Sustained-release formulations for poorly permeable cyclic peptides

Abstract

The present disclosure provides orally administered pharmaceutical compositions that are effective in providing sustained plasma levels of a therapeutic peptide in a subject. The disclosed compositions are oral dosage forms comprising a large and / or poorly permeable cyclic peptide, a fatty acid salt, a cellulose-derived polymer, and one or more pharmaceutically acceptable excipients. Methods of preparing these compositions for oral administration, and methods of treatment comprising administering these compositions, are further provided. The disclosed methods and compositions provide for a sustained release of cyclic peptide drugs while also providing enhanced bioavailability relative to immediate-release formulations.

Description

25738 SUSTAINED-RELEASE FORMULATIONS FOR POORLY PERMEABLE CYCLIC PEPTIDES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 578,501 filed August 24, 2023 and U.S. Provisional Patent Application Serial No.63 / 680,314 filed August 7, 2024, the entire contents of which are incorporated by reference herein. BACKGROUND OF THE INVENTION

[0002] The present disclosure relates to the formulation of peptides in oral dosage forms. The present disclosure relates in particular to oral dosage forms that provide sustained release of peptides and enhance their oral bioavailability in subjects.

[0003] Peptide therapeutics historically require parenteral administration, which is not preferred by patients and can be a deterrent to medication adherence. Oral peptide delivery is an especially desirable alternative, but it is limited by substantial gastrointestinal (GI) absorption barriers including the degrative conditions in the GI tract and low peptide permeability across the GI epithelium. There is particular interest in delivering impermeable cyclic peptide drugs orally, with high potency and GI stability. Macrocyclic, or high-molecular weight cyclic, peptides are generally poorly soluble and poorly permeable.

[0004] Many methods for improving oral absorption of poorly permeable molecules have been reported. Permeation enhancers (PEs), for example, have been shown to improve poorly permeable compounds’ (i.e., peptides) permeability across the GI epithelial barrier in the intestine. See Brayden et al., Advanced Drug Delivery Reviews (2020), Maher, Geoghegan & Brayden Expert Opinion on Drug Delivery (2021). However, the scientific literature indicates that PEs typically provide only modest improvement in oral bioavailability (reaching less than 2% bioavailability). See, e.g., Brown et al., Nat. Revs. Materials 5, 127-148 (2020). This limitation has been observed in all species, ranging from rat, monkey to human. The accepted mechanism by which most PEs operate is by opening the cell-tight-junctions (CTJs) present in the epithelial lining of the intestine. See Drucker, Nat. Rev. Drug Discov., 19, 277-289 (2020). The CTJs are believed to be opened through pores of limited diameter for a short amount of time (i.e., about 30 minutes). This mechanism, in turn, limits a PE’s impact on increasing peptides’ permeability and associated absolute oral bioavailability (%F). Furthermore, it is widely believed that the PE and peptide must be present together in the intestine to provide optimal permeation enhancement.

[0005] Advancements in peptide sustained release (SR) systems for delivery of peptides have been made in the past decade. SR formulations have been prepared by several approaches. SR typically provides for continuous (i.e., uninterrupted) delivery of a peptide to a subject for substantially longer than 60 minutes.

[0006] In view of these observations, there remains a need for SR formulations of macrocyclic peptides that continuously deliver peptide and permeation enhancer throughout the GI tract, thus providing significantly improved oral bioavailability. SUMMARY

[0007] The present disclosure provides oral dosage forms of high molecular weight (MW), poorly permeable peptides and permeation enhancers that provide for sustained co-release into the gastrointestinal tract over several hours. These sustained-release (or extended-release) dosage forms may provide for improved bioavailability, longer duration of therapeutic effect, higher cost-effectiveness, and greater overall therapeutic outcomes following delivery of these peptides. The provided oral dosage forms may be in the form of tablets, capsules or mini tablets. The present disclosure also provides methods and uses for the oral delivery of these improved oral dosage forms of therapeutic peptide. The disclosure provides a significant improvement in enhancing oral peptide absorption using SR formulations.

[0008] This disclosure is based, at least in part, on the observation that up to 2.5-fold improvements in bioavailability was obtained upon dosing of the disclosed compositions of cyclic peptide, permeation enhancer and cellulose-derived polymer(s). In contrast, when the same peptide and PE was formulated with an immediate-release polymer, only a fraction of the sustained release bioavailability was observed. See Brayden et al., Advanced Drug Delivery Reviews (2020), Maher, Geoghegan & Brayden Expert Opinion on Drug Delivery (2021). It has been found that oral bioavailability of poorly permeable peptides and permeation enhancers is surprisingly enhanced by the addition of a cellulose-derived polymer, such as hydroxypropyl methylcellulose (HPMC). HPMC may be formulated with the peptide (or polypeptide) and PE in a dosage form such as a tablet. The SR dosage forms described herein may release peptide and PE for up to, and longer than, 4 hours after administration and may enable a 2-4 fold improvement in bioavailability in non-human primates relative to immediate-release formulations. In some aspects, the SR dosage forms described herein may release peptide and PE for up to, and longer than, 6 hours after administration.

[0009] In view of the limitations on permeation enhancement due to the short time frame for which intestinal CTJs are kept open by PEs, it was hypothesized that a sustained release (SR)solid dosage form containing the peptide agent and a PE might provide an advantage in increasing oral bioavailability. If released concomitantly over a sustained period, the peptide and PE would remain together longer in the GI absorption window, thus providing enhanced bioavailability.

[0010] Without wishing to be bound by theory, the presence of a cellulose-derived polymer provides the disclosed compositions with sustained-release properties, such as providing continuous release of both peptide and PE at 2 hours, 4 hours, and up to 6 hours after administration, and / or a TMAXthat is between 2 and 6 hours, such as between 2 and 4 hours after administration. The peptide and PE are in contact with the small and / or middle intestinal epithelium for an extended window of time as a result. This expands the absorption window for the peptide. As such, the disclosed SR compositions provided prolonged release of the peptide and PE, which 1) overcomes the short half-life of a PE, 2) provides co-delivery of the peptide and PE at the intestinal epithelium, 3) prolongs tight junction openings to enable sustainable absorption of the peptide. This strategy can be applied to a variety of peptides and PEs at low doses and provide better oral bioavailability at a reduced cost of goods.

[0011] The invention may be most suitable for oral formulation of large peptides for which permeability is a limiting factor to effective absorption. For example, this invention may be suitable for cyclic peptides having a molecular weight of at least 1000 g / mol, and / or an apparent permeability (Papp, as measured by Caco-2 cell assay) below 1000 x 10-8cm / s (i.e., 10 x 10-6cm / s) (or simply “1000”). It is generally accepted that compounds with Pappmeasured in this range may as a result have limited oral absorption. This invention may be particularly suitable for cyclic peptides having a Papp of 100 x 10-8cm / s (or simply, “100”). This invention may be further particularly suitable for cyclic peptides having a Papp of 10.0 x 10-8cm / s (or simply, “10.0”). In various embodiments of the disclosed compositions, a cyclic peptide having a molecular weight of greater than 1000 g / mol, and / or an apparent permeability (Papp) below 10.0, and a fatty acid salt or surfactant permeation enhancer is used. In some embodiments, a cyclic peptide having a molecular weight of greater than 1000 g / mol, and / or an apparent permeability (Papp) below 1000, and a fatty acid salt or surfactant permeation enhancer is used.

[0012] Thus, in one aspect, the present disclosure provides compositions comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose-derived polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients. In another aspect, provided herein are compositions comprising: (i) a cyclic peptide having a Papp below 10.0, (ii) a fatty acid salt selected from sodium caprate,docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose-derived polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients. The cyclic peptide may have a molecular weight of at least 1000, 1050, 1100, 1200, 1300, 1400, 1500, 1750, 2000, 2100, 2250, or 2500 g / mol. The cyclic peptide may have a molecular weight greater than 2500 g / mol.

[0013] In another aspect, the present disclosure provides compositions comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, or an apparent permeability (Papp) below 10.0, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose-derived polymer equal to 20% w / w, and (iv) one or more pharmaceutically acceptable excipients. The polymer may be present in 20% w / w, or greater.

[0014] In another aspect, the present disclosure provides compositions comprising: (i) a cyclic peptide having a Papp below 100, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose-derived polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients.

[0015] In some aspects, provided herein are compositions comprising: (i) a cyclic peptide having a Papp below 1000, (ii) sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of at least 25% w / w, and (iv) one or more pharmaceutically acceptable excipients. In particular embodiments, the cyclic peptide has a Papp below 100, or below 10.0.

[0016] In various embodiments, the provided oral compositions are in the form of tablets. In some embodiments, these compositions are capsules. The provided oral compositions may be in the form of mini tablets.

[0017] In another aspect, the present disclosure provides compositions comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, or an apparent permeability (Papp) below 10.0, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose-derived polymer in an amount greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition provides a TMAX of the peptide between 2 and 4 hours of the peptide following oral administration to a mammal. These compositions may provide an absolute oral bioavailability of between 0.6 and 3.0 when administered orally to a mammal. These compositions may further provide an absolute oral bioavailability of between 0.8 and 3.0 when administered orally to a mammal. In some embodiments, the composition provides a TMAXof the peptide that is between 2 and 3 hours following oral administration. For instance, they may provide an oral bioavailability of between 0.8 and 2.0 %F, 0.8 and 3.0 %F, 1.5 and 2.0 %F, 1.5 and 2.5 %F, 1.5 and 3.0 %F, 2.0 and 2.5 %F, or 2.0 and 3.0%F. In some embodiments, the compositions provide an oral bioavailability(%F) between 1.5 and 2.0. In some embodiments, the compositions provide an oral bioavailability (%F) between 2.0 and 2.5. In various embodiments, the mammal is a primate (human or non-human primate). In some embodiments, the mammal is a human.

[0018] In another aspect, provided herein are compositions comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, or an apparent permeability (Papp) below 10.0, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose-derived polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition exhibits a release rate of the fatty acid salt at pH 6.5 of between about 50 mg / h and about 200 mg / h between 2 hours and 4 hours in vitro.

[0019] In another aspect, provided herein are compositions comprising: (i) a cyclic peptide having a Papp below 100, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a hydroxypropyl methylcellulose polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition provides an absolute oral bioavailability of between 1.5 and 2.0 when administered orally to a mammal, such as a human. In various embodiments, the cyclic peptide has a Papp below 10.0.

[0020] In various aspects, the cyclic peptides of the disclosure have a Papp of about 10.0 x 10-6cm / s (i.e., 1000 x 10-8cm / s) or below, as measured by Caco-2 Transwell™ culture assay. In some aspects, the cyclic peptides have a Papp of 5.0 x 10-6cm / s or below, 2.5 x 10-6cm / s or below, or 1.0 x 10-6cm / s or below. In some aspects, the cyclic peptides have a Papp of 100 x 10-8cm / s or below. In some aspects, the cyclic peptides have a Papp of 75.0 x 10-8cm / s or below, 50.0 x 10-8cm / s or below, 35.0 x 10-8cm / s or below, 25.0 x 10-8cm / s, 20.0 x 10-8cm / s or below, or 10.0 x 10-8cm / s or below. In some embodiments, the cyclic peptide may have a Papp of about 10.0 x 10-6cm / s or below. The cyclic peptide may have a Papp of about 5.0 x 10-6cm / s or below, 1.0 x 10-6cm / s or below, or 5.0 x 10-7cm / s or below.

[0021] The cyclic peptide may have a Papp of about 10.0 x 10-8cm / s. The cyclic peptide may have a Papp below 15.0 x 10-8cm / s, below 10.0 x 10-8cm / s, below 5.0 x 10-8cm / s, below 3.0 x 10-8cm / s, or below 1.0 x 10-8cm / s.

[0022] In another aspect, provided herein are compositions comprising: (i) a cyclic peptide having an apparent permeability (Papp) below 100, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a hydroxypropyl methylcellulose polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition provides an improved oral bioavailability of atleast about 2-fold when administered orally to a mammal, relative to a corresponding composition in which a hydroxypropyl methylcellulose polymer is substantially absent (i.e., an immediate-release formulation). In various embodiments, the cyclic peptide has a Papp below 15.0, or below 10.0. In some embodiments, the disclosed compositions and methods provide 2.1- fold, 2.2-fold, 2.3-fold, 2.4-fold or 2.5-fold, increases in bioavailability relative to this corresponding composition.

[0023] In some embodiments, the provided compositions comprise (ii) a fatty acid salt that is sodium caprate. In various embodiments, the compositions comprise between 30% and 40% w / w of sodium caprate. In various embodiments, the compositions comprise at least 30% or at least 35% w / w of sodium caprate, such as about 36% or about 40% w / w of sodium caprate. In various embodiments, the compositions comprise between 35% and 49% w / w of sodium caprate.

[0024] The disclosed compositions comprise (iii) a cellulose-derived polymer in an amount of greater than 20% w / w. Without being bound by any particular theory, the inclusion of this polymer may provide a sustained release profile to the disclosed compositions. The compositions may comprise this polymer in an amount of at least 25% w / w. In various embodiments, the compositions comprise about 25% w / w of this polymer. In some embodiments, the composition comprises the cellulose-derived polymer in an amount of at least 30% w / w. In some embodiments, the composition comprises no greater than about 40% w / w cellulose-derived polymer. In various embodiments, the compositions comprise greater than 20% and no greater than about 40% w / w of cellulose-derived polymer. The cellulose-derived polymer may be a hydroxypropyl methylcellulose (Hypromellose, or HPMC), such as a Hypromellose of a particular grade. In particular embodiments, the polymer is Hypromellose K100 (which may be referred to herein as “Methocel K100”).

[0025] In some embodiments, the polymer is Hypromellose E50 (Methocel E50). In some embodiments, the polymer is Hypromellose E6 (Methocel E6). In some embodiments, the polymer is Hypromellose E15 (Methocel E15). In some embodiments, the polymer comprises Methocel E15 and Methocel K100. In particular embodiments, the polymer comprises Methocel E15, Premium LV and Methocel K100, Premium LVCR.

[0026] In particular embodiments, the composition comprises: (i) about 3% w / w of the peptide, (ii) between about 30% and about 40% w / w of sodium caprate, (iii) about 25% w / w of the cellulose-derived polymer, and (iv) one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the following components: (i) about 7.5% w / w of the peptide, (ii) between about 30% and about 40% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In other embodiments, the composition comprises: (i) about7.5% w / w of the peptide, (ii) between about 30% and about 40% w / w of sodium caprate, and (iii) about 40% w / w of the cellulose-derived polymer. In other embodiments, the composition comprises: (i) about 10% w / w of peptide, (ii) between about 30% and about 40% w / w of sodium caprate, and (iii) about 35% w / w of the cellulose-derived polymer.

[0027] In some aspects, provided are compositions comprising: (i) a cyclic peptide having a molecular weight of at least 1100 g / mol, (ii) sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of at least about 25% (w / w), and (iv) one or more pharmaceutically acceptable excipients. In some aspects, provided are composition comprising: (i) a cyclic peptide having a Papp below 10.0, (ii) sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of at least about 25% (w / w), and (iv) one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises the following components: (i) about 7.5% w / w of the peptide, (ii) about 40% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In some embodiments, the composition comprises the following components: (i) about 3% w / w of the peptide, (ii) about 36% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In some embodiments, the composition comprises the following components: (i) about 5% w / w of the peptide, (ii) about 30% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer.

