Improved oral pharmaceutical formulations of therapeutic peptides and proteins

Abstract

The present invention relates to a solid oral pharmaceutical composition comprising (i) a core comprising a peptide or protein drug, and (ii) a first coating, wherein the first coating comprises a copolymer (A) in combination with a copolymer (B) and / or a copolymer (C) and / or a copolymer (D).

Description

[Technical field]

[0001] The present invention relates to a solid oral pharmaceutical composition comprising (i) a core comprising a peptide or protein drug, and (ii) a first coating, the first coating comprising a copolymer (A) in combination with a copolymer (B) and / or a copolymer (C) and / or a copolymer (D). This application claims priority to European Patent Application EP22159924.4, filed March 3, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] More and more peptides and proteins are becoming available as therapeutic agents. However, these biological drugs are typically limited to parenteral injections, so their full potential is not realized. Ideally, the oral route of administration is preferred. Oral administration is the most common and popular way of administering drugs because of its simplicity and convenience for patients. However, the gastrointestinal tract degrades peptide and protein drugs and prevents their absorption as intact bodies. Enzymatic degradation throughout the gastrointestinal tract and poor permeability to epithelial cells are the main reasons for their low oral bioavailability.

[0003] To improve the oral bioavailability of such therapeutic peptides and proteins, several different approaches have been proposed, including the use of absorption-enhancing technologies or the use of protease inhibitors such as soybean trypsin inhibitor, aprotinin, Bowman-Birk inhibitor, bacitracin, camostat mesylate and amastatin (Renukuntla J et al., Int J Pharm. 2013, 447(1-2):75-93; US2007 / 0087957A1). However, due to safety concerns, none of these protease inhibitors have been successful as additives in commercial peptide or polypeptide drug delivery applications.

[0004] Indeed, the development of oral dosage forms of therapeutic peptides and proteins that allow absorption into the systemic circulation has been described as one of the biggest challenges for the pharmaceutical industry (Aguirre, TAS et al., Adv Drug Deliv Rev. 2016, 106(Pt B), 223-241).

[0005] Current enteric coating technologies suffer from several limitations, such as susceptibility to negative food interactions. Oral dosing of such dosage forms in the presence of food results in significantly reduced oral bioavailability. Furthermore, Eudragit FS30D coated tablets with peptide drugs have been reported to result in a factor-reduced oral bioavailability after storage (WO2016 / 119854, Figure 3). In addition, there are numerous reports of in vivo failure of enteric coated solid oral dosage forms (Hodson AH, JR Soc Med, 1994, 87(3):183; Grosser T et al., Circulation, 2013, 127(3):377-85). In particular, enteric coatings that require a relatively high intestinal pH, such as above pH 7, are prone to dosing failure or incomplete dissolution, most likely due to small intestinal pH variations in individuals, such as too short an in vivo exposure to a high enough pH. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there remains an urgent unmet need for new and improved pharmaceutical formulations of peptide or protein drugs that are suitable for oral administration. The present invention addresses these shortcomings in the art and provides solid oral pharmaceutical compositions of peptide or protein drugs, which are particularly well suited for oral administration due to their advantageous release profile, improved bioavailability and reduced food effect.A particular advantage of the present invention is that due to the combination with the predominant time-dependent polymer, a much smaller amount of pH-dependent polymer is required.Such combination with a sufficiently large amount of time-dependent polymer results in surprisingly high oral bioavailability, reduced negative food effect, reduced variability, and avoidance of in vivo dissolution / disintegration failure.Furthermore, these compositions are advantageously storage stable. [Means for solving the problem]

[0007] Thus, the present invention provides (i) a core comprising a peptide or protein drug, and (ii) First Coating wherein the first coating comprises: (ii-1) Copolymer (A) (ii-2) in combination with copolymer (B) and / or copolymer (C) and / or copolymer (D); The copolymer (A) is (a) 20 to 90 mol % of ethyl acrylate repeat units, and (b) 10 to 80 mol% of methyl methacrylate repeating units Including, If copolymer (B) is present, (a) 25 to 75 mol % of methacrylic acid repeat units, and (b) 25 to 75 mol% of ethyl acrylate repeating units Including, When the copolymer (C) is present, (a) 25 to 60 mol % of methacrylic acid repeat units, and (b) 40 to 75 mol% of methyl methacrylate repeating units Including, If the copolymer (D) is present, (a) 5 to 20 mol % of methacrylic acid repeat units, and (b) 20 to 40 mol % of methyl methacrylate repeat units, and (c) 60 to 75 mol% methyl acrylate repeating units The present invention provides a solid oral pharmaceutical composition comprising: [Brief description of the drawings]

[0008] [Figure 1] Graph showing the PK profile of semaglutide after oral dosing of Eudragit NM30D (80%) / Eudragit FS30D (20%) coated tablets in the fasted or fed state (-○ - fasted group; -● - fed group, mean ± SE of n=6) (Example 9). [Diagram 2] FIG. 1 is a graph showing the in vitro stability of an enteric dosage form in a simulated fed state gastric medium as a function of release of octreotide (Example 18). [Diagram 3] FIG. 1 is a graph showing the in vitro stability of an enteric dosage form in a simulated fed state gastric medium as a function of leuprolide release (Example 18). [Figure 4] FIG. 1 is a graph showing the in vitro stability of an enteric dosage form in a simulated fed state gastric medium as a function of insulin release (Example 18). [Figure 5-1] FIG. 17 shows the dissolution profiles of octreotide (A), leuprolide (B) and insulin (C) from capsules coated with Eudragit L30D55 ​​(reference) or a combination of 80% Eudragit NM30D and 20% Eudragit L30D55 ​​(Example 19). [Figure 5-2] FIG. 17 shows the dissolution profiles of octreotide (A), leuprolide (B) and insulin (C) from capsules coated with Eudragit L30D55 ​​(reference) or a combination of 80% Eudragit NM30D and 20% Eudragit L30D55 ​​(Example 19). [Figure 6]Graph showing the dissolution profiles of tablets containing octreotide (black markers) and semaglutide (white markers) in SGF (1 h) and SIF pH 7.4 (5 h) with different coatings (L30D55 ​​coating: circles, NM30D / FS30D coating: squares; n=3±SD) (Example 26). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] In the context of the present invention, it has surprisingly been found that the coating of the solid oral pharmaceutical composition provided herein results in an advantageous release profile significantly below pH 7 upon oral administration, allowing release of the peptide or protein drug in the distal small intestine and improved bioavailability compared to conventional formulations of the peptide or protein drug, including formulations with a pH-dependent enteric coating. In particular, it has been found that the pharmaceutical composition according to the present invention allows dissolution at a relatively low pH between 5.5 and 6.5. The release of the peptide or protein drug in the distal small intestine (distal jejunum or ileum) is advantageous in view of the reduced activity of proteolytic enzymes compared to the proximal small intestine (duodenum and jejunum), in view of the reduced intestinal motility in this segment (leading to a reduced effect of dilution of the dissolving pharmaceutical composition, allowing a high concentration of the peptide or protein drug to achieve optimal absorption), and in view of the higher solubility of the peptide or protein drug at pH levels present in the distal jejunum or ileum compared to those present in the stomach, duodenum or proximal jejunum. In addition, it has been found that the solid oral pharmaceutical composition of the present invention exhibits an advantageous reduction in the negative food effect. This is in contrast to known formulations of various peptide or protein drugs that target the proximal gastrointestinal tract, particularly those that target and dissolve in the proximal GI tract, such as the stomach or duodenum, without a coating or with a coating consisting only of anionic polymers, where adverse food interactions have been observed (Maarbjerg SJ et al., Diabetes, 2017, 66:A321 (without coating), and Example 33 of WO2016 / 120378A1 (coating based on Eudragit FS 30 D)). Thus, the solid oral pharmaceutical composition of the present invention can deliver peptide or protein drugs with improved independence from food intake by the treated subject.

[0010] The present invention further provides a solid oral pharmaceutical composition (as described above) for use in therapy, in particular for use in the treatment or prevention of a disease / disorder (as described in further detail below). It will be understood that the disease / disorder to be treated or prevented is a disease / disorder susceptible to treatment or prevention by the respective peptide or protein drug.

[0011] The present invention likewise relates to the use of a solid oral pharmaceutical composition (as described above) for the manufacture of a medicament for the treatment or prevention of a disease / disorder. Furthermore, the present invention relates to a method for treating or preventing a disease / disorder in a subject, comprising orally administering to a subject in need thereof a solid oral pharmaceutical composition (as described above). It will be understood that a therapeutically effective amount should be administered according to this method.

[0012] The present invention also provides a method for oral delivery of a peptide or protein drug, comprising orally administering a solid oral pharmaceutical composition (as described above). The first coating preferably dissolves at a pH in the range of 5 to 7, preferably at a pH in the range of 5.5 to 6.5, and even more preferably at a pH in the range of 5.5 to 6.0. The components and optional components of the first coating, such as copolymers (A), (B), (C) and (D), are described below.

[0013] Copolymer (A) The copolymer (A) present in the first coating comprises (a) 20 to 90 mol % of ethyl acrylate repeat units and (b) 10 to 80 mol % of methyl methacrylate repeat units. The copolymer (A) is preferably a neutral or cationic copolymer.

[0014] It is particularly preferred that the copolymer (A) in the first coating is a neutral non-ionic copolymer. Preferably at least 90 mol %, more preferably at least 95 mol %, even more preferably at least 98 mol % of the repeat units in the copolymer (A) are selected from ethyl acrylate repeat units and methyl methacrylate repeat units. In particular, the copolymer (A) may consist of ethyl acrylate repeat units and methyl methacrylate repeat units. The copolymer (A) in the first coating preferably comprises 50-80 mol % of ethyl acrylate repeat units and 20-50 mol % of methyl methacrylate repeat units, more preferably 60-75 mol % of ethyl acrylate repeat units and 25-40 mol % of methyl methacrylate repeat units, even more preferably 64-68 mol % of ethyl acrylate repeat units and 32-36 mol % of methyl methacrylate repeat units. The molar ratio of ethyl acrylate repeat units to methyl methacrylate repeat units in the copolymer (A) is preferably 1.5:1 to 2.5:1, more preferably 1.8:1 to 2.2:1, even more preferably 2: 1. Corresponding preferred examples of copolymer (A) are poly(ethyl acrylate-co-methyl methacrylate) 2:1, in particular Eudragit NM 30 D, Eudragit NE 30 D or Eudragit NE 40 D.

[0015] As explained above, the copolymer (A) in the first coating can also be a cationic copolymer. Thus, the copolymer (A) in the first coating can further comprise 0.5-20 mol %, preferably 1-15 mol % of 2-(trimethylammonio)ethyl methacrylate chloride repeat units (in addition to the ethyl acrylate repeat units and the methyl methacrylate repeat units). For example, in a preferred composition, the copolymer (A) in the first coating comprises 25-39 mol % of ethyl acrylate repeat units, 60-74 mol % of methyl methacrylate repeat units, and 1-15 mol % of 2-(trimethylammonio)ethyl methacrylate chloride repeat units. When the copolymer (A) is a cationic copolymer, it is preferred that at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeat units in the copolymer (A) are selected from ethyl acrylate repeat units, methyl methacrylate repeat units, and 2-(trimethylammonio)ethyl methacrylate chloride repeat units. In particular, the copolymer (A) in the first coating may consist of ethyl acrylate repeat units, methyl methacrylate repeat units, and 2-(trimethylammonio)ethyl methacrylate chloride repeat units. The copolymer (A) in the first coating may comprise ethyl acrylate repeat units, methyl methacrylate repeat units, and 2-(trimethylammonio)ethyl methacrylate chloride repeat units, for example, in a molar ratio of 1:2:0.1 or 1:2:0.2. Corresponding preferred examples of copolymers (A) are poly(ethyl acrylate-co-methyl methacrylate-co-2-(trimethylammonio)ethyl methacrylate chloride) 1:2:0.2, in particular Eudragit RL 30 D, or poly(ethyl acrylate-co-methyl methacrylate-co-2-(trimethylammonio)ethyl methacrylate chloride) 1:2:0.1, in particular Eudragit RS 30 D.

[0016] It is generally preferred that the copolymer (A) in the first coating does not contain methyl acrylate repeat units.Accordingly, the copolymer (A) in the first coating preferably contains not more than 3 mol% of methyl acrylate repeat units, more preferably not more than 1 mol%, even more preferably not more than 0.5 mol%, even more preferably not more than 0.1 mol%, even more preferably not more than 0.01 mol%, and most preferably 0 mol% of methyl acrylate repeat units.

[0017] The copolymer (A) in the first coating is preferably obtained from an aqueous dispersion of the copolymer (A). The first coating may further comprise, in addition to the copolymer (A), one or more polymers selected from ethyl cellulose, hydroxypropyl methylcellulose (HPMC), and polyvinyl acetate. Furthermore, the present invention in a further embodiment also relates to a solid oral pharmaceutical composition as described and defined herein, wherein the first coating comprises, instead of the copolymer (A), one or more polymers selected from ethyl cellulose, hydroxypropyl methylcellulose (HPMC), and polyvinyl acetate.

[0018] Copolymer (B) The copolymer (B), when present in the first coating, comprises (a) 25-75 mol % of methacrylic acid repeat units and (b) 25-75 mol % of ethyl acrylate repeat units, preferably 45-55 mol % of methacrylic acid repeat units and 45-55 mol % of ethyl acrylate repeat units. The copolymer (B) is preferably an anionic copolymer. For example, the copolymer (B) in the first coating may comprise methacrylic acid repeat units and ethyl acrylate repeat units in a molar ratio of 0.5:1 to 1:0.5, preferably in a molar ratio of 0.8:1 to 1:08, more preferably in a molar ratio of 1:1. Preferably at least 90 mol %, more preferably at least 95 mol %, even more preferably at least 98 mol % of the repeat units in the copolymer (B) are selected from methacrylic acid repeat units and ethyl acrylate repeat units. It is further preferred that the copolymer (B) in the first coating consists of methacrylic acid repeat units and ethyl acrylate repeat units. Corresponding preferred examples of copolymers (B) are poly(methacrylic acid-co-ethyl acrylate) 1:1, in particular Eudragit L 30 D-55 or Eudragit L 100 D-55.

[0019] It is generally preferred that copolymer (B), when present in the first coating, does not contain methyl acrylate repeat units. Thus, copolymer (B) in the first coating preferably contains no more than 3 mol% of methyl acrylate repeat units, more preferably no more than 1 mol%, even more preferably no more than 0.5 mol%, even more preferably no more than 0.1 mol%, even more preferably no more than 0.01 mol%, and most preferably 0 mol% of methyl acrylate repeat units. The copolymer (B) in the first coating is preferably obtained from an aqueous dispersion of copolymer (B).

[0020] Copolymer (C) The copolymer (C), when present in the first coating, comprises (a) 25-60 mol % of methacrylic acid repeat units and (b) 40-75 mol % of methyl methacrylate repeat units. The copolymer (C) is preferably an anionic copolymer. Preferably at least 90 mol %, more preferably at least 95 mol %, even more preferably at least 98 mol % of the repeat units in the copolymer (C) are selected from methacrylic acid repeat units and methyl methacrylate repeat units. In particular, the copolymer (C) in the first coating may consist of methacrylic acid repeat units and methyl methacrylate repeat units. The copolymer (C) in the first coating is preferably a copolymer (C-1) or a copolymer (C-2) as described below. Thus, the first coating may comprise a copolymer (C-1), a copolymer (C-2), or a combination of both the copolymer (C-1) and the copolymer (C-2).

[0021] The copolymer (C-1) in the first coating comprises 25-60 mol% methacrylic acid repeat units and 40-75 mol% methyl methacrylate repeat units, preferably 45-55 mol% methacrylic acid repeat units and 45-55 mol% methyl methacrylate repeat units. Preferably at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeat units in the copolymer (C-1) are selected from methacrylic acid repeat units and methyl methacrylate repeat units. For example, the copolymer (C-1) in the first coating may comprise methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 0.5:1 to 1.5:1, preferably in a molar ratio of 0.8:1 to 1:08, more preferably in a molar ratio of 1:1. In particular, the copolymer (C-1) in the first coating may consist of methacrylic acid repeat units and methyl methacrylate repeat units. Corresponding preferred examples of copolymers (C-1) are poly(methacrylic acid-co-methyl methacrylate) 1:1, in particular Eudragit L 100 or Eudragit L 12.5.

[0022] The copolymer (C-2) in the first coating comprises 25-60 mol% methacrylic acid repeat units and 40-75 mol% methyl methacrylate repeat units, preferably 25-40 mol% methacrylic acid repeat units and 60-75 mol% methyl methacrylate repeat units. Thus, it is preferred that the copolymer (C-2) in the first coating comprises methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 1:1.5 to 1:2.5, more preferably in a molar ratio of 1:2. Preferably at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeat units in the copolymer (C-2) are selected from methacrylic acid repeat units and methyl methacrylate repeat units. In particular, the copolymer (C-2) in the first coating may consist of methacrylic acid repeat units and methyl methacrylate repeat units. A corresponding preferred example of copolymer (C-2) is poly(methacrylic acid-co-methyl methacrylate) 1:2, especially Eudragit S 100.

[0023] It is generally preferred that copolymer (C), including copolymer (C-1) and / or copolymer (C-2), when present in the first coating, does not contain methyl acrylate repeat units. Thus, copolymer (C) (or copolymer (C-1) and / or copolymer (C-2)) in the first coating preferably contains 3 mol % or less of methyl acrylate repeat units, more preferably 1 mol % or less, even more preferably 0.5 mol % or less, even more preferably 0.1 mol % or less, even more preferably 0.01 mol % or less, and most preferably 0 mol % of methyl acrylate repeat units.

[0024] The copolymer (C) in the first coating, comprising copolymer (C-1) and / or copolymer (C-2), is preferably obtained from an aqueous dispersion of the respective copolymer (i.e. copolymer (C), copolymer (C-1) or copolymer (C-2)).

[0025] Copolymer (D) Copolymer (D), when present in the first coating, comprises (a) 5-20 mol % methacrylic acid repeat units, (b) 20-40 mol % methyl methacrylate repeat units, and (c) 60-75 mol % methyl acrylate repeat units. Preferably at least 90 mol %, more preferably at least 95 mol %, even more preferably at least 98 mol % of the repeat units in copolymer (D) are selected from methacrylic acid repeat units, methyl methacrylate repeat units, and methyl acrylate repeat units.

[0026] Copolymer (D), when present in the first coating, preferably comprises 7-13 mol % methacrylic acid repeat units, 25-31 mol % methyl methacrylate repeat units, and 62-68 mol % methyl acrylate repeat units. Copolymer (D) in the first coating preferably comprises methacrylic acid repeat units, methyl methacrylate repeat units, and methyl acrylate repeat units in a molar ratio of 1:3:7. Copolymer (D), when present in the first coating, further preferably consists of methacrylic acid repeat units, methyl methacrylate repeat units, and methyl acrylate repeat units.

[0027] A corresponding preferred example of copolymer (D) is a copolymer comprising (or, more preferably, consisting of) methacrylic acid repeat units, methyl methacrylate repeat units and methyl acrylate repeat units in a molar ratio of 1:3:7, such as Eudragit FS30D.

[0028] Content of each copolymer in the first coating The content of copolymer (A) in the first coating is preferably at least 25% (w / w), more preferably at least 50% (w / w), even more preferably at least 75% (w / w), even more preferably at least 80% (w / w), even more preferably at least 90% (w / w), relative to the total weight of the first coating.

[0029] As explained above, the first coating comprises copolymer (A) in combination with copolymer (B) and / or copolymer (C) and / or copolymer (D). It is preferred that the first coating comprises copolymer (A) in combination with copolymer (B) and / or copolymer (D). It is more preferred that the first coating comprises copolymer (A) and copolymer (B). In this case, the content of copolymer (A) in the first coating is preferably at least 25% (w / w), more preferably at least 50% (w / w), even more preferably at least 75% (w / w), even more preferably at least 80% (w / w), even more preferably at least 90% (w / w) with respect to the total weight of copolymer (A) and copolymer (B) in the first coating.

[0030] Alternatively, the first coating may also comprise copolymer (A) and copolymer (C). As explained above, copolymer (C) is preferably copolymer (C-1) or copolymer (C-2). Thus, the first coating may comprise copolymer (A) and copolymer (C-1), or the first coating may comprise copolymer (A) and copolymer (C-2), or the first coating may comprise copolymer (A), copolymer (C-1) and copolymer (C-2).

[0031] When the first coating comprises copolymer (A) in combination with copolymer (B), the weight ratio of copolymer (A) to copolymer (B) is preferably within the range of 9:1 to 1:9 (e.g., 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, or 1:9). The weight ratio of copolymer (A) to copolymer (B) is more preferably within the range of 9:1 to 7:3 (e.g., 9:1, 8:2, or 7:3), and even more preferably 8:2.

