Formulations for oral administration of active agents

Abstract

A pharmaceutical composition for oral administration is disclosed herein, comprising a therapeutically active agent, salt of NAC (8-N-(2-hydroxybenzoyl)aminocaprylate) and one or more small molecule proton accepting agent(s). Methods and uses utilizing the aforementioned pharmaceutical compositions, are also disclosed herein.

Description

[0001] FORMULATIONS FOR ORAL ADMINISTRATION OF ACTIVE AGENTS

[0002] RELATED APPLICATION / S

[0003] This application claims the benefit of priority under 35 USC § 119(e) of U.S. Provisional Patent Application No. 63 / 535,504, filed on 30 August 2023, the contents of which are incorporated herein by reference in their entirety.

[0004] FIELD AND BACKGROUND OF THE INVENTION

[0005] The present invention, in some embodiments thereof, relates to drug delivery, and more particularly, but not exclusively, to formulations and / or systems for oral administration of therapeutically active agents such as, for example, therapeutically active polypeptides (e.g., proteins).

[0006] Oral administration of peptide pharmaceuticals is problematic due to degradation of peptides and / or proteins in the digestive system and poor absorption of large molecules.

[0007] U.S. Patent Application Publication No. 2007 / 0087957 describes compositions for oral administration of a protein, the compositions comprising a protein and an omega-3 fatty acid, as well as the use of such compositions for oral administration of insulin.

[0008] Qi & Ping [J Microencapsulation 2004, 21:37-45] describe administration of enteric microspheres containing insulin with SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate). The enteric microspheres are for protecting the insulin from digestive enzymes of the stomach and small intestine, and the SNAC is for enhancing absorption.

[0009] U.S. Patent Application Publication No. 2011 / 0142800 describes compositions for oral administration of a protein, 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 sodium salts thereof.

[0010] International Patent Application Publication WO 00 / 48589 describes solid oral dosage forms comprising a heparin drug in admixture with SNAC or SNAD for facilitating absorption and / or enhancing bioavailability of the heparin drug, wherein the heparin drug is reported to protect the SNAC or SNAD from precipitation during transit through acidic regions of the gastrointestinal tract.

[0011] U.S. Patent No. 8,110,547 describes compositions for buccal administration of parathyroid hormone (PTH). The composition comprises PTH or a fragment or analog thereof, as well as a delivery agent such as 4-MOAC, SNAC, SNAD, 5-CNAC and 4-CNAB. Parathyroid hormone (PTH) is secreted by the parathyroid gland as a polypeptide containing 84 amino acids. PTH has been reported to enhance bone growth when administered intermittently, with circulating levels returning to control levels within 3 hours [Martin, J Bone Metab 2014, 21:8- 20]. In contrast, prolonged elevated PTH levels enhance release of calcium from bones (bone resorption).

[0012] International PCT Patent Application Publication No. WO 2021 / 089761 describes pharmaceutical compositions comprising a PCSK9 inhibitor, SNAC and a hydrotrope capable of enhancing the solubility of SNAC at least 2-fold, such as Nipecotamide, Nicotinamide, p- hydroxybenzoic acid sodium, N,N dimethyl urea, N,N dimethyl benzamide, N,N diethyl nicotinamide, Sodium salicylate, Resorcinol, Sodium benzoate, Sodium Xylenesulfonate, Sodium p- toluenesulfonate, 1- Methylnicotinamide, Pyrogallol, Pyrocathecol, Epigallocatechin gallate, Tannic acid and Gentisic acid sodium salt hydrate.

[0013] WO 2016 / 128974 and U.S. Patent No. 10,583,177 describe a pharmaceutical composition for oral administration comprising a therapeutic agent, SNAC, and at least one antacid capable of enhancing the solubility of SNAC, such as calcium citrate, calcium gluconate, sodium gluconate, sodium citrate, sodium hydroxide, potassium gluconate, potassium citrate, potassium hydroxide, magnesium gluconate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum gluconate, aluminum citrate, and aluminum hydroxide.

[0014] International PCT Patent Application Publication No. WO 2023 / 161934 describes a pharmaceutical composition comprising a therapeutically active agent, an absorption enhancer, and a polymer comprising a plurality of alkaline groups which are effective at protecting the absorption enhancer from stomach acid, as well as enhancing bioavailability of a therapeutically active agent in compositions comprising the absorption enhancer and the therapeutically active agent, such as sodium starch glycolate and / or croscarmellose sodium.

[0015] Additional background art includes Qi et al. [Acta Pharm Sinica 2004, 39:844-848]; International Patent Application Publications WO 00 / 50386, WO 01 / 32130, WO 01 / 32596, WO 03 / 045306 and WO 2007 / 121471; Japanese Patent Application Nos. 2005281231 and 2006111558; and U.S. Patent Application Publication Nos. 2006 / 0234913 and 2013 / 0224300.

[0016] SUMMARY OF THE INVENTION

[0017] According to an aspect of some embodiments of the present invention there is provided a pharmaceutical composition for oral administration of a therapeutic active agent, the composition comprising the therapeutically active agent, a salt of NAC (8-N-(2-hydroxybenzoyl)aminocaprylate), and at least one proton accepting agent featuring pKa higher by at least 0.5 than a pKa of NAC, the at least one proton accepting agent comprises at least one small molecule substance other than an antacid.

[0018] According to some of any of the embodiments described herein, the at least one proton accepting agent is selected from an amino acid and a fatty acid salt.

[0019] According to some of any of the embodiments described herein, the at least one proton accepting agent comprises an amino acid having a side chain featuring a pKa of at least 5, preferably of at least 6.

[0020] According to some of any of the embodiments described herein, the amino acid is selected from histidine, arginine, lysine, an analog thereof and any combinations thereof.

[0021] According to some of any of the embodiments described herein, the amino acid is arginine.

[0022] According to some of any of the embodiments described herein, the at least one proton accepting agent comprises a salt of a fatty acid.

[0023] According to some of any of the embodiments described herein, the fatty acid is a mediumchain fatty acid, being of from 4 to 12, or from 6 to 12, or from 6 to 10, or from 8 to 10.

[0024] According to some of any of the embodiments described herein, the salt of the fatty acid is selected from sodium octanoate and sodium decanoate.

[0025] According to some of any of the embodiments described herein, the at least one proton accepting agent comprises a salt of a fatty acid as described herein in any of the respective embodiments and any combination thereof, and an amino acid as described herein in any of the respective embodiments and any combination thereof,.

[0026] According to some of any of the embodiments described herein, the at least one proton accepting agent comprises an amino acid as described herein in any of the respective embodiments and any combination thereof, and an antacid as described herein in any of the respective embodiments and any combination thereof,.

[0027] According to some of any of the embodiments described herein, the at least one proton accepting agent comprises a salt of a fatty acid as defined in any one of claims 6 to 8 and an antacid.

[0028] According to some of any of the embodiments described herein, the at least one antacid compound is selected from the group consisting of calcium carbonate, calcium gluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum carbonate, aluminum gluconate, aluminum citrate, and aluminum hydroxide. According to some of any of the embodiments described herein, a mol ratio of the at least one proton-accepting agent and the salt of NAC is at least 0.1:1 or ranges from 0.1:1 to 5 : 1 , or from 0.1:1 to 2:1, or from 0.2:1 to 2:1.

[0029] According to some of any of the embodiments described herein, a total concentration of the at least one proton-accepting agent in the composition is at least 5, or at least 10, weight percent of the total weight of the composition.

[0030] According to some of any of the embodiments described herein, a total concentration of the salt of NAC in the composition is at least 50 weight percent of the total weight of the composition.

[0031] According to some of any of the embodiments described herein, at least 80, or at least 90, weight percent of the composition consists of ingredients selected from the group consisting of the therapeutically active agent, the salt of NAC, and the at least one proton accepting agent.

[0032] According to some of any of the embodiments described herein, the therapeutically active agent has a molecular weight in a range of 0.5 kDa to 100 kDa.

[0033] According to some of any of the embodiments described herein, the therapeutically active agent is a polypeptide.

[0034] According to some of any of the embodiments described herein, the polypeptide is selected from an antibody, an antipathogenic peptide, an anti-viral peptide, a blood clotting factor, a C-type natriuretic peptide, a calcitonin, disitertide, an endomorphin, an erythropoietin, a gastric inhibitory polypeptide (GIP), a gastric inhibitory polypeptide receptor agonist, a glucagon, a glucagon receptor agonist, a GLP-1 (glucagon-like peptide- 1), a GLP-1 receptor agonist, a GLP-2 (glucagon-like peptide-2), a GLP-2 receptor agonist, GLP-1 receptor / glucagon receptor dual agonist, a GIP receptor / GLP- 1 receptor dual agonist, glucagon receptor / GIP receptor / GLP- 1 receptor triple agonist, GLP-2 receptor / glucagon receptor dual agonist, GLP-2 receptor / GLP- 1 receptor dual agonist, GLP- 2 receptor / GIP receptor dual agonist, oxyntomodulin, a glucocerebrosidase, a gonadotropin, a gonadotropin releasing hormone, a gonadotropin releasing hormone receptor agonist, a gonadotropin releasing hormone receptor antagonist, a granulocyte-colony stimulating factor, a growth factor, a growth hormone, a somatostatin, a somatostatin receptor agonist, a growth hormone-releasing hormone, icatibant, insulin, an interferon, an interleukin, a kappa opioid receptor agonist, a leptin, an oxytocin, an oxytocin receptor agonist, a melanocortin, a melanocortin receptor agonist, a motilin, an omentin, a parathyroid hormone or a fragment thereof, a parathyroid hormone related protein, a peptide YY, a pituitary adenylate cyclase-activating peptide (PACAP), thymopentin, a thymosin, a TNF inhibitor, a vasoactive intestinal peptide, and a vasopressin, and analogs thereof.

[0035] According to some of any of the embodiments described herein, the polypeptide is selected from the group consisting of parathyroid hormone and a fragment thereof. According to some of any of the embodiments described herein, the polypeptide comprises teriparatide.

[0036] According to some of any of the embodiments described herein, the polypeptide is selected from the group consisting of parathyroid hormone, a parathyroid hormone fragment, a parathyroid hormone long-acting analog, and a parathyroid hormone fragment long-acting analog.

[0037] According to some of any of the embodiments described herein, the polypeptide is characterized by an isoelectric point (pl) of at least 8.5.

[0038] According to some of any of the embodiments described herein, the composition is formulated such that absorption of the therapeutically active agent following oral administration of the composition is characterized by a bioavailability of the therapeutically active agent which is at least 10 % higher than a bioavailability of the therapeutically active agent following oral administration of a composition comprising the therapeutically active agent and the salt of NAC (8-N-(2- hydroxybenzoyl)aminocaprylate) without the at least one proton accepting agent.

[0039] According to some of any of the embodiments described herein, the composition is in a form of a homogeneous mixture.

[0040] According to some of any of the embodiments described herein, the composition is formulated as a unit dosage form.

[0041] According to some of any of the embodiments described herein, the unit dosage form comprises at least 50 mg of the salt of NAC.

[0042] According to some of any of the embodiments described herein, the unit dosage form is a solid unit dosage form.

[0043] According to some of any of the embodiments described herein, the composition is formulated as a tablet.

[0044] According to some of any of the embodiments described herein, the unit dosage form is soluble in gastric fluid.

[0045] According to an aspect of some embodiments of the present invention there is provided a composition as described herein in any of the respective embodiments, for use in the treatment of a condition treatable by oral administration of the therapeutically active agent in a subject in need thereof.

[0046] 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 the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0047] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

[0048] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0049] In the drawings:

[0050] FIG. 1 presents comparative plots showing the percentage recovery of SNAC over a 30- minute period incubation at room temperature in an acidic solution featuring a pH of 1.2, from test samples containing SNAC and arginine at a mol ratio of 1:1, 0.75:1, and 0.5:1 to SNAC; from test samples containing SNAC and histidine at 1.5:1 and 1:1 to SNAC, and from test samples containing SNAC alone.

[0051] FIG. 2 presents comparative plots showing the percentage recovery of SNAC over a 25- minute period incubation at 37 °C in an acidic solution featuring a pH of 1.2, from tablets containing SNAC (100 mg); SNAC (100 mg) and sodium carbonate (30 mg); SNAC (100 mg) and sodium decanoate (50 mg); and SNAC (100 mg), sodium carbonate (30 mg) and sodium decanoate (50 mg).

[0052] FIG. 3 presents comparative plots showing the percentage recovery of SNAC over a 25- minute period incubation at 37 °C in an acidic solution featuring a pH of 1.2, from tablets containing SNAC (100 mg); SNAC (100 mg) and sodium carbonate (30 mg); and SNAC (100 mg), sodium carbonate (30 mg) and arginine (50 mg).

[0053] DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0054] The present invention, in some embodiments thereof, relates to drug delivery, and more particularly, but not exclusively, to formulations and / or systems for oral administration of therapeutically active agents such as, for example, therapeutically active polypeptides (e.g., proteins).

[0055] Before explaining 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 exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. While investigating the enhancement of absorption of therapeutically active agents by a salt of NAC (e.g., SNAC; sodium 8-N-(2-hydroxybenzoyl)aminocaprylate) upon oral administration, the present inventors have uncovered that such compositions are significantly affected by inactivation of the salt of NAC, an absorption enhancer, upon contact with stomach acid, which converts the salt of NAC from a soluble carboxylate salt to an insoluble carboxylic acid. The inactivation of the salt of NAC reduces the absorption of the therapeutically active agent, thereby reducing the efficacy of the composition.

[0056] In order to overcome the abovementioned problems, the present inventors have previously designed compositions and unit dosage forms utilizing an antacid for protecting the salt of NAC and / or the therapeutically active agent from stomach acid, thereby allowing increased absorption of the therapeutically active agent (e.g., via protection of the therapeutically active agent) and / or by absorption over a longer period of time (e.g., by protection of the salt of NAC). See, for example, WO 2016 / 128974

[0057] The present inventors have further previously designed unit dosage forms so as to release a protective agent prior to release of the compound which the protective agent is intended to protect, for example, releasing an antacid for reducing acidity in a vicinity of an orally administered composition prior to exposure of a salt of NAC and / or a therapeutically active agent to stomach acid. See, for example, WO 2016 / 128974.

[0058] The present inventors have now uncovered that proton-accepting molecules can be used, either alone, or in combination with antacids as described in WO 2016 / 128974, as protective agents which are capable of protecting the therapeutically active agent and / or the salt of NAC against the effect of the acid in the gastrointestinal tract (e.g., stomach). For example, a proton-accepting agent can protect a salt of NAC (e.g., by reducing conversion of the salt of NAC from a soluble carboxylate salt to a non-soluble carboxylic acid form) from stomach acid, and maintain the salt of NAC in its solubilized, active form.

[0059] Embodiments of the present invention relate to pharmaceutical compositions, preferably pharmaceutical composition unit dosage (e.g., solid) forms, formulated for oral ingestion or oral administration, which comprise a therapeutically active agent as described herein in any of the respective embodiments, a salt of NAC, as described herein, and one or more proton accepting agent, as described herein in any of the respective embodiments. According to the present embodiments, the one or more proton accepting agent can include one or more antacid compounds as long as an additional proton accepting agent, other than an antacid compound as described herein is included in the composition. In some embodiments, the compositions described herein are designed to dissolve in gastric fluid (e.g., stomach fluid), and are aimed at exhibiting an effect of e.g., protecting the salt NAC and preventing loss of activity thereof, in the stomach, to thereby increase the absorption of co-formulated therapeutically active agents which, for example, are susceptible to degradation in the stomach or which the oral administration thereof is otherwise limited.

[0060] According to some of any of the embodiments described herein, the compositions and methods as described in WO 2016 / 128974 are excluded from the scope of the present embodiments.

[0061] As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an antacid” or “at least one antacid” may include a plurality of antacids, including mixtures thereof. For example, the term “a proton- accepting agent” or “at least one proton-accepting agent” may include a plurality of substances of compounds or agents, including mixtures thereof.

[0062] Compositions:

[0063] According to an aspect of some embodiments of the invention, there is provided a pharmaceutical composition for oral administration of a therapeutically active agent, the composition comprising the therapeutically active agent (e.g., as described herein), an absorption enhancer (e.g., a salt of NAC), and at least one proton accepting agent, as described herein in any of the respective embodiments and any combination thereof.

[0064] Absorption enhancer:

[0065] According to preferred embodiments of any of the embodiments described herein, the composition according to any of the respective embodiments described herein comprises an effective amount of an absorption enhancer, i.e., an amount of absorption enhancer effective for enhancing absorption of the therapeutically active agent in the composition.

[0066] Herein, the term “absorption enhancer” refers to a compound known to enhance absorption of macromolecular drugs (e.g., compounds having a molecular weight of at least 1 kDa) and / or BCS Class III drugs (e.g., as described herein) from the gastrointestinal tract into the circulation upon oral administration of the drug. The person skilled in the art will be aware of many such absorption enhancers. In some of any of the respective embodiments, the absorption enhancer is a compound which enhances absorption of macromolecular drugs.

[0067] In some of any of the embodiments described herein, the absorption enhancer is a fatty acid, preferably with a terminal N-(2-hydroxybenzoyl)amino group (at the omega position, i.e., the terminus distal from the carboxylate group of the fatty acid), or a salt thereof (e.g., a monosodium or disodium salt). The substituted fatty acid is preferably from 4 to 20 carbon atoms in length, optionally from 4 to 18 carbon atoms in length, optionally from 4 to 16 carbon atoms in length, optionally from 4 to 14 carbon atoms in length, optionally from 4 to 12 carbon atoms in length and optionally from 4 to 10 carbon atoms in length, including any intermediate values and subranges therebetween. In some of any of the embodiments described herein, the fatty acid is from 6 to 20 carbon atoms in length, optionally from 6 to 18 carbon atoms in length, optionally from 6 to 16 carbon atoms in length, optionally from 6 to 14 carbon atoms in length, optionally from 6 to 12 carbon atoms in length, optionally from 6 to 10 carbon atoms in length, and optionally from 8 to 10 carbon atoms in length, including any intermediate values and subranges therebetween. The fatty acid moiety may be saturated (e.g., as are caprylic acid in 8-N-(2-hydroxybenzoyl)aminocaprylic acid and decanoic acid in 10-N-(2-hydroxybenzoyl)aminodecanoic acid) or unsaturated (i.e., comprising at least one unsaturated carbon-carbon bond).

[0068] Examples of suitable fatty acids for substituted (e.g., by a terminal N-(2- hydroxybenzoyl)amino group) include, without limitation, butanoic acid, caprylic acid and decanoic acid.

[0069] The N-(2-hydroxybenzoyl)amino group may optionally be substituted or non-substituted (e.g., on the aromatic ring thereof). Suitable substituents include, for example, halo (optionally chloro) and alkoxy (optionally methoxy). Examples of substituted N-(2-hydroxybenzoyl)amino groups include, without limitation, N-(5-chlorosalicyloyl)amino, N-(4-chloro-2- hydroxybenzoyl)amino, and N-(2-hydroxy-4-methoxybenzoyl)amino.

[0070] Examples of suitable absorption enhancers include, without limitation, NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) and NAD (10-N-(2-hydroxybenzoyl)aminodecanoic acid) and salts thereof (e.g., monosodium and disodium salts); as well as derivatives thereof (e.g., derivatives substituted by chloro and / or methoxy) such as 5-CNAC (8-N-(5-chlorosalicyloyl)aminocaprylic acid) and 4-MOAC (8-N-(2-hydroxy-4-methoxybenzoyl)aminocaprylic acid) and salts thereof (e.g., monosodium and disodium salts). 4-CNAB (4-N-(2-hydroxy-4-chlorobenzoyl)aminobutanoic acid) and salts thereof (e.g., monosodium and disodium salts) are additional examples of a suitable absorption enhancer.

[0071] In some of any of the embodiments described herein, the absorption enhancer is in a form of a salt thereof, for example, a sodium salt. In exemplary embodiments, the sodium salt is a monosodium salt.

[0072] 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. Without being bound by any particular theory, it is believed that many absorption enhancers tend to be more active (at enhancing absorption) in an ionic form (e.g., a carboxylate anion, such as a fatty acid anion) than in a less soluble non-ionic form (e.g., a carboxylic acid, such as a fatty acid), and that overall activity of the absorption enhancer is strongly dependent on 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 absorption enhancer in ionic form upon dissolution following oral administration may be enhanced by providing the absorption enhancer in a form of a salt and / or by controlling a local pH in the vicinity of the absorption enhancer upon oral administration (e.g., by acid neutralization by proton accepting agents as described herein and / or even by other molecules of absorption enhancer).

[0073] 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.

[0074] According to some of any of the embodiments described herein, the absorption enhancer is inactivated by stomach acid, as described herein, and in some of these embodiments, the absorption enhancer is ionizable, 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 contacted with stomach acid (due, e.g., to precipitation).

[0075] Examples of absorption enhancers which are not expected to be inactivated by stomach acid include, without limitation, alkyl fatty acid esters (e.g., isopropyl myristate); phospholipids (e.g., phosphatidyl choline); quaternary ammonium salts, such as tetraalkyl ammonium salts (e.g., cetyltrimethylammonium salts, such as cetyltrimethylammonium bromide) and alkyl pyridinium salts (e.g., cetylpyridinium salts such as cetylpyridinium chloride); nonionic surfactants such as sorbitan- fatty acid esters (e.g., sorbitan monolaurate, sorbitan monostearate, sorbitan tristearate) and polysorbates (i.e., ethoxylated sorbitan-fatty acid esters, e.g., polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80); and N-dodecylcaprolactam.

[0076] In some of any one of the embodiments described herein, a concentration of the absorption enhancer (according to any of the respective embodiments described herein) in a composition (according to any of the respective embodiments described herein) is at least 10 weight percent; for example, from 10 to 90 weight percent, or from 10 to 80 weight percent, or from 10 to 70 weight percent, or from 10 to 60 weight percent, or from 10 to 50 weight percent, or from 10 to 40 weight percent, or from 10 to 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; for example, from 20 to 90 weight percent, or from 20 to 80 weight percent, or from 20 to 70 weight percent, or from 20 to 60 weight percent, or from 20 to 50 weight percent, or from 20 to 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; for example, from 30 to 90 weight percent, or from 30 to 80 weight percent, or from 30 to 70 weight percent, or from 30 to 60 weight percent, or from 30 to 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; for example, from 40 to 90 weight percent, or from 40 to 80 weight percent, or from 40 to 70 weight percent, or from 40 to 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; for example, from 50 to 90 weight percent, or from 50 to 80 weight percent, or from 50 to 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; for example, from 60 to 90 weight percent, or from 60 to 80 weight percent, including any intermediate values and subranges therebetween.

[0077] In some embodiments, the concentration of the absorption enhancer is at least 70 weight percent; for example, from 70 to 90 weight percent or from 70 to 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, from 80 to 90 weight percent, including any intermediate values and subranges therebetween.

[0078] In some of any of the aforementioned 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). In some of any of the aforementioned embodiments, the absorption enhancer is a salt of NAC (e.g., SNAC).

[0079] In some of any one of the embodiments relating to a unit dosage form described herein, an amount of the absorption enhancer in the unit dosage form is at least 25 mg; for example, from 25 to 1000 mg or from 25 to 500 mg or from 25 to 250 mg or from 25 to 100 mg or from 25 to 50 mg, including any intermediate values and subranges therebetween.

[0080] In some embodiments, the amount of the absorption enhancer in the unit dosage form is at least 50 mg; for example, from 50 to 1000 mg or from 50 to 500 mg or from 50 to 250 mg or from 50 to 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; for example, from 75 to 1000 mg or from 75 to 500 mg or from 75 to 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; for example, from 100 to 1000 mg or from 100 to 500 mg or from 100 to 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; for example, from 150 to 1000 mg or from 150 to 500 mg or from 150 to 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; for example, from 200 to 1000 mg or from 200 to 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; for example, from 300 to 1000 mg or from 300 to 500 mg, including any intermediate values and subranges therebetween. In some of any of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0081] In some of any one of the embodiments described herein, a concentration of the absorption enhancer (according to any of the respective embodiments described herein) in a composition (according to any of the respective embodiments described herein) is lower by at least 5 % or at least 10 % compared to a composition without a sPAA as described herein.

