JP6965474B1 - A method for suppressing white turbidity due to shaking of a prefilled syringe or cartridge product containing teriparatide or a salt thereof. - Google Patents
A method for suppressing white turbidity due to shaking of a prefilled syringe or cartridge product containing teriparatide or a salt thereof. Download PDFInfo
- Publication number
- JP6965474B1 JP6965474B1 JP2021500484A JP2021500484A JP6965474B1 JP 6965474 B1 JP6965474 B1 JP 6965474B1 JP 2021500484 A JP2021500484 A JP 2021500484A JP 2021500484 A JP2021500484 A JP 2021500484A JP 6965474 B1 JP6965474 B1 JP 6965474B1
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- Prior art keywords
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- aqueous pharmaceutical
- ionic strength
- salt
- pharmaceutical preparation
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- 150000003839 salts Chemical class 0.000 title claims abstract description 62
- 238000000034 method Methods 0.000 title claims abstract description 60
- 108010049264 Teriparatide Proteins 0.000 title claims abstract description 57
- 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 55
- 229960005460 teriparatide Drugs 0.000 title claims abstract description 50
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- BUUKFBVDKSFMHN-LKMAISLMSA-N parathar acetate Chemical compound CC(O)=O.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=1NC=NC=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=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 BUUKFBVDKSFMHN-LKMAISLMSA-N 0.000 description 7
- 229960000338 teriparatide acetate Drugs 0.000 description 7
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- A—HUMAN NECESSITIES
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Abstract
テリパラチド又はその塩および１又は２種類以上の電解質を含有する水性医薬製剤が充填されたプレフィルドシリンジまたはカートリッジ充填製剤に対する振盪ストレスによる白濁を抑制する方法であって、前記水性医薬製剤のｐＨをテリパラチド又はその塩の等電点（ｐＩ）未満とし、前記水性医薬製剤におけるイオン強度を０．２０Ｍ未満とし、かつ前記水性医薬製剤における下式で示される活量イオン強度を０．０７Ｍ以下となるように前記電解質を配合する、白濁抑制方法。I(a)：活量イオン強度、ai:各イオンの活量、ｚｉ：各イオンの電荷（ただし、各イオンとは、前記水性医薬製剤に溶解し、電離している各イオンを意味する）本発明の方法により、優れた振盪安定性を有する液状医薬製剤を提供するものであり、医薬品産業において極めて有用である。A method for suppressing cloudiness due to shaking stress on a prefilled syringe or cartridge-filled preparation filled with an aqueous pharmaceutical preparation containing teriparatide or a salt thereof and one or two or more kinds of electrolytes, wherein the pH of the aqueous pharmaceutical preparation is changed to teriparatide or The salt is set to less than the isoelectric point (pI), the ionic strength of the aqueous pharmaceutical product is less than 0.20 M, and the active ionic strength of the aqueous pharmaceutical product represented by the following formula is 0.07 M or less. A method for suppressing cloudiness, which comprises blending the electrolyte. I (a): activity ionic strength, ai: activity of each ion, zi: charge of each ion (however, each ion means each ion dissolved and ionized in the aqueous pharmaceutical preparation). The method of the present invention provides a liquid pharmaceutical preparation having excellent shaking stability, which is extremely useful in the pharmaceutical industry.
Description
本発明は、テリパラチド又はその塩を含有するプレフィルドシリンジまたはカートリッジ製剤の振盪による白濁を抑制する方法に関する。 The present invention relates to a method for suppressing white turbidity due to shaking of a prefilled syringe or cartridge preparation containing teriparatide or a salt thereof.
ＰＴＨ（副甲状腺ホルモン）は、カルシトニン類やビタミンＤ類とともに、血中カルシウム濃度の調節に関与するホルモンである。テリパラチド又はその塩を有効成分とする骨粗鬆症治療剤の製造販売が承認されており（非特許文献１）、安定性に優れるテリパラチド含有液状医薬組成物も報告されている（特許文献１）。 PTH (parathyroid hormone), along with calcitonin and vitamin D, is a hormone involved in the regulation of blood calcium concentration. The manufacture and sale of an osteoporosis therapeutic agent containing teriparatide or a salt thereof as an active ingredient has been approved (Non-Patent Document 1), and a teriparatide-containing liquid pharmaceutical composition having excellent stability has also been reported (Patent Document 1).
一方、液状医薬製剤が医薬品工場等で製造され、臨床現場に輸送されるまでに同剤に対して振盪ストレスが与えられる場合がある。 On the other hand, a liquid pharmaceutical product may be subjected to shaking stress by the time it is manufactured at a pharmaceutical factory or the like and transported to a clinical site.
また、特許文献２は、トロンボモジュリン水溶液注射用製剤を振盪したときに白濁が生じる場合があることを報告している。 Further, Patent Document 2 reports that white turbidity may occur when the thrombomodulin aqueous solution injection preparation is shaken.
一般に、水溶液中においてペプチドは親水コロイドとして分散し、ブラウン運動をしている。コロイドの分散および凝集状態には、コロイド同士のファンデルワールス相互作用や疎水性相互作用による短距離の引力とコロイドの表面電荷による長距離斥力の静電相互作用が関わっている。水溶液中に一定以上の量の塩を添加すると、ファンデルワールス力や疎水性相互作用などの引力が強まり凝集しやすくなる（非特許文献４）。 Generally, the peptide is dispersed as a hydrophilic colloid in an aqueous solution and has a Brownian motion. The dispersed and aggregated states of colloids involve short-range attractive forces due to van der Waals and hydrophobic interactions between colloids and electrostatic interactions of long-range repulsive forces due to the surface charge of colloids. When a certain amount or more of salt is added to the aqueous solution, attractive forces such as van der Waals force and hydrophobic interaction are strengthened and agglutination is likely to occur (Non-Patent Document 4).
本発明者は、テリパラチド又はその塩を含有するプレフィルドシリンジまたはカートリッジ充填製剤を振盪すると、白濁が生じることを見出した。従って、本発明の課題は、テリパラチド又はその塩を含有するプレフィルドシリンジまたはカートリッジ充填製剤の振盪ストレスによる白濁を抑制する方法を提供することである。 The present inventor has found that shaking a prefilled syringe or cartridge-filled preparation containing teriparatide or a salt thereof causes cloudiness. Therefore, an object of the present invention is to provide a method for suppressing white turbidity due to shaking stress of a prefilled syringe or a cartridge-filled preparation containing teriparatide or a salt thereof.
