Pharmaceutical compositions containing large biologically active substances and excipients

Abstract

The present invention relates to a pharmaceutical composition that efficiently increases the absorption rate of a large physiologically active substance in the body, specifically, to a pharmaceutical composition comprising (i) a large physiologically active substance and (ii) an excipient A containing a bile acid derivative, or (iii) an excipient B containing a compound having CYP450 inhibitory, antioxidant, or digestive enzyme activity inhibitory effects, as well as a method for preparing the same.

Description

[Technical field]

[0001] The present invention relates to a formulation for increasing the oral bioavailability of macromolecules. Specifically, the present invention relates to a pharmaceutical composition comprising (i) a large biologically active substance and (ii) an excipient A comprising a bile acid derivative, or (iii) an excipient B comprising a compound or its derivative having CYP450 inhibitory, antioxidant, or digestive enzyme activity inhibitory activity, and a method for producing the same. [Background technology]

[0002] In modern society, many people suffer from lifestyle-related diseases such as cardiovascular disease, diabetes, and osteoporosis due to changes in dietary habits. Diabetes, a type of lifestyle-related disease, is widespread around the world, and it is estimated that more than 1.5 million people die from diabetes every year. The global diabetes market is expected to grow at a CAGR of 12.4% from $80.15 billion in 2016 to $161.69 billion in 2022. In addition, the aging population caused by medical advances is expanding the market size in all areas, including osteoporosis and cardiovascular disease.

[0003] From the viewpoint of drug delivery method, they are broadly divided into oral dosage forms and parenteral dosage forms, and many oral dosage forms of drugs have been developed taking into consideration cost, convenience of patient administration, ease of manufacture, etc. From the viewpoint of patient treatment compliance, oral administration of therapeutic agents is generally considered to be a better route of administration than parenteral administration, especially when the nature of the therapeutic agent or the nature of the condition being treated requires multiple daily administration of the therapeutic agent. However, despite this, it is known that polymers such as polypeptides and polysaccharides are very difficult to administer orally successfully, and therefore polymers are administered parenterally, for example, by subcutaneous, intramuscular, or intravenous injection. Therefore, it is highly desirable to provide a formulation that enhances the oral bioavailability of polymers to a range that allows oral administration of such polymers. For diabetes treatment, which has a large market size and high growth potential, oral dosage forms have been developed by many companies. Specifically, DPP-4 inhibitors include Januvia from MSD, Trajenta from Boehringer Ingelheim, Zemiglo from LG Chem, Galvus from Novartis, and Onglyza and Kombiglyze from AstraZeneca, SGLT-2 inhibitors include Farxiga, Xigduo, and Jardiance from Boehringer Ingelheim from AstraZeneca, TZDs include Actos from Takeda, and Duvier from Chong Kun Dang, and also Rybelsus from Novo Nordisk, an oral GLP-1. However, among the above drugs, the DPP-4 inhibitors are sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, and gemigliptin; the SGLT-2 inhibitors are dapagliflozin, ipragliflozin, and empagliflozin; and the TZDs are thiazolidinediones, which are not macromolecular drugs.

[0004] Although the mass production of macromolecular drugs such as insulin, heparin, calcitonin, interferon, and growth hormone has become possible due to the advancement of electronic manipulation and biological processing, macromolecular drugs have problems related to their large molecular weight, which limits oral administration due to the difficulty of macromolecular drugs passing through the gastrointestinal mucosa or being easily degraded by digestive enzymes, resulting in treatment by methods such as intravenous injection and intramuscular injection. These administration forms, such as intravenous injection and intramuscular injection, have the advantage of high bioavailability and rapid onset of drug action because they enter the systemic circulation directly, but the onset of drug action by direct administration of the drug into the blood increases the risk of side effects. Furthermore, administration by injection is accompanied by low patient compliance due to pain and discomfort. In addition, self-administration may not be possible or administration may need to be performed in a hospital. In the latter case, this may be a troublesome problem when the drug has a short half-life and when repeated administration is required, and an increased burden on society may be an issue when inpatient treatment or hospitalization is required. To solve this problem, research is being conducted both domestically and internationally to produce oral drugs, but polymeric drugs generally have a bioavailability of only 0-2% when administered orally, resulting in a low success rate.

[0005] In recent years, many studies have been conducted on the oral absorption of macromolecular drugs, but the demand for oral drugs is increasing and the supply is insufficient. The present inventor aims to solve this problem by using bile acid excipients. Summary of the Invention

[0006] Problem to be solved In order to solve the above problems, the present invention aims to efficiently increase the bioabsorption rate of a large physiologically active substance by mixing the large physiologically active substance with a specific excipient to prepare a pharmaceutical composition with excellent oral absorption rate.

[0007] Means for solving the problem In order to achieve the above object, the present invention provides a pharmaceutical composition comprising (i) a large physiologically active substance and (ii) an excipient A containing a bile acid derivative, or (iii) an excipient B containing a compound or its derivative having CYP450 inhibitory, antioxidant, or digestive enzyme activity inhibitory activity.

[0008] In one aspect of the invention, (i) the large bioactive agent is a polypeptide, protein, polysaccharide, nucleotide, or analogues thereof.

[0009] In one aspect of the present invention, in (ii) excipient A, the bile acid derivative is one or more selected from the group consisting of glycocholic acid, glycocholchenodeoxycholic acid, taurocholic acid, deoxycholic acid, taurodeoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, dehydrocholic acid, and pharma- ceutically acceptable salts thereof. Furthermore, in one aspect of the present invention, the bile acid derivative is two or more selected from the above structural group.

[0010] In one embodiment of the present invention, the bile acid derivative in (ii) excipient A is one or more selected from the group consisting of glycocholic acid, taurocholic acid, deoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and pharma- ceutically acceptable salts thereof. In one embodiment of the present invention, the bile acid derivative is two or more selected from the above structural group.

[0011] In one embodiment of the present invention, the bile acid derivative in (ii) excipient A is one or more selected from the group consisting of chenodeoxycholic acid, ursodeoxycholic acid, and pharma- ceutically acceptable salts thereof. In one embodiment of the present invention, the bile acid derivative is two or more selected from the above structural group.

[0012] In another embodiment of the present invention, (ii) in excipient A, the bile acid derivative is chenodeoxycholic acid and ursodeoxycholic acid, or a pharma-ceutically acceptable salt thereof.

[0013] In another aspect of the invention, (ii) in excipient A, the bile acid derivative comprises a tight junction opening bile acid derivative.

[0014] In another aspect of the invention, (ii) in excipient A, the bile acid derivative comprises a non-tight junction opening bile acid derivative.

[0015] In one particular embodiment of the present invention, (ii) in excipient A, the bile acid derivatives comprise tight junction opening bile acid derivative A-1 and non-tight junction opening bile acid derivative A-2.

[0016] In one embodiment of the present invention, excipient B is a compound or a derivative thereof having one or more of the following activities: CYP450 inhibition, antioxidant activity, or enzyme activity inhibition activity.

[0017] In one embodiment of the present invention, in excipient B, the at least one compound or derivative thereof having a CYP450 inhibitory, antioxidant or enzyme activity inhibitory effect is selected from the group consisting of a CYP450 inhibitory compound, an antioxidant compound, a protease inhibitory compound, and pharma- ceutically acceptable salts thereof, or is two or more compounds selected from the above groups.

[0018] In one embodiment of the invention, the CYP450 inhibitor compound is propyl gallate or a pharma- ceutically acceptable salt thereof.

[0019] In one embodiment of the present invention, in the excipient B, the antioxidant compound is one or more selected from the group consisting of gallic acid, caffeic acid, lipoic acid, citric acid, acetylcarnitine, acetylcysteine, glutathione, ascorbyl compounds, tocopheryl compounds, and pharma- ceutically acceptable salts thereof, or the antioxidant compound is two or more selected from the above structural groups.

[0020] In one aspect of the invention, the ascorbyl compound is one or more selected from the group consisting of ascorbyl palmitate, ascorbyl stearate, and pharma- ceutically acceptable salts thereof.

[0021] In one aspect of the invention, the tocopheryl compound is one or more selected from the group consisting of tocopherol, tocopheryl acetate, tocopheryl succinate, and pharma- ceutically acceptable salts thereof.

[0022] In one embodiment of the present invention, the protease inhibitor compound has the effect of inhibiting enzyme activity in the digestive tract.

[0023] In one embodiment of the present invention, the protease inhibitor compound is one or more selected from the group consisting of propyl gallate, aprotinin, camostat mesilate, gabexate mesilate, soybean trypsin inhibitor (soybean Kunitz trypsin inhibitor, SBTI), soybean trypsin-chymotrypsin inhibitor (soybean Kunitz trypsin-chymotrypsin inhibitor, SBTCI), soybean Bowman-Birk inhibitor, ethylenediaminetetraacetic acid (EDTA), bacitracin, ovomucoid, citric acid, and pharma- ceutically acceptable salts thereof. Alternatively, the antioxidant compound is two or more selected from the above structural groups.

[0024] In one embodiment of the present invention, (iii) excipient B is one or more selected from the group consisting of propyl gallate, camostat mesylate, citric acid, soybean trypsin inhibitor, EDTA, and pharma- ceutically acceptable salts thereof, or the antioxidant compound is two or more selected from the above structural group.

