KR102266299B1 - Compositions of glp-1 peptides and preparation thereof - Google Patents

Abstract

The present invention includes a granule of a first type and a granule of a second type, wherein the granule of the first type comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and GLP-1 wherein said second type of granules does not contain peptides, wherein said second type of granules comprises pharmaceutical compositions comprising GLP-1 peptides and free of salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as well as intermediate granules. , to a process for the preparation of granules and compositions, and to their use in medicine.

Description

Composition of GLP-1 peptide and preparation thereof {COMPOSITIONS OF GLP-1 PEPTIDES AND PREPARATION THEREOF}

The present invention relates to compositions comprising a pharmaceutically active agent, such as GLP-1, and a delivery agent, as well as methods of their manufacture and use in the medical field.

One of the major challenges in the oral delivery of proteins and peptides is that these compounds cannot be readily transported across the membranes of the gastrointestinal tract. SNAC, a delivery agent, has already been shown to improve the bioavailability of orally administered peptides. The present invention relates to further improvement of bioavailability by oral administration of compositions of such peptides, in particular GLP-1 peptides.

In one embodiment, the present invention relates to a pharmaceutical composition comprising granules of a first type and a second type, wherein the granules of the first type are N-(8-(2-hydroxybenzoyl)amino)caprylic acid and no GLP-1 peptide, wherein the second type of granule contains a GLP-1 peptide and does not contain a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. does not In some embodiments, the term “granule” refers to small particles that are aggregated into a large mass.

In one embodiment, the invention relates to a method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising: a) GLP -1 mixing the peptide with fillers and/or binders; b) dry granulation of the mixture of step a; c) mixing the granules obtained in step b with a composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; and d) optionally adding a further lubricant, wherein the mixture of step a does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

In one embodiment, the invention relates to a method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising: a)N mixing a salt of -(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler; b) dry granulation of the mixture of step a; c) mixing the granules obtained in step b with a composition comprising a GLP-1 peptide; and d) optionally adding a further lubricant, wherein the mixture of step a does not comprise a GLP-1 peptide.

In one embodiment, the invention relates to a method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising: a) GLP -1 mixing the peptide with fillers and/or binders; b) dry granulation of the mixture of step a; c) admixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally a lubricant and/or a filler; d) dry granulation of the mixture of step c; e) mixing the granules obtained in step b with the granules obtained in step d; and f) optionally adding a further surfactant, wherein the mixture of step a does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, The mixture contains no GLP-1 peptide.

In one embodiment, the present invention relates to granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, optionally a filler, and no GLP-1 peptide. In one embodiment, the present invention relates to a method for preparing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, said method comprising: a) N-(8-(2) -mixing a salt of hydroxybenzoyl)amino)caprylic acid (such as SNAC) with a lubricant and/or filler; and b) dry granulation of the mixture of step a, wherein the mixture of step a does not comprise a GLP-1 peptide.

In one embodiment, the present invention relates to a granule comprising a GLP-1 peptide, a filler, a binder and free of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In one embodiment, the present invention relates to a method for preparing granules comprising a GLP-1 peptide, the method comprising: a) mixing the GLP-1 peptide, optionally a filler and/or a binder; and b) roller compacting the mixture of step a, wherein the mixture of step a does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

In one embodiment, the present invention relates to a pharmaceutical composition or granule obtained by a method as defined herein.

In one embodiment, the present invention relates to a composition or granule as defined herein for use in the medical field, such as for the treatment of diabetes or obesity, wherein the composition is administered orally. In one embodiment, the present invention relates to a method for the treatment of diabetes or obesity comprising administering to a patient in need thereof a composition as defined herein, said composition being administered orally.

The inventors have surprisingly found that the dissolution properties of tablets prepared from the same composition (ie the same type and the same amount of excipient and delivery agent) are determined by the design of the granules from which the tablet is formed.

In addition, the inventors have found that the dissolution behavior surprisingly has a significant effect on the bioavailability of GLP-peptides from compositions, such as tablets. Accordingly, the present inventors have found that the bioavailability of solid tablets prepared from various granule designs can be predicted from in vitro data, ie dissolution data. In one embodiment, the present invention provides compositions, granules and methods for preparing the same with improved bioavailability of GLP-1 peptide.

In general, the term "bioavailability" as used herein refers to the administered dose of an active pharmaceutical ingredient (API) and/or an active moiety, such as a GLP-1 peptide as defined herein, that has reached the systemic circulation either as such or in an otherwise active form (dose) ratio. By definition, when an API and/or active moiety is administered intravenously, its bioavailability is 100%. However, its bioavailability decreases (due to incomplete absorption and/or first-pass metabolism) when it is administered via other routes (eg orally). Knowledge of bioavailability is important when calculating the dosage when the route of administration is not an intravenous route.

Absolute oral bioavailability is calculated as the relative exposure of the API and/or active moiety in the systemic circulation after oral administration (estimated as the area under the curve in the plasma concentration versus time curve) compared to the exposure of the API after intravenous administration.

pharmaceutical composition

In some embodiments, the present invention relates to a pharmaceutical composition comprising granules of a first type and a second type, wherein the granules of the first type are N-(8-(2-hydroxybenzoyl)amino)caprylic acid of a salt, and the second type of granule contains a GLP-1 peptide. In some embodiments, the granules of the first type further comprise a lubricant, such as magnesium stearate. In some embodiments, the first type of granule further comprises a filler, such as microcrystalline cellulose. Accordingly, the first type of granules may further comprise a lubricant and optionally a filler. In some embodiments, the second type of granules further comprises a filler, such as microcrystalline cellulose. In some embodiments, the second type of granules further comprises a binder, such as povidone. Accordingly, the second type of granules may further comprise a filler and optionally a binder. In some embodiments, the composition further comprises an extragranular lubricant, such as magnesium stearate.

In some embodiments, N-(8-(2-hydroxybenzoyl)amino)caprylic acid is referred to as “NAC”.

In some embodiments, the first type of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid does not contain a GLP-1 peptide. In some embodiments, the granules of the second type of GLP-1 peptide do not contain a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, the pharmaceutical composition comprises granules of a first type and a second type, wherein the granules of the first type comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; It does not contain GLP-1 peptide, and the second type of granules contains GLP-1 peptide and does not contain a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

In some embodiments, the term “granule” refers to particles that are aggregated into larger particles.

In some embodiments, the present invention relates to a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide for dissolution test using Assay (I). The release of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid coincides with or faster than the release of the GLP-1 peptide as determined by In some embodiments, the present invention relates to a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, comprising: N-(8-(2-hydroxyl); The release of the salt of oxybenzoyl)amino)caprylic acid is simultaneous or faster than the release of the GLP-1 peptide.

In some embodiments, the term "release" is used to refer to N-(8-(2-hydroxybenzoyl)amino)caprylic acid and optionally allows assay (I) when compared to the release of a peptide of GLP-1. within 30 minutes, such as within 25, 20, 15 minutes, or such as within 10 minutes or within 5 minutes, as determined by the dissolution test used. Thus, the release can be determined within 30 minutes of a dissolution test using assay (I). In some embodiments, when it is stated that the release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is "faster than" release of said GLP-1 peptide, dissolution using assay (I) As determined by the test, within 30 minutes, such as within 25, 20, 15 minutes, or such as within 10 minutes or 5 minutes. In some embodiments, the release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is assay (I) at pH 2.5 when said to be "faster than" release of said GLP-1 peptide. It is determined within 30 minutes, such as within 25, 20, 15 minutes, or within, for example, 10 minutes or 5 minutes when determined by a dissolution test using

In some embodiments, the release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is dissolution using Assay (I) when referred to as "concurrent" with the release of said GLP-1 peptide. As determined by the test, within 30 minutes, such as within 25, 20, 15 minutes, or such as within 10 minutes or 5 minutes. In some embodiments, the release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is assay (I) at pH 2.5 when referred to as "concurrent" with the release of said GLP-1 peptide. within 30 minutes, such as within 25, 20, or 15 minutes, or within, for example, 10 minutes or 5 minutes, as determined by a dissolution test using

In some embodiments, the present invention relates to a pharmaceutical composition according to any one of the preceding claims, wherein the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is assayed at pH 2.5 ( Record the highest within the first 60 minutes as determined by the dissolution test using I). In some embodiments, the present invention relates to a pharmaceutical composition, wherein the amount of a dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is determined by a dissolution test using Assay (I) at pH 2.5. When determined, record the best within the first 30 minutes. In some embodiments, the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is within 55 minutes, such as 50, as determined by a dissolution test using Assay (I) at pH 2.5, Get your best in 45 or 40 minutes. In some embodiments, the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is within 39 or 38 minutes as determined by a dissolution test using Assay (I) at pH 2.5, such as Get your best in 37, 36 or 35 minutes. In some embodiments, the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is within 34 minutes, such as 33, as determined by a dissolution test using Assay (I) at pH 2.5. Highest in 32 or 31 minutes. In some embodiments, the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is within 31 minutes, such as 32, as determined by a dissolution test using Assay (I) at pH 2.5. Best in 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, or 60 minutes.

In some embodiments, the composition comprises granules prepared by dry granulation. In some embodiments, the composition comprises granules prepared by roller compaction. In some embodiments, the moldings from the roller compaction process are ground into granules. As used herein, the term “composition” refers to a pharmaceutical composition.

In some embodiments, the composition is in the form of a solid dosage form. In some embodiments, the composition is in the form of a tablet. In some embodiments, the composition is in the form of a capsule. In some embodiments, the composition is in the form of a sachet.

In some embodiments, the composition or granule comprises at least one pharmaceutically acceptable excipient. As used herein, the term “excipient” broadly refers to any ingredient other than the active therapeutic ingredient(s). The excipient may be an inert substance, which is inert in the sense that it has substantially no therapeutic and/or prophylactic effect on its own. Excipients can serve a variety of purposes, such as delivery agents, absorption enhancers, vehicles, fillers (also known as diluents), binders, lubricants, glidants, disintegrants, crystallization retardants, acidifying agents, alkylating agents, preservatives, as antioxidants, buffers, chelating agents, complexing agents, surfactants, emulsifying and/or solubilizing agents, sweetening, wetting, stabilizing, coloring, flavoring, and/or administration and/or improving absorption of active substances. have. A person skilled in the art can select, by routine experimentation, one or more of the excipients described above with respect to the specific desired properties of the solid oral dosage form without any undue burden. The amount of each excipient used may vary within the conventional scope in the art. Techniques and excipients that may be used in the formulation of oral dosage forms include Handbook of Pharmaceutical Excipients, 6th ed., Rowe et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharma-ceutical Society of Great Britain ( 2009); Remington: the Science and Practice of Pharmacy, 21st edition, Gennaro, Ed., Lippincott Williams & Wilkins (2005).

In some embodiments, the composition or granule is a filler such as lactose (eg, spray dried lactose, a-lactose, β-lactose, Tabletose®, various grades Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), other cellulose derivatives, sucrose, sorbitol, mannitol, dextrin, dextran, maltodextrin, dextrose, fructose, kaolin , mannitol, sorbitol, sucrose, sugar, starch or modified starch (including potato starch, corn starch and rice starch), calcium phosphate (eg monobasic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), sulfate calcium, calcium carbonate, or sodium alginate. In some embodiments, the filler is microcrystalline cellulose, such as Avicel PH 101.

In some embodiments, the composition or granules contain a binder such as lactose (eg, spray dried lactose, a-lactose, β-lactose, Tabletose®, various grades Pharmatose®, Microtose® or Fast-FloC®), microcrystalline cellulose (various grades Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted), hypromellose (HPMC) (e.g. , Methocel E, F and K, Metolose SH from Shin-Etsu, Ltd, such as, for example, 4,000 cps grades Methocel E and Metolose 60 SH, 4,000 cps grades F and Metolose 65 SH, 4,000, 15,000 and 100,000 cps grades Methocel K; and 4,000, 15,000, 39,000 and 100,000 cps grades Metolose 90 SH), methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, Other cellulose derivatives, sucrose, dextrin, maltodextrin, starch or modified starch (including potato starch, corn starch and rice starch), calcium lactate, calcium carbonate, acacia, sodium alginate, agar, carrageenan, gelatin, guar gum , pectin, PEG, or povidone. In some embodiments, the binder is povidone, such as povidone K 90.

