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 combination of copolymer (A) and copolymer (B) and / or copolymer (C) and / or copolymer (D).

Description

[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, wherein the first coating comprises a combination of a copolymer (A) and a copolymer (B) and / or a copolymer (C) and / or a copolymer (D). This application claims priority to European patent application EP 22 159 924.4 filed on March 3, 2022, the entire contents of which are incorporated herein by reference.

[0002] A growing number of peptides and proteins have become available as therapeutic agents. However, the full potential of these biopharmaceuticals has yet to be realized because they are generally limited to parenteral administration. Ideally, the oral route of administration is preferred. Oral administration is the most common and popular method of administering drugs because it is simple and convenient for patients. However, the gastrointestinal tract degrades peptide and protein drugs and prevents their absorption as intact entities. Enzymatic degradation throughout the gastrointestinal tract and poor permeability through epithelial cells are the main reasons for their low oral bioavailability.

[0003] Many different approaches have been proposed to improve the oral bioavailability of such therapeutic peptides and proteins, including the use of absorption enhancement techniques or the use of protease inhibitors such as soybean trypsin inhibitor, aprotinin, Bowman-Burke inhibitor, bacitracin, camostat mesylate and amastatin (Renukuntla J et al., Int JPharm. 2013, 447(1-2):75-93; US 2007 / 0087957 A1). However, due to safety concerns, none of these protease inhibitors have been successfully used 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 greatest challenges for the pharmaceutical industry (Aguirre, TAS et al., Adv Drug Deliv Rev. 2016, 106 (Pt B), 223-241).

[0005] Current enteric coating technology has some limitations, such as the susceptibility to negative food interactions. Oral administration of such dosage forms in the presence of food results in significantly reduced oral bioavailability. In addition, it has been reported that Eudragit FS30D-coated tablets with peptide drugs have a several-fold decrease in oral bioavailability after storage (WO 2016 / 119854, Figure 3In addition, there are many 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 pH 7 or above, are prone to administration failure or incomplete dissolution, which is likely due to individual variations in small intestinal pH, such as too short an exposure to a sufficiently high pH in vivo.

[0006] Therefore, there remains an urgent and unmet need for new and improved pharmaceutical formulations of peptide or protein drugs suitable for oral administration.

[0007] The present invention addresses these shortcomings of the art and provides solid oral pharmaceutical compositions of peptide or protein drugs that are particularly suitable for oral administration due to their favorable release characteristics, improved bioavailability, and reduced food effect. A particular advantage of the present invention is that due to the combination with a primarily time-dependent polymer, a much lower amount of pH-dependent polymer is required. Such combinations with sufficiently high amounts of time-dependent polymers result in surprisingly high oral bioavailability, reduced negative food effects, reduced variability, and avoidance of failed in vivo dissolution / disintegration. In addition, these compositions are advantageously storage-stable.

[0008] Therefore, the present invention provides a solid oral pharmaceutical composition comprising:

[0009] (i) a core comprising a peptide or protein drug, and

[0010] (ii) a first coating, wherein the first coating comprises

[0011] (ii-1) copolymer (A), and

[0012] (ii-2) copolymer (B) and / or copolymer (C) and / or copolymer (D);

[0013] wherein the copolymer (A) comprises:

[0014] (a) 20 to 90 mol-% of ethyl acrylate repeating units, and

[0015] (b) 10 to 80 mol-% methyl methacrylate repeating units;

[0016] wherein copolymer (B), if present, comprises:

[0017] (a) 25 to 75 mol-% of methacrylic acid repeating units, and

[0018] (b) 25 to 75 mol-% ethyl acrylate repeating units;

[0019] wherein copolymer (C), if present, comprises:

[0020] (a) 25 to 60 mol-% of methacrylic acid repeating units, and

[0021] (b) 40 to 75 mol-% methyl methacrylate repeating units;

[0022] wherein copolymer (D), if present, comprises:

[0023] (a) 5 to 20 mol-% of methacrylic acid repeating units, and

[0024] (b) 20 to 40 mol-% of methyl methacrylate repeating units, and

[0025] (c) 60 to 75 mol-% of methyl acrylate repeating units.

[0026] Attached photos

[0027] Figure 1 : PK profile of semaglutide after oral administration of Eudragit NM30D (80%) / Eudragit FS30D (20%) coated tablets in the fasted or fed state (-o-fasted group; -●-fed group, mean ± SE of n=6) (Example 9).

[0028] Figure 2 : In vitro stability of enteric-coated dosage forms in simulated fed gastric medium as a function of octreotide release (Example 18).

[0029] Figure 3 : In vitro stability of enteric-coated dosage forms in simulated fed gastric medium as a function of leuprolide release (Example 18).

[0030] Figure 4 : In vitro stability of enteric dosage forms in simulated fed state gastric medium as a function of insulin release (Example 18).

[0031] Figure 5 : Dissolution profiles of octreotide (A), leuprolide (B) and insulin (C) from capsules coated with Eudragit L30D55 ​​(reference) or 80% Eudragit NM30D and 20% Eudragit L30D55 ​​(Example 19).

[0032] Figure 6: Dissolution profiles of tablets containing octreotide (black marks) and semaglutide (white marks) with different coatings (L30D55 ​​coating: circles, NM30D / FS30D coating: squares; n=3±SD) in SGF (1 hour) and SIF pH 7.4 (5 hours) (Example 26).

[0033] In the context of the present invention, it is surprising to find that the coating of solid oral pharmaceutical composition provided herein produces favourable release characteristics (making peptide or protein drug release in distal small intestine) significantly lower than pH 7 after oral administration, and the bioavailability of improvement compared with conventional peptide or protein drug preparation (comprising the preparation with pH dependency enteric coating).Especially, it has been found that pharmaceutical composition of the present invention makes dissolution under relatively low pH 5.5-6.5.Considering that the activity of proteolytic enzyme is compared with proximal small intestine (duodenum and jejunum), considering that the intestinal motility in this section reduces (causing the dilution effect of dissolving pharmaceutical composition to reduce, making it possible to realize high concentration of peptide or protein drug to reach optimal absorption), and considering that compared with those existing in stomach, duodenum or proximal jejunum, the solubility of peptide or protein drug under the pH level existing in distal jejunum or ileum is higher, the release of peptide or protein drug in distal small intestine (distal jejunum or ileum) is favourable.In addition, it has been found that solid oral pharmaceutical composition of the present invention advantageously demonstrates the negative food effect of reduction. This is in contrast to known formulations of peptide or protein drugs targeted to the proximal gastrointestinal tract, particularly those that are targeted and dissolved in the proximal gastrointestinal tract, such as the stomach or duodenum, without a coating or with a coating consisting solely of anionic polymers, in which adverse food interactions have been observed (Maarbjerg SJ et al., Diabetes, 2017, 66: A321 (without coating), and Example 33 of WO 2016 / 120378A1 (coating based on Eudragit FS30D)). Thus, the solid oral pharmaceutical composition of the present invention is capable of delivering peptide or protein drugs and improving independence from food intake in individuals to be treated.

[0034] The present invention also provides a solid oral pharmaceutical composition for use in therapy (as described above), in particular for use in treating or preventing a disease / disorder (as further described below). It will be understood that the disease / disorder to be treated or prevented is a disease / disorder that is susceptible to treatment or prevention with a corresponding peptide or protein drug.

[0035] The present invention also relates to the use of a solid oral pharmaceutical composition (as described above) for the preparation of a medicament for the treatment or prevention of a disease / disorder.

[0036] Furthermore, the present invention relates to a method of treating or preventing a disease / disorder in an individual, the method comprising orally administering to an individual 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.

[0037] The present invention also provides a method for oral delivery of a peptide or protein drug, which comprises orally administering a solid oral pharmaceutical composition (as described above).

[0038] Preferably, the first coating dissolves in the pH range of 5-7, preferably in the pH range of 5.5-6.5, and even more preferably in the pH range of 5.5-6.0. The components and optional components of the first coating, such as copolymers (A), (B), (C) and (D), are described below.

[0039] Copolymer (A)

[0040] The copolymer (A) is present in the first coating and comprises (a) 20-90 mol% of ethyl acrylate repeating units and (b) 10-80 mol% of methyl methacrylate repeating units. The copolymer (A) is preferably a neutral copolymer or a cationic copolymer.

[0041] In particular, preferably, the copolymer (A) in the first coating is a neutral nonionic copolymer. Preferably, at least 90 mol%, more preferably at least 95 mol%, and even more preferably at least 98 mol% of the repeating units in the copolymer (A) are selected from ethyl acrylate repeating units and methyl methacrylate repeating units. In particular, the copolymer (A) may consist of ethyl acrylate repeating units and methyl methacrylate repeating units. The copolymer (A) in the first coating preferably comprises 50-80 mol% of ethyl acrylate repeating units and 20-50 mol% of methyl methacrylate repeating units, more preferably 60-75 mol% of ethyl acrylate repeating units and 25-40 mol% of methyl methacrylate repeating units, even more preferably 64-68 mol% of ethyl acrylate repeating units and 32-36 mol% of methyl methacrylate repeating units. The molar ratio of ethyl acrylate repeating units to methyl methacrylate repeating units in the copolymer (A) is preferably 1.5:1 to 2.5:1, more preferably 1.8:1 to 2.2:1, and even more preferably 2:1. Corresponding preferred examples of copolymers (A) are poly(ethyl acrylate-co-methyl methacrylate) 2:1, in particular Eudragit NM 30D, Eudragit NE 30D or Eudragit NE 40D.

[0042] As described above, the copolymer (A) in the first coating may also be a cationic copolymer. Thus, the copolymer (A) in the first coating may further comprise 0.5-20 mol%, preferably 1-15 mol%, of 2-(trimethylammonio)ethyl methacrylate chloride repeating units (in addition to ethyl acrylate repeating units and methyl methacrylate repeating units). For example, in a preferred composition, the copolymer (A) in the first coating comprises 25-39 mol% of ethyl acrylate repeating units, 60-74 mol% of methyl methacrylate repeating units, and 1-15 mol% of 2-(trimethylammonio)ethyl methacrylate chloride repeating units. When the copolymer (A) is a cationic copolymer, preferably at least 90 mol%, more preferably at least 95 mol%, and even more preferably at least 98 mol% of the repeating units in the copolymer (A) are selected from ethyl acrylate repeating units, methyl methacrylate repeating units, and 2-(trimethylammonio)ethyl methacrylate chloride repeating units. In particular, the copolymer (A) in the first coating may consist of ethyl acrylate repeating units, methyl methacrylate repeating units and 2-(trimethylammonio)ethyl methacrylate chloride repeating units. The copolymer (A) in the first coating may comprise ethyl acrylate repeating units, methyl methacrylate repeating units and 2-(trimethylammonio)ethyl methacrylate chloride repeating units, for example in a molar ratio of 1:2:0.1 or 1:2:0.2. Corresponding preferred examples of copolymer (A) are poly(ethyl acrylate-co-methyl methacrylate-co-2-(trimethylammonio)ethyl methacrylate chloride) 1:2:0.2, in particular Eudragit RL 30D, or poly(ethyl acrylate-co-methyl methacrylate-co-2-(trimethylammonio)ethyl methacrylate chloride) 1:2:0.1, in particular Eudragit RS 30D.

[0043] It is generally preferred that the copolymer (A) in the first coating does not contain methyl acrylate repeating units. Therefore, the copolymer (A) in the first coating preferably contains no more than 3 mol% of methyl acrylate repeating units, more preferably no more than 1 mol%, even more preferably no more than 0.5 mol%, still more preferably no more than 0.1 mol%, still more preferably no more than 0.01 mol%, and most preferably 0 mol% of methyl acrylate repeating units.

[0044] Preferably, the copolymer (A) in the first coating is obtained from an aqueous dispersion of the copolymer (A).

[0045] In addition to copolymer (A), the first coating may further comprise one or more polymers selected from ethylcellulose, hydroxypropylmethylcellulose (HPMC) and polyvinyl acetate. Furthermore, the present invention also relates in another embodiment to a solid oral pharmaceutical composition as described and defined herein, wherein the first coating comprises one or more polymers selected from ethylcellulose, hydroxypropylmethylcellulose (HPMC) and polyvinyl acetate in place of copolymer (A).

[0046] Copolymer (B)

[0047] Copolymer (B), if present in the first coating, comprises (a) 25-75 mol% of methacrylic acid repeating units and (b) 25-75 mol% of ethyl acrylate repeating units, preferably 45-55 mol% of methacrylic acid repeating units and 45-55 mol% of ethyl acrylate repeating units. Copolymer (B) is preferably an anionic copolymer. For example, copolymer (B) in the first coating may comprise methacrylic acid repeating units and ethyl acrylate repeating units in a molar ratio of 0.5:1 to 1:0.5, preferably a molar ratio of 0.8:1 to 1:08, and more preferably a molar ratio of 1:1. Preferably, at least 90 mol%, more preferably at least 95 mol%, and even more preferably at least 98 mol% of the repeating units in copolymer (B) are selected from methacrylic acid repeating units and ethyl acrylate repeating units. Furthermore, it is preferred that copolymer (B) in the first coating consists of methacrylic acid repeating units and ethyl acrylate repeating units. Corresponding preferred examples of copolymers (B) are poly(methacrylic acid-co-ethyl acrylate) 1:1, in particular Eudragit L30D-55 or Eudragit L100D-55.

[0048] It is generally preferred that copolymer (B), if present in the first coating, does not comprise methyl acrylate repeating units. Thus, copolymer (B) in the first coating preferably comprises no more than 3 mol% of methyl acrylate repeating units, more preferably no more than 1 mol%, even more preferably no more than 0.5 mol%, still even more preferably no more than 0.1 mol%, still more preferably no more than 0.01 mol%, and most preferably 0 mol% of methyl acrylate repeating units.

[0049] Preferably, the copolymer (B) in the first coating is obtained from an aqueous dispersion of the copolymer (B).

[0050] Copolymer (C)

[0051] Copolymer (C), if present in the first coating, comprises (a) 25-60 mol % of methacrylic acid repeating units and (b) 40-75 mol % of methyl methacrylate repeating units. 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 repeating units in copolymer (C) are selected from methacrylic acid repeating units and methyl methacrylate repeating units. In particular, copolymer (C) in the first coating may consist of methacrylic acid repeating units and methyl methacrylate repeating units. Copolymer (C) in the first coating is preferably copolymer (C-1) or copolymer (C-2) as described below. Therefore, the first coating may comprise copolymer (C-1), copolymer (C-2) or a combination of copolymer (C-1) and copolymer (C-2).

[0052] The copolymer (C-1) in the first coating comprises 25-60 mol% of methacrylic acid repeating units and 40-75 mol% of methyl methacrylate repeating units, preferably 45-55 mol% of methacrylic acid repeating units and 45-55 mol% of methyl methacrylate repeating units. Preferably, at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeating units in the copolymer (C-1) are selected from methacrylic acid repeating units and methyl methacrylate repeating units. For example, the copolymer (C-1) in the first coating may comprise methacrylic acid repeating units and methyl methacrylate repeating units in a molar ratio of 0.5:1 to 1.5:1, preferably a molar ratio of 0.8:1 to 1:08, and more preferably a molar ratio of 1:1. In particular, the copolymer (C-1) in the first coating may consist of methacrylic acid repeating units and methyl methacrylate repeating 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.

[0053] The copolymer (C-2) in the first coating comprises 25-60 mol% of methacrylic acid repeating units and 40-75 mol% of methyl methacrylate repeating units, preferably 25-40 mol% of methacrylic acid repeating units and 60-75 mol% of methyl methacrylate repeating units. Therefore, preferably, the copolymer (C-2) in the first coating comprises methacrylic acid repeating units and methyl methacrylate repeating 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 repeating units in the copolymer (C-2) are selected from methacrylic acid repeating units and methyl methacrylate repeating units. In particular, the copolymer (C-2) in the first coating may consist of methacrylic acid repeating units and methyl methacrylate repeating units. A corresponding preferred example of copolymer (C-2) is poly(methacrylic acid-co-methyl methacrylate) 1:2, in particular Eudragit S100.

[0054] It is generally preferred that copolymer (C), if present in the first coating, including copolymer (C-1) and / or copolymer (C-2), does not contain methyl acrylate repeating units. Thus, copolymer (C) (or copolymer (C-1) and / or copolymer (C-2)) in the first coating preferably contains no more than 3 mol% of methyl acrylate repeating units, more preferably no more than 1 mol%, even more preferably no more than 0.5 mol%, still even more preferably no more than 0.1 mol%, still more preferably no more than 0.01 mol%, and most preferably 0 mol% of methyl acrylate repeating units.

[0055] Preferably, copolymer (C), including copolymer (C-1) and / or copolymer (C-2), in the first coating is obtained from an aqueous dispersion of the respective copolymer (ie, copolymer (C), copolymer (C-1) or copolymer (C-2)).

[0056] Copolymer (D)

[0057] Copolymer (D), if present in the first coating, comprises (a) 5 to 20 mol% of methacrylic acid repeating units, (b) 20 to 40 mol% of methyl methacrylate repeating units and (c) 60 to 75 mol% of methyl acrylate repeating units. Preferably, at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeating units in copolymer (D) are selected from methacrylic acid repeating units, methyl methacrylate repeating units and methyl acrylate repeating units.

[0058] Preferably, copolymer (D), if present in the first coating, comprises 7-13 mol% of methacrylic acid repeating units, 25-31 mol% of methyl methacrylate repeating units, and 62-68 mol% of methyl acrylate repeating units. Copolymer (D) in the first coating preferably comprises methacrylic acid repeating units, methyl methacrylate repeating units, and methyl acrylate repeating units in a molar ratio of 1:3:7. Furthermore, preferably, copolymer (D), if present in the first coating, consists of methacrylic acid repeating units, methyl methacrylate repeating units, and methyl acrylate repeating units.

[0059] A corresponding preferred example of copolymer (D) is a copolymer comprising (or more preferably consisting of) methacrylic acid repeating units, methyl methacrylate repeating units and methyl acrylate repeating units in a molar ratio of 1:3:7, such as Eudragit FS30D.

[0060] Content of each copolymer in the first coating

[0061] 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), still even more preferably at least 80% (w / w), still more preferably at least 90% (w / w), relative to the total weight of the first coating.

[0062] As described above, the first coating comprises a combination of copolymer (A) and copolymer (B) and / or copolymer (C) and / or copolymer (D). Preferably, the first coating comprises a combination of copolymer (A) and copolymer (B) and / or copolymer (D). More preferably, 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), still even more preferably at least 80% (w / w), still more preferably at least 90% (w / w), relative to the total weight of copolymer (A) and copolymer (B) in the first coating.

[0063] Alternatively, the first coating may also comprise copolymer (A) and copolymer (C). As described above, copolymer (C) is preferably copolymer (C-1) or copolymer (C-2). Therefore, 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).

[0064] When the first coating comprises a combination of copolymer (A) and copolymer (B), the weight ratio of copolymer (A) to copolymer (B) is preferably in 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 in the range of 9:1-7:3 (e.g., 9:1, 8:2, or 7:3), even more preferably 8:2.

