WO2023287117A1 - Glp-1 유사체를 함유하는 경구 투여 제형 조성물 - Google Patents
Glp-1 유사체를 함유하는 경구 투여 제형 조성물 Download PDFInfo
- Publication number
- WO2023287117A1 WO2023287117A1 PCT/KR2022/009915 KR2022009915W WO2023287117A1 WO 2023287117 A1 WO2023287117 A1 WO 2023287117A1 KR 2022009915 W KR2022009915 W KR 2022009915W WO 2023287117 A1 WO2023287117 A1 WO 2023287117A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sodium
- exendin
- pharmaceutical composition
- oral administration
- glp
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 60
- 238000009472 formulation Methods 0.000 title abstract description 6
- 101100337060 Caenorhabditis elegans glp-1 gene Proteins 0.000 title 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims abstract description 67
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- 238000000034 method Methods 0.000 claims abstract description 26
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- JUFFVKRROAPVBI-PVOYSMBESA-N chembl1210015 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)N[C@H]1[C@@H]([C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@]3(O[C@@H](C[C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)C(O)=O)O2)O)[C@@H](CO)O1)NC(C)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 JUFFVKRROAPVBI-PVOYSMBESA-N 0.000 claims description 43
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- 239000004094 surface-active agent Substances 0.000 claims description 11
- AIMUHNZKNFEZSN-UHFFFAOYSA-M sodium;decane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCS([O-])(=O)=O AIMUHNZKNFEZSN-UHFFFAOYSA-M 0.000 claims description 10
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Definitions
- the present invention relates to an oral dosage form composition containing a GLP-1 analogue, and specifically, a pharmaceutical composition for oral administration comprising a hydrophobic ion-pair and an oil phase of a GLP-1 analogue, And it relates to a method for preparing the composition.
- GLP-1 (glucagon-like peptide-1) is a hormone composed of 30 amino acids and is known to exhibit therapeutic effects on diabetes by promoting insulin secretion in pancreatic beta cells and inhibiting glucagon secretion in alpha cells.
- GLP-1 and GLP-1 analogs developed to enhance its activity or stability are mainly administered by parenteral routes such as intravenous or subcutaneous injection, which significantly reduces the convenience of taking and causes rash and swelling at the injection site. There is a problem with doing
- GLP-1 analogs are peptide drugs that can be degraded by acid and digestive enzymes in the gastrointestinal tract when administered orally, and have poor absorption in the body.
- Korean Patent Publication No. 2020-0076642 as an oral formulation of GLP-1 or GLP-1 analogue discloses a formulation containing polyoxylglyceride, acylglycerol complex and polyethylene glycol as excipients
- Korean Patent Publication No. 2020-0081411 discloses a formulation containing sodium chenodeoxycholate and/or propyl gallate as an excipient
- 2016-0002945 discloses a salt of N-(8-2-hydroxybenzoyl)amino)caprylic acid
- preparations containing (SNAC) have been disclosed, no preparations for oral administration that are competitive compared to existing injection preparations have been developed yet.
- Novo Nordisk's 'Revelsus' which is currently on the market after being approved by the US FDA, it was expected that it would replace the existing GLP-1 injection, but compared to the existing injection, the efficacy is lower and must be taken with water or food. It has the disadvantage of inconvenient dosage method, such as taking it every day 30 minutes before taking the medicine and not allowing dividing or chewing the medicine, so there is a continuous demand for the development of another formulation for oral administration.
- a GLP-1 analogue and a counter ion are bound by electrostatic attraction to form a hydrophobic ion pair, which can be used as an oil or oil.
- a composition dissolved in an oil phase containing a surfactant was developed, and the present invention was completed by confirming that the degradation of the GLP-1 analog was prevented by forming an emulsion in the gastrointestinal tract upon oral administration of the composition.
- Patent Document 1 Republic of Korea Patent Publication No. 2020-0076642
- Patent Document 2 Korean Patent Publication No. 2020-0081411
- Patent Document 3 Korean Patent Publication No. 2016-0002945
- One object of the present invention is to provide (a) a hydrophobic ion-pair formed by binding a GLP-1 analog and a counter ion, and (b) an oil phase containing oil or a surfactant phase), to provide a pharmaceutical composition for oral administration.
