Oral formulation and treatment of parathyroid hormone analog

Abstract

To provide an oral formulation of parathyroid hormone analog.SOLUTION: The present invention relates to method of preventing or treating disease or disorder comprising administration of oral pharmaceutical composition comprising therapeutically effective amount of parathyroid hormone (PTH) analog and at least one degradation preventing agent, wherein said composition provides relative bioavailability of at least 0.5%, compare to subcutaneous administration. The present invention also relates to the oral pharmaceutical composition comprising therapeutically effective amount of PTH analog and least one degradation preventing agent in physically separated dosage form and wherein said PTH analogue is in enteric coated form. At least one degradation preventing agent includes combination of at least one metal containing compound and at least one reducing agent where in at least one metal containing compound is selected for group consisting of vanadium containing compound, chromium containing compound and manganese containing compound. Preferably PTH analogue are teriparatide or abaloparatide.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a method for preventing or treating a disease or disorder comprising administering an oral pharmaceutical composition comprising a therapeutically effective amount of a parathyroid hormone analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration. The present invention further relates to a method for preventing or treating a disease or disorder comprising administering an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue and at least one stabilizing agent. The present invention further relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue and at least one stabilizing agent, said PTH analogue and said at least one stabilizing agent being physically separate. The at least one stabilizing agent comprises a combination of at least one metal-containing compound and at least one reducing agent, wherein the at least one metal-containing compound is selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds. [Background technology]

[0002] Human parathyroid hormone, secreted by the parathyroid gland, is a polypeptide hormone consisting of 84 amino acids and is a regulator of calcium metabolism through its interaction with target organs including bone, kidney and intestine.

[0003] PTH analogues are active substances that are at least partially structurally similar to PTH and have at least partially similar actions to PTH.PTH analogues are anabolic agents that increase calcium absorption, stimulate new bone formation, and reduce the risk of osteoporotic fractures.The PTH analogues of the present invention include teriparatide and abaloparatide.

[0004] Teriparatide, also known as PTH(1-34), is human parathyroid hormone (1-34) that has the same sequence as the 34 N-terminal amino acids of the 84 amino acids in human parathyroid hormone, which is the biologically active region of PTH. Currently, teriparatide is available on the market as a subcutaneous, multi-dose prefilled pen injection (FORTEO, Eli Lilly and Company). FORTEO contains teriparatide prepared by recombinant DNA technology. Teriparatide is currently approved for the treatment of the following indications (daily 20 mcg of teriparatide per dose). 1. Treatment of postmenopausal women with osteoporosis who are at high risk of fracture. 2. Increasing bone mass in men with primary or secondary hypogonadism who are at high risk of fracture. 3. Treatment of men and women with glucocorticoid-induced osteoporosis who are at high risk of fracture.

[0005] Abaloparatide is an analog of human parathyroid hormone-related peptide (PTHrP(1-34)) with 41% homology to human parathyroid hormone 1-34 and 76% homology to human parathyroid hormone-related peptide. Abaloparatide is currently approved for subcutaneous administration of 80 mcg once daily for the treatment of postmenopausal women with osteoporosis who are at high risk of fracture. Preassembled individual disposable pens for subcutaneous administration are currently available.

[0006] Both teriparatide and abaloparatide can be administered subcutaneously daily. Subcutaneous administration requires daily injections, which can be very painful and reduce patient compliance. The oral route is simple and convenient and is the most preferred route of administration of therapeutic agents. However, the degradation of peptides in the digestive tract prevents their complete and substantial absorption. Thus, the poor bioavailability of the oral route is mainly due to enzymatic degradation in the digestive tract and poor membrane permeability through epithelial cells.

[0007] The patent document 1 relates to a combination of an effective amount of a calcium-containing compound with an effective amount of PTH, where the PTH is administered in a sustained release form. The patent document 1 discloses conventional stabilizers that have not been used successfully up to now.

[0008] US Patent No. 5,399,633 relates to oral mucosal delivery of PTH compositions with delivery agents such as 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid ("4-MOAC") and N-(5-chlorosalicyloyl)-8-aminocaprylic acid (5-CNAC).

[0009] US Patent No. 5,399,633 relates to a pharmaceutical composition comprising a therapeutically effective amount of a therapeutic agent and at least one salt, the salt being a salt of a medium chain fatty acid and a hydrophobic medium (castor oil, tricaprylin or a mixture thereof).

[0010] US Patent No. 5,399,633 relates to a pharmaceutical composition comprising a pharma- ceutically effective amount of a peptide-based drug and a bioavailability enhancer.

[0011] Patent Document 5 relates to a pharmaceutical composition comprising a combination of a peptide or protein drug with a pharma- ceutically acceptable copper salt / complex and / or a pharma- ceutically acceptable zinc salt / complex and a pharma- ceutically acceptable reducing agent. However, copper and zinc are involved in many metabolic pathways in mammals, and their use in long-term treatment may lead to negative interactions.

[0012] Patent Document 6 relates to a pharmaceutical composition comprising a combination of a peptide drug and a pharma- ceutically acceptable copper salt / complex and / or a pharma- ceutically acceptable zinc salt / complex and / or a pharma- ceutically acceptable iron salt / complex and a pharma- ceutically acceptable complexing agent. However, copper and zinc are involved in many metabolic pathways in mammals, and their use in long-term treatments may lead to negative interactions.

[0013] US Patent No. 5,399,633 relates to a pharmaceutical composition multi-unit dosage form comprising at least two separate unit dosage forms bound together by at least two permeable coatings and / or matrices, each of said unit dosage forms comprising a therapeutically active agent and an absorption enhancer.

[0014] Patent document 8 relates to a complex formed by teriparatide (PTH(1-34)) and a deoxycholic acid derivative of PTH or its fragment.

[0015] US Pat. No. 5,399,633 relates to the combination of chromium or vanadium with antidiabetic drugs for glucose disorders.