[0065] Similarly, when the first coating comprises a combination of copolymer (A) and copolymer (D), the weight ratio of copolymer (A) to copolymer (D) is preferably in 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 in the range of 9:1-7:3 (e.g., 9:1, 8:2, or 7:3), even more preferably 8:2.

[0066] It will be appreciated that the first coating may also comprise one or more other polymers, in particular one or more polymers selected from ethylcellulose, hydroxypropylmethylcellulose (HPMC) and polyvinyl acetate.

[0067] The first coating may for example comprise 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.

[0068] The first coating may further comprise one or more plasticizers. The one or more plasticizers are preferably selected from monoalkyl citrate, dialkyl citrate and trialkyl citrate, such as triethyl citrate, tripropyl citrate, tributyl citrate or acetyl triethyl citrate; dialkyl sebacate, such as diethyl sebacate, dipropyl sebacate or dibutyl sebacate; dialkyl phthalate, such as dimethyl phthalate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate or dioctyl phthalate; glycerol and monoglycerides, diglycerides and triglycerides, such as triacetin, tributyrin, monostearin or acetylated monoglyceride; propylene glycol and polyethylene glycol, such as PEG 300, PEG 400, PEG 600, PEG 800, PEG 1450 or PEG 3350; fatty acids, such as stearic acid, oleic acid or fatty acid esters. More preferably, the one or more plasticizers are selected from monoalkyl citrate, dialkyl citrate and trialkyl citrate, such as triethyl citrate, tripropyl citrate, tributyl citrate or acetyl triethyl citrate. Even more preferably, the first coating further comprises 10-80 wt%, preferably 40-80 wt%, based on the total weight of the first coating, of one or more selected from triethyl citrate, tripropyl citrate and tributyl citrate. An example of a preferred plasticizer is PlasACRYL, such as PlasACRYL TM HTP20 and PlasACRYL TM T20.

[0069] Preferably the first coating is obtained from an aqueous dispersion of copolymer (A) and copolymer (B) and / or copolymer (C) and / or copolymer (D), optionally together with any optional components of the first coating.

[0070] It should be understood that the first coating is external to the core comprised by the solid oral pharmaceutical composition. The first coating preferably surrounds (or completely covers) and contains the core. Although the pharmaceutical composition may also contain one or more intermediate coatings between the core and the first coating, as described below, preferably no such intermediate layers are present, i.e., the first coating is preferably directly external to (or in direct contact with) the core.

[0071] Optional second coating

[0072] The solid oral pharmaceutical composition according to the present invention may comprise an additional coating (in addition to the first coating described above). In particular, the solid oral pharmaceutical composition preferably comprises a second coating located outside the first coating, wherein the second coating comprises copolymer (C). The second coating preferably surrounds (or completely covers) and comprises the first coating. Furthermore, the second coating preferably dissolves in a pH range of 5-7, preferably in a pH range of 5.5-6.5, and more preferably in a pH range of 5.5-6.0.

[0073] The copolymer (C) in the second coating comprises 25-60 mol% of methacrylic acid repeating units and 40-75 mol% of methyl methacrylate repeating units. 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 repeating units in copolymer (C) are selected from methacrylic acid repeating units and methyl methacrylate repeating units. In particular, the copolymer (C) in the second coating may consist of methacrylic acid repeating units and methyl methacrylate repeating units. The copolymer (C) in the second coating is preferably copolymer (C-1) or copolymer (C-2), as described below. Therefore, the second coating may comprise copolymer (C-1), copolymer (C-2) or a combination of copolymer (C-1) and copolymer (C-2).

[0074] The copolymer (C-1) in the second coating comprises 25-60 mol% of methacrylic acid repeating units and 40-75 mol% of methyl methacrylate repeating units, preferably 45-55 mol% of methacrylic acid repeating units and 45-55 mol% of methyl methacrylate repeating units. Preferably, at least 90 mol%, more preferably at least 95 mol%, even more preferably at least 98 mol% of the repeating units in the copolymer (C-1) are selected from methacrylic acid repeating units and methyl methacrylate repeating units. For example, the copolymer (C-1) in the second coating may comprise methacrylic acid repeating units and methyl methacrylate repeating units in a molar ratio of 0.5:1 to 1.5:1, preferably a molar ratio of 0.8:1 to 1:08, and more preferably a molar ratio of 1:1. In particular, the copolymer (C-1) in the second coating may consist of methacrylic acid repeating units and methyl methacrylate repeating 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.

[0075] The copolymer (C-2) in the second coating comprises 25-60 mol% of methacrylic acid repeating units and 40-75 mol% of methyl methacrylate repeating units, preferably 25-40 mol% of methacrylic acid repeating units and 60-75 mol% of methyl methacrylate repeating units. Therefore, preferably, the copolymer (C-2) in the second coating comprises methacrylic acid repeating units and methyl methacrylate repeating units in a molar ratio of 1:1.5 to 1:2.5, more preferably a molar ratio of 1:2. Preferably, at least 90 mol%, more preferably at least 95 mol%, and even more preferably at least 98 mol% of the repeating units in the copolymer (C-2) are selected from methacrylic acid repeating units and methyl methacrylate repeating units. In particular, the copolymer (C-2) in the second coating can consist of methacrylic acid repeating units and methyl methacrylate repeating units. A corresponding preferred example of copolymer (C-2) is poly(methacrylic acid-co-methyl methacrylate) 1:2, in particular Eudragit S100.

[0076] It is generally preferred that the copolymer (C), including copolymer (C-1) and / or copolymer (C-2), in the second coating does not contain methyl acrylate repeating units. Therefore, the copolymer (C) (or copolymer (C-1) and / or copolymer (C-2)) in the second coating preferably contains no more than 3 mol% of methyl acrylate repeating units, more preferably no more than 1 mol%, even more preferably no more than 0.5 mol%, still even more preferably no more than 0.1 mol%, still more preferably no more than 0.01 mol%, and most preferably 0 mol% of methyl acrylate repeating units.

[0077] Preferably, copolymer (C), including copolymer (C-1) and / or copolymer (C-2), in the second coating is obtained from an aqueous dispersion of the respective copolymer (ie, copolymer (C), copolymer (C-1) or copolymer (C-2)).

[0078] The second coating may also contain one or more plasticizers. The one or more plasticizers are preferably selected from monoalkyl citrate, dialkyl citrate and trialkyl citrate, such as triethyl citrate, tripropyl citrate, tributyl citrate or acetyl triethyl citrate; dialkyl sebacate, such as diethyl sebacate, dipropyl sebacate or dibutyl sebacate; dialkyl phthalate, such as dimethyl phthalate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate or dioctyl phthalate; glycerol and monoglycerides, diglycerides and triglycerides, such as triacetin, tributyrin, monostearin or acetylated monoglyceride; propylene glycol and polyethylene glycol, such as PEG 300, PEG 400, PEG 600, PEG 800, PEG 1450 or PEG 3350; fatty acids, such as stearic acid, oleic acid or fatty acid esters. More preferably, the one or more plasticizers are selected from monoalkyl citrate, dialkyl citrate and trialkyl citrate, such as triethyl citrate, tripropyl citrate, tributyl citrate or acetyl triethyl citrate. Even more preferably, the second coating further comprises 10-80 wt%, preferably 40-80 wt%, based on the total weight of the second coating, of one or more selected from triethyl citrate, tripropyl citrate and tributyl citrate. An example of a preferred plasticizer is PlasACRYL, such as PlasACRYL TM HTP20 and PlasACRYL TM T20.

[0079] 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.

[0080] Optional intermediate coating

[0081] 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 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 comprises 5% w / w or less, more preferably 2% w / w or less, even more preferably 1% w / w or less of the solid oral pharmaceutical composition. In addition, each intermediate coating (if present) preferably comprises 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 above-mentioned minimum and maximum weight contents of intermediate coatings.

[0082] 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, and the intermediate coating comprises hydroxypropyl methylcellulose (HPMC). Even more preferably, there is only one intermediate coating, and the intermediate coating consists of hydroxypropyl methylcellulose (HPMC).

[0083] Optional third coating

[0084] The solid oral pharmaceutical composition may further comprise a third coating surrounding and containing the second coating (if present) or the first coating (if no second coating is present).

[0085] 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.

[0086] The composition of the third coating is not particularly limited. Preferably, the third coating comprises one or more copolymers selected from the group consisting of 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 (e.g., Eudragit E 100 or other Eudragit E copolymers).

[0087] Alternatively, the third coating may be a top coat. The top coat may be a film coat or an immediate release coat. Examples of suitable top coats include White (available from Colorcon, Pa., USA), II Yellow (available from Colorcon, Pa., USA), or a copolymer based on methacrylic acid and ethyl acrylate, for example a copolymer comprising at least 40% methacrylic acid repeating units and at least 40% ethyl acrylate repeating units. For example, the third coating can comprise poly(methacrylic acid-co-ethyl acrylate) 1:1.

[0088] Peptide or protein drugs

[0089] The solid oral pharmaceutical composition of the present invention comprises a core containing a peptide or protein drug. Preferably, the peptide or protein drug is present only in the core, ie, it is not present in any coating contained in the solid oral pharmaceutical composition.

[0090] The 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, and even more preferably about 10 kDa or less. In addition, it is preferred that the peptide or protein drug has a minimum molecular weight of about 300 Da or greater, more preferably about 500 Da or greater, even more preferably about 800 Da or greater, and even more preferably about 1 kDa or greater. Therefore, 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.

[0091] The molecular weight of a peptide or protein drug is expressed herein in Daltons (Da), which is a common cross-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.

[0092] 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)). Preferably, mass spectrometry is used to determine the molecular weight of a peptide or protein drug.

[0093] The peptide or protein drug can be any peptide or protein suitable for use as a drug. 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 by at least one ester bond and / or at least one amide bond; for example, a natural cyclotide; a natural cyclotide is a disulfide-rich peptide characterized by its head-to-tail cyclized peptide backbone and the interlocking arrangement of its 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 may be free of histidine residues and / or free of cysteine ​​residues. It is generally preferred that the peptide or protein drug be water-soluble, particularly at neutral pH (i.e., at about pH 7). The present invention also allows the use of peptides or protein drugs having at least one serine protease cleavage site, i.e., peptides or protein drugs comprising one or more amino acid residues that can be or are susceptible to cleavage by a serine protease. The term "peptide or protein drug" is used herein synonymously with "therapeutic peptide or protein" and "therapeutic peptide or protein drug."

[0094] The peptide or protein drug is preferably selected from insulin (preferably human insulin), insulin analogs (e.g., long-acting basal insulin analogs or protease-stable long-acting basal insulin analogs; exemplary insulin analogs include, but are not limited to, insulin lispro, insulin PEGlispro, the insulin derivative "A14E, B25H, B29K (N(eps) octadecandioyl-gGlu-OEG-OEG), desB30 human insulin" (see, e.g., US2014 / 0056953A1), insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec and the insulin analogs / derivatives described in US2014 / 0056953A1

[0225] to

[0332] of US2014 / 0056953A1), GLP-2, a GLP-2 agonist or analog (e.g., apalutamide, teduglutide or elsiglutide), glucose-dependent insulinotropic polypeptide (also known as "gastric inhibitory polypeptide" or GIP), a gastric inhibitory polypeptide (GIP) receptor agonist, elamotide, natural cyclic peptides (i.e., peptides characterized by their head-to-tail cyclized peptide backbone and their interlocked arrangement of disulfide bonds; including, for example, natural cyclic peptides having at least two disulfide bonds, preferably natural cyclic peptides having three disulfide bonds), recombinant factor VIIa (rFVIIa), eptacog alfa, amylin, an amylin analog, pramlintide, a somatostatin analog (e.g., octreotide, lanreotide, or pasireotide), goserelin (e.g., goserelin acetate), buserelin (e.g., buserelin acetate), leptin, a leptin analog (e.g., metreleptin), peptide YY (PYY), a PYY analog, glatiramer (e.g., glatiramer acetate), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, in particular, desmopressin monoacetate trihydrate), a desmopressin analog, a vasopressin receptor 2 (V2 receptor) agonist peptide, osteocalcin, an osteocalcin analog or derivative, human growth hormone (hG H), human growth hormone analogs, long-acting human growth hormone (e.g., somapacitan or hGH-CTP (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 below), glycopeptide antibiotics (e.g., glycosylated cyclic or polycyclic non-ribosomal peptides, such as vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, or decaplanin), natural cyclic peptides, bortezomib, teicoplanin, chorionic gonadotropin, follicle-stimulating hormone, sermorelin, luteinizing hormone-releasing hormone (LHRH);also known as "gonadotropin-releasing hormone"), growth hormone, calcitonin (e.g., salmon calcitonin), 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 (i.e., pegylated interferon alfa-2a), pegylated interferon alfa-2b (i.e., pegylated interferon alpha-2b), pegylated interferon beta-1a (i.e., pegylated interferon beta-1a), plasmin, vasopressin, aldesleukin, epoetin, epoetin alfa, darbepoetin alfa, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxypolyethylene glycol-epoetin beta, continuous erythropoietin receptor activator (CERA; a pegylated EPO derivative), pegylated epo, albupoetin, epo dimer analog, epo-Fc, carbamylated EPO (CEPO), synthetic erythropoietin protein (SEP), low molecular weight EPO analog (PBI-1402), filgrastim, PEG-filgrastim, interleukin-11, interleukin-23 receptor antagonist peptide, cyclosporine, glucagon, urokinase, puromycin, thyrotropin-releasing hormone (TRH), leucine-enkephalin, methionine-enkephalin, substance P (CAS No. 33507-63-0), adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), parathyroid hormone (PTH) tablets 1-34) or eneboparatide, parathyroid hormone-related protein (PTHrP), abalaparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, prostaglandin F2α receptor modulators (e.g., PDC31), abciximab (C7E3-Fab), ranibizumab, alecept, romiplostim, anakinra, abatacept, belatacept, and pharmaceutically acceptable salts thereof. If the individual / patient to be treated is a human, and if the peptide or protein drug is an endogenous peptide or protein of a human (i.e., naturally occurring in a human; e.g., insulin or glucagon), it is further preferred to use a human isoform of the corresponding peptide or protein (which can be, for example, recombinantly expressed or chemically synthesized). ;

[0095] More preferably, the peptide or protein drug is selected from GLP-2, a GLP-2 agonist or analog (e.g. apalutamide, teduglutide or esiglutide), insulin (particularly human insulin), an insulin analog (e.g. a long-acting basal insulin analog or a protease-stable long-acting basal insulin analog; exemplary insulin analogs include, but are not limited to, insulin lispro, insulin PEGlispro, the insulin derivative "A14E, B25H, B29K (N(eps) octadecandioyl-gGlu-OEG-OEG), desB30 human insulin" (see, e.g., US2014 / 0056953 A1), insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec and the insulin analogs / derivatives described in US2014 / 0056953 A1, which is incorporated herein by reference, in particular US2014 / 0056953 A1. Each of the insulin analogs / derivatives described in paragraphs

[0225] to

[0332] of A1), antibodies, recombinant factor VIIa (rFVIIa), eptacog alfa, amylin, an amylin analog, pramlintide, a somatostatin analog (e.g., octreotide, lanreotide, or pasireotide), goserelin (e.g., goserelin acetate), buserelin, peptide YY (PYY), a PYY analog, glatiramer (e.g., glatiramer acetate), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, in particular, desmopressin monoacetate trihydrate), a desmopressin analog, a vasopressin receptor 2 (V2 receptor) agonist peptide, teicoplanin, teicoplanin, Lavancin, bleomycin, ramoplanin, decaplanin, bortezomib, teicosin, sermorelin, luteinizing hormone-releasing hormone (LHRH), calcitonin (such as salmon calcitonin), pentagastrin, nesiritide, enfuvirtide, eptifibatide, cyclosporine, glucagon, puromycin, thyrotropin-releasing hormone (TRH), leucine-enkephalin, methionine-enkephalin, substance P, parathyroid hormone (PTH) fragments (such as teriparatide (PTH (1-34)), PTH (1-31), PTH (2-34)) or enipaparatide, carfilzomib, icatibant, cilengitide, prostaglandin F2α receptor modulators (such as PDC31) and pharmaceutically acceptable salts thereof.

[0096] Even more preferably, the peptide or protein drug is selected from GLP-2, a GLP-2 agonist or analog (e.g. apalutamide, teduglutide or esiglutide), insulin (e.g. human insulin), insulin analogs (e.g. insulin lispro, insulin PEGlispro, "A14E, B25H, B29K (N(eps) octadecandioyl-gGlu-OEG-OEG), desB30 human insulin", insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin or degludec), antibodies, somatostatin analogs (e.g., octreotide, lanreotide or pasireotide), leuprolide (e.g., leuprolide acetate), desmopressin (e.g., desmopressin acetate, in particular desmopressin monoacetate trihydrate), desmopressin analogs, vasopressin receptor 2 (V2 receptor) agonist peptides, parathyroid hormone (PTH) fragments (e.g., teriparatide (PTH (1-34)), PTH (1-31), PTH (2-34)) or enipaparatide and pharmaceutically acceptable salts thereof.

[0097] Even more preferably, the peptide or protein drug is selected from GLP-2, a GLP-2 agonist or analog (e.g. apalutamide, teduglutide or esiglutide), insulin (e.g. human insulin), insulin analogs (e.g. insulin lispro, insulin PEGlispro, "A14E, B25H, B29K (N (eps) octadecandioyl-gGlu-OEG-OEG), desB30 human insulin", insulin aspart, insulin glulisine, insulin glargine, insulin detemir, insulin dapoxetine ... In some embodiments, the present invention relates to a pharmaceutical composition comprising: a monoclonal antibody, a somatostatin analogue (e.g., octreotide, lanreotide or pasireotide), a somatostatin analogue (e.g., desmopressin acetate, in particular desmopressin monoacetate trihydrate), a desmopressin analogue, a vasopressin receptor 2 (V2 receptor) agonist peptide, a parathyroid hormone (PTH) fragment (e.g., teriparatide (PTH (1-34)), PTH (1-31), PTH (2-34)) or enipaparatide and pharmaceutically acceptable salts thereof.

[0098] Still more preferably, the peptide or protein drug is selected from GLP-2, a GLP-2 agonist or analog (e.g. apalutamide, teduglutide or esiglutide), insulin (e.g. human insulin), insulin analogs (e.g. insulin lispro, insulin PEGlispro, "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 (particularly therapeutic antibodies for the treatment or prevention of local intestinal diseases / disorders, such as intestinal inflammatory disorders; for example, ustekinumab or adalimumab).

[0099] As mentioned above, the peptide or protein drug may also be an insulin analog. Preferred examples of insulin analogs include, in particular, the following:

[0100] B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin;

[0101] B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)desB30 human insulin;

[0102] B29K(N(ε)octadecandioyl-γ-L-Glu)A14E B25H desB30 human insulin;

[0103] B29K(N(ε)eicosanedioyl-γ-L-Glu)A14E B25H desB30 human insulin;

[0104] B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin;

[0105] B29K(N(ε)eicosanedioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin;

[0106] B29K(N(ε)eicosanedioyl-γ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin;

[0107] B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B16H B25H desB30 human insulin;

[0108] B29K(N(ε)eicosanedioyl-γ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin; or

[0109] B29K(N(ε)octadecandioyl)A14E B25H desB30 human insulin.

