Compositions and methods for enhancing the absorption of therapeutic polypeptides from the intestines following oral administration

Abstract

Compositions and methods for enhancing the absorption of therapeutic polypeptides from the intestines following oral administration The invention provides a method for increasing the systemic bioavailability of a polypeptide therapeutic agent undergoing oral, orogastric, nasogastric, or intragastric administration, said method comprising administering said polypeptide therapeutic agent together with (i) an alginate oligomer (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (I) (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof, (II) to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine. Such methods allow for systemic treatment or prevention of a disease or condition or complication thereof which is responsive to, or which is prevented by, a polypeptide therapeutic agent via oral, orogastric, nasogastric, or intragastric administration routes. Further provided are compositions for use in such methods.

Description

[0001] 174915 / 01 pctspec

[0002] Compositions and methods for enhancing the absorption of therapeutic polypeptides from the intestines following oral administration

[0003] The present invention relates to novel and improved compositions and methods for enhancing the absorption of therapeutic polypeptides from the intestines following administration by oral, orogastric, nasogastric, and intragastric routes. More specifically, the invention relates to the use of alginate oligomers and two specific examples of gastrointestinal permeation enhancers together with therapeutic polypeptides to enhance their absorption from the intestines following administration by oral, orogastric, nasogastric, and intragastric routes. This enhances the systemic bioavailability of therapeutic polypeptides undergoing such delivery. The invention has particular utility in the context of the oral administration of therapeutic polypeptides which are typically administered by injection because of low bioavailability following oral delivery. By enhancing the systemic bioavailability of therapeutic polypeptides undergoing oral administration the effectiveness of therapeutic interventions may be enhanced, making viable treatments which are more convenient and comfortable than parenteral approaches.

[0004] The efficacy of polypeptide therapeutics is often limited by their ability to reach their targets. The mucosal surfaces of the lower gastrointestinal tract are attractive target sites for drug delivery due to their vascularity and large surface area. However, the main route to reaching those surfaces involves transit of the stomach, and polypeptide therapeutics are especially susceptible to the harsh chemical and enzymatic conditions of the gastric milieu. The very low pH and high concentrations of pepsin protease cause significant degradation of polypeptides transiting the stomach. Moreover, the entire gastrointestinal tract (mouth, pharynx, oesophagus, stomach, small intestine, large intestine, and anus) are lined with a mucus layer which serves as a physical barrier between the epithelial cell layer and the Gl tract lumen. To enter the systemic circulation therapeutic polypeptides need to cross the charged and complex polymeric “mesh” of components that make up that mucus layer. The thickness of the mucus barrier is not uniform and varies but is about 1 mm in the stomach and 100-150 μm in the colon and rectal region. As such, therapeutic polypeptides have conventionally been administered by injection, in particular intravenous or subcutaneous injection, to maximise systemic bioavailability. Administration by injection is however uncomfortable and inconvenient and so, for polypeptide therapeutics which require regular administration to maintain therapeutically effective levels systemically, long term patient adherence to treatment plans becomes a significant challenge. The production and administration costs for injectable medicaments are often greater than for oral medicaments, at least in part due to the need for sterility and hardware, and the need for a medically trained professional to administer the drug. The solid waste associated with injectable drugs also poses a biohazard and environmental burden. It would therefore be more ideal if there was the option for therapeutic polypeptides to be orally administered to patients.

[0005] Alginates are naturally occurring polysaccharides that have been found to have a number of uses, both clinical (e.g. in wound dressings, as excipients in drug formulations, and in anti-heartburn preparations) and non-clinical (e.g. in food preparation). They are linear polymers of (1-4) linked p-D-mannuronic acid (M) and / or its C-5 epimer a-L-guluronic acid (G). The primary structure of alginates can vary greatly. The M and G residues can be organised as homopolymeric blocks of contiguous M or G residues, as blocks of alternating M and G residues and single M or G residues can be found interspacing these block structures. An alginate molecule can comprise some or all of these structures and such structures might not be uniformly distributed throughout the polymer. In the extreme, there exists a homopolymer of guluronic acid (polyguluronate) or a homopolymer of mannuronic acid (polymannuronate).

[0006] Alginates have been isolated from marine brown algae (e.g. certain species of Durvillea, Lessonia and Laminaria) and bacteria such as Pseudomonas aeruginosa and Azotobacter vinelandii. Other pseudomonads (e.g. Pseudomonas fluorescens, Pseudomonas putida, and Pseudomonas mendocina) retain the genetic capacity to produce alginates and may be induced to do so even though in the wild they do not produce detectable levels of alginate.

[0007] Alginate is synthesised as polymannuronate and G residues are formed by the action of epimerases (specifically C-5 epimerases) on the M residues in the polymer. In the case of alginates extracted from algae, the G residues are predominantly organised as G blocks because the enzymes involved in alginate biosynthesis in algae preferentially introduce the G neighbouring another G, thus converting stretches of M residues into G-blocks.

[0008] Alginates are typically isolated from natural sources as large high molecular weight polymers (e.g. an average molecular weight in the range 300,000 to 500,000 Daltons). It is known, however, that such large alginate polymers may be degraded, or broken down, e.g. by chemical or enzymatic hydrolysis to produce alginate structures of lower molecular weight. Alginates that are used industrially typically have an average molecular weight in the range of 100,000 to 300,000 Daltons (such alginates are still considered to be large polymers) although alginates of an average molecular weight of approximately 35,000 Daltons have been used as excipients in pharmaceuticals.

[0009] Alginate oligomers have been recognised as having the ability to alter the physical properties of isolated sputum (from patients with cystic fibrosis and normal controls), and mucus samples from the lung and the gastrointestinal tract (Pritchard et al. Mucin structural interactions with an alginate oligomer mucolytic in cystic fibrosis sputum.

[0010] Vibrational Spectroscopy 2019; 102932; Ermund A, et al. OligoG CF-5 / 20 normalizes cystic fibrosis mucus by chelating calcium. Clin Exp Pharmacol Physiol. 2017;44, 639-647; Vitko M, et al. A novel guluronate oligomer improves intestinal transit and survival in cystic fibrosis mice. J Cyst Fibros. 2016 Nov 15(6):745-751; Pritchard MF, et al. A New Class of Safe Oligosaccharide Polymer Therapy To Modify the Mucus Barrier of Chronic Respiratory Disease. Mol Pharm. 2016 Mar 7; 13(3): 863-72.; Nordgard CT, et al.

[0011] Alterations in mucus barrier function and matrix structure induced by guluronate oligomers. Biomacromolecules. 2014 Jun 9;15(6):2294-300; Sletmoen M., et al.

[0012] Oligoguluronate induced competitive displacement of mucin-alginate interactions: relevance for mucolytic function. Soft Matter, 2012, 8, 8413; Nordgard CT, Draget KI. Oligosaccharides as modulators of rheology in complex mucus systems.

[0013] Biomacromolecules. 2011 Aug 8;12(8):3084-90).

[0014] This has led to previous proposals to exploit such properties to enhance drug delivery across mucosal surfaces, including macromolecular drugs (W02007 / 039754, W02008 / 125828). In the context of mucosal surfaces which are accessible without the need to have the alginate oligomer and the drug exposed to the conditions of the stomach, e.g. exposed mucus membranes, the respiratory tract, the genitourinary tracts, the rectum, anus, mouth, pharynx, or oesophagus, there is no particular obstacle to put such proposals into effect. However, in the context of the administration of drugs, and polypeptide therapeutics in particular, by routes which require transit of the stomach, e.g. administration by oral, orogastric, nasogastric, and intragastric routes, it has to date been assumed that to enhance the uptake of those therapeutic polypeptides with alginate oligomers, it is essential to protect both the polypeptide and the alginate oligomer from the harsh environment of the gastric milieu (e.g. by providing these elements with an enteric coating) thereby allowing passage through the stomach and delivery to the intestines where enhanced uptake can take place (W02010 / 109180).

[0015] More recently it is been shown that alginates with an average molecular weight of less than 15,000 Daltons, e.g. of 2-100 monomer residues, referred to herein as alginate oligomers, may be used together with (or in combination or conjunction with) therapeutic polypeptides during their administration by routes which require transit of the stomach, e.g. administration by oral, orogastric, nasogastric, and intragastric routes, without additional forms of substantive protection from the gastric environment, to enhance the uptake of those therapeutic polypeptides from the stomach (WO2024 / 141760). It was further shown that use of an gastrointestinal permeation enhancer (more specifically a gastrointestinal epithelial barrier permeation enhancer) together with the alginate oligomer and the therapeutic peptide during their administration by routes which require transit of the stomach, e.g. administration by oral, orogastric, nasogastric, and intragastric routes, without additional forms of substantive protection from the gastric environment, still further enhanced the uptake of those therapeutic polypeptides from the stomach.

[0016] The gastrointestinal (Gl) tract of vertebrates (mammals in particular) also referred to as the digestive tract or alimentary canal, is the continuous series of organs beginning at the mouth and ending at the anus. Specifically, this sequence consists of the mouth, the pharynx, the oesophagus, the stomach (or stomachs in ruminant mammals), the small intestine, the large intestine and the anus

[0017] A gastrointestinal permeation enhancer (also known as mucosal permeation enhancers, or simply permeation enhancers), more specifically a gastrointestinal epithelial barrier (epithelium) permeation enhancer is a compound which facilitates the translocation of other compounds from the luminal (apical) side of a gastrointestinal epithelial cell layer (e.g. a gastric epithelial layer or an epithelial layer of the small intestine or the large intestine) to the basal side of said layer. Permeation enhancers may have a paracellular and / or transcellular mode of action. There are many compounds and classes thereof which have been recognised as having such properties. SNAC (sodium N-(8-(2-hydroxybenzoyl)amino)caprylate) and C10 (sodium caprate) are two well studied examples of such agents on account of their use in authorised pharmaceutical products for the oral delivery of polypeptide therapeutic agents. Their physiological mode of action is believed to be similar, but SNAC is considered primarily as a gastrointestinal permeation enhancer for use in promoting uptake of polypeptide therapeutic agents from the stomach and C10 is considered primarily as a gastrointestinal permeation enhancer for use in promoting uptake of polypeptide therapeutic agents from the intestines (Twarog, C, et al., Comparison of the effects of the intestinal permeation enhancers, SNAC and sodium caprate (C10): Isolated rat intestinal mucosae and sacs European Journal of Pharmaceutical Sciences 158 (2021) 105685 They have not been used together.

[0018] However, it has now been found that when an alginate oligomer and two specific examples of gastrointestinal permeation enhancers (or their analogues) are administered together with a therapeutic polypeptide via oral, orogastric, nasogastric, or intragastric routes uptake of the polypeptide from the intestines, more so than the stomach, occurs and may be enhanced synergistically as compared to that which occurs in the presence of the alginate oligomer or the gastrointestinal permeation enhancers individually or in pairwise combination. These specific examples of gastrointestinal permeation enhancers are believed to have a similar physiological mode of action and so the degree by which they may enhance uptake of polypeptides from intestines when used with alginate oligomers is surprising.

[0019] Thus, the invention provides a method for increasing the systemic bioavailability of a polypeptide therapeutic agent undergoing oral, orogastric, nasogastric, or intragastric administration, said method comprising administering said polypeptide therapeutic agent together with

[0020] (i) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,

[0021] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0022]

[0023] (I) wherein:

[0024] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0025] R1is hydrogen or C1-3 alkyl;

[0026] R2is hydrogen or C1-3 alkyl;

[0027] R3is -OH;

[0028] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0029] n is an integer from 0 to 4, preferably 0 or 1, and

[0030] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0031]

[0032] wherein:

[0033] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0034] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine. References to the uptake of the polypeptide therapeutic agent from said portion of the intestine may be considered to be references to the uptake, by the body of the subject, of the polypeptide therapeutic agent, from a portion of the intestines with which the polypeptide therapeutic agent has been contacted together with the alginate oligomer, the compound of Formula I, or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof.

[0035] Uptake from the intestines, or a portion thereof, can be expressed with different but interchangeable terminology as uptake by the intestines, or a portion thereof, or uptake via the intestines, or a portion thereof.

[0036] From a more mechanistic perspective, uptake of a polypeptide therapeutic agent by a subject following oral, orogastric, nasogastric, or intragastric administration thereto may generally be considered to be the physical transfer (or translocation) of the polypeptide therapeutic agent from the lumen of the gastrointestinal tract to the blood, namely the systemic blood circulation, of the subject. Thus, uptake by a subject in such contexts can be referred to as uptake by (or into) the systemic circulation of the subject. Intestinal uptake and uptake from the intestines can be interpreted accordingly.

[0037] The gastrointestinal (Gl) tract of vertebrates (mammals in particular) also referred to as the digestive tract or alimentary canal, is the continuous series of organs beginning at the mouth and ending at the anus. Specifically, this sequence consists of the mouth, the pharynx, the oesophagus, the stomach (or stomachs in ruminant mammals), the small intestine, the large intestine and the anus. These organs can be subdivided into the upper Gl tract, consisting of the mouth, pharynx, oesophagus, and stomach(s), and the lower Gl tract (the intestinal tract), consisting of the duodenum, the jejunum, the ileum (together the small intestine), the cecum, the colon, the rectum (together the large intestine) and the anus. In certain instances, references to “the intestines” may be taken as a reference to the small intestine and the large intestine. When the invention is applied to a ruminant animal, references to “a stomach” should be taken as references to the “abomasum”. In some instances, “a portion of the intestines” is not a portion of the anus or rectum. In some instances, “a portion of the intestines” is not a portion of the anus, rectum or colon. In some instances, “a portion of the intestines” is a portion of the small intestine, e.g. a portion of the duodenum, the jejunum, and / or the ileum. In accordance with the invention uptake of the polypeptide therapeutic agent occurs from the intestines, or at least a portion thereof, and thus the above described transfer / translocation is by or into the superior mesenteric vein in the first instance, or more specifically the jejunal veins, Ileal veins, ileocolic veins, right colic vein, middle colic vein, pancreatico-duodenal veins, inferior mesenteric vein, left colic vein and / or sigmoid veins depending on the portion of the intestines in question.

[0038] Transfer / translocation of the polypeptide therapeutic agent from the gastrointestinal lumen to the blood (the blood stream or systemic circulation) of the subject involves transfer / translocation, or movement, of the polypeptide therapeutic agent across the gastrointestinal epithelium. This may be by any of the passive or active diffusion routes which exist. Thus, uptake from the intestines can also be expressed as the transfer / translocation / movement / diffusion of the polypeptide therapeutic agent from the intestinal lumen across the intestinal epithelium and into the blood (the blood stream or systemic circulation). This may further include transfer / translocation, or movement, of the polypeptide therapeutic agent across the mucus layer of the gastrointestinal epithelium.

[0039] Uptake from the stomach, uptake by the stomach, or uptake via the stomach may be interpreted analogously. In such contexts the above described transfer / translocation is by or into the splenic vein in the first instance.

[0040] Expressed differently still, uptake of the polypeptide therapeutic agent from the gastrointestinal tract, e.g. from the stomach or the intestines, can be referred to as absorption, by the body of the subject, of the polypeptide therapeutic agent from the gastrointestinal tract. The above detailed discussion of the meaning of “uptake” applies mutatis mutandis to “absorption”.

[0041] In some instances, uptake (or absorption) of the polypeptide therapeutic agent from the intestines following oral, orogastric, nasogastric, or intragastric administration to the subject will be equal to or greater, e.g. significantly greater, than uptake (or absorption) of the polypeptide therapeutic agent from the stomach. In some instances, the amount of polypeptide therapeutic agent up taken by the subject from the intestines, or a portion thereof, of is at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or 20 times the amount of polypeptide therapeutic agent up taken (absorbed) by the subject from the stomach. In some instances, uptake (or absorption) of the polypeptide therapeutic agent from the stomach occurs, but is negligible. In other instances essentially no uptake (or absorption) of the polypeptide therapeutic agent from the stomach occurs.

[0042] In some instances, less than 50%, e.g. less than, 45, 40, 35, 30, 25, 20, 15, 10, or 5% of the total amount of therapeutic agent up taken by the subject following administration is up taken from the stomach or at least before gastric emptying, e.g. as defined herein (e.g. the time before a substantial proportion of the polypeptide therapeutic agent / dosage form ceases to be resident (retained) in the stomach of the subject to which it has been administered, the time before exit of a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered from the stomach of the of the subject to which it has been administered and / or before entry to the portion of the intestines of the subject to which it has been administered), or during the typical gastric transit time of the subject, e.g. as defined herein.

[0043] In other instances, greater than 50%, e.g. greater than 55, 60, 65, 70, 75, 80, 85, 90, or 95% of the total amount of therapeutic agent up taken by the subject following administration is up taken from the intestines, or at least following gastric emptying, e.g. as defined herein (e.g. the time following that in which a substantial proportion of the polypeptide therapeutic agent / dosage form will be resident (retained) in the stomach of the subject to which it has been administered, the time following exit of a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered from the stomach of the of the subject to which it has been administered and / or entry to the portion of the intestines of the subject to which it has been administered), or over the time later than the typical gastric transit time of the subject, e.g. as defined herein.

[0044] The invention further provides an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for increasing the systemic bioavailability of a polypeptide therapeutic agent undergoing oral, orogastric, nasogastric, or intragastric administration, said method comprising administering said polypeptide therapeutic agent together with

[0045] (i) said alginate oligomer,

[0046] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0047]

[0048] (I) wherein:

[0049] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0050] R1is hydrogen or C1-3 alkyl;

[0051] R2is hydrogen or C1-3 alkyl;

[0052] R3is -OH;

[0053] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0054] n is an integer from 0 to 4, preferably 0 or 1, and

[0055] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0056] OH

[0057]

[0058] (II)

[0059] wherein:

[0060] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0061] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine. Generally, the term "systemic bioavailability" as used herein refers to the fraction of an administered dose of an active pharmaceutical ingredient (API), such as a therapeutic polypeptide as defined herein, which reaches the systemic circulation in active or reversibly deactivated form. This may be assessed at a given timepoint following administration of the API or over a given time period following administration of the API. By definition, when an API is administered intravenously, its bioavailability is 100%.

[0062] However, when it is administered via other routes, e.g. orally or subcutaneously, its bioavailability decreases (due to incomplete absorption and first-pass metabolism).

[0063] Absolute systemic bioavailability is calculated as the relative exposure of the API in systemic circulation following non-intravenous administration (e.g. mucosal, such as oral or inhalation), estimated as the area under the plasma concentration versus time curve (AUC) compared to the exposure of the API following intravenous administration.

[0064] In accordance with the invention, the use of an alginate oligomer, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or pharmaceutically acceptable salt thereof, together with a therapeutic polypeptide undergoing oral, orogastric, nasogastric, or intragastric administration to a portion of the intestines of a human or non-human animal will result in a greater measure of absolute systemic bioavailability as compared to the administration of the therapeutic polypeptide in the absence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, but otherwise in identical circumstances. In these instances, bioavailability in the presence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or 20 times that in the absence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.

[0065] In other instances in accordance with the invention, the use of an alginate oligomer, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof together with a therapeutic polypeptide undergoing oral, orogastric, nasogastric, or intragastric administration to a portion of the intestines of a human or non-human animal will result in a greater measure of absolute systemic bioavailability as compared to the administration of the therapeutic polypeptide, compound of Formula (I), and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in the absence of the alginate oligomer, but otherwise in identical circumstances. In these instances, bioavailability in the presence of the alginate oligomer may be at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or 20 times that in the absence of the alginate oligomer.

[0066] In some instances, the above described increased bioavailability of the polypeptide therapeutic agent will be observed over at least part of the time in which a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered will be present (resident / retained) in the portion of the intestines to which it has been administered.

[0067] The above described increased bioavailability of the polypeptide therapeutic agent might be seen as increased systemic bioavailability in at least part of the time following that in which a substantial proportion of the polypeptide therapeutic agent / dosage form will be resident (retained) in the stomach of the subject to which it has been administered.

[0068] The above described increased bioavailability of the polypeptide therapeutic agent might be seen in at least part of the time following exit of a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered from the stomach of the subject to which it has been administered and / or entry to the portion of the intestines of the subject to which it has been administered.

[0069] In certain instances, the above time parameters may be considered as defining the point of gastric emptying in a subject.

[0070] AUC may be calculated as the definite integral of the concentration of a drug in blood plasma as a function of time. Conveniently this may be calculated using the trapezoidal rule.

[0071] Expressed differently, the invention provides a method for the intestinal uptake of an active or reversibly deactivated polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with (i) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,

[0072] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0073]

[0074] wherein:

[0075] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0076] R1is hydrogen or C1-3 alkyl;

[0077] R2is hydrogen or C1-3 alkyl;

[0078] R3is -OH;

[0079] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0080] n is an integer from 0 to 4, preferably 0 or 1, and

[0081] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0082] OH

[0083]

[0084] (II)

[0085] wherein:

[0086] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy, to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

[0087] Likewise, the invention further provides an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for the intestinal uptake of an active or reversibly deactivated polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with

[0088] (i) said alginate oligomer,

[0089] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0090]

[0091] wherein:

[0092] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0093] R1is hydrogen or C1-3 alkyl;

[0094] R2is hydrogen or C1-3 alkyl;

[0095] R3is -OH;

[0096] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0097] n is an integer from 0 to 4, preferably 0 or 1, and

[0098] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0099]

[0100] (II)

[0101] wherein:

[0102] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0103] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

[0104] Expressed differently again, the invention provides a method for the absorption of an active or reversibly deactivated polypeptide therapeutic agent from a portion of the intestines of a human or non-human animal subject, said method comprising administering said polypeptide therapeutic agent together with

[0105] (i) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,

[0106] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0107]

[0108] wherein: X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0109] R1is hydrogen or C1-3 alkyl;

[0110] R2is hydrogen or C1-3 alkyl;

[0111] R3is -OH;

[0112] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0113] n is an integer from 0 to 4, preferably 0 or 1, and

[0114] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0115] OH

[0116]

[0117] (II)

[0118] wherein:

[0119] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0120] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in absorption of an active or reversibly deactivated form of said polypeptide therapeutic agent from said portion of the intestine.

[0121] Likewise, the invention further provides an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for the absorption of an active or reversibly deactivated polypeptide therapeutic agent from a portion of the intestines of a human or non-human animal subject, said method comprising administering said polypeptide therapeutic agent together with

[0122] (i) said alginate oligomer, (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0123]

[0124] wherein:

[0125] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0126] R1is hydrogen or C1-3 alkyl;

[0127] R2is hydrogen or C1-3 alkyl;

[0128] R3is -OH;

[0129] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0130] n is an integer from 0 to 4, preferably 0 or 1, and

[0131] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0132] OH

[0133]

[0134] (II)

[0135] wherein:

[0136] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0137] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in absorption of an active or reversibly deactivated form of said polypeptide therapeutic agent from said portion of the intestine.

[0138] Expressed differently again, the invention provides a method for increasing absorption of an active or reversibly deactivated polypeptide therapeutic agent from a portion of the intestines of a human or non-human animal subject, said method comprising administering said polypeptide therapeutic agent together with

[0139] (i) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,

[0140] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0141] R3

[0142] OR1

[0143] R2

[0144] (R4)n

[0145]

[0146] (I)

[0147] wherein:

[0148] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0149] R1is hydrogen or C1-3 alkyl;

[0150] R2is hydrogen or C1-3 alkyl;

[0151] R3is -OH;

[0152] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0153] n is an integer from 0 to 4, preferably 0 or 1, and

[0154] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof, OH

[0155]

[0156] o (II)

[0157] wherein:

[0158] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0159] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in absorption of an active or reversibly deactivated form of said polypeptide therapeutic agent from said portion of the intestine.

[0160] Likewise, the invention further provides an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for increasing absorption of an active or reversibly deactivated polypeptide therapeutic agent from a portion of the intestines of a human or non-human animal subject, said method comprising administering said polypeptide therapeutic agent together with

[0161] (i) said alginate oligomer,

[0162] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0163]

[0164] wherein: X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0165] R1is hydrogen or C1-3 alkyl;

[0166] R2is hydrogen or C1-3 alkyl;

[0167] R3is -OH;

[0168] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0169] n is an integer from 0 to 4, preferably 0 or 1, and

[0170] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0171] OH

[0172]

[0173] (II)

[0174] wherein:

[0175] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0176] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in absorption of an active or reversibly deactivated form of said polypeptide therapeutic agent from said portion of the intestine.

[0177] Increased absorption from a portion of the intestines may be seen as increased systemic bioavailability, more specifically, increased absolute bioavailability, of the polypeptide therapeutic agent over at least part of the time in which a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered will be present (resident / retained) in the portion of the intestines to which it has been administered. It might be seen as increased systemic bioavailability, more specifically, increased absolute bioavailability, in at least part of the time following that in which a substantial proportion of the polypeptide therapeutic agent / dosage form will be resident (retained) in the stomach of the subject to which it has been administered.

[0178] Increased absorption from a portion of the intestines might be seen as increased systemic bioavailability, more specifically, increased absolute bioavailability, of the polypeptide therapeutic agent in at least part of the time following exit of a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered from the stomach of the subject to which it has been administered and / or entry to the portion of the intestines of the subject to which it has been administered.

[0179] Increased absorption from a portion of the intestines might be seen as a greater Cmax over at least part of the time in which a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered will be present (resident / retained) in the portion of the intestines to which it has been administered. It might be seen as a greater Cmax in at least part of the time following that in which a substantial proportion of the polypeptide therapeutic agent / dosage form will be resident (retained) in the stomach of the subject to which it has been administered. It might be seen as a greater Cmax following exit of a substantial proportion of the polypeptide therapeutic agent / dosage form in which it was administered from the stomach of the of the subject to which it has been administered and / or entry to the portion of the intestines of the subject to which it has been administered.

[0180] Increased absorption from a portion of the intestines might also be seen as a more rapid rise in plasma concentration, and / or a reduced lag in time taken for the plasma concentration of the therapeutic polypeptide to begin to rise, under the above described timescales.

[0181] These observations may be as compared to the administration of the therapeutic polypeptide in the absence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, but otherwise in identical circumstances. In these instances, increased absorption of the polypeptide therapeutic agent in the presence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or 20 times that in the absence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.

[0182] In other instances, these observations may also be as compared to the administration of the therapeutic polypeptide, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, in the absence of the alginate oligomer, but otherwise in identical circumstances. In these instances, increased absorption of the polypeptide therapeutic agent in the presence of the alginate oligomer may be at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or 20 times that in the absence of the alginate oligomer.

[0183] Expressed differently again, the invention provides a method for improving the effectiveness of a polypeptide therapeutic agent undergoing oral, orogastric, nasogastric, or intragastric administration in the systemic treatment or prevention of a disease or condition or complication thereof which is responsive to, or which is prevented by, the polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with

[0184] (i) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,

[0185] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0186] R3

[0187] OR1

[0188] R2

[0189] , (R4)n

[0190]

[0191] (I)

[0192] wherein:

[0193] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0194] R1is hydrogen or C1-3 alkyl; R2is hydrogen or C1-3 alkyl;

[0195] R3is -OH;

[0196] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0197] n is an integer from 0 to 4, preferably 0 or 1, and

[0198] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0199] OH

[0200]

[0201] (II)

[0202] wherein:

[0203] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0204] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

[0205] Likewise, the invention further provides an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for improving the effectiveness of a polypeptide therapeutic agent undergoing oral, orogastric, nasogastric, or intragastric administration in the systemic treatment or prevention of a disease or condition or complication thereof which is responsive to, or which is prevented by, the polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with

[0206] (i) an alginate oligomer,

[0207] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0208]

[0209] (I) wherein:

[0210] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0211] R1is hydrogen or C1-3 alkyl;

[0212] R2is hydrogen or C1-3 alkyl;

[0213] R3is -OH;

[0214] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0215] n is an integer from 0 to 4, preferably 0 or 1, and

[0216] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0217] OH

[0218]

[0219] (II)

[0220] wherein:

[0221] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0222] to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine. By “improving the effectiveness of a polypeptide therapeutic” it is meant any positive effect on the therapeutic use of the polypeptide in question. This may include a greater efficacy or potency at its site of action or pharmacological receptor, longer duration of pharmacological effect, fewer or less severe side effects (systemic or local), wider therapeutic window, greater circulating plasma levels, prolonged circulating plasma levels, higher Cmax, more rapid uptake, and the like.

[0223] These observations (parameters / metrics) are as compared as compared to the administration of the therapeutic polypeptide in the absence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, but otherwise in identical circumstances. In these instances, the observation (parameter / metric) in question which is made in the presence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salts thereof, may be at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or 20 times different (in the sense of being improved) to that in the absence of the alginate oligomer, compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.

[0224] In other instances, these observations (parameters / metrics) may be as compared to the administration of the therapeutic polypeptide, compound of Formula (I), and a compound of Formula (II), or pharmaceutically a acceptable salt thereof, in the absence of the alginate oligomer, but otherwise in identical circumstances. In these instances, the observation (parameter / metric) in question which is made in the presence of the alginate oligomer may be at least 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, or 20 times different to (in the sense of being improved) that in the absence of the alginate oligomer.

[0225] Improved effectiveness may be seen in the requirement for less polypeptide to be administered in essentially the same way order to achieve the same therapeutic outcomes.

[0226] In this aspect of the invention the subject may be a subject which has, is suspected of having, or is at risk of, said disease or condition or complication thereof. Expressed differently again, the invention provides a method for systemic treatment or prevention of a disease or condition or complication thereof which is responsive to, or which is prevented by, a polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with

[0227] (i) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,

[0228] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0229]

[0230] wherein:

[0231] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0232] R1is hydrogen or C1-3 alkyl;

[0233] R2is hydrogen or C1-3 alkyl;

[0234] R3is -OH;

[0235] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0236] n is an integer from 0 to 4, preferably 0 or 1, and

[0237] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0238] OH

[0239]

[0240] (II)

[0241] wherein: Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0242] to a portion of the intestines of a human or non-human animal subject, which has, is suspected of having, or is at risk of, said disease or condition or complication thereof, by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

[0243] Likewise, the invention further provides an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for systemic treatment or prevention of a disease or condition or complication thereof which is responsive to, or which is prevented by, a polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with

[0244] (i) an alginate oligomer,

[0245] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0246]

[0247] wherein:

[0248] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0249] R1is hydrogen or C1-3 alkyl;

[0250] R2is hydrogen or C1-3 alkyl;

[0251] R3is -OH; each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0252] n is an integer from 0 to 4, preferably 0 or 1, and

[0253] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0254] OH

[0255]

[0256] (II)

[0257] wherein:

[0258] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0259] to a portion of the intestines of a human or non-human animal subject, which has, is suspected of having, or is at risk of, said disease or condition or complication thereof, by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

[0260] Likewise, the invention further provides a polypeptide therapeutic agent, for use in a method for systemic treatment or prevention of a disease or condition or complication thereof which is responsive to, or which is prevented by, said polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with

[0261] (i) an alginate oligomer, wherein said alginate oligomer has 2-100 monomer residues,

[0262] (ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0263]

[0264] (I) wherein:

[0265] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[0266] R1is hydrogen or C1-3 alkyl;

[0267] R2is hydrogen or C1-3 alkyl;

[0268] R3is -OH;

[0269] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0270] n is an integer from 0 to 4, preferably 0 or 1, and

[0271] (iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,

[0272] OH

[0273]

[0274] (II)

[0275] wherein:

[0276] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy,

[0277] to a portion of the intestines of a human or non-human animal subject, which has, is suspected of having, or is at risk of, said disease or condition or complication thereof, by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

[0278] In accordance with the invention, a systemic treatment or prevention involves the administration of the polypeptide therapeutic agent in such a way as to result in the polypeptide entering the blood circulation and becoming distributed to areas of the subject’s body which are spatially remote from the site of administration and / or uptake, specifically the intestines. The foregoing is to be interpreted in combination with the above discussion of intestinal uptake. Preferably, circulating levels of the polypeptide therapeutic agent are above levels necessary for achieving a therapeutic effect.