[0016] Currently, there are no oral formulations of PTH analogues on the market, therefore there is a need to develop oral formulations of PTH analogues that improve bioavailability and thus increase patient compliance. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] U.S. Patent Publication No. US20070155664A1 [Patent Document 2] United States Patent Publication No. US8110547B2 [Patent Document 3] United States Patent Publication No. US9566246B2 [Patent Document 4] U.S. Patent Publication No. US20110046059A1 [Patent Document 5] U.S. Patent Publication No. US20170304195A1 [Patent Document 6] International Patent Publication No. WO2017060500A1 [Patent Document 7] International Patent Publication No. WO2018033927A1 [Patent Document 8] International Patent Publication No. WO2018043942A1 [Patent Document 9] U.S. Patent Publication No. US20060252686A1

[0018] [Non-Patent Document 1] Laffleur F et al., Future Med Chem.2012, 4(17):2205-16 Summary of the Invention [Problem to be solved by the invention]

[0019] The present invention has been made in consideration of such conventional problems, and an object of the present invention is to provide a method for preventing or treating a disease or disorder. [Means for solving the problem]

[0020] In one embodiment, the invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, wherein the composition provides a relative bioavailability of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7%, or 4-6% compared to subcutaneous administration.

[0021] In one embodiment, the invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, wherein the composition provides a relative bioavailability of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7%, or 4-6% compared to subcutaneous administration.

[0022] In one embodiment, the invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, wherein the composition provides a relative bioavailability of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7% or 4-6% compared to subcutaneous administration, and wherein the oral pharmaceutical composition reaches a maximum plasma concentration (Tmax) in 45 to 90 minutes.

[0023] In one embodiment, the invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, wherein the composition provides a relative bioavailability of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7%, or 4-6% compared to subcutaneous administration, and wherein the oral pharmaceutical composition reaches a maximum plasma concentration (Tmax) in 45 to 90 minutes.

[0024] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, and said oral pharmaceutical composition further comprising at least one antidegradant.

[0025] In one embodiment, the invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, and said oral pharmaceutical composition further comprising at least one antidegradant.

[0026] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% as compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one stabilizing agent, said at least one stabilizing agent comprising a combination of at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compounds being at least one reducing agent. The organic compound may be in any form, including a salt or complex thereof.

[0027] In one embodiment, the invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one stabilizing agent, said at least one stabilizing agent comprising a combination of at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds. The metal-containing compound may be in any form, including a salt or complex thereof.

[0028] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one vanadium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, said at least one vanadium-containing compound being selected from the group consisting of vanadium(V) oxide, sodium vanadate, vanadium sulfate, vanadyl sulfate, It is selected from the group consisting of vanadium biguanide, bis(maltolato)oxavanadium(IV), vanadium acetate, vanadyl-picolinate and vanadyl citrate, in any form including salts or complexes thereof.

[0029] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one chromium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, said at least one chromium-containing compound being selected from the group consisting of chromium picolinate, chromium polynicotinate, chromium nicotinate, chromium chloride, and chromium acetate. and any form thereof, including a salt or complex thereof.

[0030] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one manganese-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, said at least one manganese-containing compound being at least one reducing agent and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, is selected from the group consisting of manganese gluconate, manganese sulfate, potassium permanganate and manganese chloride, in any form including a salt or complex thereof.

[0031] In one embodiment, the present invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one vanadium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, said at least one vanadium-containing compound being selected from the group consisting of vanadium(V) oxide, sodium vanadate, vanadium sulfate, sodium vanadate, sodium tetrahydrofuran, sodium lauryl sulfate ... The vanadyl ion exchange agent is selected from the group consisting of vanadyl sulfate, vanadyl biguanide, bis(maltolato)oxavanadium(IV), vanadyl acetate, vanadyl-picolinate and vanadyl citrate, in any form including salts or complexes thereof.

[0032] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one chromium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one chromium-containing compound being chromium picolinate, chromium polynicotinate, chromium nicotinate, chromium chloride, or the like. Chromium is selected from the group consisting of chromium and chromium acetate, in any form including a salt or complex thereof.

[0033] In one embodiment, the present invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one manganese-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, said at least one manganese-containing compound being selected from the group consisting of manganese gluconate, manganese sulfate, potassium permanganate, and Manganese chloride in any form including its salts or complexes.

[0034] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, said at least one metal-containing compound being selected from the group consisting of vanadium sulfate, chromium picolinate, and manganese gluconate, and salts thereof. or in any form including a complex.

[0035] In one embodiment, the present invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one metal-containing compound being selected from the group consisting of vanadium sulfate, chromium picolinate, and manganese gluconate. and in any form including a salt or complex thereof.

[0036] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% as compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being in any form including a salt or complex thereof; said at least one reducing agent is selected from any one or combination of ascorbic acid, reduced glutathione, cysteine, uric acid, reduced sugars, glyceraldehyde, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, glucose, galactose, lactose, maltose, thiol-containing compounds, thiomers and pharma- ceutically acceptable salts thereof.

[0037] In one embodiment, the invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being in any form including a salt or complex thereof; The at least one reducing agent is selected from ascorbic acid, reduced glutathione, cysteine, uric acid, reducing sugars, glyceraldehyde, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, glucose, galactose, lactose, maltose, thiol-containing compounds, thiomers, and pharma- ceutically acceptable salts thereof, or any combination thereof.

[0038] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent and one or more absorption enhancers, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being in any form including a salt or complex thereof; The absorption enhancer is caprylocaproyl macrogol glyceride (Labrasol (R) ALF), polyoxyethylene (20) cetyl ether (trade name Solutol HS 15) and vitamin E.

[0039] In one embodiment, the present invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, wherein the composition provides a relative bioavailability of at least 0.5% compared to subcutaneous administration, and wherein the oral pharmaceutical composition further comprises at least one metal-containing compound, at least one reducing agent, and one or more absorption enhancers, wherein the at least one metal-containing compound is selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds, and wherein the metal-containing compound is any compound including a salt or complex thereof. said absorption enhancer being selected from the group consisting of caprylocaproyl macrogol glyceride, polyoxyethylene (20) cetyl ether and vitamin E.