In some embodiments, the composition or granules contain a disintegrant such as alginic acid, alginate, microcrystalline cellulose, hydroxypropylcellulose, other cellulose derivatives, croscarmellose sodium, crospovidone, polacrylline potassium, sodium starch glycolate, starch, pre-gelatinized starch, or carboxymethyl starch (eg, PrimogelO and Explotab®).

In some embodiments, the composition or granules are formulated with lubricants such as stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes, glycerides, lightweight mineral oil, glyceryl behenate, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycol, alkyl sulfate, or sodium benzoate. In some embodiments, the composition or granules include a lubricant, such as magnesium silicate, talc, or colloidal silica. In some embodiments, the lubricant is magnesium stearate.

In some embodiments, the composition or granules may contain a crystallization retarding agent, such as povidone; solubilizing agents (also known as surfactants), such as anionic surfactants (eg, Povidone or Pluronic), cationic surfactants, nonionic surfactants, and/or zwitterionic surfactants; colorants, including dyes and pigments, such as iron oxide red or yellow, titanium dioxide, and/or talc; and/or pH controlling agents, such as one or more excipients selected from citric acid, tartaric acid, fumaric acid, sodium citrate, dicalcium phosphate, and/or dibasic sodium phosphate.

In some embodiments, the composition comprises at least 60% (w/w) delivery agent, less than 10% (w/w) binder, 5-40% (w/w) filler, and less than 10% (w/w) contains lubricants.

In some embodiments, the composition comprises at least 60% (w/w), such as 65-75% (w/w), 60-80% (w/w), or 50-90% (w/w) delivery agent. include In some embodiments, the composition comprises at least 70% (w/w), such as 70-80% (w/w) delivery agent.

In some embodiments, the composition comprises 0.1-10% (w/w), such as 0.2-4% (w/w) or 0.5-3% (w/w) binder. In some embodiments, the composition comprises 1.5-2.5% (w/w), such as 1.7-2.3% (w/w), 1.8-2.2% (w/w), or 1.9-2.1% (w/w) binder include In some embodiments, the composition comprises 1% (w/w) or 2% (w/w) binder.

In some embodiments, the composition comprises 5-40% (w/w), such as 10-30% (w/w) or 5-25% (w/w) filler. In some embodiments, the composition contains 10-25% (w/w), such as 17-23% (w/w), 18-22% (w/w), or 19-21% (w/w) fillers. include In some embodiments, the composition comprises 10.9% (w/w) or 18% (w/w) filler, or comprises 19.5% (w/w) or 20.5 (w/w) filler.

In some embodiments, the composition comprises 0.1-10% (w/w) or 0.5-5% (w/w), such as 1-3.5% (w/w) or 1% (w/w) lubricant. In some embodiments, the composition comprises 1.5-3% (w/w), such as 2.1-2.7% (w/w), 2.2-2.6% (w/w) or 2.3-2.5% (w/w) lubricant do.

Still further, the compositions or granules of the present invention may be formulated as known in the art for oral formulations of insulinotropic compounds.

The composition or granules are available in several dosage forms, for example, tablets; It may be administered in capsules, such as hard capsules, sachets or powders. The composition or granules may be further formulated with a drug carrier or drug delivery system, for example, to improve stability and/or solubility or further improve bioavailability.

In some embodiments, the weight of the tablet is in the range of 150 mg to 1000 mg, such as in the range of 300-600 mg or 350-450 mg.

In some embodiments, the present invention provides an agent comprising at least 75% (w/w) delivery agent, less than 10% (w/w) lubricant, and optionally less than 20% filler and no GLP-1 peptide. 1 relates to granules. In some embodiments, the present invention provides an agent comprising at least 80% (w/w) delivery agent, less than 10% (w/w) lubricant, and optionally less than 20% filler and no GLP-1 peptide. 1 relates to granules. In some embodiments, the first granules deliver 75-90% (w/w), such as 78-88% (w/w), 80-86% (w/w) or 82-84% (w/w) delivery. includes the In some embodiments, the first granules contain less than 10% (w/w), such as 1-3% (w/w), 1.5-2.5% (w/w) or 1.9-2.3% (w/w) lubricant. and in some embodiments, the first granules comprise less than 20%, such as 10-20% (w/w), 12-18% (w/w) or 14-17% (w/w) fillers . In some embodiments, the first granule does not comprise a GLP-1 peptide. In some embodiments, the granules comprise at least 80% (w/w) delivery agent, less than 10% (w/w) lubricant, and optionally less than 20% filler.

In some embodiments, the present invention provides N-(8-(2-hydroxybenzoyl)amino) comprising GLP-1 peptide, at least 15% (w/w) filler and less than 40% (w/w) binder The second granule does not include a salt of caprylic acid. In some embodiments, the second granule comprises at least 1%, such as 1-70% (w/w), 2-40% (w/w) or 4-30% (w/w) GLP-1 peptide . In some embodiments, the second granules comprise at least 20%, such as 40-80% (w/w) or 50-75% (w/w) filler. In some embodiments, the second granules comprise less than 30%, such as 5-30% (w/w), 10-28% (w/w) or 15-25% (w/w) binder. In some embodiments, the second granule does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, the granules comprise GLP-1 peptide, at least 15% (w/w) filler and less than 40% (w/w) binder. In some embodiments, the granules comprise GLP-1 peptide, at least 50% (w/w) filler and less than 40% (w/w) binder.

In some embodiments, the present invention relates to a composition comprising granules of a first type and a second type, wherein the granules of the first type are at least 75% (w/w) delivery agent, less than 10% (w/w) of a lubricant, optionally less than 20% filler and no GLP-1 peptide, wherein the granules of the second type comprise GLP-1 peptide, at least 15% (w/w) filler, 40% (w/w) less binder and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, the present invention relates to a composition comprising granules of a first type and a second type, wherein the granules of the first type are at least 75% (w/w) delivery agent, less than 10% (w/w) of a lubricant, less than 20% fillers and no GLP-1 peptide, wherein the second type of granules comprises GLP-1 peptides, at least 15% (w/w) fillers, less than 40% (w/w) Contains binder and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, the present invention relates to a composition comprising granules of a first type and a second type, wherein the granules of the first type are at least 75% (w/w) delivery agent, less than 10% (w/w) of a lubricant and no GLP-1 peptide, wherein the granules of the second type comprise GLP-1 peptide, at least 15% (w/w) filler, less than 40% (w/w) binder, and Does not contain salts of (8-(2-hydroxybenzoyl)amino)caprylic acid.

Methods of making pharmaceutical compositions

The compositions of the present invention can be prepared as known in the art. In some embodiments, the composition or granules may be prepared as described in the Examples herein. In some embodiments, the composition may be granulated prior to compression into tablets. In some embodiments, the granules of the present invention are prepared by dry granulation, such as by roller compaction. In some embodiments, the moldings from the roller compaction process are ground into granules. The composition may comprise one or more intragranular and extragranular portions, wherein the intragranular portion is granulated and the extragranular portion is added after granulation. The first intragranular portion may comprise a GLP-1 peptide and one or more excipients and the second intragranular portion may comprise a delivery agent and optionally one or more excipients. The first intragranular portion may include a GLP-1 peptide, filler and/or binder, and the second intragranular portion may include a delivery agent, lubricant and filler. The first intragranular portion may include a GLP-1 peptide, filler and/or binder, and the second intragranular portion may include a delivery agent, lubricant and/or filler. In some embodiments, the first intragranular portion comprises a GLP-1 agonist (ie, GLP-1 peptide), microcrystalline cellulose and/or povidone, and the second intragranular portion comprises a delivery agent, magnesium stearate and micro crystalline cellulose. In some embodiments, the first intragranular portion comprises a GLP-1 agonist (ie, GLP-1 peptide), microcrystalline cellulose and/or povidone, and the second intragranular portion comprises a delivery agent, magnesium stearate and/or or microcrystalline cellulose. The extragranular portion may comprise a lubricant. In some embodiments, the extragranular portion comprises magnesium stearate. In some embodiments, the term “filler and/or binder” or “filler and/or binder” refers to a filler and optionally a binder. In some embodiments, the term “lubricant and filler” or “lubricant and/or filler” refers to a lubricant and optionally a filler.

The various ingredients are weighed and optionally lumps removed and then combined to prepare a dry blend of tableting material. Mixing of the ingredients may be carried out until a homogeneous blend is obtained.

If granules are to be used in the tableting material, the granules can be prepared in a manner known to the person skilled in the art, for example dry granulation, in which the pharmaceutical active and/or delivery agent are compacted together with excipients to form relatively large mouldings, for example slugs or ribbons. It can be produced by technology, which is ground by grinding, and the ground material is used as a tabletting material and then compressed into tablets. Suitable equipment for dry granulation includes, but is not limited to, roller compaction devices from Gerteis, such as the Gerteis MINI-PACTOR.

A tablet press may be used to compress the tableting material into a solid oral dosage form, such as a tablet. In a tableting press tabletting material is filled into the die cavity (eg, force fed or gravity fed). The tableting material is then compressed by means of a punch under pressure. The resulting compacted product, or tablet, is then discharged from the tableting press. The above-mentioned compression process is hereinafter referred to herein as a "compression process". Suitable tableting processes include, but are not limited to, rotary tablet presses and eccentric tablet presses. Examples of tablet presses include, but are not limited to, the Fette 102i (Fette GmbH), Korsch XL100, Korsch PH 106 rotary tablet press (Korsch AG, Germany), Korsch EK-0 eccentric tablet press (Korsch AG, Germany) and Manesty F- Press (Manesty Machines Ltd., UK).

In some embodiments, the tablet manufacturing method comprises i) dry granulation of a mixture comprising a GLP-1 agonist (ie, GLP-1 peptide), a filler and a binder; ii) dry granulation of a mixture comprising a delivery agent, a lubricant and a filler; iii) mixing of granules and lubricants; and iv) compression of the blend into tablets. In some embodiments, the tablet manufacturing method comprises i) dry granulation of a mixture comprising a GLP-1 agonist (ie, GLP-1 peptide), a filler and a binder; ii) dry granulation of a mixture comprising a delivery agent, a lubricant and a filler; iii) mixing of granules and lubricants; and then iv) compression of the blend into tablets.

In some embodiments, the present invention relates to a method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, the method comprising: a) GLP -1 mixing the peptide with fillers and/or binders; b) dry granulation of the mixture of step a; c) mixing the granules obtained in step b with a composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; and d) optionally adding a further lubricant. In some embodiments, the present invention relates to a method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, the method comprising: a) N mixing a salt of -(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler; b) dry granulation of the mixture of step a; c) mixing the granules obtained in step b with a composition comprising a GLP-1 peptide; and d) optionally adding a further surfactant. In some embodiments, the present invention relates to a method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, the method comprising: a) GLP -1 mixing the peptide with fillers and/or binders; b) dry granulation of the mixture of step a; c) admixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally a lubricant and/or a filler; d) dry granulation of the mixture of step c; e) mixing the granules obtained in step b with the granules obtained in step d; and f) optionally adding a further lubricant.

In one embodiment, the invention relates to a method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising: a) GLP -1 mixing the peptide with fillers and/or binders; b) dry granulation of the mixture of step a; c) admixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally a lubricant and/or a filler; d) dry granulation of the mixture of step c; e) mixing the granules obtained in step b with the granules obtained in step d; and f) optionally adding a further lubricant, wherein the mixture of step a does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and the mixture of step c does not contain a GLP-1 peptide.

In one embodiment, the present invention relates to granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, optionally a filler and no GLP-1 peptide. In one embodiment, the present invention relates to a method for preparing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, said method comprising: a) N-(8-(2) -mixing a salt of hydroxybenzoyl)amino)caprylic acid (such as SNAC) with a lubricant and/or filler; and b) dry granulation of the mixture of step a, wherein the mixture of step a does not comprise a GLP-1 peptide.

