Hydrophobic ion pairing complex composition for oral administration of peptide drug comprising peptide drug and counterion, and method for preparing same

Abstract

The present invention relates to a hydrophobic ion pairing complex composition for oral administration, the composition comprising a peptide drug and a counterion, and a method for preparing same. More specifically, the present invention relates to a hydrophobic ion pairing (HIP) complex composition comprising two or more kinds of counterions bound to a peptide drug, and a method for preparing same.

Description

Hydrophobic ion pair complex composition including peptide drug and counter ion for oral administration of peptide drug and method for preparing same

[0001] The present invention relates to a hydrophobic ion pair complex composition comprising a peptide drug and a counter ion for oral administration, and a method for preparing the same. More specifically, the present invention relates to a hydrophobic ion pairing (HIP) complex composition comprising a peptide drug and two or more counter ions, and a method for preparing the same.

[0002] Peptide drugs are substances composed of 2 to 70 amino acids and have hormonal effects, signal transduction regulation, antibacterial, and anti-inflammatory effects in the body. Currently used peptide drugs include insulin and its analogs, glucagon-like peptide-1 (GLP-1) agonists, glucagon-like peptide-2 (GLP-2) agonists, growth hormone, insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), erythropoietin (EPO), vasopressin, thrombin inhibitors, interleukins, tumor necrosis factor (TNF) blockers, and calcineurin inhibitors.

[0003] Peptide drugs are typically administered parenterally, such as intravascular injection or subcutaneous injection. This is because peptide drugs are at high risk of degradation due to the gastrointestinal pH and various digestive enzymes when administered orally, and the low permeability of the gastrointestinal membrane leads to low bioavailability. However, oral administration offers the advantages of convenience, high patient compliance, low administration costs, and no need for specialized personnel. Furthermore, injections eliminate the risk of infection and side effects such as rash and redness. Therefore, there is a need for an oral pharmaceutical composition that is stable in the gastrointestinal tract and enhances bioavailability by increasing the permeability of the gastrointestinal membrane.

[0004] Prior technologies for oral administration of peptide drugs can be broadly categorized into chemical modification, medical devices, and drug carrier systems. Chemical modification, which alters the physicochemical properties of peptide drugs, constitutes a novel active drug substance and must therefore undergo a full regulatory approval process similar to that of new drugs during development. Medical device technology, which delivers drugs into the body through a device that operates in the gastrointestinal tract, is limited by the requirement that the drug be composed of biodegradable materials that are guaranteed to be excreted from the gastrointestinal tract or decomposed in the body. Furthermore, the manufacturing process is complex. In contrast, drug carrier system technology, utilizing lipid-based drug delivery systems (LBDDS), offers the advantage of a relatively simple manufacturing process and the ability to aid peptide drugs in penetrating the gastrointestinal membrane.

[0005] Accordingly, Korean Patent No. 10-2502308 discloses a composition comprising an antacid such as sodium bicarbonate and magnesium hydroxide and a self-microemulsifying drug delivery system (SMEDDS). While this composition can stabilize peptide drugs by adjusting the stomach's pH to 3 or higher when applied to a living body, it retains the electrical properties of charged peptide drugs, making it difficult for them to penetrate the gastrointestinal membrane.

[0006] Furthermore, Korean Patent Publication No. 10-2021-0151187 discloses a formulation comprising a lipophilic phase, a lipophilic surfactant, and / or a hydrophilic surfactant to enhance gastrointestinal membrane permeation for poorly permeable molecules, including proteins, polypeptides, peptides, or low-molecular-weight compounds. However, even in this formulation, the electrical properties of the charged peptide drug remain unchanged, limiting its penetration through the gastrointestinal membrane.

[0007] Meanwhile, when applying lipid-based drug delivery system technology to peptide drugs, there is a problem in stably encapsulating charged hydrophilic peptide drugs within the drug delivery system.

[0008] Accordingly, Korean Patent Publication No. 10-2023-0039594 discloses a technique for increasing the gastrointestinal membrane permeability of a peptide drug using a conjugate comprising quantum dots and a peptide drug, which are Ag2S quantum dots. However, the Ag2S used as quantum dots has not yet been demonstrated to be safe in humans, requiring the full regulatory approval process for new pharmaceutical additives before it can be applied to humans.

[0009] In contrast, manufacturing a complex using hydrophobic ion pairing (HIP) technology, which binds a peptide drug to a counter ion with an opposite charge, increases the lipophilicity of the peptide drug, enabling it to be effectively encapsulated within a drug delivery system.

[0010] Lu and co-workers reported a technique for encapsulating peptide antibiotics into nanocarriers by applying hydrophobic ion pairing technology to complexes (Lu HD et al., Hydrophobic Ion Pairing of Peptide Antibiotics for Processing into Controlled Release Nanocarrier Formulations, Mol. Pharmaceutics (2018) Volume 15, 216-225). However, the purpose of this technique was to increase the lipophilicity of peptide drugs by applying hydrophobic ion pairing technology to them, effectively encapsulating them into drug delivery systems, and enhancing the stability of peptide drugs in the gastrointestinal tract.

[0011] For peptide drug conjugates utilizing hydrophobic ion-pair technology to be administered to the human body and exhibit efficacy, the peptide drug must be absorbed into the body, dissociated from the complex, and remain intact as a peptide drug. These complexes utilizing prior art are designed to form strong ion-pair complexes to maintain peptide drug stability in the gastrointestinal tract. Therefore, it is difficult for the peptide drug to dissociate from these ion-pair complexes. Studies on the degree of dissociation of ion-pair complexes using prior art have shown that approximately 20-40% of the peptide drug remains undissociated.

[0012] In addition, if designed to form weak ion pair complexes to address this, not only will the efficiency of complex formation decrease, but the efficiency of encapsulation within the drug delivery system will also decrease.

[0013] To solve these problems, the inventors of the present invention have made great efforts to develop a composition in which the degree of dissociation of a peptide drug is improved from a complex using hydrophobic ion pairing (HIP) technology that binds a peptide drug and a counter ion having an opposite charge. As a result, when applying a counter ion that forms a hydrophobic ion pair for a peptide drug, the inventors have confirmed that when applying a counter ion that forms a relatively strong ion pair and a counter ion that forms a relatively weak ion pair together, the degree of dissociation of the peptide drug after absorption into the body from the manufactured complex can be improved, thereby completing the present invention.

[0014] The purpose of the present invention is to provide a hydrophobic ion pair complex composition including a peptide drug and a counter ion, in which the degree of dissociation of the peptide drug from the peptide drug complex is improved so that the peptide drug complex to which hydrophobic ion pair technology is applied can exert a pharmaceutical effect after being administered to the human body.

