KR20220052144A - Method for preparing oral pharmaceutical composition comprising teriparatide and oral pharmaceutical composition manufactured by the method - Google Patents
Method for preparing oral pharmaceutical composition comprising teriparatide and oral pharmaceutical composition manufactured by the method Download PDFInfo
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- KR20220052144A KR20220052144A KR1020200136150A KR20200136150A KR20220052144A KR 20220052144 A KR20220052144 A KR 20220052144A KR 1020200136150 A KR1020200136150 A KR 1020200136150A KR 20200136150 A KR20200136150 A KR 20200136150A KR 20220052144 A KR20220052144 A KR 20220052144A
- Authority
- KR
- South Korea
- Prior art keywords
- bile acid
- teriparatide
- preparing
- pharmaceutical composition
- acid
- Prior art date
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- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)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](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 title claims abstract description 96
- 108010049264 Teriparatide Proteins 0.000 title claims abstract description 95
- 229960005460 teriparatide Drugs 0.000 title claims abstract description 94
- 238000000034 method Methods 0.000 title claims abstract description 49
- 239000008203 oral pharmaceutical composition Substances 0.000 title claims abstract description 42
- 239000003613 bile acid Substances 0.000 claims abstract description 81
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims abstract description 78
- 238000002156 mixing Methods 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 125000000129 anionic group Chemical group 0.000 claims description 60
- -1 cationic bile acid derivative Chemical class 0.000 claims description 56
- 239000000203 mixture Substances 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 25
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- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 17
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 17
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 16
- 229960003964 deoxycholic acid Drugs 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
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- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 7
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000004380 Cholic acid Substances 0.000 claims description 4
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 claims description 4
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 claims description 4
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 4
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- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 claims description 4
- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 claims description 4
- QBYUNVOYXHFVKC-GBURMNQMSA-N taurolithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 QBYUNVOYXHFVKC-GBURMNQMSA-N 0.000 claims description 4
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
Description
본 발명은 테리파라타이드(teriparatide)를 포함하는 경구용 약학 조성물의 제조방법에 관한 것으로, 더욱 구체적으로 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체를 혼합하여 이온결합 복합체를 제조하는 단계를 포함하는 경구용 약학 조성물의 제조방법에 관한 것이다.The present invention relates to a method for preparing an oral pharmaceutical composition comprising teriparatide, and more particularly, to a method for preparing an ionic complex by mixing teriparatide, an anionic bile acid and a cationic bile acid derivative It relates to a method for preparing an oral pharmaceutical composition.
부갑상선 호르몬(parathyroid hormone; PTH)은 부갑상선에서 분비되는 84개의 아미노산으로 이루어진 폴리펩타이드로서 혈중 칼슘이온의 농도를 조절하는 주요 호르몬 중 하나이다. 이것은 뼈에서 동화작용(뼈 형성)과 이화작용의 기능을 하며 이러한 작용은 PTH에 노출되는 기간 및 패턴에 의해 달라진다. 또한, 동화작용은 간헐적인 PTH 노출에 의해 촉진되며 조골세포의 분화와 증식 또는 세포자멸사의 감소를 야기한다. 이화작용은 지속적인 PTH 노출에 의해 촉진되며 RANKL(receptor activator of nuclear factor-κB ligand)의 발현 증가 및 오스테오프로테게린 (osteoprotegerin)의 발현 감소와 관련이 있다.Parathyroid hormone (PTH) is a polypeptide composed of 84 amino acids secreted by the parathyroid glands and is one of the main hormones that control the concentration of calcium ions in the blood. It has anabolic (bone formation) and catabolic functions in the bone, and these actions depend on the duration and pattern of exposure to PTH. In addition, anabolic activity is promoted by intermittent PTH exposure, resulting in a decrease in the differentiation and proliferation of osteoblasts or apoptosis. Catabolic activity is stimulated by prolonged PTH exposure and is associated with increased expression of receptor activator of nuclear factor-κB ligand (RANKL) and decreased expression of osteoprotegerin.
부갑상선 호르몬(PTH)의 N-말단으로부터 34개의 아미노산 잔기, 즉 테리파라타이드(PTH(1-34); teriparadite)는 뼈와 콩팥에 많이 발현되어 있는 type 1 PTH 수용체의 활성화에 필수적이다. 테리파라타이드가 type 1 PTH 수용체에 결합하면 G단백질-의존적 cAMP/단백질인 산화효소 A 경로(G protein-dependent cAMP/protein kinase A pathway)를 포함하는 일련의 신호전달 체계가 활성화되고 혈장의 칼슘 농도가 조절된다. 테리파라타이드는 유전자 재조합 PTH(1-34)(rhPTH(1-34); 인간 유전자 재조합 PTH(1-34)(recombinant human PTH(1-34))로서 임상적으로 폐경 후 여성의 골다공증과 생식선 억제성 남성의 골다공증 치료에 사용된다. 간헐적인 테리파라타이드의 투여는 파골 세포보다 조골세포를 더 활성화시킴으로써 새로운 뼈의 형성을 자극하며 골다공증에서의 골절 위험을 감소시킨다. 다른 많은 골다공증 치료법들은 이화작용의 성질을 가지지 않고 오로지 파골 세포의 활성을 억제시키는 예방적인 성격의 치료법이다. 이러한 골흡수억제제(antiresorptives)에는 비스포스포네이트(bisphosphonate), 에스트로겐 수용체 조절제(estrogen receptor modulator), 칼시토닌 (calcitonin)이 포함된다. 반면, 테리파라타이드는 골절의 위험이 있으며 다른 골흡수 억제제에 반응하지 않는 환자의 골다공증 치료에 쓰일 수 있다.Thirty-four amino acid residues from the N-terminus of parathyroid hormone (PTH), namely teriparatide (PTH(1-34); teriparadite), are essential for the activation of type 1 PTH receptors, which are widely expressed in bones and kidneys. When teriparatide binds to type 1 PTH receptors, a series of signaling systems including the G protein-dependent cAMP/protein kinase A pathway are activated and plasma calcium levels are activated. is regulated Teriparatide is a recombinant human PTH (1-34) (rhPTH (1-34); Used to treat osteoporosis in suppressive men.Intermittent administration of teriparatide stimulates new bone formation and reduces the risk of fracture in osteoporosis by activating more osteoblasts than osteoclasts.Many other osteoporosis treatments are catabolic. It is a prophylactic treatment that only inhibits osteoclast activity without the properties of osteoclasts.These antiresorptives include bisphosphonates, estrogen receptor modulators, and calcitonin. On the other hand, teriparatide can be used to treat osteoporosis in patients at risk of fracture and who do not respond to other bone resorption inhibitors.
테리파라타이드는 현재 넓적다리나 복부에 2년간, 1일 1회 피하주사하는 형태로 투여되고 있다. 그러나 이러한 피하주사 방식은 환자에게 통증을 유발하고 환자들이 올바른 주사 방법을 습득해야 하는 불편함을 수반한다. 따라서 환자의 복용 순응도를 높이기 위해 PTH 펩타이드에 대한 경구투여, 경피투여, 비강투여 등의 대체 약물전달시스템의 개발이 시도되고 있다. 경구 투여의 장점으로는 환자의 편리함과 테리파라타이드의 농도가 Tmax에 도달하는 데까지 걸리는 시간이 증가한다는 점이 있다. 그러나 PTH 경구 전달의 가장 큰 문제점 중 하나는 펩타이드 자체의 경구 생체이용률이 낮다는 것이다. 이러한 문제의 원인으로는 펩타이드의 짧은 반감기, 위산과 소화관의 단백질 분해효소에 의한 분해, 큰 분자량(약 4117.72 Da)에 기인한 낮은 위장관 세포막 투과성이 있다. 따라서 환자의 복용 순응도를 높이기 위해 테리파라타이드의 새로운 투여전달시스템의 개발이 시급한 실정이다.Teriparatide is currently administered in the form of subcutaneous injection once a day for 2 years in the thigh or abdomen. However, this method of subcutaneous injection causes pain to the patient and is accompanied by inconvenience in that the patient must learn the correct injection method. Therefore, development of alternative drug delivery systems such as oral administration, transdermal administration, and nasal administration for PTH peptide is being attempted in order to increase patient compliance. Advantages of oral administration include patient convenience and an increase in the time it takes for the concentration of teriparatide to reach T max . However, one of the biggest problems with oral delivery of PTH is the low oral bioavailability of the peptide itself. The causes of these problems include the short half-life of the peptide, degradation by gastric acid and digestive tract proteases, and low gastrointestinal cell membrane permeability due to its large molecular weight (about 4117.72 Da). Therefore, there is an urgent need to develop a new administration delivery system for teriparatide in order to increase patient compliance.