[0032] Similarly, when the first coating comprises copolymer (A) in combination with copolymer (D), the weight ratio of copolymer (A) to copolymer (D) is preferably within the range of 9:1 to 1:9 (e.g., 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, or 1:9). The weight ratio of copolymer (A) to copolymer (D) is more preferably within the range of 9:1 to 7:3 (e.g., 9:1, 8:2, or 7:3), and even more preferably 8:2.

[0033] It should be understood that the first coating may further comprise one or more other polymers, in particular one or more polymers selected from ethyl cellulose, hydroxypropyl methylcellulose (HPMC), and polyvinyl acetate.

[0034] The first coating may, for example, account for at least 2% w / w, preferably 2-25% w / w, more preferably 3-20% w / w, even more preferably 3-15% w / w, relative to the total weight of the solid oral pharmaceutical composition.

[0035] The first coating may further include one or more plasticizers. The one or more plasticizers are preferably selected from mono-, di-, and tri-alkyl citrates, such as triethyl citrate, tripropyl citrate, tributyl citrate, or acetyltriethyl citrate; dialkyl sebacates, such as diethyl sebacate, dipropyl sebacate, or dibutyl sebacate; dialkyl phthalates, such as dimethyl phthalate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate, or dioctyl phthalate; glycerol and mono-, di-, and tri-glycerides, such as glyceryl triacetate, glyceryl tributyrate, glyceryl monostearate, or acetylated monoglycerides; propylene glycol and polyethylene glycols, such as PEG300, PEG400, PEG600, PEG800, PEG1450, or PEG3350; fatty acids, such as stearic acid, oleic acid, or esters of fatty acids. More preferably, the one or more plasticizers are selected from mono-, di-, and tri-alkyl citrates, such as triethyl citrate, tripropyl citrate, tributyl citrate, or acetyltriethyl citrate. Even more preferably, the first coating further comprises 10-80% by weight, preferably 40-80% by weight, of one or more selected from triethyl citrate, tripropyl citrate, and tributyl citrate, based on the total weight of the first coating. An example of a preferred plasticizer is PlasACRYL, such as PlasACRYL™ HTP20 and PlasACRYL™ T20.

[0036] The first coating is preferably obtained from an aqueous dispersion of copolymer (A) and copolymer (B) and / or copolymer (C) and / or copolymer (D), optionally further containing any of the optional components of the first coating.

[0037] It will be understood that the first coating is on the outside of the core contained in the solid oral pharmaceutical composition.The first coating preferably surrounds (or completely covers) and contains the core.The pharmaceutical composition may also contain one or more intermediate coatings between the core and the first coating, as described herein below, but it is preferred that there is no such intermediate layer, i.e., the first coating is preferably immediately outside (or directly contacts) the core.

[0038] Optional Second Coating The solid oral pharmaceutical composition according to the present invention may comprise further coatings (in addition to the first coating described above). In particular, the solid oral pharmaceutical composition preferably comprises a second coating outside the first coating, the second coating comprising a copolymer (C). The second coating preferably surrounds (or completely covers) and contains the first coating. Furthermore, the second coating preferably dissolves at a pH in the range of 5 to 7, preferably at a pH in the range of 5.5 to 6.5, more preferably at a pH in the range of 5.5 to 6.0.

[0039] The copolymer (C) in the second coating comprises 25-60 mol % of methacrylic acid repeat units and 40-75 mol % of methyl methacrylate repeat units. The copolymer (C) is preferably an anionic copolymer. Preferably at least 90 mol %, more preferably at least 95 mol %, even more preferably at least 98 mol % of the repeat units in the copolymer (C) are selected from methacrylic acid repeat units and methyl methacrylate repeat units. In particular, the copolymer (C) in the second coating may consist of methacrylic acid repeat units and methyl methacrylate repeat units. The copolymer (C) in the second coating is preferably a copolymer (C-1) or a copolymer (C-2) as described below. Thus, the second coating may comprise a copolymer (C-1), a copolymer (C-2), or a combination of both copolymers (C-1) and (C-2).

[0040] The copolymer (C-1) in the second coating comprises 25-60 mol% methacrylic acid repeat units and 40-75 mol% methyl methacrylate repeat units, preferably 45-55 mol% methacrylic acid repeat units and 45-55 mol% methyl methacrylate repeat units. Preferably at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeat units in the copolymer (C-1) are selected from methacrylic acid repeat units and methyl methacrylate repeat units. For example, the copolymer (C-1) in the second coating may comprise methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 0.5:1 to 1.5:1, preferably in a molar ratio of 0.8:1 to 1:08, more preferably in a molar ratio of 1:1. In particular, the copolymer (C-1) in the second coating may consist of methacrylic acid repeat units and methyl methacrylate repeat units. Corresponding preferred examples of copolymers (C-1) are poly(methacrylic acid-co-methyl methacrylate) 1:1, in particular Eudragit L 100 or Eudragit L 12.5.

[0041] The copolymer (C-2) in the second coating comprises 25-60 mol% methacrylic acid repeat units and 40-75 mol% methyl methacrylate repeat units, preferably 25-40 mol% methacrylic acid repeat units and 60-75 mol% methyl methacrylate repeat units. Thus, it is preferred that the copolymer (C-2) in the second coating comprises methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 1:1.5 to 1:2.5, more preferably in a molar ratio of 1:2. Preferably at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeat units in the copolymer (C-2) are selected from methacrylic acid repeat units and methyl methacrylate repeat units. In particular, the copolymer (C-2) in the second coating may consist of methacrylic acid repeat units and methyl methacrylate repeat units. A corresponding preferred example of copolymer (C-2) is poly(methacrylic acid-co-methyl methacrylate) 1:2, especially Eudragit S 100.

[0042] It is generally preferred that the copolymer (C) in the second coating, including the copolymer (C-1) and / or the copolymer (C-2), does not contain methyl acrylate repeat units. Thus, the copolymer (C) in the second coating (or the copolymer (C-1) and / or the copolymer (C-2)) preferably contains 3 mol % or less of methyl acrylate repeat units, more preferably 1 mol % or less, even more preferably 0.5 mol % or less, even more preferably 0.1 mol % or less, even more preferably 0.01 mol % or less, and most preferably 0 mol % of methyl acrylate repeat units.

[0043] The copolymer (C) in the second coating, comprising copolymer (C-1) and / or copolymer (C-2), is preferably obtained from an aqueous dispersion of the respective copolymer (i.e. copolymer (C), copolymer (C-1) or copolymer (C-2)).

[0044] The second coating may further include one or more plasticizers. The one or more plasticizers are preferably selected from mono-, di- and tri-alkyl citrates, such as triethyl citrate, tripropyl citrate, tributyl citrate, or acetyltriethyl citrate; dialkyl sebacates, such as diethyl sebacate, dipropyl sebacate, or dibutyl sebacate; dialkyl phthalates, such as dimethyl phthalate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate, or dioctyl phthalate; glycerol and mono-, di- and tri-glycerides, such as glyceryl triacetate, glyceryl tributyrate, glyceryl monostearate, or acetylated monoglycerides; propylene glycol and polyethylene glycols, such as PEG300, PEG400, PEG600, PEG800, PEG1450, or PEG3350; fatty acids, such as stearic acid, oleic acid, or esters of fatty acids. More preferably, the one or more plasticizers are selected from mono-, di- and tri-alkyl citrates, such as triethyl citrate, tripropyl citrate, tributyl citrate, or acetyltriethyl citrate. Even more preferably, the second coating further comprises 10-80% by weight, preferably 40-80% by weight, of one or more selected from triethyl citrate, tripropyl citrate and tributyl citrate, based on the total weight of the second coating. An example of a preferred plasticizer is PlasACRYL, such as PlasACRYL™ HTP20 and PlasACRYL™ T20.

[0045] The second coating may, for example, comprise at least 0.1% w / w, preferably 0.5-8% w / w, more preferably 1-5% w / w, relative to the total weight of the solid oral pharmaceutical composition.

[0046] Optional intermediate coating The solid oral pharmaceutical composition may further comprise one or more intermediate coatings located between the core and the first coating. The intermediate coating, or the innermost intermediate coating (in the case of more than one intermediate coating), may be a substantially continuous layer surrounding and containing the core of the solid oral pharmaceutical composition. Each intermediate coating (if present) preferably constitutes 5% w / w or less of the solid oral pharmaceutical composition, more preferably 2% w / w or less, even more preferably 1% w / w or less. Furthermore, each intermediate coating (if present) preferably constitutes 0.1% w / w or more, more preferably 0.5% w / w or more of the solid oral pharmaceutical composition. The present invention relates to all combinations of the aforementioned minimum and maximum contents by weight of intermediate coatings.

[0047] Each intermediate coating preferably comprises one or more polymers selected from ethyl cellulose, hydroxypropyl methylcellulose (HPMC), and polyvinyl acetate. More preferably, there is only one intermediate coating, said intermediate coating comprising hydroxypropyl methylcellulose (HPMC). Even more preferably, there is only one intermediate coating, said intermediate coating consisting of hydroxypropyl methylcellulose (HPMC).

[0048] Optional third coating The solid oral pharmaceutical composition may further comprise a third coating surrounding and containing the second coating (if present) or the first coating (if the second coating is not present).

[0049] The third coating, if present, preferably comprises at least 0.1% w / w, more preferably 0.5-8% w / w, even more preferably 1-5% w / w of the total weight of the solid oral pharmaceutical composition.

[0050] The composition of the third coating is not particularly limited.Preferably, the third coating contains one or more copolymers selected from copolymers (A), (B), (C) and (D) as defined herein.More preferably, it comprises a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, preferably in a molar ratio of 2:1:1, such as Eudragit E 100 or other Eudragit E polymers.

[0051] Alternatively, the third coating can be a topcoat. The topcoat can be a film coating or an immediate release coating. Examples of suitable topcoats include Opadry® White (available from Colorcon, Pa., USA), Opadry® II Yellow (available from Colorcon, Pa., USA), or copolymers based on methacrylic acid and ethyl acrylate, such as copolymers that contain at least 40% methacrylic acid repeat units and at least 40% ethyl acrylate repeat units. For example, the third coating can include poly(methacrylic acid-co-ethyl acrylate) 1:1.

[0052] Peptide or protein drugs The solid oral pharmaceutical composition of the present invention comprises a core containing a peptide or protein drug. The peptide or protein drug is preferably present only in the core, i.e., it is preferably not present in any coating contained in the solid oral pharmaceutical composition.

[0053] A peptide or protein drug preferably has a molecular weight of about 300 kDa or less (e.g., about 260 kDa or less, or about 220 kDa or less, or about 180 kDa or less, or about 150 kDa or less, or about 120 kDa or less, or about 100 kDa or less, or about 90 kDa or less, or about 80 kDa or less, or about 70 kDa or less, or about 60 kDa or less, or about 50 kDa or less, or about 40 kDa or less, or about 30 kDa or less, or about 20 kDa or less, or about 10 kDa or less, or about 5 kDa or less, or about 2 kDa or less, or about 1 kDa or less, or about 500 Da or less). More preferably, the peptide or protein drug has a maximum molecular weight of about 200 kDa or less, even more preferably about 150 kDa or less, even more preferably about 100 kDa or less, even more preferably about 50 kDa or less, even more preferably about 40 kDa or less, even more preferably about 30 kDa or less, even more preferably about 20 kDa or less, even more preferably about 10 kDa or less. It is further preferred that the peptide or protein drug has a minimum molecular weight of about 300 Da or more, more preferably about 500 Da or more, even more preferably about 800 Da or more, even more preferably about 1 kDa or more. Thus, it is particularly preferred that the peptide or protein drug has a molecular weight of about 300 Da to about 150 kDa, more preferably about 300 Da to about 50 kDa, even more preferably about 500 Da to about 30 kDa, even more preferably about 500 Da to about 20 kDa, even more preferably about 800 Da to about 10 kDa, and even more preferably about 1 kDa to about 6 kDa.

[0054] The molecular weight of peptide or protein drugs is herein indicated in Daltons (Da), which is an alternative name for the unified atomic mass unit (u). Thus, for example, a molecular weight of 500 Da is equivalent to 500 g / mol. The term "kDa" (kilodalton) refers to 1000 Da.

[0055] The molecular weight of a peptide or protein drug can be determined using methods known in the art, such as mass spectrometry (e.g., electrospray ionization mass spectrometry (ESI-MS) or matrix-assisted laser desorption / ionization mass spectrometry (MALDI-MS)), gel electrophoresis (e.g., polyacrylamide gel electrophoresis using sodium dodecyl sulfate (SDS-PAGE)), hydrodynamic methods (e.g., gel filtration chromatography or gradient sedimentation), or static light scattering (e.g., multi-angle light scattering (MALS)). The molecular weight of a peptide or protein drug is preferably determined using mass spectrometry.

[0056] The peptide or protein drug can be any peptide or protein suitable for use as a pharmaceutical. For example, the peptide or protein drug can be a linear peptide or protein drug or a cyclic peptide or protein drug (e.g., a cyclic peptide or protein drug cyclized through at least one ester bond and / or at least one amide bond; such as cyclotides; cyclotides are disulfide-rich peptides characterized by their head-to-tail cyclized peptide backbone and the interlocking arrangement of their disulfide bonds). It can also be a modified or derivatized peptide or protein drug, such as a PEGylated peptide or protein drug or a fatty acid acylated peptide or protein drug or a fatty diacid acylated peptide or protein drug. In addition, the peptide or protein drug can be free of histidine residues and / or free of cysteine ​​residues. It is generally preferred that the peptide or protein drug is water-soluble, especially at neutral pH (i.e., about pH 7). The present invention also enables the use of peptide or protein drugs that have at least one serine protease cleavage site, i.e., that contain one or more amino acid residues suitable or susceptible to cleavage by a serine protease. The term "peptide or protein drug" is used herein interchangeably with "therapeutic peptide or protein" and "therapeutic peptide or protein drug."

[0057] The peptide or protein drug is preferably insulin (preferably human insulin), an insulin analog (e.g., a long-acting basal insulin analog or a protease stabilized long-acting basal insulin analog; exemplary insulin analogs include, but are not limited to, insulin lispro, insulin PEG lispro, insulin derivative "A14E, B25H, B29K (N(eps)octadecandioyl-gGlu-OEG-OEG), desB30 human insulin" (see, e.g., US 2014 / 0056953 A1), insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, and reference insulin. Insulin analogues / derivatives described in US2014 / 0056953A1, which is incorporated herein by reference, in particular each of the insulin analogues / derivatives described in paragraphs

[0225] to

[0332] of US2014 / 0056953A1), GLP-2, GLP-2 agonists or analogues (e.g., apraglutide, teduglutide or elsiglutide), glucose-dependent insulinotropic polypeptide (also referred to as "gastric inhibitory polypeptide" or GIP), gastric inhibitory polypeptide (GIP) receptor agonists, elamipretide, cyclotides (i.e., peptides characterized by their head-to-tail cyclized peptide backbone and the interlocking arrangement of their disulfide bonds;For example, cyclotides having at least two disulfide bonds, preferably cyclotides having three disulfide bonds), recombinant factor VIIa (rFVIIa), eptacog alfa, amylin, amylin analogs, pramlintide, somatostatin analogs (e.g., octreotide, lanreotide, or pasireotide), goserelin (e.g., goserelin acetate), buserelin (e.g., buserelin acetate), leptin, leptin analogs (e.g., metreleptin), peptide YY (PYY), PYY analogs, glatiramer (e.g., glatiramer acetate), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate trihydrate), desmopressin analogs, vasopressin receptor 2 (V2 receptor) agonists topeptides, osteocalcin, osteocalcin analogs or derivatives, human growth hormone (hGH), human growth hormone analogs, long-acting human growth hormone (e.g., somapsitan or hGH-CTP (such as human growth hormone derivatized with the C-terminal peptide (CTP) of the beta chain of human chorionic gonadotropin (hCG)), fibroblast growth factor 21 (FGF21), antibodies (e.g., any of the exemplary antibodies described herein below), glycopeptide antibiotics (e.g., glycosylated cyclic or polycyclic non-ribosomal peptides, e.g., vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, or decaplanin), cyclotide, bortezomib, cosyntropin, chorionic gonadotropin, menotropins, sermorelin, luteinizing hormone releasing hormone (LHRH;also referred to as "gonadotropin releasing hormone"), somatropin, calcitonin (e.g., calcitonin-salmon), pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alfa-2a, interferon alfa-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alfa-2a (i.e. pegylated interferon alfa-2a), pegylated interferon alfa-2b (i.e. pegylated interferon alfa-2b), pegylated interferon beta-1a (i.e. pegylated interferon beta-1a), fibrinolysin, vasopressin, aldesleukin, epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxypolyethylene glycol-epoetin beta, and sustained-release erythropoietin receptor activator (CERA;PEGylated EPO derivatives), pegylated epo, albupoetin, epo-dimer analogs, epo-Fc, carbamylated EPO (CEPO), synthetic erythropoietin protein (SEP), low molecular weight epo analogs (PBI-1402), filgrastim, PEG-filgrastim, interleukin-11, interleukin-23 receptor antagonist peptide, cyclosporine, glucagon, urokinase, viomycin, thyrotropin releasing hormone (TRH), leucine-enkephalin, methionine-enkephalin, substance P (CAS number 33507-63-0), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), parathyroid hormone (PTH) fragments (e.g. For example, the peptide or protein drug is selected from teriparatide (also referred to as "PTH(1-34)"), PTH(1-31), PTH(2-34)) or eneboparatide, parathyroid hormone-related protein (PTHrP), abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, prostaglandin F2α receptor modulators (e.g., PDC31), abciximab (C7E3-Fab), ranibizumab, alefacept, romiplostim, anakinra, abatacept, belatacept, and pharmaceutically acceptable salts thereof. When the subject / patient to be treated is a human and the peptide or protein drug is a human endogenous peptide or protein (i.e., naturally occurring in humans; such as insulin or glucagon), it is further preferred to use a human isoform of the corresponding peptide or protein (e.g., which may be recombinantly expressed or chemically synthesized);

[0058] More preferably, the peptide or protein drug is a GLP-2, a GLP-2 agonist or analogue (e.g., apraglutide, teduglutide or ersiglutide), insulin (particularly human insulin), an insulin analogue (e.g., a long-acting basal insulin analogue or a protease stabilized long-acting basal insulin analogue;Exemplary insulin analogs include, but are not limited to, insulin lispro, insulin PEG lispro, insulin derivative "A14E, B25H, B29K (N(eps)octadecandioyl-gGlu-OEG-OEG), desB30 human insulin" (see, e.g., US 2014 / 0056953 A1), insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, and US 2014 / 0056 953A1, in particular each of the insulin analogues / derivatives described in paragraphs

[0225] to

[0332] of US2014 / 0056953A1), antibodies, recombinant factor VIIa (rFVIIa), eptacog alfa, amylin, amylin analogues, pramlintide, somatostatin analogues (e.g., octreotide, lanreotide, or pasireotide), goserelin (e.g., goserelin acetate), buserelin, peptide YY (PYY), PYY analogues, glatiramer (e.g., glatiramer tiramer acetate), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, especially desmopressin monoacetate trihydrate), desmopressin analogs, vasopressin receptor 2 (V2 receptor) agonist peptides, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, bortezomib, cosyntropin, sermorelin, luteinizing hormone releasing hormone (LHRH), calcitonin (e.g., calcitonin-salmon), pentagastrin, neseritide, enfuvirtide, estrogen, erythropoietin ... selected from petifibatide, cyclosporine, glucagon, viomycin, thyrotropin releasing hormone (TRH), leucine-enkephalin, methionine-enkephalin, substance P, parathyroid hormone (PTH) fragments (e.g., teriparatide (PTH(1-34)), PTH(1-31), PTH(2-34)) or eneboparatide, carfilzomib, icatibant, cilengitide, prostaglandin F2α receptor modulators (e.g., PDC31), and pharmaceutically acceptable salts thereof;

[0059] Even more preferably, the peptide or protein drug is a GLP-2, GLP-2 agonist or analogue (e.g., apraglutide, teduglutide or elsiglutide), insulin (e.g., human insulin), insulin analogues (e.g., insulin lispro, insulin PEG lispro, "A14E, B25H, B29K (N(eps)octadecandioyl-gGlu-OEG-OEG), desB30 human insulin", insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, or insulin. sulindegludec), antibodies, somatostatin analogues (e.g., octreotide, lanreotide, or pasireotide), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate trihydrate), desmopressin analogues, vasopressin receptor 2 (V2 receptor) agonist peptides, parathyroid hormone (PTH) fragments (e.g., teriparatide (PTH(1-34)), PTH(1-31), PTH(2-34)) or eneboparatide, and pharmaceutically acceptable salts thereof.