[0110] These insulin analogs are described and characterized, for example, in US 2014 / 0056953 A1. Particularly preferably, the insulin analog is B29K(N(ε)octadecandioyl-γ-L-Glu-OEG-OEG)A14E B25H desB30 human insulin.

[0111] As mentioned above, the peptide or protein drug may also be an antibody, preferably a monoclonal antibody, and it may in particular be a single-chain antibody or a single-domain antibody (e.g., a "Nanobody"). An example of a Nanobody that can be used as a peptide or protein drug according to the invention is caplucizumab. Caplucizumab is a single-domain antibody that can be used, for example, to treat or prevent thrombotic thrombocytopenic purpura (TPP) or thrombosis.

[0112] In particular, the peptide or protein drug may be an antibody selected from the group consisting of 3F8, 8H9, abagovomab, abciximab, abituzumab, abrezekimab, abrilumab, actoxumab, adalimumab, adecatumumab, atidortoxumab, aducanumab, afasevikumab, afelimomab, afutuzumab, alacizumab pegol, alemtuzumab, alirocumab, atumomab pentetate, and pentetate), amatuximab, anatumomab mafenatox, andecaliximab, anetumab ravtansine, anifrolumab, anrukinzumab, apolizumab, aprutumab ixadotin, arcitumomab, ascrinvacumab, aselizumab, atezolizumab, atinumab, torolimumab, avelumab, azintuxizumab vedotin), bapineuzumab, basiliximab, bavituximab, BCD-100, bectumomab, begelomab, belantamabmafodotin, belimumab, bemarituzumab, benralizumab, berlimatoxumab, bersanlimab, bertilimumab, besilesomab,bevacizumab, bezlotoxumab, biciromab, bimagrumab, bimekizumab, birtamimab, bivatuzumabmertansine, BIVV009, bleselumab, blinatumomab, blontuvetmab, blosozumab, bococizumab, brazikumab, brentuximab vedotin), briakinumab, brodalumab, brolucizumab, brontictuzumab, burosumab, cabiralizumab, camidanlumabtesirine, camrelizumab, canakinumab, cantuzumab mertansine, cantuzumab ravtansine, caplacizumab, capromab pendetide pendetide), carlumab, carotuximab, catumaxomab, cbr96-doxorubicin immunoconjugate, cedelizumab, cemiplimab, cergutuzumab amunaleukin, certolizumab pegol, cetrelimab, cetuximab, cibisatamab, citatuzumabbogatox, cixutumumab, clazakizumab, clenoliximab, clivatuzumab tetraxetan, codrituzumab,cofetuzumab pelidotin, coltuximab ravtansine, conatumumab, concizumab, cosfroviximab, crenezumab, crizanlizumab, crotedumab, CR6261, cusatuzumab, dacetuzumab, daclizumab, dalotuzumab, pegylated dapirolizumab pegol), daratumumab, dectrekumab, demcizumab, denintuzumab mafodotin, denosumab, depatuxizumab mafodotin, derlotuximab biotin, detumomab, dezamizumab, dinutuximab, diridavumab, domagrozumab, dorlimomab aritox), drozitumab, DS-8201, duligotuzumab, dupilumab, durvalumab, dusigitumab, duvortuxizumab, ecoromeximab, eculizumab, edobacomab, edrecolomab , efalizumab, efungumab, eldelumab, elezanumab, elgemtumab, elotuzumab, elsilimomab, emactuzumab, emapalumab, emibetuzumab, emicizumab,enapotamab edotin, enavatuzumab, enfortumab vedotin, enlimomab pegol, enoblituzumab, enokizumab, enoticumab, ensituximab, epitumomab cituxetan), epratuzumab, eptinezumab, erenumab, erlizumab, ertumaxomab, etaracizumab, etigilimab, etrolizumab, evinacumab, evolocumab ), exbivirumab, fanolesomab, faralimomab, faricimab, farletuzumab, fasinumab, FBTA05, felvizumab, fezakinumab, fibatuzumab, ficlatuzumab, Figitumumab, firivumab, flanvotumab, fletikumab, flotetuzumab, fontolizumab, foralumab, foravirumab, fremanezumab, fresolimumab, fulvezumab frunevetmab), fullanumab, futuximab, galcanezumab, galiximab, gancotamab, ganitumab, gantenerumab, gatipotuzumab, gavilimomab, gedivumab,Gemtuzumab ozogamicin, gevokizumab, gilvetmab, gimsilumab, girentuximab, glembatumumab vedotin, golimumab, gomiliximab, gosuranemab, guselkumab, ianalumab, ibalizumab, IBI308, ibritumomab tiuxetan, icrucumab, idarucizumab, ifabotuzumab, igovomab, iladatuzumab vedotin), IMAB362, imalumab, imaprelimab, imciromab, imgatuzumab, inclacumab, indatuximab ravtansine, vedotin-indusatumab vedotin), inebilizumab, infliximab, intetumumab, inolimomab, inotuzumabozogamicin, ipilimumab, iomab-b, iratumumab, isatuximab, iscalimab, istiratumab, itolizumab, ixekizumab, keliximab, labetuzumab, lacnotuzumab, and ladiratuzumab vedotin), lampalizumab, lanadelumab, landogrozumab, laprituximab emtansine, larcaviximab,lebrikizumab, lemalesomab, lendalizumab, lenvervimab, lenzilumab, lerdelimumab, leronlimab, lesofavumab, letolizumab, lexatumumab, libivirumab, lifastuzumab vedotin, ligelizumab, loncastuximab tesirine, losatuxizumab vedotin, lilotomab satetraxetan), lintuzumab, lirilumab, lodelcizumab, lokivetmab, lorvotuzumab mertansine, lucatumumab, lulizumab pegol, lumiliximab, lumretuzumab, atinib, lupartumab amadotin), lutikizumab, MABp1, mapatumumab, margetuximab, marstacimab, maslimomab, mavrilimumab, matuzumab, mepolizumab, metelimumab, milatuzumab, minretumomab, mirikizumab, mirvetuximab soravtansine), mitumomab, modotuximab, mogamulizumab, monalizumab, morolimumab, mosunetuzumab, motavizumab,moxetumomab pasudotox, muromonab-CD3, nacolomabtafenatox, namilumab, naptumomab estafenatox, naratuximab emtansine), narnatumab, natalizumab, navicixizumab, navivumab, naxitamab, nebacumab, necitumumab, nemolizumab, NEOD001, nerelimomab, nesvacumab, netakimab, nimotuzumab, nirsevimab, nivolumab, nofetumomab merpentan), obiltoxaximab, obinutuzumab, ocaratuzumab, ocrelizumab, odulimomab, ofatumumab, olaratumab, oleclumab, olendalizumab, olokizumab, omalizumab, OMS721, onartuzumab, ontuxizumab, onvatilimab, opicinumab, oportuzumab monatox), oregovomab, orticumab, otelixizumab, otilimab, otlertuzumab, oxelumab, ozanezumab, ozoralizumab, pagibaximab, palivizumab, pamrevlumab,Panitumumab, pankomab, panobacumab, parsatuzumab, pascolizumab, pasotuxizumab, pateclizumab, patritumab, PDR001, pembrolizumab, pemtumomab, pemtumomab perakizumab, pertuzumab, pexelizumab, pidilizumab, pinatuzumab vedotin, pintumomab, placulumab, plozalizumab, pogalizumab, polatuzumab vedotin, ponezumab, porgaviximab, prasinezumab, prezalizumab, priliximab, pritoxaximab, pritumumab, PRO 140. Quilizumab, racotumomab, radretumab, rafivirumab, ralpancizumab, ramucirumab, ranevetmab, anibizumab, raxibacumab, ravagalimab ), ravulizumab, refanezumab, regavirumab, remtolumab, reslizumab, rilotumumab, rinucumab, risankizumab, rituximab, rivabazumab pegol, robatumumab, rmab, roledumab, romilkimab,romosozumab, rontalizumab, rosmantuzumab, rovalpituzumab tesirine, rovelizumab, rozanolixizumab, ruplizumab, SA237, sacituzumab govitecan, samalizumab, samrotamab vedotin, sapelizumab, sarilumab, satralizumab, satumomab pendetide pendetide, secukinumab, selicrelumab, seribantumab, setoxaximab, setrusumab, sevirumab, sibrotuzumab, SGN-CD19A, SHP647, sifalimumab, siltuximab, simtuzumab, siplizumab, sirtratumab vedotin, sirukumab, sofituzumab vedotin), solanezumab, solitomab, sonepcizumab, sontuzumab, spartalizumab, stamulumab, sulesomab, suptavumab, sutimlimab, suvizumab, suvratoxumab, tabalumab, tacatuzumab etraxetan, tadocizumab, talacotuzumab, talizumab, tamtuvetmab, tanezumab,taplitumomab paptox, tarextumab, tavolimab, tefibazumab, telimomab aritox, vetin-telisotuzumab vedotin), tenatumomab, teneliximab, teplizumab, tepoditamab, teprotumumab, tesidolumab, tetulomab, tezepelumab, TGN1412, tibulizumab, tildrakizumab, tigatuzumab, timigutuzumab, timolumab, tiragolumab, tiragotumab, tislelizumab, vedotin-tisotumab vedotin), TNX-650, tocilizumab, tomozuotuximab, toralizumab, tosatoxumab, tositumomab, tovetumab, tralokinumab, trastuzumab, trastuzumab emtansine, TRBS07, tregalizumab, tremelimumab, trevogrumab, tucotuzumab celmoleukin), tuvirumab, ublituximab, ulocuplumab, urelumab, urtoxazumab, ustekinumab, utomilumab, vadastuximab talirine, vanalimab, vandortuzumab vedotin,Vantictumab, vanucizumab, vapaliximab, varisacumab, varlilumab, vatelizumab, vedolizumab, veltuzumab, vepalimomab, vesencumab, visilizumab, vobarilizumab, volociximab, vonlerolizumab, vopratelimab, vorsetuzumab mafodotin), votumumab, vunakizumab, xentuzumab, XMAB-5574, zalutumumab, zanolimumab, zatuximab, zenocutuzumab, ziralimumab, zolbetuximab, and zolimomab aritox.

[0113] 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 one of the following:

[0114] - 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 , a PYY analog or derivative (e.g., a long-acting fatty acid acylated PYY analog), a neuropeptide FF receptor type 2 (NPFF2R) agonist, a G protein-coupled receptor 10 (GPR10) agonist, a fatty acid acylated dual GPR10-NPFF2R co-agonist, pancreatic polypeptide, prolactin-releasing peptide (PrRP), a long-acting PrRP31 analog, a C18 lipidated PrRP31 analog (which is particularly useful for treating obesity or appetite regulation), GT001 (Gila Therapeutics), or PYY-1875 (Novo Nordisk);

[0115] - a leptin receptor agonist peptide (LEP-R), such as leptin, a leptin analogue or derivative, such as a long-acting fatty acid acylated leptin analogue;

[0116] -Ghrelin receptor antagonist peptide;

[0117] - Amylin (i.e., islet amyloid polypeptide (IAPP)), an amylin analog or derivative, such as a long-acting fatty acid acylated amylin analog, pramlintide, canagliflozin, or ZP8396;

[0118] 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

[0119] - a glucagon receptor agonist peptide, such as glucagon or a glucagon analogue or derivative, such as a long-acting acylated glucagon analogue.

[0120] The peptide or protein drug can also 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, glepaglutide, apalutamide, dapiglutide or esiglutide. Such peptide or protein drugs can be used, for example, to treat or prevent short bowel syndrome (SBS).

[0121] The peptide or protein drug can also be, for example, forigerimod, EA-230, difacillin acetate, a kappa opioid receptor (KOR) agonist, avipdtadil, a zonulin antagonist, larizolide, brimapitide, small integrin binding ligand N-linked glycoprotein (SIBLING), TPX-100, ZP9830, a Kv1.3 ion channel blocker, ZP10000, an α4β7 integrin inhibitor, a pellino-1 protein-protein interaction inhibitor peptide, BBT-401 (which can be used, for example, to treat or prevent ulcerative colitis), an α-4-β-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 above-mentioned peptide or protein drugs can be used, for example, to treat or prevent inflammatory or autoimmune disorders, including, for example, inflammatory bowel disease (IBD). In addition, the peptide or protein drug can also be a "nanobody" or an engineered antibody derived from a "heavy chain only" peptide or protein, such as an anti-IL13 / OX40L nanobody, an anti-IL-6R nanobody, wolbalizumab, a single domain antibody, or caplucizumab.

[0122] The peptide or protein drug can also be, for example, dolcanatide, a WNT5A-mimetic peptide, Foxy-5, a peptide that induces thrombospondin-1 (Tsp-1) expression in the tumor microenvironment, a cyclic pentapeptide VT1021, an antagonist of the chemokine receptor CXCR4, balixafortide, an anti-cytokine peptide, BNZ132-1-40 (19-mer PEGylated peptide), FK506-binding protein-like (FKBPL) peptide, ALM-201 (23-mer peptide drug), fexapotide triflutate, the tripeptide tyroserleutin, a luteinizing hormone-releasing hormone (LHRH) antagonist acting on the gonadotropin-releasing hormone (GnRH) receptor, ozarelix, a derivative of the natural ligand of LHRH, EP-100, a somatostatin receptor agonist, or HTL0030310. Such peptide or protein drugs may be particularly useful in treating or preventing cancer.

[0123] The peptide or protein drug may also be, for example, vosoritide (which may be particularly useful in treating or preventing achondroplasia), a relaxin receptor modulator peptide, relaxin, a relaxin analog or derivative, a long-acting acylated relaxin analog, recombinant relaxin (serelaxin), davuretadine (or NAP or AL-108), aziluplanam, or alinenetide (or GM604 or GM6).

[0124] In addition, the peptide or protein drug may also be a GLP-1 receptor agonist, such as semaglutide, liraglutide, exenatide, albiglutide, dulaglutide, lixisenatide, taseroglutide, langelatide, benaglutide, efpeglenatide, GLP-1 (7-37), GLP-1 (7-36) NH2, peptide oxyntomodulin, peptide oxyntomodulin derivatives or analogs, dual GLP-1 receptor / glucagon receptor agonists, dual GLP-1 receptor / gastric inhibitory peptide (GIP) receptor agonists or triple GLP-1 receptor / GIP receptor / glucagon receptor agonists. However, preferably, the peptide or protein drug is not a GLP-1 receptor agonist (or is not any of the above-mentioned specific GLP-1 receptor agonists). Therefore, 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.

[0125] The peptide or protein drug used according to the present invention may also be a mixture of two or more different peptide or protein drugs, including any of the specific peptide or protein drugs described above. For example, it may be preferable to use not only one of semaglutide and octreotide as the peptide or protein drug, but also a mixture of these. As another example, it is preferable to use not only one of semaglutide, octreotide, and leuprolide as the peptide or protein drug, but also a mixture of these.

[0126] The above exemplary peptide or protein drugs have been proposed in the literature as being suitable for treating or preventing a variety of different diseases / disorders, and some of these peptide or protein drugs have received marketing authorization for specific therapeutic indications. The present invention also particularly relates to solid oral pharmaceutical compositions provided herein for treating or preventing diseases / disorders suitable for treatment or prevention with the corresponding peptide or protein drugs. Similarly, the present invention relates to methods for treating or preventing diseases / disorders, comprising orally administering to an individual in need thereof a solid oral pharmaceutical composition provided herein, wherein the disease / disorder is a disease / disorder suitable for treatment or prevention with the corresponding peptide or protein drug. Preferred examples of diseases / disorders suitable for treatment or prevention with any particular peptide or protein drug according to the present invention are disclosed in (and can be derived from) the medical literature, in particular any of the following: ROTE LISTE online version (version as of the priority date or filing date of the present specification, in particular the version of September 7, 2020); ROTE LISTE 2020 (printed version, Rote Liste Service GmbH, 2020, ISBN 978-3-946057-52-9); GELBE LISTE online version (version as of the priority date or filing date of the present specification, in particular the version of September 7, 2020); GELBE LISTE 2017 (printed version, AVOXA-Mediengruppe DeutscherApotheker GmbH, 2017, ISBN 978-3774199149); Aktories K et al. (eds.), Allgemeine and Spezielle Pharmakologie and Toxikologie, Urban & Fischer Verlag / Elsevier GmbH, 12th edition, 2017, ISBN 978-3437425257; Ammon HPT et al. (eds.), Hunnius Pharmazeutisches De Gruyter, 11th edition, 2014, ISBN 978-3110309904; Otto HH et al., Arzneimittel-Ein Handbuch für und Apotheker, Wissenschaftliche Verlagsgesellschaft, 2017, ISBN 978-3804737266; ​​DrugBank (www.drugbank.ca, the version of this specification with the priority date or filing date, in particular the version dated September 7, 2020); Drugs.com (www.drugs.com, the version of this specification with the priority date or filing date, in particular the version dated September 7, 2020); Merck the European Medicines Agency (EMA) database (www.ema.europa.eu, the version of this specification sheet on the priority date or filing date, in particular the version on September 7, 2020); the U.S. Food and Drug Administration (USFDA) database (www.fda.gov, the version of this specification sheet on the priority date or filing date, in particular the version on September 7, 2020); the Japan Pharmaceuticals and Medical Devices Agency database (www.pmda.go.jp, the version of this specification sheet on the priority date or filing date, in particular the version on September 7, 2020); or the Electronic Medicines Standard Compendium (eMC) database (www.medicines.org.uk / emc / , the version of this specification sheet on the priority date or filing date, in particular the version on September 7, 2020). Examples of diseases / disorders suitable for treatment or prevention using analogs or derivatives of any particular peptide or protein drug include the same diseases / disorders suitable for treatment or prevention using the corresponding (underivatized) peptide or protein drug.In addition, preferred examples of diseases / disorders suitable for treatment or prevention with any of the above-mentioned insulins or insulin analogs include, in particular, 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 (e.g., prostate cancer or breast cancer) or estrogen-dependent conditions (e.g., endometriosis or uterine leiomyoma); buserelin may further be used, for example, for assisted reproduction; preferred examples of diseases / disorders suitable for treatment or prevention with human growth hormone (hGH) or any of the above-mentioned hGH analogs 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 epoetins or any of their analogs 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, for example, Alcalá-Barraza SR et al., J Drug Target. 2010; 18(3): 179-90) or multiple sclerosis; Preferred examples of diseases / disorders suitable for treatment or prevention with the above-mentioned filgrastim or any derivative thereof (e.g., PEG-filgrastim) include, in particular, low blood neutrophils due to various causes, such as chemotherapy, radiation poisoning, HIV or AIDS, or unknown causes; Preferred examples of diseases / disorders suitable for treatment or prevention with the above-mentioned antibody adalimumab include, in particular, inflammatory or autoimmune diseases / disorders, and more preferably selected from rheumatoid arthritis Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis (e.g., chronic psoriasis), hidradenitis suppurativa, juvenile idiopathic arthritis, and birdshot retinochoroidopathy; Preferred examples of diseases / disorders suitable for treatment or prevention with the above-mentioned antibody ustekinumab include, in particular, inflammatory or autoimmune diseases / disorders (e.g., intestinal inflammatory or intestinal autoimmune diseases / disorders), and are more preferably selected from Crohn's disease, ulcerative colitis, psoriasis (e.g., chronic psoriasis), and psoriatic arthritis.