상기와 같은 문제점을 개선하기 위한 기술이 덴마크공개특허 제01643978호에 개시되어 있다. 상기 특허는 통상의 장용성 코팅 등으로 경구 투여 후 2시간 이후 PTH가 방출되도록 하여 위장 내 약물의 분해를 최소화하여 흡수율을 향상시키고자 하였다. 그러나 PTH의 낮은 경구 생체이용률은 위장관 내 약물의 분해뿐만 아니라 약물 분자의 낮은 지질 친화도와 큰 분자량으로 장관막 투과도 자체가 낮은 것에 주로 기인하다. 따라서 일반적인 장용성 경구투여 제형으로는 PTH의 치료학적 효과를 발휘할 수 있는 충분한 경구 생체이용률을 나타내기에 부족하다. 또한, PCT/CZ2012/000025에도 테리파라타이드를 베타-글루칸, 알긴산, 키토산과 같은 수용성 다당류와 비공유 결합에 의한 복합체를 제조하여 약물의 효소에 대한 분해를 최소화하여 경구 생체이용률을 향상시키고자 하였으나, 약물 자체의 장관막 투과도를 향상시키기 위한 방안은 제시하고 있지 않다. 또한, 한국공개특허 제2017-0125793호는 치료제를 pH 및 온도로부터 안정화시키고, 장 투과성을 개선함으로써 생체이용률을 향상시키기 위한 조성물에 관한 것으로, 치료제를 양이온성 접합체와 결합하여 코어 복합체를 제조하고, 담즙산을 음이온 중합체와 공유 결합시킨 후, 상기 양이온성 접합체와 음이온성 접합체를 정전기적으로 커플링시킴으로써 위장관 내에서 담즙산 수송체를 통해 환자에 흡수되어 장간순환계로 진입할 수 있도록 하여 환자의 순응도를 향상시키고자 하였다. 그러나 상기 문헌에는 본원발명과 같이 테리파라타이드의 생체이용률을 증가시키기 위한 경구용 약학 조성물을 제조하기 위하여 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체를 혼합하여 이온결합 복합체를 제조하는 방법에 대해서는 언급된 바 없다.A technique for improving the above problems is disclosed in Danish Patent Laid-Open No. 01643978. The above patent intended to improve absorption by minimizing degradation of the drug in the stomach by allowing PTH to be released 2 hours after oral administration with a conventional enteric coating or the like. However, the low oral bioavailability of PTH is mainly due to the low intestinal membrane permeability itself due to the low lipid affinity and large molecular weight of the drug molecule as well as the degradation of the drug in the gastrointestinal tract. Therefore, a general enteric oral dosage form is insufficient to exhibit sufficient oral bioavailability to exert the therapeutic effect of PTH. In addition, in PCT/CZ2012/000025, teriparatide was prepared by non-covalent bonding of teriparatide with water-soluble polysaccharides such as glucan, alginic acid, and chitosan to minimize the degradation of the drug enzyme. A method for improving the intestinal membrane permeability of the drug itself is not suggested. In addition, Korea Patent Application Publication No. 2017-0125793 relates to a composition for improving bioavailability by stabilizing a therapeutic agent from pH and temperature and improving intestinal permeability, wherein the therapeutic agent is combined with a cationic conjugate to prepare a core complex, After covalent bonding of bile acids with anionic polymers, electrostatic coupling of the cationic and anionic conjugates allows them to be absorbed by the patient through bile acid transporters in the gastrointestinal tract and enter the enterohepatic circulation, thereby improving patient compliance wanted to do However, in the above document, as in the present invention, a method for preparing an ionic complex by mixing teriparatide, an anionic bile acid and a cationic bile acid derivative to prepare an oral pharmaceutical composition for increasing the bioavailability of teriparatide is described. nothing mentioned
한편, 펩타이드 치료제의 생체이용률을 증가시키기 위하여 펩타이드 치료제에 담즙산을 결합시키는 시도가 이루어지고 있다. 특히, 펩타이드 치료제 중 하나인 테리파라타이드를 구성하는 아미노산 서열은 음전하성인 담즙산과 결합 가능한 양전하를 띄는 아미노산과 양전하성 물질과 결합 가능한 음전하를 띄는 아미노산으로 구성된 양쪽성 펩타이드이다. 따라서 양전하를 띄는 아미노산에 음전하성 담즙산을 결합시키고 음전하를 띄는 아미노산에 양전하성 물질을 결합시킨다면 테리파라타이드의 흡수 효율을 증가시켜 생체이용률을 향상시킬 수 있을 것이다. 그러나, 상술한 바와 같이 양쪽성 펩타이드인 테리파라타이드에 음전하 물질 및 양전하 물질을 결합시키기 위하여 테리파라타이드와 음전하성 및 양전하성을 갖는 물질들을 동시에 첨가하여 이온결합을 유도할 경우, 첨가된 음전하성 물질과 양전하성 물질이 서로 먼저 결합하게 되고 이에 따라 응집 및 침전이 발생하게 되므로, 구조적으로 안정한 펩타이드 치료제를 구현하기 어려울 뿐만 아니라 순도 및 수율도 저하되는 문제가 발생할 수 있다. 또한, 약물 전달 시스템에서 이용되는 약물 용해제는 약물의 가용화, 약물의 흡수 및 침투를 증가시키기 위해 이용되나, 모든 약물에 모든 용해제가 적합하게 작용하는 것이 아니기 때문에 특정 약물에 특이적으로 현저한 효과를 나타내는 용해제를 탐색하는 것이 중요하다.On the other hand, in order to increase the bioavailability of the peptide therapeutic agent, an attempt has been made to bind a bile acid to the peptide therapeutic agent. In particular, the amino acid sequence constituting teriparatide, which is one of the peptide therapeutics, is an amphoteric peptide composed of positively charged amino acids capable of binding to negatively charged bile acids and negatively charged amino acids capable of binding to positively charged substances. Therefore, if a negatively charged bile acid is bound to an amino acid having a positive charge and a positively charged substance is bound to an amino acid having a negative charge, the absorption efficiency of teriparatide can be increased, thereby improving the bioavailability. However, as described above, in order to bind a negatively charged material and a positively charged material to teriparatide, which is an amphoteric peptide, simultaneously adding teriparatide and materials having negative and positive charges to induce ionic bonding, the added negative charge Since the material and the positively charged material are first bound to each other, and thus aggregation and precipitation occur, it is difficult to implement a structurally stable peptide therapeutic agent, but also the purity and yield may be reduced. In addition, drug solubilizing agents used in drug delivery systems are used to increase drug solubilization, drug absorption, and penetration, but not all solubilizing agents work properly for all drugs, so they show significant effects specifically for a particular drug. It is important to explore the solvent.
따라서, 테리파라타이드의 음전하를 띄는 아미노산과 결합하여 치료제의 흡수 효율을 증가시킬 수 있는 양전하성 물질과 구조적으로 안정성으로 부여할 수 있는 용해제 및 완충제를 탐색하여 테리파라타이드 펩타이드에 흡수 증진제를 특이적, 선택적으로 결합시켜 구조적으로 안정한 펩타이드 치료제를 제조하기 위한 방법의 개발이 필요하다.Therefore, specific absorption enhancers for teriparatide peptides were searched for by searching for positively charged substances that can increase the absorption efficiency of therapeutic agents by binding with the negatively charged amino acids of teriparatide, and solubilizers and buffers that can impart structural stability. , it is necessary to develop a method for preparing a structurally stable peptide therapeutic agent by selectively binding them.
이에, 본 발명자들은 상기 종래기술들의 문제점들을 극복하기 위하여 예의 연구노력한 결과, 담즙산 수송체에 특이적, 선택적으로 결합하여 약물의 흡수율을 증가시킬 수 있는 음이온성 담즙산 및 양이온성 담즙산 유도체를 테리파라타이드와 혼합하여 이온결합 복합체를 제조할 경우 경구용 약물의 흡수 효율을 증가시킬 수 있으며, 테리파라타이드에 음이온성 담즙산과 양이온성 담즙산 유도체를 결합시켜 이온결합 복합체를 제조함에 있어 완충제를 이용할 경우, 음전하를 띄는 담즙산과 양전하를 띄는 담즙산 유도체 사이의 이온결합 형성을 억제함으로써 안정한 구조를 갖는 이온결합 복합체를 제조할 수 있을 뿐만 아니라 용해제로서 디-알파-토코페롤 폴리에틸렌 글리콜 1000 석시네이트(D-α-tocopherol polyethylene glycol 1000 succinate; TPGS)를 이용할 경우 테리파라타이드의 흡수 효율을 증가시킬 수 있음을 확인하고, 본 발명을 완성하게 되었다.Accordingly, as a result of intensive research efforts to overcome the problems of the prior art, the present inventors have developed anionic bile acids and cationic bile acid derivatives capable of increasing drug absorption by specifically and selectively binding to bile acid transporters, teriparatide. The absorption efficiency of oral drugs can be increased when an ionic complex is prepared by mixing with By inhibiting the formation of ionic bonds between bile acids and positively charged bile acid derivatives, it is possible to prepare an ionic complex with a stable structure, and as a dissolving agent, di-alpha-tocopherol polyethylene glycol 1000 succinate (D-α-tocopherol polyethylene glycol) When using glycol 1000 succinate; TPGS), it was confirmed that the absorption efficiency of teriparatide could be increased, and the present invention was completed.
