KR20080106636A - Injectable ready to use solutions comprising human chorionic gonadotropin - Google Patents

Injectable ready to use solutions comprising human chorionic gonadotropin Download PDF

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KR20080106636A
KR20080106636A KR1020070054283A KR20070054283A KR20080106636A KR 20080106636 A KR20080106636 A KR 20080106636A KR 1020070054283 A KR1020070054283 A KR 1020070054283A KR 20070054283 A KR20070054283 A KR 20070054283A KR 20080106636 A KR20080106636 A KR 20080106636A
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chorionic gonadotropin
human chorionic
hcg
methionine
trehalose
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박범수
이호영
나규흠
이성희
강수형
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동아제약주식회사
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Priority to PCT/KR2008/002971 priority patent/WO2008150080A1/en
Priority to EP08765941A priority patent/EP2152296A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • A—HUMAN NECESSITIES
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    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

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Abstract

A sterilized injection solution of chorionic gonadotropin for immediate use is provided to improve stability of storage by using trehalose and methionine. A sterilized injection solution of chorionic gonadotropin for immediate use is not re-prepared from the free-dried one comprising human chorionic gonadotropin and a diluent with a concentration of 10-1,000 mug/mL, contains no heat radiating materials, and contains trehalose and methionine. Preferably the human chorionic gonadotropin is the recombination human follicle stimulating hormone.

Description

사람 융모성 성선자극호르몬 함유 즉시 사용형 주사 용액{Injectable Ready to Use Solutions comprising human Chorionic Gonadotropin}Injectable Ready to Use Solutions comprising human Chorionic Gonadotropin

본 발명은 사람 융모성 성선자극호르몬의 저장 안정한 즉시-사용형 주사 용액에 관한 것이다.The present invention relates to a storage stable, ready-to-use injection solution of human chorionic gonadotropin.

사람 융모성 성선자극호르몬(human Chorionic Gonadotropin, 이하 'hCG'라 한다)은 황체에서 스테로이드 생성을 자극하여 임신 초기에 작용하는 당 호르몬에 속하는 물질로서 태반 조직에 의하여 합성된다. hCG는 두개의 상이한 서브유니트 α와 β로 구성되어 있으며, 비공유 결합에 의하여 연결되어 있다. 단지 이합체 hCG만이 생물학적 활성을 가진다. 92개의 아미노산으로 구성된 α 서브유니트는 52번과 78번 아스파라진에 당이 붙어있으며 5개의 이황화 결합에 의해 안정화 되어있다. 145개의 아미노산으로 구성된 β 서브유니트는 13번과 30번 아스파라진과 C­말단의 4개의 세린에 당이 붙어있으며 6개의 이황화 결합에 의해 안정화 되어있다.Human Chorionic Gonadotropin (hereinafter referred to as 'hCG') is a substance belonging to a sugar hormone that acts early in pregnancy by stimulating steroid production in the corpus luteum and is synthesized by placental tissue. hCG consists of two different subunits α and β, which are linked by non-covalent bonds. Only dimeric hCG has biological activity. The α subunit, consisting of 92 amino acids, has sugar attached to asparagine 52 and 78 and is stabilized by five disulfide bonds. The β subunit, consisting of 145 amino acids, has sugar attached to four serines at 13 and 30 asparagine and the C 'terminal, and is stabilized by six disulfide bonds.

hCG 즉시-사용형 주사용액의 제조는 물리적 및 화학적 영향에 의한 활성 성 분의 감소율에 의해 유발되는 다수의 문제점을 가지고 있어 동결 건조물로부터 재 조제하여 사용한다.The preparation of hCG immediate-use injectable solutions has a number of problems caused by the reduction of the active ingredient due to physical and chemical effects, so they are re-prepared from lyophilized products.