[0127] The solid oral pharmaceutical composition according to the present invention can 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, bacterial infections of the colon or colorectal cancer. It should be understood that in this case, the peptide or protein drug contained in the core of the solid oral pharmaceutical composition should be a peptide or protein drug (in particular an antibody; such as adalimumab) that is effective against the corresponding intestinal disease / disorder.

[0128] The peptide or protein drug included in the solid oral pharmaceutical composition of the present invention can be further used in combination with one or more other therapeutic agents, particularly one or more other peptide or protein drugs (as described herein), and the one or more other therapeutic agents, particularly one or more other peptide or protein drugs (as described herein) can be present in the solid oral pharmaceutical composition of the present invention, preferably in the core of the solid oral pharmaceutical composition, or can be provided in a separate pharmaceutical composition. In the latter case, the separate pharmaceutical composition can be administered simultaneously / concomitantly with the solid oral pharmaceutical composition according to the present invention, or can be administered sequentially. Preferably, 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 peptides or protein drugs are present in the core).

[0129] It should be understood that peptide or protein drugs (including any exemplary peptide or protein drugs described herein) can exist in non-salt form or in the form of pharmaceutically acceptable salts. The corresponding pharmaceutically acceptable salts can be formed, for example, by protonating an atom carrying a lone pair of electrons susceptible to protonation (e.g., an amino group) with an inorganic or organic acid, or as salts of a carboxylic acid group with a physiologically acceptable cation, as they are well known in the art. 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 salts, meglumine salts, ethylenediamine salts, or choline salts; arylalkylamine salts such as N,N-dibenzylethylenediamine salts, benzathine penicillin salts, phenethylbenzylamine salts; heterocyclic aromatic amine salts such as pyridinium salts, picoline salts, quinolinium salts, or isoquinolinium salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benzyltrimethylammonium salts, benzyltriethylammonium salts, benzyltributylammonium salts, methyltrioctylammonium salts, or tetrabutylammonium salts; and basic amino acid salts such as arginine salts, lysine salts, or histidine salts. Exemplary acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate (e.g., phosphate, hydrogenphosphate, or dihydrogenphosphate), carbonate, bicarbonate, or perchlorate; organic acid salts such as acetate, propionate, butyrate, valerate, hexanoate, heptanoate, octanoate, cyclopentanepropionate, decanoate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, glycolate, nicotinate, benzoate, salicylate, ascorbate, or pamoate; sulfonate salts such as mesylate, esylate, 2-hydroxyethanesulfonate (isethionate), besylate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate (naphthalenesulfonate), 3-phenylsulfonate, or camphorsulfonate; and acidic amino acid salts such as aspartate or glutamate.

[0130] The solid oral pharmaceutical composition of the present invention may also contain one or more amino acids, particularly arginine (preferably L-arginine) and / or lysine (preferably L-lysine). Arginine can be used in the form of, for example, a free base (non-salt form) or a hydrochloride (HCl). Lysine can also be used, for example, in the form of a free base (non-salt form) or a hydrochloride. Amino acids, particularly arginine (e.g., L-arginine free base or L-arginine HCl) and / or lysine (e.g., L-lysine free base or L-lysine HCl) can be provided in the core of the solid oral pharmaceutical composition (together with the peptide or protein drug), which is particularly advantageous if the peptide or protein drug is an antibody. Therefore, if the peptide or protein drug is an antibody (e.g., any of the exemplary / particular antibodies described above), it is preferred that the antibody (in the core of the solid oral pharmaceutical composition) be present 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).

[0131] The solid oral pharmaceutical composition can optionally include one or more other pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, adhesives, colorants, pigments, stabilizers, preservatives, antioxidants, amino acids, reducing agents, bioadhesives and / or dissolution enhancers. In particular, it can include one or more additives selected from vitamin E, histidine, microcrystalline cellulose (MCC), mannitol, starch, sorbitol and / or lactose. The solid oral pharmaceutical composition can be prepared by technology well known to those skilled in the art (for example, the technology announced in the 20th edition of Remington's Pharmaceutical Sciences).

[0132] As described above, the solid oral pharmaceutical composition may comprise one or more solubility enhancers, for example, poly(ethylene glycol), including poly(ethylene glycol) (molecular weight of about 200 to about 5,000 Da), ethylene glycol, propylene glycol, nonionic surfactants, tyloxapol, polysorbate 20, polysorbate 80, polyethylene glycol-15-hydroxystearate, phospholipids, lecithin, dimyristoylphosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, hydroxypropyl-γ-cyclodextrin. syl-β-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxyalkyl sulfide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, vinyl acetate copolymer, vinyl pyrrolidone, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or any combination thereof.

[0133] In addition, as mentioned above, solid oral pharmaceutical composition can comprise one or more pharmaceutically acceptable carriers.Pharmaceutically acceptable carrier can be aqueous or non-aqueous reagent, for example alcohol or oil or its mixture, and can contain surfactant, softener, lubricant, stabilizer, dye, spices, preservative, acid or alkali for regulating pH, solvent, emulsifier, gelling agent, humectant, stabilizer, wetting agent, sustained-release agent, wetting agent or any other component that is usually included in the solid oral pharmaceutical composition of specific form.Pharmaceutically acceptable carrier is well known in the art, comprises for example aqueous solution such as water or physiological buffered saline or other solvent or vehicle such as ethylene glycol, glycerol and oil such as olive oil or injectable organic ester.Pharmaceutically acceptable carrier can comprise physiologically acceptable compound, it for example plays the effect of stabilizing or increasing the absorption of peptide or protein drug, for example, carbohydrate such as glucose, sucrose or dextran, antioxidant such as ascorbic acid or glutathione, chelating agent, low molecular weight protein or other stabilizer or excipient. Pharmaceutically acceptable carriers can also be selected from substances such as distilled water, benzyl alcohol, lactose, starch, talc, magnesium stearate, polyvinyl pyrrolidone, alginic acid, colloidal silica, titanium dioxide, and flavoring agents. Preferred pharmaceutically acceptable carriers, particularly 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.

[0134] Core of solid oral pharmaceutical composition

[0135] The core of the solid oral pharmaceutical composition of the present invention comprises a peptide or protein drug (as described above).

[0136] Preferably, the core of the solid oral pharmaceutical composition also 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 the peptide or protein drug, particularly through the intestinal mucosa, and is particularly advantageous if the peptide or protein drug is a macromolecule, such as a peptide or protein drug having a molecular weight of about 1 kDa or greater.

[0137] The penetration enhancer can be, for example, a zwitterionic penetration enhancer, a cationic penetration enhancer, an anionic penetration enhancer (eg, an anionic penetration enhancer comprising one or more sulfonic acid groups (-SO3H)), or a nonionic penetration enhancer.

[0138] Preferably, the penetration enhancer is selected from C 8-20 Alkanoylcarnitine (preferably lauroylcarnitine, myristoylcarnitine or palmitoylcarnitine; for example lauroylcarnitine chloride, myristoylcarnitine chloride or palmitoylcarnitine chloride), salicylic acid (preferably a salicylate such as sodium salicylate), a salicylic acid derivative (for example, 3-methoxysalicylic acid, 5-methoxysalicylic acid or homovanillic acid, C 8-20 Alkanoic acid (preferably C 8-20alkanoate, more preferably decanoate, octanoate, myristate, palmitate or stearate, such as sodium decanoate, sodium octanoate, sodium myristate, sodium palmitate or sodium stearate), citric acid (preferably citrate, such as sodium citrate), tartaric acid (preferably tartrate), fatty acid acylated amino acids (e.g., any fatty acid acylated amino acids described in US 2014 / 0056953 A1, which is incorporated herein by reference,Including but not limited to sodium lauroyl alanine, N-lauroyl-L-alanine, sodium lauroyl asparagine, N-lauroyl-L-asparagine, sodium lauroyl aspartate, N-lauroyl-L-aspartic acid, sodium lauroyl cysteine, N-lauroyl-L-cysteine, sodium lauroyl glutamate, N-lauroyl-L-glutamate, sodium lauroyl glutamine, N-lauroyl-L-glutamine, sodium lauroyl glycinate, N-lauroyl-L-glycine, sodium lauroyl histidine, N-lauroyl-L-histidine, sodium lauroyl isoleucine, N-lauroyl- L-Isoleucine, Sodium Lauroyl Leucine, N-Dodecanoyl-L-Leucine, Sodium Lauroyl Methionine, N-Dodecanoyl-L-Methionine, Sodium Lauroyl Phenylalanine, N-Dodecanoyl-L-Phenylalanine, Sodium Lauroyl Proline, N-Dodecanoyl-L-Proline, Sodium Lauroyl Serine, N-Dodecanoyl-L-Serine, Sodium Lauroyl Threonine, N-Dodecanoyl-L-Threonine, Sodium Lauroyl Tryptophan, N-Dodecanoyl-L-Tryptophan, Sodium Lauroyl Tyrosine, N-Dodecanoyl-L-Tyrosine, Sodium Lauroyl Valine, N-Dodecanoyl-L-Valine , Sodium Lauroyl Sarcosinate, N-Lauroyl-L-Sarcosine, Sodium Decanoate Alanine, N-Decanoyl-L-Alanine, Sodium Decanoate Asparagine, N-Decanoyl-L-Asparagine, Sodium Decanoate Aspartate, N-Decanoyl-L-Aspartic Acid, Sodium Decanoate Cysteine, N-Decanoyl-L-Cysteine, Sodium Decanoate Glutamate, N-Decanoyl-L-Glutamic Acid, Sodium Decanoate Glutamine, N-Decanoyl-L-Glutamine, Sodium Decanoate Glycinate, N-Decanoyl-L-Glycine, Sodium Decanoate Histidine, N-Decanoyl-L-Histidine, Sodium Decanoate Isoleucine, N-Decanoyl-L-Isoleucine, Sodium Decanoate Leucine, N-Decanoyl N-decanoyl-L-leucine, sodium methionine decanoate, N-decanoyl-L-methionine, sodium phenylalanine decanoate, N-decanoyl-L-phenylalanine, sodium proline decanoate, N-decanoyl-L-proline, sodium serine decanoate, N-decanoyl-L-serine, sodium threonine decanoate, N-decanoyl-L-threonine, sodium tryptophan decanoate, N-decanoyl-L-tryptophan, sodium tyrosine decanoate, N-decanoyl-L-tyrosine, sodium valine decanoate, N-decanoyl-L-valine, sodium sarcosinate decanoate, N-decanoyl-L-sarcosine, sodium oleoyl sarcosinate, sodium N-decylleucine, sodium stearoyl glutamate (e.g., Amisoft HS-11P), 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), Sodium N-Decyl Leucine, Sodium Cocoyl Glycinate, Sodium Cocoyl Glutamate, Sodium Lauroyl Alanine, N-Lauryl-L-Alanine, Sodium Lauroyl Asparagine, N-Lauryl-L-Asparagine, Sodium Lauroyl Aspartate, N-Lauryl-L-Aspartic Acid, Sodium Lauroyl Cysteine, N-Lauryl-L-Cysteine, Sodium Lauroyl Glutamate, N-Lauryl-L-Glutamate, Sodium Lauroyl Glutamine, N-Lauryl-L-Glutamine, Sodium Lauroyl Glycinate, N-Lauryl-L-Glycine, Sodium Lauroyl Histidine, N-Lauryl L-histidine, sodium lauroyl isoleucine, N-dodecanoyl-L-isoleucine, sodium lauroyl leucine, N-dodecanoyl-L-leucine, sodium lauroyl methionine, N-dodecanoyl-L-methionine, sodium lauroyl phenylalaninate, N-dodecanoyl-L-phenylalanine, sodium lauroyl proline, N-dodecanoyl-L-proline, sodium lauroyl serine, N-dodecanoyl-L-serine, sodium lauroyl threonine, N-dodecanoyl-L-threonine, sodium lauroyl tryptophan, N-dodecanoyl-L-tryptophan, sodium lauroyl tyrosine, N-dodecanoyl-L-tyrosine , Sodium lauroyl valine, N-dodecanoyl-L-valine, N-dodecanoyl-L-sarcosine, Sodium decanoate alanine, N-decanoyl-L-alanine, Sodium decanoate asparagine, N-decanoyl-L-asparagine, Sodium decanoate aspartate, N-decanoyl-L-aspartic acid, Sodium decanoate cysteine, N-decanoyl-L-cysteine, Sodium decanoate glutamate, N-decanoyl-L-glutamic acid, Sodium decanoate glutamine, N-decanoyl-L-glutamine, Sodium decanoate glycinate, N-decanoyl-L-glycine, Sodium decanoate histidine, N-decanoyl-L-histidine, Sodium decanoate isoleucine, N-decanoyl-L-isoleucine, Sodium leucinate, N-decanoyl-L-leucine, leucine, sodium methionine decanoate, N-decanoyl-L-methionine, sodium phenylalanine decanoate, N-decanoyl-L-phenylalanine, sodium proline decanoate, N-decanoyl-L-proline, sodium serine decanoate, N-decanoyl-L-serine, sodium threonine decanoate, N-decanoyl-L-threonine, sodium tryptophan decanoate, N-decanoyl-L-tryptophan, sodium tyrosine decanoate, N-decanoyl-L-tyrosine, sodium valine decanoate, N-decanoyl-L-valine, sodium sarcosinate decanoate, sodium oleoyl sarcosinate, and pharmaceutically acceptable salts of any of the above compounds; or, for example, C, 8-20 Alkanyl sarcosinate (e.g., lauroyl sarcosinate, such as sodium lauroyl sarcosinate) or one of the 20 standard proteinogenic α-amino acids, which are expressed as C 8-20 alkanoic acid acylation), alkyl sugars (e.g., C 1-20 Alkyl sugars, such as C8-10 Alkyl polysaccharides, such as Multitrope TM 1620-LQ-(MV); or, for example, n-octyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, n-tetradecyl-β-D-maltoside, tridecyl-β-D-maltoside, sucrose laurate, sucrose stearate, sucrose myristate, sucrose palmitate, sucrose cocoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate, coco-glucoside, or US 5,661,130 or WO 2012 / 112319, which is 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]octanoic acid (preferably N-[8-(2-hydroxybenzoyl)amino]octanoic acid salt, more preferably sodium N-[8-(2-hydroxybenzoyl)amino]octanoate, also known as "SNAC"), N-[8-(2-hydroxybenzoyl)amino]octanoic acid salt derivatives (preferably N-[8-(2-hydroxybenzoyl)amino]octanoic acid sodium salt derivatives), thiol polymers (also known as thiolate polymers; can be synthesized, for example, by immobilizing a ligand bearing a thiol group on an established polymer backbone (e.g., polyacrylic acid, carboxymethyl cellulose, or chitosan); exemplary thiol polymers include Laffleur F et al., Future Med 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]octanoic acid salt (preferably N-[8-(2-hydroxybenzoyl)amino]octanoic acid sodium salt derivatives), Chem. 2012, 4(17): 2205-16 (doi: 10.4155 / fmc.12.165), which are incorporated herein by reference), mucoadhesive polymers having a vitamin B partial structure (e.g., any mucoadhesive polymer described in US Pat. No. 8,980,238 B2, which are incorporated herein by reference; particularly including any polymer compound defined in any one of claims 1 to 3 of US Pat. No. 8,980,238 B2), calcium chelating compounds (e.g., ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), sodium citrate or polyacrylic acid), polyoxyethylene castor oil EL (also known as "Kolliphor EL"; CAS No. 61791-12-6), chitosan, N,N,N-trimethylchitosan, benzalkonium chloride, benzstatin, cetylpyridinium chloride, cetyltrimethylammonium bromide, C 2-20 Alkanol (e.g., ethanol, decyl alcohol, lauryl alcohol, myristyl alcohol, or palmityl alcohol), C 8-20 Enols (e.g., oleyl alcohol), C 8-20 Alkenic acid (e.g., oleic acid), dextran sulfate, diethylene glycol monoethyl ether (DEG), 1-dodecylazacycloheptan-2-one Caprylocaproyl polyoxylglycerides (such as, for example, caprylocaproyl polyoxyethylene-8 glycerides; which can be used, for example, as or MC8-2), ethyl caprylate, glyceryl monolaurate, lysophosphatidylcholine, methanol, C 8-20 Alkylamine, C 8-20 Alkenylamine (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 salt, such as sodium cholate), deoxycholate (e.g., sodium deoxycholate), chenodeoxycholate (e.g., sodium chenodeoxycholate), sodium glycolate, sodium glycodeoxycholate, sodium dodecyl sulfate (SDS), sodium decyl sulfate, sodium octyl sulfate, sodium laureth sulfate, N-lauryl sarcosinate, decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, dodecylpyridinium chloride, decyldimethylammoniumpropane sulfonate, myristyldimethylammoniumpropane sulfonate, palmityldimethylammoniumpropane sulfonate, ChemBetaine CAS, ChemBetaine Oleyl, nonylphenoxypolyoxyethylene, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monooleate, Triton X-100, caproic acid, heptanoic acid, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl palmitate, diethyl sebacate, sodium oleate, urea, laurylamine, caprolactam, methyl pyrrolidone, octyl pyrrolidone, methyl piperazine, phenyl piperazine, Carbopol 934P, glycyrrhetinic acid, bromelain, pinene oxide, limonene, cineole, octyldodecanol, fenchone, menthone, trimethoxypropylenemethylbenzene, cell penetrating peptides (e.g., Klaklak, polyarginine or oligoarginine (particularly octaarginine), penetrant (particularly L-penetrant), penetrant analogs (particularly PenetraMax; see, e.g., El-Sayed Khafagy et al., Eur J Pharm Biopharm. 2013; 85(3Pt A): 736-43), HIV-1 Tat, transporter or any cell penetrating peptide mentioned in US 2012 / 0065124), polyethylene glycol-15-hydroxystearate (e.g., Solutol HS15), 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), sulfoxides (e.g., (C 1-10 alkyl)-(C 1-10

[00145] In some embodiments, the present invention provides a pharmaceutically acceptable salt of a pharmaceutically acceptable salt of a pharmaceutically acceptable salt of a pharmaceutically acceptable salt of a pharmaceutically acceptable salt of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts of the pharmaceutically acceptable salts include, for example, decylmethylsulfoxide or dimethylsulfoxide, cyclopentadecalactone, 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-octanoic acid (also known as "5-CNAC"), N-(10-[2-hydroxybenzoyl]amino)decanoic acid (also known as "SNAD"), dodecyl-2-N,N-dimethylaminopropionate (also known as "DDAIP"), D-α-tocopheryl polyethylene glycol-1000 succinate (also known as "TPGS"), arginine, and pharmaceutically acceptable salts of the above compounds. Mixtures of two or more penetration enhancers can also be used, including any of the above penetration enhancers. In addition, any chemical permeation enhancer described in Whitehead K et al., Pharm Res. 2008 Jun; 25(6): 1412-9 (particularly any of those described in Table 1 of that reference), any modified amino acid disclosed in US 5,866,536 (particularly any of compounds I to CXXIII as disclosed in US 5,866,536, which are incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as a disodium salt, ethanol solvate or hydrate of any of these compounds), any modified amino acid disclosed in US 5,773,647 (particularly any of compounds 1 to 193 as disclosed in US 5,773,647, which are incorporated herein by reference, or a pharmaceutically acceptable salt or solvate thereof, such as a disodium salt, ethanol solvate or hydrate of any of these compounds), any modified amino acid disclosed in WO Any nanoparticles described in 2011 / 133198, any polymer formulations and / or hydrogels described in US 2015 / 174076 (e.g., as described in Torres-Lugo M et al., Biotechnol Prog. 2002; 18(3): 612-6) can also be used as penetration enhancers. In addition, complex lipid dispersions (e.g., combinations of insoluble surfactants or oils with soluble surfactants, and optionally with water or cosolvents) can also be used as penetration enhancers; corresponding exemplary penetration enhancers include, in particular, mixed micelles, reverse micelles, self-emulsifying systems (e.g., SEDDS, SMEDDS or SNEDDS), lipid dispersions, course emulsions or solid lipid nanoparticles (SLN). Preferably, the penetration 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]caprylic acid compound or a pharmaceutically acceptable salt thereof (particularly sodium N-[8-(2-hydroxybenzoyl)amino]caprylate).In particular, preferably, the penetration enhancer is an N-[8-(2-hydroxybenzoyl)amino]octanoic acid compound or a pharmaceutically acceptable salt thereof, particularly sodium N-[8-(2-hydroxybenzoyl)amino]octanoate.

