Treatment of osteoporosis

Abstract

A pharmaceutical composition for the treatment of osteoporosis by oral administration is provided. The composition is formulated into a tablet and contains 200 μg to 3000 μg of parathyroid hormone or a fragment thereof, at least one protease inhibitor, and sodium 8-N-(2-hydroxybenzoyl)aminocaprylate (SNAC). The composition also discloses the use of the composition in the manufacture of a medicament, and a method for treating osteoporosis using the composition.

Description

[Technical Field]

[0001] The present invention, in some aspects, relates to therapies, and more particularly, but not exclusively, to compositions and methods for the treatment of osteoporosis by oral administration. [Background technology]

[0002] Parathyroid hormone (PTH) is secreted by the parathyroid gland as a polypeptide containing 84 amino acids. PTH regulates serum calcium levels by promoting calcium release from bone (bone resorption) and calcium absorption in the intestine.

[0003] Teriparatide, a recombinant form of the first 34 amino acids of human parathyroid hormone (PTH(1-34)), is used to treat osteoporosis. It is administered by subcutaneous injection once daily at a dose of 20 μg [Riek & Towler, Mo Med 2011, 108:118-123].

[0004] PTH (including PTH(1-34)) has been reported to promote bone growth only when administered intermittently, with circulating levels returning to control levels within 3 hours [Martin, J Bone Metab 2014, 21:8-20]. In contrast, prolonged elevated PTH levels reduce bone mass by promoting bone resorption.

[0005] Oral administration of peptide drugs is problematic due to degradation of peptides in the digestive system and poor absorption of macromolecules.

[0006] US Patent Application Publication No. 2007 / 0087957 describes a composition for oral administration of a protein, comprising a protein and an omega-3 fatty acid, as well as the use of such a composition for oral administration of insulin.

[0007] Qi & Ping [J Microencapsulation 2004, 21:37-45] describe the administration of enteric-coated microspheres containing insulin with SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate). The enteric-coated microspheres are intended to protect the insulin from digestive enzymes in the stomach and small intestine, and the SNAC is intended to facilitate absorption.

[0008] U.S. Patent Application Publication No. 2011 / 0142800 describes compositions for oral administration of proteins, including a protein having a molecular weight of up to 100,000 Da, a protease inhibitor, and an absorption enhancer such as SNAC, N-(10-[2-hydroxybenzoyl]amino)decanoic acid (SNAD), 8-[N-(2-hydroxy-4-methoxybenzoyl)amino]caprylic acid (4-MOAC), 8-[N-(2-hydroxy-5-chlorobenzoyl)amino]caprylic acid (5-CNAC), and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB), and their sodium salts.

[0009] U.S. Patent No. 8,110,547 describes a composition for the buccal administration of parathyroid hormone (PTH), which comprises PTH or a fragment or analog thereof and a delivery agent such as 4-MOAC, SNAC, SNAD, 5-CNAC, and 4-CNAB.

[0010] Further background art includes Qi et al. [Acta Pharm Sinica 2004, 39:844-848]; International Patent Application Publications WO00 / 50386, WO01 / 32130, WO01 / 32596, WO03 / 045306 and WO2007 / 121471; Japanese Patent Application Nos. 2005281231 and 2006111558; and U.S. Patent Application Publication Nos. 2006 / 0234913 and 2013 / 0224300. Summary of the Invention

[0011] According to some embodiments of the present invention there is provided a pharmaceutical composition for use in the treatment of osteoporosis, the composition being for oral administration to a subject in need thereof, comprising: Parathyroid hormone or a fragment thereof, SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) and A pharmaceutical composition is provided comprising:

[0012] According to some embodiments of the invention there is provided use of the composition in the manufacture of a medicament for treating osteoporosis, wherein the medicament is for oral administration to a subject in need thereof; The composition Parathyroid hormone or a fragment thereof, SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) and The use of the present invention includes:

[0013] According to some embodiments of the invention, the treatment comprises oral administration of parathyroid hormone or a fragment thereof in an amount ranging from 200 to 3000 μg.

[0014] According to some embodiments of the invention, the composition and / or medicament is for once-daily oral administration.

[0015] According to some embodiments of the present invention there is provided a method of treating osteoporosis in a subject in need thereof, comprising the steps of: Parathyroid hormone or a fragment thereof, SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) and A method is provided for orally administering to a subject a composition comprising:

[0016] According to some embodiments of the invention, the method comprises orally administering an amount of parathyroid hormone or a fragment thereof in the range of 200 to 3000 μg.

[0017] According to some embodiments of the invention, oral administration is once daily.

[0018] According to some aspects of the invention, the fragment comprises teriparatide.

[0019] According to some embodiments of the invention, the composition further comprises at least one protease inhibitor.

[0020] According to some embodiments of the present invention, the at least one protease inhibitor comprises at least one trypsin inhibitor.

[0021] According to some embodiments of the present invention, the at least one trypsin inhibitor is selected from the group consisting of lima bean trypsin inhibitor, aprotinin, soybean trypsin inhibitor, and ovomucoid trypsin inhibitor.

[0022] According to some embodiments of the present invention, the at least one trypsin inhibitor comprises soybean trypsin inhibitor.

[0023] According to some embodiments of the present invention, the composition is formulated to provide a Cmax of parathyroid hormone or a fragment thereof in the range of 30 pg / ml to 700 pg / ml for absorption after oral administration of the composition.

[0024] According to some embodiments of the present invention, the composition comprises teriparatide, and the composition is formulated such that the absorption of teriparatide after oral administration of the composition is in the range of Cmax of 30 pg / ml to 300 pg / ml.

[0025] According to some embodiments of the present invention, the composition is formulated to provide a ratio of AUC to Cmax of 3 hours or less for absorption of parathyroid hormone or a fragment thereof following oral administration of the composition.

[0026] According to some embodiments of the present invention, the ratio of AUC to Cmax is equal to or less than 60 minutes.

[0027] According to some embodiments of the invention, the composition is formulated as a tablet.

[0028] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification and definitions contained therein shall govern. Furthermore, the materials, methods, and examples are illustrative only and are not necessarily intended to be limiting.

[0029] Some aspects of the present invention are herein described, by way of example only, with reference to the accompanying drawings. Specific reference will now be made to the details of the drawings, stressing that the details shown therein are by way of example only and are for illustrative purposes of illustrating embodiments of the invention. In this regard, it will become apparent to those skilled in the art how embodiments of the invention may be practiced, upon consideration of the description in conjunction with the drawings. [Brief explanation of the drawings]

[0030] [Figure 1A] 1A-1C are graphs showing plasma concentrations of parathyroid hormone (1-34) as a function of time following oral administration of tablets according to some embodiments of the present invention. Each of Figures 1A-1C shows data for a different subject, who received tablets at two different times (two weeks apart). [Figure 1B] 1A-1C are graphs showing plasma concentrations of parathyroid hormone (1-34) as a function of time following oral administration of tablets according to some embodiments of the present invention. Each of Figures 1A-1C shows data for a different subject, who received tablets at two different times (two weeks apart). [Figure 1C]1A-1C are graphs showing plasma concentrations of parathyroid hormone (1-34) as a function of time following oral administration of tablets according to some embodiments of the present invention. Each of Figures 1A-1C shows data for a different subject, who received tablets at two different times (two weeks apart). [Figure 2] 1 is a bar graph showing the maximum plasma concentration (Cmax) of parathyroid hormone (1-34) as a function of time following oral administration of 200, 400, 680, 1400, or 1800 μg of teriparatide, and following subcutaneous administration of 20 μg of teriparatide in some embodiments of the present invention. [Figure 3] 1 is a graph showing the plasma concentration of parathyroid hormone (1-34) as a function of time following oral administration of 1800 μg of teriparatide, subcutaneous administration of 20 μg of teriparatide, or administration of placebo in accordance with some embodiments of the present invention. [Figure 4] 1 is a graph showing plasma concentrations of cAMP as a function of time following oral administration of 680 μg of teriparatide or subcutaneous administration of 20 μg of teriparatide in accordance with some embodiments of the present invention. [Figure 5] FIG. 1 shows exemplary unit dosage forms for use in some aspects of the present invention. [Figure 6A] FIG. 1 shows an exemplary coated unit dosage form for oral administration in some aspects of the present invention. [Figure 6B] FIG. 1 shows an exemplary coated unit dosage form for oral administration in some aspects of the present invention. [Figure 6C] FIG. 1 shows an exemplary coated unit dosage form for oral administration in some aspects of the present invention. [Figure 7] FIG. 1 shows an exemplary tablet for oral administration in accordance with some embodiments of the present invention. [Figure 8] FIG. 1 shows an exemplary coated tablet for oral administration in some embodiments of the present invention. [Figure 9] FIG. 1 shows an exemplary outer layer of an oral dosage unit form according to some embodiments of the present invention. [Figure 10] FIG. 1 shows an exemplary outer layer of an oral dosage unit form according to some embodiments of the present invention. [Figure 11] FIG. 1 shows an exemplary core of an oral dosage unit form in some embodiments of the present invention. [Figure 12] FIG. 1 illustrates an exemplary drug delivery system according to some aspects of the present invention. [Figure 13] (A) shows an exemplary drug delivery system according to some embodiments of the present invention before oral administration, (B) shows an exemplary drug delivery system according to some embodiments of the present invention after oral administration in the stomach, and (C) shows an exemplary drug delivery system according to some embodiments of the present invention after oral administration in the intestine. [Figure 14] 1A-1C illustrate casings of exemplary drug delivery systems according to some aspects of the present invention. [Figure 15] 1 is a graph showing the release of SNAC as a function of time, comparing an exemplary tablet formulation without sodium bicarbonate with an exemplary tablet formulation with sodium bicarbonate. [Figure 16] 1 is a bar graph showing the relative absorption (defined as 100% absorption when co-administered with water) of teriparatide from exemplary oral formulations co-administered with 150 ml of water (HO) or 3 mg / ml aqueous sodium bicarbonate solution (HO+NaCO). DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention, in some aspects thereof, relates to therapies for the treatment of osteoporosis by oral administration, and more particularly, but not exclusively, to compositions and methods for the treatment of osteoporosis by oral administration.

[0032] Before describing at least one embodiment of the present invention in detail, it is to be understood that the invention is not necessarily limited in its applications by the details set forth below or illustrated by way of example. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0033] As discussed above, parathyroid hormone (PTH) and its fragments are known to be effective in treating osteoporosis, and this has been achieved by subcutaneous injection of PTH or its fragments.

[0034] The inventors have now discovered that by using compositions designed to overcome the poor absorption rate of parathyroid hormone when administered orally, osteoporosis can be treated more effectively with oral administration of parathyroid hormone (or fragments thereof) than with subcutaneous injection or infusion.

[0035] While investigating the enhancement of parathyroid hormone absorption by oral administration of SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), the present inventors discovered that a composition containing SNAC could provide a pharmacokinetic profile desirable for the treatment of osteoporosis. Such a composition is characterized by a relatively rapid increase in parathyroid hormone levels, followed by a relatively rapid decrease in parathyroid hormone levels. The present inventors hypothesized that oral administration of such a composition would be particularly useful for the treatment of osteoporosis, since the desired bone growth promotion in osteoporosis treatment is associated with a transient increase in parathyroid hormone levels rather than a chronic increase.

[0036] Referring now to the drawings, Figures 1A-1C show that oral administration of exemplary compositions according to some embodiments of the present invention increases plasma levels of PTH (teriparatide), followed almost immediately by a rapid decrease in plasma levels of PTH. Figure 2 shows that plasma levels of PTH are proportional to the orally administered dose. Figure 3 shows that the time it takes for orally administered PTH to be absorbed into the blood is significantly shorter than when PTH is administered subcutaneously. Figure 4 shows that absorbed PTH has a biological effect.

[0037] These results demonstrate that oral administration of the PTH-containing compositions described herein is an effective and convenient route for administering PTH and is associated with a distinctive pharmacokinetic profile that is suitable for treating, for example, osteoporosis.

[0038] According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition for use in the treatment of osteoporosis.

[0039] According to some aspects of the present invention, the composition is suitable for treating osteoporosis by oral administration of the composition, i.e., the composition provides a therapeutic effect when administered orally. Pharmaceutical compositions according to embodiments of the present invention include: Parathyroid hormone or a fragment thereof, SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) and Includes.

[0040] According to an aspect of some embodiments of the invention there is provided use of a composition of the invention in the manufacture of a medicament for the treatment of osteoporosis, said treatment being effected by oral administration of the medicament to a subject in need thereof.

[0041] According to an aspect of some embodiments of the present invention there is provided a method of treating osteoporosis in a subject in need thereof.

[0042] According to some aspects of the invention, the method is carried out by orally administering to the subject a composition described herein.

[0043] In some forms according to any of the aspects of the embodiments described herein, the compositions for oral administration as defined herein are formulated as one or more unit dosage forms.

[0044] As used herein and in the art, the term "parathyroid hormone" refers to an 84 amino acid polypeptide hormone secreted by the parathyroid gland.

[0045] As used herein, a "fragment" of parathyroid hormone refers to a polypeptide containing a portion of the above 84 amino acids of parathyroid hormone. Preferably, the fragment exhibits the biological activity of parathyroid hormone.

[0046] Teriparatide is an example of a parathyroid hormone fragment, consisting of amino acids 1-34 (i.e., the N-terminal portion) of the intact parathyroid hormone polypeptide. The term "teriparatide" is used interchangeably herein with the terms "PTH(1-34)" and "parathyroid hormone(1-34)."

[0047] For brevity herein, the term "parathyroid hormone" or its abbreviation "PTH" encompasses parathyroid hormone (e.g., having its native amino acid sequence in humans), fragments thereof, and homologs of parathyroid hormone or fragments thereof, unless otherwise indicated. For example, the terms "PTH(1-84)" and "parathyroid hormone(1-84)" herein specifically refer to the complete 84-amino acid parathyroid hormone polypeptide, while the terms "PTH(1-34)" and "parathyroid hormone(1-34)" herein refer to a specific fragment of parathyroid hormone (teriparatide).

[0048] Without being bound by any particular theory, it is believed that PTH tends to be poorly absorbed when administered orally due to its relatively large molecular weight and / or its polarity, and therefore its absorption is particularly susceptible to enhancement by SNAC activity.

[0049] Methods and Compositions As used herein, the phrase "pharmaceutical composition" (also referred to herein for brevity as "composition") refers to a formulation containing parathyroid hormone (PTH) (e.g., PTH(1-34), PTH(1-84)), other chemical components such as SNAC, and, optionally, additional components described herein. The purpose of a pharmaceutical composition is to facilitate administration of PTH.

[0050] In some aspects of any one of the embodiments described herein, the composition for oral administration further comprises at least one protease inhibitor, the types and amounts of optional protease inhibitors being described in detail herein.

[0051] In some aspects of any one of the embodiments described herein, the treatment or method of the corresponding aspect described herein comprises oral administration of at least 100 μg of PTH (e.g., PTH(1-34)). In some aspects, the treatment or method comprises oral administration of at least 200 μg of PTH (e.g., PTH(1-34)). In some aspects, the treatment or method comprises oral administration of at least 500 μg of PTH (e.g., PTH(1-34)). In some aspects, the amount of SNAC is according to any one of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In some aspects, the composition further comprises at least one protease inhibitor, the amount of which is according to any one of the ratios of protease inhibitor to PTH (e.g., PTH(1-34)) described herein.

[0052] In some aspects of any one of the embodiments described herein, the treatment or method of the corresponding aspect described herein comprises oral administration of 20 mg or less of PTH (e.g., PTH(1-34)). In some aspects, the treatment or method comprises oral administration of 10 mg or less of PTH (e.g., PTH(1-34)). In some aspects, the treatment or method comprises oral administration of 5 mg or less of PTH (e.g., PTH(1-34)). In some aspects, the treatment or method comprises oral administration of 3 mg (3000 μg) or less of PTH (e.g., PTH(1-34)). In some aspects, the treatment or method comprises oral administration of 2000 μg or less of PTH (e.g., PTH(1-34)). In some aspects, the treatment or method comprises oral administration of 1000 μg or less of PTH (e.g., PTH(1-34)). In some aspects, the amount of SNAC is according to any one of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In some embodiments, the composition further comprises at least one protease inhibitor in an amount according to any one of the ratios of protease inhibitor to PTH (e.g., PTH(1-34)) described herein.

[0053] In some aspects of any one of the embodiments described herein, the treatment or method of the corresponding aspect described herein comprises oral administration of 200 μg to 20 mg of PTH (e.g., PTH(1-34)).

[0054] In some embodiments, the treatment or method involves oral administration of 200 μg to 10 mg of PTH (e.g., PTH(1-34)). In some embodiments, the treatment or method involves oral administration of 200 μg to 5 mg of PTH (e.g., PTH(1-34)). In some embodiments, the treatment or method involves oral administration of 200 to 3000 μg of PTH (e.g., PTH(1-34)). In some embodiments, the treatment or method involves oral administration of 200 to 2000 μg of PTH (e.g., PTH(1-34)). In some embodiments, the treatment or method involves oral administration of 500 to 1000 μg of PTH (e.g., PTH(1-34)). In some embodiments, the treatment or method involves oral administration of about 750 μg of PTH (e.g., PTH(1-34)). In some embodiments, the amount of SNAC is in accordance with any one of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In some embodiments, the composition further comprises at least one protease inhibitor in an amount in accordance with any one of the ratios of protease inhibitor to PTH (e.g., PTH(1-34)) described herein.

[0055] In some aspects of any one of the embodiments described herein, oral administration according to any of the corresponding embodiments described herein occurs 1 to 3 times daily. In some aspects, the composition (e.g., formulated as a unit dosage form) is for oral administration 1 to 3 times daily.

[0056] In some aspects of any one of the embodiments described herein, oral administration according to any of the corresponding embodiments described herein occurs once or twice daily. In some aspects, the composition (e.g., formulated as a unit dosage form) is for oral administration once or twice daily.

[0057] In some aspects of any one of the embodiments described herein, the oral administration according to any of the corresponding embodiments described herein is performed once daily. In some aspects, the composition (e.g., formulated as a unit dosage form) is for once-daily oral administration.

[0058] In some aspects of any one of the embodiments described herein, the oral administration of any of the corresponding embodiments described herein is by oral administration of 1 to 3 pharmaceutical composition unit dosage forms.

[0059] In some aspects of any one of the embodiments described herein, the oral administration of any of the corresponding embodiments described herein is performed by oral administration of one to two pharmaceutical composition unit dosage forms.

[0060] In some aspects of any one of the embodiments described herein, the oral administration of any corresponding embodiment described herein is by oral administration of one pharmaceutical composition unit dosage form.

[0061] In some aspects of any one of the embodiments described herein, a composition for administration described herein (e.g., a composition unit dosage form according to any of the respective embodiments described herein) comprises at least 100 μg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises at least 200 μg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises at least 500 μg of PTH (e.g., PTH(1-34)). In some aspects, the amount of SNAC is in accordance with any one of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In some aspects, the composition further comprises at least one protease inhibitor, in an amount in accordance with any one of the ratios of protease inhibitor to PTH (e.g., PTH(1-34)) described herein.

[0062] In some aspects of any one of the embodiments described herein, a composition for administration described herein (e.g., a composition unit dosage form according to any of the respective embodiments described herein) comprises 20 mg or less of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 10 mg or less of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 5 mg (3000 μg) or less of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 3 mg (3000 μg) or less of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 2000 μg or less of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 1000 μg or less of PTH (e.g., PTH(1-34)). In some aspects, the amount of SNAC is according to any one of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In some embodiments, the composition further comprises at least one protease inhibitor in an amount according to any one of the ratios of protease inhibitor to PTH (e.g., PTH(1-34)) described herein.

[0063] In some aspects of any one of the embodiments described herein, the composition (e.g., a composition unit dosage form according to any of the respective embodiments described herein) comprises 200 μg to 20 mg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 200 μg to 10 mg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 200 μg to 5 mg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 200 to 3000 μg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 200 to 2000 μg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises 500 to 1000 μg of PTH (e.g., PTH(1-34)). In some aspects, the composition comprises about 750 μg of PTH (e.g., PTH(1-34)). In some embodiments, the amount of SNAC is in accordance with any one of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In some embodiments, the composition further comprises at least one protease inhibitor in an amount in accordance with any one of the ratios of protease inhibitor to PTH (e.g., PTH(1-34)) described herein.

[0064] Acute exposure to parathyroid hormone results in substantially different biological effects than chronic exposure, because acute exposure to the hormone results in increased net bone growth, whereas chronic exposure results in increased net bone resorption (i.e., the opposite of increased bone growth). Increased bone growth can sometimes be used, for example, to treat osteoporosis, whereas increased bone resorption is relatively undesirable in osteoporosis treatment.

[0065] Here, the phrase "substantially different biological effect" means that at least some of the effects are different in kind rather than in magnitude, e.g., a net increase in bone growth is effectively the opposite of a net increase in bone resorption.

[0066] Without being bound by any particular theory, it is believed that the pharmacokinetic profiles of the compositions described herein may provide particularly pronounced and / or consistent effects associated with acute exposure to PTH suitable for promoting significant and consistent enhancement of bone growth in, for example, the treatment of osteoporosis.

[0067] In some embodiments, the composition (eg, composition unit dosage form) is formulated to provide a ratio of AUC to Cmax of 3 hours or less for absorption of PTH following oral administration of the composition.

[0068] In some embodiments, the ratio of AUC to Cmax is less than or equal to 2 hours.

[0069] In some embodiments, the ratio of AUC to Cmax is equal to or less than 90 minutes.

[0070] In some embodiments, the ratio of AUC to Cmax is equal to or less than 60 minutes.

[0071] In some embodiments, the ratio of AUC to Cmax is less than or equal to 50 minutes.

[0072] In some embodiments, the ratio of AUC to Cmax is less than or equal to 40 minutes.

[0073] In some embodiments, the ratio of AUC to Cmax is equal to or less than 30 minutes.

[0074] In some embodiments, the ratio of AUC to Cmax is 20 minutes or less.

[0075] In some embodiments, the ratio of AUC to Cmax is 15 minutes or less.

[0076] In some embodiments, the ratio of AUC to Cmax is 10 minutes or less.

[0077] As used herein, the term "AUC" refers to the area under the curve, which represents the level (e.g., plasma level) of an administered drug (e.g., PTH) in the blood as a function of time after administration, and can be determined by measuring the plasma level of the drug (e.g., PTH) at various time points after administration, as exemplified herein.

[0078] As used herein, the term "Cmax" refers to the maximum concentration (e.g., plasma level) of an administered drug (e.g., PTH) in the blood, and can be determined by measuring the level of the drug (e.g., PTH) at various times after administration, as exemplified herein.

[0079] Because PTH is usually present in the blood to some extent before administration, the area below the baseline level is excluded from AUC and C (e.g., by subtracting the baseline level from the level measured at each time point), so that AUC and C each characterize the increase above the baseline level present after administration. The baseline can optionally be determined by measuring the level before administration and / or by using the level that decays after administration as a baseline (e.g., by curve fitting). Alternatively, or additionally, in embodiments in which the administered PTH species (e.g., teriparatide) is different from endogenous PTH, measurement of PTH can be selective for the administered PTH species (e.g., using the assays described in the Examples section herein).