- Another object of the present invention is to provide a method for preparing the pharmaceutical composition for oral administration.
- One aspect of the present invention for achieving the above object is to use (a) a hydrophobic ion-pair formed by binding a GLP-1 analog and a counter ion, and (b) an oil or surfactant It is a pharmaceutical composition for oral administration, including an oil phase comprising.
- a hydrophobic ion pair formed by binding a GLP-1 analog to a counter ion is added to an oil phase, and when the composition is exposed to an aqueous phase, an emulsion surrounding the hydrophobic ion pair is formed, thereby preventing digestion. Since it is not degraded by enzymes and can be stably absorbed to exert pharmacological effects, it can be very useful as a pharmaceutical composition for oral administration.
- GLP-1 analog refers to peptides and variants thereof that exhibit the same pharmacological activity as GLP-1 by binding to GLP-1 receptors.
- the GLP-1 analog may be exendin-4 or an exendin-4 derivative, and the exendin-4 derivative may be CA-exendin-4 (Imidazoacetyl-exendin-4), DA-exendin-4 (Desamino-histidyl-exendin-4), HY-exendin-4 (beta-hydroxy imidazopropionyl-exendin-4), CX-exendin-4 (beta-carboxyimidazopropionyl-exendin-4), DM -Exendin-4 (Dimethyl-histidyl-exendin-4), lixisenatide, liraglutide, semaglutide, dulaglutide and/or albiglutide ( albiglutide), but is not limited thereto.
- Exendin-4 is a peptide present in the salivary secretion of Heloderma suspectum (American poisonous lizard) and showing high sequence homology with the GLP-1 sequence of 53% (SEQ ID NO: 1). Exendin-4 can act on the GLP-1 receptor of insulin-secreting cells, has higher physiological activity than GLP-1 with resistance to DPP IV, and has a longer in vivo half-life of 2-4 hours than GLP-1. It has been reported (US 5,424,686). Exendin-4 in the present invention may be natural or artificially synthesized.
- the exendin-4 derivative may be a derivative obtained by chemically mutating His, the first amino acid of exendin-4. All matters described in Korean Registered Patent No. 10-1231431, which discloses derivatives of exendin-4, are incorporated herein by reference.
- exendin-4 derivatives include imidazoacetyl-exendin-4 (CA-exendin-4) by removing the alpha carbon from the first amino acid, His, and desamino-histidyl-exendin by removing the N-terminal amino group.
- exendin-4 (DA-exendin-4), beta-hydroxy imidazopropionyl-exendin-4 (HY-exendin-4) and beta-carboxy imidazopropyl-exene substituted with a hydroxyl or carboxyl group din-4 (CX-exendin-4), or dimethyl-histidyl-exendin-4 modified with two methyl residues (DM-exendin-4), but is not limited thereto. Since the exendin-4 derivatives have the same amino acid sequence structure as exendin-4 and only partially modify the first amino acid, His, they all have the same peptide structure and electrical properties.
- the present invention is characterized by the formation of ion pairs by the electrostatic attraction between the GLP-1 analogue and the counter ion, peptides and variants thereof having the same peptide structure and electrical properties as the GLP-1 analogue of the present invention are also all of the present invention. included within the scope of the invention.
- the GLP-1 analog is lixisenatide obtained by removing the 38th proline from exendin-4 and adding 6 lysine residues, or the 27th lysine in human GLP-1.
- the 26th lysine is substituted with arginine, and the 26th lysine is semaglutide acylated with stearic diacid, and GLP-1 (7-37) is linked to the Fc fragment of human IgG4.
- Two copies of dulaglutide or a GLP-1 variant in which the second alanine of human GLP-1 is substituted with glycine are composed of amino acid sequences 1-30 and 31-60, and are additionally albiglutide bound to human albumin. It may be, but is not limited thereto.
- 'counter ion' refers to an ion capable of forming a hydrophobic ion pair in a solid form by binding to a GLP-1 analogue by electrostatic attraction.