[0139] Further preferred penetration enhancers are alkyl polysaccharides, arginine or ( HS15). In particular, the penetration enhancer may be an alkyl glycoside (or a combination of two or more alkyl glycosides), which may be selected from any one of the alkyl glycosides described below.

[0140] The alkyl glycosides used as penetration enhancers according to the present invention can be synthesized by known methods, 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), US Pat. No. 3,219,656 or US 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).

[0141] Alkyl glycosides useful as penetration enhancers in the present invention may 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 -sucrose glycoside (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 (which may be synthesized according to Defaye, J. and Pederson, C., "Hydrogen Fluoride, Solvent and Reagent for Carbohydrate Conversion Technology" in Carbohydrates as Organic Raw Materials, 247-265 (ed. by FW Lichtenthaler); VCH Publishers, New York (1991); Ferenci, T., J. Bacteriol, 144:7-11 (1980) synthesis); alkyl thioglucosides, such as heptyl- or octyl-1-thio α- or β-D-glucopyranoside (Anatrace Corporation, Maumee, Ohio; see Saito, S. and Tsuchiya, T. Chem. Pharm. Bull. 33:503-508 (1985)); alkyl thiosucrose (which can be synthesized according to, for example, Binder, TP and Robyt, JF, Carboh Synthesis of alkyl maltotriosides (which can be synthesized according to Koeltzow and Urfer); long-chain aliphatic carbonic acid amides of β-amino-alkyl ethers of sucrose (which can be synthesized according to Australian Patent 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 via an amide bond (which can be synthesized according to Kunz, M., "Sucrose-based Hydrophilic Building Blocks as Intermediates for the Synthesis of Surfactants and Polymers" in Carbohydrates as Organic Raw Materials, 127-153); derivatives of isomaltosamine linked to an alkyl chain via urea (which can be synthesized according to Kunz); long-chain aliphatic carbonyl ureides of sucrose β-amino-alkyl ethers (which can be synthesized according to Gruber and Greber, pp. 95-116); and long-chain aliphatic carbonic acid amides of sucrose β-amino-alkyl ethers (which can be synthesized according to Australian Patent 382,381 (1987), Chem. Abstr., 108:1147-19 (1988) and Gruber and Greber, pp. 95-116).

[0142] The penetration enhancer may also be selected from any of the enhancers mentioned in US 8,927,497, particularly including any alkyl glycoside, any sugar alkyl ester and / or any mucosal delivery enhancer described herein.

[0143] In addition, the penetration enhancer may also be a compound of formula (I):

[0144]

[0145] in:

[0146] R 1 、R 2 、R 3 and R 4 Each independently selected from hydrogen, -OH, -NR 6 R 7 , halogen (e.g., -F, -Cl, -Br, or -I), C 1-4 Alkyl or C 1-4 alkoxy;

[0147] R 5 is 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)]; and

[0148] R 6 and R7 are independently hydrogen, oxygen, -OH or C 1-4 alkyl;

[0149] or a pharmaceutically acceptable salt or solvate thereof, in particular a disodium salt, 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., a monohydrate of the disodium salt). The above-mentioned "substituted" groups contained in formula (I) are preferably substituted by one or more (e.g., one, two or three) independently selected from halogen (e.g., -F, -Cl, -Br or -I), -OH, C 1-4 Alkyl or C 1-4 The substituent of alkoxy replaces. These compounds and preparation methods thereof are described in, for example, WO 00 / 59863, which is incorporated herein by reference. Therefore, penetration enhancers can also be " delivery agents " as described in WO 00 / 59863. Preferred embodiments of formula (I) compound include N-(5-chlorosalicyloyl)-8-aminocaprylic acid, N-(10-[2-hydroxybenzoyl] amino) decanoic acid, N-(8-[2-hydroxybenzoyl] amino) caprylic acid, the monosodium salt or disodium salt of any one of the above-mentioned compounds, the ethanol solvate of the sodium salt (for example, monosodium salt or disodium salt) of any one of the above-mentioned compounds, the monohydrate of the sodium salt (for example, monosodium salt or disodium salt) of any one of the above-mentioned compounds, and any combination thereof. In particular, preferably, formula (I) compound is the disodium salt or its monohydrate of N-(5-chlorosalicyloyl)-8-aminocaprylic acid.

[0150] In particular, preferably, the penetration enhancer is selected from sodium caprate, sodium caprylate, a mixture of sodium caprate and sodium caprylate, SNAC, sucrose laurate, caprylic capric macrogol glycerides (labrasol) and polysorbates.

[0151] In addition, the penetration enhancer can also be a salt of a medium chain fatty acid. The salt of a medium chain fatty acid is preferably C 4-18 Salts of saturated fatty acids, preferably C 4-18 Straight-chain or branched alkanoic acid, more preferably C optionally having 1, 2 or 3 C=C double bonds 6-16 Straight-chain or branched alkanoic acid, even more preferably a C 6-14 Straight chain or branched chain alkanoic acid. The salt of medium chain fatty acid is preferably C 4-18 Salts of straight-chain or branched alkanoic acids, more preferably C 6-16 Salts of straight-chain or branched alkanoic acids, even more preferably C 6-14A salt of a straight or branched chain alkanoic acid. The salt of a medium-chain fatty acid is preferably selected from valerate, hexanoate, heptanoate, caprylate, nonanoate, decanoate, undecanoate, laurate, tridecanoate, myristate, pentadecanoate, palmitate, heptadecanoate and / or stearate. More preferably, the salt of a medium-chain fatty acid is a salt of capric acid.

[0152] The salt of the medium-chain fatty acid is more preferably a sodium salt or a potassium salt. Furthermore, the salt of the medium-chain fatty acid is preferably a decanoate. Capric acid may also be referred to as decanoic acid (CH3(CH2)8COOH). A preferred decanoate is sodium decanoate (i.e., CH3(CH2)8COONa).

[0153] 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.

[0154] More preferably, the solid oral pharmaceutical composition of the present invention comprises a combination of sodium caprate and trisodium phosphate. 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.

[0155] Method for preparing solid oral pharmaceutical composition

[0156] The present invention also relates to a method for preparing the solid oral pharmaceutical composition of the present invention. The method preferably comprises the following steps:

[0157] - preparing the core, and

[0158] - Applying a first coating that completely surrounds the core.

[0159] Preferably, the first coating is applied using a first aqueous composition comprising a combination of copolymer (A) with copolymer (B) and / or copolymer (C) and / or copolymer (D). More preferably, the first coating is applied using a first aqueous composition comprising a combination of copolymer (A) with copolymer (B) and / or copolymer (D).

[0160] The first aqueous composition preferably further comprises an anti-adherent agent. The anti-adherent agent is preferably selected from glycerol monostearate, talc or PlasAcryl.

[0161] Furthermore, the first aqueous composition preferably further comprises citric acid and / or has a pH in the range of 2-5, preferably 3-4.

[0162] Preferably, the method further comprises the step of applying a second coating which completely surrounds the first coating, wherein the second coating is applied using a second aqueous composition comprising copolymer (C) as defined above. The second aqueous composition optionally further comprises an anti-adherent agent, wherein the anti-adherent agent is preferably selected from glyceryl monostearate and talc.

[0163] The method may further comprise applying any one or more of the other coatings described herein above, preferably by using an aqueous dispersion comprising the polymer and / or copolymer and the other predetermined components of the respective coating. It has been found that copolymers such as poly(methacrylic acid-co-methyl methacrylate) 1:2 (e.g. Eudragit S100) may already dissolve at a pH of less than 7, particularly at a pH of about 6.5, when applied from an aqueous dispersion.

[0164] Dosage form

[0165] The solid oral pharmaceutical composition of the present invention is preferably an oral dosage form, more preferably an oral dosage form.

[0166] Thus, the solid oral pharmaceutical composition is preferably administered orally, in particular orally (or formulated for oral administration, in particular orally). 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 to enter the gastrointestinal tract through the mouth, which may also be referred to as "oral-gastrointestinal" administration.

[0167] In a preferred embodiment, the solid oral pharmaceutical composition is orally (particularly by oral-gastrointestinal administration) administered to an individual / patient in a fed state. Therefore, it is preferred that the solid oral pharmaceutical composition is orally administered after a meal, i.e., after ingesting food (e.g., within about 1 to 2 hours after a meal). In another preferred embodiment, the solid oral pharmaceutical composition is orally (particularly by oral-gastrointestinal administration) administered to an individual / patient after fasting overnight with a meal. Therefore, it is preferred that the solid oral pharmaceutical composition be orally administered in the morning, particularly after fasting overnight, with food (e.g., breakfast).

[0168] In particular, it is preferred that the solid oral pharmaceutical composition is 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 100-1500 mg. The total weight of the solid oral pharmaceutical composition is more preferably in the range of 100-1200 mg, 200-1000 mg, 400-800 mg, or 600-900 mg. The tablet or capsule preferably has a total weight of at least 100 mg, such as 100-1200 mg, 400-800 mg, or 600-900 mg.

[0169] In addition, the core can be in the form of multi-particles. The term "multi-particles" preferably refers to particles having a volume average particle size of 0.05-2 mm as measured by laser diffraction. For example, a peptide or protein drug can be present as a plurality of particles in a permeation enhancer matrix. More preferably, the core is in the form of granules or pellets.

[0170] Even more preferably, the solid oral pharmaceutical composition is formulated into an oral dosage form for release of a peptide or protein drug in the small intestine and / or colon. More preferably, release is in the ileum. The coating of the present invention causes the peptide or protein drug to be delayed in the lower part of the small intestine. In contrast to conventional solid oral pharmaceutical compositions (mainly) based on anionic polymers that dissolve when pH is greater than 7, the delayed release of the solid oral pharmaceutical composition of the present invention is regulated by a non-ionic pH-dependent polymer. As a result, compared with coatings that mainly contain pH-dependent polymers, the small intestinal transit time is more constant, and lower changes in drug release are observed. In addition, the solid oral pharmaceutical composition of the present invention can avoid dose dumping that can occur if an individual does not reach or only reaches a pH greater than 7 for a short time.

[0171] In addition, it is preferred that the solid oral pharmaceutical composition of the present invention has a dissolution profile (according to the dissolution method of the United States Pharmacopoeia USP) wherein less than 5% of the peptide or protein drug is released within 1 hour in the acidic phase (simulated gastric fluid or 0.1 M HCl according to USP), followed by dissolution in simulated intestinal fluid at pH 6-6.5 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). During 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 at pH 6-6.5. Therefore, it is preferred that the solid oral pharmaceutical composition has a dissolution profile as determined by the USP dissolution method, wherein 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 pH 6-6.5 with a lag time of at least 1 hour, thereby releasing no more than 10% of the peptide or protein drug within the lag time, and thereby releasing more than 75% of the peptide or protein drug within 1 hour in simulated intestinal fluid at pH 6-6.5 after the lag time. As described above, the dissolution profile should be determined according to the United States Pharmacopoeia (USP, preferably the version as of September 1, 2020); however, alternatively, the dissolution profile may also be determined using a modified form of the USP dissolution method described in Examples 7, 18, or 19 below. Exemplary solid oral pharmaceutical compositions of the present invention having such dissolution profiles are described in the Examples section below.

[0172] Furthermore, it is preferred that the solid oral pharmaceutical composition of the present invention shows less than 5% release of the peptide or protein drug (preferably less than 3%, more preferably less than 1%, even more preferably no release) in a gastric media simulating a fed state, such as FEDGAS pH 6 (see Example 18), for 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.

[0173] Other preferred embodiments of the solid oral pharmaceutical composition of the present invention include compositions having a first coating comprising (or consisting of) HPMC and a second coating (external to the first coating) comprising (or consisting of) Eudragit FL 30D-55. In particular, preferably, the thickness of the coating comprising Eudragit FL 30D-55 results in a weight gain of at least 45% (w / w) relative to the weight of the first coating comprising HPMC (e.g., an empty HPMC capsule). Alternatively, preferably, the thickness of the Eudragit FL 30D-55 coating results in a weight gain of at least 30 mg, more preferably at least 40 mg, even more preferably at least 50 mg, and even more preferably at least 100 mg per dosage form (e.g., capsule or tablet). Also preferred are solid oral pharmaceutical compositions in tablet form having a coating comprising (or consisting of) Eudragit FL 30D-55 having a thickness resulting in a weight gain of at least 10% (w / w) relative to the weight of the tablet before coating with Eudragit FL 30D-55.

[0174] Furthermore, also preferred are solid oral pharmaceutical compositions according to the present invention in tablet form having a coating comprising Eudragit NM30D, with 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 present inventors have found that with the coating according to the present invention, increasing the coating weight gain leads to a further increase in oral bioavailability, in particular under fed conditions.

[0175] Typically, the physician will determine the actual dosage of the peptide or protein drug that best suits the individual. The specific dosage level and frequency of administration for any particular individual can vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, severity of a particular condition, and the treatment experienced by the individual. The precise dosage is ultimately determined by the attending physician or veterinarian.

[0176] The individual or patient to be treated according to the present invention can be an animal (e.g., a non-human animal). Preferably, the individual / patient is a mammal. More preferably, the individual / patient is a human (e.g., male or female) or a non-human mammal (e.g., a guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, marmoset, baboon, gorilla, chimpanzee, orangutan, gibbon, sheep, cattle or pig). Most preferably, the individual / patient to be treated according to the present invention is a human.

[0177] As used herein, "treatment" of a disorder or disease is well known in the art. "Treatment" of a disorder or disease means that the disorder or disease is suspected or has been diagnosed in a patient / individual. Patients / individuals suspected of having a disorder or disease typically exhibit specific clinical and / or pathological symptoms that a skilled artisan can readily attribute to a specific pathological condition (i.e., diagnose the disorder or disease).

[0178] The " treatment " of obstacle or disease can, for example, result in the cessation of obstacle or disease progression (for example, symptoms do not worsen) or the obstacle or (when the cessation of progress is only a transient property) result in the delay of disease progression. The " treatment " of obstacle or disease can also result in a partial response (for example, an improvement in symptoms) or a complete response (for example, the disappearance of symptoms) of the individual / patient suffering from the obstacle or disease. Therefore, the " treatment " of obstacle or disease can also refer to the improvement of obstacle or disease, which can, for example, result in the cessation of obstacle or disease progression or the delay of obstacle or disease progression. This partial or complete response may recur afterwards. It should be understood that individual / patient can experience a wide range of responses to treatment (for example, the exemplary responses described above). The treatment of obstacle or disease can especially include curative treatment (preferably resulting in a complete response and ultimately curing the obstacle or disease) and palliative treatment (including symptom relief).

[0179] The term "prevention" of an obstacle or disease as used herein is also well known in the art. For example, a patient / individual suspected of being susceptible to an obstacle or disease may particularly benefit from the prevention of the obstacle or disease. An individual / patient may have a susceptibility or predisposition to an obstacle or disease, including but not limited to a genetic predisposition. This tendency can be determined by standard methods or assays, using, for example, genetic markers or phenotypic indicators. It should be understood that the obstacle or disease to be prevented according to the present invention has not yet been diagnosed or cannot be diagnosed in the patient / individual (for example, the patient / individual does not show any clinical or pathological symptoms). Therefore, the term "prevention" includes the use of a peptide or protein drug according to the present invention before diagnosing or determining any clinical and / or pathological symptoms, or before being able to be diagnosed or determined by the attending physician.

[0180] 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 by an amide bond formed between the amino group of one amino acid and the carboxyl group of another amino acid. The amino acids (also referred to as amino acid residues) contained in the peptide or protein can 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), but can also be selected from 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, tert-leucine (tert-butyl-leucine), labionin, or alanine or glycine substituted with a cyclic group on 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 statine) and δ-amino acids. Preferably, the amino acid residues contained in the peptide or protein are selected from α amino acids, more preferably from 20 standard proteinogenic α amino acids (which can exist as L isomers or D isomers, preferably all as L isomers). The peptide or protein may be unmodified or may be modified, for example, at its N-terminus, its C-terminus and / or at a functional group in the side chain of any amino acid residue thereof (particularly at a side chain functional group 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. These modifications may also include covalent attachment of one or more polyethylene glycol (PEG) chains (forming a PEGylated peptide or protein), glycosylation with one or more fatty acids and / or acylation (for example, one or more C 8-30Alkanonic or alkenoic acids; forming fatty acid acylated peptides or proteins). In addition, such modified peptides or proteins may also include peptide mimetics, provided that they contain at least two amino acids linked by 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). Peptides or proteins may also form oligomers composed of two or more identical or different molecules.

[0181] The term "amino acid" refers in particular to any of the 20 standard proteinogenic alpha 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 alpha amino acids (e.g., ornithine, citrulline, homolysine, pyrrolysine, 4-hydroxyproline, alpha-methylalanine (i.e., 2-aminoisobutyric acid), norvaline, norleucine, tert-leucine (tert-butyl-leucine), labionin, or an alanine substituted with a cyclic group on the side chain). The term "amino acid" refers to amino acids such as α-amino acids, ...

[0182] The term "antibody" refers to any immunoglobulin molecule that specifically binds to a specific antigen (or with its immunoreaction). Antibody can be, for example, a monoclonal antibody or a polyclonal antibody, and preferably a monoclonal antibody. In addition, antibody (such as monoclonal antibody) can be a complete antibody (such as IgA, IgD, IgE, IgM or IgG, particularly including IgG1, IgG2, IgG3 or IgG4), a chimeric antibody, a humanized antibody, a human antibody, a heterologous conjugate antibody (such as a bispecific antibody), or it can be an antigen-binding fragment (such as Fab, Fab', F(ab')2, Fv or scFv) of any of the above-mentioned types of antibodies. Antibody can also be a single-chain antibody (scAb) or a single domain antibody (sdAb; for example, "nanoantibodies").