本発明は以下に関する。
［１］
テリパラチド又はその塩および１又は２種類以上の電解質を含有する水性医薬製剤が充填されたプレフィルドシリンジまたはカートリッジ充填製剤に対する振盪ストレスによる白濁を抑制する方法であって、前記水性医薬製剤のｐＨをテリパラチド又はその塩の等電点（ｐＩ）未満とし、前記水性医薬製剤におけるイオン強度を０．２０Ｍ未満とし、かつ前記水性医薬製剤における下式で示される活量イオン強度を０．０７Ｍ以下となるように前記電解質を配合する、白濁抑制方法。
［２］
前記水性医薬製剤のｐＨが４．０〜５．０である、［１］に記載の方法。
［３］
前記水性医薬製剤が実質的に緩衝剤（ただしテリパラチド塩から脱離する塩はここでは緩衝剤に該当しない）を含有しない、［１］または［２］に記載の方法。
［４］
前記電解質が、ナトリウム塩、塩酸塩、および酢酸塩からなる群より選択される１または２種類以上の電解質を含む、［１］〜［３］のいずれかに記載の方法。
［５］
前記電解質が、アスコルビン酸ナトリウム、塩化亜鉛、塩化アルミニウム、塩化ナトリウム、塩化カルシウム、塩化マグネシウム、臭化ナトリウム、塩化カリウム、塩酸、酢酸ナトリウム、クエン酸ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、リン酸水素ナトリウム、リン酸二水素ナトリウム、リン酸二水素カリウム、亜硫酸水素ナトリウム、およびサリチル酸ナトリウムからなる群から選択される１または２種類以上の電解質を含む、［１］〜［４］のいずれかに記載の方法。
［６］
前記プレフィルドシリンジまたはカートリッジがプラスチック製である、［１］〜［５］のいずれかに記載の方法。
［７］
テリパラチド又はその塩および１又は２種類以上の電解質を含有する水性医薬製剤が充填されたプレフィルドシリンジまたはカートリッジ充填製剤に対する振盪ストレスによる白濁を抑制する方法であって、前記水性医薬製剤の２５℃、０．１ＭＰａにおける粘度ηがη＞０．９０ｍＰａ・ｓと調整する、白濁抑制方法。
［８］
前記粘度ηを、前記水性医薬製剤への糖アルコール添加によって調整する、［７］に記載の方法。
［９］
前記糖アルコールがＤ−マンニトールを含む、［８］に記載の方法。
［１０］
テリパラチド又はその塩および１又は２種類以上の電解質を含有する水性医薬製剤が充填されたプレフィルドシリンジまたはカートリッジ充填製剤に対する振盪ストレスによる白濁を抑制する方法であって、前記水性医薬製剤に非イオン性界面活性剤を配合する、白濁抑制方法。
［１１］
前記界面活性剤が、ポリオキシエチレンソルビタン脂肪酸エステルを含む、［１０］に記載の方法。
［１２］
前記界面活性剤が、ポリソルベート８０を含む、［１０］または［１１］に記載の方法。
［１３］
前記水性医薬製剤における界面活性剤の含有量が０．０１〜０．１ｍｇ／ｍＬである、［１０］〜［１２］のいずれかに記載の方法。
［１４］
前記水性医薬製剤におけるテリパラチド又はその塩の濃度がテリパラチド換算で１２０〜１６０μｇ／ｍＬである、［１］〜［１３］のいずれかに記載の方法。
The present invention relates to the following.
[1]
A method for suppressing cloudiness due to shaking stress on a prefilled syringe or cartridge-filled preparation filled with an aqueous pharmaceutical preparation containing teriparatide or a salt thereof and one or more kinds of electrolytes, wherein the pH of the aqueous pharmaceutical preparation is teriparatide or The salt is set to less than the isoelectric point (pI), the ionic strength of the aqueous pharmaceutical product is less than 0.20 M, and the active ionic strength of the aqueous pharmaceutical product represented by the following formula is 0.07 M or less. A method for suppressing cloudiness, which comprises blending the electrolyte.
[2]
The method according to [1], wherein the pH of the aqueous pharmaceutical preparation is 4.0 to 5.0.
[3]
The method according to [1] or [2], wherein the aqueous pharmaceutical preparation does not substantially contain a buffer (however, the salt desorbed from the teriparatide salt does not correspond to a buffer here).
[4]
The method according to any one of [1] to [3], wherein the electrolyte comprises one or more electrolytes selected from the group consisting of sodium salts, hydrochlorides, and acetates.
[5]
The electrolytes are sodium ascorbate, zinc chloride, aluminum chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bromide, potassium chloride, hydrochloric acid, sodium acetate, sodium citrate, sodium carbonate, sodium hydrogencarbonate, sodium hydrogenphosphate. [1] to [4], which comprises one or more electrolytes selected from the group consisting of sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, and sodium salicylate. Method.
[6]
The method according to any one of [1] to [5], wherein the prefilled syringe or cartridge is made of plastic.
[7]
A method for suppressing white turbidity due to shaking stress on a prefilled syringe or cartridge-filled preparation filled with an aqueous pharmaceutical preparation containing teriparatide or a salt thereof and one or more kinds of electrolytes, at 25 ° C., 0 of the aqueous pharmaceutical preparation. .. A method for suppressing cloudiness in which the viscosity η at 1 MPa is adjusted to η> 0.90 mPa · s.
[8]
The method according to [7], wherein the viscosity η is adjusted by adding a sugar alcohol to the aqueous pharmaceutical preparation.
[9]
The method according to [8], wherein the sugar alcohol comprises D-mannitol.
[10]
A method for suppressing white turbidity due to shaking stress on a prefilled syringe or cartridge-filled preparation filled with an aqueous pharmaceutical preparation containing teriparatide or a salt thereof and one or more kinds of electrolytes, which is a nonionic surfactant in the aqueous pharmaceutical product. A method for suppressing cloudiness, which comprises an activator.
[11]
The method according to [10], wherein the surfactant comprises a polyoxyethylene sorbitan fatty acid ester.
[12]
The method according to [10] or [11], wherein the surfactant comprises polysorbate 80.
[13]
The method according to any one of [10] to [12], wherein the content of the surfactant in the aqueous pharmaceutical preparation is 0.01 to 0.1 mg / mL.
[14]
The method according to any one of [1] to [13], wherein the concentration of teriparatide or a salt thereof in the aqueous pharmaceutical preparation is 120 to 160 μg / mL in terms of teriparatide.
本発明によればテリパラチド又はその塩を含有するプレフィルドシリンジまたはカートリッジ充填製剤の振盪ストレスによる白濁を抑制する方法が提供される。 According to the present invention, there is provided a method for suppressing white turbidity due to shaking stress of a prefilled syringe or a cartridge-filled preparation containing teriparatide or a salt thereof.
以下、本発明を具体的な実施の形態に即して詳細に説明する。但し、本発明は以下の実施の形態に束縛されるものではなく、本発明の趣旨を逸脱しない範囲において、任意の形態で実施することが可能である。 Hereinafter, the present invention will be described in detail according to specific embodiments. However, the present invention is not bound by the following embodiments, and can be implemented in any embodiment as long as the gist of the present invention is not deviated.
本発明は、テリパラチド又はその塩および１又は２種類以上の電解質を含有する水性医薬製剤が充填されたプレフィルドシリンジまたはカートリッジ充填製剤に対する振盪ストレスによる白濁を抑制する方法である。以下、各用語について説明した後に、本発明の態様について説明する。 The present invention is a method for suppressing cloudiness due to shaking stress on a prefilled syringe or cartridge-filled preparation filled with an aqueous pharmaceutical preparation containing teriparatide or a salt thereof and one or more kinds of electrolytes. Hereinafter, aspects of the present invention will be described after each term has been described.
（１）水性医薬製剤：
本発明に係る水性医薬製剤は、後述のテリパラチド又はその塩および１又は２種類以上の電解質を含有する液状の医薬製剤であり、例えば、皮下注射用水性医薬製剤としてプレフィルドシリンジまたはカートリッジに充填され得る製剤である。 (1) Aqueous pharmaceutical preparation:
The aqueous pharmaceutical preparation according to the present invention is a liquid pharmaceutical preparation containing teriparatide or a salt thereof described later and one or more kinds of electrolytes, and can be filled in a prefilled syringe or cartridge as, for example, an aqueous pharmaceutical preparation for subcutaneous injection. It is a preparation.
本発明の方法において、水性医薬製剤における「医薬」とは、哺乳動物（ヒト、サル、ラットなど）に対して任意の疾病の予防／治療／診断に用いられる薬剤を意味する。 In the method of the present invention, the "pharmaceutical" in the aqueous pharmaceutical preparation means a drug used for the prevention / treatment / diagnosis of any disease with respect to mammals (humans, monkeys, rats, etc.).
本発明に係る水性医薬製剤の水性溶媒は、本発明の主旨を逸脱しない範囲において、後述する１または２種類以上の緩衝剤、添加剤等の各種の成分を含有していてもよい。 The aqueous solvent of the aqueous pharmaceutical preparation according to the present invention may contain various components such as one or two or more kinds of buffers and additives, which will be described later, as long as the gist of the present invention is not deviated.
（２）テリパラチド又はその塩：
本発明の方法において、テリパラチドは、フリー体のヒトＰＴＨ（１−３４）を意味する。ヒトＰＴＨ（１−３４）は、ヒト副甲状腺ホルモンであるヒトＰＴＨ（１−８４）のアミノ酸配列において、Ｎ末端側からみて第１番目から第３４番目までのアミノ酸残基からなる部分アミノ酸配列で示されるペプチドである。テリパラチドは塩の形態であることもできる。 (2) Teriparatide or its salt:
In the methods of the invention, teriparatide means free human PTH (1-34). Human PTH (1-34) is a partial amino acid sequence consisting of the first to 34th amino acid residues when viewed from the N-terminal side in the amino acid sequence of human PTH (1-84), which is a human parathyroid hormone. The peptide shown. Teriparatide can also be in the form of salts.