- the counter ion is 1-hydroxy-2-naphthoic acid (xinafoic acid), 2-naphthalene sulfonic acid (NSA), brilliant blue FCF, carboxymethyl polyethylene glycol (CM-PEG), cholesteryl hemisite Cinate, Colic Acid, Sodium Cholate, Decanoic Acid, Sodium Decanoate, Sodium Caprate, Dimyristoyl Phosphatidyl Glycerol (DMPG), Dioleoyl Phosphatidic Acid (DOPA), Docosahexaenoic Acid, Hexa Decylphosphate, linoleic acid, N,N-dipalmitoyl-L-lysine, oleic acid, sodium oleate, pamoic acid
- the counter ion is arginine-hexadecanoyl ester (AHE), arginine-nonyl ester (ANE), N-benzyl-2-phenylethanamine, chitosan, dodecylamine, hexadecyl trimethylammonium bromide ( CTAB), maprotiline, N ⁇ -deoxycolyl-L-lysyl-methylester, 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),
- the GLP-1 analog of the present invention is characterized in that it is added to the oil phase after forming a hydrophobic ion pair with the counter ion.
- the oil phase containing the oil or surfactant is (a) polyoxyl castor oil having an average number of oxyethylene units of 38 or less, and (b) oleoyl macrogol glyceride, propylene glycol fatty acid ester, propylene glycol, diethylene glycol It may include at least one selected from the group consisting of monoethyl ether, mono-di-glyceride, caprylocaproyl polyoxylglyceride, and polyoxyethylene sorbitan fatty acid ester, but is not limited thereto.
- the oil phase may further contain an absorption accelerator for the purpose of improving absorption of the GLP-1 analogue into the body.
- Absorption enhancers such as EDTA, citric acid, salicylate, SDS, sodium deoxycholate, sodium taurocholate, oleic acid, acylcarnitine, sodium caprate, sodium caprylate, salcaprozate (SNAC), 5-CNAC , dimyristoyl phosphatidylglycerol (DMPG), cetyltrimethylammonium bromide (CTAB) and/or phospholipids, but all are included within the scope of the present invention as long as they improve absorption of the GLP-1 analogue into the body.
- the pharmaceutical composition can be used very usefully for prevention or treatment of diabetes, for example.
- the therapeutic effects of GLP-1 analogs such as exendin-4 on diabetes and their pharmacological mechanisms are well known in the art.
- Another aspect of the present invention also provides a method for treating or preventing diabetes comprising administering a therapeutically effective amount of the pharmaceutical composition to a subject in need thereof.
- the subject may be a mammal including a human.
- therapeutically effective amount refers to an amount of the pharmaceutical composition effective for the treatment or prevention of diabetes.
- therapeutically effective amount means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type and severity of the subject, age, sex, type of disease, It may be determined according to the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field.
- the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, or may be administered sequentially or simultaneously with a commercially available therapeutic agent.
- the dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it can be used even at a dose determined or higher.
- the present invention provides a use of the pharmaceutical composition for use in the manufacture of a medicament for use in the treatment or prevention of diabetes.
- the pharmaceutical composition for the preparation of drugs may be mixed with acceptable adjuvants, diluents, carriers, etc., and may be prepared as a combined preparation with other active agents to have a synergistic action of the active ingredients.
- Another aspect of the present invention for achieving the above object is (a) preparing a hydrophobic ion-pair by mixing a GLP-1 analogue with a counter ion; and (b) mixing the hydrophobic ion pair into an oil phase.
- the GLP-1 analog, counter ion, hydrophobic ion pair and oil phase are as described above.
- step (a) is a step of preparing a hydrophobic ion pair of a GLP-1 analog in a solid form, and specifically, (a-1) dissolving a GLP-1 analog and a counter anion in an aqueous solution of pH 4.0; (a-2) dripping the solution of the counter anion into a solution of a GLP-1 analogue; and (a-3) recovering ion pairs from the mixture of step (a-2).
- the step (a) may include (a-4) dissolving a GLP-1 analog in an aqueous solution of pH 8.0 and dissolving a counter cation in an aqueous solution of methanol; (a-5) dripping the counter cation solution into a GLP-1 analogue solution; and (a-6) recovering ion pairs from the mixture of step (a-5), but is not limited thereto.