[0279] Systemic treatment encompasses the treatment of systemic conditions, conditions having pathologies at multiple spatially distributed loci and / or conditions having a single localised pathology remote from the site of administration and / or uptake.

[0280] The methods of the invention may include a step following the administration of the polypeptide therapeutic agent together with an alginate oligomer, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, of measuring the amount, or concentration, of the polypeptide therapeutic agent in the plasma of the subject, e.g. within 360, 330, 300, 270, 240, 210, 180, 120, 60, 30, 20, 15, 10, or 5 mins of the administration of the polypeptide therapeutic agent. In other embodiments the methods of the invention may comprise, or comprise further to the above described measuring step, a step in which systemic bioavailability or absolute systemic bioavailability of the polypeptide therapeutic agent is calculated, e.g. over 360, 330, 300, 270, 240, 210, 180, 120, 60, 30, 20, 15, 10, or 5 mins from the administration of the polypeptide therapeutic agent.

[0281] The methods of the invention may also or alternatively include a step following the administration of the polypeptide therapeutic agent together with an alginate oligomer, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or pharmaceutically acceptable salt thereof, of measuring the amount, or concentration, of the polypeptide therapeutic agent in the plasma of the subject at a time point later than the typical gastric transit time of a typical example of the subject, e.g. at a time point later than 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 210, 240, 270, 300, 330, or 360 mins from the administration of the polypeptide therapeutic agent, or at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 210, 240, 270, 300, 330, or 360 mins after the typical gastric transit time of a typical example of the subject. In other embodiments the methods of the invention may comprise, or comprise further to the above described measuring step, a step in which systemic bioavailability or absolute systemic bioavailability of the polypeptide therapeutic agent is calculated at a time point later than the typical gastric transit time of a typical example of the subject, e.g. at a time point later than 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 210, 240, 270, 300, 330, or 360 mins from the administration of the polypeptide therapeutic agent, or at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 210, 240, 270, 300, 330, or 360 mins after the typical gastric transit time of a typical example of the subject.

[0282] In these instances, the amount, or concentration, of the polypeptide therapeutic agent is measured in plasma from the superior mesenteric vein, or more specifically the jejunal veins, Ileal veins, ileocolic veins, right colic vein, middle colic vein, pancreatico-duodenal veins, inferior mesenteric vein, left colic vein and / or sigmoid veins.

[0283] It is also explicitly contemplated that the compound of Formula (I), or pharmaceutically acceptable salt thereof, may be provided for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects.

[0284] It is also explicitly contemplated that the compound of Formula (II), or pharmaceutically acceptable salt thereof, may be provided for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects.

[0285] It is also explicitly contemplated that the compound of Formula (I), or pharmaceutically acceptable salt thereof, may be provided for use together with the alginate oligomer and the compound of Formula (II), or pharmaceutically acceptable salts thereof, in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects.

[0286] It is also explicitly contemplated that the compound of Formula (II), or pharmaceutically acceptable salt thereof, may be provided for use together with the alginate oligomer and the compound of Formula (I), or pharmaceutically acceptable salt thereof, in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. It is also explicitly contemplated that the alginate oligomer may be provided for use together with the compound of Formula (II), or pharmaceutically acceptable salt thereof, and the compound of Formula (I), or pharmaceutically acceptable salt thereof, in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects.

[0287] It is also explicitly contemplated that the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof, may be provided together for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. The accompanying discussion applies mutatis mutandis to such aspects.

[0288] It is also explicitly contemplated that the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the alginate oligomer may be provided together for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. The accompanying discussion applies mutatis mutandis to such aspects.

[0289] It is also explicitly contemplated that the compound of Formula (II), or pharmaceutically acceptable salt thereof, and the alginate oligomer may be provided together for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. The accompanying discussion applies mutatis mutandis to such aspects.

[0290] It is also explicitly contemplated that the alginate oligomer, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof, may be provided together for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. The accompanying discussion applies mutatis mutandis to such aspects.

[0291] The invention still further provides a pharmaceutical kit or combination product comprising, separately or in any two-way or three-way combination,

[0292] (i) an alginate oligomer, wherein said alginate oligomer has 2-100 monomer residues, (ii) a compound of Formula (I), or pharmaceutically acceptable salt thereof, and

[0293] (iii) a compound of Formula (II), or pharmaceutically acceptable salt thereof, for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects.

[0294] The invention still further provides a pharmaceutical kit or combination product comprising, separately or in any two-way, three-way or four-way combination,

[0295] (i) an alginate oligomer, wherein said alginate oligomer has 2-100 monomer residues,

[0296] (ii) a compound of Formula (I), or pharmaceutically acceptable salt thereof, (iii) a compound of Formula (II), or pharmaceutically acceptable salt thereof, and

[0297] (iv) a polypeptide therapeutic agent

[0298] for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects.

[0299] The invention still further provides a polypeptide therapeutic agent for use in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. The accompanying discussion applies mutatis mutandis to such aspects.

[0300] In the methods of the invention the polypeptide therapeutic agent, the alginate oligomer, and the gastrointestinal permeation enhancers (namely the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof), may be administered as part of one or more dosage forms or compositions.

[0301] Said one or more dosage forms may, independently, be a dosage form which does not carry a coating in addition to the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or pharmaceutically acceptable salt thereof, which would provide substantive protection from a gastric environment.

[0302] Said one or more dosage forms may, independently, be a dosage form which does not have a structure which would provide to the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or pharmaceutically acceptable salt thereof, which is a part thereof substantive protection from a gastric environment.

[0303] Viewed differently, in these contexts the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or pharmaceutically acceptable salt thereof, are administered to a portion of the intestines in a manner which renders them (e.g. as part of a dosage form which is) substantially susceptible to the potentially deleterious actions of a gastric environment, e.g. a manner which permits or allows exposure to the gastric environment and / or potentially deleterious actions of a gastric environment.

[0304] By “substantive protection from a gastric environment” it is meant that a substantial proportion of the target agent, i.e. the agent under consideration (e.g. the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s) (the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof) administered by oral, orogastric, nasogastric, or intragastric routes is not exposed to the gastric environment, or the potentially deleterious actions of the gastric environment on the target agent are prevented, inhibited or reduced for a substantial proportion of the agent, for the time in which a substantial proportion of the agent, or the dosage form of which it is a part thereof, is resident in the stomach to which is has been administered.

[0305] Thus, “substantive protection from a gastric environment” may be considered to be the means, e.g. the above mentioned coating or structure, to delay the exposure of the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s) to the gastric environment or to delay the potentially deleterious actions of the gastric environment on the target agent, for a time which is about or greater than the time in which a substantial proportion of the agent, or the dosage form of which it is a part thereof, is resident in the stomach of the subject to which is has been administered.

[0306] This may be expressed alternatively as meaning that an insubstantial proportion of the target agent (e.g. the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s)) administered to the subject is exposed to the gastric environment, or the potentially deleterious actions of the gastric environment on the target agent are limited to an insubstantial proportion of the agent, for the time in which a substantial proportion of the agent, or the dosage form of which it is a part thereof, is resident in the stomach of the subject to which is has been administered.

[0307] In more specific terms, “substantive protection from a gastric environment” may be expressed as meaning that a substantial proportion of the target agent (e.g. the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s)), or the dosage form of which it is a part thereof, administered to the subject is stabilised (rendered stable) in the gastric environment for the time in which a substantial proportion of the agent, or the dosage form of which it is a part thereof, is resident in the stomach of the subject to which is has been administered.

[0308] This may be expressed alternatively as meaning that an insubstantial proportion of the target agent (e.g. the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s)), or the dosage form of which it is a part thereof, administered to the subject is destabilised (e.g. denatured, degraded, precipitated, congealed, or inactivated / deactivated for any reason for the agent, or dissolved, dispersed, disintegrated, eroded for the dosage form) in the gastric environment for the time in which a substantial proportion of the agent, or the dosage form of which it is a part thereof, is resident in the stomach of the subject to which is has been administered.

[0309] This may be expressed as being substantially susceptible to being destabilised (e.g. denatured, degraded, precipitated, congealed, or inactivated / deactivated for any reason for the agent, or dissolved, dispersed, disintegrated, eroded for the dosage form) in the gastric environment for the time in which a substantial proportion of the agent, e.g. the dosage form of which it is a part, is resident in the stomach to which is has been administered. It may further be expressed as being unprotected.

[0310] In certain embodiments the dosage form is a dosage form which will lose substantially all cohesion or structural integrity, e.g. is substantially dissolved, dispersed, disintegrated, disaggregated, fragmented, decomposed, eroded, or degraded in the stomach within about 240 mins of entering the stomach, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, 30, 20, 15, 10, or 5 mins of entering the stomach. Likewise, in certain embodiments, the dosage form is a dosage form which would permit a substantial proportion of the target agent to be denatured, degraded, precipitated, congealed or inactivated / deactivated in the stomach within about 240 mins of entering the stomach, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, 30, 20, 15, 10, or 5 mins of entering the stomach.

[0311] In certain embodiments the dosage form is a dosage form which will lose substantially all cohesion or structural integrity (i.e. a substantial proportion of the dosage form will lose cohesion or structural integrity), e.g. is substantially dissolved, dispersed, disintegrated, disaggregated, fragmented, decomposed, eroded, or degraded within about 240 mins of exposure to simulated gastric juice USP (consisting of, in 1000 ml water, 2.0 g NaCI, 3.2g purified pepsin (with activity 800 to 2500 units / mg of protein) and HCI (to pH 1.2)) at 37 °C with stirring at 100 rpm, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, 30, 20, 15, 10, or 5 mins of exposure to simulated gastric juice under such conditions. Dissolution testing may carried out in United States Pharmacopeia (USP) Apparatus I (100 rpm).

[0312] Likewise, in certain embodiments, the dosage form is a dosage form which would permit a substantial proportion of the target agent to be denatured, degraded, precipitated, congealed or inactivated / deactivated within about 240 mins of exposure to simulated gastric juice USP (consisting of, in 1000 ml water, 2.0 g NaCI, 3.2g purified pepsin (with activity 800 to 2500 units / mg of protein) and HCI (to pH 1.2)) at 37 °C with stirring at 100 rpm, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40, 30, 20, 15, 10, or 5 mins of exposure to simulated gastric juice under such conditions. Dissolution testing may carried out in United States Pharmacopeia (USP) Apparatus I (100 rpm).

[0313] In other instances of the methods of the invention the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof, may be administered as part of one or more dosage forms which may, independently, be a dosage form which does have a structure which would provide to the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or a pharmaceutically acceptable salt thereof, which is a part thereof substantive protection from a gastric environment. In these contexts, said one or more dosage forms may, independently, be a dosage form which carries a coating in addition to the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or a pharmaceutically acceptable salt thereof, which would provide substantive protection from a gastric environment.

[0314] A coating or any other dosage form structure which may provide “substantive protection from a gastric environment” may be considered to be one which combats, counteracts, negates, inhibits or reduces potentially deleterious effects of a gastric environment on the target agent (e.g. the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s)), or the dosage form of which it is a part, in particular for the time in which a substantial proportion of the agent, e.g. the dosage form of which it is a part, is resident in the stomach of the subject to which is has been administered.

[0315] A “substantial proportion of the target agent” may be considered to be at least 60%, e.g. at least 65%, 70%, 75%, 80%, 85%, 90% or 95% of the administered dose measured by weight. A “substantial proportion of the dosage form” may be considered to be at least 60%, e.g. at least 65%, 70%, 75%, 80%, 85%, 90% or 95% of the administered dosage form as measured by weight.

[0316] An “insubstantial proportion of the target agent” may be considered to be no more than 40%, e.g. no more than 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the administered dose as measured by weight. An “insubstantial proportion of the dosage form” may be considered to be no more than 40%, e.g. no more than 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the administered dosage form as measured by weight

[0317] The time in which a substantial proportion of the target agent / dosage form will be resident (retained) in the stomach of the subject to which it has been administered will vary between subjects, the agent in question, the constituents and physical properties of the dosage form it is a part thereof and any extraneous liquids or solids consumed with the dosage form, but may be taken to be about 15 mins to about 240 mins, e.g. about 15 mins to about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, or 240 mins, or about 15, 20, 30, 4050, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, or 230 mins to about 240 mins, following entry to the stomach. Any range which may be constructed from the foregoing values is contemplated explicitly.

[0318] This residency / retention time may be viewed as the time in which a substantial proportion of the agent, or the dosage form of which it is a part thereof, transits the stomach of the subject to which is has been administered and enters the intestines essentially unchanged (i.e. not showing deleterious effects of the gastric environment described above).

[0319] Thus, “substantive protection from a gastric environment” may be considered to be prolonged protection, i.e. protection fora substantial proportion of the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s), or the dosage form of which it is a part thereof, against exposure to the gastric environment or the potentially deleterious actions of the gastric environment on the target agent which lasts for a time sufficient to allow a substantial proportion of the agent, or the dosage form of which it is a part thereof, to transit the stomach of the subject to which it has been administered and enter the intestines essentially unchanged.

[0320] Thus, the feature of “substantive protection from a gastric environment” may be considered to be met if a substantial proportion of the target agent (e.g. the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s)), or the dosage form of which it is a part thereof, enters the intestines unchanged within about 240 mins of entering the stomach of the subject, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40 or 30 mins of entering the stomach of the subject to which it has been administered.

[0321] The term “gastric environment” refers to the physical and chemical conditions in the lumen of the stomach of the subject to which the polypeptide therapeutic agent, the alginate oligomer and the gastrointestinal permeation enhancers are administered in accordance with the invention. The precise conditions will vary between subjects, but will typical have a pH of about 1.0 to about 3.5, e.g. about 1.2 to about 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, 3.4 or 3.5 or about 1.4, 1.6, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0, 3.2, or 3.4 to about 3.5. Any range which may be constructed from the foregoing values is contemplated explicitly. The acidification agent is typically hydrochloric acid. Digestive (gastric) enzymes will also be present e.g. proteases (e.g. pepsinogen I, II and III, pepsin and rennin) and lipases (gastric lipase). The term “gastric juice” may refer to the liquid content of the lumen of the stomach and can be taken as having the same physical and chemical properties.

[0322] In certain embodiments references to a gastric environment is a reference to the gastric environment of the subject undergoing treatment.

[0323] The “potentially deleterious actions of the gastric environment” therefore means any negative effects these conditions might have on the physical, chemical or pharmaceutical properties of the polypeptide therapeutic agent, the alginate oligomer and the gastrointestinal permeation enhancers or the structural integrity of the dosage form in the absence of any protection against or mitigation thereof. For the polypeptide therapeutic agent, the alginate oligomer and the gastrointestinal permeation enhancers this includes denaturation, degradation, precipitation, gelation or inactivation / deactivation of the pharmaceutical activity of the treated agent for any reason. For the dosage form this includes dissolution, dispersion, disintegration, disaggregation, fragmentation, decomposition, erosion or any sort of loss of or breakdown in structural cohesion or integrity. Protection from such actions may occur through any mechanism, but includes physical shielding, inhibition of gastric enzyme activity and / or local neutralisation of acidic conditions.

[0324] In certain embodiments, the feature of “substantive protection from a gastric environment” may be considered to be met if an insubstantial proportion of the target agent is denatured, degraded, precipitated, congealed or inactivated / deactivated within about 240 mins of entering the stomach, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40 or 30 mins of entering the stomach of the subject to which it has been administered.

[0325] Likewise, in certain embodiments, the feature of “substantive protection from a gastric environment” may be considered to be met if an insubstantial proportion of the dosage form is lost through dissolution, dispersion, disintegration, disaggregation, fragmentation, decomposition, degradation, erosion or any sort of loss of or breakdown in structural cohesion or integrity within about 240 mins of entering the stomach, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40 or 30 mins of entering the stomach of the subject to which it has been administered. In certain embodiments denaturation, degradation, precipitation, gelation or inactivation / deactivation of the pharmaceutical or physiological activity of the treated agent is irreversible. In contrast, reversible denaturation, degradation, precipitation, gelation or inactivation / deactivation of the pharmaceutical or physiological activity of the treated agent means that the treated agent can return to its essentially normal structure and display essentially normal activity (physiological / pharmaceutical) upon transfer to a less chemically extreme environment, e.g. the blood circulation or other neutral or benign body fluid. Expressed numerically, a return to essentially normal activity may be considered to be recovery of at least 80%, e.g. at least 85%, 90%, 95% or 95% of the relevant physiological or pharmacological activity of the same amount of the untreated agent.

[0326] In certain embodiments the feature of “substantive protection from a gastric environment” may be considered to be met if an insubstantial proportion of the target agent is denatured, degraded, precipitated, congealed or inactivated / deactivated within about 240 mins of exposure to simulated gastric juice USP (consisting of, in 1000 ml water, 2.0 g NaCI, 3.2g purified pepsin (with activity 800 to 2500 units / mg of protein) and HCI (to pH 1.2)) at 37 °C with stirring at 100 rpm, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40 or 30 mins of exposure to simulated gastric juice under such conditions.

[0327] Dissolution testing may be carried out in United States Pharmacopeia (USP) Apparatus I (100 rpm).

[0328] In certain embodiments the feature of “substantive protection from a gastric environment” may be considered to be met if an insubstantial proportion of the dosage form is lost through dissolution, dispersion, disintegration, disaggregation, fragmentation, decomposition, erosion or any sort of loss of or breakdown in structural cohesion or integrity within about 240 mins of exposure to simulated gastric juice USP (consisting of, in 1000 ml water, 2.0 g NaCI, 3.2g purified pepsin (with activity 800 to 2500 units / mg of protein) and HCI (to pH 1.2)) at 37 °C with stirring at 100 rpm, e.g. within about 220, 200, 180, 160, 140, 120, 100, 80, 60, 40 or 30 mins of exposure to simulated gastric juice under such conditions. Dissolution testing may be carried out in United States Pharmacopeia (USP) Apparatus I (100 rpm).

[0329] The dosage forms of use in the invention may take any arrangement common to oral, orogastric, nasogastric, or intragastric administration techniques. Thus, the dosage form may be any pharmaceutically acceptable composition, e.g. in the form of a solution, dispersion, emulsion, powder, tablet, mini tablet, micro tablet, capsule, gel, and the like, or combinations thereof. Conveniently, the dosage form will take the form of a tablet or a liquid, mini tablet, micro tablet or powder filled capsule. These are considered to be examples of a solid dosage form. In certain embodiments the dosage form has dimensions which allow it to be swallowed by the subject undergoing treatment.

[0330] In certain embodiments the dosage form does not comprise, e.g. is not substantially made up of, an alginate oligomer in a solid, e.g. a gelled or partially gelled, form. In particular in certain embodiments the therapeutic polypeptide is not encapsulated by or otherwise associated with an alginate oligomer in a solid, e.g. a gelled or partially gelled, form such that the therapeutic polypeptide is substantively protected from the gastric environment. In certain embodiments the dosage form is not provided such that upon entry into the stomach any alginate oligomer in the dosage form does not encapsulate or otherwise associate with the polypeptide therapeutic agent, e.g. in a solid, in particular a gelled or partially gelled form, such that the therapeutic polypeptide is substantively protected from the gastric environment.

[0331] In certain embodiments the various types of components of the dosage form are not cross-linked to themselves and / or to one another. Such cross-links may be covalent or ionic, e.g. involving divalent cations. In certain embodiments, the alginate oligomer molecules in the dosage form are not cross-linked to one another. In certain embodiments, the alginate oligomer molecules in the dosage form are not cross-linked to other components in the dosage form, e.g. the polypeptide therapeutic agent.

[0332] In certain embodiments the polypeptide therapeutic agent and the alginate oligomer are not provided in the dosage form as a preformed stable non-covalently bonded complex.

[0333] In certain embodiments the polypeptide therapeutic agent is not present as part of the dosage form as a particulate form thereof. In certain embodiments the alginate oligomer is not present in the dosage form as a particulate form thereof. In other embodiments the polypeptide therapeutic agent and / or the alginate oligomer and / or the gastrointestinal permeation enhancers are not present as part of the dosage form in or on a particle. In other embodiments the dosage form does not comprise particles. References to particles above include microparticles and nanoparticles. Microparticles may be considered any particle with a particle size in the micrometre range, i.e. from about 1 µm to about 1000 µm, e.g. about 1 µm to about 900 µm, 800 µm, 700 µm, 600 µm, 500 µm, 400 µm, 300 µm, 200 µm, 100 µm, 50 µm, 40 µm, 30 µm, 20 µm, 10 µm, or 5 µm, or from about 1 µm, 5 µm, 10 µm, 20 µm, 30 µm, 40 µm, 50 µm, 100 µm, 200 µm, 300 µm, 400 µm, 500 µm, 600 µm, 700 µm, 800 µm, or 900 µm to about 1000 µm.

[0334] Nanoparticles may be considered any particle with a particle size in the nanometre range, i.e. from about 1 nm to about 1000 nm, e.g. about 1 nm to about 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 100 nm or 50 nm, or from about 50 nm, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm or 900 nm to about 1000 nm. Any ranges with endpoints which may be formed from any of the above values are expressly disclosed. In the context of nanoparticles, the term "particle size" refers to the size of a particle as measured using a dynamic light scattering method (e.g., quasi-elastic light scattering method). For example, particle sizes can be measured using dynamic light scattering instruments (e.g. Zetasizer Nano ZS model manufactured by Malvern Instruments Ltd. and ELS-8000 manufactured by Otsuka Electronics Co., Ltd.). The instruments measure Brownian motion of the particles and particle size is determined based on established dynamic light scattering methodological theory. In the context of microparticles, the term "particle size" refers to the size of a particle as measured using laser diffraction spectroscopy method. Commercial instruments are available and include the Mastersizer 3000 instrument manufactured by Malvern Instruments Ltd.

[0335] In certain embodiments the dosage form is not bioadhesive, or does not contain bioadhesive components. In certain embodiments the dosage form is not mucoadhesive or does not contain mucoadhesive components.

[0336] The polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s) may together or separately be located in and / or on any part of the dosage form, i.e. present therein or thereon. They maybe intimately mixed or present in a plurality of discrete compartments, e.g. layers. Indeed, it is expressly contemplated that multi-layered dosage form may be provided with an alginate oligomer containing layer surrounding an inner compartment or layer containing the polypeptide therapeutic agent and / or the gastrointestinal permeation enhancer(s). A further arrangement is a multilayered dosage form having an alginate oligomer containing outer layer, an innermost compartment or layer containing the polypeptide therapeutic agent and an intervening layer containing the gastrointestinal permeation enhancer(s). All other physical arrangements of these components, including alternating layers / compartments of two or more components are explicitly contemplated. The presence of excipients, e.g. any of those recited herein, alongside the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s) is explicitly contemplated. In these embodiments the excipients may vary between layers / compartments. In still further arrangements, layers of excipients, e.g. an outer coating layer may be present.

[0337] In certain instances, the dosage forms of which the therapeutic polypeptide, the alginate oligomer and / or the gastrointestinal permeation enhancer(s) (namely, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or a pharmaceutically acceptable salt thereof) of use in the invention are a part thereof may carry a coating (or barrier, layer, or film) in addition to the polypeptide therapeutic agent, the alginate oligomer, and the gastrointestinal permeation enhancers which would provide substantive protection from a gastric environment to one or more of these components.

[0338] Such a coating would be a layer of material in or on the dosage form, typically an outer or outermost layer, that would provide substantive protection from a gastric environment to the parts of the dosage form internal to the coating, e.g. the polypeptide therapeutic agent, the alginate oligomer, and the gastrointestinal permeation enhancers. Such a coating would be formed from materials in addition to the polypeptide therapeutic agent, the alginate oligomer, and the gastrointestinal permeation enhancers which are protective vis a vis the gastric environment, but the presence of the polypeptide therapeutic agent, the alginate oligomer, and / or the gastrointestinal permeation enhancer(s) in the coating is not excluded. In other embodiments the coating is not an alginate oligomer, or does not comprise an alginate oligomer.

[0339] Thus, these compositions (dosage forms) will have a so-called “enteric coating” or layer, i.e. a coating (or barrier, layer, or film) which would remain substantially non-degraded in the stomach of the subject in the time it takes for such a composition to transit the stomach. Enteric coatings are substantially insoluble in the stomach and prevent passage of gastric juice components, such as acids. In some instances, the enteric coating can be designed for either delivery to the proximal small intestine by degrading above pH 5.5 or to the distal small intestine by degrading above pH 7-7.2.

[0340] Such coatings / layers are typically prepared from polymers including fatty acids, waxes, shellac, plastics, and plant fibres. Specific examples thereof include but are not limited to methyl acrylate-methacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate, and those available under the trade name Eudragit, and alginate polymer (i.e. alginates of greater than 35 kDa). Such coatings may be applied in conventional fashion and in conventional thicknesses / amounts.

[0341] In certain instances, therapeutic polypeptide, the alginate oligomer and the gastrointestinal permeation enhancers (namely, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof) may be provided for use in the invention across one or more enteric coated monolithic compositions, e.g. an enteric capsule, enteric coated capsule or an enteric coated tablet, or across one or more different enteric coated multi-particulate compositions, e.g. enteric coated mini tablets. Such enteric coated multiparticulate forms, e.g. mini tablets, may be filled into a standard uncoated capsule.

[0342] In certain embodiments the dosage form and / or the components thereof, e.g. the alginate oligomer, are not conjugated to a polyethylene glycol polymer (PEGylated).

[0343] In certain embodiments the dosage form may consist of the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s).

[0344] In further instances, the structure of the dosage form may provide a target agent (the polypeptide therapeutic agent, the alginate oligomer and / or the gastrointestinal permeation enhancer(s)) or the dosage form of which it is a part thereof with protection from the gastric environment and / or the deleterious action of the gastric environment for a limited period of time or to a limited extent, e.g. for no more than 60 mins, or no more than 55, 50, 45, 40, 35, 30, 25, 20, 10 or 5 mins, of entering the stomach of the subject to which it has been administered, but exposure to the gastric environment and / or the deleterious action of the gastric environment will occur thereafter and before gastric transit / residence / retention of the target agent or the dosage form of which it is a part thereof in complete.

[0345] In certain specific embodiments the dosage form may have a structure in which the alginate oligomer surrounds the polypeptide therapeutic agent and provides the above described limited protection to the polypeptide therapeutic agent for the time it takes for the dosage form to reach the surface of the gastric mucosa.

[0346] The use of the alginate oligomer, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or pharmaceutically acceptable salt thereof, and optionally the polypeptide therapeutic agent in the manufacture of medicaments for use in the above described methods is further contemplated. Such medicaments may be one or more of the above described dosage forms which are administered to the human or non-human animal subject in the course of such methods.

[0347] The above described formulations, compositions and dosage forms may be used in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. In certain instances of the methods described herein, the formulations, compositions and dosage forms, or partially degraded forms thereof, will reach / contact the intestines or portion thereof. In other instances of the methods described herein, the components of the formulations, compositions and dosage forms will reach / contact the intestines or portion thereof. In other instances, both will occur to varying degrees.

[0348] By "use together" or “administered together” or the like, it is meant that the at least four therapeutically active agents of use in the invention (that is the polypeptide therapeutic agent, the alginate oligomer and the gastrointestinal permeation enhancers), are used in combination to achieve the effect in question (e.g. increased systemic bioavailability, intestinal uptake, absorption from the intestines, increased absorption from the intestines, improved effectiveness of the therapeutic polypeptide or treatment or prevention of a disease or condition or complication thereof which is responsive to the therapeutic polypeptide). It is particularly meant that an effective (e.g. pharmaceutically effective) amount of the alginate oligomer is administered at the same or substantially the same time as or prior to administering an effective (e.g. pharmaceutically effective) amount of the therapeutic polypeptide, and the same or substantially the same time as or prior to administering an effective (e.g. pharmaceutically effective) amount of each gastrointestinal permeation enhancer (namely the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt). In other embodiments the oligomer is administered separately to and after the therapeutic polypeptide and / or each gastrointestinal permeation enhancer. In still further embodiments, administration of the alginate oligomer may interspace the administration of the other agents. In still further embodiments, administration of the polypeptide therapeutic agent may interspace the administration of the other agents. The skilled person would readily be able to design a dosage regimen to maximise the effect of the alginate oligomer and therapeutic polypeptide, and the gastrointestinal permeation enhancers that are being used in the methods of the invention. " Use together" does not imply that the respective agents are present in the same dosage form, formulation or composition, and accordingly even if used, or administered, at the same or substantially the same time, the alginate oligomer and therapeutic polypeptide, and the gastrointestinal permeation enhancers, need not be present in the same dosage form, composition or formulation, but may be administered separately. Thus "separate" use / administration includes use / administration at the same or substantially the same time, or at different times, e.g. sequentially, or at different time intervals according to the desired dosage or usage regime. “Simultaneous” administration accordingly includes administration of the alginate oligomer and therapeutic polypeptide, and the gastrointestinal permeation enhancers, within the same dosage form composition or formulation, or within separate compositions / formulations administered at the same or substantially the same time. In accordance with the invention, two or three of the polypeptide therapeutic agent, the alginate oligomer, and the gastrointestinal permeation enhancers (namely the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof), may be administered in one dosage form / composition (e.g. the alginate oligomer and the therapeutic polypeptide, or the alginate oligomer and one or more of the gastrointestinal permeation enhancers, or the therapeutic polypeptide and one or more of the gastrointestinal permeation enhancers) and the other(s) administered in one or more separate dosage form / composition. It may be advantageous if all four agents are administered as a single dosage form composition, e.g. as a solution or in tablet or capsule form.

[0349] Included within the scope of "substantially the same time" is application or administration of the therapeutic polypeptide immediately or almost immediately before or after the alginate oligomer, and / or immediately or almost immediately before or after the gastrointestinal permeation enhancers. The term "almost immediately" may be read as including application or administration within one hour of the previous application or administration, preferably within 30, 20, 10, 5, 4, 3, 2 or 1 minutes. The therapeutic polypeptide can be applied or administered in a plurality of applications prior to, or with, or after the alginate oligomer and the gastrointestinal permeation enhancers. The alginate oligomer can be applied or administered in a plurality of applications prior to, or with, or after the therapeutic polypeptide and the gastrointestinal permeation enhancers. The gastrointestinal permeation enhancers can be applied or administered in a plurality of applications prior to, or with, or after the therapeutic polypeptide and the alginate oligomer.

