Formulations for oral administration of parathyroid hormone containing acid-neutralizing polymers - Patent Application 20070229633

Abstract

Described herein is a pharmaceutical composition comprising a therapeutically active agent, an absorption enhancer, and a polymer comprising a plurality of alkaline groups. The therapeutically active agent is parathyroid hormone. The concentration of the polymer in the composition is at least 10 weight percent of the total weight of the composition. The absorption enhancer is preferably a substituted or unsubstituted fatty acid or a salt thereof. Further described herein is a method of treating a disease treatable by a therapeutically active agent, comprising orally administering the pharmaceutical composition.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 313,367, filed February 24, 2022, the entire contents of which are incorporated herein by reference.

[0002] This application also claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 313,363, filed February 24, 2022, which is related to a PCT international patent application entitled "FORMULATIONS CONTAINING ACID-NEUTRAL POLYMERS FOR ORAL DELIVERY OF ACTIVE AGENT" filed on the same date herewith and having attorney docket number 95409, the entire contents of which are incorporated herein by reference.

[0003] The present invention, in some embodiments thereof, relates to drug delivery, and more particularly, but not limited to, formulations and / or systems for oral administration of therapeutically active agents, such as, but not limited to, parathyroid hormone. [Background technology]

[0004] Human 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. Teriparatide is a recombinant form of the first 34 amino acids of human PTH (hPTH(1-34)) and is used to treat osteoporosis. Administration is by subcutaneous injection once daily at a dose of 20 μg [Riek & Towler, Mo Med 2011, 108:118-123].

[0005] PTH (including PTH(1-34)) has been reported to promote bone growth and its circulating levels return to control levels within 3 hours, but only when administered intermittently [Martin, J Bone Metab 2014, 21:8-20]. In contrast, prolonged high PTH levels reduce bone mass by promoting bone resorption.

[0006] Oral administration of peptide and / or protein formulations presents problems such as degradation of the peptides and / or proteins in the digestive system and malabsorption of large molecules.

[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 to protect the insulin from digestive enzymes in the stomach and small intestine, and the SNAC to enhance absorption.

[0008] US 2011 / 0142800 describes compositions for oral administration of proteins comprising 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] WO 00 / 48589 describes a solid oral dosage form comprising a heparin drug in admixture with SNAC or SNAD to enhance absorption and / or improve bioavailability of the heparin drug, which is reported to prevent SNAC or SNAD from precipitating as it passes through acidic regions of the gastrointestinal (GI) tract.

[0010] WO 2016 / 128974 describes a pharmaceutical composition for oral administration comprising a therapeutically active agent, SNAC, and at least one antacid compound, as well as a pharmaceutical composition unit dosage form for oral administration comprising a core comprising a therapeutically active agent and SNAC, and an outer layer comprising an antacid compound and at least one protease inhibitor.

[0011] Buckley et al. [Sci Transl Med 2018, 10:eaar7047] report that when a tablet containing the peptide drug semaglutide and SNAC is orally administered, absorption of semaglutide occurs in the stomach and is limited to an area in close proximity to the tablet surface, and that SNAC only temporarily promotes absorption by preventing enzymatic degradation through a local buffering effect.

[0012] Sodium carboxymethylcellulose (CMC) is prepared by modifying cellulose with chloroacetic acid and may or may not be crosslinked. The crosslinked form, in which crosslinking occurs via the formation of ester bonds between the carboxymethyl groups and cellulose, is commonly called croscarmellose sodium (CCS) or sodium croscarmellose and is used as a superdisintegrant in pharmaceutical formulations.

[0013] Similarly, sodium starch glycolate (SSG) can be prepared by modifying starch with chloroacetic acid to form carboxymethyl groups. Sodium starch glycolate has phosphate groups (-O-P(=O)(-O) between the starch backbone. - )-O-) and can be used as a superdisintegrant.

[0014] Further background art includes Qi et al. [Acta Pharm Sinica 2004, 39:844-848], WO 00 / 50386, WO 01 / 32130, WO 01 / 32596, WO 03 / 045306, WO 03 / 045331, WO 2006 / 076692, WO 2007 / 121471, WO 2010 / 020978, WO 2012 / 080471, WO 2016 / 128970, WO 2017 / 129114, WO 2015 / 129126, WO 2016 / 129132, WO 2015 / 129147, WO 2015 / 129159, WO 2015 / 129161, WO 2015 / 129162, WO 2015 / 129163, WO 2015 / 129164, WO 2015 / 129165, WO 2015 / 129166, WO 2015 / 129167, WO 2015 / 129169 ... Examples of such compounds include WO 2016 / 128971, WO 2016 / 128972, WO 2016 / 128973, WO 2016 / 128974 and WO 2018 / 033927; JP 2005281231 A and JP 2006111558 A, U.S. Patent No. 8,110,547, and U.S. Patent Application Publication Nos. 2006 / 0234913, 2007 / 0087957 and 2013 / 0224300. Summary of the Invention

[0015] According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition comprising a therapeutically active agent, an absorption enhancer, and a polymer comprising a plurality of alkaline groups. According to an aspect of some embodiments of the present invention the therapeutically active agent consists of or comprises parathyroid hormone.

[0016] According to an embodiment of the invention, the concentration of the polymer in the pharmaceutical composition is at least 10 weight percent of the total weight of the composition.

[0017] According to an embodiment of the present invention, the absorption enhancer is a substituted or unsubstituted fatty acid or a salt thereof.

[0018] According to an aspect of some embodiments of the present invention there is provided a method of treating a disease treatable by a therapeutically active agent in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition according to any of the respective embodiments described herein.

[0019] According to some of the embodiments of the present invention, the alkaline groups are carboxylic acid groups and / or amine groups.

[0020] According to some of the embodiments of the present invention, at least a portion of the alkaline groups are carboxylic acid groups.

[0021] According to some of the embodiments of any of the present invention relating to carboxylic acid groups, at least a portion of the carboxylic acid groups are in the form of a pharma- ceutically acceptable salt.

[0022] According to some of any of the embodiments of the present invention relating to carboxylic acid groups, at least a portion of the carboxylic acid groups are in the form of a sodium salt.

[0023] According to some of any of the embodiments of the present invention, the absorption enhancer is selected from NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid), NAD (10-N-(2-hydroxybenzoyl)aminodecanoic acid), 5-CNAC (8-N-(5-chlorosalicyloyl)aminocaprylic acid), 4-MOAC (8-N-(2-hydroxy-4-methoxybenzoyl)aminocaprylic acid), 4-CNAB (4-N-(2-hydroxy-4-chlorobenzoyl)aminobutanoic acid) and salts thereof.

[0024] According to some of the embodiments of the present invention, the absorption enhancer includes NAC or a salt thereof.

[0025] According to some of the embodiments of the present invention, the concentration of the absorption enhancer is at least 50 weight percent of the total weight of the pharmaceutical composition.

[0026] According to some of the embodiments of the present invention, the concentration of the polymer is at least 20 weight percent of the total weight of the pharmaceutical composition.

[0027] According to some of the embodiments of the present invention, the total concentration of the absorption enhancer and polymer is at least 80 weight percent of the total weight of the pharmaceutical composition.

[0028] According to some of the embodiments of the present invention, the concentration of alkaline groups in the pharmaceutical composition is at least 0.1 millimole per gram.

[0029] According to some of the embodiments of the present invention, the polymer is a crosslinked polymer.

[0030] According to some of the embodiments of the present invention, the polymer comprises a polysaccharide.

[0031] According to some of any of the embodiments of the present invention relating to polysaccharides, the polysaccharide is selected from starch derivatives and cellulose derivatives.

[0032] According to some of the embodiments of the present invention, the polymer comprises a carboxymethyl group.

[0033] According to some of the embodiments of the present invention, the polymer is characterized by a pKa in the range of 1.2 to 7.5.

[0034] According to some of the embodiments of the present invention, the polymer is sodium starch glycolate and / or sodium croscarmellose.

[0035] According to some of the embodiments of the present invention, the Cmax and / or bioavailability of the composition upon oral administration is at least 50% higher than the Cmax and / or bioavailability of a corresponding pharmaceutical composition that does not contain the polymer (e.g., a composition that contains the same therapeutically active agent, the same absorption enhancer, and optionally other ingredients in the same amounts, but does not contain a polymer containing multiple alkaline groups as described herein in any of the respective embodiments).

[0036] According to some of the embodiments of the present invention, the therapeutically active agent comprises teriparatide.

[0037] According to some of the embodiments of the present invention, the therapeutically active agent comprises eneboparatide (AZP-3601), a long-acting PTH analogue.

[0038] According to some of the embodiments of the present invention, the composition is in the form of a unit dosage form.

[0039] According to some of any of the embodiments of the present invention relating to the unit dosage form, the amount of alkaline groups in the unit dosage form is at least 0.03 millimoles.

[0040] According to some of any of the embodiments of the invention relating to unit dosage forms, the unit dosage form comprises at least 50 mg of an absorption enhancer.

[0041] According to some of any of the embodiments of the invention relating to a unit dosage form, the unit dosage form comprises one or more tablets.

[0042] According to some of the embodiments of any of the present invention, the composition is for use in the treatment of a condition treatable by a therapeutically active agent, the treatment comprising oral administration of the pharmaceutical composition.

[0043] According to some of any of the embodiments of the invention relating to the treatment of a condition, the condition is selected from osteoporosis, conditions associated with bone fractures or bone defects, osteoarthritis, and hypoparathyroidism.

[0044] 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 present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0045] Some embodiments of the present invention are described herein, by way of example only, with reference to the accompanying drawings. Referring now specifically to the drawings in detail, it is stressed that the particulars shown are by way of example only and are for illustrative purposes of embodiments of the invention. In this regard, the description taken together with the drawings will make apparent to those skilled in the art how embodiments of the invention may be practiced. [Brief description of the drawings]

[0046] [Figure 1] 1 is a graph showing the pH measured after addition of SNAC to an HCl solution (pH 1.2) as a function of SNAC concentration. [Diagram 2] 1 is a graph showing the percentage of human parathyroid hormone (1-34) (PTH) (initial concentration 0.135 mg / ml) remaining after incubation with pepsin (150 μg / ml) for 3 minutes at 37° C. as a function of pH. [Figure 3A]Graph of pH measured using an MP-103 pH meter (MRC, Israel) equipped with an ELC-10-00 electrode (MRC, Israel) (FIG. 3A) or a fine wire electrode HI1083 (HANNA instruments Inc.) (FIG. 3B) as a function of added polymer concentration, showing the pH after addition of sodium alginate, sodium carboxymethylcellulose (Na-CMC), sodium starch glycolate (SSG) or sodium croscarmellose (CCS) to an HCl solution (pH 1.2). [Figure 3B] Same as above [Figure 4] FIG. 1 is a graph of the median plasma concentration of hPTH(1-34) in rats as a function of time following oral administration of minitablets containing 90 μg of hPTH(1-34), SNAC and SBTI (soybean trypsin inhibitor) with 20% sodium starch glycolate (solid line) or without sodium starch glycolate (dashed line). [Diagram 5] FIG. 1 is a graph of the median plasma concentration of hPTH(1-34) in rats as a function of time following oral administration of minitablets containing 90 μg of hPTH(1-34) and SNAC with (solid line) or without (dashed line) 30% sodium starch glycolate. [Figure 6] Photographs of tablets made with the polymers sodium starch glycolate (SSG; FIG. 6A), sodium croscarmellose (CCS; FIG. 6B), sodium carboxymethylcellulose (CMC-Na; FIG. 6C) and sodium alginate (Alg-Na; FIG. 6D) after swelling in 0.01 M HCl (pH=2) at room temperature, with pH values ​​measured at four points for each tablet (white triangles). [Figure 7] Photographs of tablets made with the polymers sodium starch glycolate (SSG; FIG. 7A) and sodium carboxymethylcellulose (CMC-Na; FIG. 7B) after swelling in porcine gastric fluid at room temperature, along with pH values ​​measured at four points for each tablet (white triangles). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The present invention, in some embodiments thereof, relates to formulations and / or systems for drug delivery, and more particularly, but not limited to, oral administration of therapeutically active agents, such as parathyroid hormone.

[0048] Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or illustrated by way of examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0049] While investigating the enhancement of absorption of a therapeutically active agent by an exemplary absorption enhancer such as SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate), the inventors have found that the ability of such absorption enhancers to enhance the absorption of a therapeutically active agent (e.g., as determined by bioavailability and / or Cmax) is adversely affected by the acidic environment of the stomach. The inventors have conceived of using basic (alkaline) compounds to enhance the performance of the absorption enhancer after oral administration by neutralizing gastric acid, and have found that polymers containing alkaline groups such as carboxylates are particularly effective in protecting the absorption enhancer from gastric acid as well as improving the bioavailability of the therapeutically active agent in a composition comprising the absorption enhancer and the therapeutically active agent.

[0050] While practicing the present invention, the inventors have shown that an exemplary polymer containing carboxylic acid groups produces a local increase in pH in simulated gastric fluid (the increase of which can reduce the protonation of an absorption enhancer such as SNAC), significantly enhancing the absorption of PTH compared to a corresponding composition containing the same absorption enhancer but without the polymer.

[0051] Referring now to the drawings, FIG. 1 shows that the exemplary absorption enhancer SNAC undergoes protonation upon contact with HCl (as present in gastric acid).

[0052] FIG. 2 shows that increasing the pH to about 6 significantly reduces the degradation of peptides by pepsin.

[0053] 3A-3B show that various carboxylic acid group-containing polymers increase the pH in a concentration-dependent manner.

[0054] 4 and 5 show that the exemplary carboxylic acid group-containing polymers significantly enhance the absorption of a therapeutically active agent in an in vivo rat model.

[0055] Figures 6A-D and Figures 7A-B show the increased local pH within tablets made with various carboxylic acid group-containing polymers after hydration in acidic aqueous solution.

[0056] According to one aspect of some embodiments of the present invention, there is provided a pharmaceutical composition comprising a therapeutically active agent, an absorption enhancer, and a polymer comprising a plurality of alkaline groups (which for brevity is also referred to herein as an "alkaline group-containing polymer" or "basic polymer" or simply "polymer").

[0057] As explained in more detail below, the alkaline group-containing polymer is also referred to herein as an acid-neutralized polymer.

[0058] According to this embodiment, the therapeutically active agent is parathyroid hormone (PTH), as defined herein.

[0059] As used herein, the terms "parathyroid hormone" and "PTH" (used synonymously in this application) refer to a polypeptide that is naturally occurring PTH (as defined herein), or an analog (e.g., a synthetic analog) thereof. An analog may be any derivative of naturally occurring PTH, such as a homolog (as defined herein), a fragment (including a fragment of a homolog), and a substituted derivative (e.g., including substituents to enhance stability and / or half-life) of naturally occurring PTH or its homologs and / or fragments, and / or modified in any other manner as described herein for the polypeptide. Preferably, an analog exhibits the biological activity of PTH.

[0060] In some of any of the embodiments described herein, the PTH is teriparatide. Teriparatide is a fragment (composed of amino acids 1-34, i.e., the N-terminal portion) of the complete human parathyroid hormone polypeptide. The term "teriparatide" is used interchangeably herein with the terms "hPTH(1-34)" and "human parathyroid hormone(1-34)".

[0061] In some of any of the embodiments described herein, the therapeutically active agent is eneboparatide (AZP-3601), a long-acting PTH analogue (with a longer plasma half-life).

[0062] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a polymer" or "at least one polymer" can include multiple polymers, including mixtures thereof.

[0063] In some such embodiments, the composition is in unit dosage form, for example, in the form of a tablet or a combination of two or more tablets (eg, minitablets).

[0064] The term "unit dosage form" as used herein describes a physically separate unit, each unit containing a predetermined amount of one or more active ingredients calculated to produce a desired therapeutic effect, together with at least one pharma- ceutically acceptable carrier, diluent, excipient, or combination thereof. Examples of suitable unit dosage forms include, but are not limited to, tablets, capsules, lozenges, dragees, wafers, sachets, patches, ampoules, vials, filled syringes, and single-dose metered dispensers. Each unit may optionally contain separate subunits (e.g., each subunit is in the form described herein, such as tablets, capsules, lozenges, dragees, etc.), which may be attached to each other or separate from each other. For example, a unit dosage form according to embodiments of the invention comprising multiple subunits can optionally be in the form of a unit dosage form comprising separate subunits bound together by a coating and / or matrix, e.g., as described in WO 2018 / 033927, which is incorporated herein by reference, or in the form of a series of dosage forms in a kit (e.g., a packaged set of separate dosage forms).