[0028] These compositions may be in the form of a tablet. Any of the disclosed compositions may be adapted for use in therapy.

[0029] In still another aspect, the present disclosure provides methods of providing sustained release of a cyclic peptide in a mammalian subject comprising: (i) combining the peptide with a polymer comprising sodium caprate, a cellulose-derived polymer (e.g., a hydroxypropyl methylcellulose polymer), and one or more pharmaceutically acceptable excipients into a matrix or multiparticulate composition; (ii) forming a tablet from the composition of (i); and (iii) administering the tablet to the subject, wherein the peptide has a molecular weight of at least 1000 g / mol. In some embodiments, the peptide has a molecular weight above 1100 g / mol. In some aspects, provided are methods of providing sustained release of a cyclic peptide in a mammalian subject, wherein the cyclic peptide has a Papp below 100 (e.g., below 10.0). In some embodiments, the components of (i) are combined into a sustained-release matrix composition. In various embodiments of these methods, the step of administering provides an absolute oral bioavailability (%F) in the mammal of between 0.6 and 2.0, 0.8 and 2.0, 0.8 and 3.0, 1.5 and 2.0, 2.0 and 2.5, 2.0 and 3.0, 1.5 and 2.5, or 1.5 and 3.0. In some embodiments, the step of administering provides an improved oral bioavailability of at least about 2-fold, relative to acorresponding tablet in which a cellulose-derived polymer, or a hydroxypropyl methylcellulose polymer, is substantially absent. In various embodiments, the mammal is a primate (human or non-human primate). In some embodiments, the mammal is a human.

[0030] The present disclosure provides methods of delivery comprising administering any of the disclosed compositions (e.g., tablet compositions) to a subject. In some embodiments, the subject is in need of treatment. In some embodiments, the subject is suffering from hypercholesterolemia.

[0031] The compositions of the present invention are suitable for use as medicaments and therapies. The present disclosure may thus provide for therapeutically effective medicaments and uses for any large and / or poorly permeable cyclic peptide drug.

[0032] The disclosed compositions may exhibit low toxicity, e.g., low to no toxicity in subjects following oral administration. These compositions may be safe and pharmaceutically acceptable. The disclosed compositions may enable usage of lower (e.g., substantially lower) doses of peptide than present orally administered peptide + PE formulations.

[0033] The disclosed compositions may comprise any active peptide ingredient that may be difficult to solubilize in oral formulations or exhibit poor bioavailability in the absence of permeation enhancement.

[0034] The summary of the compositions, methods, and uses described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG.1 shows a plot of octreotide concentration vs. time between intervals 0.25 h and 6 h after administration to rhesus subjects using two SR tablet formulations: (1) 20% HPMC K100:Caprate tablet (120 mg sodium caprate) and (2) 15% HPMC K100 tablet (180 mg sodium caprate). A plot of the concentration vs. time of a sodium caprate tablet formulation of octreotide, in which a cellulose-derived polymer is absent (“IR Caprate”), following administration to rhesus is also shown.

[0036] FIG.2 shows a plot of Cyclic Peptide 1 concentration over time between intervals 0.25 h and 6 h after administration to rhesus in a 25% HPMC K100:Caprate tablet formulation having a mass of 480 mg. A plot of the concentration vs. time of an IR Caprate formulation of Cyclic Peptide 1 (450 mg mass) following administration to rhesus is also shown.

[0037] FIGs.3A and 3B show the in vitro release rates (in mass (mg) per hour) of the sodium caprate and Cyclic Peptide 1 peptide components over 4 hours of (1) a 25% HPMCK100:Caprate Cyclic Peptide 1 tablet (white circles), and (2) a 25% HPMC K15:Caprate Cyclic Peptide 1 tablet (black circles). All tablets contained 40% w / w sodium caprate. FIG.3A shows caprate release over time, and FIG.3B shows Cyclic Peptide 1 release over time.

[0038] FIG.4 is a dot plot showing the absolute bioavailability (%F, 0 to 24 hours) of Cyclic Peptide 1 observed following the administration of (1) 25% HPMC K100:Caprate Cyclic Peptide 1 tablet (squares), (2) 25% HPMC K15:Caprate Cyclic Peptide 1 tablet (triangles), or (3) IR Caprate formulation (circles) to rhesus monkeys.

[0039] FIG.5 is a dot plot showing the absolute bioavailability (%F) of Cyclic Peptide 1 observed following the administration of (1) a single 25% HPMC K100:Caprate tablet (squares), (2) two 25% HPMC K100:Caprate tablets (triangles), or (3) IR Caprate formulation (circles) to rhesus monkeys.

[0040] FIG.6 is a dissolution profile plot that shows superimposed in vitro release rates (% dissolved) of peptide over time from tablets containing Cyclic Peptide 1 over 420 minutes (7 hours) of (1) a tablet containing sodium caprate and 30 mg peptide, wherein HPMC is absent (“IR”), (2) an HPMC E15:Caprate tablet containing 30 mg peptide (lot no. FP319604-T24001), (3) an HPMC K100:Caprate tablet containing 15 mg peptide (lot no. FP319602-T23001), and (4) an HPMC K100:Caprate tablet containing 30 mg peptide (lot no. FP319603-T23001). All tablets contained 36% w / w sodium caprate.

[0041] FIG.7 is a dissolution profile plot that shows superimposed in vitro release rates (% dissolved) of sodium caprate over time from tablets containing Cyclic Peptide 1 over 420 minutes of the four tablet formulations evaluated in FIG.6. DETAILED DESCRIPTION

[0042] The large molecular weight, hydrophilicity, and gastrointestinal (GI) instability of macrocyclic peptide therapeutics mitigate against successful oral administration, and as such the delivery route for these therapeutics is typically parenteral. In contrast, the sustained release (SR) compositions of the disclosure provide for improved bioavailability, longer duration of therapeutic effect, minimized pill burden, and lower costs of manufacture. The disclosed compositions may satisfy a need for SR formulations of macrocyclic peptides that provide continuous delivery of peptide and permeation enhancer and improved bioavailability in the plasma of mammalian subjects. The disclosed SR strategy may provide for enhanced oral macrocyclic peptide bioavailability, as the prolonged release of PE and peptide facilitates improved intestinal absorption of peptide.25738

[0043] The present invention provides pharmaceutical compositions that are effective in providing sustained therapeutically effective plasma concentrations of a therapeutic peptide agent in a subject when administered to the GI tract. In particular, the disclosed compositions and methods resolve the difficult problem of providing sustained therapeutically effective plasma concentrations of large and / or poorly permeable cyclic peptide drugs while also providing high bioavailability of the drug.

[0044] The present disclosure is directed to dosage forms comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, and / or a Papp below 10.0, (ii) a permeation enhancer that is a fatty acid salt, (iii) a cellulose-derived polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients. The fatty acid salt may be selected from selected from sodium caprate, docusate, sodium lauryl sulfate, myristate, and sodium caprylate. In particular embodiments, the fatty acid salt is sodium caprate. The disclosed dosage forms may be in the form of a tablet. The disclosed dosage forms may be in the form of a capsule or a mini-tablet.

[0045] The present disclosure is also directed to methods of providing sustained release of a large and / or poorly permeable cyclic peptide in a mammalian subject comprising: (i) combining the peptide with a polymer comprising sodium caprate, a cellulose-derived polymer (e.g., a hydroxypropyl methylcellulose polymer), and one or more pharmaceutically acceptable excipients into a matrix or multiparticulate composition; (ii) forming a tablet from the composition of (i); and (iii) administering the tablet to the subject. The present disclosure is further directed to methods of oral delivery, and methods of treatment, comprising administering any of the disclosed compositions to a mammalian subject.

[0046] Without being bound to any particular theory, it is understood that the percentage of cellulose-derived polymer and fatty acid salt in the disclosed tablet dosage forms may be modified to vary the degrees of tablet robustness, duration of the release profile, and rate of release of fatty acid salt over time.

[0047] In various embodiments, the presently disclosed compositions (e.g., tablet compositions) and methods provide for improved bioavailability of a therapeutic peptide following administration of the composition. In some embodiments, they provide for improved absolute bioavailability. In some embodiments, they provide for improved bioavailability relative to a reference dosage form, such as an immediate-release form. In some embodiments, they provide for improved bioavailability relative to a corresponding dosage form that lacks a cellulose-derived polymer. Without being bound to any particular theory, it is understood that a longer and slower release profile in vivo, e.g., over 2 to 6 hours, contributes to the increased oral25738 bioavailability of the peptide and PE in these compositions. In some embodiments, the disclosed compositions and methods provide absolute bioavailability (%F) at or greater than about 1.5, 1.6, 1.7, 1.8, 1.9, 1.92, 1.95, 1.98, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, or 5.0. In some embodiments, the disclosed compositions provide absolute bioavailability greater than 5.0 %F. In some embodiments, the disclosed compositions and methods provide increases in bioavailability of about 2.0-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold or 2.5-fold, relative to a corresponding composition in which a hydroxypropyl methylcellulose polymer is substantially absent (or, relative to immediate-release peptide-PE formulations and / or existing peptide-PE formulations). In particular embodiments, the compositions and methods provide about 2.1-fold increases in %F relative to a corresponding composition in which a hydroxypropyl methylcellulose polymer is substantially absent.

[0048] The disclosed compositions and methods may provide for increases in bioavailability of about 2.75-fold, 3.0-fold, 3.25-fold, 3.5-fold, 3.75-fold or 4-fold. The disclosed compositions and methods may provide for increases in bioavailability of about 4-fold, or above 4-fold. The disclosed compositions and methods may provide for increases in bioavailability of about 4.5- fold, 5.0-fold, or above 5.0-fold. In various embodiments, these improved bioavailabilities are achieved in primate subjects (i.e., human or non-human primate). In some embodiments, these improved bioavailabilities are achieved in humans. In the Examples described below, these improved bioavailabilities are achieved in rhesus monkeys. In the Examples described below, these improved bioavailabilities are achieved in rodents, such as rats.

[0049] The disclosed compositions and methods may provide for improved pharmacokinetics of the therapeutic peptide in vivo in a subject. The disclosed compositions are able to provide continuous release of peptide and PE up to 2 hours, up to 4 hours, and / or up to 6 hours after administration. In various embodiments, the presently disclosed compositions provide for a substantially linear release profile in vivo, and / or a substantially linear dissolution profile in vitro.

[0050] As such, these compositions provide slow, or substantially linear, downward-sloping, release rates (concentration vs. time curves) in vivo over a period time following administration to a subject. In some aspects, that period of time starts at a time beyond 60 minutes post- administration and may extend to several hours (e.g., 3, 4, 5, 6, or more than 6 hours) post- administration. In some aspects, this downward-sloping concentration vs. time curve may appear substantially “flat”. In some embodiments, these compositions provide substantially linear release rates over the majority of the time of release (such as between 2 hours and 24 hours post- administration). For example, the presently disclosed compositions may provide a substantially linear release rate over 2 to 3 hours (i.e., between 2 and 3 hours), over 2 to 4 hours, over 3 to 425738 hours, over 4 to 5 hours, over 4 to 6 hours, over 2 to 6 hours, over 2 to 5 hours, over 3 to 5 hours, or over 3 to 6 hours following administration in vivo. They may provide a substantially linear release rate over 1.5 to 3 hours, 1.5 to 4 hours, 1.5 to 5 hours, or 1.5 to 6 hours post- administration. They may provide a substantially linear release rate over 1 to 2 hours, 1 to 3 hours, 1 to 4 hours, 1 to 5 hours, or 1 to 6 hours post-administration. They may provide a substantially linear release rate over 2 hours to 24 hours, 4 hours to 24 hours, 6 hours to 24 hours, 2 hours to 12 hours, 4 hours to 12 hours, 2 hours to 8 hours, 6 hours to 8 hours, or 6 hours to 12 hours.

[0051] In various embodiments, the disclosed compositions and methods provide a delayed or sustained TMAX(time at which maximum plasma concentration (CMAX) in the subject is reached) of the peptide relative to an immediate-release formulation of the peptide. Stated another way, these compositions and methods of delivery provide a longer TMAXof the peptide than existing compositions and methods. In various embodiments, the compositions provide a TMAX of the peptide that is between 2 and 4 hours of the peptide following oral administration to a subject. In some embodiments, the TMAX is between 2 and 3 hours, 2 and 5 hours, 2 and 6 hours, 3 and 6 hours, 4 and 6 hours, or 3 and 5 hours. In some embodiments, the TMAXis about 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours. In exemplary embodiments, the TMAX is about 4 hours. In some embodiments, the subject is mammalian, such as human. These compositions may provide for a CMAX of the peptide that is later in time than those of existing oral dosage forms.

[0052] In some aspects, the disclosed compositions provide a substantially linear (fractional) cumulative absorption of the peptide over time up to 4 hours in vivo. In particular embodiments, this absorption is observed in a human subject. In some embodiments, this absorption is observed in a non-human primate. In some aspects, the compositions provide a substantially linear cumulative absorption of the peptide over time between 2 hours and 4 hours, or between 2 hours and 6 hours, in vivo. In some aspects, the compositions provide a substantially linear cumulative release rate of the peptide over time between 2 hours and 4 hours in vitro. In some aspects, the compositions provide a substantially linear cumulative release rate of the peptide over time between 2 hours and 6 hours in vitro. In some embodiments, the disclosed compositions may reduce the effect of any food intake prior to or with the peptide drug (food effect).

[0053] In some aspects, these compositions provide substantially linear (upward-sloping) release rates (also referred to herein as dissolution rates or dissolution curves) in vitro over a period time following exposure of the composition to dissolution buffer. For example, the presently disclosed compositions may provide a substantially linear dissolution rate (mass released per hour) in vitro over 0 to 4 hours, 1 to 4 hours, 0 to 6 hours, 1 to 6 hours, 2 to 3 hours,25738 over 2 to 4 hours, over 3 to 4 hours, over 4 to 5 hours, over 4 to 4.5 hours, over 4 to 6 hours, over 2 to 6 hours, over 2 to 5 hours, over 3 to 5 hours, over 3 to 6 hours, or over 0 to 7 hours following exposure of the composition to dissolution buffer. They may provide a substantially linear dissolution rate over 1.5 to 3 hours, 1.5 to 4 hours, 1.5 to 5 hours, or 1.5 to 6 hours. They may provide a substantially linear dissolution rate over 1 to 2 hours, 1 to 3 hours, 1 to 4 hours, 1 to 5 hours, or 1 to 6 hours.

