WO2024077409A1 - Oral delivery of therapeutic agents - Google Patents
Oral delivery of therapeutic agents Download PDFInfo
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- WO2024077409A1 WO2024077409A1 PCT/CN2022/123964 CN2022123964W WO2024077409A1 WO 2024077409 A1 WO2024077409 A1 WO 2024077409A1 CN 2022123964 W CN2022123964 W CN 2022123964W WO 2024077409 A1 WO2024077409 A1 WO 2024077409A1
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- pharmaceutical composition
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- pharmaceutically acceptable
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
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- 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
Definitions
- the present invention generally relates to oral delivery of therapeutic agents.
- Oral route of administration is the most preferred for drug administration.
- Oral route of administration has several advantages with better patient compliance, ease of administration and typically low cost of production, storage and distribution.
- the present disclosure relates to oral delivery of therapeutic agents, in particular, molecules such as those having high molecular weight or otherwise difficult to be absorbed through oral administration, such as polypeptides, heparins, etc.
- therapeutic agents in particular, molecules such as those having high molecular weight or otherwise difficult to be absorbed through oral administration, such as polypeptides, heparins, etc.
- the present disclosure is based, in part, on the unexpected discovery that certain fatty acids and the combination of certain fatty acids and oral absorption enhancers can achieve a synergistic effect in enhancing overall oral absorption of therapeutic agents.
- the present disclosure pertains to the use of certain fatty acids and the mixtures of certain fatty acids and functional excipients combined with formulation method of preparation to significantly enhance the gastrointestinal absorption of biologic therapeutics as a single agent or combination agents to transform approaches by which diseases are cured and alleviated.
- Biologic therapeutics as used herein are not particularly limited, and include carbohydrates, peptides, proteins, enzymes, antibodies, drug conjugates, vaccines, nucleic acids and nucleic acid-based gene therapies.
- biologic therapeutics include but not limited to unfractionated heparin, low molecular weight heparins, synthetic heparins, growth hormones, growth factors, insulins, insulin icodec, interferons, interlukins, follicular stimulating hormones, gonadotropins, erythropoeitins, incretins, semaglutide, liraglutide, exenatide, tirzepatide, PYY, oxyntomodulin, GLP-1, GLP-2, calcitonin, PTH and analogs, vancomycin, daptomycin, micafungin, anidulafungin, capsofungin, leuprolide, monoclonal antibodies.
- Functional excipients useful herein include but not limited to these molecules and their analogs: sodium undecylenate (uC11) , sodium 8- (2-hydroxybenzamido) octanoate (SNAC) , 10- ( (2-hydroxybenzoyl) amino) decanoate sodium (SNAD) , 8- (N-2-hydroxy-5-chlorobenzoyl) -amino-caprylates (5CNAC) , sodium N- (4-chlorosalicyloyl) -4-aminobutyrate (4-CNAB) , sodium N- [8- (2-hydroxy-4-methoxy) bensoyl] amino caprylate (4-MOAC) , Bis-3, 6 (4-fumarylaminobutyl) -2, 5-diketopiperazine.
- functional excipients useful herein include, for example, linear fatty acids and their salts with the number of carbons in the aliphatic chain ranging from 2 to 20.
- the medication is administered using oral dosage forms that contain an active agent of incretin therapeutics ( "incretins” ) such as GLP-1 receptor agonists (GLP-1 RA) , functional excipients such as mixtures of fatty acids and surfactants, and common excipients used in oral dosage forms such as tablets and capsules.
- incretins such as GLP-1 receptor agonists (GLP-1 RA)
- functional excipients such as mixtures of fatty acids and surfactants
- common excipients used in oral dosage forms such as tablets and capsules.
- the oral dosage forms can contain combination of active agents such as but not limited to GLP-1 RA and SGLT2i, GLP-1 RA and DPP4 inhibitors, and GLP-1 RA and insulin.
- Incretins useful for embodiments herein include but not limited GLP-1, GIP, GLP-1/GIP agonists. Incretins useful for embodiments herein also include GIP, GLP-1/GIP agonist in clinical trials, GLP-1 RA and GLP-1 analogues including but not limited to semaglutide, liraglutide, dulaglutide, lixisenatide, exenatide and others.
- SGLT2i useful for embodiments herein include but not limited to empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and others.
- DPP4 inhibitors useful for embodiments herein include but not limited to sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, and others.
- Insulin and insulin analogues useful for embodiments herein include but not limited to insulin icodec.
- the medication is administered using oral dosage forms that contain heparins, such as low molecular weight heparin (LMWH) , such as enoxaparin, bemiparin, nadroparin, reviparin, parnaparin, certoparin, dalteparin, or tinzaparin.
- LMWH low molecular weight heparin
- the present disclosure pertains to methods for the preparation of oral dosage forms such as tablets and capsules.
- mixtures of functional excipients and methods of preparation described herein can also be applied to other routes of administration.
- FIG. 1 shows a comparison of mean pharmacokinetics of semaglutide in plasma in a linear scale following oral administration of (1) formulations containing 10 mg semaglutide with 300 mg SNAC, or (2) formulations containing 10 mg semaglutide with 300 mg uC11.
- FIG. 2 shows a comparison of mean pharmacokinetics of enoxaparin in plasma in a linear scale following oral administration of (1) formulations containing 80 mg enoxaparin with 300 mg SNAC, or (2) formulations containing 80 mg enoxaparin with 300 mg uC11.
- the present disclosure generally relates to oral delivery of therapeutic agents.
- the present inventors have discovered that the combination of semaglutide with uC11 produced an unexpected higher drug absorption than formulations containing semaglutide and SNAC.
- the effective enhancement based on semaglutide plasma concentration is about 5-fold.
- the inter-individual variability is also substantially reduced.
- formulations containing enoxaparin with uC11 also provided an unexpected higher drug absorption than formulations containing enoxaparin and SNAC.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutic agent (e.g., any of those described herein) and one or more, particularly, two or more, functional excipients (e.g., any of those described herein) .
- a therapeutic agent e.g., any of those described herein
- functional excipients e.g., any of those described herein
- functional excipients refer to those excipients that can enhance the oral bioavailability of the therapeutic agent.
- the functional excipients refer to those that can increase the bioavailability of the GLP-1 agonist or heparin of a composition following oral administration.
- the pharmaceutical composition comprises one or more functional excipients that can enhance the oral absorption of the therapeutic agent.
- the one or more functional excipients include a compound of Formula I:
- R 1 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
- the one or more functional excipients include an aliphatic acid of Formula II: R 2 COOH, wherein R 2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
- the one or more functional excipients include a compound of Formula III:
- n is an integer selected from 0, 1, 2, 3, or 4;
- G 1 at each occurrence is independently OH, NH 2 , NH (C 1-4 alkyl) , N (C 1-4 alkyl) (C 1-4 alkyl) , halogen (e.g., Cl) , C 1-4 alkyl, or C 1-4 alkoxy (e.g., OCH 3 ) ; and
- L 1 is a substituted or unsubstituted C 2 -C 16 alkylene, or substituted or unsubstituted C 2 -C 16 alkenylene.
- the pharmaceutical composition is formulated for oral administration.
- a therapeutically effective plasma concentration of the therapeutic agent can be achieved following oral administration of the pharmaceutical composition herein.
- the therapeutic agent is a polypeptide described herein.
- the present disclosure provides a pharmaceutical composition comprises: a polypeptide and a compound of Formula I wherein R 1 represents an aliphatic group, or a pharmaceutically acceptable salt thereof:
- the pharmaceutical composition further comprises: an aliphatic acid of Formula II: R 2 COOH, wherein R 2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition does not comprise the aliphatic acid of Formula II or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition further comprises: a compound of Formula III:
- n is an integer selected from 0, 1, 2, 3, or 4;
- G 1 at each occurrence is independently OH, NH 2 , NH (C 1-4 alkyl) , N (C 1-4 alkyl) (C 1-4 alkyl) , halogen (e.g., Cl) , C 1 - 4 alkyl, or C 1 - 4 alkoxy (e.g., OCH 3 ) , and
- L 1 is a substituted or unsubstituted C 2 -C 16 alkylene, or substituted or unsubstituted C 2 -C 16 alkenylene.
- the pharmaceutical composition does not comprise the compound of Formula III or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition further comprises: a combination of the aliphatic acid of Formula II (e.g., any of those defined herein) and the compound of Formula III (e.g., any of those defined herein) , or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition does not comprise either of the aliphatic acid of Formula II and the compound of Formula III, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition comprises: a polypeptide described herein and a compound of Formula I (e.g., any of those defined herein) .
- the pharmaceutical composition comprises: a polypeptide described herein, a compound of Formula I (e.g., any of those defined herein) , and an aliphatic acid of Formula II: R 2 COOH, wherein R 2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition comprises: a polypeptide described herein, a compound of Formula I (e.g., any of those defined herein) and a compound of Formula III:
- n is an integer selected from 0, 1, 2, 3, or 4;
- G 1 at each occurrence is independently OH, NH 2 , NH (C 1-4 alkyl) , N (C 1-4 alkyl) (C 1-4 alkyl) , halogen (e.g., Cl) , C 1 - 4 alkyl, or C 1 - 4 alkoxy (e.g., OCH 3 ) ;
- L 1 is a substituted or unsubstituted C 2 -C 16 alkylene, or substituted or unsubstituted C 2 -C 16 alkenylene.
- the pharmaceutical composition comprises: a polypeptide, a compound of Formula I (e.g., any of those defined herein) , an aliphatic acid of Formula II (e.g., any of those defined herein) and a compound of Formula III (e.g., any of those defined herein) .
- the pharmaceutical composition comprises: a heparin described herein and a compound of Formula I (e.g., any of those defined herein) .
- the pharmaceutical composition comprises: a heparin described herein, a compound of Formula I (e.g., any of those defined herein) , and an aliphatic acid of Formula II: R 2 COOH, wherein R 2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition comprises: a heparin described herein, a compound of Formula I (e.g., any of those defined herein) and a compound of Formula III:
- n is an integer selected from 0, 1, 2, 3, or 4;
- G 1 at each occurrence is independently OH, NH 2 , NH (C 1-4 alkyl) , N (C 1-4 alkyl) (C 1-4 alkyl) , halogen (e.g., Cl) , C 1 - 4 alkyl, or C 1 - 4 alkoxy (e.g., OCH 3 ) ;
- L 1 is a substituted or unsubstituted C 2 -C 16 alkylene, or substituted or unsubstituted C 2 -C 16 alkenylene.
- the pharmaceutical composition comprises: a heparin, a compound of Formula I (e.g., any of those defined herein) , an aliphatic acid of Formula II (e.g., any of those defined herein) and a compound of Formula III (e.g., any of those defined herein) .
- the oral absorption enhancing effects observed herein for the compound of Formula I are not limited to any particular therapeutic agents.
- uC11 was shown to enhance the oral delivery for both therapeutic agents, with better efficacy than SNAC.
- the therapeutic agent useful for the pharmaceutical compositions described herein is not particularly limited.
- the therapeutic agent can include a carbohydrate, peptide, protein, antibody, vaccine, nucleic acid, etc.
- the therapeutic agent can be Biologic therapeutics as described herein.
- the therapeutic agent can be a large molecule, for example, those having a molecular weight of more than 2,000 Daltons, more than 3,000 Daltons, more than 10,000 Daltons, or more than 100,000 Daltons, etc.
- the therapeutic agent can be a carbohydrate, such as a heparin (e.g., unfractionated heparin, Low molecular weight heparins, Synthetic heparins such as Fondaparinux) or glucosamines, etc.
- a heparin e.g., unfractionated heparin, Low molecular weight heparins, Synthetic heparins such as Fondaparinux
- glucosamines etc.
- the therapeutic agent can be a polypeptide (alternatively referred to herein as peptide) , including proteins and antibodies.
- peptide alternatively referred to herein as peptide
- Useful polypeptides for embodiments herein are not particularly limited and include for example, the following agents:
- the therapeutic agent can also include a vaccine. In some embodiments, the therapeutic agent can also include a nucleic acid.
- the therapeutic agent can include an incretin therapeutics.
- the therapeutic agent can include a Glucagon-Like Peptide-1 (GLP-1) receptor agonist, e.g., any of those described herein, or any of those described in U.S. Patent Nos. 10,960,052, 8,129,343, 8,536,122, 9,278,123, 10,086,047, 10,278,923, and 10,933,120, the entire contents of each of which are herein incorporated by reference.
- the therapeutic agent can include semaglutide, liraglutide, dulaglutide, lixisenatide, or exenatide.
- incretins and peptides can include, but not limited to, PYY and PYY analogues; GLP-1/GIP receptor due agonists such as, but not limited to Tirzepatide, CT-388, SCO-094, etc. ; GLP-1/GCGR receptor due agonists, such as, but not limited to efinopegdutide, IB1362, etc.
- the pharmaceutical composition herein can include the GLP-1 receptor agonist as the only therapeutic agent. In some embodiments, the pharmaceutical composition herein can include the GLP-1 receptor agonist as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating diabetes, e.g., any of those known in the art.
- the one or more other therapeutic agent can include (1) a SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, or ertugliflozin; (2) a DPP-4 inhibitor, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin; (3) insulin or insulin analogues (e.g., Insulin icodec) ; (4) GIP, glucose-dependent insulinotropic polypeptides; and/or (5) amylin or amylin analogues.
- the one or more other therapeutic agent can also include (1) biguanides; (2) Thiazolidinediones; (3) DPP-4 inhibitors; (4) PYY; and (5) sulfonylureas.
- the pharmaceutical composition herein can include the GLP-1 receptor agonist as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating a neurological disease, such as Alzheimer's Disease.
- the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with (1) Cholinesterase inhibitors (e.g., Aricept, Exelon, Razadyne) ; (2) Glutamate regulators (e.g., Namenda) ; and/or (3) Orexin receptor antagonist (e.g., Belsomra) .
- Cholinesterase inhibitors e.g., Aricept, Exelon, Razadyne
- Glutamate regulators e.g., Namenda
- Orexin receptor antagonist e.g., Belsomra
- the therapeutic agent herein can include semaglutide.
- Semaglutide as used herein is not limited to any particular forms.
- semaglutide can be in the form of a pharmaceutically acceptable salt, such as a sodium salt.
- Semaglutide is marketed in the United States under several brandnames, including the oral tablet formulation. See Rybelsus Prescribing Information approved by the U.S. Food and Drug Administration, 2021 version, the content of which is herein incorporated by reference in its entirety.
- the peptide backbone of semaglutide is produced by yeast fermentation.
- the main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4) . A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid.
- the molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. The structure is shown below:
- the pharmaceutical composition herein can include semaglutide as the only therapeutic agent. In some embodiments, the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating diabetes, e.g., any of those known in the art.
- the one or more other therapeutic agent can include (1) a SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, or ertugliflozin; (2) a DPP-4 inhibitor, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin; (3) insulin or insulin analogue (e.g., Insulin icodec) ; (4) GIP, glucose-dependent insulinotropic polypeptides; and/or (5) amylin or amylin analogues.
- a SGLT2i such as empagliflozin, canagliflozin, dapagliflozin, or ertugliflozin
- a DPP-4 inhibitor such as sitagliptin, vildagliptin, saxagliptin, linagliptin, or aloglip
- the one or more other therapeutic agent can also include (1) biguanides; (2) Thiazolidinediones; (3) DPP-4 inhibitors; (4) PYY; and (5) sulfonylureas.
- the one or more other therapeutic agent can include one or more selected from the following: Biguanides, Sulfonylureas and meglitinides, Thiazolidinediones, Alpha-glucosidase inhibitors, other Glucagon like peptide-1 (GLP-1) receptor agonists, Dipeptidyl peptidase 4 (DPP4) inhibitors, Amylin analogue, Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, Dopamine agonists, and Bile acid sequestrants.
- the one or more other therapeutic agent can include one or more selected from the following: Metformin, Glipizide, Gliclazide, Glyburide, Glimepiride, Nateglinide, Repaglinide, Pioglitazone, Rosiglitazone, Acarbose, Miglitol, Voglibose, Exenatide, Liraglutide, Lixisenatide, Dulaglutide, Albiglutide, Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Pramlintide, Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin, Bromocriptine, and Colesevelam.
- the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating a neurological disease, such as Alzheimer's Disease.
- the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with (1) Cholinesterase inhibitors (e.g., Aricept, Exelon, Razadyne) ; (2) Glutamate regulators (e.g., Namenda) ; and/or (3) Orexin receptor antagonist (e.g., Belsomra) .
- Cholinesterase inhibitors e.g., Aricept, Exelon, Razadyne
- Glutamate regulators e.g., Namenda
- Orexin receptor antagonist e.g., Belsomra
- the pharmaceutical composition herein can include a heparin as the therapeutic agent.
- heparin refers to all forms of heparin, including, but not limited to, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin (e.g., enoxaparin (including enoxaparin sodium) , tinzaparin (including tinzaparin sodium) ) , very low molecular weight heparin, and ultra low molecular weight heparin.
- Non-limiting examples include unfractionated heparin, such as heparin sodium (e.g., heparin sodium USP, available from Scientific Protein Labs of Waunakee, Wis. ) .
- Heparin generally has a molecular weight of from about 1,000 or 5,000 to about 30,000 Daltons.
- the term “low molecular weight heparin” generally refers to heparin having an average molecular weight of less than 8000 Da and for which at least 60%of all chains have a molecular weight less than 8000 Da.
- Non-limiting examples of low molecular weight heparin include tinzaparin, enoxaprin, and daltiparin. Tinzaparin has been approved by the U.S.
- very low molecular weight heparin generally refers to heparin in which at least about 80% (by weight) of the heparin has a molecular weight of between about 1500 and about 5000 daltons.
- very low molecular weight heparin is bemiparin.
- ultra low molecular weight heparin generally refers to heparin in which at least about 80% (by weight) of the heparin has a molecular weight of between about 1000 and about 2000 daltons.
- a non-limiting examples of ultra low molecular weight heparin is fondiparinux.
- compositions herein are not limited to any particular types of heparins. Rather, the pharmaceutical compositions herein can include any of the heparin-based drugs, which include for example, unfractionated heparin (UFH) , low molecular weight heparin (LMWH) , and synthetic heparins.
- UHF unfractionated heparin
- LMWH low molecular weight heparin
- synthetic heparins synthetic heparins.
- Unfractionated heparin is a highly sulfated polysaccharide with an average molecular weight of between 15 and19 kDa (R. J. Linhardt: Heparin: structure and activity. Journal of medicinal chemistry 46, 2551-2564 (2003) ) .
- Heparin is biosynthesized in the endoplasmic reticulum and the Golgi of mast cells that are present in larger numbers in the liver, intestines, and lungs. It is extracted from food animal sources including cows and pigs, with porcine intestinal mucosa being the standard species and tissue source. Heparin binds to AT, as serine protease inhibitor, and targets coagulation proteins including factor Xa, and factor IIa (thrombin) .
- AT binds a variably sulfated pentasaccharide sequence having a central 3-O-sulfoglucosamineresidue. AT bound to heparin undergoes a conformational change, exposing a reactive loop that is acted upon and by factor Xa and thrombin catalyzing their inactivation.
- LMWH consists of smaller fragmented heparin molecules prepared through the controlled chemical or enzymatic depolymerization of unfractionated heparin (UFH) (J. Hirsh, S. S. Anand, J. L. Halperin, V. Fuster and A. H. Association: Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation 103, 2994-3018 (2001) ) .
- UHP unfractionated heparin
- the depolymerization method in the production process affects generated LMWH’s properties. More than ten LMWHs have been clinically used and they display similar biological properties, such as dalteparin, sodium, enoxaparin, and tinzaparin, etc.