[0060] Even more preferably, the peptide or protein drug is GLP-2, a GLP-2 agonist or analogue (e.g., apraglutide, teduglutide or elsiglutide), insulin (e.g., human insulin), an insulin analogue (e.g., insulin lispro, insulin PEG lispro, "A14E, B25H, B29K (N(eps)octadecandioyl-gGlu-OEG-OEG), desB30 human insulin", insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NP H insulin, or insulin degludec), antibodies, somatostatin analogues (e.g., octreotide, lanreotide, or pasireotide), desmopressin (e.g., desmopressin acetate, particularly desmopressin monoacetate trihydrate), desmopressin analogues, vasopressin receptor 2 (V2 receptor) agonist peptides, parathyroid hormone (PTH) fragments (e.g., teriparatide (PTH(1-34)), PTH(1-31), PTH(2-34)) or eneboparatide, and pharmaceutically acceptable salts thereof.

[0061] Even more preferably, the peptide or protein drug is selected from GLP-2, GLP-2 agonists or analogues (e.g. apraglutide, teduglutide or elsiglutide), insulin (e.g. human insulin), insulin analogues (e.g. insulin lispro, insulin PEG lispro, "A14E, B25H, B29K (N(eps)octadecandioyl-gGlu-OEG-OEG), desB30 human insulin", insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, or insulin degludec), and antibodies (especially therapeutic antibodies for the treatment or prevention of local intestinal diseases / disorders such as intestinal inflammatory disorders; e.g. ustekinumab or adalimumab).

[0062] As mentioned above, the peptide or protein drug may also be an insulin analogue. Preferred examples of insulin analogues include, inter alia: B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin; B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)desB30 human insulin; B29K(N(ε)octadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin; B29K(N(ε)eicosanedioyl-γ-L-Glu)A14E B25H desB30 human insulin; B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin; B29K(N(ε)eicosanedioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin; B29K(N(ε)eicosanedioyl-γ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin; B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B16H B25H desB30 human insulin; B29K(N(ε)-eicosanedioyl-γ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin; or B29K(N(ε)octadecandioyl)A14E B25H desB30 human insulin.

[0063] These insulin analogues are described and characterized, for example, in US 2014 / 0056953 A1. It is particularly preferred that the insulin analogue is B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin.

[0064] As mentioned above, peptide or protein drug can be an antibody, preferably a monoclonal antibody, and in particular can be a single chain antibody or a single domain antibody (e.g., "nanobody").An example of a nanobody that can be used as a peptide or protein drug according to the present invention is caplacizumab.Caplacizumab is a single domain antibody that can be used, for example, to treat or prevent thrombotic thrombocytopenic purpura (TPP) or thrombosis.

[0065] In particular, peptide or protein drugs include 3F8, 8H9, abagovomab, abciximab, avituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, atidortoxumab, aducanumab, afacevicumab, afelimomab, afutuzumab, alacizumab pegol, alemtuzumab, alirocumab, altumomab pentetate, amatuximab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, aprilumab ixadotin, Arcitumomab, Asclinbacumab, Acelizumab, Atezolizumab, Atinumab, Atorolimumab, Avelumab, Azintuxizumab vedotin, Bapineuzumab, Basiliximab, Bavituximab, BCD-100, Bectumomab, Begelomab, Belantamab mafodotin, Belimumab, Bemarituzumab, Benralizumab, Berlimatoxumab, Belsanlimab, Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab, Bimagrumab, Bimekizumab, Virutamimab, Bivatuzumab mertansine, BIVV009, Breselma , blinatumomab, brontuzumab, brosozumab, bococizumab, brazikumab, brentuximab vedotin, briakinumab, brodalumab, brolucizumab, brontixumab, burosumab, cabilalizumab, camidanlumab tesirin, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab vedotin, caplacizumab, capromab pendetide, carlumab, carotuximab, catumaxomab, cbr96-doxorubicin immunoconjugate, cedelizumab, cemiplimab, sergituzumab amnaleukin, certolizumab Bupegol, cetrelimab, cetuximab, civisatamab, sitatuzumab bogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab, cofetuzumab peridotin, cortuximab lavtansine, conatumumab, concizumab, cosfrobiximab, crenezumab, crizanlizumab, clotidumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, dalotuzumab, dapirorizumab pegol, daratumumab, dectrecumab, demcizumab, denintuzumab mafodotin, denosumab,Depatuxizumab mafodotin, dellotuximab biotin, detumomab, desamizumab, dinutuximab, ziridabumab, domagurozumab, dorlimomab aritox, drozitumab, DS-8201, durigotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecromeximab, eculizumab, edovacomab, edrecolomab, efalizumab, efangumab, eldelumab, elezanumab, elgemtuzumab, elotuzumab, ersilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab, enapo Tamab-edotine, Enavatuzumab, Enfortumab vedotin, Enlimomab pegol, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab, Epitumomab-situxetan, Epratuzumab, Eptinezumab, Erenumab, Erlizumab, Ertumaxomab, Etaracizumab, Etigilimab, Etrolizumab, Evinacumab, Evolocumab, Exbivirumab, Fanolesomab, Faralimomab, Faricimab, Farletuzumab, Fasinumab, FBTA05, Felvizumab, Fezakinumab, Fivatuzumab, Ficlatuzumab, Figit tuzumab, filibumab, framvotumab, fretikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, furunevetomab, furanumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gedivumab, gemtuzumab ozogamicin, gevokizumab, gilvetomab, gimsilumab, girentuximab, glembatumumab vedotin, golimumab, gomilikimab, goslanemab, guselkumab, ianalumab, ibalizumab Mab, IBI308, Ibritumomab tiuxetan, Icrucumab, Idarucizumab, Ifavotuzumab, Igovomab, Iradatuzumab vedotin, IMAB362, Imalumab, Imaprelimab, Imusiromab, Imgatuzumab, Incracumab, Indatuximab vedotin, Inebilizumab, Infliximab, Intetumumab, Inolimomab, Inotuzumab ozogamicin, Ipilimumab, Iomab-b, Iratumumab, Isatuximab, Iscalimab, Istiratumab, Itolizumab, Ixekizumab, Keliximab,Labetuzumab, Lacnotuzumab, Ladiratuzumab vedotin, Lampalizumab, Lanadelumab, Landgrozumab, Laprituximab emtansine, Ralcaviximab, Lebrikizumab, Remaresomab, Lendarizumab, Lenbervimab, Lenzilumab, Lerdelimumab, Leronlimab, Lesofabumab, Letolizumab, Lexatumumab, Ribivirumab, Rifatuzumab vedotin, Ligelizumab, Loncastuximab tesirine, Rosatuximab vedotin, Rilotomab satexetane, Lintuzumab, Lirilumab, Rodericizumab, Loxostat, Lorvotuzumab mertansine, lucatumumab, lurizumab pegol, rumiliximab, lumuletuzumab, rupartumab amadotin, rutikizumab, MABp1, mapatumumab, margetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimuab, milatuzumab, minletumomab, mirikizumab, mirvetuximab soravtansine, mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab, moxetumomab pasudotox, muromonab-CD3, nacolomab Tafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine, narutuximab, natalizumab, navicixizumab, nabivumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesbacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentane, obiltoxaximab, obinutuzumab, occaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumumab, oleculab, orendalizumab, olokizumab, omalizumab , OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oportuzumab monatox, oregovomab, olticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab, panitumumab, pancomab, panobacumab, palsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab, perakizumab, pertuzumab, pexelizumab, pidilizumab,Pinatuzumab vedotin, pintumomab, placumab, prosalizumab, pogalizumab, polatuzumab vedotin, ponezumab, polgabiximab, prasinezumab, prezarizumab, priliximab, pritoxaximab, pritumumab, PRO140, quilizumab, racotumomab, radletumab, rafivirumab, ralpancizumab, ramucirumab, ranevetomab, anivizumab, raxibacumab, ravagalimab, ravatulizumab, refanezumab, regavirumab, lemtolumab, reslizumab, rilotumumab, rinukumab, risankizumab, rituximab, Mab, rivavazumab pegol, lobatumumab, rmab, loredumab, romilkimab, romosozumab, rontalizumab, rosmantuzumab, rovalpituzumab tesirin, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samaryzumab, samrotamab vedotin, sapelizumab, sarilumab, satralizumab, satumomab pendetide, secukinumab, seliclerumab, seribantumab, setoxaximab, setrusumab, sevirumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, sirtuuki Simab, simtuzumab, siplizumab, siltratumab vedotin, sirukumab, sofituzumab vedotin, solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, sputabumab, stimulimab, subizumab, sublatoxumab, tabalumab, tacatuzumab etraxetan, tadocizumab, talicozumab, talizumab, tamtubetomab, tanezumab, taplitumomab paptox, talexuzumab, taborimab, tefibazumab, terimomab alitox, terisotuzumab vedotin, tenatumomab, teneri ximab, teplizumab, tepositamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tiburizumab, tildrakizumab, tigatuzumab, timigtuzumab, timolumab, tiragotumab, tislelizumab, tisotumab vedotin, TNX-650, tocilizumab, tomzotuximab, toralizumab, tosatoxumab, tositumomab, tobetumab, tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevoglumab, tucotuzumab celmoleukin, tuvilumab,Ublituximab, urocupulumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab butarilin, banalimab, bundletuzumab vedotin, vanticutumab, vanucizumab, bapaliximab, valisacumab, varlilumab, batelizumab, vedolizumab, veltuzumab, beparimomab, besencumab, visiri The antibody may be selected from the group consisting of izumab, bovalilizumab, volociximab, bonlerolizumab, bopratelimab, borsetuzumab mafodotin, votumumab, bunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, zenoctuzumab, diralimumab, zolbetuximab, and zolimomab alitoxin.

[0066] Furthermore, it is particularly preferred that the peptide or protein drug is an anti-obesity peptide (which may also be referred to as a "peptide anti-obesity agent"). Preferred examples of anti-obesity peptides include any of the following: - Neuropeptide Y receptor (NPY) agonist peptides, such as NPY receptor Y1, Y2, Y4 or Y5 agonist peptides, or pancreatic polypeptide receptor agonist peptides, such as neuropeptide Y, peptide YY (i.e. "PYY" or peptide tyrosine tyrosine), PYY 3-36 , PYY analogs or derivatives, such as (e.g., long-acting fatty acid acylated PYY analogs), neuropeptide FF receptor type 2 (NPFF2R) agonists, G protein-coupled receptor 10 (GPR10) agonists, fatty acid acylated dual GPR10-NPFF2R co-agonists, pancreatic polypeptide, prolactin releasing peptide (PrRP), long-acting PrRP31 analogs, C18 lipidated PrRP31 analogs (which may be used, inter alia, to treat obesity or appetite regulation), GT001 (Gila Therapeutics), or PYY-1875 (Novo Nordisk); - Leptin receptor agonist peptides (LEP-R), such as leptin, leptin analogs or derivatives, such as long-acting fatty acid acylated leptin analogs; -Ghrelin receptor antagonist peptides; - amylin (i.e. islet amyloid polypeptide (IAPP)), amylin analogues or derivatives, such as long-acting fatty acid acylated amylin analogues, pramlintide, caglilintide, or ZP8396; a gastric inhibitory polypeptide (GIP) receptor agonist peptide, such as a gastric inhibitory polypeptide (GIP) analog or derivative, such as a long-acting acylated GIP analog, a GIP agonist, a dual or triple agonist GIP peptide, or ZP6590; or - Glucagon receptor agonist peptides, such as glucagon or glucagon analogues or derivatives, such as long-acting acylated glucagon analogues.

[0067] The peptide or protein drug may further be a GLP-2 receptor agonist peptide, such as GLP-2, a GLP-2 analog or derivative, such as a long-acting acylated GLP-2 analog, teduglutide, grepaglutide, apraglutide, dapiglutide, or elsiglutide, etc. Such peptide or protein drugs may be used, for example, to treat or prevent short bowel syndrome (SBS).

[0068] Peptide or protein drugs may further include, for example, folligerimod, EA-230, difelikefalin acetate, agonists of the kappa-opioid receptor (KOR), avipudotadil, zonulin antagonists, larazotide, brimapitide, small integrin binding ligand N-linked glycoprotein (SIBLING), TPX-100, ZP9830, Kv1.3 ion channel blockers, ZP10000, α4β7 integrin inhibitors, The peptide or protein drug may be a Pellino-1 protein-protein interaction inhibitor peptide, BBT-401 (which may be used, for example, for the treatment or prevention of ulcerative colitis), an alpha-4-beta-7 (α4β7) integrin antagonist, PN-943, an interleukin (IL) receptor targeting peptide, an IL-23 receptor targeting peptide, PN-235, PN-232, an IL-23 receptor antagonist, or JNJ-77242113. The aforementioned peptide or protein drug may be used, for example, for the treatment or prevention of inflammatory or autoimmune disorders, including, for example, inflammatory bowel disease (IBD). In addition, the peptide or protein drug may also be a "nanobody" or engineered antibody derived from a "heavy chain only" peptide or protein, such as an anti-IL13 / OX40L nanobody, an anti-IL-6R nanobody, bovalilizumab, a single domain antibody, or caplacizumab.

[0069] The peptide or protein drug may further be, for example, dolucatide, Foxy-5, a WNT5A mimetic peptide, a peptide that induces thrombospondin-1 (Tsp-1) expression in the tumor microenvironment, the cyclic pentapeptide VT1021, an antagonist of the chemokine receptor CXCR4, valixafortide, an anti-cytokine peptide, BNZ132-1-40 (a 19-mer pegylated peptide), FK506 binding protein-like (FKBPL) peptide, ALM-201 (a 23-mer peptide drug), fexapotide triflutate, the tripeptide tyroseruleutide, a luteinizing hormone releasing hormone (LHRH) antagonist acting on the gonadotropin releasing hormone (GnRH) receptor, ozarelix, an LHRH natural ligand derivative, EP-100, a somatostatin receptor agonist, or HTL0030310. Such peptide or protein drugs may be used inter alia in the treatment or prevention of cancer.

[0070] The peptide or protein drug may further be, for example, vosoritide (which may be used, inter alia, for the treatment or prevention of achondroplasia), relaxin receptor modulator peptide, relaxin, relaxin analogues or derivatives, long-acting acylated relaxin analogues, serelaxin, davunetide (or NAP or AL-108), zircoplan, or arilinetide (or GM604 or GM6).

[0071] In addition, the peptide or protein drug may also be a GLP-1 receptor agonist, such as semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, taspoglutide, langrenatide, veinaglutide, efpegrenatide, GLP-1(7-37), GLP-1(7-36)NH2, oxyntomodulin, oxyntomodulin derivative or analog, dual GLP-1 receptor / glucagon receptor agonist, dual GLP-1 receptor / gastric inhibitory peptide (GIP) receptor agonist, or triple GLP-1 receptor / GIP receptor / glucagon receptor agonist, etc. However, it is preferred that the peptide or protein drug is not a GLP-1 receptor agonist (or is not any of the specific GLP-1 receptor agonists mentioned above). Thus, the present invention preferably relates to a solid oral pharmaceutical composition as described and defined herein, wherein the peptide or protein drug is not a GLP-1 receptor agonist.

[0072] The peptide or protein drug used according to the present invention can also be a mixture of two or more different peptide or protein drugs, including any of the specific peptide or protein drugs mentioned above.For example, it may be preferable to use not only one of semaglutide and octreotide as peptide or protein drug, but also a mixture of these.As another example, it may be preferable to use not only one of semaglutide, octreotide and leuprolide as peptide or protein drug, but also a mixture of these.

[0073] The above exemplary peptide or protein drugs have been proposed in the literature as suitable for the treatment or prevention of a variety of different diseases / disorders, and some of these peptide or protein drugs have already received marketing authorization for certain therapeutic indications. The present invention also relates to a solid oral pharmaceutical composition provided herein, in particular for use in the treatment or prevention of a disease / disorder suitable to be treated or prevented with the respective peptide or protein drug. Similarly, the present invention relates to a method for treating or preventing a disease / disorder, comprising orally administering to a subject in need thereof a solid oral pharmaceutical composition provided herein, wherein said disease / disorder is a disease / disorder suitable to be treated or prevented with the respective peptide or protein drug. Preferred examples of diseases / disorders suitable to be treated or prevented with any particular peptide or protein drug according to the present invention can be found in the medical literature, in particular in the ROTE LISTE online version (as of the priority date or filing date hereof, in particular the version as of September 7, 2020); ROTE LISTE 2020 (printed version, Rote Liste Service GmbH, 2020, ISBN978-3-946057-52-9); GELBE LISTE online version (as of the priority date or filing date hereof, in particular the version as of September 7, 2020); GELBE LISTE 2017 (printed version, AVOXA - Mediengruppe Deutscher Apotheker GmbH, 2017, ISBN978-3774199149); Aktories K et al. (eds.), Allgemeine und spezielle Pharmakologie und Toxikologie, Urban & Fischer Verlag / Elsevier GmbH, 12th edition, 2017, ISBN978-3437425257;Ammon HPT et al. (eds.), Hunnius Pharmazeutisches Worterbuch, De Gruyter, 11th edition, 2014, ISBN978-3110309904;Otto HH et al., Arzneimittel - Ein Handbuch fur Arzte und Apotheker, Wissenschaftliche Verlagsgesellschaft, 2017, ISBN978-3804737266; ​​DrugBank (www.drugbank.ca, as of the priority or filing date hereof, in particular the version as of September 7, 2020); Drugs.com (www.drugs.com, as of the priority or filing date hereof, in particular the version as of September 7, 2020); Merck Manuals (www.merckmanuals.com, as of the priority date or filing date of this specification, particularly the version as of September 7, 2020); European Medicines Agency (EMA) database (www.ema.europa.eu, as of the priority date or filing date of this specification, particularly the version as of September 7, 2020); United States Food and Drug Administration (USFDA) database (www.fda.gov, as of the priority date or filing date of this specification, particularly the version as of September 7, 2020); Japan Pharmaceuticals and Medical Devices Agency database (www.pmda.go.jp, as of the priority date or filing date of this specification, particularly the version as of September 7, 2020); or electronic Medicines Compendium (eMC) database (www.medicines.org.uk / emc / , as of the priority date or filing date of this specification, particularly the version as of September 7, 2020). Examples of diseases / disorders suitable for treatment or prevention with an analog or derivative of any particular peptide or protein drug include the same diseases / disorders suitable for treatment or prevention with the corresponding (underivatized) peptide or protein drug. Furthermore, preferred examples of diseases / disorders suitable for treatment or prevention with any of the insulin or insulin analogs mentioned above include, inter alia, diabetes (e.g., type 1 diabetes or type 2 diabetes);Preferred examples of diseases / disorders suitable for treatment or prevention with buserelin include, in particular, hormone-responsive cancers (such as, for example, prostate cancer or breast cancer), or estrogen-dependent conditions (such as, for example, endometriosis or uterine fibroids), which may further be used, for example, in assisted reproduction; preferred examples of diseases / disorders suitable for treatment or prevention with human growth hormone (hGH) or any of the above-mentioned hGH analogues or derivatives include, in particular, growth hormone deficiency; preferred examples of diseases / disorders suitable for treatment or prevention with fibroblast growth factor 21 (FGF21) include, in particular, cardiovascular disease, obesity, or diabetes (in particular type 2 diabetes); preferred examples of diseases / disorders suitable for treatment or prevention with any of the above-mentioned epoetin or any of its analogues or derivatives include, in particular, anemia, Alzheimer's disease (see, for example, Maurice T et al., J Psychopharmacol. 2013;27(11):1044-57), Parkinson's disease (see, e.g., Alcala-Barraza SR et al., J Drug Target. 2010;18(3):179-90), or multiple sclerosis; preferred examples of diseases / disorders suitable to be treated or prevented with the above-mentioned filgrastim or any derivative thereof (e.g., PEG-filgrastim) include, in particular, low blood neutrophils due to several causes, such as, for example, chemotherapy, radiation poisoning, HIV or AIDS, or unknown causes; preferred examples of diseases / disorders suitable to be treated or prevented with the above-mentioned antibody adalimumab include, in particular, inflammatory or autoimmune diseases Preferred examples of diseases / disorders suitable for treating or preventing with the above-mentioned antibody ustekinumab include in particular inflammatory or autoimmune diseases / disorders (e.g., intestinal inflammatory or intestinal autoimmune diseases / disorders), more preferably selected from Crohn's disease, ulcerative colitis, psoriasis (e.g., chronic psoriasis), and psoriatic arthritis; preferred examples of diseases / disorders suitable for treating or preventing with the above-mentioned antibody ustekinumab include in particular inflammatory or autoimmune diseases / disorders (e.g., intestinal inflammatory or intestinal autoimmune diseases / disorders), more preferably selected from Crohn's disease, ulcerative colitis, psoriasis (e.g., chronic psoriasis), and psoriatic arthritis;

[0074] The solid oral pharmaceutical composition according to the invention may also be used to treat or prevent intestinal diseases / disorders, in particular inflammatory, infectious or cancerous intestinal diseases / disorders, such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, colonic bacterial infectious diseases, or colorectal cancer, etc. It will be understood that the peptide or protein drug contained in the core of the solid oral pharmaceutical composition should in this case be a peptide or protein drug (in particular an antibody, e.g. adalimumab) that is effective against the respective intestinal disease / disorder.