[0054] In particular embodiments, the disclosed compositions exhibit a release rate of the fatty acid salt in the composition (e.g., tablet) of between about 50 mg / h and about 200 mg / h (e.g., between 75 mg / h and 175 mg / h, or between 60 mg / h and 100 mg / h) between 0 hours and 4 hours, 1 hour and 4 hours, or 2 hours and 4 hours in vitro following exposure of the tablet to a buffer having a pH of 6.5. In some embodiments, this release rate is between about 75 mg / h and about 200 mg / h. In some embodiments, this release rate is between about 200 mg / h and about 400 mg / h. In some embodiments, this release rate is between about 175 mg / h and about 350 mg / h. In some embodiments, the release rate is between about 50 mg / h and about 75 mg / h. This release rate may reflect a measurement at a particular timepoint, such as through liquid chromatography with tandem mass spectrometry (LC / MS / MS); or it may represent an average rate, e.g., calculated using linear regression among multiple timepoints. In particular embodiments, these compositions exhibit a release of fatty acid salt measured at a particular timepoint such as 2 hours, 3 hours or 4 hours, of between about 50 mg / h and about 175 mg / h. In some embodiments, the compositions provide a substantially linear release rate at a value between about 50 mg / h and about 200 mg / h, or about 75 mg / h and about 175 mg / h, between 2 hours and 4 hours in vitro at pH 6.5.

[0055] The disclosed compositions may exhibit an average release rate of fatty acid salt of between about 50 mg / h and about 175 mg / h between 0 hours and 6 hours, 1 hour and 6 hours, or 2 hours and 6 hours in vivo or in vitro. As such, the disclosed compositions may exhibit an average release rate of fatty acid salt of about 30, 40, 50, 60, 65, 70, 75, 80, 90, 100, 120, 125, 145, 150, 155, 175, 180, 190, 200, 225, 250, 300, 350, or 400 mg / h in vivo or in vitro. In some embodiments, an about 80 mg / h average release rate of fatty acid salt, such as sodium caprate, is exhibited by these compositions over a time period of 2 hours to 4 hours post-exposure to buffer (time 2h ^ 4h), in vivo or in vitro. An average release rate between 60 mg / h and 100 mg / h may be exhibited. An average release rate of 120 mg / h may be exhibited.

[0056] A release rate in vivo or in vitro at 4 hours at a value between about 75 mg / h and about 175 mg / h, such as 78, 79, 80, or 81 mg / h, may be exhibited. In particular embodiments, a rate of 78.66 mg / h is exhibited (see FIG.3A). A release rate at 4 hours at a value between about 17525738 mg / h and about 200 mg / h, such as 180 mg / h, may be exhibited. High release rates of fatty acid salt following the 2-hour mark in vitro indicate that the tablet may provide for increased exposure of permeation enhancer to the intestinal tight junctions following administration in vivo, which prolongs the enhanced permeation of the peptide to epithelial cells.

[0057] In some embodiments, the disclosed compositions exhibit an average release rate of the fatty acid salt in the composition (e.g., tablet) of between about 30 mg / h and 200 mg / h between 0 hours and 4 hours, 1 hour and 4 hours, 0 hours and 6 hours, or 2 hours and 4 hours in vitro following exposure of the tablet to a buffer having a pH of 6.5.

[0058] In some embodiments, the disclosed compositions exhibit a release rate of the peptide of between about 7 mg / h and about 25 mg / h between 0 hours and 4 hours, 1 hour and 4 hours, or 2 hours and 4 hours in vitro following exposure of the composition to a buffer having a pH of 6.5. As such, the disclosed compositions may exhibit an average or measured release rate of peptide of about 7, 7.5, 8, 8.25, 8.5, 8.75, 9, 10, 11, 12, 13, 14, 15, 17.5, 20, 22.5, or 25 mg / h in vitro at pH 6.5. In particular embodiments, the composition exhibits a release rate of 8.1 mg / h at 4 hours post-exposure. The disclosed compositions may exhibit an average release rate of peptide of between about 7 mg / h and about 25 mg / h between 0 hours and 6 hours, 1 hour and 6 hours, or 2 hours and 6 hours in vitro. The disclosed compositions may exhibit an average release rate of peptide of about 6 mg / h between 0 hours and 6 hours, 1 hour and 6 hours, or 2 hours and 6 hours in vitro. The disclosed compositions may exhibit an average release rate of peptide of between about 5 mg / h and about 50 mg / h between 0 hours and 4 hours, 1 hour and 4 hours, 2 hours and 4 hours, 0 hours and 6 hours, 1 hour and 6 hours, or 2 hours and 6 hours in vitro.

[0059] In various embodiments, the disclosed compositions release most (e.g., a majority) of the peptide in formulation in vivo or in vitro over a particular duration. For example, the presently disclosed compositions may provide a release of about 95%, about 92.5%, about 90%, about 85%, about 82.5%, about 80%, about 75%, about 70%, or about 65% of the total peptide in formulation over a duration of 2 to 3 hours, 2 to 4 hours, 3 to 4 hours, 4 to 5 hours, 4 to 6 hours, 2 to 6 hours, 2 to 5 hours, 3 to 5 hours, 3 to 6, or 4 to 6 hours following administration. They may provide a release of about 90-95%, 85-95%, 80-90%, 75-85%, 80-85%, 75-95%, 70-80%, 75- 80%, 70-85%, 65-75%, or 65-85% of the total peptide in formulation over a duration of 2 to 3 hours, 2 to 4 hours, 3 to 4 hours, 4 to 5 hours, 4 to 6 hours, 2 to 6 hours, 2 to 5 hours, 3 to 5 hours, 3 to 6 hours, or 4 to 6 hours. They may provide a release of about 95%, about 92.5%, about 90%, about 85%, about 80%, about 75%, about 70%, or about 65% of the total peptide in formulation over a duration of 1.5 to 3 hours, 1.5 to 4 hours, 1.5 to 5 hours, or 1.5 to 6 hours. In some embodiments, these compositions provide a release of about 95%, about 92.5%, about25738 90%, about 85%, about 80%, about 75%, about 70%, or about 65% of the total peptide in formulation over a duration of 1 to 2 hours, 1 to 3 hours, 1 to 4 hours, 1 to 5 hours, or 1 to 6 hours. In particular embodiments, these compositions provide a release of about 70-80% of the total peptide in formulation over a duration of 1.5 to 4 hours, or 2 to 4 hours.

[0060] In some embodiments, the disclosed compositions provide a release of about 95%, about 92.5%, about 90%, about 85%, about 80%, about 75%, about 70%, or about 65% of the total peptide in formulation over a duration of 2 to 3 hours, 2 to 4 hours, 3 to 4 hours, 4 to 5 hours, 4 to 6 hours, 2 to 6 hours, 2 to 5 hours, 3 to 5 hours, 3 to 6 hours, or 4 to 6 hours, following administration, while further providing absolute bioavailability (%F) at or greater than about 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.25, 5.5, 5.75, or 6.0. In particular embodiments, these compositions may provide a release of about 65-95% of total peptide in formulation over a duration of 2 to 4 hours, 3 to 4 hours, or 2 to 5 hours, while providing a %F of greater than 1.5. In some embodiments, these compositions may provide a release of about 65-95% of total peptide in formulation over a duration of 2 to 4 hours, 3 to 4 hours, or 2 to 5 hours, while providing a %F at or greater than 2.0 or 2.5.

[0061] In exemplary embodiments, these compositions provide a release of about 65-85% of total peptide in formulation over a duration of 0 to 4 hours, or longer. In additional exemplary embodiments, these compositions provide a release of about 65-75% of total peptide in formulation over a duration of 2 to 4 hours, or 2 to 6 hours. In some embodiments, these compositions may provide a release of about 65-75% of total peptide in formulation over a duration of 2 to 4 hours, while providing a %F greater than 1.5. In some embodiments, these compositions may provide a release of about 65-75% of total peptide in formulation over a duration of 2 to 4 hours, while providing a %F at or greater than 2.0 or 2.5.

[0062] In some aspects, the in vitro concentration vs. time curve of peptide and fatty acid salt (permeation enhancer) is substantially synchronous (i.e., is co-released), and thus the maximum concentration in this curve occurs at a time between 2 and 3 hours, 2 and 5 hours, 2 and 6 hours, 3 and 6 hours, 4 and 6 hours, or 3 and 5 hours.

[0063] In various embodiments, the disclosed compositions do not provide an immediate release. As such, they do not provide a release of 90-95%, 85-95%, about 80-90%, 75-85%, 80- 85%, 75-95%, 70-80%, 75-80%, 70-85%, 65-75%, or 65-85% of the total peptide in formulation in less than 1.5 hour, or less than 60 minutes, following administration.

[0064] The disclosed compositions may provide for enhanced solubilization of a peptide and permeation enhancer. For instance, the disclosed compositions may provide for enhanced solubilization of a poorly permeable therapeutic peptide and permeation enhancer in a tablet.25738

[0065] In various embodiments, the disclosed compositions release most (e.g., a majority) of both the peptide and PE in formulation in vivo or in vitro over a particular duration. For example, the presently disclosed compositions may provide a release of about 95%, about 92.5%, about 90%, about 85%, about 80%, about 75%, about 70%, or about 65% of the total amount of peptide and PE in formulation over a duration of 2 to 3 hours, 2 to 4 hours, 3 to 4 hours, 4 to 5 hours, 4 to 6 hours, 2 to 6 hours, 2 to 5 hours, 3 to 5 hours, or 3 to 6 hours following administration. They may provide a release of 90-95%, 85-95%, about 80-90%, 75-85%, 80-85%, 75-95%, 70-80%, 75-80%, 70-85%, 65-75%, or 65-85% of the total peptide and PE in formulation over a duration of 2 to 3 hours, 2 to 4 hours, 3 to 4 hours, 4 to 5 hours, 4 to 6 hours, 2 to 6 hours, 2 to 5 hours, 3 to 5 hours, or 3 to 6 hours.

[0066] In some embodiments, the disclosed compositions and methods provide for localized delivery of a substantial amount of the therapeutic peptide across the intestinal epithelium, such as the small intestinal epithelium and the proximal colon epithelium. The disclosed compositions and methods may provide for localized delivery of a substantial amount of the therapeutic peptide across the middle intestinal epithelium. In some embodiments, the compositions and methods provide for localized synchronous delivery of a substantial amount of therapeutic peptide and a permeation enhancer across the intestinal epithelium, such as the small intestinal epithelium and / or the proximal colon epithelium. Definitions

[0067] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0068] As used herein, the term “cyclic peptide” refers to a peptide molecule that has been cyclized via at least one linkage, such as an amino linkage, a thioether linkage, a macrolactam linkage, or an ester linkage. The term “macrocyclic peptide” refers to a cyclic peptide that has a molecular weight of about 900 g / mol or greater. In some embodiments, the macrocyclic peptides of the disclosure have molecular weights of at least 950 g / mol, 1000 g / mol, 1025 g / mol, 1050 g / mol, 1100 g / mol, or 1150 g / mol. The cyclic peptides of the disclosure may contain 12 or more amino acids. The cyclic peptides of the disclosure may be glycosylated. The cyclic peptides may one or more contain non-canonical amino acids.

[0069] As used herein, “medium length” and “medium chain” refer to an alkyl molecule having a chain of 8 to 14 carbon atoms. For instance, a fatty acid containing 10 carbons is a medium chain fatty acid.25738

[0070] As used herein, the term “permeation enhancer” refers to a pharmaceutically acceptable excipient that improves the absorption of an active ingredient, such as a cyclic peptide, from the GI tract. Several medium chain fatty acids, and salts thereof, are suitable as permeation enhancers for oral delivery. This term further encompasses derivatives of medium chain fatty acids. Examples of permeation enhancers include sodium caprate (C10), sodium caprylate (C8), sodium laurate (C12), docusate sodium, sodium lauryl sulfate, and myristate. Additional examples of permeation enhancers include SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, or salcaprozate sodium), acyl carnitine and Labrasol®. Additional examples include caprate, caprylate, laurate, and docusate as free bases. The permeation enhancers of the disclosure may enhance permeation through the paracellular route, i.e., promoting size-limited passage by prolonging the opening of tight junctions between intestinal epithelial cells. The permeation enhancers of the disclosure may enhance permeation through the intracellular route. In some embodiments, the permeation enhancer sodium caprate (which is also referred to herein as “caprate”) is used.

[0071] As used herein, the term “fatty acid salt” refers to a salt of an aliphatic carboxylate that is saturated or unsaturated (i.e., a fatty acid). This term encompasses the anionic, free basic form of the aliphatic carboxylate, as well as the neutral salt form (i.e., containing a counterion). For example, as used herein, myristate anion and potassium myristate are fatty acid salts. This term also encompasses surfactants and surfactant salts, such as hydrocarbons containing sulfate and / or ester moieties. These include docusate (and docusate sodium) and sodium lauryl sulfate.

[0072] As used herein in reference to a peptide agent, the term “poorly permeable” means resistant to permeability or absorption into the GI tract of a subject, or otherwise resistant to formulation with solubilizing excipients typically used for small molecule active ingredients. A peptide that is poorly permeable may have a molecular weight of at least 1000 or 1100 g / mol. A peptide that is poorly permeable may have an apparent permeability lower than 10.0. A peptide that is poorly permeable may have an apparent permeability lower than 3.0.

[0073] As used herein, the term “bioavailability” refers to the degree to which an active ingredient is absorbed into the plasma of a subject. As used herein, “orally bioavailable” means that the active ingredient (peptide), when taken by mouth (orally), can be absorbed into the plasma. As used herein, the term “absolute oral bioavailability” refers to the degree of plasma absorption following oral administration of a composition containing an active ingredient, relative to that of an intravenous administration of the same dose of the active ingredient. The term “improved oral bioavailability” refers to an increase in this degree. The unit of measurement of absolute oral bioavailability is %F. Those skilled in the art will appreciate that absolute oral25738 bioavailability, may be measured by calculating the areas under the concentration curves, from time 0 to 24 hours (AUC0^24hr) following (1) oral administration of a particular dose to a subject, and (2) intravenous administration of a particular dose to a subject, and relating these AUCvalues and dose valued in accordance with the following equation:^^^ ^^ ^^^ ^^ ^^ ^^ ^^ ^ ^^ ^^ ^^ ^ ^% ^^ ൌ ^ ^^ ^^^ ^^ ^^ ^^^ ^^ ^^ ൈ^ ^^ ^^ ^^ ^^^ ^^ ^^ ^^ ^^ ൈ 100In some embodiments, the above equation but with the AUC valuesfor (AUC)ORALand (AUC)IV. In exemplary embodiments, %F calculation is based on AUC0^24hr. AUC0-24hr (which may be referred to herein as AUC0-last) may be calculated using software such as Phoenix WinNonlin®v6.3 (Certara). For instance, it may be calculated using a linear trapezoidal, non- compartmental module of WinNonlin®v6.3. AUC values are commonly expressed in units of concentration*hours, e.g., µM∙h.

[0074] As used herein, the term “sustained release” refers to a prolonged release of an active ingredient or other substance over time. A prolonged release is typically understood as a release of substance for longer than 60 minutes. This release profile stands in contrast to an immediate release profile, which is typically 60 minutes or less. This term encompasses in vitro release and in vivo release. In some embodiments, this term is used herein to describe the release of cyclic peptide. In some embodiments, this term is used herein to describe the release of cyclic peptide agent and permeation enhancer (e.g., fatty acid salt) together. In some embodiments, the term is used to describe a synchronous release of peptide agent and permeation enhancer (e.g., fatty acid salt. In many instances, the term “extended release” is used synonymously with “sustained release”. In some instances, the term “modified release” is used synonymously with “sustained release”. Sustained release may be measured by assessing the concentrations of peptide agent and permeation enhancer in plasma samples isolated from a subject to whom was administered the agent and permeation enhancer in any of the disclosed compositions.