[0080] The ratio of AUC to C (i.e., AUC divided by C) depends on the nature of the pharmacokinetic profile of the composition, particularly the shape of the curve representing the level of PTH in the blood (e.g., plasma level) as a function of time after administration. Pharmacokinetic profiles characterized by sharp increases and decreases over short periods of time tend to have relatively low AUC to C ratios, while more gradual increases and decreases over longer periods of time tend to have relatively high AUC to C ratios.

[0081] Thus, without being bound by any particular theory, it is believed that an AUC to C ratio of 3 hours or less is associated with a relatively rapid rise and fall of PTH in the blood, as described herein by any of the corresponding embodiments.

[0082] The ratio of AUC to C is optionally calculated based on data from multiple administrations of the composition. In such cases, the ratio of AUC to C is preferably calculated for each administration, and the ratios calculated for each administration may then be averaged.

[0083] Similarly, Cmax is optionally calculated based on data from multiple administrations of the composition. In such cases, a Cmax value is preferably calculated for each administration, and the calculated Cmax values ​​for each administration may then be averaged.

[0084] Without being bound by any particular theory, it is believed that averaging data (e.g., measured blood levels of PTH) obtained from different administrations of PTH often results in broader curves, lower Cmax values, and larger AUC to Cmax ratios than observed after a single administration. Thus, Cmax values ​​and AUC to Cmax ratios calculated for averaged data (as opposed to the average of the ratios calculated for each administration, as described above) are less accurate indicators of the effect of a composition after administration.

[0085] In some aspects of any one of the embodiments described herein, the composition (e.g., a composition unit dosage form) is formulated to provide a Cmax of 30 pg / ml to 700 pg / ml PTH for absorption of PTH following oral administration of the composition. In some embodiments, the Cmax is 50 pg / ml to 450 pg / ml PTH. In some embodiments, the PTH is PTH(1-84). In some embodiments, the PTH is PTH(1-34).

[0086] In some aspects of any one of the embodiments described herein, the composition (e.g., composition unit dosage form) comprises parathyroid hormone (1-34) and is formulated to provide a Cmax of 30 pg / ml to 300 pg / ml parathyroid hormone (1-34) for absorption of parathyroid hormone (1-34) following oral administration of the composition. In some embodiments, the Cmax is 50 pg / ml to 200 pg / ml parathyroid hormone (1-34).

[0087] In some aspects of any one of the embodiments described herein, the composition (e.g., composition unit dosage form) comprises parathyroid hormone (1-84) and is formulated to provide a Cmax of 70 pg / ml to 700 pg / ml parathyroid hormone (1-84) absorption following oral administration of the composition. In some aspects, the Cmax is 100 pg / ml to 450 pg / ml parathyroid hormone (1-84).

[0088] In some aspects of any one of the embodiments described herein, the C of any PTH (including, e.g., a fragment or homologue according to any of the corresponding embodiments described herein) is molar equivalent to the C of PTH(1-34) and / or PTH(1-84) according to any of the corresponding embodiments described herein. The C according to such embodiments can be determined by multiplying the C of PTH(1-34) and / or PTH(1-84) by the ratio of the molecular weight of the PTH administered according to such embodiment to the molecular weight of PTH(1-34) and / or PTH(1-84).

[0089] In some aspects of any one of the embodiments described herein, the composition (e.g., a composition unit dosage form) is formulated to provide a Cmax of 100 pg / ml to 450 pg / ml PTH for PTH absorption following oral administration of the composition.

[0090] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) comprises PTH(1-34) and is formulated to provide a Cmax of 100 pg / ml to 200 pg / ml PTH(1-34) for absorption of PTH(1-34) following oral administration of the composition.

[0091] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) comprises PTH(1-84) and is formulated to provide a Cmax of 225 pg / ml to 450 pg / ml PTH(1-84) for absorption of PTH(1-84) following oral administration of the composition.

[0092] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) is formulated to provide a Cmax of 30 pg / ml to 225 pg / ml PTH for PTH absorption following oral administration of the composition.

[0093] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) comprises PTH(1-34) and is formulated to provide a Cmax of 30 pg / ml PTH to 100 pg / ml PTH(1-34) for absorption of PTH(1-34) following oral administration of the composition.

[0094] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) comprises PTH(1-84) and is formulated to provide a Cmax of 70 pg / ml to 225 pg / ml PTH(1-84) for absorption of PTH(1-84) following oral administration of the composition.

[0095] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) is formulated to provide a Cmax of 200 pg / ml to 700 pg / ml PTH for PTH absorption following oral administration of the composition.

[0096] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) comprises PTH(1-34) and is formulated to provide a Cmax of 200 pg / ml to 300 pg / ml PTH(1-34) for absorption of PTH(1-34) following oral administration of the composition.

[0097] In some aspects of any one of the embodiments described herein, the composition (e.g., the composition unit dosage form) comprises PTH(1-84) and is formulated to provide a Cmax of 450 pg / ml to 700 pg / ml PTH(1-84) for absorption of PTH(1-84) following oral administration of the composition.

[0098] In some aspects of any one of the embodiments described herein, the bioavailability of PTH (e.g., PTH(1-34)) upon oral administration of the composition is within the range of 0.05 to 50%. In some aspects, the bioavailability is within the range of 0.1 to 15%. In some aspects, the bioavailability is within the range of 0.2 to 5%. In some aspects, the bioavailability is within the range of 0.5 to 3%.

[0099] Without being bound by any particular theory, it is believed that SNAC significantly enhances the bioavailability of PTH.

[0100] In some aspects of any one of the embodiments described herein, the bioavailability of PTH (e.g., PTH(1-34)) upon oral administration of the composition is at least 50% higher (at least 150%) than the bioavailability of PTH (e.g., PTH(1-34)) upon oral administration of an equivalent composition that does not contain SNAC (e.g., a composition that is identical in all characteristics except for the absence of SNAC). In some aspects, the bioavailability is at least twice the bioavailability of an equivalent composition that does not contain SNAC (at least 200%). In some aspects, the bioavailability is at least four times the bioavailability of an equivalent composition that does not contain SNAC (at least 400%). In some aspects, the bioavailability is at least 10 times the bioavailability of an equivalent composition that does not contain SNAC (at least 1000%). In some embodiments, the bioavailability is at least 20 times (at least 2000%) the oral bioavailability of an equivalent composition without SNAC. In some embodiments, the bioavailability is at least 50 times (at least 5000%) the oral bioavailability of an equivalent composition without SNAC.

[0101] Some of the agents administered according to the various embodiments described herein include polypeptides or proteins, such as PTH and many of the protease inhibitors described herein, all of which should be construed consistent with the definition of the term "polypeptide" hereinafter.

[0102] Any formulation that provides the desired pharmacokinetic parameters according to any of the corresponding embodiments described herein is suitable for use according to embodiments of the present invention in treating a particular medical condition and is encompassed by the terms "pharmaceutical composition," "medicament," and "drug delivery system" as described herein.

[0103] Such formulations may contain any ingredient or combination of ingredients known to those skilled in the art as providing the desired pharmacokinetic parameters according to any of the corresponding embodiments described herein.

[0104] Any of the compositions and unit dosage forms described herein may optionally consist essentially of the ingredients described herein (e.g., PTH, SNAC, and optionally at least one protease inhibitor), or alternatively, the compositions may further comprise a suitable pharmaceutically acceptable carrier or excipient.

[0105] Hereinafter, the terms "physiologically acceptable carrier" and "pharmaceutically acceptable carrier" are used interchangeably and refer to a carrier or diluent that does not cause significant irritation to an organism and does not neutralize the biological activity and properties of the compound being administered. Adjuvants are included under these terms.

[0106] Here, the term "additive" refers to an inactive substance added to the pharmaceutical composition to facilitate the administration of the active ingredient.Exemplary additives include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0107] As used herein, the term "unit dosage form" refers to physically discrete units, each containing a predetermined quantity of one or more active ingredients calculated to produce a desired therapeutic effect, together with at least one pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0108] In some aspects of any one of the embodiments described herein, the composition is formulated as a solid composition. In some aspects, the composition is formulated as a tablet.

[0109] In some aspects of any one of the embodiments described herein, the composition consists primarily of a combination of PTH, SNAC, and optionally at least one protease inhibitor described herein, i.e., at least 50 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, and (optional) at least one protease inhibitor. In some aspects, at least 60 weight percent of the composition consists of PTH, SNAC, and (optional) at least one protease inhibitor. In some aspects, at least 70 weight percent of the composition consists of PTH, SNAC, and (optional) at least one protease inhibitor. In some aspects, at least 80 weight percent of the composition consists of PTH, SNAC, and (optional) at least one protease inhibitor. In some aspects, at least 90 weight percent of the composition consists of PTH, SNAC, and (optional) at least one protease inhibitor. In some aspects, at least 95 weight percent of the composition consists of PTH, SNAC, and (optional) at least one protease inhibitor. In some embodiments, at least 98 percent by weight of the composition consists of PTH, SNAC, and (optionally) at least one protease inhibitor. In some embodiments, the composition is formulated as a tablet.

[0110] As illustrated, but not limited to, in the examples herein, compositions that are readily soluble in the stomach and that include a large proportion (e.g., at least 50 weight percent) of PTH and SNAC and an (optional) protease inhibitor (e.g., as described herein in any of the respective embodiments) can provide a pharmacokinetic profile in which there is a rapid increase in absorbed PTH levels, followed almost immediately by a rapid decrease in absorbed PTH levels.

[0111] Without being bound by any particular theory, it is believed that both PTH and SNAC, which can promote PTH absorption, become available in the stomach immediately after oral administration (e.g., before the composition passes into the intestine), and thus dissolution, particularly relatively rapid dissolution, in gastric fluid facilitates rapid absorption of PTH. Furthermore, because SNAC is protonated (e.g., converting a carboxylate salt to a carboxylic acid), it is inactivated upon exposure to the acidic conditions of the stomach, and little or no SNAC remains that can promote PTH absorption immediately after the composition is completely dissolved in the stomach. Therefore, dissolution, particularly relatively rapid dissolution, in gastric fluid facilitates control over the time over which PTH is absorbed.

[0112] Furthermore, a pharmacokinetic profile of a rapid increase in absorbed PTH levels, followed almost immediately by a rapid decrease in absorbed PTH levels, is believed to be particularly useful for treating osteoporosis because brief exposure to PTH is associated with enhanced bone growth, which is generally desirable when treating osteoporosis, as opposed to the enhanced bone resorption associated with chronic exposure to PTH, which is generally undesirable when treating osteoporosis.

[0113] In some embodiments of any of the embodiments described herein, the composition is soluble in gastric fluid. In some embodiments, the composition dissolves in gastric fluid in 60 minutes or less. In some embodiments, the composition dissolves in gastric fluid in 50 minutes or less. In some embodiments, the composition dissolves in gastric fluid in 40 minutes or less. In some embodiments, the composition dissolves in gastric fluid in 30 minutes or less. In some embodiments, the composition dissolves in gastric fluid in 20 minutes or less. In some embodiments, the composition dissolves in gastric fluid in 15 minutes or less. In some embodiments, the composition dissolves in gastric fluid in 10 minutes or less. In some embodiments, the composition dissolves in gastric fluid in 5 minutes or less.

[0114] As used herein, the phrases "soluble in gastric fluid," "dissolves in gastric fluid," and the like refer to solubility in simulated gastric fluid without pepsin under conditions according to USP 23 Apparatus 2 (paddle) (e.g., 800 ml volume, 50 rpm), pH 2.0. Dissolution refers to the absence of visible composition at the bottom of the liquid. However, visible material suspended in the liquid is not excluded by the terms "soluble" and "dissolved." The phrase "soluble in gastric fluid," as used herein, refers to dissolution within 6 hours. A liquid composition that is miscible with simulated gastric fluid is considered to be "soluble in gastric fluid," and dissolution in this case refers to mixing of the liquid composition with the simulated gastric fluid.

[0115] Techniques for drug formulation and administration can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

[0116] Pharmaceutical compositions of some aspects of the present invention can be manufactured by processes well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0117] Thus, pharmaceutical compositions for use in accordance with some aspects of the present invention may be formulated in a conventional manner, employing one or more physiologically acceptable carriers, including additives and adjuvants, which facilitate processing of the active ingredients into pharmaceutically acceptable preparations.

[0118] Pharmaceutical compositions can be easily formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art as suitable for oral administration. Such carriers can optionally facilitate the formulation of the pharmaceutical composition as a tablet, pill, dragee, capsule, liquid, gel, syrup, slurry, suspension, etc. for oral ingestion by a patient. Pharmaceutical preparations for oral use can be prepared using solid additives, and if necessary, the resulting mixture can be milled, and after adding suitable excipients, the mixture of granules can be processed to obtain tablets or dragee cores.

[0119] Suitable additives are, in particular, fillers such as sugars, such as lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or physiologically acceptable polymers, such as polyvinylpyrrolidone (PVP). If necessary, disintegrating agents, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate), and / or lubricants, such as talc or magnesium stearate, may be added.

[0120] In some aspects of any one of the embodiments described herein, the composition (e.g., formulated as a tablet) further comprises a lubricant. In some aspects, the lubricant is present at a concentration of 5 weight percent or less, optionally 2 weight percent or less, optionally about 1 weight percent. In some aspects, the composition (e.g., formulated as a tablet) consists essentially of PTH (as described herein), SNAC, a lubricant, and optionally at least one protease inhibitor (as described herein). In some aspects, the lubricant is magnesium stearate.

[0121] Sugar-coated tablet core can be provided with suitable coating in some cases.For this purpose, concentrated sugar solution can be used, and sugar solution can contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.For identifying or characterizing different combinations of dosage of active compound, dyes or pigments can be added to tablet or sugar-coated tablet coating.

[0122] Orally usable pharmaceutical compositions include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient as a mixture with a filler such as lactose, a binder such as starch, a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active ingredient can be dissolved or suspended in a suitable liquid such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added.

[0123] In some aspects of any of the embodiments described herein, PTH and SNAC (according to any of the respective aspects described herein) are coated with an enteric coating. In some aspects, the enteric coating increases the bioavailability of PTH by reducing inactivation of SNAC and / or PTH induced by exposure to gastric conditions.

[0124] Here, the phrase "enteric coating" refers to a coating that dissolves under intestinal conditions (e.g., in an aqueous environment of at least pH 5.5 and / or in the presence of colonic bacteria) but does not dissolve under gastric conditions (e.g., in an aqueous environment in the pH range of 1 to 3.5). The enteric coating may dissolve, optionally in the duodenum, optionally in the jejunum, optionally in the ileum, and optionally in the colon, to expose the core.

[0125] In some aspects of any of the embodiments described herein relating to an enteric coating, the enteric coating comprises at least one enteric polymer. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 20 weight percent. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 30 weight percent. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 40 weight percent. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 50 weight percent. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 60 weight percent. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 70 weight percent. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 80 weight percent. In some such embodiments, the concentration of the enteric polymer in the enteric coating is at least 90 weight percent. In some such embodiments, the enteric coating consists essentially of the enteric polymer.

[0126] As used herein, the term "enteric polymer" refers to a solid polymer or mixture of polymers that is soluble in aqueous solution within the pH range of 5.5 to 8 (i.e., soluble at least partially within said pH range), but is not soluble in aqueous solution at any pH within the pH range of 1 to 3.5, and preferably is insoluble at any pH within the pH range of 1 to 5.5. When the enteric polymer is a mixture of polymers, the mixture is considered to be soluble herein under any given conditions if at least some of the polymers in the mixture are soluble under those conditions, and dissolution of the soluble polymers results in complete disintegration of the mixture (optionally into particles of 1 mm or less in diameter, optionally 0.1 mm or less in diameter).

[0127] The pH dependence of the solubility of the enteric polymer allows it to remain in the form of a solid coating not only under dry conditions (e.g., before oral administration) but also in the stomach, making it soluble in at least part of the intestine.

[0128] Many enteric polymers are known in the art, and one of ordinary skill in the art can readily select and prepare a suitable enteric polymer for dissolution at a given pH and / or in a given region of the intestine.

[0129] Examples of enteric polymers include, but are not limited to, copolymers of one or more hydrophobic monomers and one or more anionic monomers (e.g., monomers containing carboxylic acid and / or carboxylate groups), optionally in a ratio of hydrophobic to anionic monomers of about 1: 1. Such copolymers are anionic at about pH 7, and consequently water-soluble, but relatively nonionic and hydrophobic, and consequently water-insoluble, at a pH sufficient to cause protonation of nearly all of the anionic groups.

[0130] Examples of such polymers used in the art (e.g., those commercially available as Eudragit® products) include, but are not limited to, copolymers in which the anionic monomer is an acrylic acid and / or methacrylic acid monomer and the hydrophobic monomer is an ester (e.g., alkyl ester) of an acrylic acid and / or methacrylic acid monomer, such as ethyl acrylate, methyl acrylate, ethyl methacrylate, and / or methyl methacrylate monomer. For example, poly(methacrylic acid-ethyl acrylate copolymer) (with a methacrylic acid to ethyl acrylate ratio of about 1:1) is commercially available, e.g., as Eudragit® L100-55.

[0131] Further examples of enteric polymers include, but are not limited to, polyvinyl acetate phthalate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate trimellitate.

[0132] In some aspects of any one of the embodiments described herein relating to an enteric polymer, the enteric polymer is soluble in aqueous solution at pH 5.5. In some such embodiments, dissolution of the enteric polymer begins shortly after the drug delivery system reaches the intestine, e.g., the duodenum.

[0133] In some aspects of any one of the embodiments described herein relating to an enteric coating, the enteric coating is soluble in an aqueous solution at pH 5.5. In some such embodiments, dissolution of the enteric coating begins shortly after the drug delivery system reaches the intestine, e.g., the duodenum.

[0134] In some aspects of any one of the embodiments described herein relating to an enteric polymer, the enteric polymer is not soluble in aqueous solution at pH 5.5 but is soluble in aqueous solution at pH 6.0. In some such embodiments, dissolution of the enteric polymer begins relatively soon after the drug delivery system reaches the intestine, e.g., the duodenum.

[0135] In some aspects of any one of the embodiments described herein relating to an enteric coating, the enteric coating is not soluble in aqueous solution at pH 5.5, but is soluble in aqueous solution at pH 6.0. In some such embodiments, dissolution of the enteric coating begins relatively soon after the drug delivery system reaches the intestine, e.g., the duodenum.

[0136] In some aspects of any one of the embodiments described herein relating to an enteric polymer, the enteric polymer is soluble in aqueous solution at pH 6.5, but not at pH 5.5 or 6.0. In some such embodiments, dissolution of the enteric polymer begins in the small intestine (e.g., the jejunum), but optionally not in the duodenum.

[0137] In some aspects of any one of the embodiments described herein relating to an enteric coating, the enteric coating is not soluble in aqueous solution at pH 5.5 or 6.0, but is soluble in aqueous solution at pH 6.5. In some such embodiments, dissolution of the enteric coating begins in the small intestine (e.g., the jejunum), but optionally not in the duodenum.

[0138] In some aspects of any one of the embodiments described herein relating to an enteric polymer, the enteric polymer is not soluble in aqueous solution at pH 5.5, 6.0, or 6.5, but is soluble in aqueous solution at pH 7.0 and / or pH 7.5. In some such embodiments, dissolution of the enteric polymer begins in the ileum or colon, but optionally not in the duodenum or jejunum.

[0139] In some aspects of any one of the embodiments described herein relating to an enteric coating, the enteric coating is not soluble in aqueous solution at pH 5.5, 6.0, or 6.5, but is soluble in aqueous solution at pH 7.0 and / or pH 7.5. In some such embodiments, dissolution of the enteric coating begins in the ileum or colon, but optionally not in the duodenum or jejunum.

[0140] It should be understood that in some embodiments, dissolution of the enteric polymer and / or enteric coating, when initiated (e.g., as described herein) at any given pH and / or location in the gastrointestinal tract, need not be a very rapid process, and thus a significant amount of time may pass before the composition covered by the coating is exposed and / or the coating disintegrates and / or completely dissolves. The time until the core is exposed and / or the coating disintegrates and / or completely dissolves can optionally be controlled, for example, according to the thickness of the enteric coating, with thicker enteric coatings being associated with longer dissolution times.

[0141] Pharmaceutical compositions suitable for use in the context of some embodiments of the present invention include compositions containing PTH in an amount effective to achieve the intended purpose. More specifically, the compositions preferably contain a therapeutically effective amount of PTH, i.e., an amount of PTH effective to prevent, reduce, or ameliorate the symptoms of osteoporosis. Furthermore, the amount of SNAC is preferably an amount effective to promote absorption of PTH (e.g., in the manner described herein), and the amount of protease inhibitor is preferably an amount effective to inhibit degradation of PTH by proteases.

[0142] Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0143] For any preparation used in the method of the present invention, therapeutically effective amount or dosage can be estimated initially from in vitro and cell culture assays.For example, the dosage can be formulated for animal models to achieve desired concentration or titer.Using this information, the dosage that is useful in humans can be accurately determined.

[0144] The toxicity and therapeutic efficacy of PTH described herein can be determined by standard pharmaceutical procedures in vitro, in cell culture, or in experimental animals. The data obtained from these in vitro and cell culture assays and animal tests can be used to formulate a dosage range for use in humans. Dosage may vary depending on the dosage form used and the route of administration used. The exact formulation and dosage can be selected by an individual physician taking into account the patient's condition (see, for example, Fingl, et al., 1975, "The Pharmacological Basis of Therapeutics", Ch.1 p.1).

[0145] Dosage and interval can be individually adjusted to provide a level (e.g., plasma level) of PTH sufficient to induce or inhibit a biological effect (minimum effective concentration, MEC). The MEC varies for each formulation but can be estimated from in vitro data. The dose required to achieve the MEC depends on individual characteristics. Detection assays for PTH are known in the art and can be used to determine plasma concentrations of PTH.

[0146] Depending on the severity and responsiveness of the condition to be treated, dosage may be of single or multiple administrations, with the course of treatment lasting from a few hours to several weeks, or until a cure is effected or a diminution of the disease state is achieved.

[0147] The amount of composition administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.

[0148] The compositions of some embodiments of the present invention can be provided as a pack or dispenser device, e.g., an FDA-approved kit, which may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may comprise, for example, metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser device may also contain a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the agency's approval of the composition's form or administration to humans or animals. Such notice may be, for example, a label or approved package insert approved by the U.S. Food and Drug Administration for prescription drugs. Compositions containing the formulations of the present invention can also be prepared (e.g., as described herein), placed in an appropriate container, and labeled for the treatment of osteoporosis, as further described herein.

[0149] In some aspects of any one of the embodiments described herein, treatment according to any of the aspects described herein is carried out by orally administering the composition to a relatively empty stomach and small intestine.

[0150] In some aspects of any one of the embodiments described herein, oral administration of the composition occurs at least 2 hours after the most recent food intake. In some aspects, oral administration of the composition occurs at least 4 hours after the most recent food intake. In some aspects, oral administration of the composition occurs at least 6 hours after the most recent food intake. In some aspects, oral administration of the composition occurs at least 8 hours after the most recent food intake. In some aspects, oral administration of the composition occurs at least 10 hours after the most recent food intake.