- LMWHs have an average molecular weight between 4-5 kDa, a longer plasma half-life, better bioavailability at low doses, as well as a more predictable dose response characteristic than UFH. This allows out patient subcutaneous treatment with LMWH instead of inpatient intravenous administration of UFH.
- LMWHs also show low non-specific binding to macrophages, endothelial cells, platelets, osteoblasts, platelet factor 4 (PF4) , and nonspecific binding to plasma proteins reducing many of the problems associated with heparin like shorter plasma half-lives, heparin induced thrombocytopenia (HIT) , and osteoporosis.
- HIT heparin induced thrombocytopenia
- ULMWHs such as fondaparinux
- ULMWHs are even smaller heparin chains, many being homogenous compounds, ranging in size from 1.5. -3.5. kDa (Z. Liu, S. Ji, J. Sheng and F. Wang: Pharmacological effects and clinical applications of ultra low molecular weight heparins. Drug Discoveries &Therapeutics 8, 1-10 (2014) ) .
- Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor.
- Fondaparinux binds antithrombin and facilitates its inhibition of factor Xa.
- the advantages of ULMHs include a higher degree of bioavailability, longer plasma half-lives, lower bleeding risk, lower risk of osteoporosis, and penetration of the blood brain barrier.
- ULMWHs are pure Factro Xa inhibitors, having high anti-Xa activity but no anti-IIa activity. Although these ULMWHs have some significant benefits such as no substantial binding to PF4, their drawbacks include high cost and inability to be removed by other means than renal clearance.
- the heparin of the pharmaceutical compositions herein can be a low molecular weight heparin (LMWH) .
- the LMWH has an average molecular weight of about 3000 Daltons to about 7000 Daltons.
- the LMWH can be enoxaparin, bemiparin, nadroparin, reviparin, parnaparin, certoparin, dalteparin, or tinzaparin.
- the heparin of the pharmaceutical compositions herein can be enoxaparin.
- Enoxaparin is presently marketed in the United States, for example, under the brandname Lovenox, in the form of enoxaparin sodium in a sterile aqueous solution.
- Enoxaparin sodium can be obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa.
- the structure of enoxaparin sodium is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N, 6-O-disulfo-D-glucosamine at the reducing end of the chain.
- About 20% (ranging between 15%and 25%) of the enoxaparin structure contains a 1, 6 anhydro derivative on the reducing end of the polysaccharide chain.
- the drug substance of enoxaparin in Lovenox is the sodium salt.
- the average molecular weight is about 4500 daltons.
- FDA United States Food and Drug Administration's
- the heparin in the pharmaceutical compositions herein can be enoxaparin sodium.
- the heparin in the pharmaceutical compositions herein can be dalteparin, such as dalteparin sodium.
- Dalteparin sodium can be produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2, 5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5,000 and about 90%of the material within the range 2,000–9,000.
- the molecular weight distribution of enoxaparin is:
- dalteparin sodium can be represented by the chemical formula shown below according to the FDA approved label for Fragmin:
- the heparin in the pharmaceutical compositions herein can be tinzaparin, such as tinzaparin sodium.
- Tinzaparin sodium is the sodium salt of a low molecular weight heparin that can be obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum. The majority of the components have a 2-O-sulpho-4-enepyranosuronic acid structure at the non-reducing end and a 2-N, 6-O-disulpho-D-glucosamine structure at the reducing end of the chain. The average molecular weight ranges between 5, 500 and 7, 500 daltons. The molecular weight distribution is:
- tinzaparin sodium injection The structure of tinzaparin sodium can be represented by the chemical formula shown below according to the FDA approved label for Innohep (tinzaparin sodium injection) :
- the pharmaceutical composition herein comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 represents an aliphatic group, or a pharmaceutically acceptable salt thereof:
- R 1 represents an alkylene group having 1-30 carbon atoms, e.g., R 1 is - (CH 2 ) 1-18 CH 2 -.
- R 1 represents an alkylene group having 3-20 carbon atoms.
- R 1 represents an alkylene group having 5-16 carbon atoms.
- the compound of Formula I can be which has a chemical name of undecylenic acid.
- the pharmaceutical composition herein comprises a salt (such as an alkali salt, preferably sodium salt) of undecylenic acid which is also known as sodium undecylenate (uC11) .
- the pharmaceutical composition herein comprises an aliphatic acid of Formula I: R 2 COOH, wherein R 2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
- the aliphatic acid has a Formula II: R 2 COOH, wherein R 2 represents an alkyl group having 1-30 carbon atoms.
- the alkyl group can be a linear or branched chain alkyl group.
- R 2 in Formula II can be - (CH 2 ) 1-18 CH 3 .
- R 2 in Formula II can be an alkyl group having 3-20 carbon atoms.
- R 2 in Formula II can be an alkyl group having 5-16 carbon atoms.
- the aliphatic acid of Formula II is a linear aliphatic acid having 2 to 20 carbon atoms, such as caprylic acid, capric acid, or lauric acid. In any of the embodiments described herein, unless otherwise specified or contrary from context, the aliphatic acid of Formula II can be capric acid.
- the aliphatic acid of Formula II can be present in the pharmaceutical composition herein as a free acid or any pharmaceutically acceptable salt thereof, such as an alkali or alkaline salt thereof, for example, a sodium or potassium salt.
- the pharmaceutical composition herein comprises sodium caprate.
- the pharmaceutical composition herein comprises a compound of Formula III:
- the compound of Formula III can have no G 1
- n 1
- the compound of Formula III can have one G 1 substituted on the phenyl ring, i.e., n is 1.
- n is 1, and G 1 is a halogen, C 1 - 4 alkyl, or C 1 - 4 alkoxy.
- n is 1, and G 1 is Cl.
- G 1 is OCH 3 .
- L 1 in Formula II is typically a substituted or unsubstituted C 2 -C 16 alkylene.
- L 1 is an unsubstituted C 3 -C 15 alkylene.
- L 1 is an unsubstituted C 5 -C 13 alkylene.
- the alkyelene can be a straight-chained or a branched alkyelene.
- L 1 is an unsubstituted, straight-chained C 5 -C 9 alkylene.
- the compound of Formula III can be which has a chemical name of 8- (2-hydroxybenzamido) octanoic acid (ChemDraw Software, version 20.0) .
- the pharmaceutical composition herein comprises a salt (preferably sodium salt) of 8- (2-hydroxybenzamido) octanoic acid, which can be prepared using the method described in e.g. WO96/030036, WO00/046182, WO01/092206 or WO2008/028859.
- the salt of 8- (2-hydroxybenzamido) octanoic acid may be crystalline and/or amorphous.
- the delivery agent comprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvate or one third of a hydrate of the salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid as well as combinations thereof.
- the pharmaceutical composition herein comprises a salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid as described in WO2007/121318.
- the pharmaceutical composition comprises sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (referred to as “SNAC” herein) .
- the compound of Formula III can be which has a chemical name of 8- (5-chloro-2-hydroxybenzamido) octanoic acid (ChemDraw Software, version 20.0) .
- the pharmaceutical composition herein comprises a salt of 8- (5-chloro-2-hydroxybenzamido) octanoic acid.
- the compound of Formula III can be which has a chemical name 10- ( (2-hydroxybenzoyl) amino) decanoic acid.
- the pharmaceutical composition herein comprises a salt of 10- ( (2-hydroxybenzoyl) amino) decanoic acid, such as sodium 10- ( (2-hydroxybenzoyl) amino) decanoate.
- the compound of Formula III can be which has a chemical name N- (4-chlorosalicyloyl) -4-aminobutyric acid.
- the pharmaceutical composition herein comprises a salt of N- (4-chlorosalicyloyl) -4-aminobutyric acid, such as sodium N- (4-chlorosalicyloyl) -4-aminobutyrate.
- the compound of Formula III can be which has a chemical name N- [8- (2-hydroxy-4-methoxy) benzoyl] amino caprylic acid.
- the pharmaceutical composition herein comprises a salt of N- [8- (2-hydroxy-4-methoxy) benzoyl] amino caprylic acid, such as sodium N- [8- (2-hydroxy-4-methoxy) benzoyl] amino caprylate.
- the combinations of therapeutic agent, the compound of Formula I or a pharmaceutically acceptable salt thereof, the aliphatic acid of Formula II and the compound of Formula III or a pharmaceutically acceptable salt thereof are not particularly limited.
- the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof.
- a polypeptide e.g., any of those described herein, such as semaglutide
- the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula II or a pharmaceutically acceptable salt thereof.
- a polypeptide e.g., any of those described herein, such as semaglutide
- the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula III or a pharmaceutically acceptable salt thereof.
- a polypeptide e.g., any of those described herein, such as semaglutide
- the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof.
- a polypeptide e.g., any of those described herein, such as semaglutide
- uC11 e.g., any of those described herein, such as semaglutide
- the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) capric acid, a pharmaceutically acceptable salt thereof.
- a polypeptide e.g., any of those described herein, such as semaglutide
- uC11 e.g., any of those described herein, such as semaglutide
- capric acid e.g., capric acid
- the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) SNAC.
- a polypeptide e.g., any of those described herein, such as semaglutide
- uC11 e.g., any of those described herein, such as semaglutide
- SNAC SNAC
- the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof; (c) capric acid, a pharmaceutically acceptable salt thereof; and (d) SNAC.
- a polypeptide e.g., any of those described herein, such as semaglutide
- uC11 e.g., any of those described herein, such as semaglutide
- capric acid e.g., a pharmaceutically acceptable salt thereof
- SNAC SNAC
- the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium undecylenate (uC11) in an amount of about 50 mg to about 500 mg per unit dose, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg or any range between the recited value, per unit dose.
- a polypeptide e.g., any of those described herein, such as semaglutide
- sodium undecylenate (uC11) in an amount of about 50 mg to about 500 mg per unit dose, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg or any range between the recited value, per unit dose.
- the amount should be understood as the weight of the sodium salt itself, not the corresponding equivalent weight of undecylenic acid.
- the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose.
- a polypeptide e.g., any of those described herein, such as semaglutide
- sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose
- sodium caprate in an amount of about 50 mg to 500 mg per unit dose.
- the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- a polypeptide e.g., any of those described herein, such as semaglutide
- sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose
- SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose; (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose, and (d) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- a polypeptide e.g., any of those described herein, such as semaglutide
- sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose
- sodium caprate in an amount of about 50 mg to 500 mg per unit dose
- SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein) , and; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose.
- the amount of the GLP-1 agonist is not particularly limited, for example, typically, the GLP-1 agonist can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, about 150 mg or any range between the recited values.
- the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) sodium caprate in an amount of 50 mg to 500 mg per unit dose.
- the amount of the GLP-1 agonist is not particularly limited, for example, typically, the GLP-1 agonist can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, about 150 mg or any range between the recited values.
- the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein) , and; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) SNAC in an amount of 50 mg to 500 mg per unit dose.
- the amount of the GLP-1 agonist is not particularly limited, for example, typically, the GLP-1 agonist can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, about 150 mg or any range between the recited values.
- the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula II or a pharmaceutically acceptable salt thereof.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- the compound of Formula I or a pharmaceutically acceptable salt thereof e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula III or a pharmaceutically acceptable salt thereof.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- uC11 e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) capric acid, a pharmaceutically acceptable salt thereof.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- capric acid a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) SNAC.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- uC11 e.g., enoxaparin
- SNAC SNAC
- the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof; (c) capric acid, a pharmaceutically acceptable salt thereof; and (d) SNAC.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium undecylenate (uC11) in an amount of about 50 mg to about 500 mg per unit dose, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg or any range between the recited value, per unit dose.
- the amount should be understood as the weight of the sodium salt itself, not the corresponding equivalent weight of undecylenic acid.
- the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose
- sodium caprate in an amount of about 50 mg to 500 mg per unit dose.
- the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose
- SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose; (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose, and (d) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- a heparin e.g., any of those described herein, such as an LMWH, e.g., enoxaparin
- sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose
- sodium caprate in an amount of about 50 mg to 500 mg per unit dose
- SNAC in an amount of about 50 mg to about 500 mg per unit dose.
- the pharmaceutical composition comprises (a) enoxaparin; and (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose.
- the amount of the enoxaparin is not particularly limited, for example, typically, the enoxaparin can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg or any range between the recited values, or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) , per unit dose.
- IU anti-Xa international units
- the pharmaceutical composition comprises (a) enoxaparin; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) sodium caprate in an amount of 50 mg to 500 mg per unit dose.
- the amount of the enoxaparin is not particularly limited, for example, typically, the enoxaparin can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg or any range between the recited values, or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) , per unit dose.
- IU anti-Xa international units
- the pharmaceutical composition comprises (a) enoxaparin; and (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) SNAC in an amount of 50 mg to 500 mg per unit dose.
- the amount of the enoxaparin is not particularly limited, for example, typically, the enoxaparin can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg or any range between the recited values, or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) , per unit dose.
- IU anti-Xa international units
- the pharmaceutical composition can be in the form of a solid oral dosage form.
- the pharmaceutical composition herein can typically be a capsule or tablet.
- the pharmaceutical composition can be in a unit dosage form.
- the pharmaceutical composition herein can be presented in discrete units (which is referred to herein as "unit dosage forms” or “dosage units” ) , such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound (s) .
- the pharmaceutical composition can be in a unit dosage form.
- the pharmaceutical composition herein can include one or more dosage units.
- the pharmaceutical composition herein can typically be a capsule or tablet, wherein each capsule or tablet constitutes a dosage unit.
- each "unit dose" of the pharmaceutical composition refers to the dose of the pharmaceutical composition for each administration, which may contain one or more unit dosage forms or dosage units; when more than one dosage units are used to satisfy the unit dose, the dosage units can be the same or different. In preferred embodiments, each unit dose contains a single dosage unit.
- the pharmaceutical composition herein can optionally include one or more further excipients, such as those suitable for oral administration.
- the pharmaceutical composition herein includes at least one pharmaceutically acceptable excipient.
- excipient as used herein broadly refers to any component other than the active therapeutic ingredient (s) .
- the excipient may be an inert substance, an inactive substance, and/or a not medicinally active substance.
- the excipient may serve various purposes, e.g.
- excipients which may be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2009) ; and Remington: the Science and Practice of Pharmacy, 21th edition, Gennaro, Ed., Lippincott Williams &Wilkins (2005) .
- the excipients may be selected from binders, such as polyvinyl pyrrolidone (povidone) , etc.
- fillers such as cellulose powder, microcrystalline cellulose, cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxy-propylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, etc. ; lubricants and/or glidants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate, etc. ; flow control agents such as colloidal silica, talc, etc. ; crystallization retarders such as Povidone, etc. ; solubilizers such as Pluronic, Povidone, etc.
- colouring agents including dyes and pigments such as Iron Oxide Red or Yellow, titanium dioxide, talc, etc.
- pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, etc.
- surfactants and emulsifiers such as Pluronic, polyethylene glycols, sodium carboxymethyl cellulose, polyethoxylated and hydrogenated castor oil, etc. ; and mixtures of two or more of these excipients and/or adjuvants.
- the pharmaceutical composition herein can comprise a lubricant, a binder, a filler, and/or a chelating agent (e.g., ethylene diamine tetraacetate (EDTA) ) .
- a chelating agent e.g., ethylene diamine tetraacetate (EDTA)
- the pharmaceutical composition herein can also be free or substantially free of a lubricant, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a lubricant.
- the pharmaceutical composition herein can also be free or substantially free of a binder, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a binder.
- the pharmaceutical composition herein can also be free or substantially free of a filler, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a filler.
- the pharmaceutical composition herein can also be free or substantially free of a chelating agent, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a chelating agent.
- compositions can be prepared by those skilled in the art in view of the present disclosure.
- the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- a therapeutic agent e.g., any of those described herein, such as a polypeptide or heparin described herein
- a compound of Formula I described herein or pharmaceutically acceptable salt thereof e.g., any of those described herein, such as a polypeptide or heparin described herein
- the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof, and an aliphatic acid of Formula II described herein or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- a therapeutic agent e.g., any of those described herein, such as a polypeptide or heparin described herein
- an aliphatic acid of Formula II described herein or pharmaceutically acceptable salt thereof e.g., any of those described herein, such as a polypeptide or heparin described herein
- an aliphatic acid of Formula II described herein or pharmaceutically acceptable salt thereof e
- the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof, and a compound of Formula III described herein or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- a therapeutic agent e.g., any of those described herein, such as a polypeptide or heparin described herein
- a compound of Formula III described herein or pharmaceutically acceptable salt thereof e.g., any of those described herein, such as a polypeptide or heparin described herein
- a compound of Formula III described herein or pharmaceutically acceptable salt thereof e.g., any of those described here
- the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof, an aliphatic acid of Formula II described herein or pharmaceutically acceptable salt thereof, and a compound of Formula III described herein or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- a therapeutic agent e.g., any of those described herein, such as a polypeptide or heparin described herein
- a compound of Formula I described herein or pharmaceutically acceptable salt thereof e.g., an aliphatic acid of Formula II described herein or pharmaceutically acceptable salt thereof, and a compound of Formula III described herein or pharmaceutical
- the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, to form the mixture.
- the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, and the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt to form the mixture.
- the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, and the compound of Formula III described herein or pharmaceutically acceptable salt to form the mixture.
- the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and the compound of Formula III described herein or pharmaceutically acceptable salt to form the mixture.
- the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
- the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt, and the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
- the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
- the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt, the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
- the present disclosure also provides a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
- the present disclosure also provides a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt, and the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
- the present disclosure also provides a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
- the present disclosure also provides a method of preparing a composition
- a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt, the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
- the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof.
- the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof, and the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof.
- the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof, and the compound of Formula III or pharmaceutically acceptable salt thereof.
- the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the aliphatic acid of Formula III or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof, the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof, and the compound of Formula III or pharmaceutically acceptable salt thereof.
- the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the aliphatic acid of Formula III or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- the therapeutic agent e.g., any of those described herein
- the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11)
- the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values)
- the compound of Formula III or pharmaceutically acceptable salt thereof is SNAC, in an amount
- the therapeutic agent is a GLP-1 agonist or heparin (e.g., any of those described herein) , for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the recited values) ; and (b) the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) , in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and optionally (c) the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and/or optionally (d) the compound
- the therapeutic agent is semaglutide, for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the recited values) , or in an amount of about 0.1 micromole to about 2.5 micromole, such as about 0.5 micromole to about 2.5 micromole; and
- the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) , in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and for the optional (c) , the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited
- the therapeutic agent is enoxaparin, for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the recited values) , or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) ; and (b) the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) , in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and for the optional (c) , the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.
- composition comprising the therapeutic agent prepared by the method herein is also a novel composition of the present disclosure.
- the present disclosure further provides a method of preparing a pharmaceutical composition comprising mixing the composition comprising the therapeutic agent prepared by the method herein with a pharmaceutically acceptable excipient (e.g., any of those described herein) .
- a pharmaceutically acceptable excipient e.g., any of those described herein
- compositions described herein can be useful for treating a disease or disorder in a subject in need thereof, wherein the disease or disorder can be any of those known to be treatable with the therapeutic agent disclosed herein.
- the enhanced oral delivery of therapeutic agents as shown in the present disclosure can offer alternative and advantageous treatment options using these therapeutic agents.
- the present disclosure provides a method of treating type-2 diabetes or obesity, in a subject in need thereof, the method comprising orally administering the pharmaceutical composition described herein to deliver a therapeutically effective amount of the therapeutic agent (e.g., GLP-1 agonist described herein) to the subject.