[0040] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% as compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent and at least one P-glycoprotein efflux inhibitor, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being a salt or complex thereof. It may take any form.

[0041] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or a salt thereof or a complex thereof, said composition providing a relative bioavailability of at least 0.5% as compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent and at least one P-glycoprotein efflux inhibitor, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compounds being at least one reducing agent and at least one P-glycoprotein efflux inhibitor, The compound may be in any form including a salt or complex thereof.

[0042] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% as compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being in any form including a salt or complex thereof; At least one metal-containing compound (in the form of a salt thereof, a complex thereof, or a combination of a salt thereof and a complex thereof) is present in said pharmaceutical composition in a physically separated form.

[0043] In one embodiment, the present invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being in any form including a salt or complex thereof; Paratide or a salt thereof or a complex thereof and the at least one metal-containing compound (in the form of a salt thereof, a complex thereof, or a combination of a salt thereof and a complex thereof) are present in the pharmaceutical composition in physically separated forms.

[0044] In one embodiment, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% as compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being in any form including a salt or complex thereof; At least one metal-containing compound (in the form of a salt thereof, a complex thereof, or a combination of a salt thereof and a complex thereof) is present in the pharmaceutical composition in a physically separated form, the PTH analog is contained in an enteric coated dosage form, and the at least one metal-containing compound and the at least one reducing agent are in an enteric coated form.

[0045] In one embodiment, the present invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, said at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, said metal-containing compound being in any form including a salt or complex thereof; Paratide or a salt thereof or a complex thereof and the at least one metal-containing compound (in the form of a salt thereof, a complex thereof, or a combination of a salt thereof and a complex thereof) are present in the pharmaceutical composition in a physically separated form, the PTH analog is included in an enteric coated dosage form, and the at least one metal-containing compound and the at least one reducing agent are in an enteric coated form.

[0046] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability when administered orally of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7%, or 4-6% compared to subcutaneous administration.

[0047] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7%, or 4-6% compared to subcutaneous administration.

[0048] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability when administered orally of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7% or 4-6% compared to subcutaneous administration, and wherein said oral pharmaceutical composition reaches a peak plasma concentration in 45-90 minutes.

[0049] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7%, or 4-6% compared to subcutaneous administration, and the oral pharmaceutical composition reaching a peak plasma concentration in 45 to 90 minutes.

[0050] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one antidegradant.

[0051] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one antidegradant.

[0052] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one stabilizing agent, the at least one stabilizing agent comprising a combination of at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof.

[0053] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one stabilizing agent, the at least one stabilizing agent comprising a combination of at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof.

[0054] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one vanadium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one vanadium-containing compound being selected from the group consisting of vanadium(V) oxide, sodium vanadate, vanadium sulfate, vanadyl sulfate, vanadium biguanide, bis(maltolato)oxavanadium(IV) acetate, vanadyl-picolinate, and vanadyl citrate, in any form including a salt or complex thereof.

[0055] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one chromium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one chromium-containing compound being selected from the group consisting of chromium picolinate, chromium polynicotinate, chromium nicotinate, chromium chloride, and chromium acetate, in any form including a salt or complex thereof.

[0056] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one manganese-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one manganese-containing compound being selected from the group consisting of manganese gluconate, manganese sulfate, potassium permanganate, and manganese chloride, in any form including a salt or complex thereof.

[0057] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one vanadium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one vanadium-containing compound being selected from the group consisting of vanadium(V) oxide, sodium vanadate, vanadium sulfate, vanadyl sulfate, vanadium biguanide, oxaba bis(maltolate), The vanadium(IV) salt is selected from the group consisting of vanadium(IV), vanadium acetate, vanadyl-picolinate and vanadyl citrate, in any form including salts or complexes thereof.

[0058] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one chromium-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one chromium-containing compound being selected from the group consisting of chromium picolinate, chromium polynicotinate, chromium nicotinate, chromium chloride, and chromium acetate, including any of their salts or complexes. It is in the form of:

[0059] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one manganese-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one manganese-containing compound being selected from the group consisting of manganese gluconate, manganese sulfate, potassium permanganate, and manganese chloride, in any form including a salt or complex thereof. be.

[0060] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one metal-containing compound being selected from the group consisting of vanadium sulfate, chromium picolinate, and manganese gluconate, in any form including a salt or complex thereof.

[0061] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent, and optionally one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor, the at least one metal-containing compound being selected from the group consisting of vanadium sulfate, chromium picolinate, and manganese gluconate, in any form including a salt or complex thereof.

[0062] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, the metal-containing compound being in any form including salts or complexes thereof; the at least one reducing agent being selected from the group consisting of ascorbic acid, reduced glutathione, cysteine, uric acid, reduced sugars, glucose, and the like. The sugar or sugars are selected from any one or combination of ceraldehyde, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, glucose, galactose, lactose, maltose, thiol-containing compounds, thiomers and pharma- ceutically acceptable salts thereof.

[0063] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds, the metal-containing compound being in any form including salts or complexes thereof; the at least one reducing agent being selected from ascorbic acid, reduced glutathione, cysteine, uric acid, reducing sugars, glyceraldehyde, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, glucose, galactose, lactose, maltose, thiol-containing compounds, thiomers, and pharma- ceutical acceptable salts thereof, or any combination thereof.

[0064] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent, and one or more absorption enhancers, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds, the metal-containing compounds being in any form including salts or complexes thereof; the absorption enhancers being selected from the group consisting of caprylocaproyl macrogol glycerides, polyoxyethylene ethersulfate ... ethylene (20) cetyl ether and vitamin E.

[0065] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent, and one or more absorption enhancers, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof; the absorption enhancer being selected from the group consisting of caprylocaproyl macrogolglyceride, polyoxyethylene (20) cetyl ether, and vitamin E.