따라서, 본 발명의 주된 목적은 테리파라타이드(teriparatide)의 장관막 투과도 및 경구 투여 생체이용률을 증가시키고, 환자의 순응도를 개선 시킬 수 있는 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체를 혼합하여 이온결합 복합체를 제조하는 단계를 포함하는 경구용 약학 조성물의 제조방법을 제공하는 데 있다.Therefore, the main object of the present invention is to increase intestinal membrane permeability and oral administration bioavailability of teriparatide, and to improve patient compliance by mixing teriparatide, anionic bile acid and cationic bile acid derivatives. An object of the present invention is to provide a method for preparing an oral pharmaceutical composition comprising the step of preparing an ion-binding complex.
본 발명의 다른 목적은 상기 경구용 약학 조성물의 제조방법을 이용한 경구용 약학 조성물을 제공하는 데 있다.Another object of the present invention is to provide an oral pharmaceutical composition using the method for preparing the oral pharmaceutical composition.
본 발명의 한 양태에 따르면, 본 발명은 테리파라타이드(teriparatide), 음이온성 담즙산 및 양이온성 담즙산 유도체를 혼합하여 이온결합 복합체를 제조하는 단계를 포함하는 경구용 약학 조성물의 제조방법을 제공한다.According to one aspect of the present invention, there is provided a method for preparing an oral pharmaceutical composition comprising preparing an ionic complex by mixing teriparatide, an anionic bile acid and a cationic bile acid derivative.
테리파라타이드는 골다공증 치료에 사용되는 약물로서, 일반적으로 하루에 한 번 복부, 허벅지 또는 팔뚝에 피하주사 하는 형태로 투여되고 있다. 그러나 이러한 피하주사 방식은 환자에게 통증을 유발하고 환자들이 올바른 주사 방법을 습득해야 하는 불편함을 수반한다. 이에, 본 발명자들은 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체를 혼합하여 이온결합 복합체를 제조하고 이를 경구용 약학 조성물로 이용할 경우, 환자의 복용 순응도를 개선함과 동시에 경구투여를 통한 약물의 장관막 투과도 및 생체이용률을 증가시킬 수 있음을 확인하고, 본 발명을 완성하게 되었다.Teriparatide is a drug used for the treatment of osteoporosis, and is generally administered in the form of subcutaneous injection into the abdomen, thigh, or forearm once a day. However, this method of subcutaneous injection causes pain to the patient and is accompanied by inconvenience in that the patient must learn the correct injection method. Accordingly, the present inventors prepared an ionic complex by mixing teriparatide, anionic bile acid and cationic bile acid derivative and used it as an oral pharmaceutical composition, improving patient compliance and simultaneously administering the drug through oral administration. It was confirmed that the intestinal membrane permeability and bioavailability could be increased, and the present invention was completed.
본 발명에 따른 상기 용어 '음이온성 담즙산'은 테리파라타이드의 펩타이드를 구성하는 아미노산 서열 중 양전하를 띄는 아미노산과 결합 가능한 음전하를 띄는 담즙산을 의미한다. 본 발명에 따른 용어 '양이온성 담즙산 유도체'는 음전하를 띄는 담즙산에 양전하를 띄는 아미노산이 결합된 것으로, 테리파라타이드의 펩타이드를 구성하는 아미노산 서열 중 음전하를 띄는 아미노산과 결합 가능한 양전하를 띄는 담즙산 유도체를 의미한다. 본 발명에서는 음이온성 담즙산인 데옥시콜산(deoxycholic acid)에 양전하를 띄는 라이신을 화학적으로 결합시켜 제조한 Nα-deoxycholyl-L-lysyl-methylester(DCK)와 DCK의 라이신을 아르기닌(Arginin)으로 치환한 Nα-deoxycholyl-L-arginyl-methylester (DCR)을 양이온성 담즙산 유도체로 이용하였다.The term 'anionic bile acid' according to the present invention refers to a bile acid having a negative charge capable of binding to an amino acid having a positive charge in the amino acid sequence constituting the peptide of teriparatide. The term 'cationic bile acid derivative' according to the present invention refers to a bile acid derivative having a positive charge in which an amino acid having a positive charge is bound to a bile acid having a negative charge, and a bile acid derivative having a positive charge capable of binding to an amino acid having a negative charge in the amino acid sequence constituting the peptide of teriparatide. it means. In the present invention, N α -deoxychoyl-L-lysyl-methylester (DCK) prepared by chemically combining positively charged lysine with deoxycholic acid, an anionic bile acid, and lysine of DCK are substituted with arginine One N α -deoxychoyl-L-arginyl-methylester (DCR) was used as a cationic bile acid derivative.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 제조방법은 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체를 동시에 혼합할 수 있으나, 바람직하게는 음이온 담즙산 및 양이온성 담즙산 유도체를 분리하여 혼합할 수 있으며, 더욱 바람직하게는 테리파라타이드 및 양이온성 담즙산 유도체를 혼합한 후에 음이온성 담즙산을 혼합하거나, 테리파라타이드 및 음이온성 담즙산을 혼합한 후에 양이온성 담즙산 유도체를 혼합하는 것을 특징으로 한다.In the preparation method of the pharmaceutical composition for oral use of the present invention, teriparatide, an anionic bile acid and a cationic bile acid derivative may be mixed simultaneously, but preferably, an anionic bile acid and a cationic bile acid derivative are separated and mixed. More preferably, it is characterized in that the anionic bile acid is mixed after teriparatide and the cationic bile acid derivative are mixed, or the cationic bile acid derivative is mixed after teriparatide and the anionic bile acid are mixed.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 제조방법은 용해제 및 완충제를 첨가하는 단계를 더 포함하는 것을 특징으로 한다.In the preparation method of the oral pharmaceutical composition of the present invention, the preparation method is characterized in that it further comprises the step of adding a solubilizing agent and a buffer.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 제조방법은 테리파라타이드, 용해제 및 정제수를 혼합하여 제1 혼합물을 제조하는 제1 단계, 상기 제1 혼합물에 양이온성 담즙산 유도체를 첨가하여 제2 혼합물을 제조하는 제2 단계, 상기 제2 혼합물에 완충제를 첨가하여 제3 혼합물을 제조하는 제3 단계, 및 상기 제3 혼합물에 음이온성 담즙산을 첨가하여 이온결합 복합체를 제조하는 제4 단계를 포함하는 것을 특징으로 한다.In the preparation method of the pharmaceutical composition for oral use of the present invention, the preparation method comprises a first step of preparing a first mixture by mixing teriparatide, a solubilizer and purified water, and a cationic bile acid derivative added to the first mixture. 2 A second step of preparing a mixture, a third step of preparing a third mixture by adding a buffer to the second mixture, and a fourth step of preparing an ionic complex by adding an anionic bile acid to the third mixture characterized by including.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 제조방법은 테리파라타이드, 용해제 및 정제수를 혼합하여 제1 혼합물을 제조하는 제1 단계, 상기 제1 혼합물에 음이온성 담즙산을 첨가하여 제2 혼합물을 제조하는 제2 단계, 상기 제2 혼합물에 완충제를 첨가하여 제3 혼합물을 제조하는 제3 단계, 및 상기 제3 혼합물에 양이온성 담즙산 유도체를 첨가하여 이온결합 복합체를 제조하는 제4 단계를 포함하는 것을 특징으로 한다.In the preparation method of the pharmaceutical composition for oral use of the present invention, the preparation method comprises a first step of preparing a first mixture by mixing teriparatide, a solubilizer and purified water, and a second step by adding an anionic bile acid to the first mixture. A second step of preparing a mixture, a third step of preparing a third mixture by adding a buffer to the second mixture, and a fourth step of preparing an ionic complex by adding a cationic bile acid derivative to the third mixture characterized by including.