[0015] Another object of the present invention is to provide a method for preparing a hydrophobic ion pair complex composition including the peptide drug and a counter ion.

[0016] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0017] In the following description, numerous specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, specific embodiments may be practiced with one or more of these specific details or with other known methods and configurations. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Thus, the appearances of "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] Unless otherwise specifically defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs.

[0019] In order to achieve the object of the present invention, the present invention provides a hydrophobic ion pair complex composition comprising (1) a peptide drug, (2) a counter ion forming a relatively strong ion pair, and (3) a counter ion forming a relatively weak ion pair for oral administration of the peptide drug.

[0020] In order to achieve the object of the present invention, the present invention provides a method for preparing a hydrophobic ion pair complex composition comprising (1) a peptide drug for oral administration of the peptide drug, (2) a counter ion forming a relatively strong ion pair, and (3) a counter ion forming a relatively weak ion pair.

[0021] Below, each configuration is described in detail.

[0022] The “counter ion forming an ion pair” used in the present invention may be a component including at least one hydrophilic domain having at least one charged group and at least one hydrophobic domain.

[0023] The strength of hydrophobic ion pair complex formation of the “counter ion forming ion pair” used in the present invention is evaluated by comparing the strength of hydrophobic ion pair complex formation relative to the corresponding counter ion by evaluating the chain length and structure, the presence of an aromatic or cyclic structure, and / or the degree of precipitation after forming a hydrophobic ion pair complex composition with the peptide drug.

[0024]

[0025] In one specific embodiment of the present invention, the counter ion forming a relatively strong ion pair and the counter ion forming a relatively weak ion pair include a hydrophilic domain having at least one charged group and at least one hydrophobic domain.

[0026] In addition, the counter ions forming relatively strong ion pairs and the counter ions forming relatively weak ion pairs can be classified into three groups according to their relative complex formation strengths: a counter ion group having two or more alkyl carbon chains as a hydrophobic domain structure; a counter ion group including an aromatic or cyclic structure as a hydrophobic domain structure; and a counter ion group having one alkyl hydrophobic carbon chain as a hydrophobic domain structure, and the relative complex formation strengths therebetween are as follows:

[0027] Two or more alkyl carbon chains > aromatic or cyclic structure > one alkyl hydrophobic carbon chain

[0028] Therefore, in one specific embodiment of the present invention, the counter ion forming a relatively strong ion pair and the counter ion forming a relatively weak ion pair may be two or more counter ions selected from different groups among the three groups described above.

[0029] In one specific embodiment of the present invention, when selecting a counter ion forming a relatively strong ion pair and a counter ion forming a relatively weak ion pair, if the hydrophobic domain structure belongs to the same group among the three groups described above, the hydrophilic domain structure having at least one charged group included in the counter ion may be two or more different counter ions.

[0030] In one specific example of the present invention, the ion pair complex formation strength can be compared by classifying the hydrophilic domain structures contained in the counter ions into groups having sulfonate, sulfosuccinate, phosphate, sulfate, carbonate, phosphonic acid, and sulfobetaine, when the hydrophobic domain structures contained in the counter ions forming the ion pair are of the same type. The relative complex formation strengths among these groups are as follows:

[0031] Sulfonate > Sulfosuccinate > Phosphate = Sulfate > Carbonate > Phosphonic Acid = Sulfobetaine

[0032] In one specific example of the present invention, the precipitation efficiency after forming a hydrophobic ion pair complex composition with a peptide drug can be compared using the precipitation efficiency described in the literature (Claus V. et al., Counterion optimization for hydrophobic ion pairing (HIP): Unraveling the key factors, International Journal of Pharmaceutics, Vol. 647 (2023) 123507). Specifically, the manufactured complex composition was centrifuged, the supernatant was filtered, and the filtered supernatant was diluted with a diluent and the precipitation efficiency (PE) was calculated using the following equation through high-performance liquid chromatography analysis. At this time, the closer the precipitation efficiency of the formed hydrophobic ion pair complex composition is to 100%, the more it can be evaluated that a relatively strong ion is formed.

[0033]

[0034] In the above formula, C Drug after HIP is the drug concentration remaining in the supernatant after forming a hydrophobic ion pair complex composition with the peptide drug, and C Drug before HIP is the drug concentration in the solution prior to formation of the hydrophobic ion pair complex composition with the peptide drug.

[0035] According to one specific example of the present invention, when a hydrophobic ion pair complex composition with a peptide drug is formed using a counter ion that forms a relatively strong ion pair and a counter ion that forms a relatively weak ion pair, and then the precipitation efficiency (PE) is evaluated, it is preferable that the precipitation efficiency of the hydrophobic ion pair complex composition is 90% or higher. If the precipitation efficiency is less than 90%, it cannot be considered that an efficient hydrophobic ion pair complex with the peptide drug has been formed.

[0036] The peptide drug that can be used in the present invention is composed of 2 to 70 amino acids, and is a substance that has effects such as hormone action, signal transmission regulation, antibacterial and anti-inflammatory effects in the body, and refers to peptides and variants thereof that can be used for the treatment, prevention and diagnosis of diseases. For example, the peptide drug in the present invention may be, but is not limited to, human insulin, porcine insulin, recombinant insulin, rapid-acting insulin, rapid-acting insulin, intermediate-acting insulin, long-acting insulin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, beinaglutide, tirzepatide and / or supaglutide.

[0037] Additionally, the counter ion that can be used in the present invention may be a component including an anionic surfactant, a cationic surfactant, and / or a nonionic surfactant.

[0038] In one specific embodiment of the present invention, the counter ion is 1-hydroxy-2-naphthoic acid, 2-naphthalene sulfonic acid (NSA), Brilliant Blue FCF, carboxy methyl polyethylene glycol (CM-PEG), cholesteryl hemisuccinate, cholic acid, sodium cholate, decanoic acid, sodium decanoate, sodium caprate, dimyristoyl phosphatidyl glycerol (DMPG), dioleoyl phosphatidic acid (DOPA), docosahexaenoic acid, hexadecyl phosphate, linoleic acid, N,N-dipalmitoyl-L-lysine, oleic acid, sodium oleate, pamoic acid, disodium pamoate, sodium acetate, sodium cholesteryl sulfate, sodium decanesulfonate (SDES), sodium It may be at least one anion selected from the group consisting of hexadecanesulfonate (SHS), sodium deoxycholate, sodium docusate, sodium dodecyl benzenesulfonate (SDBS), sodium dodecyl sulfate, sodium laurate, sodium n-octadecyl sulfate, sodium stearate, sodium stearoyl glutamate (SSG), sodium taurodeoxycholate (STDC), sodium tetradecyl sulfate, sodium tripolyphosphate, taurocholic acid, sodium taurocholate, and vitamin E succinate, but is not limited thereto.