- the therapeutic agent e.g., GLP-1 agonist described herein
- Type 2 diabetes is a serious global public health issue, with huge burdens associated with complications resulted from the microvascular and macrovascular diseases.
- the pathogenesis of diabetes comprises changes in multiple organs, typically with elevated glycemic levels and loss or reduction of the glycemic control.
- the glycemic control for T2D with different mechanisms of actions has been demonstrated in reduced incidences of microvascular diseases, such as diabetic kidney diseases and diabetic retinopathy. (Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017; 389 (10085) : 2239–2251. ) .
- GLP-1 receptor agonists have become an important and essential medications that are widely prescribed.
- GLP-1 is mainly expressed in intestinal L cells and brainstem.
- the GLP-1 receptor (GLP-1 R) a G protein-coupled receptor, is expressed in a variety of tissues, including pancreatic islets, gastrointestinal tract, lung, cardiovascular system, kidney, nodose ganglion neurons of the vagal nerve, the hypothalamus and brainstem in the CNS (Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A.
- GLP-1 expressed from intestinal L cells can circulate and directly bind onto canonical receptors in the pancreatic islet or may indirectly signal the hepatic vagal branch within intraportal vein, potentiating glucose-induced insulin secretion and most postprandial insulin secretion (Pais R, Gribble FM, Reimann F. Stimulation of incretin secreting cells. Ther Adv Endocrinol Metab. 2016; 7 (1) : 24–42. ) .
- the signals are sent to the hypothalamus for reducing appetite, stimulating gluconeogenesis, lowering hepatic glucose output, amplifying glucose-dependent insulin release, inhibiting glucagon release, increasing cardiac output and cardioprotection, and decreasing high blood pressure (Muller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1) . Mol Metab. 2019; 30: 72–130. ) .
- the function of incretin axis is impaired in T2D with insufficient GLP-1 production, or disrupted GLP-1 action.
- GLP-1 and GLP-1 analogues have been developed as medications for treatment of T2D (Aulinger BA, Vahl TP, Prigeon RL, D’A lessio DA, Elder DA.
- T2D Aulinger BA, Vahl TP, Prigeon RL, D’A lessio DA, Elder DA.
- GLP-1 Natural GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) with a half-life at about less than 2 minutes. Therefore, many GLP-1 receptor agonist analogues (GLP-1 RA) were developed with the attempts of prolonging the half-life.
- GLP-1 analogues include: Exendin-4, liraglutide, dulaglutide, lixisenatide, semaglutide, that are approved by US Food and Drug Administration (FDA) for management of T2D.
- FDA US Food and Drug Administration
- Exendin-4 is a 53%homologous peptide extracted from the venom of a Gila monster. It is resistant to degradation by the DPP4.
- Structural modifications such as replacement of certain amino acids and/or additions of certain fatty acids were applied to prolong the half-life, allowing once weekly administration from daily administration of GLP-1 analogues; including dulaglutide, albiglutide, liraglutide, lixisenatide, semaglutide (Romera I, Cebria′n-Cuenca A, A′lvarez-Guisasola F, Gomez-Peralta F, Reviriego J. A review of practical issues on the use of glucagon-like peptide-1 receptor agonists for the management of type 2 diabetes. Diabetes Ther. 2019; 10 (1) : 5–19. ) .
- the class of GLP-1 RAs in T2D has demonstrated significant reductions in A1C and a favorable effect on weight control with minimal risk of hypoglycemia (Trujillo JM. Glucagon-like peptide-1 receptor agonists. In: White JR (ed. ) Guide to medications for the treatment of diabetes mellitus. Arlington County, VA: American Diabetes Association, 2020, pp. 190–210. ) .
- three of the GLP-1 RAs have demonstrated cardiovascular benefits; dulaglutide, liraglutide, and semaglutide (Matza LS, Boye KS, Sterward DK, et al.
- GLP-1 RAs are associated with the adverse effects, mainly GI AEs and also injection-site related AEs.
- the use of GLP-RAs may be also limited by the injection delivery route, resulting in adherence issues. Evaluating the head-to-head studies showed that the long-acting agents result in greater A1C lowering than the short-acting agents, with semaglutide leading to the greatest A1C reduction.
- exenatide XR appears to have the least impact on A1C, although it still produces more A1C lowering compared with the short-acting agents.
- weight there is more ambiguity with the differentiation between agents.
- the long-acting agents tend to produce more significant weight loss compared with the short-acting agents, with semaglutide once again taking the lead on the greatest weight reduction (Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7) : a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018; 6: 275–286.
- GI adverse effects appear to be highest with the short-acting agents as well as subcutaneous semaglutide and appear to be lowest with exenatide XR. Injection site reactions may be more common with the longer acting agents, particularly exenatide once-weekly, which can cause transient small nodules at the injection site.
- Patient satisfaction data indicate that once weekly injections result in higher patient satisfaction compared with twice daily injections.
- Discontinuation rates due to adverse events vary between agents and studies, but are low overall with less than 10%of patients in the studies discontinuing GLP-1 RA therapy due to adverse events (Wilke T, Mueller S, Groth A, et al. Nonpersistence and non-adherence of patients with type 2 diabetes mellitus in therapy with GLP-1 receptor agonists: a retrospective analysis. Diabetes Ther 2016; 7: 105–124. ) .
- the risk of hypoglycemia is low with GLP-1 RAs and rates were similar across all GLP-1 RA treatment groups.
- GLP-1 and GLP-1 analogues are peptides, that have high molecular weight with very low permeability across biological membranes, labile to gut enzymatical degradation, therefore, oral delivery of GLP-1 analogues are typically with very low oral bioavailability. Therefore, all GLP RA therapies are injectables and result in difficultly to use and fear of needles, thus acceptance and adherence of the therapies (Wilke T, Mueller S, Groth A, et al. Nonpersistence and non-adherence of patients with type 2 diabetes mellitus in therapy with GLP-1 receptor agonists: a retrospective analysis. Diabetes Ther 2016; 7: 105–124. ) .
- the first GLP-1 analogue with oral delivery was semaglutide, which was coformulated with an absorption enhancer, sodium N- (8- [2-hydroxybenzoyl] amino) caprylate (SNAC) (Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017; 318 (15) : 1460–70.290) .
- SNAC sodium N- (8- [2-hydroxybenzoyl] amino) caprylate
- the low bioavailability contributes to high variability in drug exposure in the systemic circulation.
- the low bioavailability can significantly increase cost that can become prohibitive to payors, particularly as higher doses of the drug will be needed to control obesity.
- the injectable version of semaglutide Ozempic
- the weekly dosage of 2.4 mg approved as Wegovy by FDA in 2021
- the daily dose is up to 14 mg (FDA label for Rybelsus and Wegovy) .
- the dose in the oral version needed for obesity may be up to over 50 mg.
- the sodium salt of undecylenic acid (uC11) achieved a significantly higher oral bioavailability of GLP-1 agonist (in particular semaglutide) compared to using just SNAC as enhancer.
- the method herein can advantageously use the pharmaceutical composition herein to orally administer GLP-1 agonist for the treatment of various diseases or disorders for which a GLP-1 agonist can be beneficial, such as type-2 diabetes or obesity.
- the present disclosure provides a method of orally delivering of heparin and/or for treating a disease or disorder that are treatable with heparin.
- the disease or disorder can be any of those known to be treatable with heparins, such as any of the approved indications by the U.S. FDA for enoxaparin, dalteparin, and tinzaparin, see the approved labels as of the filing date of this application.
- the enhanced oral delivery of therapeutic agents as shown in the present disclosure can offer alternative and advantageous treatment options using heparins.
- the present disclosure provides a method of treating a disease or disorder for which administering heparin such as LWMH is beneficial, e.g., deep vein thrombosis (DVT) , Sickle Cell Disease (SCD) , pre-thrombotic state/recurrent spontaneous abortion (PTS/RSA) , cancer associated thrombosis (CAT) , dyslipidemia, etc., in a subject in need thereof, the method comprising orally administering the pharmaceutical composition of any of those described herein to deliver a therapeutically effective amount of the heparin such as LMWH to the subject.
- a disease or disorder for which administering heparin such as LWMH is beneficial, e.g., deep vein thrombosis (DVT) , Sickle Cell Disease (SCD) , pre-thrombotic state/recurrent spontaneous abortion (PTS/RSA) , cancer associated thrombosis (CAT) , dyslipidemia, etc.
- the present disclosure provides a method of prophylaxis or treatment of COVID-19 infection in a subject in need thereof, the method comprising orally administering the pharmaceutical composition of any of those described herein to deliver an effective amount of the heparin such as LMWH to the subject.
- the present disclosure provides a method of treating or preventing sickle cell disease (SCD) in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- SCD sickle cell disease
- the present disclosure provides a method of treating or preventing pre-thrombotic state/recurrent spontaneous abortion (PTS/RSA) in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- PTS/RSA pre-thrombotic state/recurrent spontaneous abortion
- the present disclosure provides a method of treating or preventing cancer associated thrombosis (CAT) in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- CAT cancer associated thrombosis
- the present disclosure provides a method of prophylaxis or treatment of COVID-19 infection in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- the present disclosure provides a method of treating or preventing dyslipidemia in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- the present disclosure provides a method of treating or preventing thrombosis in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11. Any type of thrombosis can be treated or prevented with the pharmaceutical composition including, but not limited to, deep vein thrombosis (DVT) and pulmonary embolism (PE) .
- the present disclosure provides a method of treating or preventing deep vein thrombosis in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- the present disclosure provides a method of treating or preventing ischemic complications in unstable angina and/or non-Q-wave myocardial infarction in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- the present disclosure provides a method of treating or preventing deep vein thrombosis (DVT) in a subject following hip or knee replacement surgery in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- DVD deep vein thrombosis
- the present disclosure provides a method of treating or preventing DVT following abdominal surgery in patients at risk for thromboembolic complications in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- Abdominal surgery patients at risk include, but are not limited to, those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of DVT or pulmonary embolism.
- the present disclosure provides a method of treating or preventing DVT in a subject with severely restricted mobility in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
- compositions herein containing heparin can also be used for additional treatment methods which include, but are not limited to the treatment of cardiac valve replacements, both mechanical and cadaver; treatment of endocarditis; prophylaxis in patients undergoing neurological procedures, such as, but not limited to, resection of malignant brain tumors; prophylaxis in patients with acute spinal cord injury, medical conditions associated with thromboembolism, such as but not limited to, those with ischemic stroke or restricted mobility, cancer, myocardial infarction, cancer, congestive heart failure, or severe pulmonary disease; for secondary prophylaxis of venous thromboembolism during pregnancy, or for primary prophylaxis in pregnant women with inherited causes of thrombophilia (e.g.
- compositions herein can be used as a monotherapy or in a combination therapy.
- the pharmaceutical composition can be a fixed dose combination of two or more active therapeutic agents.
- Non-limiting combination therapies contemplated include the following.
- Sodium-glucose cotransporter (SGLT) proteins function independently of insulin in regulation of glucose.
- Sodium-glucose cotransporter 1 (SGLT1) proteins are high affinity and low-capacity transporters of glucose and are expressed in the small intestines as well as the proximal tubule of the kidneys.
- the SGLT1 proteins in the proximal convoluted tubule of the kidneys are responsible for less than 10%of filtered glucose reabsorption.
- Sodium-glucose cotransporter-2 (SGLT2) proteins are expressed in the proximal convoluted tubule of the kidneys and are responsible for roughly 90%of filtered glucose reabsorption (Scheen AJ.
- SGLT2 sodium-glucose co-transporter type 2
- SGLT2i have demonstrated clinically body weight control and antihypertensive benefits.
- the risk of hypoglycemia with SGLT2i is small when compared to insulin and sulfonylureas.
- GLP-1RAs and SGLT2i showed the evidence to improve clinical outcomes in diabetic patients with cardiovascular diseases.
- the new T2D pharmacotherapy guidelines have recommended the use of GLP-1RAs for prevention and treatment of obese patients with risks of atherosclerotic cardiovascular diseases, whereas SGLT-2i has been proposed for patients with a risk of chronic heart failure.
- SGLT-2i has been proposed for patients with a risk of chronic heart failure.
- systemic research especially clinical trials to further evaluate the potential additive or synergistic effects of these two classes of medications for the CV benefits, given both classes of drugs have different modes of mechanisms for treatments of T2D and diabetes.
- GLP-RA are also injectable peptides daily or weekly (except for oral semaglutide) while SGLT2i are all oral tablets administered daily. It is not feasible to develop a financially supportive combination, since such injectable and oral combinations may not be acceptable to patients in practice, and more importantly, no intellectual properties can be obtained for such direct combinations of two commercially available medications.
- oral semaglutide is absorbed in stomach facilitated by the carrier, SNAC, while SGLT2i are formulated in tablets with coated film, which target absorption in small intestine, where the absorption area is large and the villi of endothelial cells are abundant, allowing much higher permeability than in stomach.
- the present invention enables the formulations of GLP-RA and SGLT2i into the same tablets, which not only have improved oral bioavailability of GLP-RA compared to the formulation with SNAC alone, but also allow absorption of SGLT2i from the stomach.
- Such fixed-dose combination of GLP-RA and SGLT2 is in one tablet brings significant medical values with convenient use and economic feasibility.
- Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology.
- Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.
- the term “about” modifying an amount related to the invention refers to variation in the numerical quantity that can occur, for example, through routine testing and handling; through inadvertent error in such testing and handling; through differences in the manufacture, source, or purity of ingredients employed in the invention; and the like.
- “about” a specific value also includes the specific value, for example, about 10%includes 10%. Whether or not modified by the term “about” , the claims include equivalents of the recited quantities. In one embodiment, the term “about” means within 20%of the reported numerical value.
- polypeptide and peptide as used herein means a compound composed of at least five constituent amino acids connected by peptide bonds.
- the constituent amino acids may be from the group of the amino acids encoded by the genetic code and they may be natural amino acids which are not encoded by the genetic code, as well as synthetic amino acids.
- analogue as used herein referring to a polypeptide means a modified peptide wherein one or more amino acid residues of the peptide have been substituted by other amino acid residues and/or wherein one or more amino acid residues have been deleted from the peptide and/or wherein one or more amino acid residues have been deleted from the peptide and or wherein one or more amino acid residues have been added to the peptide.
- derivative as used herein in relation to a peptide means a chemically modified peptide or an analogue thereof, wherein at least one substituent is not present in the unmodified peptide or an analogue thereof, i.e. a peptide which has been covalently modified. Typical modifications are amides, 20 carbohydrates, alkyl groups, acyl groups, esters and the like.
- An example of a derivative of GLP-1 (7-37) is NE26- ( (4S) -4- (hexadecanoylamino ) -carboxy-butanoyl) [Arg34, Lys26] GLP-1- (7-37) .
- GLP-1 analogue refers to a peptide, or a compound, which is a variant of the human Glucagon-Like Peptide-1 (GLP-1 (7-37) ) .
- GLP-1 (7-37) has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1) .
- variant refers to a compound which comprises one or more amino acid substitutions, deletions, additions and/or insertions.
- the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80%or 90%sequence identity to GLP-1 (7-37) over the entire length of GLP-1 (7-37) .
- the two peptides [Aib8] GLP-1 (7-37) and GLP-1 (7-37) are aligned.
- the sequence identity of [Aib8] GLP-1 (7-37) relative to GLP-1 (7-37) is given by the number of aligned identical residues minus the number of different residues divided by the total number of residues in GLP-1 (7-37) . Accordingly, in said example the sequence identity is (31-1) /31.
- GLP-1 agonist refers to a compound, which fully or partially activates the human GLP-1 receptor.
- the GLP-1 agonist is a GLP-1 analogue, optionally comprising one substituent.
- the GLP-1 agonist is exendin-4, the sequence of which is HGEGTFITSDL SKQMEEEAVR-LFIEWLKNGGPSSGAPPPS (SEQ ID No: 2) .
- the GLP-1 agonist comprises one substituent which is covalently attached to the peptide.
- the substituent comprises a fatty acid or a fatty diacid.
- the substituent comprises a C16, C18 or C20 fatty acid.
- the substituent comprises a C16, C18 or C20 fatty diacid.
- GLP-1 RA include but not limited to semaglutide, liraglutide, dulaglutide, lixisenatide, exenatide and others.
- the GLP-1 agonist is selected from one or more of the GLP-1 agonists disclosed in WO93/19175, WO96/29342, WO98/08871, WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/027978, WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810, WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050, WO2009/030738, WO2009/030771 and WO2009/030774.
- the GLP-1 agonist is selected from the group consisting of N-epsilon37 ⁇ 2- [2- (2- ⁇ 2- [2- ( (R) -3-carboxy-3- ⁇ [1- (19-carboxynonadecanoyl) piperidine-4-carbonyl] amino ⁇ propionylamino) ethoxy] ethoxy ⁇ acetylamino) ethoxy] ethoxy ⁇ acetyl [desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37) amide; N-epsilon26 ⁇ 2- [2- (2- ⁇ 2- [2- ( (R) -3-carboxy-3- ⁇ [1- (19-carboxynonadecanoyl) piperidine-4- carbonyl] amino ⁇ propionylamino) ethoxy] ethoxy ⁇ acetylamino) ethoxy] ethoxy ⁇ ace
- solid dosage form can refer to a tablet, or a capsule filled with solids, or a capsule filled with a solution.
- treat refers to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
- terapéuticaally effective amount refers to that amount of a therapeutic agent (e.g., semaglutide or enoxaparin) sufficient to result in amelioration of one or more symptoms of a disorder or condition (e.g., Type 2 Diabetes, DVT, sickle cell disease (SCD) , etc. ) , or prevent appearance or advancement of a disorder or condition, or cause regression of or cure from the disorder or condition.
- a therapeutic agent e.g., semaglutide or enoxaparin
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- Formulation 1 prepared according to this procedure contains 10 mg of semaglutide and 300 mg SNAC.
- Formulation 2 prepared according to this procedure contains 10 mg of semaglutide and 300 mg uC11.
- the freeze-dried powder was then processed into a tablet form, which was used for the examples herein.
- the tablet formation was conducted using a manual compressor, a round tablet mold with a diameter of 10 mm, and an arc in the surface of the mold.
- Dogs were raised in separated cages. Before an experiment, two meals were supplied to the dogs at about 3 p. m. and 7 a. m. every day. The foods are fodder with water in a bowl. In the day before the experiment, after feeding the dogs at 3 p. m., the dogs were fasted overnight for about 18h. The dogs have access to water overnight, but water was removed at 1h before dosing. Before dosing, the dogs were put into a sling and then 1 ml of blood was collected from each dog’s leg vein using a sterile disposable syringe.
- Tablet oral dosing open the cages and let the dogs climb on the cage by their forelegs. Catch their mouths and open their mouths by hands. Workers will keep a dog’s mouth open and put the tablet into the dog’s throat to stimulate dogs’ deglutition reflex. After closing the dog’s mouth and keep the mouth closed for about ten seconds, the dogs would swallow the tablet naturally without any water.
- a LC-MS method with MRM mode is used to measure the plasma concentration of semaglutide.
- 150 ⁇ l of acetonitrile with internal standard was added into 50 ⁇ l of plasma to precipitate the proteins. After vortex for 30 seconds, the samples were put into sonication for two minutes. The samples were centrifuged at 15400g for 10minutes. The supernatant was then removed for analysis.
- the mass spectrum is AB (Triple Quad 6400+) , SHIMADZU.
- a Sepax Bio-C18 (4.6*150mm, 5 ⁇ m) was used.