[0075] As used herein, the term “TMAX” refers to the time at which the maximum plasma concentration following oral administration of a substance to a subject (CMAX) occurs. TMAX is expressed in hours. This term may encompass in vitro release and in vivo release. Those skilled in the art will appreciate that CMAX may be assessed following a measurement of concentration (C) over time, which is performed using any method known in the art following one or more collections of blood from the subject and isolation of plasma. CMAX and TMAX may be calculated using software such as Phoenix WinNonlin®v6.3 (Certara). In some embodiments, “TMAX” is25738 used to describe the release of cyclic peptide. In some embodiments, this term is used to describe the release of cyclic peptide and permeation enhancer (e.g., fatty acid salt) synchronously.

[0076] As used herein, the term “release rate” refers to the mass of a compound released into a dissolution medium over a specified time in vitro. Release rates may be measured in exemplary embodiments by US Pharmacopoeia General Chapter <711> Dissolution (Apparatus II – Rotating Paddles).

[0077] As used herein, the terms “substantially linear cumulative absorption”, “substantially linear fractional cumulative absorption” and “substantially linear cumulative release rate” refers to release profiles of an orally administrable compound, wherein the total (or cumulative) concentration of substance released into solution or plasma from time = 0 rises roughly linearly when measured at a first time t1 to a second time t2. The degree of fractional cumulative absorption may be represented as fraction dose input (expressed as a fraction between 0.0 and 1.0). As used herein, “cumulative absorption” represents the area under the concentration curve in vivo, and “cumulative release rate” refers to release upon dissolution in vitro.

[0078] As used herein, the term “apparent permeability” (Papp) refers to the permeability of a peptide to translocate across an intestinal epithelial cell membrane. Those skilled in the art will appreciate that Papp may be measured using a Transwell™ culture system of the human colonic adenocarcinoma cell line Caco-2 (see, e.g., Pires et al., Pharmaceutics.2021 Oct; 13(10): 1563, which is incorporated herein by reference). The unit of measure for apparent permeability may be 10-8cm / s, or 10-6cm / s. In exemplary embodiments, the unit of measure is 10-8cm / s. The cyclic peptides of the present disclosure have a Papp below 1000 x 10-8cm / s. In some aspects, the cyclic peptides have a Papp of 500 x 10-8cm / s or below, 250 x 10-8cm / s or below, 100 x 10-8cm / s or below, 75.0 x 10-8cm / s or below, 50.0 x 10-8cm / s or below, 35.0 x 10-8cm / s or below, 25.0 x 10-8cm / s or below, or 10.0 x 10-8cm / s or below. In exemplary embodiments, the peptides have a Papp of 100 x 10-8cm / s or below. In further exemplary embodiments, the peptides have a Papp of 10.0 x 10-8cm / s or below. The cyclic peptides of the present disclosure may have a Papp below 10.0 x 10-8cm / s, below 7.5 x 10-8cm / s, below 5.0 x 10-8cm / s, below 3.0 x 10-8cm / s, below 2.0 x 10-8cm / s, or below 1.0 x 10-8cm / s. Papp may be otherwise measured in accordance with any suitable method known in the art, including MDCK II culture system.

[0079] As used herein, “logD” refers to a distribution coefficient that describes the degree by which an ionizable compound, such as a cyclic peptide, tends to partition between a non-polar organic material and a polar aqueous material—i.e., the compound’s lipophilicity. LogD may vary based on the pH of the surrounding environment. As such, logD is typically expressed at physiological pH, or pH 7.4. LogD may be measured using HPLC, LC / MS, a Shake Flask assay,25738 or any other suitable method known in the art. In various embodiments, the peptides of the disclosure have a logD (at pH 7.4) below 2.0.

[0080] A “tablet” is an oral dosage form that comprises a blend of active ingredient and excipients (polymers, disintegrants, bulking agents, etc.) that has been compacted during manufacture. This term encompasses oral compressed tablets and film-coated tablets. In some embodiments, tablets that comprise a blend of peptide agent, permeation enhancer, cellulose- derived polymer, and additional excipients are provided. The tablets of the disclosure may be manufactured by compaction in a tableting press that contains one or more punches and dies.

[0081] As used herein, the term “dose” means a quantity of an agent or pharmaceutical composition administered or recommended to be administered at a particular time.

[0082] As used herein, the term “treating” or “treatment” refers to inhibiting or ameliorating a disease, condition or disorder in a subject who is experiencing or displaying the pathology or symptoms of the disease, condition or disorder. For example, inhibiting a disease, condition, or disorder refers to arresting further development of the pathology and / or symptoms of said disease, condition or disorder. Additionally, ameliorating a disease, condition or disorder, for example, refers to reversing the pathology and / or symptoms, such as decreasing the severity of the disease.

[0083] As used herein, the term “therapeutically effective amount” refers to an amount of the active ingredient (peptide) sufficient to produce the desired therapeutic effect in a human or animal, e.g., the amount necessary to treat, cure, prevent, or inhibit development and progression of a disease or the symptoms thereof and / or the amount necessary to ameliorate symptoms or cause regression of a disease. “Therapeutically effective amount” may vary depending on the structure and potency of the active ingredient and the contemplated mode of administration. One of skill in the art can readily determine a therapeutically effective amount of a given agent.

[0084] As used herein, “subject” refers to an animal, such as a human or a non-human animal to whom an experimental or approved treatment is administered. In various embodiments, the subject is mammalian. “Subjects” may include livestock animals and domestic (companion) animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals. “Subjects” may include experimental animals, such as rodents and non-human primates (NHPs). In some embodiments, the subject is a mouse or rat. In some embodiments, the subject is a primate. In some embodiments, the subject is a rhesus macaque. In some embodiments, the subject is in need of treatment of a disease, disorder, or condition. In some embodiments, the subject is a human. Whether a subject is “in need” of treatment of a disease, disorder, or condition encompasses both a determination of need by a medical professional and a25738 desire of the subject for such treatment. In some embodiments, a subject is suffering from, or is susceptible to, a disease, disorder or condition. In some embodiments, a subject does not display a symptom of a disease, disorder, or condition.

[0085] As used herein, the term “administration” and variants thereof (e.g., “administering”) in reference to the disclosed peptide agent compositions means providing the composition to a subject in need of treatment. As used herein, “orally” and variants thereof (e.g., “oral”) refers to administration via the mouth, i.e., administration of the composition through the mouth.

[0086] As used herein, “% w / w” and “wt%” refer to the weight percent of an ingredient relative to the total weight of the composition.

[0087] As used herein, the terms “enteric polymer” and “enteric coating” refer to a polymer used in oral dosage forms for delayed or intestinal site-specific drug release, that is insoluble in the acidic environment of the stomach but soluble in the less acidic environment of the intestine. These polymers, which are often anionic, prevents disintegration of the dosage form in the acidic environment of the stomach and instead promote rapid release in the intestine. Examples of enteric polymers include hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate phthalate, cellulose acetate succinate, methyl acrylate (methacrylate), ethyl acrylate, polyvinyl acetate phthalate, cellulose acetate succinate, and hydroxypropyl methylcellulose phthalate (HPMCP). In various embodiments, an enteric polymer is substantially absent from the disclosed compositions.

[0088] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in peptide chemistry are those well-known and commonly employed in the art.

[0089] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0090] As used herein, the term “about”, when used to modify a numerically defined parameter (such as a molecular weight or weight percent in a composition) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules).

[0091] All ranges disclosed herein are inclusive of the recited endpoints and independently combinable (for example, the range of “between 2 hours and 4 hours” is inclusive of the endpoints 2 hours and 4 hours, and all intermediate values). The endpoints of the ranges and any25738 values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0092] As used herein, the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also encompassing compositions or methods as “consisting of” the enumerated components, which allows the presence of only the named components or compounds, along with any combinations of pharmaceutical acceptable excipients, and excludes non-enumerated components or compounds. Such description should further be construed as also encompassing compositions or methods that “consist essentially of” the enumerated components. As used herein, “consists essentially of” means that the disclosed compositions may include small amounts (e.g., 5% or less w / w) of other components that do not materially alter the properties of the composition. Therapeutic Peptides

[0093] The disclosed compositions and methods are suitable for formulation with any poorly permeable, high molecular-weight, and / or poorly soluble therapeutic peptide. In some embodiments, the disclosed therapeutic peptides are linear in structure. In some embodiments, the peptides useful in the invention are not linear. In various embodiments, the peptides useful in the invention are cyclic. In some embodiments, the peptides are macrocyclic.

[0094] Macrocyclic peptides have gained significant interest among medicinal chemists because these molecules exhibit biologic-like specificity while boasting the size and biodistribution of many small molecules.

[0095] In various embodiments, the therapeutic peptides of the disclosed compositions have a low apparent permeability (Papp). The therapeutic peptides of the disclosure have a Papp below 1000 (x 10-8cm / s). Exemplary therapeutic peptides of the disclosure may have a Papp of about 10.0 (x 10-8cm / s), or below. In some aspects, the disclosed peptides have a Papp value of about 32, 22, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1.5, 1, 0.9, or 0.75. For example, the peptides of the disclosure may have a Papp below 3.0. In some embodiments, the peptides of the disclosure have a Papp of about 2.5 or 2.75. In some embodiments, the peptides have a Papp of about 1.5. In some embodiments, the peptides have a Papp of about 1.25, 1.0, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.60, 0.50, 0.40, 0.30, 0.20, or 0.10. In some embodiments, the peptides have a Papp of or about 8.5 or 8.6 (e.g., 8.585), or about 9.5 or 9.6 (e.g., 9.568). In some aspects, the peptides have25738 a Papp between 0.10 and 10.0. In some aspects, the peptides have a Papp between 0.10 and 1.0, such as 0.20. In some aspects, the peptides have a Papp between 0.70 and 2.70. In some aspects, the peptides have a Papp between 1.25 and 1.75.

[0096] In various embodiments, the peptides useful in the invention have a high molecular weight. For example, the peptides of the disclosure may have a molecular weight of at least 1000 g / mol (or 1000 Da, or 1 kDa). In some embodiments, the peptides of the disclosure have a molecular weight of at least 1025, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1750, 2000, 2100, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2560, 2600 g / mol, or above 2600 g / mol. The peptides may have a molecular weight of at least 1000 g / mol, 1025 g / mol, 1050 g / mol, 1100 g / mol, 1200 g / mol, 1300 g / mol, 1400 g / mol, 1500 g / mol, 1750 g / mol, 2000 g / mol, 2100 g / mol, 2250 g / mol, or 2500 g / mol. The peptides may have a molecular weight of at least 3000 g / mol, 3500 g / mol, 4000 g / mol, 5000 g / mol, or above 5000 g / mol. In some embodiments, the peptides of the disclosure have a molecular weight of at least 1100 g / mol. In some embodiments, the peptides of the disclosure have a molecular weight of at least 1150 g / mol. In some embodiments, the peptides have a molecular weight of about 1550, about 2000, about 2100, about 2400, or about 2500 g / mol. In some aspects, the peptides have a molecular weight between 1000 and 2500 g / mol, between 1150 and 2100 g / mol, or between 1150 and 2500 g / mol. In some aspects, the peptides have a molecular weight between 1500 and 2500 g / mol, or between 1550 and 2100 g / mol. The cyclic peptides may have a molecular weight between about 1100 g / mol and 2475 g / mol.

[0097] The disclosed cyclic peptides may contain or comprise 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids. In some embodiments, the cyclic peptide comprises 13, 14, or 15 amino acids. In some embodiments, the cyclic peptide consists of 13 amino acids or 14 amino acids.

[0098] The peptides useful in the invention may have a low lipophilicity at physiological pH (e.g., a pH of 7.4). Stated another way, these peptides may have a low hydrophobicity at physiological pH. In some embodiments, the peptides of the disclosure have a logD (at pH 7.4) below 5.0. In some embodiments, the peptides of the disclosure have a logD at pH 7.4 below 4.0, below 3.0, or below 2.0. In some embodiments, the logD at pH 7.4 of these peptides is at about 1.95, 1.85, 1.75, 1.65, 1.60, 1.55, 1.50, 1.40, 1.25, 1.10, 1.05, 1.00, 0.85, 0.75, 0.70, 0.65, 0.60, 0.50, 0.45, or 0.40. In some embodiments, the peptides have a logD of about 1.65, 1.60, 1.55, 1.50, 1.40, 1.25, 1.10, 1.05, or 1.00. In particular embodiments, the peptides have a logD between 0.60 and 1.75, between 0.4 and 1.75, or between 1.00 and 1.75. In particular embodiments, the25738 peptides have logD of about 1.67. In some embodiments, the peptides of the disclosure have a logD at pH 7.0 of about 1.65, 1.60, 1.55, 1.50, 1.40, 1.25, 1.10, 1.05, or 1.00.

[0099] The therapeutic peptides of the disclosed compositions and methods may be highly polar, e.g., may have a high isoelectric point (pI). In some embodiments, the therapeutic peptide of the disclosed compositions has a pI between 3.0 and 9.0. In some embodiments, the therapeutic peptide of the disclosed compositions has a pI between 4.5 and 9.0. In some embodiments, the therapeutic peptide of the disclosed compositions has a pI of 3.2. In some embodiments, the therapeutic peptide of the disclosed compositions has a pI of about 4.5. In some embodiments, the therapeutic peptide of the disclosed compositions has a pI above 3.0. In some embodiments, the therapeutic peptide of the disclosed compositions has a pI of about 5.0, 6.0, 7.0, 7.5, 8.0, 8.25, 8.5, 9.0 or 10.0. The peptide may have a pI of about 8.25 (e.g., 8.29).

[0100] The therapeutic peptides of the disclosed compositions and methods may exhibit poor solubility at pH 6.5. In some embodiments, the peptides useful in the invention exhibit solubilities of about 0.5, 0.75, 0.9, 1.0, 1.1, 1.25, 1.5, 2, 2.5, 3, 4, 5, or 6 mg / mol at pH 6.5. In some embodiments, these peptides exhibit solubilities of about 0.9 or 1.0 mg / mol.

[0101] In some embodiments, the therapeutic peptides of the disclosed compositions are approved for use in human subjects by a health authority, such as the FDA or EMA. In some embodiments, the therapeutic peptides are not approved for use in humans by a health authority. The disclosed therapeutic peptides may have demonstrated safety, absence of toxicity, and / or activity in non-human animal and / or human animal subjects, following an oral administration in the presence or absence of a permeation enhancer.

[0102] In some embodiments, the therapeutic peptides have inhibitory activity against a protein ligand or receptor, such as a membrane-bound receptor. In some embodiments, the disclosed therapeutic peptides are agonists of a protein ligand or receptor. In some embodiments, the peptide exhibits inhibitory activity against Proprotein convertase subtilisin-kexin type 9 (PCSK9), a ligand involved in the mammalian cholesterol metabolic pathway. For example, International Patent Publication No. WO 2019 / 246349, which is incorporated herein by reference, discloses cyclic peptide compounds having inhibitory activity against PCSK9.