골다공증 치료제인 테리파라타이드는 양쪽성 펩타이드이기 때문에 음전하를 띄는 음이온성 담즙산 및 양전하를 띄는 양이온성 담즙산 유도체와 이온결합이 가능하다. 이에 따라 테리파라타이드에 음전하를 띄는 음이온성 담즙산 및 양전하를 띄는 양이온성 담즙산 유도체를 모두 결합시킨다면 테리파라타이드 한 분자당 이온결합 되는 음이온성 담즙산 및 양이온성 담즙산 유도체의 수가 증가되어 약물의 흡수 효율을 더 증가시킬 수 있다. 그러나 음이온성 담즙산과 양이온성 담즙산 유도체는 서로 반대되는 전하를 가지고 있기 때문에 조성물을 혼합하는 과정에서 테리파라타이드에 이온결합 되기 전에 두 담즙산이 먼저 이온결합을 하게 되고, 이에 따라 응집 및 침전이 발생하게 된다. 따라서 테리파라타이드와 음이온성 담즙산 및 양이온성 담즙산 유도체 간의 이온결합을 통한 안정적인 구조를 갖는 이온결합 복합체를 제조하기 위해서는 음이온성 담즙산과 양이온성 담즙산 유도체의 이온결합 형성을 억제하는 것이 중요하다. 그뿐만 아니라, 특정 약물에 특이적으로 현저한 효과를 나타낼 수 있는 용해제를 선택하여 약물의 가용화, 흡수 및 침투 효과를 증가시키는 것 또한 중요하다. 이에, 본 발명에서는 테리파라타이드에 특이적으로 작용하여 현저한 효과를 나타낼 수 있는 TPGS에 용해된 테리파라타이드에 양이온성 담즙산 유도체를 먼저 결합시킨 후 완충제를 첨가하여 결합된 양이온성 담즙산 유도체의 양전하성 강도를 저하시킴으로써 음이온성 담즙산을 첨가하였을 때 음이온성 담즙산이 양이온성 담즙산 유도체와는 이온결합하지 않고 테리파라타이드와 이온결합 하도록 하여 안정한 구조를 갖는 이온결합 복합체를 형성하도록 하였다.Since teriparatide, a treatment for osteoporosis, is an amphoteric peptide, it is capable of ionic bonding with negatively charged anionic bile acids and positively charged cationic bile acid derivatives. Accordingly, if teriparatide is combined with both negatively charged anionic bile acids and positively charged cationic bile acid derivatives, the number of ionically bound anionic bile acids and cationic bile acid derivatives per molecule of teriparatide increases, thereby improving drug absorption efficiency. can be increased further. However, since the anionic bile acid and the cationic bile acid derivative have opposite charges, the two bile acids first ionic bond before they are ionically bound to teriparatide in the process of mixing the composition, thereby causing aggregation and precipitation. do. Therefore, in order to prepare an ionic complex having a stable structure through ionic bonding between teriparatide and anionic bile acid and cationic bile acid derivative, it is important to inhibit the formation of ionic bond between anionic bile acid and cationic bile acid derivative. Not only that, it is also important to select a solubilizing agent that can specifically show a significant effect on a particular drug to increase the solubilization, absorption and penetration effect of the drug. Accordingly, in the present invention, a cationic bile acid derivative is first bound to teriparatide dissolved in TPGS, which can exert a remarkable effect by acting specifically on teriparatide, and then a buffer is added to the positive charge of the bound cationic bile acid derivative. By lowering the strength, when anionic bile acid was added, the anionic bile acid did not ionically bond with the cationic bile acid derivative, but ionically binds with teriparatide to form an ionic complex with a stable structure.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 음이온성 담즙산은 담즙산 수송체에 특이적, 선택적으로 결합하여 약물의 흡수 효율을 증가시키기 위해 이용된 어떠한 담즙산도 이용가능하며, 바람직하게는 타우로리토콜산(taurolithocholic acid), 데옥시콜산(deoxycholic acid), 타우로데옥시콜산(taurodeoxycholic acid), 케노데옥시콜산(chenodeoxycholic acid), 타우로케노데옥시콜산(taurochenodeoxycholic acid), 콜산(cholic acid) 및 타우로콜산(taurocholic acid)으로 구성된 군에서 선택되는 하나 이상일 수 있으며, 더욱 바람직하게는 데옥시콜산, 케노데옥시콜산 및 타우로케노데옥시콜산로 구성된 군에서 선택되는 하나 이상인 것을 특징으로 한다. 또한, 상기 음이온성 담즙산은 담즙산의 알칼리 금속염인 담즙산염일 수 있으며, 바람직하게는 타우로리토콜산 나트륨, 데옥시콜산 나트륨, 타우로데옥시콜산 나트륨, 케노데옥시콜산 나트륨, 타우로케노데옥시콜산 나트륨, 콜산 나트륨 및 타우로콜산 나트륨으로 구성된 군에서 선택되는 하나 이상일 수 있다.In the method for preparing the pharmaceutical composition for oral use of the present invention, any bile acid used for the anionic bile acid to specifically and selectively bind to a bile acid transporter to increase drug absorption efficiency may be used, preferably tau. taurolithocholic acid, deoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, taurochenodeoxycholic acid, cholic acid And it may be at least one selected from the group consisting of taurocholic acid, and more preferably, it is characterized in that at least one selected from the group consisting of deoxycholic acid, chenodeoxycholic acid and taurochenodeoxycholic acid. In addition, the anionic bile acid may be a bile salt, which is an alkali metal salt of a bile acid, preferably sodium taurolithocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate. , it may be at least one selected from the group consisting of sodium cholate and sodium taurocholate.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 양이온성 담즙산 유도체는 테리파라타이드의 펩타이드를 구성하는 아미노산 서열 중 음전하를 띄는 아미노산과 결합시키기 위하여 음전하를 띄는 음이온성 담즙산에 양전하를 띄는 아미노산을 화학적으로 결합시킨 어떠한 담즙산 유도체도 이용가능하며, 바람직하게는 음이온성 담즙산에 라이신(Lysine) 또는 아르기닌(Arginin)이 결합된 담즙산 유도체인 것을 특징으로 한다.In the preparation method of the oral pharmaceutical composition of the present invention, the cationic bile acid derivative is a negatively charged anionic bile acid in order to bind to the negatively charged amino acid in the amino acid sequence constituting the peptide of teriparatide. Any bile acid derivative chemically bound can be used, and it is preferably characterized in that it is a bile acid derivative in which lysine or arginine is bound to an anionic bile acid.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 용해제는 약물 전달 시스템에서 약물의 가용화, 흡수 및 침투 효과를 증가시키기 위해 이용된 어떠한 용해제도 이용가능하며, 바람직하게는 디-알파-토코페롤 폴리에틸렌 글리콜 1000 석시네이트(D-α-tocopherol polyethylene glycol 1000 succinate)인 것을 특징으로 한다. 또한, 상기 완충제는 음이온성 담즙산과 양이온성 담즙산 유도체의 결합을 억제하기 위하여 양이온성 담즙산 유도체의 양전하성을 저하시킬 수 있는 어떠한 완충제도 이용가능하나, 바람직하게는 구연산(Citric acid), 인산나트륨(Sodium Phosphate), 탄산암모늄(Ammonium carbonate), 인산칼륨(Potassium phosphate) 및 아세트산(acetic acid)으로 구성된 군에서 선택되는 하나 이상일 수 있다.In the preparation method of the oral pharmaceutical composition of the present invention, the solubilizing agent may be any solubilizing agent used to increase the solubilization, absorption and penetration effect of the drug in the drug delivery system, preferably di-alpha-tocopherol polyethylene It is characterized in that it is glycol 1000 succinate (D-α-tocopherol polyethylene glycol 1000 succinate). In addition, as the buffer, any buffer capable of lowering the positive charge of the cationic bile acid derivative to inhibit the binding of the anionic bile acid to the cationic bile acid derivative may be used, but preferably citric acid, sodium phosphate ( Sodium Phosphate), ammonium carbonate (Ammonium carbonate), potassium phosphate (Potassium phosphate) and may be at least one selected from the group consisting of acetic acid (acetic acid).