[0350] Thus, the invention further provides a dosage form adapted for oral, orogastric, nasogastric, or intragastric administration to a human or non-human animal subject, said dosage form comprising

[0351] (i) a polypeptide therapeutic agent,

[0352] (ii) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,

[0353] (iii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0354]

[0355] wherein: X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy;

[0356] R1is hydrogen or C1-3 alkyl;

[0357] R2is hydrogen or C1-3 alkyl;

[0358] R3is -OH;

[0359] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and

[0360] n is an integer from 0 to 4, preferably 0 or 1, and

[0361] (iv) a compound of Formula (II)

[0362] OH

[0363]

[0364] (II)

[0365] wherein:

[0366] Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy,

[0367] wherein said dosage form has a structure which would provide to the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), and / or the compound of Formula (II), or the pharmaceutically acceptable salts thereof, substantive protection from a gastric environment.

[0368] The above detailed discussion of dosage forms of the invention applies mutatis mutandis to this aspect of the invention.

[0369] The above described formulations, compositions and dosage forms may be used in any or all of the above described methods. The accompanying discussion applies mutatis mutandis to such aspects. In certain instances of the methods described herein, the formulations, compositions and dosage forms, or partially degraded forms thereof, will reach / contact the intestines or portion thereof. In other instances of the methods described herein, the components of the formulations, compositions and dosage forms will reach / contact the intestines or portion thereof. In other instances, both will occur to varying degrees.

[0370] The use of the alginate oligomer, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or pharmaceutically acceptable salt thereof, and optionally the polypeptide therapeutic agent in the manufacture of medicaments for use in the above described methods is further contemplated. Such medicaments may be one or more of the above described dosage forms which are administered to the human or non-human animal subject in the course of such methods.

[0371] The compositions and dosage forms of which the therapeutic polypeptide, the alginate oligomer and the gastrointestinal permeation enhancers (namely the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the compound of Formula (II), or a pharmaceutically acceptable salt thereof) of use in the invention are a part thereof are administered to the subject undergoing treatment by oral, orogastric, nasogastric, or intragastric routes. The same or different routes may be used for the various dosage forms being administered in accordance with the invention. It may be convenient to use the same route. Oral administration is preferred on account of its ease and comfort for the subject and hence increase likelihood of compliance.

[0372] Intestinal uptake of an active or reversibly deactivated polypeptide therapeutic agent and / or absorption of an active or reversibly deactivated polypeptide therapeutic agent from a portion of the intestines may be measured by analysing the plasma levels of the active or reversibly deactivated polypeptide therapeutic agent in the time following at least partial gastric emptying (e.g. as defined above). Alternatively, or additionally, these phenomenon may be measured by analysing the comparative plasma levels of the active or reversibly deactivated polypeptide therapeutic agent in the superior mesenteric vein, or more specifically the jejunal veins, Ileal veins, ileocolic veins, right colic vein, middle colic vein, pancreatico-duodenal veins, inferior mesenteric vein, left colic vein and / or sigmoid veins, which drain the gastrointestinal system and the splenic vein which drains the gastric cavity. Gastric uptake / absorption from the stomach (and so not intestinal uptake / absorption) following administration will show as increase plasma concentrations in the splenic vein as compared to the superior mesenteric vein, or more specifically the jejunal veins, Ileal veins, ileocolic veins, right colic vein, middle colic vein, pancreaticoduodenal veins, inferior mesenteric vein, left colic vein and / or sigmoid veins. The same approaches may be more generally applied to a polypeptide therapeutic agent in general terms.

[0373] The methods of the invention may include a step following the administration of the polypeptide therapeutic agent together with an alginate oligomer, and the gastrointestinal permeation enhancers (namely the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof), of measuring intestinal uptake of the polypeptide therapeutic agent, or an active or reversibly deactivated form of the polypeptide therapeutic agent, and / or of measuring absorption of the polypeptide therapeutic agent, or an active or reversibly deactivated form of the polypeptide therapeutic agent, from a portion of the intestines. Any of the above described measuring techniques may be performed. These measurements may be performed within 360, 330, 300, 270, 240, 210, 180, 120, 60, 30, 20, 15, 10, or 5 mins of the administration of the polypeptide therapeutic agent, the alginate oligomer and the gastrointestinal permeation enhancers, whichever is last to be administered.

[0374] The methods of the invention may also or alternatively include a step following the administration of the polypeptide therapeutic agent together with an alginate oligomer, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a compound of Formula (II), or pharmaceutically acceptable salt thereof, of measuring intestinal uptake of the polypeptide therapeutic agent, or an active or reversibly deactivated form of the polypeptide therapeutic agent, and / or of measuring absorption of the polypeptide therapeutic agent, or an active or reversibly deactivated form of the polypeptide therapeutic agent, from a portion of the intestines. Any of the above described measuring techniques may be performed. These measurements may be performed at a time point later than the typical gastric transit time of a typical example of the subject, e.g. at a time point later than 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 210, 240, 270, 300, 330, or 360 mins from the administration of the polypeptide therapeutic agent, the alginate oligomer and the gastrointestinal permeation enhancers, whichever is last to be administered, or at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 210, 240, 270, 300, 330, or 360 mins after the typical gastric transit time of a typical example of the subject. In accordance with the invention uptake / absorption from a portion of the intestines is of the active form of the polypeptide therapeutic agent or a deactivated form which may be reversed. By this it is meant that the polypeptide therapeutic agent is taken up into the blood from the intestinal milieu, e.g. into the superior mesenteric vein, or more specifically the jejunal veins, Ileal veins, ileocolic veins, right colic vein, middle colic vein, pancreaticoduodenal veins, inferior mesenteric vein, left colic vein and / or sigmoid veins, in a form which retains the intrinsic therapeutic activity of the polypeptide, or in a form which reverts to a form displaying the intrinsic therapeutic activity of the polypeptide once in the blood stream of the subject or by the time it reaches its site of therapeutic action. In other words, the polypeptide therapeutic agent is taken up into the blood from the intestinal milieu, e.g. into the superior mesenteric vein, or more specifically the jejunal veins, Ileal veins, ileocolic veins, right colic vein, middle colic vein, pancreatico-duodenal veins, inferior mesenteric vein, left colic vein and / or sigmoid veins, in a form which may be therapeutically effective, or in a form which reverts to a therapeutically effective form once in the blood stream of the subject or by the time it reaches its site of therapeutic action. Thus, the polypeptide therapeutic agent is up taken in a substantially non-degraded, non-deactivated / inactive and / or non-denatured form, or at least a non-irreversibly deactivated / inactive and / or non-irreversibly denatured form.

[0375] As noted above, alginates typically occur as polymers of an average molecular mass of at least 35,000 Daltons, i.e. approximately 175 to approximately 190 monomer residues, although typically much higher and an alginate oligomer according to the present invention may be defined as a material obtained by fractionation (i.e. size reduction) of an alginate polymer, commonly a naturally occurring alginate. An alginate oligomer can be considered to be an alginate of an average molecular weight of less than 15,000 Daltons (i.e. less than approximately 100 monomer residues).

[0376] Accordingly, an oligomer for use according to the invention will contain 2 to 100 monomer residues, e.g. 3, 4, 5 or 6 to 100, and may contain 2, 3, 4, 5 or 6 to 75, 2, 3, 4, 5 or 6 to 50, 2, 3, 4, 5 or 6 to 40, 2, 3, 4, 5 or 6 to 35 or 2, 3, 4, 5 or 6 to 30 residues. Thus, an alginate oligomer for use according to the invention may have an average molecular weight of 350, 550, 700, 900 or 1000 to 15,000 Daltons, 350, 550, 700, 900 or 1000 to 10,000 Daltons, 350, 550, 700, 900 or 1000 to 8000 Daltons, 350, 550, 700, 900 or 1000 to 7000 Daltons, or 350, 550, 700, 900 or 1000 to 6,000 Daltons. Alternatively put, the alginate oligomer may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn) of 2 to 100, preferably 2 to 75, preferably 2 to 50, more preferably 2 to 40, 2 to 35, 2 to 30, 2 to 28, 2 to 25, 2 to 22, 2 to 20, 2 to 18, 2 to 17, 2 to 15 or 2 to 12.

[0377] Other representative ranges (whether for the number of residues, DP or DPn) include any one of 3, 4, 5, 6, 7, 8, 9, 10 or 11 to any one of 50, 45, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13 or 12.

[0378] Other representative ranges (whether for the number of residues, DP or DPn) include any one of 8, 9, 10, 11, 12, 13, 14 or 15 to any one of 50, 45, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17 or 16.

[0379] Other representative ranges (whether for the number of residues, DP or DPn) include any one of 11, 12, 13, 14, 15, 16, 17 or 18 to any one of 50, 45, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20 or 19.

[0380] In general terms, an alginate oligomer will, as noted above, contain (or comprise) guluronate or guluronic acid (G) and / or mannuronate or mannuronic acid (M) residues or units. An alginate oligomer according to the invention will preferably be composed solely, or substantially solely (i.e. consist essentially of) uronate / uronic acid residues, more particularly solely or substantially solely of G and M residues or G residues. Alternatively expressed, in the alginate oligomer of use in the present invention, at least 80%, more particularly at least 85, 90, 95 or 99% of the monomer residues may be uronate / uronic acid residues, or, more particularly G and M residues or G residues. In other words, preferably the alginate oligomer will not comprise other residues or units (e.g. other saccharide residues, or more particularly other uronic acid / uronate residues).

[0381] The alginate oligomer is preferably a linear oligomer.

[0382] The alginate oligomer may contain at least 30% guluronate (or guluronic acid) residues. Specific embodiments thus include alginate oligomers with (e.g. containing) 30 to 70% G (guluronate) residues or 70 to 100% G (guluronate) residues. Thus, a representative alginate oligomer for use according to the present invention may contain at least 70% G residues (i.e. at least 70% of the monomer residues of the alginate oligomer will be G residues).

[0383] Preferably at least 40%, 45%, 50%, 55% or 60%, more particularly at least 70% or 75%, even more particularly at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% of the monomer residues are guluronate. In one embodiment the alginate oligomer may be an oligoguluronate (i.e. a homooligomer of G, or 100% G).

[0384] In a further preferred embodiment, the above described alginates of the invention have a primary structure wherein the majority of the G residues are in so called G-blocks.

[0385] Preferably at least 50%, more preferably at least 70 or 75%, and most preferably at least 80, 85, 90, 92 or 95% of the G residues are in G-blocks. A G block is a contiguous sequence of at least two G residues, preferably at least 3 contiguous G residues, more preferably at least 4 or 5 contiguous G residues, most preferably at least 7 contiguous G residues.

[0386] In particular at least 90% of the G residues are linked 1-4 to another G residue. More particularly at least 95%, more preferably at least 98%, and most preferably at least 99% of the G residues of the alginate are linked 1-4 to another G residue.

[0387] The alginate oligomer of use in the invention is preferably a 3- to 35-mer, more preferably a 3- to 28-mer, in particular a 4- to 25-mer, e.g. a 5- to 20-mer, especially a 6- to 22-mer, in particular an 8- to 20-mer, especially a 10- to 15-mer, e.g. having a molecular weight in the range 350 to 6400 Daltons or 350 to 6000 Daltons, preferably 550 to 5500 Daltons, preferably 750 to 5000 Daltons, and especially 750 to 4500 Daltons or 2000 to 3000 Daltons or 900 to 3500 Daltons. Other representative alginate oligomers include, as mentioned above, oligomers with 5, 6, 7, 8, 9, 10, 11, 12 or 13 to 50, 45, 40, 35, 28, 25, 22 or 20 residues.

[0388] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 3-28, 4-25, 6-22, 8-20 or 10-15, or 5-18 or 7-15 or 8-12, especially 10. The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 3-24, 4-23, 5-22, 6-21, 7-20, 8-19, 9- 18, 10-17, 11-16, 12-15 or 13-14 (e.g. 13 or 14).

[0389] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 4-25, 5-24, 6-23, 7-22, 8-21, 9-20, 10-19, 11-18, 12-17, 13-16, 14-15 (e.g. 14 or 15).

[0390] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 5-26, 6-25, 7-24, 8-23, 9-22, 10-21, 11-20, 12-19, 13-18, 14-17 or 15-16 (e.g. 15 or 16).

[0391] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 4-50, 4-40, 4-35, 4-30, 4-28, 4-26, 4- 22, 4-20, 4-18, 4-16 or 4-14.

[0392] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 5-50, 5-40, 5-25, 5-22, 5-20, 5-18, 5- 23, 5-20, 5-18, 5-16 or 5-14.

[0393] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 6-50, 6-40, 6-35, 6-30, 6-28, 6-26, 6- 24, 6-20, 6-19, 6-18, 6-16 or 6-14.

[0394] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 8-50, 8-40, 8-35, 8-30, 8-28, 8-25, 8-22, 8-20, 8-18, 8-16 or 8-14.

[0395] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 9-50, 9-40, 9-35, 9-30, 9-28, 9-25, 9-22, 9-20, 9-18, 9-16 or 9-14.

[0396] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 10-50, 10-40, 10-35, 10-30, 10-28, 10-25, 10-22, 10-20, 10-18, 10-16 or 10-14. The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 11-50, 11-40, 11-35, 11-30, 11-28, 11-25, 11-22, 11-20, 11-18, 11-16 or 11-14.

[0397] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 12-50, 12-40, 12-35, 12-30, 12-28, 12-25, 12-22, 12-20, 12-18, 12-16 or 12-14.

[0398] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 13-50, 13-40, 13-35, 13-30, 13-28, 13-25, 13-22, 13-20, 13-18, 13-16 or 13-14.

[0399] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 14-50, 14-40, 14-35, 14-30, 14-28, 14-25, 14-22, 14-20, 14-18, 14-16 or 14-15.

[0400] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 15-50, 15-40, 15-35, 15-30, 15-28, 15-25, 15-22, 15-20, 15-18 or 15-16.

[0401] The alginate oligomer of the invention may have a degree of polymerisation (DP), or a number average degree of polymerisation (DPn), of 18-50, 18-40, 18-35, 18-30, 18-28, 18-25, 18-22 or 18-20.

[0402] Preferably the alginate oligomer of the invention is substantially free, preferably essentially free, of alginate oligomers having a degree of polymerisation outside of the ranges disclosed herein. This may be expressed in terms of the molecular weight distribution of the alginate oligomer of the invention, e.g. the percentage of each mole of the alginate oligomer being used in accordance with the invention which has a DP outside the relevant range. The molecular weight distribution is preferably such that no more than 10%, preferably no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1% mole has a DP of three, two or one higher than the relevant upper limit for DPn. Likewise it is preferred that no more than 10%, preferably no more than 9, 8, 7, 6, 5, 4, 3, 2, or 1% mole has a DP below a number three, two or one smaller than the relevant lower limit for DPn. Suitable alginate oligomers are described in W02007 / 039754, W02007 / 039760, WO 2008 / 125828, and W02009 / 068841, the disclosures of which are explicitly incorporated by reference herein in their entirety.

[0403] Representative suitable alginate oligomers have a DPnin the range 5 to 30, a guluronate / galacturonate fraction (FG) of at least 0.80, a mannuronate fraction (FM) of no more than 0.20, and at least 95 mole% of DP no more than 25.

[0404] Further suitable alginate oligomers have a number average degree of polymerization in the range 7 to 15 (preferably 8 to 12), a guluronate / galacturonate fraction (FG) of at least 0.85 (preferably at least 0.90), a mannuronate fraction (FM) of no more than 0.15 (preferably no more than 0.10), and having at least 95% mole with a degree of polymerization less than 17 (preferably less than 14).

[0405] Further suitable alginate oligomers have a number average degree of polymerization in the range 5 to 18 (especially 7 to 15), a guluronate / galacturonate fraction (FG) of at least 0.80 (preferably at least 0.85, especially at least 0.92), a mannuronate fraction (FM) of no more than 0.20 (preferably no more than 0.15, especially no more than 0.08), and having at least 95% mole with a degree of polymerization less than 20 (preferably less than 17).

[0406] Further suitable alginate oligomers have a number average degree of polymerization in the range 5 to 18, a guluronate / galacturonate fraction (FG) of at least 0.92, a mannuronate fraction (FM) of no more than 0.08, and having at least 95% mole with a degree of polymerization less than 20.

[0407] Further suitable alginate oligomers have a number average degree of polymerization in the range 5 to 18 (preferably 7 to 15, more preferably 8 to 12, especially about 10), a guluronate / galacturonate fraction (FG) of at least 0.80 (preferably at least 0.85, more preferably at least 0.90, especially at least 0.92, most especially at least 0.95), a mannuronate fraction (FM) of no more than 0.20 (preferably no more than 0.15, more preferably no more than 0.10, especially no more than 0.08, most especially no more than 0.05), and having at least 95% mole with a degree of polymerization less than 20 (preferably less than 17, more preferably less than 14). Further suitable alginate oligomers have a number average degree of polymerization in the range 7 to 15 (preferably 8 to 12), a guluronate / galacturonate fraction (FG) of at least 0.92 (preferably at least 0.95), a mannuronate fraction (FM) of no more than 0.08 (preferably no more than 0.05), and having at least 95% mole with a degree of polymerization less than 17 (preferably less than 14).

[0408] Further suitable alginate oligomers have a number average degree of polymerization in the range 5 to 18, a guluronate / galacturonate fraction (FG) of at least 0.80, a mannuronate fraction (FM) of no more than 0.20, and having at least 95% mole with a degree of polymerization less than 20.

[0409] Further suitable alginate oligomers have a number average degree of polymerization in the range 7 to 15, a guluronate / galacturonate fraction (FG) of at least 0.85, a mannuronate fraction (FM) of no more than 0.15, and having at least 95% mole with a degree of polymerization less than 17.

[0410] Further suitable alginate oligomers have a number average degree of polymerization in the range 7 to 15, a guluronate / galacturonate fraction (FG) of at least 0.92, a mannuronate fraction (FM) of no more than 0.08, and having at least 95% mole with a degree of polymerization less than 17.

[0411] Further suitable alginate oligomers have a number average degree of polymerization in the range 5 to 20, a guluronate fraction (FG) of at least 0.85 and a mannuronate fraction (FM) of no more than 0.15.

[0412] It will thus be seen that a particular class of alginate oligomers favoured according to the present invention is alginate oligomers defined as so-called "high G" or " G-block" oligomers i.e. having a high content of G residues or G-blocks (e.g. wherein at least 70% of the monomer residues are G, preferably arranged in G-blocks). However, other types of alginate oligomer may also be used, including in particular "high M" or " M-block" oligomers or MG-block oligomers, as described further below. Alginate oligomers with high proportions of a single monomer type, and with said monomers of this type being present predominantly in contiguous sequences of that monomer type, that may be particularly preferred, e.g. oligomers wherein at least 70% of the monomer residues in the oligomer are G residues linked 1-4 to another G-residue, or more preferably at least 75%, and most preferably at least 80, 85, 90, 92, 93, 94, 95, 96, 97, 98, 99% of the monomers residues of the oligomer are G residues linked 1-4 to another G residue. This 1-4 linkage of two G residues can be alternatively expressed as a guluronic unit bound to an adjacent guluronic unit.

[0413] In a further embodiment at least, or more particularly more than, 50% of the monomer residues of the alginate oligomer may be M residues (i.e. mannuronate or mannuronic acid). In other words, the alginate oligomer will contain at least or alternatively more than 50% mannuronate (or mannuronic acid) residues. Specific embodiments thus include alginate oligomers with (e.g. containing) 50 to 70% M (mannuronate) residues or e.g. 70 to 100% M (mannuronate) residues. Further specific embodiments also include oligomers containing 71 to 85% M residues or 85 to 100% M residues. Thus, a representative alginate oligomer for use according to this embodiment of the present invention will contain more than 70% M residues (i.e. more than 70% of the monomer residues of the alginate oligomer will be M residues).

[0414] In other embodiments at least 50% or 60%, more particularly at least 70% or 75%, even more particularly at least 80, 85, 90, 95 or 99% of the monomer residues are mannuronate. In one embodiment the alginate oligomer may be an oligomannuronate (i.e. a homooligomer of M, or 100% M).

[0415] In a further embodiment, the above described alginates of the invention have a primary structure wherein the majority of the M residues are in so called M-blocks. In this embodiment preferably at least 50%, more preferably at least 70 or 75%, and most preferably at least 80, 85, 90 or 95% of the M residues are in M-blocks. An M block is a contiguous sequence of at least two M residues, preferably at least 3 contiguous M residues, more preferably at least 4 or 5 contiguous M residues, most preferably at least 7 contiguous M residues.

[0416] In particular, at least 90% of the M residues are linked 1-4 to another M residue. More particularly at least 95%, more preferably at least 98%, and most preferably at least 99% of the M residues of the alginate are linked 1-4 to another M residue.

[0417] Other preferred oligomers are alginate oligomers wherein at least 70% of the monomer residues in the oligomer are M residues linked 1-4 to another M-residue, or more preferably at least 75%, and most preferably at least 80, 85, 90, 92, 93, 94, 95, 96, 97, 98, 99% of the monomers residues of the oligomer are M residues linked 1-4 to another M residue. This 1-4 linkage of two M residues can be alternatively expressed as a mannuronic unit bound to an adjacent mannuronic unit.

[0418] In a still further embodiment, the alginate oligomers of the invention comprise a sequence of alternating M and G residues. A sequence of at least three, preferably at least four, alternating M and G residues represents an MG block. Preferably the alginate oligomers of the invention comprise an MG block. Expressed more specifically, an MG block is a sequence of at least three contiguous residues consisting of G and M residues and wherein each non-terminal (internal) G residue in the contiguous sequence is linked 1-4 and 4-1 to an M residue and each non-terminal (internal) M residue in the contiguous sequence is linked 1-4 and 4-1 to a G residue. Preferably the MG block is at least 5 or 6 contiguous residues, more preferably at least 7 or 8 contiguous residues.

[0419] In a further embodiment the minority uronate in the alginate oligomer (i.e. mannuronate or guluronate) is found predominantly in MG blocks. In this embodiment preferably at least 50%, more preferably at least 70 or 75% and most preferably at least 80, 85, 90 or 95% of the minority uronate monomers in the MG block alginate oligomer are present in MG blocks. In another embodiment the alginate oligomer is arranged such that at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, e.g. 100% of the G and M residues in the oligomer are arranged in MG blocks.

[0420] Although at its broadest, the invention extends to embodiments wherein at least 1% but less than 100% of the monomer residues of the oligomer are G residues (i.e. guluronate or guluronic acid), more particularly, and as defined further below, at least 30% of the monomer residues are G residues. Thus, at its broadest the MG block containing alginate oligomer may contain at least 1%, but less than 100%, guluronate (or guluronic acid) residues, but generally the MG block containing alginate oligomer will contain at least 30% (or at least 35, 40 or 45% or 50% G) but less than 100% G. Specific embodiments thus include MG block containing alginate oligomers with (e.g. containing) 1 to 30% G (guluronate) residues, 30 to 70% G (guluronate) residues or 70 to 99% G (guluronate) residues. Thus, a representative MG block containing alginate oligomer for use according to the present invention may contain more than 30%, but less than 70%, G residues (i.e. more than 30%, but less than 70%, of the monomer residues of the MG block alginate oligomer will be G residues).

[0421] Preferably more than 30%, more particularly more than 35% or 40%, even more particularly more than 45, 50, 55, 60 or 65%, but in each case less than 70%, of the monomer residues of the MG block containing alginate oligomer are guluronate.

[0422] Alternatively, less than 70%, more preferably less than 65% or 60%, even more preferably less than 55, 50, 45, 40 or 35%, but in each case more than 30% of the monomer residues of the MG block containing alginate oligomer are guluronate. Any range formed by any combination of these values may be chosen. Therefore for instance the MG block containing alginate oligomer can have e.g. between 35% and 65%, 40% and 60% or 45% and 55% G residues.

[0423] In another embodiment the MG block containing alginate oligomer may have approximately equal amounts of G and M residues (e.g. ratios between 65% G / 35% M and 35% G / 65% M, for instance 60% G / 40% M and 40% G / 60% M; 55% G / 45% M and 45% G / 55% M; 53% G / 47% M and 47% G / 53% M; 51% G / 49% M and 49% G / 51% M; e.g. about 50% G and about 50% M) and these residues are arranged predominantly, preferably entirely or as completely as possible, in an alternating MG pattern (e.g. at least 50% or at least 60, 70, 80, 85, 90 or 95% or 100% of the M and G residues are in an alternating MG sequence).

[0424] In certain embodiments the terminal uronic acid residues of the oligomers of the invention do not have a double bond, especially a double bond situated between the C4 and C5 atom. Such oligomers may be described as having saturated terminal uronic acid residues. Thus, in other embodiments the alginate oligomers of the invention have unsaturated terminal uronic acid residues. The skilled man would be able to prepare oligomers with saturated terminal uronic acid residues without undue burden. This may be through the use of production techniques which yield such oligomers, or by converting (saturating) oligomers produced by processes that yield oligomers with unsaturated terminal uronic acid residues.

[0425] The alginate oligomer will typically carry a charge and so counter ions for the alginate oligomer may be any physiologically tolerable ion, especially those commonly used for charged drug substances, e.g. sodium, potassium, ammonium, chloride, mesylate, meglumine, etc. Ions which promote alginate gelation e.g. group 2 metal ions may also be used. Others may include the salt-forming ions mentioned below in the context of the therapeutic polypeptide.

[0426] While the alginate oligomer may be a synthetic material generated from the polymerisation of appropriate numbers of guluronate and mannuronate residues, the alginate oligomers of use in the invention may conveniently be obtained, produced or derived from natural sources such as those mentioned above, namely natural alginate source materials.

[0427] Polysaccharide to oligosaccharide cleavage to produce the alginate oligomer useable according to the present invention may be performed using conventional polysaccharide lysis techniques such as enzymatic digestion and acid hydrolysis. In one favoured embodiment acid hydrolysis is used to prepare the alginate oligomers on the invention. In other embodiments enzymic digestion is used with an additional processing step(s) to saturate the terminal uronic acids in the oligomers.

[0428] Oligomers may then be separated from the polysaccharide breakdown products chromatographically using an ion exchange resin or by fractionated precipitation or solubilisation or filtration. US 6,121,441 and WO 2008 / 125828, which are explicitly incorporated by reference herein in their entirety, describe a process suitable for preparing the alginate oligomers of use in the invention. Further information and discussion can be found in for example in “Handbooks of Hydrocolloids”, Ed. Phillips and Williams, CRC, Boca Raton, Florida, USA, 2000, which textbook is explicitly incorporated by reference herein in its entirety.

[0429] The alginate oligomers may also be chemically modified, including but not limited to modification to add charged groups (such as carboxylated or carboxymethylated glycans) and alginate oligomers modified to alter flexibility (e.g. by periodate oxidation).

[0430] Alginate oligomers (for example oligoguluronic acids) suitable for use according to the invention may conveniently be produced by acid hydrolysis of alginic acid from, but not limited to, Laminaria hyperbora and Lessonia nigrescens, dissolution at neutral pH, addition of mineral acid reduce the pH to 3.4 to precipitate the alginate oligomer (oligoguluronic acid), washing with weak acid, resuspension at neutral pH and freeze drying.

[0431] The alginates for production of alginate oligomers of the invention can also be obtained directly from suitable bacterial sources e.g. Pseudomonas aeruginosa or Azotobacter vinelandii.

[0432] In embodiments where alginate oligomers which have primary structures in which the majority of the G residues are arranged in G-blocks rather than as single residues are required, algal sources are expected to be most suitable on account of the fact that the alginates produced in these organisms tend to have these structures. The bacterial sources may be more suitable for obtaining alginate oligomers of different structures.

[0433] The molecular apparatus involved in alginate biosynthesis in Pseudomonas fluorescens and Azotobacter vinelandii has been cloned and characterised (WO 94 / 09124; Ertesvag, H., etal, Metabolic Engineering, 1999, Vol 1, 262-269; WO 2004 / 011628; Gimmestad, M., et al (supra)-, Remminghorst and Rehm, Biotechnology Letters, 2006, Vol 28, 1701-1712; Gimmestad, M. etal, Journal of Bacteriology, 2006, Vol 188(15), 5551-5560).

[0434] The G content of alginates (for example an algal source material) can be increased by epimerisation, for example with mannuronan C-5 epimerases from A. vinelandii or other epimerase enzymes. Thus, for example in vitro epimerisation may be carried out with isolated epimerases from Pseudomonas or Azotobacter, e.g. AlgG from Pseudomonas fluorescens or Azotobacter vinelandii or the AlgE enzymes (AlgE1 to AlgE7) from Azotobacter vinelandii. The use of epimerases from other organisms that have the capability of producing alginate, particularly algae, is also specifically contemplated. The in vitro epimerisation of low G alginates with Azotobacter vinelandii AlgE epimerases is described in detail in Ertesvag et al (supra) and Strugala et al (Gums and Stabilisers for the Food Industry, 2004, 12, The Royal Society of Chemistry, 84 - 94).

[0435] To obtain G-block containing alginates or alginate oligomers, epimerisation with one or more Azotobacter vinelandii AlgE epimerases other than AlgE4 is preferred as these enzymes are capable of producing G block structures. On the other hand AlgE4 epimerase can be used to create alginates or alginate oligomers with alternating stretches of M / G sequence or primary structures containing single G residue as it has been found that this enzyme seems preferentially to epimerise individual M residues so as to produce single G residues linked to M residues rather than producing G blocks. Particular primary structures can be obtained by using different combinations of these enzymes.

[0436] Mutated versions of these enzymes or homologues from other organisms are also specifically contemplated as of use. WO 94 / 09124 describes recombinant or modified mannuronan C-5 epimerase enzymes (AlgE enzymes) for example encoded by epimerase sequences in which the DNA sequences encoding the different domains or modules of the epimerases have been shuffled or deleted and recombined. Alternatively, mutants of naturally occurring epimerase enzymes, (AlgG or AlgE) may be used, obtained for example by site directed or random mutagenesis of the AlgG or AlgE genes.

[0437] A different approach is to create Pseudomonas and Azotobacter organisms that are mutated in some or all of their epimerase genes in such a way that those mutants produce alginates of the required structure for subsequent alginate oligomer production, or even alginate oligomers of the required structure and size (or molecular weight). The generation of a number of Pseudomonas fluorescens organisms with mutated AlgG genes is described in detail in WO 2004 / 011628 and Gimmestad, M., et al, 2003 (supra). The generation of a number of Azotobacter vinelandii organisms with mutated AlgE genes is disclosed in Gimmestad, M., etal, 2006 (supra). The skilled man would be able to use this teaching to produce new mutants that could be used to give rise to the alginate oligomers of the invention without undue burden.