[0066] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent and at least one P-glycoprotein efflux inhibitor, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof.

[0067] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide, or a salt thereof, or a complex thereof, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound, at least one reducing agent, and at least one P-glycoprotein efflux inhibitor, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds, the metal-containing compound being in any form, including a salt or complex thereof.

[0068] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof; the PTH analogue and the at least one metal-containing compound (a salt thereof, a complex thereof, or a salt and a complex thereof) are combined in a single step. (combination form) is present in said pharmaceutical composition in a physically separated form.

[0069] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof; the teriparatide or a salt or complex thereof and the at least one metal-containing compound (in the form of a salt thereof, a complex thereof, or a combination of a salt thereof and a complex thereof) is present in said pharmaceutical composition in a physically separated form.

[0070] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof; the PTH analogue and the at least one metal-containing compound (a salt thereof, a complex thereof, or a salt and a complex thereof) are combined in a single step. (a combination of the above) are present in the pharmaceutical composition in a physically separated form, the PTH analog is included in an enteric coated dosage form, and the at least one metal-containing compound and the at least one reducing agent are in an enteric coated form.

[0071] In one embodiment, the present invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one metal-containing compound and at least one reducing agent, the at least one metal-containing compound being selected from the group consisting of vanadium-containing compounds, chromium-containing compounds and manganese-containing compounds, the metal-containing compound being in any form including a salt or complex thereof; the teriparatide or a salt or complex thereof and the at least one metal-containing compound (in the form of a salt thereof, a complex thereof, or a combination of a salt thereof and a complex thereof) is present in the pharmaceutical composition in a physically separated form, the PTH analog is included in an enteric coated dosage form, and the at least one metal-containing compound and the at least one reducing agent are in an enteric coated form.

[0072] In one embodiment, the present invention provides an oral pharmaceutical composition comprising teriparatide, the composition exhibiting a maximum concentration (Cmax) of teriparatide from about 2 ng / ml to about 10 ng / ml after administration to an individual.

[0073] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a PTH analog, sodium ascorbate and vanadium sulfate.

[0074] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a PTH analog, sodium ascorbate and vanadium oxide.

[0075] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a PTH analogue, uric acid and sodium vanadate.

[0076] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a PTH analog, sodium ascorbate and manganese gluconate.

[0077] In one embodiment, the present invention provides an oral pharmaceutical composition comprising a PTH analog, reduced glutathione and chromium picolinate. [Brief description of the drawings]

[0078] [Figure 1] 1 is a graph showing teriparatide concentration (ng / ml) over time in different formulations of an example of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0079] The term "PTH analog" refers to an active substance that is at least partially structurally similar to PTH and whose action is at least partially similar to PTH.PTH analog includes the free base, pharmaceutically acceptable salt, pharmacologically active metabolite and its pharmaceutically acceptable salt, hydrate, racemate, enantiomer or complex of PTH analog.The PTH analog of the present invention includes teriparatide and abaloparatide.

[0080] The term "teriparatide" as used herein includes teriparatide free base, pharma- ceutically acceptable salts, pharmacologically active metabolites and pharma- ceutically acceptable salts, hydrates, racemates, enantiomers or complexes thereof. The teriparatide content of the teriparatide or salts or complexes used is an amount equivalent to about 0.5 mg to about 15 mg of teriparatide free base.

[0081] Unless otherwise defined, the term "abaloparatide" as used herein includes abaloparatide free base, pharma- ceutically acceptable salts, pharmacologically active metabolites and pharma- ceutically acceptable salts, hydrates, enantiomers or racemates thereof. The abaloparatide content of the abaloparatide or salts or complexes used is an amount equivalent to about 80 mg to about 8000 mg of abaloparatide free base.

[0082] "Therapeutically effective amount" or "effective amount" means the amount of a medicament that, when administered to a patient for treating a disease, is sufficient to affect the prevention or treatment of said disease. The "therapeutically effective amount" depends on the disease and its severity, as well as the age, weight and other conditions of the patient to be treated.

[0083] As used herein, the term "oral pharmaceutical composition" refers to any composition containing a PTH analog for oral administration, including, but not limited to, immediate release, delayed release, sustained release, and pulsed release dosage forms.

[0084] Relative bioavailability means the bioavailability measured by the following formula:

number

[0085] In the formula, AUC means the area under the drug blood concentration-time curve.

[0086] The term "antidegradant" refers to one or more agents that prevent the enzymatic degradation of a PTH analogue.

[0087] The term "metal-containing compound" means any material, complex, or salt that contains at least one metal ion. The term "vanadium-containing compound" means any form of vanadium-containing material, complex, or salt. The term "chromium-containing compound" means any form of chromium-containing material, complex, or salt. The term "manganese-containing compound" means any form of manganese-containing material, complex, or salt.

[0088] The term "reducing agent" refers to a substance that reduces a compound, usually by donating electrons in a reduction chemical reaction.

[0089] In one embodiment, the invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration. In one similar embodiment, the invention relates to administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide.

[0090] In another embodiment, the invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, wherein the oral pharmaceutical composition reaches a maximum plasma concentration (Tmax) in between 45 minutes and 90 minutes. In one similar embodiment, the invention relates to administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide.

[0091] In one embodiment, the invention relates to a method of preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, said composition providing a relative bioavailability of at least 0.5% compared to subcutaneous administration, said oral pharmaceutical composition further comprising at least one stabilizing agent. In one similar embodiment, the invention relates to administering to a patient in need thereof an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide. In another embodiment, the at least one stabilizing agent is at least one metal-containing compound and at least one In one or more embodiments, the oral pharmaceutical composition further comprises one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor. In another embodiment, the PTH analog and the stabilizing agent are present in the pharmaceutical composition in a physically separated form ... All of the above are in an enteric coated form.

[0092] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration. In one similar embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration.