[0025] In one embodiment of the present invention, (iii) excipient B is one or more selected from the group consisting of propyl gallate, camostat mesylate, and pharma- ceutically acceptable salts thereof, or is two or more selected from the above structural group.

[0026] In one particular embodiment of the present invention, (ii) excipient A is one or more selected from the group consisting of chenodeoxycholate, ursodeoxycholate, and pharma- ceutically acceptable salts thereof, and (iii) excipient B is one or more selected from the group consisting of propyl gallate, camostat mesylate, and pharma- ceutically acceptable salts thereof, or each excipient is two or more selected from the above group.

[0027] In one embodiment of the present invention, the pharmaceutical composition comprises an excipient A and an excipient B, and the weight ratio of excipient A to excipient B is 1:0.001-5.

[0028] In one embodiment of the present invention, the weight ratio of (i) the large biologically active substance to (ii) excipient A is 1:1-1500.

[0029] In one embodiment of the present invention, (ii) excipient A comprises two or more bile acid derivatives, the weight ratio of each being 1-1500 relative to the weight of the larger biologically active substance.

[0030] In one embodiment of the present invention, the weight ratio of (i) a large physiologically active substance to (iii) excipient B is 1:0.1-300.

[0031] In one aspect of the invention, the pharmaceutical composition is administered orally.

[0032] Furthermore, the present invention relates to a method for preparing a pharmaceutical composition comprising the steps of mixing (i) a large biologically active substance with (ii) an excipient A comprising a bile acid derivative, or (iii) an excipient B comprising a compound or derivative thereof having CYP450 inhibitory, antioxidant or enzyme activity inhibitory activity.

[0033] In one embodiment of the present invention, the weight ratio of (i) the large biologically active substance to (ii) excipient A is 1:1-1500.

[0034] In one embodiment of the present invention, the weight ratio of (i) a large physiologically active substance to (iii) excipient B is 1:0.1-300.

[0035] In one aspect of the present invention, in the above-mentioned production method, the pharmaceutical composition contains an excipient A and an excipient B, and the weight ratio of the excipient A to the excipient B is 1:0.001-5.

[0036] Effect of the Invention In the present invention, the use of two or more excipients has the advantage that decomposition of a large physiologically active substance can be prevented, and since the substance can be permeated through the intestinal membrane, the absorption rate in the body is significantly increased, resulting in excellent absorption rate. [Brief description of the drawings]

[0037] [Figure 1] FIG. 1 is a graph confirming the cytotoxicity of bile acid derivatives in Caco-2 cells. [Diagram 2] FIG. 1 shows the tight junction opening properties of bile acid derivatives and propyl gallate in Caco-2. [Diagram 3] FIG. 1 is a diagram confirming the Caco-2 cell membrane permeation pathway of bile acid derivatives. [Figure 4] FIG. 1 shows the measurement of Caco-2 cell membrane permeability of compositions containing large bioactive substances (compounds 1 and 14) and one bile acid. [Diagram 5] FIG. 1 measures the blood glucose regulating ability of a composition comprising a large bioactive substance (compound 1), one or more bile acid derivatives, and propyl gallate. [Figure 6] FIG. 1 measures the blood glucose regulating ability of a composition comprising a large bioactive substance (compound 1), one or more bile acid derivatives, and propyl gallate. [Figure 7] FIG. 14 measures the weight loss and appetite suppressant effects of a composition comprising a large bioactive agent (compound 14), one or more bile acid derivatives, and propyl gallate. [Figure 8] FIG. 14 measures the weight loss and appetite suppressant effects of a composition comprising a large bioactive agent (compound 14), one or more bile acid derivatives, and propyl gallate. [Figure 9]FIG. 1 confirms the weight loss and appetite suppressant effects of a composition comprising a large bioactive agent (compound 15), one or more bile acid derivatives, and propyl gallate. [Figure 10] FIG. 1 confirms the weight loss and appetite suppressant effects of a composition comprising a large bioactive agent (compound 15), one or more bile acid derivatives, and propyl gallate. [Figure 11] FIG. 1 confirms the weight loss and appetite suppressant effects of a composition comprising a large bioactive agent (compound 17), one or more bile acid derivatives, and propyl gallate. [Figure 12] FIG. 1 confirms the weight loss and appetite suppressant effects of a composition comprising a large bioactive agent (compound 17), one or more bile acid derivatives, and propyl gallate. [Figure 13] FIG. 1 confirms the weight loss and appetite suppressant effects of a composition comprising a large bioactive agent (compound 17), one or more bile acid derivatives, and propyl gallate. [Figure 14] FIG. 1 confirms the glycemic control ability of a composition comprising a large bioactive agent (compound 18), one or more bile acid derivatives, and propyl gallate. [Figure 15] FIG. 1 confirms the glycemic control ability of a composition comprising a large bioactive agent (compound 19), one or more bile acid derivatives, and propyl gallate. [Figure 16] FIG. 1 confirms the glycemic control ability of a composition comprising a large bioactive agent (compound 19), one or more bile acid derivatives, and propyl gallate. [Figure 17] FIG. 1 confirms the glycemic control ability of compositions comprising large bioactive substances (compounds 20, 21, and 22), one or more bile acid derivatives, and propyl gallate. BEST MODE FOR CARRYING OUT THEINVENTION

[0038] The present invention relates to a pharmaceutical composition comprising (i) a large physiologically active substance and (ii) excipient A comprising a bile acid derivative, or (iii) excipient B comprising a compound or a derivative thereof having CYP450 inhibitory, antioxidant or digestive enzyme activity inhibitory activity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, examples of the present invention will be described in detail so that those skilled in the art can easily practice the present invention.

[0040] However, the present invention can be embodied in various different forms and is not limited to the exemplary embodiments and examples described herein. Throughout the specification of the present invention, when a part "comprises" a certain component, it does not mean to exclude other components, but means that other components may also be included, unless otherwise specified.

[0041] Throughout the present specification, the terms "combinations thereof" and "combinations thereof" contained within Markush-style expressions refer to mixtures or combinations of one or more selected from the group of components set forth in the Markush-style expressions, and are meant to include one or more selected from the group of components set forth above.

[0042] In the present invention, the terms "derivative" and "analog" refer to a compound in which a part of the structure has been modified by deletion, substitution, addition, or the like.

[0043] In the present invention, the term "pharmaceutical acceptable" means that the components contained therein do not significantly irritate the living body and do not inhibit biological activity and properties.

[0044] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that has a desired biological activity without inhibiting the biological activity and properties of humans or animals, and includes, but is not limited to, inorganic acid salts (hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid), organic acid salts (acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbic acid, tannic acid, pamoic acid, alginic acid, triethylamine, cyclohexylamine, pyridine), alkali metal salts (sodium salts, potassium salts), alkaline earth metal salts (calcium salts), ammonium salts, and addition salt forms thereof.

[0045] In the present invention, bile acids are amphiphilic molecules and can promote drug permeation through biological membranes. Bile acids or their derivatives are absorbed in a form combined with the large bioactive substances of the present invention, thereby minimizing the loss of the large bioactive substances during oral administration and improving the absorption rate in the body. Furthermore, in the present invention, bile acids or their derivatives can be mixed with other excipients to further improve absorption in the body. The absorption rate in the body can be adjusted to penetrate at a desired location in the intestine according to the above combination. For example, by inhibiting the degradation of the large bioactive substances in the stomach, the formulation can reach and act in the small intestine or colon.

[0046] Furthermore, bile acid derivatives in which a portion of the bile acid is substituted, deleted or added can be appropriately selected taking into consideration cell stability, cytotoxicity, absorption rate in the body, and the like.

[0047] The present invention relates to a pharmaceutical composition comprising (i) a large biologically active substance and (ii) excipient A comprising a bile acid derivative, or (iii) excipient B comprising a compound or derivative thereof having CYP450 inhibitory, antioxidant or enzyme activity inhibitory activity.

[0048] In the present invention, large biologically active substances refer to substances that have a molecular weight known in the art, specifically, have a size of 1000 Da or more, and are active in the human or animal body.

[0049] Large bioactive substances include polypeptides, proteins, polysaccharides, nucleotides, or analogs thereof, examples of which include the following: (a) glucagon, GLP-1, GLP-2, GIP, exendin-4, exenatide, semaglutide, liraglutide, insulin, parathyroid hormone, tirzepatide, amylin, pramlintide, lipidated exendin-4, lipidated exenatide, lipidated insulin, lipidated amylin, lipidated GluB, biotinyl exendin-4, biotinyl exenatide, biotinyl amylin, biotinyl parathyroid hormone, octreotide, leuprolide, goserelin, growth hormone, etanercept, antibodies, antibody fragments, albumin and its fragments, galanin, calcitonin, secretin, histones, interferon, erythropoietin , serotonin, rituximab, trastuzumab, uricase, tissue plasminogen activator, thymoglobin, vaccines, transferrin, fibronectin, antithrombin III, filgrastim, pramlintide acetate, eptifibatide, myosin, actin, dystrophin, antivenin, IgG, IgM, HGH, thyroxine, blood clotting factor VII, blood clotting factor VIII, monoclonal antibodies, antigen fragments, interleukins, cytokines, TNF, TGF, enzymes, binding proteins, cell receptors, signaling proteins, signaling molecules, analogs thereof, and conjugates thereof, (b) glycogen, labulose, lactose, glucan, chitin, glycogen, cellulose, starch, dextrin, pectin, heparin, chitosan, schizophyllan, starch, araban, fructan, hyaluronic acid, keratan, chondroitin, xylan, analogs thereof, conjugates thereof, and (c) Ribonucleotides including AMP, GMP, UMP, CMP, IMP, XMP, etc.; deoxyribonucleotides including dAMP, dGMP, dUMP, dCMP, dIMP, dXMP, etc.; cyclic nucleotides including cAMP, cGMP, c-di-GMP, c-di-AMP, cADP, etc.; nucleoside diphosphates including ADP, GP, UDP, CDP, dADP, etc.; oligonucleotides and polynucleotides including combinations thereof; analogs thereof, conjugates thereof, etc. However, the above substances are merely examples, and large biologically active substances are not limited thereto.