In one embodiment, the present invention relates to a granule comprising a GLP-1 peptide, a filler, a binder, and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In one embodiment, the present invention relates to a method for preparing granules comprising a GLP-1 peptide, the method comprising the steps of: a) mixing the GLP-1 peptide, optionally a filler and/or a binder; and b) roller compacting the mixture of step a, wherein the mixture of step a does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

In some embodiments, the mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation has a duration of at least 20 minutes . In some embodiments, the mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation is at least 30 minutes or at least 40 minutes , for example a period of 50 minutes. In some embodiments, comprising mixing a first type of granules comprising a GLP-1 peptide with a second type of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid The mixing step has a duration of at least 15 minutes or at least 20 minutes, such as at least 25 minutes or at least 30 minutes.

In some embodiments, the present invention relates to a pharmaceutical composition obtained by a method as defined herein.

In some embodiments, the present invention relates to granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant. In some embodiments, the granules comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, and a filler. In some embodiments, the present invention relates to granules comprising a GLP-1 peptide, a filler, and a binder. In some embodiments, the granules are prepared according to the methods defined herein.

In some embodiments, the present invention relates to a method for preparing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, the method comprising: a) N-(8-(2) -mixing a salt of hydroxybenzoyl)amino)caprylic acid (such as SNAC) with a lubricant and/or filler; and b) dry granulation of the mixture of step a. In some embodiments, the mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation has a duration of at least 20 minutes . In some embodiments, the mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation is at least 30 minutes or at least 40 minutes , for example a period of 50 minutes.

In some embodiments, the present invention relates to a method for preparing granules comprising a GLP-1 peptide, the method comprising: a) mixing the GLP-1 peptide, optionally a filler and/or a binder; and b) roller compacting the mixture of step a.

In some embodiments, the present invention relates to granules obtained by a method as defined herein.

In some embodiments, the lubricant is magnesium stearate. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the binder is povidone.

In some embodiments, the term "resistance to tablet grinding" has the meaning defined in section 2.9.8 of the European Pharmacopoeia 7.5, 7th edition 2012, the resistance to grinding particularly having a jaw rate of 20 N/s can be measured in units of newtons (N) or kiloponds (kP).

In some embodiments, the term "roller compaction force" refers to the force between the rolls of a roller compactor when compacting material into a continuous strip of compacted material, as determined by a pressure transducer that converts hydraulic pressure into an electrical signal, , roller compaction force can be measured in units of kilonewtons (kN) or kilonewtons per roll width (kN/cm).

In vitro method

The dissolution of the composition of the present invention can be determined as described in Assay (I) herein. In some embodiments, dissolution testing using Assay (I) is performed at any one of pH 1.0-8.0. In some embodiments, dissolution testing using Assay (I) is performed at pH 1.0. In some embodiments, dissolution testing using Assay (I) is performed at pH 2.5. In some embodiments, dissolution testing using Assay (I) is performed at pH 6.8.

GLP-1 peptide

In one embodiment, the composition of the invention comprises a GLP-1 peptide. As used herein, the term “GLP-1 peptide” refers to a compound that fully or partially activates the human GLP-1 receptor. In some embodiments, the "GLP-1 peptide" binds to the GLP-1 receptor, eg, under an affinity constant (KD), and is 1 μM as measured by methods known in the art (see WO 98/08871). Hereinafter, for example, it activates the receptor with an efficacy (EC50) of 100 nM or less and exhibits insulinotropic activity, wherein the insulinotropic activity can be measured in an in vivo or in vitro assay known to those skilled in the art. For example, the GLP-1 peptide is obtained using elevated blood glucose (eg, the intravenous glucose tolerance test (IVGTT)); and an appropriate blood sampling regimen) and plasma insulin concentrations measured over time. In some embodiments, the GLP-1 peptide is referred to as a GLP-1 agonist.

In some embodiments, the GLP-1 peptide is a GLP-1 analog optionally comprising one substituent. As used herein, the term "analog", referring to a GLP-1 peptide (hereinafter "peptide"), means that at least one amino acid residue of the peptide is substituted with another amino acid residue and/or at least one amino acid residue is deleted from the peptide and/or or a peptide in which 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 additions or deletions of amino acid residues may occur at the N-terminus of the peptide and/or at the C-terminus of the peptide. In some embodiments, simple nomenclature is used to describe the GLP-1 peptide, e.g., [Aib8]GLP-1(7-37) is GLP-1(7-) in which the naturally occurring Ala at position 8 is substituted with Aib. 37) to name analogues. In some embodiments, the GLP-1 peptide contains up to 12, such as up to 10, 8, altered, for example, by substitutions, deletions, insertions and/or modifications, for example, compared to GLP-1 (7-37). or 6 amino acids. In some embodiments, the analog comprises up to 10 substitutions, deletions, additions and/or insertions, such as up to 9 substitutions, deletions, additions and/or insertions, e.g., compared to GLP-1 (7-37); 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 insertions, up to 4 substitutions, deletions, additions and/or insertions, or up to 3 substitutions, deletions, additions and/or insertions. Unless otherwise stated, GLP-1 contains only L-amino acids.

In some embodiments, the term "GLP-1 analog" or "analog of GLP-1" as used herein refers to a peptide, or compound, that is a variant of human glucagon-like peptide-1 (GLP-1(7-37)). say GLP-1 (7-37) has the sequence HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1). In some embodiments, the term “variant” refers to a compound comprising one or more amino acid substitutions, deletions, additions and/or insertions.

In one embodiment, the GLP-1 peptide has at least 60%, 65%, 70%, 80% or 90% sequence identity to GLP-1 (7-37) over the entire length of GLP-1 (7-37). indicates As an example of a method for determining sequence identity between two analogs, two peptides [Aib8]GLP-1 (7-37) and GLP-1 (7-37) are aligned. The sequence identity of [Aib8]GLP-1(7-37) to GLP-1(7-37) is determined by subtracting the number of different residues from the number of identical residues aligned and dividing it into the total residues of GLP-1(7-37). given by dividing by a number. Thus, the sequence identity in this example is (31-1)/31.

In one embodiment, the C-terminus of the GLP-1 peptide is an amide.

In some embodiments, the GLP-1 peptide is GLP-1(7-37) or GLP-1(7-36)amide. In some embodiments, the GLP-1 peptide is exendin-4, and its sequence is HGEGTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID No: 2).

In some embodiments, the GLP-1 peptide comprises one substituent covalently attached to the peptide. In some embodiments, the substituents include fatty acids or fatty diacids. In some embodiments, the substituents include C16, C18 or C20 fatty acids. In some embodiments, the substituent comprises a C16, C18 or C20 fatty diacid. In some embodiments, the substituent comprises Formula (X):

wherein n is at least 13, for example n is 13, 14, 15, 16, 17, 18 or 19.

In some embodiments, substituents include formula (X), where n ranges from 13 to 19, such as from 13 to 17. In some embodiments, substituents include Formula (X), wherein n is 13, 15 or 17. In some embodiments, substituents include Formula (X), wherein n is 13. In some embodiments, substituents include Formula (X), wherein n is 15. In some embodiments, substituents include Formula (X), wherein n is 17. In some embodiments, the substituents include one or more 8-amino-3,6-dioxaoctanoic acids (OEGs), such as two OEGs.

In some embodiments, the substituent is at [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanylamino)butyrylamino]) ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanyl) amino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl].

In some embodiments, the GLP-1 peptide is semaglutide, N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy- Also known as 4-(17-carboxyheptadecanylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 (7-37), WO2006 /097537, can be prepared as described in Example 4.

In some embodiments, the composition comprises a GLP-1 peptide or a pharmaceutically acceptable salt, amide or ester thereof. In some embodiments, the composition comprises one or more pharmaceutically acceptable counter ions of the GLP-1 peptide.

In some embodiments, the dosage of GLP-1 peptide ranges from 0.01 mg to 100 mg. In some embodiments, the composition or granule comprises an amount of GLP-1 peptide in the range of at least 1 mg, such as at least 5 mg or at least 10 mg. In some embodiments, the composition or granule comprises 10 mg GLP-1 peptide.

In some embodiments, the composition comprises GLP-1 peptide in an amount in the range of 0.05 to 25 μmol, such as in the range of 0.5 to 20 μmol.

In some embodiments, the GLP-1 peptide is W093/19175, W096/29342, WO98/08871, WO99/43707, WO99/43706, W099/43341, WO99/43708, WO2005/027978, WO2005/058954, WO2005/058958, one or more of the GLP-1 peptides mentioned in WO2006/005667, WO2006/037810, WO2006/037811, WO2006/097537, WO2006/097538, WO2008/023050, WO2009/030738, WO2009/030771 and WO2009/030774.