[0093] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, wherein when the composition is orally administered, the oral pharmaceutical composition reaches a peak plasma concentration in 45 to 90 minutes.In one similar embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, wherein when the composition is orally administered, the oral pharmaceutical composition reaches a peak plasma concentration in 45 to 90 minutes.

[0094] In one embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of a PTH analogue, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one stabilizing agent. In one similar embodiment, the invention relates to an oral pharmaceutical composition comprising a therapeutically effective amount of teriparatide or abaloparatide, the composition providing a relative bioavailability when administered orally of at least 0.5% compared to subcutaneous administration, the oral pharmaceutical composition further comprising at least one stabilizing agent. In another embodiment, the at least Another stabilizing agent comprises a combination of at least one metal-containing compound and at least one reducing agent, wherein the at least one metal-containing compound is selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds, and the metal-containing compound is in any form including a salt or complex thereof. In one or more embodiments, the oral pharmaceutical composition optionally further comprises one or more selected from the group consisting of an absorption enhancer and a P-glycoprotein efflux inhibitor. In another embodiment, the PTH analog and the stabilizing agent are present in the pharmaceutical composition in physically separated forms. In another embodiment, The PTH analogue and the stabilizing agent are both in an enteric coated form in the pharmaceutical composition.

[0095] PTH analogue PTH analogues are active substances that are at least partially structurally similar to PTH and have at least partially similar actions to PTH.PTH analogues are anabolic agents that increase calcium absorption, stimulate new bone formation, and reduce the risk of osteoporotic fractures.The PTH analogues of the present invention include teriparatide and abaloparatide.

[0096] Teriparatide, also known as PTH(1-34), is human parathyroid hormone (1-34) that has the same sequence as the 34 N-terminal amino acids of the 84 amino acids of human parathyroid hormone, which is the biologically active region of PTH. Currently, teriparatide is available in a subcutaneous, multi-dose prefilled pen (FORTEO, Eli Lilly and Company). FORTEO contains teriparatide prepared by recombinant DNA technology. Teriparatide is currently approved (20 mcg teriparatide per daily dose) for the treatment of the following indications: Treatment of postmenopausal women with osteoporosis who are at high risk of fracture. b. Increased bone mass in men with primary or secondary hypogonadism who are at high risk of fracture. c. Treatment of men and women with glucocorticoid-induced osteoporosis at high risk for fracture

[0097] Abaloparatide is an analog of human parathyroid hormone-related peptide (PTHrP(1-34)) with 41% homology to human parathyroid hormone 1-34 and 76% homology to human parathyroid hormone-related peptide. Abaloparatide is currently approved for subcutaneous administration of 80 mcg once daily for the treatment of postmenopausal women with osteoporosis who are at high risk of fracture. Preassembled individual disposable pens for subcutaneous administration are currently available.

[0098] The PTH analog content of the PTH analog or its salt or complex used is an amount equivalent to about 0.5 mg to about 15 mg of PTH analog free base. The teriparatide content of the teriparatide or its salt or complex used is an amount equivalent to about 0.5 mg to about 15 mg of teriparatide free base. The abaloparatide content of the abaloparatide or its salt or complex used is an amount equivalent to about 80 mg to about 800 mg of abaloparatide free base.

[0099] Relative Bioavailability Relative bioavailability means the bioavailability measured by the following formula:

[0100]

number

[0101] In one or more embodiments, the present invention relates to a method for preventing or treating a disease or disorder comprising administering to a patient in need thereof an oral pharmaceutical composition of a PTH analogue, wherein the composition provides a relative bioavailability of at least 0.5%, 0.5-10%, 1-9%, 2-8%, 3-7%, or 4-6% compared to subcutaneous administration.

[0102] Concomitant administration of antiresorptive agents In one embodiment, the invention includes the co-administration of at least one bone resorption inhibitor, including a compound selected from bisphosphonates (such as ibandronate, pamidronate, alendronate, zoledronic acid, risedronate, tiludronate, etidronate, minodronate, etc.), selective estrogen receptor modulators (raloxifene, lasofoxifene, bazedoxifene, arzoxifene, ospemifene), calcitonin, vitamin D, or mixtures thereof.

[0103] Antidegradants Antidegradants refer to one or more agents that prevent enzymatic degradation of proteins or peptides. In one or more embodiments, the antidegradant is a combination of a metal-containing compound and a reducing agent. In one or more embodiments, the antidegradant is a combination of a vanadium-containing compound, a chromium-containing compound, or a manganese-containing compound and a reducing agent.

[0104] metal-containing compounds In one or more embodiments, a metal-containing compound refers to any substance, complex, or salt that contains at least one metal ion. In one or more embodiments, the metal-containing compound is selected from the group consisting of vanadium-containing compounds, chromium-containing compounds, and manganese-containing compounds.

[0105] Vanadium-Containing Compounds Vanadium-containing compounds refer to substances, complexes, and salts containing vanadium in any form. The vanadium content of the vanadium-containing compounds is an amount equivalent to 0.5 mg to 15 mg of vanadium. In one or more embodiments, the vanadium-containing compounds are selected from the group consisting of vanadium(V) oxide, sodium vanadate, vanadium sulfate, vanadyl sulfate, vanadium biguanide, bis(maltolato)oxavanadium(IV), vanadium acetate, vanadyl-picolinate, and vanadyl citrate. In one or more embodiments, the vanadium-containing compounds are vanadium sulfate.

[0106] Chromium-Containing Compounds The chromium-containing compound refers to any substance, complex, or salt containing chromium in any form. The chromium content of the chromium-containing compound is an amount equivalent to 0.1 to 3 mg of chromium. In one or more embodiments, the chromium-containing compound is selected from the group consisting of chromium picolinate, chromium polynicotinate, chromium nicotinate, chromium chloride, and chromium acetate. In one or more embodiments, the chromium-containing compound is chromium picolinate.