[0050] In the present invention, biotinylation refers to a form in which a portion of a polypeptide, protein, polysaccharide, etc. is bound to a biotin moiety, and the biotin moiety refers to a portion or all of vitamin B, vitamin B complex, or vitamin B analogue. Furthermore, in this case, vitamin B complex refers to a complex form containing one or more vitamin B in a form in which vitamin B is bound to an amino acid, fatty acid, etc.

[0051] Furthermore, in the present invention, "lipidation" refers to a form in which a portion of a polypeptide, protein, polysaccharide, etc. is bound to a fatty acid moiety, and the fatty acid moiety refers to some or all of the carboxylic acids having a long aliphatic chain that is either saturated or unsaturated. Examples of fatty acid moieties that can be bound include caprylic acid, lauric acid, palmitic acid, stearic acid, arachidic acid, and cerotic acid, which are types of saturated acids, and myristoleic acid, palmitoleic acid, oleic acid, linoleic acid, and alpha-linolenic acid, which are types of saturated fatty acids. However, these are merely examples, and the fatty acid moiety is not limited thereto.

[0052] Furthermore, in the present invention, biotinylation / lipidation refers to a form including both biotinylation and lipidation, and means a form in which a biotin moiety and a fatty acid moiety are bound to a portion of a polypeptide, a protein, a polysaccharide, etc. Furthermore, biotinylation and lipidation may exist in a form including both biotinylation and lipidation in one amino acid (e.g., amino acid-fatty acid moiety-biotin moiety, amino acid-biotin moiety-fatty acid moiety-biotin moiety, etc.), or may exist in a form including biotinylation and lipidation in two or more different amino acids, respectively.

[0053] In one aspect of the invention, (i) the large bioactive agent is a polypeptide, protein, polysaccharide, nucleotide, or analogues thereof.

[0054] In one aspect of the invention, (i) the large bioactive substance is one or more selected from the group consisting of GLP-1, GCG, GIP, insulin, amylin, parathyroid hormone, calcitonin, heparin, human growth hormone, erythropoietin, and analogs thereof.

[0055] In one aspect of the invention, (i) the large bioactive substance is one or more selected from the group consisting of GLP-1, GCG, GIP, insulin, amylin, parathyroid hormone, and analogs thereof.

[0056] In one aspect of the invention, (i) the large bioactive agent is one or more selected from the group consisting of GLP-1 receptor agonists, GCG receptor agonists, GIP receptor agonists, GLP-1 / GCG receptor agonists, GLP-1 / GCG / GIP receptor agonists, insulin, insulin receptor agonists, amylin, amylin receptor agonists, parathyroid hormone, parathyroid hormone receptor agonists, biotinylated analogues thereof, lipidated analogues thereof, and biotinylated / lipidated analogues thereof.

[0057] In one particular aspect of the invention, (i) the large bioactive agent is one or more selected from the group consisting of GLP-1 receptor agonists, GLP-1 / GCG receptor agonists, insulin, insulin receptor agonists, amylin, amylin receptor agonists, parathyroid hormone, parathyroid hormone receptor agonists, biotinylated analogues thereof, lipidated analogues thereof, and biotinylated / lipidated analogues thereof.

[0058] In one aspect of the invention, (i) the large bioactive agent is one or more selected from the group consisting of glucagon, GLP-1 (glucagon-like peptide-1), GLP-2 (glucagon-like peptide-2), GIP (glucose-dependent insulinotropic polypeptide), exendin-4, exenatide, semaglutide, liraglutide, insulin, parathyroid hormone (PTH), tirzepatide, amylin, pramlintide, lipidated exendin-4, lipidated exenatide, lipidated insulin, lipidated amylin, lipidated GluB, biotinyl exendin-4, biotinyl exenatide, biotinyl amylin, biotinyl-PTH, octreotide, goserelin, leuprolide, growth hormone, etanercept, and analogs thereof.

[0059] Further, in one aspect of the invention, (i) the large bioactive agent is one or more selected from the group consisting of exendin-4, exenatide, semaglutide, insulin, parathyroid hormone (PTH), amylin, analogues thereof, biotinylated analogues thereof, lipidated analogues thereof, and biotinylated / lipidated analogues thereof.

[0060] Biotinylation can be achieved by amino acid, polypeptide, alkylene, amine or polyamidoamine structure.In this case, the amino acid includes lysine, 5-hydroxylysine, 4-oxalysine, 4-thialysine, 4-selenalysine, 4-thiahomolysine, 5,5-dimethyllysine, 5,5-difluorolysine, trans-4-dihydrolysine, 2,6-diamino-4-hexynoic acid, cis-4-dihydrolysine, 6-N-methyllysine, diaminopimelic acid, ornithine, 3-methylornithine, α-methylornithine, citrulline, homocitrulline, arginine, aspartic acid, asparagine, glutamic acid, glutamine, histidine, ornithine, proline, serine or threonine, but these are exemplary and amino acid is not limited thereto.

[0061] Biotinylation can be achieved by substituting or inserting a portion of the polypeptide, for example, one or more amino acids in the inactive region of the amino acid sequence shown in SEQ ID NO: 1 can be substituted or inserted with a lysine amino acid. Furthermore, for example, but not limited to, one or more of the amino acids in the inactive region of the amino acid sequence shown in SEQ ID NO: 1 can be substituted with 2-aminoisobutyric acid (Aib) or a lysine amino acid can be inserted. Furthermore, for example, any one or more amino acids in the inactive portion of the amino acid sequence can be substituted with pyroglutamic acid (pyr).

[0062] In one embodiment of the invention, the biotinylation may be a biotinylation in which the following compounds are attached: [ka] [ka] In this case, the * is the moiety attached to the amino acid.

[0063] Furthermore, in one aspect of the invention, the lipidation can be lipidation in which the following compounds are attached: [ka] In this case, the * is the moiety attached to the amino acid.

[0064] In one particular embodiment of the present invention, (i) the large bioactive substance is selected from the group consisting of SEQ ID NOs: 1 to 9 or SEQ ID NOs: 13 to 17. Furthermore, in one particular embodiment of the present invention, (i) the large bioactive substance may be a protein having the amino acid sequences of SEQ ID NOs: 10 and 11, or a protein having the amino acid sequences of SEQ ID NOs: 12 and 11.

[0065] Furthermore, in one particular embodiment of the present invention, (i) the large bioactive agent may be a polypeptide in which a biotin moiety or a fatty acid moiety is attached to one or more amino acids of the protein consisting of the above SEQ ID NOs.

[0066] In the present invention, excipients A and B aid, facilitate and enhance the absorption of large biologically active substances in vivo, thereby increasing the absorption rate.

[0067] In one embodiment of the present invention, (ii) excipient A containing a bile acid derivative and (iii) excipient B containing a compound having CYP450 inhibitory, antioxidant or enzyme activity inhibitory activity may each contain one or more types. In the present invention, the types and numbers of excipients A and B may vary depending on the types of major physiologically active substances.

[0068] In one aspect of the invention, in excipients A and B, the excipient comprises a tight junction opening compound or a non-tight junction opening compound.

[0069] In the present invention, the above tight junction opening refers to a type of opening of intercellular junctions, and specifically refers to an action mechanism that can promote absorption of active macromolecules by opening the tight junctions of epithelial cells.

[0070] In the present invention, non-tight junction opening (non-tight junction opening) refers to all mechanisms other than the tight junction opening mechanism that can improve oral absorption rate, including, for example, mechanisms such as opening of junctions other than tight junctions, mechanisms that promote binding to intestinal receptors such as reducing degradation in the digestive tract and improving gastrointestinal permeability, and adherens junctions, focal adhesions, hemidesmosomes, gap junctions, etc. in the intestine.

[0071] In one aspect of the invention, in excipients A and B, the excipient comprises one or more selected from a tight junction opening bile acid derivative, a non-tight junction opening bile acid derivative, or a non-tight junction opening compound.

[0072] In one aspect of the invention, the tight junction opening bile acid derivative may be chenodeoxycholic acid, deoxycholic acid, or a pharma- ceutically acceptable salt thereof.

[0073] In one aspect of the invention, the non-tight junction opening bile acid derivative may be ursodeoxycholic acid or a pharma- ceutically acceptable salt thereof.

[0074] In one aspect of the invention, the non-tight junction opening compound may be propyl gallate or a pharma- ceutically acceptable salt thereof.

[0075] Excipient A comprises a bile acid derivative, which as used herein includes, for example, glycocholic acid, glycocholchenodeoxycholic acid, taurocholic acid, deoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, analogs, conjugates, and the like.