[0082] In some of any one of the embodiments described herein, a concentration of the absorption enhancer (according to any of the respective embodiments described herein) in a composition (according to any of the respective embodiments described herein) is no more than 90 weight percent; or no more than 80 weight percent, or no more than 70 weight percent.

[0083] In some of any one of the embodiments described herein, a concentration of the absorption enhancer (according to any of the respective embodiments described herein) in a composition (according to any of the respective embodiments described herein) is in a range of from 10 to 80 weight percent, or from 10 to 70 weight percent, or from 10 to 60 weight percent, or from 10 to 50 weight percent, or from 10 to 30 weight percent, including any intermediate values and subranges therebetween. In some of any of the aforementioned 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). In some of any of the aforementioned embodiments, the absorption enhancer is a salt of NAC (e.g., SNAC).

[0084] In some of any one of the embodiments described herein, a total concentration of the absorption enhancer (according to any of the respective embodiments described herein), and the proton accepting agent (according to any of the respective embodiments described herein) is at least 50 weight percent (e.g., from 50 to 99.5, or from 50 to 99, or from 50 to 95, or from 50 to 90, or from 50 to 85, or from 50 to 80, or from 60 to 99.5, or from 60 to 99, or from 60 to 95, or from 60 to 90, or from 60 to 85, or from 60 to 80, or from 70 to 99.5, or from 70 to 99, or from 70 to 95, or from 70 to 90, or from 70 to 85, or from 70 to 80, weight percent, including any intermediate values and subranges therebetween). In some of any of the aforementioned 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). In some of any of the aforementioned embodiments, the absorption enhancer is a salt of NAC (e.g., SNAC).

[0085] In some of any one of the embodiments described herein, a total concentration of the absorption enhancer (according to any of the respective embodiments described herein), and the proton accepting agent (according to any of the respective embodiments described herein), is at least 70 weight percent (e.g., from 70 to 99.5, or from 70 to 99, or from 70 to 98, or from 70 to 95, or from 70 to 90, or from 70 to 86, or from 70 to 80, weight percent, including any intermediate values and subranges therebetween). In some of any of the aforementioned 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). In some of any of the aforementioned embodiments, the absorption enhancer is a salt of NAC (e.g., SNAC).

[0086] In some of any one of the embodiments described herein, a total concentration of the absorption enhancer (according to any of the respective embodiments described herein), and the proton accepting agent (according to any of the respective embodiments described herein), is at least 30 weight percent (e.g., from 30 to 99.5, or from 30 to 99, or from 30 to 98, or from 30 to 95, or from 30 to 90, or from 30 to 85, or from 30 to 80, or from 30 to 75, or from 30 to 70, or from 30 to 65, or from 30 to 60, or from 30 to 55, or from 30 to 50, or from 30 to 40 weight percent, including any intermediate values and subranges therebetween). In some of any of the aforementioned 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). In some of any of the aforementioned embodiments, the absorption enhancer is a salt of NAC (e.g., SNAC).

[0087] In some of any one of the embodiments relating to a unit dosage form described herein, a total amount of the absorption enhancer and the sPAA in the unit dosage form is at least 25 mg; for example, from 25 to 1000 mg or from 25 to 500 mg or from 25 to 250 mg or from 25 to 100 mg or from 25 to 50 mg, including any intermediate values and subranges therebetween. In some embodiments, a total amount of the absorption enhancer and the sPAA in the unit dosage form is at least 50 mg; for example, from 50 to 1000 mg or from 50 to 500 mg or from 50 to 250 mg or from 50 to 100 mg, including any intermediate values and subranges therebetween. In some embodiments, a total amount of the absorption enhancer and the sPAA in the unit dosage form is at least 75 mg; for example, from 75 to 1000 mg or from 75 to 500 mg or from 75 to 250 mg, including any intermediate values and subranges therebetween. In some embodiments, a total amount of the absorption enhancer and the sPAA in the unit dosage form is at least 100 mg; for example, from 100 to 1000 mg or from 100 to 500 mg or from 100 to 250 mg, including any intermediate values and subranges therebetween. In some embodiments, a total amount of the absorption enhancer and the sPAA in the unit dosage form is at least 150 mg; for example, from 150 to 1000 mg or from 150 to 500 mg or from 150 to 250 mg, including any intermediate values and subranges therebetween. In some embodiments, a total amount of the absorption enhancer and the sPAA in the unit dosage form is at least 200 mg; for example, from 200 to 1000 mg or from 200 to 500 mg, including any intermediate values and subranges therebetween. In some embodiments, a total amount of the absorption enhancer and the sPAA in the unit dosage form is at least 300 mg; for example, from 300 to 1000 mg or from 300 to 500 mg, including any intermediate values and subranges therebetween. In some of any of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0088] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to the therapeutically active agent in the composition is at least 1:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 1:1 to 1000:1, or from 1:1 to 500:1, or from 1:1 to 300:1, or from 1:1 to 200:1, or from 1:1 to 100:1, or from 1:1 to 50:1, or from 1:1 to 30:1, or from 1:1 to 20:1, or from 1:1 to 10:1, or from 1:1 to 5:1, or from 1:1 to 3:1, or from 1:1 to 2:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0089] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to the therapeutically active agent in the composition is at least 2:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 2:1 to 1000:1, or from 2:1 to 500:1, or from 2:1 to 300:1, or from 2:1 to 200:1, or from 2:1 to 100:1, or from 2:1 to 50:1, or from 2:1 to 30:1, or from 2:1 to 20:1, or from 2:1 to 10:1, or from 2:1 to 5:1, or from 2:1 to 3:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N- (2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0090] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to the therapeutically active agent in the composition is at least 3:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 3:1 to 1000:1, or from 3:1 to 500:1, or from 3:1 to 300:1, or from 3:1 to 200:1, or from 3:1 to 100:1, or from 3:1 to 50:1, or from 3:1 to 30:1, or from 3:1 to 20:1, or from 3:1 to 10:1, or from 3:1 to 5:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0091] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to the therapeutically active agent in the composition is at least 5:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 5:1 to 1000:1, or from 5:1 to 500:1, or from 5:1 to 300:1, or from 5:1 to 200:1, or from 5:1 to 100:1, or from 5:1 to 50:1, or from 5:1 to 30:1, or from 5:1 to 20:1, or from 5:1 to 10:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0092] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 10:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 10:1 to 1000:1, or from 10:1 to 500:1, or from 10:1 to 300:1, or from 10:1 to 200:1, or from 10:1 to 100:1, or from 10:1 to 50:1, or from 10:1 to 30:1, or from 10:1 to 20:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0093] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 20:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 20:1 to 1000:1, or from 20:1 to 500:1, or from 20:1 to 300:1, or from 20:1 to 200:1, or from 20:1 to 100:1, or from 20:1 to 50:1, or from 20:1 to 30:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N- (2-hydroxybenzoyl)aminocaprylate).

[0094] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 30:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 30:1 to 1000:1, or from 30:1 to 500:1, or from 30:1 to 300:1, or from 30:1 to 200:1, or from 30:1 to 100:1, or from 30:1 to 50:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N- (2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0095] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 50:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 50:1 to 1000:1, or from 50:1 to 500:1, or from 50:1 to 300:1, or from 50:1 to 200:1, or from 50:1 to 100:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0096] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 100:1 (absorption enhancer: therapeutically active agent), optionally in a range of from 100:1 to 1000:1, or from 100:1 to 500:1, or from 100:1 to 300:1, or from 100:1 to 200:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0097] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 200: 1 (absorption enhancer: therapeutically active agent), optionally in a range of from 200:1 to 1000:1, or from 200:1 to 500:1, or from 200:1 to 300:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0098] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 300: 1 (absorption enhancer: therapeutically active agent), optionally in a range of from 300:1 to 1000:1, or from 300:1 to 500:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0099] In some embodiments of any one of the embodiments described herein, a weight ratio of the absorption enhancer to therapeutically active agent in the composition is at least 500:1, optionally in a range of from 500:1 to 1000:1 (absorption enhancer: therapeutically active agent), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate).

[0100] Herein throughout, a salt of NAC can be any ionized form of 8-N-(2- hydroxybenzoyl)aminocaprylic acid (NAC) which provides 8-N-(2-hydroxybenzoyl)aminocaprylate and a cation. The cation is typically a monovalent cation such as sodium or potassium, although any other metallic or non-metallic cations are contemplated. In exemplary embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate, abbreviated as SNAC. Herein, whenever a salt of NAC is referred to, it can be considered as SNAC.

[0101] In some embodiments of any one of the embodiments described herein, the salt of NAC may be SNAC. In some embodiments of any of the embodiments described herein, the salt of NAC may be a compound similar to SNAC, such as SNAD (sodium 10-N-(2-hydroxybenzoyl)aminodecanoic acid). As shown below, the structure of SNAD differs from that of SNAC only in the length of the fatty acid moiety.

[0102] SNAD

[0103] In some embodiments of any one of the embodiments described herein, the NAC may optionally be replaced with a similar compound, wherein the caprylic acid moiety of NAC is replaced by another fatty acid moiety at least 6 carbon atoms in length, for example, from 6 to 20 carbon atoms in length, optionally from 6 to 18 carbon atoms in length, optionally from 6 to 16 carbon atoms in length, optionally from 6 to 14 carbon atoms in length, optionally from 6 to 12 carbon atoms in length and optionally from 6 to 10 carbon atoms in length. The fatty acid moiety may be saturated (e.g., as are caprylic acid in NAC and decanoic acid in NAD) or unsaturated (i.e., comprising at least one unsaturated carbon-carbon bond).

[0104] Proton Accepting Agent:

[0105] A proton accepting agent is also referred to herein as an acid-neutralizing substance, or as an acid-neutralizing agent, or as an acid-neutralizing compound, or, interchangeably, as a small molecule proton accepting agent, or non-polymeric proton accepting agent or substance, or is abbreviated as sPAA or simply as PAA.

[0106] According to the present embodiments, the proton accepting agent is non-polymeric, that is, it is not a substance that features a plurality of repeating units, and is a substance that typically has a molecular weight lower than 2,000 grams / mol, or lower than 1,500, or lower than 1,000, or lower than 500, grams / mol.

[0107] Herein throughout, the term “proton accepting agent” refers to any pharmaceutically acceptable compound featuring a pKa higher than the gastric pH, by at least 1 pH unit, and thus, as being at least 2, preferably at least 3, more preferably at least 5, more preferably at least 6, and more preferably higher than 7 pH units than the gastric pH.

[0108] Herein throughout, the phrase “non-polymeric proton-accepting agent”, is also referred to herein interchangeably as “non-polymeric acid-neutralizing agent” or as “small molecule proton accepting agent” or as “proton-accepting small molecule agent” or as “small proton-accepting agent” or simply as “proton-accepting agent” or abbreviated as “PAA” or “sPAA”.

[0109] Herein throughout the phrase “non-polymeric proton-accepting agent” and related phrases describe a pharmaceutically acceptable compound featuring a pKa higher than the gastric pH, by at least 1 pH unit, and thus, as being at least 2, preferably at least 3, more preferably at least 5, more preferably at least 6, and more preferably higher than 7 pH units than the gastric pH.

[0110] In some embodiments, the non-polymeric proton- accepting agent features a pKa higher than the pKa of the absorption enhancer, by at least 0.5, or at least unit. For example, when an absorption enhancer is a salt of NAC, which features pKa of about 5, the PAA features pKa of at least 5.5, preferably at least 6.

[0111] In some of any one of the respective embodiments described herein, the proton-accepting agent has a pKa of at least 2.0, optionally in a range of 2.0 to 14.0, and optionally in a range of 6.0 to 11.0 (including any intermediate values and subranges therebetween); for example, from 6.0 to 14.0, or from 6.0 to 13.0, or from 6.0 to 12.0, or from 6.0 to 11.0, or from 6.0 to 10.0, or from 6.0 to 9.0, or from 6.0 to 8.0, or from 6.0 to 7.0, or from 6.0 to 6.5, including any intermediate values and subranges therebetween. In some such embodiments, the pKa is at least 2.0, or at least 2.5, or at least 3.0, or at least 3.5, or at least 4.0, or at least 4.5, or at least 5.0, or at least 5.5, or at least 6.0, or at least 6.5, or at least 7.0, or at least 7.5, or at least 8.0, or at least 8.5, or at least 9.0, or at least 9.5, or at least 10.0, or at least 10.5, or at least 11.0, or at least 11.5, or at least 12.0, or at least 12.5, or at least 13.0, or at least 14.0, including any intermediate values and subranges therebetween.

[0112] In some of any of the embodiments described herein, the one or more proton- accepting agent(s) independently feature pKa higher by at least 0.25, or by at least 0.5, or by at least 1, or by at least 2, or by at least 3, or by at least 4, or by at least 5, or by at least 6, or by at least 7, than a pKa of the absorption enhancer.

[0113] In some of any of the embodiments described herein, the one or more proton- accepting agent(s) comprise an amino acid featuring a pKa of at least 4, or at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11, or at least 12.

[0114] Herein, the “pKa” of a non-polymeric proton-accepting agent refers to the pH in an aqueous solution of 0.1 M NaCl, at which 50 % of the acid / base (e.g., carboxylate) groups are protonated at 25 °C.

[0115] In some embodiments, the “non-polymeric proton- accepting agent” encompasses such pharmaceutically acceptable compounds which diffuse away from a solid formulation (e.g., as described herein in any of the respective embodiments), upon contacting gastric fluid (when the solid formulation starts to disintegrate and / or release its content), at diffusion kinetics similar to or no more than 50 percent faster or slower than the absorption enhancer (e.g., SNAC).

[0116] In some embodiments, the diffusion kinetics correlates to the molecular weight of the PAA and / or to its water solubility.

[0117] In some embodiments, the PAA has a molecular weight that is similar to the molecular weight of the absorption enhancer, for example, is no more than 50 %, or no more than 20 % lower or higher than the molecular weight of the absorption enhancer. For example, when the absorption enhancer is a salt of SNAC such as a sodium salt of NAC, which has a molecular weight of about 301 grams / mol, the PAA has a molecular weight lower than 1,000, preferably lower than 600, or lower than 500 grams / mol, for example, of from 100 to 600, or from 100 to 500, grams / mol, including any intermediate values and subranges therebetween.

[0118] In some of any of the embodiments described herein, the one or more proton- accepting agent(s) independently have a molecular weight in a range of 20 % to about 200 %, or from about 20 % to about 120 %, or from about 20 % to about 120 %, or from about 5 % to 150 %, optionally in a range of from 5 % to 140 %, or from 5 % to 130 %, or from 5 % to 120 %, or from 5 % to 110 %, or from 5 % to 100 %, or from 5 % to 90 %, or from 5 % to 80 %, or from 5 % to 70 %, or from 5 % to 60 %, or from 5 % to 50 %, or from 5 % to 40 %, or from 5 % to 30 %, or from 5 % to 25 %, relative the molecular weight of the absorption enhancer (e.g., is a salt of NAC such as a sodium salt of NAC), including any intermediate values and subranges therebetween.

[0119] In some embodiments, the PAA is characterized by water solubility of at least 1 mg / ml, preferably at least 10 mg / ml, at room temperature (e.g., 25 °C).

[0120] In some of any of the embodiments described herein, the one or more proton- accepting agent(s) independently feature a water solubility in a range of 20 % to about 200 %, or from about 20 % to about 120 %, or from about 20 % to about 120 %, or from about 5 % to 150 %, optionally in a range of from 5 % to 140 %, or from 5 % to 130 %, or from 5 % to 120 %, or from 5 % to 110 %, or from 5 % to 100 %, or from 5 % to 90 %, or from 5 % to 80 %, or from 5 % to 70 %, or from 5 % to 60 %, or from 5 % to 50 %, or from 5 % to 40 %, or from 5 % to 30 %, or from 5 % to 25 %, relative the water solubility of the absorption enhancer, including any intermediate values and subranges therebetween.

[0121] In some embodiments, the PAA has a molecular weight lower than 2,000, or lower than 1,500, or lower than 1,000, preferably lower than 500, grams / mol, for example, in a range of from 100 to 1,000, or from 100 to 800, or from 100 to 600, or from 100 to 300, grams / mol, and water solubility as described herein.

[0122] In some embodiments, the PAA features pKa of at least 5.5, has a molecular weight lower than 2,000, or lower than 1,500, or lower than 1,000, preferably lower than 500, grams / mol, for example, in a range of from 100 to 1,000, or from 100 to 800, or from 100 to 600, or from 100 to 300, grams / mol, and water solubility as described herein.

[0123] The therapeutically active agent and the absorption enhancer (e.g., SNAC), as described herein in any of the respective embodiments, are excluded from the scope of the phrase “small protonaccepting agent”, even though they may exhibit some ability to neutralize stomach acid, in some embodiments of the invention.

[0124] Exemplary non-polymeric proton- accepting agents that are suitable for use in the context of the present embodiments include, without limitation, antacid compounds, alkaline amino acids (amino acid residues which are protonated at physiological pH), and fatty acid salts.

[0125] Herein throughout, the term “antacid compound” refers to any pharmaceutically acceptable compound capable of neutralizing stomach acid (e.g., HC1 in aqueous solution), preferably wherein one mole of antacid compound is capable of neutralizing at least 0.5 mole of HC1, and more preferably capable of neutralizing at least 1 mole of HC1. An “antacid compound” according to some embodiments of the present invention encompasses compounds known as drugs for treating conditions associated with stomach acidity such as heartbum. In some embodiments, the at least one antacid compound is one or more of calcium carbonate, calcium gluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium oxide and magnesium hydroxide.

[0126] In some embodiments, the at least one antacid compound is one or more of calcium carbonate, calcium gluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium oxide and magnesium hydroxide.

[0127] In some embodiments, the at least one antacid compound is one or more of calcium carbonate, calcium gluconate, sodium carbonate, sodium bicarbonate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium oxide, aluminum carbonate, and aluminum hydroxide.

[0128] In some embodiments, the at least one antacid compound is one or more of calcium carbonate, calcium citrate, sodium bicarbonate, sodium hydroxide, magnesium carbonate, magnesium citrate, magnesium hydroxide, aluminum carbonate, and aluminum hydroxide.

[0129] In some embodiments, the at least one antacid compound is one or more of calcium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, magnesium carbonate, magnesium hydroxide, and aluminum hydroxide.

[0130] Amino acids that suitable for use in the context of the present embodiments include alkaline amino acids, which feature a side chain that can be positively charged in gastric pH, or which features pKa higher than the gastric pH, by at least 1 pH unit, and thus, as being at least 2, preferably at least 3, more preferably at least 5, more preferably at least 6, and more preferably higher than 7 pH units than the gastric pH. Preferably, the amino acid has a side chain that features pKa that is higher by at least 0.5, preferably by at least 1 unit than the pKa of the absorption enhancer. In some embodiments, the alkaline amino acid has a side chain that features pKa of at least 5, or at least 6, for example, of from 5 to 14, or from 6 to 14, or from 5 to 12 or from 6 to 12, or from 5 to 10 or from 6 to 10, including any intermediate values and subranges therebetween.

[0131] In some embodiments, the alkaline amino acid features pKa as described herein, and has a MW and hydrophilicity as described herein for a PAA.

[0132] The amino acid includes both D- and L- amino acids. The amino acid can be naturally occurring, amino acids that modified post-translationally in vivo and / or other amino acids that are not naturally-occurring, including, for example, hydroxyproline, phosphothreonine, hydroxylysine, isodesmosine, and ornithine.

[0133] In some embodiments, the at least one basic amino acid compound is one or more of L- histidine, D-histidine, D-N-methylhistidine, L-N-methylhistidine, D-a-methylhistidine, L-a- methylhistidine, L-arginine, D-arginine, D-N-methylarginine, L-N-methylarginine, D-a- methylarginine, L-a-methylarginine, L-lysine, D-lysine, D-N-methyllysine, L-N-methyllysine, D-a- methyllysine, and L-a-methyllysine.

[0134] In some embodiments, the at least one basic amino acid compound is one or more of D- histidine, L-histidine, L-arginine, D-arginine, L-lysine and D-lysine.

[0135] In some embodiments that amino acid is or comprises arginine, e.g., L-arginine, also referred to herein as “Arg”.

[0136] Herein and in the art, the phrase “fatty acid salt” describes a compound, or a mixture of compounds, featuring pKa higher than the gastric pH, by at least 1 pH unit, and thus, as being at least 2, preferably at least 3, more preferably at least 5, more preferably at least 6, and more preferably higher than 7 pH units higher than the gastric pH. Preferably, the fatty acid salt features pKa that is higher by at least 0.5 or by at least 1 than the pKa of the absorption enhancer. Preferably, the fatty acid salt features pKa of at least 5, or at least 6, for example, of from 5 to 14, or from 6 to 14, or from 5 to 12 or from 6 to 12, or from 5 to 10 or from 6 to 10, including any intermediate values and subranges therebetween.

[0137] In some embodiments, the alkaline amino acid features pKa as described herein, and has a MW and hydrophilicity as described herein for a PAA.

[0138] Fatty acid salts according to some of the present embodiments can be represented by Formula I:

[0139] R-C(=O)-O'Q+

[0140] Formula I wherein R is a saturated or unsaturated, linear or branched, preferably unsubstituted alkylene chain of at least 4, preferably at least 6, carbon atoms in length, and Q+is a cation, preferably a monovalent metal cation (e.g., Na+, K+), yet, any other cation, including non-metallic cations, are contemplated. The fatty acid salt thus comprises an ionized form of a fatty acid (a carboxylate anion) and a cation.

[0141] The fatty acid from which the fatty acid salt is derived can be, without limitation, a saturated or unsaturated fatty acid having 4 or more carbon atoms, preferably 6 or more carbon atoms, for example, 8 or more carbon atoms, more or 10 or more carbon atoms, in length. Exemplary fatty acids include, such as, but not limited to, butyric acid, hexanoic acid, octanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidic acid, etc.

[0142] Preferably, the fatty acid is a medium chain fatty acid, having from 4 to 14, or from 4 to 12, or from 4 to 10, or from 6 to 16, or from 6 to 12, or from 6 to 10, or from 8 to 12, or from 8 to 10, carbon atoms in length. In some of these embodiments, the fatty acid is a saturated fatty acid. In some of these embodiments, the fatty acid is an unsubstituted fatty acid. In some of these embodiments, the fatty acid is unsubstituted saturated fatty acid.

[0143] Exemplary fatty acid salts include, but are not limited to, sodium butyrate, sodium hexanoate, sodium octanoate, sodium decanoate and sodium laurate.

[0144] Exemplary fatty acid salts include, but are not limited to, sodium octanoate and sodium decanoate.

[0145] According to some of any of the embodiments described herein, the composition comprises a combination of two or more proton-accepting agent(s), for example, two or more alkaline amino acids and / or two or more fatty acid salts, as these are described herein in any of the respective embodiments; or one or more of an alkaline amino acid and one or more of a fatty acid salt; or one or more of alkaline amino acid and one or more antacid, as described herein; or one or more of a fatty acid salt and one or more of an antacid; or a combination of one or more of an alkaline amino acid, one or more of an antacid and one or more of a fatty acid salt, as described herein.

[0146] According to some embodiments, when two or more proton-accepting agent(s) are included in a composition, an additive or even synergistic effect can be provided in terms of protecting the absorption enhance and / or the absorption of the therapeutically active agent (e.g., bioavailability).