[0065] The pharmaceutical composition and / or unit dosage form according to any of the respective embodiments described herein is preferably formulated to be suitable for oral administration, e.g., as described in more detail herein. Examples of unit dosage forms formulated for oral administration include, but are not limited to, tablets, capsules, lozenges, dragees, wafers, sachets, ampoules, and vials. In exemplary embodiments, the pharmaceutical composition and / or unit dosage form according to any of the respective embodiments described herein is formulated as a tablet or a plurality of mini-tablets.

[0066] In exemplary embodiments, the pharmaceutical compositions and / or unit dosage forms according to any of the respective embodiments described herein do not include a gastroenteric coating or otherwise include a coating that is dissolvable in gastric fluids and / or that releases the contents of the composition shortly (e.g., within less than 5 minutes, less than 2 minutes, or less than 1 minute) upon contact with gastric fluids. As used herein, the phrases "oral administration," "administering orally," and the like refer to any administration via the mouth, preferably by oral ingestion, such as swallowing (as opposed to, e.g., buccal administration).

[0067] In some of any of the embodiments described herein, the compositions are formulated to allow absorption of the therapeutically active agent in the stomach, for example, by not including an enteric coating, i.e., a coating that prevents release of the agent and dissolves only in the intestine.

[0068] Without being bound by any particular theory, it is believed that PTH tends to be poorly absorbed when administered orally, for example, due to their relatively high molecular weight and / or polarity (e.g., inhibiting passage through lipid membranes in the gastrointestinal tract). Thus, it is believed that their absorption is particularly susceptible to promotion by the activity of absorption enhancers (e.g., NAC or its salts) and to increased absorption enhancer activity by alkaline group-containing polymers according to any of the respective embodiments described herein. It is further believed that the absorption of such polypeptides is further limited by degradation due to the pH-dependent activity of enzymes such as pepsin (e.g., as illustrated in the Examples section of this application), and that the increased pH associated with alkaline group-containing polymers can promote the absorption of polypeptides by reducing pepsin activity (in addition to increasing absorption enhancer activity, as described herein).

[0069] Alkaline group-containing polymer: As used herein, the term "polymer" refers to a compound having at least four repeat (skeletal) units (more preferably at least 10 repeat units, e.g., 4 to 1,000, or 10 to 1,000 repeat units, although greater numbers of repeat units are contemplated), where the repeat units are identical or similar. The term "polymer" also encompasses copolymers that contain two or more types of repeat units as described herein, e.g., at least four, or preferably at least 10, of one type of repeat unit and at least four, or preferably at least 10, of another, different type of repeat unit. The units in a copolymer may be arranged in any order.

[0070] The backbone (repeating) units making up the polymers or copolymers described herein are also referred to interchangeably herein as monomeric units or simply monomers.

[0071] The alkaline group-containing polymer contains multiple (i.e., at least two) alkaline groups per molecule. In some of the embodiments described herein, the alkaline group-containing polymer contains an average of at least 4 alkaline groups, or at least 10 alkaline groups, or at least 25 alkaline groups, or at least 50 alkaline groups, or at least 100 alkaline groups per molecule. In some of the embodiments described herein, the average number of alkaline groups per polymer molecule ranges from about 4 to about 1,000, or from about 10 to about 1,000, or from about 25 to about 1,000, or from about 50 to about 1,000, or from about 100 to about 1,000, with higher upper limits being contemplated for each of these ranges.

[0072] In some of any of the embodiments described herein, the average molecular weight of the alkaline group-containing polymer is at least 1 kDa, or at least 2 kDa, or at least 3 kDa, or at least 5 kDa, or at least 10 kDa. In some of the embodiments described herein, the average molecular weight of the alkaline group-containing polymer is in the range of about 1 kDa, or about 2 kDa, or about 3 kDa, or about 5 kDa, or about 10 kDa, or about 100 kDa, or about 200 kDa, or about 300 kDa, or about 400 kDa, or about 500 kDa, or about 600 kDa, or about 700 kDa, or about 800 kDa, or about 1,000 kDa, or about 2,000 kDa, and up to about 10,000 kDa or more (including any intermediate values ​​and subranges therebetween).

[0073] As used herein, the term "alkaline group" includes any functional group capable of accepting a proton in aqueous solution, such as a carboxylate or amine group. As these terms (e.g., by pH) are used in the art, it will be understood that upon contact with a liquid having the appropriate acidity or alkalinity, an alkaline group can be converted to an acidic group (by protonation) and vice versa (by deprotonation).

[0074] In some of any one of the respective embodiments described herein, the polymer is characterized by a pKa of at least 1.2, optionally in the range of 1.2 to 7.5, optionally 1.2 to 5.5 (including any intermediate values ​​and subranges therebetween); for example, 1.2 to 3 or 2.5 to 3.5 or 3 to 4 or 3.5 to 4.5 or 4 to 5 or 4.5 to 5.5 (including any intermediate values ​​and subranges therebetween). In some such embodiments, the pKa is at least 2.5, or at least 3, or at least 3.5; for example, 2.5 to 5.5, or 3 to 5.5, or 3.5 to 5.5, or 4 to 5.5, or 4.5 to 5.5 (including any intermediate values ​​and subranges therebetween).

[0075] As used herein, the "pKa" of a polymer refers to the pH in an aqueous solution of 0.1 M NaCl at which 50% of the acid / base (eg, carboxylate) groups are protonated at 25°C.

[0076] A carboxylic acid group is an exemplary alkaline group according to some embodiments of the present invention.

[0077] As used herein, the term "carboxylate" means, unless otherwise indicated, -C(=O)O - It refers to the carboxylic acid group (i.e., carboxylate anion) and does not include carboxylic acid groups (-C(=O)OH). It will be understood that upon contact with a liquid having appropriate acidity or alkalinity, the carboxylic acid group may be converted to a carboxylic acid group, and vice versa. For simplicity, some carboxylic acid group-containing compounds and functional groups described herein (e.g., carboxymethyl, polyacrylic acid) are shown as if they were in the carboxylic acid form, but should be understood to include carboxylic acid groups unless otherwise indicated.

[0078] The carboxylic acid group according to any of the respective embodiments described herein may be optionally associated with a counterion to form a salt, e.g., a pharma- ceutically acceptable salt. The salts (pharma- ceutically acceptable salts) of the compounds described herein may alternatively be formed during the synthesis of the compounds, e.g., during the isolation of the compounds from a reaction mixture or during the process of recrystallizing the compounds.

[0079] Examples of suitable counterions that may be included by the salts described herein include, but are not limited to, ammonium, guanidinium, lithium, sodium, potassium, calcium, and magnesium. Sodium is an exemplary counterion.

[0080] Examples of suitable carboxylic acid group-containing polymers include, but are not limited to, alginates, polyacrylic acid, polymethacrylic acid, and copolymers of acrylic acid and / or methacrylic acid, as well as salts of carboxylic acid group-containing polysaccharide derivatives (e.g., derivatives obtained by oxidation or substitution with carboxylate-containing groups, such as carboxymethyl).

[0081] Carboxylate may optionally be included by repeating monomers (backbone units) that contain carboxylate, such as uronic acid salt forms of monosaccharide units (e.g., mannuronate and guluronate monomers in alginates) and acrylates (e.g., in polyacrylates, etc.). Additionally / alternatively, carboxylate may be included by a substituent (e.g., carboxymethyl substituents, which may optionally be formed by reaction of the polymer with chloroacetic acid) attached to at least a portion of the monomer (e.g., in carboxymethyl cellulose and sodium starch glycolate, etc.). Additionally / alternatively, carboxylate may be formed by oxidation of at least a portion of the monomer (backbone unit), for example, by breaking a carbon-carbon bond, and / or by oxidation of a primary carbon (e.g., in oxidized starch, etc.). In some exemplary embodiments, the polymer includes a carboxymethyl group attached to an oxygen atom.

[0082] The amines may optionally be included by repeating monomers (backbone units) that contain amine groups, e.g., amino sugars such as 2-amino-2-deoxy sugars (e.g., glucosamine in chitosan) and alkyleneimine (e.g., ethyleneimine) residues (such as in polyethyleneimine), and / or by substituents.

[0083] The alkaline group-containing polymer may optionally contain monomers (backbone units) that do not contain alkaline groups (e.g., acrylates, methacrylates, acrylamides and methacrylamides), for example in copolymers that contain acrylic or methacrylic acid monomers, and / or substituents that do not contain alkaline groups (e.g., substituted or unsubstituted alkyl groups such as methyl, ethyl, hydroxyethyl and hydroxypropyl), for example in polymers (e.g., polysaccharides) that are also substituted with alkaline group-containing substituents.

[0084] The alkaline groups are such that, upon oral administration, they are capable of neutralizing acids by undergoing protonation to form acidic groups (e.g., carboxylic acid or ammonium groups), thereby increasing the pH of a solution in contact with the respective alkaline group-containing polymer.

[0085] Without being bound by any particular theory, it is believed that the acid-neutralizing polymers described herein are more suitable than conventional antacids because the polymers are large molecules that do not easily diffuse throughout the stomach (thus minimizing dilution of the polymer), which may result in a longer period of efficacy. The polymers described herein provide the additional beneficial effect of forming a viscous medium that reduces the influx of gastric acid into the absorption enhancer, thereby further reducing inactivation of the absorption enhancer by gastric acid, which is generally not present in conventional antacids. Additionally / alternatively, it is further believed to enhance the effect of the absorption enhancer by reducing diffusion of the absorption enhancer and / or therapeutically active agent throughout the stomach, thereby maintaining a higher local concentration of the absorption enhancer in the vicinity of the therapeutically active agent. In this manner, the composition may enhance absorption of the therapeutically effective agent for a longer period of time (e.g., by reducing the rate of inactivation of the absorption enhancer by protonation and / or dilution) and / or increase the peak rate of absorption of the therapeutically effective agent (e.g., by providing a higher local concentration of the absorption enhancer in an active form, as described herein). It is further believed that such formation of a viscous medium may facilitate adhesion of the composition to the stomach wall (e.g., by increasing the contact area between the soft medium and the stomach wall), thereby facilitating absorption through the stomach tissue.

[0086] In some embodiments of any one of the embodiments described herein, the alkaline group-containing polymer swells when contacted with water (for these embodiments, also referred to herein as "water-swellable"). In some such embodiments, the polymer is not water-soluble.

[0087] As used herein, the phrase "swells upon contact with water" refers to the ability of a material to absorb at least its own weight in water (i.e., the material has at least 100% swelling capacity) upon contact with water (e.g., pure water) at 37°C, and optionally at least twice its own weight in water (at least 200% swelling capacity) or at least 5 times its own weight (at least 500% swelling capacity) or at least 10 times its own weight or at least 20 times its own weight.

[0088] "Swelling capacity" means that the material is capable of swelling with water the weight percentage indicated of its weight before swelling. Swelling capacity (Qt) is calculated according to the formula: Qt = (Ws - Wd) / Ws * 100% where Ws is the weight after swelling and Wd is the dry weight (weight before swelling).

[0089] As used herein, the term "water-soluble" refers to a compound that has a solubility of at least 1 gram per liter in water (eg, pure water) at 37°C.

[0090] As used herein, the term "water-insoluble" refers to a compound that has a solubility of less than 1 gram per liter in water (eg, pure water) at 37°C.

[0091] A typical assay for quantitatively determining the solubility of a substance is the "shake flask method," in which an excess of a test substance is added to a volume (e.g., 100 ml) of a solvent (e.g., water) in a container (e.g., a flask or vial) and shaken under defined conditions (e.g., a temperature of 37° C.) to achieve thermodynamic equilibrium. Residual solids are then removed (e.g., by filtration and / or centrifugation) and the concentration of dissolved substance is determined by a technique such as HPLC. Concentration can optionally be determined at various time points to ensure that equilibrium has been reached.

[0092] Without being bound by any particular theory, it is believed that swelling upon contact with water (e.g., in gastric media) is advantageous because it promotes water penetration and maximizes the contact between the surrounding solution and alkaline groups upon oral administration.For example, a polymer with a lower water penetration rate (e.g., into polymer granules) may exhibit slower than optimal neutralization of gastric acid even when the amount of alkaline groups is high, for example, due to the less effective diffusion of acid to the alkaline groups.Water solubility is also effective in maximizing the contact between the surrounding solution and alkaline groups, but is further believed to be less desirable than swelling, because the dissolution of the polymer leads to undesirably non-localized effects (e.g., similar to conventional antacids described herein).

[0093] In some of any of the embodiments described herein, the polymer is a crosslinked polymer.

[0094] The polymers may be crosslinked via covalent bonds by respective covalently bonded crosslinking moieties, thereby linking two or more backbone units in the polymer, and / or via electrostatic bonds by respective electrostatically bonded crosslinking moieties (e.g., ions such as cations), thereby linking two or more backbone units in the polymer. The number of crosslinking moieties determines the degree of crosslinking of the crosslinked polymer.

[0095] Without being bound by any particular theory, it is believed that crosslinking is advantageous by being free to minimize the dissolution of the polymer (e.g., in saliva and / or stomach acid), which may result in "waste" of the polymer, and / or by promoting water absorption (e.g., by breaking the bonds between different polymer chains, thereby promoting the intrusion of water molecules between the chains). The degree of crosslinking may affect the swelling capacity. For example, insufficient crosslinking may be associated with dissolution (as opposed to swelling) and / or with reduced swelling and / or reduced water penetration. However, excessive crosslinking may reduce the swelling capacity by limiting the ability of the polymer to expand and provide space for water to invade. The degree of crosslinking should not affect the acid neutralization capacity of the polymer. The degree of crosslinking may be selected or predetermined for each selected polymer, depending on its properties, to provide the desired hydration level.

[0096] In some of any of the embodiments described herein, the polymer comprises a polysaccharide, e.g., a cross-linked polysaccharide. The polymer is optionally composed primarily (i.e., greater than 50 weight percent) of glucose units, which may optionally be linked by glycosidic bonds, such as α(1→4) and / or α(1→6) glycosidic bonds (e.g., as in starch) and / or β(1→4) glycosidic bonds (e.g., as in cellulose).

[0097] The term "monosaccharide," as used herein and as is well known in the art, refers to a simple form of sugar consisting of a single monosaccharide molecule that cannot be further broken down by hydrolysis. The most common examples of monosaccharides include glucose (dextrose), fructose, galactose, and ribose. Monosaccharides may be classified according to the number of carbon atoms of the carbohydrate, i.e., trioses having 3 carbon atoms, e.g., glyceraldehyde and dihydroxyacetone; tetroses having 4 carbon atoms, e.g., erythrose, threose and erythrulose; pentoses having 5 carbon atoms, e.g., arabinose, lyxose, ribose, xylose, ribulose and xylulose; hexoses having 6 carbon atoms, e.g., allose, altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose and tagatose; heptoses having 7 carbon atoms, e.g., mannoheptulose, sedoheptulose; octose having 8 carbon atoms, e.g., 2-keto-3-deoxy-manno-octonate; nonoses having 9 carbon atoms, e.g., sialose; and decoses having 10 carbon atoms.

[0098] Monosaccharides are the building blocks of polysaccharides (such as cellulose and starch).

[0099] The term "polysaccharide" as used herein refers to a compound containing 10 or more monosaccharide units, which are linked together via glycosyl bonds (-O-), as defined herein. The glycosyl bonds between the monosaccharide units in a polysaccharide may all be the same, or may contain more than one type of glycosyl bond, for example, glucose units are linked via α(1→4) and / or α(1→6) glycosidic bonds.

[0100] As used herein, the term "starch" encompasses polysaccharides composed of amylose (glucose units linked via α(1→4) glycosidic bonds) and amylopectin (glucose units linked via α(1→4) and α(1→6) glycosidic bonds). Different types of starches differ from each other by the ratio between amylose and amylopectin, which typically depends on the source of the starch.

[0101] In some of any of the embodiments related to polysaccharides, the polysaccharide is a starch derivative and / or a cellulose derivative, i.e., a starch and / or a cellulose (e.g., a cross-linked starch and / or a cross-linked cellulose) that is derivatized to contain alkaline (e.g., carboxylate) groups, for example, by substitution with carboxymethyl groups (e.g., its oxygen atom is bonded to a carboxymethyl group). Sodium starch glycolate is an exemplary starch derivative. Croscarmellose sodium is an exemplary cellulose derivative.

[0102] As used herein, "sodium starch glycolate" refers to any sodium salt of starch (as defined herein) substituted with carboxymethyl groups, which may be cross-linked or non-cross-linked. In some of the respective embodiments, sodium starch glycolate is a starch glycolate having phosphate groups (-O-P(=O)(-O)) linking two (or more) monosaccharide (glucose) units, respectively. - )-O-).

[0103] As used herein, "croscarmellose sodium" refers to any sodium salt of cellulose (as defined herein) substituted with carboxymethyl groups and covalently crosslinked by ester bonds between the carboxymethyl groups and the monosaccharide units.