[0076] In one aspect of the present invention, (ii) in excipient A, the bile acid derivative is one or more selected from the group consisting of glycocholic acid, glycocholchenodeoxycholic acid, taurocholic acid, deoxycholic acid, taurodeoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, dehydrocholic acid, and pharma- ceutically acceptable salts thereof.

[0077] In one aspect of the present invention, in (ii) excipient A, the bile acid derivative is two or more selected from the group consisting of glycocholic acid, glycocholchenodeoxycholic acid, taurocholic acid, deoxycholic acid, taurodeoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, dehydrocholic acid, and pharma- ceutically acceptable salts thereof.

[0078] In one embodiment of the present invention, (ii) in the excipient A, the bile acid derivative is one or more selected from the group consisting of glycocholic acid, taurocholic acid, deoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and pharma- ceutically acceptable salts thereof, or is two or more selected from the above structural groups.

[0079] Further, in one aspect of the present invention, in (ii) excipient A, the bile acid derivative is one or more selected from the group consisting of chenodeoxycholic acid, ursodeoxycholic acid, and pharma- ceutically acceptable salts thereof, or is two or more selected from the above structural group.

[0080] Further, in one embodiment of the present invention, (ii) in excipient A, the bile acid derivative includes chenodeoxycholic acid and ursodeoxycholic acid, or a pharma-ceutically acceptable salt thereof.

[0081] In excipient B, the compounds having CYP450 inhibition, antioxidant activity, or enzyme activity inhibition activity include: Polyphenolic compounds including, for example, phenolic acids such as coumaric acid, caffeic acid, ferulic acid, sinapic acid, and gallic acid, flavonoids such as quercetin, myricetin, catechin, epicatechin, epigallocatechin, apigenin, and luteolin, stilbenes such as resveratrol and pterostilbene, and lignans such as sesamin, sesamolin, nordihydroguaiaretic acid, gomisin A, and secoisolariciresinol; Carnitine compounds such as L-carnitine, D-carnitine, acetyl L-carnitine, acetyl D-carnitine, propionylcarnitine, and carnitine hydrochloride; an amino acid moiety containing at least one cysteine, cystine, or methionine; a sulfur-containing compound, such as cysteine, cystine, methionine, adenosylmethionine, glutathione, glutathione disulfide, taurine, thiamine, biotin, alpha-lipoic acid, dihydro-alpha-lipoic acid; Trypsin inhibitors of plant origin, soybean trypsin inhibitor, Bowman-Birk inhibitor, corn protease inhibitor, trypsin inhibitors of animal origin, chymostatin, nafamostat mesylate, camostat mesylate, gabexate mesylate, aprotinin, antipain, benzamidine, leupeptin, pepstatin, phosphoramidon, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF), tosyl-L-lysyl-chloromethane hydrochloride ( protease inhibitor compounds such as TLCK), tosyl-L-phenylalanyl fluoromethyl ketone (TPCK), aminophenylmethanesulfonyl fluoride hydrochloride (APMSF), diisopropyl fluorophosphate (DFP), phenylmethanesulfonyl fluoride (PMSF), ovomucoid, sepimostat, amastatin, bestatin, diprotin A, bacitracin, puromycin, citric acid, trisodium citrate, and dextrose; and Chelating agents include ethylenediaminetetraacetic acid (EDTA), chitosan-EDTA conjugates, citrate, EGTA, diethylenetriaminepentaacetic acid (DTPA), and BAPTA.

[0082] Additionally, excipient B may further comprise pharma- ceutically acceptable compounds such as, for example, vitamin C, vitamin E, alpha-tocopherol, malic acid, fumaric acid, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, sodium phosphate, calcium phosphate, potassium phosphate, galactose, glucose, maltose, and the like.

[0083] In one embodiment of the present invention, excipient B is a compound or a derivative thereof having one or more of the following activities: CYP450 inhibition, antioxidant activity, or enzyme activity inhibition activity.

[0084] In one embodiment of the present invention, in excipient B, the compound or derivative thereof having CYP450 inhibitory, antioxidant, or enzyme activity inhibitory activity is one or more selected from the group consisting of CYP450 inhibitory compounds, antioxidant compounds, protease inhibitory compounds, and pharma- ceutically acceptable salts thereof. Alternatively, the antioxidant compound is two or more selected from the above structural groups.

[0085] In one embodiment of the invention, the CYP450 inhibitor compound is propyl gallate or a pharma- ceutically acceptable salt thereof.

[0086] In one embodiment of the present invention, the antioxidant compound is one or more selected from the group consisting of gallic acid, caffeic acid, lipoic acid, citric acid, acetylcarnitine, acetylcysteine, glutathione, ascorbyl compounds, tocopherol compounds, and pharma- ceutically acceptable salts thereof, or the antioxidant compound is two or more selected from the above structural groups.

[0087] In one aspect of the invention, the ascorbyl compound is one or more selected from the group consisting of ascorbyl palmitate, ascorbyl stearate, and pharma- ceutically acceptable salts thereof.

[0088] In one aspect of the invention, the tocopheryl compound is one or more selected from the group consisting of tocopherol, tocopheryl acetate, tocopheryl succinate, and pharma- ceutically acceptable salts thereof.

[0089] Furthermore, in one embodiment of the present invention, the protease inhibitor compound has the effect of inhibiting enzyme activity in the digestive tract.

[0090] In one embodiment of the present invention, the protease inhibitor compound is one or more selected from the group consisting of propyl gallate, aprotinin, camostat mesilate, gabexate mesilate, soybean trypsin inhibitor (soybean Kunitz trypsin inhibitor, SBTI), soybean trypsin-chymotrypsin inhibitor (soybean Kunitz trypsin-chymotrypsin inhibitor, SBTCI), soybean Bowman-Birk inhibitor, ethylenediaminetetraacetic acid (EDTA), bacitracin, ovomucoid, citric acid, and pharma- ceutically acceptable salts thereof. Alternatively, the antioxidant compound is two or more selected from the above structural groups.

[0091] Further, in one embodiment of the present invention, the protease inhibitor compound is one or more selected from the group consisting of propyl gallate, camostat mesilate, soybean trypsin inhibitor, citric acid, EDTA, and pharma- ceutically acceptable salts thereof, or the antioxidant compound is two or more selected from the above structural group.

[0092] In one embodiment of the present invention, the excipient B is one or more selected from the group consisting of propyl gallate, camostat mesylate, citric acid, soybean trypsin inhibitor, EDTA, and pharma- ceutically acceptable salts thereof, or the antioxidant compound is two or more selected from the above structural group.

[0093] In one embodiment of the present invention, the excipient B is one or more selected from the group consisting of propyl gallate, camostat mesylate, and pharma- ceutically acceptable salts thereof, or two or more selected from the above structural group.

[0094] In one particular embodiment of the present invention, the bile acid derivative is one or more selected from the group consisting of chenodeoxycholate, ursodeoxycholate, and pharmaceutically acceptable salts thereof, and excipient B is propyl gallate, camostat mesylate, citric acid, soybean trypsin inhibitor, EDTA, and pharmaceutically acceptable salts thereof, or each excipient is two or more selected from the above group.

[0095] In one particular embodiment of the invention, excipient A is chenodeoxycholate and ursodeoxycholate, or pharma- ceutically acceptable salts thereof, and excipient B is propyl gallate, propyl gallate and camostat camesilate, or pharma- ceutically acceptable salts thereof.

[0096] Generally, large bioactive substances are classified as class 3 of the BCS (Biopharmaceutics Classification System), which has a limited absorption area in the digestive tract due to its high water solubility and limited use in pharmaceutical compositions. However, the use of large bioactive substances according to one embodiment of the present invention together with one excipient A and one excipient B; two excipients A and one excipient B; or two excipients A and two excipients B can increase the intestinal membrane permeability.

[0097] In one embodiment of the present invention, the pharmaceutical composition comprises an excipient A and an excipient B, and the weight ratio of excipient A to excipient B is 1:0.001-5. Specifically, the weight ratio is 1:0.002-4.9, 1:0.003-4.8, 1:0.004-4.7, and 1:0.005-4.6. More specifically, the weight ratio of excipient A to excipient B is 1:0.005-4.5.

[0098] In one embodiment of the present invention, the pharmaceutical composition comprises excipient A and excipient B, in which case the weight ratio of the large physiologically active substance to the excipient is 1:1-2000. In this case, the excipient is the weight sum of excipient A and excipient B. Specifically, the weight ratio of the large physiologically active substance to the excipient is 1:2-1900, 1:3-1850, 1:4-1800, and 1:5-1800. More specifically, the weight ratio of the large physiologically active substance to the excipient is 1:5-1750.

[0099] In one embodiment of the present invention, (ii) excipient A contains two or more bile acid derivatives, and the weight ratio of each to the weight of the large physiologically active substance is 1 to 1500. Furthermore, in one embodiment of the present invention, the weight ratio of (i) the large physiologically active substance to (iii) excipient B is 1:0.1 to 300.

[0100] In one embodiment of the present invention, the excipient A may contain, as a bile acid or a derivative thereof, one or more selected from the group consisting of glycocholic acid, taurocholic acid, deoxycholic acid, deoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and pharma- ceutically acceptable salts thereof, and the weight of each of them may be 0.1 mg / kg to 500 mg / kg. More specifically, the weight may be 0.1 mg / kg to 300 mg / kg, 0.2 mg / kg to 100 mg / kg, 0.2 mg / kg to 50 mg / kg, 0.2 mg / kg to 30 mg / kg, 0.2 mg / kg to 10 mg / kg, 0.3 mg / kg to 10 mg / kg, 0.3 mg / kg to 8 mg / kg, 0.4 mg / kg to 8 mg / kg, 0.4 mg / kg to 7 mg / kg, and 0.4 mg / kg to 6 mg / kg.