[0075] The peptide or protein drug contained in the solid oral pharmaceutical composition of the present invention may further be used in combination with one or more other therapeutic agents, in particular one or more other peptide or protein drugs (as described herein), which may be present in the solid oral pharmaceutical composition according to the present invention, preferably in the core of the solid oral pharmaceutical composition, or may be provided in a separate pharmaceutical composition. In the latter case, the separate pharmaceutical composition may be administered simultaneously / concomitantly with the solid oral pharmaceutical composition according to the present invention, or may be administered sequentially. It is preferred that any additional (other) peptide or protein drug is also provided in the core of the solid oral pharmaceutical composition according to the present invention (so that all peptide or protein drugs are present in the core).

[0076] It will be understood that peptide or protein drugs (including any of the exemplary peptide or protein drugs described herein) can exist in non-salt form or in the form of a pharmaceutically acceptable salt.The corresponding pharmaceutically acceptable salt can be formed, as is well known in the art, by protonation of an atom that has a lone pair of electrons that is susceptible to protonation, such as an amino group, or as the salt of a carboxylic acid group and a physiologically acceptable cation, for example, by inorganic or organic acid. Exemplary base addition salts include, for example, alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salt, meglumine salt, ethylenediamine salt, or choline salt; aralkylamine salts such as N,N-dibenzylethylenediamine salt, benzathine salt, benethamine salt; heterocyclic aromatic amine salts such as pyridine salt, picoline salt, quinoline salt, or isoquinoline salt; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, or tetrabutylammonium salt; and basic amino acid salts such as arginine salt, lysine salt, or histidine salt.Exemplary acid addition salts include, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate (such as, for example, phosphate, hydrogen phosphate, or dihydrogen phosphate), carbonate, bicarbonate, or perchlorate; acetate, propionate, butyrate, pentanoate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, glycolate, dihydrogen phosphate, diisopropyl ether ... Organic acid salts such as cotinate, benzoate, salicylate, ascorbate, or pamoate (embonate); sulfonate salts such as methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate (isethionate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (napsylate), 3-phenylsulfonate, or camphorsulfonate; and acidic amino acid salts such as aspartate or glutamate.

[0077] The solid oral pharmaceutical composition according to the present invention may also contain one or more amino acids, in particular arginine (preferably L-arginine) and / or lysine (preferably L-lysine). Arginine may be used, for example, in the form of free base (non-salt form) or in the form of hydrochloric acid (HCl). Lysine may also be used, for example, in the form of free base (non-salt form) or in the form of hydrochloric acid (HCl). Amino acids, in particular arginine (for example, L-arginine free base or L-arginine HCl) and / or lysine (for example, L-lysine free base or L-lysine HCl) may be provided in the core of the solid oral pharmaceutical composition (together with peptide or protein drug), which is particularly advantageous when peptide or protein drug is an antibody. Thus, where the peptide or protein drug is an antibody (e.g., any of the exemplary / specific antibodies herein above), it is preferred that the antibody is present (in the core of the solid oral pharmaceutical composition) in combination with one or more amino acids, more preferably in combination with arginine (e.g., L-arginine free base or L-arginine HCl) and / or lysine (e.g., L-lysine free base or L-lysine HCl).

[0078] The solid oral pharmaceutical composition may optionally contain one or more additional pharma- ceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants, amino acids, reducing agents, bioadhesives and / or solubility enhancers.In particular, it may contain one or more additives selected from vitamin E, histidine, microcrystalline cellulose (MCC), mannitol, starch, sorbitol and / or lactose.The solid oral pharmaceutical composition may be formulated by techniques known to those skilled in the art, such as those published in Remington's Pharmaceutical Sciences, 20th Edition.

[0079] As discussed above, the solid oral pharmaceutical composition may further comprise one or more solubility enhancers, such as poly(ethylene glycol) having a molecular weight in the range of about 200 to about 5,000 Da, ethylene glycol, propylene glycol, non-ionic surfactants, tyloxapol, polysorbate 20, polysorbate 80, macrogol-15-hydroxystearate, phospholipids, lecithin, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, di ... pyr-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl thioethers, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, vinylpyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0080] In addition, as mentioned above, the solid oral pharmaceutical composition may contain one or more pharma- ceutically acceptable carriers.The pharma-ceutically acceptable carriers may be aqueous or non-aqueous, for example, alcoholic or oily, or their mixtures, and may contain surfactants, emollients, lubricants, stabilizers, dyes, flavors, preservatives, acids or bases for adjusting pH, solvents, emulsifiers, gelling agents, moisturizers, stabilizers, wetting agents, time-release agents, water-retaining agents, or any other components that are generally included in the specific form of solid oral pharmaceutical composition.Pharmaceutically acceptable carriers are well known in the art, and include, for example, aqueous solutions such as water or physiological buffered saline, or other solvents or vehicles, for example, glycols, glycerol, and oils such as olive oil, or injectable organic esters. Pharmaceutically acceptable carriers may contain, for example, physiologically acceptable compounds that act to stabilize or increase the absorption of peptide or protein drugs, such as carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. Pharmaceutically acceptable carriers may also be selected from materials such as distilled water, benzyl alcohol, lactose, starch, talc, magnesium stearate, polyvinylpyrrolidone, alginic acid, colloidal silica, titanium dioxide, and flavoring agents. Particularly, the preferred pharmaceutically acceptable carriers for use in the core of the solid oral pharmaceutical composition of the present invention are selected from microcrystalline cellulose, mannitol, starch, sorbitol and lactose. Another preferred pharmaceutically acceptable carrier is magnesium stearate.

[0081] Core of solid oral pharmaceutical composition The core of the solid oral pharmaceutical composition of the present invention comprises a peptide or protein drug (as described above).

[0082] The core of the solid oral pharmaceutical composition preferably further comprises a permeation enhancer (also referred to as a "mucosal permeation enhancer"). The use of a permeation enhancer improves or promotes mucosal absorption / permeation of peptide or protein drugs, especially through the intestinal mucosa, and is advantageous, especially when the peptide or protein drug is a large molecule, for example, a peptide or protein drug having a molecular weight of about 1 kDa or more.

[0083] The permeation enhancer can be, for example, a zwitterionic permeation enhancer, a cationic permeation enhancer, an anionic permeation enhancer (e.g., an anionic permeation enhancer containing one or more sulfonic acid groups (-SO3H)), or a non-ionic permeation enhancer.

[0084] The permeation enhancer is C 8~20 Alkanoylcarnitines (preferably lauroylcarnitine, myristoylcarnitine or palmitoylcarnitine; e.g., lauroylcarnitine chloride, myristoylcarnitine chloride or palmitoylcarnitine chloride), salicylic acid (preferably a salicylate, e.g., sodium salicylate), salicylic acid derivatives (e.g., 3-methoxysalicylic acid, 5-methoxysalicylic acid, or homovanillic acid, etc.), 8~20 Alkanoic acid (preferably C 8~20Alkanoates, more preferably caprates, caprylates, myristates, palmitates, or stearates, such as sodium caprate, sodium caprylate, sodium myristate, sodium palmitate, or sodium stearate, citric acid (preferably a citrate, such as sodium citrate), tartaric acid (preferably a tartrate), fatty acid acylated amino acids (such as, but not limited to, sodium lauroyl alanine, N-dodecanoyl-L-alanine, sodium lauroyl aspartate, N-Dodecanoyl-L-Asparagine, Sodium Lauroyl Aspartate, N-Dodecanoyl-L-Aspartic Acid, Sodium Lauroyl Cysteinate, N-Dodecanoyl-L-Cysteine, Sodium Lauroyl Glutamate, N-Dodecanoyl-L-Glutamic Acid, Sodium Lauroyl Glutamate, N-Dodecanoyl-L-Glutamine, Sodium Lauroyl Glycinate, N-Dodecanoyl-L-Glycine, Sodium Lauroyl Histidate, N-Dodecanoyl-L-Histidine, Sodium Lauroyl Isoleucinate, N-Dodecanoyl N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methionate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalanine, N-dodecanoyl-L-phenylalanine, sodium lauroyl prophosphate, N-dodecanoyl-L-proline, sodium lauroyl serine, N-dodecanoyl-L-serine, sodium lauroyl threonate, N-dodecanoyl-L-threonine, sodium lauroyl tryptophanate, N-dodecanoyl-L-tryptophanate Tophan, sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, sodium lauroyl valinate, N-dodecanoyl-L-valine, sodium lauroyl sarcosinate, N-dodecanoyl-L-sarcosine, sodium capric alanine, N-decanoyl-L-alanine, sodium capric aspartate, N-decanoyl-L-asparagine, sodium capric aspartate, N-decanoyl-L-aspartic acid, sodium capric cysteine, N-decanoyl-L-cysteine, sodium capric glutamate,N-Decanoyl-L-glutamic acid, Capric sodium glutamate, N-Decanoyl-L-glutamine, Capric sodium glycinate, N-Decanoyl-L-glycine, Capric sodium histidinate, N-Decanoyl-L-histidine, Capric sodium isoleucinate, N-Decanoyl-L-isoleucine, Capric sodium leucinate, N-Decanoyl-L-leucine, Capric sodium methionate, N-Decanoyl-L-methionine, Capric sodium phenylalanate, N-Decanoyl-L-phenylalanine, Capric sodium prophosphate, N -Decanoyl-L-proline, sodium caprineserate, N-decanoyl-L-serine, sodium caprine threonine, N-decanoyl-L-threonine, sodium caprine tryptophanate, N-decanoyl-L-tryptophan, sodium caprine tyrosine, N-decanoyl-L-tyrosine, sodium caprine valinate, N-decanoyl-L-valine, sodium caprine sarcosine, N-decanoyl-L-sarcosine, sodium oleoyl sarcosine, sodium N-decyl leucine, sodium stearoyl glutamate (e.g., Amisoft HS-11 P), sodium myristoyl glutamate (e.g., Amisoft MS-11), sodium lauroyl glutamate (e.g., Amisoft LS-11), sodium cocoyl glutamate (e.g., Amisoft CS-11), sodium cocoyl glycinate (e.g., Amilite GCS-11), N-decyl leucine sodium, cocoyl glycine sodium, cocoyl glutamate sodium, lauroyl alanine sodium, N-dodecanoyl-L-alanine, lauroyl aspartic acid sodium, N-dodecanoyl-L-asparagine, lauroyl aspartic acid sodium, N-dodecanoyl-L-aspartic acid sodium, lauroyl cysteine ​​sodium, N-dodecanoyl-L-cysteine, lauroyl glutamic acid sodium, N-dodecanoyl-L-glutamic acid sodium, lauroyl glutamate sodium, N-dodecanoyl-L-glutamine, lauroyl glycinate sodium, N-dodecanoyl-L-glycine, lauroyl histidinate sodium, N-dodecanoyl-L-histidine,Sodium lauroyl isoleucinate, N-dodecanoyl-L-isoleucine, sodium lauroyl leucinate, N-dodecanoyl-L-leucine, sodium lauroyl methionate, N-dodecanoyl-L-methionine, sodium lauroyl phenylalanine, N-dodecanoyl-L-phenylalanine, sodium lauroyl prophosphate, N-dodecanoyl-L-proline, sodium lauroyl serine, N-dodecanoyl-L-serine, sodium lauroyl threonate, N-dodecanoyl-L-threonine, lauroyl Sodium L-tryptophanate, N-dodecanoyl-L-tryptophan, Sodium lauroyl tyrosinate, N-dodecanoyl-L-tyrosine, Sodium lauroyl valinate, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, Sodium capric alanine, N-decanoyl-L-alanine, Sodium capric aspartate, N-decanoyl-L-asparagine, Sodium capric aspartate, N-decanoyl-L-aspartic acid, Sodium capric cysteate, N-decanoyl-L-cysteine , Sodium Capric Glutamate, N-Decanoyl-L-Glutamic Acid, Sodium Capric Glutamate, N-Decanoyl-L-Glutamine, Sodium Capric Glycinate, N-Decanoyl-L-Glycine, Sodium Capric Histidinate, N-Decanoyl-L-Histidine, Sodium Capric Isoleucinate, N-Decanoyl-L-Isoleucine, Sodium Capric Leucinate, N-Decanoyl-L-Leucine, Leucine, Sodium Capric Methionate, N-Decanoyl-L-Methionine, Sodium Capric Phenylalanine Sodium capric acid, N-decanoyl-L-phenylalanine, sodium capric prophosphate, N-decanoyl-L-proline, sodium caprine serinate, N-decanoyl-L-serine, sodium caprine threonine acid, N-decanoyl-L-threonine, sodium caprine tryptophanate, N-decanoyl-L-tryptophan, sodium caprine tyrosine, N-decanoyl-L-tyrosine, sodium caprine valinate, N-decanoyl-L-valine, sodium caprine sarcosinate, sodium oleoyl sarcosine,and a pharma- ceutically acceptable salt of any of the foregoing compounds; or, for example, C, 8~20 Alkanoyl sarcosinate (e.g., lauroyl sarcosinate such as sodium lauroyl sarcosinate) or C 8~20 any of the fatty acid acylated amino acids described in US2014 / 0056953A1, which is incorporated herein by reference, including one of the 20 standard proteinogenic α-amino acids acylated with alkanoic acids), alkyl saccharides (e.g., 1~20 Alkyl saccharides, e.g., C such as Multitrope™ 1620-LQ-(MV) 8~10or for example, n-octyl-beta-D-glucopyranoside, n-dodecyl-beta-D-maltoside, n-tetradecyl-beta-D-maltoside, tridecyl-beta-D-maltoside, sucrose laurate, sucrose stearate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate, coco-glucoside, or any of the alkyl saccharides described in US 5,661,130 or WO 2012 / 112319, which are incorporated herein by reference), cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl β-cyclodextrin, or sulfobutyl ether β-cyclodextrin), N-[8-(2-hydroxybenzoyl)amino]caprylic acid (preferably N-[8-(2-hydroxybenzoyl)amino]caprylate, more preferably sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, also referred to as "SNAC"), N-[8-(2-hydroxybenzoyl)amino]caprylate derivatives (preferably sodium N-[8-(2-hydroxybenzoyl)amino]caprylate derivatives), thiomers (also referred to as thiolated polymers; can be synthesized, for example, by immobilization of sulfhydryl-bearing ligands onto a polymer backbone, such as well-established polymers, e.g., polyacrylic acid, carboxymethylcellulose, or chitosan; exemplary thiomers are described in Laffleur F et al., Future Med Chem. 2012, 4(17):2205-16 (doi:10.4155 / fmc.12.165)), mucoadhesive polymers having a vitamin B moiety (e.g., any of the mucoadhesive polymers described in US 8,980,238 B2, which is incorporated herein by reference; in particular, any of the polymeric compounds defined in any one of claims 1 to 3 of US 8,980,238 B2), calcium chelating compounds (e.g., ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), sodium citrate, or polyacrylic acid), cremophor EL (also referred to as "Kolliphor EL"; catalog number 61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, bestatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, C. 2~20 Alkanols (e.g., ethanol, decanol, lauryl alcohol, myristyl alcohol, or palmityl alcohol), C 8~20 Alkenols (e.g., oleyl alcohol), C 8~20 Alkenic acids (e.g., oleic acid), dextran sulfate, diethylene glycol monoethyl ether (transcutol), 1-dodecylazacyclo-heptan-2-one (Azone®), caprylocaproyl polyoxylglycerides (such as caprylocaproyl polyoxyl-8 glyceride; available, for example, as Labrasol® or ACCONON® MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, menthol, C 8~20 Alkylamines, C 8~20Alkenylamines (e.g., oleylamine), phosphatidylcholine, poloxamer, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate (e.g., polysorbate 20 or polysorbate 80), cholic acid (preferably a cholate, e.g., sodium cholate), deoxycholate (e.g., sodium deoxycholate), chenodeoxycholate (e.g., sodium chenodeoxycholate), sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, dodecylpyridinium chloride, decyldimethylammoniopropanesulfonate, myristyldimethylammoniopropanesulfonate, palmityldimethylammoniopropanesulfonate, ChemBetaine CAS, ChemBetaine Oleyl, Nonylphenoxypolyoxyethylene, Polyoxyethylene Sorbitan Monolaurate, Polyoxyethylene Sorbitan Monopalmitate, Sorbitan Monooleate, Triton X-100, Hexanoic Acid, Heptanoic Acid, Methyl Laurate, Isopropyl Myristate, Isopropyl Palmitate, Methyl Palmitate, Diethyl Sebaccate, Sodium Oleate, Urea, Laurylamine, Caprolactam, Methylpyrrolidone, Octylpyrrolidone, Methylpiperazine, Phenylpiperazine, Carbopol 934P, Glycyrhetinic Acid acid), bromelain, pinene oxide, limonene, cineole, octyldodecanol, fenchone, menthone, trimethoxypropylenemethylbenzene, cell membrane penetrating peptides (e.g., Klaklak, polyarginines or oligoarginines (especially octa-arginine), penetratin (especially L-penetratin), penetratin analogues (especially PenetraMax; see, e.g., El-Sayed Khafagy et al., Eur J Pharm Biopharm.2013;85(3 Pt A):736-43), HIV-1 Tat, transportan, or any of the cell membrane penetrating peptides mentioned in US2012 / 0065124), macrogol-15-hydroxystearate (e.g., Solutol HS 15), CriticalSorb (see, e.g., Illum L et al., J Control Release. 2012;162(1):194-200), taurocholate (e.g., sodium taurocholate), taurodeoxycholate (e.g., sodium taurodeoxycholate), sulfoxide (e.g., (C. 1~10 Alkyl)-(C 1~10Preferably, the permeation enhancer is selected from the group consisting of alkyl)-sulfoxides, such as decylmethylsulfoxide or dimethylsulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (also referred to as "5-CNAC"), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (also referred to as "SNAD"), dodecyl-2-N,N-dimethylaminopropionate (also referred to as "DDAIP"), D-α-tocopheryl polyethylene glycol-1000 succinate (also referred to as "TPGS"), arginine, and pharma- ceutically acceptable salts of the aforementioned compounds. Mixtures of two or more permeation enhancers, including any of the above permeation enhancers, may also be used. Further, see Whitehead K et al., Pharm. Res. 2008 Jun;25(6):1412-9 (particularly any one of those set out in Table I of this reference), any one of the modified amino acids disclosed in US 5,866,536 (particularly any one of compounds I-CXXIII as disclosed in US 5,866,536, which is incorporated herein by reference, or a pharma- ceutically acceptable salt or solvate thereof, such as the disodium salt, ethanol solvate, or hydrate of any one of these compounds), US 5,777 Any one of the modified amino acids disclosed in US 5,773,647 (particularly any one of compounds 1-193 as disclosed in US 5,773,647, which is incorporated herein by reference, or a pharma- ceutically acceptable salt or solvate thereof, such as the disodium salt, ethanol solvate, or hydrate of any one of these compounds), any of the nanoparticles described in WO2011 / 133198, any of the polymeric preparations described in US 2015 / 174076, and / or hydrogels (e.g., as described in Torres-Lugo M et al., Biotechnol Prog. 2002;18(3):612-6) may similarly be used as permeation enhancers.In addition, complex lipoid dispersions (e.g., a combination of an insoluble surfactant or oil with a soluble surfactant, and optionally water or a cosolvent) may also be used as permeation enhancers, and corresponding exemplary permeation enhancers include, inter alia, mixed micelles, reverse micelles, self-emulsifying systems (e.g., SEDDS, SMEDDS, or SNEDDS), lipid dispersions, course emulsions, or solid lipid nanoparticles (SLN). Preferably, the permeation enhancer is selected from sodium caprylate, sodium caprate, sodium laurate, sucrose laurate, sucrose stearate, sodium stearate, EDTA, polyacrylic acid, and N-[8-(2-hydroxybenzoyl)amino]caprylate or their pharma- ceutically acceptable salts thereof (e.g., sodium N-[8-(2-hydroxybenzoyl)amino]caprylate). A particularly preferred permeation enhancer is N-[8-(2-hydroxybenzoyl)amino]caprylate or a pharma- ceutically acceptable salt thereof, especially sodium N-[8-(2-hydroxybenzoyl)amino]caprylate.