[0103] In some embodiments, the therapeutic peptide has the chemical structure provided below. In some embodiments, the therapeutic peptide is the compound of Formula (I). This compound is disclosed in International Publication Nos. WO 2019 / 246349, published December 26, 2019, and WO 2023 / 023245, published February 23, 2023, and Johns et al., Circulation; 147:00 (May 2023), each of which is incorporated herein by reference. Methods of making the compound of Formula (I) are disclosed in WO 2019 / 246349. It has a molecular weight of1550.87 g / mol and a Papp of 9.568 ±1.27. In some aspects, this peptide has a Papp of 8.585 ±1.27. has the chemical structure providedas -37,42-Dicarboxy-1- [(11S,17S,20S,23S,27S,39S,42S,63S,66R)-47-fluoro-20-[(1R)-1-hydroxyethyl]-17-[(4- methoxyphenyl)methyl]-11,63- dimethyl-10,16,19,22,30,40,58,61,64,67,70-undecaoxo-28-oxa- 1,9,15,18,21,24,31,41,51,62,65,68- dodecaazanonacyclo[37.18.11.23,6.124,42.133,37.144,51.011,15.023,27.045,50]triheptac onta- 3,5,33(71),34,36,44(69),45,47,49,72-decaen-66-yl]-12,12-dimethyl-3,16,25,34,39,44-hexaoxo- 6,9,18,21,27,30-hexaoxa-2,12,15,24,33,38,43-heptaazahenhexacontan-12-ium-61-oate. Cyclic Peptide 1 is a lipidated version of Formula (I), in that it consists of Formula (I) covalently attached to a long chain fatty acid. Methods of making Cyclic Peptide 1 are disclosed in International Publication No. WO 2021 / 041770, published March 4, 2021, which is incorporated herein by reference (see Example 34). It has a molecular weight of 2470 g / mol and a Papp of 0.9200. In some embodiments, the therapeutic peptide is a lipidated peptide.Cyclic Peptide 1peptide has the chemical structure provided below as Cyclic Peptide 2. Cyclic Peptide 2 is 6-({[(11S,17S,20S,23S,27S,39S,42S,63S,66R)-47- Fluoro-20-[(1R)-1-hydroxyethyl]-17-[(4-methoxyphenyl)methyl]-11,63-dimethyl- 10,16,19,22,30,40,58,61,64,67,70-undecaoxo-28-oxa-1,9,15,18,21,24,31,41,51,62,65,68- dodecaazanonacyclo[37.18.11.23,6.124,42.133,37.144,51.011,15.023,27.045,50]triheptaconta- 3,5,33(71),34,36,44(69),45,47,49,72-decaen-66-yl]methyl}amino)-N,N,N-trimethyl-2-(2-(3- oxopropoxy)ethoxy)ethan-1-aminium chloride. Methods of making Cyclic Peptide 2 are disclosed in International Publication No. WO 2019 / 246349. Cyclic Peptide 2 has a molecular weight of 1632.4 g / mol. Cyclic Peptide 2

[0106] In some embodiments, the therapeutic peptide has the chemical structure provided below as Cyclic Peptide 4. Methods of making Cyclic Peptide 4 are disclosed in International Publication No. WO 2020 / 009805, published January 9, 2020, which is incorporated herein by reference (see Compound 031).25738 Cyclic Peptide 4therapeutic peptide has the chemical structure provided below as Cyclic Peptide 5. Methods of making Cyclic Peptide 5 are also disclosed in International Publication No. WO 2020 / 009805 (see Compound 014). 5structure provided below as Cyclic Peptide 6. Methods of making Cyclic Peptide 6 are also disclosed in International Publication No. WO 2019 / 246405, published December 26, 2019, which is incorporated herein by reference (see Compound 464).25738 Cyclic Peptide 6poor solubility, poor permeability, and / or a fast release profile when combined with a permeation enhancer. In some embodiments, these peptides exhibit a poor and / or fast release profile in vitro or in vivo.

[0110] It will be appreciated by the skilled artisan that any macrocyclic and / or poorly permeable therapeutic peptide may be used in accordance with the invention.

[0111] In some embodiments, the therapeutic peptide of the disclosed compositions has a molecular weight of about 1550 g / mol (e.g., 1550.87 g / mol). In some embodiments, this therapeutic peptide has a logD of about 1.67 (e.g., has a logD of 1.67). In some embodiments, the therapeutic peptide of the disclosed compositions has a molecular weight of about 2475 g / mol (e.g., 2470 g / mol). In some embodiments, this therapeutic peptide has a logD of about 1.55 (e.g., has a logD of 1.54). In some embodiments, the therapeutic peptide of the disclosed compositions has a molecular weight of about 1625 g / mol (e.g., 1632 g / mol). In some embodiments, this therapeutic peptide has a logD of about 1.6 (e.g., has a logD of 1.61).

[0112] In some embodiments, the therapeutic peptide of the disclosed compositions has a molecular weight of about 2100 g / mol. In some embodiments, the peptide has a logD of about 1.05 (e.g., 1.06). In some embodiments, the peptide has a Papp of about 4.0 (e.g., 3.928).

[0113] In some embodiments, the peptide has a Papp of about 32 (e.g., 31.6).

[0114] In some embodiments, the therapeutic peptide has a molecular weight of about 2045 g / mol (e.g., 2046 g / mol). In some embodiments, the peptide has a Papp of about 0.75 (e.g., 0.729). In some embodiments, the peptide has a logD of about 0.70 (e.g., 0.69). In some embodiments, the peptide is Cyclic Peptide 3, which has a molecular weight of 2046 g / mol, a Papp of 1.394, and a logD of 0.69.25738

[0115] In some embodiments, the therapeutic peptide is octreotide. Octreotide is a cyclic peptide that is a synthetic somatostatin analog (see Kim, Park & Na, Pharmaceuticals 15, 1585 (2022)). It has the formula C49H66N10O10S2, and consists of 8 amino acid residues. It has a molecular weight of 1019 g / mol. It has a permeability (Papp) of 2.67. In some embodiments, the therapeutic peptide is not octreotide.

[0116] In some embodiments, the therapeutic peptide is an insulin analog or a glucagon-like peptide (GLP-1) analog, such as a GLP-1 receptor agonist.

[0117] In some embodiments, the peptide contains one or more non-canonical amino acids. In some embodiments, the peptide contains one or more α,α-disubstituted amino acids.

[0118] The peptides useful in the invention may be formulated in any of the disclosed compositions (e.g., tablet compositions) in amorphous or crystalline form. The peptides may be formulated in free base or salt forms. In some embodiments, the peptides are formulated as crystalline salts.

[0119] The provided tablet compositions may contain any weight percentage of peptide as can be practically formulated in a selected oral dosage form, such as a tablet. In various embodiments, the compositions contain at least a therapeutically effective amount of peptide. The compositions may comprise the peptide in an amount of between 0.01% w / w and 40% w / w. In various embodiments, the compositions comprise the peptide in an amount of between about 1% w / w and about 10% w / w. The compositions may comprise the peptide in an amount of about 0.5% w / w, 1% w / w, 1.5% w / w, 2.5% w / w, 3% w / w, 4% w / w, 5% w / w, 6.5% w / w, 7.5 % w / w, 8.5 % w / w, 10% w / w, 12.5 % w / w, 15% w / w, 17.5 % w / w, 20% w / w, 25 % w / w, 30 % w / w, or 40 % w / w. In some embodiments, the compositions comprise between 5 and 10% w / w, or between 7 and 8% w / w, of peptide. In exemplary embodiments, the compositions comprise about 7.5% w / w of the peptide. In some embodiments, the compositions comprise about 5% w / w of the peptide. In some embodiments, the compositions comprise about 3% w / w of the peptide. In some embodiments, the compositions comprise about 15% w / w of the peptide.

[0120] The provided tablet compositions may comprise about 35, 40, 45, 50, 55, 60, 65, 70, 75, or more than 75 mg of peptide (e.g., 90 mg, 100 mg, or more than 100 mg peptide). The provided tablet compositions may comprise about 45 mg of peptide. Sustained-Release Tablets

[0121] The disclosed compositions (e.g., tablet compositions) comprise one or more permeation enhancers (PEs). These tablet compositions may comprise a PE that is a medium chain fatty acid salt. In some embodiments, the medium chain fatty acid salt is a saturated C8-2025738 alkanoate, such as a caprate. In some embodiments, the PE is a surfactant. In various embodiments, the PE is sodium caprate, docusate (or docusate sodium), sodium lauryl sulfate (SLS), or myristate (or potassium myristate). In some embodiments, the PE is sodium caprate. In some embodiments, the PE is a surfactant salt such as docusate sodium. In some embodiments, the PE is surfactant SLS. In some embodiments, the PE is SNAC.

[0122] In some embodiments, the composition comprises a combination of two or more PEs. In some embodiments, the PE comprises a combination of exactly two PEs. The compositions may comprise a combination of sodium caprate and SNAC. In some embodiments, the composition comprises a combination of two or more medium chain fatty acid salts.

[0123] In some embodiments, the PE is SNAC, Labrasol®, potassium laurate, potassium myristate, potassium caprate, sucrose monolaurate, sodium caprylate, acyl carnitine, Capryol 90, or neusilin. In some embodiments, the PE is Labrasol®.

[0124] Sodium caprate, or sodium decanoate, is the sodium salt of caproic acid, a 10-carbon saturated fatty acid, which can form micelles and liquid crystalline phases in aqueous solution. It is an FDA-approved food additive. Sodium caprate may help the transport of biologically active molecules and may serve to enhance the bioavailability of an API. In addition, sodium caprate is a known intestinal permeation enhancer. Known processes for preparing sodium caprate are described in B. Zacharie, et al., Organic Process Research & Development 2009, 13, 581-83. Additional processes for preparing sodium caprate that has superior powder flow and compression properties relative to commercially available forms of crystalline sodium caprate are disclosed in International Patent Application No. PCT / US2023 / 019026, filed April 19, 2023, which is incorporated herein by reference.

[0125] In some embodiments of the disclosed compositions, the amount of a fatty acid salt permeation enhancer, such as sodium caprate, can range from about 1% w / w to about 49% w / w. In another embodiment, the amount of a permeation enhancer in the pharmaceutical composition is from about 18% w / w to about 49% w / w. In a further embodiment, the amount of a permeation enhancer in the pharmaceutical composition is from about 22% w / w to about 36% w / w. In some embodiments, the amount of permeation enhancer may range from about 22% w / w to about 45% w / w. In some embodiments, the permeation enhancer is present in an amount of about 20%, 25%, 30%, 32.5%, 35%, 36%, 37.5%, 40%, 45%, or 49% w / w. In some embodiments, the permeation enhancer is present in an amount of about 36% w / w. In particular embodiments, sodium caprate is present in the tablet in an amount of 36% w / w. In various embodiments, sodium caprate is present in the disclosed compositions at a concentration of no greater than 50% w / w.25738

[0126] The disclosed tablet compositions may comprise between about 100 mg and 600 mg of a of a fatty acid salt permeation enhancer, such as sodium caprate. In some embodiments, these compositions comprise about 180 mg, about 240 mg, about 360 mg, or about 540 mg of sodium caprate. In some embodiments, the composition comprises one, two, or three tablets comprising 180 mg of sodium caprate each. In some embodiments, the composition comprises one, two, or three tablets comprising 240 mg of sodium caprate each. In some embodiments, the composition comprises one or two tablets comprising 540 mg of sodium caprate together.

[0127] The disclosed compositions comprise a cellulose-derived polymer. This polymer may provide a continuous release of both peptide and PE in vitro and / or in vivo (e.g., in a mammalian subject). In vivo, this polymer may provide a TMAX having a value that is between 2 and 6 hours, and preferably between 2 and 4 hours (most preferably, at about 4 hours), or between 2 and 3 hours and 3 and 4 hours. As such, the inclusion of this polymer may provide a sustained release profile in any of the disclosed compositions of cyclic peptide and fatty acid salt in vitro and / or in vivo. The cellulose-derived polymer constitutes a structure corresponding to a means for providing sustained release of a cyclic peptide and / or fatty acid salt (e.g., sodium caprate, docusate, sodium lauryl sulfate, and myristate) in a mammalian subject in any of the disclosed compositions and methods. For example, the cellulose-derived polymer is a structure to which a means for providing sustained release of a cyclic peptide having a molecular weight of at least 1000 g / mol or a Papp below 10.0, and a fatty acid salt in a mammalian subject corresponds.

[0128] Examples of suitable cellulose-derived polymers are HPMC, methylcellulose, ethylcellulose, propylcellulose, carboxymethyl ethylcellulose, carboxypropyl methylcellulose, and hydroxypropyl ethylcellulose polymers. Additional examples of polymers that may be suitable are microcrystalline cellulose, hydroxypropyl cellulose, butylcellulose, and nanocellulose polymers. In various embodiments, the cellulose-derived polymer is HPMC, or Hypromellose. In some embodiments, Hypromellose manufactured by Dow Chemical may be particularly suitable for the disclosed compositions. In some embodiments, Hypromellose manufactured by Dupont Chemical may be particularly suitable for the disclosed compositions.

[0129] In some embodiments, the cellulose-derived polymer is a Hypromellose of a particular grade, such as Hypromellose E50, Hypromellose E6, Hypromellose K4 (or K4M), Hypromellose K15 (or K15M) or Hypromellose K100 (or K100M). Differing grades of Hypromellose reflect differing viscosities. For instance, Hypromellose K100 exhibits a higher viscosity (as measured in centipoise, or cP) at constant temperature than Hypromellose K15. In addition, Hypromellose K100 has a higher molecular weight (1150 g / mol) than Hypromellose K15 (750 g / mol). In particular embodiments, the polymer is Hypromellose K100. In some embodiments, the polymer25738 is Hypromellose K15. In some embodiments, the polymer is Hypromellose E50 (Methocel E50). In some embodiments, the polymer is Hypromellose E6 (Methocel E6). In some embodiments, a combination of two or more Hypromellose polymers are used, such as Hypromellose E50 and Hypromellose E6. In some embodiments, the polymer is a Hypromellose that has the trade name Methocel™ (Dupont).

[0130] In some embodiments of the disclosed compositions, the amount of a cellulose-derived polymer, such as Hypromellose, can range from about 1% w / w to about 40% w / w. The compositions may comprise the cellulose-derived polymer in an amount of at least 20%, 21, 22, 22.5%, 23, 24, 25, 26, 27, 27.5, 28, 29, or 30% w / w. The compositions may comprise this polymer in an amount greater than 20% w / w. In some embodiments, the composition comprises a cellulose-derived polymer in an amount of at least 25% w / w, or at least 30% w / w. The compositions may comprise a cellulose-derived polymer in an amount between about 20% and about 40% w / w, about 25% and 30% w / w, about 20% and 30% w / w, about 25% and 40% w / w, or about 30% and 40% w / w. In particular embodiments, the compositions comprise a hydroxypropyl methylcellulose (Hypromellose) polymer in an amount between about 25% and about 40% w / w. In particular embodiments, the compositions comprise Hypromellose K100 in an amount between about 25% and about 40% w / w, such as about 40% w / w. The compositions may comprise a cellulose-derived polymer, such as Hypromellose K100 in an amount between about 30% and about 40% w / w, such as about 30% w / w or 35% w / w.