[0101] Specifically, it includes chenodeoxycholate and ursodeoxycholate, and the weight of each may be 0.1 mg / kg to 500 mg / kg. More specifically, the weight may be 0.1 mg / kg to 300 mg / kg, 0.2 mg / kg to 100 mg / kg, 0.2 mg / kg to 50 mg / kg, 0.2 mg / kg to 30 mg / kg, 0.2 mg / kg to 10 mg / kg, 0.3 mg / kg to 10 mg / kg, 0.3 mg / kg to 8 mg / kg, 0.4 mg / kg to 8 mg / kg, 0.4 mg / kg to 7 mg / kg, and 0.4 mg / kg to 6 mg / kg.

[0102] In one embodiment of the present invention, excipient B includes propyl gallate, and the weight thereof may be 0.01 mg / kg to 500 mg / kg. More specifically, the weight may be 0.01 mg / kg to 100 mg / kg, 0.01 mg / kg to 50 mg / kg, 0.01 mg / kg to 30 mg / kg, 0.01 mg / kg to 10 mg / kg, 0.01 mg / kg to 8 mg / kg, 0.01 mg / kg to 7 mg / kg, 0.01 mg / kg to 6 mg / kg, and 0.02 mg / kg to 6 mg / kg.

[0103] In one embodiment of the present invention, excipient B includes EDTA, and the weight thereof may be 0.01 mg / kg to 500 mg / kg. More specifically, the weight may be 0.01 mg / kg to 100 mg / kg, 0.01 mg / kg to 50 mg / kg, 0.01 mg / kg to 30 mg / kg, 0.01 mg / kg to 10 mg / kg, 0.01 mg / kg to 8 mg / kg, 0.01 mg / kg to 7 mg / kg, 0.01 mg / kg to 6 mg / kg, and 0.02 mg / kg to 6 mg / kg.

[0104] In one embodiment of the present invention, excipient B includes camostat mesylate, and the weight of the excipient B may be 0.001 mg / kg to 10 mg / kg. More specifically, the weight of the excipient B may be 0.001 mg / kg to 5 mg / kg, 0.002 mg / kg to 5 mg / kg, 0.003 mg / kg to 3 mg / kg, 0.005 mg / kg to 2 mg / kg, or 0.005 mg / kg to 1 mg / kg.

[0105] In one embodiment of the present invention, excipient B includes soybean Kunitz trypsin inhibitor (SBTI) and the weight amount thereof may be 0.001 mg / kg to 10 mg / kg. More specifically, the weight amount may be 0.001 mg / kg to 5 mg / kg, 0.002 mg / kg to 5 mg / kg, 0.003 mg / kg to 3 mg / kg, and 0.005 mg / kg to 1 mg / kg.

[0106] In one embodiment of the present invention, excipient B includes citric acid, and the weight thereof may be 0.01 mg / kg to 100 mg / kg. More specifically, the weight may be 0.01 mg / kg to 50 mg / kg, 0.05 mg / kg to 50 mg / kg, 0.05 mg / kg to 30 mg / kg, 0.07 mg / kg to 30 mg / kg, and 0.07 mg / kg to 20 mg / kg.

[0107] In one aspect of the invention, the pharmaceutical composition is administered orally.

[0108] Specifically, oral absorption may be improved by 0.5% or more, 0.6% or more, 0.7% or more, 0.8% or more, 0.9% or more, 1% or more, 1.1% or more, 1.2% or more, 1.3% or more, 1.4% or more, 1.5% or more, 1.6% or more, 1.7% or more, 1.8% or more, 1.9% or more, and 2% or more compared to when only the large bioactive substance is present.

[0109] In the present invention, the pharmaceutical composition may have a therapeutic effect or a preventive effect depending on the type of the large bioactive substance. In the pharmaceutical composition according to the embodiment of the present invention, the large bioactive substance may be a substance used for the prevention or treatment of diabetes, obesity, osteoporosis, fatty liver disease, irritable bowel syndrome, and neurodegenerative disease. However, these are examples, and the fatty acid moiety is not limited thereto.

[0110] In one aspect of the present invention, a pharmaceutical composition for preventing or treating diabetes, obesity, fatty liver disease, intestinal disease, and neurodegenerative disease, comprising the pharmaceutical composition, can be provided.

[0111] The pharmaceutical composition of the present invention may further include an excipient in addition to the excipient A and the excipient B. In this case, the excipient may include, but is not limited to, a stabilizer, a surfactant, a plasticizer, a lubricant, a solubilizer, a buffer, a sweetener, a base, an adsorbent, a flavoring agent, a binder, a suspending agent, an antioxidant, a gloss agent, a coating agent, a flavoring agent, a flavoring agent, a humectant, a humidity regulator, an antifoaming agent, a chewing agent, a cooling agent, a coloring agent, a sugar coating agent, an isotonicity agent, a pH adjuster, a softener, an emulsifier, an adhesive, an adhesion enhancer, a viscosity agent, a thickening agent, an effervescent agent, an excipient, a dispersant, a propellant, a disintegrating agent, a disintegrating tablet, an aroma, a dehumidifying agent, an antiseptic, a preservative, an analgesic, a solvent, a dissolving agent, a solubilizing agent, a fluidizing agent, and the like.

[0112] In the present invention, the pharmaceutical composition may further include starch, calcium carbonate, sucrose or lactose, gelatin, etc. for solid preparations, and suspensions, oral liquids, emulsions, syrups, etc. for liquid preparations, and may further include lubricants, wetting agents, sweeteners, flavorings, preservatives, etc. Furthermore, calcium or vitamin D3 may be added to improve the effectiveness as a treatment for proliferative diseases or autoimmune diseases. In the present invention, pharmaceutical preparations for oral administration may be present in unit dosage forms such as, for example, sugar-coated tablets, tablets, pills, powders, granules or capsules, and ampoules. These are prepared using known methods, for example, using conventional mixing, granulation, compounding, dissolving or lyophilization methods. For example, pharmaceutical preparations for oral administration may be prepared by mixing a large physiologically active substance with a solid carrier, granulating the mixture, adding suitable additives as necessary, and then formulating the mixture or granules into the form of tablets or sugar-coated tablets.

[0113] In one embodiment of the present invention, the pharmaceutical composition is a solid formulation. In one particular embodiment of the present invention, the pharmaceutical composition is a granule or tablet.

[0114] The dosage of the pharmaceutical composition according to one embodiment of the present invention may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of disease, but generally can be administered once a day or in divided doses within the effective daily dosage range. Furthermore, the effective dosage may be administered by several administrations every 1 to 2 weeks.

[0115] The present invention further provides a method for preparing a pharmaceutical composition, comprising the steps of: (i) mixing a large biologically active substance with (ii) excipient A comprising a bile acid derivative; or (iii) excipient B comprising a compound or derivative thereof having CYP450 inhibitory, antioxidant, or gastrointestinal enzyme activity inhibitory activity.

[0116] Further, the present invention provides a method for preparing a pharmaceutical composition, comprising the steps of preparing granules by mixing (i) a large biologically active substance with (ii) excipient A comprising a bile acid derivative, or (iii) excipient B comprising a compound having CYP450 inhibitory, antioxidant or gastrointestinal enzyme activity inhibitory activity or its derivative, and preparing tablets using a tablet press and then coating them in a coating machine.

[0117] In the present invention, the mixing step can be appropriately adjusted according to the properties of the major bioactive substances and excipients. For example, but not limited to, simple mixing, wet granulation and dry granulation methods can be carried out.

[0118] The specific types, weight ratios, and amounts of excipient A and excipient B used are as described above.

[0119] Furthermore, the present invention relates to a prophylactic or therapeutic method comprising the pharmaceutical composition.

[0120] Additionally, the present invention relates to methods, including pharmaceutical compositions, for preventing or treating diabetes, obesity, fatty liver disease, bowel disease, and neurodegenerative diseases.

[0121] The present invention will be described in detail below using examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples and experimental examples.