[0104] Carboxymethyl groups (or any other alkaline groups) substitute for monosaccharides at one or more positions -O=CH2-C(=O)-O -To form an alkaline group, the carboxymethyl group (or any other alkaline group) may be attached to one or more of the hydroxyl substituents of one or more of the monosaccharide (e.g., glucose) units that make up the polysaccharide. In some embodiments, a carboxymethyl group (or any other alkaline group) is attached to at least the hydroxyl methyl group of one or more of the glucose units that make up the polysaccharide. In some embodiments, a carboxymethyl group (or any other alkaline group) is attached to at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or nearly all of the monosaccharide units that make up the polysaccharide. In some of these embodiments, a carboxymethyl group (or any other alkaline group) is attached to the monosaccharide unit that comprises it, and further, in some of these embodiments, a carboxymethyl group (or any other alkaline group) is attached to the hydroxyl methyl substituent of glucose.

[0105] In some of any of the embodiments described herein, the concentration of the polymer comprising multiple alkaline groups (according to any of the respective embodiments described herein) in the composition is at least 10 weight percent. In some such embodiments, the concentration of the polymer is at least 15 weight percent. In some embodiments, the concentration of the polymer is at least 20 weight percent. In some embodiments, the concentration of the polymer is at least 25 weight percent. In some embodiments, the concentration of the polymer is at least 30 weight percent. In some embodiments, the concentration of the polymer is at least 35 weight percent. In some embodiments, the concentration of the polymer is at least 40 weight percent. In some embodiments, the concentration of the polymer is at least 50 weight percent. In some embodiments, the concentration of the polymer is at least 60 weight percent. In some embodiments, the concentration of the polymer is at least 70 weight percent. In some embodiments, the concentration of the polymer is at least 80 weight percent. In some embodiments, the concentration of the polymer is at least 90 weight percent.

[0106] "Weight percent" (or w / w%, or wt %) means the weight of a indicated substance out of the total weight of the composition in which it is contained.

[0107] In some of the embodiments described herein, the concentration of the polymer containing multiple alkaline groups (according to any of the respective embodiments described herein) in the composition is 10 to 90 weight percent of the total weight of the composition, or 10 to 80, or 10 to 70, or 10 to 50, or 10 to 40, or 10 to 30, or 20 to 90, or 20 to 80, or 20 to 70, or 20 to 60, or 20 to 50, or 20 to 40, or 20 to 50, or 20 to 60, or 20 to 70, or 20 to 80, or 20 to 90, or 20 to 50, or 20 to 40, or 20 to 90, or 20 to 90, or 20 to 90, or 20 to 10 ... 30, or 30-90, or 30-80, or 30-70, or 30-60, or 30-50, or 30-40, or 40-90, or 40-80, or 40-70, or 40-60, or 40-50, or 50-90, or 50-80, or 50-70, or 50-60, or 60-90, or 60-80, or 60-70, or 80-90, or 70-80, or 80-90 weight percent (including any intermediate values ​​and subranges therebetween).

[0108] Without being bound by any particular theory, it is believed that the relatively high concentrations of water-absorbing (e.g., water-swellable) polymers such as sodium starch glycolate and sodium croscarmellose (e.g., compared to compositions using such polymers as disintegrants) are associated with the generation of a viscous medium upon contact with aqueous solutions (e.g., gastric acid) that limits diffusion in the vicinity of the composition, which is significantly different from their effect at lower concentrations (e.g., accelerating the disintegration of solid compositions).

[0109] Compositions using such polymers as disintegrants further differ from compositions according to some embodiments of the present invention in that disintegrants are also typically used in compositions that also contain a large amount of insoluble components, such as microcrystalline cellulose (as opposed to compositions that contain a large amount of water-soluble components, such as SNAC), for example because the mechanism of the disintegrant involves exerting an internal force on a solid insoluble component and / or because the large amount of water-soluble components makes the composition easily soluble, which would result in an excess of disintegrant.

[0110] In some of any of the embodiments relating to polysaccharides described herein, the polysaccharide is characterized by a degree of substitution that is at least 0.1, e.g., in the range of 0.1-2 or 0.1-1.5 or 0.1-1 or 0.1-0.5 or 0.1-0.3 or 0.1-0.2 (including any intermediate values ​​and subranges therebetween). In some such embodiments, the degree of substitution is at least 0.2, e.g., in the range of 0.2-2 or 0.2-1.5 or 0.2-1 or 0.2-0.5 (including any intermediate values ​​and subranges therebetween). In some embodiments, the degree of substitution is at least 0.3, e.g., in the range of 0.3-2 or 0.3-1.5 or 0.3-1 or 0.3-0.5 (including any intermediate values ​​and subranges therebetween). In some embodiments, the degree of substitution is at least 0.4, for example, in the range of 0.4 to 2, or 0.4 to 1.5, or 0.4 to 1, including any intermediate values ​​and subranges therebetween.

[0111] As used herein, "degree of substitution" refers to the ratio of functional groups containing an alkaline group or its conjugate acid, such as a carboxylate or carboxylic acid group (e.g., a carboxymethyl group), to the monomers (backbone units) of a polymer (e.g., the monosaccharide units of a polysaccharide).

[0112] In some of the respective embodiments described herein, the concentration of the alkaline group of the polymer in the composition is at least 0.03 millimoles per gram of the composition, for example, 0.03-5 millimoles / gram, or 0.03-2 millimoles / gram, or 0.03-1 millimoles / gram, or 0.03-0.5 millimoles / gram, or 0.03-0.2 millimoles / gram (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of the alkaline group of the polymer is at least 0.1 millimoles per gram of the composition, for example, 0.1-5 millimoles / gram, or 0.1-2 millimoles / gram, or 0.1-1 millimoles / gram, or 0.1-0.5 millimoles / gram (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of alkaline groups in the polymer is at least 0.2 millimoles per gram of the composition, such as 0.2-5 millimoles / gram or 0.2-2 millimoles / gram or 0.2-1 millimoles / gram or 0.2-0.5 millimoles / gram (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of alkaline groups in the polymer is at least 0.5 millimoles per gram of the composition, such as 0.5-5 millimoles / gram or 0.5-2 millimoles / gram or 0.5-1 millimoles / gram (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of alkaline groups in the polymer is at least 1 millimoles per gram of the composition, such as 1-5 millimoles / gram or 1-2 millimoles / gram (including any intermediate values ​​and subranges therebetween).

[0113] In some of any of the embodiments described herein, the composition is a unit dosage form composition, and the amount of alkaline groups of the polymer in the unit dosage form (correlated to the acid neutralizing ability of the polymer in the unit dosage form) is at least 0.03 millimolar, for example, 0.03 to 10 millimolar, or 0.03 to 3 millimolar, or 0.03 to 1 millimolar, or 0.03 to 0.3 millimolar (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of alkaline groups in the unit dosage form is at least 0.1 millimolar, for example, 0.1 to 10 millimolar, or 0.1 to 3 millimolar, or 0.1 to 1 millimolar (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of alkaline groups in the unit dosage form is at least 0.3 millimolar, for example, 0.3 to 10 millimolar, or 0.3 to 3 millimolar (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of alkaline group in the unit dosage form is at least 1 millimolar, for example, from 1 to 10 millimolar (including any intermediate values ​​and subranges therebetween).

[0114] As mentioned above, the alkaline group-containing polymer according to any of the embodiments described herein may optionally comprise two or more (for example, at least three or at least four) different polymers (for example, in a mixture) that contain alkaline groups.Thus, for example, sodium starch glycolate may account for a portion of all alkaline group-containing polymers, for example, at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent, or at least 90 weight percent of the alkaline group-containing polymer (according to any of the embodiments described herein), and the remainder is one or more alkaline group-containing polymers other than sodium starch glycolate. Alternatively or in addition, croscarmellose sodium may comprise a portion of all alkaline group-containing polymers, for example at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent, or at least 90 weight percent (according to any of the respective embodiments described herein) of the alkaline group-containing polymers, with the remainder being one or more alkaline group-containing polymers other than croscarmellose sodium.

[0115] It is noted that polymers generally comprise populations of molecules that typically have different sizes and slightly different geometries (e.g., branching patterns and / or sequences of monomers in copolymers). According to standard practice in the art, such populations of molecules are not considered to represent "different polymers". Rather, "different polymers" refers to polymers that are chemically different, e.g., composed of different monomers (backbone units) and / or crosslinkers and / or have different degrees of crosslinking.

[0116] The effect of the polymer on the absorption of the therapeutically active agent can be optionally determined by comparing the absorption upon oral administration of the composition according to the embodiment of the present invention with a corresponding composition that contains the same amount of other components than the alkaline group-containing polymer (e.g., the alkaline group-containing polymer is 50 weight percent or less of the composition according to the embodiment of the present invention), whereby the total mass is lower (due to the absence of the alkaline group-containing polymer). In some such embodiments, both compositions are in the form of tablets, the tablets have the same cross section (e.g., diameter of the circular cross section), and the tablet with the lower weight is thinner in the axis perpendicular to the cross section of the tablet.

[0117] Alternatively, the effect of the polymer on the absorption of the therapeutically active agent may optionally be determined by comparing the absorption upon oral administration of a composition according to an embodiment of the present invention with a corresponding composition comprising an absorption enhancer instead of the alkaline group-containing polymer (e.g., the corresponding composition is identical in all respects except for the presence of the additional absorption enhancer in place of the polymer), whereby the total mass of the composition is the same (e.g., when the alkaline group-containing polymer is greater than 50 weight percent of the composition according to an embodiment of the present invention).

[0118] In some embodiments of any one of the embodiments described herein, the Cmax and / or bioavailability of the composition (i.e., the therapeutically active agent in the composition) after oral administration is at least 20% higher (120% of its level) than the Cmax and / or bioavailability of the corresponding composition without the alkaline group-containing polymer. In some embodiments, the Cmax and / or bioavailability is at least 50% higher (150% of its level) than the Cmax and / or bioavailability of the corresponding composition without the alkaline group-containing polymer after oral administration. In some embodiments, the Cmax and / or bioavailability is at least twice the Cmax and / or bioavailability of the corresponding composition without the alkaline group-containing polymer after oral administration (200% of its level). In some embodiments, the Cmax and / or bioavailability is at least four times the Cmax and / or bioavailability of the corresponding composition without the alkaline group-containing polymer after oral administration (400% of its level). In some embodiments, the Cmax and / or bioavailability is at least 6 times (600% of its level) the Cmax and / or bioavailability after oral administration of the corresponding composition without the alkaline group-containing polymer. In some embodiments, the Cmax and / or bioavailability is at least 10 times (1000% of its level) the Cmax and / or bioavailability after oral administration of the corresponding composition without the alkaline group-containing polymer.

[0119] Cmax and / or bioavailability can optionally be determined by orally administering the composition to a subject (e.g., a human subject) and determining the level of therapeutically active agent in the blood at frequent intervals by taking blood samples.

[0120] Bioavailability can be determined using standard techniques known in the art (e.g., data processing algorithms) by comparing the ratio of the area under the curve following oral administration (e.g., over a 12 or 24 hour period) to the area under the curve over the same period for an intravenously administered therapeutically active agent. The therapeutically active agent may be injected at a lower dose (e.g., for safety reasons) and the area under the curve can be normalized to the total amount administered.

[0121] Absorption enhancers: According to a preferred embodiment of any of the embodiments described herein, the compositions according to any of the respective embodiments described herein comprise an effective amount of an absorption enhancer, i.e., an amount of the absorption enhancer effective to enhance absorption of the therapeutically active agent in the composition.

[0122] As used herein, the term "absorption enhancer" refers to a compound known to enhance the absorption of macromolecular drugs (e.g., compounds having a molecular weight of at least 1 kDa) from the gastrointestinal tract into the circulation following oral administration of the drug. Those skilled in the art will be aware of many such absorption enhancers.

[0123] In some of any of the embodiments described herein, the absorption enhancer is optionally a fatty acid having a terminal N-(2-hydroxybenzoyl)amino group (at the omega position, i.e., the end distal from the carboxylic acid group of the fatty acid), or a salt thereof (e.g., monosodium or disodium salt). Alternatively, the fatty acid may optionally be an unsubstituted fatty acid (e.g., caproic acid, caprylic acid, capric acid, lauric acid, oleic acid, and / or stearic acid).

[0124] The fatty acids (substituted or unsubstituted) are preferably 4-20 carbon atoms in length, optionally 4-18 carbon atoms in length, optionally 4-16 carbon atoms in length, optionally 4-14 carbon atoms in length, optionally 4-12 carbon atoms in length, and optionally 4-10 carbon atoms in length (including any intermediate values ​​and subranges therebetween). In some of any of the embodiments described herein, the fatty acids are 6-20 carbon atoms in length, optionally 6-18 carbon atoms in length, optionally 6-16 carbon atoms in length, optionally 6-14 carbon atoms in length, optionally 6-12 carbon atoms in length, optionally 6-10 carbon atoms in length, and optionally 8-10 carbon atoms in length (including any intermediate values ​​and subranges therebetween). The fatty acid moiety can be saturated (e.g., caprylic acid in 8-N-(2-hydroxybenzoyl)aminocaprylic acid and decanoic acid in 10-N-(2-hydroxybenzoyl)aminodecanoic acid) or unsaturated (i.e., contains at least one unsaturated carbon-carbon bond).

[0125] Examples of suitable fatty acids (eg, for substitution with a terminal N-(2-hydroxybenzoyl)amino group) include, but are not limited to, butanoic acid, caprylic acid, and decanoic acid.

[0126] The N-(2-hydroxybenzoyl)amino group may be optionally substituted (e.g., on its aromatic ring) or unsubstituted. Suitable substituents include, for example, halo (optionally chloro) and alkoxy (optionally methoxy). Examples of substituted N-(2-hydroxybenzoyl)amino groups include, but are not limited to, N-(5-chlorosalicyloyl)amino, N-(4-chloro-2-hydroxybenzoyl)amino, and N-(2-hydroxy-4-methoxybenzoyl)amino.

[0127] Examples of suitable absorption enhancers include, but are not limited to, NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) and NAD (10-N-(2-hydroxybenzoyl)aminodecanoic acid) and their salts (e.g., monosodium and disodium salts), as well as derivatives thereof (e.g., chloro- and / or methoxy-substituted derivatives), such as 5-CNAC (8-N-(5-chlorosalicyloyl)aminocaprylic acid) and 4-MOAC (8-N-(2-hydroxy-4-methoxybenzoyl)aminocaprylic acid) and their salts (e.g., monosodium and disodium salts). 4-CNAB (4-N-(2-hydroxy-4-chlorobenzoyl)aminobutanoic acid) and their salts (e.g., monosodium and disodium salts) are further examples of suitable absorption enhancers.

[0128] In some of any of the embodiments described herein, the absorption enhancer is in the form of a salt thereof, for example, a sodium salt. In an exemplary embodiment, the sodium salt is a monosodium salt.

[0129] In some of any of the embodiments described herein, the absorption enhancer is NAC or NAD, or a salt thereof. In some such embodiments, the absorption enhancer is NAC or a salt thereof.

[0130] As shown below, the structure of NAD (shown as its sodium salt, also referred to as "SNAD") differs from that of NAC (shown as its sodium salt, also referred to as "SNAC") only in the length of the fatty acid moiety. Additional absorption enhancers related to NAC and NAD based on various fatty acid lengths will be readily apparent to one of skill in the art.

[0131] [ka]

[0132] Without being bound by any particular theory, it is believed that many absorption enhancers tend to be more active (at promoting absorption) in ionic form (e.g., carboxylate anions, such as fatty acid anions) than in less soluble non-ionic form (e.g., carboxylic acids, such as fatty acids), and that the overall activity of the absorption enhancer is strongly dependent on the concentration of the more active form. For example, the activity of the less soluble non-ionic form may be reduced by precipitation. It is further believed that the amount of ionic form of the absorption enhancer upon dissolution after oral administration may be enhanced by providing the absorption enhancer in a salt form and / or by controlling the local pH in the vicinity of the absorption enhancer after oral administration (e.g., by neutralization of acid by alkaline groups of the polymers described herein and / or even by other molecules of the absorption enhancer).

[0133] According to some of any of the embodiments described herein, the absorption enhancer is an ionizable material (compound), and in some of these embodiments, the absorption enhancer is more active in its ionic form.

[0134] According to some of any of the embodiments described herein, the absorption enhancer is inactivated by gastric acid as described herein, and in some of these embodiments, the absorption enhancer is ionizable and is more active in its ionic form, and at least a portion of the absorption enhancer is in a non-ionic (less active) form when in contact with gastric acid (e.g., by precipitation).