[0151] In some aspects of any one of the embodiments described herein, oral administration of the composition occurs at least 2 hours after consuming the most recent food or drink. In some aspects, oral administration of the composition occurs at least 4 hours after consuming the most recent food or drink. In some aspects, oral administration of the composition occurs at least 6 hours after consuming the most recent food or drink. In some aspects, oral administration of the composition occurs at least 8 hours after consuming the most recent food or drink. In some aspects, oral administration of the composition occurs at least 10 hours after consuming the most recent food or drink.

[0152] In some aspects of any one of the embodiments described herein, oral administration of composition is carried out before eating in the morning.In some aspects, oral administration of composition is carried out before eating in the morning.Such administration of unit dosage form and / or drug delivery device in the morning (for example, after sleeping) may be the most convenient method for the subject, in order to ensure that a considerable time has passed between oral administration and the most recent intake of food (and possibly drink).

[0153] In some aspects of any one of the embodiments described herein, oral administration of the composition occurs at least 10 minutes before a meal (e.g., the subject should refrain from eating for at least 10 minutes after administration). In some aspects, oral administration of the composition occurs at least 20 minutes before a meal. In some aspects, oral administration of the composition occurs at least 30 minutes before a meal. In some aspects, oral administration of the composition occurs at least 60 minutes (1 hour) before a meal. In some aspects, oral administration of the composition occurs at least 2 hours before a meal. In some aspects, oral administration of the composition occurs at least 3 hours before a meal. In some aspects, oral administration of the composition occurs at least 4 hours before a meal.

[0154] In some aspects of any one of the embodiments described herein, oral administration of the composition occurs at least 10 minutes before eating or drinking (e.g., the subject should refrain from eating or drinking for at least 10 minutes after administration). In some aspects, oral administration of the composition occurs at least 20 minutes before eating or drinking. In some aspects, oral administration of the composition occurs at least 30 minutes before eating or drinking. In some aspects, oral administration of the composition occurs at least 60 minutes (1 hour) before eating or drinking. In some aspects, oral administration of the composition occurs at least 2 hours before eating or drinking. In some aspects, oral administration of the composition occurs at least 3 hours before eating or drinking. In some aspects, oral administration of the composition occurs at least 4 hours before eating or drinking.

[0155] Without being bound by any particular theory, it is believed that food (and possibly beverages) in the stomach and small intestine may interact with SNAC and / or PTH in a manner detrimental to efficient and predictable PTH absorption. Furthermore, oral administration of the compositions described herein to an empty stomach (e.g., in the morning) allows for release of PTH and SNAC at various locations in the intestine, whereas food ingested after oral administration (e.g., during the day after administration of the morning composition) generally remains "behind" the PTH and SNAC in the gastrointestinal tract, thereby reducing the interaction of the ingested food with SNAC and / or PTH.

[0156] As the composition passes through the gastrointestinal tract after oral administration, the therapeutically active agent and SNAC can optionally be released in a controlled manner (e.g., in any of the corresponding embodiments described herein), thereby providing control over the pharmacokinetic profile of PTH.

[0157] In some aspects of any one of the embodiments described herein, the composition is formulated such that the release rate (as a function of time) of PTH and SNAC is characterized by at least two peaks (multimodal release rate), e.g., as described herein in any of the respective embodiments. In some such embodiments, the multimodal release rate is achieved by oral administration of a unit dosage form comprising multiple populations of particles having enteric coatings (e.g., each population having a different enteric coating), as described herein according to any of the respective embodiments.

[0158] In some embodiments, the multi-modal release rate is associated with intermittent controlled periods during which blood PTH levels are in an optimal range (e.g., high enough to have a beneficial effect, but not to toxic levels), e.g., each peak in the release rate is associated with an intermittent period of levels in the optimal range. Such a pharmacokinetic profile may optionally mimic, for example, the profile of oral administration of multiple doses at different times.

[0159] Without being bound by any particular theory, it is believed that the use of a single oral dose to achieve absorption over multiple controlled periods is advantageous for the use of PTH with SNAC in the treatment of osteoporosis compared to the use of multiple oral doses of PTH with SNAC, because it is impractical to administer all of the doses on a relatively empty stomach (e.g., as described herein).

[0160] Protease inhibitors: In some aspects of any of the embodiments described herein, the composition further comprises at least one protease inhibitor.

[0161] As used herein, the term "protease inhibitor" refers to a compound that reduces the proteolytic activity of a protease, e.g., the proteolytic activity of a protease that inactivates PTH as described herein. The term "protease inhibitor" encompasses, for example, both large molecules (e.g., proteins) and small molecules, as well as both natural and synthetic compounds.

[0162] In some aspects of any of the embodiments described herein, the at least one protease inhibitor comprises at least one trypsin inhibitor, hi some aspects, the at least one protease inhibitor consists essentially of one or more trypsin inhibitors.

[0163] Examples of trypsin inhibitors that can be used in any one of the embodiments described herein include, but are not limited to, lima bean trypsin inhibitor, aprotinin, soybean trypsin inhibitor, ovomucoid trypsin inhibitor, and any combination thereof. In some embodiments, at least one trypsin inhibitor includes soybean trypsin inhibitor (SBTI). In some embodiments, at least one trypsin inhibitor (and optionally at least one protease inhibitor) consists essentially of SBTI.

[0164] In some aspects of any of the embodiments described herein, the at least one protease inhibitor comprises at least one serpin. In some aspects, the at least one protease inhibitor consists essentially of one or more serpins.

[0165] Examples of serpins that can be used in any one of the embodiments described herein include, but are not limited to, alpha 1-antitrypsin, antitrypsin-related protein, alpha 1-antichymotrypsin, kallistatin, protein C inhibitor, cortisol-binding globulin, thyroxine-binding globulin, angiotensinogen, centerin, protein Z-related protease inhibitor, vaspin, monocyte / neutrophil elastase inhibitor, plasminogen activator inhibitor-2, squamous cell carcinoma anti- These include serpin-1 (SCCA-1), squamous cell carcinoma antigen-2 (SCCA-2), maspin, proteinase inhibitor 6 (PI-6), megsin, serpin B8 (PI-8), serpin B9 (PI-9), bomapin, yucopin, fulpin / headpin, antithrombin, heparin cofactor II, plasminogen activator inhibitor 1, glial-derived nexin, pigment epithelium-derived factor, alpha 2-antiplasmin, complement 1 inhibitor, 47 kDa heat shock protein (HSP47), neuroserpin, and punctupin.

[0166] In some aspects of any of the embodiments described herein, the at least one protease inhibitor comprises at least one cysteine ​​protease inhibitor, hi some aspects, the at least one protease inhibitor consists essentially of one or more cysteine ​​protease inhibitors.

[0167] Examples of cysteine ​​protease inhibitors that can be used in any one of the embodiments described herein include, but are not limited to, type 1 cystatin, type 2 cystatin, human cystatins C, D, S, SN and SA, cystatin E / M, cystatin F, and type 3 cystatin (including kininogens).

[0168] In some aspects of any of the embodiments described herein, the at least one protease inhibitor comprises at least one threonine protease inhibitor, hi some aspects, the at least one protease inhibitor consists essentially of one or more threonine protease inhibitors.

[0169] Examples of threonine protease inhibitors that can be used in any one of the embodiments described herein include, but are not limited to, bortezomib, MLN-519, ER-807446, and TMC-95A.

[0170] In some aspects of any of the embodiments described herein, the at least one protease inhibitor comprises at least one aspartic protease inhibitor, hi some aspects, the at least one protease inhibitor consists essentially of one or more aspartic protease inhibitors.

[0171] Examples of aspartic protease inhibitors that can be used in any one of the embodiments described herein include, but are not limited to, alpha 2-macroglobulin, pepstatin A, aspartic protease inhibitor 11, aspartic protease inhibitor 1, aspartic protease inhibitor 2, aspartic protease inhibitor 3, aspartic protease inhibitor 4, aspartic protease inhibitor 5, aspartic protease inhibitor 6, aspartic protease inhibitor 7, aspartic protease inhibitor 8, aspartic protease inhibitor 9, pepsin inhibitor Dit33, and protease A inhibitor 3.

[0172] In some aspects of any of the embodiments described herein, the at least one protease inhibitor comprises at least one metalloprotease inhibitor, hi some aspects, the at least one protease inhibitor consists essentially of one or more metalloprotease inhibitors.

[0173] Examples of metalloproteinase inhibitors that can be used in any one of the embodiments described herein include, but are not limited to, angiotensin-1 converting enzyme inhibitor peptide, antihemorrhagic factor BJ46a, beta-casein, proteinase inhibitor CeKI, venom metalloproteinase inhibitor DM43, carboxypeptidase A inhibitor, smpI, IMPI, alkaline proteinase, latexin, carboxypeptidase inhibitor, antihemorrhagic factor HSF, testican-3, SPOCK3, TIMP1, metalloproteinase inhibitor 1, metalloproteinase inhibitor 2, TIMP2, metalloproteinase inhibitor 3, TIMP3, metalloproteinase inhibitor 4, TIMP4, putative metalloproteinase inhibitor tag-225, tissue inhibitor of metalloproteinase, WAP, Kazal inhibitor, immunoglobulin, and Kunitz and NTR domain-containing protein 1.

[0174] Examples of protease inhibitors that can be used in any one of the embodiments described herein include, but are not limited to, AEBSF-HCl, ε-aminocaproic acid, α1-antichymotrypsin, antipain, antithrombin III, α1-antitrypsin, APMSF (4-amidinophenyl-methanesulfonyl-fluoride), sprotinin, benzamidine, chymostatin, DFP (diisopropylfluorophosphate), leupeptin, 4-(2-aminoethyl)-benzenesulfonyl fluoride hydrochloride, PMSF (phenylmethylsulfonyl fluoride), TLCK (1-chloro-3-tosylamido-7-amino-2-heptanone), TPCK (1-chloro-3-tosylamido-4-phenyl-2-butanone), pentamidine isothionate, pepstatin, guanidinium, α2-macroglobulin, zinc chelators, and iodoacetic acid.

[0175] In some aspects of any one of the embodiments described herein, the amount of the protease inhibitor in the compositions for administration described herein is at least about 0.1 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 0.2 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 0.3 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 0.4 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 0.6 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 0.8 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 1 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 1.5 mg. In some aspects, the amount of the protease inhibitor in the compositions for administration described herein is at least about 2 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 2.5 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 3 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 5 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 7 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 10 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 12 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 15 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 20 mg.In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 30 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 50 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 70 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 100 mg.

[0176] In some aspects of any one of the embodiments described herein, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.1 to 1 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.2 to 1 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.3 to 1 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.5 to 1 mg.

[0177] In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.1-2 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.2-2 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.3-2 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is in the range of 0.5-2 mg. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is in the range of 1-2 mg.

[0178] In some aspects of any one of the embodiments described herein, the amount of protease inhibitor in the compositions for administration described herein is in the range of 1-10 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 2-10 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 3-10 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 5-10 mg.

[0179] In some aspects of any one of the embodiments described herein, the amount of protease inhibitor in the compositions for administration described herein is in the range of 1-20 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 2-20 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 3-20 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 5-20 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 10-20 mg.

[0180] In some aspects of any one of the embodiments described herein, the amount of protease inhibitor in the compositions for administration described herein is in the range of 10-100 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 20-100 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 30-100 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 50-100 mg.

[0181] In some aspects of any one of the embodiments described herein, the amount of protease inhibitor in the compositions for administration described herein is in the range of 10-200 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 20-200 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 30-200 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 50-200 mg. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is in the range of 100-200 mg.

[0182] In some aspects of any one of the embodiments described herein, the amount of protease inhibitor in the compositions for administration described herein is at least about 10 kallikrein inactivator units (kiu). In some aspects, the amount of protease inhibitor in the compositions for administration described herein is at least about 12 k.iu. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is at least about 15 k.iu. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is at least about 20 k.iu. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is at least about 30 k.iu. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is at least about 40 k.iu. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is at least about 50 k.iu. In some aspects, the amount of protease inhibitor in the compositions for administration described herein is at least about 70 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 100 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 150 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 200 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 300 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 500 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 700 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 1000 k.iu.In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 1500 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 3000 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 4000 k.iu. In some embodiments, the amount of protease inhibitor in the compositions for administration described herein is at least about 5000 k.iu.

[0183] As used herein and in the art, the term "kallikrein inactivator unit" (kiu) refers to the amount of a protease inhibitor that exhibits 50% inhibition of 2 units of kallikrein (e.g., in an aqueous solution at the optimal pH and volume for activity of the protease inhibitor).

[0184] In some aspects of any one of the embodiments described herein, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 1:1 to 5:1 (protease inhibitor:PTH). In some aspects, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 5:1 to 10:1 (protease inhibitor:PTH). In some aspects, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 10:1 to 20:1 (protease inhibitor:PTH). In some aspects, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 20:1 to 30:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 30:1 to 40:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 40:1 to 50:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 50:1 to 75:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 75:1 to 100:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 100:1 to 200:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 200:1 to 300:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 300:1 to 400:1 (protease inhibitor:PTH). In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) is within the range of 400:1 to 500:1 (protease inhibitor:PTH).In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0185] SNAC: In some aspects of any one of the embodiments described herein, SNAC may optionally be replaced with an analogous compound, such as SNAD (sodium 10-N-(2-hydroxybenzoyl)aminodecanoate). As shown below, the structure of SNAD differs from that of SNAC only in the length of the fatty acid moiety.

[0186] [ka]

[0187] In some aspects of any one of the embodiments described herein, SNAC may optionally be replaced with an analog in which the caprylic acid portion of SNAC is replaced with another fatty acid portion that is at least 6 carbon atoms in length, e.g., 6 to 20 carbon atoms in length, optionally 6 to 18 carbon atoms in length, optionally 6 to 16 carbon atoms in length, optionally 6 to 14 carbon atoms in length, optionally 6 to 12 carbon atoms in length, and optionally 6 to 10 carbon atoms in length. The fatty acid portion may be saturated (e.g., caprylic acid in SNAC, decanoic acid in SNAD) or unsaturated (i.e., containing at least one unsaturated carbon-carbon bond).

[0188] In some aspects of any one of the embodiments described herein, the concentration of SNAC in the compositions described herein is in the range of 2.5 to 99.4 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 2.5 to 10 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 8 to 15 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 10 to 20 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 15 to 30 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 20 to 40 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 30 to 50 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 40 to 60 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 50 to 70 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 2.5 to 10 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 2.5 to 10 weight percent. In some of the above embodiments, the concentration of SNAC is in the range of 70 to 99.4 weight percent.

[0189] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1 (SNAC:PTH). In some aspects, the ratio is about 7.5:1. In some aspects, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0190] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1 (SNAC:PTH). In some aspects, the ratio is about 15:1. In some of the above embodiments, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0191] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 20:1 to 30:1 (SNAC:PTH). In some aspects, the ratio is about 25:1. In some of the above embodiments, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0192] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 30:1 to 50:1 (SNAC:PTH). In some aspects, the ratio is about 40:1. In some of the above embodiments, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0193] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 50:1 to 100:1 (SNAC:PTH). In some aspects, the ratio is about 75:1. In some aspects, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0194] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 100:1 to 200:1 (SNAC:PTH). In some aspects, the ratio is about 150:1. In some aspects, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0195] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 200:1 to 300:1 (SNAC:PTH). In some aspects, the ratio is about 250:1. In some aspects, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0196] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 300:1 to 500:1 (SNAC:PTH). In some aspects, the ratio is about 400:1. In some aspects, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 10:1 to 20:1, optionally about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0197] In some aspects of any one of the embodiments described herein, the weight ratio of SNAC to PTH (e.g., PTH(1-34)) is in the range of 500:1 to 1000:1 (SNAC:PTH). In some aspects, the ratio is about 750:1. In some aspects, the composition further comprises a protease inhibitor. In some of the above embodiments in which the composition comprises a protease inhibitor, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 1:1 to 5:1 (protease inhibitor:PTH), optionally about 3:1. In some aspects, the weight ratio of the protease inhibitor to PTH (e.g., PTH(1-34)) is in the range of 5:1 to 10:1, optionally about 7.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 10:1 to 20:1, and optionally is about 15:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 20:1 to 30:1, and optionally is about 25:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 30:1 to 40:1, and optionally is about 35:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 40:1 to 50:1, and optionally is about 45:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 50:1 to 75:1, and optionally is about 62.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 75:1 to 100:1, and optionally is about 87.5:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 100:1 to 200:1, and optionally is about 150:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 200:1 to 300:1, and optionally is about 250:1.In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 300:1 to 400:1, and optionally is about 350:1. In some embodiments, the weight ratio of protease inhibitor to PTH (e.g., PTH(1-34)) ranges from 400:1 to 500:1, and optionally is about 450:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0198] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is at least about 0.1 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 0.2 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 0.3 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 0.4 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 0.6 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 0.8 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 1 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 1.5 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 2 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 2.5 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is at least about 3 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 5 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 7 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 10 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 12 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 15 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 20 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 30 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 50 mg.In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 70 mg. In some embodiments, the amount of SNAC in the compositions for administration described herein is at least about 100 mg. In some embodiments, the amount of PTH (e.g., PTH(1-34)) is in accordance with any one of the ratios of SNAC to PTH (e.g., PTH(1-34)) described herein. In some embodiments, the composition further comprises at least one protease inhibitor in an amount in accordance with any one of the ratios of protease inhibitor to PTH (e.g., PTH(1-34)) described herein.

[0199] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 0.1 to 1 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 0.2 to 1 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 0.3 to 1 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 0.5 to 1 mg.

[0200] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 0.1 to 2 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 0.2 to 2 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 0.3 to 2 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 0.5 to 2 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 1 to 2 mg.

[0201] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 1 to 10 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 2 to 10 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 3 to 10 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 5 to 10 mg.

[0202] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 1-20 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 2-20 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 3-20 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 5-20 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 10-20 mg.

[0203] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 10-100 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 20-100 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 30-100 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 50-100 mg.

[0204] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 10-200 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 20-200 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 30-200 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 50-200 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 100-200 mg.

[0205] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 10-500 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 20-500 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 30-500 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 50-500 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 100-500 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 200-500 mg.

[0206] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 10-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 20-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 30-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 50-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 100-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 200-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 500-1000 mg.

[0207] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 10-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 20-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 30-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 50-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 100-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 200-1000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 500-1000 mg.

[0208] In some aspects of any one of the embodiments described herein, the amount of SNAC in the compositions for administration described herein is in the range of 10-2000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 20-2000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 30-2000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 50-2000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 100-2000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 200-2000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 500-2000 mg. In some aspects, the amount of SNAC in the compositions for administration described herein is in the range of 1000-2000 mg.

[0209] In some aspects of any one of the embodiments described herein, at least 50 weight percent of the composition consists of SNAC. In some aspects, at least 60 weight percent of the composition consists of SNAC. In some aspects, at least 70 weight percent of the composition consists of SNAC. In some aspects, at least 80 weight percent of the composition consists of SNAC. In some aspects, at least 90 weight percent of the composition consists of SNAC.

[0210] Without being bound by any particular theory, it is believed that compositions with a high proportion of SNAC as a salt tend to dissolve more readily in aqueous solutions such as gastric fluid, which is desirable in some embodiments of the present invention.

[0211] Described next are exemplary compositions and / or methods or treatments using the same that can provide the desirable pharmacokinetic properties described herein in any one of the corresponding embodiments and in any combination thereof.

[0212] Protectant: In some forms according to any of the aspects of the embodiments described herein, the method or treatment further comprises oral administration of a protectant agent.

[0213] In some embodiments according to any of the aspects of the embodiments described herein, the composition for oral administration of PTH further comprises a protectant. In some aspects, the composition is formulated as one or more unit dosage forms (e.g., according to any of the corresponding embodiments described herein). The unit dosage form can be formulated in any form suitable for oral administration, including solid and / or liquid. In some aspects, the unit dosage form is a solid unit dosage form. In some aspects, the composition is formulated as a tablet.

[0214] Here, the term "protective agent" refers to an agent that can protect PTH and / or SNAC against enzymes and / or acids in the gastrointestinal tract. For example, a protease inhibitor can protect PTH from the activity of proteases, and an antacid can protect SNAC and / or PTH from gastric acid (e.g., acid-induced denaturation) (e.g., by reducing the conversion of SNAC from its carboxylate salt to its carboxylic acid form).

[0215] In some aspects of any of the embodiments described herein, the composition includes at least one antacid compound (e.g., according to any of the corresponding embodiments described herein). In some such embodiments, the composition further includes at least one protease inhibitor (e.g., according to any of the corresponding embodiments described herein).

[0216] Without being bound by any particular theory, it is believed that compositions containing PTH and SNAC are significantly affected by the inactivation of SNAC when contacted with gastric acid, which converts SNAC from a soluble carboxylate salt to an insoluble carboxylic acid.The inactivation of SNAC may reduce the absorption of PTH, thereby reducing the efficacy of the composition.In addition, protease inhibitors used to protect PTH from proteolysis may also be at least partially inactivated when contacted with gastric acid, further reducing the efficacy of the composition.In addition, since much of the PTH is inactivated by proteases before the proteases are inhibited by the protease inhibitors, the ability of protease inhibitors to protect PTH from protease activity in the digestive system is thought to be limited.

[0217] In some aspects of any of the embodiments described herein, the composition is in the form of a homogenous mixture such that the protectant (optionally, an antacid compound) is uniformly dispersed between the SNAC and the therapeutically active agent (and optionally, any additional ingredients present).

[0218] The inventors have further designed the unit dosage form so that the release of the protectant precedes the release of the compound it is intended to protect, e.g., releasing an antacid to reduce acidity in the vicinity of the orally administered composition before SNAC and / or PTH are exposed to gastric acid, and / or releasing a protease inhibitor to inhibit proteases before PTH is exposed to the proteases.

[0219] In some aspects of any of the embodiments described herein, the composition is formulated as a unit dosage form comprising a core and an outer layer, wherein the core comprises PTH and SNAC, and the outer layer comprises at least one protectant.

[0220] In some of the embodiments of any of the embodiments described herein, the protectant is a protease inhibitor according to any of the corresponding embodiments described herein.

[0221] In some of the embodiments of any of the embodiments described herein, the protectant is an antacid compound according to any of the corresponding embodiments described herein.

[0222] In some of any of the embodiments described herein, the unit dosage form includes at least one protectant that is an antacid compound (according to any of the corresponding embodiments described herein) and at least one protectant that is a protease inhibitor (according to any of the corresponding embodiments described herein).

[0223] As used herein, the term "antacid compound" refers to any pharmaceutically acceptable compound capable of neutralizing gastric acid (e.g., HCl in an aqueous solution), with one mole of antacid compound preferably being capable of neutralizing at least 0.5 moles of HCl, and more preferably at least 1 mole of HCl. PTH, SNAC, and protease inhibitors described herein are excluded from the scope of the term "antacid compound," even though they may exhibit some ability to neutralize gastric acid in some embodiments of the invention.

[0224] Examples of antacid compounds (according to any of the corresponding embodiments described herein) that may be used in any one of the embodiments described herein relating to one or more antacid compounds include, but are not limited to, calcium carbonate, calcium gluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum carbonate, aluminum gluconate, aluminum citrate, and aluminum hydroxide.

[0225] The unit dosage form may be any shape suitable for an orally administered pharmaceutical dosage form, including, but not limited to, any three-dimensional shape having a substantially rectangular (including substantially square), substantially circular, and / or substantially oval cross-section along at least one axis. For example, the unit dosage form may be substantially box-like in shape having a substantially rectangular cross-section (optionally with rounded corners) along three axes, a substantially cylindrical shape having a substantially circular and / or substantially oval cross-section along one axis and a substantially rectangular cross-section (optionally with rounded corners) along two axes, or a substantially spherical or oval shape having a substantially circular and / or oval cross-section along three axes.