本発明の方法において、テリパラチドの塩としては、テリパラチドと１種又は２種以上の揮発性有機酸とによって形成される任意の塩が挙げられる。揮発性有機酸としては、トリフルオロ酢酸、蟻酸、酢酸などが例示される。フリー体のテリパラチドと揮発性有機酸とが塩を形成する際の両者の比率は、当該塩を形成する限りにおいて特に限定されない。中でも、揮発性有機酸としては、酢酸が好ましい。即ち、本発明の方法におけるテリパラチドの塩としては、テリパラチド酢酸塩を好ましく例示できる。 In the method of the present invention, the salt of teriparatide includes any salt formed by teriparatide and one or more volatile organic acids. Examples of the volatile organic acid include trifluoroacetic acid, formic acid, and acetic acid. The ratio of the free teriparatide and the volatile organic acid to form a salt is not particularly limited as long as the salt is formed. Of these, acetic acid is preferable as the volatile organic acid. That is, as the salt of teriparatide in the method of the present invention, teriparatide acetate can be preferably exemplified.
テリパラチド又はその塩は、ペプチドであることから、その等電点（ｐＩ）を有する。ｐＩの測定については、公知の方法（例えばＨＰＬＣや電気泳動などを用いた方法）により実施可能である。一般的に、テリパラチド又はその塩のｐＩは、８．３又は８．３〜８．４であることが知られている（特許文献１、特許文献３）。 Since teriparatide or a salt thereof is a peptide, it has an isoelectric point (pI) thereof. The measurement of pI can be carried out by a known method (for example, a method using HPLC, electrophoresis or the like). Generally, the pI of teriparatide or a salt thereof is known to be 8.3 or 8.3 to 8.4 (Patent Documents 1 and 3).
本発明に係る水性医薬製剤に含有されるテリパラチド又はその塩の濃度は特に限定されないが、好適には以下を例示できる。即ち、テリパラチドとして、下限としては５０μｇ／ｍＬ以上であることが好ましく、７０μｇ／ｍＬ以上、１００μｇ／ｍＬ以上、１００μｇ／ｍＬ超、１１０μｇ／ｍＬ以上、更には１２０μｇ／ｍＬ以上であることがより好ましい。また、上限としては５００μｇ／ｍＬ以下であることが好ましく、２５０μｇ／ｍＬ以下、２５０μｇ／ｍＬ未満、２００μｇ／ｍＬ以下、１８０μｇ／ｍＬ以下、更には１６０μｇ／ｍＬ以下であることがより好ましい。範囲としては、５０〜２５０μｇ／ｍＬ、７０〜１８０μｇ／ｍＬ、好ましくは１００〜１６０μｇ／ｍＬ、さらに好ましくは１２０〜１６０μｇ／ｍＬを挙げることができる。中でも、１４１μｇ／ｍＬを最も好ましく例示できる。 The concentration of teriparatide or a salt thereof contained in the aqueous pharmaceutical preparation according to the present invention is not particularly limited, but the following can be preferably exemplified. That is, the lower limit of teriparatide is preferably 50 μg / mL or more, more preferably 70 μg / mL or more, 100 μg / mL or more, more than 100 μg / mL, 110 μg / mL or more, and further preferably 120 μg / mL or more. .. The upper limit is preferably 500 μg / mL or less, more preferably 250 μg / mL or less, less than 250 μg / mL, 200 μg / mL or less, 180 μg / mL or less, and further preferably 160 μg / mL or less. Examples of the range include 50 to 250 μg / mL, 70 to 180 μg / mL, preferably 100 to 160 μg / mL, and more preferably 120 to 160 μg / mL. Of these, 141 μg / mL can be most preferably exemplified.
本発明に係る水性医薬製剤に含有されるテリパラチド又はその塩のモル濃度は、好適には以下を例示できる。即ち、テリパラチドとして、下限としては１２μＭ以上であることが好ましく、１７μＭ以上、２４μＭ以上、２４μＭ超、２６μＭ以上、更には２９μＭ以上であることがより好ましい。また、上限としては１２１μＭ以下であることが好ましく、６１μＭ以下、６１μＭ未満、４９μＭ以下、４４μＭ以下、更には３９μＭ以下であることがより好ましい。範囲としては、１２〜６１μＭ、好ましくは１７〜４４μＭ、好ましくは２４〜３９μＭ、さらに好ましくは２９〜３９μＭを挙げることができる。中でも、３４μＭを最も好ましく例示できる。 The molar concentration of teriparatide or a salt thereof contained in the aqueous pharmaceutical preparation according to the present invention can preferably be exemplified as follows. That is, the lower limit of teriparatide is preferably 12 μM or more, more preferably 17 μM or more, 24 μM or more, more than 24 μM, 26 μM or more, and further preferably 29 μM or more. The upper limit is preferably 121 μM or less, more preferably 61 μM or less, less than 61 μM, 49 μM or less, 44 μM or less, and further preferably 39 μM or less. The range may be 12 to 61 μM, preferably 17 to 44 μM, preferably 24-39 μM, and even more preferably 29 to 39 μM. Among them, 34 μM can be most preferably exemplified.
本発明に係る「テリパラチド又はその塩」がテリパラチド塩である場合、本発明に係る水性医薬製剤においてテリパラチド塩が乖離して生成する塩は、本発明に係る緩衝剤と見做されない。 When the "teriparatide or a salt thereof" according to the present invention is a teriparatide salt, the salt produced by dissociating the teriparatide salt in the aqueous pharmaceutical preparation according to the present invention is not regarded as a buffer according to the present invention.
（３）電解質：
本発明の方法において、電解質とは、溶媒中に溶解した際に、陽イオンと陰イオンに電離する物質を意味する。電解質としては、酸、塩基、及び塩が挙げられる。 (3) Electrolyte:
In the method of the present invention, the electrolyte means a substance that ionizes into cations and anions when dissolved in a solvent. Electrolytes include acids, bases, and salts.
ここで、酸は、有機酸であっても無機酸であってもよい。有機酸として、例えば、酢酸やクエン酸を例示することができ、酢酸を好ましく例示できる。無機酸として、例えば、塩酸や硫酸を挙げることができ、中でも塩酸が好ましく利用される。 Here, the acid may be an organic acid or an inorganic acid. As the organic acid, for example, acetic acid and citric acid can be exemplified, and acetic acid can be preferably exemplified. Examples of the inorganic acid include hydrochloric acid and sulfuric acid, and among them, hydrochloric acid is preferably used.
ここで、塩基は、特に限定されず、例えば、水酸化ナトリウムを例示できる。 Here, the base is not particularly limited, and examples thereof include sodium hydroxide.
塩も特に限定されず、有機塩であってもよく無機塩であってもよい。有機塩とは、有機酸と無機塩基からなる塩、無機酸と有機塩基からなる塩、又は、有機酸と有機塩基からなる塩であり、無機塩とは、無機酸と無機塩基からなる塩を意味する。 The salt is also not particularly limited, and may be an organic salt or an inorganic salt. The organic salt is a salt composed of an organic acid and an inorganic base, a salt composed of an inorganic acid and an organic base, or a salt composed of an organic acid and an organic base, and an inorganic salt is a salt composed of an inorganic acid and an inorganic base. means.
塩として、例えば、ナトリウム塩、塩酸塩、酢酸塩が例示される。有機塩として、例えば、アミノ酸塩酸塩（L-アルギニン塩酸塩など）、酢酸塩（酢酸ナトリウムなど）が好ましく例示される。無機塩として、塩化ナトリウム、塩化カルシウムなどが例示される。 Examples of salts include sodium salts, hydrochlorides, and acetates. As the organic salt, for example, amino acid hydrochloride (L-arginine hydrochloride and the like) and acetate (sodium acetate and the like) are preferably exemplified. Examples of the inorganic salt include sodium chloride and calcium chloride.