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 테리파라타이드는 약학 조성물 총 중량 대비 0.1 내지 50중량% 포함될 수 있으며, 바람직하게는 0.1 내지 40 중량%, 더욱 바람직하게는 0.1 내지 20중량% 포함되는 것을 특징으로 한다. 상기 테리파라타이드의 함량이 0.1 중량% 미만일 경우 치료 효과가 미미할 수 있으며, 50 중량% 초과할 경우 테리파라타이드의 함량이 음이온성 담즙산 및 양이온성 담즙산 유도체보다 높아 이온결합 복합체가 충분히 이루어지기 어려워 담즙산 유도체를 통한 장관막의 투과도 증진 효과를 기대하기 어렵다.In the method for preparing the oral pharmaceutical composition of the present invention, the teriparatide may be included in an amount of 0.1 to 50% by weight, preferably 0.1 to 40% by weight, more preferably 0.1 to 20% by weight, based on the total weight of the pharmaceutical composition. characterized in that it is included. When the content of teriparatide is less than 0.1% by weight, the therapeutic effect may be insignificant. When the content of teriparatide exceeds 50% by weight, the content of teriparatide is higher than that of anionic bile acids and cationic bile acid derivatives. It is difficult to expect the effect of enhancing the permeability of the intestinal membrane through the derivative.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 음이온 담즙산은 테리파라타이드 1몰 대비 1 내지 20몰로 포함될 수 있으며, 바람직하게는 1 내지 15몰, 더욱 바람직하게는 1 내지 10몰로 포함되는 것을 특징으로 한다. 상기 음이온성 담즙산이 1몰 미만으로 포함될 경우 이온결합 복합체를 형성하지 않아 투과도의 증가가 이루어지지 않는 문제점이 발생할 수 있으며, 20몰을 초과할 경우 테리파라타이드 이외에 DCK와 음이온성 담즙산의 이온결합 가능성 때문에 이온결합 효율성의 문제점이 발생할 수 있다.In the method for preparing the oral pharmaceutical composition of the present invention, the anionic bile acid may be included in 1 to 20 moles relative to 1 mole of teriparatide, preferably 1 to 15 moles, more preferably 1 to 10 moles. characterized. When the anionic bile acid is contained in an amount of less than 1 mole, there may be a problem that the permeability is not increased because an ionic bond complex is not formed. Therefore, a problem of ionic bonding efficiency may occur.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 양이온 담즙산 유도체는 테리파라타이드 1몰 대비 0.1 내지 10몰로 포함될 수 있으며, 바람직하게는 0.1 내지 5몰, 더욱 바람직하게는 0.1 내지 2몰로 포함되는 것을 특징으로 한다. 상기 양이온성 담즙산 유도체가 0.1몰 미만으로 포함될 경우 이온결합 복합체를 형성하지 않아 투과도의 증가가 이루어지지 않는 문제점이 발생할 수 있으며, 10몰을 초과할 경우 자체적으로 큰 파티클이 조립되어 용해도의 증가와 함께 투과도를 방해하는 문제점이 발생할 수 있다.In the method for preparing the oral pharmaceutical composition of the present invention, the cationic bile acid derivative may be included in an amount of 0.1 to 10 moles relative to 1 mole of teriparatide, preferably 0.1 to 5 moles, more preferably 0.1 to 2 moles. characterized in that When the amount of the cationic bile acid derivative is less than 0.1 mol, it does not form an ionic complex and thus the permeability is not increased. A problem that interferes with the transmittance may occur.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 약학 조성물은 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체를 1:1:1 내지 1:5:10 몰비로 포함할 수 있으며, 더욱 바람직하게는 1:4:8 몰비로 포함되는 것을 특징으로 한다. 상기 범위를 벗어날 경우, 혼합체의 침전이 발생하여 경구용 약학 조성물의 제조에 바람직하지 못하다.In the method for preparing an oral pharmaceutical composition of the present invention, the pharmaceutical composition may include teriparatide, anionic bile acid and cationic bile acid derivative in a molar ratio of 1:1:1 to 1:5:10, more preferably It is characterized in that it is included in a molar ratio of 1:4:8. When it is out of the above range, precipitation of the mixture occurs, which is not preferable for the preparation of an oral pharmaceutical composition.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 용해제는 테리파라타이드 1 중량부에 대하여, 0.1 내지 100 중량부로 포함될 수 있으며, 바람직하게는 0.1 내지 80 중량부, 더욱 바람직하게는 1 내지 70중량부로 포함되는 것을 특징으로 한다.In the method for preparing the oral pharmaceutical composition of the present invention, the solubilizing agent may be included in an amount of 0.1 to 100 parts by weight, preferably 0.1 to 80 parts by weight, more preferably 1 to 70 parts by weight based on 1 part by weight of teriparatide. It is characterized in that it is included in parts by weight.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 완충제는 조성물 총 중량 대비 0.1 내지 5 중량%로 포함될 수 있으며, 바람직하게는 1 내지 4 중량%, 더욱 바람직하게는 1 내지 3 중량%로 포함되는 것을 특징으로 한다. 상기 완충제가 0.1 중량% 미만으로 포함될 경우 담즙산과 테리파라타이드의 결합이 불안정하여 약물 효능(BA)이 감소하는 문제점이 발생할 수 있으며, 5 중량%를 초과할 경우 증량에 대한 효과가 크지 않는 문제점이 발생할 수 있다.In the method for preparing the oral pharmaceutical composition of the present invention, the buffer may be included in an amount of 0.1 to 5% by weight, preferably 1 to 4% by weight, more preferably 1 to 3% by weight relative to the total weight of the composition. characterized by being When the buffer is included in an amount of less than 0.1% by weight, the binding between bile acid and teriparatide is unstable, so that the drug efficacy (BA) may decrease, and if it exceeds 5% by weight, the effect on the increase is not large. can occur
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 제조방법은 제조된 이온결합 복합체에 제산제, 윤활유 및 바인더를 혼합하여 과립을 제조한 후, 정제의 형태로 압착하여 코팅하는 단계를 더 포함하는 것을 특징으로 한다.In the preparation method of the oral pharmaceutical composition of the present invention, the preparation method further comprises the step of preparing granules by mixing an antacid, a lubricant and a binder with the prepared ionic bond complex, and then compressing and coating the granules in the form of tablets characterized in that
본 발명의 다른 한 양태에 따르면, 본 발명은 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체로 이루어진 이온결합 복합체를 포함하는 경구용 약학 조성물을 제공한다.According to another aspect of the present invention, there is provided an oral pharmaceutical composition comprising an ionic complex comprising teriparatide, an anionic bile acid and a cationic bile acid derivative.
본 발명의 경구용 약학 조성물에 있어서, 상기 이온결합 복합체는 용해제 및 완충제를 더 포함하는 것을 특징으로 한다.In the oral pharmaceutical composition of the present invention, the ion-binding complex is characterized in that it further comprises a solubilizing agent and a buffer.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 음이온성 담즙산은 담즙산 수송체에 특이적, 선택적으로 결합하여 약물의 흡수 효율을 증가시키기 위해 이용된 어떠한 담즙산도 이용가능하며, 바람직하게는 타우로리토콜산(taurolithocholic acid), 데옥시콜산(deoxycholic acid), 타우로데옥시콜산(taurodeoxycholic acid), 케노데옥시콜산(chenodeoxycholic acid), 타우로케노데시콜산(taurochenodeoxycholic acid), 콜산(cholic acid) 및 타우로콜산(taurocholic acid)으로 구성된 군에서 선택되는 하나 이상일 수 있으며, 더욱 바람직하게는 데옥시콜산, 케노데옥시콜산 및 타우로케노데옥시콜산로 구성된 군에서 선택되는 하나 이상인 것을 특징으로 한다. 또한, 상기 음이온성 담즙산은 담즙산의 알칼리 금속염인 담즙산염일 수 있으며, 바람직하게는 타우로리토콜산 나트륨, 데옥시콜산 나트륨, 타우로데옥시콜산 나트륨, 케노데옥시콜산 나트륨, 타우로케노데옥시콜산 나트륨, 콜산 나트륨 및 타우로콜산 나트륨으로 구성된 군에서 선택되는 하나 이상일 수 있다.In the method for preparing the pharmaceutical composition for oral use of the present invention, any bile acid used for the anionic bile acid to specifically and selectively bind to a bile acid transporter to increase drug absorption efficiency may be used, preferably tau. taurolithocholic acid, deoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, taurochenodeoxycholic acid, cholic acid And it may be at least one selected from the group consisting of taurocholic acid, and more preferably, it is characterized in that at least one selected from the group consisting of deoxycholic acid, chenodeoxycholic acid and taurochenodeoxycholic acid. In addition, the anionic bile acid may be a bile salt, which is an alkali metal salt of a bile acid, preferably sodium taurolithocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate. , it may be at least one selected from the group consisting of sodium cholate and sodium taurocholate.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 양이온성 담즙산 유도체는 테리파라타이드의 펩타이드를 구성하는 아미노산 서열 중 음전하를 띄는 아미노산과 결합시키기 위하여 음전하를 띄는 음이온성 담즙산에 양전하를 띄는 아미노산을 화학적으로 결합시킨 어떠한 담즙산 유도체도 이용가능하며, 바람직하게는 음이온성 담즙산에 라이신(Lysine) 또는 아르기닌(Arginin)이 결합된 담즙산 유도체인 것을 특징으로 한다.In the preparation method of the oral pharmaceutical composition of the present invention, the cationic bile acid derivative is a negatively charged anionic bile acid in order to bind to the negatively charged amino acid in the amino acid sequence constituting the peptide of teriparatide. Any bile acid derivative chemically bound can be used, and it is preferably characterized in that it is a bile acid derivative in which lysine or arginine is bound to an anionic bile acid.