[0107] The manganese-containing compound refers to any form of manganese-containing substance, complex, or salt. The manganese-containing compound has a manganese content of 0.5 mg to 5 mg of manganese. In one or more embodiments, the manganese-containing compound is selected from the group consisting of manganese gluconate, manganese sulfate, potassium permanganate, and manganese chloride. In one or more embodiments, the manganese-containing compound is manganese gluconate.

[0108] Reducing Agent A reducing agent is a substance that reduces a compound, usually by donating electrons in a reduction chemical reaction. In one embodiment, the reducing agent is selected from ascorbic acid, reduced glutathione, cysteine, uric acid, reducing sugar, glyceraldehyde, α-tocopherol, vitamin A, α-lipoic acid, dihydro-α-lipoic acid, glucose, galactose, lactose, maltose, thiol-containing compounds, thiomers and pharma-ceutically acceptable salts thereof, or combinations thereof. In one embodiment, the pharmaceutical composition comprises at least one reducing agent, and the unit dose of the at least one reducing agent is about 1 mg to about 1000 mg.

[0109] Absorption enhancers The terms "absorption enhancer" and "permeation enhancer" are synonymous and are used interchangeably herein to encompass within their meaning absorption enhancers and permeation enhancers known or understood by those of skill in the art. In one embodiment, at least one absorption enhancer or permeation enhancer is administered to improve or enhance mucosal absorption of the PTH analog in the gastrointestinal tract. In one embodiment, the at least one absorption enhancer or permeation enhancer is selected from either zwitterionic absorption enhancers and non-ionic absorption enhancers or combinations thereof. In one embodiment, the at least one absorption enhancer is a C8-20 alkanoylcarnitine (preferably lauroylcarnitine, myristoylcarnitine or palmitoylcarnitine; e.g., lauroylcarnitine chloride, myristoylcarnitine chloride or paimitoylcarnitine chloride), salicylic acid (preferably a salicylate such as sodium salicylate), a salicylic acid derivative (such as 3-methoxysalicylic acid, 5-methoxysalicylic acid or homovanillic acid), a C8-20 alkanoic acid (preferably a C8-20 alkanoate, more preferably sodium caprate, sodium caprylate, sodium myristate). , caprates such as sodium palmitate or sodium stearate, caprylates, myristates, palmitates or stearates, citric acid (preferably a citrate such as sodium citrate), sodium lauroyl alanine, N-dodecanoyl-L-alanine, sodium lauroyl aspartate, N-dodecanoyl-L-asparagine, sodium lauroyl aspartate, N-dodecanoyl-L-aspartic acid, sodium lauroyl cysteine, N-dodecanoyl-L-cysteine, sodium lauroyl glutamate, N-dodecanoyl-L-glutamic acid, lauroyl glutamate sodium lauroyl amine, N-dodecanoyl-L-glutamine, sodium lauroyl glycinate, N-dodecanoyl-L-glycine, sodium lauroyl histidinate, N-dodecanoyl-L-histidine, sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methionine, N-dodecanoyl-L-methionine, sodium lauroyl phenylalanine, N-dodecanoyl-L-phenylalanine, sodium lauroyl prophosphate, N-dodecanoyl-L-proline, sodium lauroyl serine, N-dodecanoyl-L-serine, sodium lauroyl threonine, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-Dodecanoyl-L-Valine, Sodium Lauroyl Sarcosinate, N-Dodecanoyl-L-Sarcosine, Sodium Caprate Alanine, N-Decanoyl-L-Alanine, Sodium Aspartate Caprate, N-Decanoyl-L-Asparagine, Sodium Aspartate Caprate, N-Decanoyl-L-Aspartic Acid, Sodium Caprate Cysteine, N-Decanoyl-L-Cysteine, Sodium Caprate Glutamate, N-Decanoyl-L-Glutamic Acid, Sodium Caprate Glutamate, N-Decanoyl-L-Glutamic Acid, Sodium Glycine Caprate, N-Decanoyl-L-Glycine, Sodium Caprate Histidinate, N-Decanoyl-L-Histidine, Sodium Caprate Isoleucine, N-Decanoyl-L-Isoleucine, Sodium Caprate Leucine, N -Decanoyl-L-leucine, sodium caprate methionine, N-decanoyl-L-methionine, sodium caprate phenylalanine, N-decanoyl-L-phenylalanine, sodium caprate prophosphate, N-decanoyl-L-proline, sodium caprate serine, N-decanoyl-L-serine, sodium threonate caprate, N-decanoyl-L-threonine, sodium tryptophanate caprate, N-decanoyl-L-tryptophan, sodium caprate tyrosine, N-decanoyl-L-tyrosine, sodium caprate valinate, N-decanoyl-L-valine, sodium caprate sarcosine, N-decanoyl-L-sarcosine, sodium oleoyl sarcosine, sodium N-decyl leucine, sodium stearoyl glutamate (trade name Amisoft HS-11P), sodium myristoyl glutamate (trade name Amisoft MS-11), sodium lauroyl glutamate (trade name Amisoft LS-11), sodium cocoyl glutamate (trade name Amisoft CS-11), sodium cocoyl glycinate (trade name AmiliteGCS-11), pharma- ceutically acceptable salts or commercial products of the above compounds, such as sodium N-decyl leucine, sodium cocoyl glycine, sodium cocoyl glutamate, and C8-20 alkanoyl sarcosinate (sodium lauroyl sarcosinate, etc.) One of the 20 C8-20 acylated standard proteinogenic α-amino acids, such as 1620-LQ-(MV), alkyl sugars (C1-20 alkyl sugars, such as C8-10 alkyl polysaccharides) or n-octyl-β-D glucopyranoside, or n-dodecyl-β-D maltoside), cyclodextrins (α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, or sulfobutylether-β-cyclodextrin), sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC), thiomers (including those disclosed in Non-Patent Document 1), calcium chelating compounds (ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), sodium citrate, or polyacrylic acid), polyoxyethylene castor oil ethers (cremophor EL;Product name KolliphorR EL;CASNo61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, C2-20 alkanol (e.g. ethanol, decanol, lauryl alcohol, myristyl alcohol, palmityl alcohol), C8-20 alkenol (oleyl alcohol, etc.), C8-20 alkenoic acid (oleic acid, etc.), dextran sulfate, diethylene glycol monoethyl ether (trade name TRANSCUTOLR), 1-dodecylazacycloheptan-2-one (Azone), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, C8-20 alkylamine, C8-20 alkenylamine (oleylamine, etc.), phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glyco The absorption enhancer may be selected from any one or combination of the above, such as ethanol monolaurate, polysorbate (polysorbate 80), deoxycholic acid (sodium deoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), taurocholic acid (such as sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), sucrose laurate, sulfoxides ((C1-10 alkyl)-(C1-10 alkyl)-sulfoxides such as decyl methyl sulfoxide or dimethyl sulfoxide), cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid, dodecyl 2-(N,N-dimethylamino)propionic acid, D-α-tocopheryl polyethylene glycol-1000 succinate (TPGS) and pharma- ceutically acceptable salts of the above compounds. In one embodiment, any two or more absorption enhancers, including those listed above, may be used in combination. However, any one or combination of two or more absorption enhancers known or understood to those of ordinary skill in the art may be used for the intended purposes described herein without departing from the scope and spirit of the present invention.