本発明の方法における有機塩及び無機塩は、無水物であってもよく、水和物であってもよい。例えば、酢酸ナトリウム水和物は通常３水和物として市販されており、これをそのまま本発明における無機塩として利用することもでき、あるいは、脱水処理を経て得られる酢酸ナトリウム無水物を有機塩として利用することもできる。 The organic salt and the inorganic salt in the method of the present invention may be anhydrous or hydrated. For example, sodium acetate hydrate is usually marketed as a trihydrate, and this can be used as it is as an inorganic salt in the present invention, or sodium acetate anhydride obtained through dehydration treatment can be used as an organic salt. It can also be used.
本願明細書において、「酢酸ナトリウム水和物」は、「酢酸ナトリウム３水和物」を意味する。 In the specification of the present application, "sodium acetate hydrate" means "sodium acetate trihydrate".
本発明に係る水性医薬製剤における電解質の濃度は、下限としては２５０μｇ／ｍＬ以上、５００μｇ／ｍＬ以上、６００μｇ／ｍＬ以上、１ｍｇ／ｍＬ以上、又は、２ｍｇ／ｍＬ以上であることが好ましく、３ｍｇ／ｍＬ以上、５．５ｍｇ／ｍＬ以上であることがさらに好ましく、中でも５．８ｍｇ／ｍＬ以上であることがより好ましい。一方、上限としては２５０ｍｇ／ｍＬ以下、１００ｍｇ／ｍＬ以下、又は２５ｍｇ／ｍＬ以下、１５ｍｇ／ｍＬ以下、１０ｍｇ／ｍＬ以下であることが好ましく、中でも８．８ｍｇ／ｍＬ以下であることがより好ましい。ここで、電解質を２種以上含有する場合には、電解質の合計濃度を指す。 The lower limit of the concentration of the electrolyte in the aqueous pharmaceutical preparation according to the present invention is preferably 250 μg / mL or more, 500 μg / mL or more, 600 μg / mL or more, 1 mg / mL or more, or 2 mg / mL or more, preferably 3 mg / mL or more. It is more preferably mL or more and 5.5 mg / mL or more, and more preferably 5.8 mg / mL or more. On the other hand, the upper limit is preferably 250 mg / mL or less, 100 mg / mL or less, or 25 mg / mL or less, 15 mg / mL or less, 10 mg / mL or less, and more preferably 8.8 mg / mL or less. Here, when two or more kinds of electrolytes are contained, it refers to the total concentration of the electrolytes.
本発明に係る水性医薬製剤における電解質のモル濃度は、下限としては４．３ｍＭ以上、８．６ｍＭ以上、１０．３ｍＭ以上、１７．１ｍＭ以上、又は、３４．２ｍＭ以上であることが好ましく、５１．３ｍＭ以上、９４．１ｍＭ以上であることがさらに好ましく、中でも９９．２ｍＭ以上であることがより好ましい。一方、上限としては４．２８Ｍ以下、１．７１Ｍ以下、又は４２７．８ｍＭ以下、２５６．７ｍＭ以下、１７１．１ｍＭ以下であることが好ましく、中でも１５０．６ｍＭ以下であることがより好ましい。ここで、電解質を２種以上含有する場合には、電解質の合計モル濃度を指す。 The molar concentration of the electrolyte in the aqueous pharmaceutical preparation according to the present invention is preferably 4.3 mM or more, 8.6 mM or more, 10.3 mM or more, 17.1 mM or more, or 34.2 mM or more as the lower limit, 51. It is more preferably 0.3 mM or more and 94.1 mM or more, and more preferably 99.2 mM or more. On the other hand, the upper limit is preferably 4.28 M or less, 1.71 M or less, or 427.8 mM or less, 256.7 mM or less, 171.1 mM or less, and more preferably 150.6 mM or less. Here, when two or more kinds of electrolytes are contained, it refers to the total molar concentration of the electrolytes.
本発明に係る水性医薬製剤におけるテリパラチド又はその塩と電解質の質量比（テリパラチド又はその塩：電解質）は、下限としては例えば１：２以上、１：３以上、１：４以上、又は１：７以上であることが好ましく、１：１０以上、１：１４以上、１：１５以上であることがさらに好ましく、中でも１：２０以上、１：３５以上であることがより好ましく、１：３９以上、１：４１以上であることが最も好ましい。一方、上限としては例えば１：１７７０以下、１：７１０以下、１：５００以下であることが好ましく、１：１８０以下、１：１１０以下、１：８０以下であることがより好ましく、１：６２以下であることが最も好ましい。 The mass ratio of teriparatide or its salt to the electrolyte (teriparatide or its salt: electrolyte) in the aqueous pharmaceutical preparation according to the present invention is, for example, 1: 2 or more, 1: 3 or more, 1: 4 or more, or 1: 7 as the lower limit. It is preferably 1:10 or more, 1:14 or more, 1:15 or more, more preferably 1:20 or more, 1:35 or more, and 1:39 or more. Most preferably, it is 1:41 or more. On the other hand, the upper limit is, for example, 1: 1770 or less, 1: 710 or less, 1: 500 or less, more preferably 1: 180 or less, 1: 110 or less, 1: 80 or less, and 1:62. Most preferably:
本発明に係る水性医薬製剤におけるテリパラチド又はその塩と電解質のモル比（テリパラチド又はその塩：電解質）は、下限としては例えば１：０以上、１：２５０以上、１：３００以上、１：５００以上、１：１０００以上、１：１５００以上、１：２７５０以上、又は１：２９００以上であることが好ましい。一方、上限としては例えば１：１２５０００以下、１：５００００以下、１：１２５００以下、１：７５００以下、１：５０００以下、または１：４４００以下であることが好ましい。 The molar ratio of teriparatide or its salt to the electrolyte (teriparatide or its salt: electrolyte) in the aqueous pharmaceutical preparation according to the present invention is, for example, 1: 0 or more, 1: 250 or more, 1: 300 or more, 1: 500 or more as the lower limit. , 1: 1000 or more, 1: 1500 or more, 1: 2750 or more, or 1: 2900 or more. On the other hand, the upper limit is preferably, for example, 1: 125,000 or less, 1: 50,000 or less, 1: 12500 or less, 1: 7500 or less, 1: 5000 or less, or 1: 4400 or less.
本発明の方法において電解質は、後述する緩衝剤及び／又は添加剤の成分とは同一成分であってもよく、異なる成分であってもよい。 In the method of the present invention, the electrolyte may be the same component as the components of the buffer and / or the additive described later, or may be different components.
（４）振盪による白濁又は分解の抑制
本発明の方法において、振盪とは、本発明に係るプレフィルドシリンジまたはカートリッジ充填製剤を揺れ動かすことを意味し、例えば、搬送時のトラックが与える振動、包装貨物―振動試験法（ランダム試験方法、正弦波掃引試験方法）の適用による振動（JIS Z 0232）、振盪苛酷試験（例：１６０回／分、２５℃）の適用による振動が包含される。 (4) Suppression of white turbidity or decomposition by shaking In the method of the present invention, shaking means shaking the prefilled syringe or cartridge-filled preparation according to the present invention, for example, vibration caused by a truck during transportation, packaged cargo. -Vibration due to application of vibration test method (random test method, sine wave sweep test method) (JIS Z 0232) and vibration due to application of shaking severe test (example: 160 times / min, 25 ° C) are included.
本発明の方法において、白濁とは、本発明のプレフィルドシリンジまたはカートリッジ充填製剤の外観上観察し得る白い濁りを意味する。従前から、製剤を振盪することで白濁することが報告されている（特許文献２）。 In the method of the present invention, the white turbidity means a white turbidity that can be observed from the appearance of the prefilled syringe or the cartridge-filled preparation of the present invention. Previously, it has been reported that the pharmaceutical product becomes cloudy by shaking (Patent Document 2).
（５）本発明の態様１
本発明の第１の態様（態様１と称することもある）として、水性医薬製剤を特定の範囲のイオン強度及び特定の範囲の活量イオン強度となるように調整する方法が挙げられる。 (5) Aspect 1 of the present invention
As a first aspect (sometimes referred to as aspect 1) of the present invention, there is a method of adjusting an aqueous pharmaceutical preparation so as to have an ionic strength in a specific range and an activity ionic strength in a specific range.