[0183] As used herein, the term "dissolved" preferably refers to a state in which a layer (whose dissolution is to be determined) has been sufficiently dissolved by a solution having a specific pH value such that it becomes permeable (particularly for peptide or protein drugs, such as teduglutide). Whether a given layer is dissolved can be determined by using, for example, the United States Pharmacopeia (USP) General Chapter <711> The dissolution is determined in the dissolution apparatus 1 described above.

[0184] The term "surrounding" is used herein synonymously with "covering" or "completely covering."

[0185] As used herein, the terms "optional," "optionally," and "may" indicate that the indicated feature may be present but may not be present. Whenever the terms "optional," "optionally," or "may" are used, the present invention specifically contemplates both possibilities, namely, the presence of the corresponding feature, or the absence of the corresponding feature. For example, if a component of a composition is indicated as "optional," the present invention specifically contemplates both possibilities, namely, the presence of the corresponding component (included in the composition) or the absence of the corresponding component in the composition.

[0186] As used herein, unless expressly stated otherwise or contradicted by context, the term "comprising" (or "comprise, comprises," "contain, contains, or containing") has the meaning of "especially containing," i.e., "containing among other optional elements..." In addition, the term also includes the narrower meanings of "essentially consisting of" and "consisting of." For example, the term "A comprises B and C" has the meaning of "A especially contains B and C," where A may include other optional elements (e.g., "A contains B, C, and D" would also be included), but the term also includes the meaning of "A consists essentially of B and C" and the meaning of "A consists of B and C" (i.e., A does not contain other components other than B and C).

[0187] As used herein, the term "about" refers to ±10% of the stated value, preferably ±5% of the stated value, and especially refers to the exact value stated.

[0188] Unless specifically indicated otherwise, all properties and parameters referred to herein (including any amount / concentration expressed, for example, as "mg / mL" or "% (v / v)", and any pH value) are preferably measured under standard ambient temperature and pressure conditions, in particular at 25°C (298.15K) and an absolute pressure of 101.325 kPa (1 atm).

[0189] In addition, it should be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or preferred features / embodiments. In particular, the present invention specifically relates to all combinations of preferred features described herein.

[0190] Throughout this specification, numerous references are cited, including patents, patent applications, and scientific literature. The disclosures of these references, while not considered relevant to the patentability of the present invention, are hereby incorporated by reference in their entirety. More specifically, all references are hereby incorporated by reference to the same extent as if each individual reference were specifically and individually indicated to be incorporated by reference.

[0191] According to the above detailed description, the present invention particularly relates to the following items:

[0192] 1. A solid oral pharmaceutical composition comprising:

[0193] (i) a core comprising a peptide or protein drug, and

[0194] (ii) a first coating, wherein the first coating comprises

[0195] (ii-1) copolymer (A), and

[0196] (ii-2) copolymer (B) and / or copolymer (C) and / or copolymer (D);

[0197] wherein the copolymer (A) comprises:

[0198] (a) 20-90 mol% of ethyl acrylate repeating units, and

[0199] (b) 10-80 mol% of methyl methacrylate repeating units;

[0200] wherein copolymer (B), if present, comprises:

[0201] (a) 25-75 mol% of methacrylic acid repeating units, and

[0202] (b) 25-75 mol% of ethyl acrylate repeating units;

[0203] wherein copolymer (C), if present, comprises:

[0204] (a) 25-60 mol% of methacrylic acid repeating units, and

[0205] (b) 40-75 mol% of methyl methacrylate repeating units;

[0206] wherein copolymer (D), if present, comprises:

[0207] (a) 5-20 mol% of methacrylic acid repeating units, and

[0208] (b) 20-40 mol% of methyl methacrylate repeating units, and

[0209] (c) 60-75 mol% of methyl acrylate repeating units.

[0210] 2. The solid oral pharmaceutical composition according to claim 1, wherein the first coating comprises

[0211] (ii-1) copolymer (A), and

[0212] (ii-2) Copolymer (B) and / or copolymer (D).

[0213] 3. The solid oral pharmaceutical composition according to item 1 or 2, wherein the copolymer (A) in the first coating comprises 60-75 mol% of ethyl acrylate repeating units and 25-40 mol% of methyl methacrylate repeating units.

[0214] 4. The solid oral pharmaceutical composition according to any one of items 1 to 3, wherein the copolymer (A) in the first coating comprises ethyl acrylate repeating units and methyl methacrylate repeating units in a molar ratio of 2:1.

[0215] 5. A solid oral pharmaceutical composition according to any one of items 1 to 4, wherein the copolymer (A) in the first coating comprises not more than 3 mol% of methyl acrylate repeating units, preferably wherein 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%, yet even more preferably not more than 0.01 mol%, still more preferably 0 mol% of methyl acrylate repeating units.

[0216] 6. The solid oral pharmaceutical composition according to any one of items 1 to 5, wherein the copolymer (A) in the first coating consists of ethyl acrylate repeating units and methyl methacrylate repeating units.

[0217] 7. The solid oral pharmaceutical composition according to any one of items 1 to 6, wherein the copolymer (A) in the first coating is a neutral nonionic copolymer.

[0218] 8. The solid oral pharmaceutical composition according to item 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 repeating units.

[0219] 9. The solid oral pharmaceutical composition according to any one of items 1, 2 and 8, wherein the copolymer (A) in the first coating comprises 25-39 mol% of ethyl acrylate repeating units, 60-74 mol% of methyl methacrylate repeating units and 1-15 mol% of 2-(trimethylammonio)ethyl methacrylate chloride repeating units.

[0220] 10. The solid oral pharmaceutical composition according to any one of items 1, 2, 8 and 9, wherein the copolymer (A) in the first coating comprises ethyl acrylate repeating units, methyl methacrylate repeating units and 2-(trimethylammonio)ethyl methacrylate chloride repeating units in a molar ratio of 1:2:0.1 or 1:2:0.2.

[0221] 11. A solid oral pharmaceutical composition according to any one of items 1, 2 and 8 to 10, wherein the copolymer (A) in the first coating comprises not more than 3 mol% of methyl acrylate repeating units, preferably wherein 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%, yet even more preferably not more than 0.01 mol%, still more preferably 0 mol% of methyl acrylate repeating units.

[0222] 12. The solid oral pharmaceutical composition according to any one of items 1, 2, and 8 to 11, wherein the copolymer (A) in the first coating consists of ethyl acrylate repeating units, methyl methacrylate repeating units, and 2-(trimethylammonio)ethyl methacrylate chloride repeating units.

[0223] 13. The solid oral pharmaceutical composition according to any one of items 1, 2 and 8 to 12, wherein the copolymer (A) in the first coating is a cationic copolymer.

[0224] 14. The solid oral pharmaceutical composition according to any one of items 1 to 13, wherein the copolymer (B) in the first coating comprises 45-55 mol% of methacrylic acid repeating units and 45-55 mol% of ethyl acrylate repeating units.

[0225] 15. The solid oral pharmaceutical composition according to any one of items 1 to 14, wherein the copolymer (B) in the first coating comprises methacrylic acid repeating units and ethyl acrylate repeating units in a molar ratio of 1:1.

[0226] 16. A solid oral pharmaceutical composition according to any one of items 1 to 15, wherein the copolymer (B) in the first coating comprises not more than 3 mol% of methyl acrylate repeating units, preferably wherein 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%, yet even more preferably not more than 0.01 mol%, still more preferably 0 mol% of methyl acrylate repeating units.

[0227] 17. The solid oral pharmaceutical composition according to any one of items 1 to 16, wherein the copolymer (B) in the first coating consists of methacrylic acid repeating units and ethyl acrylate repeating units.

[0228] 18. The solid oral pharmaceutical composition according to any one of items 1 to 17, wherein the copolymer (C) in the first coating comprises 45-55 mol% of methacrylic acid repeating units and 45-55 mol% of methyl methacrylate repeating units.

[0229] 19. The solid oral pharmaceutical composition according to any one of items 1 to 18, wherein the copolymer (C) in the first coating comprises methacrylic acid repeating units and methyl methacrylate repeating units in a molar ratio of 1:1.

[0230] 20. A solid oral pharmaceutical composition according to any one of items 1 to 19, wherein the copolymer (C) in the first coating comprises not more than 3 mol% of methyl acrylate repeating units, preferably wherein 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%, yet even more preferably not more than 0.01 mol%, still more preferably 0 mol% of methyl acrylate repeating units.

[0231] 21. The solid oral pharmaceutical composition according to any one of items 1 to 20, wherein the copolymer (C) in the first coating consists of methacrylic acid repeating units and methyl methacrylate repeating units.

[0232] 22. The solid oral pharmaceutical composition according to any one of items 1 to 17, wherein the copolymer (C) in the first coating comprises 25-40 mol% of methacrylic acid repeating units and 60-75 mol% of methyl methacrylate repeating units.

[0233] 23. The solid oral pharmaceutical composition according to any one of items 1 to 17 and 22, wherein the copolymer (C) in the first coating comprises methacrylic acid repeating units and methyl methacrylate repeating units in a molar ratio of 1:2.

[0234] 24. A solid oral pharmaceutical composition according to any one of items 1 to 17, 22 and 23, wherein the copolymer (C) in the first coating comprises not more than 3 mol% of methyl acrylate repeating units, preferably wherein 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%, yet even more preferably not more than 0.01 mol%, still more preferably 0 mol% of methyl acrylate repeating units.

[0235] 25. The solid oral pharmaceutical composition according to any one of items 1 to 17 and 22 to 24, wherein the copolymer (C) in the first coating consists of methacrylic acid repeating units and methyl methacrylate repeating units.

[0236] 26. The solid oral pharmaceutical composition according to any one of items 1 to 25, wherein the copolymer (C) in the first coating is obtained from an aqueous dispersion of the copolymer (C).

[0237] 27. The solid oral pharmaceutical composition according to any one of items 1 to 26, wherein the copolymer (D) in the first coating comprises 7-13 mol% of methacrylic acid repeating units, 25-31 mol% of methyl methacrylate repeating units and 62-68 mol% of methyl acrylate repeating units.

[0238] 28. The solid oral pharmaceutical composition according to any one of items 1 to 27, wherein the copolymer (D) in the first coating comprises methacrylic acid repeating units, methyl methacrylate repeating units and methyl acrylate repeating units in a molar ratio of 1:3:7.

[0239] 29. The solid oral pharmaceutical composition according to any one of items 1 to 28, wherein the copolymer (D) in the first coating consists of methacrylic acid repeating units, methyl methacrylate repeating units and methyl acrylate repeating units.

[0240] 30. A solid oral pharmaceutical composition according to any one of items 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.

[0241] 31. A solid oral pharmaceutical composition according to any one of items 1 to 30, wherein the first coating comprises copolymer (A) and copolymer (B), 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 copolymer (A) and copolymer (B) in the first coating.

[0242] 32. A solid oral pharmaceutical composition according to any one of items 1 to 30, wherein the first coating comprises copolymer (A) and copolymer (C), wherein copolymer (C) is as defined in any one of items 18 to 21.

[0243] 33. A solid oral pharmaceutical composition according to any one of items 1 to 30, wherein the first coating comprises copolymer (A) and copolymer (C), wherein copolymer (C) is as defined in any one of items 22 to 26.

[0244] 34. A solid oral pharmaceutical composition according to any one of items 1 to 33, wherein the first coating comprises, in addition to copolymer (A), one or more polymers selected from ethylcellulose, hydroxypropylmethylcellulose (HPMC) and polyvinyl acetate, or said polymers replace copolymer (A).

[0245] 35. A solid oral pharmaceutical composition according to any one of items 1, 3 to 26 and 30 to 34, wherein the first coating does not comprise any copolymer (D) as defined in any one of items 1 or 27 to 29.

[0246] 36. The solid oral pharmaceutical composition according to any one of items 1 to 35, wherein the first coating dissolves in the pH range of 5-7, preferably in the pH range of 5.5-6.5, more preferably in the pH range of 5.5-6.0.

[0247] 37. The solid oral pharmaceutical composition according to any one of items 1 to 36, further comprising:

[0248] (iii) a second coating on the outside of the first coating, wherein the second coating comprises copolymer (C);

[0249] wherein the copolymer (C) comprises:

[0250] (a) 25-60 mol% of methacrylic acid repeating units, and

[0251] (b) 40-75 mol% of methyl methacrylate repeating units.

[0252] 38. The solid oral pharmaceutical composition according to item 37, wherein the copolymer (C) in the second coating comprises 45-55 mol% of methacrylic acid repeating units and 45-55 mol% of methyl methacrylate repeating units.

[0253] 39. The solid oral pharmaceutical composition according to item 37 or 38, wherein the copolymer (C) in the second coating comprises methacrylic acid repeating units and methyl methacrylate repeating units in a molar ratio of 1:1.

[0254] 40. A solid oral pharmaceutical composition according to any one of items 37 to 39, wherein the copolymer (C) in the second coating comprises not more than 3 mol% of methyl acrylate repeating units, preferably wherein 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%, yet even more preferably not more than 0.01 mol%, still more preferably 0 mol% of methyl acrylate repeating units.

[0255] 41. The solid oral pharmaceutical composition according to item 37, wherein the copolymer (C) in the second coating layer consists of methacrylic acid repeating units and methyl methacrylate repeating units.

[0256] 42. The solid oral pharmaceutical composition according to item 37 or 41, wherein the copolymer (C) in the second coating comprises 25-40 mol% of methacrylic acid repeating units and 60-75 mol% of methyl methacrylate repeating units.

[0257] 43. The solid oral pharmaceutical composition according to any one of items 37, 41 and 42, wherein the copolymer (C) in the second coating comprises methacrylic acid repeating units and methyl methacrylate repeating units in a molar ratio of 1:2.

[0258] 44. A solid oral pharmaceutical composition according to any one of items 37 and 41 to 43, wherein the copolymer (C) in the second coating comprises not more than 3 mol% of methyl acrylate repeating units, preferably wherein 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%, yet even more preferably not more than 0.01 mol%, still more preferably 0 mol% of methyl acrylate repeating units.

[0259] 45. The solid oral pharmaceutical composition according to any one of items 37 and 41 to 44, wherein the copolymer (C) in the second coating consists of methacrylic acid repeating units and methyl methacrylate repeating units.

[0260] 46. ​​The solid oral pharmaceutical composition according to any one of items 1 to 45, wherein the second coating dissolves in the pH range of 5-7, preferably in the pH range of 5.5-6.5, more preferably in the pH range of 5.5-6.0.

[0261] 47. The solid oral pharmaceutical composition according to any one of items 1 to 46, wherein the peptide or protein drug has a molecular weight equal to or less than about 300 kDa, preferably a molecular weight equal to or less than about 150 kDa.

[0262] 48. A solid oral pharmaceutical composition according to any one of items 1 to 47, wherein the peptide or protein drug is selected from insulin, an insulin analog, insulin lispro, insulin PEGlispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B25HdesB30 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 B25HdesB30 human insulin, B25HdesB30 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, B29K(N(ε)eicosanedioyl-γ-L-Glu-OEG-OEG)A14E B16H B25H desB30 human insulin, B29K(N(ε)octadecandioyl)A14EB25HdesB30 human insulin, GLP-2, GLP-2 analog, GLP-2 agonist, teduglutide, esiglutide, glucose-dependent insulinotropic polypeptide, elamitriptyline, natural cyclic peptide, recombinant factor VIIa, eptacog alfa, amylin, an amylin analog, pramlintide, a somatostatin analog, octreotide, lanreotide, pasireotide, goserelin, buserelin, leptin, a leptin analog, metreleptin, peptide YY, a peptide YY analog, glatiramer, leuprorelin, desmopressin, a desmopressin analog, a vasopressin receptor 2 agonist peptide, osteocalcin, an osteocalcin analog or derivative, human growth hormone, human growth hormone Analogs, long-acting human growth hormone, fibroblast growth factor 21, parsitol, hGH-CTP, antibodies, glycopeptide antibiotics, glycosylated cyclic or polycyclic non-ribosomal peptide antibiotics, vancomycin, teicoplanin, telavancin, bleomycin, ramoplanin, decaplanin, natural cyclic peptides, bortezomib, teicoplanin, chorionic gonadotropin, follicle-stimulating hormone, sermorelin, luteinizing hormone-releasing hormone, growth hormone, calcitonin, salmon calcitonin, pentagastrin, oxytocin, nesiritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alfa-2a, stem cell transplants Interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, pegylated interferon alpha-2a, pegylated interferon alpha-2b, pegylated interferon beta-1a, plasmin, vasopressin, aldesleukin, epoetin, epoetin alpha, darbepoetin alpha, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxypolyethylene glycol-epoetin beta, continuous erythropoietin receptor activator, pegylated epo, albupoetin, epo dimer analog, epo-Fc, carbamylated epo, synthetic erythropoietin protein, low molecular weight epo analog PBI-1402 , filgrastim, PEG-filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, puromycin, thyrotropin-releasing hormone, leucine-enkephalin, methionine-enkephalin, substance P, adrenocorticotropic hormone, parathyroid hormone, parathyroid hormone fragment, teriparatide, PTH (1-31), PTH (2-34), parathyroid hormone-related protein, abalaparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, prostaglandin F2α receptor modulators, PDC31, abciximab, ranibizumab, alecept, romiplostim, anakinra, abatacept, belatacept and pharmaceutically acceptable salts thereof.

[0263] 49. A solid oral pharmaceutical composition according to any one of items 1 to 47, wherein the peptide or protein drug is selected from GLP-2, a GLP-2 agonist, a GLP-2 analogue, teduglutide, esiglutide, insulin, human insulin, an insulin analogue, insulin lispro, insulin PEGlispro, A14E B25H B29K(N(eps)octadecandioyl-gGlu-OEG-OEG)desB30 human insulin, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, an antibody, a somatostatin analogue, octreotide, lanreotide, pasireotide, desmopressin, a desmopressin analogue, a vasopressin receptor 2 agonist peptide, a parathyroid hormone fragment, teriparatide, PTH (1-31) and PTH (2-34).

[0264] 50. A solid oral pharmaceutical composition according to any one of items 1 to 47, wherein the peptide or protein drug is selected from GLP-2, a GLP-2 agonist, a GLP-2 analogue, teduglutide, esiglutide, insulin, human insulin, an insulin analogue, insulin lispro, insulin PEGlispro, 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 an antibody.

[0265] 51. A solid oral pharmaceutical composition according to any one of items 1 to 50, wherein the core further comprises one or more permeation enhancers.

[0266] 52. The solid oral pharmaceutical composition according to any one of items 1 to 51, wherein the solid oral pharmaceutical composition is an oral dosage form.

[0267] 53. The solid oral pharmaceutical composition according to any one of items 1 to 52, wherein the solid oral pharmaceutical composition is in the form of a capsule.

[0268] 54. The solid oral pharmaceutical composition according to any one of items 1 to 52, wherein the solid oral pharmaceutical composition is in the form of a tablet.