[0110] P-glycoprotein efflux inhibitors P-glycoprotein is an efflux transporter that can transport drug molecules from the cytoplasm to the intestinal lumen for excretion. These transporters are located on the luminal side of small intestinal epithelial cells. It limits the bioavailability of some oral pharmaceuticals. In one or more embodiments, the P-glycoprotein efflux function inhibitor is selected from the group consisting of naringin, piperine, bergamottin, quercetin, quinidine, quinine, reserpine, ritonavir, tariquidar and verapamil.

[0111] Pharmaceutical Compositions As used herein, the term "oral pharmaceutical composition" refers to any composition containing a PTH analog for oral administration, including, but not limited to, immediate release, delayed release, sustained release and pulsed release dosage forms.

[0112] In one or more embodiments, the therapeutically effective amount of the PTH analogue and the at least one stabilizing agent contained in the pharmaceutical composition are present in said pharmaceutical composition in physically separated forms.

[0113] In one or more embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a PTH analog in an enteric coated form and a combination of a metal-containing compound and a reducing agent in an enteric coated form.

[0114] Oral pharmaceutical compositions may be prepared by any conventional technique, including, but not limited to, dry granulation, wet granulation, melt granulation, direct compression, extrusion spheronization or compressible coating.

[0115] In one embodiment, the oral pharmaceutical dosage form is a tablet (coated or uncoated tablet), a capsule (soft gelatin capsule, hard gelatin capsule, hydroxypropyl methylcellulose (HPMC) capsule or hydroxypropyl methylcellulose phthalate (HPMCP) capsule), a capsule-in-capsule, a tablet in capsule, a lozenge, ), troches, soft capsules, ovules, solutions, emulsions, suspensions, syrups, elixirs, reconstitutable powders and granules, dispersible powders and granules, medicated gums, chewable tablets, effervescent tablets, multi-particulate dosage forms, and the like, or combinations thereof. However, any or combination of oral pharmaceutical dosage forms known or understood by those of skill in the art may be used for the intended purposes described herein without departing from the scope and spirit of the present invention.

[0116] In one embodiment, the pharmaceutical composition further comprises any one or more pharma- ceutically acceptable excipients, including, but not limited to, carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, and / or solubilizers, or combinations thereof. In one embodiment, the pharmaceutical composition further comprises any one or more pharma- ceutically acceptable excipients, including, but not limited to, vitamin E, histidine, microcrystalline cellulose (MCC), mannitol, starch, sorbitol, and / or lactose ... Said pharmaceutical compositions can be formulated by any technique known or understood by those skilled in the art without departing from the scope and spirit of the present invention and used for the intended purposes described herein.

[0117] In one embodiment, the at least one solubilizing agent is polyethylene glycol (including polyethylene glycol having a molecular weight in the range of about 200 to about 5000 Da), ethylene glycol, propylene glycol, a nonionic surfactant, tyloxapol, polysorbate 80, macrogol-15-hydroxystearate, a phospholipid, a lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, a cyclodextrin, an α-cyclodextrin, a β-cyclodextrin, a γ-cyclodextrin, a hydroxyethyl-β ... hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodexin, dihydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin , dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioether, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and the like, or a combination thereof.

[0118] The compositions of any embodiment of the present invention may be enterically coated using any known method. Enteric polymers include hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate succinate, alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer, shellac, cellulose acetate phthalate, starch glycolate, polacrilin, methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, and cellulose acetate trimellitate. The composition can also be prepared using a pre-formed capsule made of an enteric polymer, which is also considered to be in an enteric coated form.

[0119] Formulation T1 [Table 1]

[0120] Formulation T2 [Table 2]

[0121] Formulation T3 [Table 3]

[0122] Formulation T4 [Table 4]

[0123] Formulation T5 [Table 5]

[0124] Formulation T6 [Table 6]

[0125] Formulation T7 [Table 7]

[0126] Formulation T8 [Table 8]

[0127] Formulation T9 [Table 9]

[0128] Formulation T10 [Table 10] [Preparation method]

[0129] Granulation process A. Preparation of Binder Solution: 75.0 mg of HPMC E5 was dissolved in 25.0 mL of deionized water to prepare a 0.3% W / V HPMC E5 solution. B. Preparation of Powder Blend: All ingredients except liquid excipients were precisely weighed and mixed in a plastic bag for 5 minutes. C. Addition of Binder: Weighed liquid excipients were added into the HPMC E5 (0.3%) binder solution along with the peptide, and the resulting mixture was added dropwise to wet granulate. D. Drying of granules: The granules were dried overnight on a silica bed in a vacuum desiccator. E. Sieving of Granules: The dried granules were passed through a #40 mesh stainless steel screen, collected in a suitable glass container and stored at room temperature. [Research Steps]