タンパク質等の溶解度は溶液に添加した塩のイオン種にも影響を受ける（ホフマイスター系列）ことが知られており、イオンの種類を考慮に入れていないイオン強度のみによって振盪安定性を十分に説明することはできないだろうと考えられる。一方、本態様の方法では、驚くべきことに、イオンの種類に配慮しつつ、溶液中のイオンの実効濃度である「活量」を用いて独自に定義した「活量イオン強度」が特定範囲内である場合に振盪安定性に優れることを新たに見出した。 It is known that the solubility of proteins and the like is also affected by the ionic species of the salt added to the solution (Hofmeister series), and the shaking stability is sufficiently maintained only by the ionic strength without taking the ionic type into consideration. I don't think it can be explained. On the other hand, in the method of this embodiment, surprisingly, the "activity ionic strength" uniquely defined by using the "activity" which is the effective concentration of ions in the solution is specified in a specific range while considering the type of ions. It was newly found that the shaking stability is excellent when it is inside.
水性医薬製剤を特定の範囲のイオン強度及び特定の範囲の活量イオン強度となるように調整する方法としては、例えば、適量の１又は２種類以上の電解質を製剤に配合することが挙げられる。 As a method of adjusting the aqueous pharmaceutical preparation so as to have a specific range of ionic strength and a specific range of activity ionic strength, for example, an appropriate amount of one or two or more kinds of electrolytes may be blended in the preparation.
本発明の態様１において、水性医薬製剤のｐＨをテリパラチド又はその塩のｐＩ未満とすることは、テリパラチド全体の電荷をプラス状態に誘導することで、同製剤におけるイオン強度や活量イオン強度による白濁抑制の制御がさらに良好化するであろう観点から、好ましい。 In aspect 1 of the present invention, setting the pH of the aqueous pharmaceutical preparation to less than the pI of teriparatide or a salt thereof induces the charge of the entire teriparatide to be in a positive state, thereby causing cloudiness due to the ionic strength or activity ionic strength of the same preparation. It is preferable from the viewpoint that the control of suppression will be further improved.
ここで、テリパラチド又はその塩のｐＩ未満とは、先述の通り、具体的には、８．３〜８．４未満（又は８．３未満）を意味するが、テリパラチド全体の電荷をプラス状態に維持するｐＨという観点から、後述の通り、水性医薬製剤のｐＨを中性又は酸性（ｐＨが８．０以下）とすることであってもよい。 Here, less than the pH of teriparatide or a salt thereof specifically means less than 8.3 to 8.4 (or less than 8.3) as described above, but the charge of the entire teriparatide is in a positive state. From the viewpoint of the pH to be maintained, the pH of the aqueous pharmaceutical preparation may be neutral or acidic (pH is 8.0 or less) as described later.
（６）イオン強度：
第１の態様に係る水性医薬製剤のイオン強度Ｉとは、溶液に適用されるような標準の化学的定義を意味し、下記式（１）により表される。
The ionic strength I of the aqueous pharmaceutical preparation according to the first aspect means a standard chemical definition as applied to a solution, and is represented by the following formula (1).
（７）活量係数および活量：
第１の態様の方法において、水性医薬製剤におけるあるイオンの活量係数γiおよび活量ａｉは、イオン強度が０．２０Ｍ未満の場合において、デバイ−ヒュッケル則により、下記の式により与えられる（非特許文献５〜６）。
In the method of the first aspect, the activity coefficient γ i and the activity ai of an ion in the aqueous pharmaceutical preparation are given by the following formula according to the Debye-Huckel rule when the ionic strength is less than 0.20 M. (Non-Patent Documents 5 to 6).
第１の態様に係る水性医薬製剤のイオン強度（Ｍ）は、好適には以下を例示できる。即ち、上限としては例えば０．２０Ｍ未満、０．１９Ｍ以下、０．１８Ｍ以下、０．１７Ｍ以下、０．１６Ｍ以下、０．１５Ｍ以下、または０．１４Ｍ以下とすることが好ましい。下限としては例えば０．００５Ｍ以上、０．０１Ｍ以上、０．０２Ｍ以上、または０．０３Ｍ以上とすることが好ましい。範囲としては、０〜０．１９Ｍ、０．０１〜０．１７Ｍ、０．０１〜０．１５Ｍ、０．０１〜０．１２Ｍ、または０．０１〜０．１０Ｍとすることが好ましい。 The ionic strength (M) of the aqueous pharmaceutical preparation according to the first aspect can preferably be exemplified as follows. That is, the upper limit is preferably, for example, less than 0.20 M, 0.19 M or less, 0.18 M or less, 0.17 M or less, 0.16 M or less, 0.15 M or less, or 0.14 M or less. The lower limit is preferably, for example, 0.005M or more, 0.01M or more, 0.02M or more, or 0.03M or more. The range is preferably 0 to 0.19M, 0.01 to 0.17M, 0.01 to 0.15M, 0.01 to 0.12M, or 0.01 to 0.10M.
（８）活量イオン強度：
本明細書において、本態様に係る水性医薬製剤の活量イオン強度Ｉ（ａ）を、以下にて定義する。活量イオン強度（Ｍ）は、イオン強度Ｉの計算に算入した各イオンの活量を、下記（４）式に算入することにより得る。
In the present specification, the activity ionic strength I (a) of the aqueous pharmaceutical preparation according to this embodiment is defined below. The activity ionic strength (M) is obtained by incorporating the activity of each ion included in the calculation of the ionic strength I into the following equation (4).
第１の態様に係る水性医薬製剤の活量イオン強度は、好適には以下を例示できる。即ち、上限としては例えば０．２０Ｍ以下、０．１８Ｍ以下、０．１４Ｍ以下、０．１３Ｍ以下、０．１０Ｍ以下、０．０８Ｍ以下、０．０７Ｍ以下、０．０６Ｍ以下、または０．０５Ｍ以下とすることが好ましい。下限としては例えば０．００５Ｍ以上、０．０１Ｍ以上、０．０２Ｍ以上、または０．０３Ｍ以上とすることが好ましい。範囲としては、０．００５〜０．０７Ｍ、０．０１〜０．０７Ｍ、０．０１〜０．０６Ｍ、０．０１〜０．０５Ｍ、または０．０１〜０．０４Ｍとすることが好ましい。 The activity ionic strength of the aqueous pharmaceutical preparation according to the first aspect can preferably be exemplified as follows. That is, the upper limit is, for example, 0.20 M or less, 0.18 M or less, 0.14 M or less, 0.13 M or less, 0.10 M or less, 0.08 M or less, 0.07 M or less, 0.06 M or less, or 0.05 M. The following is preferable. The lower limit is preferably, for example, 0.005M or more, 0.01M or more, 0.02M or more, or 0.03M or more. The range is preferably 0.005 to 0.07M, 0.01 to 0.07M, 0.01 to 0.06M, 0.01 to 0.05M, or 0.01 to 0.04M.
（９）イオン強度と活量イオン強度の組合せ：
第１の態様に係る水性医薬製剤のイオン強度（Ｍ）と第１の態様に係る水性医薬製剤の活量イオン強度（Ｍ）の組合せは前記範囲において特に限定されないが、１つの好ましい組合せ態様として、下記表のように、イオン強度が０．２０Ｍ未満であって、かつ、活量イオン強度が０．０７Ｍ以下の組合せを挙げることができる。 (9) Combination of ionic strength and activity ionic strength:
The combination of the ionic strength (M) of the aqueous pharmaceutical preparation according to the first aspect and the activity ionic strength (M) of the aqueous pharmaceutical preparation according to the first aspect is not particularly limited in the above range, but as one preferable combination embodiment. As shown in the table below, a combination having an ionic strength of less than 0.20 M and an activity ionic strength of 0.07 M or less can be mentioned.
（１０）本発明の態様２
本発明の第２の態様（態様２と称することもある）として、水性医薬製剤に界面活性剤を配合する方法が挙げられる。 (10) Aspect 2 of the present invention
As a second aspect of the present invention (sometimes referred to as aspect 2), a method of blending a surfactant with an aqueous pharmaceutical preparation can be mentioned.