[0438] A further approach is to delete or inactivate the endogenous epimerase genes from an Azotobacter or a Pseudomonas organism and then to introduce one or more exogenous epimerase genes, which may or may not be mutated (i.e. may be wild-type or modified) and the expression of which may be controlled, for example by the use of inducible or other "controllable promoters". By selecting appropriate combinations of genes, alginates of predetermined primary structure can be produced.

[0439] A still further approach would be to introduce some or all of the alginate biosynthesis machinery of Pseudomonas and / or Azotobacter into a non-alginate producing organism (e.g. E. coli) and to induce the production of alginate from these genetically modified organisms. When these culture-based systems are used, the primary structure of the alginate or alginate oligomer products can be influenced by the culture conditions. It is well within the capabilities of the skilled man to adjust culture parameters such as temperature, osmolarity, nutrient levels / sources and atmospheric parameters in order to manipulate the primary structure of the alginates produced by a particular organism.

[0440] References to " G residues / G" and " M residues / M" or to guluronic acid or mannuronic acid, or guluronate or mannuronate are to be read interchangeably as references to guluronic acid / guluronate and mannuronic acid / mannuronate (specifically a-L-guluronic acid / guluronate and p-D-mannuronic acid / mannuronate), and further include derivatives thereof in which one or more available side chains or groups have been modified without resulting in a capacity to increase systemic bioavailability, intestinal uptake, absorption from at least a portion of the intestines, increased absorption from at least a portion of the intestines, improved effectiveness of the therapeutic polypeptide or treatment or prevention of a disease or condition or complication thereof which is responsive to the therapeutic polypeptide) that is substantially lower than that of the unmodified oligomer. Common saccharide modifying groups would include acetyl, sulphate, amino, deoxy, alcohol, aldehyde, ketone, ester and anhydro groups. Any of these groups may be used to modify the alginate oligomers according to the present invention. The alginate oligomers may also be chemically modified to add charged groups (such as carboxylated or carboxymethylated glycans), and to alter flexibility (e.g. by periodate oxidation). The skilled person would be aware of still further chemical modifications that can be made to the monosaccharide subunits of oligosaccharides and these can be applied to the alginate oligomers of the invention. In other embodiments the alginate oligomers are unmodified, i.e. consist of unmodified G and / or M residues.

[0441] The invention encompasses the use of a single alginate oligomer or a multi plicity / pl urality, e.g. mixture, of different alginate oligomers. Thus, the methods, uses dosage forms, formulations and compositions of the invention may involve or comprise at least one, or one or more, alginate oligomers. Thus, for example, a combination of different alginate oligomers (e.g. two, three, four, five or more) may be used. In this regard, a combination of alginate oligomers may be selected that together give a profile of properties advantageous to the practice of the invention. This may be a combination of different oligomer sizes, different G and M contents and / or different monomer arrangements.

[0442] References herein to “an” or “the” alginate oligomer should be construed as extending to such embodiments, unless context specifically dictates otherwise. In particular, compositions, dosage form, or formulations described herein as “consisting of” a set of components of which “an alginate oligomer” is one, include combinations (multiplicity / plurality) of alginate oligomers as that aforementioned component.

[0443] In certain instances, the alginate oligomer is not an alginate which acts as a gastrointestinal epithelial barrier (epithelium) permeation enhancer in the stomach and / or the intestines (e.g. small intestines (including any of the duodenum, the jejunum, and / or the ileum) or large intestines (e.g. any of the cecum, the colon, the rectum) of the subject. In certain embodiments the alginate oligomer is not an alginate which acts as a gastrointestinal epithelial barrier (epithelium) permeation enhancer in any part of the Gl tract of the subject.

[0444] The therapeutic polypeptide, which term includes therapeutic proteins and therapeutic peptides, polypeptide therapeutic agents and polypeptide therapeutics and the like, may be any peptide or polypeptide capable or exerting a therapeutic effect in an animal subject, either directly or indirectly. The polypeptide can therefore be an activator of a signalling pathway that results in physiological effects, or may be a mediator of such a pathway through effects on the intermediates of such pathways. The polypeptide can exert effects by promoting or interfering with physiological reactions or interaction between biological molecules in the subject, or may be an enzyme which can promote physiological effects through its activity on the components of the cells of the subject or the biological molecules therein. This is not an exhaustive list.

[0445] The polypeptide, which term includes peptides, oligopeptides and proteins, may be a polypeptide found naturally in the subject or other animals or may be a fragment, analogue and / or derivative thereof. The polypeptide may be an artificial construct comprising naturally occurring amino acid sequences or fragments thereof, or man-made amino acid sequences. The amino acid units may be those found in naturally occurring proteins, or may be artificial amino acids or modified forms of natural amino acids, e.g. D forms. The polypeptide may be a protein with a natural physiological functional or comprise an amino acid sequence that has other biological effects when introduced into physiological systems, e.g. an antigen. Antigens may be from parasitic or infective species optionally conjugated to an immunogenic carrier. Such species may for example be bacteria, viruses, yeasts or fungi. The therapeutic polypeptide may be of any size, though typically it will be of at least 500 Da, e.g. at least 750 Da, 1 kDa, 1.5 kDa, 2 kDa, 5kDa, 10 kDa, 20 kDa, 50kDa or 100 kDa. In other embodiments it will be less than 2 MDa, e.g. less than 1,5MDa, 1 MDa, 500kDa, or 200 kDa. Any range with endpoints constructed from any of these values is expressly contemplated.

[0446] Thus, the therapeutic polypeptide may be, or be an analogue of, peptide hormones / growth factors (e.g. insulin, glucagon, glucagon-like peptide-1, amylin (islet amyloid polypeptide; IAPP), peptide YY (PYY; peptide tyrosine tyrosine), oxyntomodulin, somatostatin, angiotensin II endothenlin, gastrin, growth hormone, gonadotrophin, erythropoietin, colony-stimulating factors (e.g. G-CSF), VEGF, EGF, HGF, PDGF, FGF, neurotrophins (e.g. nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4), cytokines (e.g. TNF, IL-1, IL-6, IL-8, IL-10, IFN-y, IFN-a, IFN-, IFN-E, IFN-K and IFN-co, GDF-15), blood factors (e.g. Factor VII, Factor VIII and Factor IX), and enzymes (e.g. glucocerebrosidases, Cas9, Cas 12, Cas 13). The amino acid sequences for such peptides are available from the technical literature.

[0447] Further specific examples include adrenocorticotropic hormone (ACTH), corticotropinreleasing factor, angiotensin, calcitonin, insulin, glucagon, glucagon-like peptide-1, amylin, peptide YY, oxyntomodulin, glucagon-like peptide-2, insulin-like growth factor, insulin-like growth factor-2, gastric inhibitory peptide, growth hormone releasing factor, pituitary adenylate cyclase activating peptide, secretin, enterogastrin, somatostatin, somatotropin, somatomedin, parathyroid hormone, thrombopoietin, follicle-stimulating hormone, erythropoietin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, oxytocin, interferon, and analogues thereof, superoxide dismutase, Cas9, Cas 12, Cas 13, asparaginase, arginase, arginine deaminase, adenosine deaminase and ribonuclease. In certain embodiments the therapeutic polypeptide is not angiotensin, calcitonin, insulin, insulin-like growth factor, or insulin-like growth factor-2.

[0448] In certain embodiments the polypeptide therapeutic agent is not lysozyme, or a lysosome derived polypeptide, or a lysosome, or another enzyme, e.g. L-asparagase. In other embodiments the polypeptide may be or comprise an immunoglobulin amino acid sequence, e.g. an amino sequence derived from IgG, IgA, IgM, IgE, or IgD. The immunoglobulin amino acid sequence may be a fragment, e.g. Fc, Fv, Fab, Fab2, scFV, and variations. In certain embodiments the therapeutic polypeptide may be a therapeutic antibody, in particular a monoclonal antibody. Examples of therapeutic antibodies include bimagrumab, alemtuzumab, bevacizumab, cetuximab, ofatumumab, panitumumab, rituximab, trastuzumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, sutimlimab, anifrolumab, bimekizumab, tralokinumab, evinacumab, aducanumab, ansuvimab, atoltivimab, teprotumumab, eptinezumab, crizanlizumab, brolucizumab, risankizumab, romosozumab, galcanezumab, erenumab, ibalizumab, emicizumab, benralizumab, ocrelizumab, sarilumab, dupilumab, bezlotoxumab, ixekizumab, alirocumab, vedolizumab, tocilizumab, canakinumab, infliximab, adalimumab, omalizumab, efalizumab, golimumab, ustekinumab, certolizumab pegol, ibritumomab or tositumomab.

[0449] In other embodiments the polypeptide may be a polypeptide antibiotic, e.g. anti-infective and antitumor antibiotics, examples of which include actinomycin, gramicidin, tyrocidine, bleomycin, bacitracin, colistin, and polymyxin B.

[0450] In other embodiments the polypeptide may be an antimicrobial peptide or protein, e.g. a host defence peptide or an innate immune peptide. Such peptides are natural or synthetic peptides that have antibacterial, antiviral, antifungal and / or antiparasitic activity. Natural examples may be found in the Antimicrobial Peptide Database hosted by the University of Nebraska Medical Center (aps.unmc.edu / home).

[0451] The term “polypeptide therapeutic agent” and the like encompasses peptides which carry a non-peptide chemical group, e.g. a carbohydrate, lipid, nucleic acid or polyol group. In certain embodiments the polypeptide may be an acylated or PEGylated polypeptide, e.g. an acylated or PEGylated form of any of those disclosed above which is designed to have an increased plasma half-life.

[0452] In further embodiments the polypeptide may be a fusion or chimeric protein of two or more polypeptides or fragments thereof, e.g. any of the specific examples thereof fused to albumin or Fc, or fragments thereof which increase plasma half-life. In certain specific embodiments the therapeutic polypeptide may be an entero-pancreatic hormone, e.g. an incretin peptide, or analogue / mimetic thereof, e.g. glucagon, glucagon-like protein 1, gastric inhibitory peptide (glucose-dependent insulinotropic polypeptide (GIP)) amylin, peptide YY, oxyntomodulin, and exendin-4 peptide. Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism. Such peptides or analogues / mimetics thereof may be considered as agonists for the glucagon receptor, the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide- 1 (GLP-1) receptor, the amylin receptor and / or the peptide YY receptor. In certain embodiments, the therapeutic polypeptide may be dual incretin peptide mimetic compound that is an agonist for the receptors for GIP and GLP-1. The therapeutic polypeptide may be a triple incretin peptide mimetic compound that is an agonist for the receptors for GIP, GLP-1, and glucagon. In more preferred embodiments the polypeptide is an agonist for the human forms of the above discussed receptors.

[0453] Thus, in certain specific embodiments the therapeutic polypeptide may be dulaglutide (Trulicity), exenatide (Byetta), liraglutide (Victoza), semaglutide (Ozempic, Wegovy and Rybelsus), tirzepatide (Mounjaro), albiglutide (Eperzan / Tanzeum), lixisenatide (Lyxumia / Adlyxin), polyethylene glycol loxenatide (Fulaimei) and LY3437943 (retatrutide).

[0454] Likewise, in certain specific embodiments the therapeutic polypeptide may be cotadutide; taspoglutide; langlenatide; beinaglutide; efpeglenatide; LY3502970 (Eli Lilly); LY3537031 (Eli Lilly); LY3493269 (Eli Lilly); HM12525A / JNJ-64565111 (Efmopegdutide; Hanmi Pharmaceuticals); MOD6030 / 1; Prolor / OPKO Biological); SAR425899 (Sanofi);

[0455] MEDI0382 (Medlmmune); MK8521 (Merck); ZP2929 / BI 456906 (Zealand-Boehringer); NN9709 / NNC0090-2746 / MAR709 / RG7697 / R06811135 (Novo Nordisk); SAR441255 (Sanofi); C2816 (Medimmune); ZP3022 (Zealand); NNC 9204-1177 (NN9277) (Novo Nordisk); JNJ-54728518 (Janssen); LY2944876 / TT-401 (Transition Therapeutics); CPD86 (Eli Lilly); SAR438335 (Sanofi); ZP-l-98 (Zealand); ZP-DI-70 (Zealand); HM15211 (Hanmi Pharmaceuticals); NN9423 / MAR423 (Novo Nordisk / Marcadia), PB-719 (PegBio); DD01 (D& D Pharma); survodutide (Boehringer Ingelheim); pramlintide (Symlin of Amylin Pharmaceuticals) cagrilintide (Novo Nordisk); PYY1875 / NNC0165-1875 (Novo Nordisk); pemvidutide (Altimmune); AMG 133 (Amgen); dapiglutide / ZP7570 (Zealand); NN 1213 (Eli Lilly); AZD6234 (AstraZeneca); AZD9550 (AstraZeneca); ZP8396 (Zealand); HM15136 (Hanmi Pharmaceuticals); NNC0165-1562 (Novo Nordisk); Y-14 (Zihipp); VK2735 (Viking Therapeutics); SCO-094 (Scohia Pharma); CT-388 (Carmot Therapeutics);

[0456] Amycretin / NNC0487-0111 (Novo Nordisk); Dacra QWII / KBP089 (Eli Lilly); and ZP6590 (Zealand)..

[0457] In certain specific embodiments the therapeutic polypeptide may be the incretin analogues disclosed in WO 2019 / 125929 and WO2019125938, which are incorporated herein by reference.

[0458] In certain specific embodiments the therapeutic polypeptide may be an oxyntomodulin peptide or analogue / mimetic thereof, e.g. mazdutide / LY3305677 (Eli Lilly). These may be GLP-1 receptor and / or glucagon receptor agonists.

[0459] In certain specific embodiments the therapeutic polypeptide may be any one of the polypeptide incretin analogues referred to in WO 2015 / 185640, WO 2015 / 086733, WO 2015 / 155139, WO 2013 / 164483 or WO 2015 / 086728, which are incorporated herein by reference.

[0460] In certain specific embodiments the therapeutic polypeptide may be any one of the polypeptide incretin analogues referred to in WO 93 / 19175, WO 96 / 29342, WO 98 / 08871, WO 99 / 43707, WO 99 / 43706, WO 99 / 43341, WO 99 / 43708, WO 2005 / 027978, WO 2005 / 058954, WO 2005 / 058958, WO 2006 / 005667, WO 2006 / 037810, WO 2006 / 037811, WO 2006 / 097537, WO 2006 / 097538, WO 2008 / 023050, WO 2009 / 030738, WO 2009 / 030771, or WO 2009 / 030774, each of which is incorporated herein by reference.

[0461] The polypeptide therapeutic may be a fusion protein formed of any of the polypeptides, especially the incretin analogues, referred to herein.

[0462] In certain specific embodiments the therapeutic polypeptide may be a GDF-15 (growth / differentiation factor-15) receptor agonist, e.g. LY3463251, NNC0247-0829 (Novo Nordisk) and JNJ-9090 / CIN-109 (CinRx Pharma)

[0463] In these embodiments the methods of the invention may be directed to the treatment of any disease / disorder involving GLP-1, GIP, glucagon, amylin, peptide YY, or oxyntomodulin (including any disease / disorder involving, or mediated by, a deficiency of GLP-1, GIP, glucagon, amylin, peptide YY, or oxyntomodulin or deficient GLP-1, GIP, glucagon, amylin, peptide YY, or oxyntomodulin signalling). Thus, in these embodiments, the methods of the invention may be directed to the treatment of excess body weight, obesity, diabetes mellitus type II, insulin resistance, prediabetes, gestational diabetes, diabetes mellitus type I, hyperlipemia, metabolic syndrome, cardiovascular diseases (including atherosclerosis, myocardial infarction, coronary heart disease, stroke, heart insufficiency, heart failure (acute or chronic), coronary artery disease, cardiomyopathy, reperfusion injury, cerebral ischemia, left ventricular hypertrophy, arrhythmia, cardiac dysrhythmia, syncope, angina pectoris, stenosis, or restenosis coronary artery diseases), hypertension, fatty liver disease, non-alcoholic steatohepatitis (NASH), chronic kidney disease and polycystic ovary syndrome (PCOS), neuronal dysfunction (e.g. dementia, Alzheimer’s and Parkinson’s Diseases), and to the treatment of conditions and complications associated with (attributed to / caused by) such disorders.

[0464] Such diseases may also be treated by GDF-15 receptor agonists and / or bimagrumab.

[0465] Common side effects observed with polypeptide incretin analogues, GDF-15 receptor agonists and / or bimagrumab may be nausea, vomiting, diarrhoea, abdominal pain and constipation. These effects might be reduced in accordance with the invention because the invention is expected to allow the use of lower doses.

[0466] GIP is a 42-amino acid gastrointestinal regulatory peptide that plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic beta cells in the presence of glucose and protecting pancreatic beta cells. Human GIP has the amino acid sequence: YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO: 2). GLP-1 is a 37- amino acid peptide that stimulates insulin secretion, protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying and food intake which leads to weight loss. Human GLP-1 (7-37) has the amino acid sequence:

[0467] HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1). GIP and GLP-1 are known as incretins; incretin receptor signalling exerts physiologically relevant action critical for glucose homeostasis. In normal physiology, GIP and GLP-1 are secreted from the gut following a meal, and these incretins enhance the physiological response to food including sensation of satiety, insulin secretion, and nutrient disposal. T2D patients have impaired incretin responses. Amylin is a 37 amino acid residue peptide which is co-secreted with insulin from the β-cells of the pancreas. Amylin plays a key role in postprandial satiety regulation by acting on amylin receptors in the brainstem to reduce food intake and improves glucose metabolism by delaying gastric emptying and inhibiting glucagon secretion. Human amylin has the amino acid sequence:

[0468] KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY (SEQ ID NO: 10).

[0469] Peptide YY is a 36 amino acid residue peptide which is co-secreted from the intestinal L cells together with GLP-1 following food intake. Following secretion, peptide YY is rapidly cleaved by dipeptidyl peptidase-4 (DPP-4) to its active form (PYY3-36). This form acts on neuropeptide Y receptor type 2 (Y2R). Y2R receptor is present in the brain and its agonism results in a reduction in food intake and increased satiety. Human PYY3-36has the amino acid sequence: IKPEAPREDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 11). Human PPY has the amino acid sequence:

[0470] YPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRY (SEQ ID NO: 12).

[0471] Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesised inter alia in the L-cells in the distal ileum, in the pancreas and in the brain. Human GLP-1 (7-37) has the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1). Processing of preproglucagon to give GLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells. A simple system is used to describe fragments and analogues of this peptide. Thus, for example, Gly8-GLP-1(7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the amino acid residues Nos.

[0472] 1 to 6 and substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys34(Nε-tetradecanoyl)-GLP-1 (7-37) designates GLP-1 (7-37) wherein the ε-amino group of the Lys residue in position 34 has been tetradecanoylated. Where reference in this text is made to C-terminally extended GLP1 analogues, the amino acid residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in position 39 is also Arg unless otherwise indicated and the optional amino acid residue in position 40 is Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence in human preproglucagon unless otherwise indicated.

[0473] Likewise for N-terminally extended GLP1 analogues the amino acid sequence of this extension is as in the corresponding sequence in human preproglucagon. The term " GLP-1 agonist" as used herein refers to a compound, which fully or partially activates the human GLP-1 receptor, it is thus interchangeable with the term " GLP-1 receptor agonist". In some embodiments the " GLP-1 agonist" binds to a GLP-1 receptor, e.g., with an affinity constant (KD) or activate the receptor with a potency (EC50) of below 1 μM, e.g. below 100 nM as measured by methods known in the art (see e.g. WO 98 / 08871) and exhibits insulinotropic activity, where insulinotropic activity may be measured in vivo or in vitro assays known to those of ordinary skill in the art. For example, the GLP-1 agonist may be administered to an animal with increased blood glucose (e.g. obtained using an Intravenous Glucose Tolerance Test (IVGTT), a person skilled in the art will be able to determine a suitable glucose dosage and a suitable blood sampling regime, e.g. depending on the species of the animal, for the IVGTT) and the plasma insulin concentration measured over time.

[0474] The terms " GIP agonist", “glucagon agonist”, “amylin agonist”, “peptide YY agonist”, " GIP receptor agonist", “glucagon receptor agonist”, “amylin receptor agonist”, and “peptide YY receptor agonist” may be interpreted analogously.

[0475] In some embodiments the GLP-1 agonist is a GLP-1 analogue, optionally comprising one substituent. The term "analogue" as used herein referring to a GLP-1 peptide (hereafter "peptide") means a peptide wherein at least one amino acid residue of the peptide has been substituted with another amino acid residue and / or wherein at least one amino acid residue has been deleted from the peptide and / or wherein at least one amino acid residue has been added to the peptide and / or wherein at least one amino acid residue of the peptide has been modified. Such addition or deletion of amino acid residues may take place at the N-terminal of the peptide and / or at the C-terminal of the peptide.

[0476] GLP-1 analogues include fusion proteins comprising one or more copies of GLP-1, or substitution variants thereof, and one or more additional polypeptides, e.g. albumin. This includes albiglutide, a peptide consisting of 645 proteinogenic amino acids with 17 disulfide bridges linking amino acids 113-122, 135-151, 150-161, 184-229, 228-237, 260-306, 305-313, 325-339, 338-349, 376-421, 420-429, 452-498, 497-508, 521-537, 536-547, 574-619, 618-627. Amino acids 1–30 and 31–60 constitute two copies of modified human GLP-1, the alanine at position 2 having been exchanged for a glycine, and the remaining sequence encoding human albumin. In some embodiments the GLP-1 agonist is a derivative of GLP-1 or a GLP-1 analogue. In the present text, the parent peptide from which such a derivative is formally derived is in some places referred to as the " GLP-1 moiety" of the derivative. The GLP-1 moiety may be a natural GLP-1 amino acid sequence, a fragment thereof, or an analogue of such amino acid sequences. The term "derivative" is used in the present context of GLP-1 peptides and analogues thereof to designate a peptide in which one or more of the amino acid residues of the parent peptide have been chemically modified, e.g. by alkylation, acylation, ester formation or amide formation.

[0477] In some embodiments the GLP-1 agonist is a derivative of exendin-4. This includes lixisenatide, a C-terminal amide modified peptide consisting of the first 39 amino acids in the sequence of Heloderma suspectum exendin-4 with the proline at position 38 omitted and six lysine residues added to the C terminus.

[0478] In some embodiments the GLP-1 agonist is a derivative of GIP. Human GIP has the amino acid sequence: YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO: 2).

[0479] One such example is LY3437943 (retatrutide), a peptide consisting of 39 amino acids engineered from the amino acid sequence of human GIP with three non-coded amino acid substitutions ( Aib (a-amino isobutyric acid) at positions 2 and 20, and aMeL (a-methyl-L-leucine) at position 13) and a C20 fatty diacid moiety conjugated via an AEEA y Glu linker at the position 17 lysine residue (Coskun et al, Clinical and Translational Report; Volume 34 (9), 1234-1247; WO2019125938).

[0480] In certain specific embodiments the therapeutic polypeptide may be liraglutide and structurally related analogues thereof. Liraglutide has the structure of Formula III (SEQ ID NO: 3) and as shown in Figure 5A

[0481] < If.

[0482]

[0483] n l sll\ 'm I I <. O X VKI H \\\ I X < <«>u (Formula III) In certain embodiments, the therapeutic polypeptide may be a GLP-1 derivative as described in WO 98 / 08871, e.g. a GLP-1 derivative wherein at least one amino acid residue of the parent peptide has a lipophilic substituent attached with the proviso that if only one lipophilic substituent is present and this substituent is attached to the N-terminal or to the C-terminal amino acid residue of the parent peptide then this substituent is an alkyl group or a group which has an w-carboxylic acid group.

[0484] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative having only one lipophilic substituent.

[0485] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative having only one lipophilic substituent which substituent is an alkyl group or a group which has an w-carboxylic acid group and is attached to the N-terminal amino acid residue of the parent peptide.

[0486] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative having only one lipophilic substituent which substituent is an alkyl group or a group which has an w-carboxylic acid group and is attached to the C-terminal amino acid residue of the parent peptide.

[0487] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative having only one lipophilic substituent which substituent can be attached to any one amino acid residue which is not the N-terminal or C-terminal amino acid residue of the parent peptide.

[0488] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein two lipophilic substituents are present.

[0489] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein two lipophilic substituents are present, one being attached to the N-terminal amino acid residue while the other is attached to the C-terminal amino acid residue.

[0490] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein two lipophilic substituents are present, one being attached to the N-terminal amino acid residue while the other is attached to an amino acid residue which is not the N-terminal or the C-terminal amino acid residue.

[0491] In another embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein two lipophilic substituents are present, one being attached to the C-terminal amino acid residue while the other is attached to an amino acid residue which is not the N-terminal or the C-terminal amino acid residue.

[0492] In a further embodiment, the therapeutic polypeptide may be a derivative of GLP-1 (7-C), wherein C is selected from the group consisting of 38, 39, 40, 41, 42, 43, 44 and 45 which derivative has just one lipophilic substituent which is attached to the C-terminal amino acid residue of the parent peptide.

[0493] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the lipophilic substituent comprises from 4 to 40 carbon atoms, e.g. from 8 to 25 carbon atoms.

[0494] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to an amino acid residue in such a way that a carboxyl group of the lipophilic substituent forms an amide bond with an amino group of the amino acid residue.

[0495] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to an amino acid residue in such a way that an amino group of the lipophilic substituent forms an amide bond with a carboxyl group of the amino acid residue.

[0496] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer.

[0497] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent, optionally via a spacer, is attached to the e-amino group of a Lys residue contained in the parent peptide. In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an unbranched alkane a, co-dicarboxylic acid group having 1 to 7 methylene groups, preferably two methylene groups which spacer forms a bridge between an amino group of the parent peptide and an amino group of the lipophilic substituent.

[0498] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or a dipeptide such as Gly-Lys. In the present text, the expression "a dipeptide such as Gly-Lys" is used to designate a dipeptide wherein the C-terminal amino acid residue is Lys, His orTrp, preferably Lys, and wherein the N-terminal amino acid residue is selected from the group consisting of Ala, Arg, Asp, Asn, Gly, Glu, Gin, He, Leu, Vai, Phe and Pro.

[0499] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of a Lys residue or a dipeptide containing a Lys residue, and the other amino group of the Lys residue or a dipeptide containing a Lys residue forms an amide bond with a carboxyl group of the lipophilic substituent.

[0500] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein an amino group of the parent peptide forms an amide bond with a carboxylic group of the amino acid residue or dipeptide spacer, and an amino group of the amino acid residue or dipeptide spacer forms an amide bond with a carboxyl group of the lipophilic substituent.

[0501] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys and wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of the amino acid residue spacer or dipeptide spacer, and the carboxyl group of the amino acid residue spacer or dipeptide spacer forms an amide bond with an amino group of the lipophilic substituent.

[0502] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein a lipophilic substituent is attached to the parent peptide by means of a spacer which is an amino acid residue except Cys, or is a dipeptide such as Gly-Lys, and wherein a carboxyl group of the parent peptide forms an amide bond with an amino group of a spacer which is Asp or Glu, or a dipeptide spacer containing an Asp or Glu residue, and a carboxyl group of the spacer forms an amide bond with an amino group of the lipophilic substituent.

[0503] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which comprises a partially or completely hydrogenated cyclopentanophenathrene skeleton.

[0504] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a straight-chain or branched alkyl group.

[0505] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is the acyl group of a straight-chain or branched fatty acid.

[0506] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is an acyl group selected from the group consisting of CH3(CH2)nCO-, wherein n is an integer from 4 to 38, preferably an integer from 4 to 24, e.g. selected from the group consisting of CH3(CH2)eCO-, CHs ChDsCO-, CH3(CH2) CO-, CH3(CH2)I2CO-, CH3(CH2)i4CO-, CH3(CH2)i6CO-, CH3(CH2)i8CO-, CH3(CH2)2OCO-, and CH3(CH2)22CO-,

[0507] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is an acyl group of a straight-chain or branched alkane a,w-dicarboxylic acid.

[0508] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is an acyl group selected from the group consisting of HOOC(CH2)mCO-, wherein m is an integer from 4 to 38, preferably an integer from 4 to 24, e.g. selected from the group consisting of HOOC(CH2)i4CO-, HOOC(CH2)i4CO-, HOOC(CH2)I6CO-, HOOC(CH2)I8CO-, HOOC(CH2)2OCO-, and HOOC(CH2)22CO-,

[0509] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula CH3(CH2)p((CH2)qCOOH)CHNHCO(CH2)2CO-, wherein p and q are integers and p+q is an integer of from 8 to 33, preferably from 12 to 28.

[0510] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula CH3(CH2)rCONHCH(COOH)(CH2)2CO-, wherein r is an integer of from 10 to 24.

[0511] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula CH3(CH2)SCONHCH((CH2)2COOH)CO-, wherein s is an integer of from 8 to 24.

[0512] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula COOH(CH2)tCO- wherein t is an integer of from 8 to 24.

[0513] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NHCO(CH2)UCH3, wherein u is an integer of from 8 to 18.

[0514] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NHCOCH((CH2)2COOH)NH-CO(CH2)WCH3, wherein w is an integer of from 10 to 16.

[0515] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NHCO(CH2)2CH(COOH)NHCO(CH2)XCH3, wherein x is an integer of from 10 to 16. In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which is a group of the formula -NHCH(COOH)(CH2)4NHCO(CH2)2CH(COOH)NHCO(CH2)yCH3, wherein y is zero or an integer of from 1 to 22.

[0516] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative having a lipophilic substituent which can be negatively charged. Such a lipophilic substituent can for example be a substituent which has a carboxyl group.

[0517] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative the parent peptide of which is selected from the group consisting of GLP-1 (1-45) or an analogue thereof.

[0518] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative derived from a GLP-1 fragment selected from the group consisting of GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) and GLP1 (7-41) or an analogue thereof.

[0519] In a further embodiment, the therapeutic polypeptide may be a GLP-1 analogue derived from a GLP-1 analogue selected from the group consisting of GLP-1 (1-35), GLP-1 (1-36), GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1(1-38), GLP-1(1-39), GLP-1(1-40) and GLP-1(1-41) or an analogue thereof.

[0520] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten amino acid residues have been exchanged with any a-amino acid residue.

[0521] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the designation analogue comprises derivatives wherein a total of up to fifteen, preferably up to ten amino acid residues have been exchanged with any a-amino acid residue which can be coded for by the genetic code.

[0522] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the designation analogue comprises derivatives wherein a total of up to six amino acid residues have been exchanged with another a-amino acid residue which can be coded for by the genetic code.

[0523] In a further embodiment, the therapeutic polypeptide may be a GLP-I(A-B) derivative wherein A is an integer from 1 to 7 and B is an integer from 38 to 45 or an analogue thereof comprising one lipophilic substituent attached to the C-terminal amino acid residue and, optionally, a second lipophilic substituent attached to one of the other amino acid residues.