[0226] In any one of several embodiments described herein, the outer layer comprises one or more protease inhibitors and one or more antacid compounds. In some such embodiments, the outer layer consists essentially of one or more protease inhibitors and one or more antacid compounds. Alternatively, in some such embodiments, the outer layer comprises one or more additives in combination with the protease inhibitors and antacid compounds.

[0227] In any one of several embodiments described herein, the outer layer comprises one or more protease inhibitors and does not comprise an antacid compound. In some such embodiments, the outer layer consists essentially of one or more protease inhibitors. Alternatively, in some such embodiments, the outer layer comprises a combination of one or more additives and a protease inhibitor.

[0228] In any one of several embodiments described herein, the outer layer comprises one or more antacid compounds and does not comprise a protease inhibitor. In some such embodiments, the outer layer consists essentially of one or more antacid compounds. Alternatively, in some such embodiments, the outer layer comprises a combination of one or more additives and an antacid compound.

[0229] Throughout this specification, the phrase "free" encompasses the presence of trace amounts (e.g., less than 0.1 weight percent, optionally less than 0.05 weight percent, optionally less than 0.02 weight percent, and optionally less than 0.01 weight percent) of the indicated substance as well as the complete absence of the indicated substance.

[0230] In any one of several embodiments described herein, the concentration of PTH (by weight percentage) in the outer layer is lower than the concentration of PTH in the core. In any one of several embodiments described herein, the concentration of PTH (by weight percentage) in the outer layer is less than 50% of the concentration of PTH in the core. In some embodiments, the concentration in the outer layer is less than 20% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 10% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 5% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 2% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 1% of the concentration in the core. In some embodiments, the outer layer does not contain PTH.

[0231] In any one of several embodiments described herein, the concentration of SNAC (by weight percentage) in the outer layer is lower than the concentration of SNAC in the core. In any one of several embodiments described herein, the concentration of SNAC (by weight percentage) in the outer layer is less than 50% of the concentration of SNAC in the core. In some embodiments, the concentration in the outer layer is less than 20% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 10% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 5% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 2% of the concentration in the core. In some embodiments, the concentration in the outer layer is less than 1% of the concentration in the core. In some embodiments, the outer layer does not comprise SNAC. In some embodiments, the outer layer does not comprise PTH and does not comprise SNAC.

[0232] In any one of several embodiments described herein, the outer layer covers the entire surface of the core.

[0233] In any one of several embodiments described herein, the outer layer does not cover the entire surface of the core. In some embodiments in which the outer layer does not cover the entire surface of the core, the outer layer is divided into multiple unconnected layers (e.g., two, three, four, or more than four layers), each unconnected layer covering a different area of ​​the surface of the core. In such embodiments, the phrase "outer layer" refers collectively to all such unconnected layers. In some embodiments, the outer layer is divided into two unconnected layers covering opposite sides of the core. In alternative embodiments in which the outer layer does not cover the entire surface of the core, the outer layer is in the form of a single continuous layer.

[0234] In some embodiments of any one of the compositions described herein, the outer layer covers at least 30% of the surface area of ​​the core. In some embodiments, the outer layer covers at least 40% of the surface area of ​​the core. In some embodiments, the outer layer covers at least 50% of the surface area of ​​the core. In some embodiments, the outer layer covers at least 60% of the surface area of ​​the core. In some embodiments, the outer layer covers at least 70% of the surface area of ​​the core. In some embodiments, the outer layer covers at least 80% of the surface area of ​​the core. In some embodiments, the outer layer covers at least 90% of the surface area of ​​the core.

[0235] In some aspects of any one of the embodiments described herein, the protease inhibitor and / or antacid compound in the outer layer is uniformly distributed throughout the outer layer.

[0236] In some aspects of any one of the embodiments described herein, the protease inhibitor and / or antacid compound in the outer layer is distributed non-uniformly throughout the outer layer.

[0237] In some such embodiments, the protease inhibitor and / or antacid compound are within particles (e.g., microspheres containing the protease inhibitor and / or antacid compound), and the outer layer further comprises a material (e.g., a filler and / or a binder) between the particles.

[0238] Alternatively or additionally, in some embodiments, the outer layer comprises two or more layers (e.g., concentric layers) with each layer within the outer layer having a different composition. For example, the outer layer may optionally comprise a first layer comprising one of a protease inhibitor and / or an antacid compound, a second layer comprising another of a protease inhibitor and / or an antacid compound, and optionally one or more additional layers each comprising a different inhibitor and / or antacid compound.

[0239] In some aspects of any one of the embodiments described herein, the core further comprises, in addition to PTH and SNAC, one or more protease inhibitors and / or antacid compounds.

[0240] In some aspects of any one of the embodiments described herein, the core consists essentially of PTH and SNAC, or a combination of PTH, SNAC and a protease inhibitor and / or antacid compound.

[0241] In some aspects of any one of the embodiments described herein, the core comprises a combination of one or more additives with PTH and SNAC (and optionally a protease inhibitor and / or an antacid compound).

[0242] In some aspects of any one of the embodiments described herein, the core comprises PTH, SNAC, and one or more antacid compounds. In some aspects, the core consists essentially of a combination of PTH, SNAC, and an antacid compound. Alternatively, in some aspects, the core comprises a combination of one or more additives and PTH, SNAC, and an antacid compound.

[0243] In some aspects of any one of the embodiments described herein, the core comprises PTH, SNAC, and one or more protease inhibitors. In some aspects, the core consists essentially of a combination of PTH, SNAC, and a protease inhibitor. Alternatively, in some aspects, the core comprises a combination of one or more additives and PTH, SNAC, and a protease inhibitor.

[0244] In some aspects of any one of the embodiments described herein, the PTH and / or SNAC in the core is uniformly distributed throughout the core.

[0245] In some aspects of any one of the embodiments described herein, the PTH and / or SNAC in the core is distributed non-uniformly throughout the core.

[0246] In some such embodiments, the PTH and / or SNAC is within a particle (e.g., a microsphere containing PTH and / or SNAC), and the core comprises a material (e.g., a filler and / or binder) between the particles.

[0247] Alternatively or additionally, in some embodiments, the core comprises an inner portion and an outer portion (e.g., concentrically arranged), each portion within the core having a different composition, e.g., the core may optionally comprise an outer portion comprising PTH and an inner portion comprising SNAC, or vice versa.

[0248] In any one of several embodiments described herein, the unit dosage form further comprises a coating covering the outer surface of the outer layer described herein, and optionally (in embodiments in which the outer layer does not cover the entire core) a region of the core surface that is not covered by the outer layer. In some aspects, the coating is formed from a material that dissolves in at least a portion of the gastrointestinal tract.

[0249] In some aspects of any one of the embodiments described herein, the coating is an enteric coating (eg, an enteric coating according to any of the corresponding embodiments described herein).

[0250] In some aspects of any one of the embodiments described herein, the coating dissolves under gastric conditions (e.g., only in an aqueous environment, optionally at a low pH), thereby exposing the outer layer. Such a coating is optionally adapted to alter the appearance of the unit dosage form (e.g., for aesthetic enhancement and / or labeling), for flavoring and / or flavor masking, and / or to protect the outer layer and / or core (e.g., from mechanical damage, air, light, and / or liquids).

[0251] Dissolution of the unit dosage form in the gastrointestinal system primarily involves dissolution of the outer layer initially (optionally after dissolution of a coating, if present), thereby releasing the protease inhibitor and / or antacid compound in the outer layer prior to release of PTH and SNAC from the core.

[0252] In some aspects of any one of the embodiments described herein, the unit dosage form is formulated as a tablet. In some aspects, the unit dosage form is formulated as a multi-layer tablet (e.g., a three-layer tablet), where the outer layer forms the upper and lower layers, and the core is formulated as a middle layer sandwiched between the upper and lower layers. Exemplary tablets are shown in Figures 7 and 8 herein. Any of the multi-layer tablets described herein can optionally be manufactured according to any technique known in the art for manufacturing multi-layer tablets (e.g., a three-layer tablet), including, but not limited to, the technique described in Shende et al. [Int J Drug Delivery 2012, 4:418-426] (the contents of which are incorporated herein by reference).

[0253] In some aspects of any one of the embodiments described herein, the unit dosage form consists essentially of PTH, SNAC, and at least one protective agent (protease inhibitor and / or antacid compound) in combination as described herein, i.e., at least 50 weight percent of the unit dosage form consists of ingredients selected from the group consisting of PTH, SNAC, and at least one protective agent. In some aspects, at least 60 weight percent of the unit dosage form consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 70 weight percent of the unit dosage form consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 80 weight percent of the unit dosage form consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 90 weight percent of the unit dosage form consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 95 weight percent of the unit dosage form consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 98 weight percent of the unit dosage form consists of PTH, SNAC, and at least one protective agent. In some embodiments, the unit dosage form is formulated as a tablet.

[0254] In some aspects of any one of the embodiments described herein, the outer layer and core described herein consist primarily of a combination of PTH, SNAC, and at least one protective agent (protease inhibitor and / or antacid compound) described herein, i.e., at least 50 weight percent of the total weight of the outer layer and core consists of components selected from the group consisting of PTH, SNAC, and at least one protective agent. In some aspects, at least 60 weight percent of the total weight of the outer layer and core consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 70 weight percent of the total weight of the outer layer and core consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 80 weight percent of the total weight of the outer layer and core consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 90 weight percent of the total weight of the outer layer and core consists of PTH, SNAC, and at least one protective agent. In some aspects, at least 95 weight percent of the total weight of the outer layer and core consists of PTH, SNAC, and at least one protective agent. In some embodiments, at least 98 weight percent of the total weight of the outer layer and the core consists of PTH, SNAC, and at least one protective agent. In some embodiments, the outer layer and the core are formulated as part of a tablet. In some embodiments, the tablet is a multi-layer tablet (e.g., a three-layer tablet).

[0255] Referring now to the drawings, Figures 5A-5C show the cross-sectional structure of an exemplary unit dosage form 100 according to some related embodiments of the present invention. The unit dosage form 100 includes a core 110 and an outer layer 120. The embodiments shown in Figures 5A-5C differ in that Figure 5A is an exemplary embodiment in which the outer layer 120 covers the entire core 110, Figure 5B is an exemplary embodiment in which the outer layer 120 is divided into disconnected layers that cover different regions of the core 110 (such that the outer layer 120 does not cover the entire core 110), and Figure 5C is an exemplary embodiment in which the outer layer 120 is a single continuous layer that does not cover the entire core 110. The unit dosage form 100 is optionally substantially rectangular in cross-section along at least one axis (as shown in Figures 5A-5C). However, it should be understood that the cross-section may have different shapes (e.g., substantially circular and / or substantially oval), and the shapes depicted in Figures 5(A)-(C) are not intended to be limiting.

[0256] Outer layer 120 comprises, and optionally consists essentially of, one or more protease inhibitors and / or antacid compounds according to any one of the embodiments described herein for the composition of an outer layer. Alternatively, outer layer 120 comprises a combination of one or more additives and a protease inhibitor and / or antacid compound (e.g., according to one of the corresponding embodiments described herein).

[0257] In some embodiments, outer layer 120 comprises one or more protease inhibitors (e.g., according to one of the corresponding embodiments described herein), optionally does not comprise an antacid compound, and optionally consists essentially of one or more protease inhibitors (e.g., according to one of the corresponding embodiments described herein). Alternatively, outer layer 120 comprises a combination of one or more additives and a protease inhibitor (e.g., according to one of the corresponding embodiments described herein).

[0258] In some embodiments, outer layer 120 includes one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein), optionally does not include a protease inhibitor, and optionally consists essentially of one or more antacid compounds. Alternatively, outer layer 120 includes a combination of one or more additives and an antacid compound (e.g., according to one of the corresponding embodiments described herein).

[0259] In some embodiments, the concentration of PTH (as a weight percentage) in outer layer 120 is lower than the concentration of PTH in core 110 (e.g., according to one of the corresponding embodiments described herein). In some embodiments, outer layer 120 does not include PTH.

[0260] In some embodiments, the concentration of SNAC (as a weight percentage) in outer layer 120 is lower than the concentration of SNAC in core 110 (e.g., according to one of the corresponding embodiments described herein). In some embodiments, outer layer 120 does not include SNAC. In some embodiments, outer layer 120 does not include PTH and does not include SNAC.

[0261] 6A-6C show the cross-sectional structure of an exemplary unit dosage form 200 according to some related embodiments of the present invention. The unit dosage form 200 shown in FIGS. 6A-6C corresponds to the unit dosage form 100 (in any one of the corresponding embodiments described herein) as shown in FIGS. 5A-5C, respectively, and differs from the unit dosage form 100 in that the unit dosage form 200 further includes a coating 230. The unit dosage form 200 includes a core 210 and an outer layer 220, which correspond to the core 110 and outer layer 120, respectively, of the unit dosage form 100 described herein in any one of the corresponding embodiments.

[0262] The differences between the embodiments shown in Figures 6A-6C are that Figure 6A is an exemplary embodiment in which outer layer 220 covers the entire core 210, Figure 6B is an exemplary embodiment in which outer layer 220 covers different regions of core 210 and is divided into unconnected layers (such that outer layer 220 does not cover the entire core 210), and Figure 6C is an exemplary embodiment in which outer layer 220 is a single continuous layer that does not cover the entire core 210.

[0263] The unit dosage form 200 is optionally substantially rectangular in cross-section along at least one axis (as shown in Figures 6A-6C). However, it should be understood that the cross-section may have different shapes (e.g., substantially circular and / or substantially oval), and the shapes shown in Figures 6A-6C are not intended to be limiting.

[0264] Coating 230 has a composition according to any one of the embodiments described herein relating to coatings, and optionally is formed from a material that dissolves in at least a portion of the gastrointestinal tract (e.g., according to one of the corresponding embodiments described herein).

[0265] In some aspects of any one of the embodiments described herein, coating 230 is an enteric coating described herein (eg, according to one of the corresponding embodiments).

[0266] In some aspects of any one of the embodiments described herein, coating 230 dissolves under conditions in the stomach (e.g., according to one of the corresponding embodiments described herein), thereby exposing outer layer 220. Coating 230 is optionally adapted to alter the appearance of unit dosage form 200 (e.g., for aesthetic enhancement and / or labeling), for flavoring and / or flavor masking, and / or to protect outer layer 220 and / or core 210 (e.g., from mechanical injury, air, light, and / or liquids), e.g., according to one of the corresponding embodiments described herein.

[0267] In some aspects of any one of the embodiments described herein, coating 230 is an enteric coating (e.g., according to one of the corresponding embodiments described herein), outer layer 220 comprises one or more protease inhibitors (e.g., according to one of the corresponding embodiments described herein), and core 210 comprises PTH and SNAC, and optionally one or more protease inhibitors (e.g., according to one of the corresponding embodiments described herein). In some such embodiments, unit dosage form 200 is formulated as a tablet (e.g., optionally as shown in FIG. 8).

[0268] In embodiments in which coating 230 is an enteric coating, dissolution of unit dosage form 200 in the gastrointestinal tract involves dissolution of enteric coating 230 in the intestine, followed by dissolution of primarily outer layer 220, thereby releasing the protease inhibitor in the outer layer prior to release of PTH and SNAC from core 210.

[0269] In some of any of the embodiments in which coating 230 is an enteric coating, outer layer 220 and / or core 210 do not include an antacid.

[0270] In some aspects of any one of the embodiments described herein, coating 230 is a coating that dissolves under gastric conditions (e.g., according to one of the corresponding embodiments described herein), outer layer 220 includes one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein), and core 210 includes PTH and SNAC, and optionally one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein). In such embodiments, initial dissolution of unit dosage form 200 in the gastrointestinal tract primarily involves dissolution of coating 230 and outer layer 220 in the stomach, thereby releasing the antacid compound from the outer layer and reducing acidity in the stomach (e.g., near the unit dosage form) prior to release of PTH and SNAC from core 210.

[0271] In some aspects of any one of the embodiments in which coating 230 is a coating that dissolves under gastric conditions, outer layer 220 and / or core 210 do not include a protease inhibitor.

[0272] In some aspects of any one of the embodiments described herein, unit dosage form 200 is formulated as a coated tablet. In some aspects, unit dosage form 200 is formulated as a coated multi-layer tablet (e.g., a tri-layer tablet) in which outer layers 220 form upper and lower layers, and core 210 is formulated as a middle layer sandwiched between the upper and lower layers. An exemplary coated tablet is shown in FIG. 8. After any of the coated multi-layer tablets described herein are optionally manufactured using any technique known in the art for manufacturing multi-layer tablets, the tablet can be coated using any tablet coating technique known in the art.

[0273] 7 shows the structure of an exemplary unit dosage form according to some aspects of the present invention in the form of a tablet 300. Tablet 300 includes a core 310 and an outer layer 320, which correspond to core 110 and outer layer 120, respectively, of unit dosage form 100 described in any one of the corresponding embodiments herein (e.g., those relating to (B) of FIG. 5).

[0274] The cross-section of tablet 300 is optionally substantially circular (as shown in FIG. 7) or substantially oval in cross-section, however, it should be understood that tablets may have different shapes and the shape shown in FIG. 7 is not intended to be limiting.

[0275] Outer layer 320 includes layer 330 on the front (e.g., circular or oval) surface and layer 340 on the back (e.g., circular or oval) surface of tablet 300. Layers 330 and 340 are optionally not connected, with outer layer 320 being divided into two unconnected layers corresponding to outer layer 120 in Figure 5(B).

[0276] Outer layer 320 optionally covers at least 50% of the surface area of ​​core 310, optionally at least 60%, optionally at least 70%, optionally at least 80%, and optionally at least 90% of core 310.

[0277] Outer layer 320 includes one or more protease inhibitors and / or antacid compounds, as described for outer layer 120 according to any one of the corresponding embodiments described herein. In some embodiments, outer layer 320 includes one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein).

[0278] In some aspects of any one of the embodiments described herein, outer layer 320 does not include a protease inhibitor. Optionally, outer layer 320 consists essentially of one or more antacid compounds. Alternatively, outer layer 320 includes a combination of one or more additives and an antacid compound (e.g., according to one of the corresponding embodiments described herein).

[0279] In some aspects of any one of the embodiments described herein, outer layer 320 includes one or more protease inhibitors in addition to one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein). Optionally, outer layer 320 consists essentially of one or more protease inhibitors and one or more antacid compounds. Alternatively, outer layer 320 includes one or more additives in combination with a protease inhibitor and an antacid compound (e.g., according to one of the corresponding embodiments described herein).

[0280] Core 310 comprises tablet PTH and SNAC, and optionally further comprises one or more protease inhibitors and / or antacid compounds, as described for core 110 according to any one of the corresponding embodiments described herein. In some embodiments, core 310 comprises one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein).

[0281] The initial dissolution of tablet 300 in the gastrointestinal system primarily involves dissolution of outer layer 320, thereby releasing the protease inhibitor and / or antacid compound therein prior to the release of PTH and SNAC from core 310.

[0282] 8 shows the cross-sectional structure of an exemplary unit dosage form according to some aspects of the present invention in the form of a coated tablet 400. Tablet 400 corresponds to tablet 300 (in any one of the corresponding embodiments described herein), but differs in that tablet 400 further comprises an enteric coating 430. Tablet 400 comprises a core 410, an outer layer 420, and an enteric coating 430, which correspond respectively to core 210, outer layer 220, and coating 230 of unit dosage form 200 described in any one of the corresponding embodiments herein (e.g., with respect to FIG. 6B).

[0283] Enteric coating 430 may optionally be an enteric coating according to any one of the embodiments described herein for enteric coatings, such as for coating 230 (e.g., according to one of the corresponding embodiments).

[0284] The cross-section of tablet 400 optionally has a substantially circular or substantially oval cross-section (as shown in FIG. 8), however, it should be understood that tablets may have different shapes and the shape shown in FIG. 8 is not intended to be limiting.

[0285] Outer layer 420 includes layer 440 on the front (e.g., circular or oval) face of tablet 400 and layer 450 on the back (e.g., circular or oval) face. Layers 440 and 450 are optionally unconnected, with outer layer 420 split into two unconnected layers, corresponding to outer layer 220 in Figure 6B.

[0286] Outer layer 420 optionally covers at least 50% of the surface of core 410, optionally at least 60%, optionally at least 70%, optionally at least 80%, and optionally at least 90% of the surface of core 410.

[0287] Outer layer 420 includes one or more protease inhibitors and / or antacid compounds, as described for outer layer 120 and / or outer layer 220 according to any one of the corresponding embodiments described herein. In some aspects of any one of the embodiments described herein, outer layer 420 does not include an antacid compound. Optionally, outer layer 420 consists essentially of one or more inhibitors. Alternatively, outer layer 420 includes a combination of one or more additives and a protease inhibitor.

[0288] Core 410 comprises the PTH and SNAC of the tablet, and optionally further comprises one or more protease inhibitors and / or antacid compounds, as described for core 110 and / or core 210 according to any one of the corresponding embodiments described herein. In some embodiments, core 410 comprises one or more protease inhibitors. In some embodiments, core 410 does not comprise an antacid compound.

[0289] Dissolution of tablet 400 in the gastrointestinal system involves dissolution of enteric coating 430 in the intestine, followed by dissolution of primarily outer layer 420, thereby releasing the protease inhibitors in the outer layer prior to release of PTH and SNAC from core 410.

[0290] 9 shows the composition of an exemplary outer layer 500 according to some of the embodiments of the present invention. The outer layer 500 corresponds to any outer layer described herein (e.g., outer layer 120, 220, 320, and / or 420) in any of the corresponding embodiments described herein, and has an inner surface 510 facing the core described herein and an outer surface 520 facing the coating described herein and / or the surface of the unit dosage form described herein. The outer layer 500 includes a first compound 530 (sometimes a single compound, sometimes a combination of compounds), represented by a rectangle, and a second compound 540 (sometimes a single compound, sometimes a combination of compounds), represented by a circle. Optionally, additional compounds (not shown) may also be included in the outer layer 500.

[0291] The distribution of compounds 530 and 540 may be uneven in some cases, with compound 530 more concentrated near outer surface 520 than near inner surface 510, and / or compound 540 more concentrated near inner surface 510 than near outer surface 520, as shown in Figure 9. Thus, a concentration gradient exists between surfaces 510 and 520. In some embodiments, dissolution of outer layer 500 results in dissolution of compound 530 preceding dissolution of compound 540.

[0292] Alternatively, the distribution of compounds 530 and 540 is uniform and no concentration gradient exists between surfaces 510 and 520 .

[0293] In some of any of the embodiments described herein, compound 530 is one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein), and compound 540 is one or more protease inhibitors and / or additives (e.g., according to one of the corresponding embodiments described herein).

[0294] In some of any of the embodiments described herein, compound 530 is one or more protease inhibitors (e.g., according to one of the corresponding embodiments described herein), and compound 540 is one or more antacid compounds and / or additives (e.g., according to one of the corresponding embodiments described herein).