[0122] <Embodiment 1: Combination of large physiologically active substances and excipients> Large bioactive substances The large physiologically active substances (polymers) shown in Table 1 below were used. The type and amount of each large physiologically active substance used are shown in Table 1. In this case, exendin-4 derivatives, lipidated insulin, lipidated amylin, etc. can be prepared according to the methods disclosed in Korean Patent Application Nos. 10-2019-0064370, 10-2020-0163362, 10-2020-0163363, and 10-2020-0065484. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0123] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0124] Excipients As excipients, the substances shown in Table 2 below were used. Each excipient is as shown in Table 2. [Table 2]

[0125] <Embodiment 2: Confirmation of tight junction opening ability of bile acid derivatives and propyl gallate> <Experimental Example 1> Cytotoxicity of bile acid derivatives in Caco-2 cells The cytotoxicity of the excipients was evaluated using Caco-2 cells using the following method: First, 1 × 10 cells per well were placed in a 96-well plate to confirm the amount of intracellular accumulation. 5 Distribute Caco-2 cells in CO 2 The culture was performed in an incubator at 37°C. The culture medium was removed from each well and replaced with fresh medium. Then, 2.5 μL of the prepared excipient was added, and the mixture was incubated with CO 2The cells were cultured at 37°C in an incubator. After 2 hours, each well was treated with 100 μL of luciferase reagent (Promega, #G7571) and incubated at room temperature. After 10 minutes, the luminescence value of each well was measured. The cell viability (%) was calculated as follows, and the analysis results are shown in Figure 1. As shown in Figure 1, it was confirmed that the cytotoxicity of DC and CDC was similar, and that UDC had the least toxicity. Cell viability (%) = (luminescence value / control luminescence value) x 100

[0126] <Experimental Example 2> Confirmation of the tight junction opening properties of bile acid derivatives and propyl gallate in Caco-2 cells. The tight junction opening and non-tight junction opening properties of excipients were evaluated by changes in TEER values ​​using Caco-2 cell monolayers. First, 1.5 × 10 cells per well were placed in a 12-transwell plate to form a Caco-2 cell monolayer. 5 Aliquot the cells and incubate at 37 °C with CO. 2 The cells were cultured under these conditions for 3 to 4 weeks. In the first week, the medium was changed every 2 days, and thereafter, the medium was changed every 3 days. In the experiments, samples were used 3 to 4 weeks after seeding. To evaluate the degree of damage to the Caco-2 cell monolayer by the excipients, the degree of cells cultured as a monolayer on a semipermeable membrane was measured by the difference in electrical resistance between the apical and basolateral sides. First, the transwells used in each test were washed using washing buffer (HBSS), replaced with medium, and incubated at 37 °C in CO 2 Equilibrate in an incubator for 15 min. 500 μL of prepared excipient was added to the apical side, and the basolateral side was treated with 1.5 mL of medium without excipient, after which the change in TEER value was measured using a Millicell ERS-2 Voltohmmeter at each time point (0, 5, 15, 30, 45, 60, 90, 120 min) from the time of treatment. The TEER change (%) was calculated as follows, and the analysis results are shown in Figure 2. TEER change (%) = (TEER value / control TEER value) x 100

[0127] As shown in Figure 2, the excipients with tight junction opening properties were CDC and DC, and the excipients with non-tight junction opening properties were UDC and PG, based on the change in TEER value. It was confirmed that even the excipients with tight junction opening properties had reversible tight junction opening properties that returned to normal levels within 60 to 120 minutes after treatment.

[0128] <Embodiment 3> Measurement of Caco-2 cell membrane permeation pathway of bile acid derivatives Using Caco-2 cell monolayers, the excipient-induced changes in permeability of each permeability pathway marker were evaluated using the following method: First, 1.5 × 10 cells per well were placed in a 12-transwell plate to form a Caco-2 cell monolayer. 5 Aliquot the cells and incubate at 37 °C with CO. 2 The cells were cultured under these conditions for 3 to 4 weeks. In the first week, the medium was changed every 2 days, and thereafter, the medium was changed every 3 days. In the experiments, samples were used 3 to 4 weeks after seeding. To verify the formation of a cell monolayer, the TEER value and Lucifer Yellow value were measured, and the TEER value was measured at 300 Ω cm. 2 Only cell monolayers with TEER values ​​equal to or greater than 0.01 and measured Lucifer Yellow transmittance within 3% were used in the study. Transwells used for each study were washed with transport medium (HBSS) and incubated at 37°C in CO 2 After 1 h of incubation in a CO incubator, 500 µL of bile acid derivatives and permeability markers were added to the apical side, and 1.5 mL of drug-free transport medium was applied to the basolateral side, followed by incubation at 37 °C in a CO 2 The cells were incubated in an incubator for 2 hours. At this time, fluorescein isothiocyanate-dextran (FD4) was used as a paracellular marker, and metoprolol was used as a transcellular marker to confirm the change in permeability coefficient due to bile acid derivative treatment. After 2 hours, 1 mL of samples were taken from the basolateral side, and the permeability coefficient (Papp value) of the drug was measured using enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (HPLC). The permeability coefficient (Papp) value was calculated as follows, and the analysis results are shown in Figure 3. -Papp(10-7 cm / s) = (dC r / d t )xV r / (AxC 0 ) (*dC r - concentration of the transmitted sample, d t - Drug treatment time, V r - Basolateral volume, A - Transwell area, C 0 -Initial applied drug concentration)

[0129] As shown in Figure 3, CDC enhances both paracellular and transcellular transport in the Caco-2 test system. In the case of UDC, no enhancing effect on the two transport mechanisms was found.

[0130] <Embodiment 4> Preparation of a formulation containing a large physiologically active substance (compounds 1 and 14) and one type of bile acid, and measurement of Caco-2 cell membrane permeability of the large physiologically active substance in the formulation First, to form a Caco-2 cell monolayer, 1.5 × 10 cells were placed in each well of a 12-transwell plate. 5 Aliquot the cells and incubate at 37 °C with CO. 2 The cells were cultured under these conditions for 3 to 4 weeks. In the first week, the medium was changed every 2 days, and thereafter, the medium was changed every 3 days. In the experiments, samples were used 3 to 4 weeks after seeding. To verify the formation of a cell monolayer, the TEER value and Lucifer Yellow value were measured, and the TEER value was measured at 300 Ω cm. 2 Only cell monolayers with TEER values ​​equal to or greater than 0.01 and measured Lucifer Yellow transmittance within 3% were used in the studies. Transwells used in each study were washed with transport medium (HBSS) and then incubated at 37°C in CO 2 After 1 h of incubation in a CO incubator, 500 μL of large bioactive substances (50 μM) and bile acid derivatives (100 μM) were added to the apical side, and 1.5 mL of drug-free transport medium was added to the basolateral side. 2The incubation was carried out in an incubator for 2 hours. After 2 hours, 1 mL samples were taken from the basolateral side, and the permeability coefficient (Papp value) of the drug was measured using enzyme-linked immunosorbent assay (ELISA). The permeability coefficient (Papp) value was calculated as follows, and the analysis results are shown in Figure 4. -Papp(10 -7 cm / s) = (dC r / d t )xV r / (AxC 0 ) (*dC r - concentration of the transmitted sample, d t - Drug treatment time, V r - Basolateral volume, A - Transwell area, C 0 -Initial applied drug concentration)

[0131] As shown in FIG. 4, this experimental example confirmed that in the Caco-2 test, UDC had no effect of improving the permeability of large physiologically active substances, while CDC had the effect of improving the permeability of large physiologically active substances.

[0132] <Embodiment 5> Preparation of a formulation containing a large physiologically active substance (compound 6), one bile acid derivative, and propyl gallate and measurement of intestinal absorption rate Biotinyl exenatide derivative (compound 6) was formulated by dissolving in the corresponding vehicle (saline or 0.5% CMC in saline) using the excipient composition shown in Table 2, and the pharmaceutical behavior by intestinal absorption was compared through intraduodenal administration to Sprague-Dawley rats. The results are shown in Table 3 below. [Table 3-1] [Table 3-2]

[0133] <Embodiment 6> Evaluation of the stability of a large biologically active substance in a formulation containing a large biologically active substance (compound 6), one bile acid derivative, and propyl gallate The stability of the large bioactive substance in one bile acid derivative and propyl gallate formulations was evaluated for three bile acid derivatives with high bioavailability through intestinal absorption. Compound 6 was stored at 40°C for 2 weeks using the excipient composition shown in Table 3, and then dissolved in the corresponding solvent (0.02% polysorbate 80 in 10 mM PBS, pH 7.4). The solution was then filtered and the change in purity of the large bioactive substance (compound 6) was analyzed by HPLC, and the results are shown in Table 4. Analysis of the change in purity of the test substances after storage at 40°C for 2 weeks confirmed that the stability of the large bioactive substance (compound 6) in DC and propyl gallate compositions was the lowest. [Table 4]

[0134] <Embodiment 7> Preparation of a formulation containing a large physiologically active substance, one bile acid derivative, and propyl gallate and measurement of intestinal absorption rate The materials containing the compounds in Table 1 were formulated by dissolving them in the corresponding vehicle (0.02% polysorbate 80 in saline) with the excipient composition shown in Table 4. The pharmaceutical behaviors were compared after administration to the duodenum of experimental rats (SD rats). The results are shown in Table 5. [Table 5]

[0135] <Embodiment 8> Preparation of a formulation containing a large physiologically active substance (compound 10), one or more bile acid derivatives, and propyl gallate, and measurement of intestinal absorption rate A large bioactive substance (compound 10) was formulated by dissolving it in a vehicle with the excipient composition shown in Table 6. Here, the vehicle was formulated by appropriately mixing polysorbate 80, propylene glycol, CMC, saline or phosphate buffer. After administering the above formulations to the duodenum of experimental rats, the pharmaceutical behavior was compared. The results are shown in Table 6 below. [Table 6]

[0136] <Embodiment 9> Preparation of a formulation containing a large physiologically active substance (compound 24), one bile acid derivative, and propyl gallate and measurement of intestinal absorption rate A large bioactive substance (compound 24) was formulated by dissolving it in the corresponding vehicle (0.02% polysorbate 80 in 10 mM PBS, pH 7.4) using the excipient composition shown in Table 6 above. After administration of the above formulation to the duodenum of experimental rats, C max The corresponding results are compared to those obtained by administering compound 23, a larger bioactive agent that does not contain a biotin moiety, in the same formulation and are shown in Table 7 below. [Table 7]

[0137] <Embodiment 10> Preparation of a solid formulation containing a large physiologically active substance (compound 14), one or more bile acid derivatives, and propyl gallate, and measurement of oral absorption rate Solid formulations of a large bioactive substance (compound 14) were prepared using the excipient compositions shown in Table 8 and the pharmacokinetic behavior was compared after oral administration to beagle dogs.