[0524] In a further embodiment, a parent peptide for a GLP-1 derivative of use in the invention is selected from the group consisting of Arg26-GLP-1(7-37); Arg34-GLP- 1(7-37); Lys36-GLP-1(7-37); Arg26,34Lys36-GLP-1(7-37); Arg26,34Lys38GLP-1(7-38); Arg26,34Lys39-GLP-1(7-39); Arg26,34Lys40-GLP- 1(7-40); Arg26Lys36-GLP- 1(7-37); Arg34Lys36-GLP-1(7-37); Arg26Lys39-GLP1(7-39); Arg34Lys40-GLP- 1(7-40); Arg26,34Lys36,39-GLP-1(7-39); Arg26,34Lys36,40-GLP-1(7-40); Gly8Arg26-GLP-1(7-37); Gly8Arg34-GLP-1(7-37); Gly8Lys36-GLP-1 (7-37); Gly8Arg26,34Lys36-GLP-1 (7-37); Gly8Arg26,34Lys39-GLP-1 (7-39); Gly8Arg26,34Lys40-GLP-1(7-40); Gly8Arg26Lys36-GLP- 1(7-37); Gly8Arg34Lys36-GLP-1 (7-37); Gly8Arg26Lys39-GLP-1 (7-39); Gly8Arg34Lys40-GLP1 (7-40);

[0525] Gly8Arg26,34Lys36,39-GLP-1 (7-39) and Gly8Arg26,34Lys36,40-GLP-1 (7-40).

[0526] In a further embodiment, a parent peptide for a GLP-1 derivative of use in the invention is selected from the group consisting of Arg26,34Lys38GLP-1(7-38); Arg26,34Lys39GLP-1(7-39); Arg26,34Lys40GLP-1(7-40); Arg26,34Lys41 GLP-1 (7-41); Arg26,34Lys42GLP-1(7-42); Arg26,34Lys43GLP-1(7-43); Arg26,34Lys44GLP-1(7-44); Arg26,34Lys45GLP-1(7-45); Arg26,34Lys38GLP-1(1-38); Arg26,34Lys39GLP-1(1-39); Arg26,34Lys40GLP-1(1-40); Arg26,34Lys41GLP-1(1-41); Arg26,34Lys42GLP-1(1-42); Arg26,34Lys43GLP-1(1-43); Arg26,34Lys44GLP-1(1-44); Arg26,34Lys45GLP-1(1-45); Arg26,34Lys38GLP-1(2-38); Arg26,34Lys39GLP-1(2-39); Arg26,34Lys40GLP-1(2-40); Arg26,34Lys41GLP-1(2-41); Arg26,34Lys42GLP-1(2-42); Arg26,34Lys43GLP-1(2-43); Arg26,34Lys44GLP-1(2-44); Arg26,34Lys45GLP-1(2-45); Arg26,34Lys38GLP-1(3-38); Arg26,34Lys39GLP-1(3-39); Arg26,34Lys40GLP-1(3-40); Arg26,34Lys41 GLP-1 (3-41); Arg26,34Lys42GLP-1(3-42); Arg26,34Lys43GLP-1(3-43); Arg26,34Lys44GLP-1(3-44); Arg26,34Lys45GLP-1(3-45); Arg26,34Lys38GLP-1(4-38); Arg26,34Lys39GLP-1(4-39); Arg26,34Lys40GLP-1(4-40); Arg26,34Lys41 GLP-1 (4-41); Arg26,34Lys42GLP-1(4-42); Arg26,34Lys43GLP-1(4-43); Arg26,34Lys44GLP-1(4-44); Arg26,34Lys45GLP-1(4-45); Arg26,34Lys38GLP- 1(5-38); Arg26,34Lys39GLP-1(5-39); Arg26,34Lys40GLP-1(5-40); Arg26,34Lys41GLP-1(5-41); Arg26,34Lys42GLP-1(5-42); Arg26,34Lys43GLP-1(5-43); Arg26,34Lys44GLP-1(5-44); Arg26,34Lys45GLP-1(5-45); Arg26,34Lys38GLP-1(6-38); Arg26,34Lys39GLP-1(6-39); Arg26,34Lys40GLP-1(6-40); Arg26,34Lys41GLP-1(6-41); Arg26,34Lys42GLP-1(6-42); Arg26,34Lys43GLP-1(6-43); Arg26,34Lys44GLP-1(6-44); Arg26,34Lys45GLP-1(6-45); Arg26Lys38GLP1(1-38); Arg34Lys38GLP-1(1-38); Arg26,34Lys36,38GLP-1(1-38); Arg26Lys38GLP- 1(7-38); Arg34Lys38GLP-1(7-38); Arg26,34Lys36,38GLP-1(7-38); Arg26, 34Lys38GLP- 1 (7-38); Arg26Lys39G LP1 (1-39); Arg34Lys39G LP- 1 (1-39);

[0527] Arg26,34Lys36,39GLP-1 (1-39); Arg26Lys39GLP-1 (7-39); Arg34Lys39GLP-1 (7-39) and Arg26,34Lys36,39GLP-1 (7-39).

[0528] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the parent peptide is selected from the group consisting of Arg26-GLP- 1(7-37), Arg34-GLP-1 (7-37), Lys36-GLP-1 (7-37), Arg26,34Lys36-GLP-1 (7-37), Arg26Lys36-GLP-1 (7- 37), Arg34Lys36-GLP-1 (7-37), Gly6Arg26-GLP-1 (7-37), Gly8Arg34-GLP-1 (7-37), Gly8Lys36-GLP-1 (7- 37), Gly8Arg26,34Lys-GLP-1 (7-37), Giy8Arg26Lys36-GLP-1 (7-37) and Gly8Arg34Lys36-GLP-1 (7-37).

[0529] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the parent peptide is selected from the group consisting of Arg26Lys38-GLP- 1(7-38), Arg26,34Lys38-GLP-1 (7-38), Arg26,34Lys36,38-GLP-1 (7-38), Gly8Arg26Lys38-GLP-1 (7- 38) and Gly8Arg26,34Lys36,38-GLP-1(7-38).

[0530] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the parent peptide is selected from the group consisting of Arg26Lys39-GLP- 1(7-39), Arg26,34Lys36,39-GLP-1 (7-39), Gly8Arg26Lys39-GLP-1 (7-39) and

[0531] Gly8Arg26, 34Lys36, 39-G LP- 1 (7-39).

[0532] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative wherein the parent peptide is selected from the group consisting of Arg34Lys40-GLP- 1(7-40), Arg26,34Lys36,40-GLP-1(7-40), Gly8Arg34Lys40-GLP-1(7-40) and Gly8Arg26,34Lys36,40-GLP-1(7-40),

[0533] In a further embodiment, the therapeutic polypeptide may be a GLP-1 derivative which is selected from the group consisting of: Lys26(Nε-tetradecanoyl)-GLP-1 (7-37);

[0534] Lys34(Nε-tetradecanoyl)-GLP-1 (7-37);

[0535] Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-37);

[0536] Gly8Lys26(Nε-tetradecanoyl)-GLP-1 (7-37);

[0537] Gly8Lys34(N£-tetradecanoyl)-G LP- 1 (7-37);

[0538] Gly8Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-37); Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-37);

[0539] Lys26(N£-tetradecanoyl)-G LP- 1 (7-38);

[0540] Lys34(N£-tetradecanoyl)-GLP-1 (7-38);

[0541] Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-38);

[0542] Gly8Lys26(N£-tetradecanoyl)-GLP-1(7-38);

[0543] Gly8Lys34(N£-tetradecanoyl)-GLP-1(7-38);

[0544] Gly8Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-38); Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-38);

[0545] Lys26(N£-tetradecanoyl)-GLP- 1(7-39);

[0546] Lys34(N£-tetradecanoyl)-GLP-1 (7-39);

[0547] Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-39);

[0548] Gly8Lys26(N£-tetradecanoyl)-GLP-1(7-39);

[0549] Gly8Lys34(Nε-tetradecanoyl)-GLP-1 (7-39);

[0550] Gly8Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-39); Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-39);

[0551] Lys26(N£-tetradecanoyl)-G LP- 1 (7-40);

[0552] Lys34(Nε-tetradecanoyl)-GLP-1 (7-40);

[0553] Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-40);

[0554] Gly8Lys26(N£-tetradecanoyl)-GLP-1(7-40);

[0555] Gly8Lys34(N£-tetradecanoyl)-GLP-1(7-40);

[0556] Gly8Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-40); Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-40);

[0557] Lys26(N£-tetradecanoyl)-G LP- 1 (7-36);

[0558] Lys34(N£-tetradecanoyl)-G LP- 1 (7-36);

[0559] Lys26,34-bis(N£-tetradecanoyl)-GLP-1 (7-36);

[0560] Gly8Lys26(N£-tetradecanoyl)-GLP-1(7-36);

[0561] Gly8Lys34(N£-tetradecanoyl)-GLP-1(7-36);

[0562] Gly8Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-36); Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-36); Lys26(N£-tetradecanoyl)-G LP- 1 (7-35);

[0563] Lys34(N£-tetradecanoyl)-GLP-1 (7-35);

[0564] Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-35);

[0565] Gly8Lys26(N£-tetradecanoyl)-GLP-1(7-35);

[0566] Gly8Lys34(N£-tetradecanoyl)-GLP-1(7-35);

[0567] Gly8Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-35);

[0568] Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-35);

[0569] Lys26(N£-tetradecanoyl)-GLP-1 (7-36)amide;

[0570] Lys34(N£-tetradecanoyl)-GLP-1(7-36)amide;

[0571] Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-36)amide;

[0572] Gly8Lys26(N£-tetradecanoyl)-GLP-1(7-36)amide;

[0573] Gly8Lys34(N£-tetradecanoyl)-GLP-1(7-36)amide;

[0574] Gly8Lys26,34-bis(N£-tetradecanoyl)-GLP-1(7-36)amide; Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-36)amide;

[0575] Gly8Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-37);

[0576] Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-37);

[0577] Gly8Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-37);

[0578] Arg26,34Lys36(N£-tetradecanoyl)-GLP-1(7-37);

[0579] Gly8Arg26, 34Lys36(N£-tetradecanoyl)-G LP- 1 (7-37);

[0580] Gly8Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-38);

[0581] Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-38);

[0582] Gly8Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-38);

[0583] Arg26,34Lys36(N£-tetradecanoyl)-GLP-1(7-38);

[0584] Arg26,34 Lys38(N£-tetradecanoyl)-GLP-1 (7-38);

[0585] Gly8Arg26,34Lys36(N£-tetradecanoyl)-GLP-1(7-38);

[0586] Gly8Arg26Lys34(N£-tetradecanoyl)-GLP-1(7-39);

[0587] Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-39);

[0588] Gly8Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-39);

[0589] Arg26,34Lys36(Nε-tetradecanoyl)-GLP-1(7-39);

[0590] Gly8Arg26,34Lys36(N£-tetradecanoyl)-GLP-1(7-39);

[0591] Gly8Arg26Lys34(Nε-tetradecanoyl)-GLP-1 (7-40);

[0592] Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-40);

[0593] Gly8Lys26(N£-tetradecanoyl)Arg34-GLP-1(7-40);

[0594] Arg26,34Lys36(N£-tetradecanoyl)-GLP-1(7-40);

[0595] Gly8Arg26,34Lys36(Nε-tetradecanoyl)-GLP-1(7-40); Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0596] Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0597] Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0598] Gly8Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0599] Gly8Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0600] Gly8Lys26,34-bis(Nε-(ω-carboxynonadecanoyl))-GLP-1(7-37); Lys26(N£-(w-carboxynonadecanoyl))-GLP-1 (7-38);

[0601] Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-38);

[0602] Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-38);

[0603] Gly8Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-38);

[0604] Gly8Lys34(Nε-(ω-carboxynonadecanoyl))-GLP-1(7-38);

[0605] Gly8Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-38); Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0606] Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0607] Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0608] Gly8Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0609] Gly8Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0610] Gly8Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-39); Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-40);

[0611] Lys34(Nε-(ω-carboxynonadecanoyl))-GLP-1 (7-40);

[0612] Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-40);

[0613] Gly8Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-40);

[0614] Gly8Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-40);

[0615] Gly8Lys26,34-bis(Nε-(ω-carboxynonadecanoyl))-GLP-1(7-40);

[0616] Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-36);

[0617] Lys34(N£-(w-carboxynonadecanoyl))-GLP-1 (7-36);

[0618] Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1 (7-36);

[0619] Gly8Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-36);

[0620] Gly8Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-36);

[0621] Gly8Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1 (7-36); Lys26(N£-(w-carboxynonadecanoyl))-GLP-1 (7-36)amide;

[0622] Lys34(N£-(w-carboxynonadecanoyl))-GLP-1 (7-36)amide;

[0623] Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-36)amide; Gly8Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-36)amide; Gly8Lys34(Nε-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide; Gly8Lys26,34-bis(Nε-(ω-carboxynonadecanoyl))-GLP-1(7-36)amide; Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-35);

[0624] Lys34(N£-(w-carboxynonadecanoyl))-GLP-1 (7-35);

[0625] Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-35);

[0626] Gly8Lys26(N£-(w-carboxynonadecanoyl))-GLP-1(7-35);

[0627] Gly8Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-35);

[0628] Gly8Lys26,34-bis(N£-(w-carboxynonadecanoyl))-GLP-1(7-35);

[0629] Arg26Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0630] Gly8Arg26Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0631] Lys26(N£-(w-carboxynonadecanoyl))Arg34-GLP- 1(7-37);

[0632] Gly8Lys26(N£-(w-carboxynonadecanoyl))Arg34-GLP-1(7-37);

[0633] Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1(7-37);

[0634] Gly8Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1(7-37); Arg26Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-38);

[0635] Gly8Arg26Lys34(Nε-(ω-carboxynonadecanoyl))-GLP-1 (7-38); Lys26(N£-(w-carboxynonadecanoyl))Arg34-GLP- 1(7-38);

[0636] Gly8Lys26(Nε-(ω-carboxynonadecanoyl))Arg34-GLP-1 (7-38);

[0637] Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1(7-38);

[0638] Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1(7-38);

[0639] Gly8Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1 (7-38); Arg26Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0640] Gly8Arg26Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0641] Lys26(N£-(w-carboxynonadecanoyl))Arg34-GLP- 1(7-39);

[0642] Gly8Lys26(N£-(w-carboxynonadecanoyl))Arg34-GLP-1(7-39);

[0643] Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1(7-39);

[0644] Gly8Arg26,34Lys36(Nε-(ω-carboxynonadecanoyl))-GLP-1(7-39); Arg26Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-40);

[0645] Gly8Arg26Lys34(N£-(w-carboxynonadecanoyl))-GLP-1(7-40);

[0646] Lys26(Nε-(ω-carboxynonadecanoyl))Arg34-GLP-1(7-40);

[0647] Gly8Lys26(N£-(w-carboxynonadecanoyl))Arg34-GLP-1(7-40);

[0648] Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1(7-40);

[0649] Gly8Arg26,34Lys36(N£-(w-carboxynonadecanoyl))-GLP-1(7-40); Lys26(N£-(7-deoxycholoyl))-GLP-1 (7-37);

[0650] Lys34(Nε-(7-deoxycholoyl))-GLP-1 (7-37);

[0651] Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-37); Gly8Lys26(N£-(7-deoxycholoyl))-GLP-1(7-37);

[0652] Gly8Lys34(N£-(7-deoxycholoyl))-GLP-1(7-37);

[0653] Gly8Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-37); Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-37);

[0654] Lys26(N£-(7-deoxycholoyl)-GLP- 1(7-38);

[0655] Lys34(N£-(7-deoxycholoyl)-GLP- 1(7-38);

[0656] Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0657] Gly8Lys26(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0658] Gly8Lys34(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0659] Gly8Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-38); Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0660] Lys26(N£-(7-deoxycholoyl))-GLP-1 (7-39);

[0661] Lys34(Nε-(7-deoxycholoyl))-GLP-1 (7-39);

[0662] Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-39);

[0663] Gly8Lys26(N£-(7-deoxycholoyl))-GLP-1(7-39);

[0664] Gly8Lys34(N£-(7-deoxycholoyl))-GLP-1(7-39);

[0665] Gly8Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-39); Arg26Lys34(N£-(7-deoxycholoyl)-GLP-1(7-39);

[0666] Lys26(N£-(7-deoxycholoyl))-GLP- 1(7-40);

[0667] Lys34(N£-(7-deoxycholoyl))-GLP-1 (7-40);

[0668] Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-40);

[0669] Gly8Lys26(N£-(7-deoxycholoyl))-GLP-1(7-40);

[0670] Gly8Lys34(N£-(7-deoxycholoyl))-GLP-1(7-40);

[0671] Gly8Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1 (7-40); Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-40);

[0672] Lys26(Nε-(7-deoxycholoyl))-GLP-1 (7-36);

[0673] Lys34(N£-(7-deoxycholoyl))-GLP- 1(7-36);

[0674] Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-36);

[0675] Gly8Lys26(N£-(7-deoxycholoyl))-GLP-1(7-36);

[0676] Gly8Lys34(N£-(7-deoxycholoyl))-GLP-1(7-36);

[0677] Gly8Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-36); Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-36);

[0678] Lys26(N£-(7-deoxycholoyl))-GLP-1(7-35);

[0679] Lys34(N£-(7-deoxycholoyl))-GLP-1 (7-35);

[0680] Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-35); Gly8Lys26(N£-(7-deoxycholoyl))-GLP-1(7-35);

[0681] Gly8Lys34(N£-(7-deoxycholoyl))-GLP-1(7-35);

[0682] Gly8Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-35);

[0683] Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-35);

[0684] Lys26(N£-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0685] Lys34(N£-(7-deoxycholoyl))-GLP-1 (7-36)amide;

[0686] Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0687] Gly8Lys26(N£-(7-deoxycholoyl))-GLP-1(7-36)amide;

[0688] Gly8Lys34(N£-(7-deoxycholoyl))-GLP-1 (7-36)amide;

[0689] Gly8Lys26,34-bis(N£-(7-deoxycholoyl))-GLP-1(7-36)amide; Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1 (7-36)amide;

[0690] Gly8Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-37);

[0691] Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1(7-37);

[0692] Gly8Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1(7-37);

[0693] Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1(7-37);

[0694] Gly8Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1 (7-37);

[0695] Lys26(N£-(choloyl))-GLP-1(7-37);

[0696] Lys34(N£-(choloyl))-GLP-1(7-37);

[0697] Lys26,34-bis(N£-(choloyl))-GLP-1 (7-37);

[0698] Gly8Lys26(Nε-(choloyl))-GLP-1 (7-37);

[0699] Gly8Lys34(N£-(choloyl))-GLP-1(7-37);

[0700] Gly8Lys26,34-bis(N£-(choloyl))-GLP-1(7-37);

[0701] Arg26Lys34(N£-(choloyl))-GLP-1(7-37);

[0702] Gly8Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0703] Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1 (7-38);

[0704] Gly8Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1(7-38);

[0705] Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0706] Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0707] Gly8Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1(7-38);

[0708] Lys26(N£-(choloyl))-GLP-1(7-38);

[0709] Lys34(N£-(choloyl))-GLP-1(7-38);

[0710] Lys26,34-bis(N£-(choloyl))-GLP-1(7-38);

[0711] Gly8Lys26(N£-(choloyl))-GLP-1(7-38);

[0712] Gly8Lys34(N£-(choloyl))-GLP-1(7-38);

[0713] Gly8Lys26,34-bis(N£-(choloyl))-GLP-1 (7-38); Arg26Lys34(N£-(choloyl))-GLP-1 (7-38);

[0714] Gly8Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-39);

[0715] Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1(7-39);

[0716] Gly8Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1(7-39);

[0717] Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1(7-39);

[0718] Gly8Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1(7-39); Lys26(N£-(choloyl))-GLP-1 (7-39);

[0719] Lys34(N£-(choloyl))-GLP-1(7-39);

[0720] Lys26,34-bis(N£-(choloyl))-GLP-1(7-39);

[0721] Gly8Lys26(N£-(choloyl))-GLP-1(7-39);

[0722] Gly8Lys34(N£-(choloyl))-GLP-1(7-39);

[0723] Gly8Lys26,34-bis(N£-(choloyl))-GLP-1(7-39);

[0724] Arg26Lys34(N£-(choloyl))-GLP-1(7-39), Gly8Arg26Lys34(N£-(7-deoxycholoyl))-GLP-1(7-40);

[0725] Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1(7-40);

[0726] Gly8Lys26(N£-(7-deoxycholoyl))Arg34-GLP-1(7-40);

[0727] Arg26,34Lys36(N£-(7-deoxycholoyl))-GLP-1(7-40);

[0728] Gly8Arg26,34Lys36(Nε-(7-deoxycholoyl))-GLP-1(7-40); Lys26(Nε-(choloyl))-GLP-1 (7-40);

[0729] Lys34(Nε-(choloyl))-GLP-1 (7-40);

[0730] Lys26,34-bis(N£-(choloyl))-GLP-1(7-40);

[0731] Gly8Lys26(N£-(choloyl))-GLP-1 (7-40);

[0732] Gly8Lys34(N£-(choloyl))-GLP-1(7-40);

[0733] Gly8Lys26,34-bis(N£-(choloyl))-GLP-1(7-40);

[0734] Arg26Lys34(N£-(choloyl))-GLP-1(7-40);

[0735] Lys26(N£-(choloyl))-GLP-1 (7-36);

[0736] Lys34(N£-(choloyl))-GLP-1(7-36);

[0737] Lys26,34-bis(N£-(choloyl))-GLP-1(7-36);

[0738] Gly8Lys26(N£-(choloyl))-GLP-1(7-36);

[0739] Gly8Lys34(N£-(choloyl))-GLP-1(7-36);

[0740] Gly8Lys26,34-bis(N£-(choloyl))-GLP-1(7-36);

[0741] Arg26Lys34(N£-(choloyl))-GLP-1(7-36);

[0742] Lys26(N£-(choloyl))-GLP-1(7-35); Lys34(N£-(choloyl))-GLP-1(7-35);

[0743] Lys26,34-bis(N£-(choloyl))-GLP-1(7-35);

[0744] Gly8Lys26(N£-(choloyl))-GLP-1(7-35);

[0745] Gly8Lys34(N£-(choloyl))-GLP-1 (7-35);

[0746] Gly8Lys26,34-bis(N£-(choloyl))-GLP-1(7-35);

[0747] Arg26Lys34(N£-(choloyl))-GLP-1(7-35);

[0748] Lys26(N£-(choloyl))-GLP-1 (7-36)amide;

[0749] Lys34(N£-(choloyl))-GLP-1 (7-36)amide;

[0750] Lys26,34-bis(N£-(choloyl))-GLP-1(7-36)amide;

[0751] Gly8Lys26(Nε-(choloyl))-GLP-1 (7-36)amide;

[0752] Gly8Lys34(N£-(choloyl))-GLP-1(7-36)amide;

[0753] Gly8Lys26,34-bis(N£-(choloyl))-GLP-1(7-36)amide; Arg26Lys34(N£-(choloyl))-GLP-1(7-36)amide;

[0754] Gly8Arg26Lys34(N£-(choloyl))-GLP-1(7-37);

[0755] Lys26(N£-(choloyl))Arg34-GLP-1(7-37);

[0756] Gly8Lys26(Nε-(choloyl))Arg34-GLP-1 (7-37);

[0757] Arg26,34Lys36(N£-(choloyl))-GLP-1(7-37);

[0758] Gly8Arg26,34Lys36(N£-(choloyl))-GLP-1(7-37);

[0759] Lys26(N£-(lithocholoyl))-GLP-1 (7-37);

[0760] Lys34(N£-(lithocholoyl))-GLP-1(7-37);

[0761] Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-37);

[0762] Gly8Lys26(Nε-(lithocholoyl))-GLP-1(7-37);

[0763] Gly8Lys34(Nε-(lithocholoyl))-GLP-1(7-37);

[0764] Gly8Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-37); Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-37);

[0765] Gly8Arg26Lys34(N£-(choloyl))-GLP-1(7-38);

[0766] Lys26(N£-(choloyl))Arg34-GLP-1(7-38);

[0767] Gly8Lys26(N£-(choloyl))Arg34-GLP-1(7-38);

[0768] Arg26,34Lys36(N£-(choloyl))-GLP-1(7-38);

[0769] Arg26,34Lys38(N£-(choloyl))-GLP-1(7-38);

[0770] Gly8Arg26,34Lys36(N£-(choloyl))-GLP-1(7-38);

[0771] Lys26(N£-(lithocholoyl))-GLP-1 (7-38);

[0772] Lys34(N£-(lithocholoyl))-GLP-1(7-38);

[0773] Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-38);

[0774] Gly8Lys26(N£-(lithocholoyl))-GLP-1(7-38); Gly8Lys34(N£-(lithocholoyl))-GLP-1(7-38);

[0775] Gly8Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-38); Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-38);

[0776] Gly8Arg26Lys34(N£-(choloyl))-GLP-1(7-39);

[0777] Lys26(N£-(choloyl))Arg34-GLP-1(7-39);

[0778] Gly8Lys26(N£-(choloyl))Arg34-GLP-1(7-39);

[0779] Arg26,34Lys36(N£-(choloyl))-GLP-1(7-39);

[0780] Gly8Arg26,34Lys36(Nε-(choloyl))-GLP-1(7-39); Lys26(N£-(lithocholoyl))-GLP-1(7-39);

[0781] Lys34(N£-(lithocholoyl))-GLP-1(7-39);

[0782] Lys26,34-bis(N£-(lithocholoyl))-GLP-1 (7-39);

[0783] Gly8Lys26(N£-(lithocholoyl))-GLP-1(7-39);

[0784] Gly8Lys34(N£-(lithocholoyl))-GLP-1(7-39);

[0785] Gly8Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-39); Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-39);

[0786] Gly8Arg26Lys34(N£-(choloyl))-GLP-1 (7-40);

[0787] Lys26(N£-(choloyl))Arg34-GLP-1(7-40);

[0788] Gly8Lys26(N£-(choloyl))Arg34-GLP-1(7-40);

[0789] Arg26,34Lys36(N£-(choloyl))-GLP-1(7-40);

[0790] Arg26,34Lys38(N£-(choloyl))-GLP-1(7-40);

[0791] Gly8Arg26,34Lys36(N£-(choloyl))-GLP-1(7-40); Lys26(N£-(lithocholoyl))-GLP-1 (7-40);

[0792] Lys34(N£-(lithocholoyl))-GLP-1(7-40);

[0793] Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-40);

[0794] Gly8Lys26(N£-(lithocholoyl))-GLP-1(7-40);

[0795] Gly8Lys34(N£-(lithocholoyl))-GLP-1(7-40);

[0796] Gly8Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-40); Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-37);

[0797] Lys26(N£-(lithocholoyl))-GLP-1 (7-36);

[0798] Lys34(N£-(lithocholoyl))-GLP-1(7-36);

[0799] Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-36);

[0800] Gly8Lys26(Nε-(lithocholoyl))-GLP-1(7-36);

[0801] Gly8Lys34(N£-(lithocholoyl))-GLP-1(7-36);

[0802] Gly8Lys26,34-bis(Nε-(lithocholoyl))-GLP-1(7-36); Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-36), Lys26(N£-(lithocholoyl))-GLP-1(7-35);

[0803] Lys34(N£-(lithocholoyl))-GLP-1 (7-35);

[0804] Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-35);

[0805] Gly8Lys26(N£-(lithocholoyl))-GLP-1(7-35);

[0806] Gly8Lys34(N£-(lithocholoyl))-GLP-1(7-35);

[0807] Gly8Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-35);

[0808] Arg26Lys34(N£-(lithocholoyl))-GLP-1 (7-35);

[0809] Lys26(N£-(lithocholoyl))-GLP-1-(7-36)amide;

[0810] Lys34(N-(lithocholoyl))-GLP-1(7-36)amide;

[0811] Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-36)amide;

[0812] Gly8Lys26(N£-(lithocholoyl))-GLP-1(7-36)amide;

[0813] Gly8Lys34(N£-(lithocholoyl)-GLP-1(7-36)amide;

[0814] Gly8Lys26,34-bis(N£-(lithocholoyl))-GLP-1(7-36)amide; Arg26Lys34(N£-(lithocholoyl))-GLP-1 (7-36)amide;

[0815] Gly8Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-37);

[0816] Lys26(N£-(lithocholoyl))Arg34-GLP-1(7-37);

[0817] Gly8Lys26(N£-(lithocholoyl))Arg34-GLP-1(7-37);

[0818] Arg26,34Lys36(N£-(lithocholoyl))-GLP-1(7-37);

[0819] Gly8Arg26,34Lys36(N£-(lithocholoyl))-GLP-1(7-37);

[0820] Gly8Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-38);

[0821] Lys26(N£-(lithocholoyl))AFS34-GLP-1 (7-38);

[0822] Gly8Lys26(N£-(lithocholoyl))Arg34-GLP-1(7-38);

[0823] Arg26,34Lys36(N£-(lithocholoyl))-GLP-1(7-38);

[0824] Arg26,34Lys36(N£-(lithocholoyl))-GLP-1(7-38);

[0825] Gly8Arg26,34Lys36(N£-(lithocholoyl))-GLP-1(7-38);

[0826] Gly8Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-39);

[0827] Lys26(N£-(lithocholoyl))Arg34-GLP-1(7-39);

[0828] Gly8Lys26(N£-(lithocholoyl))Arg34-GLP-1(7-39);

[0829] Arg26,34Lys36(N£-(lithocholoyl))-GLP-1(7-39);

[0830] Gly8Arg26,34Lys36(N£-(lithocholoyl))-GLP-1(7-39);

[0831] Gly8Arg26Lys34(N£-(lithocholoyl))-GLP-1(7-40);

[0832] Lys26(N£-(lithocholoyl))Arg34-GLP-1 (7-40);

[0833] Gly8Lys26(N£-(lithocholoyl))Arg34-GLP-1(7-40);

[0834] Arg26,34Lys36(N£-(lithocholoyl))-GLP-1 (7-40) and Gly8Arg26,34Lys36(N£-(lithocholoyl))-GLP-1 (7-40).

[0835] In certain embodiments the therapeutic polypeptide may be a GLP-1 agonist disclosed in WO 2012 / 080471 or WO 2013 / 189988, e.g. semaglutide and structurally related analogues thereof. Semaglutide has the structure shown in Formula IV (SEQ ID NO: 4) and Figure 5B

[0836]

[0837] (Formula IV)

[0838] In some embodiments a simple nomenclature is used to describe the GLP-1 agonist, e.g., [AibS] GLP-1 (7-37) designates an analogue of GLP-1 (7-37) wherein the naturally occurring Ala in position 8 has been substituted with Aib. In some embodiments the GLP-1 agonist comprises a maximum of twelve, such as a maximum of 10, 8 or 6, amino acids which have been altered, e.g., by substitution, deletion, insertion and / or modification, compared to e.g. GLP-1 (7-37). In some embodiments the analogue comprises up to 10 substitutions, deletions, additions and / or insertions, such as up to 9 substitutions, deletions, additions and / or insertions, up to 8 substitutions, deletions, additions and / or insertions, up to 7 substitutions, deletions, additions and / or insertions, up to 6 substitutions, deletions, additions and / or insertions, up to 5 substitutions, deletions, additions and / or insertions, up to 4 substitutions, deletions, additions and / or insertions or up to 3 substitutions, deletions, additions and / or insertions, compared to e.g. GLP-1 (7-37). Unless otherwise stated the GLP-1 comprises only L-amino acids.