[0039] In one specific embodiment of the present invention, the counter ion is arginine-hexadecanoyl ester (AHE), arginine-nonyl ester (ANE), N-benzyl-2-phenylethanamine, chitosan, dodecylamine, hexadecyl trimethylammonium bromide (CTAB), maprotiline, N,N'-dibenzyl ethylenediamine, N,N-dimethyl dodecylamine, N,N-dimethyl hexylamine, N,N-dimethyl octadecylamine, stearylamine, tetrabutyl ammonium bromide (TBAB), tetraheptyl ammonium bromide (THA), tetrahexyl ammonium bromide, tetraoctyl ammonium bromide (TOAB), tetrapentyl ammonium bromide (TPA), and triethylamine (TEA), 1-hexadecylpyridinium chloride, It may be at least one cation selected from the group consisting of N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium, dodecyltrimethylammonium bromide, dioleyl phosphatidylethanolamine, stearyldimethylbenzyl ammonium chloride, trimethyltetradecylammonium, and hexadecylamine, but is not limited thereto.

[0040] In one specific example of the present invention, the degree of dissociation of the hydrophobic ion pair complex composition with the peptide drug can be compared using the dissociation degree described in the literature (Nazir I. et al., Self-emulsifying drug delivery systems: Impact of stability of hydrophobic ion pairs on drug release, International Journal of Pharmaceutics, Vol. 561 (2019) 197-205). Specifically, 1 mg of the prepared complex composition is added to 1 mL of phosphate buffer solution (50 mM, pH 7.4), mixed in a roller shaker at 60 rpm until the measurement time, and then centrifuged. 100 μL of the supernatant is taken, placed in a 10 mL volumetric flask, mixed with a diluent to the mark, and the dissociation degree (DD) is calculated using the following equation through high-performance liquid chromatography analysis. At this time, the hydrophobic ion pair complex composition of the present invention can be evaluated as having a good dissociation ability as the bonding rate approaches 0%.

[0041]

[0042] In the above formula, C Drug in supernatant is the drug concentration in the supernatant after the evaluation test, and C Initial drug in HIP is the drug concentration in the complex composition before the evaluation test. At this time, the hydrophobic ion pair complex composition of the present invention, when evaluated by the above test method, may have a degree of dissociation of 15% or less at the 2-hour point, preferably 10% or less, and more preferably 5% or less.

[0043] In one embodiment of the present invention, the hydrophobic ion pair complex composition may be administered in a lipid carrier, microparticle, hydrogel, nanoparticle, liposome, or the like containing oil and / or surfactant for oral delivery, but is not limited thereto.

[0044] In one specific embodiment of the present invention, the hydrophobic ion pair complex composition can be encapsulated in a lipid carrier comprising oil and / or surfactant to form a drug delivery system.

[0045] In one specific embodiment of the present invention, the lipid carrier comprising oil and / or surfactant may include at least one selected from the group consisting of polyoxyl castor oil, oleoyl macrogol glycerides, propylene glycol fatty acid esters, propylene glycol, diethylene glycol monoethyl ether, mono-di-glycerides, caprylocaproyl polyoxylglycerides, polyoxyethylene sorbitan fatty acid esters, sodium taurocholate, polyoxyl 40 hydrogenated castor oil, medium chain triglycerides, polyoxyl 35 castor oil, propylene glycol monocaprylate, glyceryl monooleate, oleic acid, oleyl polyoxyl-6 glycerides, isopropyl myristate, 1,3-propanediol, 1,3-butanediol, glycerol polyethylene glycol ricinoleate, and polyethylene glycol, but is not limited thereto.

[0046] In one embodiment of the present invention, the lipid carrier may be composed of, but is not limited to, an oil, a nonionic surfactant having an HLB greater than 12, and / or a nonionic surfactant having an HLB less than 12.

[0047] In one specific embodiment of the present invention, the lipid delivery vehicle may additionally include a penetration enhancer for the purpose of increasing the permeability of the peptide drug through the gastrointestinal membrane.

[0048] In one specific example of the present invention, the penetration enhancer includes a substance that promotes the penetration of the active ingredient through a biological membrane, and specific examples thereof include citric acid, sodium salicylate, ethylenediaminetetraacetic acid (EDTA), methoxy salicylates, sodium lauryl sulfate, polyoxyethylene, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, 23-lauryl ether, cetylpyridinium chloride, and cetyltrimethyl ammonium bromide. bromide), sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lauric acid / propylene glycol, methyloleate, lysophosphatidylcholine, phosphatidylcholine, unsaturated cyclic ureas, cyclodextrins, aprotinin, azone, dextran sulfate, menthol,Polysorbate 80, sulfoxides, alkyl glycosides, chitosan-4-thiobutylamide, chitosan-4-thiobutylamide / GSH, chitosan-cysteine, poly acrylic acid-homocysteine), polycarbophil-cysteine, polycarbophil-cysteine / GSH, chitosan-4-thioethylamide / GSH, polyoxyethylated glycolysed glycerides, It may include at least one selected from the group consisting of diethylene glycol monoethylether, a mixture of glycerol and PEG 1500 esters of long fatty acids, or chitosan-4-thio-glycholic acid, but is not limited thereto.

[0049] In one specific example of the present invention, the degree of intestinal permeation of the hydrophobic ion pair complex composition can be compared using the apparent permeability constant described in the literature (Noh G. et al., Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus, International Journal of Biological Macromolecules, Vol. 225 (2023) 911-922). Specifically, 2×10 intestinal epithelial cell lines were seeded in a 12-well permeable cell culture vessel (12-well transwell). 5 After dividing into cells, culture for 3 weeks to form a monolayer. The test samples are each added to the apical side of the cells, and Hanks' Balanced Salt Solution (Hanks' Balanced Salt Solution) without the test sample is added to the basolateral side. The incubation is performed for 4 hours in a carbon dioxide incubator at 37°C. Each test sample is recovered and analyzed using high-performance liquid chromatography. The degree of intestinal permeability is evaluated by calculating the apparent permeability coefficient (Papp) using the following equation.