[0138] For the solid formulation, the large bioactive substances, bile acid derivatives, propyl gallate and common excipients used for manufacturing solid formulations (such as mannitol, crospovidone, stearate, etc.) were mixed therein, which were manufactured into granules using a dry granulation method, and then manufactured into tablets using a tablet press. Then, enteric coating was performed using a coating machine. By adjusting the amount of binder and disintegrant, the tablets were manufactured into immediate release tablets and sustained release tablets. For the immediate release tablets, more than 80% of the large bioactive substances were dissolved within 60 minutes under dissolution conditions (pH 6.8, 50 rpm, 37°C), and for the sustained release tablets, more than 80% of the large bioactive substances were dissolved within 360 minutes under dissolution conditions (pH 6.8, 50 rpm, 37°C). [Table 8-1] [Table 8-2]

[0139] <Embodiment 11> Measurement of blood glucose regulating ability of a preparation containing a large physiologically active substance (compound 1), one or more bile acid derivatives, and propyl gallate To confirm glucose tolerance, formulations containing combinations of large bioactive substances and excipients were orally administered to mice, and the efficacy of glycemic control was then measured by intraperitoneal glucose tolerance test (IPGTT). Large bioactive substances (compound 1) were formulated by dissolving in vehicle (0.02% polysorbate 80 in 10 mM PBS, pH 7.4) with the excipient composition shown in Table 9 below. [Table 9]

[0140] To measure abdominal glucose tolerance in an animal model, 9-week-old male mice (C57BL / 6) were orally administered 100 μl of sample (25 nmol / kg based on compound 1) at -20 minutes, and then 200 μl of glucose (2 g / kg) was intraperitoneally injected, and the changes in blood glucose in blood collected from the tail vein were observed at -20, 0, 20, 40, 60, 90, and 120 minutes. The measurement results are shown in Figure 5.

[0141] As shown in Figure 5, it was confirmed that the use of two bile acids as absorption enhancers instead of one increased the ability to regulate glucose upon oral absorption. Among the two bile acids, it was confirmed that the CDC+DC+propyl gallate and CDC+UDC+propyl gallate formulations had the best blood glucose regulating effect.

[0142] Furthermore, the CDC+DC+PG formulation and CDC+UDC+PG formulation with the best glucose regulation ability were prepared and left at room temperature for 1 day, then orally administered to mice, and the efficacy of blood glucose regulation was measured by intraperitoneal glucose tolerance test. This confirmed that the effect of the stability of large bioactive substances in the formulations is applicable to the efficacy of large bioactive substances. As shown in Figure 6, the results confirmed that after 1 day, the efficacy of the CDC+UDC+PG formulation was maintained, but the efficacy of the CDC+DC+PG formulation was reduced to 82%.

[0143] <Embodiment 12> Confirmation of weight loss and appetite suppression effects by oral administration of a large physiologically active substance (compound 14), one or more bile acid derivatives, and a propyl gallate formulation After oral administration of a formulation containing a large bioactive substance (compound 14) and an excipient to mice, changes in mouse body weight were observed. Specifically, the dose of compound 14 was 1000 nmol / kg, and the excipient concentrations in the administered formulation were CDC 6.8 mg / mL, UDC 13.6 mg / mL, and PG 13.6 mg / mL. A vehicle of 0.02% polysorbate 80 in 10 mM PBS (pH 7.4) was used.

[0144] Obese mice were induced in 6-week-old male mice (C57BL / 6) by feeding them a high-fat diet for 16 weeks, and then a substance combining a biotin moiety and a fatty acid moiety (compound 14) was orally administered daily for 4 weeks using a formulation containing two types of bile acid derivatives and propyl gallate. Body weight changes were confirmed, and a decrease in food intake and body weight loss were confirmed. The measurement results are shown in Figures 7 and 8.

[0145] <Embodiment 13> Preparation of a formulation containing a large physiologically active substance (compound 15), one or more bile acid derivatives, and propyl gallate or an enzyme inhibitor, and measurement of intestinal absorption rate in rats A large bioactive substance (compound 15) was formulated by dissolving it in the corresponding vehicle (0.02% polysorbate 80 in 10 mM PBS (pH 7.4)) using the excipient composition shown in Table 9. After the samples were administered into the duodenum at doses of 100 and 500 μg / kg, respectively, to laboratory rats (SD rats) weighing approximately 200 g, serum was collected and the change in blood drug concentration over time was measured using enzyme-linked immunosorbent assay (ELISA). Blood samples were collected from the jugular vein. The results were calculated as average values, and the results are shown in Table 10. [Table 10]

[0146] <Embodiment 14> Measurement of blood glucose control ability by oral absorption of a preparation containing a large physiologically active substance (compound 15), one or more bile acid derivatives, and propyl gallate or an enzyme inhibitor The large bioactive substance (compound 15) was formulated by dissolving it in the corresponding vehicle (0.02% polysorbate 80 in 10 mM PBS (pH 7.4)) with the excipient composition shown in Table 10. To confirm glucose tolerance, the formulation containing the combination of the large bioactive substance and the excipient was orally administered to mice, and then the efficacy of blood glucose regulation was measured by intraperitoneal glucose tolerance test (IPGTT). First, to measure abdominal glucose tolerance in an animal model, 9-week-old male mice (C57BL / 6) were orally administered 100 μl of sample (25 nmol / kg based on compound 1) at -30 minutes, and then 200 μl of glucose (2 g / kg) was intraperitoneally injected, and the change in blood glucose level in blood collected from the tail vein was observed at -20, 0, 20, 40, 60, 90, and 120 minutes. The measurement results are shown in Table 11. [Table 11]

[0147] <Embodiment 15> Confirmation of weight loss and appetite suppression effects by oral administration of a large physiologically active substance (compound 15), one or more bile acid derivatives, and a propyl gallate formulation After oral administration of a formulation containing a large bioactive substance (compound 15) and an excipient to mice, changes in mouse body weight were confirmed. Specifically, the dose of compound 15 was 1000 nmol / kg, and the excipient concentrations in the formulation used were CDC 6.8 mg / mL, UDC 13.6 mg / mL, and PG 13.6 mg / mL. A vehicle of 0.02% polysorbate 80 in 10 mM PBS (pH 7.4) was used. Obese mice were induced by feeding 6-week-old male mice (C57BL / 6) a high-fat diet for 16 weeks, and then a GLP-1 receptor agonist (compound 15) combined with a fatty acid moiety was orally administered daily for 3 weeks using a bile acid absorption enhancer formulation, and changes in body weight were confirmed. As a result, a decrease in food intake and weight loss were confirmed. The measurement results are shown in Figures 9 and 10.

[0148] <Embodiment 16> Confirmation of weight loss and appetite suppression effects by oral administration of a large physiologically active substance (compound 17), one or more bile acid derivatives, and a propyl gallate formulation After orally administering a formulation containing a large physiologically active substance (compound 17) and an excipient to mice, changes in mouse body weight and antidiabetic effects were confirmed. Specifically, the dose of compound 17 was 300-1000 nmol / kg, and the excipient concentrations in the formulation used were CDC 6.8 mg / mL, UDC 13.6 mg / mL, and PG 13.6 mg / mL. A vehicle of 0.02% polysorbate 80 in 10 mM PBS (pH 7.4) was used. Obese mice were induced by feeding 6-week-old male mice (C57BL / 6) a high-fat diet for 16 weeks, and then body weight changes were confirmed by orally administering a GLP-1 / glucagon receptor dual agonist (compound 17) combining a biotin moiety and a fatty acid moiety every day for 3 weeks using a bile acid absorption enhancer formulation. Reductions in food intake, weight loss, and antidiabetic effects were confirmed. The measurement results are shown in Figures 11 to 13.

[0149] <Embodiment 17> Measurement of blood glucose control ability by oral administration of a large physiologically active substance (compound 18), one or more bile acid derivatives, and a propyl gallate preparation To confirm glucose tolerance, the efficacy of blood glucose regulation was measured using an intraperitoneal glucose tolerance test (IPGTT) after oral administration to mice of a formulation made by combining a large bioactive substance, GLP-1 / Glucagon / GIP receptor triple agonist (compound 18), which combines biotin and fatty acid moieties, with excipients in Table 12 below. [Table 12]

[0150] First, to measure abdominal glucose tolerance in an animal model, 100 μl of sample (25 nmol / kg based on compound 1) was orally administered to 9-week-old male mice (C57BL / 6) at -20 minutes, and then 200 μl of glucose (2 g / kg) was intraperitoneally injected, and the changes in blood glucose levels in blood collected from the tail vein were observed at -20, 0, 20, 40, 60, 90, and 120 minutes. The measurement results are shown in Figure 14. It was confirmed that when two types of bile acids were used as absorption enhancers instead of one type, the ability to regulate glucose in response to oral absorption was increased.