[0130] After each teriparatide formulation was administered to the distal small intestine (ileum) of SD rats, the amount of teriparatide in rat plasma was quantified using an ELISA kit. The reference formulation was administered to the tail (n=3) at a dose of 10 mcg per animal. The test formulations were then administered to each animal (n=3). One capsule labeled MIRA was crushed in a mortar and pestle, transferred to a microcentrifuge tube, mixed with 2ml / kg Tris buffer, and administered via a catheter into the ileum of one animal. Five minutes later, one capsule labeled Polyamide was crushed in a mortar and pestle, transferred to a microcentrifuge tube, mixed with 2ml / kg Tris buffer, and administered via a catheter into the ileum of the same animal. One capsule labeled MIRA (stored in an icebox) was crushed in a mortar and pestle, transferred to a microcentrifuge tube, mixed with 2 ml / kg Tris buffer, and administered via a catheter into the ileum of one animal. After 5 minutes, the active pharmaceutical ingredient and one polyamide capsule (stored in an icebox) were crushed in a mortar and pestle, transferred to a microcentrifuge tube, mixed with 2 ml / kg Tris buffer and administered via a catheter into the ileum of the same animals. During the dosing period, blood samples were collected at 0, 5, 10, 15, 20, 30, 60, and 120 min after dosing. Blood was collected by puncturing the orbital sinus with a glass capillary tube, and approximately 100 μl of blood was collected into prefilled Na-EDTA microcentrifuge tubes. Blood samples were centrifuged at 5000 rpm for 5 min at 4°C to obtain plasma. Plasma samples were stored at -80°C until analysis. [Research results]

[0131] [Table 11]

[0132] Formulation T11 [Table 12]

[0133] [Manufacturing process] I. Inner capsule 1. All inactive ingredients No. 2 to 6 were precisely weighed out. 2. Microcrystalline cellulose, mannitol, and hydroxypropyl methylcellulose were sieved through a #40 mesh sieve. 3. Preparation of granulation solvent: Required amount of pure water was weighed into a glass beaker, after which Kolliphore HS15 was dissolved in it while stirring with a glass rod until a clear solution was formed. 4. The prepared solution was added dropwise to the mixture from step 2 and mixed manually to reach the end point of granulation. 5. The resulting wet material was dried in a hot air oven at 50°C. 6. The dried granules were sieved through a #40 mesh screen. 7. Croscarmellose sodium was sieved through #40 and added to step 6 by geometric mixing method in a plastic bag. 8. If required, the granular blend is weighed and mixed with the required amount of active pharmaceutical ingredient (teriparatide) and the active pharmaceutical ingredient and base granules are sieved through a #40 mesh sieve. 9. The resulting blend was hand mixed in a plastic bag to ensure uniformity of contents, then sieved through a #40 mesh. 10. Capsules (size 3) were filled to a target weight of 130.0 mg. II. Outer capsule 11. Accurately weigh out all the ingredients (No. 7 to 11) in the table, sift through a #40 mesh screen, and then mix in a plastic bag. 12. The size 3 capsule filled in step 10 was placed inside a size 0 enteric capsule. 13. After step 12, the blend prepared in step 11 was loaded into size 0 enteric capsules with a net fill of 150 mg. 14. Packaging: The capsules were packed in polyethylene containers and the containers were sparged with nitrogen before sealing. [Dissolution test]

[0134] [Table 13]

[0135] Formulation T12 [Table 14]

[0136] [Manufacturing process] I. Inner capsule 1. All inactive ingredients No. 2 to 6 were precisely weighed out. 2. Microcrystalline cellulose, mannitol, and hydroxypropyl methylcellulose were sieved through a #40 mesh sieve. 3. Preparation of granulation solvent: Required amount of pure water was weighed into a glass beaker, after which Kolliphore HS15 was dissolved in it while stirring with a glass rod until a clear solution was formed. 4. The prepared solution was added dropwise to the mixture from step 2 and mixed manually to reach the end point of granulation. 5. The resulting wet material was dried in a hot air oven at 50°C. 6. The dried granules were sieved through a #40 mesh screen. 7. Croscarmellose sodium was sieved through #40 and added to step 6 by geometric mixing method in a plastic bag. 8. If required, the granular blend is weighed and mixed with the required amount of active pharmaceutical ingredient (teriparatide) and the active pharmaceutical ingredient and base granules are sieved through a #40 mesh sieve. 9. The resulting blend was hand mixed in a plastic bag to ensure uniformity of contents, then sieved through a #40 mesh. 10. Capsules (size 3) were filled to a target weight of 130.0 mg. II. Outer capsule 11. Accurately weigh out all the ingredients (No. 7 to 11) in the table, sift through a #40 mesh screen, and then mix in a plastic bag. 12. The size 3 capsule filled in step 10 was placed inside a size 0 enteric capsule. 13. After step 12, the blend prepared in step 11 was loaded into size 0 enteric capsules with a net fill of 150 mg. 14. Packaging: The capsules were packed in polyethylene containers and the containers were sparged with nitrogen before sealing. [Dissolution test]

[0137] [Table 15]

Claims

1. a therapeutically effective amount of an enteric coated parathyroid hormone analog selected from teriparatide or abaloparatide, and at least one stabilizing agent; The stabilizing agent comprises a combination of at least one metal-containing compound and at least one reducing agent; the metal-containing compound is selected from the group consisting of vanadium sulfate, chromium picolinate, and manganese gluconate; the reducing agent is selected from the group consisting of ascorbic acid, reduced glutathione, α-tocopherol, and pharma- ceutically acceptable salts thereof, and combinations thereof; An oral pharmaceutical composition that provides a relative bioavailability of at least 0.5% when administered orally compared to subcutaneous administration.

2. 2. The oral pharmaceutical composition of claim 1, comprising the parathyroid hormone analog and the at least one stabilizing agent in physically separated form.

3. 10. The oral pharmaceutical composition of claim 1, further comprising at least one absorption enhancer.

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