[0135] It is further believed that the formation of a viscous medium may enhance the effect of absorption enhancers that are not inactivated by stomach acid, for example, by maintaining a higher local concentration of the absorption enhancer in the vicinity of the therapeutically active agent and / or by promoting adhesion of the composition to the stomach wall (e.g., as described herein).

[0136] Additionally or alternatively, the control over local pH associated with the polymer may protect the therapeutically active agent from inactivation by gastric acid (whether or not the absorption enhancer is inactivated by gastric acid), for example inactivation associated with pepsin activity in the presence of a suitably acidic pH (as described elsewhere herein).

[0137] According to some of any of the embodiments described herein, the absorption enhancer is not inactivated by gastric acid, e.g., the absorption enhancer is not ionizable and / or its ionized form and its non-ionized form exhibit the same activity and / or is not converted to a less active form upon contact with gastric acid (e.g., the absorption enhancer is itself acidic).

[0138] Examples of absorption enhancers that are not expected to be inactivated by gastric acid include, but are not limited to, alkyl fatty acid esters (e.g., isopropyl myristate); phospholipids (e.g., phosphatidylcholine); quaternary ammonium salts, such as tetraalkylammonium salts (e.g., cetyltrimethylammonium salts such as cetyltrimethylammonium bromide) and alkylpyridinium salts (e.g., cetylpyridinium salts such as cetylpyridinium chloride); non-ionic surfactants, such as sorbitan-fatty acid esters (e.g., sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate) and polysorbates (i.e., ethoxylated sorbitan-fatty acid esters, such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80); and N-dodecylcaprolactam.

[0139] In some of the embodiments described herein, the concentration of the absorption enhancer (according to any of the embodiments described herein) in the composition (according to any of the embodiments described herein) is at least 10 weight percent, e.g., 10-90 weight percent, or 10-80 weight percent, or 10-70 weight percent, or 10-60 weight percent, or 10-50 weight percent, or 10-40 weight percent, or 10-30 weight percent (including any intermediate values ​​and subranges therebetween). In some such embodiments, the concentration of the absorption enhancer is at least 20 weight percent, e.g., 20-90 weight percent, or 20-80 weight percent, or 20-70 weight percent, or 20-60 weight percent, or 20-50 weight percent, or 20-40 weight percent (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of the absorption enhancer is at least 30 weight percent, e.g., 30-90 weight percent, or 30-80 weight percent, or 30-70 weight percent, or 30-60 weight percent, or 30-50 weight percent (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of the absorption enhancer is at least 40 weight percent, e.g., 40-90 weight percent, or 40-80 weight percent, or 40-70 weight percent, or 40-60 weight percent (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of the absorption enhancer is at least 50 weight percent, e.g., 50-90 weight percent, or 50-80 weight percent, or 50-70 weight percent (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of the absorption enhancer is at least 60 weight percent, e.g., 60-90 weight percent, or 60-80 weight percent (including any intermediate values ​​and subranges therebetween). In some embodiments, the concentration of the absorption enhancer is at least 70 weight percent, for example, 70-90 weight percent, or 70-80 weight percent (including any intermediate values ​​and subranges therebetween).In some embodiments, the concentration of the absorption enhancer is at least 80 weight percent, for example, 80 to 90 weight percent (including any intermediate values ​​and subranges therebetween).

[0140] In some of any of the above embodiments, the absorption enhancer is NAC, NAD, 5-CNAC, 4-MOAC and / or 4-CNAB, or a salt thereof (e.g., a sodium salt thereof).

[0141] In some of the embodiments described herein, the total concentration of the absorption enhancer (according to any of the respective embodiments described herein) and the polymer comprising an alkaline group (according to any of the respective embodiments described herein) is at least 80 weight percent (e.g., 80 to 100 weight percent, including any intermediate values ​​and subranges therebetween). In some such embodiments, the concentration of the absorption enhancer (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent. Alternatively or in addition, in some embodiments, the concentration of the polymer comprising an alkaline group (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent. In some of any of the above embodiments, the absorption enhancer is NAC, NAD, 5-CNAC, 4-MOAC and / or 4-CNAB, or a salt thereof (e.g., a sodium salt thereof).

[0142] In some of the embodiments described herein, the total concentration of the absorption enhancer (according to any of the respective embodiments described herein) and the polymer comprising an alkaline group (according to any of the respective embodiments described herein) is at least 90 weight percent (e.g., 90 to 100 weight percent, including any intermediate values ​​and subranges therebetween). In some such embodiments, the concentration of the absorption enhancer (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent. Alternatively or in addition, in some embodiments, the concentration of the polymer comprising an alkaline group (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent. In some of any of the above embodiments, the absorption enhancer is NAC, NAD, 5-CNAC, 4-MOAC and / or 4-CNAB, or a salt thereof (e.g., a sodium salt thereof).

[0143] In some of the embodiments described herein, the total concentration of the absorption enhancer (according to any of the respective embodiments described herein) and the polymer comprising an alkaline group (according to any of the respective embodiments described herein) is at least 95 weight percent (e.g., 95 to 100 weight percent, including any intermediate values ​​and subranges therebetween). In some such embodiments, the concentration of the absorption enhancer (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent. Alternatively or in addition, in some embodiments, the concentration of the polymer comprising an alkaline group (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent. In some of any of the above embodiments, the absorption enhancer is NAC, NAD, 5-CNAC, 4-MOAC and / or 4-CNAB, or a salt thereof (e.g., a sodium salt thereof).

[0144] In some of any one of the embodiments described herein, the total concentration of the absorption enhancer (according to any of the respective embodiments described herein) and the polymer comprising an alkaline group (according to any of the respective embodiments described herein) is at least 98 weight percent. In some such embodiments, the concentration of the absorption enhancer (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent. In some embodiments, the concentration of the polymer comprising an alkaline group (e.g., according to any of the respective embodiments described herein) is at least 10 weight percent, or at least 20 weight percent, or at least 30 weight percent, or at least 40 weight percent, or at least 50 weight percent, or at least 60 weight percent, or at least 70 weight percent, or at least 80 weight percent. In some of any of the above embodiments, the absorption enhancer is NAC, NAD, 5-CNAC, 4-MOAC and / or 4-CNAB, or a salt thereof (e.g., a sodium salt thereof).

[0145] In some of the embodiments relating to any one of the unit dosage forms described herein, the amount of the absorption enhancer in the unit dosage form is at least 25 mg, e.g., 25-1000 mg, or 25-500 mg, or 25-250 mg, or 25-100 mg, or 25-50 mg (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of the absorption enhancer in the unit dosage form is at least 50 mg, e.g., 50-1000 mg, or 50-500 mg, or 50-250 mg, or 50-100 mg (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of the absorption enhancer in the unit dosage form is at least 75 mg, e.g., 75-1000 mg, or 75-500 mg, or 75-250 mg (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of the absorption enhancer in the unit dosage form is at least 100 mg, e.g., 100-1000 mg or 100-500 mg or 100-250 mg (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of the absorption enhancer in the unit dosage form is at least 150 mg, e.g., 150-1000 mg or 150-500 mg or 150-250 mg (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of the absorption enhancer in the unit dosage form is at least 200 mg, e.g., 200-1000 mg or 200-500 mg (including any intermediate values ​​and subranges therebetween). In some embodiments, the amount of the absorption enhancer in the unit dosage form is at least 300 mg, e.g., 300-1000 mg or 300-500 mg (including any intermediate values ​​and subranges therebetween). In some of any of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0146] In some embodiments of any one of the embodiments described herein, the weight ratio of the absorption enhancer to the therapeutically active agent in the composition is at least 1:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 1:1 to 1000:1, or 1:1 to 500:1, or 1:1 to 300:1, or 1:1 to 200:1, or 1:1 to 100:1, or 1:1 to 50:1, or 1:1 to 30:1, or 1:1 to 20:1, or 1:1 to 10:1, or 1:1 to 5:1, or 1:1 to 3:1, or 1:1 to 2:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0147] In some embodiments of any one of the embodiments described herein, the weight ratio of the absorption enhancer to the therapeutically active agent in the composition is at least 2:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 2:1 to 1000:1, or 2:1 to 500:1, or 2:1 to 300:1, or 2:1 to 200:1, or 2:1 to 100:1, or 2:1 to 50:1, or 2:1 to 30:1, or 2:1 to 20:1, or 2:1 to 10:1, or 2:1 to 5:1, or 2:1 to 3:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0148] In some embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 3:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 3:1 to 1000:1, or 3:1 to 500:1, or 3:1 to 300:1, or 3:1 to 200:1, or 3:1 to 100:1, or 3:1 to 50:1, or 3:1 to 30:1, or 3:1 to 20:1, or 3:1 to 10:1, or 3:1 to 5:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0149] In some embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 5:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 5:1 to 1000:1, or 5:1 to 500:1, or 5:1 to 300:1, or 5:1 to 200:1, or 5:1 to 100:1, or 5:1 to 50:1, or 5:1 to 30:1, or 5:1 to 20:1, or 5:1 to 10:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0150] In some embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 10:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 10:1 to 1000:1, or 10:1 to 500:1, or 10:1 to 300:1, or 10:1 to 200:1, or 10:1 to 100:1, or 10:1 to 50:1, or 10:1 to 30:1, or 10:1 to 20:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0151] In some embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 20:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 20:1 to 1000:1, or 20:1 to 500:1, or 20:1 to 300:1, or 20:1 to 200:1, or 20:1 to 100:1, or 20:1 to 50:1, or 20:1 to 30:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0152] In some embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 30:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 30:1 to 1000:1, or 30:1 to 500:1, or 30:1 to 300:1, or 30:1 to 200:1, or 30:1 to 100:1, or 30:1 to 50:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0153] In some embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 50:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 50:1 to 1000:1, or 50:1 to 500:1, or 50:1 to 300:1, or 50:1 to 200:1, or 50:1 to 100:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0154] In some embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 100:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 100:1 to 1000:1, or 100:1 to 500:1, or 100:1 to 300:1, or 100:1 to 200:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0155] In some of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 200:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 200:1 to 1000:1, or 200:1 to 500:1, or 200:1 to 300:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0156] In some of the embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 300:1 (absorption enhancer:therapeutic active agent), and optionally ranges from 300:1 to 1000:1, or from 300:1 to 500:1 (absorption enhancer:therapeutic active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0157] In some of the embodiments of any one of the embodiments described herein, the weight ratio of absorption enhancer to therapeutically active agent in the composition is at least 500:1, and optionally ranges from 500:1 to 1000:1 (absorption enhancer:therapeutically active agent), including any intermediate values ​​and subranges therebetween. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0158] Use and Indications: In some embodiments of any of the embodiments described herein, a composition according to any of the respective embodiments described herein is for use in treating a disease treatable by a therapeutically active agent (according to any of the respective embodiments described herein), wherein the treatment comprises oral administration of the composition.

[0159] According to an aspect of some embodiments of the present invention, there is provided a method of treating a disease treatable by oral administration of a therapeutically active agent (according to any of the respective embodiments described herein) in a subject in need of such treatment, the method comprising orally administering to the subject a composition according to any of the respective embodiments described herein comprising the respective therapeutically active agent (according to any of the respective embodiments described herein).

[0160] Conditions treatable by therapeutically active agents include conditions in which the activity of PTH is beneficial.

[0161] Conditions treatable according to embodiments of the present invention include, but are not limited to, osteoporosis, conditions associated with bone fractures or bone defects, osteoarthritis, and hypoparathyroidism.

[0162] With respect to conditions associated with bone fractures, the terms "treat" and "treatment" include, for example, at least partially, substantially healing the bone fracture (e.g., a nonunion that does not heal without intervention), substantially increasing the rate at which the bone fracture heals, substantially ameliorating or preventing the appearance of symptoms of the bone fracture (e.g., pain, loss of function of a body part, defective bone formation), and, for example, preventing or reducing the likelihood (e.g., prophylaxis) of bone fracture occurring due to the condition. The treatment of bone fractures described herein may optionally be performed in combination with standard treatments for bone fractures, such as bone fixation (e.g., with a cast) and / or surgery.

[0163] Examples of conditions associated with fractures include, but are not limited to, non-union, any condition associated with stress fractures (optionally, the condition is the stress fracture itself).

[0164] As used herein and in the art, the phrase "non-union" refers to a condition in which a fracture is present and there is no reasonable expectation that the fracture will heal without intervention.

[0165] One skilled in the art can readily determine the presence of a bony nonunion.

[0166] In some embodiments of any of the embodiments relating to nonunion, bone nonunion is determined based on failure of the fracture site to heal six months after the fracture occurred and / or lack of progression of callus formation at the fracture site over a four week interval (e.g., as described by Giannotti et al. [Clin Cases Miner Bone Metab 2013, 10:116-120]).

[0167] As used herein and in the art, the phrase "stress fracture" refers to a fracture caused by repeated stress (eg, from running and / or jumping) over a long period of time.

[0168] In some embodiments, treating a condition associated with a stress fracture includes increasing the rate at which an existing stress fracture heals.

[0169] In some embodiments, treating a condition associated with stress fractures includes, for example, reducing the likelihood of a stress fracture occurring in a subject susceptible to stress fractures, including, but not limited to, athletes, runners, soldiers, and others subjected to significant physical activity.

[0170] As used herein, the phrase "bone defect" encompasses any loss of a portion of a bone, including loss of bone due to trauma (e.g., loss of a fragment of bone due to a fracture), surgery (e.g., surgical removal of bone to remove cancer cells), bone resorption, acquired pathology (e.g., loss of a portion of bone due to resorption due to an acquired pathology) and / or congenital pathology (e.g., congenital bone malformation associated with one or more defects in the bone structure), a gap between a bone and an implant intended to provide osseointegration (including, but not limited to, an implant secured to the bone via, for example, a bolt or screw).

[0171] Examples of conditions associated with bone resorption include, but are not limited to, bone resorption associated with inflammatory diseases (e.g., periodontitis), which may include bone resorption near sites of inflammation, and alveolar bone resorption associated with lost teeth.

[0172] As used herein, the terms "osseointegration" and "osseointegrated" refer to the formation of a direct structural connection between living bone and an implant (e.g., without intervening connective tissue), including, but not limited to, bone growth into an implant (e.g., a porous implant), a process also known in the art as "osseointegration."

[0173] With respect to conditions associated with bone defects, the terms "treat" and "treatment" include, for example, substantially healing the bone defect at least partially (e.g., replacing at least a portion of the lost bone by bone regeneration), substantially increasing the rate at which the bone defect heals (e.g., the rate of bone regeneration), substantially ameliorating or preventing the appearance of symptoms of the bone defect (e.g., pain, loss of function of a body part, defective bone formation), and preventing or causing (e.g., preventing) the formation of a bone defect, e.g., the formation of a bone defect due to bone resorption. The treatment of bone defects described herein can optionally be performed in combination with standard treatments for the respective bone defects.

[0174] In some embodiments of any of the respective embodiments described herein, the condition is alveolar bone resorption. In some of these embodiments, the method or treatment is for preserving and / or regenerating alveolar bone. Examples of alveolar bone resorption include, but are not limited to, resorption associated with missing teeth and resorption associated with inflammation (e.g., periodontitis).

[0175] In some embodiments, the method or treatment is for preserving and / or regenerating alveolar bone around a dental implant (e.g., a dental implant that includes or supports an artificial tooth, a crown, a dental bridge, and / or a fixed denture), e.g., for holding the dental implant in place, thereby increasing the usefulness of the implant and / or the likelihood of success of the dental implant. In some embodiments, the method or treatment is performed after dental implantation, e.g., to promote regeneration of alveolar bone (e.g., alveolar bone characterized by missing teeth and / or bone loss associated with bone resorption due to periodontitis). In alternative or further embodiments, the method or treatment is performed before dental implantation when a significant amount of time is expected to pass before dental implantation, e.g., to preserve alveolar bone by preventing or reducing alveolar bone resorption (e.g., when a tooth is lost).

[0176] In some embodiments according to any of the respective embodiments described herein, the bone defect is in the skull (cranium or mandible). In some embodiments, the bone defect is a calvarial bone defect.

[0177] Without being bound by any particular theory, it is believed that bone in the skull (eg, the calvarium) is particularly susceptible to poor healing of bone defects and promotion of bone growth would be beneficial.

[0178] In some embodiments of any of the respective embodiments described herein, the method and / or treatment includes promoting osseointegration of the implant, for example, by promoting bone growth in a gap between the bone (e.g., the calvarial bone) and the implant. The condition can optionally be any condition in which osseointegration of the implant is beneficial.