- the parameters of the LC-MS are summarized below:
- Semaglutide ion pairs 1029.2 m/z ⁇ 136.1m/z, collision energy is 100V.
- the terminal half-life of semaglutide was determined based on the terminal log-linear phase.
- the area under the concentration-time (AUC) of semaglutide was calculated using the linear trapezoidal rule.
- the inter-individual variability was assessed with the coefficient of variation (CV) , calculated by the standard deviation divided by the mean.
- Semaglutide + SNAC oral formulations containing semaglutide and SNAC in 10mg and 300mg, respectively, were administered to dogs as shown above.
- concentration-time profiles of semaglutide are shown in Fig. 1.
- the formulation containing uC11 showed a substantial improvement of AUC and Cmax, in about 5.3 and 5.5 folds higher, respectively. Also, the CV of Cmax and AUC was significantly reduced, which is clinically important, because the smaller inter-individual difference means that medications to the patients are safer (smaller proportion of patients receive unnecessary high exposure) and more efficacious (smaller proportion of patients receive sub-therapeutic exposure) .
- the plasma anti-factor X activity post dose of 80 mg Enoxaparin formulated in 300 mg SNAC or in 300 mg uC11 was shown in Figure 2.
- the enoxaparin formulations were prepared similar to the semaglutide formulations in Example 1, except that enoxaparin was used instead.
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Abstract
Provided herein are pharmaceutical compositions comprising therapeutic agent (s) and functional excipients that can enhance oral bioavailability of the therapeutic agent (s). Also provided herein are methods of preparing the pharmaceutical composition and methods of using the same for treating various diseases or disorders such as type-2 diabetes.
Description
Field of the Invention
In various embodiments, the present invention generally relates to oral delivery of therapeutic agents.
Background Art
Delivery via oral route is the most preferred for drug administration. Oral route of administration has several advantages with better patient compliance, ease of administration and typically low cost of production, storage and distribution.
For large molecules, however, very few can be administered via the oral route for the following reasons: 1) pre-systemic degradation due to the acidity in the stomach, and enzymes in the gastro intestinal (GI) tract; 2) low absorption across epithelial cells that line absorption surfaces such as those in the GI tract; and 3) post absorption degradation, such as the first pass metabolism.
BRIEF SUMMARY
In various embodiments, the present disclosure relates to oral delivery of therapeutic agents, in particular, molecules such as those having high molecular weight or otherwise difficult to be absorbed through oral administration, such as polypeptides, heparins, etc. The present disclosure is based, in part, on the unexpected discovery that certain fatty acids and the combination of certain fatty acids and oral absorption enhancers can achieve a synergistic effect in enhancing overall oral absorption of therapeutic agents.
In some embodiments, the present disclosure pertains to the use of certain fatty acids and the mixtures of certain fatty acids and functional excipients combined with formulation method of preparation to significantly enhance the gastrointestinal absorption of biologic therapeutics as a single agent or combination agents to transform approaches by which diseases are cured and alleviated.
Biologic therapeutics as used herein are not particularly limited, and include carbohydrates, peptides, proteins, enzymes, antibodies, drug conjugates, vaccines, nucleic acids and nucleic acid-based gene therapies. For example, biologic therapeutics include but not limited to unfractionated heparin, low molecular weight heparins, synthetic heparins, growth hormones, growth factors, insulins, insulin icodec, interferons, interlukins, follicular stimulating hormones, gonadotropins, erythropoeitins, incretins, semaglutide, liraglutide, exenatide, tirzepatide, PYY, oxyntomodulin, GLP-1, GLP-2, calcitonin, PTH and analogs, vancomycin, daptomycin, micafungin, anidulafungin, capsofungin, leuprolide, monoclonal antibodies.
Functional excipients useful herein include but not limited to these molecules and their analogs: sodium undecylenate (uC11) , sodium 8- (2-hydroxybenzamido) octanoate (SNAC) , 10- ( (2-hydroxybenzoyl) amino) decanoate sodium (SNAD) , 8- (N-2-hydroxy-5-chlorobenzoyl) -amino-caprylates (5CNAC) , sodium N- (4-chlorosalicyloyl) -4-aminobutyrate (4-CNAB) , sodium N- [8- (2-hydroxy-4-methoxy) bensoyl] amino caprylate (4-MOAC) , Bis-3, 6 (4-fumarylaminobutyl) -2, 5-diketopiperazine. In addition, functional excipients useful herein include, for example, linear fatty acids and their salts with the number of carbons in the aliphatic chain ranging from 2 to 20.
In certain illustrative embodiments, the medication is administered using oral dosage forms that contain an active agent of incretin therapeutics ( "incretins" ) such as GLP-1 receptor agonists (GLP-1 RA) , functional excipients such as mixtures of fatty acids and surfactants, and common excipients used in oral dosage forms such as tablets and capsules. Functional excipients useful herein include but not limited to sodium undecylenate (uC11) , sodium N- [8 (-2-hydroxybenzoyl) amino] caprylate (SNAC) , 8- (N-2-hydroxy-5-chlorobenzoyl) -amino-caprylic acid (5-CNAC) , [Bis-3, 6 (4-fumarylaminobutyl) -2, 5-diketopiperazine, salts of linear fatty acids, and combinations thereof. In other embodiments, the oral dosage forms can contain combination of active agents such as but not limited to GLP-1 RA and SGLT2i, GLP-1 RA and DPP4 inhibitors, and GLP-1 RA and insulin. Incretins useful for embodiments herein include but not limited GLP-1, GIP, GLP-1/GIP agonists. Incretins useful for embodiments herein also include GIP, GLP-1/GIP agonist in clinical trials, GLP-1 RA and GLP-1 analogues including but not limited to semaglutide, liraglutide, dulaglutide, lixisenatide, exenatide and others. SGLT2i useful for embodiments herein include but not limited to empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and others. DPP4 inhibitors useful for embodiments herein include but not limited to sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, and others. Insulin and insulin analogues useful for embodiments herein include but not limited to insulin icodec.
In certain illustrative embodiments, the medication is administered using oral dosage forms that contain heparins, such as low molecular weight heparin (LMWH) , such as enoxaparin, bemiparin, nadroparin, reviparin, parnaparin, certoparin, dalteparin, or tinzaparin.
In yet other embodiments, the present disclosure pertains to methods for the preparation of oral dosage forms such as tablets and capsules. In further embodiments, mixtures of functional excipients and methods of preparation described herein can also be applied to other routes of administration.
Exemplary embodiments of the present disclosure are also shown in claims 1-54 as described herein.
It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention herein.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows a comparison of mean pharmacokinetics of semaglutide in plasma in a linear scale following oral administration of (1) formulations containing 10 mg semaglutide with 300 mg SNAC, or (2) formulations containing 10 mg semaglutide with 300 mg uC11.
FIG. 2 shows a comparison of mean pharmacokinetics of enoxaparin in plasma in a linear scale following oral administration of (1) formulations containing 80 mg enoxaparin with 300 mg SNAC, or (2) formulations containing 80 mg enoxaparin with 300 mg uC11.
The present disclosure generally relates to oral delivery of therapeutic agents. As detailed herein, the present inventors have discovered that the combination of semaglutide with uC11 produced an unexpected higher drug absorption than formulations containing semaglutide and SNAC. The effective enhancement based on semaglutide plasma concentration is about 5-fold. The inter-individual variability is also substantially reduced. Similarly, it was observed that formulations containing enoxaparin with uC11 also provided an unexpected higher drug absorption than formulations containing enoxaparin and SNAC.
In a broad aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutic agent (e.g., any of those described herein) and one or more, particularly, two or more, functional excipients (e.g., any of those described herein) . Unless otherwise contrary from context, functional excipients as used herein refer to those excipients that can enhance the oral bioavailability of the therapeutic agent. For example, in some embodiments, the functional excipients refer to those that can increase the bioavailability of the GLP-1 agonist or heparin of a composition following oral administration.
Typically, the pharmaceutical composition comprises one or more functional excipients that can enhance the oral absorption of the therapeutic agent. In some embodiments, the one or more functional excipients include a compound of Formula I:
wherein R
1 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
In some embodiments, the one or more functional excipients include an aliphatic acid of Formula II: R
2COOH, wherein R
2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
In some embodiments, the one or more functional excipients include a compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
n is an integer selected from 0, 1, 2, 3, or 4;
G
1 at each occurrence is independently OH, NH
2, NH (C
1-4 alkyl) , N (C
1-4 alkyl) (C
1-4 alkyl) , halogen (e.g., Cl) , C
1-4 alkyl, or C
1-4 alkoxy (e.g., OCH
3) ; and
L
1 is a substituted or unsubstituted C
2-C
16 alkylene, or substituted or unsubstituted C
2-C
16 alkenylene.
Typically, the pharmaceutical composition is formulated for oral administration. Preferably, a therapeutically effective plasma concentration of the therapeutic agent can be achieved following oral administration of the pharmaceutical composition herein.
In some embodiments, the therapeutic agent is a polypeptide described herein. For example, in some embodiments, the present disclosure provides a pharmaceutical composition comprises: a polypeptide and a compound of Formula I wherein R
1 represents an aliphatic group, or a pharmaceutically acceptable salt thereof:
In some embodiments, the pharmaceutical composition further comprises: an aliphatic acid of Formula II: R
2COOH, wherein R
2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition does not comprise the aliphatic acid of Formula II or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition further comprises: a compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
n is an integer selected from 0, 1, 2, 3, or 4;
G
1 at each occurrence is independently OH, NH
2, NH (C
1-4 alkyl) , N (C
1-4 alkyl) (C
1-4 alkyl) , halogen (e.g., Cl) , C
1-
4 alkyl, or C
1-
4 alkoxy (e.g., OCH
3) , and
L
1 is a substituted or unsubstituted C
2-C
16 alkylene, or substituted or unsubstituted C
2-C
16 alkenylene. However, in some embodiments, the pharmaceutical composition does not comprise the compound of Formula III or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition further comprises: a combination of the aliphatic acid of Formula II (e.g., any of those defined herein) and the compound of Formula III (e.g., any of those defined herein) , or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition does not comprise either of the aliphatic acid of Formula II and the compound of Formula III, or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition comprises: a polypeptide described herein and a compound of Formula I (e.g., any of those defined herein) .
In some embodiments, the pharmaceutical composition comprises: a polypeptide described herein, a compound of Formula I (e.g., any of those defined herein) , and an aliphatic acid of Formula II: R
2COOH, wherein R
2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition comprises: a polypeptide described herein, a compound of Formula I (e.g., any of those defined herein) and a compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
n is an integer selected from 0, 1, 2, 3, or 4;
G
1 at each occurrence is independently OH, NH
2, NH (C
1-4 alkyl) , N (C
1-4 alkyl) (C
1-4 alkyl) , halogen (e.g., Cl) , C
1-
4 alkyl, or C
1-
4 alkoxy (e.g., OCH
3) ;
and
L
1 is a substituted or unsubstituted C
2-C
16 alkylene, or substituted or unsubstituted C
2-C
16 alkenylene.
In some embodiments, the pharmaceutical composition comprises: a polypeptide, a compound of Formula I (e.g., any of those defined herein) , an aliphatic acid of Formula II (e.g., any of those defined herein) and a compound of Formula III (e.g., any of those defined herein) .
In some embodiments, the pharmaceutical composition comprises: a heparin described herein and a compound of Formula I (e.g., any of those defined herein) .
In some embodiments, the pharmaceutical composition comprises: a heparin described herein, a compound of Formula I (e.g., any of those defined herein) , and an aliphatic acid of Formula II: R
2COOH, wherein R
2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutical composition comprises: a heparin described herein, a compound of Formula I (e.g., any of those defined herein) and a compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
n is an integer selected from 0, 1, 2, 3, or 4;
G
1 at each occurrence is independently OH, NH
2, NH (C
1-4 alkyl) , N (C
1-4 alkyl) (C
1-4 alkyl) , halogen (e.g., Cl) , C
1-
4 alkyl, or C
1-
4 alkoxy (e.g., OCH
3) ;
and
L
1 is a substituted or unsubstituted C
2-C
16 alkylene, or substituted or unsubstituted C
2-C
16 alkenylene.
In some embodiments, the pharmaceutical composition comprises: a heparin, a compound of Formula I (e.g., any of those defined herein) , an aliphatic acid of Formula II (e.g., any of those defined herein) and a compound of Formula III (e.g., any of those defined herein) .
Therapeutic agents
It is believed that the oral absorption enhancing effects observed herein for the compound of Formula I (e.g., uC11) are not limited to any particular therapeutic agents. For example, as described herein, although enoxaparin and semaglutide belong to two different classes of compounds, uC11 was shown to enhance the oral delivery for both therapeutic agents, with better efficacy than SNAC.
The therapeutic agent useful for the pharmaceutical compositions described herein is not particularly limited. For example, the therapeutic agent can include a carbohydrate, peptide, protein, antibody, vaccine, nucleic acid, etc. In some embodiments, the therapeutic agent can be Biologic therapeutics as described herein. In some embodiments, the therapeutic agent can be a large molecule, for example, those having a molecular weight of more than 2,000 Daltons, more than 3,000 Daltons, more than 10,000 Daltons, or more than 100,000 Daltons, etc.
For example, in some embodiments, the therapeutic agent can be a carbohydrate, such as a heparin (e.g., unfractionated heparin, Low molecular weight heparins, Synthetic heparins such as Fondaparinux) or glucosamines, etc.
In some embodiments, the therapeutic agent can be a polypeptide (alternatively referred to herein as peptide) , including proteins and antibodies. Useful polypeptides for embodiments herein are not particularly limited and include for example, the following agents:
1. GLP-1 and analogs
a) GLP-1
b) Semaglutide
c) Liraglutide
d) Exenatide
e) Tirzepatide
f) Lixisenatide
g) Efinopegdutide
h) Cotadutide
2. Teduglutide
3. Pramlintide
4. PYY
5. Oxyntomodulin
6. Glucagon
7. Calcitonin
8. Octreotide
9. PTH and analogs
a) Teriparatide
10. Etelcalcetide
11. Oxytocin
12. Antibiotics
a) Vancomycin
b) Daptomycin
c) Dalbavancin
d) Oritavancin
e) Telavancin
13. Antifungals
a) Micafungin
b) Anidulafungin
c) Capsofungin
14. Vasopressin
15. Leuprolide
16. Nesiritide
17. Enfuvirtide
18. Growth hormones and analogs
19. Pegvisomant
20. Mecasermin (rhIGF-1)
21. GnRH
a) Histrelin
22. Dibotermin-α
23. Palifermin
24. Becaplermin2
25. Adrenocorticotropin
26. Somatostatin
27. Oxodotreotide
28. Pasireotide
29. Trypsin
30. Insulin and analogs
a) Insulin
b) Insulin icodec
c) Insulin detemir
d) Insulin glargine
e) Insulin lispro
f) Insulin glulisine
g) Insulin aspart
31. Interferons
a) Interferon alfacon 1
b) Interferon-α2a
c) Interferon-α2b
d) Interferon-αn3
e) Interferon-β1a
f) Interferon-β1b
g) Interferon-γ1b
32. Interlukins
a) Oprelvekin
h) Aldesleukin
i) Denileukin
33. Follicular stimulating hormone
34. Human chorionic gonadotropin
35. Lutropin-α
36. Erythropoietin
37. Epoetin-α
38. Darbepoetin-α
39. Filgrastim
40. Pegfilgrastim
41. Sargramostim
42. Alteplase
43. Reteplase
44. Tenecteplase
45. Urokinase
46. Factor VIIa
47. Factor VIII
48. Factor IX
49. Antithrombin III
50. Protein C
51. Drotrecogin-α
52. β-Glucocerebrosidase
53. Alglucosidase-α
54. Laronidase
55. Idursulphase
56. Galsulphase
57. Agalsidase-β
58. α-1-Proteinase inhibitor
59. Lactase2
60. Pancreatic enzymes
61. Adenosine deaminase
62. Immunoglobulins
63. Albumin
64. Lepirudin
65. Bivalirudin
66. Streptokinase
67. Anistreplase
68. Crizanlizumab
69. Etanercept
70. Adalimumab
71. Infliximab
72. Bevacizumab
73. Trastuzumab
74. Rituximab
75. Copaxone
76. Patisiran
77. Givosiran
78. Lumasiran
In some embodiments, the therapeutic agent can also include a vaccine. In some embodiments, the therapeutic agent can also include a nucleic acid.
In some preferred embodiments, the therapeutic agent can include an incretin therapeutics. For example, in some preferred embodiments, the therapeutic agent can include a Glucagon-Like Peptide-1 (GLP-1) receptor agonist, e.g., any of those described herein, or any of those described in U.S. Patent Nos. 10,960,052, 8,129,343, 8,536,122, 9,278,123, 10,086,047, 10,278,923, and 10,933,120, the entire contents of each of which are herein incorporated by reference. In some preferred embodiments, the therapeutic agent can include semaglutide, liraglutide, dulaglutide, lixisenatide, or exenatide. Other incretins and peptides can include, but not limited to, PYY and PYY analogues; GLP-1/GIP receptor due agonists such as, but not limited to Tirzepatide, CT-388, SCO-094, etc. ; GLP-1/GCGR receptor due agonists, such as, but not limited to efinopegdutide, IB1362, etc.
In some preferred embodiments, the pharmaceutical composition herein can include the GLP-1 receptor agonist as the only therapeutic agent. In some embodiments, the pharmaceutical composition herein can include the GLP-1 receptor agonist as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating diabetes, e.g., any of those known in the art. In some embodiments, the one or more other therapeutic agent can include (1) a SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, or ertugliflozin; (2) a DPP-4 inhibitor, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin; (3) insulin or insulin analogues (e.g., Insulin icodec) ; (4) GIP, glucose-dependent insulinotropic polypeptides; and/or (5) amylin or amylin analogues. In some embodiments, the one or more other therapeutic agent can also include (1) biguanides; (2) Thiazolidinediones; (3) DPP-4 inhibitors; (4) PYY; and (5) sulfonylureas.
In some embodiments, the pharmaceutical composition herein can include the GLP-1 receptor agonist as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating a neurological disease, such as Alzheimer's Disease. For example, in some embodiments, the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with (1) Cholinesterase inhibitors (e.g., Aricept, Exelon, Razadyne) ; (2) Glutamate regulators (e.g., Namenda) ; and/or (3) Orexin receptor antagonist (e.g., Belsomra) .