국제공개특허공보 제88/010270호에는 뇨유래 난포자극호르몬(Follicle Stimulating Hormone, FSH)를 락토스와 인간 혈청 알부민으로 안정화시킨 동결 건조 제제에 대해서 기술되어 있고, 유럽특허공보 제448146호에는 시트르산과 같은 디카르복시산으로 안정화한 고나도트로핀 동결 건조 제제에 대해서 기술되어 있다. 또한, 국제공개특허공보 제93/011788호에는 동결 건조된 고나도트로핀 제제를 만들기 위해 수크로스 또는/및 글리신을 이용하여 안정시키는 방법에 대해 기재되어 있다. 특히, hCG의 안정성을 유지하기 위한 바람직한 부형제로서 수크로스를 제시하고 있으며, 수크로스에 의해 제공되는 동결건조된 제약학적 조성물에서 안정도가 락토스 또는 만니톨에 의해 제공되는 안정도보다 크다는 것을 보여준다.International Publication No. 88/010270 describes a lyophilized formulation in which urine-derived follicle stimulating hormone (FSH) is stabilized with lactose and human serum albumin, and European Patent Publication No. 448146 A gonadotropin lyophilized formulation stabilized with dicarboxylic acid is described. International Publication No. 93/011788 also describes a method of stabilizing with sucrose or / and glycine to make a lyophilized gonadotropin formulation. In particular, sucrose has been suggested as a preferred excipient to maintain the stability of hCG and shows that the stability in lyophilized pharmaceutical compositions provided by sucrose is greater than that provided by lactose or mannitol.

그러나 동결건조 제제를 투여하는 경우에는, 약물의 이중적인 취급이 필요한데, 우선 동결건조된 케익을 재 조제한 다음 투여하고, 더구나 일부 경우에는 가용화 문제 때문에 분말의 완전한 용해를 위해서 장기간 진탕하는 것이 필요할 수 있다.However, when lyophilized formulations are administered, dual handling of the drug is required, which may require first re-forming the lyophilized cake and then administering it, and in some cases, prolonged shaking for complete dissolution of the powder due to solubilization issues.

또한 hCG 즉시-사용형 주사용액으로 인간 혈청 알부민(HSA) 등을 첨가제로 사용하는 기술이 개발되어 있으나, 인간 혈청 알부민 사용은 바이러스 감염, 응집 체 형성 및 최근 문제가 되고 있는 프라이온의 감염 등의 문제점을 갖는다. 따라서 동결 건조된 제제가 아니면서 인간 혈청 알부민이 첨가되지 않은 액상 제제의 개발이 요구된다.In addition, hCG immediate-use injectable solutions have been developed that use human serum albumin (HSA) as an additive.However, human serum albumin has been used for viral infection, aggregate formation, and infection of prion. I have a problem. Therefore, there is a need for the development of liquid formulations which are not lyophilized formulations and which do not contain human serum albumin.

hCG 즉시-사용형 주사용액의 안정화와 관련한 종래 기술로는 국제공개특허공보 제93/022335호에 액상 폴리펩타이드를 안정화하기 위한 pH 5.0~5.5의 시트르산 완충액에 대해 언급되어 있으며, 국제공개특허공보 제96/029095호에는 만니톨과 pH 7.0의 아세트산 또는 숙신산 또는 인산염으로 구성된 hCG의 액상 조성물에 대해 기재하고 있다. 상기 출원에서는 동일한 pH의 완충액 조건에서 실시된 안정화제에 따른 안정도를 비교하였는데, 액상 제제에 있어서 만니톨에 의해 제공되는 안정도가 수크로스, 글리신, 글루코스, 락토스 및 염화나트륨에 의해 제공되는 안정도보다 크다는 것을 보여준다. 미국특허공보 제5929028호는 pH 6.5~7.2의 25~100 mM 시트르산, 1~10 mM 메티오닌, 25~300 mM 수크로스 및 비이온성 계면활성제로 구성된 액상 고나도트로핀의 안정화된 제형에 대해 기술하고 있다.Prior art related to the stabilization of hCG immediate-use injectable solutions is disclosed in International Patent Publication No. 93/022335 for citric acid buffers with pH 5.0 to 5.5 for stabilizing liquid polypeptides. 96/029095 describes liquid compositions of hCG consisting of mannitol and acetic acid or succinic acid or phosphate at pH 7.0. The application compares the stability according to the stabilizers carried out under buffer conditions of the same pH, showing that the stability provided by mannitol in liquid formulations is greater than that provided by sucrose, glycine, glucose, lactose and sodium chloride. . US Patent No. 5929028 describes a stabilized formulation of liquid gonadotropin consisting of 25-100 mM citric acid, 1-10 mM methionine, 25-300 mM sucrose, and a nonionic surfactant at pH 6.5-7.2. have.