In some embodiments, the GLP-1 peptide is N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecane) Oil) piperidine-4-carbonyl] amino} propionylamino) ethoxy] ethoxy} acetylamino) ethoxy] ethoxy} acetyl [desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1 ( 7-37) amide; N-epsilon26{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanyl)piperidine-4-carbonyl) ]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Arg34]GLP-1-(7-37); N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxy-nonadecanyl)piperidine-4-carbo nyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonyl) amino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1-( 7-37) amide; N-epsilon26-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP -1-(7-37); N-epsilon26-{4-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl }[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino)methyl]cyclohexanecarbonyl}amino) )butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino) )methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino) )methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) )amides; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino) )methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7 -37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(trans-19-carboxy-nonadecanylamino) )methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37) )amides; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino) )methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7 -37); N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({4-[(19-carboxy-nonadecanylamino)methyl] cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8,Lys26]GLP-1(7-37)amide; N-epsilon26[2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-carboxynonadecanylamino]methyl)cyclohexylcarbonyl) amino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Lys26]GLP-1(7-37)amide;N-epsilon37-[2- (2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino)methyl]cyclohexane-carbonyl) }amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);N-epsilon37- [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino)methyl]cyclohexane) carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37) ; N-epsilon 26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetra) zol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7- 37);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 -37);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 -37);N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{4-[4-(16-( 1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyryl amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34 ); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35) ; N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazole) -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-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-35); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyryl-amino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys33,Arg34]GLP-1-(7 -34); N-epsilon26-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-36) amides; 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-(1H-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; N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1 -(7-37)amide; N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP -1-(7-37)amide; N-epsilon37{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxy-nonadecanyl)piperidine-4-carbo nyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)amide; N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanyl)piperidine-4-carbonyl) ]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl[Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide; N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-carboxyheptadecanoyl)piperidin-4-ylcarbonyl) amino]3-carboxy-propionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Phe(m-CF3)28]GLP-1- (7-37)amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino) )methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37) )amides; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino) )methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,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-nonadecanylamino) )methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7 -37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxy-nonadecanylamino) )methyl]cyclohexane-carbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1 -(7-37); N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1 -(7-37)amide; N-epsilon37-[2-(2-{2-[(S)-4-carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazole) -5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP -1-(7-37)amide; N-epsilon37-(3-((2-(2-(2-(2-(2-hexadecyloxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy))propionyl)[desaminoHis7 ,Glu22,Arg26,Arg34,Lys37]GLP-1(7-37)-amide; To N-epsilon37-{2-(2-(2-(2-[2-(2-(4-(hexadecanoylamino)-4-carboxybutyryl-amino)ethoxy)ethoxy]acetyl) oxy)ethoxy)acetyl)}-[desaminoHis7,Glu22,Arg26,Glu30,Arg34,Lys37]GLP-1-(7-37)amide; 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; 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; N-epsilon37-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7- 37) amide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanylamino)butyrylamino]ethoxy}) ethoxy)acetylamino]ethoxy}ethoxy)acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon37-(2-{2-[2-((S)-4-carboxy-4-{(S)-4-carboxy-4-[(S)-4-carboxy-4-(19-) carboxy-nonadecanylamino)butyrylamino]butyrylamino}butyrylamino)ethoxy]ethoxy}acetyl)[desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-butyl-2H-tetrazole-5) -yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[desaminoHis7,Glu22, Arg26,Arg34,Lys37]GLP-1 (7-37); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanylamino)-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-heptadecanylamino)-butyrylamino]- ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][Aib8,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37)peptide; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanylamino)-butyrylamino]- ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl][desaminoHis7,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37); 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 peptides; N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanylamino) methyl]cyclohexanecarbonyl}amino)butyryl-amino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37 ); N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy-heptadecanylamino)-butyrylamino]- ethoxy}-ethoxy)-acetylamino]-ethoxy}-ethoxy)-acetyl]-[Aib8,Glu22,Arg26,Arg34,Aib35,Lys37]GLP-1-(7-37); N-epsilon37-[(S)-4-carboxy-4-(2-{2-[2-(2-{2-[2-(17-carboxyheptadecanylamino)ethoxy]ethoxy}acetyl amino)ethoxy]ethoxy}acetylamino)butyryl][Aib8,Glu22,Arg26,34,Lys37]GLP-1(7-37); To N-epsilon37-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanylamino)-4(S)-carboxybutyrylamino]ethoxy) oxy]acetylamino)ethoxy]ethoxy)acetyl][lmPr7,Glu22,Arg26,34,Lys37], GLP-1-(7-37); N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyryl) amino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, 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; N-epsilon 26(17-carboxyheptadecanyl)-[Aib8,Arg34]GLP-1-(7-37)-peptide; N-epsilon 26-(19-carboxynonadecanyl)-[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-(4-{[N-(2-carboxyethyl)-N-(15-carboxypentadecanoyl)amino]methyl}benzoyl[Arg34]GLP-1-(7-37); N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetyl amino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4)] -(19-carboxynonadecanylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7- 37); to N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanylamino)-4(S)-carboxybutyrylamino] oxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][3-(4-imidazolyl)propionyl7,Arg34]GLP-1-(7-37);N-epsilon26-[2- To (2-[2-(2-[2-(2-[4-(17-carboxyheptadecanylamino)-(carboxymethyl-amino)acetylamino]ethoxy)ethoxy]acetylamino)ethoxy] oxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyhepta) Decanoylamino)-3(S)-sulfopropionylamino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);N-epsilon 26-[2-(2-[2-(2-[2-(2-[4-(17-carboxyheptadecanylamino)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetyl amino)ethoxy]ethoxy)acetyl][Gly8,Arg34]GLP-1-(7-37);N-epsilon26-[2-(2-[2-(2-[2-(2-[4)] -(17-carboxyheptadecanylamino)-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-carboxyheptadecanylamino)-4(S)-carboxybutyrylamino) ]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34,P ro37]GLP-1-(7-37)amide; Aib8,Lys26(N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(pentadecanoylamino)-4-carboxybutyrylamino)ethoxy)ethoxy] acetyl)ethoxy)ethoxy)acetyl)}), Arg34)GLP-1H(7-37)-OH; 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); 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); N-epsilon2626-[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); N-epsilon26{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(15-(N-((S)-1,3-dica Voxypropyl)carbamoyl)pentadecanoylamino)-(S)-4-carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl} [Aib8,Arg34]GLP-1-(7-37); N-epsilon26-[2-(2-[2-(2-[2-(2-[4-{[N-(2-carboxyethyl)-N-(17-carboxy-heptadecanyl)amino] methyl}benzoyl)amino](4(S)-carboxybutyryl-amino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37); N-epsilon 26-{(S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-((S)-4-carboxy-4-( 19-carboxy-nonadecanylamino)butyrylamino)butyrylamino)butyrylamino)butyrylamino}[Aib8,Arg34]GLP-1-(7-37); N-epsilon 26-4-(17-carboxyheptadecanyl-amino)-4(S)-carboxybutyryl-[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-{3-[2-(2-{2-[2-(2-{2-[2-(2-[4-(17-carboxyheptadecanylamino)-4(S)- carboxybutyrylamino]ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]propionyl}[Aib8,Arg34]GLP-1-(7-37); N-epsilon26-{2-(2-(2-(2-[2-(2-(4-(17-carboxyheptadecanylamino)-4-carboxybutyrylamino)ethoxy)ethoxy]acetyl )ethoxy)ethoxy)acetyl)}-[Aib8,22,27,30,35,Arg34,Pro37,Lys26]GLP-1(7-37)amide; N-epsilon26-[2-(2-[2-[4-(21-carboxyuneicosanoylamino)-4(S)-carboxybutyrylamino]ethoxy]ethoxy)acetyl][Aib8,Arg34 ]GLP-1-(7-37); and 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). In one embodiment, the GLP-1 peptide is N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-) Carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, 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 (Compound A).

In one embodiment, the GLP-1 peptide is N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecane) Oilamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 (7-37), also called semaglutide.

In one embodiment, the GLP-1 peptide is synthesized by appropriate derivatization of an appropriate peptide backbone generated by peptide synthesis (eg, Merrifield-type solid phase synthesis) or recombinant DNA techniques known in the art of peptide synthesis and peptide chemistry. can be manufactured.

In one embodiment, the preparation of peptides such as GLP-1 (7-37) and GLP-1 analogs is well known in the art. The GLP-1 portion (or fragment thereof) of the GLP-1 peptide of the invention can be prepared by, for example, classical peptide synthesis, for example solid phase peptide synthesis using t-Boc or Fmoc chemistry or other well-established techniques. can be prepared, e.g. Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999, Florencio Zaragoza Dorwald, Organic Synthesis on solid Phase", Wiley-VCH Verlag GmbH, 2000 and "Fmoc Solid Phase" Peptide Synthesis", Edited by WC Chan and PD White, Oxford University Press, 2000.

In one embodiment, the GLP-1 peptide is cultured by recombinant methods, ie, host cells containing a DNA sequence encoding the GLP-1 peptide and capable of expressing the peptide under conditions permitting expression of the peptide in a suitable nutrient medium. It can be manufactured by Non-limiting examples of host cells suitable for expression of these peptides include Escherichia coli , Saccharomyces cerevisiae , as well as mammalian BHK or CHO cell lines.

In one embodiment, a GLP-1 peptide of the invention comprising an unnatural amino acid and/or a covalently attached N-terminal mono- or dipeptide mimetic can be prepared, eg, as described in the experimental section. Or, see, for example, Hodgson et al: "The synthesis of Peptides and proteins containing non-natural amino acids", Chemical Society Reviews, vol. 33, no. 7 (2004), p. 422-430; and WO 2009/083549 A1, entitled “Semi-recombinant preparation of GLP-1 analogues”.

Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

The delivery agent used in the present invention is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, the delivery agent is an absorption enhancer. The structural formula of N-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (I):

In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is in the caprylic acid form and/or in the caprylate form. In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises one monovalent cation, two monovalent cations, or one divalent cation. In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is the sodium salt, potassium salt and calcium of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. salts are selected from the group consisting of.

Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate can be prepared using the methods described, for example, in WO96/030036, WO00/046182, WO01/092206 or WO2008/028859. .

The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline and/or amorphous. In some embodiments, the delivery agent is an anhydride, monohydrate, dihydrate, trihydrate, solvate or 1/3 hydrate of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as well as combinations thereof. includes In some embodiments, the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid as described in WO2007/121318. salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, any polymorph thereof.

In some embodiments, the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (referred to herein as "SNAC"), also known as sodium 8-(salicyloylamino)octanoate. .

In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition ranges from 0.6-3.5 mmol. In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is at least 0.6 mmol, such as selected from the group of at least 0.8 mmol or at least 0.9 mmol. In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is at most 2.5 mmol. In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in the composition is 0.6-2.0 mmol. In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is 1 mmol, such as 1.08 mmol.

In some embodiments, the amount of SNAC in the composition ranges from 100-1000 mg. In some embodiments, the amount of SNAC in the composition is at least 150 mg or at least 250 mg. In some embodiments, the amount of SNAC in the composition is at most 800 mg, such as at most 700 mg or at most 600 mg. In some embodiments, the amount of SNAC in the composition is 300 mg.

In some embodiments, the molar ratio between the GLP-1 agonist (ie, the GLP-1 peptide) and the delivery agent in the composition is less than 10, such as less than 5 or less than 1. In some embodiments, the molar ratio between the GLP-1 agonist (ie, the GLP-1 peptide) and the delivery agent in the composition is less than 1/10, such as less than 1/100 or less than 5/1000.

pharmaceutical prescription

The present invention also relates to a composition or granule of the present invention for use as a medicament. In one embodiment, the composition or granules are administered orally.

In a specific embodiment, the composition or granules of the present invention can be used for the following medical treatment, all preferably relate to diabetes either way:

(i) prevention and/or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes mellitus, MODY (adult onset diabetes in juveniles), gestational diabetes, and/or or a decrease in HbA1C;

(ii) delaying or preventing the progression of diabetic disease, such as progression of type 2 diabetes, delaying progression of impaired glucose tolerance (IGT) to insulin-demanding type 2 diabetes, and/or insulin in non-insulin-requiring type 2 diabetes delayed progression to nephrogenic type 2 diabetes;

(iii) improving β-cell function, such as reducing β-cell apoptosis, increasing β-cell function and/or β-cell mass, and/or restoring glucose sensitivity to β-cells;

(iv) prevention and/or treatment of cognitive impairment;

(v) the prevention and/or treatment of eating disorders, such as obesity, eg by reducing food intake, weight loss, suppression of appetite, induction of satiety; treatment or prevention of binge eating disorder, bulimia, and/or obesity induced by administration of antipsychotics or steroids; decreased gastric motility; and/or delayed gastric emptying;

(vi) diabetic complications such as neuropathy, including peripheral neuropathy; nephropathy; or prevention and/or treatment of retinopathy;

(vii) improvement of lipid parameters, such as prevention and/or treatment of dyslipidemia, lowering of total serum lipids; HDL lowering; small, dense LDL lowering; VLDL lowering; lowering triglycerides; lowering cholesterol; increased HDL; lowering plasma levels of lipoprotein a (Lp(a)) in humans; inhibition of apolipoprotein a (apo(a)) generation in vitro and/or in vivo;

(iix) cardiovascular diseases such as Syndrome X; atherosclerosis; myocardial infarction; coronary heart disease; stroke, cerebral ischemia; premature heart or premature cardiovascular disease, such as left ventricular hypertrophy; coronary artery disease; essential hypertension; acute hypertensive emergency; cardiomyopathy; heart insufficiency; exercise tolerance; chronic heart failure; arrhythmia; cardiac dysrhythmia; faint; atherosclerosis; mild chronic heart failure; angina pectoris; cardiac bypass reocclusion; intermittent claudication (obstructive atherosclerosis); diastolic dysfunction; and/or prevention and/or treatment of contractile dysfunction;

(ix) gastrointestinal diseases such as inflammatory bowel syndrome; small intestine syndrome, or Crohn's disease; Indigestion; and/or prevention and/or treatment of gastric ulcer;

(x) prophylaxis and/or treatment of fatal diseases, such as treatment of critically ill patients, patients with the fatal disease multiple nephropathy (CIPNP), and/or patients with potentially CIPNP; prevention of fatal disease or the occurrence of CIPNP; prevention, treatment and/or cure of systemic inflammatory response syndrome (SIRS) in a patient; and/or preventing or reducing the likelihood that the patient will experience bacteremia, sepsis and/or septic shock during hospitalization; and/or

(xi) Prevention and/or treatment of polycystic ovary syndrome (PCOS).

In certain embodiments, the prescription is selected from the group consisting of (i)-(iii) and (v)-(iix), such as prescriptions (i), (ii), and/or (iii); or prescription (v), prescription (vi), prescription (vii), and/or prescription (iix).

In another specific embodiment, the prescription is (i). In a further specific embodiment, the prescription is (v). In yet a further specific embodiment, the prescription is (iix).