本発明においては、上記の第１の態様と第２の態様を組み合わせることもできる。従って、態様２においても、電解質を配合することができ、イオン強度及び活量イオン強度は、前記した態様１での数値範囲をそのまま好適な範囲として選択することができる。 In the present invention, the above-mentioned first aspect and the second aspect can be combined. Therefore, even in the second aspect, the electrolyte can be blended, and the ionic strength and the activity ionic strength can be selected as they are from the numerical range in the above-mentioned aspect 1 as a suitable range.
界面活性剤を配合した場合、活量イオン強度が多少高めであっても、白濁を抑制することができ、活量イオン強度を０．１３Ｍ以下とすることができる。従って、態様２における活量イオン強度は、例えば０．１３Ｍ以下、０．１２Ｍ以下、０．１１Ｍ以下、０．１０Ｍ以下、０．０９Ｍ以下、０．０８Ｍ以下、または０．０７Ｍ以下とすることが好ましい。下限としては例えば０．００５Ｍ以上、０．０１Ｍ以上、０．０２Ｍ以上、または０．０３Ｍ以上とすることが好ましい。範囲としては、０．００５〜０．１３Ｍ、０．０１〜０．１２Ｍ、０．０１〜０．１０Ｍ、０．０１〜０．０８Ｍ、または０．０１〜０．０７Ｍとすることが好ましい。 When a surfactant is blended, cloudiness can be suppressed even if the activity ionic strength is slightly higher, and the activity ionic strength can be set to 0.13 M or less. Therefore, the activity ionic strength in aspect 2 is, for example, 0.13 M or less, 0.12 M or less, 0.11 M or less, 0.10 M or less, 0.09 M or less, 0.08 M or less, or 0.07 M or less. Is preferable. The lower limit is preferably, for example, 0.005M or more, 0.01M or more, 0.02M or more, or 0.03M or more. The range is preferably 0.005 to 0.13M, 0.01 to 0.12M, 0.01 to 0.10M, 0.01 to 0.08M, or 0.01 to 0.07M.
第２の態様に係る水性医薬製剤のイオン強度（Ｍ）と第２の態様に係る水性医薬製剤の活量イオン強度（Ｍ）の１つの好ましい組合せ態様として、下記表のように、イオン強度が０．２０Ｍ未満であって、かつ、活量イオン強度が０．１３Ｍ以下の組合せを挙げることができる。 As one preferable combination of the ionic strength (M) of the aqueous pharmaceutical preparation according to the second aspect and the activity ionic strength (M) of the aqueous pharmaceutical preparation according to the second aspect, the ionic strength is as shown in the table below. Examples thereof include combinations having an activity ionic strength of less than 0.20 M and an activity ionic strength of 0.13 M or less.
第２の態様の方法において使用できる界面活性剤としては、非イオン性界面活性剤が好ましい。非イオン性界面活性剤は、イオン強度や活量イオン強度という因子とは独立して、振盪ストレスに対する安定化効果を奏するだろうと考えるからである。 As the surfactant that can be used in the method of the second aspect, a nonionic surfactant is preferable. This is because we believe that nonionic surfactants will have a stabilizing effect on shaking stress, independent of factors such as ionic strength and activity ionic strength.
非イオン性界面活性剤は、特に限定されないが、例えば、脂肪酸ポリオキシエチレンソルビタンエステルが好ましく、中でも、ポリソルベート８０、ポリソルベート６０、ポリソルベート２０が好ましい。また、非イオン性界面活性剤として、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコールなども例示できる。 The nonionic surfactant is not particularly limited, but for example, the fatty acid polyoxyethylene sorbitan ester is preferable, and among them, polysorbate 80, polysorbate 60, and polysorbate 20 are preferable. Further, examples of the nonionic surfactant include polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene sorbitan monolaurate, and polyoxyethylene (160) polyoxypropylene (30) glycol. can.
界面活性剤の含有量は、特に制限されないが、下限としては、０．００１ｍｇ／ｍＬ以上、０．００５ｍｇ／ｍＬ以上、０．０１ｍｇ／ｍＬ以上、０．０２ｍｇ／ｍＬ以上、０．０３ｍｇ／ｍＬ以上、０．０５ｍｇ／ｍＬ以上、０．１ｍｇ／ｍＬ以上であることが好ましく、上限としては１ｍｇ／ｍＬ以下、０．５ｍｇ／ｍＬ以下、０．３ｍｇ／ｍＬ以下、０．２ｍｇ／ｍＬ以下であることが好ましい。 The content of the surfactant is not particularly limited, but the lower limit is 0.001 mg / mL or more, 0.005 mg / mL or more, 0.01 mg / mL or more, 0.02 mg / mL or more, 0.03 mg / mL. As mentioned above, it is preferably 0.05 mg / mL or more and 0.1 mg / mL or more, and the upper limit is 1 mg / mL or less, 0.5 mg / mL or less, 0.3 mg / mL or less, 0.2 mg / mL or less. It is preferable to have.
（１１）緩衝剤：
本発明の方法に係る水性医薬製剤においては、任意に緩衝剤を含有することができる。緩衝剤は、水溶液のｐＨを安定化させることができる、医薬分野で一般的に使用されるものであれば特に限定されない。本発明の方法に係る緩衝剤として、例えば、酢酸、酒石酸、乳酸、クエン酸、ホウ酸、リン酸、炭酸及びその塩を挙げることができる。より具体的には、酢酸及び酢酸ナトリウム、クエン酸及びクエン酸三ナトリウム、炭酸水素ナトリウム及び炭酸ナトリウム、リン酸二水素ナトリウム及びリン酸水素二ナトリウムを例示できる。このような緩衝剤は、本発明に係る水性医薬製剤において、所望の活量イオン強度を達成するために添加されることもある。 (11) Buffer:
The aqueous pharmaceutical preparation according to the method of the present invention may optionally contain a buffer. The buffer is not particularly limited as long as it can stabilize the pH of the aqueous solution and is generally used in the pharmaceutical field. Examples of the buffer according to the method of the present invention include acetic acid, tartaric acid, lactic acid, citric acid, boric acid, phosphoric acid, carbonic acid and salts thereof. More specifically, acetic acid and sodium acetate, citric acid and trisodium citrate, sodium hydrogen carbonate and sodium carbonate, sodium dihydrogen phosphate and disodium hydrogen phosphate can be exemplified. Such a buffer may be added in the aqueous pharmaceutical preparation according to the present invention in order to achieve the desired activity ionic strength.
本発明に係る水性医薬製剤は緩衝剤を含有する水性医薬製剤であってもよく、実質的に緩衝剤が含まれない水性医薬製剤であってもよい。中でも実質的に酢酸緩衝剤が含まれない水性医薬製剤が好ましい。 The aqueous pharmaceutical preparation according to the present invention may be an aqueous pharmaceutical preparation containing a buffer, or may be an aqueous pharmaceutical preparation substantially free of a buffer. Of these, an aqueous pharmaceutical preparation that does not substantially contain an acetate buffer is preferable.
ここで緩衝剤が「実質的に」含まれないとは、緩衝剤が全く含まれない場合の他に、仮に含まれるとしても、例えば、テリパラチド又はその塩や他の添加物の分解、サルファー処理等のアルカリ対策してないガラス容器に入れた時のアルカリ溶出など、薬液の成分やその反応物、薬液を充填している容器や容器から薬液に溶出される成分、及び、保存時の外部環境が薬液に与える様々な影響などに起因する経時的なｐＨ変動を抑制できない緩衝剤の含有を、含有とみなさないという意味である。 Here, "substantially" the absence of a buffer means that the buffer is not contained at all, and even if it is contained, for example, decomposition of teriparatide or a salt thereof or other additives, sulfation treatment. Ingredients of chemicals and their reactants, such as alkali elution when placed in a glass container without measures against alkali, components eluted into the chemicals from the container or container filled with the chemicals, and the external environment during storage. This means that the inclusion of a buffer that cannot suppress the pH fluctuation over time due to various effects on the chemical solution is not considered to be contained.