본 발명자들은 인간 혈청 알부민이 첨가되지 않은 hCG의 저장 안정한 즉시-사용형 주사 용액에 관하여 연구하던 중에 트레할로스 및 메치오닌을 함유시킨 hCG 즉시-사용형 주사 용액에서 보관안정성이 매우 우수함을 밝혀냄으로써 본 발명을 완성하였다.The inventors of the present invention have found that, while studying storage stable, ready-to-use injection solutions of hCG without the addition of human serum albumin, the present inventors have found that storage stability is very good in hCG immediate-use injection solutions containing trehalose and methionine. Completed.

본 발명은 hCG의 저장 안정한 즉시-사용형 주사 용액을 제공하는 것을 목적으로 한다.The present invention aims to provide a storage stable, ready-to-use injection solution of hCG.

본 발명은 트레할로스 및 메치오닌으로 안정화된 hCG를 함유하는 즉시-사용형 주사 용액에 관한 것이다.The present invention relates to ready-to-use injection solutions containing hCG stabilized with trehalose and methionine.

상기 목적을 달성하기 위하여, 본 발명은 트레할로스 및 메치오닌을 포함하는 것이 필수적으로 이루어지고, hCG와 부형제로 이루어진 동결건조물로부터 재 조제되지 않고, pH를 6.0~8.0로 조정시킨, 발열성 물질을 함유하지 않고 보관안정한 hCG 즉시-사용형 주사 용액을 제공한다.In order to achieve the above object, the present invention essentially comprises trehalose and methionine, does not contain a pyrogenic substance, which is not re-formulated from the lyophilisate consisting of hCG and excipients, and the pH is adjusted to 6.0-8.0. Provide stable hCG immediate-use injection solutions without storage.

hCG는 천연 공급원, 예를 들면 사람의 소변으로부터 분리할 수 있고, 또한 재조합 DNA 기술에 의한 핵심 분야, 즉 DNA로 형질도입된 CHO(Chinese Hamster Ovary) 세포에서 발현시켜 얻을 수 있으며, 10 내지 1000 ug/ml, 바람직하게는 250 내지 500 ug/ml의 재조합 사람 난포 자극호르몬을 포함할 수 있다.hCG can be isolated from natural sources, such as human urine, and also obtained by expression in key fields by recombinant DNA technology, that is, in Chinese Hamster Ovary (CHO) cells transduced with DNA, 10-1000 ug / ml, preferably 250 to 500 ug / ml recombinant human follicle stimulating hormone.

트레할로스는 10 내지 100 mg/ml, 바람직하게는 60 mg/ml, 메치오닌은 0.1 내지 1mg/ml, 바람직하게는 0.5 mg/ml를 포함하며, 인산염 완충액에 의해 조정되는 pH는 6.0~8.0, 특히 7.0이 바람직하다.Trehalose comprises 10 to 100 mg / ml, preferably 60 mg / ml, methionine contains 0.1 to 1 mg / ml, preferably 0.5 mg / ml, and the pH adjusted by phosphate buffer is 6.0-8.0, in particular 7.0 This is preferred.

본 발명은 상기 제약학적 액상 조성물의 제조 공정을 제공하는데, 상기 공정은 부형제를 함유하는 완충액에 hCG 용액을 희석시키는 단계로 구성되며, 본 발명의 용액은 밀봉 용기에, 특히 유리로 된 용기에 제공된다. 당해 용액은 이러한 방법에 의해 단위 용량 형태 또는 다중 용량 형태로서 제공될 수 있다.The present invention provides a process for preparing the pharmaceutical liquid composition, which process comprises diluting an hCG solution in a buffer containing an excipient, wherein the solution of the present invention is provided in a sealed container, especially in a glass container. do. The solution may be provided in unit dose form or multidose form by this method.

다음 실시예 및 실험예로 본 발명을 설명한다.The present invention is described by the following examples and experimental examples.