[0085] Further preferred permeation enhancers are alkyl polysaccharides, arginine or CriticalSorb® (Solutol® HS 15). In particular, the permeation enhancer may be an alkyl glycoside (or a combination of two or more alkyl glycosides), which may be selected from any of the alkyl glycosides described below.

[0086] Alkyl glycosides used as permeation enhancers according to the present invention can be synthesized by known procedures, i.e., chemically as described, for example, in Rosevear et al., Biochemistry 19:4108-4115 (1980) or Koeltzow and Urfer, J. Am. Oil Chem. Soc., 61:1651-1655 (1984), U.S. Pat. No. 3,219,656 or U.S. Pat. No. 3,839,318, or enzymatically as described, for example, in Li et al., J. Biol. Chem., 266:10723-10726 (1991) or Gopalan et al., J. Biol. Chem. 267:9629-9638 (1992).

[0087] Alkyl glycosides for use as permeation enhancers in the present invention include, but are not limited to, alkyl glycosides such as octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl-, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl-α- or β-D-maltoside, -glucoside or -sucroside (which may be synthesized according to Koeltzow and Urfer; Anatrace Inc., Maumee, Ohio; Calbiochem, San Diego, Calif.; Fluka Chemie, Switzerland); alkyl thiomaltosides such as heptyl-, octyl-, dodecyl-, tridecyl-, and tetradecyl-β-D-thiomaltoside (Defaye, J. and Pederson, C., "Hydrogen Fluoride, Solvent and Reagent for Carbohydrate Conversion Technology", Carbohydrates as Organic Raw Materials, Vol. 11, No. 1, 2002, pp. 1171-1175 ... Materials, 247-265 (ed. F.W. Lichtenthaler) VCH Publishers, New York (1991); Ferenci, T., J. Bacteriol, 144:7-11 (1980); alkyl thioglucosides, such as heptyl- or octyl 1-thio α- or β-D-glucopyranoside (Anatrace, Inc., Maumee, Ohio; Saito, S. and Tsuchiya, T. Chem. Pharm. Bull. 33:503-508 (1985); alkylthiosucrose (which can be synthesized, for example, according to Binder, TP and Robyt, JF, Carbohydr. Res. 140:9-20 (1985)); alkyl maltotriosides (which can be synthesized according to Koeltzow and Urfer); long-chain aliphatic carbonamides of sucrose β-amino-alkyl ethers (Austrian Patents 382, ​​381 (1987); Chem. Abstr., 108:114719 (1988) and Gruber and Greber pp.95-116); derivatives of palatinose and isomaltamine linked to an alkyl chain by an amide bond (which may be synthesized according to Kunz, M., "Sucrose-based Hydrophilic Building Blocks as Intermediates for the Synthesis of Surfactants and Polymers", Carbohydrates as Organic Raw Materials, 127-153); derivatives of isomaltamine linked to an alkyl chain by a urea (which may be synthesized according to Kunz); long-chain aliphatic ureidocarbonates of sucrose β-amino-alkyl ethers (which may be synthesized according to Gruber and Greber, pp. 95-116); and long-chain aliphatic amide carbonates of sucrose β-amino-alkyl ethers (which may be synthesized according to Austrian Patents 382, ​​381 (1987), Chem. Abstr., 108:114719 (1988) and Gruber and Greber, pp. 95-116).

[0088] The permeation enhancer may also be selected from any of the enhancers mentioned in this document, including in particular any of the alkyl glycosides, any of the saccharide alkyl esters, and / or any of the mucosal delivery enhancers described in US 8,927,497.

[0089] Additionally, the permeation enhancer may also be represented by the following formula (I):

[0090] [ka]

[0091] (In the formula, R 1 , R 2 , R 3 and R 4 each independently represents hydrogen, -OH, or -NR 6 R 7 , halogen (e.g., -F, -Cl, -Br or -I), C 1~4 Alkyl or C1~4 alkoxy; R 5 is a substituted or unsubstituted C 2~16 Alkylene, substituted or unsubstituted C 2~16 Alkenylene, substituted or unsubstituted C 1~12 Alkyl(arylene) [e.g., substituted or unsubstituted C 1~12 alkyl(phenylene)], or substituted or unsubstituted aryl (C 1~12 alkylene) [e.g., substituted or unsubstituted phenyl (C 1~12 alkylene)] R 6 and R 7 are each independently hydrogen, oxygen, -OH or C 1~4 (It is alkyl) or a pharma- ceutically acceptable salt or solvate thereof, in particular the disodium salt thereof, an alcohol solvate (e.g., a methanol solvate, an ethanol solvate, a propanol solvate, or a propylene glycol solvate, or any such solvate of the disodium salt; in particular, an ethanol solvate or an ethanol solvate of the disodium salt), or a hydrate thereof (e.g., the monohydrate of the disodium salt). The "substituted" groups contained in formula (I) referred to above are preferably halogen (e.g., -F, -Cl, -Br or -I), -OH, C 1~4 Alkyl or C 1~4The compound is substituted with one or more (e.g., one, two, or three) substituents independently selected from alkoxy. Such compounds and methods for their preparation are described, for example, in WO00 / 59863, which is incorporated herein by reference. Thus, the permeation enhancer can also be a "delivery agent" as described in WO00 / 59863. Preferred examples of the compound of formula (I) include N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl]amino)decanoic acid, N-(8-[2-hydroxybenzoyl]amino)caprylic acid, the monosodium or disodium salt of any one of the aforementioned compounds, the ethanol solvate of the sodium salt (e.g., monosodium or disodium salt) of any one of the aforementioned compounds, the monohydrate of the sodium salt (e.g., monosodium or disodium salt) of any one of the aforementioned compounds, and any combination thereof. A particularly preferred compound of formula (I) is the disodium salt of N-(5-chlorosalicyloyl)-8-aminocaprylic acid or its monohydrate.

[0092] It is particularly preferred that the permeation enhancer is selected from sodium caprate, sodium caprylate, a mixture of sodium caprate and sodium caprylate, SNAC, sucrose laurate, labrasol and polysorbates.

[0093] Additionally, the permeation enhancer may also be a salt of a medium chain fatty acid. The salt of the medium chain fatty acid is preferably a C 4~18 Saturated fatty acids, preferably C, optionally having 1, 2 or 3 C=C double bonds. 4~18 Linear or branched alkanoic acids, more preferably C, optionally having 1, 2 or 3 C=C double bonds. 6~16 Linear or branched alkanoic acids, even more preferably C, optionally having 1, 2 or 3 C=C double bonds. 6~14 The salts of linear or branched alkanoic acids are preferably C 4~18 Linear or branched alkanoic acids, more preferably C 6~16 Linear or branched alkanoic acids, even more preferably C6~14 It is a salt of a linear or branched alkanoic acid. The salt of a medium chain fatty acid is preferably selected from the salts of valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid and / or stearic acid. More preferably, the salt of a medium chain fatty acid is a salt of capric acid.

[0094] The salt of the medium chain fatty acid is more preferably a sodium salt or a potassium salt. More preferably, the salt of the medium chain fatty acid is a salt of capric acid. Capric acid may also be referred to as decanoic acid (CH3(CH2)8COOH). The preferred salt of capric acid is sodium caprate (i.e., CH3(CH2)8COONa).

[0095] The solid oral pharmaceutical composition of the present invention preferably further comprises one or more enzyme inhibitors. Preferred enzyme inhibitors include trisodium phosphate (Na3PO4), arginine and lysine.

[0096] More preferably, the solid oral pharmaceutical composition of the present invention comprises a combination of sodium caprate and trisodium phosphate. Even more preferably, the core of the solid oral pharmaceutical composition of the present invention comprises sodium caprate, trisodium phosphate and a peptide or protein drug.

[0097] Method for preparing a solid oral pharmaceutical composition The present invention further relates to a method for preparing the solid oral pharmaceutical composition of the present invention, the method preferably comprising the steps of: - preparing a core; - applying a first coating completely surrounding the core; Includes.

[0098] Preferably, the first coating is applied using a first aqueous composition comprising copolymer (A) in combination with copolymer (B) and / or copolymer (C) and / or copolymer (D). More preferably, the first coating is applied using a first aqueous composition comprising copolymer (A) in combination with copolymer (B) and / or copolymer (D).

[0099] The first aqueous composition preferably further comprises an anti-adherent agent, which is preferably selected from glycerol monostearate, talc or PlasAcryl. In addition, the first aqueous composition preferably further comprises citric acid and / or has a pH in the range of 2-5, preferably 3-4.

[0100] Preferably, the method further comprises the step of applying a second coating completely surrounding the first coating, the second coating being applied using a second aqueous composition comprising a copolymer (C) as defined above. The second aqueous composition optionally further comprises an anti-blocking agent, the anti-blocking agent being preferably selected from glycerol monostearate and talc.

[0101] The method may further comprise the step of applying any one or more of the other coatings herein above, preferably by using an aqueous dispersion comprising the polymer and / or copolymer and other intended components of the respective coating. It has been found that copolymers such as poly(methacrylic acid-co-methyl methacrylate) 1:2 (e.g. Eudragit S 100) can dissolve already at a pH below 7, in particular at a pH of about 6.5, when applied from an aqueous dispersion.

[0102] Dosage form The solid oral pharmaceutical composition of the present invention is preferably an oral dosage form, more preferably an oral dosage form.

[0103] Thus, the solid oral pharmaceutical composition is preferably administered orally, in particular orally (or formulated for oral administration, in particular oral administration). Even more preferably, the solid oral pharmaceutical composition is administered by oral ingestion, in particular by swallowing. Thus, the solid oral pharmaceutical composition can be administered through the mouth into the gastrointestinal tract, which may also be referred to as "oral-gastrointestinal" administration.

[0104] In a preferred embodiment, the solid oral pharmaceutical composition is administered orally (particularly by oral-gastrointestinal administration) to a subject / patient in a fed state. Thus, the solid oral pharmaceutical composition is preferably administered orally after a meal, i.e. after ingestion of food (e.g. within about 1-2 hours after a meal). In a further preferred embodiment, the solid oral pharmaceutical composition is administered orally (particularly by oral-gastrointestinal administration) to a subject / patient with a meal after an overnight fast. Thus, the solid oral pharmaceutical composition is preferably administered orally in the morning with food (e.g. breakfast), particularly after an overnight fast.

[0105] In particular, the solid oral pharmaceutical composition is preferably in the form of a capsule or tablet. The total weight of the solid oral pharmaceutical composition, such as a capsule or tablet, may be in the range of 100 mg to 1500 mg. The total weight of the solid oral pharmaceutical composition is more preferably in the range of 100 mg to 1200 mg, 200 mg to 1000 mg, 400 mg to 800 mg, or 600 mg to 900 mg. The tablet or capsule preferably has a total weight of at least 100 mg, for example, 100 mg to 1200 mg, 400 mg to 800 mg, or 600 mg to 900 mg.

[0106] Furthermore, the core may be in the form of multiparticulates. The term "multiparticulates" preferably refers to particles having a volume average particle size of 0.05 to 2 mm as determined by laser diffraction. For example, a peptide or protein drug may be present in the form of multiple particles within a matrix of a permeation enhancer. More preferably, the core is in the form of granules or pellets.

[0107] Even more preferably, the solid oral pharmaceutical composition is formulated as an oral dosage form for the release of peptide or protein drug in the small intestine and / or colon. The release in the ileum is more preferred. The coating as presented in the present invention allows the delayed release of peptide or protein drug mainly in the lower part of the small intestine. In contrast to conventional solid oral pharmaceutical compositions (mainly) based on anionic polymers that dissolve at pH above 7, the delayed release by the solid oral pharmaceutical composition of the present invention is regulated by non-ionic pH-independent polymers. As a result, the small intestine transit time is more constant and less fluctuation in drug release is observed compared to coatings that mainly contain pH-dependent polymers. In addition, the dose dumping that may occur when subjects do not reach or reach a pH above 7 in only a short time can be avoided by the solid oral pharmaceutical composition of the present invention.

[0108] Furthermore, the solid oral pharmaceutical composition according to the present invention preferably has a dissolution profile (dissolution method according to the United States Pharmacopoeia, USP) in which less than 5% of the peptide or protein drug is released in the acidic stage (simulated gastric fluid according to USP or 0.1 M HCl) within 1 hour, followed by dissolution in simulated intestinal fluid with a pH between 6 and 6.5 with a lag time of at least 1 hour (more preferably at least 1.5 hours, even more preferably at least 2 hours, even more preferably at least 2.5 hours). Within the lag time, no more than 10% of the peptide or protein drug is released. After the lag time, more than 75% of the peptide or protein drug is released within 1 hour in simulated intestinal fluid with a pH between 6 and 6.5. Thus, the solid oral pharmaceutical composition preferably has a dissolution profile as determined by the USP dissolution method, in which less than 5% of the peptide or protein drug is released in simulated gastric fluid within 1 hour, followed by dissolution in simulated intestinal fluid at a pH between 6 and 6.5 with a lag time of at least 1 hour, whereby no more than 10% of the peptide or protein drug is released within the lag time, whereby after the lag time, more than 75% of the peptide or protein drug is released within 1 hour in simulated intestinal fluid at a pH between 6 and 6.5. As explained above, the dissolution profile should be determined according to the US Pharmacopoeia (USP, preferably the version as of September 1, 2020), but alternatively, the dissolution profile can also be determined using a modified version of the USP dissolution method described in Examples 7, 18 or 19 herein below. Exemplary solid oral pharmaceutical compositions according to the present invention having such dissolution profiles are described in the Examples section below.

[0109] It is further preferred that the solid oral pharmaceutical composition according to the present invention exhibits less than 5% (preferably less than 3%, more preferably less than 1%, and even more preferably no release) release of the peptide or protein drug in a period of at least 1 hour, preferably at least 2 hours, more preferably at least 3 hours, and most preferably at least 4 hours in a simulated fed state gastric medium, such as FEDGAS pH 6 (see Example 18).

[0110] Further preferred examples of solid oral pharmaceutical compositions according to the invention include compositions having a first coating comprising (or consisting of) HPMC and a second coating (outside the first coating) comprising (or consisting of) Eudragit FL 30 D-55. In particular, it is preferred that the coating with Eudragit FL 30 D-55 has a thickness that results in a weight gain of at least 45% (w / w) with respect to the weight of the first coating with HPMC (e.g. an empty HPMC capsule). Alternatively, it is preferred that the coating with Eudragit FL 30 D-55 has a thickness that results in a weight gain of at least 30 mg per dosage form (e.g. a capsule or tablet), more preferably at least 40 mg, even more preferably at least 50 mg, even more preferably at least 100 mg. Also preferred is a solid oral pharmaceutical composition in the form of a tablet having a coating comprising (or consisting of) Eudragit FL 30 D-55, the coating having a thickness resulting in a weight gain of at least 10% (w / w) (with respect to the weight of the tablet before coating with Eudragit FL 30 D-55).

[0111] Furthermore, also preferred is a solid oral pharmaceutical composition according to the invention in the form of a tablet having a coating comprising Eudragit NM30D, having a coating weight gain of at least 10% (w / w) (e.g. at least 15% (w / w), at least 20% (w / w), or at least 25% (w / w)) relative to the weight of the uncoated tablet (i.e. before application of the coating comprising Eudragit NM30D). Surprisingly, the inventors have found that increasing the coating weight gain with a coating according to the invention further increases the oral bioavailability, especially under fed conditions.

[0112] Typically, a physician will determine the actual dosage of peptide or protein drug that is most suitable for each individual subject.The specific dosage level and frequency of administration for any particular individual subject may vary and depend on a variety of factors, including the activity of the particular compound used, metabolic stability and the length of action of the compound, age, body weight, overall health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the particular condition, and the individual subject being treated.The exact dosage is ultimately left to the discretion of the attending physician or veterinarian.

[0113] The subject or patient treated according to the present invention may be an animal (e.g., a non-human animal). Preferably, the subject / patient is a mammal. More preferably, the subject / patient is a human (e.g., a male human or a female human) or a non-human mammal (e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, a cat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, a cow, or a pig, etc.). Most preferably, the subject / patient treated according to the present invention is a human.

[0114] The term "treatment" of disorder or disease as used herein is well known in the art. "Treatment" of disorder or disease implies that the disorder or disease is suspected or diagnosed in the patient / subject. The patient / subject suspected of suffering from disorder or disease typically shows certain clinical and / or pathological symptoms that the skilled artisan can easily attribute to a certain pathological condition (i.e., diagnose the disorder or disease).

[0115] "Treatment" of a disorder or disease may, for example, result in the halt of the progression of the disorder or disease (e.g., no worsening of symptoms) or the slowing of the progression of the disorder or disease (where the halt of progression is merely of a temporary nature). "Treatment" of a disorder or disease may also result in a partial response (e.g., improvement of symptoms) or a complete response (e.g., disappearance of symptoms) of the subject / patient suffering from the disorder or disease. Thus, "treatment" of a disorder or disease may also refer to an improvement of the disorder or disease, which may, for example, result in the halt of the progression of the disorder or disease or the slowing of the progression of the disorder or disease. Such a partial or complete response may be followed by a relapse. It should be understood that a subject / patient may experience a wide range of responses to treatment (e.g., exemplary responses as described herein above). Treatment of a disorder or disease may include, inter alia, curative treatment (preferably resulting in a complete response and ultimately a cure of the disorder or disease) and palliative treatment (including the alleviation of symptoms).

[0116] The term "prevention" of a disorder or disease as used herein is also well known in the art. For example, a patient / subject suspected of being susceptible to a disorder or disease may particularly benefit from the prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition to the disorder or disease, including but not limited to a genetic predisposition. Such predisposition may be determined by standard methods or assays, for example, using genetic markers or phenotypic indicators. It should be understood that the disorder or disease prevented according to the present invention has not been or cannot be diagnosed in the patient / subject (e.g., the patient / subject does not show any clinical or pathological symptoms). Thus, the term "prevention" includes the use of a peptide or protein drug according to the present invention before any clinical and / or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the attending physician.

[0117] The terms "peptide" and "protein", as in the expression "peptide or protein drug", are used interchangeably herein and refer to a polymer of two or more amino acids linked via an amide bond formed between the amino group of one amino acid and the carboxyl group of another amino acid. The amino acids contained in a peptide or protein, also referred to as amino acid residues, may be selected from the 20 standard proteinogenic α-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val), although non-proteinogenic and / or non-standard α-amino acids (e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, α-methylalanine (i.e., 2-aminoisopropylacrylamide, 2-aminoisopropylacrylamide, 1-amino ... butyric acid), norvaline, norleucine, tellureucine (tert-leucine), labionine, or alanine or glycine substituted with a cyclic group in the side chain, such as cyclopentylalanine, cyclohexylalanine, phenylalanine, naphthylalanine, pyridylalanine, thienylalanine, cyclohexylglycine, or phenylglycine, as well as β-amino acids (e.g., β-alanine), γ-amino acids (e.g., γ-aminobutyric acid, isoglutamine, or statins) and δ-amino acids. Preferably, the amino acid residues contained in the peptide or protein are selected from α-amino acids, more preferably from the 20 standard proteinogenic α-amino acids (which may exist as L- or D-isomers, preferably all as L-isomers). A peptide or protein may be unmodified or modified, for example, at its N-terminus, its C-terminus and / or at functional groups in the side chains of any of its amino acid residues (in particular at the side chain functional groups of one or more Lys, His, Ser, Thr, Tyr, Cys, Asp, Glu, and / or Arg residues).Such modifications may include, for example, the attachment of any of the protecting groups described for the corresponding functional groups in Wuts PG & Greene TW, Greene's protective groups in organic synthesis, John Wiley & Sons, 2006. Such modifications may include the covalent attachment of one or more polyethylene glycol (PEG) chains (to form a PEGylated peptide or protein), glycosylation, and / or acylation with one or more fatty acids (e.g., one or more C. 8~30 The modified peptides or proteins may also include alkane or alkenoic acids; forming fatty acid acylated peptides or proteins. In addition, such modified peptides or proteins may also include peptidomimetics, provided that they contain at least two amino acids linked via an amide bond (formed between the amino group of one amino acid and the carboxyl group of another amino acid). The amino acid residues contained in the peptide or protein may, for example, exist as a linear molecular chain (forming a linear peptide or protein) or may form one or more rings (corresponding to a cyclic peptide or protein). The peptide or protein may also form an oligomer consisting of two or more identical or different molecules.

[0118] The term "amino acid" refers specifically to any one of the twenty standard proteinogenic α-amino acids (i.e., Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val), but also to non-proteinogenic and / or non-standard α-amino acids (e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, α-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, tellurine (tert-leucine), α-amino acids (e.g., α-amino acids ... It also refers to β-amino acids (e.g., β-alanine), γ-amino acids (e.g., γ-aminobutyric acid, isoglutamine, or statins) and / or δ-amino acids and any other compounds that contain at least one carboxylic acid group and at least one amino group. Unless otherwise defined, "amino acid" preferably refers to an α-amino acid, more preferably any one of the 20 standard proteinogenic α-amino acids (which may exist as L- or D-isomers, and preferably exist as L-isomers).