In one embodiment, the present invention relates to a composition or granule of the present invention for the treatment of diabetes or obesity, wherein the granule is administered orally. In one embodiment, the present invention relates to a method of treating diabetes or obesity comprising orally administering to a patient in need thereof a composition comprising the composition or granules of the present invention.

Prescription for type 2 diabetes, and/or obesity is particularly preferred.

specific embodiments

The following are specific embodiments of the present invention.

1. A pharmaceutical composition comprising granules of a first type and a second type, wherein the granules of the first type comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, The two types of granules are pharmaceutical compositions comprising a GLP-1 peptide.

2. The pharmaceutical composition according to the preceding embodiment, wherein the granules of the first type do not comprise a GLP-1 peptide.

3. A pharmaceutical composition according to any one of the preceding embodiments, wherein said second type of granule does not comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

4. The pharmaceutical composition according to any one of the preceding embodiments, wherein the granules of the first type further comprise a lubricant, such as magnesium stearate.

5. A pharmaceutical composition according to any one of the preceding embodiments, wherein the granules of the first type further comprise a filler, such as microcrystalline cellulose.

6. The pharmaceutical composition according to any one of the preceding embodiments, wherein the second type of granules further comprises a filler, such as microcrystalline cellulose.

7. The pharmaceutical composition according to any one of the preceding embodiments, wherein the second type of granules further comprises a binder, such as povidone.

8. The pharmaceutical composition according to any one of the preceding embodiments, wherein the granules are prepared by dry granulation, eg roller compaction.

9. A pharmaceutical composition according to any one of the preceding embodiments, wherein the release of said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is simultaneous or faster than the release of the GLP-1 peptide.

10. The release of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and/or the GLP-1 peptide is determined by dissolution test using assay (I), wherein the release is optionally A pharmaceutical composition according to any one of the preceding embodiments, which is determined within 30 minutes of said dissolution test.

11. A pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, comprising N-(8-(2-hydroxybenzoyl)amino)caprylic acid The release of said salt of the pharmaceutical composition is simultaneous or faster than the release of the GLP-1 peptide as determined by a dissolution test using Assay (I).

12. characterized in that the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is highest within the first 60 minutes as determined by a dissolution test using method (I) at pH 2.5 , a pharmaceutical composition according to any one of the preceding embodiments.

13. Within 55 minutes, such as 50, 45, when the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is determined by dissolution test using method (I) at pH 2.5 A pharmaceutical composition according to any one of the preceding embodiments, characterized in that it peaks within 40, 39, 38, 37, 36, 35, 34, 33, 32, or 31 minutes.

14. characterized in that the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is highest within the first 30 minutes as determined by a dissolution test using method (I) at pH 2.5 , a pharmaceutical composition according to any one of the preceding embodiments.

15. Within 31 minutes, such as 32, 33, when the amount of the dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is determined by dissolution test using method (I) at pH 2.5 A pharmaceutical composition according to any one of the preceding embodiments, characterized in that it peaks within 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, or 60 minutes.

16. Within 30 minutes when the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is determined by dissolution test using method (I) at pH 2.5, such as 25, 20, A pharmaceutical composition according to any one of the preceding embodiments, characterized in that it peaks within 15, 10, or 5 minutes.

17. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that said dissolution test using assay (I) is carried out at any one of pH 1.0-8.0.

18. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that said dissolution test using assay (I) is carried out at pH 1.0.

19. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that said dissolution test using assay (I) is carried out at pH 2.5.

20. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that said dissolution test using assay (I) is carried out at pH 6.8.

21. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.

22. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the GLP-1 peptide comprises an albumin binding moiety.

23. GLP-peptide is N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanylamino)buty) A pharmaceutical according to any one of the preceding embodiments, characterized in that it is reylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 (7-37). composition.

24. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition further comprises one or more pharmaceutically acceptable excipients.

25. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a solid dosage form.

26. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a tablet.

27. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a capsule.

28. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a sachet.

29. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that it further comprises any combination of the features according to embodiments 1-28.

30. A method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising:

a) mixing the GLP-1 peptide with a filler and/or a binder;

b) dry granulation of the mixture of step a;

c) mixing the granules obtained in step b with a composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; and

d) optionally adding a further lubricant

How to include.

31. A method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising:

a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler;

b) dry granulation of the mixture of step a;

c) mixing the granules obtained in step b with a composition comprising a GLP-1 peptide; and

d) optionally adding a further lubricant

How to include.

32. A method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising:

a) mixing the GLP-1 peptide with a filler and/or a binder;

b) dry granulation of the mixture of step a;

c) admixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally a lubricant and/or a filler;

d) dry granulation of the mixture of step c;

e) mixing the granules obtained in step b with the granules obtained in step d; and

f) optionally adding a further lubricant

How to include.

33. The method according to any one of embodiments 30-32, characterized in that the dry granulation is roller compaction.

34. The method according to any one of embodiments 30-33, characterized in that said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.

35. The method according to any one of embodiments 30-34, characterized in that the GLP-1 peptide is semaglutide.

36. The method according to any one of embodiments 30-35, characterized in that said lubricant and/or said further lubricant is magnesium stearate.

37. The method according to any one of embodiments 30-36, characterized in that the filler is microcrystalline cellulose.

38. The method according to any one of embodiments 30-37, characterized in that the binder is povidone.

39. Said mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation is at least 20 minutes, such as at least 30 minutes or The method according to any one of embodiments 30-38, characterized in that it has a period of at least 40 minutes, such as 50 minutes.

40. Said mixing comprising mixing granules of a first type comprising a GLP-1 peptide with granules of a second type comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid The method according to any one of embodiments 30-39, characterized in that the step has a duration of at least 15 minutes or at least 20 minutes, such as 25 minutes or at least 30 minutes.

41. A pharmaceutical composition obtained by the method as defined in any one of embodiments 30-40.

42. A pharmaceutical composition as defined in any one of embodiments 1-29 or 41 for use in medicine.

43. The pharmaceutical composition as defined in any one of embodiments 1-29 or 41 for the treatment of diabetes or obesity.

44. A pharmaceutical composition according to embodiments 42 or 43, characterized in that said pharmaceutical composition is administered orally.

45. A method of treating diabetes or obesity comprising administering to a patient in need thereof a composition comprising the pharmaceutical composition as defined in any one of embodiments 1-29 or 41.

46. The method according to embodiment 45, characterized in that the composition is administered orally.

47. Granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant and a filler.

48. Granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant.

49. Granules comprising GLP-1 peptide, fillers and binders.

50. The granule according to any one of embodiments 47-49, characterized in that the lubricant is magnesium stearate.

51. The granule according to any one of embodiments 47-50, characterized in that the filler is microcrystalline cellulose.

52. The granule according to any one of embodiments 47-51, characterized in that the binder is povidone.

53. The granule according to any one of embodiments 47-52, characterized in that the granule is prepared according to the method specified in any one of embodiments 30-40.

54. A process for the preparation of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, said process comprising:

a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (such as SNAC) with a lubricant and/or filler; and

b) dry granulation of the mixture of step a

How to include.

55. The method according to embodiment 54, characterized in that the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.

56. The method according to embodiment 54 or 55, characterized in that the lubricant is magnesium stearate.

57. Said mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation is at least 20 minutes, such as at least 30 minutes or The method according to any one of embodiments 54-56, characterized in that it has a period of at least 40 minutes, such as 50 minutes.

58. A method for preparing a granule comprising a GLP-1 peptide, said method comprising:

a) mixing the GLP-1 peptide, optionally a filler and/or a binder; and

b) roller compaction of the mixture of step a

How to include.

59. The method according to embodiment 58, characterized in that the GLP-1 peptide is semaglutide.

60. The method according to any one of embodiments 58-59, characterized in that the binder is povidone.

61. The method according to any one of embodiments 58-60, characterized in that the filler is microcrystalline cellulose.

62. The method according to any one of embodiments 58-61, characterized in that the dry granulation is roller compaction.

63. A granule obtained by the method as defined in any one of embodiments 58-62.

64. A method of increasing the oral bioavailability of a GLP-1 peptide comprising administering to a patient in need thereof a composition as defined in any one of embodiments 1-29 or 41.

65. Any one of the preceding embodiments, characterized in that said simultaneous or faster release is determined within 30 minutes, such as within 25, 20, 15 or 10 minutes, as determined by a dissolution test using assay (I). A pharmaceutical composition according to

66. The preceding embodiments, characterized in that the simultaneous or faster release is determined within 30 minutes, such as within 25, 20, 15 or 10 minutes, as determined by a dissolution test using assay (I) at pH 2.5 A pharmaceutical composition according to any one of the preceding claims.

Additional specific embodiments

The following are further specific embodiments of the present invention:

1. A pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, comprising N-(8-(2-hydroxybenzoyl)amino)caprylic acid The release of said salt of the pharmaceutical composition is simultaneous with or faster than the release of said GLP-1 peptide as determined by a dissolution test using Assay (I).

2. characterized in that the amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is highest within the first 30 minutes as determined by dissolution test using method (I) at pH 2.5, A pharmaceutical composition according to the preceding embodiment.

3. The amount of dissolved salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is within 31 minutes as determined by dissolution test using method (I) at pH 2.5, such as 32, 33, 34 , 35, 36, 37, 38, 39, 40, 45, 50, 55, or 60 minutes. A pharmaceutical composition according to any one of the preceding embodiments.

4. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the dissolution test using assay (I) is carried out at any one of pH 1.0-8.0.

5. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the dissolution test using assay (I) is carried out at pH 1.0.

6. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the dissolution test using assay (I) is carried out at pH 2.5.

7. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the dissolution test using method (I) is carried out at pH 6.8.

8. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.

9. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the GLP-1 peptide comprises an albumin binding moiety.

10. GLP-peptide is N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanylamino)buty A pharmaceutical according to any one of the preceding embodiments, characterized in that it is reylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1 (7-37). composition.

11. A pharmaceutical composition comprising granules of a first type and a second type, wherein the granules of the first type comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, The two types of granules are pharmaceutical compositions comprising a GLP-1 peptide.

12. Pharmaceutical composition according to embodiment 11, characterized in that the first type of granules further comprises a lubricant, such as magnesium stearate.

13. Pharmaceutical composition according to embodiment 11 or 12, characterized in that the granules of the first type further comprise fillers such as microcrystalline cellulose.

14. A pharmaceutical composition according to any one of embodiments 11 to 13, characterized in that the second type of granules further comprises a filler, such as microcrystalline cellulose.

15. The pharmaceutical composition according to any one of embodiments 11 to 14, characterized in that the second type of granules further comprises a binder, such as povidone.

16. Pharmaceutical composition according to any one of embodiments 11 to 15, characterized in that the granules are prepared by dry granulation, such as roller compaction.

17. A pharmaceutical composition according to any one of embodiments 11 to 16, characterized in that it further comprises any combination of features according to embodiments 1-10.

18. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition further comprises one or more pharmaceutically acceptable excipients.

19. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a solid dosage form.

20. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a tablet.

21. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a capsule.

22. A pharmaceutical composition according to any one of the preceding embodiments, characterized in that the composition is in the form of a sachet.

23. A method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising:

a) mixing the GLP-1 peptide with a filler and/or a binder;

b) dry granulation of the mixture of step a;

c) mixing the granules obtained in step b with a composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid; and

d) optionally adding a further lubricant

How to include.

24. A method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising:

a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler;

b) dry granulation of the mixture of step a;

c) mixing the granules obtained in step b with a composition comprising a GLP-1 peptide; and

d) optionally adding a further lubricant

How to include.

25. A method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, said method comprising:

a) mixing the GLP-1 peptide with a filler and/or a binder;

b) dry granulation of the mixture of step a;

c) admixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, optionally a lubricant and/or a filler;

d) dry granulation of the mixture of step c;

e) mixing the granules obtained in step b with the granules obtained in step d; and

f) optionally adding a further lubricant

How to include.

26. The method according to any one of embodiments 23-25, characterized in that the dry granulation is roller compaction.