[0050]

[0051] In the above equation, dQ / dt is the amount of drug that penetrates the cell per unit time, and A is the cell area (cm 2 ) and Ci are the initial drug concentration values ​​applied to the apical part of the cell. At this time, the apparent permeation constant has a value greater than 0, and the higher the value, the better the intestinal permeation can be evaluated.

[0052] In one specific example of the present invention, the hydrophobic ion pair complex composition of the present invention has an apparent permeability constant of 2.0×10 when evaluated by the above evaluation method. -6 It can be more than cm / s.

[0053] In one specific embodiment of the present invention, a method for preparing a hydrophobic ion pair complex composition may include: (1) a step of dissolving a peptide drug in an acidic or basic aqueous solution; (2) a step of dissolving a counter ion forming a relatively strong ion pair and a counter ion forming a relatively weak ion pair in the aqueous solution to prepare a mixed counter ion aqueous solution; (3) a step of mixing the mixed counter ion aqueous solution of step (2) with the peptide solution of step (1); (4) a step of centrifuging a precipitate generated in the process of step (3) to separate the precipitate; and (5) a step of lyophilizing the precipitate of step (4).

[0054] In one specific embodiment of the present invention, a method for preparing a lipid carrier comprising a hydrophobic ion pair complex composition may include: (1) preparing a hydrophobic ion pair complex composition; (2) preparing a lipid carrier comprising an oil and / or a surfactant; and (3) mixing the hydrophobic ion pair complex of step (1) into the lipid carrier of step (2).

[0055] In one specific embodiment of the present invention, a method for producing a lipid carrier comprising a hydrophobic ion pair complex composition may include the steps of (1) producing a hydrophobic ion pair complex composition; (2) mixing an oil and / or a surfactant into the hydrophobic ion pair complex composition of step (1); (3) mixing an oil and / or a surfactant; and (4) mixing the mixture of step (3) into the mixture of step (2).

[0056] In one specific embodiment of the present invention, a method for preparing a lipid carrier comprising a hydrophobic ion pair complex composition may include: (1) preparing a hydrophobic ion pair complex composition; (2) preparing a lipid carrier comprising oil and / or a surfactant and a penetration enhancer; and (3) mixing the hydrophobic ion pair complex of step (1) into the lipid carrier of step (2).

[0057] In one specific embodiment of the present invention, a method for producing a lipid carrier comprising a hydrophobic ion pair complex composition may include the steps of (1) producing a hydrophobic ion pair complex composition; (2) mixing an oil and / or a surfactant with the hydrophobic ion pair complex composition of step (1); (3) mixing an oil and / or a surfactant and a penetration enhancer; and (4) mixing the mixture of step (3) with the mixture of step (2).

[0058] In one specific embodiment of the present invention, there may be provided a pharmaceutical composition for oral administration comprising a hydrophobic ion pair complex composition encapsulated in a lipid carrier comprising oil and / or surfactant.

[0059] In one specific embodiment of the present invention, the pharmaceutical composition for oral administration includes tablets, powders, capsules, and granules.

[0060] In one specific example of the present invention, the tablet includes a tablet for the purpose of oral administration, including a dispersible tablet that is stored in tablet form and then suspended in water for use when taking, an effervescent tablet, a rapid-disintegrating tablet that can be taken without water because the formulation itself dissolves or disintegrates in the oral cavity, or a mucoadhesive tablet that adheres to the oral / gastrointestinal mucosa to continuously release the drug.

[0061] In one specific example of the present invention, the capsule comprises a soft capsule or a hard capsule.

[0062] The pharmaceutical composition according to the present invention may include at least one selected from the group consisting of a bitter taste improving agent, a disintegrating agent, a binder, a lubricant, an excipient, a foaming agent, a mucoadhesive agent, a colorant, a preservative, a stabilizer, a moisturizer, a buffer, an antibacterial agent, an antioxidant, a pH regulator, or an absorption promoter, but is not limited thereto.

[0063] The bitter taste improving agent according to the present invention includes all bitter taste masking agents, sweeteners or flavoring agents that are commercially permitted for human use, and specific examples thereof include crospovidone, aspartame, ascorbic acid, citric acid, thaumatin, maltitol, sorbitol, mannitol, erythritol, lactitol, xylitol, reduced starch saccharides, saccharin, licorice extract, stevia sweetener, mogrososide, sucrose, isomerized sugar, paratinose, isomaltooligosaccharide, malto-oligosaccharide, fructo-oligosaccharide, soybean oligosaccharide, fructose, sucrose, It may include at least one selected from the group consisting of lactose, maltose, glucose, xylose, isomerized lactose, galacto-oligosaccharide, xylo-oligosaccharide, corn syrup, or fruit flavor, but is not limited thereto.

[0064] The disintegrant according to the present invention includes a substance that promotes the disintegration of tablets, and specific examples thereof include crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, cross-linked sodium carboxymethyl cellulose, calcium phosphate, lactose, corn starch, simethicone, sorbitol, microcrystalline cellulose, sodium lauryl sulfate, sodium gluconate, crystalline cellulose, light anhydrous silicic acid, hydroxypropyl cellulose, gelatinized starch, polyethylene glycol 6000, It may include at least one selected from the group consisting of polysorbate 80, polysorbate 20, poloxamer, povidone, sodium bicarbonate, or precipitated calcium carbonate, but is not limited thereto.

[0065] The binder according to the present invention includes a substance that provides binding force to a mixture constituting a tablet and facilitates molding, and specific examples thereof include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, pregelatinized starch, hydroxypropylmethylcellulose phthalate, polyethylene glycol 6000, polyethylene glycol 4000, polyvinyl alcohol, poloxamer, povidone, talc, crospovidone, sodium croscarboxymethylcellulose, copovidone, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, gelatin, purified shellac, purified water, pregelatinized starch, sodium starch glycolate, starch, low-substituted hydroxypropyl cellulose, silicon dioxide, It may include at least one selected from the group consisting of liquid paraffin, lactose, corn starch, ethanol, ethylcellulose, gum arabic, magnesium stearate, stearic acid, cetostearyl alcohol, powdered cellulose, sucrose, microcrystalline cellulose, methacrylic acid copolymer, methylcellulose, meglumine, mannitol, lecithin, honey, glycerin, hydrogenated castor oil, light anhydrous silicic acid, or crystalline cellulose, but is not limited thereto.

