of 10-50 wt. % of the total weight of the formulation,
wherein the synthetic or natural poorly permeable 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).
9 . The method of claim 8 , wherein the pharmaceutical composition comprises at least one hydrophilic surfactant with a hydrophilic lipophilic balance (“HLB”) above 10 in an amount of 1-30 wt. % of the total weight of the formulation.
10 . The method of claim 9 , wherein the at least one hydrophilic surfactant is selected from the group consisting of polyoxyethylene (20) monooleate, PEG 8 caprylic/capric glycerides, PEG 6 caprylic/capric glycerides, poly(oxyethylene)(4)Lauryl ether and mixtures thereof.
11 . The method of claim 8 , wherein the triglycerides of fatty acids are medium chain fatty acids.
12 . The method of claim 8 , wherein the lipophilic surfactant comprises a mixture of mono and diglyceride of medium chain fatty acids.
13 . The method of claim 8 , wherein the formulation does not include water.
14 . The method of claim 8 , wherein the pharmaceutical formulation is in a delayed release dosage form comprising a coated dosage form whose release is pH dependent.