본 발명의 경구용 약학 조성물의 제조방법에 있어서, 상기 용해제는 약물 전달 시스템에서 약물의 가용화, 흡수 및 침투 효과를 증가시키기 위해 이용된 어떠한 용해제도 이용가능하며, 바람직하게는 디-알파-토코페롤 폴리에틸렌 글리콜 1000 석시네이트(D-α-tocopherol polyethylene glycol 1000 succinate)인 것을 특징으로 한다. 또한, 상기 완충제는 음이온성 담즙산과 양이온성 담즙산 유도체의 결합을 억제하기 위하여 양이온성 담즙산 유도체의 양전하성을 저하시킬 수 있는 어떠한 완충제도 이용가능하나, 바람직하게는 구연산(Citric acid), 인산나트륨(Sodium Phosphate), 탄산암모늄(Ammonium carbonate), 인산칼륨(Potassium phosphate) 및 아세트산(acetic acid)으로 구성된 군에서 선택되는 하나 이상일 수 있다.In the preparation method of the oral pharmaceutical composition of the present invention, the solubilizing agent may be any solubilizing agent used to increase the solubilization, absorption and penetration effect of the drug in the drug delivery system, preferably di-alpha-tocopherol polyethylene It is characterized in that it is glycol 1000 succinate (D-α-tocopherol polyethylene glycol 1000 succinate). In addition, as the buffer, any buffer capable of lowering the positive charge of the cationic bile acid derivative to inhibit the binding of the anionic bile acid to the cationic bile acid derivative may be used, but preferably citric acid, sodium phosphate ( Sodium Phosphate), ammonium carbonate (Ammonium carbonate), potassium phosphate (Potassium phosphate) and may be at least one selected from the group consisting of acetic acid (acetic acid).
본 발명의 일 실험예에 따르면, 테리파라타이드, 음이온성 담즙산, 양이온성 담즙산 유도체 및 용해제를 이용하여 본 발명의 제조방법에 따라 제조된 이온결합 복합체(실시예 1 내지 6)의 경우, 테리파라타이드 단독(비교예 2) 및 테리파라타이드, 양이온성 담즙산 유도체 복합체(비교예 3)보다 생체이용률이 더 향상된 것을 확인하였다. 이러한 결과는, 양이온성 담즙산 유도체뿐만 아니라 음이온성 담즙산을 함께 포함할 경우, 테리파라타이드와 더 많은 이온결합이 이루어지기 때문에 생체이용률을 현저히 향상시킬 수 있으므로, 테리파라타이드를 포함하는 경구용 약학 조성물에서 테리파라타이드의 생체이용률을 증가시키기 위해서는 음이온 담즙산과 양이온성 담즙산 유도체를 모두 포함하는 것이 적합함을 시사한다(실험예 1 참조).According to an experimental example of the present invention, in the case of the ionic binding complexes (Examples 1 to 6) prepared according to the preparation method of the present invention using teriparatide, anionic bile acid, a cationic bile acid derivative and a solubilizing agent, teripara It was confirmed that the bioavailability was more improved than that of Tide alone (Comparative Example 2) and teriparatide and the cationic bile acid derivative complex (Comparative Example 3). According to these results, when the cationic bile acid derivative as well as the anionic bile acid are included, the bioavailability can be significantly improved because more ionic bonds are formed with teriparatide, and thus the oral pharmaceutical composition containing teriparatide In order to increase the bioavailability of teriparatide, it suggests that it is suitable to include both anionic bile acids and cationic bile acid derivatives (see Experimental Example 1).
전술한 바와 같이, 테리파라타이드를 음이온성 담즙산 및 양이온성 담즙산 유도체를 이용하여 이온결합 복합체를 제조할 경우, 상기 제조된 이온결합 복합체를 포함하는 경구용 약학 조성물의 장관막 투과도 및 생체이용률을 향상시킬 수 있으며, 환자의 순응도를 개선할 수 있다. As described above, when teriparatide is used as an anionic bile acid and a cationic bile acid derivative to prepare an ionic complex, the intestinal membrane permeability and bioavailability of the oral pharmaceutical composition comprising the prepared ionic complex are improved. and can improve patient compliance.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하기로 한다. 이들 실시예는 단지 본 발명을 예시하기 위한 것이므로, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and therefore, the scope of the present invention is not to be construed as being limited by these examples.
제조예production example 1: One: 데옥시콜산deoxycholic acid 유도체의 제조 (1) Preparation of derivatives (1)
데옥시콜산(deoxycholic acid) 유도체는 데옥시콜산에 양전하를 띄는 라이신을 화학적으로 결합시킴으로써 제조하였다. 먼저, 26g의 데옥시콜산을 800mL의 테트라히드로푸란(tetrahydrofuran)에 용해시킨다. 별도로 20g의 H-Lys(Boc)-OMe·HCl을 N-메틸모포린(N-methyl morpholine) 7.4mL 및 에틸클로로포르메이트(ethyl chloroformate) 6.4mL의 혼합 용매에 용해시킨다. 상기 데옥시콜산 용액에 H-Lys(Boc)-OMe·HCl 용액을 첨가한 후 30분간 교반한 다음 2시간 동안 환류시킨다. 상온에서 밤새 교반하여 얻어진 반응 침전물을 여과한 다음 잔여 용매를 증발시킨다. 건조한 침전물을 클로로포름(chloroform)과 메탄올(methanol)을 이용하여 컬럼 크로마토그래피를 통해 정제한 다음 냉각수조(ich batch)에서 염화아세틸(acetyl chloride)과 메탄올(methanol)의 혼합용매에 용해시킨다. 용매를 제거한 후 잔류물을 다시 물에 용해하고 클로로포름(chloroform)으로 3회 세척한 다음 수층을 취해 동결건조하여 데옥시콜산 유도체인 Nα-deoxycholyl-L-lysyl-methylester(DCK)를 제조하였다.Deoxycholic acid derivatives were prepared by chemically binding lysine having a positive charge to deoxycholic acid. First, 26 g of deoxycholic acid is dissolved in 800 mL of tetrahydrofuran. Separately, 20 g of H-Lys(Boc)-OMe·HCl is dissolved in a mixed solvent of 7.4 mL of N-methyl morpholine and 6.4 mL of ethyl chloroformate. H-Lys(Boc)-OMe.HCl solution was added to the deoxycholic acid solution, stirred for 30 minutes, and then refluxed for 2 hours. The reaction precipitate obtained by stirring at room temperature overnight was filtered, and then the residual solvent was evaporated. The dried precipitate is purified through column chromatography using chloroform and methanol, and then dissolved in a mixed solvent of acetyl chloride and methanol in a cooling water bath (ich batch). After removing the solvent, the residue was dissolved in water again, washed with chloroform three times, and the aqueous layer was taken and lyophilized to prepare N α -deoxychoyl-L-lysyl-methylester (DCK), a deoxycholic acid derivative.
제조예production example 2: 2: 데옥시콜산deoxycholic acid 유도체의 제조 (2) Preparation of derivatives (2)
Nα-deoxycholyl-L-lysyl-methylester(DCK) 2g을 메탄올(MeOH) 20ml에 용해한다. 이어서 N,N-디이소프로필에틸아민(DIPEA) 2.44ml를 가하고 실온에서 5분 동안 교반한다. 트리아졸-구아니딘(Triazole-guanidine) 0.775g을 투입하고 실온에서 1시간 동안 교반한다. 반응 완결 후 감압농축한다. 오일 타입의 혼합물을 메틴올(MeOH) 3ml에 용해 시킨 후 아세토니트릴(Acetonitrile) 300ml에 30분 동안 천천히 적가하여 분산시켜 고체상태의 물질을 생성한다. 상온에서 1시간동안 교반 후 여과한다. 얻어진 고체를 동결건조기 -65℃에서 3시간 동안 건조시켜 목적 화합물인 Nα-deoxycholyl-L-arginyl-methylester(DCR) 1.64g을 얻었다.Dissolve 2 g of N α -deoxycholyl-L-lysyl-methylester (DCK) in 20 ml of methanol (MeOH). Then, 2.44 ml of N,N-diisopropylethylamine (DIPEA) was added and stirred at room temperature for 5 minutes. Add 0.775 g of triazole-guanidine and stir at room temperature for 1 hour. After completion of the reaction, it was concentrated under reduced pressure. After dissolving the oil-type mixture in 3 ml of methylol (MeOH), it is slowly added dropwise to 300 ml of acetonitrile for 30 minutes and dispersed to produce a solid substance. After stirring at room temperature for 1 hour, it is filtered. The obtained solid was dried at -65°C in a freeze dryer for 3 hours to obtain 1.64 g of the target compound, N α -deoxycholyl-L-arginyl-methylester (DCR).
실시예Example 1 내지 6: 이온결합 복합체의 제조 1 to 6: Preparation of ionic complexes
정제수에 테리파라타이드와 용해제로서 디-알파-토코페롤 폴리에틸렌 글리콜 1000 석시네이트(D-α-tocopherol polyethylene glycol 1000 succinate; TPGS)를 용해시킨 후, 교반 하면서 별도로 제조한 양이온성 담즙산 수용액을 서서히 첨가하여 복합체 용액을 제조한다. 이때 테리파라타이드와 양이온성 담즙산의 몰비율이 1:2 또는 1:4가 되도록 양이온성 담즙산 수용액을 서서히 첨가한다. 이후 상기 복합체 용액을 교반하면서 별도로 제조한 음이온성 담즙산 수용액을 서서히 첨가하여 이온결합 복합체를 제조한다. 이때 테리파라타이드와 음이온성 담즙산의 몰비율이 1:4 또는 1:8이 되도록 음이온성 담즙산 수용액을 서서히 첨가한다. 최종 혼합액을 원심 분리한 후 동결건조하여 아래 표 1의 조성으로 분말상태의 테리파라타이드 이온결합 복합체를 제조하였다.After dissolving teriparatide and di-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) as a solubilizer in purified water, a separately prepared cationic bile acid aqueous solution was slowly added while stirring to obtain a complex. Prepare the solution. At this time, the cationic bile acid aqueous solution is slowly added so that the molar ratio of teriparatide and the cationic bile acid is 1:2 or 1:4. Then, while stirring the complex solution, a separately prepared anionic bile acid aqueous solution is slowly added to prepare an ionic complex. At this time, the anionic bile acid aqueous solution is slowly added so that the molar ratio of teriparatide and anionic bile acid is 1:4 or 1:8. The final mixture was centrifuged and then lyophilized to prepare a powdery teriparatide ion-binding complex with the composition shown in Table 1 below.
