US-12622968-B2 - Formulation for oral delivery of proteins, peptides and small molecules with poor permeability

Abstract

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.

Inventors

• Vincent PLASSAT
• Benoit Hilbold
• Aurélia GALUS
• Thomas POINTEAUX
• JULIEN MEISSONNIER
• Gene M. Dubowchik
• CHARLES M. CONWAY
• Rajesh Kumar

Assignees

• R.P. SCHERER TECHNOLOGIES, LLC
• PFIZER IRELAND PHARMACEUTICALS

Dates

Publication Date

20260512

Application Date

20200410

Claims (14)

1. 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. 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. 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. 4 . The formulation of claim 1 , wherein the triglycerides of fatty acids are medium chain fatty acids.
5. 5 . The formulation of claim 1 , wherein the lipophilic surfactant comprises a mixture of mono and diglyceride of medium chain fatty acids.
6. 6 . The formulation of claim 1 , wherein the formulation does not include water.
7. 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. 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. 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. 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. 11 . The method of claim 8 , wherein the triglycerides of fatty acids are medium chain fatty acids.
12. 12 . The method of claim 8 , wherein the lipophilic surfactant comprises a mixture of mono and diglyceride of medium chain fatty acids.
13. 13 . The method of claim 8 , wherein the formulation does not include water.
14. 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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/US2020/027800, filed on Apr. 10, 2020, which claims the priority of U.S. Provisional Application No. 62/832,508, filed Apr. 11, 2019, the entire contents of each of which are incorporated herein by reference. FIELD OF THE DISCLOSURE This disclosure relates to a formulation for oral delivery of proteins, peptides and small molecules with poor permeability. More specifically, this disclosure relates to a pharmaceutical formulation intended for oral delivery of any molecule synthetic or natural with poor permeability or salts or solvates thereof having a therapeutic activity. BACKGROUND OF THE INVENTION Poorly permeable molecules are compounds that have poor absorption through the intestinal membrane. As such, they are administered intravenously or subcutaneously. Because of their poor absorption through the intestinal membrane, their clinical use is considerably restricted given the need to be administered IV and dosed several times a day (e.g., insulin for diabetics). These poorly permeable compounds are identified as BCS class III and class IV compounds in the classification proposed by Amidon G L et al in A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability (Pharm Res. 1995 March; 12(3):413-20.), which is hereby incorporated by reference in its entirety. SUMMARY OF THE INVENTION Applicants have developed formulations for orally administered molecules with poor permeability. The molecule may be a CGRP inhibitor. These formulations are highly beneficial for patients that require dosing several times a day. In order to prepare such formulations for oral delivery of poorly permeable CGRP inhibitors, Applicants had to overcome at least this poor permeability against the intestinal membrane; and for some of those inhibitors in particular peptides and proteins the chemical and physical instability in the gastrointestinal tract and specifically, the loss of activity due to acidic conditions in the stomach; and enzymatic degradation throughout the intestine. Accordingly, Applicants developed delayed release coated dosage form that can deliver poorly permeable CGRP inhibitors in the intestine with in-situ production of permeation enhancer to increase its bioavailability. In U.S. Pat. No. 9,259,389, the inventors found that a digestible reverse emulsion can increase bioavailability of oligosaccharides. Unexpectedly, Applicants found that a solution of lipid excipients with a poorly permeable molecule dispersed as a powder in the formulation can allow better results of bioavailability for this specific class of molecules (i.e., BCS Class III and Class IV compounds in the classification proposed by Amidon G L et al (Pharm Res. 1995 March; 12(3):413-20.)). Specifically, Applicants found that for poorly permeable molecules, specifically BCS Class II protein and peptide compounds, the formulation without addition of water can be beneficial. Without being bound by any theory, it is believed that water tends to cause this class of the poorly permeable molecules to aggregate together. More particularly, Applicants found that when they did not include water in the formulation comprising a solution of lipid based excipients with the poorly permeable BCS Class III protein or peptide molecule or salt dispersed as a powder in the formulation, higher results of bioavailability were achieved for this specific class of molecules. In contrast, the removal of water was detrimental for saccharides of U.S. Pat. No. 9,259,389. In addition, Applicants can increase the drug load when the API can be dispersed as a powder without the need to solubilize the active pharmaceutical ingredient (“API”) in water given there is no need to solubilize the API. Furthermore, the formulation is inherently more physically stable because lipid excipients can be in solution as a sing e phase. Thus, there may be no need to add a stabilizing agent such as silicon dioxide to stabilize the phases. In some embodiments, a thickener may be added for manufacturing purposes to maintain homogeneity of the API powder in suspension during the process. In some embodiments, the thickener can be silicon dioxide. Lastly, compared to other formulations found in literature using excipients such as permeation enhancers, the formulations disclosed herein can use only generally recognized as safe excipients or already marketed ingredients. In some embodiments, a pharmaceutical formulation comprising a synthetic or natural poorly permeable CGRP inhibitors 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 polyo