[0179] Examples of implants in which osseointegration may be promoted include, but are not limited to, artificial dental roots, bone grafts (e.g., bone allografts), chin implants, craniofacial prostheses (e.g., artificial ears, eyes and / or noses), bone-anchored artificial limbs, bone-anchored hearing aids, and artificial joints (e.g., for hip and / or knee replacements).

[0180] As used herein, the term "implant" refers to any device, at least a portion of which is placed into a subject, encompasses artificial devices and implants, and may include synthetic materials, autografts (e.g., bone harvested from a different area of ​​a subject, such as the iliac crest or jaw), allografts (e.g., bone harvested from an individual other than the subject, optionally from a cadaver), xenografts (e.g., bone from a different species, optionally from bovine bone or coral), or any combination thereof. Examples of synthetic materials that may be included in implants (e.g., implants intended to be osseointegrated) include, but are not limited to, hydroxyapatite, calcium carbonate, tricalcium phosphate, polymers (e.g., poly(methyl methacrylate), poly(hydroxyethyl methacrylate)), ceramics, and metals (e.g., titanium).

[0181] In some embodiments of any one of the embodiments described herein relating to the treatment of conditions associated with osteoporosis and / or bone fractures or bone defects, oral administration according to any of the respective embodiments described herein is performed 1-4 times per day. In some such embodiments, oral administration according to any of the respective embodiments described herein is performed 1-3 times per day. In some embodiments, oral administration according to any of the respective embodiments described herein is performed once or twice per day. In some embodiments, oral administration according to any of the respective embodiments described herein is performed once per day.

[0182] In some embodiments of any one of the embodiments described herein relating to the treatment of conditions associated with bone fracture or bone defect, oral administration is performed once a day or less. In some such embodiments, oral administration is performed once every two days. In some such embodiments, oral administration is performed twice a week. In some such embodiments, oral administration is performed once a week or less.

[0183] In some embodiments of any one of the embodiments described herein relating to oral administration once a day or less frequently, the treatment is prophylactic treatment (to prevent or reduce the likelihood and / or size of fractures and / or bone defects), i.e., the subject does not necessarily have a fracture and / or bone defect at the time of treatment.

[0184] In some embodiments, the prophylactic treatment is for stress fractures, for example, in a subject susceptible to stress fractures (eg, as described herein).

[0185] In some embodiments, the prophylactic treatment is for preventing or reducing alveolar bone loss associated with alveolar bone resorption, for example, in a subject susceptible to alveolar bone resorption (as described herein). Subjects with periodontitis and / or subjects who have lost teeth are non-limiting examples of subjects susceptible to alveolar bone resorption.

[0186] Without being bound by any particular theory, it is believed that for prophylactic applications, relatively low dosages (eg, when administered by relatively infrequent oral administration) are preferable over higher dosages.

[0187] Compositions for oral administration (as described herein) may be particularly advantageous for indications where frequent administration of a therapeutically active agent is desirable.

[0188] In some embodiments of any one of the embodiments described herein relating to the treatment of hypoparathyroidism, oral administration according to any of the respective embodiments described herein is performed at least twice a day (e.g., 2-6 times a day). In some such embodiments, oral administration according to any of the respective embodiments described herein is performed at least three times a day (e.g., 3-6 times a day). In some embodiments, oral administration according to any of the respective embodiments described herein is performed at least four times a day (e.g., 4-6 times a day).

[0189] Without being bound by any particular theory, it is believed that frequent administration of PTH as described in any of the respective embodiments herein provides a relatively steady increase in PTH levels in the body, which is advantageous in treating hypoparathyroidism.

[0190] It is anticipated that many related treatments for PTH-mediated conditions will be developed during the life of the patent issuing from this application, and the scope of the phrases "therapeutically active agent" and "disease treatable by... a therapeutically active agent" is intended to include speculatively all such new technology.

[0191] Without being bound by any particular theory, it is believed that the compositions according to some embodiments described herein can provide a pharmacokinetic profile characterized by a short period of PTH absorption and an acute (as opposed to chronic) PTH exposure that promotes bone growth (as opposed to chronic exposure that promotes bone resorption), which is particularly advantageous for the treatment of some of the indications described herein (e.g., osteoporosis and / or bone fractures).

[0192] In some embodiments, the composition (e.g., composition unit dosage form) is formulated such that absorption of the therapeutically active agent following oral administration of the composition is characterized by a Tmax of 60 minutes or less. In some embodiments, Tmax is 50 minutes or less. In some embodiments, Tmax is 40 minutes or less. In some embodiments, Tmax is 30 minutes or less. In some embodiments, Tmax is 20 minutes or less. In some embodiments, Tmax is 15 minutes or less. In some embodiments, Tmax is 10 minutes or less.

[0193] In some embodiments, the composition (e.g., composition unit dosage form) is formulated such that absorption of the therapeutically active agent following oral administration of the composition is characterized by a ratio of AUC to Cmax of 3 hours or less. In some embodiments, the ratio of AUC to Cmax is 2 hours or less. In some embodiments, the ratio of AUC to Cmax is 90 minutes or less. In some embodiments, the ratio of AUC to Cmax is 60 minutes or less. In some embodiments, the ratio of AUC to Cmax is 50 minutes or less. In some embodiments, the ratio of AUC to Cmax is 40 minutes or less. In some embodiments, the ratio of AUC to Cmax is 30 minutes or less. In some embodiments, the ratio of AUC to Cmax is 20 minutes or less. In some embodiments, the ratio of AUC to Cmax is 15 minutes or less. In some embodiments, the ratio of AUC to Cmax is 10 minutes or less.

[0194] As used herein, the term "AUC" refers to the area under the curve that represents the level of an administered drug in the blood (e.g., plasma level) as a function of time after administration, and may be determined by measuring the plasma level of the drug at various time points after administration, as exemplified herein.

[0195] As used herein, the term "Cmax" refers to the maximum concentration of an administered drug in the blood (e.g., plasma level), and may be determined by measuring the level of the drug at various times after administration, as exemplified herein.

[0196] As used herein, the term "Tmax" refers to the time from administration to the point at which the maximum concentration of the administered drug in the blood (e.g., plasma level) occurs, and may be determined by measuring the level of the drug at various times after administration, as exemplified herein.

[0197] Since some PTH is normally present in the blood prior to dosing, the areas below the baseline value are removed from AUC and Cmax (e.g., by subtracting the baseline value from the measurements at each time point), such that AUC and Cmax each represent the aspect of the increase above baseline that occurs following dosing. The baseline may optionally be determined by measuring a pre-dose value and / or determining (e.g., by curve fitting) the baseline to which that value decays following dosing. Alternatively or additionally, in embodiments where the species of compound administered (e.g., teriparatide) is different from endogenous PTH, measurement of the therapeutically active agent may be selective for the agent administered.

[0198] The ratio of AUC to Cmax (i.e., AUC divided by Cmax) will depend on the nature of the pharmacokinetic profile of the composition, in particular the shape of the curve representing the level of therapeutically active agent in the blood (e.g., plasma level) as a function of time after administration. Pharmacokinetic profiles characterized by rapid increases and decreases within a short period of time will tend to have a relatively low ratio of AUC to Cmax, while pharmacokinetic profiles characterized by more gradual increases and decreases over a longer period of time will tend to have a relatively high ratio of AUC to Cmax.

[0199] Thus, without being bound by any particular theory, it is believed that a ratio of AUC to Cmax that is 3 hours or less is associated with a relatively rapid increase and decrease in the level of the therapeutically active agent in the blood, as described herein according to any of the respective embodiments.

[0200] The ratio of AUC to Cmax is optionally calculated based on data from multiple administrations of the composition. In such cases, the ratio of AUC to Cmax is preferably calculated for each administration, and then the ratios calculated for each administration can be averaged.

[0201] Similarly, the Cmax and / or Tmax are optionally calculated based on data from multiple administrations of the composition. In such cases, the Cmax and / or Tmax values ​​are preferably calculated for each administration, and then the Cmax and / or Tmax values ​​calculated for each administration may be averaged.

[0202] Without being bound by any particular theory, it is believed that averaging data (e.g., measured blood concentrations of a therapeutically active agent) from different administrations of a therapeutically active agent often results in broader curves, lower Cmax values, and greater ratios of AUC to Cmax than those observed after a single administration. Thus, the Cmax values ​​and AUC to Cmax ratios calculated for averaged data are less accurate indicators of the effect of a composition after administration (as opposed to the average of the ratios calculated for each administration, as described above).

[0203] Formulation of the Composition: Each of the compositions and unit dosage forms described herein optionally consists essentially of the functional components described above (e.g., a therapeutically active agent, an absorption enhancer, and an alkaline group-containing polymer according to any of the embodiments described herein in any of the respective sections of the present specification), or the composition further comprises a suitable pharma- ceutically acceptable carrier and / or excipient.

[0204] Hereinafter, the phrases "physiologically acceptable carrier" and "pharmaceutical acceptable carrier", which may be used interchangeably, refer to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the activity (e.g., biological activity) and properties of a functional ingredient (e.g., a therapeutically active agent). Adjuvants are included in these phrases.

[0205] As used herein, the term "excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch (e.g., non-modified types of starch), cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0206] In some embodiments of any one of the embodiments described herein, the composition is formulated as a solid composition, for example, a solid unit dosage form.In some embodiments, the composition is formulated as a tablet or a combination of tablets (for example, multiple mini tablets).In some embodiments, the composition is formulated as a capsule as described herein, for example, including multiple mini tablets and / or powder, and has a coating that is soluble in gastric fluid (for example, at gastric pH) or releases the capsule contents immediately (for example, within less than 5 minutes, or less than 2 minutes, or less than 1 minute) when contacted with gastric fluid.

[0207] The components of the formulation (including but not limited to any two or more of the alkaline group-containing polymer, the absorption enhancer, and the therapeutically active agent of any of the respective embodiments described herein) may optionally be homogeneously mixed or non-uniformly distributed throughout the composition.

[0208] Techniques for formulating and administering drugs may be found in the latest edition of "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, incorporated herein by reference.

[0209] Pharmaceutical compositions and unit dosage forms of the several embodiments of the present invention may be manufactured by methods well known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0210] Pharmaceutical compositions and unit dosage forms for use in accordance with some embodiments of the present invention herein may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, that facilitate processing of the active ingredient into pharma- ceutically usable preparations.

[0211] Pharmaceutical compositions and unit dosage forms can be easily formulated by combining the active compound with pharma- ceutically acceptable carriers well known in the art so that they are suitable for oral administration. Such carriers can optionally facilitate the formulation of pharmaceutical compositions as tablets (including mini-tablets), pellets, pills, dragees, capsules, powders, granules, elixirs, tinctures, liquids, gels, syrups, slurries, suspensions, emulsions, and the like, for oral administration to patients. Pharmacological preparations for oral use can be made with solid excipients, optionally milling the resulting mixture, adding suitable auxiliaries as necessary, and then processing the mixture of granules to obtain tablets or dragee cores. Pharmaceutical compositions and unit dosage forms suitable for oral administration include, but are not limited to, immediate release, time-controlled release, sustained release, and delayed release pharmaceutical dosage forms. In some of any of the respective embodiments, the pharmaceutical compositions formulated for oral administration are solid compositions, such as tablets, capsules, powders, or granules.

[0212] Suitable excipients are in particular fillers such as sugars including lactose, sucrose, mannitol or sorbitol, cellulose preparations such as methylcellulose, hydroxypropylmethyl-cellulose, unmodified starches such as corn, wheat, rice and / or potato starch, gelatin, tragacanth gum and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If necessary, lubricants such as talc or magnesium stearate may be added.

[0213] In some embodiments of any one of the embodiments described herein, any one of the compositions or unit dosage forms (e.g., formulated as a tablet) described herein further comprises a lubricant. In some embodiments, the lubricant is included at a concentration of 5 weight percent or less, optionally 2 weight percent or less, optionally about 1 weight percent. In some embodiments, the compositions or unit dosage forms (e.g., formulated as a tablet) described herein consist essentially of a therapeutically active agent (as described herein), an absorption enhancer, a lubricant, an alkaline group-containing polymer, and an optional protease inhibitor (as described herein). In some embodiments, the lubricant is magnesium stearate.

[0214] The compositions or unit dosage forms (e.g., formulated as tablets) described herein may alternatively or in addition include additives and / or further agents, such as antioxidants, solvents, odor absorbers, chelating agents, preservatives, thickening agents, colorants or coloring agents (pigments, nacre, water-soluble dyes), dispersants, fillers, flavoring agents and bactericides.

[0215] Dragee cores are optionally provided with a suitable coating.For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer liquid and suitable organic solvents or solvent mixtures.Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0216] Pharmaceutical compositions that can be used orally include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and plasticizers, such as glycerol or sorbitol, pullulan, or HPMC. Push-fit capsules may contain active ingredients mixed with fillers such as lactose, binders such as starch, lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added.

[0217] In some of any of the embodiments described herein, the pharmaceutical compositions and / or unit dosage forms according to any of the respective embodiments described herein do not include a gastrointestinal coating or otherwise include a coating that is dissolvable in the gastrointestinal tract (e.g., in gastric fluids) and / or releases its contents shortly (e.g., within 5 minutes or less, or 2 minutes or less, or 1 minute or less / within) upon contact with gastric fluids.

[0218] Pharmaceutical compositions suitable for use in connection with some embodiments of the present invention include compositions in which the therapeutically active agent is included in an amount effective to achieve the intended purpose. More specifically, the compositions preferably include a therapeutically effective amount of the therapeutically active agent, i.e., an amount of the therapeutically active agent effective to prevent, reduce or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Furthermore, the amount of the absorption enhancer is preferably effective to promote absorption of the therapeutically active agent (e.g., in the methods described herein). The amount of the protease inhibitor (if present) is preferably effective to inhibit degradation of the therapeutically active agent (e.g., a polypeptide agent) by proteases.

[0219] Determination of a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0220] For any formulation used in the methods of the present invention, the therapeutically effective amount or dose can be initially estimated from in vitro and cell culture assays. For example, a dose can be formulated in an animal model to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.

[0221] Toxicity and therapeutic efficacy of the therapeutically active agents described herein can be determined in vitro, in cell cultures or in experimental animals by standard pharmaceutical procedures. Data obtained from these in vitro and cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. Dosages can vary depending on the dosage form used and the route of administration used. The exact formulation and dosage can be chosen by the individual physician in view of the patient's condition (see, for example, Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.1).

[0222] Dosage and intervals can be individually adjusted to provide a level (e.g., plasma level) of therapeutically active agent sufficient to induce or inhibit a biological effect (minimal effective concentration, MEC). The MEC varies for each formulation but can be estimated from in vitro data. The dosage required to achieve the MEC depends on individual characteristics. Detection assays can be used to determine plasma concentrations.

[0223] In some of any of the embodiments described herein, the dose of therapeutically active agent according to any of the corresponding embodiments described herein (e.g., the amount of active agent in a unit dosage form composition according to any of the corresponding embodiments described herein) is at least 50 μg of therapeutically active agent. In some embodiments, the dose is at least 100 μg of therapeutically active agent. In some embodiments, the dose is at least 200 μg of therapeutically active agent. In some embodiments, the dose is at least 500 μg of therapeutically active agent. In some embodiments, the dose is at least 1000 μg of therapeutically active agent. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0224] In some of any of the embodiments described herein, the dose of therapeutically active agent according to any of the corresponding embodiments described herein (e.g., the amount of active agent in a unit dosage form composition according to any of the corresponding embodiments described herein) is 3000 μg or less (e.g., 50-3000 μg, or 100-3000 μg, or 200-3000 μg, or 500-3000 μg, or 1000-3000) of therapeutically active agent. In some embodiments, the dose is 2000 μg or less (e.g., 50-2000 μg, or 100-2000 μg, or 200-2000 μg, or 500-2000 μg, or 1000-2000) of therapeutically active agent. In some embodiments, the dosage is 1000 μg or less (e.g., 50-1000 μg, or 100-1000 μg, or 200-1000 μg, or 500-1000 μg) of therapeutically active agent. In some of the above embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0225] Depending on the severity and responsiveness of the condition to be treated, administration may be of single or multiple administrations, with the course of treatment lasting from a few hours to a few weeks, or until a cure is effected or a diminution of the condition is achieved.

[0226] The amount of a 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.

[0227] Each administration may optionally be performed using a single dosage form, or multiple unit dosage forms. Multiple unit dosage forms may optionally be used for convenience only (e.g., two or three unit dosage forms are used) or to reduce variability in absorption according to any of the respective embodiments described in WO 2018 / 033927, for example, at least three or at least four unit dosage forms are used (e.g., 3-10 or 4-10 (including any intermediate values ​​and subranges therebetween).