[0147] In some of any of the embodiments described herein, a total concentration of the one or more small proton- accepting agent(s) (according to any of the respective embodiments described herein) in the composition is at least 1 weight percent of the total weight of the composition. In some such embodiments, the total concentration of the one or more small proton- accepting agent(s) is at least 2 weight percent. In some such embodiments, total concentration of the one or more small protonaccepting agent(s) is at least 3 weight percent. In some such embodiments, total concentration of the one or more small proton-accepting agent(s) is at least 4 weight percent. In some such embodiments, the total concentration of the one or more small proton- accepting agent(s) is at least 5 weight percent. In some such embodiments, the total concentration of the one or more small proton-accepting agent(s) is at least 10 weight percent. In some such embodiments, the total concentration of the one or more small proton-accepting agent(s) is at least 15 weight percent. In some embodiments, the total concentration of the one or more small proton- accepting agent(s) is at least 20 weight percent. In some embodiments, the concentration of the small proton- accepting agent is at least 25 weight percent. In some embodiments, total concentration of the one or more small proton-accepting agent(s) is at least 30 weight percent. In some embodiments, the total concentration of the one or more small proton-accepting agent(s) is at least 35 weight percent. In some embodiments, the total concentration of the one or more small proton- accepting agent(s) is at least 40 weight percent. In some embodiments, the total concentration of the one or more small proton- accepting agent(s) is at least 50 weight percent. In some embodiments, the total concentration of the one or more small proton-accepting agent(s) is at least 60 weight percent. In some embodiments, the total concentration of the one or more small proton- accepting agent(s) is at least 70 weight percent. In some embodiments, the total concentration of the one or more small proton-accepting agent(s) is at least 80 weight percent. In some embodiments, the total concentration of the one or more small protonaccepting agent(s) is at least 90 weight percent.

[0148] In some of any of the embodiments described herein, a total concentration of the one or more small proton- accepting agent(s) (according to any of the respective embodiments described herein) in the composition ranges from 1 to 90, or from 5 to 90 weight percent, of the total weight of the composition, or from 5 to 80, or from 5 to 70, or from 5 to 50, or from 5 to 40, or from 5 to 30, or from 10 to 90, or from 10 to 80, or from 10 to 70, or from 10 to 50, or from 10 to 40, or from 10 to 30, or from 20 to 90, or from 20 to 80, or from 20 to 70, or from 20 to 60, or from 20 to 50, or from 20 to 40, or from 20 to 30, or from 30 to 90, or from 30 to 80, or from 30 to 70, or from 30 to 60, or from 30 to 50, or from 30 to 40, or from 40 to 90, or from 40 to 80, or from 40 to 70, or from 40 to 60, or from 40 to 50, or from 50 to 90, or from 50 to 80, or from 50 to 70, or from 50 to 60, or from 60 to 90, or from 60 to 80, or from 60 to 70, or from 80 to 90, or from 70 to 80, or from 80 to 90, weight percent, of the total weight of the composition, including any intermediate values and subranges therebetween.

[0149] In some of any of the embodiments described herein, a total concentration of the one or more small proton- accepting agent(s) (according to any of the respective embodiments described herein) in the composition ranges from 1 to 50 weight percent, or from 5 to 50 weight percent, of the total weight of the composition, or from 5 to 40, or from 5 to 30, or from 5 to 20, or from 5 to 10, or from 10 to 50, or from 10 to 40, or from 10 to 30, or from 10 to 20, weight percent, of the total weight of the composition, including any intermediate values and subranges therebetween. In some of any of the embodiments described herein, a total concentration of the one or more small proton- accepting agent(s) (according to any of the respective embodiments described herein) in the composition ranges from 10 to 60 weight percent, or from 10 to 50 weight percent, of the total weight of the composition, or from 10 to 40, or from 10 to 30, or from 20 to 60, or from 20 to 50, or from 20 to 40, or from 20 to 30, weight percent, of the total weight of the composition, including any intermediate values and subranges therebetween.

[0150] By “weight percent” (or w / w %, or % wt.) it is meant the weight of the indicated substance out of the total weight of a composition comprising same.

[0151] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton-accepting agent(s) to the absorption enhancer in the composition is at least 1:20 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 1:20 to 20:1, or from 1:10 to 10:1, or from or from 9:1 to 1:9, or from 1:8 to 8:1, or from 1:7 to 7:1, or from 1:6 to 6:1, or from 1:5 to 5:1, or from 1:4 to 4:1, or from 1:3 to 3:1, or from 1:2 to 2:1, including any intermediate values and subranges therebetween.

[0152] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton- accepting agent(s) to the absorption enhancer is in a range of from 1:10 to 1:1, or from 1:5 to 1:1, or from 1:4 to 1:1, or from 1:3 to 1:1, or from 1:2 to 1:1, including any intermediate values and subranges therebetween, or is about 1: 1.

[0153] In some of the aforementioned 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, a mol ratio of the one or more proton-accepting agent(s) to the absorption enhancer is at least 0.05:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.05:1 to 10:1, or from 0.05:1 to 9:1, or from 0.05:1 to 8:1, or from 0.05:1 to 7:1, or from 0.05:1 to 6:1, or from 0.05:1 to 5:1, or from 0.05:1 to 4:1, or from 0.05:1 to 3:1, or from 0.05:1 to 2:1, or from 0.05:1 to 1:1, or from 0.05:1 to 0.5:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned 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 embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton-accepting agent(s) to the absorption enhancer is at least 0.06:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.06:1 to 10:1, or from 0.06:1 to 9:1, or from 0.06:1 to 8:1, or from 0.06:1 to 7:1, or from 0.06:1 to 6:1, or from 0.06:1 to 5:1, or from 0.06:1 to 4:1, or from 0.06:1 to 3:1, or from 0.06:1 to 2:1, or from 0.06:1 to 1:1, or from 0.06:1 to 0.5:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned 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 embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton-accepting agent(s) to the absorption enhancer is at least 0.07:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.07:1 to 10:1, or from 0.07:1 to 9:1, or from 0.07:1 to 8:1, or from 0.07:1 to 7:1, or from 0.07:1 to 6:1, or from 0.07:1 to 5:1, or from 0.07:1 to 4:1, or from 0.07:1 to 3:1, or from 0.07:1 to 2:1, or from 0.07:1 to 1:1, or from 0.07:1 to 0.5:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned 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 embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton-accepting agent(s) to the absorption enhancer is at least 0.08:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.08:1 to 10:1, or from 0.08:1 to 9:1, or from 0.08:1 to 8:1, or from 0.08:1 to 7:1, or from 0.08:1 to 6:1, or from 0.08:1 to 5:1, or from 0.08:1 to 4:1, or from 0.08:1 to 3:1, or from 0.08:1 to 2:1, or from 0.08:1 to 1:1, or from 0.08:1 to 0.5:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned 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] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton-accepting agent(s) to the absorption enhancer is at least 0.09:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.09:1 to 10:1, or from 0.09:1 to 9:1, or from 0.09:1 to 8:1, or from 0.09:1 to 7:1, or from 0.09:1 to 6:1, or from 0.09:1 to 5:1, or from 0.09:1 to 4:1, or from 0.09:1 to 3:1, or from 0.09:1 to 2:1, or from 0.09:1 to 1:1, or from 0.09:1 to 0.5:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0159] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton- accepting agent(s) to the absorption enhancer is at least 0.1:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.1:1 to 10:1, or from 0.1:1 to 9:1, or from 0.1:1 to 8:1, or from 0.1:1 to 7:1, or from 0.1:1 to 6:1, or from 0.1:1 to 5:1, or from 0.1:1 to 4:1, or from 0.1:1 to 3:1, or from 0.1:1 to 2:1, or from 0.1:1 to 1:1, or from 0.1:1 to 0.5:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N- (2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0160] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton- accepting agent(s) to the absorption enhancer is at least 0.1:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.1 to 1000:1, or from 0.1:1 to 500:1, or from 0.1:1 to 300:1, or from 0.1:1 to 200:1, or from 0.1:1 to 100:1, or from 0.1:1 to 50:1, or from 0.1:1 to 30:1, or from 0.1:1 to 20:1, or from 0.1:1 to 10:1, or from 0.1:1 to 5:1, or from 0.1:1 to 3:1, or from 0.1:1 to 2:1, or from 0.1 to 1:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0161] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton- accepting agent(s) to the absorption enhancer is at least 0.2: 1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0. 2 to 1000:1, or from 0.2:1 to 500:1, or from 0.2:1 to 300:1, or from 0.2:1 to 200:1, or from 0.2:1 to 100:1, or from 0.2:1 to 50:1, or from 0.2:1 to 30:1, or from 0.2:1 to 20:1, or from 0.2:1 to 10:1, or from 0.2:1 to 5:1, or from 0.2:1 to 3:1, or from 0.2:1 to 2:1, or from 0.2 to 1:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0162] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton- accepting agent(s) to the absorption enhancer is at least 0.3:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.3 to 1000:1, or from 0.3:1 to 500:1, or from 0.3:1 to 300:1, or from 0.3:1 to 200:1, or from 0.3:1 to 100:1, or from 0.3:1 to 50:1, or from 0.3:1 to 30:1, or from 0.3:1 to 20:1, or from 0.3:1 to 10:1, or from 0.3:1 to 5:1, or from 0.3:1 to 3:1, or from 0.3:1 to 2:1, or from 0.3 to 1:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0163] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton- accepting agent(s) to the absorption enhancer is at least 0.4: 1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.4 to 1000:1, or from 0.4:1 to 500:1, or from 0.4:1 to 300:1, or from 0.4:1 to 200:1, or from 0.4:1 to 100:1, or from 0.4:1 to 50:1, or from 0.4:1 to 30:1, or from 0.4:1 to 20:1, or from 0.4:1 to 10:1, or from 0.4:1 to 5:1, or from 0.4:1 to 3:1, or from 0.4:1 to 2:1, or from 0.4 to 1:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0164] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton- accepting agent(s) to the absorption enhancer is at least 0.5:1 (at least one proton accepting agent: absorption enhancer), optionally in a range of from 0.5 to 1000:1, or from 0.5:1 to 500:1, or from 0.5:1 to 300:1, or from 0.5:1 to 200:1, or from 0.5:1 to 100:1, or from 0.5:1 to 50:1, or from 0.5:1 to 30:1, or from 0.5:1 to 20:1, or from 0.5:1 to 10:1, or from 0.5:1 to 5:1, or from 0.5:1 to 3:1, or from 0.5:1 to 2:1, or from 0.5 to 1:1 (at least one proton accepting agent: absorption enhancer), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0165] In certain embodiments, the amount or concentration of each of the absorption enhancer, and the one or more proton-accepting agent(s) within a composition can be determined by initially selecting an amount of the absorption enhancer based on the respective embodiments. Subsequently, a molar ratio between the absorption enhancer and the one or more proton-accepting agent(s) is selected. The remaining weight of the composition is then constituted by the therapeutically active agent, and optionally additional agents (e.g., a lubricant). The total amount of each component also depends on a selected weight and / or size of the composition, in case of solid oral compositions.

[0166] In some embodiments of any one of the embodiments described herein relating to a small proton-accepting agent, a total amount of the one or more small proton- accepting agent(s) in a composition as described herein, is at least 0.1 mg. In some embodiments, the total amount of small proton-accepting agent(s) is at least 0.5 mg. In some embodiments, the total amount of the one or more small proton-accepting agent(s) is at least 1 mg. In some embodiments, the amount of small proton-accepting agent(s) is at least 2 mg. In some embodiments, the amount of small protonaccepting agent(s) is at least 5 mg. In some embodiments, the amount of small proton- accepting agent(s) is at least 10 mg. In some embodiments, the amount of small proton-accepting agent(s) is at least 20 mg.

[0167] In some embodiments of any one of the embodiments described herein relating to a small proton-accepting agent, a total amount of the one or more small proton- accepting agent(s) in a composition as described herein, is in a range of from 10 to 60, or from 10 to 50, or from 20 to 60, or from 20 to 50, or from 30 to 60, or from 30 to 50 mg, including any intermediate values and subranges therebetween. In some embodiments of any one of the embodiments described herein relating to a small proton-accepting agent, a total amount of the one or more small proton- accepting agent(s) in a composition as described herein, is in a range of from 0.1 to 50, or from 0.1 to 40, or from 0.1 to 30, or from 0.1 to 20, or from 1 to 50, or from 1 to 40, or from 1 to 30, or from 1 to 20, or from 1 to 10, mg, including any intermediate values and subranges therebetween. In some embodiments of any one of the embodiments described herein relating to a small proton- accepting agent, a total amount of the small proton-accepting agent(s) in a composition as described herein, is in a range of from 0.1 to 50, or from 0.1 to 40, or from 0.1 to 30, or from 0.1 to 20, or from 1 to 50, or from 1 to 40, or from 1 to 30, or from 1 to 20, or from 1 to 10, mg, including any intermediate values and subranges therebetween.

[0168] In some embodiments of any one of the embodiments described herein relating to a small proton-accepting agent, a total amount of the one or more proton-accepting agent(s) in a composition as described herein, is in a range of from 50 to 500, or from 50 to 400, or from 50 to 300, or from 50 to 200, or from 50 to 100, or from 100 to 200, or from 100 to 300, or from 100 to 400, or from 100 to 500, or from 200 to 500, or from 200 to 400, or from 200 to 300, or from 300 to 500, or from 300 to 400, or from 400 to 500 mg, including any intermediate values and subranges therebetween.

[0169] In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0170] The effect of the small proton- accepting agent(s) on the percentage recovery of SNAC may be determined by comparing percentage recovery of a composition according to embodiments of the invention with a corresponding composition comprising the same amount of other ingredients other than the small proton-accepting agent, such that the total mass is lower (due to the absence of small proton-accepting agent). In such embodiments, both compositions are in a form of a tablet, and the tablets have the same cross-section (e.g., diameter of a circular cross-section), and the tablet with a lower weight is thinner in the axis perpendicular to the cross-section of the tablet.

[0171] The effect of the small proton- accepting agent(s) on absorption of the therapeutically active agent may optionally be determined by comparing absorption upon oral administration of a composition according to embodiments of the invention with a corresponding composition comprising the same amount of other ingredients other than the small proton- accepting agent, such that the total mass is lower (due to the absence of small proton-accepting agent). In such embodiments, both compositions are in a form of a tablet, and the tablets have the same cross-section (e.g., diameter of a circular cross-section), and the tablet with a lower weight is thinner in the axis perpendicular to the cross-section of the tablet.

[0172] In some embodiments of any one of the embodiments described herein, a Cmax and / or bioavailability of the composition (i.e., of the therapeutically active agent in the composition) upon oral administration is at least 20 % higher than (120 % of the level of) a Cmax and / or bioavailability of a corresponding composition without the small proton-accepting agent. In some embodiments, the Cmax and / or bioavailability is at least 50 % higher than (150 % of the level of) the Cmax and / or bioavailability upon oral administration of a corresponding composition without small protonaccepting agent. In some embodiments, the Cmax and / or bioavailability is at least twice (200 % of the level of) the Cmax and / or bioavailability upon oral administration of a corresponding composition without the small proton-accepting agent. In some embodiments, the Cmax and / or bioavailability is at least four- fold (400 % of the level of) the Cmax and / or bioavailability upon oral administration of a corresponding composition without the small proton- accepting agent. In some embodiments, the Cmax and / or bioavailability is at least six-fold (600 % of the level of) the Cmax and / or bioavailability upon oral administration of a corresponding composition without the small proton-accepting agent. In some embodiments, the Cmax and / or bioavailability is at least ten-fold (1000 % of the level of) the Cmax and / or bioavailability upon oral administration of a corresponding composition without the small proton-accepting agent.

[0173] Cmax and / or bioavailability may optionally be determined by administering the composition orally to subjects (e.g., human subjects) and determining a level of the therapeutically active agent in the blood at frequent intervals by taking blood samples.

[0174] Bioavailability may be determined by comparing a ratio of an area under the curve upon oral administration (e.g., over the course of 12 or 24 hours) to an area under curve over the same time period for intravenously administered therapeutically active agent, using standard techniques (e.g., data processing algorithms) known in the art. The therapeutically active agent may be injected at a lower dose (e.g., for safety reasons) and the areas under curve normalized to the total amount administered.

[0175] It is to be noted that when two of more proton accepting agents are used, and the combination provides at least an additive effect and optionally a synergistic effect, an amount of each PAA can be lower than its amount when used alone, as long as a total amount (concentration) is in accordance with any of the respective embodiments as described herein.

[0176] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton accepting agent(s) to the salt of NAC is at least 0.05: 1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.05:1 to 10:1, or from 0.05:1 to 10:1, or from 0.05:1 to 9:1, or from 0.05:1 to 8:1, or from 0.05:1 to 7:1, or from 0.05:1 to 6:1, or from 0.05:1 to 5:1, or from 0.05:1 to 4:1, or from 0.05:1 to 3:1, or from 0.05:1 to 2:1, or from 0.05:1 to 1:1, or from 0.05:1 to 0.5:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate.

[0177] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton accepting agent(s) to the salt of NAC is at least 0.06:1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.06:1 to 10:1, or from 0.06:1 to 9:1, or from 0.06:1 to 8:1, or from 0.06:1 to 7:1, or from 0.06:1 to 6:1, or from 0.06:1 to 5:1, or from 0.06:1 to 4:1, or from 0.06:1 to 3:1, or from 0.06:1 to 2:1, or from 0.06:1 to 1:1, or from 0.06:1 to 0.5:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2- hydroxybenzoyl)aminocaprylate.

[0178] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton accepting agent(s) to the salt of NAC is at least 0.07:1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.07:1 to 10:1, or from 0.07:1 to 9:1, or from 0.07:1 to 8:1, or from 0.07:1 to 7:1, or from 0.07:1 to 6:1, or from 0.07:1 to 5:1, or from 0.07:1 to 4:1, or from 0.07:1 to 3:1, or from 0.07:1 to 2:1, or from 0.07:1 to 1:1, or from 0.07:1 to 0.5:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2- hydroxybenzoyl)aminocaprylate.

[0179] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton accepting agent(s) to the salt of NAC is at least 0.08:1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.08:1 to 10:1, or from 0.08:1 to 9:1, or from 0.08:1 to 8:1, or from 0.08:1 to 7:1, or from 0.08:1 to 6:1, or from 0.08:1 to 5:1, or from 0.08:1 to 4:1, or from 0.08:1 to 3:1, or from 0.08:1 to 2:1, or from 0.08:1 to 1:1, or from 0.08:1 to 0.5:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2- hydroxybenzoyl)aminocaprylate.

[0180] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton accepting agent(s) to the salt of NAC is at least 0.09:1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.09:1 to 10:1, or from 0.09:1 to 9:1, or from 0.09:1 to 8:1, or from 0.09:1 to 7:1, or from 0.09:1 to 6:1, or from 0.09:1 to 5:1, or from 0.09:1 to 4:1, or from 0.09:1 to 3:1, or from 0.09:1 to 2:1, or from 0.09:1 to 1:1, or from 0.09:1 to 0.5:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2- hydroxybenzoyl)aminocaprylate.

[0181] In some embodiments of any one of the embodiments described herein, a mol ratio of the one or more proton accepting agent(s) to the salt of NAC is at least 0.1:1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.1:1 to 10: 1 , or from 0.1:1 to 9: 1 , or from 0.1:1 to 8:1, or from 0.1:1 to 7:1, or from 0.1:1 to 6:1, or from 0.1:1 to 5:1, or from 0.1:1 to 4:1, or from 0.1:1 to 3 : 1 , or from 0.1 : 1 to 2: 1 , or from 0.1 : 1 to 1 : 1 , or from 0.1:1 to 0.5 : 1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate.

[0182] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton accepting agent(s) to the salt of NAC is at least is at least 0.1:1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.1 to 1000: 1 , or from 0.1:1 to 500: 1 , or from 0.1:1 to 300:1, or from 0.1:1 to 200:1, or from 0.1:1 to 100:1, or from 0.1:1 to 50:1, or from 0.1:1 to 30:1, or from 0.1:1 to 20:1, or from 0.1:1 to 10:1, or from 0.1:1 to 5:1, or from 0.1:1 to 3:1, or from 0.1:1 to 2:1, or from 0.1 to 1:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate.

[0183] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton accepting agent(s) to the salt of NAC is at least is at least 0.2: 1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0. 2 to 1000:1, or from 0.2: 1 to 500:1, or from 0.2:1 to 300:1, or from 0.2:1 to 200:1, or from 0.2:1 to 100:1, or from 0.2:1 to 50:1, or from 0.2:1 to 30:1, or from 0.2:1 to 20:1, or from 0.2:1 to 10:1, or from 0.2:1 to 5:1, or from 0.2:1 to 3:1, or from 0.2:1 to 2:1, or from 0.2 to 1:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate.

[0184] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton accepting agent(s) to the salt of NAC is at least 0.3 : 1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.3 to 1000:1, or from 0.3:1 to 500:1, or from 0.3:1 to 300:1, or from 0.3:1 to 200:1, or from 0.3:1 to 100:1, or from 0.3:1 to 50:1, or from 0.3:1 to 30:1, or from 0.3:1 to 20:1, or from 0.3:1 to 10:1, or from 0.3:1 to 5:1, or from 0.3:1 to 3:1, or from 0.3:1 to 2: 1 , or from 0.3 to 1:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate.

[0185] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton accepting agent(s) to the salt of NAC is at least is at least 0.4: 1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.4 to 1000:1, or from 0.4: 1 to 500:1, or from 0.4:1 to 300:1, or from 0.4:1 to 200:1, or from 0.4:1 to 100:1, or from 0.4:1 to 50:1, or from 0.4:1 to 30:1, or from 0.4:1 to 20:1, or from 0.4:1 to 10:1, or from 0.4:1 to 5:1, or from 0.4:1 to 3:1, or from 0.4:1 to 2:1, or from 0.4 to 1:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate.

[0186] In some embodiments of any one of the embodiments described herein, a weight ratio of the one or more proton accepting agent(s) to the salt of NAC is at least is at least 0.5:1 (at least one proton accepting agent: salt of NAC), optionally in a range of from 0.5 to 1000:1, or from 0.5:1 to 500:1, or from 0.5:1 to 300:1, or from 0.5:1 to 200:1, or from 0.5:1 to 100:1, or from 0.5:1 to 50:1, or from 0.5:1 to 30:1, or from 0.5:1 to 20:1, or from 0.5:1 to 10:1, or from 0.5:1 to 5:1, or from 0.5:1 to 3:1, or from 0.5:1 to 2:1, or from 0.5 to 1:1 (at least one proton accepting agent: salt of NAC), including any intermediate values and subranges therebetween. In some of the aforementioned embodiments, the salt of NAC is sodium 8-N-(2-hydroxybenzoyl)aminocaprylate.

[0187] Whenever a weight ratio or a mol ratio are described herein, the ratio relates to one PAA, or, when two or more PAAs are included, the ratio relates to the total amount of the PAAs versus a salt of NAC or to each PAA alone versus a salt of NAC.

[0188] Therapeutically active agent:

[0189] Compositions described herein are particularly suitable for enhancing the absorption of therapeutically active agents whose absorption upon oral administration is limited, for example, by a large molecular weight, strong hydrophilicity (e.g., which inhibits crossing of lipid membranes in the gastrointestinal tract), and / or degradation in the gastrointestinal tract (e.g., by proteolysis), for example, degradation in the stomach by pepsin and / or stomach acid.

[0190] In some embodiments of any one of the embodiments described herein, the therapeutically active agent according to any of the respective embodiments described herein has a molecular weight of at least 0.5 kDa. In some embodiments, the molecular weight is in a range of from 0.5 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 30 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 20 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 10 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 7.5 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 0.5 to 5 kDa, including any intermediate values and subranges therebetween.

[0191] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 1 kDa. In some embodiments, the molecular weight is in a range of from 1 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 30 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 20 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 10 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 7.5 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 1 to 5 kDa, including any intermediate values and subranges therebetween. In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 2 kDa. In some embodiments, the molecular weight is in a range of from 2 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 2 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 2 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 2 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from

[0192] 2 to 30 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 2 to 20 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 2 to 10 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 2 to 7.5 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 2 to 5 kDa, including any intermediate values and subranges therebetween.

[0193] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 3 kDa. In some embodiments, the molecular weight is in a range of from 3 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 3 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 3 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 3 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from

[0194] 3 to 30 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 3 to 20 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 3 to 10 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 3 to 7.5 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 3 to 5 kDa, including any intermediate values and subranges therebetween.