[0119] The term "antibody" refers to any immunoglobulin molecule that specifically binds (or is immunologically reactive with) a particular antigen. The antibody may be, for example, a monoclonal or polyclonal antibody, preferably a monoclonal antibody. Furthermore, the antibody (e.g., a monoclonal antibody) may be a whole antibody (e.g., IgA, IgD, IgE, IgM or IgG, including IgG1, IgG2, IgG3 or IgG4, among others), a chimeric antibody, a humanized antibody, a human antibody, a heteroconjugate antibody (e.g., a bispecific antibody), or an antigen-binding fragment of any of the aforementioned types of antibodies (e.g., Fab, Fab', F(ab')2, Fv, or scFv, etc.). The antibody may also be a single chain antibody (scAb) or a single domain antibody (sdAb; e.g., a "nanobody").

[0120] The term "dissolved" as used herein preferably refers to a state in which the layer for which dissolution is determined is sufficiently dissolved by a solution having a specified pH value (particularly for peptide or protein drugs such as teduglutide) such that it becomes permeable. Whether a given layer is soluble or not can be determined according to the United States Pharmacopeia (USP) General Provisions. <711> This can be determined by using the dissolution apparatus 1 as described in Dissolution.

[0121] The term "surround" is used herein synonymously with "cover" or "completely cover." As used herein, the terms "optional", "optionally" and "may" mean that the indicated feature may be present, but may not be present. Whenever the terms "optional", "optionally" or "may" are used, the present invention relates in particular to both possibilities, i.e., the possibility that the corresponding feature is present, or alternatively, the possibility that the corresponding feature is not present. For example, when a component of a composition is indicated as "optional", the present invention relates in particular to both possibilities, i.e., the possibility that the corresponding component is present (contained in the composition) or the possibility that the corresponding component is not present in the composition.

[0122] As used herein, the term "comprising" (or "comprise", "comprises", "contain", "contains", or "containing") has the meaning of "containing, among other things", i.e., "containing, among other optional elements", unless expressly indicated otherwise or contradicted by context. In addition, the term also includes the narrower meanings of "consisting essentially of" and "consisting of". For example, the term "A comprising B and C" has the meaning of "A containing, among other things, B and C", where A may contain further optional elements (e.g., "A containing B, C, and D" is also included), but the term also includes the meanings of "A consisting essentially of B and C" and "A consisting of B and C" (i.e., A does not include any other components other than B and C).

[0123] As used herein, the term "about" refers to ±10% of the indicated numerical value, preferably ±5% of the indicated numerical value, and especially the exact numerical value indicated. Unless expressly indicated otherwise, all properties and parameters referred to in this specification (including, for example, any amounts / concentrations expressed in "mg / ml" or "% (v / v)", and any pH values) are preferably determined at standard ambient temperature and pressure conditions, in particular at a temperature of 25° C. (298.15 K) and at an absolute pressure of 101.325 kPa (1 atm).

[0124] Furthermore, it should be understood that the present invention particularly relates to any and all combinations of the features and embodiments described herein, including any combination of the general and / or preferred features / embodiments. In particular, the present invention particularly relates to all combinations of the preferred features described herein.

[0125] In this specification, several documents are cited, including patents, patent applications and scientific literature. The disclosures of these documents are not considered relevant to the patentability of this invention, but are incorporated herein by reference in their entirety. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference.

[0126] In accordance with the above detailed description, the present invention particularly relates to the following provisions: 1. (i) a core comprising a peptide or protein drug; and (ii) First Coating wherein the first coating comprises: (ii-1) Copolymer (A) (ii-2) in combination with copolymer (B) and / or copolymer (C) and / or copolymer (D); The copolymer (A) is (a) 20 to 90 mol % of ethyl acrylate repeat units, and (b) 10 to 80 mol% of methyl methacrylate repeating units Including, If copolymer (B) is present, (a) 25 to 75 mol % of methacrylic acid repeat units, and (b) 25 to 75 mol% of ethyl acrylate repeating units Including, When the copolymer (C) is present, (a) 25 to 60 mol % of methacrylic acid repeat units, and (b) 40 to 75 mol% of methyl methacrylate repeating units Including, If the copolymer (D) is present, (a) 5 to 20 mol % of methacrylic acid repeat units, and (b) 20 to 40 mol % of methyl methacrylate repeat units, and (c) 60 to 75 mol% methyl acrylate repeating units 1. A solid oral pharmaceutical composition comprising:

[0127] 2. The first coating is (ii-1) Copolymer (A) (ii-2) The solid oral pharmaceutical composition according to clause 1, in combination with copolymer (B) and / or copolymer (D).

[0128] 3. The solid oral pharmaceutical composition according to clause 1 or 2, wherein the copolymer (A) in the first coating comprises 60-75 mol % of ethyl acrylate repeat units and 25-40 mol % of methyl methacrylate repeat units.

[0129] 4. The solid oral pharmaceutical composition according to any one of clauses 1 to 3, wherein the copolymer (A) in the first coating comprises ethyl acrylate repeat units and methyl methacrylate repeat units in a molar ratio of 2:1.

[0130] 5. The solid oral pharmaceutical composition according to any one of clauses 1 to 4, wherein the copolymer (A) in the first coating comprises not more than 3 mol% of methyl acrylate repeat units, preferably the copolymer (A) comprises not more than 1 mol%; more preferably not more than 0.5 mol%; even more preferably not more than 0.1 mol%; even more preferably not more than 0.01 mol%; and even more preferably 0 mol% of methyl acrylate repeat units.

[0131] 6. The solid oral pharmaceutical composition according to any one of clauses 1 to 5, wherein the copolymer (A) in the first coating consists of ethyl acrylate repeat units and methyl methacrylate repeat units.

[0132] 7. The solid oral pharmaceutical composition according to any one of clauses 1 to 6, wherein the copolymer (A) in the first coating is a neutral non-ionic copolymer. 8. The solid oral pharmaceutical composition according to clause 1 or 2, wherein the copolymer (A) in the first coating further comprises 0.5-20 mol %, preferably 1-15 mol % of 2-(trimethylammonio)ethyl methacrylate chloride repeat units.

[0133] 9. The solid oral pharmaceutical composition according to any one of clauses 1, 2 and 8, wherein the copolymer (A) in the first coating comprises 25-39 mol % of ethyl acrylate repeat units, 60-74 mol % of methyl methacrylate repeat units, and 1-15 mol % of 2-(trimethylammonio)ethyl methacrylate chloride repeat units.

[0134] 10. The solid oral pharmaceutical composition according to any one of clauses 1, 2, 8 and 9, wherein the copolymer (A) in the first coating comprises ethyl acrylate repeat units, methyl methacrylate repeat units, and 2-(trimethylammonio)ethyl methacrylate chloride repeat units in a molar ratio of 1:2:0.1 or 1:2:0.2.

[0135] 11. The solid oral pharmaceutical composition according to any one of clauses 1, 2 and 8 to 10, wherein the copolymer (A) in the first coating comprises not more than 3 mol% of methyl acrylate repeat units, preferably the copolymer (A) comprises not more than 1 mol%, more preferably not more than 0.5 mol%, even more preferably not more than 0.1 mol%, even more preferably not more than 0.01 mol%, even more preferably 0 mol% of methyl acrylate repeat units.

[0136] 12. The solid oral pharmaceutical composition according to any one of clauses 1, 2 and 8 to 11, wherein the copolymer (A) in the first coating consists of ethyl acrylate repeat units, methyl methacrylate repeat units, and 2-(trimethylammonio)ethyl methacrylate chloride repeat units.

[0137] 13. The solid oral pharmaceutical composition according to any one of clauses 1, 2 and 8 to 12, wherein the copolymer (A) in the first coating is a cationic copolymer. 14. The solid oral pharmaceutical composition according to any one of clauses 1 to 13, wherein the copolymer (B) in the first coating comprises 45-55 mol % of methacrylic acid repeat units and 45-55 mol % of ethyl acrylate repeat units.

[0138] 15. The solid oral pharmaceutical composition according to any one of clauses 1 to 14, wherein the copolymer (B) in the first coating comprises methacrylic acid repeat units and ethyl acrylate repeat units in a molar ratio of 1:1.

[0139] 16. The solid oral pharmaceutical composition according to any one of clauses 1 to 15, wherein the copolymer (B) in the first coating comprises not more than 3 mol% of methyl acrylate repeat units, preferably the copolymer (B) comprises not more than 1 mol%, more preferably not more than 0.5 mol%, even more preferably not more than 0.1 mol%, even more preferably not more than 0.01 mol%, even more preferably 0 mol% of methyl acrylate repeat units.

[0140] 17. The solid oral pharmaceutical composition according to any one of clauses 1 to 16, wherein the copolymer (B) in the first coating consists of methacrylic acid repeat units and ethyl acrylate repeat units.

[0141] 18. The solid oral pharmaceutical composition according to any one of clauses 1 to 17, wherein the copolymer (C) in the first coating comprises 45-55 mol % of methacrylic acid repeat units and 45-55 mol % of methyl methacrylate repeat units.

[0142] 19. The solid oral pharmaceutical composition according to any one of clauses 1 to 18, wherein the copolymer (C) in the first coating comprises methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 1:1.

[0143] 20. The solid oral pharmaceutical composition according to any one of clauses 1 to 19, wherein the copolymer (C) in the first coating comprises not more than 3 mol% of methyl acrylate repeat units, preferably the copolymer (C) comprises not more than 1 mol%; more preferably not more than 0.5 mol%; even more preferably not more than 0.1 mol%; even more preferably not more than 0.01 mol%; and even more preferably 0 mol% of methyl acrylate repeat units.

[0144] 21. The solid oral pharmaceutical composition according to any one of clauses 1 to 20, wherein the copolymer (C) in the first coating consists of methacrylic acid repeat units and methyl methacrylate repeat units.

[0145] 22. The solid oral pharmaceutical composition according to any one of clauses 1 to 17, wherein the copolymer (C) in the first coating comprises 25-40 mol % of methacrylic acid repeat units and 60-75 mol % of methyl methacrylate repeat units.

[0146] 23. The solid oral pharmaceutical composition according to any one of clauses 1 to 17 and 22, wherein the copolymer (C) in the first coating comprises methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 1:2.

[0147] 24. The solid oral pharmaceutical composition according to any one of clauses 1 to 17, 22 and 23, wherein the copolymer (C) in the first coating comprises not more than 3 mol% of methyl acrylate repeat units, preferably the copolymer (C) comprises not more than 1 mol%, more preferably not more than 0.5 mol%, even more preferably not more than 0.1 mol%, even more preferably not more than 0.01 mol%, even more preferably 0 mol% of methyl acrylate repeat units.

[0148] 25. The solid oral pharmaceutical composition according to any one of clauses 1 to 17 and 22 to 24, wherein the copolymer (C) in the first coating consists of methacrylic acid repeat units and methyl methacrylate repeat units.

[0149] 26. The solid oral pharmaceutical composition according to any one of clauses 1 to 25, wherein the copolymer (C) in the first coating is obtained from an aqueous dispersion of copolymer (C). 27. The solid oral pharmaceutical composition according to any one of clauses 1 to 26, wherein the copolymer (D) in the first coating comprises 7 to 13 mol % of methacrylic acid repeat units, 25 to 31 mol % of methyl methacrylate repeat units, and 62 to 68 mol % of methyl acrylate repeat units.

[0150] 28. The solid oral pharmaceutical composition according to any one of clauses 1 to 27, wherein the copolymer (D) in the first coating comprises methacrylic acid repeat units, methyl methacrylate repeat units, and methyl acrylate repeat units in a molar ratio of 1:3:7.

[0151] 29. The solid oral pharmaceutical composition according to any one of clauses 1 to 28, wherein the copolymer (D) in the first coating consists of methacrylic acid repeat units, methyl methacrylate repeat units, and methyl acrylate repeat units.

[0152] 30. The solid oral pharmaceutical composition according to any one of clauses 1 to 29, wherein the content of copolymer (A) in the first coating is at least 25% (w / w), preferably at least 50% (w / w), more preferably at least 75% (w / w), even more preferably at least 80% (w / w), and even more preferably at least 90% (w / w), relative to the total weight of the first coating.

[0153] 31. The solid oral pharmaceutical composition according to any one of clauses 1 to 30, wherein the first coating comprises copolymer (A) and copolymer (B), and the content of copolymer (A) in the first coating is at least 25% (w / w), preferably at least 50% (w / w), more preferably at least 75% (w / w), even more preferably at least 80% (w / w), and even more preferably at least 90% (w / w), relative to the total weight of copolymer (A) and copolymer (B) in the first coating.

[0154] 32. The solid oral pharmaceutical composition according to any one of the preceding clauses, wherein the first coating comprises a copolymer (A) and a copolymer (C), wherein the copolymer (C) is as defined in any one of the preceding clauses 18 to 21.

[0155] 33. The solid oral pharmaceutical composition according to any one of the preceding clauses, wherein the first coating comprises a copolymer (A) and a copolymer (C), wherein the copolymer (C) is as defined in any one of the preceding clauses 22 to 26.

[0156] 34. The solid oral pharmaceutical composition according to any one of clauses 1 to 33, wherein the first coating further comprises, in addition to or instead of the copolymer (A), one or more polymers selected from ethyl cellulose, hydroxypropyl methylcellulose (HPMC), and polyvinyl acetate.

[0157] 35. The solid oral pharmaceutical composition according to any one of clauses 1, 3 to 26 and 30 to 34, wherein the first coating does not contain a copolymer (D) as defined in any one of clauses 1 or 27 to 29.

[0158] 36. The solid oral pharmaceutical composition according to any one of clauses 1 to 35, wherein the first coating dissolves at a pH in the range of 5 to 7, preferably at a pH in the range of 5.5 to 6.5, more preferably at a pH in the range of 5.5 to 6.0.

[0159] 37.(iii) further comprising a second coating on the outside of the first coating, the second coating comprising a copolymer (C); The copolymer (C) (a) 25 to 60 mol % of methacrylic acid repeat units, and (b) 40 to 75 mol% of methyl methacrylate repeating units 37. The solid oral pharmaceutical composition according to any one of the preceding clauses, comprising:

[0160] 38. The solid oral pharmaceutical composition according to clause 37, wherein the copolymer (C) in the second coating comprises 45-55 mol % of methacrylic acid repeat units and 45-55 mol % of methyl methacrylate repeat units.

[0161] 39. The solid oral pharmaceutical composition according to clause 37 or 38, wherein the copolymer (C) in the second coating comprises methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 1:1.

[0162] 40. The solid oral pharmaceutical composition according to any one of clauses 37 to 39, wherein the copolymer (C) in the second coating comprises not more than 3 mol% of methyl acrylate repeat units, preferably the copolymer (C) comprises not more than 1 mol%; more preferably not more than 0.5 mol%; even more preferably not more than 0.1 mol%; even more preferably not more than 0.01 mol%; even more preferably 0 mol% of methyl acrylate repeat units.

[0163] 41. The solid oral pharmaceutical composition according to clause 37, wherein the copolymer (C) in the second coating consists of methacrylic acid repeat units and methyl methacrylate repeat units. 42. The solid oral pharmaceutical composition according to clause 37 or 41, wherein the copolymer (C) in the second coating comprises 25-40 mol % of methacrylic acid repeat units and 60-75 mol % of methyl methacrylate repeat units.

[0164] 43. The solid oral pharmaceutical composition according to any one of clauses 37, 41 and 42, wherein the copolymer (C) in the second coating comprises methacrylic acid repeat units and methyl methacrylate repeat units in a molar ratio of 1:2.

[0165] 44. The solid oral pharmaceutical composition according to any one of clauses 37 and 41 to 43, wherein the copolymer (C) in the second coating comprises not more than 3 mol% of methyl acrylate repeat units, preferably the copolymer (C) comprises not more than 1 mol%, more preferably not more than 0.5 mol%, even more preferably not more than 0.1 mol%, even more preferably not more than 0.01 mol%, even more preferably 0 mol% of methyl acrylate repeat units.

[0166] 45. The solid oral pharmaceutical composition according to any one of clauses 37 and 41 to 44, wherein the copolymer (C) in the second coating consists of methacrylic acid repeat units and methyl methacrylate repeat units.

[0167] 46. ​​The solid oral pharmaceutical composition according to any one of clauses 1 to 45, wherein the second coating dissolves at a pH in the range of 5 to 7, preferably at a pH in the range of 5.5 to 6.5, more preferably at a pH in the range of 5.5 to 6.0.

[0168] 47. A solid oral pharmaceutical composition according to any one of clauses 1 to 46, wherein the peptide or protein drug has a molecular weight of about 300 kDa or less, preferably a molecular weight of about 150 kDa or less.

[0169] 48. The peptide or protein drug is insulin, insulin analogues, insulin lispro, insulin PEG lispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG) desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)eicosanedioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(ε)eicosandioyl-γ-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K(N(ε)eicosandioyl-γ-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(ε)hexadecandioyl-γ-L-Glu) A14E B16H B25H desB30 human insulin, B29K(N(ε)eicosandioyl-γ-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K(N(ε)octadecandioyl) A14E B25H desB30 human insulin, GLP-2, GLP-2 analogs, GLP-2 agonists, teduglutide, elsiglutide, glucose-dependent insulinotropic polypeptide, elamipretide, cyclotide, recombinant factor VIIa, eptacog alfa, amylin, amylin analogs, pramlintide, somatostatin analogs, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, leptin analogs, metreleptin, peptide YY, peptide YY analogs, glatiramer, leuprolide, desmopressin, desmopressin analogs, vasopressin receptor 2 agonist peptides, osteocalcin, osteocalcin analogs or derivatives, human growth hormone, human growth hormone analogs, long-acting human growth hormone,Fibroblast growth factor 21, somapsitan, hGH-CTP, antibodies, glycopeptide antibiotics, glycosylated cyclic or polycyclic nonribosomal peptide antibiotics, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, cyclotide, bortezomib, cosyntropin, chorionic gonadotropin, menotropins, sermorelin, luteinizing hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, doxorubicin, tetracycline, tetracycline-salmon ... Lunase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alfa-2a, interferon alfa-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, peginterferon alfa-2a, peginterferon alfa-2b, peginterferon beta-1a, fibrinolysin, vasopressin, aldesleukin, epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin Epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxypolyethylene glycol-epoetin beta, sustained-release erythropoietin receptor activator, pegylated epo, albupoetin, epo-dimer analog, epo-Fc, carbamylated EPO, synthetic erythropoietic protein, low molecular weight epo analog PBI-1402, filgrastim, PEG-filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin , methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, parathyroid hormone fragments, teriparatide, PTH(1-31), PTH(2-34), parathyroid hormone-related protein, abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, prostaglandin F2α receptor modulators, PDC31, abciximab, ranibizumab, alefacept, romiplostim, anakinra, abatacept, belatacept, and pharma- ceutically acceptable salts thereof.48. The solid oral pharmaceutical composition according to any one of clauses 1 to 47.

[0170] 49. The solid oral pharmaceutical composition according to any one of clauses 1 to 47, wherein the peptide or protein drug is selected from GLP-2, GLP-2 agonists, GLP-2 analogues, teduglutide, elsiglutide, insulin, human insulin, insulin analogues, insulin lispro, insulin PEG lispro, A14E B25H B29K(N(eps)octadecandioyl-gGlu-OEG-OEG)desB30 human insulin, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, antibodies, somatostatin analogues, octreotide, lanreotide, pasireotide, desmopressin, desmopressin analogues, vasopressin receptor 2 agonist peptides, parathyroid hormone fragments, teriparatide, PTH(1-31), and PTH(2-34).

[0171] 50. The solid oral pharmaceutical composition according to any one of clauses 1 to 47, wherein the peptide or protein drug is selected from GLP-2, GLP-2 agonists, GLP-2 analogues, teduglutide, elsiglutide, insulin, human insulin, insulin analogues, insulin lispro, insulin PEG lispro, A14E B25H B29K(N(eps)octadecandioyl-gGlu-OEG-OEG)desB30 human insulin, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, and antibodies.

[0172] 51. The solid oral pharmaceutical composition according to any one of clauses 1 to 50, wherein the core further comprises one or more permeation enhancers. 52. A solid oral pharmaceutical composition according to any one of clauses 1 to 51, which is in an oral dosage form.

[0173] 53. A solid oral pharmaceutical composition according to any one of clauses 1 to 52, in the form of a capsule. 54. A solid oral pharmaceutical composition according to any one of clauses 1 to 52, in the form of a tablet.