[0228] The compositions of some embodiments of the present invention may be provided in a pack or dispenser device, such as an FDA approved kit, if desired, which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise 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 may also be accompanied by 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 approval by the agency of the form of the composition or its administration to humans or animals. Such notice may, for example, be of a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved package insert. The compositions including the formulations of the present invention may also be prepared (e.g., as described herein), placed in a suitable container, and labeled for treating an indicated disease, as further detailed herein.

[0229] In some embodiments of any one of the embodiments described herein, when the therapeutically active agent is a polypeptide, the composition comprises at least one protease inhibitor, for example, the type of protease inhibitor, the concentration and / or absolute amount of the protease inhibitor, and / or the ratio of the protease inhibitor to the absorption enhancer and / or the therapeutically active agent, each of which is based on any one of the embodiments related to the protease inhibitor described in US Patent Publication No. 2011 / 0142800, WO 2016 / 128972, and WO 2018 / 033927. The contents of the above documents (especially those related to the protease inhibitor) are incorporated herein by reference.

[0230] Throughout this specification, the term "protease inhibitor" refers to a compound that reduces the proteolytic activity of a protease (e.g., the proteolytic activity of which inactivates a therapeutically active agent described herein). The term "protease inhibitor" encompasses, for example, both macromolecules (e.g., proteins) and small molecules, and both natural and synthetic compounds.

[0231] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one trypsin inhibitor, hi some embodiments, the at least one protease inhibitor consists essentially of one or more trypsin inhibitors.

[0232] Examples of trypsin inhibitors that may 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, the at least one trypsin inhibitor comprises soybean trypsin inhibitor (SBTI). In some embodiments, the at least one trypsin inhibitor (and optionally the at least one protease inhibitor) consists essentially of SBTI.

[0233] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one serpin. In some embodiments, the at least one protease inhibitor consists essentially of one or more serpins.

[0234] Examples of serpins that may be used in any one of the embodiments described herein include, but are not limited to, α1-antitrypsin, antitrypsin-related protein, α1-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 antigen-1 (S These include CCA-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, alpha2-antiplasmin, complement 1 inhibitor, heat shock protein of 47 kDa (HSP47), neuroserpin, and punctupin.

[0235] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one cysteine ​​protease inhibitor, hi some embodiments, the at least one protease inhibitor consists essentially of one or more cysteine ​​protease inhibitors.

[0236] Examples of cysteine ​​protease inhibitors that may be used in any one of the embodiments described herein include, but are not limited to, cystatin type 1, cystatin type 2, human cystatins C, D, S, SN, and SA, cystatin E / M, cystatin F, and cystatin type 3 (including kininogen).

[0237] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one threonine protease inhibitor, hi some embodiments, the at least one protease inhibitor consists essentially of one or more threonine protease inhibitors.

[0238] Examples of threonine protease inhibitors that may be used in any one of the embodiments described herein include, but are not limited to, bortezomib, MLN-519, ER-807446, and TMC-95A.

[0239] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one aspartic protease inhibitor, hi some embodiments, the at least one protease inhibitor consists essentially of one or more aspartic protease inhibitors.

[0240] Examples of aspartic protease inhibitors that may 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.

[0241] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one metalloprotease inhibitor, hi some embodiments, the at least one protease inhibitor consists essentially of one or more metalloprotease inhibitors.

[0242] Examples of metalloproteinase inhibitors that may be used in any one of the embodiments described herein include, but are not limited to, angiotensin-1 converting enzyme inhibitor peptides, antihemorrhagic factor BJ46a, β-casein, proteinase inhibitor CeKI, snake 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 metalloproteinases, WAP, Kazal type inhibitors, immunoglobulins, and Kunitz-type and NTR domain-containing protein 1.

[0243] Examples of protease inhibitors that may 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 isethionate, pepstatin, guanidinium, α2-macroglobulin, zinc chelators, and iodoacetic acid.

[0244] In some embodiments of any one of the embodiments described herein, the amount of the protease inhibitor in the unit dosage form described herein is at least about 0.1 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 0.2 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 0.3 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 0.4 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 0.6 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 0.8 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 1 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 1.5 mg. In some embodiments, the amount of the protease inhibitor in the unit dosage form described herein is at least about 2 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 2.5 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 3 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 5 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 7 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 10 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 12 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 15 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 20 mg.In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 30 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 50 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 70 mg. In some embodiments, the amount of protease inhibitor in the unit dosage forms described herein is at least about 100 mg.

[0245] In some embodiments of any one of the embodiments described herein, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.1 to 1 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.2 to 1 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.3 to 1 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.5 to 1 mg.

[0246] In some embodiments of any one of the embodiments described herein, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.1 to 2 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.2 to 2 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.3 to 2 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 0.5 to 2 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 1 to 2 mg.

[0247] In some embodiments of any one of the embodiments described herein, the amount of protease inhibitor in a unit dosage form described herein ranges from 1 to 10 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 2 to 10 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 3 to 10 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 5 to 10 mg.

[0248] In some embodiments of any one of the embodiments described herein, the amount of protease inhibitor in a unit dosage form described herein ranges from 1 to 20 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 2 to 20 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 3 to 20 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 5 to 20 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 10 to 20 mg.

[0249] In some embodiments of any one of the embodiments described herein, the amount of protease inhibitor in a unit dosage form described herein ranges from 10 to 100 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 20 to 100 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 30 to 100 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 50 to 100 mg.

[0250] In some embodiments of any one of the embodiments described herein, the amount of protease inhibitor in a unit dosage form described herein ranges from 10 to 200 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 20 to 200 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 30 to 200 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 50 to 200 mg. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein ranges from 100 to 200 mg.

[0251] In some embodiments of any one of the embodiments described herein, the amount of protease inhibitor in the unit dosage form described herein is at least about 10 kallikrein inactivator units (kiu). In some embodiments, the amount of protease inhibitor in the unit dosage form described herein is at least about 12 k.iu. In some embodiments, the amount of protease inhibitor in the unit dosage form described herein is at least about 15 k.iu. In some embodiments, the amount of protease inhibitor in the unit dosage form described herein is at least about 20 k.iu. In some embodiments, the amount of protease inhibitor in the unit dosage form described herein is at least about 30 k.iu. In some embodiments, the amount of protease inhibitor in the unit dosage form described herein is at least about 40 k.iu. In some embodiments, the amount of protease inhibitor in the unit dosage form described herein is at least about 50 k.iu. In some embodiments, the amount of protease inhibitor in the unit dosage form described herein is at least about 70 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 100 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 150 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 200 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 300 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 500 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 700 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 1000 k.iu.In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 1500 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 3000 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 4000 k.iu. In some embodiments, the amount of protease inhibitor in a unit dosage form described herein is at least about 5000 k.iu.

[0252] As used herein and in the art, "kallikrein inactivation unit" (kiu) refers to the amount of a protease inhibitor that has the ability to inhibit 2 units of kallikrein by 50% (e.g., in an aqueous solution at the optimal pH and solution volume for activity of the protease inhibitor).

[0253] In some embodiments of any one of the embodiments described herein, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 1:1 to 5:1 (protease inhibitor:therapeutic active agent). In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 5:1 to 10:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 10:1 to 20:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 20:1 to 30:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 30:1 to 40:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 40:1 to 50:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 50:1 to 75:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 75:1 to 100:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 100:1 to 200:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 200:1 to 300:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 300:1 to 400:1. In some embodiments, the weight ratio of the protease inhibitor to the therapeutically active agent ranges from 400:1 to 500:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0254] Additional definitions: As used herein, the term "polypeptide" refers to a polymer (as described herein) comprising at least four amino acid residues linked by peptide bonds or analogs thereof, and optionally only by peptide bonds themselves. In some embodiments, a polypeptide comprises at least 10 amino acid residues or analogs thereof. In some embodiments, a polypeptide comprises at least 20 amino acid residues or analogs thereof. In some embodiments, a polypeptide comprises at least 30 amino acid residues or analogs thereof. In some embodiments, a polypeptide comprises at least 50 amino acid residues or analogs thereof. The term "polypeptide" encompasses naturally occurring polypeptides (e.g., degradation products, synthetically synthesized polypeptides, and / or recombinant polypeptides), including, but not limited to, naturally occurring proteins, fragments and substituted derivatives of naturally occurring proteins, and homologs of naturally occurring proteins and / or fragments and / or substituted derivatives thereof, as well as peptidomimetics (typically synthetically synthesized polypeptides) and polypeptide analogs, peptoids and semipeptoids, which may have modifications, for example, that render the polypeptide 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.The method for preparing peptidomimetic compounds is well known in the art and is described, for example, in Quantitative Drug Design, CA Ramsden Gd., Chapter 17.2, F. Choplin Pergamon Press (1992), which is incorporated by reference as if fully set forth herein.More details on this subject are provided herein.

[0255] A peptide bond (-CO-NH-) in a polypeptide can be replaced by, for example, an N-methylated amide bond (-N(CH3)-CO-), an ester bond (-C(=O)-O-), a ketomethylene bond (-CO-CH2-), a sulfinylmethylene bond (-S(=O)-CH2-), an α-aza bond (-NH-N(R)-CO-) (where R is any alkyl, e.g., methyl), an amine bond (-CH2-NH-), a sulfide bond (-C(=O)-CO- ... The alkyl group may be substituted with an olefin double bond (-H-S-), an ethylene bond (-CH-CH-), a hydroxyethylene bond (-CH(OH)-CH-), a thioamide bond (-CS-NH-), an olefin double bond (-CH=CH-), a fluorinated olefin double bond (-CF=CH-), a retroamide bond (-NH-CO-), a peptide derivative (-N(R)-CH-CO-), where R is a naturally occurring "normal" side chain on a carbon atom.

[0256] These modifications can occur at any of the bonds along the polypeptide chain and even at several (2-3) bonds simultaneously.

[0257] The natural aromatic amino acids, Trp, Tyr and Phe, may be substituted with non-natural 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.

[0258] Polypeptides of some embodiments of the invention (eg, therapeutically active agents described herein) may also include one or more modified amino acids or one or more non-amino acid monomers (eg, fatty acids, complex carbohydrates, etc.).

[0259] The term "amino acid" or "amino acids" is understood to include the 20 naturally occurring amino acids, amino acids that are post-translationally modified in vivo, including, for example, hydroxyproline, phosphoserine, and phosphothreonine, as well as other unusual amino acids, including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, norvaline, norleucine, and ornithine. Additionally, the term "amino acid" includes both D- and L-amino acids.

[0260] The following Tables A and B list natural amino acids (Table A), and non-conventional or modified amino acids (eg, synthetic, Table B), that may be used with some embodiments of the present invention.

[0261] [Table 1]

[0262] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0263] The polypeptides of some embodiments of the invention (e.g., the therapeutically active agents described herein) are preferably used in linear form, although it will be understood that cyclic forms of the polypeptides may also be used where cyclization does not significantly interfere with the characteristics of the polypeptide.

[0264] In some embodiments of any one of the embodiments described herein, the polypeptide is water-soluble, as defined herein.

[0265] Water-soluble polypeptides preferably contain one or more unnatural or natural polar amino acids, including, but not limited to, serine and threonine, which can increase the water solubility of the polypeptide due to their hydroxyl-containing side chains. Optionally, a homologue of a polypeptide is selected to be more water-soluble than the parent polypeptide, for example, by substituting one or more amino acids in the polypeptide with a polar amino acid.

[0266] Polypeptides of some embodiments of the present invention (e.g., therapeutically active agents 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.

[0267] In general, these methods involve the sequential addition of one or more amino acids or suitably protected amino acids to a growing polypeptide chain. Usually, either the amino or carboxyl group of the first amino acid is protected by 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 (amino or carboxyl) group, under conditions suitable for forming an amide bond. 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, either sequentially or simultaneously, to obtain the final polypeptide compound. Simple modifications of this general procedure make it possible to add more than one amino acid at a time to the growing chain, such as by coupling a protected tripeptide with a suitably protected dipeptide (under conditions that do not racemize the chiral centers) to form a pentapeptide after deprotection. Further description of peptide synthesis is disclosed in US Pat. No. 6,472,505.

[0268] A preferred method of preparing the polypeptide compounds of some embodiments of the present invention (eg, the therapeutically active agents described herein) involves solid phase peptide synthesis.

[0269] Large scale polypeptide synthesis is described by Andersson et al. [Biopolymers 2000;55:227-250].

[0270] As used herein, a "homolog" of a given polypeptide 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, more preferably at least 98% homology. In some embodiments, a homolog of a given polypeptide further shares a therapeutic activity with the given polypeptide. The percentage of homology refers to the percentage of amino acid residues in a first polypeptide sequence that match the corresponding residues in a second polypeptide sequence compared to the first polypeptide. Generally, the polypeptides are aligned to obtain maximum homology. Various techniques are known in the art for performing comparison of amino acid sequences to assess the degree of identity, 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, or the practitioner may use non-default parameters depending on his or her experimental and / or other requirements (see, e.g., the website at URL www(dot)ncbi(dot)nlm(dot)nih(dot)gov).

[0271] As used herein, the terms "amine" and "amino" each refer to the group -NR'R", where R' and R" each are hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic (bonded to the amine nitrogen through a ring carbon thereof), aryl, or heteroaryl (bonded to the amine nitrogen through a ring carbon thereof), as defined herein. Alternatively, R' and R" can optionally be joined to form a heteroalicyclic ring (as defined herein). Optionally, R' and R" and R'" are hydrogen or alkyl containing 1 to 4 carbon atoms. Optionally, at least one of R' and R" is hydrogen, and optionally both are hydrogen. If substituted, the carbon atom of the R' and R" hydrocarbon portion bonded to the nitrogen atom of the amine is not substituted with oxo, such that R' and R" are not (for example) carbonyl, C-carboxy, or amido (as these groups are defined herein).

[0272] As used throughout this specification, the term "alkyl" refers to any saturated aliphatic hydrocarbon, including straight-chain and branched-chain groups. Preferably, the alkyl group has 1-20 carbon atoms. Whenever a numerical range, e.g., "1-20," is described herein, it indicates that the group, in this case the hydrocarbon, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. More preferably, the alkyl is a medium-sized alkyl having 1-10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1-4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent can be, for example, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

[0273] As used herein, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon containing at least one carbon-carbon double bond, including straight-chain and branched-chain groups. Preferably, the alkenyl group has 2-20 carbon atoms. More preferably, the alkenyl is a medium-sized alkenyl having 2-10 carbon atoms. Most preferably, unless otherwise indicated, the alkenyl is a lower-sized alkenyl having 2-4 carbon atoms. The alkenyl group may be substituted or unsubstituted. A substituted alkenyl can have one or more substituents, each of which can independently be, for example, alkynyl, cycloalkyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, sulfonamide, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino.

[0274] As used herein, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon containing at least one carbon-carbon triple bond, including straight-chain and branched-chain groups. Preferably, an alkynyl group has 2-20 carbon atoms. More preferably, an alkynyl is a medium-sized alkynyl having 2-10 carbon atoms. Most preferably, unless otherwise indicated, an alkynyl is a lower-sized alkynyl having 2-4 carbon atoms. An alkynyl group can be substituted or unsubstituted. A substituted alkynyl can have one or more substituents, each of which can independently be, for example, cycloalkyl, alkenyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, sulfonamide, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino.

[0275] A "cycloalkyl" group refers to a saturated or unsaturated all-carbon monocyclic or fused ring (i.e., rings sharing adjacent pairs of carbon atoms) group in which one or more of the rings does not have a completely conjugated pi-electron system. Examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane. Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituent may be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, sulfonamide, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein. When a cycloalkyl group is unsaturated, it may contain at least one carbon-carbon double bond and / or at least one carbon-carbon triple bond.

[0276] An "aryl" group refers to an all-carbon monocyclic or fused-ring polycyclic ring (i.e., rings which share adjacent pairs of carbon atoms) having a completely conjugated pi-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, and anthracenyl. Aryl groups can be substituted or unsubstituted. When substituted, the substituent can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

[0277] A "heteroaryl" group refers to a single ring or fused rings (i.e., rings sharing adjacent pairs of atoms) having one or more atoms in the ring, such as, for example, nitrogen, oxygen, and sulfur, and further having a completely conjugated pi-electron system. Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, and purine. Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituent can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.

[0278] A "heteroalicyclic" group refers to a monocyclic or fused ring group having one or more atoms, such as nitrogen, oxygen, and sulfur, in the ring. The ring may also have one or more double bonds. However, the ring does not have a completely conjugated pi-electron system. Heteroalicyclic rings may be substituted or unsubstituted. When substituted, the substituent may be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfonate, sulfate, cyano, nitro, azido, phosphonyl, phosphinyl, oxo, imine, oxime, hydrazone, carbonyl, thiocarbonyl, urea group, thiourea group, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, S-thiocarbamyl, C-amide, N-amide, C-carboxy, O-carboxy, sulfonamide, guanyl, guanidinyl, hydrazine, hydrazide, thiohydrazide, and amino, as these terms are defined herein.Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine, etc.