[0066] The excipient according to the present invention includes a substance that serves to dilute the active ingredient in the tablet, and specific examples thereof include hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, calcium sulfate, sulfur, safflower oil, pregelatinized starch, synthetic aluminum silicate, castor oil, hydroxypropyl methylcellulose phthalate, polyoxyl 40 hydrogenated castor oil, polyethylene glycol 6000, polyethylene glycol 4000, poloxamer, povidone, glucose, pectin, paraffin, talc, sodium bicarbonate, magnesium carbonate, sodium carbonate, crospovidone, sodium croscarboxymethylcellulose, copovidone, kaolin, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose, precipitated calcium carbonate, gelatin, pregelatinized starch, sodium starch glycolate, It may include at least one selected from the group consisting of starch, low-substituted hydroxypropyl cellulose, xylitol, sucrose fatty ester, calcium phosphate, calcium hydrogen phosphate, silicon dioxide, eudragit, lactose, corn starch, ethylcellulose, stearyl alcohol, D-sorbitol, cellucose, cetanol, polyethylene oxide, magnesium oxide, xanthan gum, beta-cyclodextrin, sucrose, microcrystalline cellulose, D-mannitol, ludipress, dextrin, glyceryl behenate, magnesium aluminate silicate, magnesium aluminum silicate, magnesium silicate, citric acid, light anhydrous silicic acid, or crystalline cellulose, but is not limited thereto.

[0067] The lubricant according to the present invention includes a substance that plays a role in smoothly performing the compression operation of the mixture during tablet manufacturing, and specific examples thereof include magnesium stearate, stearic acid, talc, synthetic aluminum silicate, sodium stearyl fumarate, polyethylene glycol 6000, polyethylene glycol 4000, kaolin, sodium starch glycolate, sucrose esters of fatty acids, silicon dioxide, corn starch, silicone fluid 350 centistokes, simethicone, polyoxyl 40 stearate, glyceryl monostearate, sodium lauryl sulfate, glyceryl behenate, magnesium silicate, and hydrogenated oil. It may include, but is not limited to, one or more selected from the group consisting of oil, hard fat), or light anhydrous silicic acid.

[0068] The foaming agent according to the present invention includes a substance that generates bubbles by reacting with water, and a specific example is a mixture of sodium bicarbonate and an organic acid, preferably a mixture of sodium bicarbonate and citric acid or sodium bicarbonate and tartaric acid, but is not limited thereto.

[0069] The mucoadhesive according to the present invention includes a material having a property of being able to adhere to a biological mucosa, and specific examples thereof include polycarbophil, carbomer, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, xanthan gum, guar gum, hydroxypropyl guar, chitosan, carrageenan, sodium alginate, polyhydroxybutyrate, poly(ecaprolactone), poly(ortho esters), poly(cyano acrylates), polyphosphazenes, polyvinyl alcohol, poly(ethylene oxide), It may include, but is not limited to, one or more selected from the group consisting of gelatin, povidone, or methacrylic acid copolymer.

[0070] The penetration enhancer according to the present invention includes a substance that promotes the penetration of an active ingredient through a biological membrane, and specific examples thereof include citric acid, sodium salicylate, ethylenediaminetetraacetic acid (EDTA), methoxy salicylates, sodium lauryl sulfate, polyoxyethylene, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, 23-lauryl ether, cetylpyridinium chloride, cetyltrimethyl ammonium bromide, Sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lauric acid / propylene glycol, methyloleate, lysophosphatidylcholine, phosphatidylcholine, unsaturated cyclic ureas, cyclodextrins, aprotinin, azone, dextran sulfate, menthol,Polysorbate 80, sulfoxides, alkyl glycosides, chitosan-4-thiobutylamide, chitosan-4-thiobutylamide / GSH, chitosan-cysteine, poly acrylic acid-homocysteine), polycarbophil-cysteine, polycarbophil-cysteine / GSH, chitosan-4-thioethylamide / GSH, polyoxyethylated glycolysed glycerides, It may include at least one selected from the group consisting of diethylene glycol monoethylether, a mixture of glycerol and PEG 1500 esters of long fatty acids, or chitosan-4-thio-glycholic acid, but is not limited thereto.

[0071] According to the present invention, if necessary, a coloring agent may be included in the tablet, and may include at least one selected from titanium dioxide, iron oxide, magnesium carbonate, calcium sulfate, magnesium oxide, magnesium hydroxide, or aluminum lake, and as a preservative, at least one selected from benzoic acid, methylparaben, ethylparaben, or propylparaben may be added, and in addition, a moisturizer, buffer, antibacterial agent, or antioxidant may be additionally included.

[0072] Specific examples of pharmaceutical excipients that can be used in the pharmaceutical composition for oral administration according to the present invention are described in Handbook of Pharmaceutical Excipients (PJ Sheskey, et al., Handbook of Pharmaceutical Excipients, Pharmaceutical Press, Ninth Edition, 2020), and techniques for preparing solid compositions are described in Remington: The Science and Practice of Pharmacy (A. Adejare, Remington: The Science and Practice of Pharmacy, Elsevier, Twenty-third Edition, 2020). The pharmaceutical composition for oral administration of the present invention can be prepared by methods known to those skilled in the art of pharmacy, including the methods described above.

[0073] The pharmaceutical composition for oral administration according to the present invention can be preserved for long periods of time even under high-humidity conditions by being sealed with low moisture permeability. The sealed packaging with low moisture permeability can be any packaging that is difficult to penetrate, and may include airtight packaging that prevents moisture intrusion or sealed packaging that prevents the intrusion of gases or microorganisms.

[0074] The sealed packaging according to the present invention is a packaging composed of materials that prevent moisture intrusion, such as glass, plastic, aluminum, and moisture-proof paper. Examples thereof include bottles (glass bottles, plastic bottles, etc.), PTP packaging, or strip packaging. In addition, to enhance moisture-proofing properties, the sealed packaging may be combined with a desiccant, or the PTP-packaged pharmaceutical composition may be refilled into an aluminum pillow.

[0075] The PTP packaging according to the present invention is a tablet or capsule packaging form. After forming a sheet according to the type of pharmaceutical, the pharmaceutical is filled into the slit, and the sheet is sealed with aluminum foil. Generally, polyvinyl chloride can be used for the sheet, but a combination of vinyl chloride and polyvinylidene chloride can be used for a form with enhanced moisture resistance. Any material with excellent moisture resistance can be used, and the thickness of the material can be increased to enhance moisture resistance.

[0076] The hydrophobic ion-pair complex composition for oral administration of a peptide drug of the present invention forms a microemulsion upon contact with gastrointestinal fluid upon oral administration, thereby preventing the peptide from being degraded by digestive enzymes and ensuring stability in the gastrointestinal tract. Furthermore, the formation of fine droplets facilitates interaction with the gastrointestinal membrane through a large surface area, and the surfactant acts as a penetration enhancer, opening tight junctions between epithelial cells to increase permeability. This enables oral administration of peptide drugs as an alternative to injections, thereby improving patient compliance and resulting in better therapeutic effects, as well as reducing manufacturing and distribution costs. Furthermore, the degree of dissociation of the peptide drug from the hydrophobic ion-pair complex absorbed by the body is enhanced, thereby enhancing drug efficacy.