[0174] 55. A solid oral pharmaceutical composition according to any one of clauses 1 to 54, wherein the core is in the form of multiparticulates, preferably the core is in the form of granules or pellets. 56. A solid oral pharmaceutical composition according to any one of clauses 1 to 55 for use in therapy.

[0175] 57. A solid oral pharmaceutical composition according to any one of clauses 1 to 55 for use in the treatment or prevention of a disease / disorder. 58. A solid oral pharmaceutical composition for use according to clause 56 or 57, which is administered orally.

[0176] 59. Use of a solid oral pharmaceutical composition according to any one of clauses 1 to 55 for the manufacture of a medicament for the treatment or prevention of a disease / disorder. 60. A method for treating or preventing a disease / disorder in a subject in need thereof, comprising orally administering to the subject a therapeutically effective amount of a solid oral pharmaceutical composition according to any one of clauses 1 to 55.

[0177] 61. A method for delivering a peptide or protein drug to a subject in need thereof, comprising orally administering to the subject a solid oral pharmaceutical composition described in any one of clauses 1 to 55.

[0178] The present invention further comprises: (i) a core comprising a peptide or protein drug (as described herein above), and (ii) First Coating wherein the first coating comprises Eudragit NM30D; the first coating optionally further comprises copolymer (B) and / or copolymer (C) and / or copolymer (D); The copolymer (A) is (a) 20 to 90 mol % of ethyl acrylate repeat units, and (b) 10 to 80 mol% of methyl methacrylate repeating units Including, If copolymer (B) is present, (a) 25 to 75 mol % of methacrylic acid repeat units, and (b) 25 to 75 mol% of ethyl acrylate repeating units Including, When the copolymer (C) is present, (a) 25 to 60 mol % of methacrylic acid repeat units, and (b) 40 to 75 mol% of methyl methacrylate repeating units Including, If the copolymer (D) is present, (a) 5 to 20 mol % of methacrylic acid repeat units, and (b) 20 to 40 mol % of methyl methacrylate repeat units, and (c) 60 to 75 mol% methyl acrylate repeating units The present invention relates to a solid oral pharmaceutical composition comprising:

[0179] The general and preferred features described herein above, including the methods and uses described herein, apply equally to the solid oral pharmaceutical compositions described in this paragraph. The present invention will now be described with reference to the following examples, which are merely illustrative and should not be construed as limiting the scope of the invention. EXAMPLES

[0180] material The following materials were used in the examples: All Eudragit polymers and PlasAcryl were obtained from Evonik (Germany). All other chemicals were obtained from Sigma Aldrich (Austria) or VWR (Austria).

[0181] EUDRAGIT NM 30 D: Aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate. Chemical / IUPAC name: Poly(ethyl acrylate-co-methyl methacrylate) 2:1.

[0182] EUDRAGIT® L 30 D-55: An aqueous dispersion of an anionic copolymer based on methacrylic acid and ethyl acrylate. The ratio of free carboxyl groups to ester groups is approximately 1:1.

[0183] EUDRAGIT S 100 Anionic copolymer based on methacrylic acid and methyl methacrylate; chemical name: poly(methacrylic acid-co-methyl methacrylate) 1:2.

[0184] EUDRAGIT L 100 Anionic copolymer based on methacrylic acid and methyl methacrylate; chemical name: poly(methacrylic acid-co-methyl methacrylate) 1:1.

[0185] EUDRAGIT FS30D Anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid; Chemical name: Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1

[0186] Example 1: Coating of HPMC capsules with a combination of 80% Eudragit NM 30 D and 20% Eudragit L 30 D-55 Preparation of Eudragit dispersion: 109 g of Eudragit NM 30 D was adjusted to pH approx. 3 with 1.3 ml of 20% (w / w) citric acid solution. 67 g of distilled water was added under conventional stirring. 28 g of Eudragit L 30 D-55 was added, followed by 2 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0187] Coating of HPMC Capsules: Empty size 1 HPMC capsules weighing approximately 70 mg each were coated with the Eudragit dispersion to final weights of 95 mg, 119 mg, and 125 mg using a Glatt GC1 lab coater.

[0188] Example 2: Coating of HPMC capsules with a combination of 75% Eudragit NM 30 D and 25% Eudragit L 30 D-55 Preparation of Eudragit dispersion: 100 g of Eudragit NM 30 D was adjusted to pH approx. 3 with 1.3 ml of 20% (w / w) citric acid solution. 67 g of distilled water was added under conventional stirring. Then 33.3 g of Eudragit L 30 D-55 was added, followed by 2 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0189] Coating of HPMC Capsules: Empty size 1 HPMC capsules weighing approximately 70 mg each were coated with the Eudragit dispersion to a final weight of 115 mg using a Glatt GC1 lab coater.

[0190] Example 3: Eudragit L 100 top coating on coated capsules from Example 2 Preparation of dispersion: 20g Eudragit L 100 was dispersed in 100ml distilled water. 11.2ml 1N NH3 was added slowly under continuous stirring. Stirring was continued for 60 minutes. Then 10g triethyl citrate (TEC) was added and stirring was continued for another 60 minutes. Separately, 10g talc was homogenized in 50g water with a high shear mixer (Ultra Turrax). Both dispersions were combined under continuous stirring with a conventional stirrer.

[0191] Top-coating of capsules: Capsules from Example 2 (having a weight of 115 mg) were top-coated with the Eudragit L 100 dispersion obtained above to a final weight of 130 mg using a Glatt GC1 lab coater.

[0192] Example 4: Eudragit S 100 top coating on coated capsules from Example 2 Preparation of dispersion: 19.9g Eudragit S 100 was dispersed in 100ml distilled water. 13.5ml 1N NH3 was slowly added under continuous stirring. Stirring was continued for 60 minutes. Then 10g triethyl citrate (TEC) was added and stirring was continued for another 60 minutes. Separately, 10g talc was homogenized in 50g water with a high shear mixer (Ultra Turrax). Both dispersions were combined under continuous stirring with a conventional stirrer.

[0193] Top-coating of capsules: Capsules from Example 2 (having a weight of 115 mg) were top-coated with the Eudragit S 100 dispersion obtained above to a final weight of 132 mg using a Glatt GC1 lab coater.

[0194] Example 5: Enteric coating of HPMC capsules with Eudragit S100 redispersion containing 50% TEC Preparation of Eudragit aqueous dispersion: 99.4 g of EUDRAGIT® S 100 was slowly added to 500 ml of water and stirred with a conventional stirrer for approximately 5 minutes. Then 67.5 g of 1N NH3 was slowly added to the EUDRAGIT® suspension and stirred for about 60 minutes. Then 49.7 g of triethyl citrate (TEC) was added to the EUDRAGIT® suspension and stirred again for 60 minutes. 49.7 g of talc was homogenized in 233.7 g of water for 10 minutes with a high shear mixer (e.g. Ultra Turrax). The talc suspension was then poured into the EUDRAGIT® dispersion while stirring with a conventional stirrer. Finally, the spray suspension was passed through a 0.5 mm sieve and stirred continuously.

[0195] Coating of HPMC capsules: HPMC capsules were coated with Eudragit aqueous dispersion to a weight gain of 18%, 60% and 64% (calculated relative to the weight of the empty capsule) using a Glatt GC1 lab coater.

[0196] Example 6: Enteric coating of HPMC capsules with Eudragit S100 redispersion containing 70% TEC Preparation of Eudragit aqueous dispersion: 99.4 g of EUDRAGIT® S 100 was slowly added to 500 ml of water and stirred with a conventional stirrer for approximately 5 minutes. Then 67.5 g of 1N NH3 was slowly added to the EUDRAGIT® suspension and stirred for about 60 minutes. Then 70 g of triethyl citrate (TEC) was added to the EUDRAGIT® suspension and stirred again for 60 minutes. 49.7 g of talc was homogenized in 233.7 g of water for 10 minutes with a high shear mixer (e.g. Ultra Turrax). The talc suspension was then poured into the EUDRAGIT® dispersion while stirring with a conventional stirrer. Finally, the spray suspension was passed through a 0.5 mm sieve and stirred continuously.

[0197] Enteric coating of HPMC capsules: HPMC capsules were coated with Eudragit aqueous dispersion to a weight gain of 30%, 50% and 63% (calculated relative to the weight of the empty capsule) using a Glatt GC1 lab coater.

[0198] Example 7: Dissolution testing of coated capsules The pre-coated capsules prepared in any of Examples 1-6 can be filled with peptide or protein drugs and sodium caprate. Dissolution studies are performed in an Erweka DT light 126 using the basket method at 37°C and a rotation speed of 75 rpm. A modified version of the United States Pharmacopeia (USP) method is used. The capsules are placed in the basket and the basket is placed in an open blue cap bottle containing 100 ml of the matching dissolution medium. The blue cap bottle is in direct contact with water, ensuring an inner core temperature of the blue cap bottle of 37°C (the temperature is checked with an external thermometer before starting the test). The basket is first placed in simulated gastric fluid according to USP for 1 hour, then in simulated intestinal fluid (SIF) according to USP with pH 6.0 for 1 hour, then in SIF according to USP with pH 6.5 for 1 hour, and finally in SIF according to USP with pH 6.8. 1 ml samples are removed after 60 minutes and at further predefined time points. 40 μl of sample is injected into an HPLC system using a reversed-phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Waters Xselect CSH C18). Sampling is performed until complete capsule dissolution, defined by peptide or protein drug release of >75% of theoretical release value. Following this procedure, it can be demonstrated that capsules (or other oral dosage forms) coated according to the present invention exhibit an advantageous dissolution profile that shows no drug release at the acid stage, followed by a lag time at gut pH levels, followed by a fast release of peptide or protein drug.

[0199] Example 8: Enteric coating of tablets containing semaglutide and sodium caprate with 80% Eudragit NM30D and 20% Eudragit FS30D Tablet preparation: A homogenous powder blend was prepared with 240 mg semaglutide, 6 g sodium caprate, 2.64 g galenIQ 720, 1.56 g Avicel PH-101 and 120 mg magnesium stearate. Mixing was first performed in a mortar and then in a Topitec powder blender. Aliquots of 880 mg were compressed into tablets using a Korsch EK0 single punch tablet press with an average compression force of approximately 15 kN.

[0200] Preparation of Eudragit dispersion: 160 g of Eudragit NM 30 D was adjusted to a pH of about 3 with 2.0 ml of 20% (w / w) citric acid solution. 100 g of distilled water was added under conventional stirring. 42 g of Eudragit FS30D was added, followed by 3 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0201] Tablet Coating: Tablets were blended with empty size 1 HPMC capsules and coated with the Eudragit dispersion obtained above using a Glatt GC1 lab coater to a final tablet weight of about 934 mg, which corresponds to a coating weight gain of about 54 mg per tablet or a weight gain of 6.1% (w / w), which corresponds to about 42 mg of Eudragit NM30D (dry matter) per tablet.

[0202] Example 9: In vivo food interaction study following oral administration of semaglutide tablets to Beagle dogs Since the presence of food in the stomach can interfere with the performance of orally administered peptide drugs, food interactions were evaluated when tablets from Example 8 were orally administered with or without food. Animals were fasted overnight for at least 12 hours prior to dose administration on day 0. After sample collection, animals were provided with food 8 hours after dosing. On the experimental day, an intravenous catheter was placed in the saphenous or cephalic vein for blood sampling (20G, 1 inch intravenous catheter). Tablets were orally administered with 10 ml of water. Within 5 minutes after drug administration, fed dogs received a 50 g light meal (Hill's I / D for dogs) and fasted animals remained fasted for an additional 8 hours. A baseline blood sample was collected, followed by oral administration of one tablet per animal. Blood samples were collected in red top tubes at time points 0, 1, 2, 4, 8, 12, 24 and 48 and centrifuged at 1,500 g and 4° C. for 10 minutes. Serum samples were duplicated and kept at -80°C for further analysis by ELISA technique (Semaglutide Peninsula Laboratories International, Inc. Catalogue No. S-1530). The results thus obtained are shown in Figure 1.

[0203] Results: The fed group had a delayed onset (mean T max. ) was observed. The mean AUC 0-48hrs There was no statistical difference between the mean and mean bioavailability of semaglutide. Consumption of 50 grams of dog food within 5 minutes of tablet administration had no effect on the bioavailability of semaglutide compared to a cohort of animals that did not consume food. The tablet coating from Example 8 prevented the negative food effect.

[0204] Example 10: Preparation of tablets with octreotide and leuprolide Tablet preparation: A homogenous powder blend of 260 mg octreotide, 130 mg leuprolide, 6.5 g sodium caprate, 2.86 g galenIQ 720, 1.69 g Avicel PH-101, and 130 mg magnesium stearate was prepared. Mixing was first performed in a mortar and then in a Topitec powder blender. Aliquots of 890 mg were compressed into tablets using a Korsch EK0 single punch tablet press with an average compression force of approximately 15 kN.

[0205] Example 11: Enteric coating of tablets containing octreotide and leuprolide with 80% Eudragit NM30D and 20% Eudragit L30 D-55 Preparation of Eudragit dispersion: 107 g of Eudragit NM 30 D was adjusted to pH approx. 3 with 1.3 ml of 20% (w / w) citric acid solution. 67 g of distilled water was added under conventional stirring. 28 g of Eudragit L 30 D-55 was added, followed by 2 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0206] Tablet coating: Tablets from Example 10 were blended with placebo tablets of comparable weight and slightly different dimensions (to allow separation after the coating process) and coated with the Eudragit dispersion obtained above using a Glatt GC1 lab coater to a final weight of 954 mg, which corresponds to a coating weight gain of 64 mg per tablet or a weight gain of 7.2% (w / w), which corresponds to approximately 50 mg of Eudragit NM30D (dry matter) per tablet.

[0207] Example 12: Enteric coating of tablets containing octreotide and leuprolide with Eudragit L30 D-55 (reference tablet) Preparation of Eudragit dispersion: 56.9 g of distilled water was added to 114 g of Eudragit L 30 D-55 under conventional stirring, followed by 29.1 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0208] Tablet Coating: Tablets from Example 10 were coated with Eudragit dispersion using a Glatt GC1 lab coater to a final weight of 956 mg (66 mg weight gain per tablet) associated with a weight gain of 7.4% (w / w).

[0209] Example 13: Preparation of tablets with human insulin Tablet preparation: A homogenous powder blend was prepared with 96 mg human insulin, 6.0 g sodium caprate, 2.64 g galenIQ 720, 1.56 g Avicel PH-101, and 120 mg magnesium stearate. Mixing was first performed in a mortar and then in a Topitec powder blender. Aliquots of 868 mg were compressed into tablets using a Korsch EK0 single punch tablet press with an average compression force of approximately 15 kN.

[0210] Example 14: Enteric coating of tablets containing human insulin with 80% Eudragit NM30D and 20% Eudragit L30 D-55 Preparation of Eudragit dispersion: 107 g of Eudragit NM 30 D was adjusted to pH approx. 3 with 1.3 ml of 20% (w / w) citric acid solution. 67 g of distilled water was added under conventional stirring. 28 g of Eudragit L 30 D-55 was added, followed by 2 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0211] Tablet coating: Tablets were blended with placebo tablets of comparable weight and slightly different dimensions (to allow for separation after the coating process) and coated with the Eudragit dispersion obtained above using a Glatt GC1 lab coater to a final weight of 913 mg associated with a coating weight gain of 45 mg per tablet or 5.2% (w / w).

[0212] Example 15: Enteric coating of tablets containing human insulin with Eudragit L30 D-55 (reference tablet) Preparation of Eudragit dispersion: 56.9 g of distilled water was added to 114 g of Eudragit L 30 D-55 under conventional stirring, followed by 29.1 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0213] Tablet Coating: Tablets from Example 13 were coated with Eudragit dispersion using a Glatt GC1 lab coater to a final weight of 916 mg (48 mg weight gain per tablet) associated with a weight gain of 5.6% (w / w).

[0214] Example 16: Enteric coating of HPMC capsules with Eudragit L 30 D-55 (reference capsule) Preparation of Eudragit dispersion: 56.9 g of distilled water was added to 114 g of Eudragit L 30 D-55 under conventional stirring, followed by 29.1 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0215] Coating of HPMC Capsules and Tablets: Empty size 1 HPMC capsules weighing approximately 70 mg each were coated with the Eudragit dispersion to a final capsule weight of 104 mg (weight gain of 34 mg per capsule) using a Glatt GC1 lab coater.

[0216] Example 17: Enteric coating of capsules with 80% Eudragit NM30D and 20% Eudragit FS30D Preparation of Eudragit dispersion: 160.5 g of Eudragit NM 30 D was adjusted to pH approx. 3 with 2.0 ml of 20% (w / w) citric acid solution. 100.5 g of distilled water was added under conventional stirring. 42 g of Eudragit FS30D was added followed by 3 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0217] Capsule Coating: Empty size 1 HPMC capsules were coated with the Eudragit dispersion obtained above using a Glatt GC1 lab coater to a final capsule weight of approximately 102 mg associated with a coating weight gain of approximately 32 mg per size 1 capsule.

[0218] Example 18: Stability of enteric solid dosage forms containing different peptides in FEDGAS The purpose of this experiment is to demonstrate the robustness of the coated solid dosage forms according to the invention in simulated fed-state gastric media. Coated tablets from Examples 11, 12, 14, 15 and pre-coated capsules from Examples 1, 16 and 17 were used, with capsules loaded with 20 mg octreotide, 10 mg leuprolide, 8 mg insulin and 200 mg sodium caprate. Dissolution tests were performed in FEDGAS (fed-state simulated gastric fluid) at pH 6. FEDGAS™ pH 6 was prepared according to the protocol from Biorelevant (www.biorelevant.com). For each 100 ml of final media, 4.1 ml of Biorelevant buffer pH 6, 81.4 g water and 17 g FEDGAS gel were mixed together. Dissolution studies were performed in an Erweka DT light 126 using the basket method at 37°C and a rotation speed of 75 rpm. A modified version of the United States Pharmacopeia (USP) method was used. The capsules and tablets were placed in a basket and the basket was placed in an open blue cap bottle containing 100 ml of FEDGAS pH6 medium. The blue cap bottle was in direct contact with water to ensure a core temperature inside the blue cap bottle of 37° C. (The temperature was checked with an external thermometer before the start of the test). The basket was placed in the FEDGAS pH6 medium for 6 hours. 1 ml samples were removed after 60 minutes and at further predefined time points. 40 μl samples were injected into an HPLC system using a reversed-phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Waters Xselect CSH C18).

[0219] The results thus obtained are shown in Figures 2, 3 and 4. 1. Eudragit NM30D increases the robustness of enteric-coated solid dosage forms containing peptides under simulated fed conditions 2. The coated tablets according to the present invention are more robust than coated capsules under simulated eating conditions. 3. Coatings containing a combination of Eudragit NM30D and Eudragit FS30D show superior stability compared to all other coatings under simulated feeding conditions.

[0220] Example 19: Dissolution test of coated capsules The pre-coated capsules from Examples 1 and 16 were filled with 20 mg octreotide, 10 mg leuprolide, 8 mg insulin and 200 mg sodium caprate, respectively. Dissolution studies were performed on an Erweka DT light 126 using the basket method at 37°C and a rotation speed of 75 rpm. A modified version of the United States Pharmacopeia (USP) method was used. The capsules were placed in the basket and the basket was placed in an open blue cap bottle containing 100 ml of the matching dissolution medium. The blue cap bottle was in direct contact with water, ensuring an inner core temperature of the blue cap bottle of 37°C (the temperature was confirmed with an external thermometer before starting the test). The basket was first placed in simulated gastric fluid according to USP for 1 hour, then in simulated intestinal fluid (SIF) according to USP with pH 6.0 for 3 hours. 1 ml samples were taken after 60 minutes and at further time points. 40 μl of sample was injected into an HPLC system using a reversed phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Waters Xselect CSH C18).

[0221] The results thus obtained are shown in Figures 5A, 5B and 5C. These results show that all capsules are stable in the acid stage, but only the capsules coated with a significant amount of Eudragit NM30D demonstrate a lag time at later intestinal pH 6 levels, followed by a fairly fast release profile.

[0222] Example 20: In vivo evaluation of enteric-coated tablets containing insulin and sodium caprate following oral administration to cynomolgus monkeys Preparation of insulin tablets: A homogenous powder blend was prepared with 50 mg human insulin, 1.160 g sodium caprate, 510 mg galenIQ 720, 300 mg Avicel PH-101, and 20 mg magnesium stearate. Mixing was first performed in a mortar and then in a Topitec powder blender. Aliquots of 204 mg were compressed into tablets using a Korsch EK0 single punch tablet press with an average compression force of approximately 18 kN.