[0151] <Embodiment 18> Measurement of blood glucose regulation ability by oral administration of a large physiologically active substance (compound 19), one or more bile acid derivatives, and a propyl gallate preparation To confirm glucose tolerance, the efficacy of blood glucose regulation was measured using an intraperitoneal glucose tolerance test (IPGTT) after oral administration to mice of a formulation made by combining insulin (compound 19), a large bioactive substance having a fatty acid moiety, with excipients in Table 13 below. [Table 13]

[0152] First, to measure abdominal glucose tolerance in an animal model, 9-week-old male mice (C57BL / 6) were orally administered 100 μl of sample (25 nmol / kg based on compound 1) at -20 min, then 200 μl of glucose (2 g / kg) was intraperitoneally injected, and the changes in blood glucose in blood collected from the tail vein were observed at -20, 0, 20, 40, 60, 90, and 120 min. The measurement results are shown in Figure 15. It was confirmed that when two types of bile acids were used as absorption enhancers instead of one, the ability to regulate glucose in response to oral absorption was increased. It was confirmed that among the two types of bile acids, CDC+DC, CDC+UDC, and propyl gallate formulations had the best glycemic control efficacy.

[0153] Furthermore, the CDC+DC+PG formulation and CDC+UDC+PG formulation with the best glucose regulating ability were left at room temperature for 1 day, then orally administered to mice, and the efficacy of blood glucose regulation was measured by intraperitoneal glucose tolerance test. This confirmed that the effect of the stability of large physiologically active substances in the formulation is applicable to the efficacy of large physiologically active substances. As shown in Figure 16, the efficacy of the CDC+UDC+PG formulation was maintained after 1 day, but it was confirmed that the blood glucose lowering effect of the CDC+DC+PG formulation was reduced to 64%-76% compared to the control group 20 minutes after administration of the test substance.

[0154] <Embodiment 19> Measurement of blood glucose regulation ability by oral administration of large physiologically active substances (compounds 20, 21, and 22), one or more bile acid derivatives, and propyl gallate preparations To confirm glucose tolerance, after oral administration to mice, preparations made by combining insulin (compound 21) with biotin as a large bioactive substance, and insulin (compound 22) with a biotin moiety or a fatty acid moiety and an excipient were administered to mice, and the effectiveness of blood glucose regulation was measured using an intraperitoneal glucose tolerance test (IPGTT). First, to measure abdominal glucose tolerance in an animal model, 9-week-old male mice (C57BL / 6) were orally administered 100 μl of sample (25 nmol / kg based on compound 1) at -20 minutes, and then 200 μl of glucose (2 g / kg) was intraperitoneally injected, and the change in blood glucose level in blood collected from the tail vein was observed at -20, 0, 20, 40, 60, 90, and 120 minutes. The measurement results are shown in FIG. 17. It was confirmed that the glucose regulation ability in response to oral absorption was increased when the biotin moiety and fatty acid moiety were combined with insulin, compared to when only biotin was combined with insulin.

[0155] <Embodiment 20> Measurement of blood glucose regulation ability by oral administration of large physiologically active substances (compounds 25 to 37), one or more bile acid derivatives, and propyl gallate preparations After a single oral administration of a formulation using a combination of a large bioactive substance and an excipient to mice, the body weight change was observed for 24 hours. Amylin derivatives having biotin (compounds 26, 29, 32, 35) and amylin derivatives having biotin and a fatty acid moiety (compounds 27, 30, 33, 36) were orally administered as a single dose using a bile acid absorption enhancer formulation to determine the body weight change, and the weight loss after 24 hours was confirmed. The measurement results are shown in Table 14. [Table 14]

[0156] As shown above in Examples 1-20, it was observed that there was an overall improvement in efficacy and pharmacokinetic parameters due to the presence of the large bioactive agent when used in conjunction with an excipient compared to when the large bioactive agent was administered alone.

[0157] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. The above description of the invention is for illustrative purposes, and those skilled in the art will understand that the invention may be easily modified into other specific forms without changing its technical spirit or essential characteristics. Therefore, it should be understood that the above embodiments are merely illustrative in all respects and not restrictive. For example, each component described as singular may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined form. All changes or modifications derived from the meaning and scope of the claims described below and their equivalent concepts should be construed as being within the scope of the invention.

[0158] Industrial Applicability The present invention can increase the absorption rate of large biologically active substances in the body and can be used in the pharmaceutical industry.

Claims

1. 1. A pharmaceutical composition comprising: (i) a large bioactive substance; (ii) an excipient A comprising one or more bile acid derivatives, or (iii) an excipient B containing one or more compounds or derivatives thereof having one or more effects selected from a CYP450 inhibitory effect, an antioxidant effect, and a gastrointestinal enzyme activity inhibitory effect; The pharmaceutical composition comprising:

2. 10. The pharmaceutical composition of claim 1, wherein the large bioactive agent comprises a polypeptide, a protein, a polysaccharide, a nucleotide, or an analog thereof.

3. 2. The pharmaceutical composition according to claim 1, wherein in the excipient A, the bile acid derivative is at least one selected from the group consisting of glycocholic acid, glycocholchenodeoxycholic acid, taurocholic acid, deoxycholic acid, taurodeoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, lithocholic acid, dehydrocholic acid, and pharmaceutically acceptable salts thereof.

4. 2. The pharmaceutical composition according to claim 1, wherein in the excipient A, the bile acid derivative is at least one selected from the group consisting of glycocholic acid, taurocholic acid, deoxycholic acid, cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, and pharmaceutically acceptable salts thereof.

5. 2. The pharmaceutical composition according to claim 1, wherein in the excipient A, the bile acid derivative is at least one selected from the group consisting of chenodeoxycholic acid, ursodeoxycholic acid, and pharmaceutically acceptable salts thereof.

6. 2. The pharmaceutical composition of claim 1, wherein in said excipient A, said bile acid derivative comprises a tight junction-opening bile acid derivative.

7. 2. The pharmaceutical composition of claim 1, wherein in said excipient A, said bile acid derivative comprises a non-tight junction opening bile acid derivative.

8. 2. The pharmaceutical composition according to claim 1, wherein in said excipient A, said bile acid derivatives comprise tight junction-opening bile acid derivative A-1 and non-tight junction-opening bile acid derivative A-2.

9. 2. The pharmaceutical composition according to claim 1, wherein the excipient B comprises a compound or a derivative thereof having two or more activities selected from a CYP450 inhibitory activity, an antioxidant activity, and a gastrointestinal enzyme activity inhibitory activity.

10. 2. The pharmaceutical composition according to claim 1, wherein in the excipient B, the compound or derivative thereof having a CYP450 inhibitory activity, an antioxidant activity, or a gastrointestinal enzyme activity inhibitory activity is at least one selected from the group consisting of a CYP450 inhibitory compound, an antioxidant compound, a protease inhibitory compound, and a pharmaceutically acceptable salt thereof.

11. 11. The pharmaceutical composition of claim 10, wherein the CYP450 inhibitor compound is propyl gallate, or a pharmaceutically acceptable salt thereof.

12. 11. The pharmaceutical composition of claim 10, wherein the antioxidant compound is at least one selected from the group consisting of gallic acid, caffeic acid, lipoic acid, citric acid, acetylcarnitine, acetylcysteine, glutathione, ascorbyl compounds, tocopheryl compounds, and pharmaceutically acceptable salts thereof.

13. 11. The pharmaceutical composition of claim 10, wherein the protease inhibitor compound is at least one selected from the group consisting of propyl gallate, aprotinin, camostat mesilate, gabexate mesilate, soybean Kunitz trypsin inhibitor (SBTI), soybean Kunitz trypsin-chymotrypsin inhibitor (SBTCI), soybean Bowman-Birk inhibitor, EDTA, bacitracin, ovomucoid, citric acid, and pharmaceutically acceptable salts thereof.

14. 2. The pharmaceutical composition of claim 1, wherein excipient B comprises propyl gallate; and at least one selected from the group consisting of camostat mesylate, citric acid, soybean trypsin inhibitor, and EDTA.

15. 2. The pharmaceutical composition according to claim 1, wherein the excipient B is at least one selected from the group consisting of propyl gallate, camostat mesylate, and pharmaceutically acceptable salts thereof.

16. In the excipient A, the bile acid derivative is at least one selected from the group consisting of chenodeoxycholate, ursodeoxycholate, and pharmaceutically acceptable salts thereof; 2. The pharmaceutical composition according to claim 1, wherein the excipient B is at least one selected from the group consisting of propyl gallate, camostat mesylate, and pharmaceutically acceptable salts thereof.

17. 2. The pharmaceutical composition of claim 1, wherein the weight ratio of said large biologically active substance to said excipient A is 1:1-1500.

18. 2. The pharmaceutical composition of claim 1, wherein the excipient A comprises two or more bile acid derivatives, each in a weight ratio of 1 to 1500 relative to the weight of the large biologically active substance.

19. 2. The pharmaceutical composition according to claim 1, wherein the weight ratio of said large physiologically active substance to said excipient B is 1:0.1-300.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the pharmaceutical composition is formulated for oral administration.

21. A method for producing the pharmaceutical composition according to any one of claims 1 to 19, comprising: (i) the large bioactive substance; and (ii) an excipient A comprising one or more bile acid derivatives, or (iii) Excipient B containing one or more compounds or derivatives thereof having one or more effects selected from a CYP450 inhibitory effect, an antioxidant effect, and a gastrointestinal enzyme activity inhibitory effect. The method further comprises the step of mixing

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