[0077] Figure 1 is a graph comparing the dissociation degree of hydrophobic ion pair complexes of Examples 1 to 4 and Comparative Examples over time in a pH 7.4 phosphate buffer solution.

[0078] Figure 2 is a graph comparing the dissociation degree of hydrophobic ion pair complexes of Examples 5 to 8 and Comparative Examples over time in a pH 7.4 phosphate buffer solution.

[0079] Figure 3 is a graph comparing the apparent permeability constant over time for Examples 12 and 13 and Comparative Examples 8 and 9 using an intestinal epithelial cell line (Caco-2 cell).

[0080] Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the invention. The present invention may be implemented in various different forms and is not limited to the embodiments, test examples, etc. described herein.

[0081] Examples 1-11

[0082] A hydrophobic ion pair complex composition was prepared using the following manufacturing method according to the ingredients and contents in Tables 1 and 2:

[0083] (1) A step of dissolving a peptide drug in a 0.01 M HCl aqueous solution;

[0084] (2) A step of preparing a mixed counter ion aqueous solution by dissolving counter ions in an aqueous solution;

[0085] (3) A step of mixing the mixed counter ion aqueous solution of step (2) into the peptide drug solution of step (1);

[0086] (4) A step of separating the sediment by centrifuging the sediment generated in the process of step (3); and

[0087] (5) A step of freeze-drying the sediment of step (4).

[0088] Distinctive ingredient Example (unit: mg) 123456 Peptide drug Human insulin 100.0 100.0 100.0 100.0 100.0 100.0 Counter ion Sodium dodecyl sulfate 6.0 12.0 18.0 24.0 Sodium dodecyl benzene sulfonate 29.0 22.0 14.0 7.0 29.0 22.0 Sodium docusate 9.0 18.0

[0089] Ingredients Example (unit: mg) 7891011 Peptide drug Human insulin 100.0 100.0 Semaglutide 100.0 Tizepatide 100.0 100.0 Counter ion Sodium dodecyl sulfate 14.0 4.8 Sodium dodecyl benzene sulfonate 28.0 7.0 16.9 8.7 2.9 Sodium docusate 37.0 21.6 14.8

[0090] Example 12

[0091] An oral pharmaceutical composition containing a hydrophobic ion pair complex composition was prepared using the following manufacturing method:

[0092] (1) A step of preparing a hydrophobic ion pair complex composition of Example 2;

[0093] (2) A step of mixing 2,890 mg of Transcutol P as an auxiliary surfactant into the hydrophobic ion pair complex composition of step (1);

[0094] (3) A step of preparing a pharmaceutical composition for oral administration by mixing 1,490 mg of capriol 90 as an oil and 5,620 mg of Tween 80 as a surfactant in the mixture of step (2); and

[0095] (4) Step of diluting (50-fold dilution) the pharmaceutical composition for oral administration of step (3) in 489,866 mg of Hanks'Balanced Salt Solution.

[0096] Example 13

[0097] An oral pharmaceutical composition containing a hydrophobic ion pair complex composition was prepared using the following manufacturing method:

[0098] (1) A step of preparing a hydrophobic ion pair complex composition of Example 2;

[0099] (2) A step of mixing 2,890 mg of Transcutol P as an auxiliary surfactant into the hydrophobic ion pair complex composition of step (1);

[0100] (3) A step of preparing a pharmaceutical composition for oral administration by mixing 1,490 mg of capriol 90 as an oil and 5,620 mg of Tween 80 as a surfactant in the mixture of step (2); and

[0101] (4) Step of diluting (25-fold dilution) the pharmaceutical composition for oral administration of step (3) in 239,866 mg of Hanks'Balanced Salt Solution.

[0102] Comparative Examples 1-6

[0103] A hydrophobic ion pair complex composition was prepared using the following manufacturing method according to the ingredients and contents in Table 3:

[0104] (1) A step of dissolving a peptide drug in a 0.01 M HCl aqueous solution;

[0105] (2) A step of preparing a counter ion aqueous solution by dissolving a counter ion in an aqueous solution;

[0106] (3) A step of mixing the counter ion solution of step (2) into the peptide drug solution of step (1);

[0107] (4) A step of separating the sediment by centrifuging the sediment generated in the process of step (3); and

[0108] (5) A step of freeze-drying the sediment of step (4).

[0109] Comparison of ingredients (unit: mg) 123456 Peptide drug Human insulin 100.0 100.0 100.0 100.0 Semaglutide 100.0 Tizepatide 100.0 Counter ions Sodium dodecyl sulfate 29.8 6.0 Sodium dodecyl benzene sulfonate 36.0 Sodium docusate 45.9 Sodium laurate 16.6 9.7 Sodium stearate 6.3 14.9 Sodium n-octadecyl sulfate 7.7

[0110] Comparative Example 7

[0111] 100 mg of human insulin, a peptide drug, was dissolved in 499,900 mg of Hanks' Balanced Salt Solution to prepare the same drug concentration as in Example 9.

[0112] Comparative Example 8

[0113] 100 mg of human insulin, a peptide drug, was dissolved in 249,900 mg of Hanks' Balanced Salt Solution to prepare the same drug concentration as in Example 10.

[0114] Test Example 1. Comparison of the precipitation properties of hydrophobic ion pair complexes.

[0115] The precipitation degree of the hydrophobic ion pair complexes of Examples 1 and 2, which formed a hydrophobic ion pair complex composition with a peptide drug using a counter ion that forms a relatively strong ion pair and a counter ion that forms a relatively weak ion pair used in the present invention, and Comparative Examples 4 to 6, which used two types of counter ions that form ion pairs of relatively similar strength, was compared and measured. The number of measurements was performed three times, and the measurement results are shown in Table 4. As shown in Table 4, Examples 1 and 2 had precipitation degrees of 94.4% and 97.7%, respectively, whereas Comparative Example 4 could not be measured below the measured value, and Comparative Examples 5 and 6 had precipitation degrees of 5.7% and 49.8%, respectively, which were relatively low compared to the examples. From these results, it was confirmed that the hydrophobic ion pair complex of the present invention is a complex with excellent precipitation degree.