[0295] 10 shows the composition of an exemplary outer layer 600 according to some of the embodiments of the present invention. Outer layer 600 corresponds to any outer layer described herein (e.g., outer layers 120, 220, 320, 420, and / or 520) in any of the corresponding embodiments described herein, and has an inner surface 610 facing a core described herein and an outer surface 620 facing a coating described herein and / or a surface of a unit dosage form described herein. Outer layer 600 includes a first compound 630 (sometimes a single compound, sometimes a combination of compounds), represented by a rectangle, and a second compound 640 (sometimes a single compound, sometimes a combination of compounds), represented by a circle. Optionally, additional compounds (not shown) may also be included in outer layer 600.

[0296] 10, the distribution of compounds 630 and 640 may be uneven, with more compound 630 concentrated near one or more regions of the unit dosage form surface (e.g., on the right-hand side of FIG. 10) than near other regions of the unit dosage form surface (e.g., on the left-hand side of FIG. 10), and / or more compound 640 concentrated near one or more regions of the unit dosage form surface (e.g., on the left-hand side of FIG. 10) than near other regions of the unit dosage form surface (e.g., on the right-hand side of FIG. 10). Thus, a concentration gradient exists across the plane of outer layer 600.

[0297] Alternatively, the distribution of compounds 630 and 640 is uniform and there is no concentration gradient across the plane of outer layer 600 .

[0298] In some of any of the embodiments described herein, compound 630 is one or more antacid compounds (e.g., according to one of the corresponding embodiments described herein), and compound 640 is one or more protease inhibitors and / or additives (e.g., according to one of the corresponding embodiments described herein).

[0299] In some of any of the embodiments described herein, compound 630 is one or more protease inhibitors (e.g., according to one of the corresponding embodiments described herein), and compound 640 is one or more antacid compounds and / or additives (e.g., according to one of the corresponding embodiments described herein).

[0300] 11 shows the composition of an exemplary core 700 according to some of the embodiments of the present invention. Core 700 corresponds to any of the cores described herein (e.g., cores 110, 210, 310, and / or 410) in any of the corresponding embodiments described herein, and may optionally be combined with any of the outer layers described herein.

[0301] As shown in FIG. 11, the distribution of one or more compounds in the core 700 may be non-uniform, with the one or more compounds concentrated within the particle 710 at least partially separated by interstitial material 720.

[0302] Particles 710 optionally contain PTH and / or SNAC (e.g., according to one of the corresponding embodiments described herein) at a concentration greater than the concentration of PTH and / or SNAC in stromal material 720. Particles 710 may also contain heterogeneous particles with different compositions (e.g., one containing SNAC and one containing PTH). Particles 710 optionally are in the form of granules and / or microspheres.

[0303] Interstitial material 720 optionally does not include PTH and / or SNAC. Interstitial material 720 optionally includes, and optionally consists essentially of, one or more additives (e.g., according to one of the corresponding embodiments described herein), such as a filler and / or a binder.

[0304] Alternatively, the distribution of the compounds in the core 700 is uniform.

[0305] In some aspects of any one of the embodiments described herein, at least 50 weight percent of the cores described herein (e.g., any one of cores 110, 210, 310, and 410) are composed of SNAC. In some aspects, at least 60 weight percent of the cores described herein (e.g., any one of cores 110, 210, 310, and 410) are composed of SNAC. In some aspects, at least 70 weight percent of the cores described herein (e.g., any one of cores 110, 210, 310, and 410) are composed of SNAC. In some aspects, at least 80 weight percent of the cores described herein (e.g., any one of cores 110, 210, 310, and 410) are composed of SNAC. In some aspects, at least 90 weight percent of the cores described herein (e.g., any one of cores 110, 210, 310, and 410) are composed of SNAC.

[0306] Without being bound by any particular theory, it is believed that compositions (e.g., unit dosage forms and / or cores described herein) having a high proportion of SNAC that is a salt tend to dissolve more readily in aqueous solutions, such as gastric fluid, which is desirable in some embodiments of the present invention.

[0307] In some aspects of any one of the embodiments described herein, the unit dosage form (e.g., any one of unit dosage form 100, unit dosage form 200, and tablet 300) dissolves in gastric fluid (as defined herein). In some such embodiments, the unit dosage form does not include an enteric coating, thereby facilitating dissolution in gastric fluid. In some aspects, the unit dosage form dissolves in gastric fluid within 60 minutes. In some aspects, the unit dosage form dissolves in gastric fluid within 50 minutes. In some aspects, the unit dosage form dissolves in gastric fluid within 40 minutes. In some aspects, the unit dosage form dissolves in gastric fluid within 30 minutes. In some aspects, the unit dosage form dissolves in gastric fluid within 20 minutes. In some aspects, the unit dosage form dissolves in gastric fluid within 15 minutes. In some aspects, the unit dosage form dissolves in gastric fluid within 10 minutes. In some aspects, the unit dosage form dissolves in gastric fluid within 5 minutes.

[0308] In some aspects of any one of the embodiments described herein, the unit dosage form (eg, any one of unit dosage form 100, unit dosage form 200, and tablet 300) does not dissolve in gastric fluids.

[0309] In some aspects of any one of the embodiments described herein, the unit dosage form is formulated so that the bioavailability of PTH, which characterizes the absorption of PTH after oral administration of the unit dosage form, is at least 10% higher than the bioavailability of PTH after oral administration of a unit dosage form composition consisting of the core of the unit dosage form described above, but without the outer layer described herein. In some aspects, the bioavailability is at least 20% higher (at a level of at least 120%) than the bioavailability of the core upon oral administration. In some aspects, the bioavailability is at least 50% higher (at a level of at least 150%) than the bioavailability of the core upon oral administration. In some aspects, the bioavailability is at least twice the bioavailability of the core upon oral administration (at a level of at least 200%). In some aspects, the bioavailability is at least four times the bioavailability of the core upon oral administration (at a level of at least 400%). In some embodiments, the bioavailability is at least 10 times (at least 1000%) the bioavailability of the core upon oral administration. In some embodiments, the bioavailability is at least 20 times (at least 2000%) the bioavailability of the core upon oral administration.

[0310] Without being bound by any particular theory, it is believed that the protectant significantly increases bioavailability by protecting SNAC, thereby increasing the amount of active SNAC remaining available to facilitate absorption of PTH, and / or protects PTH, thereby increasing the amount of PTH that remains active upon absorption.

[0311] In some aspects of any one of the embodiments described herein relating to a composition comprising an antacid compound, the composition consists essentially of a combination of PTH, SNAC, and at least one antacid compound described herein. That is, at least 50 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, and at least one antacid compound. In some aspects, at least 60 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, and at least one antacid compound. In some aspects, at least 70 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, and at least one antacid compound. In some aspects, at least 80 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, and at least one antacid compound. In some aspects, at least 90 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, and at least one antacid compound. In some aspects, at least 95 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, and at least one antacid compound. In some embodiments, at least 98 percent by weight of the composition consists of ingredients selected from the group consisting of PTH, SNAC, and at least one antacid compound. In some embodiments, the composition is formulated as a tablet.

[0312] In some aspects of any one of the embodiments described herein relating to a composition comprising an antacid compound, the composition optionally further comprises at least one protease inhibitor, and at least 50 weight percent of the composition consists of components selected from the group consisting of PTH, SNAC, at least one antacid compound, and at least one protease inhibitor. In some aspects, at least 60 weight percent of the composition consists of PTH, SNAC, at least one antacid compound, and at least one protease inhibitor. In some aspects, at least 70 weight percent of the composition consists of PTH, SNAC, at least one antacid compound, and at least one protease inhibitor. In some aspects, at least 80 weight percent of the composition consists of PTH, SNAC, at least one antacid compound, and at least one protease inhibitor. In some aspects, at least 90 weight percent of the composition consists of PTH, SNAC, at least one antacid compound, and at least one protease inhibitor. In some aspects, at least 95 weight percent of the composition consists of PTH, SNAC, at least one antacid compound, and at least one protease inhibitor. In some embodiments, at least 98 percent by weight of the composition consists of PTH, SNAC, at least one antacid compound, and at least one protease inhibitor. In some embodiments, the composition is formulated as a tablet.

[0313] In some aspects of any one of the embodiments described herein relating to a composition comprising an antacid compound, the composition is formulated so that the bioavailability of PTH upon oral administration of the composition is at least 10% higher than the bioavailability of PTH upon oral administration of a composition comprising PTH and SNAC without at least one antacid compound (e.g., the same composition as the composition except for the absence of the antacid compound). In some aspects, the bioavailability is at least 20% higher (at a level of at least 120%) than the bioavailability upon oral administration of a composition comprising PTH and SNAC without at least one antacid compound. In some aspects, the bioavailability is at least 50% higher (at a level of at least 150%) than the bioavailability upon oral administration of a composition comprising PTH and SNAC without at least one antacid compound. In some aspects, the bioavailability is at least twice (at a level of at least 200%) the bioavailability upon oral administration of a composition comprising PTH and SNAC without at least one antacid compound. In some embodiments, the bioavailability is at least four times (at a level of at least 400%) the bioavailability upon oral administration of a composition comprising PTH and SNAC without at least one antacid compound. In some embodiments, the bioavailability is at least ten times (at a level of at least 1000%) the bioavailability upon oral administration of a composition comprising PTH and SNAC without at least one antacid compound. In some embodiments, the bioavailability is at least 20 times (at a level of at least 2000%) the bioavailability upon oral administration of a composition comprising PTH and SNAC without at least one antacid compound.

[0314] Antacids can be advantageously used in combination with PTH and SNAC without the need to combine all ingredients in a single composition.

[0315] In some aspects of any one of the embodiments described herein, the method or treatment according to any of the corresponding embodiments described herein further comprises co-administering to the subject an antacid composition comprising at least one antacid compound as defined herein (e.g., at least one antacid compound described herein) and / or at least one gastric acid secretion inhibitor, and a composition comprising PTH and SNAC (e.g., as described herein according to any of the corresponding embodiments).

[0316] As used herein, the phrase "gastric acid secretion inhibitor" refers to any agent that reduces the secretion of acid into the stomach, but does not necessarily have an effect on acid already secreted. Examples of gastric acid secretion inhibitors that can be used in any of the embodiments of the antacid compositions described herein include, but are not limited to, H2 receptor antagonists such as cimetidine, famotidine, nizatidine, and ranitidine, and proton pump inhibitors such as omeprazole, lansoprazole, dexlansoprazole, esomeprazole, rabeprazole, and ilaprazole.

[0317] In some aspects of any one of the embodiments described herein relating to the co-administration of an antacid composition, the antacid composition is optionally any antacid composition known in the art (e.g., a commercially available antacid composition).

[0318] In some aspects of any one of the embodiments described herein relating to the simultaneous administration of an antacid composition, the simultaneous administration includes administering the antacid composition before or simultaneously with the composition comprising PTH and SNAC.

[0319] In some aspects of any one of the embodiments described herein in which an antacid composition is administered simultaneously with a composition comprising PTH and SNAC, the antacid composition comprises at least one antacid compound as defined herein (e.g., according to any of the corresponding embodiments described herein).

[0320] In some aspects of any one of the embodiments described herein relating to the co-administration of an antacid composition comprising at least one gastric acid secretion inhibitor, the co-administration comprises administering the antacid composition prior to the administration of a composition comprising PTH and SNAC (e.g., according to any of the corresponding embodiments described herein).

[0321] Without being bound by any particular theory, antacid compounds (compounds capable of neutralizing stomach acid) as defined herein are generally effective in immediately reducing acidity in the stomach and / or its region (because acid neutralization occurs as a relatively rapid chemical reaction), but have limited long-term effect on further acid secretion into the stomach. Thus, they are believed to be particularly effective when administered simultaneously with or shortly (e.g., within 90 minutes) of a composition comprising PTH and SNAC.

[0322] Furthermore, although gastric acid secretion inhibitors are generally effective in reducing gastric acidity over a relatively long period of time (due to the long-term inhibition of gastric acid secretion), they have limited effect on acidity immediately after administration because they do not have a significant effect on acid already present in the stomach, and therefore are believed to be particularly effective when administered before a composition containing PTH and SNAC.

[0323] Here, the term "concurrently" refers to an event (e.g., administration of an antacid composition) occurring within a time period of 5 minutes before to 5 minutes after another event (e.g., administration of a composition comprising PTH and SNAC), and in some embodiments, within a time period of 1 minute before to 1 minute after the other event (e.g., administration of an antacid composition).

[0324] In some embodiments, the simultaneous co-administration is accomplished by swallowing the two compositions simultaneously.

[0325] In some aspects of any one of the embodiments described herein relating to the simultaneous administration of at least one antacid composition, administering the antacid composition before administering the composition comprising PTH and SNAC comprises administering the antacid composition within five days prior to administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within four days prior to administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within three days prior to administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within two days prior to administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within one day (24 hours) prior to administering the composition comprising PTH and SNAC. In some aspects, the antacid composition comprises a proton pump inhibitor.

[0326] In some aspects of any one of the embodiments described herein involving co-administration of at least one antacid composition, the antacid composition is administered at least about 1 day (e.g., at least about 24 hours) before administration of the composition comprising PTH and SNAC, e.g., about 1 to about 5 days (e.g., about 2 to about 4 days, optionally about 3 days) before administration of the composition comprising PTH and SNAC. In some aspects, the antacid composition comprises a proton pump inhibitor.

[0327] In some of the embodiments of any of the embodiments described herein, the antacid composition is optionally administered at least 12 hours before the administration of the composition comprising PTH and SNAC, and the antacid composition comprises a proton pump inhibitor.

[0328] In some aspects of any one of the embodiments described herein relating to simultaneous administration of at least one antacid composition, administering the antacid composition before administering the composition comprising PTH and SNAC comprises administering the antacid composition within 16 hours of administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 12 hours of administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 10 hours of administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 8 hours of administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 6 hours of administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 4 hours of administering the composition comprising PTH and SNAC. In some aspects, the antacid composition comprises an H2 receptor antagonist.

[0329] In some aspects of any one of the embodiments described herein involving simultaneous administration of at least one antacid composition, the antacid composition is administered at least about 2 hours, e.g., about 2 to about 10 hours (e.g., 2 to 8 hours, 2 to 6 hours, 2 to 4 hours) before administration of the composition comprising PTH and SNAC. In some aspects, the antacid composition comprises an H2 receptor antagonist or a proton pump inhibitor. In some aspects, the antacid composition comprises an H2 receptor antagonist.

[0330] In some of the embodiments of any of the embodiments described herein, where the antacid composition is administered at least 2 hours, but less than 12 hours, before the administration of the composition comprising PTH and SNAC, the antacid composition comprises an H2 receptor antagonist.

[0331] In some aspects of any one of the embodiments described herein relating to simultaneous administration of at least one antacid composition, administering the antacid composition before administering the composition comprising PTH and SNAC comprises administering the antacid composition within 90 minutes before the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 60 minutes before administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 30 minutes before administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 20 minutes before administering the composition comprising PTH and SNAC. In some aspects, the antacid composition is administered within 10 minutes before administering the composition comprising PTH and SNAC. In some aspects, the antacid composition comprises an antacid compound (as defined herein).

[0332] In some aspects of any one of the embodiments described herein relating to the co-administration of at least one antacid composition, the composition comprising PTH and SNAC is substantially the same as any one of the compositions described herein comprising PTH, SNAC, and an antacid compound, except for the absence of the antacid compound.

[0333] In some embodiments, the composition comprising PTH and SNAC and / or the antacid composition further comprises at least one protease inhibitor (eg, one or more protease inhibitors described herein).

[0334] In some embodiments, the composition comprising PTH and SNAC and / or the antacid composition is formulated as a unit dosage form.The unit dosage form can be formulated in any form suitable for oral administration, such as solid and / or liquid.In some embodiments, the unit dosage form (for example, the unit dosage form of the composition comprising PTH and SNAC) is a solid unit dosage form.In some embodiments, the unit dosage form (for example, the unit dosage form of the composition comprising PTH and SNAC) is formulated as a tablet.

[0335] In some embodiments, the compositions comprising PTH and SNAC and / or the antacid composition (e.g., in solid form) each dissolve in gastric fluid (as defined herein). In some embodiments, each composition dissolves in gastric fluid within 60 minutes. In some embodiments, each composition dissolves in gastric fluid within 50 minutes. In some embodiments, each composition dissolves in gastric fluid within 40 minutes. In some embodiments, each composition dissolves in gastric fluid within 30 minutes. In some embodiments, each composition dissolves in gastric fluid within 20 minutes. In some embodiments, each composition dissolves in gastric fluid within 15 minutes. In some embodiments, each composition dissolves in gastric fluid within 10 minutes. In some embodiments, each composition dissolves in gastric fluid within 5 minutes.

[0336] In some embodiments, neither the composition comprising a therapeutically active agent and SNAC nor the antacid composition (eg, in solid form) dissolves in gastric fluids (as defined herein).

[0337] In some aspects of any one of the embodiments described herein involving the co-administration of at least one antacid composition, the bioavailability of PTH, characterizing the absorption of PTH after co-administration, is at least 10% higher than the bioavailability of PTH after oral administration of a composition comprising PTH and SNAC without the co-administration of an antacid composition. In some aspects, the bioavailability is at least 20% higher (at least 120%) than the bioavailability without the co-administration of an antacid composition. In some aspects, the bioavailability is at least 50% higher (at least 50% of that level) than the bioavailability without the co-administration of an antacid composition. In some aspects, the bioavailability is at least twice the bioavailability without the co-administration of an antacid composition (at least 200%). In some aspects, the bioavailability is at least four times the bioavailability without the co-administration of an antacid composition (at least 400%). In some embodiments, the bioavailability is at least 10 times (at a level of at least 1000%) the bioavailability when the antacid composition is not co-administered. In some embodiments, the bioavailability is at least 20 times (at a level of at least 2000%) the bioavailability when the antacid composition is not co-administered.

[0338] Any one or more of the antacid compounds described herein can be used in any one of the embodiments described herein that use an antacid compound.

[0339] In some embodiments, the at least one antacid compound is selected from the group consisting of calcium carbonate, calcium gluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium oxide, and magnesium hydroxide.

[0340] In some embodiments, the at least one antacid compound is selected from the group consisting of calcium carbonate, calcium gluconate, sodium carbonate, sodium bicarbonate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium oxide, aluminum carbonate, and aluminum hydroxide.

[0341] In some embodiments, the at least one antacid compound is selected from the group consisting of calcium carbonate, calcium citrate, sodium bicarbonate, sodium hydroxide, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum carbonate, and aluminum hydroxide.

[0342] In some embodiments, the at least one antacid compound is selected from the group consisting of calcium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium carbonate, magnesium hydroxide, and aluminum hydroxide.

[0343] In some aspects of any one of the embodiments described herein relating to antacid compounds, the total amount of antacid compound (e.g., in the core of a unit dosage form described herein and / or in a unit dosage form described herein) administered in accordance with any of the corresponding embodiments of the methods or treatments described herein is such that at least one antacid compound comprises at least 0.00001 molar equivalents of base. In some aspects, at least one antacid compound comprises at least 0.00003 molar equivalents of base. In some aspects, at least one antacid compound comprises at least 0.0001 molar equivalents of base. In some aspects, at least one antacid compound comprises at least 0.0003 molar equivalents of base. In some aspects, at least one antacid compound comprises at least 0.001 molar equivalents of base. In some aspects, at least one antacid compound comprises at least 0.002 molar equivalents of base. In some aspects, at least one antacid compound comprises at least 0.003 molar equivalents of base. In some aspects, at least one antacid compound comprises at least 0.005 molar equivalents of base. In some embodiments, at least one antacid compound comprises at least 0.01 molar equivalents of base, hi some embodiments, at least one antacid compound comprises no more than 0.03 molar equivalents of base.

[0344] Here, 1 molar equivalent of base refers to the amount of a basic compound (e.g., an antacid compound described herein) that can neutralize 1 mole of HCl (e.g., in an aqueous solution). In determining the molar equivalent of base in an antacid compound described herein, each mole of hydroxide ion and / or bicarbonate ion is considered to be capable of neutralizing 1 mole of HCl, each mole of carbonate ion is considered to be capable of neutralizing 2 moles of HCl, and each mole of citrate ion (if fully deprotonated) is considered to be capable of neutralizing 3 moles of HCl.

[0345] In some aspects of any one of the embodiments described herein relating to an antacid compound, the total amount of antacid compound administered in accordance with any of the corresponding embodiments of the methods or treatments described herein (e.g., in the core of a unit dosage form described herein and / or in a unit dosage form described herein) is at least 0.5 mg. In some aspects, the amount of antacid compound is at least 1 mg. In some aspects, the amount of antacid compound is at least 2 mg. In some aspects, the amount of antacid compound is at least 5 mg. In some aspects, the amount of antacid compound is at least 10 mg. In some aspects, the amount of antacid compound is at least 25 mg. In some aspects, the amount of antacid compound is at least 50 mg. In some aspects, the amount of antacid compound is at least 100 mg. In some aspects, the amount of antacid compound is at least 200 mg. In some aspects, the amount of antacid compound is at least 300 mg. In some aspects, the amount of antacid compound is at least 400 mg. In some aspects, the amount of antacid compound is at least 500 mg. In some aspects, the amount of antacid compound is at least 750 mg. In some aspects, the amount of antacid compound is at least 1 gram.

[0346] Casing: In some aspects of any one of the embodiments described herein, the composition comprising PTH and SNAC (according to any of the corresponding embodiments described herein) forms part of a drug delivery system that includes a casing and the composition comprising PTH and SNAC contained within the casing.

[0347] The casing according to such an embodiment of the invention includes at least two components to be connected and at least one fastener for maintaining the connection of the components under gastric conditions, and the casing is configured such that upon removal of the fastener, a breach is formed in the casing.

[0348] Here, the term "casing" refers to a structure that encloses an internal volume and separates the internal volume from the surrounding environment. The term "casing" encompasses structures of any shape, such as deformable structures that easily change shape (e.g., casings formed from soft materials, e.g., in the form of soft pouches), as well as rigid structures, provided that the ability to separate the internal volume from the surrounding environment is maintained.

[0349] Here, the term "anchoring portion" refers to a component of the casing characterized by a structure and chemical composition suitable for performing the function of maintaining the connection of the components under gastric conditions. The casing may optionally include one anchoring portion or multiple anchoring portions (e.g., two anchoring portions, three anchoring portions, four anchoring portions, more than four anchoring portions). By maintaining the connection of the components under gastric conditions, the anchoring portion may optionally provide control over the release of PTH in the composition, particularly by preventing release in the stomach while allowing release in the intestine.

[0350] For simplicity, retainers are referred to in the singular throughout this specification (e.g., "a retainer," "the retainer"). Use of the singular should not be construed to mean that only one retainer is present and / or that only one retainer is referred to by any given description, unless this is explicitly indicated. Rather, unless indicated to the contrary, a description of a retainer (in the singular) according to any one of the embodiments described herein should be construed to refer to any one or more retainers in the casing, and possibly each retainer in the casing (in embodiments in which the casing has more than one retainer).

[0351] Here, for the sake of brevity, the at least two components connected together are also referred to herein as "casing components." This use of the phrase "casing components" is not intended to mean that the casing does not include other components in any sense. For example, the casing includes at least one component, such as a fastener described herein, that is not referred to herein as a "casing component."

[0352] As used herein, the term "coupled" refers to a state in which two or more objects are in physical contact, overlapping, and / or proximity.