- Another aspect of the present invention includes (a) preparing a hydrophobic ion-pair by mixing a GLP-1 analog with a counter ion; (b) adding the hydrophobic ion pair to a mixture of medium chain triglyceride (MCT) and propylene glycol; and (c) adding at least one selected from the group consisting of polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, oleoyl macrogolglyceride and propylene glycol fatty acid ester to the mixture prepared in step (b) and mixing. It is a method for preparing a pharmaceutical composition for oral administration comprising the step of.
- Another aspect of the present invention includes (a) preparing a hydrophobic ion-pair by mixing a GLP-1 analog with a counter ion;
- step (c) adding at least one selected from the group consisting of medium chain triglyceride, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil and oleoyl macrogolglyceride to the mixture prepared in step (b) It is a method for preparing a pharmaceutical composition for oral administration comprising the step of adding and mixing.
- a mixture of propylene glycol, a hydrophilic co-solvent, and medium-chain triglycerides or propylene glycol fatty acid ester is first hydrophobic, compared to simply adding a hydrophobic ion pair to an oil mixture.
- a hydrophobic ion pair By adding an ion pair to minimize dispersion and then mixing the rest of the oil component, the gastrointestinal enzymatic degradation stability can be increased.
- Another aspect of the present invention is a pharmaceutical composition for oral administration prepared by the above production method.
- Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below.
- embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
- "include” a certain component throughout the specification means that other components may be further included without excluding other components unless otherwise stated.
- composition for oral administration of the present invention When the pharmaceutical composition for oral administration of the present invention is exposed to an aqueous phase, an emulsion surrounding hydrophobic ion pairs is formed, so that it is not decomposed by digestive enzymes and is stably absorbed to exert pharmacological effects.
- a pharmaceutical composition for oral administration can be very useful.
- Figure 2 shows the results of testing the stability of the compositions of Examples 1 to 2 and Comparative Examples 1 to 3 in simulated intestinal fluid.
- Figure 3 shows the results of testing the stability of the compositions of Examples 3 to 4 and Comparative Examples 4 to 6 in artificial gastric juice.
- Figure 4 shows the results of testing the stability of the compositions of Examples 3 to 4 and Comparative Examples 4 to 6 in simulated intestinal fluid.
- Figure 5 shows the results of testing the stability of the compositions of Examples 5 to 7 in artificial gastric juice.
- Figure 6 shows the results of testing the stability of the compositions of Comparative Examples 7 to 9 in artificial gastric juice.
- Figure 7 shows the results of testing the stability of the compositions of Examples 5 to 7 in simulated intestinal fluid.
- Figure 8 shows the results of testing the stability of the compositions of Comparative Examples 7 to 9 in simulated intestinal fluid.
- Figure 9 shows the results of testing the stability of the compositions of Comparative Examples 10 to 11 in artificial gastric juice.
- compositions for oral administration containing CA-exendin-4, an analogue of GLP-1 were prepared.
- CA-exendin-4 and sodium docusate were dissolved in a pH 4.0 solution, respectively, to form cations and negative ions were made.
- the dissolved sodium docusate solution was added dropwise to the CA-exendin-4 solution to obtain a hydrophobic solid composition.
- the solid composition was dissolved in the oil phase (mixture of oil or surfactant) specified in Table 1 to obtain the final pharmaceutical composition.
- compositions for oral administration containing exendin-4, an analogue of GLP-1 were prepared.
- exendin-4 and tetraheptylammonium bromide were dissolved in pH 8.0 solution and 50% methanol solution, respectively. Anions and cations were made visible. The dissolved tetraheptylammonium bromide solution was added dropwise to the exendin-4 solution to obtain a hydrophobic solid composition.
- the solid composition was dissolved in the oil phase (mixture of oil or surfactant) specified in Table 2 to obtain the final pharmaceutical composition.
- compositions for oral administration containing exendin-4, an analogue of GLP-1 were prepared.
- exendin-4 and tetraheptylammonium bromide were dissolved in pH 8.0 solution and 50% methanol solution, respectively. Anions and cations were made visible. The dissolved tetraheptylammonium bromide solution was added dropwise to the exendin-4 solution to obtain a hydrophobic solid composition.