[0116] Sedimentation rate (%) (mean ± standard deviation) Example 194.4 ± 0.4 Example 297.7 ± 0.2 Comparative Example 4 - Comparative Example 55.7 ± 0.1 Comparative Example 649.8 ± 0.3

[0117] Test Example 2. Comparison of the dissociation degree of hydrophobic ion pair complexes in pH 7.4 phosphate buffer solution (1)

[0118] In order for a hydrophobic ion-pair complex to exhibit a medicinal effect after being absorbed into the human body, the peptide drug must dissociate and remain in a separate state from the complex formed in the blood. Accordingly, the degree of dissociation of the hydrophobic ion-pair complexes of Examples 1 to 4 and Comparative Examples 1 and 2 at different time points was measured in a 50 mM pH 7.4 phosphate buffer solution. The number of measurements was performed three times, and the measurement results are shown in Fig. 1. As shown in Fig. 1, all of the measured examples had a residual amount of 10% or less at 2 hours. However, Comparative Examples 1 and 2 had residual amounts of 24.8% and 26.6% at 2 hours, respectively. From these results, it was confirmed that the hydrophobic ion-pair complex of the present invention is an excellent complex that can efficiently exhibit a medicinal effect after being absorbed into the human body.

[0119] Test Example 3. Comparison of the dissociation degree of hydrophobic ion pair complexes in pH 7.4 phosphate buffer solution (2)

[0120] In order for a hydrophobic ion-pair complex to exhibit a medicinal effect after being absorbed into the human body, the peptide drug must dissociate from the complex formed in the blood and exist in a separate state. Accordingly, the degree of dissociation of the hydrophobic ion-pair complexes of Examples 5 to 8 and Comparative Examples 2 to 3 was measured at different time points in a 50 mM pH 7.4 phosphate buffer solution. The number of measurements was performed three times, and the measurement results are shown in Fig. 2. As shown in Fig. 2, the remaining amounts of Examples 5 to 7 were all 10% or less at 2 hours. However, the remaining amounts of Comparative Examples 2 and 3 at 2 hours were 26.6% and 20.8%, respectively. From these results, it was confirmed that the hydrophobic ion-pair complex of the present invention is an excellent complex that can efficiently exhibit a medicinal effect after being absorbed into the human body.

[0121] Test Example 4. Evaluation of Apparent Permeability Constant Using Intestinal Epithelial Cell Line (Caco-2 Cell)

[0122] In order to confirm the intestinal permeation effect of the pharmaceutical composition for oral administration containing the hydrophobic ion pair complex composition, the apparent permeation constants were compared using intestinal epithelial cell lines for Examples 12 and 13 and Comparative Examples 7 and 8. The intestinal epithelial cell lines were seeded at 2×10 in a 12-well permeable cell culture vessel (12-well transwell). 5After dividing into cells, they were cultured for 3 weeks to form a monolayer. The test samples (Example 12, Example 13, Comparative Examples 7 and 8) were each added to the apical side of the cells, and Hanks' Balanced Salt Solution without the test sample was added to the basolateral side, and the experiment was performed for 2 or 4 hours in a carbon dioxide incubator at 37°C. The test samples were each recovered and analyzed using high-performance liquid chromatography. The permeability was evaluated by calculating the apparent permeability coefficient (Papp) using the following equation.

[0123]

[0124] Here, dQ / dt is the amount of drug that penetrates the cell per unit time, and A is the cell area (cm 2 ) and Ci are the initial drug concentration values ​​applied to the apical part of the cell.

[0125] The evaluation was performed three times, and the evaluation results are shown in Figure 3. As seen in Figure 3, in Comparative Examples 7 and 8, no drug was detected at both 2 and 4 hours, whereas in Examples 12 and 13, 2.5×10 were detected at 2 hours, respectively. -6 cm / s and 4.8×10 -6 cm / s and at 4 hours, 5.1×10 -6 cm / s and 9.7×10 -6 cm / s. In particular, the drug permeation amount tended to increase over time. From these results, it was confirmed that the pharmaceutical composition for oral administration containing the hydrophobic ion-pair complex composition of the present invention exhibited excellent intestinal permeation.

Claims

1. A hydrophobic ion pair complex composition for oral administration of a peptide drug, (1) Peptide drugs; (2) counter ions that form relatively strong ion pairs; and (3) A hydrophobic ion pair complex composition for oral administration of a peptide drug containing a counter ion forming a relatively weak ion pair.

2. In paragraph 1, The counter ions forming the relatively strong ion pair and the counter ions forming the relatively weak ion pair include a hydrophilic domain having at least one charged group and at least one hydrophobic domain, A group of counter ions having two or more alkyl carbon chains as the hydrophobic domain structure; A group of counter ions including an aromatic or cyclic structure as the hydrophobic domain structure; and The hydrophobic domain structure is classified into three groups of counter ion groups having one alkyl hydrophobic carbon chain, A hydrophobic ion pair complex composition for oral administration of a peptide drug having two or more counter ions selected from different groups among three groups.

3. In paragraph 1, The counter ions forming the relatively strong ion pair and the counter ions forming the relatively weak ion pair include a hydrophilic domain having at least one charged group and at least one hydrophobic domain, A group of counter ions having two or more alkyl carbon chains as the hydrophobic domain structure; A group of counter ions including an aromatic or cyclic structure as the hydrophobic domain structure; and The hydrophobic domain structure is classified into three groups of counter ion groups having one alkyl hydrophobic carbon chain, A hydrophobic ion pair complex composition for oral administration of a peptide drug, wherein the hydrophilic domain structures having at least one charged group included in the counter ion are two or more different counter ions, when the hydrophobic domain structures belong to the same group.

4. In paragraph 1, When a hydrophobic ion pair complex composition with a peptide drug is formed using a counter ion that forms a relatively strong ion pair and a counter ion that forms a relatively weak ion pair, and the precipitation efficiency (PE) is evaluated according to the following formula, a hydrophobic ion pair complex composition for oral administration of a peptide drug having a precipitation efficiency of 90% or more: In the above formula, C Drug after HIP is the drug concentration remaining in the supernatant after forming a hydrophobic ion pair complex composition with the peptide drug, and C Drug before HIP is the drug concentration in the solution prior to formation of the hydrophobic ion pair complex composition with the peptide drug.

5. In paragraph 1, A hydrophobic ion pair complex composition for oral administration of a peptide drug, wherein the peptide drug is at least one selected from the group consisting of human insulin, porcine insulin, recombinant insulin, rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, beinaglutide, tirzepatide, and supaglutide.