27. The method according to any one of embodiments 23-26, characterized in that said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.

28. The method according to any one of embodiments 23-27, characterized in that the GLP-1 peptide is semaglutide.

29. The method according to any one of embodiments 23-28, characterized in that said lubricant and/or said further lubricant is magnesium stearate.

30. The method according to any one of embodiments 23-29, characterized in that the filler is microcrystalline cellulose.

31. The method according to any one of embodiments 23-30, characterized in that the binder is povidone.

32. Said mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation is at least 20 minutes, such as at least 30 minutes or The method according to any one of embodiments 23-31, characterized in that it has a period of at least 40 minutes, such as 50 minutes.

33. Said mixing comprising mixing granules of a first type comprising a GLP-1 peptide with granules of a second type comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid The method according to any one of embodiments 23-32, characterized in that the step has a duration of at least 15 minutes or at least 20 minutes, such as 25 minutes.

34. A pharmaceutical composition obtained by the method as defined in any one of embodiments 23-33.

35. A pharmaceutical composition as defined in any one of embodiments 1-22 or 34 for use in medicine.

36. The pharmaceutical composition as defined in any one of embodiments 1-22 or 34 for the treatment of diabetes or obesity.

37. A pharmaceutical composition according to embodiment 35 or 36, characterized in that said pharmaceutical composition is administered orally.

38. A method of treating diabetes or obesity comprising administering to a patient in need thereof a composition comprising the pharmaceutical composition as defined in any one of embodiments 1-22 or 34.

39. The method according to embodiment 38, characterized in that the composition is administered orally.

40. Granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant and a filler.

41. Granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant.

42. A granule comprising a GLP-1 peptide, a filler and a binder.

43. The granule according to any one of embodiments 40-42, characterized in that the lubricant is magnesium stearate.

44. The granule according to any one of embodiments 40-43, characterized in that the filler is microcrystalline cellulose.

45. The granule according to any one of embodiments 40-44, characterized in that the binder is povidone.

46. The granule according to any one of embodiments 40-45, characterized in that the granule is prepared according to the method specified in any one of embodiments 23-34.

47. A process for the preparation of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, said process comprising:

a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (such as SNAC) with a lubricant and/or filler; and

b) dry granulation of the mixture of step a

How to include.

48. The method according to embodiment 47, characterized in that the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.

49. The method according to embodiment 47 or 48, characterized in that the lubricant is magnesium stearate.

50. Said mixing step comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and/or filler prior to dry granulation is at least 30 minutes or at least 40 minutes, such as The method according to any one of embodiments 47-49, characterized in that it has a period of 50 minutes.

51. A method for preparing a granule comprising a GLP-1 peptide, said method comprising:

a) mixing the GLP-1 peptide, optionally a filler and/or a binder; and

b) roller compaction of the mixture of step a

How to include.

52. The method according to embodiment 51, characterized in that the GLP-1 peptide is semaglutide.

53. The method according to any one of embodiments 51-52, characterized in that the binder is povidone.

54. The method according to any one of embodiments 47-53, characterized in that the filler is microcrystalline cellulose.

55. The method according to any one of embodiments 47-54, characterized in that the dry granulation is roller compaction.

56. A granule obtained by the method as defined in any one of embodiments 47-55.

57. The granule according to any one of embodiments 40-46 or 56 for use in medicine.

58. The granule as defined in any one of embodiments 40-46 or 56 for the treatment of diabetes or obesity.

59. The granule according to embodiment 57 or 58, characterized in that the granule is administered orally as a pharmaceutical composition.

60. A method of treating diabetes or obesity comprising orally administering to a patient in need thereof a pharmaceutical composition comprising the granules as defined in any one of embodiments 40-46 or 56.

61. The method according to embodiment 60, characterized in that the pharmaceutical composition is administered orally.

Example

Materials and Methods

General manufacturing method

dry granulation

Dry granulation was performed by roller compaction on a Gerteis MINI-PACTOR smooth roll set as described in Table 1.

Settings for dry granulation on a roller compactor variable Set agitator speed 5.0 rpm roll speed 1.5 or 3.0 rpm gap 1.0 mm power 5.0 or 6.0 kN/cm granulator screen 0.63 mm wire screen Granulator speed 60 rpm

The roller compaction force, i.e. the force between the rollers of the roller compactor when compacting the material into a continuous strip of compacted material, was determined by a pressure transducer that converts hydraulic pressure into an electrical signal, which in kilonewtons (kN). ) or in kilonewtons per roll width (kN/cm). Dry granulation was followed by grinding of the molding into granules.

tablet manufacturing

Tablets were produced on a Korsch PH106 or Fette 102i equipped with a gravity feeder and a set of punches, and convex oval tablets measuring 13 mm x 7.5 mm without marks were obtained. The press speed of the Korsch PH106 was set at about 25 rpm, and the counter pressure was adjusted to 40 kN. The press speed of the Fette 102i was set at about 20 rpm. The fill volume was adjusted to obtain a tablet with a target weight of 407.7 mg. The compression force was set to obtain a tablet having a crushing strength of about 180±20N for Korsch PH106 and about 128N for Fette 102i.

crush resistance of tablets

The crush resistance of the tablets was determined according to section 2.9.8 of the European Pharmacopoeia 7.5, 7th edition 2012 at a main velocity of 20 N/s.

Common detection and characterization methods

Method (I): dissolution test

The dissolution test was performed in accordance with US Pharmacopoeia 35 at a paddle rotation speed of 50 rpm using device 2 For testing at pH 1.0, 2.5 or 6.8, 500 mL dissolution medium of 0.1 N hydrochloric acid (pH 1.0), 0.05 M phthalate buffer (pH 2.5), or 0.05 M phosphate buffer (pH 6.8), respectively, was used at a temperature of 37 °C. became All dissolution media had a content of 0.1% Tween 80. Sample aliquots were removed at appropriate intervals and samples with acidic medium were neutralized with tribasic sodium phosphate to prevent precipitation. Sample content was determined using the RP-HPLC method for dual detection of SNAC and GLP-1 (eg, semaglutide). The HPLC method was based on gradient elution on a C8 column. The solvent system was trifluoroacetic acid and acetonitrile, with UV detection at 210 and 335 nm. Sample content is calculated based on the peak areas of the SNAC and GLP-1 (eg semaglutide) peaks relative to the peak areas of the SNAC and GLP-1 (eg semaglutide) reference, respectively, in the chromatogram became The released amount of SNAC and GLP-1 (eg semaglutide) was calculated as a percentage relative to the nominal content of the tablet, ie 300 mg/tablet SNAC and 10 mg/tablet GLP-1 (eg semaglutide) , then optionally corrected for the actual content in the tablet. The actual content in the purification was determined using assay (III).

Assay (II): Bioavailability in Dogs

Animals, Dosing and Blood Sampling: Male and female beagle dogs weighing approximately 6-22 kg were included in the study during the study period. Dogs were dosed in a fasted state and fed approximately 4 hours after dosing. The formulations were typically administered by oral administration to dogs in groups of 8 (eg 4 males and 4 females).

Bioavailability studies were performed as single-dose (SD) studies or multiple-dose (MD) studies. In the MD study, formulations were administered in 5 consecutive dosing acts in each study (once daily dosing).

Blood samples were drawn to cover the pharmacokinetic profile. The following time points may be an example of an SD blood sampling schedule: pre-dose, post-dose 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 24, 48, 72, 96, 120, 144, 192 and 240 hours. The following time points may be an example of an MD blood sampling plan: a blood sampling plan equivalent to the SD blood sampling plan before dose, 0.5, 1.5 and 3 hours post-dose after each dosing act and after the last dose act.

Plasma Preparation: All blood samples were collected in test tubes containing EDTA for stabilization and kept on ice until centrifugation. Plasma was separated from whole blood by centrifugation, and the plasma was stored at -20°C or lower until analysis.

Plasma Sample Analysis: Plasma was analyzed for semaglutide using luminescent oxygen channeling immunoassay (LOCI). The LOCI assay uses donor beads coated with streptoavidin and acceptor beads conjugated with a monoclonal antibody that binds to the mid-molecular region of GLP-1 (eg, semaglutide). The remaining monoclonal antibodies specific for the N-terminal epitope were biotinylated. In this assay, three reactants are combined with GLP-1 (eg, semaglutide) to form a two-site immunocomplex. Illumination of this complex releases singlet oxygen atoms from the donor bead, becoming a channel to the acceptor bead, triggering chemiluminescence, which was measured in an EnVision plate reader. The amount of light was proportional to the concentration of semaglutide, and the lower limit of quantitation (LLOQ) was 100 pM.

Pharmacokinetic calculations: GLP-1 (eg, semaglutide) plasma concentration data includes the PC-based software WinNonlin, v. Noncompartmental pharmacokinetic analyzes were performed using version 5.2 or later (Pharsight, Mountain View, CA 94041, USA). The following pharmacokinetic parameters were estimated for each individual dog: area under the curve (AUC), and dose normalized AUC (AUC/D). Bioavailability (F) was calculated as fraction absorbed (in %) based on dose normalized AUC (AUC _{inf./D) following oral and intravenous administration.} Summary statistics of pharmacokinetic results are expressed as arithmetic mean.

Assay (III): Analysis of the amount of GLP-1 and SNAC

For assay analysis, tablets were dissolved using _{0.05M Na 2} HP0 ₄ containing 0.01% Tween 20 as extraction buffer. Sample content was determined using the RP-HPLC method for dual detection of SNAC and GLP-1 (eg, semaglutide). The HPLC method was based on gradient elution on a C8 column. The solvent system was trifluoroacetic acid and acetonitrile, with UV detection at 210 and 335 nm. Sample content is calculated based on the peak areas of the SNAC and GLP-1 (eg semaglutide) peaks relative to the peak areas of the SNAC and GLP-1 (eg semaglutide) reference, respectively, in the chromatogram became The content was reported as an average of 10 tablets.

Example 1: Preparation of a tablet composition comprising GLP-1 and SNAC

A tablet composition comprising GLP-1 and SNAC was prepared with the ingredients shown in Table 2. Compound A is N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino) ]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, 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.

Composition of the tablet composition ingredient Amount (mg/tablet) function semaglutide or
compound A 10 active raw material SNAC 300 delivery agent Microcrystalline Cellulose (Avicel PH 101) 80 filler Povidon K 90 (Kollidon 90F) 8 bookbinder magnesium stearate 9.7 slush total amount 407.7

Tablet compositions were prepared by mixing the ingredients listed in Table 2 in different ways. The tablet composition consisted of a first type of granules, in some cases a second type of granules, as well as an extragranular raw material mixed with the first type of granules, and the second type of granules, if any. The preparation of granules by roller compaction and the preparation of tablets from the tablet composition were as described in the general preparation method. The design of the tablet composition is shown in Table 3.

Design of the tablet composition (the amount of each component in mg/tablet is indicated in parentheses) tablet composition Granular composition of the first type (mg/tablet) Granular composition of the second type (mg/tablet) Extragranular raw material (mg/tablet) B SNAC (300),
Magnesium Stearate (7.7) semaglutide (10),
microcrystalline cellulose (80),
Povidone (8) Magnesium Stearate (2) C SNAC (300),
semaglutide (10),
Magnesium Stearate (7.7)
- microcrystalline cellulose (80),
povidone (8),
Magnesium Stearate (2) D SNAC (300),
semaglutide (10),
povidone (8),
Magnesium Stearate (7.7) - microcrystalline cellulose (80),
Magnesium Stearate (2) E SNAC (300),
semaglutide (10),
microcrystalline cellulose (80),
povidone (8),
Magnesium Stearate (7.7) - Magnesium Stearate (2) F SNAC (300),
microcrystalline cellulose (57),
Magnesium Stearate (7.7) semaglutide (10), microcrystalline cellulose (23),
Povidone (8) Magnesium Stearate (2) G SNAC (300),
Magnesium Stearate (7.7) compound A (10),
microcrystalline cellulose (80),
Povidone (8) Magnesium Stearate (2) H SNAC (300),
microcrystalline cellulose (57),
Magnesium Stearate (7.7) compound A (10), microcrystalline cellulose (23),
Povidone (8) Magnesium Stearate (2)

Further details on the preparation of tablet compositions are provided below. Tablet composition B

The magnesium stearate for the first granular portion was passed through a 355 μm sieve. Magnesium stearate was hand mixed with SNAC in a stainless steel bowl of the corresponding volume. Two cycles of geometric dilution were applied by mixing for about 60 seconds until this blend was visually homogeneous. Transfer the remaining amount of SNAC to a blender and premix at 25 rpm for 2 minutes. The SNAC and magnesium stearate premix was added to the blender and mixing was performed at 25 rpm for 20 minutes. The blend was roller compacted. The granules were sieved through a 180 μm mesh.