[0195] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 4 kDa. In some embodiments, the molecular weight is in a range of from 4 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 4 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 4 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 4 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from

[0196] 4 to 30 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 4 to 20 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 4 to 10 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 4 to 7.5 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 4 to 5 kDa, including any intermediate values and subranges therebetween.

[0197] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 5 kDa. In some embodiments, the molecular weight is in a range of from 5 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 5 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 5 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 5 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from

[0198] 5 to 30 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 5 to 20 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 5 to 10 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 5 to 7.5 kDa, including any intermediate values and subranges therebetween.

[0199] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 10 kDa. In some embodiments, the molecular weight is in a range of from 10 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 10 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 10 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 10 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 10 to 30 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 10 to 20 kDa, including any intermediate values and subranges therebetween.

[0200] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 20 kDa. In some embodiments, the molecular weight is in a range of from 20 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 20 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 20 to 75 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 20 to 50 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 20 to 30 kDa, including any intermediate values and subranges therebetween.

[0201] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 50 kDa. In some embodiments, the molecular weight is in a range of from 50 to 150 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 50 to 100 kDa, including any intermediate values and subranges therebetween. In some embodiments, the molecular weight is in a range of from 50 to 75 kDa, including any intermediate values and subranges therebetween.

[0202] Without being bound by any particular theory, it is believed that agents having a relatively high molecular weight (e.g., at least 0.5 kDa, at least 1 kDa, at least 2 kDa, at least 3 kDa, at least 4 kDa) tend to be less efficiently absorbed upon oral administration than relatively small molecules (e.g., molecules having a molecular weight of less than 0.5 kDa, or less than 1 kDa) and therefore, their absorption is particularly susceptible to enhancement by activity of an absorption enhancer (e.g., NAC or a salt thereof) according to any of the respective embodiments described herein.

[0203] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is a polypeptide or nucleic acid.

[0204] Without being bound by any particular theory, it is believed that agents which are polypeptides or nucleic acids tend to be poorly absorbed upon oral administration, for example, due to their polarity and / or relatively large molecular weight; and therefore, their absorption is particularly susceptible to enhancement by activity of an absorption enhancer (e.g., NAC or a salt thereof) and to increasing absorption enhancer activity by a proton- accepting non-polymeric agent according to any of the respective embodiments described herein. It is further believed that absorption of polypeptides is further limited by degradation by pH-dependent activity of enzymes such as pepsin, and that a pH increase associated with a proton-accepting agent can enhance absorption of a polypeptide by reducing pepsin activity (in addition to increasing absorption enhancer activity, as described herein). In some embodiments of any one of the embodiments described herein, the therapeutically active agent is a polypeptide.

[0205] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is a polypeptide having a molecular weight as described herein in any of the respective embodiments and any combination thereof.

[0206] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is a hormone and / or cytokine (e.g., a hormone), an enzyme, and / or an antigen (e.g., wherein the composition serves as a vaccine). In some embodiments, the hormone and / or cytokine is a polypeptide hormone and / or cytokine, or an analog thereof.

[0207] Herein, an “analog” of a given polypeptide or nucleic acid encompasses various derivatives (e.g., synthetic analogs) of the polypeptide / nucleic acid, such as homologs (as defined herein), fragments (including fragments of a homolog) and substituted derivatives (e.g., comprising a substituent for enhancing stability and / or half-life) of the polypeptide / nucleic acid or homolog and / or fragment thereof. Preferably, the analog exhibits a biological activity of the polypeptide / nucleic acid.

[0208] Examples of polypeptides which may be utilized (per se or as analogs thereof) as therapeutically active agents according to embodiments of the invention include, without limitation, an antibody (e.g., monoclonal antibody), an antipathogenic peptide such as an antibacterial peptide (e.g., bacitracin, boceprevir, dalbavancin, daptomycin, enfuvirtide, oritavancin, teicoplanin, telaprevir, telavancin, vancomycin, and guavanin) and an antiviral peptide (e.g. bulevirtide), a blood clotting factor, a C-type natriuretic peptide (including derivatives thereof such as vosiritide), a calcitonin, disitertide, an endomorphin (e.g., endomorphin- 1 and / or, endomorphin-2), an erythropoietin (e.g., darbepoetin), etelcalcitide, a gastric inhibitory polypeptide (GIP) or other GIP receptor agonist (e.g. tirzepatide) , a glucagon or other glucagon receptor agonist, a GLP-1 (glucagon- like peptide- 1, including derivatives thereof such as liraglutide, semaglutide, taspoglutide, albiglutide and dulaglutide), a GLP-1 receptor agonist (including GLP-1 receptor / glucagon receptor dual agonists) such as exendin-4 (including exenatide and lixisenatide), a GLP-2 (glucagon-like peptide- 2, including derivatives thereof such as teduglutide, apraglutide and glepaglutide) or other GLP-2 receptor agonist (including GLP-2 receptor / glucagon receptor or GLP-2 receptor / GLP- 1 receptor dual agonists such as dapiglutide, or GLP-2 receptor / GLP- 1 receptor / glucagon receptor triple agonists), oxyntomodulin, a glucocerebrosidase, a gonadotropin (e.g., a follicle stimulating hormone, including derivatives thereof such as corifollitropin alfa), a gonadotropin releasing hormone (GnRH) or other GnRH receptor agonist (e.g., leuprorelin, buserelin, histrelin, goserelin, deslorelin, nafarelin and triptorelin), a GnRH receptor antagonist (e.g., degarelix, acyline, cetrorelix and ganirelix), a granulocyte-colony stimulating factor (G-CSF, e.g., filgrastim), a growth factor (e.g., insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF), activity-dependent neurotrophic factor (including davunetide), and / or ciliary neurotrophic factor (including axokine, a homolog of a fragment of ciliary neurotrophic factor)), a growth hormone (e.g., somatotropin (a.k.a. growth hormone 1) and / or growth hormone 2 and / or the long acting acylated somapacitan), a growth hormone-inhibiting hormone, a.k.a. somatostatin or other somatostatin receptor agonist (including octreotide, romurtide, lanreotide, and pasireotide), a growth hormone-releasing hormone (including sermorelin, , CJC- 1293 and CJC- 1295), icatibant, insulin, an interferon, an interleukin, a kappa opioid receptor agonist such as a peripherally-restricted kappa opioid receptor agonist (e.g., difelikefalin, CR665, JT09 and dynorphins), a leptin, an oxytocin or other oxytocin receptor agonist, a melanocortin or other melanocortin receptor agonist (e.g., a melanocyte- stimulating hormone, afamelanotide, bremelanotide, melanotan II, modimelanotide, setmelanotide, alsactide, and tetracosactide), a motilin, an omentin, a parathyroid hormone, a parathyroid hormone related protein (including abaloparatide, a homolog of a parathyroid hormone related protein fragment, a parathyroid hormone, and a long acting analog Eneboparatide (AZP-3601)), a peptide YY, a pituitary adenylate cyclase-activating peptide (PACAP), thymopentin, a thymosin (e.g., thymosin al), a TNF inhibitor (e.g., infliximab, adalimumab, certolizumab, golimumab and / or etanercept), a vasoactive intestinal peptide (e.g., aviptadil), and a vasopressin (including derivatives thereof such as desmopressin). Insulin, glucagon, GLP-1, GLP-2, parathyroid hormone, parathyroid hormone related protein, erythropoietin, calcitonin, gastric inhibitory polypeptide, gonadotropin releasing hormone, growth hormone-inhibiting hormone, melanocortins, motilin, leptin, peptide YY, vasopressin, vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide (PACAP), growth hormones, growth factors, and G-CSF are non-limiting examples of polypeptide hormones. Interferons, interleukins, erythropoietin, omentin and G-CSF are non-limiting examples of polypeptide cytokines.

[0209] According to some of any of the embodiments described herein, the polypeptide is selected from an antibody, an antipathogenic peptide, a blood clotting factor, a C-type natriuretic peptide, a calcitonin, disitertide, an endomorphin, an erythropoietin, a glucagon, a glucagon receptor agonist, a GLP-1 (glucagon-like peptide- 1), a GLP-1 receptor agonist (including GLP-1 receptor / glucagon receptor dual agonist), a gastric inhibitory polypeptide (GIP), a gastric inhibitory polypeptide receptor agonist (including a GIP receptor / GLP- 1 receptor dual agonist and glucagon receptor / GIP receptor / GLP- 1 receptor triple agonist), a GLP-2 (glucagon-like peptide-2), a GLP-2 receptor agonist (including GLP-2 receptor / glucagon receptor dual agonist, GLP-2 receptor / GLP- 1 receptor dual agonist or GLP-2 receptor / GIP receptor dual agonist), oxyntomodulin, a glucocerebrosidase, a gonadotropin, a gonadotropin releasing hormone, a gonadotropin releasing hormone receptor agonist, a gonadotropin releasing hormone receptor antagonist, a granulocyte-colony stimulating factor, a growth factor, a growth hormone, a somatostatin, a somatostatin receptor agonist, somapacitan, a growth hormone-releasing hormone, icatibant, an anti-viral peptide (e.g., bulevirtide), insulin, an interferon, an interleukin, a kappa opioid receptor agonist (e.g., a peripherally-restricted kappa opioid receptor agonist), a leptin, an oxytocin, an oxytocin receptor agonist, a melanocortin, a melanocortin receptor agonist, a motilin, an omentin, a parathyroid hormone or a fragment thereof or a long-acting analog thereof, a parathyroid hormone related protein, a peptide YY, a pituitary adenylate cyclase- activating peptide (PACAP), thymopentin, a thymosin, a TNF inhibitor, a vasoactive intestinal peptide, and a vasopressin, and analogs thereof.

[0210] According to some of any of the embodiments described herein, the polypeptide has a relatively long plasma half-life, due, for example, the presence of functional groups that have high affinity to plasma albumin, as, for example, in acylated peptides. Such polypeptides are also referred to herein as long-acting polypeptides or as long-acting analogs. Exemplary long-acting s polypeptides include like semaglutide, liraglutide, tirzepatide, Eneboparatide (AZP-3601) and somapacitan.

[0211] Therapeutically active agents according to embodiments of the invention may optionally exhibit more than one activity described herein; for example, a GLP-1 receptor agonist may optionally be a GLP-1 receptor / GLP-2 receptor dual agonist (e.g., dapiglutide), a GIP receptor / GLP- 1 receptor dual agonist and / or a glucagon receptor / GIP receptor / GLP- 1 receptor triple agonist, and a GLP-2 receptor agonist may optionally be a glucagon receptor / GLP-2 receptor dual agonist and / or a GIP receptor / GLP-2 receptor dual agonist.

[0212] An antibody according to any of the respective embodiments described herein any optionally be a single-domain antibody.

[0213] Herein and in the art, a “single-domain antibody” (also known in the art as a “nanobody”) refers to an antibody fragment consisting of a monomeric variable antibody domain (e.g., as opposed to a typical antibody structure which comprises four polypeptide chains, each of which comprise a variable antibody domain). Single-domain antibodies may optionally be prepared by reproducing a single variable domain (e.g., by recombinant protein technology) of a more conventional antibody (e.g., 4-chain antibody) or of a heavy-chain antibody from a camelid or a cartilaginous fish (e.g., shark).

[0214] Without being bound by any particular theory, it is believed that the molecular weight of the single-domain antibody (typically about 12 kDa to about 15 kDa) is particularly suitable for oral administration using an absorption enhancer (according to any of the embodiments described herein).

[0215] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is parathyroid hormone (PTH) or a fragment thereof. Herein, the term “parathyroid hormone” or its abbreviation “PTH” encompasses parathyroid hormone (having a naturally occurring amino acid sequence, e.g., an 84-amino acid sequence in humans) and fragments and / or homologs and / or long acting derivatives or analogs of the parathyroid hormone.

[0216] Teriparatide is an example of a parathyroid hormone fragment, composed of amino acids 1- 34 (i.e., an N-terminal portion) of the full human parathyroid hormone polypeptide. The term “teriparatide” is used interchangeably herein with the terms “hPTH(l-34)” and “human parathyroid hormone (1-34)”.

[0217] Eneboparatide (AZP-3601) is an example of a parathyroid hormone long-acting analog.

[0218] Herein, for the sake of brevity, the term “parathyroid hormone” or its abbreviation “PTH” encompasses parathyroid hormone (having a naturally occurring amino acid sequence, e.g., in humans), fragments thereof and homologs or analogs (e.g., long-acting) of the parathyroid hormone or the fragment thereof, except where indicated otherwise.

[0219] Examples of nucleic acids which may be utilized (per se or as analogs thereof) as therapeutically active agents according to embodiments of the invention include, without limitation, antisense nucleic acids (e.g., milasen, eteplirsen, fomiversen, golodirsen, inotersen, mipomersen, nusinersen, tofersen, tominersen, viltolarsen, and volanesorsen), small interfering RNA (e.g., givosiran, inclisiran, lumasiran, and patisiran), micro RNA, RNA aptamers (e.g., pegapatanib), messenger RNA (e.g., of an mRNA vaccine), and DNA (e.g., of a DNA vaccine).

[0220] It has been reported that therapeutically active agents which exhibit more than one of the following criteria tend to be poorly absorbed upon oral administration (when administered alone), a phenomenon referred to in the art as “Lipinski’s rule of 5”:

[0221] (i) a total number of nitrogen-hydrogen bonds and oxygen hydrogen bonds (which are typically hydrogen bond donors) which is more than 5;

[0222] (ii) a total number of nitrogen and oxygen atoms (which are typically hydrogen bond acceptors) which is more than 5;

[0223] (iii) an octanol-water partition coefficient (log P) which is greater than 5; and / or

[0224] (iv) a molecular weight of at least 500 Da (0.5 kDa).

[0225] The abovementioned criteria (i) and (ii) are associated with hydrogen bonding and hydrophilicity; whereas criteria (iii) is associated with lipophilicity.

[0226] As described herein, therapeutically active agents poorly absorbed upon oral administration when administered alone are particularly suitable for being included in compositions as described herein, in order to enhance their absorption. In some embodiments of any one of the embodiments described herein, the therapeutically active agent meets at least one of the abovementioned criteria (i), (ii), (iii) and (iv). In some embodiments, the therapeutically active agent meets at least two of the abovementioned criteria (i), (ii), (iii) and (iv). In some embodiments, the therapeutically active agent meets at least three of the abovementioned criteria (i), (ii), (iii) and (iv). In some embodiments, the therapeutically active agent meets all four of the abovementioned criteria (i), (ii), (iii) and (iv).

[0227] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of at least 0.5 kDa, in accordance with any one of the embodiments described herein relating to a molecular weight of at least 0.5 kDa, and further meets at least one of the abovementioned criteria (i), (ii) and (iii). In some such embodiments, the therapeutically active agent meets at least two of the abovementioned criteria (i), (ii) and (iii).

[0228] Dihydroergotamine and fondaparinux are non-limiting examples of non-peptidic agents having a molecular weight of at least 0.5 kDa, which are poorly absorbed upon oral administration.

[0229] In some embodiments of any one of the embodiments described herein, the therapeutically active agent has a molecular weight of less than 0.5 kDa, and meets at least one of the abovementioned criteria (i), (ii) and (iii). In some such embodiments, the therapeutically active agent meets at least two of the abovementioned criteria (i), (ii) and (iii). In some such embodiments, the therapeutically active agent meets all three of the abovementioned criteria (i), (ii) and (iii).

[0230] In addition, ionic molecules tend to be poorly absorbed upon oral administration, generally due to a considerably reduced ability to cross lipid membranes. Whether a molecule is ionic or nonionic often depends on pH, which varies according to location in the gastrointestinal tract. In general, it is believed that the more a therapeutically active agent is in ionic form in the gastrointestinal tract, the more likely it is to be poorly absorbed upon oral administration.

[0231] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at a pH of 7.0.

[0232] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at a pH of 6.0.

[0233] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at a pH of 5.0.

[0234] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at a pH of 4.0.

[0235] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at a pH of 3.0. In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at a pH of 2.0.

[0236] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at a pH of 1.0.

[0237] Examples of such agents include, without limitation, compounds comprising at least one basic group (e.g., amine group) which is positively charged at a pH of 7.0 (or less).

[0238] Herein, a compound is considered “ionic” when it comprises at least one functional group which is charged in at least 50 % of the molecules in a population of molecules of the compound under designated conditions (e.g., in an aqueous solution at a designated pH value or range of pH values). The skilled person will be readily capable of determining whether a functional group is charged in at least 50 % of the molecules, for example, by determining a pKa value associated with the functional group. An ionic compound, as defined herein, may optionally have a net negative charge, optionally a net positive charge, and optionally an equal number of negatively charged functional groups and positively functional groups, resulting in no net charge.

[0239] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic in an aqueous solution at all pH values within a range of from 5.0 to 7.0. In some embodiments, the therapeutically active agent is ionic in an aqueous solution at all pH values within a range of from 5.0 to 8.0. In some embodiments, the therapeutically active agent is ionic in an aqueous solution at all pH values within a range of from 4.0 to 9.0. In some embodiments, the therapeutically active agent is ionic in an aqueous solution at all pH values within a range of from 3.0 to 10.0. In some embodiments, the therapeutically active agent is ionic in an aqueous solution at all pH values within a range of from 2.0 to 11.0.

[0240] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic at a pH value and / or range according to any one of the abovementioned embodiments, and further has a molecular weight of at least 0.5 kDa, in accordance with any one of the embodiments described herein relating to a molecular weight of at least 0.5 kDa.

[0241] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is ionic at a pH value and / or range according to any one of the abovementioned embodiments, and further has a molecular weight of less than 0.5 kDa.

[0242] Examples of ionic therapeutically active agents which tend to have a molecular weight of less than 0.5 kDa, and which tend to exhibit poor absorption upon oral administration, include, without limitation, bisphosphonates (e.g., for use in treating osteoporosis and related conditions) such as alendronate, clodronate, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate and zoledronate; and cromolyn (e.g., cromolyn sodium). When the therapeutically active agent is a polypeptide, it is in ionic form in accordance with its isoelectric point (pl).

[0243] Herein and in the art, an isoelectric point (pl) of a polypeptide is the pH at which the protein carries no net electrical charge, that is, is in a non-ionic form. At this point, the number of positively charged groups equals the number of negatively charged groups, making the protein electrically neutral. The pl of a polypeptide can be experimentally determined or calculated based on the amino acid sequence of the protein, taking into account the pKa values of its ionizable groups (such as the side chains of acidic and basic amino acids).

[0244] According to some of any of the embodiments described herein, the therapeutically active agent is a polypeptide featuring pl of at least 1.0, or of at least 2.0, or of at least 3.0, or of at least 4.0, or of at least 5.0, or of at least 6.0, or of at least 7.0, or of at least 8.0, or of at least 8.5, or of at least 9.0, or higher. According to some of any of the embodiments described herein, the therapeutically active agent is a polypeptide featuring pl higher than 8.0, for example, from 8.0 to 14.0, or from 8.0 to 12.0, or from 8.0 to 10.0, or from 8.5 to 10.0.

[0245] In some embodiments of any one of the embodiments described herein, the therapeutically active agent is a Class III agent according to the Biopharmaceutics Classification System (BCS), as provided by the U.S. FDA, that is, the therapeutically active agent is characterized by low permeability and high solubility.

[0246] In the context of the BCS, the phrase “low permeability” refers herein and in the art to absorption of less than 90 % of a given agent upon oral administration in humans (in the absence of absorption enhancer), as determined by mass-balance determination and / or in comparison to an intravenous dose.

[0247] In some embodiments, absorption of a Class III therapeutically active agent is less than 50 % upon oral administration (in the absence of absorption enhancer). In some embodiments, absorption is less than 20 % upon oral administration (in the absence of absorption enhancer). In some embodiments, absorption is less than 10 % upon oral administration (in the absence of absorption enhancer). In some embodiments, absorption is less than 5 % upon oral administration (in the absence of absorption enhancer). In some embodiments, absorption is less than 2 % upon oral administration (in the absence of absorption enhancer). In some embodiments, absorption is less than 1 % upon oral administration (in the absence of absorption enhancer). In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2-hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate). In the context of the BCS, the phrase “high solubility” refers herein and in the art to an amount of therapeutically active agent in an administered dose being soluble in 250 ml or less of water over a pH range of 1 to 7.5.

[0248] In some of any of the embodiments described herein, the composition is a unit dosage form composition, and the unit dosage form comprises at least 50 pg of therapeutically active agent. In some embodiments, the unit dosage form comprises at least 100 pg of therapeutically active agent. In some embodiments, the unit dosage form comprises at least 200 pg of therapeutically active agent. In some embodiments, the unit dosage form comprises at least 500 pg of therapeutically active agent. In some embodiments, the amount of absorption enhancer in the unit dosage form is in accordance with any one of the ratios of absorption enhancer to therapeutically active agent described herein. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0249] In some of any of the embodiments described herein, the composition is a unit dosage form composition, and the unit dosage form comprises 3000 pg or less of therapeutically active agent. In some embodiments, the unit dosage form comprises 2000 pg or less of therapeutically active agent. In some embodiments, the unit dosage form comprises 1000 pg or less of therapeutically active agent. In some embodiments, the amount of absorption enhancer in the unit dosage forms is in accordance with any one of the ratios of absorption enhancer to therapeutically active agent described herein. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0250] In some of any of the embodiments described herein, the composition is a unit dosage form composition, and the unit dosage form comprises from 100 to 100000 pg, or from 100 to 50000 pg, or from 100 to 30000 pg, or from 100 to 10000 pg, 100 to 8000 pg, 100 to 5000 pg 100 to 3000 pg of therapeutically active agent, including any intermediate values and subranges therebetween. In some embodiments, the unit dosage form comprises from 200 to 2000 pg of therapeutically active agent, including any intermediate values and subranges therebetween. In some embodiments, the unit dosage form comprises from 500 to 1000 pg of therapeutically active agent, including any intermediate values and subranges therebetween. In some embodiments, the unit dosage form comprises from 1000 to 3000 pg of therapeutically active agent, including any intermediate values and subranges therebetween. In some embodiments, the unit dosage form comprises from 1500 to 2500 pg of therapeutically active agent, including any intermediate values and subranges therebetween. In some embodiments, the therapeutically active agent is a parathyroid hormone or a fragment thereof. In some embodiments, the therapeutically active agent is teriparatide. In some embodiments, the amount of absorption enhancer in the unit dosage forms is in accordance with any one of the ratios of absorption enhancer to therapeutically active agent described herein. In some of the aforementioned embodiments, the absorption enhancer is NAC (8-N-(2- hydroxybenzoyl)aminocaprylic acid) or a salt thereof (e.g., sodium 8-N-(2- hydroxybenzoyl)aminocaprylate).

[0251] Protease Inhibitor:

[0252] In some embodiments of any one of the embodiments described herein, when the therapeutically active agents is a polypeptide, the composition further comprises at least one protease inhibitor, for example, a type of protease inhibitor, a concentration and / or absolute amount of protease inhibitor, and / or a ratio of protease inhibitor to absorption enhancer and / or therapeutically active agent according to any one of the embodiments relating to a protease inhibitor described in any of U.S. Patent Application Publication No. 2011 / 0142800, and International Patent Application Publications WO 2016 / 128972 and WO 2018 / 033927, the contents of each of which (especially contents relating to protease inhibitors) are incorporated herein.

[0253] Herein throughout, the term “protease inhibitor” refers to a compound which reduces a proteolytic activity of a protease, for example, a proteolytic activity which inactivates a therapeutically active agent described herein. The term “protease inhibitor” encompasses, for example, both large molecules (e.g., proteins) and small molecules, as well as both naturally occurring compounds and synthetic compounds.

[0254] In some embodiments of any one of the embodiments described herein, the at least one protease inhibitor included in any of the compositions (including composition unit dosage forms) described herein comprises at least one trypsin inhibitor. In some embodiments, the at least one protease inhibitor consists essentially of one or more trypsin inhibitor(s).

[0255] Examples of trypsin inhibitor which may be utilized in any one of the embodiments described herein include, without limitation, 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 (an optionally the at least one protease inhibitor) consists essentially of SBTI.