[0131] In particular embodiments, the compositions comprise Hypromellose E50 and / or E6 in an amount between about 25% and about 40% w / w, such as about 40% w / w. The compositions may comprise a cellulose-derived polymer, such as Hypromellose E50 and / or E6 in an amount between about 30% and about 40% w / w, such as about 30% w / w or 35% w / w. The compositions may comprise both Hypromellose E50 and E6.

[0132] The provided tablet compositions may comprise about 100 mg, 120 mg, 140 mg, 150 mg, 160 mg, 180 mg, 200 mg, 220 mg, or 240 mg of cellulose-derived polymer. The provided tablet compositions may comprise about 150 mg of cellulose-derived polymer.

[0133] The disclosed tablet compositions may comprise a w / w ratio of 7.5:40:25 of the peptide, the sodium caprate, and the Hypromellose K100, respectively. They may comprise a w / w ratio of 3:36:25 of the peptide, the sodium caprate, the Hypromellose K100. In other embodiments, they comprise a w / w ratio of 5:30:25 of the peptide, the sodium caprate, the Hypromellose K100. The disclosed tablet compositions may comprise a w / w ratio selected from 7.5:35:25, 10:35:25, 10:40:25, 7.5:35:30, 10:35:30, 3:36:25, 5:30:25, 1.5:36:25, and 10:40:30, of the peptide, the sodium caprate, and the Hypromellose K100, respectively.25738

[0134] In particular embodiments, the composition comprises the following components: (i) about 7.5% w / w of the peptide, wherein the peptide is the compound of Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2, (ii) about 40% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In some embodiments, the composition comprises (i) about 7.5% w / w of the peptide, wherein the peptide is Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2, (ii) about 40% w / w of sodium caprate, and (iii) about 30% w / w of the cellulose-derived polymer. In some embodiments, the composition comprises (i) about 7.5% w / w of the peptide, wherein the peptide is Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2, (ii) about 40% w / w of sodium caprate, and (iii) about 40% w / w of the cellulose-derived polymer.

[0135] In particular embodiments, the composition comprises the following components: (i) about 3% w / w of the peptide, wherein the peptide is the compound of Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2, (ii) about 36% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In some embodiments, the composition comprises (i) about 1.5% w / w of the peptide, wherein the peptide is Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2, (ii) about 30% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In some embodiments, the composition comprises (i) about 3% w / w of the peptide, wherein the peptide is Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2, (ii) about 30% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In some embodiments, the composition comprises (i) about 5% w / w of the peptide, wherein the peptide is Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2, (ii) about 30% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer.

[0136] In some embodiments, the composition comprises the following components: (i) the compound of Formula (I), (ii) about 40% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer (e.g., a hydroxypropyl methylcellulose polymer). The composition may comprise Formula (I) in an amount of about 7.5% or 10% w / w.

[0137] In some embodiments, the composition comprises the following components: (i) the compound of Cyclic Peptide 1, (ii) about 36% w / w of sodium caprate, (iii) about 25% w / w of the cellulose-derived polymer, and (iv) one or more pharmaceutically acceptable excipients. The composition may comprise Cyclic Peptide 1 in an amount of about 1.5%, 3%, 7.5% or 10% w / w. In some aspects, the composition comprises Cyclic Peptide 1 in an amount of about 3%. In some aspects, the composition comprises Cyclic Peptide 1 in an amount of about 1.5%.

[0138] The composition may comprise: (i) about 3% w / w of Formula (I), (ii) between about 36% and 40% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. In particular embodiments, the composition comprises about 36% w / w of sodium caprate.25738

[0139] In other embodiments, the composition may comprise: (i) about 7.5% w / w of Formula (I), (ii) about 35% (e.g., 36%) w / w of sodium caprate, and (iii) about 25% w / w of the cellulose- derived polymer. The composition may comprise: (i) about 3% w / w of Formula (I), (ii) 35% or 36% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. The composition may comprise: (i) about 1.5% w / w of Formula (I), (ii) 35% or 36% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. The composition may comprise: (i) about 5% w / w of Formula (I), (ii) about 30% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer. The composition may comprise: (i) about 7.5% w / w of Formula (I), (ii) about 35% w / w of sodium caprate, and (iii) about 30% w / w of the cellulose- derived polymer. The composition may comprise: (i) about 7.5% w / w of Formula (I), (ii) about 40% w / w of sodium caprate, and (iii) about 30% w / w of the cellulose-derived polymer. The composition may comprise: (i) about 10% w / w of Formula (I), (ii) about 40% w / w of sodium caprate, and (iii) about 30% w / w of the cellulose-derived polymer. The composition may comprise: (i) about 10% w / w of Formula (I), (ii) about 40% w / w of sodium caprate, and (iii) about 35% w / w of the cellulose-derived polymer. The composition may comprise: (i) about 10% w / w of Formula (I), (ii) about 35% w / w of sodium caprate, and (iii) about 30% w / w of the cellulose-derived polymer.

[0140] The forms of the present disclosure may be formulated and administered in solid dosage forms, such as tablets, mini tablets, pills, capsules, powders, or granules, which are intended for oral administration. Oral dosage forms may be manufactured by standard methods, including wet and dry granulation. In various embodiments, the dosage form is an oral compressed tablet. Formulation of the compositions according to the disclosure can conveniently be by methods known from the art, for example, as described in Remington’s Pharmaceutical Sciences, 18th ed., 1990, and Remington: The Science and Practice of Pharmacy, 22nd ed., 2012.

[0141] The dosage forms described herein may be formulated as the active pharmaceutical ingredient and may be administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as “excipients”) suitably selected with respect to the intended form of administration and consistent with conventional pharmaceutical practices, that is, oral tablets, oral capsules, oral suspensions, or oral formulations.

[0142] For instance, for oral administration in the form of a tablet, the tablet comprises one or more oral, non-toxic, pharmaceutically acceptable excipients (such as lactose, starch, sucrose, glucose, magnesium (Mg) stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like). In some embodiments, the disclosed tablets comprise lactose. In some embodiments, the tablets comprise an excipient selected from microcrystalline cellulose, mannitol, starch,25738 dicalcium phosphate, calcium carbonate, sodium carbonate, lactose, casein, caseinate, albumin, gelatin, acacia, mesoporous silica, colloidal silica (or colloidal silicon dioxide), or combinations thereof.

[0143] In some embodiments, the disclosed compositions comprise a diluent selected from a polyethylene glycol (e.g., PEG300), macrogol (PEG4000)), mannitol, lactose, or combinations thereof. In some embodiments, the disclosed compositions comprise a disintegrant excipient. The disintegrant may be selected from croscarmellose sodium, crospovidone, or sodium starch glycolate. In some embodiments, the disintegrant is magnesium stearate. In a further embodiment, the disintegrant is croscarmellose sodium. In some embodiments, the disclosed compositions comprise a glidant selected from silicon dioxide, starch, talc, magnesium stearate, or tricalcium phosphate. In some embodiments, the compositions comprise colloidal silicon dioxide. In some embodiments, the disclosed compositions comprise a lubricant selected from magnesium stearate or sodium stearyl fumarate, or both. The disclosed compositions may comprise a solubilizing agent selected from propylene glycol, polysorbate 80, sorbitol, cremophor EL, castor oil, corn oil, cottonseed oil, safflower oil, sesame oil, soybean oil, peppermint oil, olive oil, miglyol, glycerin, or combinations thereof.

[0144] Additional pharmaceutically acceptable excipients that may be included as appropriate include one or more tableting agents, bulking agents, osmotic agents, tonicity enhancing agents, flavoring agents, chelating agents, sugars, surfactants, polyols, stabilizers, emulsifiers, salts, fillers, and preservatives. In some embodiments, a microcrystalline cellulose polymer, such as Avicel® (e.g., Avicel® PH101 and PH102), may be included. The disclosed pharmaceutical compositions may be non-toxic to recipients at the dosages and concentrations employed.

[0145] In some embodiments, the disclosed tablets comprise multiparticulates. In some embodiments, the disclosed tablets comprise a matrix. In some embodiments, the disclosed tablets do not contain nanoparticulates.

[0146] It will be appreciated that the disclosed tablet compositions are suitable for treatment of any of various diseases, disorders, or conditions. In some aspects, the disclosed tablets are suitable for treatment of a cardiovascular disease. In some aspects, the disclosed tablets are suitable for treatment of atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular disease and cardiometabolic conditions in an animal or human subject. For example, the disclosed tablets may be used to treat hypercholesterolemia.

[0147] Accordingly, methods of treatment are also provided. In some aspects, the method is for treatment of a cardiovascular disease. In some aspects, the method is for treatment of25738 atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, and related cardiovascular disease and cardiometabolic conditions in an animal or human subject. Methods of treatment of hypercholesterolemia are provided.

[0148] It will be appreciated that the disclosed tablets may be administered to a subject according to any dosage schedule or regimen. In some embodiments, one or more tablets (such as two tablets) are administered to the subject simultaneously or sequentially. In particular embodiments, two tablets are administered to the subject simultaneously. In particular embodiments, two tablets are administered to the subject sequentially. The use of two tablets provided high release rates of permeation enhancer. For instance, the use of two tablets released 480 mg of sodium caprate over 4 hours (an average rate of 120 mg / h) and achieved bioavailability of about 2.0 %F (see FIG.5). Each of these tablets may have masses of 600 mg or greater.

[0149] In some embodiments, the disclosed compositions comprise a capsule dosage form. In some embodiments, the disclosed compositions do not contain a capsule dosage form. The disclosed compositions may not contain an enteric polymer or enteric coating. The disclosed compositions may not contain a Eudragit® polymer. The disclosed compositions may not contain a Eudragit® L, Eudragit® S, Eudragit® RL, or Eudragit® RS polymer. The disclosed compositions may not contain an HPMC capsule. For instance, the disclosed compositions may not contain an HPMC QualiV® or Vcaps® Enteric capsule. In some embodiments, the disclosed compositions do not contain a metal salt or complex.

[0150] In some embodiments, the disclosed compositions do not contain an octreotide peptide. In some embodiments, the disclosed compositions do not contain a somatostatin analog. In some embodiments, the disclosed compositions do not contain a linear peptide.

[0151] In some embodiments, the disclosed compositions do not comprise an immediate- release polymer. In some embodiments, the disclosed compositions do not comprise a delayed- release polymer, a rate-controlling polymer, a controlled-release polymer, a mucoadhesive polymer, or a mucoadhesive coating. In various embodiments, the disclosed compositions and methods do not contain a polymer adapted for delayed-release formulations. The disclosed compositions may not contain a polymer adapted for stabilization of cyclic peptides. In some embodiments, the disclosed compositions do not comprise HPMCAS or HPMCP. In some embodiments, the disclosed compositions do not comprise a polymer sub-coating or seal coating. In some aspects, the disclosed oral dosage forms may not be film-coated tablets.

[0152] In some embodiments, the disclosed compositions and methods are not intended for treatment of local GI diseases, such as IBD and Crohn’s Disease. In some embodiments, the25738 disclosed compositions are not intended for targeted delivery to the GI tract (i.e., delivery to the GI organs), such as delivery to the colon. General Procedures

[0153] The pharmaceutical compositions of the present disclosure may be prepared in a manner by means of mixing, blending, tableting, and dissolving.

[0154] In some aspects of this preparation, a method of generating the disclosed tablets contains the following steps: (1) A fatty acid salt permeation enhancer (e.g., sodium caprate) is added to a suitable vessel. (2) Deionized water or phosphate buffer (PBS) is added to the vessel and stirring is initiated, visually confirming complete dissolution of the fatty acid salt. (3) The pH of the well-mixed fatty acid salt solution is adjusted to pH 8.0-9.0 for solubilization. (4) The peptide is added and fully dissolved by gently stirring.

[0155] In particular embodiments, the steps involved in the preparation comprise: (1) The following ingredients are combined (in any order) in an amber bottle: cyclic peptide, sodium caprate, cellulose-derived polymer Hypromellose K100 or K15 (Dow), Avicel, lactose, and colloidal silica. (2) These combined materials were blended on a Turbula®powder blender mixer, e.g., for 10 min at 46 revolutions per minute (revs / min). (3) Magnesium stearate is added to the mixture and blended on Turbula®, e.g., for 3 min at 46 revs / min, until a powder is formed. (4) 600 mg of this powder is weighed and filled into a compaction simulator die manually. (5) In the compaction simulator, a sequence(s) is arranged and completed to conduct load control compression, adjusted to 100 mPa. Abbreviations: AbbreviationIV Intravenous h hours i i

[0156] The following examples are meant to be illustrative and should not be construed as further limiting. These examples are given solely for the purpose of illustration and are not intended to be construed as limitations of the present invention as many variations thereof are possible without departing from the spirit and scope of the invention. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference. Example 1

[0157] A first objective was to compare the bioavailability in rat of compositions comprising octreotide and permeation enhancers (e.g., sodium caprate) using rat intraduodenual (ID) bolus and infusion administration to mimic immediate release and sustained release formulations, respectively, to evaluate whether the sustained release of peptide and permeation enhancer increased peptide oral bioavailability. Methods

[0158] Formulations containing solutions of octreotide (Novartis) and the PE sodium caprate were generated. The composition of PE in the formulations is shown in Table 1. Each formulation has a peptide concentration of 4 mg / ml. Table 1. Rat ID Dosing Octreotide Formulation Composition (liquid) Formulation Composition

[0159] The formulations in Table 1 were prepared as follows: 3.0 g or 0.975 g of sodium caprate was added to a 20 mL flask.10 mL of deionized water was added and stirred until fully dissolved. Octreotide was added to the sodium caprate solution (4mg / ml) and stirred until fully dissolved. Animals, Dosing, and Blood Sampling

[0160] The pharmacokinetic studies were performed in fasted male Wistar rats (of 250-450 g weight) (n = 3 for each formulation). The intraduodenual bolus studies were performed by dosingthe formulation in an amount of 2.5 ml / kg weight of subject. For ID infusion studies, the dosing solution was instilled into the duodenum with 0.25 mg / ml of sodium caprate at 0.1 ml / min over 60 min. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 7, 12, 18, 24 h post ID dosing.

[0161] A solution for IV administration (0.5 mg / kg octreotide, 1 mg / ml in saline) was administered to rats with a dose of 0.5 ml / kg in the same rat in one dosing group (n=3). An ID bolus dosing of octreotide in PBS (caprate-absent) was used as a negative control. Blood samples were collected at the intervals 0, 0.03, 0.13, 0.25, 0.5, 12, 4, 7, 12, 18, 24 h post-IV dosing. Preparation and Analysis of Plasma Samples

[0162] Blood samples from the rats were collected and immediately centrifuged, and plasma was collected and stored at -20 ºC until LC / MS / MS analysis.

[0163] The plasma was analyzed for octreotide concentration using LC / MS / MS. All peptide stocks were prepared in DMSO at 10 mM. Standards and quality controls were prepared by using an HP D300 Digital Dispenser (HP, Palo Alto, CA). Plasma proteins were precipitated by adding acetonitrile (ACN) at 1:4 v / v ratio. Supernatant obtained from centrifugation (at 3645 x g) of precipitated plasma samples were directly injected for LC / MS / MS analysis.