- the solid composition was first added to a mixture of medium chain triglycerides (MCT) or propylene glycol fatty acid ester and hydrophilic co-solvent propylene glycol, and then the remaining oils specified in Table 3 were added to obtain a final pharmaceutical composition.
- MCT medium chain triglycerides
- propylene glycol fatty acid ester and hydrophilic co-solvent propylene glycol were added to obtain a final pharmaceutical composition.
- Comparative Example 2 Preparation of a composition containing CA-exendin-4 without ion pairing
- CA-Exendin-4 was directly mixed into an oil phase without undergoing a hydrophobic ion pair formation process.
- Comparative Example 3 Preparation of a composition containing an ion pair of CA-exendin-4 without an oil phase
- exendin-4 was directly mixed into an oil phase without undergoing a hydrophobic ion pair formation process.
- compositions for oral administration containing exendin-4, an analogue of GLP-1 were prepared.
- exendin-4 and tetraheptylammonium bromide were dissolved in pH 8.0 solution and 50% methanol solution, respectively. Anions and cations were made visible. The dissolved tetraheptylammonium bromide solution was added dropwise to the exendin-4 solution to obtain a hydrophobic solid composition.
- the solid composition was added to the oil phase and hydrophilic co-solvent mixture specified in Table 8 or the oil phase specified in Table 9 to obtain the final pharmaceutical composition.
- Test Example 1 Evaluation of enzymatic degradation in vitro
- Comparative Example 4 it was confirmed that Exendin-4 was dissolved in the aqueous phase and easily decomposed by enzymes.
- Comparative Example 5 even if exendin-4 is dispersed in a hydrophobic medium containing oil to form an emulsion, exendin-4 cannot be encapsulated inside the emulsion and is easily decomposed by artificial gastric or intestinal fluid. .
- Comparative Example 6 Even in the case of Comparative Example 6, it was confirmed that the hydrophobic ion pair including exendin-4 was dispersed in the digestive enzyme solution and easily decomposed by artificial gastric juice or artificial intestinal juice (FIGS. 3 and 4).
- the composition containing the GLP-1 analog of the present invention forms a hydrophobic ion pair using the GLP-1 analog and a counter ion and includes it in the oil phase, thereby forming the GLP-1 analog alone and hydrophobic ion.
- the composition of the present invention can be very useful for oral administration of GLP-1 analogues.
- Test Example 2 Evaluation of enzymatic degradation in vitro according to manufacturing method
- Examples 5 to 7 were confirmed to show stability for 30 minutes and 15 minutes or more in artificial gastric juice and artificial intestinal fluid, respectively (FIGS. 5 and 7), but Comparative Examples 7 to 11, in which hydrophobic ion pairs were relatively dispersed, It was confirmed that almost all decomposition occurred even at 0 minutes, and the decomposition rate was very fast compared to Examples 5 to 7 (FIGS. 6 and 8 to 10).
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Abstract
Description
Claims (21)
- (a) GLP-1 유사체와 카운터 이온 (counter ion)이 결합하여 형성된 소수성 이온쌍 (ion-pair), 및(b) 오일 또는 계면활성제를 포함하는 오일상 (oil phase)을 포함하는, 경구투여용 약학적 조성물.
- 제1항에 있어서,상기 GLP-1 유사체는 엑센딘-4 (exendin-4), CA-엑센딘-4 (Imidazoacetyl-exendin-4), DA-엑센딘-4 (Desamino-histidyl-exendin-4), HY-엑센딘-4 (beta-hydroxy imidazopropionyl-exendin-4), CX-엑센딘-4 (beta-carboxyimidazopropionyl-exendin-4), DM-엑센딘-4 (Dimethyl-histidyl-exendin-4), 릭시세나티드 (lixisenatide), 리라글루티드 (liraglutide), 세마글루티드 (semaglutide), 둘라글루티드 (dulaglutide) 및 알비글루티드 (albiglutide)로 이루어진 군에서 선택된 어느 하나 이상인, 경구투여용 약학적 조성물.