[0839] In some embodiments the term “GLP-1 agonist”, “GLP-1 receptor agonist”, " GLP-1 analogue" or "analogue of GLP-1" as used interchangeably herein refers to a peptide, or a compound, which is a variant of the human Glucagon-Like Peptide-1 (GLP-1 (7-37)). GLP-1(7-37) has the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1). In some embodiments the term "variant" refers to a compound which comprises one or more amino acid substitutions, deletions, additions and / or insertions. In one embodiment the GLP-1 agonist exhibits at least 60%, 65%, 70%, 80% or 90% sequence identity to GLP-1 (7-37) over the entire length of GLP-1 (7-37). As an example of a method for determination of sequence identity between two analogues the two peptides [Aib8]GLP-1(7-37) and GLP-1 (7-37) are aligned. The sequence identity of [Aib8]GLP-1(7-37) relative to GLP-1 (7-37) is given by the number of aligned identical residues minus the number of different residues divided by the total number of residues in GLP-1 (7-37).

[0840] Accordingly, in said example the sequence identity is (31 -1 ) / 31.

[0841] In one embodiment the C-terminal of the GLP-1 agonist is an amide.

[0842] In some embodiments the GLP-1 agonist is GLP-1 (7-37) or GLP-1 (7-36)amide. In some embodiments the GLP-1 agonist is exendin-4, the sequence of which is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 5).

[0843] In some embodiments the GLP-1 agonist comprises one substituent which is covalently attached to the peptide. In some embodiments the substituent comprises a fatty acid or a fatty diacid. In some embodiments the substituent comprises a C16, C18 or C20 fatty acid. In some embodiments the substituent comprises a C16, C18 or C20 fatty diacid. In some embodiments the substituent comprises formula (V)

[0844] O

[0845]

[0846] 0(V), wherein n is at least 13, such as n is 13, 14, 15, 16, 17, 18 or 19. In some embodiments the substituent comprises formula (V), wherein n is in the range of 13 to 19, such as in the range of 13 to 17. In some embodiments the substituent comprises formula (V), wherein n is 13, 15 or 17. In some embodiments the substituent comprises formula (V), wherein n is 13. In some embodiments the substituent comprises formula (V), wherein n is 15. In some embodiments the substituent comprises formula (V), wherein n is 17. In some embodiments the substituent comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as two OEG.

[0847] In some embodiments the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4- (17-carboxyheptadecanoylamino) butyrylamino]ethoxy}ethoxy)acetylamino] eth-oxyjeth oxy) acetyl]. In some embodiments the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl} ami-no)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

[0848] In some embodiments the GLP-1 agonist is semaglutide, also known as N- epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino) bu-tyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1(7-37), which may be prepared as described in W02006 / 097537, Example 4, which is incorporated herein by reference.

[0849] In some embodiments the GLP-1 agonist is in the form of a pharmaceutically acceptable salt, amide, or ester thereof. In some embodiments the GLP-1 agonist comprises one or more pharmaceutically acceptable counter ions.

[0850] In some embodiments the dosage of GLP-1 agonist is in the range of 0.01 mg to 100 mg. In some embodiments a composition for administering the GLP-1 agonist comprises an amount of a GLP-1 agonist in the range of 0.1 to 40 mg or 1 to 20 mg. In some embodiments the composition comprises an amount of a GLP-1 agonist in the range of 5 to 20 mg, such as in the range of 5 to 15 mg, such as 5 mg, such as 10 mg, such as 15 mg, such as 20 mg.

[0851] In some embodiments the composition comprises an amount of a GLP-1 agonist in the range of 0.05 to 25 pmol, such as in the range of 0.5 to 2.5 pmol.

[0852] In some embodiments the GLP-1 agonist is selected from one or more of the GLP-1 agonists mentioned in W093 / 19175, W096 / 29342, WO98 / 08871, WO99 / 43707, WO99 / 43706, W099 / 43341, WO99 / 43708, WG2005 / 027978, WG2005 / 058954, WG2005 / 058958, WG2006 / 005667, WG2006 / 037810, WG2006 / 037811, WG2006 / 097537, WG2006 / 097538, WG2008 / 023050, WG2009 / 030738, WG2009 / 030771, WG2009 / 030774, WO 2011 / 080102, WO 2011 / 080103, WO 2012 / 062803, WO 2012 / 062804, WO 2012 / 140117, WO 2014 / 005858, WO 2014 / 177683, WO 2015 / 000942, all of which are incorporated herein by reference.

[0853] In some embodiments the GLP-1 agonist is a structural analogue of semaglutide, e.g. selected from the group consisting of: N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1 -(19-carboxynonadecanoyl) piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino) ethoxy]ethoxy}acetyl [desaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1(7-37)amide;

[0854] N-epsilon26{2-[2-(2-{2- [2-((R)-3-carboxy-3-{[1 -(19-carboxynonadecanoyl) piperidine-4-carbonyl]amino} propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxyjacetyl [desaminoHis7, Arg34] GLP-1-(7-37);

[0855] N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1 -(19-carboxy- nonadecanoyl) piperidine-4-carbonyl]amino}propionylamino)ethoxy] ethoxy}

[0856] acetylamino)ethoxy] ethoxy}acetyl[Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0857] N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy] ethoxy)acetyl] [, DesaminoHis7, Glu22 Arg26, Arg 34, Phe(m-CF3)28]GLP-1-(7-37)amide;

[0858] N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl] cyclohexanecarbonyl}amino)butyryl] [Aib8, Arg34]GLP-1-(7-37);

[0859] N-epsilon26-{4-[(S)-4- carboxy-4-({trans-4-[(19-carboxynonadecanoylamino) methyl]cyclohexanecarbonyl} amino)butyrylamino]butyryl}[Aib8, Arg34]GLP-1-(7-37);

[0860] N-epsilon26-[2-(2-{2-[(S)-4- carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino) methyl]cyclohexanecarbonyl} amino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37);

[0861] N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy} ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37)amide;

[0862] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy- 4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino) butyrylamino] ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0863] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino) butyryla-mino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Arg26, Arg34, Lys 37]GLP-1-(7-37)amide;

[0864] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino) butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37);

[0865] N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19- carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino] ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8, Lys 26]GLP-1 (7-37)amide;

[0866] N-epsilon26 [2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanoylamino] methyl) cyclohexyl carbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy] acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Lys26] GLP-1 (7-37)amide;

[0867] N-epsilon37-[2-(2-{2-[2-(2-{2- [(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl} amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Arg26, Arg34, Lys37]GLP-1-(7-37);

[0868] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl} amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys37]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7- 37);

[0869] N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37);

[0870] N-epsilon26-[2-(2-{2- [(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]hexanoylamino} butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37);

[0871] N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4- carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7- 34);

[0872] N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol- 5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-34);

[0873] N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-34);

[0874] N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino} butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-35);

[0875] N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino] ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-35);

[0876] N-epsilon26-[2-(2-{2-[(S)-4-carboxy- 4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy }ethoxy)acetyl] [Aib8, Arg34]GLP-1 -(7-36)amide; N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino] hexanoylaminojbutyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-35);

[0877] N-epsilon26-[2-(2-{2- [(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Lys33, Arg34]GLP-1-(7-34);

[0878] N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-36)amide;

[0879] N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1 H-tetrazol-5-yl)hexadecanoylsulfamoyl) butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy) acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8, Lys26, Arg34]GLP-1-(7-36)amide;

[0880] N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0881] N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino] ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1-(7-37)amide;

[0882] N- epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1 -(19-carboxy-nonadecanoyl) piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxyjacetyl [desaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1(7-37)amide;

[0883] N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1 -(19-carboxynonadecanoyl) piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy] ethoxyjacetyl [Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide; N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyhepta-decanoyl)piperidin-4-ylcarbonylamino]3-carboxy-propionylamino)ethoxy)ethoxy]acetylamino)ethoxy] ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Phe(m-CF3)28] GLP-1-(7-37)amide;

[0884] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy} ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0885] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexane-carbonyl}amino)butyrylamino] ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0886] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl] cyclohexane-carbonyl}amino)butyrylamino] ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37);

[0887] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino) methyl]cyclohexane-carbonyl}amino)butyrylamino] ethoxyjethoxy) acetylamino] ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys37]GLP-1-(7-37);

[0888] N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoyl-sulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0889] N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(IH-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino) butyrylamino]ethoxy}ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0890] N-epsilon37-(3-((2-(2-(2-(2-(2-Hexadecyloxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)) propionyl)[DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1(7-37)-amide; N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}- [desaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys37] GLP-1-(7-37)amide;

[0891] N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxy-butyryl-amino) ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[desaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0892] N-epsilon37-(2-(2-(2-(2-(2-(2-(2-(2-(2-(octadecanoyl-amino)ethoxy)ethoxy) acetylamino)ethoxy) ethoxy)acetylamino) ethoxy) ethoxy) acetyl)[desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37)amide;

[0893] N- epsilon37-[4-(16-(1 H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl] [Desamino-His7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37)amide;

[0894] N-epsilon37-[2-(2-{2-[2-(2-{2- [(S)-4-carboxy-4-(19-carboxynonadecanoylamino) butyrylamino] ethoxyjethoxy) acetylamino]ethoxy} ethoxy)acetyl] [DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7- 37);

[0895] N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19- carboxy-nonadecanoylamino)butyrylamino] butyrylamino} butyrylamino)ethoxy]ethoxy} acetyl)[DesaminoHis7, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37);

[0896] N-epsilon37-{2-[2-(2- {(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl] butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 (7-37);

[0897] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37); N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17- carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}- ethoxy)-acetyl] [Aib8, Glu22, Arg26, Arg34,epsilon-Lys37]GLP-1-(7-37)peptide;

[0898] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl] [desaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1 -(7-37);

[0899] N-epsilon36-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(15-carboxy-pentadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl] [desaminoHis7, Glu22, Arg26, Glu30, Arg34, Lys36] GLP-1-(7-37)-Glu-Lys peptide;

[0900] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans- 4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] [Aib8, Glu22, Arg26, Arg34, Lys37]GLP-1-(7-37);

[0901] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy- heptadecanoylamino)-butyrylamino]-ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)- acetyl]-[Aib8, Glu22, Arg26, Arg34, Aib35, Lys37]GLP-1-(7-37);

[0902] N-epsilon37-[(S)-4- carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanoylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetylamino) butyryl] [Aib8, Glu22, Arg26,34, Lys37] GLP-1 (7- 37);

[0903] N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)- carboxybutyry-lamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [ImPr7, Glu22, Arg26,34, Lys37], GLP-1 -(7-37);

[0904] N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxy- phenoxy) decanoylamino] butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy) ethoxy]acetyl}-[Aib8, Arg34, Lys37]GLP-1(7-37)-OH;

[0905] N-epsilon26 (17-carboxyhepta-decanoyl)-[Aib8, Arg34]GLP-1-(7-37)-peptide; N-epsilon26-(19-carboxynonadecanoyl)-[Aib8, Arg34]GLP-1-(7-37);

[0906] N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypenta-decanoyl)amino] methyl}benzoyl[Arg34]GLP-1-(7-37);

[0907] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy] acetylamino) ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37);

[0908] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(19-carboxynonadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy] acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37);

[0909] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy] acetylamino)ethoxy]ethoxy)acetyl] [3-(4-lmidazolyl)Propionyl7, Arg34]GLP-1-(7-37);

[0910] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-(carboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37);

[0911] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-3(S)- Sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37);

[0912] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Gly8, Arg34] GLP-1-(7-37);

[0913] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37)-amide; N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)- 4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]

[0914] Aib8, Arg34, Pro37]GLP-1 -(7-37)amide;

[0915] N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino) ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}[Aib8, Lys26, Arg34] GLP-1 (7-37)-OH;

[0916] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2- carboxyethyl)-N-(17-carboxyheptadecanoyl) amino]methyl}benzoyl)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1(7-37);

[0917] N-alpha7-formyl, N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Arg34]GLP-1-(7-37);

[0918] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanoylamino)-4(S)-carboxy-butyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Glu22, Arg34] GLP-1-(7-37);

[0919] N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3- dicarboxypropyl) carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino] ethoxy)ethoxy] ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl} [Aib8, Arg34]GLP- 1-(7-37);

[0920] N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanoyl)amino]methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy) eth-oxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Arg34] GLP-1(7-37);

[0921] N-epsilon26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-(19-carboxy-nonadecanoylamino)butyrylamino)butyrylamino)butyrylamino) butyrylamino} [Aib8, Arg34]GLP-1-(7-37);

[0922] N-epsilon26-4-(17-carboxyheptadecanoyl-amino)-4(S)-carboxybutyryl-[Aib8, Arg34]GLP-1-(7-37); N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4- (17-carboxyheptadecanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy] propionyl}[Aib8, Arg34]GLP-1-(7-37);

[0923] N-epsilon26- {2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanoylamino)-4-carboxybutyrylamino) ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35, Arg34, Pro37, Lys26] GLP-1 (7-37)amide;

[0924] N-epsilon26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino] ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37); and

[0925] N-epsilon26- [2-(2-[2-(2-[2-(2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl] [Aib8, Arg34]GLP-1-(7-37).

[0926] The therapeutic polypeptide may be a GIP analogue. Certain GIP analogues have been described as exhibiting both GIP and GLP- 1 activity in WO 2013 / 164483, WO 2014 / 192284, and WO 2011 / 119657, which are incorporated herein by reference. Further GIP analogues exhibiting both GIP and GLP-1 like activity (i.e. agonists of GLP-1 receptor and GIP receptor) include those recited in WO 2016 / 111971, which are incorporated herein by reference. The therapeutic polypeptide may be any of these polypeptides. This includes tirzepatide and structurally related analogues thereof.

[0927] Thus, GIP-GLP-1 co-agonist (also referred to as dual agonists) compounds of use in the invention include those of Formula VI (SEQ ID NO: 6)

[0928] YX1EGTFTSDYSIX2LDKIAQKAX3VQWLIAGGPSSGAPPPS; (Formula VI)

[0929] wherein Xi is Aib; X2 is Aib; K at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side-chain with ([2-(2-Amino-ethoxy)- ethoxy]-acetyl)2-(YGIu)a-CO-(CH2)b-CO2H wherein a is 1 to 2 and b is 10 to 20; X3 is Phe or 1-Nal; and the C-terminal amino acid is optionally amidated as a C-terminal primary amide, or a pharmaceutically acceptable salt thereof.

[0930] 'Aib" is alpha amino isobutyric acid, and "1-Nal" is 1-Naphthylalanine. In certain embodiments, b is 14 to 18, preferably 16 to 18, or 18.

[0931] In certain embodiments, the C-terminal amino acid is amidated as a C-terminal primary amide.

[0932] Tirzepatide is an example of an incretin peptide analogue. Incretins such as GIP are a group of metabolic hormones that stimulate a decrease in blood glucose levels. Incretins are released after eating and augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism.

[0933] Tirzepatide may be considered as a dual agonist for the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide- 1 (GLP-1) receptor. Tirzepatide has been marketed under the brand name Mounjaro, and has the structure shown in Formula VII (SEQ ID NO: 7) and Figure 5C.

[0934] H f « t176 CO jHHo C 1HoHo £!>i HjN-Y-N^ J-E-G-T-F-T-S-D-Y-S-l-N -U-L-D-K-I-A-Q-H'^IJ-A-F-V-Q W-L-I-A-G-G-P-S-S-G-A-P-P-P-S-CONHJ

[0935]

[0936] Me Me Me ft Me ’* ow(Formula VII)

[0937] Tirzepatide is also known as (2S)-2-[[20-[[(5S)-6-[[(2S,3S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1 -oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-2-methylpropanoyl]amino]-4-carboxybutanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3- phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-2-methylpropanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-6-oxohexyl]amino]-20-oxoicosanoyl]amino]-5-[2-[2-[2-[2-[2-(carboxymethoxy)ethoxy]ethylamino]-2-oxoethoxy]ethoxy]ethylamino]-5-oxopentanoic acid.

[0938] GIP-GLP-1 co-agonist compounds of use in the invention may also include those recited in WO 2020 / 023386, e.g. those of Formula VIII (SEQ ID NO: 13):

[0939] R 1 Xi X2X3GTX6T S DX10X11 Xi 2X13X14 DX1 eXi 7AX19X20X21 X22X23X24X25X20X27 X28X29X30X31

[0940] wherein:

[0941] R1 is a modification of the N-terminal amino group wherein the modification is selected from the group consisting of Ac and absent;

[0942] Xi is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY,

[0943] X2 is selected from the group consisting of Aib, aMeP, A, P, and D-Ala;

[0944] orXi and X2 combine to form desH- ^[NHCOj-Aib;

[0945] X3 is selected from the group consisting of E, N, Aad, and cTA;

[0946] Xe is selected from the group consisting of F, aMeF, and aMeF(2F);

[0947] X10 is selected from the group consisting of A, L, H, 3Pal, 4Pal, V, Y, E, aMeF, aMeF(2F), I, aMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2)qCO2H;

[0948] X11 is selected from the group consisting of S, aMeS, and D-Ser;

[0949] X12 is selected from the group consisting of I, S, D-lle, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qCO2H;

[0950] X13 is selected from the group consisting of Nle, Aib, L, aMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qCO2H;

[0951] X14 is selected from the group consisting of L and K, wherein K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker;

[0952] X16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, aMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qCO2H; X17 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker;

[0953] X19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-(CO-(CH2)qCO2H;

[0954] X20 is selected from the group consisting of Aib, Q, H, R, K, aMeK, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qCO2H;

[0955] X21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qCO2H;

[0956] X22 is selected from the group consisting of F and aMeF;

[0957] X23 is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)qCO2H;

[0958] X24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qCO2H;

[0959] X25 is selected from the group consisting of Y and aMeY;

[0960] X26 is selected from the group consisting of L, aMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qCO2H;

[0961] X27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qCO2H;

[0962] X28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qCO2H;

[0963] X29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)qCO2H;

[0964] X30 is selected from the group consisting of C, G, G-R2 and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-CO2H;

[0965] X31 is absent or is selected from the group consisting of

[0966] PX32X33X34-R2 (SEQ ID NO: 14),

[0967] PX32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 15), PX32X33X34X35X36X37X38X39X40-R2 (SEQ ID NO: 16),

[0968] K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-CO2H]X32X33X34-R2 (SEQ ID NO: 17),

[0969] K[(2-[2- (2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q- CO2H]X32X33X34X35X36X37X38X39-R2 (SEQ ID NO: 18), and

[0970] K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q- C02H]X32X33X34X35X36X37X38X39X4O-R2 (SEQ ID NO: 19); wherein:

[0971] X32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q- CO2H];

[0972] X33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q- CO2H];

[0973] X34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-CO2H];

[0974] X35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)q- CO2H];

[0975] X36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q- CO2H];

[0976] X37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q- CO2H];

[0977] X38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q- CO2H];

[0978] X39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino- ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-CO2H];

[0979] X40 is selected from the group consisting of C and K[(2-[2-(2-amino- ethoxy)- ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-CO2H];

[0980] q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and

[0981] R2 is a modification of the C-terminal group, wherein the modification is NH2 or absent; or a pharmaceutically acceptable salt thereof;

[0982] wherein if X30 is G-R2, then X31 is absent;

[0983] wherein no more than one of X10, X12, X13, X14, X16, X17, X19, X20, X21, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, and X40 may be a substituent that contains a fatty acid; and

[0984] wherein no more than one of X30, X34, X39, and X40 may be C; and

[0985] wherein if one of X30, X34, X39, and X40 is C, then none of X10, X12, X13, X14, X16, X17, Xl9, X20, X2I, X23, X24, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38,

[0986] X39, and X40 is a substituent that contains a fatty acid.

[0987] In an embodiment of Formula VIII, q is 16. In an embodiment of Formula VIII, X31 is selected from the group consisting of PX32X33X34X35X36X37X38X39X40-R2 and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)q-CO2H]X32X33X34X35X36X37X38X39-R2. In an embodiment of Formula VIII, the Xn amino acid that is conjugated to a fatty acid is a natural amino acid. In an embodiment of Formula VIII, X17 is selected from the group consisting of K, Q and I.

[0988] In an embodiment of Formula VIII, K is conjugated to a C16-C22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker.

[0989] In an embodiment of Formula VIII, X14 orXi? is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i6-CO2H,

[0990] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i8-CO2H,

[0991] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i4-CO2H,

[0992] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i8-CO2H,

[0993] K(2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)-(y-Glu)-(Trx)-CO-(CH2)i8-CO2H,

[0994] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(Trx)-(γ-Glu)-CO-(CH2)i8-CO2H,

[0995] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(γ-Glu)-CO-(CH2)i8-CO2H,

[0996] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-(εK)-(εK)-CO-(CH2)i8-CO2H,

[0997] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)2-CO-(CH2)i8-CO2H,

[0998] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i8-CO2H,

[0999] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2)i6-CO2H,

[1000] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(εK)-CO-(CH2)i4-CO2H, and

[1001] KDab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Dab-(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)- CO-(CH2)i8-CO2H.

[1002] In an embodiment of Formula VIII, X14 or X17 is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i6-CO2H,

[1003] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i8-CO2H,

[1004] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i4-CO2H, and

[1005] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-CO-(CH2)i8-CO2H.

[1006] In an embodiment of Formula VIII X14 or X17 is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i6-CO2H,

[1007] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i8-CO2H, and

[1008] K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i4-CO2H.

[1009] In an embodiment of Formula VIII, X14 or X17 is selected from the group consisting of K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(Y-Glu)-CO-(CH2)i8-CO2H and K(2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(y-Glu)-CO-(CH2)i6-CO2H.

[1010] In an embodiment of Formula VIII, X14 or X17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(y-Glu)b-CO-(CH2)q-CO2H, wherein a is 2, b is 1, and q is selected from the group consisting of 18 and 20.

[1011] In an embodiment of Formula VIII, X14 or X17 is K(2-[2-(2- amino-ethoxy)-ethoxy]-acetyl)a-(y-Glu)b-CO-(CH2)q-CO2H, wherein a is 2, b is 1 and q is 18.

[1012] In an embodiment of Formula VIII, X14 or X17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)a-(y-Glu)b-CO-(CH2)q-CO2H, wherein, a is 2, b is 1, and q is 20.

[1013] As used herein the term “amino acid” means both naturally occurring amino acids and unnatural amino acids. The amino acids are typically depicted using standard one letter codes (e.g., L = leucine), as well as alpha-methyl substituted residues of natural amino acids (e.g., a-methyl leucine, or aMeL and a-methyl lysine, or aMeK) and certain other unnatural amino acids, such as alpha amino isobutyric acid, or “Aib,” “4Pal,” “Orn,” and the like. The structures of these amino acids appear below:

[1014]

[1015] desH- Ψ[NHCO]-Aib desHis-Aib desY αMeP

[1016]

[1017] As used herein “Orn” means ornithine. As used herein “4Pal” means 3-(4-Pyridyl)-L-alanine. As used herein “aMeF(2F)” means alpha-methyl 2-F-phenylalanine. As used herein “aMeY,” aaMeK,” and “aMeL” mean alpha methyl tyrosine, alpha methyl lysine, and alpha methyl leucine, respectively. As used herein, “e” and “D-Glu” mean D-glutamic acid. As used herein “D-His” and “h” each mean D-histidine. As used herein “D-Tyr”and “y” each means D-tyrosine. As used herein “D-Ser” and “s” means means D-serine. As used herein “D-Ala” and “a” each means D-alanine. As used herein, “aMeF(2F)” means alpha-methyl-F(2F) and alpha-methyl-Phe(2F). As used herein, “aMeF”, means alpha-methyl-F and alpha-methyl-Phe. As used herein, “aMeY”, means alpha-methyl-Tyr. As used herein “aMeK”, means alpha-methyl-Lys. As used herein, “aMeL”, means alpha-methyl-Leu. As used herein, “aMeS”, means alpha-methyl-serine and alpha-methyl-Ser. As used herein “aMeP”, means alpha-methyl-proline and alpha-methyl-Pro. As used herein, “desH”, means desHis. As used herein, “desY”, means desTyr.

[1018] When Xi is DesH and X2 is Aib, and the DesH and Aib can combine to form a group as illustrated above, DesH-Ψ[NHCO]-Aib. When used herein with reference to Formula VIII, the term “amino acid conjugated to a C16-C22 fatty acid” refers to any natural or unnatural amino acid with a functional group that has been chemically modified to conjugate to a fatty acid by way of a covalent bond to the fatty acid or, preferably, by way of a linker. Examples of such functional groups include amino, carboxyl, chloro, bromo, iodo, azido, alkynyl, alkenyl, and thiol groups. Examples of natural amino acids which include such functional groups include K (amino), C (thiol), E (carboxyl) and D (carboxyl). In an embodiment the conjugated amino acid is K.

[1019] As noted above, in an embodiment of Formula VIII, a fatty acid moiety is conjugated via a linker or a direct bond. In an embodiment of Formula VIII, a fatty acid moiety is conjugated, preferably via a linker, to a K at position 14 or 17. In an embodiment of Formula VIII, the conjugation is an acylation. In an embodiment of Formula VIII, the conjugation is to the epsilon-amino group of the K side-chain. In an embodiment of Formula VIII, a fatty acid moiety is conjugated, via a linker, to a K at position 17.

[1020] In an embodiment of Formula VIII, a fatty acid moiety is conjugated directly, without a linker, to a natural or unnatural amino acid with a functional group available for conjugation. In certain preferred embodiments the conjugated amino acid is selected from the group consisting of K, C, E and D. In particularly preferred embodiments the conjugated amino acid is K. In such embodiments, the conjugation is to the epsilon-amino group of the K side-chain.

[1021] In an embodiment of Formula VIII, the linker comprises one to four amino acids, an amino polyethylene glycol carboxylate, or mixtures thereof. In an embodiment, the amino polyethylene glycol carboxylate has the following formula:

[1022] H-{NH-CH2-CH2-[O-CH2-CH2]p-O-(CH2)z-CO}r-OH, wherein p is any integer from

[1023] 1 to 12, z is any integer from 1 to 20, and r is 1 or 2.

[1024] In an embodiment of Formula VIII, an amino acid is conjugated to a fatty acid via a linker, wherein the linker is one to two amino acids selected from the group consisting of Glu and y-Glu. In an embodiment the linker is one to two (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties.

[1025] In an embodiment of Formula VIII, a fatty acid is conjugated with a linker, and the linker comprises one or more (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties, in combination with zero or one to four amino acids. In an embodiment, the linker may comprise one to four Glu or y-Glu amino acid residues. In an embodiment, the linker may comprise 1 or 2 Glu or y-Glu amino acid residues. In an embodiment of Formula VIII, a fatty acid is conjugated via a linker wherein, the linker comprises either 1 or 2 y-Glu amino acid residues. In an embodiment of Formula VIII, a fatty acid is conjugated via a linker wherein the linker may comprise one to four amino acid residues (such as, for example Glu and y-Glu amino acids) used in combination with up to 36 (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. Specifically, in an embodiment of Formula VIII, a fatty acid is conjugated via a linker wherein, the linker constitutes combinations of one to four Glu and y-Glu amino acids and one to four (2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl) moieties. In an embodiment of Formula VIII, a fatty acid is conjugated via a linker wherein the linker is comprised of combinations of one or two y-Glu amino acids and one or two (2- [2-(2-Amino-ethoxy)-ethoxy] -acetyl) moieties. In an embodiment of Formula VIII, a fatty acid is conjugated via a linker wherein the linker and fatty acid components have the following formula:

[1026] (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)a-(y-Glu)b-CO-(CH2)q-CO2H, wherein a is 1 or 2, b is 1 or 2 and q is 16 or 18. In an embodiment, a is 2, b is 1 and q is 18; and the structure is:

[1027]

[1028] In an embodiment, a is 1, b is 2 and q is 18; and the structure is:

[1029]

[1030] In an embodiment a is 1, b is 1, and q is 18; and the structure is:

[1031]

[1032] The term “C16-C22 fatty acid as used herein in relation to Formula VIII means a carboxylic acid with between 16 and 22 carbon atoms. In an embodiment, the C16-C22 fatty acid suitable for use herein can be a saturated diacid. In an embodiment, the fatty acid is C20-C22. In an embodiment q is selected from the group consisting of 14, 16, 18, and 20. In an embodiment q is selected from 18 and 20. In an embodiment q is 18. In an embodiment q is 20.

[1033] In an embodiment of Formula VIII, the specific saturated C16-C22 fatty acid may be, but are not limited to, hexadecanedioic acid (C16 diacid), heptadecanedioic acid (C17 diacid), octadecanedioic acid (C18 diacid), nonadecanedioic acid (C19 diacid), eicosanedioic acid (C20 diacid), heneicosanedioic acid (C21 diacid), docosanedioic acid (C22 diacid), including branched and substituted derivatives thereof.

[1034] In an embodiment of Formula VIII, the C16-C22 fatty acid is selected from the group consisting of a saturated C18 diacid, a saturated C19 diacid, a saturated C20 diacid, and branched and substituted derivatives thereof. In an embodiment, the C16-C22 fatty acid is selected from the group consisting of stearic acid, arachadic acid and eicosanedioic acid. In an embodiment, the C16-C22 fatty acid is arachadic acid.

[1035] Specific examples of Formula VIII include, but are not limited to:

[1036] Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2(Formula IX) (SEQ ID NO: 20).

[1037] The structure of Formula IX is depicted below and in Figure 5E using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, K17, Aib20, D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded: o

[1038]

[1039] Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(y-Glu)-CO-(CH2)16-CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2(Formula X) (SEQ ID NO: 21).

[1040] The structure of Formula X is depicted below and in Figure 5F using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:

[1041]

[1042] Y-Aib-EGT-aMeF(2F)-TSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2(Formula XI) (SEQ ID NO: 22).

[1043] The structure of Formula XI is depicted below and in Figure 5G using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been expanded:

[1044]

[1045] Y-Aib-EGT-aMeF(2F)-TSD-4Pal-SI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H)AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGPSSGAPPPS-NH2(Formula XII) (SEQ ID NO: 23).

[1046] The structure of Formula XII is depicted below and in Figure 5H using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, 4Pal10, aMeL13, Orn16, K17, Aib20, D-Glu24 aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

[1047]

[1048] Y-Aib-EGT-aMeF(2F)-TSDVSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H)AQ-Aib-EFI-(D-Glu)-aMeY-LIEGGPSSGAPPPS-NH2(Formula XIII) (SEQ ID NO: 24).

[1049] The structure of Formula XIII is depicted below and in Figure 5I using the standard single letter amino acid codes with the exception of residues Aib2, aMeF(2F)6, aMeLI3, Orn16, K17, Aib20, D-Glu24,aMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

[1050]

[1051] Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-AFIEYLIAGGPSSGAPPPS-NH2(Formula XVI) (SEQ ID NO: 25).