[0164] Liquid chromatography analysis was carried out on a Waters Acquity i-class UPLC system (equipped with Waters i-class Binary Pumps and a Waters SM-FTN autosampler refrigerated at 10°C during analysis. Chromatographic separation was performed on a Waters Acquity HSS T3 (2.1 mm x 50mm, 1.8 μm) C18 column maintained at 40ºC with an injection volume of 10 μL. The mobile phase consisting of a solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile) was delivered at a flow rate of 750 μL / min. The LC gradient started from 95 / 5 % (A / B) and changed to 5 / 95% (A / B) from 0.25 to 1.75 min (ramp) and maintained at this ratio for 0.42 min (step). The gradient was decreased to 95 / 5% (A / B) at 2.17 min (step) maintained at this ratio for 1.0 min. Detection was carried out using a triple quadrupole tandem mass spectrometer (API4500, AB Sciex; Foster City, CA) equipped with an electrospray interface (ESI). Ions were created in the positive ion mode setting the sprayer voltage at 5.0 kV and the ion source temperature at 500°C. The common parameters and the nitrogen flow values for nebulizer gas (Gas 1), auxiliary gas (Gas 2), curtain gas and the gas for collision-activated dissociation (CAD) were set at 50, 60, 40, and 8, respectively. The Analyst 1.7.1 software (AB Sciex) was used to control the MS-MS system and MultiQuant 3.0.3 for data analyses. Detection of the cyclic peptides was performed in the multiple reaction-monitoring mode.

[0165] Pharmacokinetic parameters were obtained using non-compartmental methods (Watson LIMS® version 7.6.1). The areas under the plasma concentration-time curve (AUC0-t) were25738 calculated from the first time point (0 min) up to the last time point with measurable peptide concentration using the linear / log-linear trapezoidal rule. The remaining area under the plasma concentration-time curve (AUC0-∞) was estimated by dividing the observed concentration at the last time point by the elimination rate constant. This value was added to AUC0-t to estimate the AUC0-∞. The maximum plasma concentration (CMAX) and the time at which maximum concentration occurred (TMAX) were obtained by inspection of the plasma concentration-time data. The percent absolute bioavailability (%F) was calculated as per the below equation: The absolute bioavailability (i.e., relative to a corresponding intravenous dose of octreotide) was calculated from the areas under the curve of plots of plasma concentration of peptide as afunction of time.%^^ ൌ^ ^^ ^^ ^^^ ^^ ^^ ^ ^^ ^^ ^^ ^^^ ^^ ^^^^^ ^^ ^^^ ^^ ^^ ൈ^ ^^ ^^ ^^ ^^^ ^^ ^^ ൈ 100Results

[0166] In the absence of sodium caprate, the absolute bioavailability of octreotide was 0.082%. The rat ID bolus dosing with sodium caprate increased the plasma bioavailability to 2.64%, as shown in Table 2. But a dramatically more significant improvement in bioavailability was observed with rat ID infusion dosing. A 1 hour ID infusion provided a roughly 170-fold increase in bioavailability relative to the caprate-absent control, to 14.02%. Table 2. Pharmacokinetic parameters for octreotide / sodium caprate ID bolus and infusion dosing. Formulation Dosing TMAX(h) CMAX(uM) AUC0-lastAUC0-∞F(%) (uM∙hr) (uM∙hr) 5Example 2: Octreotide and Cyclic Peptide 1 oral formulation pharmacokinetics

[0167] A second objective was to evaluate the bioavailability in rhesus monkey subjects of compositions comprising macrocyclic peptides, such as octreotide and Cyclic Peptide 1, in a sustained release tablet formulation, in accordance with the disclosure.

[0168] All excipients listed in Table 3, except magnesium stearate, were weighed and added into an amber bottle. Materials were blended on a Turbula®mixer for 10 min at 46 revs / min. Magnesium stearate was blended on Turbula®for 3 mins at 46 revs / min. P-17030-B tool and instrumented die were installed. The compaction simulator was warmed and the LVDT was zeroed using an 8mm gauge.600 mg of this powder was weighed and filled into a compaction25738 simulator die manually. A simulator sequence to conduct load control compression to 100 mPa was completed. Table 3. Octreotide SR tablet Formulation Composition Tablet Composition expressed as per tablet (“ / tab”) A B edpolymer is absent, was prepared as a negative control.3.2 g of sodium caprate was added to a 250 ml vessel, and then 200 ml of 50 mM phosphate buffer at pH 7 was added. Stirring was initiated and mixed until fully dissolved.180 mg of octreotide was added to a different 250 ml vessel, and then 180 ml of this dissolved sodium caprate solution (16mg / ml) was added to the vessel and stirred until fully dissolved. Methods Animals, Dosing, and Blood Sampling

[0170] Pharmacokinetic studies were performed in fasted male rhesus (8-10 kg) (n = 3 for each formulation). An IV bolus of 3 mg / kg peptide was administered into the right cephalic vein of each rhesus subject with a 23-gauge needle attached to a 3 mL syringe. Serial blood samples (1 ml / sample) were collected with 3 mL syringes and 23-gauge needles by venipuncture of the left cephalic vein. Blood samples were collected prior to administration of tramadol to the subjects at the intervals 0.25, 0.5, 1, 2, 4, 6, and 24 h after tablet administration.

[0171] Tablet formulations A and B were administered orally at a dose of 5 mg / kg by oral gavage. The sodium caprate solution formulation was administrated at a volume of 5 mL / kg. The blood samples were collected with a catheter implanted in the iliac artery (via vascular access port) for blood sampling. At any time, if the vascular access port was not patent, then the blood samples were collected from either the femoral or saphenous vein. Blood samples were collected prior to tramadol administration and 0.25, 0.5, 1, 2, 4, 6, and 24 h after tablet administration.25738 Preparation of Plasma

[0172] Blood samples were collected from the subjects and immediately centrifuged, and plasma was collected and stored at -20 ºC, until an LC / MS / MS analysis procedure as described in Example 1 was performed. Results

[0173] Table 4 shows the absolute bioavailability of octreotide from a single dosing of the SR tablet formulations in Table 3 relative to an immediate-release (“IR”) sodium caprate formulation of octreotide in which no Hypromellose polymer was present, which is referred to herein as the “IR Caprate Solution” formulation. Figure 1 shows the PK plot of octreotide concentration over time between intervals 0.25 h and 6 h after administration.

[0174] These results show that the bioavailability of octreotide was significantly improved following administration of the tablet containing 20% Hypromellose compared to the IR Caprate Solution formulation. Although the subject was dosed with 80 mg / kg of caprate from the IR Caprate Solution, which represents a much higher amount than the 12 mg / kg of caprate dosed in in the 20% K100 SR tablet formulation, the SR tablet formulation provided increased octreotide absorption. In other words, the SR tablet provided greater peptide absorption despite the substantially lower dose of permeation enhancer. Specifically, a roughly 2-fold improvement in bioavailability from 0.43 to 0.842 %F was observed. A shift in TMAXfrom 2 hours to 4 hours was observed in the 20% Hypromellose K100 tablet relative to the IR Caprate formulation. The plot of octreotide plasma concentration following administration of the 20% K100 tablet was substantially flat between 2 hours and 6 hours, indicating a substantially linear release rate over 2 to 6 hours.

[0175] Therefore, SR Tablet A, which released 120 mg sodium caprate over approximately 4 hours (i.e., an average rate of 30 mg / h), provided a substantially improved oral absorption relative to The IR Caprate Solution. It is notable that the amounts (% w / w) of Hypromellose K100 and sodium caprate in the SR Tablets appeared to be critical to improving tablet robustness, release profile, and the rate of release of PE, to achieve a desired bioavailability enhancement. Table 4. Rhesus pharmacokinetic parameters for oral dosing SR tablet and caprate solution Formulation TMAXCMAX(µM) AUC0-lastF(%)25738 Example 3: Cyclic Peptide 1: K100 and Cyclic Peptide 1:K15 oral formulation pharmacokinetics

[0176] A third objective was to evaluate the sustained release strategy for Cyclic Peptide 1 in rhesus monkeys.

[0177] To prepare the IR Caprate formulation, 18 g of sodium caprate was added to a 250 ml vessel, then 200 ml of 50 mM phosphate buffer pH 7 was added and stirring was initiated and mixed until fully dissolved.180 mg of Cyclic Peptide 1 was added to a 250 ml vessel, 180 ml of sodium caprate (90 mg / ml) was added and stirred until fully dissolved.

[0178] All excipients listed in Table 5, except magnesium stearate, were weighed and added into an amber bottle. Materials were blended on Turbula as described in Example 2. The tablets were generated and compression-tested as in Example 2. The weights of Tablet C and Tablet D was about 600 mg each. Table 5. Exemplary Cyclic Peptide 1 SR tablet Formulation Composition Tablet Composition expressed as per tablet (“ / tab”) C D: HPMC K100 and K15. As the amount of sodium caprate in each SR tablet formulation was the same (40% w / w), the amount of sodium caprate (“Caprate”) release per time in the local gastrointestinal area was expected to differ between the two tablets. The K100 tablet was hypothesized to exhibit a lower release rate of sodium caprate while exhibiting a longer duration of release. Comparing the performance of the K100 and K15 SR tablets may thus facilitate the understanding the desired release rate and duration to achieve improved bioavailability. Tablets containing (1) 25% HPMC K100:Caprate Cyclic Peptide 1, and (2) 25% HPMC K15:Caprate Cyclic Peptide 1 were exposed to buffer at pH 6.5 for at least 4 hours. Concentrations of the25738 caprate and Cyclic Peptide 1 peptide components were sampled at intervals 0.5, 1, 2 and 4 h following exposure.

[0180] Figures 3A and 3B show the in vitro release characterizations of the sodium caprate and peptide components over 4 hours within these tablets. Release of caprate and peptide at particular timepoints was measured using LC / MS / MS. The in vitro dissolution profiles of the K100 and K15 SR tablets reflect that the K100 SR tablets provide sustained release for at least 4 hours (TMAX ≥4h), and the K15 SR tablets provide sustained release for at least 2 hours (TMAX ≥2h), for Cyclic Peptide 1 and caprate. These values are consistent with the TMAXvalues reflected in Figure 2. The average release rates of sodium caprate (FIG.3A) and Cyclic Peptide 1 (FIG.3B) from the K100 and K15 tablets are indicated. For example, the amount of sodium caprate released from 0 h to 4h from the K100 tablet was 240 mg. At the 4-hour time point, the measured release rate of caprate was 78.66 mg / h. The average amount (or concentration) of Cyclic Peptide 1 released from 0 h to 4h from the K100 tablet was 45 mg. At the 4-hour time point, the release rate of Cyclic Peptide 1 was 19.98 mg / h. It should be noted that since the peptide concentration was near the limit of detection, considerable variability in the peptide sustained release dissolution rate was observed.

[0181] As another example, at the 2-hour time point, the measured release rate from the K100 tablet of caprate was 154.8 mg / h, and of Cyclic Peptide 1 was 48.87 mg / h.

[0182] The high measured release rates of sodium caprate in vitro (e.g., 78.66 mg / h) indicate that the K100 tablet may provide for substantially increased exposure of permeation enhancer to the intestinal tight junctions following administration in vivo.

[0183] Next, these tablets were evaluated in vivo. Rhesus subjects were administered (1) 25% HPMC K100:Caprate Cyclic Peptide 1, (2) 25% HPMC K15:Caprate Cyclic Peptide 1, or (3) IR Caprate formulation of Cyclic Peptide 1, and absolute bioavailability of Cyclic Peptide 1 was measured. About 9 rhesus subjects received IR Caprate formulation, while about 3 subjects received each type of SR tablet. As shown in Figure 4, the highest bioavailability (about 1.0) was observed following administration of the K100 SR tablet. Only about 0.4 %F was observed in most subjects receiving the IR Caprate formulation of Cyclic Peptide 1.

[0184] Read together, the results shown in Figures 1 to 4 indicate that the sustained release strategy of HPMC K100 tablets is reproduced across macrocyclic peptides Cyclic Peptide 1 and octreotide, relative to the IR formulation, exhibiting about 20% oral bioavailability improvement. It appears that a longer duration of release of peptide and PE together favors peptide absorption by the intestinal epithelia.25738

[0185] Next, the HPMC K100 SR tablets strategy was optimized. It was evaluated whether increasing the amount of sodium caprate released from the tablet improves peptide absorption. To that end, two Cyclic Peptide 1:K100 tablets were administered to rhesus subjects.

[0186] As shown in Figure 5, a greater than 2-fold improvement of bioavailability was observed in administering two tablets (triangles) relative to a single tablet (squares). A single tablet provided 240 mg of sodium caprate, while two tablets provided 480 mg of sodium caprate (which amounted to 5 mg / kg subject). Specifically, a bioavailability of about 2.0 %F was achieved. The results in Figure 5 indicate that enhanced oral bioavailability may be achieved by optimizing the amount (mass) and duration of sodium caprate release. Example 4: Cyclic Peptide 3 SR oral formulation / solid dosage form

[0187] Representative SR oral solid dosage forms (formulations) were prepared for Cyclic Peptide 3 and are exemplified in Table 6.

[0188] All excipients listed in Table 6, except magnesium stearate, were weighed and added into an amber bottle. Materials were blended on Turbula as described in Example 2. Six tablet formulations were generated and compression-tested as in Example 2: Formulations Z, AA, AB, AC, AD, and AE. The weights of these tablets were 1200 mg each. These tablets were prepared using HPMC (Methocel) E50 and E6 polymers. Each of these tablet formulations contains 25% w / w total of Methocel E50 and E6 polymers. The nominal viscosities (in centipoise) of all formulations are indicated at bottom. Table 6. Cyclic Peptide 3 SR tablet Formulation Compositions Formulation Z Formulation AA Formulation AB it25738 Formulation Z Formulation AA Formulation AB ittExample 5: Cyclic Peptide 1 SR oral formulation / solid dosage form

[0189] Additional exemplary SR oral solid dosage forms (formulations) were prepared for Cyclic Peptide 1 (“CP 1”), as exemplified in Table 7, below. The dissolution profiles of these formulations were evaluated.

[0190] All excipients listed in Table 7, except magnesium stearate, were weighed and added into an amber bottle. Materials were blended on Turbula, and three tablet formulations were generated and compression-tested in the manner described above: Formulations 1) 30mg CP1 SR 4h, 2) 15mg CP1 SR 4h, and 3) 30mg CP1 SR 2h. The suffixes “4h” and “2h” in the names of the formulations refer to the targeted time at which roughly 80% of peptide has been dissolved. Lot numbers of the formulations are provided below these names in Table 7.