- 제1항에 있어서,상기 카운터 이온은 1-히드록시-2-나프토익산 (xinafoic acid), 2-나프탈렌 설폰산 (NSA), 브릴리언트 블루 FCF, 카복시 메틸 폴리에틸렌 글리콜 (CM-PEG), 콜레스테릴 헤미석시네이트, 콜릭산, 소듐 콜레이트, 데카노익산, 소듐 데카노에이트, 소듐 카프레이트, 디미리스토일 포스파티딜 글리세롤 (DMPG), 디올레오일 포스파티딕산 (DOPA), 도코사헥사에노익산, 헥사데실포스페이트, 리놀레익산, N,N-디팔미토일-L-라이신, 올레익산, 소듐 올레이트, 파모익산, 디소듐 파모에이트, 소듐 아세테이트, 소듐 콜레스테릴 설페이트, 소듐 데칸설포네이트 (SDES), 소듐 데옥시콜레이트, 소듐 도큐세이트, 소듐 도데실 벤젠설포네이트 (SDBS), 소듐 도데실 설페이트, 소듐 라우레이트, 소듐 n-옥타데실 설페이트, 소듐 스테아레이트, 소듐 스테아로일 글루타메이트 (SSG), 소듐 타우로데옥시콜레이트 (STDC), 소듐 테트라데실 설페이트, 소듐 트리폴리포스페이트, 타우로콜릭산, 소듐 타우로콜레이트, 및 비타민 E 석시네이트로 이루어진 군으로부터 선택된 어느 하나 이상의 음이온인, 경구투여용 약학적 조성물.
- 제1항에 있어서,상기 카운터 이온은 알지닌-헥사데카노일 에스터 (AHE), 알지닌-노닐 에스터 (ANE), N-벤질-2-페닐에탄아민, 키토산, 도데실아민, 헥사데실 트리메틸암모늄 브로마이드 (CTAB), 마프로틸린, Nα-데옥시콜릴-L-라이실-메틸에스터, N,N'-디벤질 에틸렌디아민, N,N-디메틸 도데실아민, N,N-디메틸 헥실아민, N,N-디메틸 옥타데실아민, 스테아릴아민, 테트라부틸 암모늄 브로마이드 (TBAB), 테트라헵틸 암모늄 브로마이드 (THA), 테트라헥실 암모늄 브로마이드, 테트라옥틸 암모늄 브로마이드 (TOAB), 테트라펜틸 암모늄 브로마이드 (TPA), 및 트리에틸아민 (TEA)으로 이루어진 군으로부터 선택된 어느 하나 이상의 양이온인, 경구투여용 약학적 조성물.
- 제1항에 있어서, 상기 오일 또는 계면활성제를 포함하는 오일상은(a) 옥시에틸렌 유닛의 평균 수가 38 이하인 폴리옥실 캐스터 오일, 및(b) 올레오일 마크로골글리세라이드, 프로필렌글리콜지방산에스터, 프로필렌글리콜, 디에틸렌글리콜 모노에틸에터, 모노-디-글리세라이드, 카프릴로카프로일 폴리옥실글리세라이드 및 폴리옥시에틸렌소르비탄지방산에스터로 이루어진 군에서 선택된 어느 하나 이상을 포함하는, 경구투여용 약학적 조성물.
- 제5항에 있어서,상기 오일상은 GLP-1 유사체의 흡수촉진제를 추가로 포함하는, 경구투여용 약학적 조성물.
- 제6항에 있어서,상기 흡수촉진제는 EDTA, 시트르산, 살리실레이트, SDS, 소듐 데옥시콜레이트, 소듐 타우로콜레이트, 올레인산, 아실카르니틴, 소듐 카프레이트, 소듐 카프릴레이트, 살카프로제이트 (SNAC), 5-CNAC, 디미리스토일 포스파티딜글리세롤 (DMPG), 세틸트리메틸암모늄 브로마이드 (CTAB) 및 포스포리피드로 이루어진 군으로부터 선택된 어느 하나 이상인, 경구투여용 약학적 조성물.
- 제1항 내지 제7항 중 어느 한 항에 있어서,상기 약학적 조성물은 당뇨병의 예방 또는 치료용인, 경구투여용 약학적 조성물.
- (a) GLP-1 유사체를 카운터 이온 (counter ion)과 혼합하여 소수성 이온쌍 (ion-pair)을 제조하는 단계; 및(b) 상기 소수성 이온쌍을 오일상 (oil phase)에 혼합하는 단계를 포함하는, 경구투여용 약학적 조성물의 제조방법.