Lithocholic acid (LC)와 Chenodeoxycholic acid sodium salt (CDC)는 Tokyo Chemical Industry Co., Ltd.에서 구입하였고, Deoxycholic acid sodium salt (DC)는 BLD pharm에서, Taurochenodeoxycholic acid sodium salt (TCDC)는 Angel pharmatech에서 구입하였다.Lithocholic acid (LC) and Chenodeoxycholic acid sodium salt (CDC) were purchased from Tokyo Chemical Industry Co., Ltd., Deoxycholic acid sodium salt (DC) was purchased from BLD pharm, and Taurochenodeoxycholic acid sodium salt (TCDC) was purchased from Angel pharmatech. did
중량gun
weight
비교예comparative example 1 내지 3: 이온결합 복합체의 제조 1 to 3: Preparation of ionic complexes
비교예 1은 피하투여를 위하여 정제수에 테리파라타이드만 용해시킨 것으로, 생리식염수에 녹인 테리파라타이드 용액을 20㎍/kg로 투여하였다. 비교에 2는 공장 내 투여를 위하여 정제수에 테리파라타이드만 용해시킨 것으로, 정제수에 녹인 테리파라타이드 용액을 100㎍/kg로 투여하였다. 비교예 3은 정제수에 테리파라타이드를 용해시킨 후, 별도로 제조한 양이온성 담즙산 수용액을 서서히 첨가하여 복합체 용액을 제조하였다. 구체적인 조성 및 함량은 아래 표 2와 같다.In Comparative Example 1, only teriparatide was dissolved in purified water for subcutaneous administration, and a teriparatide solution dissolved in physiological saline was administered at 20 μg/kg. In Comparative 2, only teriparatide was dissolved in purified water for in-plant administration, and a teriparatide solution dissolved in purified water was administered at 100 μg/kg. In Comparative Example 3, after dissolving teriparatide in purified water, a separately prepared aqueous cationic bile acid solution was slowly added to prepare a complex solution. Specific composition and content are shown in Table 2 below.
실험예Experimental example 1: 경구 제제의 1: oral formulation 랫드rat 생체 이용률의 확인 Confirmation of bioavailability
암컷 Sprague-Dawley 랫드(200~250g, 6~7주령)에 케타민(ketamine, 45mg/kg)과 자일라진(xylazine, 5mg/kg)을 복강 내 주사하여 마취시킨 후, 랫드의 복부를 절개하여 소장을 꺼내고 상기에서 제조한 실시예 1 및 실시예 6과 비교예 2 및 비교예 3을 정제수에 분산시킨 다음 테리파라타이드 100 μg/kg에 해당하는 양을 400μL씩 근위 공장(proximal jejunum)에 주입하였다. 또한 상대적 생체이용률을 평가하기 위해 별도로 생리식염수에 녹인 테리파라타이드 용액 150μL를 테리파라타이드로서 20μg/kg에 해당하는 양을 피하주사(비교예 1) 하였다.Female Sprague-Dawley rats (200-250 g, 6-7 weeks old) were anesthetized by intraperitoneal injection of ketamine (45 mg/kg) and xylazine (5 mg/kg), After taking out and dispersing the Examples 1 and 6 and Comparative Examples 2 and 3 prepared above in purified water, an amount corresponding to 100 μg/kg of teriparatide was injected into the proximal jejunum by 400 μL. . In addition, in order to evaluate the relative bioavailability, 150 μL of a separately dissolved teriparatide solution in physiological saline was subcutaneously injected at an amount corresponding to 20 μg/kg as teriparatide (Comparative Example 1).
약물 투여 후, 일정 시간 간격으로 150μL씩 혈액 샘플을 채취하여 50μL의 3.8% 시트르산나트륨 수용액과 혼합하였다. 이후 혈액 시료를 2,500 xg, 4℃ 조건에서 15분 동안 원심분리한 후, 혈장을 취해 -70℃에 보관하였다. 혈장 중 테리파라타이드의 농도는 human PTH (1-34) ELISA kit(ALPCO Diagnostics, USA)를 사용해 620nm 파장에서 측정하였다. 약동학적 파라미터들은 WinNonlin® Software (ver. 5.3; Pharsight Corporation, USA)을 사용하여 non-compartment method를 통해 추정하여 표 3에 나타냈다.After drug administration, 150 μL of blood samples were collected at regular time intervals and mixed with 50 μL of 3.8% sodium citrate aqueous solution. Thereafter, the blood sample was centrifuged for 15 minutes at 2,500 xg, 4°C, and plasma was collected and stored at -70°C. The concentration of teriparatide in plasma was measured at a wavelength of 620 nm using the human PTH (1-34) ELISA kit (ALPCO Diagnostics, USA). Pharmacokinetic parameters were estimated through a non-compartment method using WinNonlin ® Software (ver. 5.3; Pharsight Corporation, USA) and shown in Table 3.
주사subcutaneously
injection
(mg/kg)Dosage
(mg/kg)
a Tmax, Cmax에 도달한 시간 a T max , time to reach C max
b Cmax, 최대혈장농도 b C max , maximum plasma concentration
c AUClast, 0에서 마지막 혈장농도 측정시간까지의 혈장농도-시간 곡선 아래 면적 c AUC last , the area under the plasma concentration-time curve from 0 to the time of the last plasma concentration measurement
d AUCinf, 0에서 무한대까지의 혈장농도-시간 곡선 아래 면적 d AUC inf , the area under the plasma concentration-time curve from 0 to infinity
f 생체이용률, (AUClast , 공장 내 투여/투여용량 테리파라타이드 , 공장 내 투여)/(AUClast , 피하주사/투여용량테리파라타이드, 피하주사) × 100 f Bioavailability, (AUC last , jejunum/dose teriparatide , jejunum)/(AUC last , subcutaneous injection /dose teriparatide, subcutaneous injection ) × 100
그 결과, 실시예들(1 내지 6)의 테리파라타이드, 음이온성 담즙산, 양이온성 담즙산 유도체 및 용해제를 이용하여 제조한 복합체를 투여한 경우, 테리파라타이드 단독(비교예 2) 또는 테리파라타이드 및 양이온성 담즙산 유도체(비교예 2)를 투여한 경우와 비교하였을 때, Cmax, AUClast, 및 생체이용률이 대부분 증가하였다.As a result, when the complex prepared using the teriparatide, anionic bile acid, cationic bile acid derivative and solubilizer of Examples (1 to 6) was administered, teriparatide alone (Comparative Example 2) or teriparatide And compared with the case of administering the cationic bile acid derivative (Comparative Example 2), C max , AUC last , and bioavailability were mostly increased.
Claims (23)
A method for preparing an oral pharmaceutical composition comprising preparing an ionic complex by mixing teriparatide, an anionic bile acid and a cationic bile acid derivative.
상기 제조방법은 테리파라타이드 및 양이온성 담즙산 유도체를 혼합한 후에 음이온성 담즙산을 혼합하는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The preparation method is a method for preparing an oral pharmaceutical composition, characterized in that the anionic bile acid is mixed after mixing teriparatide and the cationic bile acid derivative.
상기 제조방법은 테리파라타이드 및 음이온성 담즙산을 혼합한 후에 양이온성 담즙산 유도체를 혼합하는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The preparation method is a method for preparing an oral pharmaceutical composition, characterized in that the cationic bile acid derivative is mixed after mixing the teriparatide and the anionic bile acid.
상기 제조방법은 용해제 및 완충제를 첨가하는 단계를 더 포함하는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The method for preparing an oral pharmaceutical composition, characterized in that it further comprises the step of adding a solubilizing agent and a buffer.