[0256] 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 serpin(s).

[0257] Examples of serpins which may be utilized in any one of the embodiments described herein, include, without limitation, alpha 1 -antitrypsin, antitrypsin-related protein, alpha 1 -antichymotrypsin, kallistatin, protein C inhibitor, cortisol binding globulin, thyroxine-binding globulin, angiotensinogen, centerin, protein Z-related protease inhibitor, vaspin, monocyte / neutrophil elastase inhibitor, plasminogen activator inhibitor-2, squamous cell carcinoma antigen- 1 (SCCA-1), squamous cell carcinoma antigen-2 (SCCA-2), maspin, proteinase inhibitor 6 (PI-6), megsin, serpin B8 (PI-8), serpin B9 (PI-9), bomapin, yukopin, hurpin / headpin, antithrombin, heparin cofactor II, plasminogen activator inhibitor 1, glia-derived nexin, pigment epithelium derived factor, alpha 2- antiplasmin, complement 1 -inhibitor, 47 kDa heat shock protein (HSP47), neuroserpin and panepin.

[0258] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one cysteine protease inhibitor. In some embodiments, the at least one protease inhibitor consists essentially of one or more cysteine protease inhibitor(s).

[0259] Examples of cysteine protease inhibitors which may be utilized in any one of the embodiments described herein include, without limitation, type 1 cystatins, type 2 cystatins, human cystatins C, D, S, SN, and SA, cystatin E / M, cystatin F, and type 3 cystatins (including kininogens).

[0260] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one threonine protease inhibitor. In some embodiments, the at least one protease inhibitor consists essentially of one or more threonine protease inhibitor(s).

[0261] Examples of threonine protease inhibitors which may be utilized in any one of the embodiments described herein include, without limitation, bortezomib, MLN-519, ER-807446 and TMC-95A.

[0262] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one aspartic protease inhibitor. In some embodiments, the at least one protease inhibitor consists essentially of one or more aspartic protease inhibitor(s).

[0263] Examples of aspartic protease inhibitors which may be utilized in any one of the embodiments described herein, include, without limitation, a2-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.

[0264] In some embodiments of any of the embodiments described herein, the at least one protease inhibitor comprises at least one metalloprotease inhibitor. In some embodiments, the at least one protease inhibitor consists essentially of one or more metalloprotease inhibitor(s).

[0265] Examples of metalloprotease inhibitors which may be utilized in any one of the embodiments described herein, include, without limitation, angiotensin- 1 -converting enzyme inhibitory peptide, antihemorrhagic factor BJ46a, beta-casein, proteinase inhibitor CeKI, venom metalloproteinase inhibitor DM43, carboxypeptidase A inhibitor, smpl, IMPI, alkaline proteinase, latexin, carboxypeptidase inhibitor, antihemorrhagic factor HSF, testican-3, SP0CK3, TIMP1, metalloproteinase inhibitor 1, metalloproteinase inhibitor 2, TIMP2, metalloproteinase inhibitor 3, TIMP3, metalloproteinase inhibitor 4, TIMP4, putative metalloproteinase inhibitor tag-225, tissue inhibitor of metalloprotease, WAP, kazal inhibitor, immunoglobulin, and kunitz and NTR domaincontaining protein 1.

[0266] Examples of protease inhibitors which may be utilized in any one of the embodiments described herein also include, without limitation, AEBSF-HC1, 8-aminocaproic acid, al- antichymotypsin, antipain, antithrombin III, al -antitrypsin, APMSF (4-amidinophenyl-methane sulfonyl-fluoride), sprotinin, benzamidine, chymostatin, DFP (diisopropylfluoro-phosphate), leupeptin, 4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride, PMSF (phenylmethyl sulfonyl fluoride), TECK (l-chloro-3-tosylamido-7-amino-2-heptanone), TPCK (l-chloro-3-tosylamido-4- phenyl-2-butanone), pentamidine isothionate, pepstatin, guanidium, a2-macroglobulin, a chelating agent of zinc, and iodoacetate.

[0267] In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in composition or a unit dosage form described herein is at least about 0.1 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 0.2 mg. In some embodiments, the amount of a protease inhibitor in composition or a unit dosage form described herein is at least about 0.3 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 0.4 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 0.6 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 0.8 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 1 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 1.5 mg. In some embodiments, the amount of a protease inhibitor a composition or in a unit dosage form described herein is at least about 2 mg. In some embodiments, the amount of a protease inhibitor in a composition or unit dosage form described herein is at least about 2.5 mg. In some embodiments, the amount of a protease inhibitor in a composition or unit dosage form described herein is at least about 3 mg. In some embodiments, the amount of a protease inhibitor in a composition or unit dosage form described herein is at least about 5 mg. In some embodiments, the amount of a protease inhibitor in a composition or unit dosage form described herein is at least about 7 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 10 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 12 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 15 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 20 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 30 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 50 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 70 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 100 mg.

[0268] In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.1 to 1 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.2 to 1 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.3 to

[0269] 1 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.5 to 1 mg.

[0270] In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.1 to

[0271] 2 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.2 to 2 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.3 to 2 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 0.5 to 2 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 1 to 2 mg.

[0272] In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in a composition or unit dosage form described herein is in a range of from 1 to 10 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 2 to 10 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 3 to 10 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 5 to 10 mg. In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 1 to 20 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 2 to 20 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 3 to 20 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 5 to 20 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 10 to 20 mg.

[0273] In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 10 to 100 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 20 to 100 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 30 to 100 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 50 to 100 mg.

[0274] In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 10 to 200 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 20 to 200 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 30 to 200 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 50 to 200 mg. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is in a range of from 100 to 200 mg.

[0275] In some embodiments of any one of the embodiments described herein, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 10 kallikrein inactivator units (k.i.u.). In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 12 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 15 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 20 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 30 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 40 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 50 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 70 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 100 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 150 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 200 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 300 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 500 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 700 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 1000 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 1500 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 3000 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 4000 k.i.u. In some embodiments, the amount of a protease inhibitor in a composition or a unit dosage form described herein is at least about 5000 k.i.u.

[0276] Herein and in the art, a “kallikrein inactivating unit” (k.i.u) refers to an amount of protease inhibitor that has the ability to inhibit 2 units of kallikrein by 50 % (e.g., in aqueous solution at an optimal pH and solution volume for activity of the protease inhibitor).

[0277] In some embodiments of any one of the embodiments described herein, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 1:1 to 5:1 (protease inhibitor: therapeutically active agent). In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 5:1 to 10:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 10:1 to 20:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 20:1 to 30:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 30:1 to 40:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 40:1 to 50:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 50:1 to 75:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 75:1 to 100:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 100: 1 to 200: 1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 200:1 to 300:1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 300: 1 to 400: 1. In some embodiments, a weight ratio of protease inhibitor to therapeutically active agent is in a range of from 400:1 to 500:1. In some embodiments, the protease inhibitor is soybean trypsin inhibitor.

[0278] According to some embodiments of any of the embodiments described herein, the composition is devoid of a protease inhibitor.

[0279] Formulation of Compositions:

[0280] Each of the compositions and unit dosage forms described herein optionally consist essentially of the functional ingredients described hereinabove (e.g., a therapeutically active agent, an absorption enhancer, a non-polymeric proton-accepting agent, and optionally a protease inhibitor, each according to any of the embodiments described herein in any of the respective sections herein), or alternatively, the composition further comprises suitable pharmaceutically acceptable carriers and / or excipients.

[0281] Hereinafter, the phrases “physiologically acceptable carrier” and “pharmaceutically acceptable carrier”, which may be interchangeably used, refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the activity (e.g., biological activity) and properties of the functional ingredient (e.g., a therapeutically active agent). An adjuvant is included under these phrases.

[0282] Herein the term “excipient” refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch (e.g., types of nonmodified starch), cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0283] In some embodiments of any one of the embodiments described herein, the composition is formulated as a solid composition, e.g., a solid unit dosage form. In some embodiments, the composition is formulated as a tablet or as a combination of tablets (e.g., a plurality of minitablets). In some embodiments, the composition is formulated as a capsule, as described herein, which comprises, for example, a plurality of minitablets and / or a powder, and which has a coating that is dissolvable in a gastric fluid (e.g., in gastric pH) or otherwise releases the capsule’s content immediately (e.g., within less than 5 minutes, or less than 2 minutes or less than 1 minutes) upon contacting aa gastric fluid.

[0284] Ingredients of the formulation (including, but not limited to, any two or more of the absorption enhancer, the non-polymeric proton-accepting agent and therapeutically active agent of any of the respective embodiments described herein) may optionally be mixed in a homogeneous manner or be distributed throughout the composition in a heterogeneous manner.

[0285] Techniques for formulation and administration of drugs may be found in “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, latest edition, which is incorporated herein by reference.

[0286] In some embodiments of any one of the embodiments described therein, the pharmaceutical compositions can be formulated to contain only the absorption enhancer and therapeutically active agent. This pharmaceutical composition can thereafter be co-administered with at least one protonaccepting agent to a subject in need thereof. In some embodiments, the proton- accepting agent may be administered concurrently with the administration of the pharmaceutical composition. In some embodiments, the proton-accepting agent may be administered within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 120 minutes, 180 minutes, or 240 minutes, before or after the administration of the pharmaceutical composition.

[0287] Pharmaceutical compositions and unit dosage forms of some embodiments of the invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

[0288] Pharmaceutical compositions and unit dosage forms for use in accordance with some embodiments of the invention may thus be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically.

[0289] The pharmaceutical composition and unit dosage forms can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art as being suitable for oral administration. Such carriers optionally facilitate formulation of the pharmaceutical composition as tablets (including minitablets), pellets, pills, dragees, capsules, powders, granules, elixirs, tinctures, liquids, gels, syrups, slurries, suspensions, emulsions and the like, for oral administration to a patient. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Pharmaceutical composition and unit dosage forms suitable for oral administration include, but are not limited to, rapid-release, time controlled-release, extended-release, and delayed-release pharmaceutical dosage forms. In some of any of the respective embodiments, a pharmaceutical composition formulated for oral administration is a solid composition, for example, tablet, capsule, powder or granules. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, lubricants may be added, such as talc or magnesium stearate.

[0290] In some embodiments of any one of the embodiments described herein, any one of the compositions or unit dosage forms described herein (e.g., formulated as a tablet) further comprises a lubricant. In some embodiments, the lubricant is included in a concentration of 5 weight percent or less, optionally 2 weight percent or less, and optionally about 1 weight percent. In some embodiments, the composition or unit dosage form described herein (e.g., formulated as a tablet) consists essentially of the therapeutically active agent (as described herein), absorption enhancer, lubricant, and optional protease inhibitor (as described herein). In some embodiments, the lubricant is magnesium stearate.

[0291] The compositions or unit dosage forms described herein (e.g., formulated as a tablet) may alternatively or in addition comprise additives and / or additional agents, such as, for example, antioxidants, glidants, solvents, odor absorbers, chelating agents, preservatives, thickeners, colorants or coloring agents (pigments, nacres, water-soluble dyestuffs), dispersants, fillers, flavoring agents and bactericides.

[0292] Dragee cores are optionally provided with suitable coatings. For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0293] Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol, pullulan, or HPMC. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0294] In some of any of the embodiments described herein, the pharmaceutical composition and / or unit dosage form according to any of the respective embodiments described herein is devoid of a gastroenteric coating, or otherwise comprises a coating that is dissolvable in the GI tract (e.g., in gastric fluid) and / or which otherwise releases the contents immediately (e.g., within no more than 5 minutes, or no more than 2 minutes or no more than one minute) upon contacting a gastric fluid. Pharmaceutical compositions suitable for use in context of some embodiments of the invention include compositions wherein the therapeutically active agent is contained in an amount effective to achieve the intended purpose. More specifically, the composition preferably comprises a therapeutically effective amount of therapeutically active agent, that is, an amount of therapeutically active agent effective to prevent, alleviate or ameliorate symptoms of a disorder or prolong the survival of the subject being treated. Furthermore, an amount of absorption enhancer is preferably effective for enhancing absorption of the therapeutically active agent (e.g., in a manner described herein); and an amount of protease inhibitor (if present) is preferably effective for inhibiting degradation of the therapeutically active agent (e.g., a polypeptide agent) by a protease.

[0295] Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0296] For any preparation used in the methods of the invention, the therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays. For example, a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.

[0297] Toxicity and therapeutic efficacy of the therapeutically active agent described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals. The data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon the dosage form employed and the route of administration utilized. The exact formulation and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p.l).

[0298] Dosage amount and interval may be adjusted individually to provide levels (e.g., plasma levels) of the therapeutically active agent sufficient to induce or suppress a biological effect (minimal effective concentration, MEC). The MEC will vary for each preparation, but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics. Detection assays can be used to determine plasma concentrations.

[0299] Depending on the severity and responsiveness of the condition to be treated, dosing can be of a single or a plurality of administrations, with course of treatment lasting from several hours to several weeks or until cure is effected or diminution of the disease state is achieved.

[0300] The amount of a composition to be 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. Each dosing may optionally be effected using a single dosage form, or a plurality of unit dosage forms. A plurality of unit dosage forms may optionally be used merely for convenience (e.g., wherein two or three unit dosage forms are used), or alternatively, to reduce variability in absorption according to any of the respective embodiments described in International Patent Application Publication No. WO 2018 / 033927, for example, wherein at least three or at least four unit dosage forms are used (e.g., from 3 to 10 or from 4 to 10, including any intermediate values and subranges therebetween).

[0301] Compositions of some embodiments of the invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, 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 accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert. Compositions comprising a preparation of the invention may also be prepared (e.g., as described herein), placed in an appropriate container, and labeled for treatment of an indicated condition, as is further detailed herein.

[0302] According to exemplary embodiments, the composition is a formulated as a solid form, for example, as a solid unit dosage form such as a tablet or a mini-tablet.

[0303] According to exemplary embodiments, an amount of the therapeutically active agent in a solid unit dosage form ranges from 0.1 to 5 mg, or from 0.1 to 2 mg, or from 0.1 to 1 mg, or from 0.2 to 3 mg, or from 0.2 to 2 mg, or from 0.2 to 1 mg, including any intermediate values and subranges therebetween. Higher amounts, for example, up to 100 mg are also contemplated, in accordance with any of the embodiments described herein.

[0304] The term “unit dosage form”, as used herein, describes physically discrete units, each unit containing a predetermined quantity of one or more active ingredient(s) calculated to produce the desired therapeutic effect, in association with at least one pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0305] According to some of any of the embodiments described herein, the pharmaceutical composition is in a form of a homogeneous mixture, such that the proton accepting agent is uniformly dispersed among the salt of NAC and therapeutically active agent (and optionally any additional ingredient present). According to some of any of the embodiments described herein, the pharmaceutical composition is in a solid form.

[0306] In some embodiments, the composition is formulated as a unit dosage form.

[0307] The unit dosage form may be formulated in any form suitable for oral administration, including solid and / or liquid forms.

[0308] In some embodiments, the unit dosage form is a solid unit dosage form. In some embodiments, the composition is formulated as a tablet.

[0309] In some embodiments, the unit dosage form (e.g., solid unit dosage form) is soluble in gastric fluid. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 60 minutes. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 50 minutes. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 40 minutes. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 30 minutes. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 20 minutes. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 15 minutes. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 10 minutes. In some embodiments, the unit dosage form dissolves in gastric fluid in no more than 5 minutes.

[0310] In some embodiments, the unit dosage form (e.g., solid unit dosage form) is not soluble in gastric fluid.

[0311] In some embodiments of any one of the embodiments described herein, the composition consists primarily of the combination of therapeutically active agent, a salt of NAC, and at least one proton accepting agent as described herein, that is, at least 50 weight percent of the composition consists of ingredients selected from the group consisting of a therapeutically active agent, a salt of NAC and at least one proton accepting agent. In some embodiments, at least 60 weight percent of the composition consists of a therapeutically active agent, a salt of NAC and at least one proton accepting agent. In some embodiments, at least 70 weight percent of the composition consists of a therapeutically active agent, a salt of NAC and at least one proton accepting agent. In some embodiments, at least 80 weight percent of the composition consists of a therapeutically active agent, a salt of NAC and at least one proton accepting agent. In some embodiments, at least 90 weight percent of the composition consists of a therapeutically active agent, a salt of NAC and at least one proton accepting agent. In some embodiments, at least 95 weight percent of the composition consists of a therapeutically active agent, a salt of NAC and at least one proton accepting agent. In some embodiments, at least 98 weight percent of the composition consists of a therapeutically active agent, a salt of NAC and at least one proton accepting agent. In some embodiments, the composition is formulated as a tablet.

[0312] In some embodiments of any one of the embodiments described herein, at least 50 weight percent the composition consists of the salt of NAC. In some embodiments, at least 60 weight percent of composition consists of the salt of NAC. In some embodiments, at least 70 weight percent of composition consists of the salt of NAC. In some embodiments, at least 80 weight percent of composition consists of the salt of NAC. In some embodiments, at least 90 weight percent of composition consists of the salt of NAC.

[0313] In some embodiments of any one of the embodiments described herein, at least 50 weight percent the composition consists of the salt of NAC and the PAA. In some embodiments, at least 60 weight percent of composition consists of the salt of NAC and the PAA. In some embodiments, at least 70 weight percent of composition consists of the salt of NAC and the PAA. In some embodiments, at least 80 weight percent of composition consists of the salt of NAC and the PAA. In some embodiments, at least 90 weight percent of composition consists of the salt of NAC and the PAA. In some of these embodiments, a mol ratio or weight ratio of the SNAC and one or more PAAs is as described herein in any of the respective embodiments.

[0314] In some embodiments of any one of the embodiments described herein, the composition is formulated such that a bioavailability of the therapeutically active agent upon oral administration of the composition is at least 10 % higher than a bioavailability of the therapeutically active agent upon oral administration of a composition comprising the therapeutically active agent and the salt of NAC without the at least one proton accepting agent (e.g., being identical in all aspects except for the absence of the proton accepting agent(s)). In some embodiments, the bioavailability is at least 20 % higher than (120 % of the level of) the bioavailability upon oral administration of a composition comprising the therapeutically active agent and the salt of NAC without the at least one proton accepting agent. In some embodiments, the bioavailability is at least 50 % higher than (150 % of the level of) the bioavailability upon oral administration of a composition comprising the therapeutically active agent and the salt of NAC without the at least one proton accepting agent. In some embodiments, the bioavailability is at least twice (200 % of the level of) the bioavailability upon oral administration of a composition comprising the therapeutically active agent and the salt of NAC without the at least one proton accepting agent. In some embodiments, the bioavailability is at least four-fold (400 % of the level of) the bioavailability upon oral administration of a composition comprising the therapeutically active agent and the salt of NAC without the at least one proton accepting agent. In some embodiments, the bioavailability is at least ten-fold (1000 % of the level of) the bioavailability upon oral administration of a composition comprising the therapeutically active agent and the salt of NAC without the at least one proton accepting agent. In some embodiments, the bioavailability is at least twenty-fold (2000 % of the level of) the bioavailability upon oral administration of a composition comprising the therapeutically active agent and SNAC without the at least one proton accepting agent.

[0315] The effect of the proton accepting agent(s) on the percentage recovery of the salt of NAC may be determined by comparing percentage recovery of a composition according to embodiments of the invention with a corresponding composition comprising the same amount of other ingredients other than the proton accepting agent, such that the total mass is lower (due to the absence of the proton accepting agent). In such embodiments, both compositions are in a form of a tablet, and the tablets have the same cross-section (e.g., diameter of a circular cross-section), and the tablet with a lower weight is thinner in the axis perpendicular to the cross-section of the tablet.

[0316] The effect of the proton accepting agent(s) on absorption of the therapeutically active agent may optionally be determined by comparing absorption upon oral administration of a composition according to embodiments of the invention with a corresponding composition comprising the same amount of other ingredients other than the proton accepting agent, such that the total mass is lower (due to the absence of the proton accepting agent). In such embodiments, both compositions are in a form of a tablet, and the tablets have the same cross-section (e.g., diameter of a circular cross-section), and the tablet with a lower weight is thinner in the axis perpendicular to the cross-section of the tablet.

[0317] Bioavailability may be determined by comparing a ratio of an area under the curve upon oral administration (e.g., over the course of 12 or 24 hours) to an area under curve over the same time period for intravenously administered therapeutically active agent, using standard techniques (e.g., data processing algorithms) known in the art. The therapeutically active agent may be injected at a lower dose (e.g., for safety reasons) and the areas under curve normalized to the total amount administered.

[0318] According to some of any of the embodiments described herein, the unit dosage form comprises a core and an external layer.

[0319] According to some of these embodiments, the core comprises the therapeutically active agent and the salt of NAC (e.g., sodium 8-N-(2-hydroxybenzoyl)aminocaprylate); and the external layer comprises the at least one proton-accepting agent.

[0320] The unit dosage form may have any shape suitable for orally administered pharmaceutical dosage forms, including, without limitation, any 3 -dimensional shape having a substantially rectangular (including substantially square), substantially circular and / or substantially oval crosssection along at least one axis. For example, the unit dosage form may have a substantially box-like shape, having a substantially rectangular cross-section (optionally with rounded comers) along 3 axes; a substantially cylindrical shape, having substantially circular and / or substantially oval crosssection along one axis, and a substantially rectangular cross-section (optionally with rounded corners) along 2 axes; or a substantially spherical or ovoid shape, having a substantially circular and / or substantially oval cross-section along 3 axes.

[0321] In some of any one of the embodiments described herein, the external layer comprises one or more proton- accepting agents, as described herein in any of the respective embodiments, and optionally further comprises a protease inhibitor, as described herein, if included in the composition. In some such embodiments, the external layer consists essentially of one or more proton-accepting agents. Alternatively, in some such embodiments, the external layer comprises a combination of one or more excipients with the proton- accepting agent(s).

[0322] In some of any one of the embodiments described herein, the external layer comprises one or more proton-accepting agent(s), and is devoid of protease inhibitors. In some such embodiments, the external layer consists essentially of one or more proton- accepting agent(s). Alternatively, in some such embodiments, the external layer comprises a combination of one or more excipients with the proton-accepting agent(s).

[0323] Herein throughout, the phrase “devoid of’ encompasses the presence of minute amounts of the indicated substance (for example, less than 0.1 weight percent, optionally less than 0.05 weight percent, optionally less than 0.02 weight percent, and optionally less than 0.01 weight percent) as well as the complete absence of the indicated substance.

[0324] In some of any one of the embodiments described herein, a concentration (as a weight percentage) of therapeutically active agent in the external layer is lower than a concentration of the therapeutically active agent in the core. In some of any one of the embodiments described herein, a concentration (as a weight percentage) of therapeutically active agent in the external layer is less than 50 % of a concentration of the therapeutically agent in the core. In some embodiments, the concentration in the external layer is less than 20 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 10 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 5 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 2 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 1 % of the concentration in the core. In some embodiments, the external layer is devoid of the therapeutically active agent.

[0325] In some of any one of the embodiments described herein, a concentration (as a weight percentage) of the salt of NAC in the external layer is lower than a concentration of the salt of NAC in the core. In some of any one of the embodiments described herein, a concentration (as a weight percentage) of the salt of NAC in the external layer is less than 50 % of a concentration of the salt of NAC in the core. In some embodiments, the concentration in the external layer is less than 20 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 10 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 5 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 2 % of the concentration in the core. In some embodiments, the concentration in the external layer is less than 1 % of the concentration in the core. In some embodiments, the external layer is devoid of a salt of NAC. In some embodiments, the external layer is devoid of the therapeutically active agent and devoid of a salt of NAC.

[0326] In some of any one of the embodiments described herein, the external layer covers the whole surface of the core.

[0327] In some of any one of the embodiments described herein, the external layer does not cover the whole surface of the core. In some embodiments wherein the external layer does not cover the whole surface of the core, the external layer is separated into a plurality of unconnected layers (e.g., 2 layers, 3 layers, 4 layers, or more than 4 layers), each of the unconnected layers covering a different region of the surface of the core. In such embodiments, the phrase “external layer” refers collectively to all such unconnected layers. In some embodiments, the external layer is separated into two unconnected layers which cover opposite sides of the core. In alternative embodiments wherein the external layer does not cover the whole surface of the core, the external layer is in a form of a single continuous layer.