6. In paragraph 1, The counter ions are 1-hydroxy-2-naphthoic acid (xinafoic acid), 2-naphthalene sulfonic acid (NSA), brilliant blue FCF, carboxy methyl polyethylene glycol (CM-PEG), cholesteryl hemisuccinate, cholic acid, sodium cholate, decanoic acid, sodium decanoate, sodium caprate, dimyristoyl phosphatidyl glycerol (DMPG), dioleoyl phosphatidic acid (DOPA), docosahexaenoic acid, hexadecyl phosphate, linoleic acid, N,N-dipalmitoyl-L-lysine, oleic acid, sodium oleate, pamoic acid, disodium pamoate, sodium acetate, sodium cholesteryl sulfate, sodium decanesulfonate (SDES), sodium hexadecanesulfonate (SHS), sodium A hydrophobic ion pair complex composition for oral administration of a peptide drug, wherein the peptide drug is at least one anion selected from the group consisting of deoxycholate, sodium docusate, sodium dodecyl benzenesulfonate (SDBS), sodium dodecyl sulfate, sodium laurate, sodium n-octadecyl sulfate, sodium stearate, sodium stearoyl glutamate (SSG), sodium taurodeoxycholate (STDC), sodium tetradecyl sulfate, sodium tripolyphosphate, taurocholic acid, sodium taurocholate, and vitamin E succinate.

7. In paragraph 1, The above counter ions are arginine-hexadecanoyl ester (AHE), arginine-nonyl ester (ANE), N-benzyl-2-phenylethanamine, chitosan, dodecylamine, hexadecyl trimethylammonium bromide (CTAB), maprotiline, N,N'-dibenzyl ethylenediamine, N,N-dimethyl dodecylamine, N,N-dimethyl hexylamine, N,N-dimethyl octadecylamine, stearylamine, tetrabutyl ammonium bromide (TBAB), tetraheptyl ammonium bromide (THA), tetrahexyl ammonium bromide, tetraoctyl ammonium bromide (TOAB), tetrapentyl ammonium bromide (TPA), and triethylamine (TEA), 1-hexadecylpyridinium chloride, A hydrophobic ion pair complex composition for oral administration of a peptide drug, wherein the cation is at least one selected from the group consisting of N-(1-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium, dodecyltrimethylammonium bromide, dioleyl phosphatidylethanolamine, stearyldimethylbenzyl ammonium chloride, trimethyltetradecylammonium, and hexadecylamine.

8. In paragraph 1, The hydrophobic ion pair complex composition above is a hydrophobic ion pair complex composition for oral administration of a peptide drug having a dissociation degree (DD) of 15% or less at 2 hours when evaluated using the following formula: In the above formula, C Drug in supernatant is the drug concentration in the supernatant after the evaluation test, and C Initial drug in HIP is the drug concentration in the complex composition before the evaluation test.

9. In paragraph 1, The above hydrophobic ion pair complex composition has an apparent permeability coefficient (Papp) of 2.0×10 when calculated using the following equation. -6 Hydrophobic ion-pair complex composition for oral administration of peptide drugs having a viscosity of cm / s or more: In the above equation, dQ / dt is the amount of drug that penetrates the cell per unit time, and A is the cell area (cm 2 ) and Ci are the initial drug concentration values ​​applied to the apical part of the cell.

10. A hydrophobic ion pair complex composition for oral administration of a peptide drug according to any one of claims 1 to 9; and A pharmaceutical composition for oral administration comprising at least one component selected from the group consisting of lipid carriers, microparticles, hydrogels, nanoparticles and liposomes comprising oil and / or surfactants.

11. A pharmaceutical composition for oral administration further comprising a penetration promoter in claim 10.

12. In claim 10, the lipid carrier comprising the oil and / or surfactant is a pharmaceutical composition for oral administration, which is at least one component selected from the group consisting of polyoxyl castor oil, oleoyl macrogol glycerides, propylene glycol fatty acid esters, propylene glycol, diethylene glycol monoethyl ether, mono-di-glycerides, caprylocaproyl polyoxylglycerides, polyoxyethylene sorbitan fatty acid esters, sodium taurocholate, polyoxyl 40 hydrogenated castor oil, medium-chain triglycerides, polyoxyl 35 castor oil, propylene glycol monocaprylate, glyceryl monooleate, oleic acid, oleyl polyoxyl-6 glycerides, isopropyl myristate, 1,3-propanediol, 1,3-butanediol, glycerol polyethylene glycol ricinoleate, and polyethylene glycol.

13. In the 11th paragraph, the penetration promoter is citric acid, sodium salicylate, ethylenediaminetetraacetic acid (EDTA), methoxy salicylates, sodium lauryl sulfate, polyoxyethylene, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, benzalkonium chloride, 23-lauryl ether, cetylpyridinium chloride, cetyltrimethyl ammonium bromide, sodium glycocholate. sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, oleic acid, capric acid, lauric acid, lauric acid / propylene glycol, methyloleate, lysophosphatidylcholine, phosphatidylcholine, unsaturated cyclic ureas, cyclodextrins, aprotinin, azone, dextran sulfate, menthol, polysorbate 80,Sulfoxides, alkyl glycosides, chitosan-4-thiobutylamide, chitosan-4-thiobutylamide / GSH, chitosan-cysteine, poly acrylic acid-homocysteine), polycarbophil-cysteine, polycarbophil-cysteine / GSH, chitosan-4-thioethylamide / GSH, polyoxyethylated glycolysed glycerides, diethylene glycol monoethylether, A pharmaceutical composition for oral administration, comprising at least one component selected from the group consisting of a mixture of glycerol and PEG 1500 esters of long fatty acids and chitosan-4-thio-glycholic acid.

14. A method for producing a lipid delivery vehicle comprising a hydrophobic ion pair complex composition for oral administration of a peptide drug according to Article 1, (1) A step of preparing a hydrophobic ion pair complex composition; (2) a step of preparing a lipid carrier comprising oil and / or surfactant and penetration enhancer; and (3) A method for producing a pharmaceutical composition for oral administration, comprising a step of mixing the hydrophobic ion pair complex composition of step (1) into the lipid carrier of step (2).

15. A method for producing a lipid delivery vehicle comprising a hydrophobic ion pair complex composition for oral administration of a peptide drug according to Article 1, (1) A step of preparing a hydrophobic ion pair complex composition; (2) a step of mixing oil and / or surfactant into the hydrophobic ion pair complex composition of step (1); (3) a step of mixing oil and / or surfactant and penetration promoter; and (4) A method for preparing a pharmaceutical composition for oral administration, comprising the step of mixing the mixture of step (3) into the mixture of step (2).

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