<실시예 1> 부형제 함유 hCG 즉시-사용형 주사 용액의 제조Example 1 Preparation of Excipient-Containing hCG Immediate-Use Injection Solution

500 ug/ml의 재조합 hCG를 함유하는 10mM의 인산염 완충액(pH 7.0)에서 4가지의 각기 다른 안정화제로 안정화된 주사 용액을 제조하였다. 안정화제 또는 부형제로는 트레할로스, 만니톨, 수크로스, 락토스를 이용하였다. 재조합 hCG를 함유하는 주사 용액은 표 1에 기재한 조성을 갖도록 제조하였다. 트레할로스의 경우 주사용 증류수(600ml)에 인산(0.98g)과 트윈 20(0.2g)을 첨가한다. pH는 수산화나트륨으로 7.0으로 조정한다. 트레할로스(60g)을 첨가하고 재조합 hCG 용액(500mg)을 부형제 용액에 첨가하고, pH를 점검 후 필요 시 1M 수산화나트륨으로 pH를 7.0 ± 0.2로 조정한다.Injection solutions stabilized with four different stabilizers were prepared in 10 mM phosphate buffer (pH 7.0) containing 500 ug / ml recombinant hCG. Trehalose, mannitol, sucrose and lactose were used as stabilizers or excipients. Injection solutions containing recombinant hCG were prepared to have the compositions shown in Table 1. In the case of trehalose, phosphoric acid (0.98 g) and Tween 20 (0.2 g) are added to distilled water (600 ml) for injection. The pH is adjusted to 7.0 with sodium hydroxide. Trehalose (60 g) is added and recombinant hCG solution (500 mg) is added to the excipient solution, the pH is checked and if necessary the pH is adjusted to 7.0 ± 0.2 with 1 M sodium hydroxide.

Figure 112007040603880-PAT00001
Figure 112007040603880-PAT00001

<< 실시예Example 2> 아미노산 함유 hCG 즉시-사용형 주사 용액의 제조 2> Preparation of Amino Acid-Containing hCG Immediate-Use Injection Solution

조성물의 제조는 실시예 1에서와 동일하게 하며 재조합 hCG 용액(500mg)을 부형제 용액에 첨가하기 전에 부형제 용액에 메치오닌 등의 아미노산을 추가한다. 조성물은 표 2에 나타내었다.Preparation of the composition is the same as in Example 1 and amino acid such as methionine is added to the excipient solution before adding the recombinant hCG solution (500 mg) to the excipient solution. The composition is shown in Table 2.

Figure 112007040603880-PAT00002
Figure 112007040603880-PAT00002

<< 실험예Experimental Example 1> 부형제에 따른 hCG 즉시-사용형 주사 용액의 보관안정성 측정 1> Determination of storage stability of hCG immediate-use injection solutions according to excipients

상기 실시예 1에서 제조된 주사 용액은 주사용 증류수 1L로 조정 후 멸균 필터로 여과 후 조성물 부분 표본 1ml을 밀폐된 3ml 바이알에 넣고 4℃, 25℃, 40℃에서 보관하며 HPSEC(high-performance size-exclusion chromatography)와 역상 HPLC 방법을 사용하여 안정성 테스트를 실시하여 HPSEC에 의한 결과는 표 3에, 역상 HPLC 방법에 의한 결과는 표 4에 나타내었다.The injection solution prepared in Example 1 was adjusted to 1 L of distilled water for injection, filtered through a sterile filter, and then 1 ml of the composition partial sample was placed in a closed 3 ml vial and stored at 4 ° C., 25 ° C., and 40 ° C., and HPSEC (high-performance size). The stability test was carried out using -exclusion chromatography) and the reverse phase HPLC method.

분석 결과 표 3 및 표 4에서 알 수 있는 바와 같이, 트레할로스가 다른 안정화제에 비하여 그 안정성이 우수한 것으로 나타났다.As can be seen in Table 3 and Table 4, trehalose showed superior stability compared to other stabilizers.