[0279] An "azido" group is -N=N + =N - Refers to the base.

[0280] An "alkoxy" group refers to any of an -O-alkyl, an -O-alkenyl, an -O-alkynyl, an -O-cycloalkyl, and an -O-heteroalicyclic group, as defined herein.

[0281] An "aryloxy" group refers to both an --O-aryl and an --O-heteroaryl group, as defined herein.

[0282] A "hydroxy" group refers to an --OH group.

[0283] A "thiohydroxy" or "thiol" group refers to a --SH group.

[0284] A "thioalkoxy" group refers to any of an -S-alkyl, -S-alkenyl, -S-alkynyl, -S-cycloalkyl, and -S-heteroalicyclic group, as defined herein.

[0285] A "thioaryloxy" group refers to both an --S-aryl and an --S-heteroaryl group, as defined herein.

[0286] A "carbonyl" or "acyl" group refers to a -C(=O)-R' group, where R' is defined above.

[0287] A "thiocarbonyl" group refers to a -C(=S)-R' group, where R' is as defined herein.

[0288] A "C-carboxy" group refers to a -C(=O)-O-R' group, where R' is as defined herein.

[0289] An "O-carboxy" group refers to an R'C(=O)-O- group, where R' is as defined herein.

[0290] A "carboxylic acid" group refers to a -C(=O)OH group.

[0291] An "oxo" group refers to a ═O group.

[0292] An "imine" group refers to a ═N—R′ group, where R′ is as defined herein.

[0293] An "oxime" group refers to a =N-OH group.

[0294] A "hydrazone" group refers to a ═N-NR′R″ group, where R′ and R″ are as defined herein.

[0295] A "halo" group refers to a fluorine, chlorine, bromine or iodine.

[0296] A "sulfinyl" group refers to a -S(=O)-R' group, where R' is as defined herein.

[0297] A "sulfonyl" group refers to a -S(=O)2-R' group, where R' is as defined herein.

[0298] A "sulfonate" group refers to a -S(=O)2-O-R' group, where R' is as defined herein.

[0299] A "sulfate" group refers to an -OS(=O)2-O-R' group, where R' is as defined herein.

[0300] A "sulfonamide" or "sulfonamido" group, as defined herein, includes both S-sulfonamido and N-sulfonamido groups.

[0301] An "S-sulfonamido" group refers to a -S(=O)2-NR'R'' group, where each of R' and R'' are as defined herein.

[0302] An "N-sulfonamido" group refers to an R'S(=O)2-NR''- group, where R' and R'' are as defined herein.

[0303] An "O-carbamyl" group refers to an --OC(.dbd.O)--NR'R'' group, where each of R' and R'' are as defined herein.

[0304] An "N-carbamyl" group refers to an R'OC(=O)-NR''- group, where each of R' and R'' are as defined herein.

[0305] An "O-thiocarbamyl" group refers to an --OC(.dbd.S)--NR'R'' group, where each of R' and R'' are as defined herein.

[0306] An "N-thiocarbamyl" group refers to an R'OC(=S)NR''- group, where R' and R'' are as defined herein.

[0307] An "S-thiocarbamyl" group refers to a -SC(=O)-NR'R'' group, where each of R' and R'' are as defined herein.

[0308] An "amide" or "amido" group, as defined herein, includes C-amide and N-amide groups.

[0309] A "C-amido" group refers to a -C(=O)-NR'R'' group, where each of R' and R'' are as defined herein.

[0310] An "N-amido" group refers to an R'C(=O)-NR''- group, where R' and R'' are as defined herein.

[0311] A "urea group" refers to a -N(R')-C(=O)-NR''R''' group, where each of R', R'', and R'' are as defined herein.

[0312] A "thiourea group" refers to a -N(R')-C(=S)-NR''R''' group, where R', R'', and R'' are as defined herein.

[0313] A "nitro" group refers to a -NO2 group.

[0314] A "cyano" group refers to a -C≡N group.

[0315] The term "phosphonyl" or "phosphonate" refers to a -P(=O)(OR')(OR'') group, with R' and R'' as defined above.

[0316] The term "phosphate" refers to a -OP(=O)(OR')(OR'') group, with each of R' and R'' being as defined above.

[0317] The term "phosphinyl" refers to a -PR'R'' group, where R' and R'' are as defined above.

[0318] The term "hydrazine" refers to the group -NR'-NR''R''', where R', R'', and R''' are as defined above.

[0319] As used herein, the term "hydrazide" refers to the group -C(=O)-NR'NR''R''', where R', R'', and R''' are as defined herein.

[0320] As used herein, the term "thiohydrazide" refers to the group -C(=S)-NR'NR''R''', where R', R'', and R''' are as defined herein.

[0321] A "guanidinyl" group refers to a -RaNC(=NRd)-NRbRc group, where each of Ra, Rb, Rc, and Rd can be as defined herein for R' and R''.

[0322] A "guanyl" or "guanine" group refers to a RaRbNC(=NRd)- group, where Ra, Rb, and Rd are as defined herein.

[0323] For any of the embodiments described herein, each of the compounds described herein (including the therapeutically active agents, absorption enhancers, and polymers) may be in the form of a salt, e.g., a pharma- ceutically acceptable salt, and / or in the form of a prodrug.

[0324] As used herein, the phrase "pharmaceutically acceptable salt" refers to a charged species of the parent compound and its counterion, which is typically used to adjust the solubility characteristics of the parent compound and / or reduce significant irritation to an organism by the parent compound without abrogating the biological activity and properties of the administered compound. Alternatively, pharmaceutically acceptable salts of the compounds described herein may be formed during the synthesis of the compounds, for example, during the process of isolating the compounds from a reaction mixture or recrystallizing the compounds.

[0325] For some of the embodiments of the present invention, pharma- ceutically acceptable salts of the compounds described herein can optionally be acid addition salts and / or base addition salts.

[0326] An acid addition salt comprises at least one basic (e.g., amine and / or guanidinyl) group of the compound in positively charged form (e.g., the basic group is protonated) in combination with at least one counterion derived from a selected acid to form a pharma- ceutically acceptable salt. Thus, an acid addition salt of a compound described herein can be a complex formed between one or more basic groups of the compound and one or more equivalents of an acid.

[0327] A base addition salt comprises at least one acidic (e.g., carboxylic acid) group of a compound in negatively charged form (e.g., the acidic group is deprotonated) in combination with at least one counterion derived from a selected base to form a pharma- ceutically acceptable salt. Thus, a base addition salt of a compound described herein may be a complex formed between one or more acidic groups of the compound and one or more equivalents of a base.

[0328] Depending on the stoichiometric ratio between the charged groups in the compound and the counterions in the salt, acid and / or base addition salts can be either mono- or poly-addition salts.

[0329] The phrase "mono-addition salt," as used herein, refers to a salt in which the stoichiometric ratio between the counterion and the charged form of the compound is 1:1, such that the addition salt contains one molar equivalent of counterion per one molar equivalent of the compound.

[0330] The phrase "polyaddition salt," as used herein, refers to a salt in which the stoichiometric ratio between the counterion and the charged form of the compound is greater than 1:1, e.g., 2:1, 3:1, 4:1, etc., such that the addition salt contains two or more molar equivalents of counterion per molar equivalent of compound.

[0331] Examples of pharma- ceutically acceptable salts would be, but are not limited to, ammonium or guanidinium cations and their acid addition salts, and / or carboxylate anions and their base addition salts.

[0332] Base addition salts may include cationic counterions, such as sodium, potassium, ammonium, calcium, magnesium, etc., which form pharma- ceutically acceptable salts.

[0333] Acid addition salts may include a variety of organic and inorganic acids, such as, but not limited to, hydrochloric acid resulting in hydrochloric acid addition salts, hydrobromic acid resulting in hydrobromic acid addition salts, acetic acid resulting in acetic acid addition salts, ascorbic acid resulting in ascorbic acid addition salts, benzenesulfonic acid resulting in besylic acid addition salts, camphorsulfonic acid resulting in camphorsulfonic acid addition salts, citric acid resulting in citric acid addition salts, maleic acid resulting in maleic acid addition salts, malic acid resulting in malic acid addition salts, methanesulfonic acid resulting in methanesulfonic acid (mesylic acid) addition salts, naphthalenesulfonic acid resulting in naphthalenesulfonic acid addition salts, oxalic acid resulting in oxalic acid addition salts, phosphoric acid resulting in phosphoric acid addition salts, toluenesulfonic acid resulting in p-toluenesulfonic acid addition salts, succinic acid resulting in succinic acid addition salts, sulfuric acid resulting in sulfuric acid addition salts, tartaric acid resulting in tartrate addition salts, and trifluoroacetic acid resulting in trifluoroacetic acid addition salts. Each of these acid addition salts may be either mono- or poly-addition salts, as these terms are defined herein.

[0334] As used herein, the term "prodrug" refers to a compound that is converted to an active compound (e.g., a compound of the formula described above) in the body. Prodrugs are typically designed to facilitate administration, for example, by facilitating absorption. Prodrugs may include active compounds that have been modified, for example, with an ester group, e.g., any one or more of the hydroxyl groups of the compound are replaced with an acyl group, optionally (C 1~4 )-acyl (e.g., acetyl) groups to form ester groups, and / or any one or more of the carboxylic acid groups of the compound are modified with an alkoxy or aryloxy group, optionally with a (C 1~4 )-alkoxy (eg, methyl, ethyl) groups to form ester groups.

[0335] Additionally, each of the compounds described herein (including the therapeutically active agents, absorption enhancers, and polymers), including salts thereof, may be in the form of a solvate or hydrate thereof.

[0336] The term "solvate" refers to a complex of variable stoichiometry (e.g., di-, tri-, tetra-, penta-, hexa-, etc.) formed by a solute (a heterocyclic compound described herein) and a solvent, where the solvent does not interfere with the biological activity of the solute.

[0337] The term "hydrate" refers to a solvate as defined above where the solvent is water.

[0338] The compounds described herein may be available as polymorphs, and the present embodiments further encompass any isomorphs of the compounds and any combinations thereof.

[0339] The compounds and structures described herein encompass any stereoisomers, including enantiomers and diastereomers, of the compounds described herein, unless a particular stereoisomer is specifically indicated.

[0340] As used herein, the term "enantiomer" refers to a stereoisomer of a compound that can be superimposed on its counterpart only by complete inversion / reflection (mirror image) of each other. Enantiomers are said to have "chirality" because they point to each other like right and left hands. Enantiomers have identical chemical and physical properties except when they are present in an environment (such as any living system) that has chirality itself. In the context of this embodiment, the compound may exhibit one or more chiral centers, each of which may exhibit the (R) or (S) configuration and any combination, and compounds according to some embodiments of the present invention may have any of their chiral centers exhibiting the (R) or (S) configuration.

[0341] The term "diastereomers" as used herein refers to stereoisomers that are not enantiomers of each other. Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more, but not all, of the equivalent (related) stereocenters and are not mirror images of each other. If two diastereomers differ from each other at only one stereocenter, they are epimers. Each stereocenter (chiral center) results in two different configurations and thus two different stereoisomers. In the context of the present invention, the embodiments of the present invention encompass compounds with multiple chiral centers that occur in any combination of configurations, i.e., any diastereomers.

[0342] As used herein, the term "about" refers to ±10%.

[0343] The terms "comprises," "comprising," "includes," "including," "having" and their conjugations mean "including, but not limited to."

[0344] The term "consisting of" means "including and limited to."

[0345] The term "consisting essentially of" means that the composition, method, or structure may include additional ingredients, steps, and / or moieties only if the additional ingredients, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0346] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range such as 1-6 should be considered to have specifically disclosed subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as individual numerical values ​​within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0347] Whenever a numerical range is given herein, it is meant to include any recited numerical value (fractional or integer) within the given range. The phrases "range between" a first designated number and a second designated number and "range" from a first designated number to a second designated number are used interchangeably and are meant to include the first and second designated numbers and all fractional and integer numbers therebetween.

[0348] As used herein, the term "method" refers to methods, means, techniques, and procedures for accomplishing a given task, and includes, but is not limited to, methods, means, techniques, and procedures known by, or readily developable from, those known by, those skilled in the art of chemistry, pharmacology, biology, biochemistry, and medicine.

[0349] As used herein, the term "treating" includes inhibiting, substantially inhibiting, slowing or halting the progression of a condition, substantially ameliorating a clinical or cosmetic symptom of a condition, or substantially preventing the appearance of a clinical or cosmetic symptom of a condition.

[0350] It will be understood that certain 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, for brevity, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any suitable subcombination, or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not considered essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0351] Various embodiments and aspects of the present invention as delineated above and as claimed in the claims section below find experimental support in the following examples. EXAMPLES

[0352] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting manner.

[0353] Materials and Methods material: Croscarmellose sodium (Parteck® CCS; cross-linked form; CAS No. 74811-65-7) was obtained from Merck. Sodium alginate (CAS No. 9005-38-3), average molecular weight 300-350 kDa, viscosity at room temperature 350-500 mPa (non-crosslinked), was obtained from Carl Roth. Sodium carboxymethylcellulose (CMC), CAS No. 9004-32-4 (non-crosslinked), low viscosity (43 mPa at room temperature), was obtained from Merck or Ashland. Sodium starch glycolate type A (Primojel®, cross-linked form, CAS No. 9063-38-1), average molecular weight 2,000 kDa, viscosity at room temperature less than 200 mPa, was obtained from DFE Pharma.

[0354] Measuring pH with a pH meter: Test substances were dissolved in various volumes of 0.1 M HCl solution (pH 1.2) at concentrations of 1, 2, 4, 10, 20, 50, 100 and 150 mg / ml. To ensure that the pH remained stable, the solution pH was measured immediately after dissolution and up to 26 hours later using an ELC-10-00 electrode (MRC, Israel) or a MP-103 pH meter (MRC, Israel) equipped with a fine wire electrode HI1083 (HANNA instruments Inc.). The highest pH value obtained during the experiment was recorded to compare the acid neutralization capacity of each substance.

[0355] Other pH measurements were made by adding a suitable colorimetric pH indicator solution to the test medium.

[0356] Example 1 Effect of basic polymers on the pH of simulated gastric fluid. The effect of basic polymers on gastric juice and the behavior of SNAC in gastric juice was investigated using HCl solution as simulated gastric juice.

[0357] SNAC and the basic polymers sodium alginate, sodium carboxymethylcellulose in non-crosslinked (Na-CMC) and crosslinked (croscarmellose sodium, CCS) forms, and sodium starch glycolate (SSG) were dissolved in various volumes of 0.1 M HCl solution (pH 1.2) at concentrations of 1, 2, 4, 10, 20, 50, 100 and 150 mg / ml, and the solution pH was measured using an MP-103 pH meter (MRC, Israel) equipped with an ELC-10-00 electrode (MRC, Israel) as described in the Materials and Methods section above.

[0358] As shown in FIG. 1, after addition to an HCl solution (pH 1.2), SNAC dissolved rapidly and increased the pH in a concentration-dependent manner, with the pH 5 minutes after dissolution being approximately 1.5 after addition of 10 mg / ml SNAC, 6.5 after addition of 20 mg / ml SNAC, and approximately 7.5 after addition of 100 mg / ml SNAC.

[0359] These results indicate that a significant proportion of SNAC is converted under gastric conditions from the salt to the corresponding carboxylic acid (NAC), which is much less soluble in water than the salt and is not an effective permeation enhancer.

[0360] The effect of pH on peptide proteolysis by pepsin was determined by incubating 13.5 μg / ml human parathyroid hormone (1-34) (hPTH(1-34)) with 150 μg / ml pepsin at various pH values ​​and determining the percentage of hPTH(1-34) remaining. The amount of hPTH(1-34) remaining after addition of 150 μg / ml pepsin at 37° C. was determined in media with different pH values, followed by immediate (10 s) vortexing and centrifugation at 4000 RCF for 3 min at 4° C. The following media were used: simulated gastric fluid (pH 2) prepared from 0.01 M HCl and NaCl; phthalate buffer (pH 4 or 5); and phosphate buffer (pH 6 or 7).

[0361] As shown in FIG. 2, proteolysis of hPTH(1-34) was inhibited when the pH was increased to about pH 6 or above.

[0362] Taken together, the above results indicate that SNAC can inhibit peptide degradation by pepsin under gastric conditions by increasing the pH, at the expense of at least a partial loss of the active salt form of the absorption enhancer.