[0328] In some of any one of the embodiments described herein, the external layer covers at least 30 % of the surface area of the core. In some embodiments, the external layer covers at least 40 % of the surface area of the core. In some embodiments, the external layer covers at least 50 % of the surface area of the core. In some embodiments, the external layer covers at least 60 % of the surface area of the core. In some embodiments, the external layer covers at least 70 % of the surface area of the core. In some embodiments, the external layer covers at least 80 % of the surface area of the core. In some embodiments, the external layer covers at least 90 % of the surface area of the core.

[0329] In some embodiments of any one of the embodiments described herein, the proton- accepting agent(s) in the external layer is / are distributed homogeneously throughout the external layer.

[0330] In some embodiments of any one of the embodiments described herein, the proton- accepting agent(s)in the external layer is / are distributed inhomogeneously throughout the external layer.

[0331] In some such embodiments, the proton-accepting agent(s) and optionally the protease inhibitor(s), if present, is / are within particles (e.g., microspheres containing the proton-accepting agent(s) and optionally the protease inhibitor(s), and the external layer further comprises a material (e.g., a filler and / or binder) between the particles.

[0332] Alternatively or additionally, in some embodiments, the external layer comprises two or more layers (e.g., concentric layers), wherein each layer within the external layer has a different composition. For example, the external layer may optionally comprise a first layer which comprises one of the proton- accepting agent(s) and / or of the protease inhibitor(s), if present, a second layer which comprises another of the proton- accepting agent(s) and / or the protease inhibitor(s), if present, , and optionally one or more additional layers, each comprising different proton- accepting agent(s) and / or protease inhibitor(s).

[0333] In some embodiments of any one of the embodiments described herein, the core further comprises one or more proton- accepting agent(s), in addition to a therapeutically active agent and the salt of NAC.

[0334] In some embodiments of any one of the embodiments described herein, the core consists essentially of the therapeutically active agent and the salt of NAC or a combination of the therapeutically active agent, a salt of NAC, and a proton- accepting agent(s).

[0335] In some embodiments of any one of the embodiments described herein, the core comprises a combination of one or more excipients with the therapeutically active agent and the salt of NAC (and optionally the protease inhibitor(s) and / or proton- accepting agent(s)).

[0336] In some embodiments of any one of the embodiments described herein, the core comprises a therapeutically active agent, a salt of NAC and one or more proton- accepting agent(s), as described herein. In some embodiments, the core consists essentially of a combination of the therapeutically active agent, a salt of NAC and the proton-accepting agent(s). Alternatively, in some embodiments, the core comprises a combination of one or more excipients with the therapeutically active agent, a salt of NAC and proton- accepting agent(s).

[0337] In some embodiments of any one of the embodiments described herein, the therapeutically active agent and / or the salt of NAC and / or the PAA, if present, in the core are distributed homogeneously throughout the core.

[0338] In some embodiments of any one of the embodiments described herein, the therapeutically active agent and / or the salt of NAC and / or the PAA, if present, in the core are distributed inhomogeneously throughout the core.

[0339] In some such embodiments, the therapeutically active agent and / or the salt of NAC are within particles (e.g., microspheres containing the therapeutically active agent and / or the salt of NAC and / or the PAA, if present in the core), and the core comprises a material (e.g., a filler and / or binder) between the particles. Alternatively or additionally, in some embodiments, the core comprises an inner portion and an outer portion (e.g., configured concentrically), wherein each portion within the core has a different composition. For example, the core may optionally comprise an outer portion which comprises the therapeutically active agent and an inner portion which comprises the salt of NAC, or vice versa.

[0340] In some of any one of the embodiments described herein, the unit dosage form further comprises a coating which coats the outer surface of the external layer described herein, and optionally also a region of a core surface which is not covered by an external layer (in embodiments wherein the external layer does not cover the whole core). In some embodiments, the coating is formed from material which dissolves in at least a portion of the gastrointestinal tract.

[0341] In some embodiments of any one of the embodiments described herein, when the coating coats only a portion of the outer surface of the external layer, the coating is an enteric coating , that is, a coating which dissolves under conditions in the intestines (e.g., in an aqueous environment having a pH of at least 5.5 and / or in the presence of colonic bacteria), thereby exposing the external layer, but does not dissolve under conditions in the stomach (e.g., in an aqueous environment having a pH in a range of from 1 to 3.5). An enteric coating may optionally dissolve in the duodenum, optionally in the jejunum, optionally in the ileum, and optionally in the colon. Many enteric coatings are known in the art, and the skilled person will be readily capable of selecting and preparing a suitable enteric coating for dissolving in a pre-determined region of the intestines.

[0342] In some embodiments of any one of the embodiments described herein, the coating dissolves under conditions in the stomach (e.g., in an aqueous environment, optionally only when a low pH is present), thereby exposing the external layer. Such a coating is optionally adapted for altering an appearance of the unit dosage form (e.g., for aesthetic enhancement and / or labeling), to provide flavor and / or mask flavor, and / or to protect the external layer and / or core (e.g., from mechanical insult, air, light and / or liquids).

[0343] Dissolution of the unit dosage form in the gastrointestinal system initially comprises primarily dissolution of the external layer (optionally after dissolution of a coating, if present), to thereby, for example, releasing the proton accepting agent(s) in the external layer prior to release of therapeutically active agent and the salt of NAC from the core.

[0344] In some embodiments of any one of the embodiments described herein, the unit dosage form is formulated as a tablet. In some embodiments, the unit dosage form is formulated as a multi-layered tablet (e.g., a 3-layered tablet), in which the external layer forms an upper layer and a lower layer, and the core is formulated as a middle layer sandwiched between the upper layer and a lower layer. Any of the multi-layered tablets described herein may optionally prepared according to any technique known in the art for preparing multi-layered tablets (e.g., 3-layered tablet), including, without limitation a technique described by Shende et al. \Int J Drug Delivery 2012, 4:418-426], the contents of which are incorporated herein by reference.

[0345] In some embodiments of any one of the embodiments described herein, the unit dosage form consists primarily of the combination of therapeutically active agent, the salt of NAC, and protonaccepting agent(s), that is, at least 50 weight percent of the unit dosage form consists of ingredients selected from the group consisting of a therapeutically active agent, a salt of NAC and protonaccepting agent(s). In some embodiments, at least 60 weight percent of the unit dosage form consists of a therapeutically active agent, a salt of NAC and proton-accepting agent(s). In some embodiments, at least 70 weight percent of the unit dosage form consists of a therapeutically active agent, a salt of NAC and proton-accepting agent(s). In some embodiments, at least 80 weight percent of the unit dosage form consists of a therapeutically active agent, a salt of NAC and proton- accepting agent(s). In some embodiments, at least 90 weight percent of the unit dosage form consists of a therapeutically active agent, a salt of NAC and proton-accepting agent(s). In some embodiments, at least 95 weight percent of the unit dosage form consists of a therapeutically active agent, a salt of NAC and protonaccepting agent(s). In some embodiments, at least 98 weight percent of the unit dosage form consists of a therapeutically active agent, a salt of NAC and proton-accepting agent(s). In some embodiments, the unit dosage form is formulated as a tablet.

[0346] In some embodiments, the external layer and core are formulated as parts of a tablet. In some embodiments, the tablet is a multi-layered tablet (e.g., 3 -layered tablet).

[0347] Herein throughout, the phrases “soluble in gastric fluid”, “dissolves in gastric fluid” and the like refer to solubility of a composition in simulated gastric fluid without pepsin, at pH 2.0, under conditions according to USP 23 Apparatus 2 (paddle) (e.g., 800 ml volume, 50 rotations per minute). Dissolution is indicated by absence of visible composition at the bottom of the fluid. However, visible material suspended in the liquid is not excluded by the terms “soluble” and “dissolution”. The phrase “soluble in gastric fluid” refers herein to dissolution within a period of 6 hours. A liquid composition miscible with simulated gastric fluid is considered herein to be “soluble in gastric fluid”, wherein the dissolution is the mixing of the liquid composition with the simulated gastric fluid.

[0348] In some embodiments of any one of the embodiments described herein, a concentration of the salt of NAC in a composition described herein or in a core of a unit dosage form described herein is in a range of from 2.5 to 99.4 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 2.5 to 10 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 8 to 15 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 10 to 20 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 15 to 30 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 20 to 40 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 30 to 50 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 40 to 60 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 50 to 70 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 2.5 to 10 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 2.5 to 10 weight percent. In some of the aforementioned embodiments, the concentration of the salt of NAC is in a range of from 70 to 99.4 weight percent.

[0349] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to the therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 5:1 to 10:1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 7.5:1.

[0350] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 10:1 to 20:1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 15:1.

[0351] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 20:1 to 30:1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 25:1.

[0352] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 30:1 to 50:1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 40:1.

[0353] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 50: 1 to 100: 1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 75:1.

[0354] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 100: 1 to 200: 1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 150:1.

[0355] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 200: 1 to 300: 1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 250:1.

[0356] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of NAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 300: 1 to 500: 1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 400:1.

[0357] In some embodiments of any one of the embodiments described herein, a weight ratio of the salt of SNAC to therapeutically active agent in a composition described herein or in a core of a unit dosage form described herein is in a range of from 500:1 to 1000:1 (salt of NAC: therapeutically active agent). In some embodiments, the ratio is about 750:1.

[0358] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is at least about 0.1 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 0.2 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 0.3 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 0.4 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 0.6 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 0.8 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 1 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 1.5 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 2 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 2.5 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 3 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 5 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 7 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 10 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 12 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 15 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 20 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 30 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 50 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 70 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is at least about 100 mg.

[0359] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.1 to 1 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.2 to 1 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.3 to 1 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.5 to 1 mg.

[0360] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.1 to 2 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.2 to 2 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.3 to 2 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 0.5 to 2 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 1 to 2 mg.

[0361] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 1 to 10 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 2 to 10 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 3 to 10 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 5 to 10 mg.

[0362] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 1 to 20 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 2 to 20 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 3 to 20 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 5 to 20 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 10 to 20 mg.

[0363] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 10 to 100 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 20 to 100 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 30 to 100 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 50 to 100 mg.

[0364] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 10 to 200 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 20 to 200 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 30 to 200 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 50 to 200 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 100 to 200 mg.

[0365] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 10 to 500 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 20 to 500 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 30 to 500 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 50 to 500 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 100 to 500 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 200 to 500 mg.

[0366] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 10 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 20 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 30 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 50 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 100 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 200 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 500 to 1000 mg.

[0367] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 10 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 20 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 30 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 50 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 100 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 200 to 1000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 500 to 1000 mg.

[0368] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 10 to 2000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 20 to 2000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 30 to 2000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 50 to 2000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 100 to 2000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 200 to 2000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 500 to 2000 mg. In some embodiments, the amount of the salt of NAC in a unit dosage form described herein is in a range of from 1000 to 2000 mg.

[0369] In some embodiments of any one of the embodiments described herein relating to an amount of the salt of NAC in a unit dosage form, the amount of therapeutically active agent is in accordance with any one of the ratios of the salt of NAC to therapeutically active agent described herein.

[0370] In some embodiments of any one of the embodiments described herein relating to an amount of the salt of NAC in a unit dosage form, the amount of the one or more PAAs is in accordance with any one of the ratios of the salt of NAC to therapeutically active agent described herein.

[0371] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is at least about 0.1 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 0.2 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is at least about 0.3 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 0.4 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 0.6 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is at least about 0.8 mg. In some embodiments, the amount of a protonaccepting agent in a unit dosage form described herein is at least about 1 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is at least about 1.5 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 2 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 2.5 mg. In some embodiments, the amount of a protonaccepting agent in a unit dosage form described herein is at least about 3 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is at least about 5 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 7 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 10 mg. In some embodiments, the amount of a protonaccepting agent in a unit dosage form described herein is at least about 12 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is at least about 15 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 20 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 30 mg. In some embodiments, the amount of a protonaccepting agent in a unit dosage form described herein is at least about 50 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is at least about 70 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is at least about 100 mg.

[0372] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 0.1 to 1 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 0.2 to 1 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 0.3 to 1 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 0.5 to 1 mg. In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 0.1 to 2 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 0.2 to 2 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 0.3 to 2 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 0.5 to 2 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 1 to 2 mg.

[0373] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 1 to 10 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 2 to 10 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 3 to 10 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 5 to 10 mg.

[0374] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 1 to 20 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 2 to 20 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 3 to 20 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 5 to 20 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 10 to 20 mg.

[0375] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 10 to 100 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 20 to 100 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 30 to 100 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 50 to 100 mg.

[0376] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 10 to 200 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 20 to 200 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 30 to 200 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 50 to 200 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 100 to 200 mg.

[0377] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 100 to 2000 mg. In some embodiments, the amount of a proton- accepting agent in a unit dosage form described herein is in a range of from 100 to 200 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 100 to 1000 mg. In some embodiments, the amount of a proton-accepting agent in a unit dosage form described herein is in a range of from 500 to 1000 mg. In some embodiments, the amount of a protonaccepting agent in a unit dosage form described herein is in a range of from 1000 to 2000 mg.

[0378] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 1 to 20 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 2 to 20 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 3 to 20 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 5 to 20 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 10 to 20 mg.

[0379] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 10 to 100 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 20 to 100 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 30 to 100 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 50 to 100 mg.

[0380] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 10 to 200 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 20 to 200 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 30 to 200 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 50 to 200 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 100 to 200 mg.

[0381] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 10 to 500 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 20 to 500 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 30 to 500 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 50 to 500 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 100 to 500 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 200 to 500 mg.

[0382] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 10 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 20 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 30 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 50 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 100 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 200 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 500 to 1000 mg.

[0383] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 10 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 20 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 30 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 50 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 100 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 200 to 1000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 500 to 1000 mg.

[0384] In some embodiments of any one of the embodiments described herein relating to a unit dosage form, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 10 to 2000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 20 to 2000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 30 to 2000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 50 to 2000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 100 to 2000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 200 to 2000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 500 to 2000 mg. In some embodiments, a total amount of the salt of NAC and the proton accepting agent(s) in a unit dosage form described herein is in a range of from 1000 to 2000 mg.

[0385] Applications:

[0386] According to an aspect of some embodiments of the present invention, a composition as described herein in any of the respective embodiments and any combination thereof is usable, or is for use, in treating a medical condition treatable by the therapeutically active agent.

[0387] According to an aspect of some embodiments of the present invention, there is provided a use of a composition as described herein in any of the respective embodiments and any combination thereof in the manufacture of a medicament for treating a medical condition treatable by the therapeutically active agent.

[0388] According to an aspect of some embodiments of the present invention, there is provided a method of treating a medical condition treatable by a therapeutically active agent as described herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition as described herein in any of the respective embodiments and any combination thereof.

[0389] A proton accepting agent may be utilized advantageously in combination with a therapeutically active agent and the salt of NAC, without necessarily combining all of the ingredients in a single composition.

[0390] According to another aspect of embodiments of the invention, there is provided a method of treating a condition treatable by oral administration of a therapeutically active agent in a subject in need thereof, the method comprising co-administering to the subject, at least one proton accepting agent comprising at least one proton accepting agent, as defined herein (e.g., at least one proton accepting agent described herein), and / or basic amino acids, and / or fatty acid salts.; and a composition comprising the therapeutically active agent (e.g., as described herein) and the salt of NAC.

[0391] According to another aspect of embodiments of the invention, there is provided a use of a composition comprising a therapeutically active agent and the salt of NAC in the preparation of a medicament for use in the treatment of a condition treatable by oral administration of the therapeutically active agent in a subject in need thereof, wherein the treatment comprises coadministering at least one proton accepting agent as described herein in any of the respective embodiments and any combination thereof.

[0392] According to another aspect of embodiments of the invention, there is provided a composition comprising a therapeutically active agent and the salt of NAC, for use in the treatment of a condition treatable by oral administration of the therapeutically active agent in a subject in need thereof, wherein the treatment comprises co-administering at least one proton accepting agent as described herein in any of the respective embodiments and any combination thereof. In some embodiments of any one of the embodiments described herein relating to co-administering, the co-administering comprises administering the at least one proton accepting agent, for example, as a composition that further comprises a pharmaceutically acceptable carrier, prior to or concomitantly with the composition comprising the therapeutically active agent and the salt of NAC.

[0393] In some embodiments, the proton- accepting agent or the composition comprising same may be administered concurrently with the administration of the pharmaceutical composition. In some embodiments, the proton-accepting agent may be administered within 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 120 minutes, 180 minutes, or 240 minutes, before or after the administration of the pharmaceutical composition. In some embodiments, the composition comprising the therapeutically active agent, the PAA and the salt of NAC is formulated as a unit dosage form. The unit dosage form may be formulated in any form suitable for oral administration, including solid and / or liquid forms. In some embodiments, the unit dosage form (e.g., a unit dosage form of the composition comprising the therapeutically active agent and the salt of NAC) is a solid unit dosage form. In some embodiments, the unit dosage form (e.g., a unit dosage form of the composition comprising the therapeutically active agent, the PAA and the salt of NAC) is formulated as a tablet.

[0394] According to some of any of the embodiments that relate to co-administering the proton accepting agent with a composition comprising the therapeutically active agent and the salt of NAC, the proton accepting agent can form a part of a pharmaceutical composition, which can further comprise a pharmaceutically acceptable carrier. Such a composition is also referred to herein as acid neutralizing composition. In some embodiments, the composition comprising the proton accepting agent is formulated as a unit dosage form, as described herein.

[0395] In some embodiments, the composition comprising the therapeutically active agent and the salt of NAC and the proton accepting agent (e.g., in solid form) are each soluble in gastric fluid (as defined herein). In some embodiments, the compositions each dissolve in gastric fluid in no more than 60 minutes. In some embodiments, the compositions each dissolve in gastric fluid in no more than 50 minutes. In some embodiments, the compositions each dissolve in gastric fluid in no more than 40 minutes. In some embodiments, the compositions each dissolve in gastric fluid in no more than 30 minutes. In some embodiments, the compositions each dissolve in gastric fluid in no more than 20 minutes. In some embodiments, the compositions each dissolve in gastric fluid in no more than 15 minutes. In some embodiments, the compositions each dissolve in gastric fluid in no more than 10 minutes. In some embodiments, the compositions each dissolve in gastric fluid in no more than 5 minutes.

[0396] In some embodiments of any of the embodiments described herein, the composition according to any of the respective embodiments described herein is for use in the treatment of a condition treatable by the therapeutically active agent (according to any of the respective embodiments described herein), the treatment comprising oral administration of the composition.

[0397] According to an aspect of some embodiments of the invention, there is provided a method of treating a condition treatable by oral administration of a therapeutically active agent (according to any of the respective embodiments described herein) in a subject in need thereof, 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). The skilled person will be capable of determining which conditions are treatable by oral administration of any given therapeutically active agent described herein.

[0398] Examples of conditions treatable according to embodiments of the invention include, without limitation, hyperglycemia and / or diabetes (e.g., wherein the therapeutically active agent is an insulinlike growth factor, an insulin, a GLP-1 or GLP-1 receptor agonist, or another agent which reduces blood glucose levels); hypoglycemia (e.g., wherein the therapeutically active agent is a growth hormone-inhibiting hormone, glucagon, or another agent which increases blood glucose levels); osteoporosis and conditions associated with a bone fracture or bone defect (e.g., wherein the therapeutically active agent is a PTH, parathyroid hormone related protein, GLP-2 or GLP-2 receptor agonist, or calcitonin); hypoparathyroidism (e.g., wherein the therapeutically active agent is a PTH); obesity (e.g., wherein the therapeutically active agent is peptide YY, a ciliary neurotrophic factor, a GLP-1 or GLP-1 receptor agonist, a growth hormone-inhibiting hormone, or a growth hormone); osteoarthritis (e.g., wherein the therapeutically active agent is a GLP- 1 , GLP- 1 receptor agonist and / or PTH) an inflammatory condition and / or autoimmune condition (e.g., wherein the therapeutically active agent is a TNF inhibitor, interferon, interleukin, growth hormone, or vasoactive intestinal peptide); pain and / or pruritus, such as uremic pruritus (e.g., wherein the therapeutically active agent is an endomorphin and / or kappa opioid receptor agonist); growth deficiency (e.g., wherein the therapeutically active agent is a growth hormone); hereditary angioedema (e.g., wherein the therapeutically active agent is icatibant); lipodystrophy (e.g., wherein the therapeutically active agent is a leptin or a growth hormone-releasing hormone); a fatty liver disease such as non-alcoholic steatohepatitis (e.g., wherein the therapeutically active agent is a growth hormone-releasing hormone); short bowel syndrome (e.g., wherein the therapeutically active agent is a GLP-2 or GLP- 2 receptor agonist, or a growth hormone); a hormone or enzyme deficiency (e.g., wherein the therapeutically active agent is a hormone or enzyme described herein which is deficient); tissue damage (e.g., wherein the therapeutically active agent is a growth factor); bleeding due to tissue damage or a bleeding disorder such as hemophilia (e.g., wherein the therapeutically active agent is a blood clotting factor or vasopressin); anemia (e.g., wherein the therapeutically active agent is an erythropoietin); leukopenia (e.g., wherein the therapeutically active agent is a G-CSF); a proliferative disease or disorder such as cancer, endometriosis or acromegaly (e.g., wherein the therapeutically active agent is an interleukin, interferon, erythropoietin, growth hormone-inhibiting hormone, GnRH, GnRH receptor antagonist or disitertide); infertility or other condition treatable by in vitro fertilization (e.g., wherein the therapeutically active agent is a gonadotropin or gonadotropin receptor agonist, a GnRH or a GnRH receptor agonist, or a GnRH receptor antagonist); and an infection such as a bacterial or viral infection (e.g., wherein the therapeutically active agent is an antipathogenic peptide, an antibody or interferon).

[0399] Without being bound by any particular theory, it is believed that compositions described herein facilitate absorption in the stomach (rather than in the intestines), and that this is particularly advantageous in treating subjects in which intestinal function may be deficient, such as short bowel syndrome.

[0400] Examples of suitable conditions in which activity of growth hormone and / or analogs thereof include, without limitation, bums, fibromyalgia, growth hormone deficiency, heart failure, inflammatory and / or autoimmune conditions (e.g., Crohn’s disease, ulcerative colitis and / or multiple sclerosis), muscle deterioration (e.g., wasting associated with AIDS), obesity, short bowel syndrome, and short stature and / or growth deficiency (e.g., severe idiopathic short stature or short stature associated with Turner syndrome, chronic kidney failure, Prader-Willi syndrome, and / or intrauterine growth restriction).

[0401] Examples of suitable conditions in which activity of GHRH and / or analogs thereof, and / or inducing release of growth hormone, is beneficial, include, without limitation, cognitive impairment (e.g., associated with agent, such as mild cognitive impairment, with pre- Alzheimer’s symptoms (preonset Alzheimer’s) and / or with dementia); sleep impairment (e.g., age-related sleep impairment); a disease or disorder associated with fat accumulation and / or hypercholesterolemia; a catabolic / wasting condition; a growth hormone deficiency (e.g., for providing a growth hormone replacement therapy, and / or treating idiopathic short stature); a disease or disorder associated with immunodeficiency; a disease or disorder associated with elevated cholesterol level, non-HDL cholesterol level, triglyceride level and / or total cholesterol / HDL cholesterol ratio (e.g., for reducing the elevated level and / or ratio); a disease or disorder associated with lean body mass and / or elevated trunk fat, visceral fat, visceral adipose tissue, visceral adipose tissue / subcutaneous adipose tissue ratio and / or abdominal girth (e.g., for improving any of the aforementioned parameters); a decrease in female fertility (e.g., as part of a fertility treatment in women); a lactation failure; a GHRH receptor-related tumor; hypothalamic pituitary dwarfism; a wound and / or bum (e.g., for improving healing); a debilitating infection (acute or chronic); and a disease or disorder associated with deficient and / or decreased bone formation (e.g., osteoporosis).