[0353] The connected components may optionally be different portions of a single component, which different portions may be separated from one another upon removal of the fasteners. For example, in some embodiments, the connected components form different ends of a flexible component, the flexible component being folded upon itself, and the formation of a casing tear (e.g., upon removal of the fasteners) may be accomplished by unfolding the flexible component to separate the ends.

[0354] In some embodiments, the connection is such that the connected casing components are connected to one another.

[0355] In some embodiments, the linked casing components form a capsule shell. The casing components can be formed from any material known in the art that is suitable for forming capsule shells for pharmaceutical use. In some embodiments, the casing comprises, for example, two casing components, each of which is half of a capsule shell when telescoped to form the capsule shell. In some embodiments, the casing comprises more than two casing components (e.g., three or four casing components) that telescope to form the capsule shell.

[0356] Examples of mechanisms for maintaining the connection, optionally with one or more fasteners, include, but are not limited to, casing components, optionally coupled to each casing component (e.g., multiple casing components coupled to the same fastener), casing components, optionally blocking movement of each casing component (e.g., casing components need not be coupled, but are physically restrained from separating from one another), and clamping of the casing components.

[0357] As used herein, the term "clamping" refers to the act of holding objects together by applying pressure that compresses one object against another.

[0358] Clamping can maintain the connection of the casing components, for example, by opposing movement of the casing component perpendicular to the surface of another casing component (e.g., by pressing the casing component in an opposing direction, i.e., against the surface) and / or by opposing movement (e.g., sliding) of the casing component parallel to the surface of another casing component (e.g., by increasing friction between the two components).

[0359] In some of the embodiments described herein, the fastener is an adhesive (e.g., glue) that adheres the casing components together, thereby maintaining the connection of at least two casing components (e.g., in the form of a capsule shell). Optionally, the adhesive is present at the interface between the casing components. Alternatively, or in addition, the adhesive adheres to the casing components at a location other than the interface between the casing components, for example, at the outer and inner surfaces of the casing (e.g., capsule shell surfaces).

[0360] Here, the terms "cleft" and "cleft formation" and variations thereof refer to the formation of an opening in the casing that connects the interior volume of the casing to the surrounding environment and is large enough to allow leakage of PTH contained within the casing.

[0361] In some embodiments, the formation of the breach in the casing upon removal of the fastener of the casing is such that the area of ​​the breach formed in the casing is at least 10% of the surface area of ​​the casing before the breach formed in the casing. In some embodiments, the area of ​​the breach formed in the casing is at least 20% of the surface area of ​​the casing before the breach formed in the casing. In some embodiments, the area of ​​the breach formed in the casing is at least 30% of the surface area of ​​the casing before the breach formed in the casing. In some embodiments, the area of ​​the breach formed in the casing is at least 40% of the surface area of ​​the casing before the breach formed in the casing. In some embodiments, the area of ​​the breach formed in the casing is at least 50% of the surface area of ​​the casing before the breach formed in the casing.

[0362] Here, "removal" of a fastener refers to a hypothetical situation in which the casing changes only in that the fastener is no longer present. While such a situation is hypothetical rather than a real-world physical process, it is useful for describing the construction of casings according to many embodiments of the present invention.

[0363] It should be understood that the fasteners may be partially degraded or otherwise altered without removal in a manner that results in the formation of tears in the casing, possibly to a degree substantially similar to that which occurs upon removal of the fasteners. When such cases are described herein, the partial degrading and / or alteration of the fasteners is not referred to as "removal" of the fasteners.

[0364] In some of the embodiments of any of the embodiments described herein, the formation of a breach in the casing upon removal of the fastener is effected by separation of the casing components.

[0365] In some of the embodiments of any of the embodiments described herein, the fasteners form part of the casing that holds the casing together, so that the absence of the fasteners themselves (i.e., without any further changes in the casing, such as movement of a casing component) results in the formation of a breach in the casing. In some aspects, the separation of a casing component results in the formation of a further breach in the casing.

[0366] In some of the embodiments of any of the embodiments described herein, the absence of the fastener itself (i.e., without any further changes in the casing, such as movement of a casing component) does not form a breach in the casing, but rather removal of the fastener results in the formation of a breach in the casing due to separation of the casing components.

[0367] In some of the embodiments described herein, the absence of the fastener itself (i.e., without any further changes in the casing, such as movement of a casing component) does not result in the formation of a breach that is 30% or more of the casing's surface area before the breach is formed (e.g., no breach is formed, or a breach that is less than 30% of the casing's surface area is formed). In some embodiments, the absence of the fastener itself does not result in the formation of a breach in the casing that is 20% or more of the casing's surface area before the breach is formed. In some embodiments, the absence of the fastener itself does not result in the formation of a breach in the casing that is 10% or more of the casing's surface area before the breach is formed. In some embodiments, the absence of the fastener itself does not result in the formation of a breach in the casing that is 5% or more of the casing's surface area before the breach is formed. In some embodiments, the absence of the fastener itself does not result in the formation of a breach in the casing that is 2% or more of the casing's surface area before the breach is formed.

[0368] Optionally, each of the casing components is connected to each of the other casing components in the casing.

[0369] Alternatively, the casing components can be divided into multiple sets (e.g., two sets, three sets, four sets, or more than four sets), with each casing component in each set interlocking with each of the other casing components in the same set, but not necessarily interlocking with casing components in other sets. Any one casing component may belong to one such set or more than one such set. For example, if a casing includes three casing components, components I, II, and III, where component II interlocks with components I and III but components I and III do not interlock with each other, the casing can be considered to have two sets of casing components, one set consisting of components I and II and the other set consisting of components II and III.

[0370] Optionally, a fastener (optionally each fastener in the casing) maintains the connection of a set of casing components (each of the casing components is connected to each of the other casing components in the set).

[0371] Alternatively, any one fastener may optionally maintain the connection of two or more sets of casing components (as described herein).

[0372] In some cases, any one set of connected casing components is maintained connected by a single fastener.

[0373] Alternatively, two or more fasteners optionally act together to maintain connection of the same set of casing components.

[0374] In some embodiments where two or more fasteners maintain connection of the same set of casing components, the casing is configured such that the casing will form a breach upon removal of any one of the fasteners.

[0375] In some embodiments where two or more fasteners maintain the connection of the same set of casing components, the casing is configured such that the casing does not tear upon removal of one fastener, but rather tears only upon removal of two or more of said fasteners, and optionally tears only upon removal of each of said fasteners.

[0376] In some aspects of any one of the embodiments described herein, the drug delivery system is configured such that an internal force induces separation of the casing components upon removal of the fastener.

[0377] Here, the term "internal force" refers to a force applied by one or more components of a drug delivery system, such as a casing and / or materials within the casing. For example, a component under tension and / or compression can apply a force to a neighboring component or material, and in some cases, the drug delivery system can be configured such that such forces induce separation of casing components.

[0378] Here, "inducing" separation of the casing components means that the force tends to cause separation of the casing components upon removal of the fastener, and optionally the fastener is configured to oppose the separation-inducing force (until the fastener is removed or the force ceases to be obstructed).

[0379] The internal force in the drug delivery system may optionally be present at any time (e.g., starting from the time of manufacture of the drug delivery system), or alternatively, the internal force is present only under certain conditions (e.g., upon exposure to aqueous fluids, such as in the gastrointestinal tract). The internal force may optionally be applied by at least a portion of the casing and / or a material contained within the casing.

[0380] In some aspects of any one of the embodiments described herein, the drug delivery system is configured such that an internal force induces separation of the casing components upon removal of the fastener. Rather, separation of the casing components is induced by, for example, random movement, intestinal fluid flow, peristalsis, and / or other external forces.

[0381] In some aspects of any one of the embodiments described herein, the fastening portion forms a portion of an outer surface of the casing such that at least a portion of the fastening portion is exposed to the environment surrounding the casing.

[0382] In some aspects of any one of the embodiments described herein, the fastener is adhered to the outer surface of at least two casing components, and optionally forms part of the outer surface of the casing, thereby maintaining the connection of the casing components.

[0383] In some embodiments, the presence of the fasteners on the outer surface renders them sensitive to the environment, e.g., such that in certain circumstances, the fasteners cease to maintain connection of the casing components (e.g., due to dissolution of at least a portion of the fasteners, as described herein).

[0384] In some aspects of any one of the embodiments described herein, the anchoring moiety comprises an enteric polymer (as defined herein).

[0385] Due to the pH dependence of the solubility of enteric polymers, they can act as solid substances in the stomach and under dry conditions (e.g., before oral administration), but dissolve in at least a portion of the intestine. Thus, the structure of the anchoring portion comprising an enteric polymer is affected by the location of the casing in the gastrointestinal tract.

[0386] In some aspects of any one of the embodiments described herein, the enteric polymer is soluble in an aqueous solution at pH 5.5. In some such embodiments, dissolution of the enteric polymer occurs shortly after the drug delivery system reaches the intestine, e.g., the duodenum.

[0387] In some aspects of any one of the embodiments described herein, the enteric polymer is not soluble in an aqueous solution at pH 5.5, but is soluble in an aqueous solution at pH 6.0. In some such embodiments, dissolution of the enteric polymer occurs relatively soon after the drug delivery system reaches the intestine, e.g., the duodenum.

[0388] In some aspects of any one of the embodiments described herein, the enteric polymer is soluble in an aqueous solution at pH 6.5, but not in an aqueous solution at pH 5.5 or 6.0. In some such embodiments, dissolution of the enteric polymer occurs in the small intestine (e.g., the jejunum), but optionally not in the duodenum.

[0389] In some aspects of any one of the embodiments described herein, the enteric polymer is not soluble in aqueous solutions at pH 5.5, 6.0, or 6.5, but is soluble in aqueous solutions at pH 7.0 and / or pH 7.5. In some such embodiments, dissolution of the enteric polymer occurs in the ileum or colon, and optionally not in the duodenum or jejunum.

[0390] In some aspects of any one of the embodiments described herein, the anchoring moiety is substantially composed of an enteric polymer. In such embodiments, the entire anchoring moiety is potentially soluble under intestinal conditions. However, such anchoring moiety may lose functionality (e.g., lose the ability to maintain the connection of the casing components) upon partial dissolution of the anchoring moiety, for example, well before the entire anchoring moiety is dissolved.

[0391] In some aspects of any one of the embodiments described herein, the anchoring portion comprises an enteric polymer and at least one substance other than the enteric polymer (e.g., a substance that is water-insoluble at any pH in the gastrointestinal tract). In some such embodiments, the enteric polymer and other substances in the anchoring portion are configured such that dissolution of the enteric polymer in the anchoring portion causes the anchoring portion to lose its functionality (e.g., lose its ability to maintain the connection of the casing components).

[0392] In some aspects of any one of the embodiments described herein, the fastener loses its functionality (e.g., loses its ability to maintain connection of the casing components) by being separated (e.g., by disassembly) into two or more unconnected parts, e.g., a portion of the fastener attached to one casing component ceases to be connected to a portion of the fastener attached to another casing component.

[0393] In some aspects of any one of the embodiments described herein, the fastener loses its functionality (e.g., loses its ability to maintain connection of the casing components) by breaking down (not necessarily breaking down into two or more unconnected parts) to form a tear. For example, if the fastener forms part of the casing that holds the casing together, a tear formed in the fastener itself will cause a tear to form in the casing.

[0394] In some aspects of any one of the embodiments described herein, for example, if the fastener is adhered to a casing component (prior to its disassembly), the fastener loses its functionality (e.g., loses the ability to maintain connection of the casing components) upon detachment (e.g., by disassembly) from one or more casing components.

[0395] In some aspects of any one of the embodiments described herein, the fastener loses its functionality (e.g., loses the ability to maintain connection of the casing components) by being deformed (e.g., by disassembly), for example, by losing the shape necessary to maintain connection of the casing components (e.g., a shape suitable for clamping the casing components).

[0396] In some aspects of any one of the embodiments described herein, the casing comprises a tubular structure.

[0397] Here, the phrase "tubular structure" refers to a structure (e.g., an open cylinder or its topological equivalent) having an outer surface, an inner surface surrounding an internal volume, and two openings substantially opposite the tubular structure and connecting the internal volume to the periphery of the tubular structure. Optionally, the tubular structure has a substantially circular and / or substantially oval cross-section, which is a plane perpendicular to the axis between the two openings. However, alternative shapes are also encompassed by the phrase "tubular structure."

[0398] Optionally, the two openings of the tubular structure are capped to form a casing.

[0399] Here, the term "lidding" refers to an existing structure (also referred to herein as a "cap") covering an opening of another structure (e.g., a tubular structure) to close the opening. The cap may optionally be a fastener and / or a casing component as described herein. Optionally, the cap has a concave surface surrounding the opening, and the end of the tubular structure fits within the concave surface of the cap.

[0400] In some aspects of any one of the embodiments described herein, at least one opening of the tubular structure described herein is capped by a fastener. In some such embodiments, removal of the fastener forms a breach in the casing by exposing the opening of the tubular structure. In some aspects, two openings of the tubular structure are each capped by a fastener (e.g., two separate fasteners).

[0401] In some aspects of any one of the embodiments described herein, the casing comprises a flexible component (e.g., as described herein) comprising a flexible sheet folded into a tubular structure.

[0402] As used herein, the phrase "flexible sheet" refers to a three-dimensional structure, one dimension of which is thin enough to allow the sheet to be folded into a tubular structure.

[0403] In embodiments involving a flexible sheet folded into a tubular structure, different sides of the sheet that become connected upon folding into the tubular structure are considered herein to be different connected casing components.

[0404] Optionally, separation of the casing components is accomplished by folding the flexible sheet (eg, thereby breaking the tubular structure).

[0405] Additionally or alternatively, separation of the casing components may be achieved by a mechanism other than folding of the flexible sheet, for example, by exposing an opening in the tubular structure (e.g., by at least partial movement of one or two caps covering the tubular structure).

[0406] In embodiments involving a flexible sheet folded into a tubular structure, each end of the tubular structure is capped by a fastener (e.g., as described herein), and optionally separation of the casing components is achieved by unfolding the flexible sheet upon removal of one and / or both fasteners capping the tubular structure.

[0407] In some aspects of any one of the embodiments described herein, the drug delivery system further comprises a substance that swells upon contact with water, the substance being contained within a casing, and the casing being configured such that the substance swells when the casing comes into contact with an aqueous liquid (e.g., fluid in the stomach and / or intestines). In some cases, the swelling of the substance can be used to generate the internal force described herein. By swelling upon contact with water, the substance can optionally facilitate controlled release of the composition comprising PTH and SNAC, particularly release in a time-dependent manner, for example, the degree of swelling (and, in some cases, the internal force) being correlated with the duration of exposure to aqueous liquid (e.g., time from oral administration).

[0408] In some aspects of any one of the embodiments described herein, the casing is at least partially water-permeable, such that upon contact with an aqueous liquid, water penetrates the casing and causes the water-swellable material to expand. In some aspects, the casing is water-permeable in a portion adjacent to the water-swellable material. In some aspects, the casing is water-permeable only in a portion of the casing adjacent to the water-swellable material, while other portions of the casing are water-impermeable.

[0409] In some aspects of any one of the embodiments described herein, the water-permeable portion of the casing contains at least one perforation that allows water to pass through. In some aspects, the portion comprises multiple perforations. The perforations are preferably small enough to allow water to pass through but prevent leakage of substances within the casing (e.g., substances that swell upon contact with water, PTH, SNAC). Techniques for forming small perforations in drug delivery systems are known in the art and include, for example, laser perforation.

[0410] In some aspects of any one of the embodiments described herein, the casing contains a first compartment containing a substance that swells upon contact with water and a second compartment containing a composition comprising PTH and SNAC. In some aspects, formation of a breach in the casing upon removal of the fastener is achieved by separation of the casing components, and the casing is configured such that separation of the casing components forms a breach in the region containing the second compartment, i.e., the breach forms near the composition comprising PTH and SNAC.

[0411] In some embodiments, the first and second compartments are separated by a barrier that limits or prevents contact between the contents of the two compartments (e.g., the substance that swells upon contact with water and the composition comprising PTH and SNAC). In some embodiments, the barrier is movable upon expansion of the substance that swells upon contact with water. In some embodiments, the barrier moves such that upon expansion of the substance, the first compartment expands and the second compartment contracts, thereby compressing the composition comprising PTH and SNAC.

[0412] In some embodiments, the casing is configured so that the composition comprising PTH and SNAC in the second compartment does not come into contact with a substance that swells upon contact with water, a water-permeable portion of the casing, or a fastener (optionally on the outer surface of the casing) before a breach forms in the casing. Without being bound by any particular theory, such embodiments are particularly suitable for avoiding potential incompatibilities between PTH and / or SNAC and substances that provide specific chemical and / or physical properties used for controlled release (e.g., a substance that swells upon contact with water, a water-permeable portion of the casing, and / or a fastener that is sensitive to location in the gastrointestinal tract).

[0413] In some embodiments, compression of the composition comprising PTH and SNAC results in an internal force on at least a portion of the casing surrounding the second compartment, which in some cases facilitates the sudden formation of a relatively large cleft (e.g., a cleft of a size described herein), thereby allowing for rapid release of the PTH and SNAC.

[0414] In some embodiments, compression of the composition comprising PTH and SNAC results in migration of the composition comprising PTH and SNAC to an area where a cleft will form in the casing upon removal of the fastener, e.g., an area adjacent to the fastener. Optionally, such migration of the composition comprising PTH and SNAC facilitates rapid release of PTH and SNAC once the cleft has formed.

[0415] Various materials that swell upon contact with water and are suitable for use in drug delivery systems are known in the art and can optionally be used in embodiments of the present invention. Such materials are commonly referred to in the art as "disintegrants." Any material known in the art as a "disintegrant" (including the term "superdisintegrant") suitable for use in drug delivery systems is encompassed herein by the phrase "material that swells upon contact with water." Examples of such materials include, but are not limited to, povidone, crospovidone, croscarmellose (e.g., croscarmellose sodium), carboxymethylcellulose (e.g., carboxymethylcellulose calcium, carboxymethylcellulose sodium), hydroxypropyl methylcellulose, starch (e.g., corn starch, potato starch, wheat starch, tapioca starch, rice starch), modified starch (e.g., sodium starch glycolate), and silicon dioxide (e.g., colloidal silicon dioxide).

[0416] In some aspects of any one of the embodiments described herein, the material that swells upon contact with water is water-insoluble at 37°C. Examples of water-insoluble materials that swell upon contact with water include, but are not limited to, cross-linked hydrophilic polymers such as crospovidone and croscarmellose, and starch and its derivatives. Water-insolubility can be beneficial in reducing leakage of the material from the casing (e.g., through the perforations described herein), which may reduce the degree of swelling of the material within the casing.

[0417] As discussed herein, with the exception of at least a portion of the fastener portion, various portions of the casing, e.g., casing components and barriers according to corresponding embodiments described herein, and portions of the fastener portion (e.g., a fastener portion that includes, but does not consist of, an enteric polymer described herein), may be made from a variety of materials, including relatively inert materials.

[0418] In some aspects of any one of the embodiments described herein, such portions of the casing comprise, and optionally consist of, a polymeric material. In some aspects, the polymeric material is a hydrophobic polymeric material. Examples of hydrophobic polymeric materials include, but are not limited to, ethyl cellulose and other hydrophobic cellulose ethers, polyvinyl acetate, polyethylene, poly(methyl methacrylate), poly(ethyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), and copolymers thereof (e.g., poly(ethylene-vinyl acetate copolymer), poly(ethyl acrylate-methyl methacrylate copolymer)).

[0419] In some aspects of any one of the embodiments described herein, the hydrophobic polymeric material is characterized by being water-insoluble and not absorbing more than 20 weight percent water (weight of absorbed water relative to weight of material) at pH 7.0. In some aspects, the hydrophobic polymeric material is characterized by not absorbing more than 10 weight percent water at pH 7.0. In some aspects, the hydrophobic polymeric material is characterized by not absorbing more than 5 weight percent water at pH 7.0. In some aspects, the hydrophobic polymeric material is characterized by not absorbing more than 2 weight percent water at pH 7.0. In some aspects, the hydrophobic polymeric material is characterized by not absorbing more than 1 weight percent water at pH 7.0.

[0420] Without being bound by any particular theory, it is believed that hydrophobic polymeric materials tend to be relatively inert due to their lack of ability to form non-covalent bonds, such as hydrogen bonds and ionic bonds, which are typically associated with hydrophobicity.

[0421] In some aspects of any one of the embodiments described herein, the casing is formed from at least one material (e.g., a polymeric material) that is water-insoluble at pH 7.0, with the optional exception of any enteric polymer described herein that is water-soluble at pH 7.0. It should be understood that the material that is water-insoluble at pH 7.0 may optionally be an enteric polymer that is only soluble at a pH above 7.0. In such embodiments, that portion of the casing comprises, and optionally consists of, a polymeric material.

[0422] In some cases, the material comprises a mixture of water-insoluble and water-soluble polymers, where the mixture dissolves only slowly in aqueous solution (e.g., when the percentage of water-soluble polymer in the mixture is small). Such a material is considered to be water-insoluble herein if less than 1 gram dissolves in 1 liter of aqueous solution (with gentle stirring) at 37°C within 24 hours.

[0423] The drug delivery systems described herein can, in some cases, be formulated to provide desired pharmacokinetics, which can be achieved, for example, by selecting the appropriate configuration of the casing, the shape and / or thickness of the fastening portion, the pH dependency of the enteric polymer contained in the fastening portion, the amount and / or type of material that swells upon contact with water, and / or the water permeability of the water-permeable portion of the casing described herein.

[0424] In some aspects of any one of the embodiments described herein, the drug delivery system is formulated so that once the casing is broken, absorption of PTH occurs rapidly. It should be understood that the rapid release of PTH and SNAC allows for control of the release location in the gastrointestinal tract. This is because, as the formulation moves through the gastrointestinal tract, gradual release from the formulation generally results in release of PTH and SNAC over a long portion of the intestinal tract.

[0425] Without being bound by any particular theory, it is believed that the drug delivery systems according to some embodiments described herein are particularly suitable for achieving rapid release of PTH and SNAC and absorption of PTH (after a controlled delay before rupture of the casing) because the clefts are large enough to allow for rapid release (and subsequent absorption) of the entire amount of PTH and SNAC in the drug delivery system, in some cases. On the other hand, alternative methods (e.g., methods for releasing drugs in the intestine rather than the stomach), such as using slowly disintegrating and / or dissolving coatings and / or compositions, result in a relatively slow release of PTH and SNAC from small openings due to the slowly disintegrating / dissolving coating and / or the slowly disintegrating / dissolving composition comprising PTH and SNAC.

[0426] In some aspects of any one of the embodiments described herein, rapidity of release from the drug delivery system refers to absorption of PTH after oral administration of the drug delivery system having an AUC to C ratio of 3 hours or less, as described in any of the corresponding embodiments described herein.

[0427] In some aspects of any one of the embodiments described herein, the drug delivery system enhances the efficacy of delivery of PTH (e.g., as reflected by bioavailability) compared to administering the contents of a composition comprising PTH and SNAC without the use of a casing described herein. The enhanced efficacy may be due, for example, to protection of the PTH, SNAC, and / or protease inhibitor from gastric conditions.