[0363] To obtain a beneficial increase in pH while reducing the loss of the active form of the absorption enhancer, the effect on pH after adding various concentrations of different polymers containing carboxylic acid groups (sodium alginate, sodium starch glycolate, sodium carboxymethylcellulose, and sodium croscarmellose) to a 0.1 M HCl solution (pH 1.2) was also evaluated. Figure 3A shows the pH values ​​measured using an MP-103 pH meter (MRC, Israel) equipped with an ELC-10-00 electrode (MRC, Israel), and Figure 3B shows the pH values ​​measured using an MP-103 pH meter (MRC, Israel) equipped with a fine wire electrode HI1083 (HANNA instruments Inc.).

[0364] As shown in Figures 3A and 3B, each of the polymers tested exhibited a concentration-dependent increase in pH, with pH values ​​of approximately 4-4.5 being obtained at the higher concentrations tested.

[0365] The sodium alginate, Na-CMC, CCS and sodium starch glycolate test powders form gels (of various viscosities) after addition to aqueous media, and the dispersion of the polymer in such gels may be inhomogeneous. To evaluate whether the acid neutralizing ability of the polymer is determined by the concentration of the polymer in the gel, a preliminary study was carried out in which the polymer in powder form was added to an acidic medium without mixing. The pH value was measured using a suitable pH indicator solution.

[0366] The powder forms of the polymers provided a localized acid neutralizing effect: sodium starch glycolate dissolved rapidly with strong acid neutralization, sodium croscarmellose dissolved rapidly with weaker acid neutralization, sodium carboxymethylcellulose did not dissolve well but showed some acid neutralization, and sodium alginate showed little acid neutralization (data not shown).

[0367] These results indicate that, among the polymers tested, sodium starch glycolate (and to some extent sodium croscarmellose) has a particularly strong local acid neutralizing effect in powder form and is therefore particularly suitable for non-enteric coated formulations containing absorption enhancers such as SNAC.

[0368] Without being bound by any particular theory, it is believed that the limited effectiveness of sodium carboxymethylcellulose and sodium alginate is related to the slow penetration of water into the polymer matrix, while the particularly effective acid neutralization of sodium starch glycolate is related, at least in part, to its rapid water absorption (swelling).

[0369] Because sodium starch glycolate and sodium croscarmellose demonstrated the strongest local acid neutralizing capacity, further experiments were conducted with these polymers.

[0370] To assess the maximum acid neutralizing capacity of the polymers, the experiment was repeated with each polymer compressed into a tablet form.

[0371] In a pilot study, flat round 100 mg tablets were formed from sodium starch glycolate or croscarmellose sodium using a 6 mm punch and a compression force of 2 tons, and the tablets were placed in 40 ml of HCl solutions of various pH levels (1.2, 1.5 or 2.0) (static dissolution). A water bath was used to maintain a temperature of 37° C. The resulting pH values ​​were measured using a suitable pH indicator solution.

[0372] Although the sodium starch glycolate tablets and the croscarmellose sodium tablets exhibited different swelling patterns, both exhibited comparable neutralization strengths in HCl solutions (data not shown). The sodium starch glycolate tablets provided greater acid neutralization than the croscarmellose sodium tablets for each initial pH tested (the effectiveness of localized acid neutralization was greater at higher initial pHs).

[0373] These results indicate that sodium starch glycolate and croscarmellose sodium may be equally effective at increasing the pH of gastric fluids to at least about 4, but that sodium starch glycolate is more effective than sodium croscarmellose for increasing the pH of gastric fluids to at least about 5. This indicates that sodium starch glycolate is more effective at neutralizing acid than sodium croscarmellose.

[0374] In further testing, 100 mg sodium starch glycolate tablets were prepared using an 8 mm round punch and a compression force of 1.5 tons. The tablets were dissolved without shaking in a weigh boat containing 50 ml of 0.01 M HCl solution (pH 2.0, 37° C.) and the local pH was measured.

[0375] Measurement of the pH in the vicinity of the tablet by adding an indicator to the solution showed that the local pH was approximately 7.

[0376] These results indicate that sodium starch glycolate increases the local pH to values ​​well above pH 5 (the pKa of SNAC), thereby promoting the dissolution of SNAC at concentrations effective for the action of SNAC and related compounds as absorption enhancers, and also inhibiting peptide degradation by pepsin (which is only active at low pH).

[0377] Without being bound by any particular theory, it is believed that the localized nature of the observed pH increase is related to a viscous gel that forms upon polymer dissolution (hydration and relaxation upon wetting), which restricts the transport of acid from outside the localized region with a higher pH. Due to this heterogeneity, it is further believed that the determination of local pH represents a more important parameter than the pH of the medium as a whole. For example, the generally smaller increase in the pH of the medium as a whole (FIGS. 3A-B) can be explained as reflecting an average of the pH of the proximal region of the tablet, where the acid is effectively neutralized, and the pH of the distal region, where the pH is less affected.

[0378] In further testing, 100 mg tablets were formed from various polymers (e.g., sodium starch glycolate, sodium croscarmellose, sodium carboxymethylcellulose, and sodium alginate) using an 8 mm round punch and a compression force of 2 tons. The effect of the tablets on local pH was compared when the tablets were placed in a 0.01 M HCl solution (pH 2.0, 37° C.). The pH was measured by adding an indicator to the solution.

[0379] Sodium starch glycolate tablets swelled and disintegrated rapidly, producing a strong localized acid neutralizing effect. Croscarmellose sodium tablets also disintegrated rapidly, but produced a weaker localized acid neutralizing effect. Sodium carboxymethylcellulose tablets swelled slowly, showing some localized acid neutralization. Sodium alginate tablets remained intact and showed little localized acid neutralization (data not shown).

[0380] Additionally, control tablets prepared with hydroxypropylmethylcellulose (HPMC), a polymer that does not have anionic groups, were similarly tested and showed no observable effect on pH.

[0381] Due to the gradual hydration of the tablet, the acid neutralizing effect of the polymer in the swollen matrix may be non-uniform. Therefore, the pH at different locations of the tablet matrix was evaluated in a further set of experiments as follows.

[0382] Tablets of 200 mg were prepared from sodium alginate, Na-CMC, CCS or sodium starch glycolate (SSG) using a 10 mm round punch and 1 tonne compression force. Each tablet was placed in the center of a dish containing 100 ml of 0.01 M HCl solution (pH 2.0, room temperature) and after hydration, the local pH was measured at four different points in the swollen tablet matrix as shown in Figure 6A (for SSG), B (for CCS), C (for Na-CMC; CMC-Na) and D (for sodium alginate; Alg-Na): (i) in the HCl solution outside the formed gel boundary (approximately 2-3 cm from the surface of the swollen matrix), (ii) at the surface of the swollen matrix, (iii) at a midpoint between the surface and center of the swollen matrix (approximately 0.5-1 cm from the surface and center, respectively), and (iv) at the center of the swollen matrix. Measurement of the local pH inside the tablet was made possible by using a pH meter equipped with a fine wire electrode (as described in the Materials and Methods section).

[0383] As shown in Figures 6A-D, the SSG tablet swelled and disintegrated quickly, producing a strong localized acid neutralization effect in the center of the swollen matrix that reached a pH of 5.7 (Figure 6A). The CCS tablet also swelled quickly and produced a slightly weaker localized acid neutralization effect (Figure 6B). The CMC-Na tablet swelled slowly and showed a strong localized acid neutralization (Figure 6C), and the Alg-Na tablet showed the slowest swelling rate and a localized acid neutralization similar to CCS (Figure 6D). For all tested polymers, the pH values ​​measured in the center of the swollen matrix were higher than in other regions, further supporting the concentration-dependent acid neutralization ability of the polymers.

[0384] The results of these two sets of experiments show that for all tested alkaline polymers, the local pH increase inside the matrix reaches a maximum pH value of about 5-6. Such pH values ​​are consistent with the pH desired to maintain SNAC in a soluble salt form when its pKa is about 5. This pH increase therefore reduces SNAC precipitation, thereby achieving a high concentration of dissolved SNAC, which is required for SNAC (and other absorption enhancers) to act as an absorption enhancer. The local pH increase also inhibits peptide degradation by pepsin (which is only active at low pH). These results further indicate that alkaline (basic) polymers exhibit limited diffusion in acidic solutions and therefore may have a stronger and / or more sustained effect on pH by affecting pH primarily locally.

[0385] In yet another set of experiments, SSG, an example of a fast swelling polymer that produces a high local pH, and CMC-Na, an example of a slow swelling polymer that produces a high local pH, were further tested in porcine gastric fluid (obtained endoscopically from anesthetized adult female domestic pig (sus scrofa domesticus)). 200 mg tablets were prepared from each polymer using a 10 mm round punch and 1 tonne compression force. Each tablet was placed in the center of a dish containing 100 ml of porcine gastric fluid at room temperature, and after hydration (wetting), the local pH was measured at four different points (i)-(iv) of the swollen tablet matrix as described above for the data shown in Figures 6A-D. The results are shown in Figure 7A for SSG and in Figure 7B for CMC-Na, similar to those shown in Figures 6A and C, respectively.

[0386] Taken together, the above results indicate that alkaline group-containing polymers, particularly sodium starch glycolate and sodium croscarmellose, can effectively neutralize acid in localized regions (e.g., in the stomach), thereby reducing the protonation and inactivation of SNAC and the degradation of peptides by pepsin in such regions. This phenomenon is particularly important when the polymer, SNAC, and peptide or polypeptide are co-localized (e.g., within a single dosage form), allowing for sustained SNAC-induced absorption of the peptide or polypeptide.

[0387] Example 2 Effect of sodium starch glycolate on peptide absorption in an in vivo rat model The ability of sodium starch glycolate (SSG) to enhance drug absorption was evaluated in an in vivo rat model using teriparatide (hPTH(1-34)) as a model peptide drug and SNAC as a model absorption enhancer.

[0388] The formulations were prepared using the compositions shown in Table 1. All materials were in dry powder form and were geometrically mixed using a mortar and pestle. The mini-tablets were then punched using a 2 mm punch and 0.5 ton / cm. 2 A mold was then used to prepare the mixture.

[0389] [Table 3]

[0390] Male Wistar rats (250-300 grams) were divided into groups receiving the different formulations (as described in Table 1). Food was withheld the night before and during the experiment, and water was withheld for 1 hour before and during the experiment. Rats were administered the mini-tablets using a custom-made intragastric gavage tube. Blood was collected from the cheek at the indicated time points. Plasma was separated and hPTH(1-34) was quantified by a commercial Elisa kit for the determination of hPTH(1-34) in plasma or cell culture medium (Quidel Corp., Athens, OH, USA; Cat. No. 60-3900).

[0391] As shown in FIG. 4 and Table 2 below, inclusion of 20% sodium starch glycolate in an exemplary formulation containing SBTI resulted in approximately 1.5-fold higher median Cmax and AUC (area under the curve) compared to the corresponding formulation without sodium starch glycolate.

[0392] As shown in FIG. 5 and Table 2 below, the inclusion of 30% sodium starch glycolate in the exemplary formulation (without SBTI) resulted in approximately 4-fold higher median Cmax and AUC (area under the curve) compared to the corresponding formulation without sodium starch glycolate.

[0393] As further shown in Figures 4 and 5, sodium starch glycolate increased plasma levels of hPTH(1-34) during the elimination phase, indicating sustained absorption.

[0394] [Table 4]

[0395] These results support those of Example 1 and confirm the ability of sodium starch glycolate to significantly increase the absorption of a polypeptide co-administered with an absorption enhancer such as SNAC and to modulate the pharmacokinetic profile in the presence and absence of protease inhibitors.

[0396] Example 3 Effect of sodium starch glycolate on peptide absorption in an in vivo porcine model The ability of sodium starch glycolate (SSG) to enhance drug absorption was further evaluated in an in vivo porcine model using teriparatide (hPTH(1-34)) as a model peptide drug and SNAC as a model absorption enhancer. This model allows for the testing of unit dosage forms with dimensions conventional for human use.

[0397] Formulations with and without 25% SSG were prepared using the compositions shown in Table 3. All materials were in dry powder form and were geometrically mixed using a mortar and pestle. Tablets were then prepared from the mixture using a manual press.

[0398] The resulting tablets were orally administered to female Sinclair minipigs (18-20 kg) at different clinic visits. The pigs were food-deprived the night before and during the experiment, and water-deprived for 1 h before and during the experiment. Administration was facilitated by a custom-made device for oral administration with approximately 30 ml of water. Blood was collected from the jugular vein through an indwelling cannula at the designated time points. Plasma was separated and hPTH(1-34) was quantified using a commercially available Elisa kit for the determination of hPTH(1-34) in plasma or cell culture medium (Quidel Corp., Athens, OH, USA; Cat# 60-3900).

[0399] [Table 5]

[0400] As shown in Table 4, formulations containing sodium starch glycolate consistently produced higher Cmax and AUC values ​​than the corresponding formulations without sodium starch glycolate, and plasma levels remained higher during the elimination phase.

[0401] These results further support the ability of alkaline group-containing polymers to enhance the absorption of polypeptides in the presence of absorption enhancers.

[0402] [Table 6]

[0403] 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 all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0404] It is the intention of the applicants that all publications, patents, and patent applications mentioned herein are incorporated herein by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated as being incorporated herein by reference. Furthermore, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. To the extent section headings are used, they should not be construed as necessarily limiting. Additionally, any priority documents of this application are incorporated herein by reference in their entirety.

Claims

1. 1. An oral pharmaceutical composition comprising a parathyroid hormone as a therapeutically active agent, an absorption enhancer, and a polymer containing a plurality of alkaline groups, wherein the concentration of the polymer in the composition is at least 10 weight percent of the total weight of the composition, and the absorption enhancer is a substituted or unsubstituted fatty acid or a salt thereof.

2. The composition of claim 1 , wherein the alkaline groups are carboxylic acid groups and / or amine groups.

3. The composition of claim 2 wherein at least a portion of the alkaline groups are carboxylic acid groups.

4. The composition of claim 3 , wherein at least a portion of the carboxylic acid groups are in the form of a pharmaceutically acceptable salt.

5. The composition of claim 4 , wherein at least a portion of the carboxylic acid groups are in the form of a sodium salt.

6. 2. The composition of claim 1, wherein the absorption enhancer is selected from NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid), NAD (10-N-(2-hydroxybenzoyl)aminodecanoic acid), 5-CNAC (8-N-(5-chlorosalicyloyl)aminocaprylic acid), 4-MOAC (8-N-(2-hydroxy-4-methoxybenzoyl)aminocaprylic acid), 4-CNAB (4-N-(2-hydroxy-4-chlorobenzoyl)aminobutanoic acid), and salts thereof.

7. The composition of claim 6 , wherein the absorption enhancer comprises NAC or a salt thereof.

8. 8. The composition of claim 7, wherein the concentration of the absorption enhancer is at least 50 weight percent.

9. The composition of claim 1 , wherein the total concentration of the absorption enhancer and the polymer is at least 80 weight percent.

10. The composition of claim 9, wherein the total concentration of the absorption enhancer and the polymer is at least 90 weight percent.

11. 10. The composition of claim 1, wherein the concentration of said alkaline groups in said composition is at least 0.1 millimoles per gram.

12. The composition of claim 1 , wherein the polymer is a crosslinked polymer.

13. The composition of claim 12 , wherein the polymer comprises a polysaccharide.

14. 14. The composition of claim 13, wherein the polysaccharide is selected from starch derivatives and cellulose derivatives.

15. The composition of claim 14 , wherein the polymer comprises a carboxymethyl group.

16. 16. The composition of claim 15, wherein the pKa of the polymer is in the range of 1.2 to 7.

5.

17. 17. The composition of claim 16, wherein the polymer is sodium starch glycolate and / or croscarmellose sodium.

18. 2. The composition of claim 1, wherein the Cmax and / or bioavailability of the composition upon oral administration is at least 50% higher than the Cmax and / or bioavailability of a corresponding composition without the polymer.

19. 10. The composition of claim 1, wherein the therapeutically active agent is or comprises teriparatide.

20. 10. The composition of claim 1, wherein the therapeutically active agent is eneboparatide (AZP-3601).

21. The composition of claim 1 in the form of a unit dosage form.

22. 22. The composition of claim 21, wherein the amount of the alkaline group in the unit dosage form is at least 0.03 millimoles.

23. 23. The composition of claim 22, wherein the unit dosage form comprises at least 50 mg of the absorption enhancer.

24. 24. The composition of claim 23, wherein the unit dosage form comprises one or more tablets.

25. 10. The composition of claim 1, for use in treating a condition treatable by said therapeutically active agent, said treatment comprising oral administration of said composition.

26. 26. The composition of claim 25, for use in treating a condition selected from osteoporosis, conditions associated with fractures or bone defects, osteoarthritis, and hypoparathyroidism.

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