[0402] Examples of diseases or disorders associated with fat accumulation and / or hypercholesterolemia include, without limitation, obesity (abdominal obesity, optionally with metabolic disorders and / or relative GH deficiency), abdominal adiposity, metabolic syndrome, lipohypertrophy, lipoatrophy, lipodystrophy (e.g., HIV- associated lipodystrophy), dyslipidemia, hypertriglyceridemia, non-alcoholic fatty liver, and non-alcoholic steatohepatitis. Without being bound by any particular theory, it is believed that compositions comprising a GHRH (or analog thereof) according to any of the respective embodiments described herein can promote absorption for a brief period of time (e.g., by facilitating absorption briefly in the stomach), thereby resulting in a pulse-like pharmacokinetic profile. Such a pharmacokinetic profile can be advantageous in that it mimics the profile of GHRH injections.

[0403] A treatment according to any of the embodiments described herein (e.g., using GHRH or related agent) may optionally be for enhancing an immune reaction, for example, for treating a disease or disorder associated with immunodeficiency.

[0404] Examples of diseases or disorders associated with immunodeficiency include, without limitation, T-cell immunodeficiency, immunodeficiency associated with aging, immunodeficiency associated with HIV inf ection / AIDS, and immunodeficiency associated with high-dose chemotherapy and / or radiotherapy.

[0405] A treatment according to any of the embodiments described herein (e.g., using GHRH or related agent) may optionally be for enhancing anabolism (e.g., for example to increase muscle mass and / or function), for example, for treating a catabolic / wasting conditions.

[0406] Examples of catabolic / wasting conditions include, without limitation, acute or chronic renal failure (e.g., acute or chronic renal failure wasting), chronic heart failure (e.g., chronic heart failure wasting), chronic obstructive pulmonary disease (COPD), cystic fibrosis (e.g., cystic fibrosis wasting in adults), frailty, bums, infections (e.g., sepsis), muscular dystrophy, congestive heart failure, neurodegenerative conditions (e.g., Alzheimer’s or pre- Alzheimer’s syndrome, and / or amyotrophic lateral sclerosis), AIDS, protein malnutrition following long-term corticosteroid therapy, following non-union bone fracture, hip fracture, trauma, or major surgery (e.g., post-surgical problems), osteoporosis, long-term immobilization, cancer-related cachexia, sarcopenia (e.g., age-related sarcopenia), and gastrointestinal malabsorption (e.g., short bowel syndrome and / or Crohn’s disease), e.g., in elderly subjects.

[0407] Examples of suitable conditions in which activity of GLP-1 and / or analogs thereof (e.g., GLP- 1 receptor agonists) is beneficial include, without limitation, addiction (e.g., alcohol addiction and / or drug abuse), adipocyte dysfunction, Alzheimer’s Disease, arthritis (e.g., osteoarthritis and / or gout), cardiovascular diseases and disorders (e.g., atherosclerosis (including coronary artery disease), angina pectoris, endothelial dysfunction, impaired vascular compliance, left ventricular hypertrophy, hypertension, myocardial infarction (e.g., necrosis and / or apoptosis), peripheral arterial disease, peripheral vascular disease, pulmonary hypertension, stroke (e.g., hemorrhagic stroke and / or ischemic stroke), thrombosis, transient ischemic attacks and / or congestive heart failure), cataract, cirrhosis, diabetes (including Type 1 diabetes and / or Type 2 diabetes; e.g., pre-diabetes (including impaired fasting plasma glucose), idiopathic Type 1 diabetes (Type lb), latent autoimmune diabetes in adults, early-onset Type 2 diabetes, youth-onset atypical diabetes, malnutrition-related diabetes, gestational diabetes, and maturity onset diabetes of the young), diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL cholesterol, and low HDL cholesterol), eating disorders (including binge eating syndrome, bulimia nervosa, excessive sugar craving, and syndromic obesity such as Prader-Willi and Bardet-Biedl syndromes), erectile dysfunction, fibrosis, gastrointestinal diseases and disorders (e.g., inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, ulcerative colitis and / or irritable bowel syndrome), hepatocellular carcinoma, hyper-apo B lipoproteinemia, hyperglycemia, hyperinsulinemia, hyperuricemia, impaired cognition, impaired glucose metabolism, impaired glucose tolerance, insulin resistance (including hepatic insulin resistance), intermittent claudication, ketosis, kidney diseases and disorders (e.g., acute kidney disorder, chronic renal failure, glomerulosclerosis, tubular dysfunction, and / or pro-inflammatory changes to the proximal tubules), macular degeneration, metabolic acidosis, metabolic syndrome, non-alcoholic fatty liver, non-alcoholic steatohepatitis, obesity (including hypothalamic obesity and monogenic obesity) and related comorbidities (e.g., osteoarthritis and urine incontinence), osteoporosis, Parkinson’s Disease, polycystic ovary syndrome, post-prandial lipemia, premenstrual syndrome, psoriasis, restenosis (e.g., vascular restenosis and / or restenosis after angioplasty), schizophrenia, skin and connective tissue diseases and disorders, sleep apnea, traumatic brain injury, ulcerations (e.g., foot ulcerations), visceral adipose deposition, and weight gain associated with a therapeutic agent (e.g., steroids and / or antipsychotics).

[0408] Examples of suitable conditions in which activity of GLP-2 and / or analogs thereof (e.g., GLP- 2 receptor agonists) is beneficial include, without limitation, chemotherapy-induced adverse effects (e.g., abdominal cramping, bacterial translocation, diarrhea, gastrointestinal bleeding, malabsorption, mucositis and / or vomiting), cul-de-sac syndrome, digestion disorders, enteritis (e.g., radiation enteritis and / or infectious or post-infectious enteritis), inflammatory bowel disease, malabsorption syndromes, malnutrition (e.g., cachexia and / or anorexia), short-bowel syndrome (e.g., associated with surgical resection, congenital defect and / or disease-associated loss of absorption in the bowel), small intestine damage (e.g., associated with chemotherapy and / or toxic agents), celiac sprue (e.g., arising from gluten-induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemic sprue, ulcers (e.g., peptic ulcers, drug-induced ulcers, and / or ulcers associated with a pathogen), and ulcerative colitis.

[0409] A treatment according to any of the embodiments described herein (e.g., using GHRH, growth hormone, GLP-1, GLP-2, or related agent) may optionally be for improving a parameter associated with lipids and / or body structure. Examples of such improvements include, without limitation, decreasing cholesterol level, non-HDL cholesterol level, triglyceride level and / or total cholesterol / HDL cholesterol ratio, increasing lean body mass, and decreasing trunk fat, visceral fat, visceral adipose tissue, visceral adipose tissue / subcutaneous adipose tissue ratio and / or abdominal girth.

[0410] For conditions associated with chemotherapy, according to any of the respective embodiments described herein, the chemotherapeutic agent may be, for example, altretamine, bleomycin, busulfan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxycarbamide, idarubicin, ifosfamide, irinotecan, liposomal doxorubicin, leucovorin, lomustine, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, raltitrexed, streptozocin, tegafur-uracil, temozolomide, thiotepa, thioguanine, topotecan, treosulfan, vinblastine, vincristine, vindesine, and / or vinorelbine.

[0411] Examples of suitable conditions in which activity (e.g., peripheral activity) of a kappa opioid receptor and / or kappa opioid receptor agonist is beneficial include, without limitation, congestive heart failure, edema (e.g., associated with congestive heart disease and / or inappropriate antidiuretic hormone secretion), glaucoma, hypertension, ileus (e.g., post-operative ileus and / or opioid-induced bowel dysfunction), inflammation (e.g., autoimmune inflammation, throat inflammation and / or inflammation associated with a drug, such as an NSAID), hypokalemia, hyponatremia, liver cirrhosis, nephrotic syndrome, pain (e.g., acute pain, chronic pain, cutaneous pain, hyperalgesia, neuropathic pain, ocular pain, somatic pain, throat pain, and / or visceral pain), pruritus, and tussis.

[0412] Examples of neuropathic pain treatable according to any of the respective embodiments of the invention include, without limitation, diabetic pain, chemotherapy-induced pain, migraine headache, nerve encroaching metastatic cancer pain, trigeminal neuralgia, viral pain (e.g., herpes zoster- associated pain), and neuropathic pain associated with traumatic injury and / or surgical procedures.

[0413] Examples of ocular pain treatable according to any of the respective embodiments of the invention include, without limitation, pain associated with chemical bum, conjunctivitis, corneal abrasion and / or irritation, comeal ulcer, episcleritis, herpes zoster ophthalmicus, interstitial keratitis, iritis (e.g., acute iritis), keratoconjunctivitis sicca, ocular laceration, orbital cellulites, orbital floor fracture, orbital pseudotumor, pemphigus, photo-refractive keratectomy, scleritis, sclerokeratitis, trachoma and / or uveitis.

[0414] Examples of throat pain treatable according to any of the respective embodiments of the invention include, without limitation, pain associated with bronchitis (e.g., acute bronchitis), bums (e.g., pharyngeal bums), cancer (e.g., laryngeal cancer), common cold, contact ulcers, gingivitis (e.g., acute necrotizing ulcerative gingivitis), herpes simplex lesions, influenza, mononucleosis, laryngitis (e.g., acute laryngitis), peritonsillar abscess, pharyngitis, rhinitis (e.g., allergic rhinitis), sinusitis (e.g., acute sinusitis), and / or tonsillitis.

[0415] Further examples of pain treatable according to any of the respective embodiments of the invention include, without limitation, pain associated with arthritis (e.g., rheumatoid arthritis and / or osteoarthritis), cancer (e.g., breakthrough cancer pain), cirrhosis, dysmenorrhea, endometriosis, a gastrointestinal disease or disorder (e.g., bile duct stone, cholecystitis, colitis, diverticulitis, dyspepsia, esophagitis, gallstone, gastritis, gastroenteritis, gastro-esophageal reflux disease, gastric or duodenal ulcer, inflammatory bowel disease, intestinal obstruction, irritable bowel syndrome, pancreatitis, perforated ulcer, ulcerative colitis), hepatic abscess, hepatitis, interstitial cystitis, kidney stone, menopause (e.g., hot flashes), ovarian cyst, mastitis, pelvic inflammatory disease, peritonitis, polynephritis (e.g., acute polynephritis), prostatitis, pyelonephritis (e.g., acute pyelonephritis), surgery (e.g., arthroplasty) or other medical procedure, such as a biopsy (e.g., following appendectomy, cervical biopsy, cholecystectomy colectomy, colonic resection, colonoscopy, colostomy, cystoscopy, endometrial biopsy, gastrectomy, hernia repair, hysterectomy, hysteroscopy, open colorectal surgery, pelvic laparoscopy, prostatectomy, splenectomy, tubal ligation, and / or vasectomy), a toxin (e.g., insect toxin), urinary tract stone, and / or uterine cramping.

[0416] Examples of pruritus treatable according to any of the respective embodiments of the invention include, without limitation, anal pruritus (e.g., associated with hemorrhoids), drug-induced pruritus (e.g., mu opioid-induced pruritus), ocular pruritus (e.g., associated with conjunctivitis), otitic pruritus, uremic pruritus (e.g., in subjects undergoing hemodialysis), and pruritus associated with cholestasis (e.g., associated with primary biliary cholangitis, intrahepatic cholestasis of pregnancy, chronic cholestatic liver disease, uremia, malignant cholestasis and / or jaundice), animal (e.g., insect) bites or stings and / or a dermatological disease or disorder (e.g., dermatitis (including atopic and contact dermatitis), lichen planus, lichen simplex chronicus, pediculosis, polycythemia vera, psoriasis, scabies, thyrotoxicosis, tinea pedis, urticarial and / or vaginitis).

[0417] In the context of medical conditions associated with bone fractures, the terms “treating” and “treatment” encompass, for example, substantially healing, at least in part, a bone fracture (e.g., a fracture non-union which does not heal without intervention), substantially increasing a rate at which a bone fracture heals, substantially ameliorating or preventing the appearance of symptoms of a bone fracture (e.g., pain, loss of functionality of a portion of the body, defective bone formation), and preventing or reducing the likelihood of a bone fracture occurring, for example, due to a medical condition (e.g., prophylaxis). Treatment of a bone fracture as described herein may optionally be performed in combination with standard treatments of bone fractures, such as immobilization of bones (e.g., with a cast) and / or surgery.

[0418] Examples of conditions associated with a bone fracture include, without limitation, a fracture non-union, any medical condition associated with a stress fracture (optionally the condition is a stress fracture per se).

[0419] Herein and in the art, the phrase “fracture non-union” refers to a medical condition in which a bone fracture is present, and there is no reasonable expectation that the fracture will heal without intervention.

[0420] The skilled person will be readily capable of determining a presence of a fracture non-union.

[0421] In some embodiments according to any of the embodiments relating to non-unions, a fracture non-union is determined based on non-consolidation at the fracture site 6 months after the fracture was formed, and / or based on an absence of progress in callus formation at the fracture site at 4 week intervals (e.g., as described by Giannotti et al. [Clin Cases Miner Bone Metab 2013, 10: 116-120]).

[0422] Herein and in the art, the phrase "stress fracture" refers to a bone fracture caused by repeated stress over time (e.g., by running and / or jumping).

[0423] In some embodiments, treating a medical condition associated with a stress fracture comprises increasing a rate at which an existing stress fracture heals.

[0424] In some embodiments, treating a medical condition associated with a stress fracture comprises reducing the likelihood of a stress fracture occurring, for example, in a subject susceptible to stress fractures. Examples of subjects susceptible to stress fractures include, without limitation, athletes, runners, soldiers and other people subject to considerable physical exercise.

[0425] Herein, the phrase “bone defect” encompasses any missing portion of a bone, including, bone missing due to trauma (e.g., wherein a bone fracture results in a missing bone fragment), surgery (e.g., wherein bone is surgically removed in order to remove cancer cells), resorption of bone, an acquired medical condition (e.g., wherein an acquired medical condition causes a portion of a bone to disappear via resorption) and / or congenital conditions (e.g., wherein a congenitally misshapen bone is associated with one or more defects in the bone structure), a space between a bone and an implant intended to be osseointegrated with the bone (including, but not limited to, an implant anchored in a bone, for example, via a bolt or screw).

[0426] Examples of medical conditions involving resorption of bone include, without limitation, bone resorption associated with inflammatory conditions (e.g., periodontitis), which may comprise resorption of bone near the site of inflammation, and resorption of alveolar bone associated with a missing tooth. Herein, the terms “osseointegration” and “osseointegrated” refer to formation of a direct structural connection (e.g., without intervening connective tissue) between living bone and an implant; and includes, but is not limited to, growth of bone into an implant (e.g., a porous implant), a process also known in the art as “osseoincorporation”.

[0427] In the context of medical conditions associated with bone defects, the terms “treating” and “treatment” encompass, for example, substantially healing, at least in part, a bone defect (e.g., replacement of at least a portion of missing bone by bone regeneration), substantially increasing a rate at which a bone defect heals (e.g., a rate of bone regeneration), substantially ameliorating or preventing the appearance of symptoms of a bone defect (e.g., pain, loss of functionality of a portion of the body, defective bone formation), and preventing or reducing formation of a bone defect (e.g., prophylaxis), for example, formation of a bone defect by bone resorption. Treatment of a bone defect as described herein may optionally be performed in combination with standard treatments of the respective bone defect.

[0428] In some embodiments according to any of the respective embodiments described herein, the medical condition is resorption of alveolar bone. In some of these embodiments, the method or treatment is for preserving and / or regenerating alveolar bone. Examples of resorption of alveolar bone include, without limitation, resorption associated with a missing tooth and resorption associated with inflammation (e.g., periodontitis).

[0429] In some embodiments, the method or treatment is for preserving and / or regenerating alveolar bone surrounding a dental implant (e.g., a dental implant which comprises or supports a prosthetic tooth, crown, dental bridge and / or fixed denture), for example, to hold the dental implant in place, thereby increasing the utility of the implant and / or the likelihood of success of the dental implantation. In some embodiments, the method or treatment is effected following implantation of a dental implant, for example, in order to promote regeneration of alveolar bone (e.g., alveolar bone characterized by a bone defect associated with resorption of the bone due to a missing tooth and / or periodontitis). In alternative or additional embodiments, the method or treatment is effected prior to implantation of a dental implant, for example, in order to preserve alveolar bone by preventing or reducing alveolar bone resorption (e.g., upon loss of a tooth, when a significant amount of time is expected to pass before implantation of a dental implant.

[0430] In some embodiments according to any of the respective embodiments described herein, the bone defect is in the skull (cranium or lower jawbone). In some embodiments, the bone defect is a calvarial bone defect. Without being bound by any particular theory, it is believed that bone in the skull (e.g., in the calvaria) is particularly susceptible to poor healing of bone defects, in which promotion of bone growth would be advantageous.

[0431] In some embodiments according to any of the respective embodiments described herein, the method and / or treatment comprises promoting osseointegration of an implant, for example, by promoting bone growth in a space between a bone (e.g., calvarial bone) and the implant. The medical condition may optionally be any medical condition for which osseointegration of an implant is beneficial.

[0432] Examples of implants for which osseointegration may be promoted include, without limitation, dental implants, bone grafts (e.g., bone allografts), chin implants, craniofacial prostheses (e.g., artificial ears, eyes and / or noses), bone-anchored limb prostheses, bone-anchored hearing aids, and joint prostheses (e.g., for hip and / or knee replacement).

[0433] Herein, the term “implant” refers to any device, wherein at least a portion of the device is placed in a subject, and encompasses man-made devices and transplanted tissue, and may comprise synthetic materials, an autograft (e.g., bone harvested from a different region of the subject, such as the iliac crest or chin), an allograft (e.g., bone harvested from an individual other than the subject, optionally a cadaver), a xenograft (e.g., bone from a different species, optionally bovine bone or coral) or any combination thereof. Examples of synthetic material which may be included in an implant (e.g., an implant intended to be osseointegrated) include, without limitation, hydroxyapatite, calcium carbonate, tricalcium phosphate, polymers (e.g., poly(methyl methacrylate), poly(hydroxyethyl methacrylate)), ceramics and metals (e.g., titanium).

[0434] In some embodiments of any one of the embodiments described herein relating to treatment of osteoporosis and / or a condition associated with a bone fracture or bone defect using PTH, oral administration according to any of the respective embodiments described herein is effected from 1 to 4 times per day. In some such embodiments, the oral administration according to any of the respective embodiments described herein is effected from 1 to 3 times per day. In some embodiments, the oral administration according to any of the respective embodiments described herein is effected once or twice per day. In some embodiments, the oral administration according to any of the respective embodiments described herein is effected once per day.

[0435] In some embodiments of any one of the embodiments described herein relating to treatment of a condition associated with a bone fracture or bone defect using PTH is effected once per day or less. In some such embodiments, the oral administration is effected once every two days. In some such embodiments, the oral administration is effected twice per week. In some such embodiments, the oral administration is effected once per week or less. In some embodiments of any one of the embodiments described herein relating to oral administration once per day or less frequently, the treatment is a prophylactic treatment (for preventing or reducing the likelihood and / or size of a bone fracture and / or bone defect), that is, the subject does not necessarily have a bone fracture and / or bone defect at the time of treatment.

[0436] In some embodiments, the prophylactic treatment is for stress fractures, for example, in a subject susceptible to stress fractures (e.g., as described herein).

[0437] In some embodiments, the prophylactic treatment is for preventing or reducing an alveolar bone defect associated with resorption of alveolar bone, for example, in a subject susceptible to alveolar bone resorption (e.g., as described herein). Subjects afflicted by periodontitis and / or subjects missing a tooth are non-limiting examples of subjects susceptible to alveolar bone resorption.

[0438] Without being bound by any particular theory, it is believed that relatively low dosages (e.g., as effected by a relatively low frequency of oral administration) are more suitable than high dosages for prophylactic applications.

[0439] Compositions for oral administration (as described herein) may be particularly convenient for indications in which frequent administration of a therapeutically active agent is desirable.

[0440] In some embodiments of any one of the embodiments described herein relating to treatment of hypoparathyroidism with PTH, the oral administration according to any of the respective embodiments described herein is effected at least twice per day (e.g., from 2 to 6 times per day). In some such embodiments, the oral administration according to any of the respective embodiments described herein is effected at least 3 times per day (e.g., from 3 to 6 times per day). In some embodiments, the oral administration according to any of the respective embodiments described herein is effected at least 4 times per day (e.g., from 4 to 6 times per day).

[0441] 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 the treatment of hypoparathyroidism.

[0442] Without being bound by any particular theory, it is believed that compositions according to some embodiments of the invention are characterized by rapid absorption (e.g., associated with absorption via stomach tissue, prior to reaching the intestines), which is particularly advantageous for certain applications; for example, for obtaining a pulse-like pharmacokinetic profile (e.g., of GHRH or PTH), or for treatment of acute, difficult-to-tolerate conditions or symptoms, such as pain and / or pruritus.

[0443] In some embodiments, the rapid administration is characterized by an average Tmax of the composition upon oral administration is no more than 60 minutes, or no more than 50 minutes, or no more than 40 minutes, or no more than 30 minutes, or no more than 20 minutes, or no more than 15 minutes, or even no more than 10 minutes.

[0444] As used herein the term “Tmax” refers to the time from administration to the time point at which maximal concentration of an administered agent in the blood (e.g., plasma levels) occurs, and can be determined by measuring levels of the agent at various time points following administration, as exemplified herein.

[0445] 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 which is 3 hours or lower. In some embodiments, the ratio of AUC to Cmax is 2 hours or lower. In some embodiments, the ratio of AUC to Cmax is 90 minutes or lower. In some embodiments, the ratio of AUC to Cmax is 60 minutes or lower. In some embodiments, the ratio of AUC to Cmax is 50 minutes or lower. In some embodiments, the ratio of AUC to Cmax is 40 minutes or lower. In some embodiments, the ratio of AUC to Cmax is 30 minutes or lower. In some embodiments, the ratio of AUC to Cmax is 20 minutes or lower. In some embodiments, the ratio of AUC to Cmax is 15 minutes or lower. In some embodiments, the ratio of AUC to Cmax is 10 minutes or lower.

[0446] As used herein the term “AUC” refers to the area under a curve which represents levels of an administered agent in the blood (e.g., plasma levels) as a function of time following administration, and can be determined by measuring plasma levels of the agent at various time points following administration, as exemplified herein.

[0447] As used herein the term “Cmax” refers to the maximal concentration of an administered agent in the blood (e.g., plasma levels), and can be determined by measuring levels of the agent at various time points following administration, as exemplified herein.

[0448] The ratio of AUC to Cmax (i.e., AUC divided by Cmax) will depend on the nature of the pharmacokinetic profile of the composition, particularly on the shape of the curve which represents levels of the therapeutically active agent in the blood (e.g., plasma levels) as a function of time following administration. Pharmacokinetic profiles characterized by a sharp increase and decrease within a brief period of time will tend to have a relatively low ratio of AUC to Cmax, whereas pharmacokinetic profiles characterized by a more gradual increase and decrease over a broader period of time will tend to have a relatively high ratio of AUC to Cmax.

[0449] Thus, without being bound by any particular theory, it is believed that a ratio of AUC to Cmax which is 3 hours or lower, as described herein according to any of the respective embodiments, is associated with a relatively sharp increase and decrease of levels of therapeutically active agent in the blood. The ratio of AUC to Cmax is optionally calculated based on data from multiple administrations of the composition. In such cases, a ratio of AUC to Cmax is preferably calculated for each administration, and then the ratios calculated for each administration may be averaged.

[0450] Similarly, the Cmax and / or Tmax are optionally calculated based on data from multiple administrations of the composition. In such cases, a Cmax and / or Tmax value is preferably calculated for each administration, and then the Cmax and / or Tmax values calculated for each administration may be averaged.