In more preferred embodiments, the therapeutic agent herein can include semaglutide. Semaglutide as used herein is not limited to any particular forms. For example, in some embodiments, semaglutide can be in the form of a pharmaceutically acceptable salt, such as a sodium salt. Semaglutide is marketed in the United States under several brandnames, including the oral
tablet formulation. See Rybelsus Prescribing Information approved by the U.S. Food and Drug Administration, 2021 version, the content of which is herein incorporated by reference in its entirety. As described therein, the peptide backbone of semaglutide is produced by yeast fermentation. The main protraction mechanism of semaglutide is albumin binding, facilitated by modification of position 26 lysine with a hydrophilic spacer and a C18 fatty di-acid. Furthermore, semaglutide is modified in position 8 to provide stabilization against degradation by the enzyme dipeptidyl-peptidase 4 (DPP-4) . A minor modification was made in position 34 to ensure the attachment of only one fatty di-acid. The molecular formula is C187H291N45O59 and the molecular weight is 4113.58 g/mol. The structure is shown below:
In some preferred embodiments, the pharmaceutical composition herein can include semaglutide as the only therapeutic agent. In some embodiments, the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating diabetes, e.g., any of those known in the art. In some embodiments, the one or more other therapeutic agent can include (1) a SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, or ertugliflozin; (2) a DPP-4 inhibitor, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin; (3) insulin or insulin analogue (e.g., Insulin icodec) ; (4) GIP, glucose-dependent insulinotropic polypeptides; and/or (5) amylin or amylin analogues. In some embodiments, the one or more other therapeutic agent can also include (1) biguanides; (2) Thiazolidinediones; (3) DPP-4 inhibitors; (4) PYY; and (5) sulfonylureas. In some embodiments, the one or more other therapeutic agent can include one or more selected from the following: Biguanides, Sulfonylureas and meglitinides, Thiazolidinediones, Alpha-glucosidase inhibitors, other Glucagon like peptide-1 (GLP-1) receptor agonists, Dipeptidyl peptidase 4 (DPP4) inhibitors, Amylin analogue, Sodium-glucose cotransporter 2 (SGLT-2) inhibitors, Dopamine agonists, and Bile acid sequestrants. In some embodiments, the one or more other therapeutic agent can include one or more selected from the following: Metformin, Glipizide, Gliclazide, Glyburide, Glimepiride, Nateglinide, Repaglinide, Pioglitazone, Rosiglitazone, Acarbose, Miglitol, Voglibose, Exenatide, Liraglutide, Lixisenatide, Dulaglutide, Albiglutide, Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Gemigliptin, Anagliptin, Teneligliptin, Alogliptin, Trelagliptin, Omarigliptin, Evogliptin, Gosogliptin, Pramlintide, Canagliflozin, Dapagliflozin, Empagliflozin, Ipragliflozin, Bromocriptine, and Colesevelam.
In some embodiments, the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with one or more other therapeutic agent that is useful for treating a neurological disease, such as Alzheimer's Disease. For example, in some embodiments, the pharmaceutical composition herein can include semaglutide as one therapeutic agent in combination with (1) Cholinesterase inhibitors (e.g., Aricept, Exelon, Razadyne) ; (2) Glutamate regulators (e.g., Namenda) ; and/or (3) Orexin receptor antagonist (e.g., Belsomra) .
In some embodiments, the pharmaceutical composition herein can include a heparin as the therapeutic agent. The term “heparin” as used herein refers to all forms of heparin, including, but not limited to, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin (e.g., enoxaparin (including enoxaparin sodium) , tinzaparin (including tinzaparin sodium) ) , very low molecular weight heparin, and ultra low molecular weight heparin. Non-limiting examples include unfractionated heparin, such as heparin sodium (e.g., heparin sodium USP, available from Scientific Protein Labs of Waunakee, Wis. ) . Heparin generally has a molecular weight of from about 1,000 or 5,000 to about 30,000 Daltons. The term “low molecular weight heparin” generally refers to heparin having an average molecular weight of less than 8000 Da and for which at least 60%of all chains have a molecular weight less than 8000 Da. Non-limiting examples of low molecular weight heparin include tinzaparin, enoxaprin, and daltiparin. Tinzaparin has been approved by the U.S. Food &Drug Administration for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered in conjunction with warfarin sodium. The sodium salt of tinazaparin is available under the trademark Innohep
TM from Pharmion Corporation of Boulder, Colo. The term “very low molecular weight heparin” generally refers to heparin in which at least about 80% (by weight) of the heparin has a molecular weight of between about 1500 and about 5000 daltons. A non-limiting example of very low molecular weight heparin is bemiparin. The term “ultra low molecular weight heparin” generally refers to heparin in which at least about 80% (by weight) of the heparin has a molecular weight of between about 1000 and about 2000 daltons. A non-limiting examples of ultra low molecular weight heparin is fondiparinux.
The pharmaceutical compositions herein are not limited to any particular types of heparins. Rather, the pharmaceutical compositions herein can include any of the heparin-based drugs, which include for example, unfractionated heparin (UFH) , low molecular weight heparin (LMWH) , and synthetic heparins.
Unfractionated heparin is a highly sulfated polysaccharide with an average molecular weight of between 15 and19 kDa (R. J. Linhardt: Heparin: structure and activity. Journal of medicinal chemistry 46, 2551-2564 (2003) ) . Heparin is biosynthesized in the endoplasmic reticulum and the Golgi of mast cells that are present in larger numbers in the liver, intestines, and lungs. It is extracted from food animal sources including cows and pigs, with porcine intestinal mucosa being the standard species and tissue source. Heparin binds to AT, as serine protease inhibitor, and targets coagulation proteins including factor Xa, and factor IIa (thrombin) . AT binds a variably sulfated pentasaccharide sequence having a central 3-O-sulfoglucosamineresidue. AT bound to heparin undergoes a conformational change, exposing a reactive loop that is acted upon and by factor Xa and thrombin catalyzing their inactivation.
LMWH consists of smaller fragmented heparin molecules prepared through the controlled chemical or enzymatic depolymerization of unfractionated heparin (UFH) (J. Hirsh, S. S. Anand, J. L. Halperin, V. Fuster and A. H. Association: Guide to anticoagulant therapy: Heparin: a statement for healthcare professionals from the American Heart Association. Circulation 103, 2994-3018 (2001) ) . The depolymerization method in the production process affects generated LMWH’s properties. More than ten LMWHs have been clinically used and they display similar biological properties, such as dalteparin, sodium, enoxaparin, and tinzaparin, etc. Most LMWHs have an average molecular weight between 4-5 kDa, a longer plasma half-life, better bioavailability at low doses, as well as a more predictable dose response characteristic than UFH. This allows out patient subcutaneous treatment with LMWH instead of inpatient intravenous administration of UFH. LMWHs also show low non-specific binding to macrophages, endothelial cells, platelets, osteoblasts, platelet factor 4 (PF4) , and nonspecific binding to plasma proteins reducing many of the problems associated with heparin like shorter plasma half-lives, heparin induced thrombocytopenia (HIT) , and osteoporosis.
ULMWHs, such as fondaparinux, are even smaller heparin chains, many being homogenous compounds, ranging in size from 1.5. -3.5. kDa (Z. Liu, S. Ji, J. Sheng and F. Wang: Pharmacological effects and clinical applications of ultra low molecular weight heparins. Drug Discoveries &Therapeutics 8, 1-10 (2014) ) . Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor. Fondaparinux binds antithrombin and facilitates its inhibition of factor Xa. The advantages of ULMHs include a higher degree of bioavailability, longer plasma half-lives, lower bleeding risk, lower risk of osteoporosis, and penetration of the blood brain barrier. ULMWHs are pure Factro Xa inhibitors, having high anti-Xa activity but no anti-IIa activity. Although these ULMWHs have some significant benefits such as no substantial binding to PF4, their drawbacks include high cost and inability to be removed by other means than renal clearance.
In some preferred embodiments, the heparin of the pharmaceutical compositions herein can be a low molecular weight heparin (LMWH) . In some specific embodiments, the LMWH has an average molecular weight of about 3000 Daltons to about 7000 Daltons. In some embodiments, the LMWH can be enoxaparin, bemiparin, nadroparin, reviparin, parnaparin, certoparin, dalteparin, or tinzaparin.
For example, in some preferred embodiments, the heparin of the pharmaceutical compositions herein can be enoxaparin. Enoxaparin is presently marketed in the United States, for example, under the brandname Lovenox, in the form of enoxaparin sodium in a sterile aqueous solution. Enoxaparin sodium can be obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. The structure of enoxaparin sodium is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N, 6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15%and 25%) of the enoxaparin structure contains a 1, 6 anhydro derivative on the reducing end of the polysaccharide chain.
*X=Percent of polysaccharide chain containing 1, 6, anhydro derivative on the reducing end
The drug substance of enoxaparin in Lovenox is the sodium salt. The average molecular weight is about 4500 daltons. According to the United States Food and Drug Administration's ( "FDA" ) approved label for Lovenox, the molecular weight distribution of enoxaparin is:
<2000 daltons ≤20%
2000 to 8000 daltons ≥68%
>8000 daltons ≤18%
In some embodiments, the heparin in the pharmaceutical compositions herein can be enoxaparin sodium.
In some embodiments, the heparin in the pharmaceutical compositions herein can be dalteparin, such as dalteparin sodium. Dalteparin sodium can be produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulfated polysaccharide chains (oligosaccharide, containing 2, 5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5,000 and about 90%of the material within the range 2,000–9,000. According to the FDA approved label for Fragmin (dalteparin sodium injection) , the molecular weight distribution of enoxaparin is:
· <3000 daltons 3.0–15%
· 3,000 to 8,000 daltons 65.0–78.0%; and
· >8,000 daltons 14.0–26.0%
The structure of dalteparin sodium can be represented by the chemical formula shown below according to the FDA approved label for Fragmin:
In some embodiments, the heparin in the pharmaceutical compositions herein can be tinzaparin, such as tinzaparin sodium. Tinzaparin sodium is the sodium salt of a low molecular weight heparin that can be obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa using heparinase from Flavobacterium heparinum. The majority of the components have a 2-O-sulpho-4-enepyranosuronic acid structure at the non-reducing end and a 2-N, 6-O-disulpho-D-glucosamine structure at the reducing end of the chain. The average molecular weight ranges between 5, 500 and 7, 500 daltons. The molecular weight distribution is:
· <2,000 Daltons <10%
· 2,000 to 8,000 Daltons 60%to 72%
· >8,000 Daltons 22%to 36%
The structure of tinzaparin sodium can be represented by the chemical formula shown below according to the FDA approved label for Innohep (tinzaparin sodium injection) :
Compound of Formula I
Typically, the pharmaceutical composition herein comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R
1 represents an aliphatic group, or a pharmaceutically acceptable salt thereof:
In some embodiments, in Formula I, R
1 represents an alkylene group having 1-30 carbon atoms, e.g., R
1 is - (CH
2)
1-18CH
2-.
In some embodiments, in Formula I, R
1 represents an alkylene group having 3-20 carbon atoms.
In some embodiments, in Formula I, R
1 represents an alkylene group having 5-16 carbon atoms.
In some preferred embodiments, the compound of Formula I can be
which has a chemical name of undecylenic acid. In preferred embodiments, the pharmaceutical composition herein comprises a salt (such as an alkali salt, preferably sodium salt) of undecylenic acid which is also known as sodium undecylenate (uC11) .
Aliphatic acid of Formula II
Typically, the pharmaceutical composition herein comprises an aliphatic acid of Formula I: R
2COOH, wherein R
2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof.
Useful aliphatic acids are not particularly limited. For example, in some embodiments, the aliphatic acid has a Formula II: R
2COOH, wherein R
2 represents an alkyl group having 1-30 carbon atoms. The alkyl group can be a linear or branched chain alkyl group. For example, in some embodiments, R
2 in Formula II can be - (CH
2)
1-18CH
3. In some embodiments, R
2 in Formula II can be an alkyl group having 3-20 carbon atoms. In some embodiments, R
2 in Formula II can be an alkyl group having 5-16 carbon atoms. In some embodiments, the aliphatic acid of Formula II is a linear aliphatic acid having 2 to 20 carbon atoms, such as caprylic acid, capric acid, or lauric acid. In any of the embodiments described herein, unless otherwise specified or contrary from context, the aliphatic acid of Formula II can be capric acid.
The aliphatic acid of Formula II can be present in the pharmaceutical composition herein as a free acid or any pharmaceutically acceptable salt thereof, such as an alkali or alkaline salt thereof, for example, a sodium or potassium salt. In some preferred embodiments, the pharmaceutical composition herein comprises sodium caprate.
Compound of Formula III
Typically, the pharmaceutical composition herein comprises a compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.
In some embodiments, the compound of Formula III can have no G
1
substituents on the phenyl ring, i.e., n is 0.
In some embodiments, the compound of Formula III can have one G
1 substituted on the phenyl ring, i.e., n is 1. In some embodiments, in Formula III, n is 1, and G
1 is a halogen, C
1-
4 alkyl, or C
1-
4 alkoxy. In some embodiments, in Formula III, n is 1, and G
1 is Cl. In some embodiments, in Formula II, n is 1, and G
1 is OCH
3.
L
1 in Formula II is typically a substituted or unsubstituted C
2-C
16 alkylene. For example, in some embodiments, L
1 is an unsubstituted C
3-C
15 alkylene. In some embodiments, L
1 is an unsubstituted C
5-C
13 alkylene. The alkyelene can be a straight-chained or a branched alkyelene. For example, in some embodiments, L
1 is an unsubstituted, straight-chained C
5-C
9 alkylene.
In some preferred embodiments, the compound of Formula III can be
which has a chemical name of 8- (2-hydroxybenzamido) octanoic acid (ChemDraw Software, version 20.0) . In preferred embodiments, the pharmaceutical composition herein comprises a salt (preferably sodium salt) of 8- (2-hydroxybenzamido) octanoic acid, which can be prepared using the method described in e.g. WO96/030036, WO00/046182, WO01/092206 or WO2008/028859. The salt of 8- (2-hydroxybenzamido) octanoic acid (alternatively known as N- (8- (2-hydroxybenzoyl) amino) caprylic acid) may be crystalline and/or amorphous. In some embodiments the delivery agent comprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvate or one third of a hydrate of the salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid as well as combinations thereof. In some embodiments, the pharmaceutical composition herein comprises a salt of N- (8- (2-hydroxybenzoyl) amino) caprylic acid as described in WO2007/121318.
In more preferred embodiments, the pharmaceutical composition comprises sodium N- (8- (2-hydroxybenzoyl) amino) caprylate (referred to as “SNAC” herein) .
In some preferred embodiments, the compound of Formula III can be
which has a chemical name of 8- (5-chloro-2-hydroxybenzamido) octanoic acid (ChemDraw Software, version 20.0) . In some embodiments, the pharmaceutical composition herein comprises a salt of 8- (5-chloro-2-hydroxybenzamido) octanoic acid.
In some embodiments, the compound of Formula III can be
which has a chemical name 10- ( (2-hydroxybenzoyl) amino) decanoic acid. In some embodiments, the pharmaceutical composition herein comprises a salt of 10- ( (2-hydroxybenzoyl) amino) decanoic acid, such as sodium 10- ( (2-hydroxybenzoyl) amino) decanoate.
In some embodiments, the compound of Formula III can be
which has a chemical name N- (4-chlorosalicyloyl) -4-aminobutyric acid. In some embodiments, the pharmaceutical composition herein comprises a salt of N- (4-chlorosalicyloyl) -4-aminobutyric acid, such as sodium N- (4-chlorosalicyloyl) -4-aminobutyrate.
In some embodiments, the compound of Formula III can be
which has a chemical name N- [8- (2-hydroxy-4-methoxy) benzoyl] amino caprylic acid. In some embodiments, the pharmaceutical composition herein comprises a salt of N- [8- (2-hydroxy-4-methoxy) benzoyl] amino caprylic acid, such as sodium N- [8- (2-hydroxy-4-methoxy) benzoyl] amino caprylate.
The combinations of therapeutic agent, the compound of Formula I or a pharmaceutically acceptable salt thereof, the aliphatic acid of Formula II and the compound of Formula III or a pharmaceutically acceptable salt thereof are not particularly limited.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula II or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula III or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) capric acid, a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) SNAC.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide) ; (b) uC11, or a pharmaceutically acceptable salt thereof; (c) capric acid, a pharmaceutically acceptable salt thereof; and (d) SNAC.
In some embodiments, the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium undecylenate (uC11) in an amount of about 50 mg to about 500 mg per unit dose, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg or any range between the recited value, per unit dose. The amount should be understood as the weight of the sodium salt itself, not the corresponding equivalent weight of undecylenic acid.
In some embodiments, the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose.
In some embodiments, the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
In some embodiments, the pharmaceutical composition comprises (a) a polypeptide (e.g., any of those described herein, such as semaglutide; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose; (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose, and (d) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
In some specific embodiments, the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein) , and; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose. The amount of the GLP-1 agonist is not particularly limited, for example, typically, the GLP-1 agonist can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, about 150 mg or any range between the recited values.
In some specific embodiments, the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) sodium caprate in an amount of 50 mg to 500 mg per unit dose. The amount of the GLP-1 agonist is not particularly limited, for example, typically, the GLP-1 agonist can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, about 150 mg or any range between the recited values.
In some specific embodiments, the pharmaceutical composition comprises (a) a GLP-1 agonist (e.g., any of those described herein) , and; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) SNAC in an amount of 50 mg to 500 mg per unit dose. The amount of the GLP-1 agonist is not particularly limited, for example, typically, the GLP-1 agonist can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, about 150 mg or any range between the recited values.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula II or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) the compound of Formula I or a pharmaceutically acceptable salt thereof, and (c) the compound of Formula III or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) capric acid, a pharmaceutically acceptable salt thereof.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof; and (c) SNAC.
In some preferred embodiments, the pharmaceutical composition herein comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) uC11, or a pharmaceutically acceptable salt thereof; (c) capric acid, a pharmaceutically acceptable salt thereof; and (d) SNAC.
In some embodiments, the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium undecylenate (uC11) in an amount of about 50 mg to about 500 mg per unit dose, such as about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg or any range between the recited value, per unit dose. The amount should be understood as the weight of the sodium salt itself, not the corresponding equivalent weight of undecylenic acid.
In some embodiments, the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose.
In some embodiments, the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and (c) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
In some embodiments, the pharmaceutical composition comprises (a) a heparin (e.g., any of those described herein, such as an LMWH, e.g., enoxaparin) ; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose; (c) sodium caprate in an amount of about 50 mg to 500 mg per unit dose, and (d) SNAC in an amount of about 50 mg to about 500 mg per unit dose.
In some specific embodiments, the pharmaceutical composition comprises (a) enoxaparin; and (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose. The amount of the enoxaparin is not particularly limited, for example, typically, the enoxaparin can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg or any range between the recited values, or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) , per unit dose.
In some specific embodiments, the pharmaceutical composition comprises (a) enoxaparin; (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) sodium caprate in an amount of 50 mg to 500 mg per unit dose. The amount of the enoxaparin is not particularly limited, for example, typically, the enoxaparin can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg or any range between the recited values, or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) , per unit dose.
In some specific embodiments, the pharmaceutical composition comprises (a) enoxaparin; and (b) sodium uC11 in an amount of about 50 mg to about 500 mg per unit dose, and; (c) SNAC in an amount of 50 mg to 500 mg per unit dose. The amount of the enoxaparin is not particularly limited, for example, typically, the enoxaparin can be in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 80 mg, about 100 mg, about 150 mg or any range between the recited values, or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) , per unit dose.
In any of the embodiments described herein, unless otherwise specified or contrary from context, the pharmaceutical composition can be in the form of a solid oral dosage form. For example, the pharmaceutical composition herein can typically be a capsule or tablet. In any of the embodiments described herein, unless otherwise specified or contrary from context, the pharmaceutical composition can be in a unit dosage form.
In some embodiments, the pharmaceutical composition herein can be presented in discrete units (which is referred to herein as "unit dosage forms" or "dosage units" ) , such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound (s) . In any of the embodiments described herein, unless otherwise specified or contrary from context, the pharmaceutical composition can be in a unit dosage form. To be clear, the pharmaceutical composition herein can include one or more dosage units. For example, the pharmaceutical composition herein can typically be a capsule or tablet, wherein each capsule or tablet constitutes a dosage unit. As used herein, each "unit dose" of the pharmaceutical composition refers to the dose of the pharmaceutical composition for each administration, which may contain one or more unit dosage forms or dosage units; when more than one dosage units are used to satisfy the unit dose, the dosage units can be the same or different. In preferred embodiments, each unit dose contains a single dosage unit.