- 제9항에 있어서,상기 단계 (a)는(a-1) GLP-1 유사체와 카운터 음이온을 각각 pH 4.0 수용액에 용해시키는 단계;(a-2) 상기 카운터 음이온의 용액을 GLP-1 유사체 용액에 점적하는 단계; 및(a-3) 상기 단계 (a-2)의 혼합물로부터 이온쌍을 회수하는 단계를 포함하는, 경구투여용 약학적 조성물의 제조방법.
- 제9항에 있어서, 상기 단계 (a)는(a-4) GLP-1 유사체를 pH 8.0 수용액에 용해시키고 카운터 양이온을 메탄올 수용액에 용해시키는 단계;(a-5) 상기 카운터 양이온의 용액을 GLP-1 유사체 용액에 점적하는 단계; 및(a-6) 상기 단계 (a-5)의 혼합물로부터 이온쌍을 회수하는 단계를 포함하는, 경구투여용 약학적 조성물의 제조방법.
- 제9항에 있어서,상기 GLP-1 유사체는 엑센딘-4 (exendin-4), CA-엑센딘-4 (Imidazoacetyl-exendin-4), DA-엑센딘-4 (Desamino-histidyl-exendin-4), HY-엑센딘-4 (beta-hydroxy imidazopropionyl-exendin-4), CX-엑센딘-4 (beta-carboxyimidazopropionyl-exendin-4), DM-엑센딘-4 (Dimethyl-histidyl-exendin-4), 릭시세나티드 (lixisenatide), 리라글루티드 (liraglutide), 세마글루티드 (semaglutide), 둘라글루티드 (dulaglutide) 및 알비글루티드 (albiglutide)로 이루어진 군에서 선택된 어느 하나 이상인, 경구투여용 약학적 조성물의 제조방법.
- 제9항에 있어서,상기 카운터 이온은 1-히드록시-2-나프토익산 (xinafoic acid), 2-나프탈렌 설폰산 (NSA), 브릴리언트 블루 FCF, 카복시 메틸 폴리에틸렌 글리콜 (CM-PEG), 콜레스테릴 헤미석시네이트, 콜릭산, 소듐 콜레이트, 데카노익산, 소듐 데카노에이트, 소듐 카프레이트, 디미리스토일 포스파티딜 글리세롤 (DMPG), 디올레오일 포스파티딕산 (DOPA), 도코사헥사에노익산, 헥사데실포스페이트, 리놀레익산, N,N-디팔미토일-L-라이신, 올레익산, 소듐 올레이트, 파모익산, 디소듐 파모에이트, 소듐 아세테이트, 소듐 콜레스테릴 설페이트, 소듐 데칸설포네이트 (SDES), 소듐 데옥시콜레이트, 소듐 도큐세이트, 소듐 도데실 벤젠설포네이트 (SDBS), 소듐 도데실 설페이트, 소듐 라우레이트, 소듐 n-옥타데실 설페이트, 소듐 스테아레이트, 소듐 스테아로일 글루타메이트 (SSG), 소듐 타우로데옥시콜레이트 (STDC), 소듐 테트라데실 설페이트, 소듐 트리폴리포스페이트, 타우로콜릭산, 소듐 타우로콜레이트, 및 비타민 E 석시네이트로 이루어진 군으로부터 선택된 어느 하나 이상의 음이온인, 경구투여용 약학적 조성물의 제조방법.
- 제9항에 있어서,상기 카운터 이온은 알지닌-헥사데카노일 에스터 (AHE), 알지닌-노닐 에스터 (ANE), N-벤질-2-페닐에탄아민, 키토산, 도데실아민, 헥사데실 트리메틸암모늄 브로마이드 (CTAB), 마프로틸린, Nα-데옥시콜릴-L-라이실-메틸에스터, N,N'-디벤질 에틸렌디아민, N,N-디메틸 도데실아민, N,N-디메틸 헥실아민, N,N-디메틸 옥타데실아민, 스테아릴아민, 테트라부틸 암모늄 브로마이드 (TBAB), 테트라헵틸 암모늄 브로마이드 (THA), 테트라헥실 암모늄 브로마이드, 테트라옥틸 암모늄 브로마이드 (TOAB), 테트라펜틸 암모늄 브로마이드 (TPA), 및 트리에틸아민 (TEA)으로 이루어진 군으로부터 선택된 어느 하나 이상의 양이온인, 경구투여용 약학적 조성물의 제조방법.