緩衝剤が水性医薬製剤に「実質的に」含まれないとみなされる例として、極微量の緩衝剤が水性医薬製剤に含まれる場合を挙げることができる。その量は選択される緩衝剤によって異なり得るが、例えば１ｍＭ以下、好ましくは０．５ｍＭ以下、更に好ましくは０．１ｍＭ以下の濃度の緩衝剤が水性医薬製剤に含まれていたとしても、緩衝剤は水性医薬製剤に「実質的に」含まれないとみなされる。 An example in which the buffer agent is considered to be "substantially" not contained in the aqueous pharmaceutical product may be the case where a very small amount of the buffer agent is contained in the aqueous pharmaceutical product. The amount may vary depending on the buffer selected, but even if the aqueous pharmaceutical preparation contains a buffer having a concentration of, for example, 1 mM or less, preferably 0.5 mM or less, more preferably 0.1 mM or less. Is considered to be "substantially" not included in the aqueous pharmaceutical product.
緩衝剤が水性医薬製剤に「実質的に」含まれないとみなされる別の例としては、ｐＨが特定範囲又は特定値である本発明の水性医薬製剤の態様において、同範囲或いは値の下限及び上限からそれぞれ±１の範囲においては少なくとも緩衝能を有さない緩衝剤の含有を挙げることができる。例えば、ｐＨが４〜５の水性医薬製剤を用いる態様において、ｐＨが３〜６の範囲においては少なくとも緩衝能を有さない緩衝剤を含有する場合や、ｐＨが４．６である本発明の水性医薬製剤の態様において、ｐＨが３．６〜５．６の範囲においては少なくとも緩衝能を有さない緩衝剤を含有する場合には、本態様に係る水性医薬製剤には緩衝剤が「実質的に」含まれないとみなされる。 As another example in which the buffer is considered to be "substantially" not included in the aqueous pharmaceutical product, in the embodiment of the aqueous pharmaceutical product of the present invention in which the pH is in a specific range or a specific value, the same range or the lower limit of the value and the lower limit of the value and In the range of ± 1 from the upper limit, at least the content of a buffer having no buffering ability can be mentioned. For example, in the embodiment of using an aqueous pharmaceutical preparation having a pH of 4 to 5, a buffer having at least no buffering ability in the pH range of 3 to 6 is contained, or the pH of the present invention is 4.6. In the embodiment of the aqueous pharmaceutical preparation, when a buffer having at least no buffering ability is contained in the pH range of 3.6 to 5.6, the buffer is "substantially" in the aqueous pharmaceutical preparation according to this embodiment. It is considered not to be included.
緩衝剤が水性医薬製剤に「実質的に」含まれないとみなされる別の例としては、ｐＨが特定範囲又は特定値の水性医薬製剤を用いる態様において、緩衝剤のｐＫａ±１が同ｐＨ範囲又は値に含まれない又は重複しないような緩衝剤が水性医薬製剤に含まれる場合を挙げることができる。例えば、酢酸緩衝剤のｐＫａ（実際には酢酸のｐＫａである。）は４．７６であるから、この±１は３．７６〜５．７６となり、ｐＨが３．７６未満や５．７６超を示す水性医薬製剤に酢酸緩衝剤が含まれていても、酢酸緩衝剤は水性医薬製剤に「実質的に」含まれないとみなされる。 As another example in which the buffer is considered to be "substantially" not included in the aqueous pharmaceutical product, the pH of the buffer is in the same pH range in the embodiment in which the aqueous pharmaceutical product has a specific pH range or a specific value. Alternatively, the case where a buffering agent that is not included in the value or does not overlap is included in the aqueous pharmaceutical preparation can be mentioned. For example, since the pKa of the acetic acid buffer (actually the pKa of acetic acid) is 4.76, this ± 1 is 3.76 to 5.76, and the pH is less than 3.76 or more than 5.76. The acetate buffer is considered to be "substantially" absent from the aqueous pharmaceutical formulation, even though the aqueous pharmaceutical formulation is considered to contain an acetate buffer.
なお、リン酸は多価酸であって３種類のｐＫａ（２．１２、７．２１、１２．３２）を有することになることから、Ｈ３ＰＯ４とＮａＨ２ＰＯ４、ＮａＨ２ＰＯ４とＮａ２ＨＰＯ４、Ｎａ２ＨＰＯ４とＮａ３ＰＯ４のそれぞれの組み合わせは、個々のｐＨ範囲における緩衝作用を有することになるが、その組み合わせが特に明示されていない場合、上記３つのｐＫａのうちいずれのｐＫａについてもその±１が特定されたｐＨの範囲に含まれない又は重複しないような水性医薬製剤にリン酸緩衝剤が含まれていてもリン酸緩衝剤は水性医薬製剤に「実質的に」含まれないとみなされる。Since phosphoric acid is a polyhydric acid and has three types of pKa (2.12, 7.21, 12.32), H 3 PO 4 , NaH 2 PO 4 , and NaH 2 PO 4. And Na 2 HPO 4 , and each combination of Na 2 HPO 4 and Na 3 PO 4 will have a buffering effect in the individual pH range, but unless the combination is specified, the above three pKa Even if the phosphate buffer is contained in the aqueous pharmaceutical preparation such that ± 1 of any of these pKa is not included in or overlaps with the specified pH range, the phosphate buffer is "substantially" in the aqueous pharmaceutical preparation. It is considered not to be included.
なお、本発明に係る水性医薬製剤にある弱酸（例：酢酸）の共役塩基（例：酢酸ナトリウム）が含まれているが、その弱酸（例：酢酸）が前記製剤に含まれない場合、同共役塩基は、本発明に係る緩衝剤と見做されない。しかし、前述のように、同共役塩基が本発明に係る「電解質」に相当する場合には、本発明に係る「電解質」である。 If a conjugate base (eg, sodium acetate) of a weak acid (eg, acetic acid) in the aqueous pharmaceutical preparation according to the present invention is contained, but the weak acid (eg, acetic acid) is not contained in the preparation, the same shall apply. Conjugate bases are not considered buffers according to the invention. However, as described above, when the conjugate base corresponds to the "electrolyte" according to the present invention, it is the "electrolyte" according to the present invention.
（１２）添加剤：
本発明に係る水性医薬製剤には、各種の添加物を任意に配合することもできる。任意の添加剤として、態様２で挙げた界面活性剤の他、例えば、可溶化剤、安定化剤、等張化剤、ｐＨ調節剤、防腐剤（保存剤）などを挙げることができる。このような添加剤は、本発明の水性医薬製剤において、所望の活量イオン強度や粘度を達成するために添加されることもある。 (12) Additives:
Various additives can be optionally added to the aqueous pharmaceutical preparation according to the present invention. As the optional additive, in addition to the surfactant mentioned in the second aspect, for example, a solubilizer, a stabilizer, an isotonic agent, a pH adjuster, a preservative (preservative) and the like can be mentioned. Such an additive may be added in the aqueous pharmaceutical preparation of the present invention in order to achieve a desired activity ionic strength or viscosity.
本発明に係る可溶化剤として、プロピレングリコール、ジプロピレングリコール、プチレングリコール、ポリエチレングリコールなどを例示できる。 Examples of the solubilizer according to the present invention include propylene glycol, dipropylene glycol, petitene glycol, polyethylene glycol and the like.
本発明に係る等張化剤として、Ｄ−マンニトール、精製白糖、ソルビトール、グルコース、グリセリン、プロピレングリコール、塩化ナトリウム、塩化カリウムなどを例示できる。 Examples of the tonicity agent according to the present invention include D-mannitol, purified sucrose, sorbitol, glucose, glycerin, propylene glycol, sodium chloride, potassium chloride and the like.
本発明に係るｐＨ調節剤として、希塩酸、硫酸、燐酸、水酸化ナトリウム、水酸化カルシウム、水酸化マグネシウム、トリエタノールアミン、などを例示できる。 Examples of the pH adjuster according to the present invention include dilute hydrochloric acid, sulfuric acid, phosphoric acid, sodium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, and the like.