[0451] Without being bound by any particular theory, it is believed that averaging data (e.g., measured blood levels of therapeutically active agent) from different administrations of therapeutically active agent will frequently result in a broader curve, a lower Cmax value, and larger ratio of AUC to Cmax, than that which is observed after a single administration. Hence, a Cmax value and a ratio of AUC to Cmax calculated for averaged data (as opposed to an average of ratios calculated for each administration, as described hereinabove) is a less accurate indicator of the effect of the composition following administration.

[0452] Each of the compositions and unit dosage forms described herein optionally consist essentially of the functional ingredients described hereinabove (e.g., a therapeutically active agent, an absorption enhancer, and a proton-accepting agent, each according to any of the embodiments described herein in any of the respective sections herein), or alternatively, the composition further comprises suitable pharmaceutically acceptable carriers and / or excipients, as described herein.

[0453] In some embodiments of any one of the embodiments described herein, the composition is formulated as a solid composition, e.g., a solid unit dosage form. In some embodiments, the composition is formulated as a tablet or as a combination of tablets (e.g., a plurality of minitablets). In some embodiments, the composition is formulated as a capsule, as described herein, which comprises, for example, a plurality of minitablets and / or a powder, and which has a coating that is dissolvable in a gastric fluid (e.g., in gastric pH) or otherwise releases the capsule’s content immediately (e.g., within less than 5 minutes, or less than 2 minutes or less than 1 minutes) upon contacting aa gastric fluid.

[0454] Ingredients of the formulation (including, but not limited to, any two or more of the absorption enhancer, the proton- accepting agent and therapeutically active agent of any of the respective embodiments described herein may optionally be mixed in a homogeneous manner or be distributed throughout the composition in a heterogeneous manner.

[0455] Miscellaneous definitions:

[0456] Herein, the term “polypeptide” refers to a polymer comprising at least 4 amino acid residues linked by peptide bonds or analogs thereof (as described herein), and optionally only by peptide bonds per se. In some embodiments, the polypeptide comprises at least 10 amino acid residues or analogs thereof. In some embodiments, the polypeptide comprises at least 20 amino acid residues or analogs thereof. In some embodiments, the polypeptide comprises at least 30 amino acid residues or analogs thereof. In some embodiments, the polypeptide comprises at least 50 amino acid residues or analogs thereof. The term “polypeptide” encompasses native polypeptides (e.g., degradation products, synthetically synthesized polypeptides and / or recombinant polypeptides), including, without limitation, native proteins, fragments of native proteins and homologs of native proteins and / or fragments thereof; as well as peptidomimetics (typically, synthetically synthesized polypeptides) and peptoids and semipeptoids which are polypeptide analogs, which may have, for example, modifications rendering the polypeptides more stable while in a body or more capable of penetrating into cells. Such modifications include, but are not limited to N terminus modification, C terminus modification, peptide bond modification, backbone modifications, and residue modification. Methods for preparing peptidomimetic compounds are well known in the art and are specified, for example, in Quantitative Drug Design, C.A. Ramsden Gd., Chapter 17.2, F. Choplin Pergamon Press (1992), which is incorporated by reference as if fully set forth herein. Further details in this respect are provided herein.

[0457] Peptide bonds (-CO-NH-) within the polypeptide may be substituted, for example, by N- methylated amide bonds (-N(CH3)-CO-), ester bonds (-C(=O)-O-), ketomethylene bonds (-CO-CH2- ), sulfinylmethylene bonds (-S(=O)-CH2-), a-aza bonds (-NH-N(R)-CO-), wherein R is any alkyl (e.g., methyl), amine bonds (-CH2-NH-), sulfide bonds (-CH2-S-), ethylene bonds (-CH2-CH2-), hydroxyethylene bonds (-CH(OH)-CH2-), thioamide bonds (-CS-NH-), olefinic double bonds (- CH=CH-), fluorinated olefinic double bonds (-CF=CH-), retro amide bonds (-NH-CO-), peptide derivatives (-N(R)-CH2-CO-), wherein R is the "normal" side chain, naturally present on the carbon atom.

[0458] These modifications can occur at any of the bonds along the polypeptide chain and even at several (2-3) bonds at the same time.

[0459] Natural aromatic amino acids, Trp, Tyr and Phe, may be substituted by non-natural aromatic amino acids such as l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), naphthylalanine, ring- methylated derivatives of Phe, halogenated derivatives of Phe or O-methyl-Tyr.

[0460] The polypeptides of some embodiments of the invention (e.g., a therapeutically active agent and / or a protease inhibitor described herein) may also include one or more modified amino acids or one or more non-amino acid monomers (e.g. fatty acids, complex carbohydrates etc.). The term "amino acid" or "amino acids" is understood to include the 20 naturally occurring amino acids; those amino acids often modified post-translationally in vivo, including, for example, hydroxyproline, phosphoserine and phosphothreonine; and other unusual amino acids including, but not limited to, 2-aminoadipic acid, hydroxylysine, isodesmosine, nor-valine, nor-leucine and ornithine. Furthermore, the term "amino acid" includes both D- and L-amino acids.

[0461] Tables A and B below list naturally occurring amino acids (Table A), and non-conventional or modified amino acids (e.g., synthetic, Table B) which can be used with some embodiments of the invention. Table A Table B

[0462] The polypeptides of some embodiments of the invention (e.g., a therapeutically active agent and / or a protease inhibitor described herein) are preferably utilized in a linear form, although it will be appreciated that in cases where cyclization does not severely interfere with polypeptide characteristics, cyclic forms of the polypeptide can also be utilized.

[0463] In some embodiments of any one of the embodiments described herein, the polypeptide is water-soluble.

[0464] Herein, the term “water-soluble” refers to a compound having a solubility of at least 1 gram per liter in an aqueous solution at pH 7.

[0465] Water-soluble polypeptides preferably include one or more non-natural or natural polar amino acids, including but not limited to serine and threonine which are capable of increasing polypeptide water-solubility due to their hydroxyl-containing side chain. Optionally, a homolog of a polypeptide is selected so as to be more water-soluble than the parent polypeptide, for example, by replacing one or more amino acids in the polypeptide with polar amino acids.

[0466] The polypeptides of some embodiments of the invention (e.g., a therapeutically active agent and / or a protease inhibitor described herein) may be synthesized by any techniques that are known to those skilled in the art of peptide synthesis. For solid phase peptide synthesis, a summary of the many techniques may be found in J. M. Stewart and J. D. Young, Solid Phase Peptide Synthesis, W. H. 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.

[0467] In general, these methods comprise the sequential addition of one or more amino acids or suitably protected amino acids to a growing polypeptide chain. Normally, 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 either be attached to an inert solid support or utilized in solution by adding the next amino acid in the sequence having the complimentary (amino or carboxyl) group suitably protected, under conditions suitable for forming the amide linkage. The protecting group is then removed from this newly added amino acid residue and the next amino acid (suitably protected) is then added, and so forth. After all the desired amino acids have been linked in the proper sequence, any remaining protecting groups (and any solid support) are removed sequentially or concurrently, to afford the final polypeptide compound. By simple modification of this general procedure, it is possible to add more than one amino acid at a time to a growing chain, for example, by coupling (under conditions which do not racemize chiral centers) a protected tripeptide with a properly protected dipeptide to form, after deprotection, a pentapeptide and so forth. Further description of peptide synthesis is disclosed in U.S. Pat. No. 6,472,505.

[0468] A preferred method of preparing the polypeptide compounds of some embodiments of the invention (e.g., a therapeutically active agent and / or a protease inhibitor described herein) involves solid phase peptide synthesis.

[0469] Large scale polypeptide synthesis is described by Andersson et al. [Biopolymers 2000; 55:227-250],

[0470] Herein, a “homolog” of a given polypeptide refers to a polypeptide that exhibits at least 80 % homology, preferably at least 90 % homology, and more preferably at least 95 % homology, and more preferably at least 98 % homology to the given polypeptide. 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 which match a corresponding residue of a second polypeptide sequence to which the first polypeptide is being compared. Generally, the polypeptides are aligned to give maximum homology. A variety of strategies are known in the art for performing comparisons of amino acid or nucleotide sequences in order to assess degrees of identity, including, for example, manual alignment, computer assisted sequence alignment and combinations thereof. A number of algorithms (which are generally computer implemented) for performing sequence alignment are widely available, or can be produced by one of skill in the art. Representative algorithms include, e.g., the local homology algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2: 482); the homology alignment algorithm of Needleman and Wunsch (J. Mol. Biol., 1970, 48: 443); the search for similarity method of Pearson and Lipman (Proc. Natl. Acad. Sci. (USA), 1988, 85: 2444); and / or by computerized 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 etc. When utilizing BLAST and Gapped BLAST programs, default parameters of the respective programs may be used. Alternatively, the practitioner may use nondefault parameters depending on his or her experimental and / or other requirements (see for example, the Web site having URL www(dot)ncbi(dot)nlm(dot)nih(dot)gov).

[0471] It is expected that during the life of a patent maturing from this application many relevant therapeutically active agents and many relevant treatments of conditions by therapeutically active agents will be developed, and the scope of the phrases “therapeutically active agent” and “condition treatable by... therapeutically active agent” are intended to include all such new technologies a priori.

[0472] As used herein the term “about” refers to ± 10 %.

[0473] The terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".

[0474] The term “consisting of’ means “including and limited to”.

[0475] The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0476] The word “exemplary” is used herein to mean “serving as an example, instance or illustration”. Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0477] The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict.

[0478] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a therapeutically active agent" may include a plurality of compounds, including mixtures thereof.

[0479] Throughout this application, various embodiments of this 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. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0480] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween. As used herein the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0481] As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

[0482] Herein throughout, “Dalton” or “Da” is considered as equivalent to gram / mol, and kDa is considered as equivalent to 1,000 grams / mol.

[0483] In some embodiments of any one of the embodiments described herein, the unit dosage form and / or composition according to any of the aspects described herein is for use in the treatment of a condition treatable by oral administration of the therapeutically active agent (e.g., a condition described herein).

[0484] According to another aspect of embodiments of the invention, there is provided a use of a unit dosage form and / or composition according to any of the aspects described herein in the preparation of a medicament for use in the treatment of a condition treatable by oral administration of the therapeutically active agent (e.g., a condition described herein).

[0485] According to another aspect of embodiments of the invention, there is provided a method of treating a condition treatable by oral administration of a therapeutically active agent in a subject in need thereof (e.g., a condition and therapeutically active agent described herein), the method comprising orally administering to the subject a unit dosage form and / or composition according to any of the aspects described herein which comprises the therapeutically active agent.

[0486] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, 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 to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0487] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples. EXAMPLES

[0488] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

[0489] EXAMPLE 1

[0490] Materials:

[0491] Arginine (CAS No 74-79-3) was obtained from Tokyo Chemical Industry ltd.

[0492] Histidine (CAS No. 36653-82-4) was obtained from Sigma Aldrich.

[0493] Sodium Benzoate (CAS No. 532-32-1) was obtained from SDFCL.

[0494] Sodium Bicarbonate (CAS No. 144-55-8) was obtained from Sigma Aldrich.

[0495] Sodium Glucoante (CAS No. 527-07-1) was obtained from TCI.

[0496] Sodium Salicylate (CAS No. 54-21-7) was obtained from Roth.

[0497] Tri Sodium Citrate (CAS No. 68-04-2) was obtained from Acros organic.

[0498] Sodium Decanoate (CAS No. 1002-62-6) was obtained from Algene.

[0499] Sodium Octanoate (CAS No. 1984-06-1) was obtained from Sigma Aldrich.

[0500] SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate; (CAS No. 203787-91-1)) was prepared in-house by reacting O-acetylsalicyloyl chloride with 8-aminocaprylic acid.

[0501] SNAC solubility determination in gastric conditions:

[0502] Experiments were performed with solutions of 40 mg / ml SNAC in water, at room temperature. The tested alkaline amino acids were added, each separately, to the solutions at various mol ratios to SNAC, as shown in Table 1 below.

[0503] Table 1 Next, HC1 was added to each solution to produce a pH of 1.2 in water, representing pH of a fasted stomach. A solution of SNAC alone (without amino acid) served as a control. An additional set of solutions containing SNAC and each of the tested amino acids was prepared in water only, without HC1. A sample taken at 0 time point from these solutions served as a reference for a faction of 100 % soluble SNAC.

[0504] Samples were taken from each of the other solutions at predetermined time-points of 0.5, 5, 10, 20, and 30 minutes following the HC1 addition, filtered through a PTFE 0.22 pm filter and analyzed by High-Performance Liquid Chromatography (HPLC). The amount of SNAC in the samples taken from the HC1 solutions was compared to the above-mentioned fraction representing 100% soluble SNAC, to thereby determine the faction of soluble SNAC in each tested sample, representing the % recovery of SNAC.

[0505] The amount of soluble SNAC in each sample, which represents the material available to act as permeability enhancer, was determined by High-Performance Liquid Chromatography (HPLC), performed on Agilent 1100 series HPLC equipped with UV detector, Cosmosil C18 250*4.6 mm, 5 um column, using 45:55 ACN: 0.1% v / v H3PO4 85% in water as eluent. Results:

[0506] As discussed hereinabove, SNAC has been shown to transiently increase membrane fluidity as a function of its concentration, thus increasing transcellular transport of large, polar molecules (such as peptides) found in close proximity. SNAC is the sodium salt form of salcaprozate (or NAC). NAC is a weak base with a pKa of 4.5-5 with low solubility in water (0.25 mg / ml). At an acidic medium, as in the stomach, SNAC is protonated, and the obtained NAC precipitates. Consequently, the amount of soluble SNAC available for permeability enhancement is reduced.

[0507] While, as is also discussed hereinabove, the present inventors have previously studied the effect of antacids and of polymers featuring a plurality of alkaline groups, as protecting agents that are capable of protecting SNAC from precipitating in a form NAC in the stomach, the present inventors have now studied the effect of additional agents and of combinations of various agents as protective agents.

[0508] The present inventors have therefore studied the effect of alkaline amino acids as such protonaccepting agents, as described in the Materials and Methods section hereinabove.

[0509] FIG. 1 presents the obtained data.

[0510] As shown in FIG. 1, the incorporation of arginine into SNAC samples significantly increased the soluble fraction of the permeability enhancer protecting it from precipitation, in a dose-dependent manner. Samples with a SNAC:Arginine mol ratio of 1:1 achieved approximately 100 percent recovery of SNAC. Samples containing SNAC:Arginine mol ratio of 0.75 and 0.5 showed reduced efficacy but still exhibited approximately 4.5x and 3.5x recovery, respectively, compared to a sample with only SNAC. SNAC samples incorporating histidine showed an increase in recovery reaching 30 and 25 percent recovery in samples containing SNAC:Histidine mol ratios of 1.5 and 1, respectively.

[0511] Additional tests were performed similarly incorporating trisodium citrate and sodium gluconate into SNAC samples, and were found to not affect the soluble fraction of SNAC (data not shown).

[0512] Similar tests are performed using lysine as an exemplary alkaline amino acid, a mol ratios to SNAC of 1:2, 1:1.5, 1:1, 0.75:1, 0.5:1 and / or 0.25:1

[0513] Additional tests are performed similarly using a fatty acid salt as described herein in any of the respective embodiments, with and without an alkaline amino acid as described herein.

[0514] Additional tests are performed similarly using a fatty acid salt as described herein in any of the respective embodiments, with and without an antacid as described herein in any of the respective embodiments.

[0515] EXAMPLE 2

[0516] The effect of various PAAs as described under the Materials and Experimental Methods under Example 1 hereinabove were further tested.

[0517] Tablets containing SNAC (100 mg) alone, or combined with sodium decanoate (50 mg), sodium carbonate (30 mg), or a combination of sodium decanoate (50 mg) and sodium carbonate (30 mg), were dissolved in 125 mL of an aqueous solution featuring pH=2 and thereby simulating gastric fluid of a human subject in the morning following administration of the tablet with 100 ml.

[0518] Tests were performed in USP 2 dissolution apparatus with paddle rotation speed of 50 rpm. To measure dissolution profile of SNAC in the simulated gastric medium, samples were taken at different time points, filtered through a PTFE 0.22 pm filter and analysed by High-Performance Liquid Chromatography (Agilent 1100 series HPLC equipped with UV detector, Cosmosil C18 250*4.6 mm, 5 um column, using 45:55 ACN: 0.1% v / v H3PO4 85% in water as eluent).

[0519] The obtained data is shown in FIG. 2 and demonstrate an improved SNAC recovery in the presence of sodium decanoate or sodium carbonate, compared to SNAC alone, and a substantially improved (synergistic) effect in the presence of sodium decanoate and sodium carbonate.

[0520] Similar tests were performed with tablets containing SNAC (100 mg) alone, or combined with sodium carbonate (30 mg), or a combination of arginine (50 mg) and sodium carbonate (30 mg), and the results are presented in FIG. 3. As can be seen, a substantially improved SNAC recovery was observed when arginine was combined with sodium carbonate, compared to both SNAC alone and SNAC and sodium carbonate.

[0521] EXAMPLE 3

[0522] The ability of small molecules proton accepting agent(s) to increase the bioavailability of a therapeutically active agent co-formulated with an absorption enhancer as described herein, was assessed in an in vivo pig or rat model.

[0523] Test animals were divided into groups, and each animal was administered intragastrically by endoscopic device orally with either a control formulation, comprised of SNAC and a polypeptide therapeutically active agent, or a test formulation, comprised of SNAC, the selected therapeutically active agent and a selected small molecule proton- accepting agent as described herein.

[0524] The effect of a combination of SNAC and exemplary small molecule proton-accepting agents, or exemplary combinations thereof, at various mol ratios, on absorption of the exemplary polypeptide therapeutically active agent was assessed in an in vivo pig model, which allows testing of orally administered unit dosage forms with conventional dimensions that are applicable also in humans.

[0525] All formulations’ constituents were in a dry powder form and mixed geometrically using mortar and pestle. Thereafter, round flat tablets were prepared from the mixes using a punch and dye and dental manual press.

[0526] In studies conducted in pigs, the obtained tablets were administered intra-gastrially at monitored conditions with the aid of endoscope into the stomachs of 2 male and 2 female mini-pigs (about 45 kg) for each tested group on different visits. Pigs were deprived of food the night before the experiments and during the experiment and deprived of water an hour before the experiment and during the experiment.

[0527] Blood samples were taken from the jugular vein through an indwelling cannula at predetermined time points during the first hour post-dose (which reflects the absorption phase). Plasma was separated and the concentration of the tested therapeutically active agent in plasma was quantified using a suitable technique.

[0528] In studies conducted in rats, two minitablets (about 20 mg each) were administered by intragastric gavage to SD rats following 12 hours fasting period.

[0529] In an exemplary assay, tablets containing SNAC (56 % by weight), an exemplary therapeutically active polypeptide, sodium carbonate (1:1 mol ratio to SNAC) and sodium decanoate (CIO) (0.5:1 mol ratio to SNAC), were administered to rats. Each tablet contained 1 mg of the polypeptide active agent, 0.2 mg magnesium stearate, 4 mg CIO, 4.4 mg sodium carbonate, and 12.4 mg SNAC. The obtained Cmax was higher than 3,000 pg / mol, and the AUClast was higher than 50,000 pg-min / ml, representing an efficient performance.

[0530] Additional tests are performed similarly using an alkaline amino acid as described herein and an antacid as described herein in any of the respective embodiments.

[0531] Although the 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. It is the intent of the applicant(s) that all publications, patents and patent applications referred to in this specification are to be incorporated in their entirety by reference into the specification, as if each individual publication, patent or patent application was specifically and individually noted when referenced that it is to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is / are hereby incorporated herein by reference in its / their entirety.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition for oral administration of a therapeutic active agent, the composition comprising the therapeutically active agent, a salt of NAC (8-N-(2- hydroxybenzoyl)aminocaprylate), and at least one proton accepting agent featuring pKa higher by at least 0.5 than a pKa of NAC, said at least one proton accepting agent comprising at least one small molecule substance other than an antacid.

2. The composition of claim 1, wherein said at least one proton accepting agent is selected from an amino acid and a fatty acid salt.

3. The composition of any one of claims 1 to 2, wherein said at least one proton accepting agent comprises an amino acid having a side chain featuring a pKa of at least 5, preferably of at least 6.

4. The composition of claim 3, wherein said amino acid is selected from histidine, arginine, lysine, an analog thereof and any combinations thereof.

5. The composition of any one of claims 1 to 4, wherein said amino acid is arginine.

6. The composition of any one of claims 1 to 5, wherein said at least one proton accepting agent comprises a salt of a fatty acid.

7. The composition of any one of claims 1 to 6, wherein said fatty acid is a mediumchain fatty acid, being of from 4 to 12, or from 6 to 12, or from 6 to 10, or from 8 to 10.

8. The composition of any one of claims 1 to 7, wherein said salt of said fatty acid is selected from sodium octanoate and sodium decanoate.

9. The composition of any one of claims 1 to 8, wherein said at least one proton accepting agent comprises a salt of a fatty acid as defined in any one of claims 6 to 8 and an amino acid as defined in any one of claims 3 to 5.

10. The composition of any one of claims 1 to 9, wherein said at least one proton accepting agent comprises an amino acid as defined in any one of claims 3 to 5 and an antacid.

11. The composition of any one of claims 1 to 10, wherein said at least one proton accepting agent comprises a salt of a fatty acid as defined in any one of claims 6 to 8 and an antacid.

12. The composition of any one of claims 1 to 11, wherein said at least one antacid compound is selected from the group consisting of calcium carbonate, calcium gluconate, calcium citrate, sodium carbonate, sodium bicarbonate, sodium gluconate, sodium citrate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium gluconate, potassium citrate, potassium hydroxide, magnesium carbonate, magnesium gluconate, magnesium citrate, magnesium hydroxide, magnesium oxide, aluminum carbonate, aluminum gluconate, aluminum citrate, and aluminum hydroxide.

13. The composition of any one of claims 1 to 12, wherein a mol ratio of said at least one proton-accepting agent and said salt of NAC is at least 0.1 : 1 or ranges from 0.1 : 1 to 5 : 1 , or from 0.1:1 to 2:1, or from 0.2:1 to 2:1.

14. The composition of any one of claims 1 to 13, wherein a total concentration of said at least one proton-accepting agent in the composition is at least 5, or at least 10, weight percent of the total weight of the composition.

15. The composition of any one of claims 1 to 14, wherein a total concentration of said salt of NAC in the composition is at least 50 weight percent of the total weight of the composition.

16. The composition of any one of claims 1 to 15, wherein at least 80, or at least 90 weight percent of the composition consists of ingredients selected from the group consisting of said therapeutically active agent, said salt of NAC, and said at least one proton accepting agent.

17. The composition of any one of claims 1 to 16, wherein said therapeutically active agent has a molecular weight in a range of 0.5 kDa to 100 kDa.

18. The composition of any one of claims 1 to 17, wherein said therapeutically active agent is a polypeptide.

19. The composition of claim 18, wherein said polypeptide is selected from the group consisting of parathyroid hormone, a parathyroid hormone fragment, a parathyroid hormone long- acting analog, and a parathyroid hormone fragment long-acting analog.

20. The composition of claim 18, wherein said polypeptide is characterized by an isoelectric point (pl) of at least 8.5.

21. The composition of any one of claims 1 to 20, being formulated such that absorption of said therapeutically active agent following oral administration of the composition is characterized by a bioavailability of said therapeutically active agent which is at least 10 % higher than a bioavailability of said therapeutically active agent following oral administration of a composition comprising said therapeutically active agent and said salt of NAC (8-N-(2- hydroxybenzoyl)aminocaprylate) without said at least one proton accepting agent.

22. The composition of any one of claims 1 to 21, being in a form of a homogeneous mixture.

23. The composition of any one of claims 1 to 22, being formulated as a unit dosage form.

24. The composition of claim 23, wherein said unit dosage form is a solid unit dosage form.

25. The composition of claim 24, being formulated as a tablet.

26. The composition of any one of claims 24 to 25, wherein said unit dosage form is soluble in gastric fluid.

27. The composition of any one of claims 1 to 26, for use in the treatment of a condition treatable by oral administration of said therapeutically active agent in a subject in need thereof.

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