The pharmaceutical composition herein can optionally include one or more further excipients, such as those suitable for oral administration. For example, in some embodiments, the pharmaceutical composition herein includes at least one pharmaceutically acceptable excipient. The term “excipient” as used herein broadly refers to any component other than the active therapeutic ingredient (s) . The excipient may be an inert substance, an inactive substance, and/or a not medicinally active substance. The excipient may serve various purposes, e.g. as a carrier, vehicle, filler, binder, lubricant, glidant, disintegrant, flow control agents, crystallization retarders, solubilizers, stabilizer, colouring agent, flavouring agent, surfactant, enzyme inhibitors, basifiers, acidifiers, emulsifier and/or to improve administration, and/or absorption of the active substance, tablet coating agents to control the dissolution rates of the solid dosage form according to the pH in the GI tract. A person skilled in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the solid oral dosage form by routine experimentation and without any undue burden. The amount of each excipient used may vary within ranges conventional in the art. Techniques and excipients which may be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 6th edition, Rowe et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2009) ; and Remington: the Science and Practice of Pharmacy, 21th edition, Gennaro, Ed., Lippincott Williams &Wilkins (2005) . In some embodiments the excipients may be selected from binders, such as polyvinyl pyrrolidone (povidone) , etc. ; fillers such as cellulose powder, microcrystalline cellulose, cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxy-propylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, etc. ; lubricants and/or glidants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate, etc. ; flow control agents such as colloidal silica, talc, etc. ; crystallization retarders such as Povidone, etc. ; solubilizers such as Pluronic, Povidone, etc. ; colouring agents, including dyes and pigments such as Iron Oxide Red or Yellow, titanium dioxide, talc, etc. ; pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, etc. ; surfactants and emulsifiers such as Pluronic, polyethylene glycols, sodium carboxymethyl cellulose, polyethoxylated and hydrogenated castor oil, etc. ; and mixtures of two or more of these excipients and/or adjuvants.
In some embodiments, the pharmaceutical composition herein can comprise a lubricant, a binder, a filler, and/or a chelating agent (e.g., ethylene diamine tetraacetate (EDTA) ) . However, in some embodiments, the pharmaceutical composition herein can also be free or substantially free of a lubricant, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a lubricant. In some embodiments, the pharmaceutical composition herein can also be free or substantially free of a binder, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a binder. In some embodiments, the pharmaceutical composition herein can also be free or substantially free of a filler, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a filler. In some embodiments, the pharmaceutical composition herein can also be free or substantially free of a chelating agent, such as having less than 0.1%by weight, less than 0.05%by weight, less than 0.01%by weight, or non-detectable amount, of a chelating agent. Method of Preparation
The pharmaceutical compositions can be prepared by those skilled in the art in view of the present disclosure.
In some embodiments, the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
In some embodiments, the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof, and an aliphatic acid of Formula II described herein or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
In some embodiments, the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof, and a compound of Formula III described herein or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
In some embodiments, the present disclosure also provides a method of preparing a pharmaceutical composition comprising a therapeutic agent, which comprises: (a) mixing the therapeutic agent (e.g., any of those described herein, such as a polypeptide or heparin described herein) with a compound of Formula I described herein or pharmaceutically acceptable salt thereof, an aliphatic acid of Formula II described herein or pharmaceutically acceptable salt thereof, and a compound of Formula III described herein or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
In some embodiments, the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, to form the mixture.
In some embodiments, the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, and the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt to form the mixture.
In some embodiments, the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, and the compound of Formula III described herein or pharmaceutically acceptable salt to form the mixture.
In some embodiments, the therapeutic agent is mixed with the compound of Formula I described herein or pharmaceutically acceptable salt thereof, the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and the compound of Formula III described herein or pharmaceutically acceptable salt to form the mixture.
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt, and the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing semaglutide and a compound of Formula I or a pharmaceutically acceptable salt, the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt, and the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt, and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the present disclosure also provides a method of preparing a composition comprising (a) mixing enoxaparin and a compound of Formula I or a pharmaceutically acceptable salt, the aliphatic acid of Formula II described herein or pharmaceutically acceptable salt, and a compound of Formula III described herein or pharmaceutically acceptable salt and (b) freeze-drying the mixture formed in (a) .
In some embodiments, the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
In some embodiments, the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof, and the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose. In some embodiments, the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
In some embodiments, the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof, and the compound of Formula III or pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose. In some embodiments, the aliphatic acid of Formula III or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
In some embodiments, the mixing in (a) further comprises mixing the polypeptide or heparin, the compound of Formula I or pharmaceutically acceptable salt thereof, the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof, and the compound of Formula III or pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose. In some embodiments, the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose. In some embodiments, the aliphatic acid of Formula III or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
In some specific embodiments, in the methods above as applicable, (a) the therapeutic agent (e.g., any of those described herein) is in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the recited values) ; and (b) the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) , in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and optionally (c) the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and/or optionally (d) the compound of Formula III or pharmaceutically acceptable salt thereof is SNAC, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) , per unit dose.
In some specific embodiments, in the methods above as applicable, (a) the therapeutic agent is a GLP-1 agonist or heparin (e.g., any of those described herein) , for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the recited values) ; and (b) the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) , in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and optionally (c) the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and/or optionally (d) the compound of Formula III or pharmaceutically acceptable salt thereof is SNAC, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) , per unit dose.
In some specific embodiments, in the methods above as applicable, (a) the therapeutic agent is semaglutide, for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the recited values) , or in an amount of about 0.1 micromole to about 2.5 micromole, such as about 0.5 micromole to about 2.5 micromole; and (b) the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) , in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and for the optional (c) , the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and/or for the optional (d) , the compound of Formula III or pharmaceutically acceptable salt thereof is SNAC, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) , per unit dose.
In some specific embodiments, in the methods above as applicable, (a) the therapeutic agent is enoxaparin, for example, in an amount of about 1 mg to about 200 mg (e.g., about 10 mg, about 50 mg, about 100 mg, or any range between the recited values) , or in an amount of about 1000 anti-Xa international units (IU) to about 25,000 IU (e.g., about 2500, 5000, 7500, 10000, 12500, 15000, 18000, or any range between the recited values) ; and (b) the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) , in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and for the optional (c) , the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) ; and/or for the optional (d) , the compound of Formula III or pharmaceutically acceptable salt thereof is SNAC, in an amount of about 50 mg to about 500 mg (e.g., about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 500 mg, or any range between the recited values) , per unit dose.
The composition comprising the therapeutic agent prepared by the method herein is also a novel composition of the present disclosure.
In some embodiments, the present disclosure further provides a method of preparing a pharmaceutical composition comprising mixing the composition comprising the therapeutic agent prepared by the method herein with a pharmaceutically acceptable excipient (e.g., any of those described herein) .
Method of Treatment
The pharmaceutical compositions described herein can be useful for treating a disease or disorder in a subject in need thereof, wherein the disease or disorder can be any of those known to be treatable with the therapeutic agent disclosed herein. The enhanced oral delivery of therapeutic agents as shown in the present disclosure can offer alternative and advantageous treatment options using these therapeutic agents.
For example, in some embodiments, the present disclosure provides a method of treating type-2 diabetes or obesity, in a subject in need thereof, the method comprising orally administering the pharmaceutical composition described herein to deliver a therapeutically effective amount of the therapeutic agent (e.g., GLP-1 agonist described herein) to the subject.
Incretins are an important class of medications for treatment of diabetes and obesity, including GLP-1, GIP, PYY, etc. GLP-1 receptor agonists have become an important and essential medications that are widely prescribed. GLP-1 is mainly expressed in intestinal L cells and brainstem. The GLP-1 receptor (GLP-1 R) , a G protein-coupled receptor, is expressed in a variety of tissues, including pancreatic islets, gastrointestinal tract, lung, cardiovascular system, kidney, nodose ganglion neurons of the vagal nerve, the hypothalamus and brainstem in the CNS (Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci U S A. 1992; 89 (18) : 8641–8645. ) . GLP-1 expressed from intestinal L cells can circulate and directly bind onto canonical receptors in the pancreatic islet or may indirectly signal the hepatic vagal branch within intraportal vein, potentiating glucose-induced insulin secretion and most postprandial insulin secretion (Pais R, Gribble FM, Reimann F. Stimulation of incretin secreting cells. Ther Adv Endocrinol Metab. 2016; 7 (1) : 24–42. ) . The signals are sent to the hypothalamus for reducing appetite, stimulating gluconeogenesis, lowering hepatic glucose output, amplifying glucose-dependent insulin release, inhibiting glucagon release, increasing cardiac output and cardioprotection, and decreasing high blood pressure (Muller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1) . Mol Metab. 2019; 30: 72–130. ) . The function of incretin axis is impaired in T2D with insufficient GLP-1 production, or disrupted GLP-1 action. Therefore, GLP-1 and GLP-1 analogues have been developed as medications for treatment of T2D (Aulinger BA, Vahl TP, Prigeon RL, D’A lessio DA, Elder DA. The incretin effect in obese adolescents with and without type 2 diabetes: impaired or intact? Am J Physiol Endocrinol Metab. 2016; 310 (9) : E774–781) .
Natural GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) with a half-life at about less than 2 minutes. Therefore, many GLP-1 receptor agonist analogues (GLP-1 RA) were developed with the attempts of prolonging the half-life. Such GLP-1 analogues include: Exendin-4, liraglutide, dulaglutide, lixisenatide, semaglutide, that are approved by US Food and Drug Administration (FDA) for management of T2D. Exendin-4 is a 53%homologous peptide extracted from the venom of a Gila monster. It is resistant to degradation by the DPP4. Structural modifications such as replacement of certain amino acids and/or additions of certain fatty acids were applied to prolong the half-life, allowing once weekly administration from daily administration of GLP-1 analogues; including dulaglutide, albiglutide, liraglutide, lixisenatide, semaglutide (Romera I, Cebria′n-Cuenca A, A′lvarez-Guisasola F, Gomez-Peralta F, Reviriego J. A review of practical issues on the use of glucagon-like peptide-1 receptor agonists for the management of type 2 diabetes. Diabetes Ther. 2019; 10 (1) : 5–19. ) .
The class of GLP-1 RAs in T2D has demonstrated significant reductions in A1C and a favorable effect on weight control with minimal risk of hypoglycemia (Trujillo JM. Glucagon-like peptide-1 receptor agonists. In: White JR (ed. ) Guide to medications for the treatment of diabetes mellitus. Arlington County, VA: American Diabetes Association, 2020, pp. 190–210. ) . In addition, three of the GLP-1 RAs have demonstrated cardiovascular benefits; dulaglutide, liraglutide, and semaglutide (Matza LS, Boye KS, Sterward DK, et al. Crossover clinical trial assessing patient preference between the dulaglutide pen and the semaglutide pen (PREFER) . Diabetes Met Obes 2020; 22: 355–364) . The use of GLP-1 RAs is associated with the adverse effects, mainly GI AEs and also injection-site related AEs. The use of GLP-RAs may be also limited by the injection delivery route, resulting in adherence issues. Evaluating the head-to-head studies showed that the long-acting agents result in greater A1C lowering than the short-acting agents, with semaglutide leading to the greatest A1C reduction. Out of the long-acting agents, exenatide XR appears to have the least impact on A1C, although it still produces more A1C lowering compared with the short-acting agents. In regards to weight, there is more ambiguity with the differentiation between agents. The long-acting agents tend to produce more significant weight loss compared with the short-acting agents, with semaglutide once again taking the lead on the greatest weight reduction (Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7) : a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018; 6: 275–286. ) (Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4) : a randomized, double-blind, phase 3a trial. Lancet 2019; 394: 39–50. ) . GI adverse effects appear to be highest with the short-acting agents as well as subcutaneous semaglutide and appear to be lowest with exenatide XR. Injection site reactions may be more common with the longer acting agents, particularly exenatide once-weekly, which can cause transient small nodules at the injection site. Patient satisfaction data indicate that once weekly injections result in higher patient satisfaction compared with twice daily injections. Discontinuation rates due to adverse events vary between agents and studies, but are low overall with less than 10%of patients in the studies discontinuing GLP-1 RA therapy due to adverse events (Wilke T, Mueller S, Groth A, et al. Nonpersistence and non-adherence of patients with type 2 diabetes mellitus in therapy with GLP-1 receptor agonists: a retrospective analysis. Diabetes Ther 2016; 7: 105–124. ) . The risk of hypoglycemia is low with GLP-1 RAs and rates were similar across all GLP-1 RA treatment groups. Importantly, current guidelines prioritize the use of GLP-1 RAs with demonstrated CV benefit (dulaglutide, liraglutide, and semaglutide) in patients with atherosclerotic CV disease (ASCVD) and ASCVD risk, independent of baseline A1C.
GLP-1 and GLP-1 analogues are peptides, that have high molecular weight with very low permeability across biological membranes, labile to gut enzymatical degradation, therefore, oral delivery of GLP-1 analogues are typically with very low oral bioavailability. Therefore, all GLP RA therapies are injectables and result in difficultly to use and fear of needles, thus acceptance and adherence of the therapies (Wilke T, Mueller S, Groth A, et al. Nonpersistence and non-adherence of patients with type 2 diabetes mellitus in therapy with GLP-1 receptor agonists: a retrospective analysis. Diabetes Ther 2016; 7: 105–124. ) .
The first GLP-1 analogue with oral delivery was semaglutide, which was coformulated with an absorption enhancer, sodium N- (8- [2-hydroxybenzoyl] amino) caprylate (SNAC) (Davies M, Pieber TR, Hartoft-Nielsen ML, Hansen OKH, Jabbour S, Rosenstock J. Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA. 2017; 318 (15) : 1460–70.290) . Although the mechanisms of how SNAC enables the oral absorption of semaglutide are still unclear; tentatively, one or multiple of the following MOAs could be involved: Reduction of enzymatical degradation, optimizing the physicochemical properties of the drug for membrane transport, and enhanced transit fluidity of biological membrane. In the PIONEER trials, the oral semaglutide co-formulated with SNAC has shown efficacy and safety inpatients and the product
received its FDA approval on 20 September, 2019 (Bucheit J, Pamulapati LG, Carter N, Malloy K, Dixon DL, Sisson EM. Oral semaglutide: a review of the first oral glucagon-like peptide-1 receptor agonist. Diabetes Technol Ther. 2020; 1: 10–8) . However, while SNAC was shown to enhance the absorption of semaglutide, the oral bioavailability (BA%) was still very low, about 0.5-1%in humans (FDA Clinical Pharmacology Review; https: //
www. accessdata. fda. gov/drugsatfda_docs/nda/2019/213051Orig1s000ClinPharmR. pd
f) .
The low bioavailability contributes to high variability in drug exposure in the systemic circulation. In addition, the low bioavailability can significantly increase cost that can become prohibitive to payors, particularly as higher doses of the drug will be needed to control obesity. As an example, in the case of semaglutide, the injectable version of semaglutide (Ozempic) has once weekly dosage at 0.5 to 1 mg for diabetic control; while the weekly dosage of 2.4 mg (approved as Wegovy by FDA in 2021) is needed for obesity control. In the oral version of semaglutide (Rybelsus) , the daily dose is up to 14 mg (FDA label for Rybelsus and Wegovy) . The dose in the oral version needed for obesity may be up to over 50 mg. Chemical or semi-biosynthesis of semaglutide as a modified peptide is costly; currently the cost of semaglutide as an active product ingredient (API) is around US dollar 0.8 per milligram (mg) . Therefore, for daily 14 mg of Rybelsus for diabetes indication, the cost of goods (COGs) is around US dollar 336 per month, which is almost approaching the cost of commercial product ($770 per month as priced by Novo Nodisk) https: // www. goodrx. com/rybelsus. For daily 50 mg, for potential indications such as obesity, the COGs is about USD 1200 per month and will exceed the acceptable pricing for the payers. Therefore, it is critical and essential to develop an oral formulation of semaglutide with improved BA%, reduced variability, and control the COGs to allow extension of treatment for obesity, fulfilling the medical values of GLP-1 therapeutics and benefiting healthcare of patients with T2D and obesity, as well as reducing the financial burden of healthcare systems.
As discussed herein, the sodium salt of undecylenic acid (uC11) achieved a significantly higher oral bioavailability of GLP-1 agonist (in particular semaglutide) compared to using just SNAC as enhancer. Thus, the method herein can advantageously use the pharmaceutical composition herein to orally administer GLP-1 agonist for the treatment of various diseases or disorders for which a GLP-1 agonist can be beneficial, such as type-2 diabetes or obesity.
In some embodiments, the present disclosure provides a method of orally delivering of heparin and/or for treating a disease or disorder that are treatable with heparin. For example, the disease or disorder can be any of those known to be treatable with heparins, such as any of the approved indications by the U.S. FDA for enoxaparin, dalteparin, and tinzaparin, see the approved labels as of the filing date of this application. The enhanced oral delivery of therapeutic agents as shown in the present disclosure can offer alternative and advantageous treatment options using heparins.
In some embodiments, the present disclosure provides a method of treating a disease or disorder for which administering heparin such as LWMH is beneficial, e.g., deep vein thrombosis (DVT) , Sickle Cell Disease (SCD) , pre-thrombotic state/recurrent spontaneous abortion (PTS/RSA) , cancer associated thrombosis (CAT) , dyslipidemia, etc., in a subject in need thereof, the method comprising orally administering the pharmaceutical composition of any of those described herein to deliver a therapeutically effective amount of the heparin such as LMWH to the subject. In some embodiments, the present disclosure provides a method of prophylaxis or treatment of COVID-19 infection in a subject in need thereof, the method comprising orally administering the pharmaceutical composition of any of those described herein to deliver an effective amount of the heparin such as LMWH to the subject.
In some specific embodiments, the present disclosure provides a method of treating or preventing sickle cell disease (SCD) in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of treating or preventing pre-thrombotic state/recurrent spontaneous abortion (PTS/RSA) in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of treating or preventing cancer associated thrombosis (CAT) in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of prophylaxis or treatment of COVID-19 infection in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of treating or preventing dyslipidemia in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of treating or preventing thrombosis in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11. Any type of thrombosis can be treated or prevented with the pharmaceutical composition including, but not limited to, deep vein thrombosis (DVT) and pulmonary embolism (PE) .
In some specific embodiments, the present disclosure provides a method of treating or preventing deep vein thrombosis in a human in need thereof, the method comprising orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of treating or preventing ischemic complications in unstable angina and/or non-Q-wave myocardial infarction in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of treating or preventing deep vein thrombosis (DVT) in a subject following hip or knee replacement surgery in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
In some specific embodiments, the present disclosure provides a method of treating or preventing DVT following abdominal surgery in patients at risk for thromboembolic complications in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11. Abdominal surgery patients at risk include, but are not limited to, those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of DVT or pulmonary embolism.
In some specific embodiments, the present disclosure provides a method of treating or preventing DVT in a subject with severely restricted mobility in a subject in need thereof by orally administering an effective amount of one or more pharmaceutical compositions described herein, such as those comprising LMWH and uC11.