[1052] Y-Aib-EGTFTSDYSI-aMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2(Formula XVII) (SEQ ID NO:26).

[1053] (D-Tyr)-Aib-EGTFTSDYSI-aMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH2(Formula XVIII) (SEQ ID NO:27).

[1054] (D-Tyr)-Aib-EGTFTSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-AFI-(D-Glu)-YLIAGGPSSGAPPPS-NH2(Formula XIX) (SEQ ID NO: 28).

[1055] (D-Tyr)-Aib-EGTFTSDYSI-aMeL-LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFIE-aMeY-LIAGGPSSGAPPPS-NH2(Formula XX) (SEQ ID NO: 29).

[1056] (D-Tyr)-Aib-EGTFTSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)18-CO2H)AQ-Aib-EFIE-aMeY-LIAGGPSSGAPPPS-NH2(Formula XXI) (SEQ ID NO: 30).

[1057] (D-Tyr)-Aib-EGTFTSDYSI-aMeL-LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)16-CO2H)AQ-Aib-AFIE-aMeY-LIAGGPSSGAPPPS-NH2(Formula XXII) (SEQ ID NO: 31). Certain incretin mimetics have been described as exhibiting GIP, GLP- 1, and glucagon like activity (i.e. agonists of GLP-1 receptor, GIP receptor and glucagon receptor) in WO 2019 / 125929 and WO 2019 / 125938, which are incorporated herein by reference. This includes retatrutide (LY3437943) and structurally related analogues thereof. Retatrutide may be considered a structural analogue of tirzepatide and vice versa. The therapeutic polypeptide may be any of these polypeptides

[1058] Thus, GIP-GLP-1-glucagon triple co-agonist compounds (incretin analogues) of use in the invention include those of Formula XIV (SEQ ID NO: 8):

[1059] YX2QGTFTSDYSIX13LDKX17AX19X20AFIEYLLX28X29GPSSX34APPPS, (Formula XIV)

[1060] wherein:

[1061] X2 is Aib,

[1062] X13is L or aMeL,

[1063] X17 is any amino acid with a functional group available for conjugation, and the functional group is conjugated to a C 16-C 22 fatty acid, optionally via a linker

[1064] X19 is Q or A,

[1065] X20is Aib, aMeK (a-methyl-L-lysine), Q or H,

[1066] X28 is E or A,

[1067] X29 is G or Aib,

[1068] X34 is G or Aib, and wherein the C-terminal amino acid is optionally amidated.

[1069] In certain embodiments the amino acid with the functional group available for conjugation at position X17 is selected from the group consisting of K, C, E and D, and preferably is K.

[1070] In certain embodiments the linker comprises one to four amino acids, preferably Glu or yGlu. In other embodiments the linker further comprises a structure of:

[1071] H-{NH-CH2-CH2-[O-CH2-CH2]m-O-(CH2)p-CO}n-OH, wherein m is any integer from 1 to 12, n is any integer from 1 to 12, and p is 1 or 2. 8.

[1072] In certain embodiments the linker further comprises one to four (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) (i.e. AEEA) moieties. In certain specific embodiments the X17 is a K chemically modified through conjugation to an epsilon-amino group of a K side-chain with the following structure:

[1073] (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) -(yGlu)b-CO-(CH2)c-CO2H, wherein a is 0, 1 or 2; b is 1 or 2; and c is an integer between 16 to 18.

[1074] In certain specific embodiments the triple agonist incretin analogue is retatrutide (LY3437943), the structure of which is shown in Formula XV (SEQ ID NO: 9) and Figure 5D:

[1075] YAibQGTFTSDYSIaMeLLDK17QAibAFIEYLLEGGPSSGAPPPS-CONH2(Formula XV), wherein K is conjugated via an (AEEA) y Glu linker to a C20 fatty diacid moiety.

[1076] In other instances, an incretin mimetic may be a GLP-1 and glucagon co-agonist, e.g. survodutide, mazdutide, pemvidutide, efinopegdutide, orAZD9550.

[1077] In other instances, an incretin mimetic may be an amylin receptor agonist, e.g. pramlintide, NN1213, AZD6234, ZP8396, or a dual amylin and GLP-1 agonist, e.g. cagrilintide

[1078] In other instances, an incretin mimetic may be a peptide YY agonist, e.g.

[1079] PYY1875 / NNC0165-1875, NNC0165-1562, orY-14.

[1080] In certain specific embodiments the therapeutic polypeptide may be a GDF-15 (growth / differentiation factor-15) receptor agonist, e.g. LY3463251, NNC0247-0829 (Novo Nordisk) and JNJ-9090 / CIN-109 (CinRx Pharma).

[1081] The therapeutic polypeptide may be used in the methods described herein or provided in the compositions or dosage forms described herein in non-salt form or in the form of a pharmaceutically acceptable salt. A corresponding pharmaceutically acceptable salt may be formed, e.g., by protonation of an atom carrying an electron lone pair which is susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as a salt of a carboxylic acid group with a physiologically acceptable cation as they are well-known in the art. Exemplary base addition salts comprise, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts comprise, for example: mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate salts, nitrate salts, phosphate salts (such as, e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate salts), carbonate salts, hydrogencarbonate salts or perchlorate salts; organic acid salts such as acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, glycolate, nicotinate, benzoate, salicylate, ascorbate, or pamoate (embonate) salts; sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate salts; and acidic amino acid salts such as aspartate or glutamate salts.

[1082] The methods, uses, dosage forms, formulations and compositions of the invention may involve or comprise multiple / a plurality of therapeutic polypeptides. Thus, the methods, uses, dosage forms, formulations and compositions of the invention may involve or comprise at least one, or one or more, therapeutic polypeptide(s) (e.g. at least two, three or four therapeutic polypeptides; or two, three, four or more therapeutic polypeptides). These may be structural or functional analogues of each other, or therapeutic polypeptides from different structural or functional classes. References herein to “a” or “the” polypeptide should be construed as extending to such embodiments, unless context specifically dictates otherwise. In particular, compositions described herein as “consisting of’ a set of components of which “a therapeutic polypeptide” is one, include combinations (multiplicity / plurality) of therapeutic polypeptides as that aforementioned component.

[1083] In accordance with the invention a compound of Formula (I) has the structure o

[1084] R2O

[1085]

[1086] wherein:

[1087] X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy;

[1088] R1is hydrogen or C1-3 alkyl;

[1089] R2is hydrogen or C1-3 alkyl;

[1090] R3is -OH;

[1091] each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; and n is an integer from 0 to 4, preferably 0 or 1.

[1092] In certain embodiments Formula (I) is Formula (la):

[1093]

[1094] In certain embodiments Formula (I) is Formula (lb):

[1095] o

[1096]

[1097] In certain instances of Formula (I), (la) and (lb, each R4are is independently selected from hydrogen, -OH, and halogen.

[1098] In Formula (I), (la) and (lb) references to halogen may be -F, -Cl, -Bror-I, preferably -F or -Cl.

[1099] In Formula (I), (la) and (lb) each C1-3 alkyl group may independently be methyl or ethyl.

[1100] In Formula (I), (la) and (lb) each C1-3 alkoxy group may independently be methoxy or ethoxy.

[1101] In Formula (I), (la) and (lb) the substituted, saturated or unsaturated hydrocarbon chain may be substituted with halogen and / or -OH

[1102] In Formula (I), (la) and (lb) the substituted saturated or unsaturated hydrocarbon chain may be substituted with one or more (e.g., one, two, or three) of said substituent groups.

[1103] In Formula (I), (la) and (lb) the hydrocarbon chain of X may be branched or unbranched.

[1104] In Formula (I), (la) and (lb) the hydrocarbon chain of X may be C5-14, Ce-14, C7-14, Cs-14, C9-14, C10-14, C11-14, C12-14, C13-14, or C4-5, C4-6, C4-7, C4-8, C4-9, C4-10, C4-11, C4-12, or C4-13- Thus, the hydrocarbon chain of X may be an optionally substituted, saturated or unsaturated C4, C5, Ce, C7, Cs, C9, C10, C11, C12, C13, or Ci4 hydrocarbon chain, e.g. an optionally substituted, saturated or unsaturated C5, C7, C9, C11, or C13, hydrocarbon chain. In each case the hydrocarbon chain may be linear or branched, and may have 1, 2 or 3 double carbon to carbon bonds and / or 1, 2 or 3 triple carbon to carbon bonds.

[1105] Thus, X may be an optionally substituted, branched or unbranched C4-14, C5-14, Ce-14, C7-14, Cs-14, C9-14, C10-14, C11-14, C12-14, C13-14, or C4-5, C4-6, C4-7, C4-8, C4-9, C4-10, C4-11, C4-12, or C4-13 alkylene, alkenylene, or alkynylene. Thus, X may be an optionally substituted, branched or unbranched C4, C5, Ce, C7, Cs, C9, C10, C11, C12, C13, or C14 alkylene, alkenylene, or alkynylene, e.g. an optionally substituted, branched or unbranched Cs, C7, C9, C11, or C13, alkylene, alkenylene, or alkynylene. Compounds of Formula (I) and methods for their preparation are described, e.g., in US 57773647, US 5866536 and WO 00 / 59863, the disclosures of which are incorporated herein by reference.

[1106] Preferred examples of the compounds of formula (I) include N-(5-chlorosalicyloyl)-8-aminocaprylic acid (also referred to as 5-CNAC, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid), N-(10-[2-hydroxybenzoyl]amino)decanoic acid, and N-(8-[2-hydroxybenzoyl]amino)caprylic acid (also referred to as N-(8-(2-hydroxybenzoyl)amino)caprylic acid, 8-(salicyloylamino) octanoic acid, 8-[(2-hydroxybenzoyl)amino]octanoic acid, salcaprozate)

[1107] The structural formula of N-(8-(2- hydroxybenzoyl)amino)caprylate is shown in Formula (lc),

[1108] O

[1109]

[1110] Formula (lc)

[1111] The compounds of Formula I and lc may be used in the invention as salts thereof, e.g. comprising one monovalent cation, two monovalent cations or one divalent cation.

[1112] Exemplary base addition salts comprise, for example: alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Sodium, potassium and calcium salts of the compounds of Formula I and Ic may be preferred.

[1113] In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of the sodium salt, potassium salt and calcium salt of N-(8- (2-hydroxybenzoyl)amino)caprylic acid. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate may be prepared using the method described in e.g. W096 / 030036, WO00 / 046182, W001 / 092206 or W02008 / 028859, which are incorporated herein by reference.

[1114] A particularly preferred salt of Formula (I) is the sodium salt of N-(8- (2-hydroxybenzoyl)amino)caprylic acid (SNAC, sodium salcaprozate, sodium N-(8-(2-hydroxybenzoyl)amino)caprylate, sodium N-(8-(2-hydroxybenzoyl)amino)caprylate, sodium 8-(2-hydroxybenzamido)octanoate.

[1115] A further particularly preferred salt of Formula (I) is the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.

[1116] The compound of Formula (I), or salt thereof, may have a pH buffering property in a gastric environment (simulated or natural). That is a dosage form, e.g. a solid dosage form, comprising compound of Formula (I) or salt thereof, when placed in a gastric environment (simulated or natural) will cause the pH in its immediate vicinity to be more neutral that the gastric environment in which it was placed.

[1117] In accordance with the invention a compound of Formula (II) has the structure

[1118] OH

[1119]

[1120] O (II)

[1121] wherein Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or C1-3 alkoxy In Formula (II) the substituted saturated or unsaturated hydrocarbon chain may be substituted with one or more (e.g., one, two, or three) of said substituent groups.

[1122] In Formula (II) each C1-3 alkyl group may independently be methyl or ethyl.

[1123] In Formula (II) each C1-3 alkoxy group may independently be methoxy or ethoxy.

[1124] In Formula (II) the substituted, saturated or unsaturated hydrocarbon chain may be substituted with halogen and / or -OH

[1125] In Formula (II) references to halogen may be -F, -Cl, -Br or -I, preferably -F or -Cl.

[1126] In Formula (II) the hydrocarbon chain of Y may be branched or unbranched.

[1127] In Formula (II) the hydrocarbon chain of Y may be C5-14, Ce-14, C7-14, Cs-14, C9-14, C10-14, Cn-14, C12-14, C13-14, or C4-5, C4-6, C4-7, C4-8, C4-9, C4-10, C4-11, C4-12, or C4-13- Thus, the hydrocarbon chain of Y may be an optionally substituted, saturated or unsaturated, C4, C5, Ce, C7, Cs, C9, C10, C11, C12, C13, or C14 hydrocarbon chain, e.g. an optionally substituted, saturated or unsaturated C5, C7, C9, C11, or C13, hydrocarbon chain. In each case the hydrocarbon chain may be linear or branched, and may have 1, 2 or 3 double carbon to carbon bonds and / or 1, 2 or 3 triple carbon to carbon bonds.

[1128] Thus, Y may be an optionally substituted, branched or unbranched, C4-14, C5-14, Ce-14, C7-14, Cs-14, C9-14, C10-14, C11-14, C12-14, C13-14, or C4-5, C4-6, C4-7, C4-8, C4-9, C4-10, C4-11, C4-12, or C4-13 alkyl, alkenyl, or alkynyl group. Thus, Y may be an optionally substituted, branched or unbranched, C4, C5, Ce, C7, Cs, C9, C10, C11, C12, C13, or Ci4 alkyl, alkenyl, or alkynyl group, e.g. an optionally substituted, branched or unbranched, Cs, C7, C9, C11, or C13, alkyl, alkenyl, or alkynyl group.

[1129] It will be seen that the compound of Formula (II) is a substituted or unsubstituted, saturated or unsaturated, C5-15 fatty acid. The C5-15 fatty acid may be a Ce-14 fatty acid, C7-14 fatty acid, a C8-i4fatty acid, a C9-i4fatty acid, a C -i4fatty acid, a Cn-i4fatty acid, a C12-14 fatty acid, a C13-14 fatty acid, a Ce-7 fatty acid, a Ce-s fatty acid, a Ce-9 fatty acid, a Ce- fatty acid, a Ce-ii fatty acid, a C6-12 fatty acid, or a Ce-isfatty acid, each of which may be a linear or branched alkanoic acid which optionally has 1, 2 or 3 carbon to carbon double bonds and / or carbon to carbon triple bonds. Thus, the C5-15 fatty acid may be a C5, Ce, C7, Cs, C9, C10, C11, C12, C13, C14 or Cis fatty acid each of which may be a linear or branched alkanoic acid which optionally has 1, 2 or 3 carbon to carbon double bonds and / or carbon to carbon triple bonds. Substitutions as defined above may also be included.

[1130] The C5-15 fatty acid may be selected from caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid and / or pentadecanoic acid. Preferably, the fatty acid is caprylic acid, pelargonic acid, and / or capric acid. More preferably the fatty acid is capric acid.

[1131] The compound of Formula (II) may be used in the invention as salts thereof, e.g. comprising one or more cations.

[1132] Exemplary base addition salts comprise, for example: alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkyl amine salts such as N, N-dibenzylethylenediamine salts, benzathine salts, benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts.

[1133] The salt of the compound of Formula (II) may be a sodium salt or a potassium salt.

[1134] A preferred salt of a compound of Formula (II) is a salt of capric acid. Capric acid may also be referred to as decanoic acid (CH3(CH2)sCOOH). A preferred salt of capric acid is sodium caprate (i.e. CH3(CH2)sCOONa) also referred to as C10.

[1135] The invention encompasses the use of a compound of Formula (I), or pharmaceutically acceptable salt thereof, or a multi plicity / pl urality, e.g. mixture, of different compounds of Formula (I), and / or different pharmaceutically acceptable salts thereof. This includes the same compound of Formula I, but different salts thereof, and different compounds of Formula I, but in the same salt form. Thus, the methods, uses, dosage forms, formulations and compositions of the invention may involve or comprise at least one, or one or more, compound(s) of Formula (I), or pharmaceutically acceptable salt(s) thereof. Thus, for example, a combination of different compound(s) of Formula (I), or pharmaceutically acceptable salt(s) thereof, may be used. In this regard, a combination of compound(s) of Formula (I), or pharmaceutically acceptable salt(s) thereof, may be selected that together give a profile of properties advantageous to the practice of the invention. This may be a combination of different carbon chain lengths. References herein to “an” or “the” compound of Formula (I), or pharmaceutically acceptable salt thereof, should be construed as extending to such embodiments, unless context specifically dictates otherwise. In particular, compositions, dosage forms, or formulations described herein as “consisting of’ a set of components of which “a compound of Formula (I), or pharmaceutically acceptable salt thereof” is one, include combinations (multiplicity / plurality) of compounds of Formula (I), or pharmaceutically acceptable salts thereof, as that aforementioned component.

[1136] The invention encompasses the use of a compound of Formula (II), or pharmaceutically acceptable salt thereof, or a multiplicity / plurality, e.g. mixture, of different compounds of Formula (II), and / or different pharmaceutically acceptable salts thereof. This includes the same compound of Formula (II), but different salts thereof, and different compounds of Formula (II), but in the same salt form. Thus, the methods, uses, dosage forms, formulations and compositions of the invention may involve or comprise at least one, or one or more, compound(s) of Formula (II), or pharmaceutically acceptable salt(s) thereof. Thus, for example, a combination of different compound(s) of Formula (II), or pharmaceutically acceptable salt(s) thereof, may be used. In this regard, a combination of compound(s) of Formula (II), or pharmaceutically acceptable salt(s) thereof, may be selected that together give a profile of properties advantageous to the practice of the invention. This may be a combination of different carbon chain lengths. References herein to “an” or “the” compound of Formula (II), or pharmaceutically acceptable salt thereof, should be construed as extending to such embodiments, unless context specifically dictates otherwise. In particular, compositions, dosage forms, or formulations described herein as “consisting of’ a set of components of which “a compound of Formula (II), or pharmaceutically acceptable salt thereof” is one, include combinations (multiplicity / plurality) of compounds of Formula (II), or pharmaceutically acceptable salts thereof, as that aforementioned component.

[1137] The compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof, of use in the invention will independently function as a gastrointestinal permeation enhancer (also known as mucosal permeation enhancer, or simply a permeation enhancer), more specifically as a gastrointestinal epithelial barrier (epithelium) permeation enhancer. As such, they will be capable of facilitating the translocation of other compounds (e.g. polypeptide therapeutic agents as defined herein) from the luminal (apical) side of a gastrointestinal epithelial cell layer (e.g. a gastric epithelial layer or an epithelial layer of the small intestine or the large intestine) to the basal side of said layer. The compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof, of use in the invention may independently have a paracellular and / or transcellular mode of action.

[1138] Further gastrointestinal permeation enhancers may be used together with the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof, of use in the invention will in accordance with the invention. These may be selected from the following non-exhaustive list: EDTA, citric acid, a salicylate, oleic acid, lauric acid, acylcarnitine, acyl choline, and acylated amino acid, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium taurodeoxycholate, sodium dihydrofusidate, sodium glycodihydrofusidate, sodium glycolate, sodium lauryl sulphate, dioctyl sodium sulfosuccinate, sucrose fatty acid esters, lactose fatty acid esters, lauroyl carnitine, dodecyl maltoside, dodecyl phosphatidylcholine, rhamnolipids, polysorbates, polyoxyethylene-8 lauryl ether, Tween80, sucrose laurate, macrogol-8 glycerides, lauroylcarnitine chloride, sodium cholate, choline geranate, chitosan, chitosan glutamate, N-sulfanto-N, O-carboxymethylchitosan (SNOCC), N-Trimethylated Chitosan Chloride (TMC), ethanol, penetratin, Zonula occludens toxin (Zot), AG fragment of Zot, polycarbophyl-cysteine conjugate(PCP-Cys), Permeant Inhibitor of Phosphatase (PIP-250 and PIP-640).

[1139] Such additional permeation enhancer is not an alginate oligomer. In certain instances, the additional permeation enhancer is not, or does not comprise, a polypeptide or peptide. In some embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is at least 0.6 mmol, such as selected from the group consisting of at least 0.65 mmol, at least 0.7 mmol, at least 0.75 mmol, at least 0.8 mmol, at least 0.8 mmol, at least 0.9 mmol, at least 0.95 mmol and at least 1 mmol. Any range which may be constructed with endpoints having the above values are expressly contemplated. In some embodiments the amount of the compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in the composition is in the range of 0.6-2.1 mmol or 0.6-1.9 mmol. In some embodiments the amount of the compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in the composition is in the range of 0.7-1.7 mmol or 0.8-1.3 mmol.

[1140] In some embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is up to 2.1 mmol, such as selected from the group consisting of up to 2.1 mmol, up to 2 mmol, up to 1.9 mmol, up to 1.8 mmol, up to 1.7 mmol, up to 1.6 mmol, up to 1.5 mmol, up to 1.4 mmol, up to 1.3 mmol, up to 1.2 mmol and up to 1.1 mmol. Any range which may be constructed with endpoints having the above values are expressly contemplated. In some embodiments the amount of the compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, is 1 mmol, such as 1.08 mmol.

[1141] In other embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is less than 0.6 mmol, such as selected from the group consisting of less than 0.55 mmol, of less than 0.5 mmol, of less than 0.45 mmol. Any range which may be constructed with endpoints having the above values are expressly contemplated.

[1142] In some embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is less than 50% w / w, e.g. less than 45% w / w, 40% w / w, 35% w / w, 30 % w / w, 25% w / w, 20% w / w, 15% w / w or 10% w / w. Any range which may be constructed with endpoints having the above values are expressly contemplated.

[1143] In some embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is at least 30 mg, e.g. at least 50, 70, 90, 110, 130, 150, or 170 mg. In some embodiments the amount of the compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in the composition is at least 175 mg, such as an amount selected from the group consisting of at least 200 mg, at least 210 mg, at least 220 mg, at least 230 mg, at least 240 mg, at least 250 mg, at least 260 mg, at least 270 mg and at least 280 mg. Any range which may be constructed with endpoints having the above values are expressly contemplated.

[1144] In some embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is in the range of 30 to 200 mg, e.g. 50, 70, 90, 110, 130, 150, 170, or 190 mg to 200 mg, or 50 to 70, 90, 110, 130, 150, 170, 190 mg or 200 mg. In some embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is in the range of 175-575 mg, such as 200-500 mg or 250-400 mg. In some embodiments the amount of the compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in the composition is up to 575 mg, such as an amount selected from the group consisting of up to 550 mg, up to 525 mg, up to 500 mg, up to 475 mg, up to 450 mg, up to 425 mg, up to 400 mg, up to 375 mg, up to 350 mg and up to 325 mg. Any range which may be constructed with endpoints having the above values are expressly contemplated.

[1145] In some embodiments the amount of the compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in the composition or dosage form is about 300, 200, 100, 50 or 30 mg. Any range which may be constructed with endpoints having the above values are expressly contemplated.

[1146] In some embodiments the molar ratio between the therapeutic polypeptide (e.g. GLP-1 receptor agonist) and permeation enhancer(s) in the composition or dosage form is less than 10, such as less than 5 or less than 1.

[1147] In some embodiments the amount of a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, in a composition or dosage form containing the therapeutic polypeptide and optionally the alginate oligomer and / or the compound of Formula (II), or salt thereof, is less than 175 mg, e.g. less than 170 mg, 165 mg, 160 mg, 155 mg, 150 mg, 145 mg, 140 mg, 135 mg, 130 mg, 125 mg, 120 mg, 115 mg, 110 mg, 105 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, or 40 mg. Any range which may be constructed with endpoints having the above values are expressly contemplated.

[1148] In these above described embodiments, the composition or dosage form, e.g. in the form of a tablet, has a weight in the range of 50 to 1000 mg, e.g. 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 to 1000 mg, or 100 to 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg. Any range which may be constructed with endpoints having the above values are expressly contemplated.

[1149] In these above described embodiments, the composition or dosage form, e.g. in the form of a tablet, has a weight in the range of 175 mg to 1000 mg, such as in the range of 175-250 mg, 300-500 mg or 500-900 mg, or such as about 200 mg, about 400 mg or about 700 mg. In some of these above described embodiments, the weight of the tablet is in the range of 200 mg to 1000 mg, such as in the range of 500-700 mg or 600-1000 mg, or such as about 200 mg, about 400 mg, about 600 mg or about 800 mg.

[1150] The above discussion of compositions or dosage forms primarily containing a compound of Formula (I), e.g. N-(8-(2-hydroxybenzoyl) amino)caprylic acid, or salt thereof, and the therapeutic polypeptide is explicitly applicable to analogous compositions or dosage forms primarily containing a compound of Formula (II), or pharmaceutically acceptable salt thereof, and the therapeutic polypeptide. The resultant composition or dosage forms are expressly contemplated as part of the invention.

[1151] In specific embodiments of the various aspects of the invention described herein, references to the alginate oligomer is to a high G alginate oligomer, e.g. of at least 80% or 85% G. In specific embodiments of the various aspects of the invention described herein, references to the alginate oligomer is to an alginate oligomer which has 2 to 40 monomer residues, e.g. with a weight average molecular weight of 2600Da. In specific embodiments of the various aspects of the invention described herein, references to the gastrointestinal permeation enhancers (compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof) are SNAC and sodium caprate. In specific embodiments of the various aspects of the invention described herein, references to the polypeptide therapeutic agent is to a compound of Formula VI or Formula XIV, e.g. tirzepatide or retatrutide, respectively, preferably retatrutide. In more specific embodiments of the above, all of these features apply.

[1152] In even more specific embodiments of the various aspects of the invention described herein, references to the alginate oligomer is to an alginate oligomer which has 5 to 20 monomer residues, e.g. with a weight average molecular weight of 3200 Da. In specific embodiments of the various aspects of the invention described herein, references to the alginate oligomer is to an alginate oligomer which has 90-95% G residues. In specific embodiments of the various aspects of the invention described herein, references to the gastrointestinal permeation enhancers (compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof) are SNAC and sodium caprate. In specific embodiments of the various aspects of the invention described herein, references to the polypeptide therapeutic agent is to a compound of Formula IV or Formula XII, e.g. tirzepatide or retatrutide, respectively, preferably retatrutide. In more specific embodiments of the above, all of these features apply.

[1153] The subject may be any human or non-human animal subject, but more particularly may be a human or a non-human vertebrate, e.g. a non-human mammal, bird, amphibian, fish or reptile. In a preferred embodiment the subject is a mammalian subject. The animal may be a livestock or a domestic animal or an animal of commercial value, including laboratory animals or an animal in a zoo or game park. Representative animals therefore include dogs, cats, rabbits, mice, guinea pigs, hamsters, horses, pigs, sheep, goats and cows. Veterinary uses of the invention are thus covered. The subject may be viewed as a patient. Preferably the subject is a human. In some embodiments the subject is not a ruminant mammal.

[1154] The gastrointestinal (Gl) tract of vertebrates(mammals in particular), also referred to as the digestive tract or alimentary canal, is the continuous series of organs beginning at the mouth and ending at the anus. Specifically, this sequence consists of the mouth, the pharynx, the oesophagus, the stomach (or stomachs in ruminant mammals), the small intestine, the large intestine and the anus. These organs can be subdivided into the upper Gl tract, consisting of the mouth, pharynx, oesophagus, and stomach(s), and the lower Gl tract (the intestinal tract), consisting of the duodenum, the jejunum, the ileum (together the small intestine), the cecum, the colon, the rectum (together the large intestine) and the anus. In certain instances, references to “the intestines” may be taken as a reference to the small intestine and the large intestine. When the invention is applied to a ruminant animal, references to “a stomach” should be taken as references to the “abomasum”. In some instances, “a portion of the intestines” is not a portion of the anus or rectum. In some instances, “a portion of the intestines” is not a portion of the anus, rectum or colon. In some instances, “a portion of the intestines” is a portion of the small intestine, e.g. a portion of the duodenum, the jejunum, and / or the ileum.

[1155] " Treatment" when used generally in relation to the treatment of a disease or medical condition in a subject in accordance with the invention is used broadly herein to include any therapeutic effect, i.e. any beneficial effect in relation to the disease or on the condition. Thus, not only included is eradication or elimination of the disease or condition, or cure of the subject, but also an improvement in the disease or condition of the subject. Thus, included for example, is an improvement in any symptom or sign of the disease or condition, or in any clinically accepted indicator of the disease / condition. T reatment thus includes both curative and palliative therapy, e.g. of a pre-existing or diagnosed disease / condition, i.e. a reactionary treatment.

[1156] " Prevention" as used generally herein refers to any prophylactic or preventative effect. It thus includes delaying, limiting, reducing or preventing the disease or condition or the onset of the disease or condition, or one or more symptoms or indications thereof, for example relative to the disease or condition or symptom or indication prior to the prophylactic treatment. Prophylaxis thus explicitly includes both absolute prevention of occurrence or development of the disease or condition, or symptom or indication thereof, and any delay in the onset or development of the disease or condition or symptom or indication, or reduction or limitation on the development or progression of the disease condition or symptom or indication.

[1157] In the following section describing examples of dosage forms and composition of use in the invention, references to an alginate oligomer is a reference to an alginate oligomer having 2-100 monomer residues and as further defined herein.

[1158] In the following section describing examples of dosage forms and composition of use in the invention, references to a, or one or more, gastrointestinal permeation enhancer(s) is a reference to a compound of Formula (I), or pharmaceutically acceptable salt thereof, and / or a compound of Formula (II), or pharmaceutically acceptable salt thereof, as defined herein.

[1159] The skilled person will be able to formulate, alone or in various combinations, the alginate oligomers and the therapeutic polypeptides and the gastrointestinal permeation enhancers (the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the compound of Formula (II), or pharmaceutically acceptable salt thereof) of use in the invention into pharmaceutical compositions and dosage forms that are suitable for use in the above described aspects and embodiments of the invention according to any of the conventional methods known in the art and widely described in the literature.

[1160] More specifically, the alginate oligomers of use in the invention may be incorporated, optionally together with the polypeptide therapeutic agent and / or the gastrointestinal permeation enhancer(s), with one or more conventional carriers, diluents and / or excipients, to produce conventional galenic preparations such as tablets, mini tablets, microtablets, pills, granules, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, soft and hard capsules, and the like.

[1161] Likewise, the polypeptide therapeutic agents of use in the invention may be incorporated, optionally together with the alginate oligomer and / or the gastrointestinal permeation enhancer(s), with one or more conventional carriers, diluents and / or excipients, to produce conventional galenic preparations such as tablets, mini tablets, microtablets, pills, granules, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, soft and hard capsules, and the like.

[1162] Likewise, the gastrointestinal permeation enhancers of use in the invention may individually or together be incorporated, optionally together with the alginate oligomer and / or the polypeptide therapeutic agent, with one or more conventional carriers, diluents and / or excipients, to produce conventional galenic preparations such as tablets, mini tablets, microtablets, pills, granules, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, soft and hard capsules, and the like.