[0428] In some aspects of any one of the embodiments described herein, the drug delivery system is formulated so that the absorption of PTH after oral administration of the drug delivery system is at least 20% higher (at a level of at least 120%) than the bioavailability of PTH after oral administration of a composition comprising PTH and SNAC (according to any of the corresponding embodiments described herein) without the drug delivery system casing, i.e., the same composition within the drug delivery system casing. In some aspects, the bioavailability is at least 50% higher (at a level of at least 150%) than the bioavailability when administered orally without the casing. In some aspects, the bioavailability is at least twice (at a level of at least 200%) the bioavailability when administered orally without the casing. In some aspects, the bioavailability is at least twice (at a level of at least 200%) the bioavailability when administered orally without the casing. In some aspects, the bioavailability is at least four times (at a level of at least 400%) the bioavailability when administered orally without the casing. In some embodiments, the bioavailability is at least 10 times (at least 1000%) the bioavailability when administered orally without a casing. In some embodiments, the bioavailability is at least 20 times (at least 2000%) the bioavailability when administered orally without a casing.

[0429] Coated particles: In some forms according to any of the aspects of the embodiments described herein, the composition comprising PTH and SNAC (according to any of the corresponding embodiments described herein) forms part of a drug delivery system comprising a plurality of solid particles. The solid particles comprise a core comprising the composition comprising PTH and SNAC and an enteric coating (according to any of the corresponding embodiments described herein). In some aspects, the coating covers the entire surface of the core.

[0430] In some embodiments, the enteric coating comprises an enteric polymer (as defined herein), for example, according to any of the corresponding embodiments described herein for enteric polymers.

[0431] The location in the gastrointestinal tract at which dissolution of the enteric coating begins can be controlled based on the pH dependence of the enteric coating and / or enteric polymer, as described herein in connection with any of the corresponding embodiments.

[0432] When dissolution of the enteric polymer and / or enteric coating begins at any given pH and / or location in the gastrointestinal tract (e.g., as described herein), dissolution of the enteric polymer and / or enteric coating need not be a very rapid process, and a significant amount of time may pass before the core is exposed and / or the coating disintegrates and / or completely dissolves. The time until the core is exposed and / or the coating disintegrates and / or completely dissolves can optionally be controlled, for example, according to the thickness of the enteric coating, with thicker enteric coatings being associated with longer dissolution times.

[0433] In some aspects of any one of the embodiments described herein, complete dissolution of the enteric coating occurs after at least 10 minutes of exposure to an aqueous solution at a pH at which the enteric coating dissolves (e.g., pH 5.5, 6.0, 6.5, or 7.0, as described herein). In some aspects, complete dissolution of the enteric coating occurs after at least 30 minutes of exposure to such an aqueous solution. In some aspects, complete dissolution of the enteric coating occurs after at least 60 minutes of exposure to such an aqueous solution. In some aspects, complete dissolution of the enteric coating occurs after at least 1200 minutes of exposure to such an aqueous solution.

[0434] In some aspects of any one of the embodiments described herein, the drug delivery system comprises multiple particles held together, e.g., encapsulated together and / or bound by a binding material. In some such embodiments, the capsule (e.g., a gelatin capsule) and / or the binding material are selected to degrade under gastric conditions (e.g., due to low pH and / or susceptibility to enzymatic proteolysis in the stomach), thereby releasing the particles and allowing them to travel individually through the gastrointestinal tract.

[0435] The particles may optionally be in any of a variety of forms, including tablets, granules, and microspheres. Coated tablets are generally a preferred form of solid coated particles in drug delivery system embodiments containing a small number (e.g., 1-4) of solid particles, and coated microspheres are generally a preferred form of solid coated particles in drug delivery system embodiments containing a large number (e.g., at least 10, 100, 1,000) of solid particles.

[0436] Tablets, microspheres, and further particle types can be manufactured using known methods, such as spheronization methods to produce microspheres and compression methods to produce tablets. Additionally, several coating techniques are known to those skilled in the art, including, but not limited to, spray coating, dip coating, and the like.

[0437] In some aspects of any of the embodiments described herein, the drug delivery system comprises multiple populations of solid particles (solid particles described herein according to any of the corresponding embodiments), each population characterized by a different release profile of PTH and / or SNAC in its core.

[0438] Without being bound by any particular theory, it is believed that oral administration of multiple populations, each exhibiting a different release profile, via a single drug delivery system can mimic the effect of administering different doses of PTH (with SNAC).

[0439] Here, the term "population" includes individual solid particles as well as multiple solid particles, for example, at least 2 solid particles, at least 5 solid particles, at least 10 solid particles, at least 20 solid particles, at least 50 solid particles, at least 100 solid particles, at least 200 solid particles, at least 500 solid particles, at least 1,000 solid particles, or at least 10,000 solid particles. Thus, for example, multiple populations of solid particles may in some cases consist of two different solid particles, each of which may represent a population. Alternatively, some or all of the multiple populations may contain multiple particles.

[0440] In some aspects of any of the embodiments described herein relating to populations comprising two or more solid particles, the solid particles of each population are substantially similar, e.g., produced by the same technique.

[0441] In some aspects of any of the embodiments described herein, the drug delivery system comprises two populations of solid particles.

[0442] In some aspects of any of the embodiments described herein, the drug delivery system comprises at least three populations of solid particles. In some aspects, the drug delivery system comprises exactly three populations of solid particles.

[0443] In some aspects of any of the embodiments described herein, the drug delivery system comprises at least four populations of solid particles. In some aspects, the drug delivery system comprises exactly four populations of solid particles.

[0444] In some aspects of any of the embodiments described herein, at least one population of solid particles comprises 1 to 3 solid particles. In some aspects, at least one population of solid particles comprises 1 or 2 solid particles. In some aspects, at least one population of solid particles comprises 1 solid particle.

[0445] In some aspects of any of the embodiments described herein, each population of solid particles consists of 1 to 3 solid particles. In some aspects, each population of solid particles consists of 1 or 2 solid particles. In some aspects, each population of solid particles consists of 1 solid particle.

[0446] In some aspects of any of the embodiments described herein, at least one population of solid particles comprises at least 4 solid particles. In some aspects, at least one population of solid particles comprises at least 10 solid particles. In some aspects, at least one population of solid particles comprises at least 30 solid particles. In some aspects, at least one population of solid particles comprises at least 100 solid particles.

[0447] In some aspects of any of the embodiments described herein, each population of solid particles comprises at least 4 solid particles. In some aspects, each population of solid particles comprises at least 10 solid particles. In some aspects, each population of solid particles comprises at least 30 solid particles. In some aspects, each population of solid particles comprises at least 100 solid particles.

[0448] In some aspects of any of the embodiments described herein, each population of solid particles is characterized by a different structure of the solid particles.

[0449] It is important to understand that the solid particles in a population need not have identical structures; rather, the variables defining the structure (e.g., coating thickness, particle size, and / or concentration of components in the coating and / or core) may optionally conform to a statistical distribution (such as, but not limited to, normal and / or Poisson distribution), where the "structure" of the solid particles characterizing the population refers to the structure with the highest probability, i.e., mode (e.g., as defined by the mode of the variable). Thus, for example, given a first population represented by a distribution in which the particle coating thickness has a mode of 0.1 mm and a standard deviation of 0.05 mm, and a second population represented by a distribution in which the coating thickness has a mode of 0.5 mm and a standard deviation of 0.2 mm, the populations are characterized by different structures (the 0.1 mm coating thickness structure and the 0.5 mm coating thickness structure), even though the population distributions may in some cases overlap.

[0450] In some aspects of any of the embodiments described herein, the structure of the solid particles in the drug delivery system (including particles in all populations) is multimodal (i.e., has two or more peaks), with each mode associated with a different population of solid particles.

[0451] In some aspects of any of the embodiments described herein, the populations are characterized by different coatings. In some such embodiments, the populations are characterized by different enteric coatings. The coatings (e.g., enteric coatings) can optionally differ in any aspect, such as coating composition (e.g., concentration and / or type of enteric polymer) and / or coating dimensions (e.g., thickness).

[0452] In some embodiments, the populations are characterized by different enteric coating thicknesses, hi some embodiments, the enteric coatings in each population characterized by different coating thicknesses are composed of the same components (e.g., the enteric coatings of different populations differ only in their thickness).

[0453] Without being bound by any particular theory, it is believed that the coating characteristics in general, and the coating thickness in particular, are particularly suitable for controlling the release profile of PTH (and SNAC) from the particles, for example, using a relatively thin coating in one population to obtain a relatively rapid release from that population, and using a relatively thick coating in another population to obtain a relatively slower release from that population.

[0454] In some aspects of any of the embodiments described herein, the drug delivery system is formulated such that the release rate of PTH as a function of time (i.e., the amount of PTH released per unit time) at pH 6 is characterized by at least two peaks (i.e., the release rate as a function of time is a multimodal function). In such embodiments, each peak can effectively represent a separate dose of PTH (with SNAC), i.e., the drug delivery system can be considered to release at least two doses at different times.

[0455] In some aspects of any of the embodiments described herein, the drug delivery system is formulated so that the release rate of PTH as a function of time (i.e., the amount of PTH released per unit time) at pH 7 is characterized by at least two peaks (i.e., the release rate as a function of time is a multimodal function).

[0456] The release rate at pH 6 and / or pH 7 is determined by gently stirring (optionally 50 revolutions / minute according to USP paddle method II (USP23)) the drug delivery system in an aqueous solution (optionally 1 liter) at 37°C, optionally containing citrate (optionally 0.1 M) as a buffering agent.

[0457] In some embodiments, multimodal release rates under any given conditions (e.g., pH 6 and / or pH 7) are obtained using populations characterized by different enteric coating thicknesses (e.g., according to any of the corresponding embodiments described herein), where the enteric coatings (e.g., according to any of the corresponding embodiments described herein) are soluble under such conditions (e.g., pH 6 and / or pH 7). In such embodiments, particles with thicker coatings sometimes take longer to dissolve than particles with thinner coatings, and populations characterized by relatively thin coatings are associated with relatively earlier peaks in the release rate, while populations characterized by relatively thicker coatings are associated with slower peaks in the release rate.

[0458] Without being bound by any particular theory, oral administration of a drug delivery system with a multimodal release rate from solid particles is particularly suitable for mimicking the effect of release from solid particles, and such a system is believed to mimic the effect of multiple oral administrations of PTH (and SNAC) at different times while avoiding the inconveniences associated with multiple administrations. For example, a bimodal release can mimic the effect of two oral administrations, with the first peak corresponding to the first oral administration and the second (later) peak mimicking the effect of the second (later) oral administration. Similarly, a trimodal (three peaks) release can mimic the effect of three oral administrations, and so on.

[0459] Furthermore, the lower the release level in the trough separating the two peaks compared to the release level at the peak, the more efficiently oral administration of the drug delivery system appears to mimic the effect of multiple oral administrations of PTH (with SNAC) at different times.

[0460] Furthermore, by providing discrete, transient doses of PTH, such drug delivery systems are believed to enhance the bone growth-promoting effects of PTH, which is desirable for treating osteoporosis (rather than enhancing bone resorption, which is generally undesirable for treating osteoporosis, as would be expected from continuous, gradual release of PTH).

[0461] In some aspects of any of the embodiments described herein relating to a release rate as a function of time characterized by at least two peaks, the at least two peaks are separated by a trough that is less than 75% of the level of the two peaks separated by the trough. In some embodiments, the at least two peaks are separated by a trough that is less than 50% of the level of the two peaks separated by the trough. In some embodiments, the at least two peaks are separated by a trough that is less than 25% of the level of the two peaks separated by the trough. In some embodiments, the at least two peaks are separated by a trough that is less than 10% of the level of the two peaks separated by the trough.

[0462] In some aspects of any of the embodiments described herein relating to release rates characterized by at least two peaks as a function of time, the at least two peaks are at least 30 minutes apart. In some embodiments, the two peaks are at least 60 minutes apart. In some embodiments, the two peaks are at least 2 hours apart. In some embodiments, the two peaks are at least 4 hours apart. In some embodiments, the two peaks are at least 6 hours apart.

[0463] In some aspects of any of the embodiments described herein relating to populations characterized by different enteric coatings, at least some of the different enteric coatings are characterized by different pH-dependent solubility profiles, ie, each population in the drug delivery system is characterized by a different pH-dependent solubility profile than the other populations.

[0464] Here, "pH-dependent solubility profile" refers to the pH values ​​at which a substance (eg, an enteric coating) is water soluble as defined herein.

[0465] In some aspects of any of the embodiments described herein relating to enteric coatings characterized by different pH-dependent solubility profiles, the enteric coatings are characterized by a difference in the lowest pH value (within the range of 5-8) at which each enteric coating is water-soluble (as defined herein). In some aspects, the difference in the lowest pH value (within the range of 5-8) at which each enteric coating is water-soluble is at least 0.2 pH units (e.g., one enteric coating is water-soluble at pH 6.0 and another enteric coating is water-insoluble up to at least pH 6.2). In some embodiments, the difference between the lowest pH values ​​at which each enteric coating is water-soluble is at least 0.5 pH units (e.g., one enteric coating is water-soluble at pH 6.0 and another enteric coating is water-insoluble up to at least pH 6.5). In some embodiments, the difference between the lowest pH values ​​at which each enteric coating is water-soluble is at least 1 pH unit (e.g., one enteric coating is water-soluble at pH 5.5 and another enteric coating is water-insoluble up to at least pH 6.5). In some embodiments, the difference between the lowest pH values ​​at which each enteric coating is water-soluble is at least 1.5 pH units (e.g., one enteric coating is water-soluble at pH 5.5 and another enteric coating is water-insoluble up to at least pH 7.0).

[0466] Without being bound by any particular theory, populations characterized by differences in the lowest pH value (within the range of 5 to 8) at which each enteric coating remains water-soluble release the core contents (PTH and SNAC) at different times after oral administration. This is because an orally administered product is typically exposed to gradually increasing pH in the gastrointestinal tract over several hours, starting with a highly acidic pH in the stomach, followed by a weakly acidic pH in the proximal portion, and then a near-neutral pH in the distal portion. Furthermore, for each population, release of the core contents is believed to occur primarily at the time and location when the gradually increasing pH reaches the lowest pH value (within the range of 5 to 8) at which each enteric coating remains water-soluble.

[0467] In some aspects of any of the embodiments described herein relating to populations characterized by different pH-dependent solubility profiles, the drug delivery system further includes populations having enteric coatings characterized by different enteric coating thicknesses (e.g., according to any of the corresponding embodiments described herein).

[0468] In some aspects of any of the embodiments described herein relating to populations characterized by different pH-dependent solubility profiles, the populations are characterized by enteric coatings that have substantially the same enteric coating thickness (e.g., according to any of the corresponding embodiments described herein).

[0469] In some aspects of any one of the embodiments described herein, the drug delivery system is formulated such that the absorption of PTH as a function of time after oral administration (e.g., the pharmacokinetic profile) is characterized by at least two peaks in blood PTH levels.

[0470] In such an embodiment, the time to each of the first two peaks may be defined as the first Tmax and the second Tmax, respectively.

[0471] As used herein, the term "Tmax" refers to the time taken from administration to achieve the maximum concentration (eg, plasma level) of an agent (eg, PTH) in the blood.

[0472] In some aspects of any one of the embodiments described herein, the first Tmax is 30 minutes or less and the second Tmax is at least 60 minutes. In some aspects, the second Tmax is at least 2 hours. In some aspects, the second Tmax is at least 4 hours. In some aspects, the second Tmax is at least 6 hours. In some aspects, the second Tmax is at least 8 hours.

[0473] In some aspects of any one of the embodiments described herein, the first Tmax is 60 minutes or less and the second Tmax is at least 2 hours (120 minutes). In some aspects, the second Tmax is at least 4 hours. In some aspects, the second Tmax is at least 6 hours. In some aspects, the second Tmax is at least 8 hours.

[0474] In some aspects of any one of the embodiments described herein, the first Tmax is 2 hours or less and the second Tmax is at least 4 hours. In some aspects, the second Tmax is at least 6 hours. In some aspects, the second Tmax is at least 8 hours.

[0475] In some aspects of any of the embodiments described herein relating to a pharmacokinetic profile characterized by at least two peaks, the at least two peaks are separated by a trough that is less than 75% of the level of the two peaks separated by the trough. In some embodiments, the at least two peaks are separated by a trough that is less than 50% of the level of the two peaks separated by the trough. In some embodiments, the at least two peaks are separated by a trough that is less than 25% of the level of the two peaks separated by the trough. In some embodiments, the at least two peaks are separated by a trough that is less than 10% of the level of the two peaks separated by the trough.

[0476] In some aspects of any of the embodiments described herein relating to a pharmacokinetic profile characterized by at least two peaks, the at least two peaks are at least 30 minutes apart. In some embodiments, the two peaks are at least 60 minutes apart. In some embodiments, the two peaks are at least 2 hours apart. In some embodiments, the two peaks are at least 4 hours apart. In some embodiments, the two peaks are at least 6 hours apart.

[0477] Other definitions: The term "osteoporosis" used herein refers to the medical condition characterized by the decrease of bone mass and bone density, and includes, for example, primary type 1 osteoporosis (generally associated with menopause), primary type 2 osteoporosis (generally associated with aging, for example, age 75 years or older), and secondary osteoporosis (generally associated with chronic disease or disorder, and / or long-term use of drugs such as glucocorticoids).The presence or absence of osteoporosis can be determined according to any standard used in medical circles.In some cases, osteoporosis is defined according to the standards of the World Health Organization, and refers to the condition of bone mineral density that is 2.5 standard deviations or more lower than the average peak bone mass (average in young and healthy adults), for example, as measured by dual-energy X-ray absorptiometry.

[0478] As used herein, the term "polypeptide" includes native polypeptides (e.g., degradation products, synthetically synthesized polypeptides, and / or recombinant polypeptides), including, but not limited to, native proteins, fragments of native proteins, and homologs of native proteins and / or fragments thereof. It also includes peptidomimetics (typically synthetically synthesized polypeptides) and polypeptide analogs, such as peptoids and semipeptoids, that have modifications that render the polypeptide (e.g., PTH and / or protease inhibitors) more stable in the body or more permeable to cells. Such modifications include, but are not limited to, N-terminal modifications, C-terminal modifications, peptide bond modifications, backbone modifications, and residue modifications. Methods for producing peptidomimetic compounds are well known in the art and are specified, for example, in Quantitative Drug Design, CA Ramsden Gd., Chapter 17.2, F. Choplin Pergamon Press (1992). The disclosure of this document is incorporated herein by reference as if fully set forth herein, and further details regarding this will be provided later in this specification.

[0479] Peptide bonds (-CO-NH-) in polypeptides (e.g., PTH and / or protease inhibitors) can be substituted, for example, with N-methylated amide bonds (-N(CH3)-CO-), ester bonds (-C(=O)-O-), ketomethylene bonds (-CO-CH2-), sulfinylmethylene bonds (-S(=O)-CH2-), α-aza bonds (-NH-N(R)-CO-) (where R is any alkyl (e.g., methyl)), amine bonds (-CH2-NH -), sulfide bond (-CH2-S-), ethylene bond (-CH2-CH2-), hydroxyethylene bond (-CH(OH)-CH2-), thioamide bond (-CS-NH-), olefinic double bond (-CH=CH-), fluorinated olefinic double bond (-CF=CH-), retroamide bond (-NH-CO-), peptide derivative (-N(R)-CH2-CO-), where R is a "normal" side chain naturally occurring on a carbon atom.

[0480] These modifications may occur at any bond along the polypeptide chain, and may occur at multiple (2 to 3) bonds simultaneously.

[0481] The naturally occurring aromatic amino acids Trp, Tyr and Phe may be substituted with unnatural aromatic amino acids such as 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), naphthylalanine, ring-methylated derivatives of Phe, halogenated derivatives of Phe or O-methyl-Tyr.

[0482] Polypeptides of some embodiments of the present invention (e.g., PTH and / or protease inhibitors described herein) may also include one or more modified amino acids or one or more non-amino acid monomers (e.g., fatty acids, complex carbohydrates, etc.).

[0483] The term "amino acid" or "amino acids" should be understood to include the 20 naturally occurring amino acids, amino acids that are post-translationally modified in vivo, such as hydroxyproline, phosphoserine, and phosphothreonine, as well as other unusual amino acids, such as, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, norvaline, norleucine, and ornithine. Furthermore, the term "amino acid" includes both D- and L-amino acids.

[0484] Tables 1 and 2 below list naturally occurring amino acids (Table 1) and non-conventional or modified amino acids (e.g., synthetic, Table 2) that can be used with some embodiments of the present invention.

[0485] [Table 1]

[0486] [Table 2-1]

[0487] [Table 2-2]

[0488] [Table 2-3]

[0489] It will be appreciated that although the polypeptides of some embodiments of the present invention (e.g., the PTH and / or protease inhibitors described herein) are preferably used in a linear form, cyclic polypeptides can also be used if cyclization does not significantly interfere with the characteristics of the polypeptide.

[0490] In some aspects of any one of the embodiments described herein, the polypeptide (eg, PTH and / or protease inhibitor) is water soluble.

[0491] As used throughout this specification, the term "soluble" refers to a compound having a solubility of at least 1 gram / liter in a particular solvent at 37°C.

[0492] For example, the term "water-soluble" refers to a compound having a solubility of at least 1 gram per liter in an aqueous solution at pH 7, unless another pH is expressly indicated.

[0493] Water-soluble polypeptides preferably contain one or more polar amino acids (unnatural or natural), including, but not limited to, serine and threonine, which can increase the water solubility of a polypeptide due to their hydroxyl-containing side chains. For example, a polypeptide homolog may be selected in which one or more amino acids in the polypeptide are substituted with polar amino acids, resulting in a polypeptide that is, in some cases, more water-soluble than the parent polypeptide.

[0494] Polypeptides of some embodiments of the present invention (e.g., PTH and / or protease inhibitors described herein) can be synthesized by any technique known to those skilled in the art of peptide synthesis. For solid-phase peptide synthesis, overviews of many techniques can be found in JM Stewart and JD Young, Solid Phase Peptide Synthesis, WH Freeman Co. (San Francisco), 1963, and J. Meienhofer, Hormonal Proteins and Peptides, vol. 2, p. 46, Academic Press (New York), 1973. For classical solution synthesis, see G. Schroder and K. Lupke, The Peptides, vol. 1, Academic Press (New York), 1965.

[0495] Generally, these methods involve the sequential addition of one or more amino acids or suitably protected amino acids to a growing polypeptide chain. Typically, either the amino or carboxyl group of the first amino acid is protected with a suitable protecting group. The protected or derivatized amino acid can then be attached to an inert solid support or used in solution by adding the next amino acid in the sequence, which has a suitably protected complementary group (amino or carboxyl), under conditions suitable for amide bond formation. The protecting group is then removed from this newly added amino acid residue, followed by the addition of the next amino acid (suitably protected), and so on. After all the desired amino acids have been linked in the appropriate sequence, any remaining protecting groups (and any solid support) are removed sequentially or simultaneously to yield the final polypeptide compound. Simple modifications of this general procedure also allow the addition of more than one amino acid at a time to a growing chain; for example, a protected tripeptide can be coupled to a suitably protected dipeptide (under conditions that do not racemize the chiral center), followed by deprotection to form a pentapeptide. Further description of peptide synthesis is disclosed in US Pat. No. 6,472,505.