[0191] The weights of these tablets were 1000 mg each. Each of these tablet formulations contained 36% w / w sodium caprate and 25% w / w total of HPMC polymers.25738 Table 7. Exemplary Cyclic Peptide 1 SR tablet Formulation Compositions 30mg CP1 SR, 4h 15mg CP1 SR, 4h 30mg CP1 SR, 2h FP319603-T23001 FP319602-T23001 FP319604-T24001 t d anIR Caprate Solution tablet containing 30 mg Cyclic Peptide 1 and 36% w / w sodium caprate was assessed, over a period of 7 hours. Dissolution was performed using a medium of 25 mM Phosphate Buffer, pH 6.8, and the following dissolution parameters: Vessel size: 1000 mL Medium Volume: 500 mL Medium Temperature: 37°C ± 0.5°C Rotation Speed: 75 rpm Sinker: Japanese Pharmacopeia (JP) Sinker Basket Filter: 10 μm full flow cannula filters

[0193] Dissolution was performed according to US Pharmacopoeia General Chapter <711> Dissolution (Apparatus II – Rotating Paddles).500 mL of dissolution medium was transferred to each vessel and allowed to equilibrate to 37°C ± 0.5°C. Each individual tablet (a total of 6 replicates) was placed in a JP sinker.

[0194] Each tablet with sinker was added to each vessel. Samples were collected at 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 420 minutes. Sampling of the IR Caprate solution ended at 120 minutes, and sampling of the 30mg CP1 SR, 2h formulation ended at 240 minutes. At each sampling point, 1.0 mL was sampled with the autosampler into a HPLC vial from each25738 vessel and filtered through 10 μm full flow canula filters. The concentrations of Cyclic Peptide 1 and sodium caprate were measured using an HPLC method for quantification.

[0195] The plots of percent of mass dissolved over time of peptide and sodium caprate are shown in Figures 6 and 7, respectively. These plots indicates that the SR Tablet formulations containing Methocel K100 (Hypromellose K100) exhibited smooth, first-order dissolution behavior from 0 hours to over 4 hours (240 minutes), and even from 0 hours to 6 hours (360 minutes). In particular, about 80% of caprate (more specifically, 76% and 81%, respectively) was dissolved in a substantially linear fashion up to 4 hours in the first and second “4h” tablets, and the remaining 20% of caprate dissolved more slowly over the next 120 minutes (up to 6h) (see FIG.7). Similarly, about 80% of peptide was dissolved in a substantially linear fashion up to 4 hours in both “4h” tablets, and the remaining 20% of peptide dissolved more slowly over the next 100-120 minutes (up to 6h) (see FIG.6). Average release rates over 4 hours of about 6.1 mg / h and about 72 mg / h were observed for peptide and caprate, respectively, in the 30 mg, 4h tablet.

[0196] The “4h” tablet containing 15 mg of peptide exhibited the longest sustained release behavior for the peptide and caprate components.

[0197] In the “2h” tablet, the use of Methocel E15 provided greater than 2 hours of dissolution of peptide and caprate. At the 3-hour timepoint, 97% of caprate was dissolved.

[0198] This in vitro dissolution data indicates that the exemplified tablet formulations provide greater than 4 hours of substantially linear, sustained release of Cyclic Peptide 1 and permeation enhancer. It further suggests that these formulations provide up to 6 hours of sustained release of peptide and permeation enhancer.

[0199] The average release rates provided in this Example were established in accordance with US Pharmacopoeia-defined Apparatus II. As would be appreciated by one of skill in the art, changes in the dissolution method conditions or the use of other methods, such as non-traditional pharmacopeial methods, may result in different (yet similar) average release rates.

[0200] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0201] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and25738 individually indicated to be incorporated by reference herein in its entirety for all purposes. Other embodiments are within the following claims.

Claims

25738 WHAT IS CLAIMED IS:

1. A composition comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, or an apparent permeability (Papp) below 10.0, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose- derived polymer in an amount greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition provides a TMAX between 2 and 4 hours of the peptide following oral administration to a mammal.

2. The composition of claim 1, wherein the composition provides a TMAXbetween 2 and 3 hours following administration.

3. The composition of claim 1, wherein the composition provides a TMAX between 3 and 4 hours following administration.

4. The composition of any one of claims 1-3, wherein the composition provides an absolute oral bioavailability (%F) in the mammal of between 0.8 and 2.0, 0.8 and 3.0, 1.5 and 2.0, 2.0 and 2.5, 2.0 and 3.0, 1.5 and 2.5, or 1.5 and 3.

0.

5. The composition of any one of claims 1-4, wherein the composition provides an absolute oral bioavailability in the mammal of between 1.5 and 2.

0.

6. A composition comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, or an apparent permeability (Papp) below 10.0, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose- derived polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition exhibits a release rate of the fatty acid salt at pH 6.5 of between about 30 mg / h and about 200 mg / h between 2 hours and 4 hours in vitro.

7. The composition of claim 6, wherein the composition exhibits a release rate of the fatty acid salt at pH 6.5 of 78.66 mg / h between 2 hours and 4 hours in vitro.25738 8. The composition of any one of claims 1-7, wherein the cyclic peptide has a molecular weight of at least 1000 g / mol, 1050 g / mol, 1100 g / mol, 1200 g / mol, 1300 g / mol, 1400 g / mol, 1500 g / mol, 1750 g / mol, 2000 g / mol, 2100 g / mol, 2250 g / mol, or 2500 g / mol.

9. The composition of any one of claims 1-8, wherein the cyclic peptide has a Papp below 10.0, below 3.0, or below 1.

0.

10. The composition of any of claims 1-9, wherein the peptide has a Papp below 3.

0.

11. The composition of any of claims 1-5, wherein the composition exhibits a substantially linear cumulative absorption of the peptide over a time period of between 2 hours and 4 hours following administration to a subject in vivo.

12. The composition of any of claims 6-10, wherein the composition exhibits a substantially linear cumulative release rate of the peptide over a time period of between 2 hours and 4 hours in vitro.

13. The composition of any of claims 1-12, wherein the fatty acid salt of (ii) is sodium caprate.

14. The composition of claim 13, wherein the composition comprises at least 30% w / w of sodium caprate.

15. The composition of claim 13 or 14, wherein the composition comprises between about 36% and about 40% w / w of sodium caprate.

16. The composition of any of claims 1-15, wherein the composition comprises between about 1% and 10% w / w of the peptide.

17. The composition of any of claims 1-16, wherein the composition comprises about 7.5% w / w of the peptide.25738 18. The composition of any of claims 1-16, wherein the composition comprises about 5% w / w of the peptide.

19. The composition of any of claims 1-16, wherein the composition comprises about 3% w / w of the peptide.

20. The composition of any of claims 1-16, wherein the composition comprises about 1.5% w / w of the peptide.

21. The composition of any of claims 1-19, wherein the composition comprises at least 25% w / w of the cellulose-derived polymer.

22. The composition of any of claims 1-21, wherein the composition comprises between about 25% and about 40% w / w of the cellulose-derived polymer.

23. The composition of any of claims 1-17, 19 and 20, wherein the composition comprises (i) about 7.5% w / w of the peptide, (ii) about 40% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer.

24. The composition of any of claims 1-14, 19, 21 and 22, wherein the composition comprises (i) about 3% w / w of the peptide, (ii) about 36% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer.

25. The composition of any of claims 1-14, 18, 21 and 22, wherein the composition comprises (i) about 5% w / w of the peptide, (ii) about 30% w / w of sodium caprate, and (iii) about 25% w / w of the cellulose-derived polymer.

26. The composition of any of claims 1-25, wherein the composition comprises about 45 mg of the peptide.

27. The composition of any of claims 1-26, wherein the cellulose-derived polymer comprises a hydroxypropyl methylcellulose polymer selected from Hypromellose K15, Hypromellose K100, Hypromellose E50, and Hypromellose E6.25738 28. The composition of any of claims 1-27, wherein the cellulose-derived polymer comprises Hypromellose K100.

29. The composition of any of claims 1-28, wherein the composition comprises about 25% Hypromellose K100 w / w.

30. The composition of any of claims 1-29, wherein the cyclic peptide is the compound of Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2.

31. The composition of any of claims 1-30, wherein the cyclic peptide is the compound of Formula (I).

32. The composition of any of claims 1-31, wherein the cyclic peptide has a molecular weight of at least 1100 g / mol.

33. The composition of any of claims 1-32, wherein the cyclic peptide has a molecular weight between about 1100 g / mol and 2475 g / mol.

34. The composition of any of claims 1-33, wherein the cyclic peptide has an isoelectric point between 3.0 and 9.0, or a logD between 0.60 and 1.

75.

35. The composition of any of claims 1-34, wherein the cyclic peptide has an isoelectric point of about 8.25, or a logD of about 1.

67.

36. The composition of any of claims 1-35, wherein the composition comprises a disintegrant excipient.

37. A composition comprising: (i) a cyclic peptide having an apparent permeability (Papp) below 100, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a hydroxypropyl methylcellulose polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition provides an absolute oral bioavailability of between 1.5 and 2.0 when administered orally to a mammal.25738 38. The composition of claim 37, wherein the composition comprises at least 25% w / w of the hydroxypropyl methylcellulose polymer.

39. A composition comprising: (i) a cyclic peptide having an apparent permeability (Papp) below 100, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a hydroxypropyl methylcellulose polymer in an amount of greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition provides an improved oral bioavailability of at least about 2-fold when administered orally to a mammal, relative to a corresponding composition in which a hydroxypropyl methylcellulose polymer is substantially absent.

40. The composition of claim 39, wherein the composition provides an improved oral bioavailability of 2.0-fold, 2.1-fold, 2.2-fold, 2.3-fold, 2.4-fold or 2.5-fold.

41. The composition of claim 39 or 40, wherein the composition comprises at least 25% w / w of the hydroxypropyl methylcellulose polymer.

42. The composition of any of claims 37-41, wherein the hydroxypropyl methylcellulose polymer comprises Hypromellose K100.

43. The composition of any of claims 37-42, wherein the fatty acid salt is sodium caprate.

44. The composition of any of claims 37-43, wherein the cyclic peptide has a molecular weight of at least 1000 g / mol, 1050 g / mol, 1100 g / mol, or 1150 g / mol.

45. The composition of any one of claims 37-44, wherein the cyclic peptide has a Papp below 10.0, below 3.0, or below 1.

0.

46. The composition of any of claims 37-45, wherein the cyclic peptide has a Papp below 3.

0.

47. The composition of any of claims 37-46, wherein the cyclic peptide is the compound of Formula (I).25738 48. A composition comprising: (i) a cyclic peptide having a molecular weight of at least 1100 g / mol, (ii) sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of at least 25% w / w, and (iv) one or more pharmaceutically acceptable excipients.

49. A composition comprising: (i) a cyclic peptide having a Papp below 10.0, (ii) sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of at least 25% w / w, and (iv) one or more pharmaceutically acceptable excipients.

50. The composition of claim 48 or 49, wherein the hydroxypropyl methylcellulose polymer comprises Hypromellose K100.

51. The composition of any of claims 48-50, wherein the composition comprises about 25% Hypromellose K100 w / w.

52. The composition of any of claims 48-50, wherein the composition comprises about 7.5% w / w of the peptide.

53. The composition of claim 50-52, wherein the composition comprises a w / w ratio of 7.5:40:25 of the peptide, the sodium caprate, the Hypromellose K100, respectively.

54. The composition of any of claims 48-50, wherein the composition comprises about 3% w / w of the peptide.

55. The composition of any of claims 50, 51 and 54, wherein the composition comprises a w / w ratio of 3:36:25 of the peptide, the sodium caprate, the Hypromellose K100, respectively.

56. The composition of any of claims 48-51, wherein the composition comprises about 5% w / w of the peptide.

57. The composition of any of claims 50, 51 and 56, wherein the composition comprises a w / w ratio of 5:30:25 of the peptide, the sodium caprate, the Hypromellose K100, respectively.25738 58. The composition of any of claims 48-57, wherein the cyclic peptide is the compound of Formula (I), Cyclic Peptide 1, or Cyclic Peptide 2.

59. The composition of any of claims 48-58, wherein the cyclic peptide is the compound of Formula (I).

60. The composition of any of claims 48-59, wherein the cyclic peptide has an isoelectric point between 4.5 and 9.0, or a logD between 0.60 and 1.

75.

61. The composition of any one of claims 1-60, wherein an enteric polymer is substantially absent.

62. The composition of any one of claims 27-61, wherein the hydroxypropyl methylcellulose polymer comprises Hypromellose E50 or Hypromellose E6.

63. The composition of any one of claims 27-61, wherein the hydroxypropyl methylcellulose polymer comprises Hypromellose E50 and Hypromellose E6.

64. The composition of any one of claims 37-63, wherein the composition provides a TMAX between about 2 and 4 hours of the peptide, in vitro or in vivo.

65. The composition of any one of claims 1-64, wherein the composition comprises: (i) about 3% w / w of the peptide, (ii) between about 30% and about 40% w / w of sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of about 25% w / w, and (iv) one or more pharmaceutically acceptable excipients.

66. The composition of any one of claims 1-65, wherein the composition is in the form of a tablet.

67. A composition comprising: (i) the compound of Formula (I), (ii) between about 30% and about 40% w / w of sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of about 25% w / w, and (iv) one or more pharmaceutically acceptable excipients.

68. The composition of claim 67, wherein the composition comprises about 7.5% w / w of the compound of Formula (I).

69. The composition of claim 67, wherein the composition comprises about 3% w / w of the compound of Formula (I).

70. A composition comprising: (i) the compound of Cyclic Peptide 1, (ii) about 36% w / w of sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of about 25% w / w, and (iv) one or more pharmaceutically acceptable excipients.

71. The composition of claim 70, wherein the composition comprises about 3% w / w of the compound of Cyclic Peptide 1.

72. A composition comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, or a Papp below 1000, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a cellulose-derived polymer in an amount greater than 20% w / w, and (iv) one or more pharmaceutically acceptable excipients, wherein the composition provides a TMAXbetween 2 and 4 hours of the peptide following oral administration to a mammal.

73. A composition comprising: (i) a cyclic peptide having a Papp below 1000, (ii) sodium caprate, (iii) a hydroxypropyl methylcellulose polymer in an amount of at least 25% w / w, and (iv) one or more pharmaceutically acceptable excipients.

74. A means for providing sustained release of a cyclic peptide having a molecular weight of at least 1000 g / mol, or a Papp below 1000, and a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate in a mammalian subject.

75. A composition comprising: (i) a cyclic peptide having a molecular weight of at least 1000 g / mol, or a Papp below 1000, (ii) a fatty acid salt selected from sodium caprate, docusate, sodium lauryl sulfate, and myristate, (iii) a means for providing sustained release of the cyclic peptide and fatty acid salt in a mammalian subject, and (iv) one or more pharmaceutically acceptable excipients.

76. A method of providing sustained release of a cyclic peptide in a mammalian subject comprising: (i) combining the peptide with a polymer comprising sodium caprate, a hydroxypropyl methylcellulose polymer, and one or more pharmaceutically acceptable excipients into a matrix or multiparticulate composition; (ii) forming a tablet from the composition of (i); and (iii) administering the tablet to the subject, wherein the peptide has a molecular weight of at least 1100 g / mol.

77. A method of providing sustained release of a cyclic peptide in a mammalian subject comprising: (i) combining the peptide with a polymer comprising sodium caprate, a hydroxypropyl methylcellulose polymer, and one or more pharmaceutically acceptable excipients into a matrix or multiparticulate composition; (ii) forming a tablet from the composition of (i); and (iii) administering the tablet to the subject, wherein the peptide has a Papp below 100.

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