The pharmaceutical compositions herein containing heparin can also be used for additional treatment methods which include, but are not limited to the treatment of cardiac valve replacements, both mechanical and cadaver; treatment of endocarditis; prophylaxis in patients undergoing neurological procedures, such as, but not limited to, resection of malignant brain tumors; prophylaxis in patients with acute spinal cord injury, medical conditions associated with thromboembolism, such as but not limited to, those with ischemic stroke or restricted mobility, cancer, myocardial infarction, cancer, congestive heart failure, or severe pulmonary disease; for secondary prophylaxis of venous thromboembolism during pregnancy, or for primary prophylaxis in pregnant women with inherited causes of thrombophilia (e.g. deficiencies in thrombin III, protein C, protein S, Factor V, Leiden mutation, prothrombin polymorphism, hyperhomocysteinemia) ; for embolisms associated with atrial fibrillation or those with concurrent prosthetic valves and atrial fibrillation; for cardioversion of atrial fibrillation or atrial flutter; for disseminated intravascular coagulation; to reduce the risk of complications in patients undergoing percutaneous coronary intervention, percutaneous transluminal coronary angioplasty, arthrectomy, coronary or other vessel stent implantation, ischemic cerebrovascular accident, hemodialysis, peripheral vascular interventions, acute myocardial infarction; unstable angina and non-ST-Segment Elevation Myocardial infarction; cerebral thromboembolism; complications of pregnancy, including but not limited to pregnancy loss in women with a history of antiphospholipid antibodies/antiphospholipid syndrome with or without fetal loss, fetal death or fetal miscarriage. Other uses of heparin may be found in Drug Information, American Society of Health System Pharmacists, 2005, which is incorporated herein by reference.
Combination therapies
The pharmaceutical compositions herein can be used as a monotherapy or in a combination therapy. For example, in some embodiments, the pharmaceutical composition can be a fixed dose combination of two or more active therapeutic agents. Non-limiting combination therapies contemplated include the following.
Combination of GLP-RA and SGLT2i: cardiovascular benefits. Sodium-glucose cotransporter (SGLT) proteins function independently of insulin in regulation of glucose. Sodium-glucose cotransporter 1 (SGLT1) proteins are high affinity and low-capacity transporters of glucose and are expressed in the small intestines as well as the proximal tubule of the kidneys. The SGLT1 proteins in the proximal convoluted tubule of the kidneys are responsible for less than 10%of filtered glucose reabsorption. Sodium-glucose cotransporter-2 (SGLT2) proteins are expressed in the proximal convoluted tubule of the kidneys and are responsible for roughly 90%of filtered glucose reabsorption (Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015 Jan; 75 (1) : 33–59. ) . There are several SGLT2 selective inhibitors approved by FDA. Including canagliflozin, dapagliflozin, and empagliflozin. Of the three FDA approved drugs, empagliflozin has the greatest selectivity for SGLT2 compared to SGLT1, while canagliflozin is the least selective (Shubrook JH, Bokaie BB, Adkins SE. Empagliflozin in the treatment of type 2 diabetes: evidence to date. Drug design, development and therapy. 2015; 9: 5793–803. ) . SGLT2i have demonstrated clinically body weight control and antihypertensive benefits. The risk of hypoglycemia with SGLT2i is small when compared to insulin and sulfonylureas. (Desouza CV, Gupta N, Patel A. Cardiometabolic Effects of a New Class of Antidiabetic Agents. Clin Ther. 2015 Jun 1; 37 (6) : 1178–94. )
Recent studies demonstrated that there was no increased risk for major adverse cardiovascular events with GLP-RAs, such as dapagliflozin and empagliflozin. More importantly, studies showed that in T2D patients with high risk of cardiovascular disease events, SGLT2 inhibition demonstrated significant CV benefits, such as a 38%relative risk reduction in death from cardiovascular causes in the empagliflozin group versus the placebo group (Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2015 Nov 26; 373 (22) : 2117–28. This was a pivotal cardiovascular outcomes trial for empagliflozin. ) .
GLP-1RAs and SGLT2i showed the evidence to improve clinical outcomes in diabetic patients with cardiovascular diseases. The new T2D pharmacotherapy guidelines have recommended the use of GLP-1RAs for prevention and treatment of obese patients with risks of atherosclerotic cardiovascular diseases, whereas SGLT-2i has been proposed for patients with a risk of chronic heart failure. However, there are no systemic research, especially clinical trials to further evaluate the potential additive or synergistic effects of these two classes of medications for the CV benefits, given both classes of drugs have different modes of mechanisms for treatments of T2D and diabetes.
The key reason of not having robust clinical research on the combinations of GLP-RA and SGLT2i may be explained on the commercial or financial basis. GLP-RA are also injectable peptides daily or weekly (except for oral semaglutide) while SGLT2i are all oral tablets administered daily. It is not feasible to develop a financially supportive combination, since such injectable and oral combinations may not be acceptable to patients in practice, and more importantly, no intellectual properties can be obtained for such direct combinations of two commercially available medications.
Commercially, the only available oral GLP-RA is Rybelsus, which however, has too low BA%, which makes it economically challenging in combinations. Technically, oral semaglutide is absorbed in stomach facilitated by the carrier, SNAC, while SGLT2i are formulated in tablets with coated film, which target absorption in small intestine, where the absorption area is large and the villi of endothelial cells are abundant, allowing much higher permeability than in stomach.
In some embodiments, the present invention enables the formulations of GLP-RA and SGLT2i into the same tablets, which not only have improved oral bioavailability of GLP-RA compared to the formulation with SNAC alone, but also allow absorption of SGLT2i from the stomach. Such fixed-dose combination of GLP-RA and SGLT2 is in one tablet brings significant medical values with convenient use and economic feasibility.
Definitions
As used herein, the singular form “a” , “an” , and “the” , includes plural references unless it is expressly stated or is unambiguously clear from the context that such is not intended.
The term “and/or” as used in a phrase such as “A and/or B” herein is intended to include both A and B; A or B; A (alone) ; and B (alone) . Likewise, the term “and/or” as used in a phrase such as “A, B, and/or C” is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone) ; B (alone) ; and C (alone) .
Headings and subheadings are used for convenience and/or formal compliance only, do not limit the subject technology, and are not referred to in connection with the interpretation of the description of the subject technology. Features described under one heading or one subheading of the subject disclosure may be combined, in various embodiments, with features described under other headings or subheadings. Further it is not necessarily the case that all features under a single heading or a single subheading are used together in embodiments.
As used herein, the term “about” modifying an amount related to the invention refers to variation in the numerical quantity that can occur, for example, through routine testing and handling; through inadvertent error in such testing and handling; through differences in the manufacture, source, or purity of ingredients employed in the invention; and the like. As used herein, “about” a specific value also includes the specific value, for example, about 10%includes 10%. Whether or not modified by the term “about” , the claims include equivalents of the recited quantities. In one embodiment, the term “about” means within 20%of the reported numerical value.
The term "polypeptide" and "peptide" as used herein means a compound composed of at least five constituent amino acids connected by peptide bonds. The constituent amino acids may be from the group of the amino acids encoded by the genetic code and they may be natural amino acids which are not encoded by the genetic code, as well as synthetic amino acids.
The term "analogue" as used herein referring to a polypeptide means a modified peptide wherein one or more amino acid residues of the peptide have been substituted by other amino acid residues and/or wherein one or more amino acid residues have been deleted from the peptide and/or wherein one or more amino acid residues have been deleted from the peptide and or wherein one or more amino acid residues have been added to the peptide.
The term "derivative" as used herein in relation to a peptide means a chemically modified peptide or an analogue thereof, wherein at least one substituent is not present in the unmodified peptide or an analogue thereof, i.e. a peptide which has been covalently modified. Typical modifications are amides, 20 carbohydrates, alkyl groups, acyl groups, esters and the like. An example of a derivative of GLP-1 (7-37) is NE26- ( (4S) -4- (hexadecanoylamino ) -carboxy-butanoyl) [Arg34, Lys26] GLP-1- (7-37) .
In some embodiments the term “GLP-1 analogue” as used herein refers to a peptide, or a compound, which is a variant of the human Glucagon-Like Peptide-1 (GLP-1 (7-37) ) . GLP-1 (7-37) has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1) . In some embodiments the term “variant” refers to a compound which comprises one or more amino acid substitutions, deletions, additions and/or insertions.
In some embodiments, the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80%or 90%sequence identity to GLP-1 (7-37) over the entire length of GLP-1 (7-37) . As an example of a method for determination of sequence identity between two analogues the two peptides [Aib8] GLP-1 (7-37) and GLP-1 (7-37) are aligned. The sequence identity of [Aib8] GLP-1 (7-37) relative to GLP-1 (7-37) is given by the number of aligned identical residues minus the number of different residues divided by the total number of residues in GLP-1 (7-37) . Accordingly, in said example the sequence identity is (31-1) /31.
The term "GLP-1 agonist" as used herein refers to a compound, which fully or partially activates the human GLP-1 receptor. In some embodiments, the GLP-1 agonist is a GLP-1 analogue, optionally comprising one substituent. In some embodiments the GLP-1 agonist is exendin-4, the sequence of which is HGEGTFITSDL SKQMEEEAVR-LFIEWLKNGGPSSGAPPPS (SEQ ID No: 2) . In some embodiments the GLP-1 agonist comprises one substituent which is covalently attached to the peptide. In some embodiments the substituent comprises a fatty acid or a fatty diacid. In some embodiments the substituent comprises a C16, C18 or C20 fatty acid. In some embodiments the substituent comprises a C16, C18 or C20 fatty diacid. Examples of GLP-1 RA include but not limited to semaglutide, liraglutide, dulaglutide, lixisenatide, exenatide and others.
In some embodiments, the GLP-1 agonist is selected from one or more of the GLP-1 agonists disclosed in WO93/19175, WO96/29342, WO98/08871, WO99/43707, WO99/43706, WO99/43341, WO99/43708, WO2005/027978, WO2005/058954, WO2005/058958, WO2006/005667, WO2006/037810, WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050, WO2009/030738, WO2009/030771 and WO2009/030774.
In some embodiments, the GLP-1 agonist is selected from the group consisting of N-epsilon37 {2- [2- (2- {2- [2- ( (R) -3-carboxy-3- { [1- (19-carboxynonadecanoyl) piperidine-4-carbonyl] amino} propionylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetyl [desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37) amide; N-epsilon26 {2- [2- (2- {2- [2- ( (R) -3-carboxy-3- { [1- (19-carboxynonadecanoyl) piperidine-4- carbonyl] amino} propionylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetyl [desaminoHis7, Arg34] GLP-1- (7-37) ; N-epsilon37 {2- [2- (2- {2- [2- ( (S) -3-carboxy-3- { [1- (19-carboxynonadecanoyl) piperidine-4-carbonyl] amino} propionylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetyl [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- [2- (2- [2- (2- ( (R) -3- [1- (17-carboxyheptadecanoyl) piperidin-4-ylcarbonylamino] 3-carboxypropionylamino) ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [ , DesaminoHis7, Glu22 Arg26, Arg 34, Phe (m-CF3) 28] GLP-1- (7-37) amide; N-epsilon26- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxynonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyryl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- {4- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxynonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] butyryl} [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [(19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethox y) acetylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {4- [ (trans-19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Arg26, Arg34, Lys 37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg 34, Lys37] GLP-1- (7-37) ; N-epsilon26 [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl [Aib8, Lys 26] GLP-1 (7-37) amide; N-epsilon26 [2- (2- [2- (2- [2- (2- ( (S) -2- [trans-4- ( (9-carboxynonadecanoylamino] methyl) cyclohexylcarbonylamino] -4-carboxybutanoylamino) ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Lys26] GLP-1 (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHi s7, Arg26, Arg34, Lys37] GLP-1- (7-37) ; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethox y) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys37] GLP-1- (7-37) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {4- [4- (16- (1H-tetrazol-5-yl) -hexadecanoylsulfamoyl) butyrylamino] -butyrylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoyl-sulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {6- [4- (16- (1H-tetrazol-5-yl) hexadecanoyl-sulfamoyl) butyrylamino] hexanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {4- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] butyrylamino} butyrylamino) butyrylamino] e thoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-34) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] -dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-34) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {6- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] hexanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-34) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoyl-sulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethox y) acetyl] [Aib8, Arg34] GLP-1- (7-35) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {6- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] hexanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-35) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {6- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] hexanoylamino} butyrylamino) butyrylamino ] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-36) amide; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {6- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] hexanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-35) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] dodecanoylamino} butyryl-amino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Lys33, Arg34] GLP-1- (7-34) ; N-epsilon26- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylami no] ethoxy} ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-36) amide; N-epsilon26- [2- (2- {2- [2- (2- {2- [2- (2- {2- [2- (2- {2- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [Aib8, Lys26, Arg34] GLP-1- (7-36) amide; N-epsilon37- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP -1- (7-37) amide; N-epsilon37 {2- [2- (2- {2- [2- ( (R) -3-carboxy-3- { [1- (19-carboxy-nonadecanoyl) piperidine-4-carbonyl] amino} propionylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetyl [desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37) amide; N-epsilon37 {2- [2- (2- {2- [2- ( (S) -3-carboxy-3- { [1- (19-carboxynonadecanoyl) piperidine-4-carbonyl] amino} propionylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetyl [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- [2- (2- [2- (2- ( (R) -3- [1- (17-carboxyhepta-decanoyl) piperidin-4-ylcarbonylamino] 3-carboxy-propionylamino) ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Phe (m-CF3) 28] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) ; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxy-nonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys37] GLP-1- (7-37) ; N-epsilon37- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [ (S) -4-carboxy-4- ( (S) -4-carboxy-4- {12- [4- (16- (1H-tetrazol-5-yl) hexadecanoylsulfamoyl) butyrylamino] dodecanoylamino} butyrylamino) butyrylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- (3- ( (2- (2- (2- (2- (2-Hexadecyloxyethoxy) ethoxy) ethoxy) ethoxy) ethoxy) ) propionyl) [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37) -amide; N-epsilon37- {2- (2- (2- (2- [2- (2- (4- (hexadecanoylamino) -4-carboxybutyryl-amino) ethoxy) ethoxy] acetyl) ethoxy) ethoxy) acetyl) } - [desaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- {2- (2- (2- (2- [2- (2- (4- (hexadecanoylamino) -4-carboxybutyryl-amino) ethoxy) ethoxy] acetyl) ethoxy) ethoxy) acetyl) } - [desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- (2- (2- (2- (2- (2- (2- (2- (2- (2- (octadecanoyl-amino) ethoxy) ethoxy) acetylamino) ethoxy) ethoxy) acetylamino) ethoxy) ethoxy) acetyl) [desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37) amide; N-epsilon37- [4- (16- (1H-Tetrazol-5-yl) hexadecanoylsulfamoyl) butyryl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) amide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- (19-carboxynonadecanoylamino) butyrylamino] ethoxy} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) ; N-epsilon37- (2- {2- [2- ( (S) -4-carboxy-4- { (S) -4-carboxy-4- [ (S) -4-carboxy-4- (19-carboxy-nonadecanoylamino) butyrylamino] butyrylamino} butyrylamino) ethoxy] ethoxy} acetyl) [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP -1- (7-37) ; N-epsilon37- {2- [2- (2- { (S) -4- [ (S) -4- (12- {4- [16- (2-tert-Butyl-2H-tetrazol-5-yl) -hexadecanoylsulfamoyl] butyrylamino} dodecanoylamino) -4-carboxybutyrylamino] -4-carboxybutyrylamino} ethoxy) ethoxy] acetyl} [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37) ; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- (17-carboxy-heptadecanoylamino) -butyrylamino] -ethoxy} -ethoxy) -acetylamino] -ethoxy} -ethoxy) -acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) ; N-alpha37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- (17-carboxy-heptadecanoylamino) -butyrylamino] -ethoxy} -ethoxy) -acetylamino] -ethoxy} -ethoxy) -acetyl] [Aib8, Glu22, Arg26, Arg34, epsilon-Lys37] GLP-1- (7-37) peptide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- (17-carboxy-heptadecanoylamino) -butyrylamino] -ethoxy} -ethoxy) -acetylamino] -ethoxy} -ethoxy) -acetyl] [desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) ; N-epsilon36- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- (15-carboxy-pentadecanoylamino) -butyrylamino] -ethoxy} -ethoxy) -acetylamino] -ethoxy} -ethoxy) -acetyl] [desaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys36] GLP-1- (7-37) -Glu-Lys peptide; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- ( {trans-4- [ (19-carboxynonadecanoylamino) methyl] cyclohexanecarbonyl} amino) butyrylamino] ethox y} ethoxy) acetylamino] ethoxy} ethoxy) acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37] GLP-1- (7-37) ; N-epsilon37- [2- (2- {2- [2- (2- {2- [ (S) -4-carboxy-4- (17-carboxyheptadecanoylamino) -butyrylamino] -ethoxy} -ethoxy) -acetylamino] -ethoxy} -ethoxy) -acetyl] - [Aib8, Glu22, Arg26, Arg34, Aib35, Lys37] GLP-1- (7-37) ; N-epsilon37- [ (S) -4-carboxy-4- (2- {2- [2- (2- {2- [2- (17-carboxyheptadecanoylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl] [Aib8, Glu22, Arg26, 34, Lys37] GLP-1 (7-37) ; N-epsilon37- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [ImPr7, Glu22, Arg26, 34, Lys37] , GLP-1- (7-37) ; N-epsilon26- {2- [2- (2- {2- [2- (2- { (S) -4-carboxy-4- [10- (4-carboxyphenoxy) decanoylamino] butyrylamino} ethoxy) ethoxy] acetylamino} ethoxy) ethoxy] acetyl} , N-epsilon37- {2- [2- (2- {2- [2- (2- { (S) -4-carboxy-4- [10- (4-carboxyphenoxy) decanoylamino] butyrylamino} ethoxy) ethoxy] acetylamino} ethoxy) ethoxy] acetyl} - [Aib8, Arg34, Lys37] GLP-1 (7-37) -OH; N-epsilon26 (17-carboxyheptadecanoyl) - [Aib8, Arg34] GLP-1- (7-37) -peptide; N-epsilon26- (19-carboxynonadecanoyl) - [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- (4- { [N- (2-carboxyethyl) -N- (15-carboxypentadecanoyl) amino] methyl} benzoyl [Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (19-carboxynonadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [3- (4-Imidazolyl) Propionyl7, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) - (carboxymethyl-amino) acetylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -3 (S) -Sulfopropionylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Gly8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) -amide; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34, Pro37] GLP-1- (7-37) amide; Aib8, Lys26 (N-epsilon26- {2- (2- (2- (2- [2- (2- (4- (pentadecanoylamino) -4-carboxybutyrylamino) ethoxy) ethoxy] acetyl) ethoxy) ethoxy) acetyl) } ) , Arg34) GLP-1- (7-37) -OH; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- { [N- (2-carboxyethyl) -N- (17-carboxyheptadecanoyl) amino] methyl} benzoyl) amino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1 (7-37) ; N-alpha7-formyl, N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoyl-amino) -4 (S) -carboxy-butyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Arg34] GLP-1- (7-37) ; N-epsilon2626- [2- (2- [2- (2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxy-butyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Glu22, Arg34] GLP-1- (7-37) ; N-epsilon26 {3- [2- (2- {2- [2- (2- {2- [2- (2- [4- (15- (N- ( (S) -1, 3-dicarboxypropyl) carbamoyl) pentadecanoylamino) - (S) -4-carboxybutyrylamino] ethoxy) ethoxy] ethoxy} ethoxy) ethoxy] ethoxy} ethoxy) ethoxy] propionyl} [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- [2- (2- [2- (2- [2- (2- [4- { [N- (2-carboxyethyl) -N- (17-carboxy-heptadecanoyl) amino] methyl} benzoyl) amino] (4 (S) -carboxybutyryl-amino) ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1 (7-37) ; N-epsilon26- { (S) -4-carboxy-4- ( (S) -4-carboxy-4- ( (S) -4-carboxy-4- ( (S) -4-carboxy-4- (19-carboxy-nonadecanoylamino) butyrylamino) butyrylamino) butyrylamino) butyrylamino} [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26-4- (17-carboxyheptadecanoyl-amino) -4 (S) -carboxybutyryl- [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- {3- [2- (2- {2- [2- (2- {2- [2- (2- [4- (17-carboxyheptadecanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] ethoxy} ethoxy) ethoxy] ethoxy} ethoxy) ethoxy] pr opionyl} [Aib8, Arg34] GLP-1- (7-37) ; N-epsilon26- {2- (2- (2- (2- [2- (2- (4- (17-carboxyheptadecanoylamino) -4-carboxybutyrylamino) ethoxy) ethoxy] acetyl) ethoxy) ethoxy) acetyl) } - [Aib8, 22, 27, 30, 35, Arg34, Pro37, Lys26] GLP-1 (7-37) amide; N-epsilon26- [2- (2- [2- [4- (21-carboxyuneicosanoylamino) -4 (S) -carboxybutyrylamino] ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) ; and N-epsilon26- [2- (2- [2- (2- [2- (2- [4- (21-carboxyuneicosanoylamino) -4 (S) -carboxybutyrylamino] ethoxy) ethoxy] acetylamino) ethoxy] ethoxy) acetyl] [Aib8, Arg34] GLP-1- (7-37) .