[0496] A preferred method for producing polypeptide compounds of some embodiments of the present invention (eg, PTH and / or protease inhibitors described herein) involves solid phase peptide synthesis.

[0497] Large-scale polypeptide synthesis is described by Andersson et al. [Biopolymers 2000; 55:227-250].

[0498] Herein, a "homologue" of a given polypeptide (e.g., PTH(1-84) or a fragment thereof) refers to a polypeptide that exhibits at least 80% homology to the given polypeptide, preferably at least 90% homology, more preferably at least 95% homology, and more preferably at least 98% homology. In some embodiments, a homologue of a given polypeptide also has a therapeutic activity similar to that of the given polypeptide. The percentage of homology refers to the percentage of amino acid residues in a first polypeptide sequence that correspond to the amino acid residues of a second polypeptide sequence compared to the first polypeptide. Generally, polypeptides are aligned to maximize homology. Various strategies for comparing amino acid or nucleotide sequences to assess the degree of identity are known in the art, including, for example, manual alignment, computer-assisted sequence alignment, and combinations thereof. Several algorithms (generally computer-implemented) for performing sequence alignment are widely available or can be created by those skilled in the art. Representative algorithms include, for example, the Smith and Waterman local homology algorithm (Adv. Appl. Math., 1981, 2: 482), the Needleman and Wunsch homology alignment algorithm (J. Mol. Biol., 1970, 48: 443), the Pearson and Lipman similarity search method (Proc. Natl. Acad. Sci. (USA), 1988, 85: 2444), and / or computer implementations of these algorithms (e.g., GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Dr., Madison, Wis.). Readily available computer programs incorporating such algorithms include, for example, BLASTN, BLASTP, gapped BLAST, PILEUP, CLUSTALW, and the like.When using BLAST and Gapped BLAST programs, the default parameters of the respective programs can be used. A practitioner may alternatively use non-default parameters depending on his or her experience and / or other requirements (see, for example, the website at URL www(dot)ncbi(dot)nlm(dot)nihgov).

[0499] As used herein, the term "about" refers to ±10%.

[0500] The terms "comprises," "comprising," "includes," "including," "having," and their cognates mean "including but not limited to."

[0501] The term "consisting of" means "including and limited to."

[0502] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0503] As used herein, the word "exemplary" means "serving as an example, instance, or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features of other embodiments.

[0504] As used herein, the word "optionally" means "provided in some aspects and not provided in other embodiments." Any particular embodiment of the present invention may include multiple "optional" features unless such features are inconsistent.

[0505] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the terms "a protease inhibitor" and / or "antacid compound" may include a plurality of compounds (including mixtures thereof).

[0506] Throughout this application, various embodiments of the present invention may be presented in range form. It should be understood that the description in range form is merely for convenience and brevity and should not be construed as an indefinite limitation on the scope of the present invention. Accordingly, the description of a range should be considered to specifically disclose all possible subranges within that range as well as each individual numerical value within that range. For example, the description of a range such as 1 to 6 should be considered to specifically disclose subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as each individual numerical value within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0507] Whenever a range of numerical values ​​is given herein, it is intended to include any recited numerical value (fractional or integer) within the given range. The phrases "ranging between" a first designated number and a second designated number, as well as "ranging from" a first designated number to a second designated number, are used interchangeably herein and are intended to include the first and second designated numbers and all fractional and integer numbers therebetween.

[0508] As used herein, the term "method" means ways, means, techniques, and procedures for accomplishing a given task, and includes, but is not limited to, methods, means, techniques, and procedures known to those of ordinary skill in the art of chemistry, pharmacology, biology, biochemistry, and medicine, or readily developable from known methods, means, techniques, and procedures by those skilled in the art.

[0509] As used herein, the term "treating" refers to halting, substantially inhibiting, slowing, or reversing the progression of a condition, including substantially ameliorating clinical or cosmetic symptoms associated with the condition, or substantially preventing the appearance of clinical or cosmetic symptoms associated with the condition.

[0510] It is to be understood that features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or combination with other embodiments described herein. Features described in connection with various embodiments are not deemed essential to those embodiments, unless the embodiment is inoperable without the feature.

[0511] Various embodiments and aspects of the invention as delineated above and as claimed in the claims below find experimental support in the following examples.

[0512] Example Reference is now made to the following examples, which together with the above descriptions further illustrate some embodiments of the invention and are not intended to be limiting thereof.

[0513] material 8-Aminocaprylic acid was obtained from Alfa-Aesar. Magnesium stearate was obtained from Sigma-Aldrich. O-acetylsalicyloyl chloride was obtained from Sigma-Aldrich. Soybean trypsin inhibitor (SBTI) was obtained from Sigma-Aldrich. Teriparatide was purchased from Bachem. Sodium bicarbonate was obtained from Merck. SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) was prepared by reacting O-acetylsalicyloyl chloride with 8-aminocaprylic acid. [Example]

[0514] Pharmacokinetic profile of orally administered parathyroid hormone (PTH) Pharmacokinetic Study Design: A 3-month, open-label, comparative pharmacokinetic study was conducted in healthy volunteers. Each volunteer received the same oral tablet containing 0.75 mg of teriparatide, recombinant parathyroid hormone (1-34), at each of two clinic visits.

[0515] The formulation consisted of teriparatide (0.75 mg), SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), soybean trypsin inhibitor (SBTI), and a small amount of magnesium stearate.

[0516] The tablets were administered in the morning after an 8-hour overnight fast, followed immediately by 150 ml of water. At each visit, a standard meal was served 3 hours after drug administration. Patients did not consume alcoholic or caffeinated beverages. There was a 2-week gap between two visits.

[0517] To determine parathyroid hormone (1-34) (PTH(1-34)) concentrations, blood samples (4 ml each) were drawn from a forearm vein via an indwelling catheter at designated times during each visit. After each sample, the cannula was flushed with 1.5 ml of saline. Additionally, to avoid sample dilution, 1 ml of blood was drawn and discarded before the next sample. Blood samples were collected at the following time points: baseline (pre-dose), 10, 15, 20, 30, 45, 60, 75, 90, 105 min, 2, 3, 4, and 5 h post-dose. Each blood sample was collected in a single tube containing EDTA (ethylenediaminetetraacetic acid) and placed on ice. Within 15 min of collection, the sample was centrifuged (2500 rpm) for 10 min at 4°C to separate the plasma and divide it into two or three aliquots. Each aliquot was transferred to an appropriately labeled polypropylene tube and stored at approximately -20°C pending analysis. PTH(1-34) levels were measured using the IDS-iSYS automated assay for measuring intact PTH(1-34) in human plasma or serum. Assay results do not include levels of PTH(1-84), such as endogenous PTH.

[0518] result: As shown in Table 3 below and Figures 1A-1C, the pharmacokinetic profile of administered parathyroid hormone (1-34) was characterized by a rapid increase in plasma levels followed by a rapid decline, with peak parathyroid hormone (1-34) concentrations (Cmax) occurring within 20 minutes of administration. As further shown therein, Cmax remained relatively constant across different doses in a given subject. As further shown in Figures 1A-1C, parathyroid hormone (1-34) levels returned to baseline levels within 60 minutes of tablet administration.

[0519] [Table 3]

[0520] As further shown in Figures 1A-1C, particularly Figures 1B and 1C, the peak PTH plasma level is so narrow that even a small variation in Tmax (e.g., from 10 to 20 minutes) results in different pharmacokinetic curves that are barely overlapping.

[0521] This result demonstrates the importance of data derived from individual measurements as opposed to data averaged from different measurements: Averaging different measurements, even from a single subject, results in broader, lower curves that do not accurately represent the rapidity of the rise and fall of plasma levels. [Example]

[0522] Phase I clinical trial of oral parathyroid hormone (PTH) A Phase I clinical trial of an exemplary oral formulation containing teriparatide (parathyroid hormone (1-34)) was conducted at Hadassah Clinical Research Center. 42 healthy volunteers were included throughout the study.

[0523] The formulations consisted of teriparatide (200, 400, 680, 1400, or 1800 μg), SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), soybean trypsin inhibitor, and magnesium stearate.

[0524] The tablets were administered in the morning after an 8-hour overnight fast, immediately followed by 150 ml of water. At each visit, a standard meal was served 3 hours after drug administration. Patients did not consume alcoholic or caffeinated beverages.

[0525] To determine parathyroid hormone concentrations, blood samples (4 ml each) were drawn from a forearm vein via an indwelling catheter at predetermined time points. After each sample, the cannula was flushed with 1.5 ml of saline. Furthermore, to avoid sample dilution, 1 ml of blood was drawn and discarded before the next sample. Blood samples were drawn at the following time points: baseline (pre-dose), 15, 30, 45, 60, 75, 90, 105 minutes, 2 hours, 3 hours, 4 hours, and 5 hours post-dose. Each blood sample was collected in a single tube containing EDTA (ethylenediaminetetraacetic acid) and placed on ice. Within 15 minutes of blood collection, the sample was centrifuged (2500 rpm) at 4°C for 10 minutes to separate the plasma and divide it into two or three aliquots. Each aliquot was transferred to an appropriately labeled polypropylene tube and stored at approximately -20°C pending analysis. PTH levels were measured using the IDS-iSYS automated assay for measuring intact PTH in human plasma or serum.

[0526] Oral administration of teriparatide was performed at doses of 200, 400, 680, 1400, or 1800 μg, as described above. The Cmax of PTH(1-34) for each oral dose was compared to the Cmax of PTH(1-34) for a subcutaneous injection of 20 μg of teriparatide.

[0527] As shown in Figure 2, the Cmax of PTH(1-34) after oral administration was dose-proportional, with oral administration of approximately 750 μg of teriparatide producing a Cmax equivalent to subcutaneous administration of 20 μg of teriparatide.

[0528] As shown in Figure 3, oral administration of 1800 μg teriparatide and subcutaneous administration of 20 μg teriparatide were characterized by similar Cmax values, with the main difference in the pharmacokinetic profiles being a much more rapid decline in PTH levels following administration with oral administration compared to subcutaneous administration. It should be understood that the pharmacokinetic profiles for individual doses were characterized by narrower, higher curves than those shown in Figure 3, but averaging data from different measurements resulted in broader, lower curves due to slight variations in Tmax (as discussed in Example 1).

[0529] Furthermore, to confirm the biological activity of the administered PTH, plasma levels of cAMP, a known marker of PTH activity, were determined after oral administration of 680 μg of teriparatide or subcutaneous injection of 20 μg of teriparatide, as described above.

[0530] As shown in Figure 4, oral administration of 680 μg teriparatide and subcutaneous administration of 20 μg teriparatide increased plasma cAMP levels to a similar extent, confirming that orally administered PTH is bioactive.

[0531] These results indicate that oral administration of PTH results in a bioactive increase in PTH levels that lasts for a shorter period than that obtained by subcutaneous administration.

[0532] Because chronic exposure to PTH has the opposite effect (enhanced bone resorption) to intermittent exposure to PTH, increasing PTH levels in the blood for a short period of time may be advantageous in enhancing bone growth. [Example]

[0533] Casing containing parathyroid hormone and swelling substance A drug delivery system comprising a casing encapsulating the active ingredients parathyroid hormone and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) according to some aspects of the present invention (either per se or formulated as a pharmaceutical composition according to any of the corresponding embodiments described herein) is optionally assembled as shown in FIG. 12.

[0534] The first casing component (A) is filled with a substance (B) that swells upon contact with water, followed by a barrier (C), and the active ingredients (parathyroid hormone and SNAC) (D), optionally in granular form. The second casing component (E) is then contacted with the first casing component (A), thereby encapsulating (B), (C), and (D). A layer of enteric polymer (not shown) according to any of the corresponding embodiments described herein is then formed on at least a portion of the outer surfaces of the casing components (A) and (E). The adhesion of the layer to at least a portion of each of components (A) and (E) prevents separation of components (A) and (B). Assembly may be performed so that the active ingredient (D) does not come into contact with any material in the drug delivery system other than the casing components (A) and / or (E) and the barrier (C).

[0535] Figures 13(A)-(C) show the release mechanism of active ingredients (parathyroid hormone and SNAC) from drug delivery systems according to some embodiments of the present invention (optionally assembled as described above and shown in Figure 12).

[0536] Figure 13A shows a drug delivery system according to some aspects of the present invention prior to administration. The drug delivery system includes a first casing component 1320, at least a portion of which (optionally, a perforated portion) is water-permeable, and a second casing component 1310 in contact with the first casing component 1320. The second casing component 1310 is preferably water-impermeable. The area where components 1310 and 1320 contact is coated with a layer 1330 of enteric polymer (according to any of the corresponding embodiments described herein) adhered to the outer surfaces of both components 1310 and 1320, thereby preventing separation of components 1310 and 1320 from each other. Enclosed by casings 1310 and 1320 is a substance 1340 that swells upon contact with water, a barrier 1350, and optionally, granular active ingredients (parathyroid hormone and SNAC) 1360.

[0537] Figure 13B shows the drug delivery system shown in Figure 13A after contact with stomach contents following oral administration. The drug delivery system includes the same components as above, except that substance 1340 has expanded due to penetration of aqueous fluids in the stomach through casing component 1320 (optionally through one or more perforations in component 1320). As a result of the expansion of substance 1340, barrier 1350 moves toward active ingredient 1360, and optionally active ingredient 1360 moves toward casing component 1310 and / or is compressed by the movement of barrier 1350 (e.g., the volume of the void near active ingredient 1360 decreases). The expansion of substance 1340 optionally results in a force being applied to casing component 1310, which is transmitted by the movement of barrier 1350 and active ingredient 1360 (e.g., the resistance of active ingredient 1360 to compression). Because the enteric polymer does not dissolve in the acidic environment of the stomach, enteric polymer layer 1330 remains substantially intact and continues to prevent components 1310 and 1320 from separating from one another, even in the presence of any forces applied to casing component 1310 as described above.

[0538] Figure 13C shows the drug delivery system shown in Figures 13A and 13B after contact with intestinal contents following oral administration. The enteric polymer layer ruptures as a result of dissolution of the enteric polymer in the mildly acidic or non-acidic intestinal environment (e.g., at least pH 5.5), and in some cases, this rupture is further facilitated by the forces applied to the casing component 1310. Upon rupture, the layer no longer prevents the casing components from separating from one another. The casing components separate, and the active ingredients, parathyroid hormone and SNAC, are rapidly released from the casing.

[0539] Prior to separation of the casing components and release of the parathyroid hormone and SNAC, the parathyroid hormone and SNAC are not in contact with any material of the drug delivery system except, as the case may be, casing components 1310 and / or 1320 and barrier 1350 .

[0540] Casing components 1310, 1320, (A) and / or (E) are optionally comprised of a polymeric material that is insoluble in water at pH 7.0, and optionally a hydrophobic polymeric material such as ethyl cellulose. Additionally or alternatively, casing components 1310, 1320, (A) and / or (E) are optionally comprised of a polymer that is insoluble in water at pH 7.0, and optionally a hydrophobic polymer mixed with a small amount of a hydrophilic polymer, which mixture dissolves only slowly in aqueous solution.

[0541] Material 1340 and / or material (B) are optionally materials recognized in the art as disintegrants suitable for pharmaceutical use.

[0542] Barrier 1350 and / or barrier (C) are optionally comprised of a polymeric material that is insoluble in water at pH 7.0, optionally a hydrophobic polymeric material such as ethyl cellulose. Additionally or alternatively, barrier 1350 and / or barrier (C) are optionally comprised of a polymer that is insoluble in water at pH 7.0, optionally a hydrophobic polymer mixed with a small amount of a hydrophilic polymer, which mixture dissolves only slowly in aqueous solution.

[0543] The enteric polymer (eg, of layer 1330) is optionally a poly(methacrylic acid-ethyl acrylate copolymer) (optionally with a ratio of methacrylic acid to ethyl acrylate of about 1:1), such as Eudragit® L100-55.

[0544] The polymeric substances or polymers described above that are water-insoluble at pH 7.0 are optionally comprised of enteric polymers that are soluble at pHs above 7.0 (eg, in the colon).

[0545] The active ingredients optionally include SNAC in an amount described in any of the corresponding embodiments described herein, and a therapeutically effective amount of parathyroid hormone, which optionally is parathyroid hormone(1-34) (e.g., teriparatide), optionally in an amount described in any of the corresponding embodiments described herein. [Example]

[0546] A parathyroid hormone-containing casing formed from a sheet folded into a tubular structure FIG. 14 illustrates a casing structure according to some embodiments of the present invention.

[0547] The polymer sheet (A) is folded into a tubular structure. A cap (B) comprises, or optionally consists essentially of, an enteric polymer (according to any of the corresponding embodiments described herein) and is attached to both ends of the tubular structure, thereby forming a sealed casing and preventing the tubular structure from folding unfolded onto sheet (A). The cap is optionally attached by adhesive. Alternatively or additionally, attachment is achieved by friction, associated with pressure applied by sheet (A) to the inner surface of the cap, and optionally by pressure, associated with resistance to folding of the sheet.

[0548] The active ingredients, parathyroid hormone and SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) (not shown), are placed in the casing, optionally before attachment of both caps, or optionally after attachment of one cap but before attachment of the second cap.

[0549] Upon partial and / or complete dissolution of the enteric polymer in one or both caps (B) in the intestinal environment, unfolding of the sheet (A) occurs, thereby rapidly releasing the parathyroid hormone and SNAC from the casing.

[0550] Sheet (A) is optionally composed of a polymeric material that is insoluble in water at pH 7.0, and optionally a hydrophobic polymeric material such as ethyl cellulose. Additionally or alternatively, sheet (A) is composed of a polymer that is insoluble in water at pH 7.0, and optionally a hydrophobic polymer mixed with a small amount of a hydrophilic polymer, such a mixture only slowly dissolving in aqueous solution.

[0551] The enteric polymer is optionally a poly(methacrylic acid-ethyl acrylate copolymer) (optionally with a ratio of methacrylic acid to ethyl acrylate of about 1:1), such as Eudragit® L100-55.

[0552] The polymeric substances or polymers described above that are water-insoluble at pH 7.0 are optionally comprised of enteric polymers that are soluble at pHs above 7.0 (eg, in the colon).

[0553] The active ingredients optionally include SNAC in an amount described in any of the corresponding embodiments described herein, and a therapeutically effective amount of parathyroid hormone, which optionally is parathyroid hormone(1-34) (e.g., teriparatide), optionally in an amount described in any of the corresponding embodiments described herein. [Example]

[0554] Effect of antacids on the release profile of compositions containing parathyroid hormone and SNAC Two tablet formulations were prepared containing the same amounts of SNAC, trypsin inhibitor, and teriparatide (parathyroid hormone (1-34)). One formulation also contained 100 mg of sodium bicarbonate, while the other formulation did not. Both tablets were in the form of a homogeneous mixture.

[0555] Each tablet formulation was subjected to a dissolution test in 100 ml of simulated gastric buffer (without pepsin), pH 2.0, and 37°C according to USP23 Apparatus 2 (paddle) at 50 revolutions per minute. The amount of SNAC released from each sample was determined by chromatography using an HPLC system equipped with a Cosmosil™ 5C18-MS-II (4.6 ID x 250 mm) column. The mobile phase consisted of 50% acetonitrile and 50% phosphoric acid solution (0.1%). The flow rate was 1 ml / min, and the injection volume was 25 μl. The amount of SNAC released was calculated as a percentage of the amount of SNAC in the formulation.

[0556] As shown in Figure 15, sodium bicarbonate significantly enhanced the dissolution of SNAC in the tablets and retained the soluble fraction of SNAC.

[0557] These results indicate that formulations containing antacids such as sodium bicarbonate can significantly enhance the effect of the absorption enhancer SNAC when treating osteoporosis with orally administered PTH. [Example]

[0558] Effect of antacids on the pharmacokinetic profile of orally administered parathyroid hormone (PTH) An open-label, comparative pharmacokinetic study was conducted in 10 healthy volunteers. At different visits, each volunteer received the same oral tablet containing 0.75 mg of teriparatide, recombinant parathyroid hormone (1-34) (PTH(1-34)). At the first visit, the tablet was administered with 150 ml of water, while at the second visit, the tablet was administered with 150 ml of 3 mg / ml aqueous sodium bicarbonate solution.

[0559] The formulation consisted of teriparatide (0.75 mg), SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), soybean trypsin inhibitor (SBTI), and a small amount of magnesium stearate.

[0560] Tablets were administered in the morning after an 8-hour overnight fast. At each visit, a standard meal was served 3 hours after drug administration. Patients did not consume alcoholic or caffeinated beverages. There was a 2-week gap between two visits.

[0561] Blood samples were drawn to determine PTH(1-34) concentrations, and PTH(1-34) levels were measured with the IDS-iSYS automated assay using the procedure described above in Example 1. Relative absorption was determined based on the AUC (area under the curve) parameter.

[0562] As shown in Figure 16, co-administration with sodium bicarbonate solution increased the absorption of PTH(1-34) from orally administered formulations by approximately 35% compared to co-administration of the formulation with water.

[0563] These results indicate that coadministration with an antacid enhances the ability of SNAC to promote the absorption of orally administered PTH for the treatment of osteoporosis.

[0564] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace the present invention all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0565] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Furthermore, citation or identification of any reference in this application should not be construed as an admission that such reference is prior art to the present application. The use of section headings should not necessarily be construed as limiting.

Claims

1. 1. A pharmaceutical composition for use in the treatment of osteoporosis, formulated into a tablet for administration by oral ingestion to a subject in need of treatment, a parathyroid hormone or a fragment thereof in the range of 200 μg to 3000 μg, wherein the fragment exhibits the biological activity of parathyroid hormone; at least one protease inhibitor; SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), the weight ratio of the at least one protease inhibitor to the parathyroid hormone or fragment thereof is from 1:1 to 20:1, and the weight ratio of the SNAC to the parathyroid hormone or fragment thereof is from 100:1 to 1000:1; A pharmaceutical composition, wherein at least 95 percent by weight of said pharmaceutical composition consists of said parathyroid hormone or said fragment, said SNAC, and said at least one protease inhibitor.

2. 10. The pharmaceutical composition of claim 1, wherein the concentration of the SNAC is in the range of 70 to 99.4 percent by weight.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the fragment comprises teriparatide.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the at least one protease inhibitor comprises at least one trypsin inhibitor.

5. 5. The pharmaceutical composition of claim 4, wherein the at least one trypsin inhibitor is selected from the group consisting of lima bean trypsin inhibitor, aprotinin, soybean trypsin inhibitor, and ovomucoid trypsin inhibitor.

6. 5. The pharmaceutical composition of claim 4, wherein the at least one trypsin inhibitor comprises soybean trypsin inhibitor.

7. The pharmaceutical composition according to any one of claims 1 to 6, which is for oral administration once a day.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, formulated to provide a Cmax of 30 pg / ml to 700 pg / ml for absorption of the parathyroid hormone or fragment following oral administration of the pharmaceutical composition.

9. 9. The pharmaceutical composition of claim 8, comprising teriparatide, formulated to provide a Cmax of teriparatide absorption in the range of 30 pg / ml to 300 pg / ml after oral administration of the pharmaceutical composition.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, formulated to provide an AUC to Cmax ratio of 3 hours or less for absorption of the parathyroid hormone or fragment following oral administration of the pharmaceutical composition.

11. 11. The pharmaceutical composition of claim 10, wherein the ratio of AUC to Cmax is 60 minutes or less.

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