[0269] 55. The solid oral pharmaceutical composition according to any one of items 1 to 54, wherein the core is in the form of multiparticulates, preferably wherein the core is in the form of granules or pellets.

[0270] 56. A solid oral pharmaceutical composition according to any one of items 1 to 55 for use in therapy.

[0271] 57. The solid oral pharmaceutical composition according to any one of items 1 to 55, for use in the treatment or prevention of a disease / disorder.

[0272] 58. The solid oral pharmaceutical composition for use according to item 56 or 57, wherein the solid oral pharmaceutical composition is to be administered orally.

[0273] 59. Use of a solid oral pharmaceutical composition according to any one of items 1 to 55 for the preparation of a medicament for the treatment or prevention of a disease / disorder.

[0274] 60. A method of treating or preventing a disease / disorder in an individual in need thereof, the method comprising orally administering to said individual a therapeutically effective amount of a solid oral pharmaceutical composition according to any one of items 1 to 55.

[0275] 61. A method of delivering a peptide or protein drug to a subject in need thereof, the method comprising orally administering to the subject a solid oral pharmaceutical composition according to any one of items 1 to 55.

[0276] The present invention also relates to a solid oral pharmaceutical composition comprising:

[0277] (i) a core comprising a peptide or protein drug (as described above), and

[0278] (ii) a first coating, wherein the first coating comprises Eudragit NM30D,

[0279] wherein the first coating optionally further comprises copolymer (B) and / or copolymer (C) and / or copolymer (D);

[0280] wherein the copolymer (A) comprises:

[0281] (a) 20 to 90 mol-% of ethyl acrylate repeating units, and

[0282] (b) 10 to 80 mol-% methyl methacrylate repeating units;

[0283] wherein copolymer (B), if present, comprises:

[0284] (a) 25 to 75 mol-% of methacrylic acid repeating units, and

[0285] (b) 25 to 75 mol-% ethyl acrylate repeating units;

[0286] wherein copolymer (C), if present, comprises:

[0287] (a) 25 to 60 mol-% of methacrylic acid repeating units, and

[0288] (b) 40 to 75 mol-% methyl methacrylate repeating units;

[0289] wherein copolymer (D), if present, comprises:

[0290] (a) 5 to 20 mol-% of methacrylic acid repeating units, and

[0291] (b) 20 to 40 mol-% of methyl methacrylate repeating units, and

[0292] (c) 60 to 75 mol-% of methyl acrylate repeating units.

[0293] The general and preferred features described above, including the methods and uses described herein, apply analogously to the solid oral pharmaceutical compositions described in this paragraph.

[0294] The present invention will now be described with reference to the following examples, which are illustrative only and should not be construed as limiting the scope of the invention. Example

[0295] Material

[0296] The following materials were used in the experimental examples:

[0297] All Eudragit polymers and PlasAcryl were obtained from Evonik (Germany). All other chemicals were obtained from Sigma Aldrich (Austria) or VWR (Austria).

[0298] EUDRAGIT NM 30D:

[0299] Aqueous dispersion of a neutral copolymer based on ethyl acrylate and methyl methacrylate. Chemical name / IUPAC name: Poly(ethyl acrylate-co-methyl methacrylate) 2:1.

[0300] L 30D-55:

[0301] 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.

[0302] EUDRAGIT S100

[0303] Anionic copolymer based on methacrylic acid and methyl methacrylate; chemical name: Poly(methacrylic acid-co-methyl methacrylate) 1:2.

[0304] EUDRAGIT L 100

[0305] Anionic copolymer based on methacrylic acid and methyl methacrylate; chemical name: Poly(methacrylic acid-co-methyl methacrylate) 1:1.

[0306] Eudragit FS30D

[0307] 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

[0308] Example 1: Coating of HPMC capsules with a combination of 80% Eudragit NM 30D and 20% Eudragit L 30D-55

[0309] Preparation of Eudragit dispersion Adjust the pH of 109 g of Eudragit NM30D to approximately 3 with 1.3 mL of 20% (w / w) citric acid solution. Add 67 g of distilled water with conventional stirring. Add 28 g of Eudragit L 30D-55, followed by 2 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0310] HPMC capsule coating Empty size 1 HPMC capsules (each capsule weighing approximately 70 mg) were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to final weights of 95 mg, 119 mg, and 125 mg.

[0311] Example 2: Coating of HPMC capsules with a combination of 75% Eudragit NM 30D and 25% Eudragit L 30D-55

[0312] Preparation of Eudragit dispersion Adjust the pH of 100 g of Eudragit NM30D to approximately 3 with 1.3 mL of 20% (w / w) citric acid solution. Add 67 g of distilled water with conventional stirring. Then add 33.3 g of Eudragit L 30D-55, followed by 2 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0313] HPMC capsule coating Empty size 1 HPMC capsules (each capsule weighing approximately 70 mg) were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to a final weight of 115 mg.

[0314] Example 3: Eudragit L 100 top coating on the coated capsules of Example 2

[0315] Preparation of dispersionDisperse 20 g of Eudragit L 100 in 100 mL of distilled water. Slowly add 11.2 mL of 1N NH3 while stirring continuously. Continue stirring for 60 minutes. Then add 10 g of triethyl citrate (TEC) and continue stirring for another 60 minutes. Separately, homogenize 10 g of talc in 50 g of water using a high shear mixer (Ultra Turrax). Combine the two dispersions while stirring continuously using a conventional stirrer.

[0316] Capsule top coating Capsules from Example 2 (weight 115 mg) were top-coated with the Eudragit L 100 dispersion obtained above using a Glatt GC1 laboratory coater to a final weight of 130 mg.

[0317] Example 4: Eudragit S100 top coating on the coated capsules of Example 2

[0318] Preparation of dispersion Disperse 19.9 g of Eudragit S100 in 100 mL of distilled water. Slowly add 13.5 mL of 1N NH3 while stirring continuously. Continue stirring for 60 minutes. Then add 10 g of triethyl citrate (TEC) and continue stirring for another 60 minutes. Separately, homogenize 10 g of talc in 50 g of water using a high shear mixer (Ultra Turrax). Combine the two dispersions while stirring continuously using a conventional stirrer.

[0319] Capsule top coating Capsules from Example 2 (weight 115 mg) were top-coated with the Eudragit S100 dispersion obtained above using a Glatt GC1 laboratory coater to a final weight of 132 mg.

[0320] Example 5: Enteric coating of HPMC capsules using Eudragit S100 redispersion containing 50% TEC

[0321] Preparation of Eudragit aqueous dispersion :99.4g S100 was slowly added into 500 mL of water and stirred with a conventional stirrer for about 5 minutes. Then 67.5 g of 1N NH3 was slowly added into the The suspension was stirred for about 60 minutes. Then 49.7 g of triethyl citrate (TEC) was added 49.7 g of talc were homogenized in 233.7 g of water using a high shear mixer (e.g. Ultra Turrax) for 10 minutes. The talc suspension was then poured into Finally, the spray suspension was passed through a 0.5 mm sieve with continuous stirring.

[0322] HPMC capsule coating HPMC capsules were coated with Eudragit aqueous dispersion using a Glatt GC1 laboratory coater to a weight gain of 18%, 60% and 64% (based on the weight of the empty capsules).

[0323] Example 6: Enteric coating of HPMC capsules with Eudragit S100 redispersion containing 70% TEC

[0324] Preparation of Eudragit aqueous dispersion :99.4g S100 was slowly added into 500 mL of water and stirred with a conventional stirrer for about 5 minutes. Then 67.5 g of 1N NH3 was slowly added into the The suspension was stirred for about 60 minutes. Then 70 g of triethyl citrate (TEC) was added 49.7 g of talc were homogenized in 233.7 g of water using a high shear mixer (e.g. Ultra Turrax) for 10 minutes. The talc suspension was then poured into Finally, the spray suspension was passed through a 0.5 mm sieve with continuous stirring.

[0325] Enteric coating of HPMC capsules HPMC capsules were coated with Eudragit aqueous dispersion using a Glatt GC1 laboratory coater to a weight gain of 30%, 50% and 63% (based on the weight of the empty capsules).

[0326] Example 7: Dissolution test of coated capsules

[0327] Pre-coated capsules prepared as in any of Examples 1-6 can be filled with a peptide or protein drug and sodium decanoate. Dissolution studies were performed using an Erweka DT lamp 126 at 37°C and 75 rpm using the basket method. A modified version of the United States Pharmacopoeia (USP) method was used. The capsules were placed in a basket, and the basket was placed in an open blue-capped bottle containing 100 mL of the corresponding dissolution medium. The blue-capped bottle was in direct contact with water, ensuring that the core temperature inside the blue-capped bottle was 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) at pH 6.0 according to USP for 1 hour, then in SIF at pH 6.5 according to USP for 1 hour, and finally in SIF at pH 6.8 according to USP. 1 mL samples were taken after 60 minutes and at other predetermined time points. 40 μL of sample was injected into the HPLC system using a reverse phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Waters Xselect CSH C18). Sampling was performed until complete capsule dissolution, which was defined by peptide or protein drug release > 75% of the theoretical release value. After this process, it was demonstrated that the capsules (or other oral dosage forms) coated according to the present invention exhibited a favorable dissolution profile, showing no drug release in the acid phase, followed by a lag time at intestinal pH levels, and then rapid release of the peptide or protein drug.

[0328] Example 8: Enteric coating of tablets containing semaglutide and sodium decanoate and 80% Eudragit NM30D and 20% Eudragit FS30D

[0329] Tablet preparation A homogeneous powder mixture containing 240 mg semaglutide, 6 g sodium decanoate, 2.64 g galenIQ 720, 1.56 g Avicel PH-101, and 120 mg magnesium stearate was prepared. The mixture was first blended in a mortar and pestle and then in a Topitec powder mixer. An 880 mg aliquot was compressed into tablets using a Korsch EKO single punch tablet press with an average compression force of approximately 15 kN.

[0330] Preparation of Eudragit dispersion Adjust the pH of 160 g of Eudragit NM30D to approximately 3 with 2.0 mL of 20% (w / w) citric acid solution. Add 100 g of distilled water with conventional stirring. Add 42 g of Eudragit FS30D, followed by 3 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0331] Tablet coating:The tablets were mixed with size 1 empty HPMC capsules and coated using a Glatt GC1 laboratory coater with the Eudragit dispersion obtained above to a final tablet weight of approximately 934 mg, which involved a coating weight increase of approximately 54 mg per tablet or a weight increase of 6.1% (w / w). This involved approximately 42 mg of Eudragit NM30D (dry matter) per tablet.

[0332] Example 9: In vivo food interaction study after oral administration of semaglutide tablets to beagle dogs

[0333] When the tablets of Example 8 were orally administered with or without food, food interactions were evaluated because the presence of food in the stomach may interfere with the efficacy of orally administered peptide drugs. Before administration on Day 0, animals were fasted overnight for at least 12 hours. After sample collection, food was provided to the animals 8 hours after administration. On the day of the experiment, an intravenous catheter was placed on the saphenous vein or cephalic vein for blood sampling (20G, 1 inch intravenous catheter). The tablets were orally administered with 10 mL of water. Within 5 minutes after drug administration, the dogs in the fed group received a 50 g light meal (Hill's I / D dog food), and the animals in the fasted group remained fasted for another 8 hours. Baseline blood samples were collected, and then each animal was orally administered a single tablet. Blood samples were collected into 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 replicated and kept at −80° C. for further analysis by ELISA technique (Semagutide Penisula Laboratories International, company catalog number S-1530). The results thus obtained are shown in Figure 1 middle.

[0334] result In the fed group, delayed onset (mean T max ). Average AUC between fasting group and fed group 0-48小时 There was no statistical difference. Consumption of 50 g of canine food within 5 minutes after tablet administration had no effect on the bioavailability of semaglutide compared to the group of animals that did not receive any food. The tablet coating of Example 8 prevented the negative food effect.

[0335] Example 10: Preparation of Octreotide and Leuprorelin Tablets

[0336] Tablet preparationA homogeneous powder mixture containing 260 mg of octreotide, 130 mg of leuprolide, 6.5 g of sodium decanoate, 2.86 g of galenIQ720, 1.69 g of Avicel PH-101, and 130 mg of magnesium stearate was prepared. The mixture was first blended in a mortar and pestle and then in a Topitec powder mixer. An 890 mg aliquot was compressed into tablets using a Korsch EKO single punch tablet press with an average compression force of approximately 15 kN.

[0337] Example 11: Enteric coating of tablets containing octreotide and leuprolide and 80% Eudragit NM30D and 20% Eudragit L30 D-55

[0338] Preparation of Eudragit dispersion Adjust the pH of 107 g of Eudragit NM30D to approximately 3 with 1.3 mL of 20% (w / w) citric acid solution. Add 67 g of distilled water with conventional stirring. Add 28 g of Eudragit L 30D-55, followed by 2 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0339] Tablet coating: The tablets of Example 10 were mixed with placebo tablets of comparable weight and slightly different size (to allow for separation after the coating process) and coated with the Eudragit dispersion obtained above using a Glatt GC1 laboratory coater to a final weight of 954 mg, which involved a coating weight increase of 64 mg per tablet or a weight increase of 7.2% (w / w). This involved approximately 50 mg of Eudragit NM30D (dry matter) per tablet.

[0340] Example 12: Enteric coating of tablets containing octreotide and leuprolide and Eudragit L30 D-55 (reference tablets)

[0341] Preparation of Eudragit dispersion: 56.9 g of distilled water were added to 114 g of Eudragit L30D-55 under normal stirring, followed by 29.1 g of Plasacryl T20. The final composition was stirred for 15 minutes using a conventional stirrer.

[0342] Tablet coating: The tablets of Example 10 were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to a final weight of 956 mg (66 mg weight gain per tablet), which involved a weight gain of 7.4% (w / w).

[0343] Example 13: Preparation of human insulin tablets

[0344] Tablet preparation Preparation contains a uniform powder mixture of 96mg human insulin, 6.0g sodium caprate, 2.64g galenIQ 720, 1.56g Avicel PH-101 and 120mg magnesium stearate. First, mix in a mortar and pestle, then mix with a Topitec powder mixer. With a Korsch EKO single punch tablet press, 868mg aliquots are compressed into tablets with an average compression force of approximately 15kN.

[0345] Example 14: Enteric coating of tablets containing human insulin and 80% Eudragit NM30D and 20% Eudragit L30 D-55

[0346] Preparation of Eudragit dispersion Adjust the pH of 107 g of Eudragit NM30D to approximately 3 with 1.3 mL of 20% (w / w) citric acid solution. Add 67 g of distilled water with conventional stirring. Add 28 g of Eudragit L 30D-55, followed by 2 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0347] Tablet coating: The tablets were mixed with placebo tablets of comparable weight and slightly different size (to allow for separation after the coating process) and coated with the Eudragit dispersion obtained above using a Glatt GC1 laboratory coater to a final weight of 913 mg, which involved a coating weight increase of 45 mg or 5.2% (w / w) per tablet.

[0348] Example 15: Enteric coating of tablets containing human insulin and Eudragit L30 D-55 (reference tablets)

[0349] Preparation of Eudragit dispersion: 56.9 g of distilled water were added to 114 g of Eudragit L30D-55 under normal stirring, followed by 29.1 g of Plasacryl T20. The final composition was stirred for 15 minutes using a conventional stirrer.

[0350] Tablet coating: The tablets of Example 13 were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to a final weight of 916 mg (48 mg weight gain per tablet), which involved a weight gain of 5.6% (w / w).

[0351] Example 16: Enteric coating of HPMC capsules using Eudragit L 30D-55 (reference capsules)

[0352] Preparation of Eudragit dispersion:56.9 g of distilled water were added to 114 g of Eudragit L30D-55 under normal stirring, followed by 29.1 g of Plasacryl T20. The final composition was stirred for 15 minutes using a conventional stirrer.

[0353] HPMC capsule and tablet coating: Empty size 1 HPMC capsules (weighing approximately 70 mg each) were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to a final capsule weight of 104 mg (34 mg weight gain per capsule).

[0354] Example 17: Enteric coating of capsules using 80% Eudragit NM30D and 20% Eudragit FS30D

[0355] Preparation of Eudragit dispersion Adjust the pH of 160.5 g of Eudragit NM 30D to approximately 3 with 2.0 mL of 20% (w / w) citric acid solution. Add 100.5 g of distilled water with conventional stirring. Add 42 g of Eudragit FS30D, followed by 3 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0356] Capsule coating: Empty HPMC capsules No. 1 were coated with the Eudragit dispersion obtained above using a Glatt GC1 laboratory coater to a final capsule weight of approximately 102 mg, which involved a coating weight increase of approximately 32 mg per No. 1 capsule.

[0357] Example 18: Stability of enteral solid dosage forms containing different peptides in FEDGAS

[0358] The purpose of this test is to demonstrate the stability of the coated solid dosage form of the present invention in a gastric medium simulating a fed state. Coated tablets of Examples 11, 12, 14, and 15 and pre-coated capsules of Examples 1, 16, and 17 were used, and the capsules were filled with 20 mg of octreotide, 10 mg of leuprolide, 8 mg of insulin, and 200 mg of sodium decanoate. Dissolution testing was performed in FEDGAS (simulated gastric fluid in a fed state) at pH 6. FEDGAS was prepared according to the protocol of Biorelation (www.biorelevant.com). TMpH 6. For every 100 mL of final culture medium, 4.1 mL of Biorelevant buffer at pH 6, 81.4 g of water, and 17 g of FEDGAS gel were mixed together. Dissolution studies were conducted using an Erweka DT lamp 126 at 37°C and 75 rpm using the basket method. A modified version of the United States Pharmacopoeia (USP) method was used. Capsules and tablets were placed in a basket, and the basket was placed in an open blue-capped bottle containing 100 mL of FEDGAS pH 6 medium. The blue-capped bottle was in direct contact with the water, ensuring that the core temperature inside the blue-capped bottle was 37°C (the temperature was confirmed with an external thermometer before starting the test). The basket was placed in the FEDGAS medium at pH 6 for 6 hours. 1 mL samples were taken after 60 minutes and at other predetermined time points. 40 μL of the sample was injected into the HPLC system using a reverse phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Waters Xselect CSH C18).

[0359] The results are shown in Figure 2 、 3 and 4, these results suggest that

[0360] 1. Eudragit NM30D increases the stability of enteric-coated solid dosage forms containing peptides under simulated fed conditions

[0361] 2. The coated tablets of the present invention are more stable than coated capsules under simulated feeding conditions

[0362] 3. The coating comprising the combination of Eudragit NM30D and Eudragit FS30D produced superior stability under simulated fed conditions compared to all other coatings.

[0363] Example 19: Dissolution test of coated capsules

[0364] 20 mg of octreotide, 10 mg of leuprorelin, 8 mg of insulin, and 200 mg of sodium decanoate were loaded into pre-coated capsules from Examples 1 and 16, respectively. Dissolution studies were performed using an Erweka DT lamp 126 at 37°C and 75 rpm using the basket method. A modified version of the United States Pharmacopoeia (USP) method was used. The capsules were placed in a basket, and the basket was placed in an open blue-capped bottle containing 100 mL of the corresponding dissolution medium. The blue-capped bottle was in direct contact with water, ensuring that the core temperature inside the blue-capped bottle was 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, and then in simulated intestinal fluid (SIF) at pH 6.0 according to USP for 3 hours. 1 mL samples were taken after 60 minutes and at other predetermined time points. 40 μL of the sample was injected into an HPLC system using a reverse phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Waters Xselect CSH C18).