[1163] Such formulations may be any pharmaceutically acceptable composition, e.g. in the form of a solution, dispersion, emulsion, powder, tablet, mini tablets, microtablets, granules, capsule, gel, and the like, comprising any of the formulation components specifically recited herein. Conveniently, the formulation will take the form of a tablet or a liquid or powder / pellet filled capsule, but this is not an exhaustive list.

[1164] Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, tragacanth, gelatine, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, water, water / ethanol, water / glycol, water / polyethylene, hypertonic saltwater, glycol, propylene glycol, methyl cellulose, methylhydroxybenzoates, propyl hydroxybenzoates, talc, magnesium stearate, mineral oil or fatty substances such as hard fat or suitable mixtures thereof.

[1165] The compositions may additionally include lubricating agents, wetting agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavouring agents, buffering agents, and the like. In certain embodiments agents which would provide substantive protection to the polypeptide therapeutic agent, the alginate oligomer, and / or the gastrointestinal permeation enhancer(s), and the dosage form more generally, from the gastric environment, e.g. buffering agents and enzyme (protease) inhibitors are included, but in other embodiments they are not included.

[1166] Excipients for tablet, mini tablet, microtablet, capsule and solid or semi-solid mixture formulations may include diluents, binders, lubricants, disintegrants, gildants, stabilisers, and surfactants. Sweeteners, flavourings, and colourants can also be added in order to get an acceptable product even though they do not directly affect the performance of the formulation.

[1167] Cellulose, starch, monosaccharides, disaccharides, carbonates, and polyvinylpyrrolidone may act as fillers, binders and disintegrants in solid dosage forms. Fatty acids, stearates and silicates may act as lubricants in solid dosage forms.

[1168] Excipients for aqueous liquid formulations may, in addition to the water (e.g. purified or sterilised water) vehicle include co-solvents, buffers, surface active agents, rheology modifiers, preservatives, and antioxidants. Sweeteners, flavourings, and colourants can also be added in order to get an acceptable product even though they do not directly affect the performance of the formulation.

[1169] Compositions or dosage forms comprising the polypeptide therapeutic agent, in particular the lipid modified incretin analogues described herein, may comprise one or more solubility enhancers, such as, e.g., poly(ethylene glycol), including poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 20, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrins, a-cyclodextrin, p-cyclodextrin, y-cyclodextrin, hydroxyethyl-p-cyclodextrin, hydroxypropyl-p-cyclodextrin, hydroxyethyl-y-cyclodextrin, hydroxypropyl-y-cyclodextrin, dihydroxypropyl-p-cyclodextrin, sulfobutylether-p-cyclodextrin, sulfobutylether-y-cyclodextrin, glucosyl-a-cyclodextrin, glucosyl-p-cyclodextrin, diglucosyl-p-cyclodextrin, maltosyl-a-cyclodextrin, maltosyl-p-cyclodextrin, maltosyl-y-cyclodextrin, maltotriosyl-p-cyclodextrin, maltotriosyl-y-cyclodextrin, dimaltosyl-p-cyclodextrin, methyl-p-cyclodextrin, carboxyalkyl thioethers, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, vinyl acetate copolymers, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[1170] The alginate oligomer may be administered in doses of 0.01 to 10 g, e.g. 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 to 10g, or 0.05 to 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 or 10g, orO.lg to 10g, 0.5g to 5g, 0.8g to 3g, or 1g to 2g, e.g. about 2g. These may be daily or bis daily doses.

[1171] The compound of Formula (I), or pharmaceutically acceptable salt thereof, may be administered in doses of 0.01 to 10 g, e.g. 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 to 10g, or 0.05 to 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 or 10g, or 0.1g to 10g, 0.5g to 5g, 0.8g to 3g, or 1g to 2g, e.g. about 2g. These may be daily or bis daily doses.

[1172] The compound of Formula (II), or pharmaceutically acceptable salt thereof, may be administered in doses of 0.01 to 10 g, e.g. 0.05, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 to 10g, or 0.05 to 0.1, 0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0 or 10g, or 0.1g to 10g, 0.5g to 5g, 0.8g to 3g, or 1g to 2g, e.g. about 2g. These may be daily or bis daily doses.

[1173] A representative tablet (or mini tablet or microtablet) to be used to administer an alginate oligomer in accordance with the invention may contain up to 99%, up to 95%, 90%, 85% or 80%, e.g. 50 to 95%, 55 to 95%, 60 to 95%, 65 to 95%, 70 to 95%, 75 to 95%, 80 to 95%, 85 to 95%, 90 to 95%, 50 to 90%, 50 to 90%, 55 to 90%, 60 to 90%, 65 to 90%, 70 to 90%, 75 to 90%, 80 to 90%, 85 to 90%, 50 to 90%, 55 to 85%, 60 to 80% or, 65 to 75% w / w of the oligomer, the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents (e.g. the therapeutic polypeptide and / or the gastrointestinal permeation enhancer(s)) if being used in the same composition.

[1174] An enteric coated tablet to be used to administer an alginate oligomer in accordance with the invention to the intestines may contain up to 99%, up to 95%, 90%, 85% or 80%, e.g.

[1175] 50 to 95%, 55 to 95%, 60 to 95%, 65 to 95%, 70 to 95%, 75 to 95%, 80 to 95%, 85 to 95%, 90 to 95%, 50 to 90%, 50 to 90%, 55 to 90%, 60 to 90%, 65 to 90%, 70 to 90%, 75 to 90%, 80 to 90%, 85 to 90%, 50 to 90%, 55 to 85%, 60 to 80% or, 65 to 75% w / w of the oligomer, the remainder being comprised of pharmaceutically acceptable excipients, including the enteric coating (e.g. polymers including fatty acids, waxes, shellac, plastics, and plant fibres, including methyl acrylate-methacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate, and those available under the trade name Eudragit) and, optionally, other active agents (e.g. the therapeutic polypeptide and / or the gastrointestinal permeation enhancer(s)) if being used in the same composition.

[1176] A representative powder for oral administration of an alginate oligomer in accordance with the invention following admixture with food or beverages may contain up to 100%, e.g. up to 99%, 95%, 90%, 85%, 80%, 75% or 70%, e.g. 50 to 90%, 55 to 90%, 60 to 90%, 65 to 90%, 70 to 90%, 75 to 90%, 80 to 90%, 85 to 90%, 50 to 85%, 55 to 85%, 60 to 85%, 65 to 85%, 70 to 85%, 75 to 85%, 80 to 85%, 50 to 80%, 55 to 80%, 60 to 80%, 65 to 80%, 70 to 80%, 75 to 80%, 50 to 70%, 55 to 70%, 60 to 70%, or 65 to 70%w / w of the alginate oligomer, the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents (e.g. the therapeutic polypeptide and / or the gastrointestinal permeation enhancer(s)) if being used in the same composition.

[1177] A representative solution to be used to administer an alginate oligomer in accordance with the invention may contain up to 1 to 25%, 1 to 20%, e.g. 1 to 15%, 1 to 10%, 1 to 9%, 1 to 8%, 1 to 7% or 1 to 6%, 5 to 25%, 5 to 20%, 5 to 15%, 5 to 10%, 5 to 9%, 5 to 8%, 5 to 7%, 5 to 6%, 8 to 25%, 8 to 20%, 8 to 15%, 8 to 10%, 9 to 25%, 9 to 20%, or 9 to 15% w / v or w / w of the alginate oligomer, the remainder being comprised of pharmaceutically acceptable excipients, e.g. water, and / or other active agents (e.g. the therapeutic polypeptide and / or the gastrointestinal permeation enhancer(s)) if being used in the same composition.

[1178] A representative tablet to be used to administer one or more gastrointestinal permeation enhancer(s) in accordance with the invention may contain up to 99%, up to 95%, 90%, 85% or 80%, e.g. 50 to 95%, 55 to 95%, 60 to 95%, 65 to 95%, 70 to 95%, 75 to 95%, 80 to 95%, 85 to 95%, 90 to 95%, 50 to 90%, 50 to 90%, 55 to 90%, 60 to 90%, 65 to 90%, 70 to 90%, 75 to 90%, 80 to 90%, 85 to 90%, 50 to 90%, 55 to 85%, 60 to 80% or, 65 to 75% w / w of the gastrointestinal permeation enhancer(s), the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents (e.g. the therapeutic polypeptide and / or alginate oligomer) if being used in the same composition.

[1179] A representative enteric coated tablet to be used to administer one or more gastrointestinal permeation enhancer(s) in accordance with the invention to the intestines may contain up to 99%, up to 95%, 90%, 85% or 80%, e.g. 50 to 95%, 55 to 95%, 60 to 95%, 65 to 95%, 70 to 95%, 75 to 95%, 80 to 95%, 85 to 95%, 90 to 95%, 50 to 90%, 50 to 90%, 55 to 90%, 60 to 90%, 65 to 90%, 70 to 90%, 75 to 90%, 80 to 90%, 85 to 90%, 50 to 90%, 55 to 85%, 60 to 80% or, 65 to 75% w / w of the gastrointestinal permeation enhancer(s), the remainder being comprised of pharmaceutically acceptable excipients, including the enteric coating (e.g. polymers including fatty acids, waxes, shellac, plastics, and plant fibres including methyl acrylate-methacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate, and those available under the trade name Eudragit) and, optionally, other active agents (e.g. the therapeutic polypeptide and / or alginate oligomer) if being used in the same composition.

[1180] A representative powder for oral administration of one or more gastrointestinal permeation enhancer(s) in accordance with the invention following admixture with food or beverages may contain up to 100%, e.g. up to 99%, 95%, 90%, 85%, 80%, 75% or 70%, e.g. 50 to 90%, 55 to 90%, 60 to 90%, 65 to 90%, 70 to 90%, 75 to 90%, 80 to 90%, 85 to 90%, 50 to 85%, 55 to 85%, 60 to 85%, 65 to 85%, 70 to 85%, 75 to 85%, 80 to 85%, 50 to 80%, 55 to 80%, 60 to 80%, 65 to 80%, 70 to 80%, 75 to 80%, 50 to 70%, 55 to 70%, 60 to 70%, or 65 to 70% w / w of the gastrointestinal permeation enhancer(s), the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents (e.g. the therapeutic polypeptide and / or the alginate oligomer) if being used in the same composition.

[1181] A representative solution to be used to administer one or more gastrointestinal permeation enhancer(s) in accordance with the invention may contain up to 1 to 25%, 1 to 20%, e.g. 1 to 15%, 1 to 10%, 1 to 9%, 1 to 8%, 1 to 7% or 1 to 6%, 5 to 25%, 5 to 20%, 5 to 15%, 5 to 10%, 5 to 9%, 5 to 8%, 5 to 7%, 5 to 6%, 8 to 25%, 8 to 20%, 8 to 15%, 8 to 10%, 9 to 25%, 9 to 20%, or 9 to 15% w / v or w / w of the gastrointestinal permeation enhancer(s), the remainder being comprised of pharmaceutically acceptable excipients, e.g. water, and / or other active agents (e.g. the therapeutic polypeptide and / or the alginate oligomer) if being used in the same composition.

[1182] A representative tablet to be used to administer a polypeptide therapeutic agent in accordance with the invention may contain up to 10%, up to 9.5%, 9.0%, 8.5%, 8.0%, 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, 0.5% or 0.1%, e.g. 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 to 10%, or 0.1 to 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10%, or 5.0 to 9.5%, 5.5 to 9.5%, 6.0 to 9.5%, 6.5 to 9.5%, 7.0 to 95.%, 7.5 to 9.5%, 8.0 to 9.5%, 8.5 to 9.5%, 9.0 to 9.5%, 5.0 to 9.0%, 5.0 to 9.0%, 5.5 to 9.0%, 6.0 to 9.0%, 6.5 to 9.0%, 7.0 to 9.0%, 7.5 to 9.0%, 8.0 to 9.0%, 8.5 to 9.0%, 5.0 to 9.0%, 5.5 to 8.5%, 6.0 to 8.0% or, 6.5 to 7.5% w / w of the polypeptide therapeutic agent, the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents (e.g. the gastrointestinal permeation enhancer(s) and / or alginate oligomer) if being used in the same composition.

[1183] A representative enteric coated tablet to be used to administer a polypeptide therapeutic agent in accordance with the invention to the intestines may contain up to 10%, up to 9.5%, 9.0%, 8.5%, 8.0%, 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, 0.5% or 0.1%, e.g. 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 to 10%, or 0.1 to 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10%, or 5.0 to 9.5%, 5.5 to 9.5%, 6.0 to 9.5%, 6.5 to 9.5%, 7.0 to 95.%, 7.5 to 9.5%, 8.0 to 9.5%, 8.5 to 9.5%, 9.0 to 9.5%, 5.0 to 9.0%, 5.0 to 9.0%, 5.5 to 9.0%, 6.0 to 9.0%, 6.5 to 9.0%, 7.0 to 9.0%, 7.5 to 9.0%, 8.0 to 9.0%, 8.5 to 9.0%, 5.0 to 9.0%, 5.5 to 8.5%, 6.0 to 8.0% or, 6.5 to 7.5% w / w of the polypeptide therapeutic agent, the remainder being comprised of pharmaceutically acceptable excipients, including the enteric coating (e.g. polymers including fatty acids, waxes, shellac, plastics, and plant fibres including methyl acrylatemethacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate, and those available under the trade name Eudragit) and, optionally, other active agents (e.g. the gastrointestinal permeation enhancer(s) and / or alginate oligomer) if being used in the same composition.

[1184] A representative powder for oral administration of a polypeptide therapeutic agent in accordance with the invention following admixture with food or beverages may contain up to 10%, up to 9.5%, 9.0%, 8.5%, 8.0%, 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, 0.5% or 0.1%, e.g. 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 to 10%, or 0.1 to 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10%, or 5.0 to 9.5%, 5.5 to 9.5%, 6.0 to 9.5%, 6.5 to 9.5%, 7.0 to 95.%, 7.5 to 9.5%, 8.0 to 9.5%, 8.5 to 9.5%, 9.0 to 9.5%, 5.0 to 9.0%, 5.0 to 9.0%, 5.5 to 9.0%, 6.0 to 9.0%, 6.5 to 9.0%, 7.0 to 9.0%, 7.5 to 9.0%, 8.0 to 9.0%, 8.5 to 9.0%, 5.0 to 9.0%, 5.5 to 8.5%, 6.0 to 8.0% or, 6.5 to 7.5% w / w of the polypeptide therapeutic agent, the remainder being comprised of pharmaceutically acceptable excipients and / or other active agents (e.g. the gastrointestinal permeation enhancer(s) and / or the alginate oligomer) if being used in the same composition.

[1185] A representative solution to be used to administer a polypeptide therapeutic agent in accordance with the invention may contain up to 10%, up to 9.5%, 9.0%, 8.5%, 8.0%, 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, 0.5% or 0.1%, e.g. 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 to 10%, or 0.1 to 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10%, or 5.0 to 9.5%, 5.5 to 9.5%, 6.0 to 9.5%, 6.5 to 9.5%, 7.0 to 95.%, 7.5 to 9.5%, 8.0 to 9.5%, 8.5 to 9.5%, 9.0 to 9.5%, 5.0 to 9.0%, 5.0 to 9.0%, 5.5 to 9.0%, 6.0 to 9.0%, 6.5 to 9.0%, 7.0 to 9.0%, 7.5 to 9.0%, 8.0 to 9.0%, 8.5 to 9.0%, 5.0 to 9.0%, 5.5 to 8.5%, 6.0 to 8.0% or, 6.5 to 7.5% w / v or w / w of the polypeptide therapeutic agent, the remainder being comprised of pharmaceutically acceptable excipients, e.g. water, and / or other active agents (e.g. the gastrointestinal permeation enhancer(s) and / or the alginate oligomer) if being used in the same composition.

[1186] A representative tablet to be used to administer an alginate oligomer, one or more gastrointestinal permeation enhancer(s) and a polypeptide therapeutic agent in accordance with the invention may contain 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the alginate oligomer, 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the gastrointestinal permeation enhancer(s), 1 to 10% (e.g. 2, 3, 4, 5, 6, 7, 8, 9 to 10%, or 2 to 3, 4, 5, 6, 7, 8, 9, or 10%) w / v or w / w of the polypeptide therapeutic agent, to a maximum of 100% with any remainder being comprised of pharmaceutically acceptable excipients.

[1187] A representative enteric coated tablet to be used to administer an alginate oligomer, one or more gastrointestinal permeation enhancer(s) and a polypeptide therapeutic agent in accordance with the invention to the intestines may contain 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the alginate oligomer, 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the gastrointestinal permeation enhancer(s), 1 to 10% (e.g. 2, 3, 4, 5, 6, 7, 8, 9 to 10%, or 2 to 3, 4, 5, 6, 7, 8, 9, or 10%) w / v or w / w of the polypeptide therapeutic agent, 0.1 to 5% (e.g. 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4 to 5%, or 0.1 to 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, or 5%) w / v or w / w of the enteric coating (e.g. polymers including fatty acids, waxes, shellac, plastics, and plant fibres including methyl acrylatemethacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate, and those available under the trade name Eudragit) to a maximum of 100% with any remainder being comprised of pharmaceutically acceptable excipients.

[1188] A representative powder for oral administration of an alginate oligomer, one or more gastrointestinal permeation enhancer(s) and a polypeptide therapeutic agent in accordance with the invention following admixture with food or beverages may contain 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the alginate oligomer, 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the gastrointestinal permeation enhancer(s), 1 to 10% (e.g. 2, 3, 4, 5, 6, 7, 8, 9 to 10%, or 2 to 3, 4, 5, 6, 7, 8, 9, or 10%) w / v or w / w of the polypeptide therapeutic agent, to a maximum of 100% with any remainder being comprised of pharmaceutically acceptable excipients.

[1189] A representative solution to be used to administer an alginate oligomer, one or more gastrointestinal permeation enhancer(s) and a polypeptide therapeutic agent in accordance with the invention may contain 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the alginate oligomer, 20 to 60% (e.g. 25, 30, 35, 40, 50 or 55 to 60%, or 25 to 30, 35, 40, 50, 55 or 60%) w / v or w / w of the gastrointestinal permeation enhancer(s), 1 to 10% (e.g. 2, 3, 4, 5, 6, 7, 8, 9 to 10%, or 2 to 3, 4, 5, 6, 7, 8, 9, or 10%) w / v or w / w of the polypeptide therapeutic agent, to a maximum of 100% with any remainder being comprised of pharmaceutically acceptable excipients. A tablet of use in the present invention may consist of about 0.1% to 100% w / w in total of a polypeptide therapeutic agent, an alginate oligomer and the gastrointestinal permeation enhancers, and 0 to about 99.9% w / w in total of further excipients. For example, the tablet may consist of about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% to 100% w / w, or about 0.1% to about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% w / w in total of a polypeptide therapeutic agent, an alginate oligomer, and gastrointestinal permeation enhancers, and about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% to about 99% w / w, or about 0.1% to about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99% w / w in total of further excipients. Any ranges with end points which may be formed from any of these values are explicitly contemplated.

[1190] An enteric coated tablet of use in the present invention may consist of about 0.1% to 100% w / w in total of a polypeptide therapeutic agent, an alginate oligomer, the gastrointestinal permeation enhancers and the enteric coating (e.g. polymers including fatty acids, waxes, shellac, plastics, and plant fibres including methyl acrylate-methacrylic acid copolymers, methyl methacrylate-methacrylic acid copolymers, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), cellulose acetate trimellitate, and those available under the trade name Eudragit), and 0 to about 99.9% w / w in total of further excipients. For example, the tablet may consist of about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% to 100% w / w, or about 0.1% to about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% w / w in total of a polypeptide therapeutic agent, alginate oligomer, th...

Claims

CLAIMS1. An alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for increasing the systemic bioavailability of a polypeptide therapeutic agent undergoing oral, orogastric, nasogastric, or intragastric administration, said method comprising administering said polypeptide therapeutic agent together with (i) said alginate oligomer,(ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,wherein:X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy;R1is hydrogen or C1-3 alkyl;R2is hydrogen or C1-3 alkyl;R3is -OH;each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; andn is an integer from 0 to 4, preferably 0 or 1, and(iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,OH(II)wherein:Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy,to a portion of the intestines of a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

2. An alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues, for use in a method for systemic treatment or prevention of a disease or condition or complication thereof which is responsive to, or which is prevented by, a polypeptide therapeutic agent, said method comprising administering said polypeptide therapeutic agent together with(i) an alginate oligomer,(ii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,R3?W VY°R'r 0(R4)n(I) wherein:X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy;R1is hydrogen or C1-3 alkyl;R2is hydrogen or C1-3 alkyl;R3is -OH;each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; andn is an integer from 0 to 4, preferably 0 or 1, and(iii) a compound of Formula (II), or a pharmaceutically acceptable salt thereof,OH(II)wherein:Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy,to a portion of the intestines of a human or non-human animal subject, which has, is suspected of having, or is at risk of, said disease or condition or complication thereof, by oral, orogastric, nasogastric, or intragastric administration, wherein said portion of the intestines is contacted with (i), (ii), (iii) and said polypeptide therapeutic agent in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

3. A dosage form adapted for oral, orogastric, nasogastric, or intragastric administration to a human or non-human animal subject, said dosage form comprising (i) a polypeptide therapeutic agent,(ii) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,(iii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,wherein:X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy;R1is hydrogen or C1-3 alkyl;R2is hydrogen or C1-3 alkyl;R3is -OH;each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; andn is an integer from 0 to 4, preferably 0 or 1, and(iv) a compound of Formula (II), or pharmaceutically acceptable salt thereof,OH(II)wherein:Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy,for use in a method for increasing the systemic bioavailability of said polypeptide therapeutic agent when undergoing oral, orogastric, nasogastric, or intragastric administration, said method comprising administering said dosage form to a human or non-human animal subject by oral, orogastric, nasogastric, or intragastric administration, wherein a portion of the intestines is contacted with (i)-(iv) in amounts which result in uptake of the polypeptide therapeutic agent from said portion of the intestine.

4. A dosage form adapted for oral, orogastric, nasogastric, or intragastric administration to a human or non-human animal subject, said dosage form comprising (i) a polypeptide therapeutic agent,(ii) an alginate oligomer, wherein said alginate oligomer has 2 to 100 monomer residues,(iii) a compound of Formula (I), or a pharmaceutically acceptable salt thereof,(I) wherein:X is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy;R1is hydrogen or C1-3 alkyl;R2is hydrogen or C1-3 alkyl;R3is -OH;each R4is independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy; andn is an integer from 0 to 4, preferably 0 or 1, and(iv) a compound of Formula (II), or pharmaceutically acceptable salt thereof,(II)wherein:Y is an optionally substituted, saturated or unsaturated, hydrocarbon chain containing 4 to 14 carbon atoms, said substitutions independently selected from halogen, -OH, C1-3 alkyl or Ci-3alkoxy,wherein said dosage form has a structure which would provide to the polypeptide therapeutic agent, the alginate oligomer, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and / or the compound of Formula (II), or pharmaceutically acceptable salt thereof, substantive protection from a gastric environment.

5. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 4, wherein the alginate oligomer has a degree of polymerisation (DP), or a number average degree of polymerisation (DPn) of(i) 2 to 75, 2 to 50, 2 to 35, 2 to 30, 2 to 25, 2 to 22, 2 to 20, 2 to 18, 2 to 16 or 2 to 14,(ii) 4 to 100, 4 to 75, 4 to 50, 4 to 35, 4 to 30, 4 to 25, 4 to 22, 4 to 20, 4 to 18, 4 to 16 or 4 to 14,(iii) 6 to 50, 6 to 35, 6 to 30, 6 to 25, 6 to 22, 6 to 20, 6 to 18, 6 to 16 or 6 to 14, or(iv) 8 to 50, 8 to 35, 8 to 30, 8 to 25, 8 to 22, 8 to 20, 8 to 18, 8 to 16 or 8 to 14, or(v) 10 to 50, 10 to 35, 10 to 30, 10 to 25, 10 to 22, 10 to 20, 10 to 18, or 10 to 14.

6. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 4, wherein the alginate oligomer is a 2- to 35-mer, 2- to 30-mer, 3- to 35-mer, 3- to 28-mer, 4- to 25-mer, 5- to 20-mer, 6- to 22-mer, 8- to 20-mer, or 10- to 15-mer.

7. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 6, wherein the alginate oligomer has at least 70%, at least 80%, at least 85%, at least 90% G, at least 95%, or 100% G residues, preferably wherein at least 80% of the G residues are arranged in G-blocks.

8. The alginate oligomer for use, the dosage form for use, or the dosage form use of any one of claims 1 to 6, wherein the alginate oligomer has at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% M residues, preferably wherein at least 80% of the M residues are arranged in M blocks.

9. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 6, wherein at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or 100% of the G and M residues in the oligomer are arranged in MG blocks.

10. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 9, wherein the polypeptide therapeutic agent is, or is an analogue of (i) a peptide hormone or growth factor(ii) a cytokine(iii) an enzyme, or(iv) a blood factor.

11. The alginate oligomer for use, the dosage form for use, or the dosage form of claim 10, wherein the polypeptide therapeutic agent is, or is an analogue of G-CSF, VEGF, EGF, HGF, PDGF, FGF, NGF, BDNF, neurotrophin-3, neurotrophin-4, TNF, IL-1, IL-6, IL-8, IL-10, IFN-y, IFN-a, IFN-, IFN-E, IFN-K and IFN-w, Factor VII, Factor VIII and Factor IX, adrenocorticotropic hormone (ACTH), corticotropin-releasing factor, angiotensin, endothenlin, calcitonin, insulin, glucagon, glucagon-like peptide-1, glucagon-like peptide-2, amylin, peptide YY, oxyntomodulin, GDF-15, insulin-like growth factor, insulin-like growth factor-2, gastric inhibitory peptide, growth hormone releasing factor, pituitary adenylate cyclase activating peptide, secretin, enterogastrin, somatostatin, somatotropin, somatomedin, parathyroid hormone, thrombopoietin, follicle-stimulating hormone, erythropoietin, gastrin, growth hormone, gonadotrophin, hypothalamic releasing factors, prolactin, thyroid stimulating hormones, endorphins, enkephalins, vasopressin, oxytocin, interferon, and analogues thereof, superoxide dismutase, asparaginase, arginase, arginine deaminase, adenosine deaminase and ribonuclease.

12. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 9, wherein the polypeptide therapeutic agent is or comprises an immunoglobulin amino acid sequence.

13. The alginate oligomer for use, the dosage form for use, or the dosage form of claim 12, wherein the therapeutic polypeptide is a therapeutic antibody, preferably selected from bimagrumab, alemtuzumab, bevacizumab, cetuximab, ofatumumab, panitumumab, rituximab, trastuzumab, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, sutimlimab, anifrolumab, bimekizumab, tralokinumab, evinacumab, aducanumab, ansuvimab, atoltivimab, teprotumumab, eptinezumab, crizanlizumab, brolucizumab, risankizumab, romosozumab, galcanezumab, erenumab, ibalizumab, emicizumab, benralizumab, ocrelizumab, sarilumab, dupilumab, bezlotoxumab, ixekizumab, alirocumab, vedolizumab, tocilizumab,canakinumab, infliximab, adalimumab, omalizumab, efalizumab, golimumab, ustekinumab, certolizumab pegol, ibritumomab or tositumomab.

14. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 9, wherein the polypeptide therapeutic agent is a polypeptide antibiotic, preferably actinomycin, gramicidin, tyrocidine, bleomycin, bacitracin, colistin, and polymyxin B.

15. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 9, wherein the polypeptide therapeutic agent is an antimicrobial peptide or protein.

16. The alginate oligomer for use or the dosage form for use of claim 14 or claim 15, wherein the disease or conditions is a microbial, preferably bacterial or fungal, infection.

17. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 9, wherein the polypeptide therapeutic agent is incretin peptide or an analogue / mimetic thereof, preferably glucagon-like protein 1, gastric inhibitory peptide (glucose-dependent insulinotropic polypeptide (GIP)), amylin, peptide YY, oxyntomodulin, GDF-15, and / or exendin-4 peptide.

18. The alginate oligomer for use, the dosage form for use, or the dosage form of claim 17, wherein the polypeptide therapeutic agent is selected from dulaglutide, exenatide, liraglutide, semaglutide, tirzepatide, albiglutide, lixisenatide, polyethylene glycol loxenatide, retatrutide (LY3437943), cotadutide; taspoglutide; langlenatide; beinaglutide; efpeglenatide; mazdutide / LY3305677; LY3502970; LY3537031; LY3493269;HM12525A / JNJ-64565111; MOD6030 / 1; SAR425899; MEDI0382; MK8521; ZP2929 / BI 456906; NN9709 / NNC0090-2746 / MAR709 / RG7697 / R06811135; SAR441255; C2816; ZP3022; NNC 9204-1177 (NN9277); JNJ-54728518; LY2944876 / TT-401; CPD86;SAR438335; ZP-l-98; ZP-DI-70; HM15211; NN9423 / MAR423, PB-719; DD01, survodutide; pramlintide; cagrilintide; PYY1875 / NNC0165-1875; pemvidutide; AMG 133; dapiglutide / ZP7570; NN1213; AZD6234; AZD9550; ZP8396; HM15136; NNC0165-1562; Y-14; VK2735; SCO-094; CT-388; Amycretin / NNC0487-0111; Dacra QWII / KBP089; and ZP6590 and Formulas IX to XIII and XVI to XXII.19 The alginate oligomer for use or the dosage form for use of claim 17 or claim 18, wherein the disease or condition is excess body weight, obesity, diabetes mellitus type II, insulin resistance, prediabetes, gestational diabetes, diabetes mellitus type I, hyperlipemia, metabolic syndrome, cardiovascular diseases (including atherosclerosis, myocardial infarction, coronary heart disease, stroke, heart insufficiency, heart failure (acute or chronic), coronary artery disease, cardiomyopathy, reperfusion injury, cerebral ischemia, left ventricular hypertrophy, arrhythmia, cardiac dysrhythmia, syncope, angina pectoris, stenosis, or restenosis coronary artery diseases), hypertension, fatty liver disease, non-alcoholic steatohepatitis (NASH), chronic kidney disease and polycystic ovary syndrome (PCOS), neuronal dysfunction (e.g. dementia, Alzheimer’s and Parkinson’s Diseases), and complications associated with said diseases and conditions.

20. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 19, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, is N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, or N-(8-[2-hydroxybenzoyl]amino)caprylic acid or the sodium salts thereof, preferably SNAC21. The alginate oligomer for use, the dosage form for use, or the dosage form of any one of claims 1 to 20, wherein the compound of Formula (II), or pharmaceutically acceptable salt thereof, is caprylic acid, sodium caprylate, capric acid, sodium caprate (sodium decanoate; C10), preferably sodium caprate.

22. The alginate oligomer for use, the dosage form for use, or the dosage form of claim 20, wherein the compound of Formula (I), or pharmaceutically acceptable salt thereof, is SNAC, the compound of Formula (II), or pharmaceutically acceptable salt thereof, is sodium caprate, and the polypeptide therapeutic agent is retatrutide.

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