- 제9항에 있어서, 상기 오일 또는 계면활성제를 포함하는 오일상은(a) 옥시에틸렌 유닛의 평균 수가 38 이하인 폴리옥실 캐스터 오일, 및(b) 올레오일 마크로골글리세라이드, 프로필렌글리콜지방산에스터, 프로필렌글리콜, 디에틸렌글리콜 모노에틸에터, 모노-디-글리세라이드, 카프릴로카프로일 폴리옥실글리세라이드 및 폴리옥시에틸렌소르비탄지방산에스터로 이루어진 군에서 선택된 어느 하나 이상을 포함하는, 경구투여용 약학적 조성물의 제조방법.
- 제15항에 있어서,상기 오일상은 GLP-1 유사체의 흡수촉진제를 추가로 포함하는, 경구투여용 약학적 조성물의 제조방법.
- 제16항에 있어서,상기 흡수촉진제는 EDTA, 시트르산, 살리실레이트, SDS, 소듐 데옥시콜레이트, 소듐 타우로콜레이트, 올레인산 아실카르니틴, 소듐 카프레이트, 소듐 카프릴레이트, 살카프로제이트 (SNAC), 5-CNAC, 디미리스토일 포스파티딜글리세롤 (DMPG), 세틸트리메틸암모늄 브로마이드 (CTAB) 및 포스포리피드로 이루어진 군으로부터 선택된 어느 하나 이상인, 경구투여용 약학적 조성물의 제조방법.
- 제9항 내지 제17항 중 어느 한 항의 제조방법으로 제조된, 경구투여용 약학적 조성물.
- (a) GLP-1 유사체를 카운터 이온 (counter ion)과 혼합하여 소수성 이온쌍 (ion-pair)을 제조하는 단계;(b) 상기 소수성 이온쌍을 중쇄중성지방 (Medium Chain Triglyceride) 및 프로필렌글리콜의 혼합물에 첨가하는 단계; 및(c) 상기 (b) 단계에서 제조된 혼합물에 폴리옥실 35 캐스터 오일, 폴리옥실 40 수소화 캐스터 오일, 올레오일 마크로골글리세라이드 및 프로필렌글리콜지방산에스터로 이루어진 군에서 선택된 어느 하나 이상을 첨가하여 혼합하는 단계를 포함하는, 경구투여용 약학적 조성물의 제조방법.
- (a) GLP-1 유사체를 카운터 이온 (counter ion)과 혼합하여 소수성 이온쌍 (ion-pair)을 제조하는 단계;(b) 상기 소수성 이온쌍을 프로필렌글리콜지방산에스터 및 프로필렌글리콜의 혼합물에 첨가하는 단계; 및(c) 상기 (b) 단계에서 제조된 혼합물에 중쇄중성지방 (Medium Chain Triglyceride), 폴리옥실 35 캐스터 오일, 폴리옥실 40 수소화 캐스터 오일 및 올레오일 마크로골글리세라이드로 이루어진 군에서 선택된 어느 하나 이상을 첨가하여 혼합하는 단계를 포함하는, 경구투여용 약학적 조성물의 제조방법.
- 제19항 또는 제20항의 제조방법으로 제조된, 경구투여용 약학적 조성물.
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- 2021-12-24 KR KR1020210187101A patent/KR20230010571A/ko active Search and Examination
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2022
- 2022-07-08 WO PCT/KR2022/009915 patent/WO2023287117A1/ko active Application Filing
- 2022-07-08 EP EP22842379.4A patent/EP4371577A1/en active Pending
- 2022-07-08 CN CN202280049052.0A patent/CN117651567A/zh active Pending
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EP4371577A1 (en) | 2024-05-22 |
KR20230010571A (ko) | 2023-01-19 |
CN117651567A (zh) | 2024-03-05 |
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