Weigh semaglutide, microcrystalline cellulose and povidone for the second granular portion directly into a stainless steel ball to reduce the amount and mix by hand for at least 3 minutes until visually homogeneous, then this premix Transferred to a 1000 mL Duma bottle. Close the Duma bottle with a lid and shake it by hand like a tumbler for 1 minute. The blend was roller compacted.

To reduce the content, these two types of granules were added to a blending vessel and mixed at 32 rpm for 5 minutes. Extragranular magnesium stearate was mixed with the granular blend by manual mixing using doubling in volume after mixing for 30 seconds at 32 rpm in a turbuler mixer. Tablets were prepared from this composition.

Tablet composition C

Magnesium stearate for the granular portion was passed through a 355 μm sieve. Magnesium stearate was hand mixed with SNAC in a stainless steel bowl of the corresponding volume. Two cycles of geometric dilution were applied by mixing for about 60 seconds until this blend was visually homogeneous. Transfer the remaining amount of SNAC to a blender and premix at 25 rpm for 2 minutes. The SNAC and magnesium stearate premix was added to the blender and mixing was performed at 25 rpm for 20 minutes. Semaglutide was geometrically diluted with SNAC and magnesium stearate mixed from the blender by hand mixing for at least 60 seconds until visually homogeneous. Next, this premix was added to the mixed SNAC and magnesium stearate. The mixing step was completed by mixing in a blender at 25 rpm for 10 minutes. The blend was roller compacted.

All other ingredients except granules and extragranular magnesium stearate were added to a blending vessel to reduce content, and mixed at 32 rpm for 5 minutes. Extragranular magnesium stearate was mixed with the granular blend by manual mixing using doubling in volume after mixing for 30 seconds at 32 rpm in a turbuler mixer. Tablets were prepared from this composition.

Tablet composition D

Magnesium stearate for the granular portion was passed through a 355 μm sieve. Magnesium stearate was hand mixed with SNAC in a stainless steel bowl of the corresponding volume. Two cycles of geometric dilution were applied by mixing for about 60 seconds until this blend was visually homogeneous. Transfer the remaining amount of SNAC to a blender and premix at 25 rpm for 2 minutes. The SNAC and magnesium stearate premix was added to the blender and mixing was performed at 25 rpm for 20 minutes. Semaglutide and povidone were weighed down in a stainless steel bowl to reduce the amount and the ingredients were mixed by hand until visually homogeneous. A geometric dilution was then performed using the SNAC and magnesium stearate mixed from the blender by hand mixing for at least 60 seconds until visually homogeneous. Next, this premix was added to the mixed SNAC and magnesium stearate. The mixing step was completed by mixing in a blender at 25 rpm for 10 minutes. The blend was roller compacted.

Granules and microcrystalline cellulose were added to a blending vessel for content reduction and mixed at 32 rpm for 5 minutes. Extragranular magnesium stearate was mixed with the granular blend by manual mixing using doubling in volume after mixing for 30 seconds at 32 rpm in a turbuler mixer. Tablets were prepared from this composition.

Tablet composition E

Magnesium stearate for the granular portion was passed through a 355 μm sieve. Magnesium stearate was hand mixed with SNAC in a stainless steel bowl of the corresponding volume. Two cycles of geometric dilution were applied by mixing for about 60 seconds until this blend was visually homogeneous. Transfer the remaining amount of SNAC to a blender and premix at 25 rpm for 2 minutes. The SNAC and magnesium stearate premix was added to the blender and mixing was performed at 25 rpm for 20 minutes. Semaglutide, microcrystalline cellulose and povidone were weighed into a stainless steel bowl to reduce the amount and the ingredients were mixed by hand until visually homogeneous. A geometric dilution was then performed using the SNAC and magnesium stearate mixed from the blender by hand mixing for at least 60 seconds until visually homogeneous. Next, this premix was added to the mixed SNAC and magnesium stearate. The mixing step was completed by mixing in a blender at 25 rpm for 10 minutes. The blend was roller compacted.

Extragranular magnesium stearate was mixed with the granular blend by manual mixing using doubling in volume after mixing for 30 seconds at 32 rpm in a turbuler mixer. Tablets were prepared from this composition.

Tablet composition F

The magnesium stearate for the first granular portion was passed through a 355 μm sieve. Magnesium stearate was hand mixed with SNAC in a stainless steel bowl of the corresponding volume. Two cycles of geometric dilution were applied by mixing for about 60 seconds until this blend was visually homogeneous. Transfer the remaining amount of SNAC to a blender and premix at 25 rpm for 2 minutes. The SNAC and magnesium stearate premix was added to the blender and mixing was performed at 25 rpm for 20 minutes. The microcrystalline cellulose was geometrically diluted with the SNAC and magnesium stearate mixed from the blender by hand mixing for at least 60 seconds until visually homogeneous. Next, this premix was added to the mixed SNAC and magnesium stearate. The mixing step was completed by mixing in a blender at 25 rpm for 10 minutes. The blend was roller compacted.

Weigh semaglutide, microcrystalline cellulose (Avicel PH 101, FMC Biopolymer) and povidone (Kollidon 90F, BASF) for the second granular part directly into a stainless steel ball to reduce the amount and until visually homogeneous. After mixing by hand for at least 3 minutes, this premix was transferred to a 500 mL Duma bottle. Close the Duma bottle with a lid and shake it by hand like a tumbler for 1 minute. The blend was roller compacted.

To reduce the content, these two types of granules were added to a blending vessel and mixed at 32 rpm for 5 minutes. Extragranular magnesium stearate was mixed with the granular blend by manual mixing using doubling in volume after mixing for 30 seconds at 32 rpm in a turbuler mixer. Tablets were prepared from this composition.

Tablet composition G

The magnesium stearate for the first granular portion was passed through a 355 μm sieve. Magnesium stearate was hand mixed with SNAC in a plastic bag of the corresponding volume. Two cycles of geometric dilution were applied by mixing for about 60 seconds. After addition of the remaining SNAC, the SNAC and magnesium stearate premix was added to the blender and mixing was performed at 25 rpm for 50 minutes. The blend was roller compacted. Granules were sieved through 1000 and 90 μm mesh.

Weigh the compound A, microcrystalline cellulose and povidone for the second granular portion directly into a stainless steel bowl to reduce the amount and mix by hand for at least 3 minutes until visually homogeneous, then add 500 mL of this premix transferred to Duma disease. The Duma bottle was closed with a lid and shaken by hand like a tumbler for 3 minutes. The blend was roller compacted.

These two types of granules were added to the blending vessel and mixed at 25 rpm for 20 minutes. Extragranular magnesium stearate was passed through a 355 μm sieve and mixed with the granular blend by manual mixing using doubling in volume after 2 minutes of mixing at 25 rpm in a turbuler mixer. Tablets were prepared from this composition.

Tablet composition H

The magnesium stearate for the first granular portion was passed through a 355 μm sieve. Magnesium stearate was hand mixed with SNAC in a plastic bag of the corresponding volume. Two cycles of geometric dilution were applied by mixing for about 60 seconds. After addition of the remaining SNAC, the SNAC and magnesium stearate premix was added to the blender and mixing was performed at 25 rpm for 50 minutes. Next, microcrystalline cellulose was added to the mixed SNAC and magnesium stearate, and the mixing step was completed by mixing in a blender at 25 rpm for 20 minutes. The blend was roller compacted.

Weigh out compound A, microcrystalline cellulose (Avicel PH 101, FMC Biopolymer) and povidone (Kollidon 90F, BASF) for the second granular part directly into a stainless steel ball to reduce the amount and at least until visually homogeneous. After mixing by hand for 3 minutes, this premix was transferred to a 500 mL Duma bottle. Close the Duma bottle with a lid and shake it by hand like a tumbler for at least 3 minutes. The blend was roller compacted.

These two types of granules were added to the blending vessel and mixed at 25 rpm for 20 minutes. Extragranular magnesium stearate was passed through a 355 μm sieve and mixed with the granular blend by manual mixing using doubling in volume after 2 minutes of mixing at 25 rpm in a turbuler mixer. Tablets were prepared from this composition.

Example 2: Dissolution of GLP-1 and SNAC from Tablet Composition B

The dissolution of semaglutide and SNAC from tablet composition B was determined using assay (I) described herein. A result is shown in Table 4. The corrected results are adjusted for the content of semaglutide or SNAC as determined by assay using assay (III) described herein. The corrected results indicate that SNAC is released faster than semaglutide during the first 20 min of lysis. Furthermore, it indicates that the difference between the rapid release of SNAC compared to semaglutide is maximum in the dissolution medium with a pH value of 2.5. Finally, these data indicate that the amount of dissolved SNAC in the dissolution medium with pH values of 1.0 and 2.5 is highest within the initial 45 min and 30 min, respectively.

Dissolution of semaglutide and SNAC from tablet composition B Dissolution time (min) pH of the dissolution medium 1.0 2.5 6.8 Semaglutide released (% of total) SNAC released (% of total) Semaglutide released (% of total) SNAC released (% of total) Semaglutide released (% of total) SNAC released (% of total) 0 0 0 0 0 0 0 0 0 0 0 0 0 5 - - - - 8 9 19 19 - - - - 10 9 10 13 13 17 18 28 28 - - - - 15 - - - - 22 24 32 32 45 49 53 52 20 17 18 19 19 27 29 34 34 - - - - 30 20 22 20 20 35 38 33 33 74 81 81 80 45 23 25 20 20 42 46 30 30 86 94 92 91 60 24 26 19 19 46 50 28 28 92 100 96 95 Correction for actual content Yes no Yes no Yes no Yes no Yes no Yes no

Example 3: Dissolution of GLP-1 and SNAC from Tablet Composition C The dissolution of semaglutide and SNAC from tablet composition C was determined using assay (I) described herein. A result is shown in Table 5. The results indicate that SNAC is released more slowly than semaglutide after the initial 5 min of dissolution in dissolution media with low pH values of 1.0 and 2.5. The corrected results are adjusted for the content of semaglutide or SNAC as determined by assay using assay (III) described herein. During the first 5 min of calibrated dissolution in dissolution medium with a pH value of 2.5, SNAC is released equally rapidly as semaglutide. In addition, the corrected dissolution value indicates that SNAC is released faster than semaglutide in the dissolution medium with a pH value of 6.8.

Dissolution of semaglutide and SNAC from tablet composition C Dissolution time (min) pH of the dissolution medium 1.0 2.5 6.8 Semaglutide released (% of total) SNAC released (% of total) Semaglutide released (% of total) SNAC released (% of total) Semaglutide released (% of total) SNAC released (% of total) 0 0 0 0 0 0 0 0 0 0 0 0 0 5 - - - - 11 12 11 11 - - - - 10 14 16 11 11 20 22 19 19 - - - - 15 - - - - 24 27 23 23 45 50 48 47 20 23 25 16 16 28 31 25 25 - - - - 30 27 30 18 18 34 38 28 28 77 85 80 79 45 30 33 19 19 41 46 29 29 88 98 93 91 60 31 34 18 18 46 51 27 27 94 104 99 97 Correction for actual content Yes no Yes no Yes no Yes no Yes no Yes no

Example 4: Dissolution of GLP-1 and SNAC from Tablet Composition D The dissolution of semaglutide and SNAC from tablet composition C was determined using assay (I) described herein. A result is shown in Table 6. The results indicate that SNAC is released more slowly than semaglutide after the initial 5 min of dissolution in dissolution media with low pH values of 1.0 and 2.5. The corrected results are adjusted for the content of semaglutide or SNAC as determined by assay using assay (III) described herein. During the first 5 min of calibrated dissolution in dissolution medium with a pH value of 2.5, SNAC is released equally rapidly as semaglutide. In addition, the corrected dissolution value indicates that SNAC is released faster than semaglutide in the dissolution medium with a pH value of 6.8.