Figure 112007040603880-PAT00003
Figure 112007040603880-PAT00003

Figure 112007040603880-PAT00004
Figure 112007040603880-PAT00004

<< 실험예Experimental Example 2> 아미노산에 따른 hCG 즉시-사용형 주사 용액의 보관안정성 측정 2> Determination of storage stability of hCG immediate-use injection solutions according to amino acids

실시예 2에서 제조된 재조합 hCG 주사 용액(500mg)을 실험예 1에서와 마찬가지로 4℃, 25℃, 40℃에 샘플을 보관하고 HPSEC와 역상 HPLC를 사용하여 안정성 테스트를 실시하여 HPSEC에 의한 결과는 표 5에, 역상 HPLC 방법에 의한 결과는 표 6에 나타내었다.Recombinant hCG injection solution prepared in Example 2 (500mg) was stored at 4 ℃, 25 ℃, 40 ℃ as in Experimental Example 1 and subjected to stability test using HPSEC and reverse phase HPLC, the results by HPSEC In Table 5, the results by the reversed phase HPLC method are shown in Table 6.

분석 결과 표 5 및 표 6에서 알 수 있는 바와 같이, 메치오닌의 존재에서 재조합 hCG의 안정성은 증가하는 것으로 나타났다. 또한, 메치오닌의 양이 증가할수록 액상 조성물의 안정성은 더 증가하는 것으로 나타났다.As can be seen in Tables 5 and 6, the stability of recombinant hCG was increased in the presence of methionine. In addition, as the amount of methionine increased, the stability of the liquid composition was found to increase.

Figure 112007040603880-PAT00005
Figure 112007040603880-PAT00005

Figure 112007040603880-PAT00006
Figure 112007040603880-PAT00006

이상에서 상세히 설명한 바와 같이, 본 발명은 비환원당의 일종인 트레할로스와 메치오닌을 함유함으로써 사람 융모성 성선자극호르몬의 저장 안정한 즉시-사용형 주사 용액을 제조할 수 있으며, 동결건조물로부터 재 조제되지 않으며, 첨가제로 인간 혈청 알부민을 사용하지 않고 장기간 사용에도 보관 안정 가능한 사람 융모성 성선자극호르몬의 주사 용액을 제조할 수 있다.As described in detail above, the present invention can prepare a storage stable ready-to-use injection solution of human chorionic gonadotropin by containing trehalose and methionine, which are two kinds of non-reducing sugars, and are not prepared from lyophilized products. An injection solution of human chorionic gonadotropin which can be stored and stable even for long-term use without using human serum albumin as an additive can be prepared.

Claims (4)

10 내지 1000 μg/ml의 농도로, 사람 융모성 성선자극호르몬 및 부형제로 이루어진 동결건조물로부터 재 조제되지 않고, 발열성 물질을 함유하지 않으며 트레할로스 및 메치오닌을 필수적으로 함유하는 것에 의해서만 보관 안정한 사람 융모성 성선자극호르몬의 즉시 사용형 멸균 주사 용액.Human chorionicity stable at a concentration of 10 to 1000 μg / ml, not re-formed from a lyophilized product of human chorionic gonadotropin and excipients, containing no pyrogenic material and essentially containing trehalose and methionine Ready-to-use sterile injection solution of gonadotropin. 제 1 항에 있어서, 사람 융모성 성선자극호르몬은 재조합 사람 난포 자극호르몬인 것을 특징으로 하는 사람 융모성 성선자극호르몬의 즉시 사용형 멸균 주사 용액.2. The ready-to-use sterile injection solution of human chorionic gonadotropin according to claim 1, wherein the human chorionic gonadotropin is a recombinant human follicle stimulating hormone. 제 1 항에 있어서, 10 내지 100 mg/ml의 트레할로스과 0.1 내지 1mg/ml의 메치오닌으로 구성되는 것을 특징으로 하는 사람 융모성 성선자극호르몬의 즉시 사용형 멸균 주사 용액.The ready-to-use sterile injectable solution of human chorionic gonadotropin according to claim 1, which is composed of 10 to 100 mg / ml trehalose and 0.1 to 1 mg / ml methionine. 제 4 항에 있어서, 60 mg/ml의 트레할로스 및 0.5 mg/ml의 메치오닌으로 구성되는 것을 특징으로 하는 사람 융모성 성선자극호르몬의 즉시 사용형 멸균 주사 용액.5. The ready-to-use sterile injectable solution of human chorionic gonadotropin according to claim 4, which consists of 60 mg / ml trehalose and 0.5 mg / ml methionine.
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