[0365] The results obtained are shown in Figure 5 A, 5B and 5C. These results indicate that all capsules were stable in the acid phase, but only the capsules coated with a significant amount of Eudragit NM30D showed a lag time at intestinal pH 6 followed by a relatively fast release profile.

[0366] Example 20: In vivo evaluation of enteric-coated tablets containing insulin and sodium caprate after oral administration to cynomolgus monkeys

[0367] Preparation of Insulin Tablets: A homogeneous powder mixture containing 50 mg human insulin, 1.160 g sodium caprate, 510 mg galenIQ 720, 300 mg Avicel PH-101, and 20 mg magnesium stearate was prepared. The mixture was first blended in a mortar and pestle and then in a Topitec powder mixer. A 204 mg aliquot was compressed into tablets using a Korsch EKO single punch tablet press with an average compression force of approximately 18 kN.

[0368] Enteric coating of tablets using 80% Eudragit NM 30D and 20% Eudragit L 30D-55 (Sample 20a):

[0369] Preparation of Eudragit dispersion Adjust the pH of 214 g of Eudragit NM30D to approximately 3 with 2.6 mL of 20% (w / w) citric acid solution. Add 134 g of distilled water with conventional stirring. Add 56 g of Eudragit L 30D-55, followed by 4 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0370] Tablet coating: Tablets were coated with the Eudragit dispersion obtained above to a final weight of 217.5 mg using a Glatt GC1 laboratory coater, which involved a coating weight gain of 6.5% (w / w) per tablet.

[0371] Enteric coating of tablets containing human insulin using Eudragit L30 D-55 (reference tablets, sample 20b):

[0372] Preparation of Eudragit dispersion: 85.5 g of distilled water was added to 171 g of Eudragit L30D-55 under normal stirring, followed by 43.5 g of Plasacryl T20. The final composition was stirred for 15 minutes using a conventional mixer. Tablets were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to a final weight of 217.0 mg, which resulted in a weight gain of 6.5% (w / w).

[0373] The enteric-coated insulin tablets described above were orally administered to female cynomolgus monkeys weighing 3.0 to 4.2 kg who had fasted overnight. Blood was collected at 0 (before administration), 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 0 (before administration), 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 using a commercial high-sensitivity human insulin ELISA kit. A summary of the obtained pharmacokinetic parameters is shown in Table 1.

[0374] Table 1: Pharmacokinetic parameters following oral administration of insulin tablets to cynomolgus monkeys

[0375]

[0376] Example 21: In vivo evaluation after oral administration of enteric-coated tablets containing leuprorelin and sodium decanoate to cynomolgus monkeys

[0377] Preparation of Leuprorelin and Octreotide Tablets: A homogeneous powder mixture containing 110 mg of octreotide, 55 mg of leuprorelin, 1.210 g of sodium decanoate, 550 mg of galenIQ 720, 330 mg of Avicel PH-101, and 55 mg of magnesium stearate was prepared. This mixture was first blended in a mortar and pestle and then in a Topitec powder mixer. 210 mg aliquots were compressed into tablets using a Korsch EKO single punch tablet press with an average compression force of approximately 25 kN.

[0378] Enteric coating of tablets using 80% Eudragit NM30D and 20% Eudragit L30 D-55 (Sample 21a):

[0379] Preparation of Eudragit dispersion Adjust the pH of 120 g of Eudragit NM30D to approximately 3 with 1.5 mL of 20% (w / w) citric acid solution. Add 75 g of distilled water with conventional stirring. Add 31.5 g of Eudragit L 30D-55, followed by 2.25 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0380] Tablet coating: Tablets were coated with the Eudragit dispersion obtained above to a final weight of 225 mg using a Glatt GC1 laboratory coater, which involved a coating weight gain of 7% (w / w) per tablet.

[0381] Enteric coating of tablets containing human insulin using Eudragit L30 D-55 (reference tablets, sample 21b):

[0382] Preparation of Eudragit dispersion: 60 g of distilled water was added to 120 g of Eudragit L30D-55 under normal stirring, followed by 30 g of Plasacryl T20. The final composition was stirred for 15 minutes using a conventional mixer. Tablets were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to a final weight of 221 mg, which resulted in a 6% (w / w) weight gain.

[0383] Enteric-coated leuprorelin / octreotide tablets were orally administered to female cynomolgus monkeys that had fasted overnight. Blood was collected at 0 (pre-administration), 30, 60, 90, 120, 150, 180, and 240 minutes after oral administration of a reference tablet coated with Eudragit L30D-55. Blood was collected at 0 (pre-administration), 120, 150, 180, 210, 240, 270, 300, 330, and 360 minutes after oral administration of a tablet coated with 80% Eudragit NM30D and 20% Eudragit L30D-55. Leuprorelin plasma concentrations were analyzed using a commercial leuprorelin ELISA kit purchased from BMA Biomedicals. A summary of the pharmacokinetic parameters obtained is shown in Table 2.

[0384] Table 2: Pharmacokinetic parameters following oral administration of leuprorelin tablets to cynomolgus monkeys

[0385]

[0386] Example 22: In vivo evaluation of enteric-coated tablets containing octreotide and sodium decanoate after oral administration to cynomolgus monkeys

[0387] The enteric-coated octreotide tablets of Example 21 were orally administered 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 coated with Eudragit L30D-55 (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 coated with 80% Eudragit NM30D and 20% Eudragit L30D-55 (sample 21a). Octreotide plasma concentrations were analyzed using a commercial octreotide ELISA kit from BMA Biomedicals. A summary of the pharmacokinetic parameters obtained is shown in Table 3.

[0388] Table 3: Pharmacokinetic parameters of octreotide tablets after oral administration to cynomolgus monkeys

[0389]

[0390] Example 23: In vivo evaluation of an enteric-coated solid oral dosage form containing semaglutide and sodium decanoate after endoscopic administration to the duodenum of pigs

[0391] Preparation of tablets: Tablets were prepared each containing 20 mg semaglutide, 500 mg sodium decanoate, 220 mg sorbitol, 130 mg Avicel, and 10 mg magnesium stearate.

[0392] Tablet coating:

[0393] Reference tablet B: The tablet was coated with Eudragit L30D-55

[0394] Coated Tablets C: Tablets were coated with a mixture of 80% Eudragit NM30D and 20% Eudragit L30D-55

[0395] Coated tablets D: Tablets were coated with a mixture of 80% Eudragit NM30D and 20% Eudragit FS30D

[0396] Endoscopic Administration in Pigs: The formulation was administered directly into the duodenum of anesthetized pigs using a gastroscope. Blood was collected at time 0 before administration and at 1, 2, 4, 6, 8, and 24 hours after administration. Plasma concentrations of semaglutide were analyzed by LC-MS. The results are shown in Table 4. Only the enteric-coated tablets coated according to the present invention produced significant plasma levels of semaglutide.

[0397] Table 4: Pharmacokinetic parameters of semaglutide following enteral administration of solid dosage form in pigs

[0398]

[0399] LoQ refers to limit of quantitation.

[0400] Example 24: Enteric coating of octreotide and semaglutide tablets using Eudragit L30D-55 (reference tablets)

[0401] Tablet preparation A homogeneous powder mixture of 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 was prepared. The mixture was first blended in a mortar and pestle and then in a Topitec powder mixer. An 880 mg aliquot was compressed into tablets using a Korsch EKO single punch tablet press with an average compression force of approximately 11 kN.

[0402] Preparation of Eudragit dispersion: 58 g of distilled water were added to 114 g of Eudragit L30D-55 under normal stirring, followed by 29 g of Plasacryl T20. The final composition was stirred for 15 minutes using a conventional stirrer.

[0403] Tablet coating: Tablets were coated with Eudragit dispersion using a Glatt GC1 laboratory coater to a final weight of 931 mg (51 mg weight gain per tablet), which involved a weight gain of 5.8% (w / w).

[0404] Example 25: Enteric coating of octreotide and semaglutide tablets using 70% Eudragit NM30D and 30% Eudragit FS30D

[0405] Tablet preparation A homogeneous powder mixture of 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 was prepared. The mixture was first blended in a mortar and pestle and then in a Topitec powder mixer. An 880 mg aliquot was compressed into tablets using a Korsch EKO single punch tablet press with an average compression force of approximately 11 kN.

[0406] Preparation of Eudragit dispersionAdjust the pH of 140 g of Eudragit NM30D to approximately 3 with 2.0 mL of 20% (w / w) citric acid solution. Add 100 g of distilled water with conventional stirring. Add 60 g of Eudragit FS30D, followed by 3 g of Plasacryl T20. Stir the final composition for 15 minutes using a conventional stirrer.

[0407] Tablet coating: The tablets were mixed with size 1 empty HPMC capsules and coated with the Eudragit dispersion obtained above using a Glatt GC1 laboratory coater to a final tablet weight of approximately 927 mg, which involved a coating weight increase of approximately 47 mg per tablet or a weight increase of 5.4% (w / w).

[0408] Example 26: Dissolution of Octreotide and Semaglutide Tablets

[0409] The tablets of Examples 24 and 25 were used for dissolution studies. The dissolution studies were performed using an Erweka DT lamp 126 using the basket method at 37°C and a rotation speed of 75 rpm. A modified version of the United States Pharmacopoeia (USP) method was used. The tablets were placed in a basket and the basket was placed in an open blue-capped bottle containing 100 mL of the corresponding dissolution medium (SGF or SIF, as described below). The blue-capped bottle was in direct contact with water, ensuring that the core temperature inside the blue-capped bottle was 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 and then in simulated intestinal fluid (SIF) at pH 7.4 according to USP for 5 hours. 1 mL samples were taken after 60 minutes and at additional predetermined time points. 40 μL of the sample was injected into the HPLC system using a reverse phase gradient method (water / acetonitrile + 0.1% trifluoroacetic acid; column: Kinetex C18, Phenomenex). The results of the dissolution studies are shown in Figure 6 middle.

[0410] In summary, the in vivo studies reported above (see Examples 20 to 23) used structurally different peptides, i.e.

[0411] a) Insulin (a polypeptide with disulfide bonds)

[0412] b) Leuprorelin (linear peptide)

[0413] c) Octreotide (cyclic peptide)

[0414] d) Semaglutide (fatty acid acylated peptide)

[0415] Improved oral bioavailability of sodium decanoate tablets was demonstrated when the enteric coating comprised Eudragit NM30D and a pH-dependent Eudragit polymer such as Eudragit L30D-55 or Eudragit FS30D.

[0416] These results further demonstrate that the solid oral pharmaceutical compositions of the present invention exhibit highly favorable pharmacokinetic properties, including advantageously improved oral bioavailability, as demonstrated in vivo using monkeys and pigs.

Claims

1. 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 (ii-1) a copolymer (A), and (ii-2) copolymer (B) and / or copolymer (C) and / or copolymer (D); Wherein the copolymer (A) comprises: (a) 20 to 90 mol-% of ethyl acrylate repeating units, and (b) 10 to 80 mol-% of methyl methacrylate repeating units; wherein copolymer (B), if present, comprises: (a) 25 to 75 mol-% of methacrylic acid repeating units, and (b) 25 to 75 mol-% ethyl acrylate repeating units; wherein copolymer (C), if present, comprises: (a) 25 to 60 mol-% of methacrylic acid repeating units, and (b) 40 to 75 mol-% methyl methacrylate repeating units; Wherein copolymer (D), if present, comprises: (a) 5 to 20 mol-% of methacrylic acid repeating units, and (b) 20 to 40 mol-% of methyl methacrylate repeating units, and (c) 60 to 75 mol-% of methyl acrylate repeating units; The peptide or protein drug is preferably not a GLP-1 receptor agonist.

2. The solid oral pharmaceutical composition according to claim 1, wherein the first coating comprises (ii-1) a copolymer (A), and (ii-2) Copolymer (B) and / or copolymer (D).

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

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

1.

5. The solid oral pharmaceutical composition according to claim 1 or 2, wherein the copolymer (A) in the first coating further comprises 0.5-20 mol%, preferably 1-15 mol% of methacrylate 2-(trimethylammonio)ethyl ester chloride repeating units.

6. The solid oral pharmaceutical composition according to any one of claims 1 to 5, wherein the copolymer (B) in the first coating comprises 45-55 mol% of methacrylic acid repeating units and 45-55 mol% of ethyl acrylate repeating units.

7. The solid oral pharmaceutical composition according to any one of claims 1 to 6, wherein the copolymer (B) in the first coating comprises methacrylic acid repeating units and ethyl acrylate repeating units in a molar ratio of 1:

1.

8. The solid oral pharmaceutical composition according to any one of claims 1 to 7, wherein the copolymer (B) in the first coating consists of methacrylic acid repeating units and ethyl acrylate repeating units.

9. A solid oral pharmaceutical composition according to any one of claims 1 to 8, wherein the first coating comprises copolymer (A) and copolymer (B), wherein the content of copolymer (A) in the first coating relative to the total weight of copolymer (A) and copolymer (B) 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).

10. The solid oral pharmaceutical composition according to any one of claims 1 to 9, further comprising: (iii) a second coating on the outside of the first coating, wherein the second coating comprises copolymer (C); Wherein the copolymer (C) comprises: (a) 25-60 mol% of methacrylic acid repeating units, and (b) 40-75 mol % of methyl methacrylate repeating units.

11. A solid oral pharmaceutical composition according to any one of claims 1 to 10, wherein the molecular weight of the peptide or protein drug is equal to or less than about 300 kDa, preferably equal to or less than about 150 kDa.

12. A solid oral pharmaceutical composition according to any one of claims 1 to 11, wherein the peptide or protein drug is selected from insulin, insulin analogs, insulin lispro, insulin PEGlispro, insulin aspart, insulin glulisine, insulin glargine, insulin detemir, NPH insulin, insulin degludec, B29K(N(ε)hexadecandioyl-γ-L-Glu)A14E B25HdesB30 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 B25HdesB30 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, B29K(N(ε)octadecandioyl)A14EB25HdesB30 Human insulin, GLP-2, GLP-2 analogs, GLP-2 agonists, teduglutide, esiglutide, glucose-dependent insulinotropic polypeptide, elamitide, natural cyclic peptide, 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 peptide, osteocalcin, osteocalcin analogs or derivatives, human growth hormone, human growth hormone Analogs, long-acting human growth hormone, fibroblast growth factor 21, parsitin, hGH-CTP, antibodies, glycopeptide antibiotics, glycosylated cyclic or polycyclic non-ribosomal peptide antibiotics, vancomycin, teicoplanin, telavancin, bleomycin, ramuplanin, decaplanin, natural cyclic peptides, bortezomib, teicoplanin, chorionic gonadotropin, follicle-stimulating hormone, sermorelin, luteinizing hormone-releasing hormone, growth hormone, calcitonin, salmon calcitonin, pentagastrin, oxytocin, nesiritide, anakinra, enfuvirtide, pegvisomant, dornase alfa, lepirudin, anidulafungin, eptifibatide, interferon alfacon-1, interferon alpha-2a, stem cell transplant interferon alpha-2b, interferon beta-1a, interferon beta-1b, interferon gamma-1b, pegylated interferon alpha-2a, pegylated interferon alpha-2b, pegylated interferon beta-1a, plasmin, vasopressin, aldesleukin, epoetin, epoetin alpha, darbepoetin alpha, epoetin beta, epoetin delta, epoetin omega, epoetin zeta, epoetin theta, methoxypolyethylene glycol-epoetin beta, continuous erythropoietin receptor activator, pegylated epo, albupoetin, epo dimer analog, epo-Fc, carbamylated epo, synthetic erythropoietin protein, low molecular weight epo analog PBI-1402 , filgrastim, PEG-filgrastim, interleukin-11, cyclosporine, glucagon, urokinase, puromycin, 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, abaparatide, linaclotide, carfilzomib, icatibant, ecallantide, cilengitide, prostaglandin F2α receptor modulators, PDC31, abciximab, ranibizumab, alecept, romiplostim, anakinra, abatacept, belatacept and pharmaceutically acceptable salts thereof.

13. A solid oral pharmaceutical composition according to any one of claims 1 to 11, wherein the peptide or protein drug is selected from GLP-2, a GLP-2 agonist, a GLP-2 analog, teduglutide, esigglutide, insulin, human insulin, an insulin analog, insulin lispro, insulin PEGlispro, 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).

14. A solid oral pharmaceutical composition according to any one of claims 1 to 11, wherein the peptide or protein drug is selected from anti-obesity peptides, neuropeptide Y receptor (NPY) agonist peptides, NPY receptor Y1 agonist peptides, NPY receptor Y2 agonist peptides, NPY receptor Y4 agonist peptides, NPY receptor Y5 agonist peptides, pancreatic polypeptide receptor agonist peptides, neuropeptide Y, peptide YY, 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, canagliflozin, 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 agonist peptides, GLP-2, GLP-2 analogs or derivatives, long-acting acylated GLP-2 analogs, teduglutide, gleglutide, apaluglutide, dapiglutide, esiglutide, fulimud, EA-230, difaline acetate, kappa-opioid receptor (KOR) agonists, avitidine, zonulin antagonists, larazolamid, brimatide, small integrin binding ligand N-linked glycoprotein (SIBLING), TPX-100, ZP9830, Kv1.3 ion channel blockers, ZP10000, α4β7 integrin inhibitor, pellino-1 protein-protein interaction inhibitor peptide, BBT-401, α-4-β-7 (α4β7) integrin antagonist, PN-943, interleukin (IL) receptor targeting peptide, IL-23 receptor targeting peptide, PN-235, PN-232, IL-23 receptor antagonist, JNJ-77242113, nanobody, anti-IL13 / OX40L nanobody, anti-IL-6R nanobody, wolbalizumab, single domain antibody, caplucizumab, docanatide, WNT5A-mimetic peptide, Foxy-5, induced thrombospondin-1 (Ts p-1), cyclic pentapeptide VT1021, CXCR4 antagonist, barifotide, anti-cytokine peptide, BNZ132-1-40, FK506-binding protein-like (FKBPL) peptide, ALM-201, fisapotide trifluoroacetate, tyroserleutide, luteinizing hormone-releasing hormone (LHRH) antagonist acting on gonadotropin-releasing hormone (GnRH) receptor, ozarek, LHRH natural ligand derivative, EP-100, somatostatin receptor agonist, HTL0030310, vosoritide, relaxin receptor modulator peptide, relaxin, relaxin analog or derivative, long-acting acylated relaxin analog, recombinant relaxin, davuretin, azithromycin and alinenetide.

15. The solid oral pharmaceutical composition according to any one of claims 1 to 14, wherein the solid oral pharmaceutical composition is an oral dosage form; preferably, wherein the solid oral pharmaceutical composition is in the form of a capsule or tablet, or wherein the core is in the form of multi-particulates, granules or pellets.

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