Dissolution of semaglutide and SNAC from tablet composition C dissolution time
(minute) pH of the dissolution medium 1.0 2.5 6.8 Released semaglutide
(% of total) Released SNAC
(% of total) Released semaglutide
(% of total) Released SNAC
(% of total) Released semaglutide
(% of total) Released SNAC
(% of total) 0 0 0 0 0 0 0 0 0 0 0 0 0 5 - - - - 11 12 11 11 - - - - 10 10 11 8 8 17 19 16 16 - - - - 15 - - - - 21 23 19 19 33 37 35 35 20 17 19 12 12 23 26 20 20 - - - - 30 23 26 15 15 28 31 22 22 59 66 62 62 45 26 29 16 16 33 37 24 24 75 83 77 77 60 27 30 15 15 38 42 25 25 82 91 84 84 Correction for actual content Yes no Yes no Yes no Yes no Yes no Yes no

Example 5: Dissolution of GLP-1 and SNAC from Tablet Composition E The dissolution of semaglutide and SNAC from tablet composition E was determined using assay (I) described herein. A result is shown in Table 7. The corrected results are adjusted for the content of semaglutide or SNAC as determined by assay using assay (III) described herein. The results indicate that SNAC is released more slowly than semaglutide during the entire dissolution time in a dissolution medium with a pH value of 1.0. In a dissolution medium with a pH value of 2.5, the results indicate that SNAC is initially released faster than semaglutide during the first 10 to 15 min of dissolution and then is released slowly. In addition, these data indicate that the amount of dissolved SNAC in the dissolution medium with a pH value of 2.5 peaks within the initial 20 min. Finally, the corrected dissolution value indicates that SNAC is released faster than semaglutide in the dissolution medium with a pH value of 6.8.

Dissolution of semaglutide and SNAC from tablet composition E dissolution time
(minute) pH of the dissolution medium 1.0 2.5 6.8 Released semaglutide
(% of total) Released SNAC
(% of total) Released semaglutide
(% of total) Released SNAC
(% of total) Released semaglutide
(% of total) Released SNAC
(% of total) 0 0 0 0 0 0 0 0 0 0 0 0 5 - - - - 21 23 22 22 - - - - 10 15 17 12 12 38 42 40 40 - - - - 15 - - - - 50 56 46 46 47 53 51 51 20 23 26 16 16 57 64 43 43 - - - - 30 28 31 16 16 63 71 37 37 76 85 79 79 45 32 36 17 17 68 76 31 31 86 96 89 89 60 36 40 17 17 70 78 28 28 90 101 93 93 Correction for actual content Yes no Yes no Yes no Yes no Yes no Yes no

Example 6: Dissolution of GLP-1 and SNAC from Tablet Composition F The dissolution of semaglutide and SNAC from tablet composition F was determined using assay (I) described herein. A result is shown in Table 8. The corrected results are adjusted for the content of semaglutide or SNAC as determined by assay using assay (III) described herein. The corrected results indicate that SNAC is released faster than semaglutide during the first 20 to 30 minutes of lysis. Furthermore, it indicates that the difference between the rapid release of SNAC compared to semaglutide is maximum in the dissolution medium with a pH value of 2.5. Finally, these data indicate that the amount of dissolved SNAC in the dissolution medium with a pH value of 2.5 is highest within the initial 30 min, respectively.

Dissolution of semaglutide and SNAC from tablet composition F dissolution time
(minute) pH of the dissolution medium 1.0 2.5 6.8 Released semaglutide
(% of total) Released SNAC
(% of total) Released semaglutide
(% of total) Released SNAC
(% of total) Released semaglutide
(% of total) Released SNAC
(% of total) 0 0 0 0 0 0 0 0 0 0 0 0 0 5 - - - - 9 10 17 17 - - - - 10 8 9 10 10 20 22 31 31 - - - - 15 - - - - 28 31 40 40 51 56 56 56 20 12 13 13 13 33 36 43 43 - - - - 30 15 17 15 15 38 42 42 42 75 82 79 79 45 19 21 16 16 43 47 39 39 85 93 88 88 60 21 23 16 16 48 53 38 38 89 98 93 93 Correction for actual content Yes no Yes no Yes no Yes no Yes no Yes no

Example 7: Bioavailability of GLP-1 in Dogs from Tablet Composition BF The bioavailability of GLP-1 from tablet composition BF was determined in dogs according to Assay (II) described herein. A result is shown in Table 9.

Bioavailability of GLP-1 in Dogs from Tablet Compositions B-F tablet composition Bioavailability of GLP-1 in Dogs (%F) B 0.7 C 0.5 D 0.3 E 0.4 F 1.0

The results show that tablet composition F provided a bioavailability of 1.0%. The results show that tablet composition B provided a bioavailability of 0.7%. The results show that tablet composition C provided a bioavailability of 0.5%. The results show that tablet composition E provided a bioavailability of 0.4%. The results show that tablet composition D provided a bioavailability of 0.3%. Example 8: Dissolution of GLP-1 and SNAC from Tablet Composition G

The dissolution of compound A and SNAC from tablet composition G was determined using assay (I) described herein. A result is shown in Table 10. The results indicate that SNAC is released faster than Compound A during the first 20 minutes of dissolution. Furthermore, it indicates that the difference between the rapid release of SNAC compared to compound A is maximum in the dissolution medium with a pH value of 2.5. Finally, these data indicate that the amount of dissolved SNAC in the dissolution medium with a pH value of 2.5 is highest within the initial 45 min, respectively.

Dissolution of compound A and SNAC from tablet composition G dissolution time
(minute) pH of the dissolution medium 2.5 6.8 Compound A released (% of total) Released SNAC
(% of total) Released Compound A
(% of total) Released SNAC
(% of total) 0 0 0 0 0 5 9 17 - - 10 16 24 - - 15 21 26 38 49 20 25 28 - - 30 32 28 70 79 45 39 28 85 92 60 43 26 91 96 120 - - 95 101

Example 9: Dissolution of GLP-1 and SNAC from Tablet Composition H The dissolution of Compound A and SNAC from Tablet Composition H was determined using Assay (I) described herein. A result is shown in Table 11. The results indicate that SNAC is released faster than Compound A during the first 20 minutes of dissolution. Furthermore, it indicates that the difference between the rapid release of SNAC compared to compound A is maximum in the dissolution medium with a pH value of 2.5. Finally, these data indicate that the amount of dissolved SNAC in the dissolution medium with a pH value of 2.5 peaks within the initial 30 min.

Dissolution of compound A and SNAC from tablet composition H dissolution time
(minute) pH of the dissolution medium 2.5 6.8 Released Compound A
(% of total) Released SNAC
(% of total) Released Compound A
(% of total) Released SNAC
(% of total) 0 0 0 0 0 5 10 19 - - 10 19 31 - - 15 26 37 37 47 20 31 38 - - 30 36 34 63 75 45 42 29 74 83 60 46 27 79 87 120 - - 89 97

Example 10: Bioavailability of GLP-1 in Dogs from Tablet Composition GH The bioavailability of GLP-1 from tablet composition GH was determined in dogs according to Assay (II) described herein. A result is shown in Table 12.

Bioavailability of GLP-1 in Dogs from Tablet Compositions G-H tablet composition Bioavailability of GLP-1 in Dogs (%F) G 2.1 H 2.5

The results show that tablet composition G provided a bioavailability of 2.1%. The results show that tablet composition H provided a bioavailability of 2.5%. While specific features of the invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will now occur to those skilled in the art. Accordingly, it should be understood that the appended claims are intended to cover all such modifications and variations that fall within the true spirit of the present invention.

SEQUENCE LISTING <110> Novo Nordisk A/S <120> Compositions of GLP-1 peptides and preparation thereof <130> 8481.204-WO <160> 2 <170> PatentIn version 3.3 <210> 1 <211> 31 <212> PRT <213> Homo sapiens <400> 1 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 <210> 2 <211> 40 <212> PRT <213> Heloderma suspectum <400> 2 His Gly Glu Gly Thr Phe Ile Thr Ser Asp Leu Ser Lys Gln Met Glu 1 5 10 15 Glu Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro 20 25 30 Ser Ser Gly Ala Pro Pro Pro Ser 35 40

Claims (27)

A pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, comprising:
wherein the release of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is simultaneous or faster than the release of the GLP-1 peptide as determined by a dissolution test using assay (I). ,
The GLP-1 peptide is N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)buty) Lylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37) (semaglutidine), N-epsilon26-{2-[2 -(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino }ethoxy)ethoxy]acetyl}, or N-epsilon37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4) In -carboxy-phenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-OH selected pharmaceutical composition. The pharmaceutical composition according to claim 1, characterized in that the dissolution test using assay (I) is carried out at any one of pH 1.0-8.0, or at pH 1.0, 2.5, or 6.8. The method of claim 1 , wherein the release is determined within 30 minutes, or within 25 minutes, 20 minutes, 15 minutes, or within 10 minutes or 5 minutes as determined by a dissolution test using assay (I) at pH 2.5. A pharmaceutical composition, characterized in that The method of claim 1, wherein the dissolved amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is within the first 60 minutes as determined by a dissolution test using method (I) at pH 2.5; or 55 minutes, 50 minutes, 45 minutes, 40 minutes, 39 minutes, 38 minutes, 37 minutes, 36 minutes, 35 minutes, 34 minutes, 33 minutes, 32 minutes, 31 minutes, or 30 minutes. pharmaceutical composition. The method of claim 1, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is the sodium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, potassium A pharmaceutical composition, characterized in that it is a salt or calcium salt, or sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). The pharmaceutical composition of claim 1 , wherein the GLP-1 peptide comprises a substituent comprising a fatty acid or a fatty diacid. The method of claim 1, wherein the GLP-1 peptide is N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxy) Heptadecanylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1(7-37) (semaglutidine) , pharmaceutical compositions. The method of claim 1, wherein the GLP-1 peptide is N-epsilon26-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-() 4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, 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. The pharmaceutical composition of claim 1 , wherein the composition further comprises one or more pharmaceutically acceptable excipients. The pharmaceutical composition according to claim 1, characterized in that the composition is in the form of a solid dosage form, tablet, capsule, or sachet. 6. Pharmaceutical composition according to claim 5, characterized in that the amount of SNAC in the composition is in the range of 100-1000 mg. A method for preparing a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide, the method comprising:
a) mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and filler;
b) dry granulation of the mixture of step a;
c) mixing the granules obtained in step b with a composition comprising a GLP-1 peptide; and
d) optionally adding a further lubricant
How to include. 13. The method of claim 12, wherein the lubricant is magnesium stearate. 13. The method of claim 12, wherein the filler is microcrystalline cellulose. 13. The method of claim 12, wherein the dry granulation is roller compaction. 13. The method of claim 12, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC. 13. The method of claim 12, wherein the GLP-1 peptide is semaglutidine. 18. A mixing step according to any one of claims 12 to 17, comprising mixing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid with a lubricant and filler prior to the dry granulation. has a duration of at least 20 minutes, at least 30 minutes, at least 40 minutes, or at least 50 minutes. 18. A pharmaceutical composition prepared according to any one of claims 12 to 17. 12. A pharmaceutical composition as defined in any one of claims 1 to 11 for the treatment of diabetes or obesity, wherein said composition is administered orally. A pharmaceutical composition as defined in claim 19 for the treatment of diabetes or obesity, wherein said composition is administered orally. delete delete delete delete delete delete