상기 제조방법은,
테리파라타이드, 용해제 및 정제수를 혼합하여 제1 혼합물을 제조하는 제1 단계;
상기 제1 혼합물에 양이온성 담즙산 유도체를 첨가하여 제2 혼합물을 제조하는 제2 단계;
상기 제2 혼합물에 완충제를 첨가하여 제3 혼합물을 제조하는 제3 단계; 및
상기 제3 혼합물에 음이온성 담즙산을 첨가하여 이온결합 복합체를 제조하는 제4 단계; 를 포함하는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
5. The method of claim 4,
The manufacturing method is
A first step of preparing a first mixture by mixing teriparatide, a solubilizing agent and purified water;
a second step of preparing a second mixture by adding a cationic bile acid derivative to the first mixture;
a third step of preparing a third mixture by adding a buffer to the second mixture; and
a fourth step of preparing an ionic complex by adding an anionic bile acid to the third mixture; A method for preparing an oral pharmaceutical composition comprising a.
상기 제조방법은,
테리파라타이드, 용해제 및 정제수를 혼합하여 제1 혼합물을 제조하는 제1 단계;
상기 제1 혼합물에 음이온성 담즙산을 첨가하여 제2 혼합물을 제조하는 제2 단계;
상기 제2 혼합물에 완충제를 첨가하여 제3 혼합물을 제조하는 제3 단계; 및
상기 제3 혼합물에 양이온성 담즙산 유도체를 첨가하여 이온결합 복합체를 제조하는 제4 단계; 를 포함하는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
5. The method of claim 4,
The manufacturing method is
A first step of preparing a first mixture by mixing teriparatide, a solubilizing agent and purified water;
a second step of preparing a second mixture by adding an anionic bile acid to the first mixture;
a third step of preparing a third mixture by adding a buffer to the second mixture; and
a fourth step of preparing an ionic complex by adding a cationic bile acid derivative to the third mixture; A method for preparing an oral pharmaceutical composition comprising a.
상기 음이온성 담즙산은 타우로리토콜산(taurolithocholic acid), 데옥시콜산(deoxycholic acid), 타우로데옥시콜산(taurodeoxycholic acid), 케노데옥시콜산(chenodeoxycholic acid), 타우로 케노데옥시콜산(taurochenodeoxycholic acid), 콜산(cholic acid) 및 타우로콜산(taurocholic acid)으로 구성된 군에서 선택되는 하나 이상, 또는 그 염인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The anionic bile acids include taurolithocholic acid, deoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, and taurochenodeoxycholic acid. ), at least one selected from the group consisting of cholic acid and taurocholic acid, or a salt thereof.
상기 양이온성 담즙산 유도체는 음이온성 담즙산에 라이신(Lysine) 또는 아르기닌(Arginin)이 결합된 담즙산 유도체인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The cationic bile acid derivative is a bile acid derivative in which lysine or arginine is bound to an anionic bile acid.
상기 용해제는 디-알파-토코페롤 폴리에틸렌 글리콜 1000 석시네이트(D-α-tocopherol polyethylene glycol 1000 succinate)인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
5. The method of claim 4,
The dissolving agent is di-alpha-tocopherol polyethylene glycol 1000 succinate (D-α-tocopherol polyethylene glycol 1000 succinate), characterized in that the oral pharmaceutical composition preparation method.
상기 완충제는 구연산(Citric acid), 인산나트륨(Sodium Phosphate), 탄산암모늄(Ammonium carbonate), 인산칼륨(Potassium phosphate) 및 아세트산(acetic acid)으로 구성된 군에서 선택되는 하나 이상인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
5. The method of claim 4,
The buffer is citric acid, sodium phosphate (Sodium Phosphate), ammonium carbonate (Ammonium carbonate), potassium phosphate (Potassium phosphate) and acetic acid (acetic acid) Oral pharmaceutical, characterized in that at least one selected from the group consisting of A method for preparing the composition.
상기 테리파라타이드는 약학 조성물 총 중량 대비 0.1 내지 50중량% 포함되는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The method for producing a pharmaceutical composition for oral use, characterized in that the teriparatide is contained in an amount of 0.1 to 50% by weight based on the total weight of the pharmaceutical composition.
상기 음이온 담즙산은 테리파라타이드 1몰 대비 1 내지 20몰로 포함되는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The method for preparing an oral pharmaceutical composition, characterized in that the anionic bile acid is contained in an amount of 1 to 20 moles relative to 1 mole of teriparatide.
상기 양이온 담즙산 유도체는 테리파라타이드 1몰 대비 0.1 내지 10몰로 포함되는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The method for preparing an oral pharmaceutical composition, characterized in that the cationic bile acid derivative is contained in an amount of 0.1 to 10 moles relative to 1 mole of teriparatide.
상기 약학 조성물은 테리파라타이드, 음이온성 담즙산 및 양이온성 담즙산 유도체를 1:1:1 내지 1:5:10 몰비로 포함하는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The pharmaceutical composition comprises teriparatide, an anionic bile acid and a cationic bile acid derivative in a molar ratio of 1:1:1 to 1:5:10.
상기 용해제는 테리파라타이드 1 중량부에 대하여, 0.1 내지 100 중량부로 포함되는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
5. The method of claim 4,
The solubilizing agent is based on 1 part by weight of teriparatide, the method for producing a pharmaceutical composition for oral use, characterized in that contained in 0.1 to 100 parts by weight.
상기 완충제는 조성물 총 중량 대비 0.1 내지 5 중량%로 포함되는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
5. The method of claim 4,
The buffering agent is a method for producing an oral pharmaceutical composition, characterized in that contained in 0.1 to 5% by weight based on the total weight of the composition.
상기 제조방법은 제조된 이온결합 복합체에 제산제, 윤활유 및 바인더를 혼합하여 과립을 제조한 후, 정제의 형태로 압착하여 코팅하는 단계를 더 포함하는 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
According to claim 1,
The manufacturing method further comprises the step of preparing granules by mixing an antacid, lubricating oil and a binder with the prepared ionic bond complex, and then compressing and coating in the form of a tablet.
An oral pharmaceutical composition comprising an ionic complex comprising teriparatide, an anionic bile acid and a cationic bile acid derivative.
상기 이온결합 복합체는 용해제 및 완충제를 더 포함하는 것을 특징으로 하는 경구용 약학 조성물.
19. The method of claim 18,
The ionic complex is an oral pharmaceutical composition, characterized in that it further comprises a solubilizing agent and a buffer.
상기 음이온성 담즙산은 타우로리토콜산(taurolithocholic acid), 데옥시콜산(deoxycholic acid), 타우로데옥시콜산(taurodeoxycholic acid), 케노데옥시콜산(chenodeoxycholic acid), 타우로 케노데옥시콜산(taurochenodeoxycholic acid), 콜산(cholic acid) 및 타우로콜산(taurocholic acid)으로 구성된 군에서 선택되는 하나 이상, 또는 그 염인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
19. The method of claim 18,
The anionic bile acids include taurolithocholic acid, deoxycholic acid, taurodeoxycholic acid, chenodeoxycholic acid, and taurochenodeoxycholic acid. ), at least one selected from the group consisting of cholic acid and taurocholic acid, or a salt thereof.
상기 양이온성 담즙산 유도체는 음이온성 담즙산에 라이신(Lysine) 또는 아르기닌(Arginin)이 결합된 담즙산 유도체인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
19. The method of claim 18,
The cationic bile acid derivative is a bile acid derivative in which lysine or arginine is bound to an anionic bile acid.
상기 용해제는 디-알파-토코페롤 폴리에틸렌 글리콜 1000 석시네이트(D-α-tocopherol polyethylene glycol 1000 succinate)인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
20. The method of claim 19,
The dissolving agent is di-alpha-tocopherol polyethylene glycol 1000 succinate (D-α-tocopherol polyethylene glycol 1000 succinate), characterized in that the oral pharmaceutical composition preparation method.
상기 완충제는 구연산(Citric acid), 인산나트륨(Sodium Phosphate), 탄산암모늄(Ammonium carbonate), 인산칼륨(Potassium phosphate) 및 아세트산(acetic acid)으로 구성된 군에서 선택되는 하나 이상인 것을 특징으로 하는 경구용 약학 조성물의 제조방법.
20. The method of claim 19,
The buffer is citric acid, sodium phosphate (Sodium Phosphate), ammonium carbonate (Ammonium carbonate), potassium phosphate (Potassium phosphate) and acetic acid (acetic acid) Oral pharmaceutical, characterized in that at least one selected from the group consisting of A method for preparing the composition.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1643978A1 (en) | 1967-07-12 | 1971-07-01 | Bayer Ag | Process for the preparation of neopentylglycol-carbonic acid mixed esters |
| KR20170125793A (en) | 2014-10-31 | 2017-11-15 | 유니버시티 오브 유타 리서치 파운데이션 | Compositions and methods for bile acid particles |
-
2020
- 2020-10-20 KR KR1020200136150A patent/KR20220052144A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1643978A1 (en) | 1967-07-12 | 1971-07-01 | Bayer Ag | Process for the preparation of neopentylglycol-carbonic acid mixed esters |
| KR20170125793A (en) | 2014-10-31 | 2017-11-15 | 유니버시티 오브 유타 리서치 파운데이션 | Compositions and methods for bile acid particles |
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