[0223] Enteric coating of tablets with 80% Eudragit NM30D and 20% Eudragit L30 D-55 (Sample 20a): Preparation of Eudragit dispersion: 214 g of Eudragit NM 30 D was adjusted to pH approx. 3 with 2.6 ml of 20% (w / w) citric acid solution. 134 g of distilled water was added under conventional stirring. 56 g of Eudragit L 30 D-55 was added, followed by 4 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0224] Tablet Coating: Tablets were coated with the Eudragit dispersion obtained above using a Glatt GC1 lab coater to a final weight of 217.5 mg associated with a coating weight gain of 6.5% (w / w).

[0225] Enteric coating of tablets containing human insulin with Eudragit L30 D-55 (reference tablet, sample 20b): Preparation of Eudragit dispersion: 85.5 g of distilled water was added to 171 g of Eudragit L 30 D-55 under conventional stirring, followed by 43.5 g of Plasacryl T20. The final composition was stirred for 15 minutes with a conventional stirrer. Tablets were coated with the Eudragit dispersion using a Glatt GC1 lab coater to a final weight of 217.0 mg associated with a weight gain of 6.5% (w / w).

[0226] Enteric-coated insulin tablets as described above were orally dosed to overnight fasted female cynomolgus monkeys weighing between 3.0 and 4.2 kg. Blood was collected at time points 0 (pre-dose), 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours after oral administration of the reference tablet of sample 20b. Blood was collected at time points 0 (pre-dose), 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 and 6 hours after oral administration of the tablet of sample 20a. Human insulin plasma concentrations were analyzed with a commercially available highly sensitive human insulin ELISA kit from Abcam®. A summary of the obtained pharmacokinetic parameters is shown in Table 1.

[0227] [Table 1]

[0228] Example 21: In vivo evaluation of enteric-coated tablets containing leuprolide and sodium caprate following oral administration in cynomolgus monkeys Preparation of leuprolide and octreotide tablets: A homogenous powder blend was prepared with 110 mg octreotide, 55 mg leuprolide, 1.210 g sodium caprate, 550 mg galenIQ 720, 330 mg Avicel PH-101, and 55 mg magnesium stearate. Mixing was first performed in a mortar and then in a Topitec powder blender. Aliquots of 210 mg were compressed into tablets using a Korsch EK0 single punch tablet press with an average compression force of approximately 25 kN.

[0229] Enteric coating of tablets with 80% Eudragit NM30D and 20% Eudragit L30 D-55 (Sample 21a): Preparation of Eudragit dispersion: 120 g of Eudragit NM 30 D was adjusted to pH approx. 3 with 1.5 ml of 20% (w / w) citric acid solution. 75 g of distilled water was added under conventional stirring. 31.5 g of Eudragit L 30 D-55 was added, followed by 2.25 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0230] Tablet Coating: Tablets were coated with the Eudragit dispersion obtained above using a Glatt GC1 lab coater to a final weight of 225 mg associated with a coating weight gain of 7% (w / w).

[0231] Enteric coating of tablets containing human insulin with Eudragit L30 D-55 (reference tablet, sample 21b): Preparation of Eudragit dispersion: 60 g of distilled water was added to 120 g of Eudragit L 30 D-55 under conventional stirring, followed by 30 g of Plasacryl T20. The final composition was stirred for 15 minutes with a conventional stirrer. Tablets were coated with the Eudragit dispersion using a Glatt GC1 lab coater to a final weight of 221 mg associated with a weight gain of 6% (w / w).

[0232] Enteric coated leuprolide / octreotide tablets were orally dosed to overnight fasted female cynomolgus monkeys. Blood was collected at 0 (pre-dose), 30, 60, 90, 120, 150, 180 and 240 minutes after oral administration of a reference tablet with Eudragit L30D-55 coating. Blood was collected at 0 (pre-dose), 120, 150, 180, 210, 240, 270, 300, 330 and 360 minutes after oral administration of tablets with 80% Eudragit NM30D and 20% Eudragit L30D-55 coating. Leuprolide plasma concentrations were analyzed with a commercially available leuprolide ELISA kit from BMA Biomedicals. A summary of the pharmacokinetic parameters obtained is shown in Table 2.

[0233] [Table 2]

[0234] Example 22: In vivo evaluation of enteric-coated tablets containing octreotide and sodium caprate following oral administration in cynomolgus monkeys Enteric coated octreotide tablets from Example 21 were orally dosed to cynomolgus monkeys. Blood was collected at 0 (pre-dose), 30, 60, 90, 120, 150, 180 and 240 minutes after oral administration of a reference tablet with Eudragit L30D-55 coating (sample 21b). Blood was collected at 0 (pre-dose), 120, 150, 180, 210, 240, 270, 300, 330 and 360 minutes after oral administration of a tablet with 80% Eudragit NM30D and 20% Eudragit L30D-55 coating (sample 21a). Octreotide plasma concentrations were analyzed with a commercially available octreotide ELISA kit from BMA Biomedicals. A summary of the pharmacokinetic parameters obtained is shown in Table 3.

[0235] [Table 3]

[0236] Example 23: In vivo evaluation of an enteric-coated solid oral dosage form containing semaglutide and sodium caprate following gastroscopic administration into the porcine duodenum Tablet preparation: Tablets were prepared each having 20 mg semaglutide, 500 mg sodium caprate, 220 mg sorbitol, 130 mg Avicel and 10 mg magnesium stearate.

[0237] Tablet Coating: Reference tablet B: The tablet was coated with Eudragit L30D-55. Coated tablet C: The tablet was coated with a mixture of 80% Eudragit NM30D and 20% Eudragit L30D-55. Coated tablet D: The tablet was coated with a mixture of 80% Eudragit NM30D and 20% Eudragit FS30D. Gastroscopic administration to pigs: The formulations were dosed gastroscopically directly into the duodenum of anaesthetised pigs. Blood was collected at time 0 before dosing and at 1, 2, 4, 6, 8 and 24 hours after dosing. Plasma concentrations of semaglutide were analysed by LC-MS. The results are shown in Table 4. Only the enteric coated tablets according to the invention produced significant plasma levels of semaglutide.

[0238] [Table 4]

[0239] LoQ refers to the limit of quantitation. Example 24: Enteric coating of octreotide and semaglutide tablets with Eudragit L30D-55 (reference tablet) Tablet preparation: A homogenous powder blend was prepared with 410 mg semaglutide, 410 mg octreotide, 10.25 g sodium caprate, 4.1 g sorbitol (Neosorb), 2.665 g Avicel PH-101 and 205 mg magnesium stearate. Mixing was first performed in a mortar and then in a Topitec powder blender. Aliquots of 880 mg were compressed into tablets using a Korsch EK0 single punch tablet press with an average compression force of approximately 11 kN.

[0240] Preparation of Eudragit dispersion: 58 g of distilled water was added to 114 g of Eudragit L 30 D-55 under conventional stirring, followed by 29 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0241] Tablet coating: Tablets were coated with the Eudragit dispersion using a Glatt GC1 lab coater to a final weight of 931 mg (51 mg weight gain per tablet) associated with a weight gain of 5.8% (w / w).

[0242] Example 25: Enteric coating of octreotide and semaglutide tablets with 70% Eudragit NM30D and 30% Eudragit FS30D Tablet preparation: A homogenous powder blend was prepared with 410 mg semaglutide, 410 mg octreotide, 10.25 g sodium caprate, 4.1 g sorbitol (Neosorb), 2.665 g Avicel PH-101 and 205 mg magnesium stearate. Mixing was first performed in a mortar and then in a Topitec powder blender. Aliquots of 880 mg were compressed into tablets using a Korsch EK0 single punch tablet press with an average compression force of approximately 11 kN.

[0243] Preparation of Eudragit dispersion: 140 g of Eudragit NM 30 D was adjusted to a pH of about 3 with 2.0 ml of 20% (w / w) citric acid solution. 100 g of distilled water was added under conventional stirring. 60 g of Eudragit FS30D was added, followed by 3 g of Plasacryl T20. The final composition was stirred with a conventional stirrer for 15 minutes.

[0244] Tablet Coating: Tablets were blended with empty size 1 HPMC capsules and coated with the Eudragit dispersion obtained above using a Glatt GC1 lab coater to a final tablet weight of approximately 927 mg associated with a coating weight gain of approximately 47 mg per tablet or a weight gain of 5.4% (w / w).

[0245] Example 26: Dissolution of enteric coated octreotide and semaglutide tablets Tablets from Examples 24 and 25 were used for the dissolution study. The dissolution study was carried out on an Erweka DT light 126 using the basket method at 37°C and a rotation speed of 75 rpm. A modified version of the United States Pharmacopeia (USP) method was used. The tablets were placed in the basket and the basket was placed in an open blue cap bottle containing 100 ml of the corresponding dissolution medium (SGF or SIF as mentioned below). The blue cap bottle was in direct contact with water, ensuring a core temperature inside the blue cap bottle of 37°C (the temperature was confirmed with an external thermometer before starting the test). The basket was first placed in simulated gastric fluid (SGF) according to USP for 1 hour, then in simulated intestinal fluid (SIF) according to USP with a pH of 7.4 for 5 hours. 1 ml samples were taken after 60 minutes and at further predetermined time points. 40 μl of sample was injected into an HPLC system using a reversed-phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Kinetex C18, Phenomenex). The results from the dissolution study are shown in FIG.

[0246] In conclusion, structurally distinct peptides, i.e. a) Insulin (a polypeptide with disulfide bonds) b) Leuprolide (linear peptide) c) Octreotide (cyclic peptide) d) Semaglutide (fatty acid acylated peptide) The in vivo studies reported above (see Examples 20-23) with Eudragit NM30D showed improved oral bioavailability in sodium caprate tablets when the enteric coating contained Eudragit NM30D in combination with a pH-dependent Eudragit polymer such as Eudragit L30D-55 or Eudragit FS30D.

[0247] These results further confirm that the solid oral pharmaceutical compositions according to the present invention exhibit highly advantageous pharmacokinetic properties, including advantageously improved oral bioavailability, as demonstrated in vivo using monkeys and pigs.

Claims

1. (i) a core comprising a peptide or protein drug; and (ii) First Coating wherein the first coating comprises: (ii-1) Copolymer (A) (ii-2) in combination with copolymer (B) and / or copolymer (C) and / or copolymer (D), The copolymer (A) is (a) 20 to 90 mol % of ethyl acrylate repeat units, and (b) 10 to 80 mol % of methyl methacrylate repeating units Including, If copolymer (B) is present, (a) 25 to 75 mol % of methacrylic acid repeat units, and (b) 25 to 75 mol % of ethyl acrylate repeating units Including, If copolymer (C) is present, (a) 25 to 60 mol % of methacrylic acid repeat units, and (b) 40 to 75 mol % of methyl methacrylate repeating units Including, If copolymer (D) is present, (a) 5 to 20 mol % of methacrylic acid repeat units, and (b) 20 to 40 mol % of methyl methacrylate repeat units, and (c) 60 to 75 mol % of methyl acrylate repeating units Including, Solid oral pharmaceutical compositions.

2. The first coating comprises: (ii-1) Copolymer (A) (ii-2) The solid oral pharmaceutical composition according to claim 1, comprising in combination with copolymer (B) and / or copolymer (D).

3. 2. The solid oral pharmaceutical composition of claim 1, wherein the copolymer (A) in the first coating comprises 60-75 mol % of ethyl acrylate repeat units and 25-40 mol % of methyl methacrylate repeat units.

4. 2. The solid oral pharmaceutical composition of claim 1, wherein the copolymer (A) in the first coating comprises ethyl acrylate repeat units and methyl methacrylate repeat units in a molar ratio of 2:

1.

5. 2. The solid oral pharmaceutical composition of claim 1, wherein the copolymer (A) in the first coating further comprises 0.5 to 20 mol % of 2-(trimethylammonio)ethyl methacrylate chloride repeat units.

6. 2. The solid oral pharmaceutical composition of claim 1, wherein the copolymer (B) in the first coating comprises 45-55 mol % of methacrylic acid repeat units and 45-55 mol % of ethyl acrylate repeat units.

7. 2. The solid oral pharmaceutical composition of claim 1, wherein the copolymer (B) in the first coating comprises methacrylic acid repeat units and ethyl acrylate repeat units in a 1:1 molar ratio.

8. 2. The solid oral pharmaceutical composition of claim 1, wherein the copolymer (B) in the first coating consists of methacrylic acid repeat units and ethyl acrylate repeat units.

9. 2. The solid oral pharmaceutical composition of claim 1, wherein the first coating comprises copolymer (A) and copolymer (B), and the content of copolymer (A) in the first coating is at least 25% (w / w) with respect to the total weight of copolymer (A) and copolymer (B) in the first coating.

10. A solid oral pharmaceutical composition as described in claim 9, wherein the content of copolymer (A) in the first coating is at least 50% (w / w) with respect to the total weight of copolymer (A) and copolymer (B) in the first coating.

11. A solid oral pharmaceutical composition as described in claim 9, wherein the content of copolymer (A) in the first coating is at least 75% (w / w) with respect to the total weight of copolymer (A) and copolymer (B) in the first coating.

12. (iii) further comprising a second coating on the outside of the first coating, the second coating comprising copolymer (C); The copolymer (C) (a) 25 to 60 mol % of methacrylic acid repeat units, and (b) 40 to 75 mol % of methyl methacrylate repeating units 2. The solid oral pharmaceutical composition of claim 1, comprising:

13. The solid oral pharmaceutical composition of any one of claims 1 to 12, wherein the peptide or protein drug is not a GLP-1 receptor agonist.

14. 13. The solid oral pharmaceutical composition of claim 1, wherein the peptide or protein drug has a molecular weight of about 300 kDa or less.

15. A solid oral pharmaceutical composition according to any one of claims 1 to 12, wherein the peptide or protein drug has a molecular weight of about 150 kDa or less.

16. The peptide or protein drug may be insulin, an insulin analog, insulin lispro, insulin PEG lispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG) desB30 human insulin, B29K(N(ε)octadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K(N(ε)eicosandioyl-γ-L-Glu)A14E B25H desB30 human insulin, B29K (N(ε)octadecandioyl-γ-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K (N(ε)eicosandioyl-γ-L-Glu-OEG-OEG) A14E B25H desB30 human insulin, B29K (N(ε)eicosandioyl-γ-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K (N(ε)hexadecandioyl-γ-L-Glu) A14E B16H B25H desB30 human insulin, B29K (N(ε)eicosandioyl-γ-L-Glu-OEG-OEG) A14E B16H B25H desB30 human insulin, B29K (N(ε) octadecandioyl) A14E B25H desB30 human insulin, GLP-2, GLP-2 analogs, GLP-2 agonists, teduglutide, elsiglutide, glucose-dependent insulinotropic polypeptide, elamipretide, cyclotide, recombinant factor VIIa, eptacog alfa, amylin, amylin analogs, pramlintide, somatostatin analogs, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, leptin analogs, metreleptin, peptide YY, peptide YY analogs, glatiramer, leuprolide, desmopressin, desmopressin analogs, vasopressin receptor 2 agonist peptides, osteocalcin, osteocalcin analogs or derivatives, human growth hormone, human growth hormone analogs, long-acting human growth hormone, fibroblast growth factor 21,somapsitan, hGH-CTP, antibodies, glycopeptide antibiotics, glycosylated cyclic or polycyclic nonribosomal peptide antibiotics, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, cyclotide, bortezomib, cosyntropin, chorionic gonadotropin, menotropin, sermorelin, luteinizing hormone-releasing hormone, somatropin, calcitonin, calcitonin-salmon, pentagastrin, oxytocin, neseritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, Lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alfa-2a, interferon alfa-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, pegylated interferon alfa-2a, pegylated interferon alfa-2b, pegylated interferon beta-1a, fibrinolysin, vasopressin, aldesleukin, epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta , epoetin omega, epoetin zeta, epoetin theta, methoxypolyethylene glycol-epoetin beta, sustained-release erythropoietin receptor activator, pegylated epo, albupoetin, epo-dimer analog, epo-Fc, carbamylated EPO, synthetic erythropoietic protein, low molecular weight epo analog PBI-1402, filgrastim, PEG-filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, viomycin, thyrotropin-releasing hormone, leucine-enkephalin, methyl selected from onin-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, parathyroid hormone fragment, teriparatide, PTH(1-31), PTH(2-34), parathyroid hormone-related protein, abaloparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, prostaglandin F2α receptor modulators, PDC31, abciximab, ranibizumab, alefacept, romiplostim, anakinra, abatacept, belatacept, and pharmaceutically acceptable salts thereof;A solid oral pharmaceutical composition according to any one of claims 1 to 12.

17. 13. The solid oral pharmaceutical composition of any one of claims 1 to 12, wherein the peptide or protein drug is selected from GLP-2, GLP-2 agonists, GLP-2 analogs, teduglutide, elsiglutide, insulin, human insulin, insulin analogs, insulin lispro, insulin PEG lispro, A14E B25H B29K(N(eps)octadecandioyl-gGlu-OEG-OEG)desB30 human insulin, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, antibodies, somatostatin analogs, octreotide, lanreotide, pasireotide, desmopressin, desmopressin analogs, vasopressin receptor 2 agonist peptides, parathyroid hormone fragments, teriparatide, PTH(1-31), and PTH(2-34).

18. The peptide or protein drug may be an anti-obesity peptide, a neuropeptide Y receptor (NPY) agonist peptide, a NPY receptor Y1 agonist peptide, a NPY receptor Y2 agonist peptide, a NPY receptor Y4 agonist peptide, a NPY receptor Y5 agonist peptide, a pancreatic polypeptide receptor agonist peptide, a neuropeptide Y, a peptide YY, a PYY ３－３６ , PYY analogs or derivatives, long-acting fatty acid-acylated PYY analogs, neuropeptide FF receptor type 2 (NPFF2R) agonists, G protein-coupled receptor 10 (GPR10) agonists, fatty acid-acylated dual GPR10-NPFF2R co-agonists, pancreatic polypeptide, prolactin-releasing peptide (PrRP), long-acting PrRP31 analogs, C18 lipidated PrRP31 analogs, GT001, PYY-1875, leptin receptor agonist peptides, leptin, leptin analogs or derivatives, long-acting fatty acid-acylated leptin analogs, ghrelin receptor antagonist peptides, amylin, amylin analogs or derivatives, long-acting fatty acid acylated amylin analogs, pramlintide, caglilintide, ZP8396, gastric inhibitory polypeptide (GIP) receptor agonist peptides, gastric inhibitory polypeptide (GIP) analogs or derivatives, long-acting acylated GIP analogs, GIP agonists, dual or triple agonist GIP peptides, ZP6590, glucagon receptor agonist peptides, glucagon, glucagon analogs or derivatives, long-acting acylated glucagon analogs, GLP-2 receptor agonists Peptides, GLP-2, GLP-2 analogs or derivatives, long-acting acylated GLP-2 analogs, teduglutide, grepaglutide, apraglutide, dapiglutide, elsiglutide, foligelimod, EA-230, difelikefalin acetate, kappa-opioid receptor (KOR) agonists, avipudotadil, zonulin antagonists, larazotide, brimapitide, small integrin-binding ligand N-linked glycoprotein (SIBLING), TPX-100, ZP9830, Kv1.3 ion channel blockers, ZP10000, α4β7 integrin inhibitors, pellino-1 protein-protein interaction inhibitor peptides, BBT-401, alpha-4-beta-7 (α4β7) integrin antagonists, PN-943, interleukin (IL) receptor targeting peptides, IL-23 receptor targeting peptides, PN-235, PN-232, IL-23 receptor antagonists, JNJ-77242113, nanobodies, anti-IL13 / OX40L nanobodies, anti-IL-6R nanobodies, bovalilizumab, single domain antibodies, caplacizumab, dolucanatide, WNT5A mimetic peptides, Foxy-5,Thrombospondin-1 (Tsp-1) expression-inducing peptide, cyclic pentapeptide VT1021, CXCR4 antagonist, valixafortide, anti-cytokine peptide, BNZ132-1-40, FK506-binding protein-like (FKBPL) peptide, ALM-201, fexapotide triflutate, tyroseruleutide, luteinizing hormone-releasing hormone (LHRH) acting on gonadotropin-releasing hormone (GnRH) receptors 13. The solid oral pharmaceutical composition of any one of claims 1 to 12, wherein the compound is selected from the group consisting of antagonists, ozarelix, LHRH natural ligand derivatives, EP-100, somatostatin receptor agonists, HTL0030310, vosoritide, relaxin receptor modulator peptides, relaxin, relaxin analogs or derivatives, long-acting acylated relaxin analogs, serelaxin, davunetide, zilcoplan, and arilinetide.

19. 13. The solid oral pharmaceutical composition of claim 1, wherein the solid oral pharmaceutical composition is an oral dosage form.

20. The solid oral pharmaceutical composition of claim 19, wherein the solid oral pharmaceutical composition is in the form of a capsule or tablet, or the core is in the form of multiparticulates, granules, or pellets.

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