The term solid dosage form can refer to a tablet, or a capsule filled with solids, or a capsule filled with a solution.
As used herein, the terms "treat, " "treating, " "treatment, " and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
The term “therapeutically effective amount, ” as used herein, refers to that amount of a therapeutic agent (e.g., semaglutide or enoxaparin) sufficient to result in amelioration of one or more symptoms of a disorder or condition (e.g., Type 2 Diabetes, DVT, sickle cell disease (SCD) , etc. ) , or prevent appearance or advancement of a disorder or condition, or cause regression of or cure from the disorder or condition.
The term “subject” (alternatively referred to herein as “patient” ) as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
Examples
Example 1.
This example shows that the combination of semaglutide with sodium undecylenate has produced an unexpected higher drug absorption than SNAC. The effective enhancement based on semaglutide plasma concentration is about 5-fold.
Preparation of Formulations
Appropriate amounts of drug (e.g., semaglutide sodium) and excipients, such as sodium undecylenate ( "uC11" ) , and other optional excipients if present, were mixed in water to form a solution. The solution was then freeze dried to provide the formulations.
Representative procedure for preparing formulation containing semaglutide, and uC11: Weigh semaglutide sodium and add it into a glass vial. Add ~15ml of water to dissolve each 65mg of semaglutide sodium. Then weigh uC11 and add it into above semaglutide water solution, and stir the solution to make all excipients dissolved. The solution was then freeze-dried.
The freeze-dried powder was then processed into a tablet form, which was used for the examples herein. The tablet formation was conducted using a manual compressor, a round tablet mold with a diameter of 10 mm, and an arc in the surface of the mold.
Dogs were raised in separated cages. Before an experiment, two meals were supplied to the dogs at about 3 p. m. and 7 a. m. every day. The foods are fodder with water in a bowl. In the day before the experiment, after feeding the dogs at 3 p. m., the dogs were fasted overnight for about 18h. The dogs have access to water overnight, but water was removed at 1h before dosing. Before dosing, the dogs were put into a sling and then 1 ml of blood was collected from each dog’s leg vein using a sterile disposable syringe.
Tablet oral dosing: open the cages and let the dogs climb on the cage by their forelegs. Catch their mouths and open their mouths by hands. Workers will keep a dog’s mouth open and put the tablet into the dog’s throat to stimulate dogs’ deglutition reflex. After closing the dog’s mouth and keep the mouth closed for about ten seconds, the dogs would swallow the tablet naturally without any water.
After dosing, 1ml of blood samples were collected into EDTA anticoagulant tubes at the following time points: 0min, 30min, 1h, 2h, and 6h from the dog’s foreleg vein. After turning upside down for several times for mixing, the blood samples were centrifuged at 3500 rpm for ten minutes. The supernatant plasma samples were removed to clean the tubes and stored at -20℃ in the freezer before measurements. After the collection of the 6h time point samples, the dogs were released, and food and water were returned to them then.
A LC-MS method with MRM mode is used to measure the plasma concentration of semaglutide. 150μl of acetonitrile with internal standard was added into 50μl of plasma to precipitate the proteins. After vortex for 30 seconds, the samples were put into sonication for two minutes. The samples were centrifuged at 15400g for 10minutes. The supernatant was then removed for analysis. The mass spectrum is AB (Triple Quad 6400+) , SHIMADZU. A Sepax Bio-C18 (4.6*150mm, 5μm) was used. The parameters of the LC-MS are summarized below:
Mobile phase: A: H2O (0.1%Formic acid and 5mM ammonium acetate; B: ACN (0.2%Formic acid)
Flow rate: 1ml/min
Column temperature: 40℃
CAD (psi) : 12
Gas1 (psi) : 60
IS(V) : 5500
CUR (psi) : 40
Gas2 (psi) : 55
TEM (℃) : 600
Mode: ESI/+
Semaglutide ion pairs: 1029.2 m/z~136.1m/z, collision energy is 100V.
Experimental results:
Experimental results in beagle dogs are summarized for the pharmacokinetics of semaglutide.
The terminal half-life of semaglutide was determined based on the terminal log-linear phase. The area under the concentration-time (AUC) of semaglutide was calculated using the linear trapezoidal rule. The inter-individual variability was assessed with the coefficient of variation (CV) , calculated by the standard deviation divided by the mean.
Semaglutide + SNAC In this test, oral formulations containing semaglutide and SNAC in 10mg and 300mg, respectively, were administered to dogs as shown above. The concentration-time profiles of semaglutide are shown in Fig. 1. The mean pharmacokinetic parameters (N=6 dogs) are summarized in Table 1. The mean Cmax and AUC0-6 hr were about 16 nM (CV%=134%) and 76 h. nM (CV%=140%) , respectively. The corresponding inter-individual variability (IIV) measured by coefficient of variation)
Semaglutide + sodium undecylenate (uC11) In this test, oral formulations containing semaglutide and uC11 in 10 mg, and 300 mg, respectively, were administered to dogs as shown above. The concentration-time profiles of semaglutide are shown in Fig. 1. The mean pharmacokinetic parameters are summarized in Table 1. The mean Cmax and AUC0-6 hr were about 84 nM (CV%=97%) and 419 nM (100%) , respectively.
Table 1: Summary of Pharmacokinetic Results
In comparison to the formulation containing SNAC, the formulation containing uC11 showed a substantial improvement of AUC and Cmax, in about 5.3 and 5.5 folds higher, respectively. Also, the CV of Cmax and AUC was significantly reduced, which is clinically important, because the smaller inter-individual difference means that medications to the patients are safer (smaller proportion of patients receive unnecessary high exposure) and more efficacious (smaller proportion of patients receive sub-therapeutic exposure) .
Example 2.
This example shows that the combination of enoxaparin with sodium undecylenate has produced an unexpected higher drug absorption than SNAC.
The plasma anti-factor X activity post dose of 80 mg Enoxaparin formulated in 300 mg SNAC or in 300 mg uC11 was shown in Figure 2. The enoxaparin formulations were prepared similar to the semaglutide formulations in Example 1, except that enoxaparin was used instead.
The result showed that both SNAC and uC11 are functional carriers, able to facilitate the oral absorption of Enoxaparin and result in pharmacodynamic activity in plasma. Apparently, uC11 was more effective than SNAC at the current amount of carriers and study conditions.
It is to be appreciated that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections may set forth one or more but not all exemplary embodiments of the present invention as contemplated by the inventor (s) , and thus, are not intended to limit the present invention and the appended claims in any way.
The present invention has been described above with the aid of functional building blocks illustrating the implementation of specified functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternate boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed.
With respect to aspects of the invention described as a genus, all individual species are individually considered separate aspects of the invention. If aspects of the invention are described as "comprising" a feature, embodiments also are contemplated "consisting of or " consisting essentially of” the feature.
The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying knowledge within the skill of the art, readily modify and/or adapt for various applications such specific embodiments, without undue experimentation, without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phraseology or terminology herein is for the purpose of description and not of limitation, such that the terminology or phraseology of the present specification is to be interpreted by the skilled artisan in light of the teachings and guidance.
The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
All of the various aspects, embodiments, and options described herein can be combined in any and all variations.
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.
Claims (54)
- The pharmaceutical composition of claim 1, further comprising:(a) an aliphatic acid of Formula II: R 2COOH, wherein R 2 represents an aliphatic group, or a pharmaceutically acceptable salt thereof; or(b) a compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein:L 1 is a substituted or unsubstituted C 2-C 16 alkylene, or substituted or unsubstituted C 2-C 16 alkenylene;n is an integer selected from 0, 1, 2, 3, or 4; andG 1 at each occurrence is independently OH, NH 2, NH (C 1-4 alkyl) , N (C 1-4 alkyl) (C 1-4 alkyl) , halogen (e.g., Cl) , C 1- 4 alkyl, or C 1- 4 alkoxy (e.g., OCH 3) ; or(c) a combination of the aliphatic acid of Formula II and the compound of Formula III, or a pharmaceutically acceptable salt thereof.
- The pharmaceutical composition of claim 1 or 2, formulated for oral administration.
- The pharmaceutical composition of any of claims 1-3, which upon oral administration to a human subject in need thereof, delivers a therapeutically effective amount of the polypeptide to the human subject.
- The pharmaceutical composition of any of claims 1-4, wherein in Formula I, R 1 represents an alkylene group having 1-30 carbon atoms, e.g., R 1 is - (CH 2) 1-18CH 2-.
- The pharmaceutical composition of any of claims 1-4, wherein in Formula I, R 1 represents an alkylene group having 3-20 carbon atoms.
- The pharmaceutical composition of any of claims 1-4, wherein in Formula I, R 1 represents an alkylene group having 5-16 carbon atoms.
- The pharmaceutical composition of claim 1-4, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is an alkali undecylenate, preferably, sodium undecylenate.
- The pharmaceutical composition of any of claims 2-8, wherein the aliphatic acid of Formula II is a linear aliphatic acid having 2 to 20 carbon atoms, such as caprylic acid, capric acid, or lauric acid.
- The pharmaceutical composition of claim 2-8, wherein the aliphatic acid of Formula II is capric acid.
- The pharmaceutical composition of any of claims 2-10, wherein in Formula III, n is 0.
- The pharmaceutical composition of any of claims 2-10, wherein in Formula III, n is 1 and G 1 is halogen, C 1- 4 alkyl, or C 1- 4 alkoxy.
- The pharmaceutical composition of any of claims 2-10, wherein in Formula III, n is 1 and G 1 is Cl or OCH 3.
- The pharmaceutical composition of any of claims 11-13, wherein in Formula III, L 1 is a substituted or unsubstituted C 2-C 16 alkylene.
- The pharmaceutical composition of any of claims 11-13, wherein in Formula III, L 1 is an unsubstituted C 3-C 15 alkylene.
- The pharmaceutical composition of any of claims 11-13, wherein in Formula III, L 1 is an unsubstituted C 5-C 13 alkylene.
- The pharmaceutical composition of any of claims 11-13, wherein in Formula III, L 1 is an unsubstituted, straight-chained C 5-C 9 alkylene.
- The pharmaceutical composition of any of claims 11-19, comprising a sodium salt of the compound of Formula III.
- The pharmaceutical composition of any of claims 1-21, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- The pharmaceutical composition of any of claims 2-22, wherein the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- The pharmaceutical composition of any of claims 2-23, wherein the compound of -Formula III or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- The pharmaceutical composition of any of claims 1-24, wherein the therapeutic agent is a polypeptide.
- The pharmaceutical composition of claim 25, wherein the polypeptide is a Glucagon-Like Peptide-1 (GLP-1) receptor agonist. (e.g., US10960052) .
- The pharmaceutical composition of claim 25 or 26, wherein the polypeptide is semaglutide, liraglutide, dulaglutide, lixisenatide, or exenatide.
- The pharmaceutical composition of any of claims 25-27, further comprises a SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, or ertugliflozin.
- The pharmaceutical composition of any of claims 25-28, further comprises insulin and insulin analogue.
- The pharmaceutical composition of any of claims 25-29, further comprises amylin and amylin analogue.
- The pharmaceutical composition of any of claims 1-24, wherein the therapeutic agent is a low molecular weight heparin (LWMH) .
- The pharmaceutical composition of claim 31, wherein the LMWH has an average molecular weight of about 3000 Daltons to about 7000 Daltons.
- The pharmaceutical composition of any of claims 31-32, wherein the LMWH is enoxaparin, bemiparin, nadroparin, reviparin, parnaparin, certoparin, dalteparin, or tinzaparin.
- The pharmaceutical composition of any of claims 1-33, further comprising a lubricant, a binder, a filler, and/or a chelating agent (e.g., ethylene diamine tetraacetate (EDTA) ) .
- The pharmaceutical composition of any of claims 1-34, in the form of a solid oral dosage form, such as capsule or tablet.
- A method of treating a disease or disorder, e.g., type-2 diabetes or obesity, in a subject in need thereof, the method comprising orally administering the pharmaceutical composition of any of claims 1-35 to deliver a therapeutically effective amount of the polypeptide to the subject.
- A method of preparing the pharmaceutical composition of any of claims 1-35, the method comprising (a) mixing the therapeutic agent (e.g., a polypeptide or a heparin) with the compound of Formula I or pharmaceutically acceptable salt thereof; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- A method of preparing the pharmaceutical composition of any of claims 2-35, the method comprising (a) mixing the therapeutic agent (e.g., a polypeptide or a heparin) with the compound of Formula I or pharmaceutically acceptable salt thereof, and the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- A method of preparing the pharmaceutical composition of any of claims 2-35, the method comprising (a) mixing the therapeutic agent (e.g., a polypeptide or a heparin) with the compound of Formula I or pharmaceutically acceptable salt thereof, and the compound of Formula III or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- A method of preparing the pharmaceutical composition of any of claims 2-35, the method comprising (a) mixing the therapeutic agent (e.g., a polypeptide or a heparin) with the compound of Formula I or pharmaceutically acceptable salt thereof, the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof, and the compound of Formula III or pharmaceutically acceptable salt thereof to form a mixture; (b) freeze-drying the mixture formed in (a) to form a freeze-dried mixture; and optionally (c) mixing the freeze-dried mixture with a pharmaceutically acceptable excipient.
- The method of claim 37, wherein the mixing in (a) comprises mixing the therapeutic agent (e.g., a polypeptide or a heparin) with a sodium salt of the compound in Formula I.
- The method of claim 38, wherein the mixing in (a) comprises mixing the therapeutic agent (e.g., a polypeptide or a heparin) with a sodium salt of the compound in Formula I, and the sodium salt of the aliphatic acid in Formula II.
- The method of claim 39, wherein the mixing in (a) comprises mixing the therapeutic agent (e.g., a polypeptide or a heparin) with a sodium salt of the compound in Formula I, and the sodium salt of the compound in Formula III.
- The method of claim 40, wherein the mixing in (a) comprises mixing the therapeutic agent (e.g., a polypeptide or a heparin) with a sodium salt of the compound in Formula I, the sodium salt of the aliphatic acid in Formula II, and the sodium salt of the compound in Formula III..
- The method of any one of claims 37-44, wherein the therapeutic agent is semaglutide, liraglutide, dulaglutide, lixisenatide, or exenatide.
- The method of any one of claims 37-44, wherein the therapeutic agent is enoxaparin, bemiparin, nadroparin, reviparin, parnaparin, certoparin, dalteparin, or tinzaparin.
- The method of any one of claims 37-46, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is sodium undecylenate (uC11) .
- The method of any one of claims 38 and 40-47, wherein the aliphatic acid of Formula II or pharmaceutically acceptable salt thereof is sodium caprate.
- The method of any one of claims 39-48, wherein the compound of Formula III or pharmaceutically acceptable salt thereof is SNAC.
- The method of any of claims 37-49, wherein the compound of Formula I or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- The method of any of claims 38 and 40-50, wherein the compound of Formula II or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- The method of any of claims 39-51, wherein the compound of Formula III or pharmaceutically acceptable salt thereof is in an amount of about 50 mg to about 500 mg per unit dose.
- The composition prepared by the method of any one of claims 37-52.
- A method of preparing a pharmaceutical composition comprising mixing the composition of claim 53 with a pharmaceutically acceptable excipient.
Priority Applications (2)
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PCT/CN2022/123964 WO2024077409A1 (en) | 2022-10-09 | 2022-10-09 | Oral delivery of therapeutic agents |
PCT/CN2023/123368 WO2024078410A1 (en) | 2022-10-09 | 2023-10-08 | Oral delivery of therapeutic agents |
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PCT/CN2022/123964 WO2024077409A1 (en) | 2022-10-09 | 2022-10-09 | Oral delivery of therapeutic agents |
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PCT/CN2022/123964 WO2024077409A1 (en) | 2022-10-09 | 2022-10-09 | Oral delivery of therapeutic agents |
PCT/CN2023/123368 WO2024078410A1 (en) | 2022-10-09 | 2023-10-08 | Oral delivery of therapeutic agents |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103906528A (en) * | 2011-06-24 | 2014-07-02 | 安米林药品有限责任公司 | Methods of treating diabetes with sustained release formulations of GLP-1 receptor agonists |
CN106794252A (en) * | 2014-10-07 | 2017-05-31 | 塞浦路迈德有限责任公司 | For the pharmaceutical preparation of oral delivery peptide or protein matter medicine |
WO2018065634A1 (en) * | 2016-10-07 | 2018-04-12 | Cyprumed Gmbh | Pharmaceutical compositions for the nasal delivery of peptide or protein drugs |
CN108135962A (en) * | 2015-10-07 | 2018-06-08 | 塞浦路迈德有限责任公司 | For the pharmaceutical preparation of oral delivery peptide medicament |
CN109498559A (en) * | 2018-11-30 | 2019-03-22 | 复旦大学 | A kind of oral preparation and preparation method thereof loading treating diabetes polypeptide |
WO2021162532A2 (en) * | 2020-02-14 | 2021-08-19 | 주식회사 지투지바이오 | Pharmaceutical composition comprising sustained-release microspheres including glp-1 analogue or pharmaceutically acceptable salt thereof |
-
2022
- 2022-10-09 WO PCT/CN2022/123964 patent/WO2024077409A1/en unknown
-
2023
- 2023-10-08 WO PCT/CN2023/123368 patent/WO2024078410A1/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103906528A (en) * | 2011-06-24 | 2014-07-02 | 安米林药品有限责任公司 | Methods of treating diabetes with sustained release formulations of GLP-1 receptor agonists |
CN106794252A (en) * | 2014-10-07 | 2017-05-31 | 塞浦路迈德有限责任公司 | For the pharmaceutical preparation of oral delivery peptide or protein matter medicine |
CN108135962A (en) * | 2015-10-07 | 2018-06-08 | 塞浦路迈德有限责任公司 | For the pharmaceutical preparation of oral delivery peptide medicament |
WO2018065634A1 (en) * | 2016-10-07 | 2018-04-12 | Cyprumed Gmbh | Pharmaceutical compositions for the nasal delivery of peptide or protein drugs |
CN109498559A (en) * | 2018-11-30 | 2019-03-22 | 复旦大学 | A kind of oral preparation and preparation method thereof loading treating diabetes polypeptide |
WO2021162532A2 (en) * | 2020-02-14 | 2021-08-19 | 주식회사 지투지바이오 | Pharmaceutical composition comprising sustained-release microspheres including glp-1 analogue or pharmaceutically acceptable salt thereof |
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