本発明に係る防腐剤（保存剤）として、パラオオキシ安息香酸メチル、パラオオキシ安息香酸エチル、パラオオキシ安息香酸プロピル、安息香酸ナトリウム、フェノール、クレゾール、ソルビン酸、ベンジルアルコールなどを例示できる。 Examples of the preservative (preservative) according to the present invention include methyl paraooxybenzoate, ethyl paraooxybenzoate, propyl paraooxybenzoate, sodium benzoate, phenol, cresol, sorbic acid, and benzyl alcohol.
本発明に係る安定化剤として、マンニトール、キシリトール、ソルビトール、スクロース、グルコース、トレハロース、マルトース、ラクトース、メチオニン、ヒスチジン、デキストラン４０、メチルセルロース、ゼラチン、亜硫酸ナトリウム、メタ亜硫酸ナトリウム、Ｌ−プロリン、ベタイン、エクトイン、ヒドロキシエクトイン、Ｌ−アルギニン或いはその塩酸塩、Ｌ−ヒスチジン或いはその塩酸塩、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン、２−ヒドロキシプロプル−β−シクロデキストリン、Ｌ−リジン或いはその塩酸塩、Ｎ−アセチル−ＤＬ−トリプトファンなどを例示できる。安定化剤として、Ｌ−プロリン、Ｌ−アルギニン或いはその塩酸塩、α−シクロデキストリン、β−シクロデキストリン、Ｌ−リジン或いはその塩酸塩、マンニトール及びメチオニンを好ましく例示でき、Ｌ−アルギニン或いはその塩酸塩を最も好ましく例示できる。 Stabilizers according to the present invention include mannitol, xylitol, sorbitol, sucrose, glucose, trehalose, maltose, lactose, methionine, histidine, dextran 40, methylcellulose, gelatin, sodium sulfite, sodium metasulfate, L-proline, betaine, ectin. , Hydroxyectin, L-arginine or its hydrochloride, L-histidine or its hydrochloride, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropru-β-cyclodextrin, L-lysine or Examples thereof include the hydrochloride salt, N-acetyl-DL-tryptophan and the like. As the stabilizer, L-proline, L-arginine or a hydrochloride thereof, α-cyclodextrin, β-cyclodextrin, L-lysine or a hydrochloride thereof, mannitol and methionine can be preferably exemplified, and L-arginine or a hydrochloride thereof can be preferably exemplified. Can be most preferably exemplified.
（１２−１）Ｌ−アルギニン／Ｌ−アルギニン塩酸塩：
本発明に係る水性医薬製剤にＬ−アルギニン又はＬ−アルギニン塩酸塩を配合することができる。Ｌ−アルギニン塩酸塩は、水性製剤中でイオンとして存在することから、所望の範囲のイオン強度や所望の範囲の活量イオン強度を達成する目的としても添加できる。 (12-1) L-Arginine / L-Arginine Hydrochloride:
L-arginine or L-arginine hydrochloride can be added to the aqueous pharmaceutical preparation according to the present invention. Since L-arginine hydrochloride exists as an ion in an aqueous preparation, it can also be added for the purpose of achieving a desired range of ionic strength and a desired range of activity ionic strength.
Ｌ−アルギニン又はＬ−アルギニン塩酸塩の含有量は、特に制限されないが、Ｌ−アルギニン塩酸塩として、下限としては、１．０ｍｇ／ｍＬ以上、２．０ｍｇ／ｍＬ以上、３．０ｍｇ／ｍＬ以上、３．５ｍｇ／ｍＬ以上であることが好ましく、上限としては１００ｍｇ／ｍＬ以下、８０ｍｇ／ｍＬ以下、６０ｍｇ／ｍＬ以下、５２ｍｇ／ｍＬ以下、５０ｍｇ／ｍＬ以下であることが好ましい。
（１２−２）Ｄ−マンニトール：
本発明に係る水性医薬製剤にＤ−マンニトールを配合することができる。The content of L-arginine or L-arginine hydrochloride is not particularly limited, but the lower limit of L-arginine hydrochloride is 1.0 mg / mL or more, 2.0 mg / mL or more, 3.0 mg / mL or more. , 3.5 mg / mL or more, and the upper limit is preferably 100 mg / mL or less, 80 mg / mL or less, 60 mg / mL or less, 52 mg / mL or less, and 50 mg / mL or less.
(12-2) D-mannitol:
D-mannitol can be added to the aqueous pharmaceutical preparation according to the present invention.
Ｄ−マンニトールの含有量は、特に制限されないが、テリパラチド又はその塩の含有量の１０〜１０００倍程度（質量比）含まれることが好ましい。
（１２−３）メチオニン：
本発明に係る水性医薬製剤にメチオニンを配合することができる。The content of D-mannitol is not particularly limited, but is preferably contained in an amount of about 10 to 1000 times (mass ratio) the content of teriparatide or a salt thereof.
(12-3) Methionine:
Methionine can be added to the aqueous pharmaceutical preparation according to the present invention.
本発明に係る水性医薬製剤にメチオニンを添加する際には、テリパラチド又はその塩の含有量の０．１倍（質量比）以上含まれることが好ましく、０．３倍以上、０．５倍以上、又は０．７倍以上含まれることが更に好ましい。メチオニン添加量の上限については、本発明に係る水性医薬製剤に溶解される範囲において特に限定されないが、例えば、１０．０倍以下、又は５．０倍以下をそれぞれ好ましく例示でき、２．０倍以下を更に好ましく例示でき、１．０倍以下を最も好ましく例示できる。本発明の水性医薬製剤に対するメチオニン添加量として、０．５〜１．０倍程度（テリパラチド又は塩に対する質量比）を好ましく例示できる。 When methionine is added to the aqueous pharmaceutical preparation according to the present invention, it is preferably contained in an amount of 0.1 times (mass ratio) or more, 0.3 times or more, 0.5 times or more the content of teriparatide or a salt thereof. , Or 0.7 times or more is more preferable. The upper limit of the amount of methionine added is not particularly limited as long as it is dissolved in the aqueous pharmaceutical preparation according to the present invention, but for example, 10.0 times or less or 5.0 times or less can be preferably exemplified, and 2.0 times or less. The following can be more preferably exemplified, and 1.0 times or less can be most preferably exemplified. The amount of methionine added to the aqueous pharmaceutical preparation of the present invention is preferably about 0.5 to 1.0 times (mass ratio to teriparatide or salt).
（１３）ｐＨ：
本発明に係る水性医薬製剤のｐＨは特に限定されない。 (13) pH:
The pH of the aqueous pharmaceutical preparation according to the present invention is not particularly limited.
本発明に係る水性医薬製剤のｐＨは、好適には以下を例示できる。即ち、中性又は酸性（ｐＨが８．０以下）であることができ、下限としては例えば３．０以上、３．６以上、３．８以上、４．０以上、４．０超、４．１以上、４．２以上、４．４以上、４．６以上、４．６超、４．７以上、又は４．７超とすることが好ましい。また、上限としては例えば７．０以下、７．０未満、６．０以下、５．０以下、５．０未満、又は４．９以下とすることが好ましい。これら上下限値については、いずれの組み合わせによる範囲としてもよいが、中でも、５．０未満とすることが好ましく、更には、３．０以上かつ５．０未満、３．６以上かつ５．０未満、４．０以上かつ５．０未満、とすることが好ましく、中でも、４．０以上かつ４．９以下の範囲を最も好ましく例示でき、４．７以上かつ４．９以下の範囲とすることもできる。
本発明に係る水性医薬製剤のｐＨは、公知の方法により、例えば、緩衝剤やｐＨ調節剤を用いて調整することができる。The pH of the aqueous pharmaceutical preparation according to the present invention can preferably be exemplified as follows. That is, it can be neutral or acidic (pH is 8.0 or less), and the lower limit is, for example, 3.0 or more, 3.6 or more, 3.8 or more, 4.0 or more, 4.0 or more, 4 It is preferably 1.1 or more, 4.2 or more, 4.4 or more, 4.6 or more, 4.6 or more, 4.7 or more, or 4.7 or more. The upper limit is preferably, for example, 7.0 or less, less than 7.0, 6.0 or less, 5.0 or less, less than 5.0, or 4.9 or less. These upper and lower limit values may be in the range of any combination, but among them, it is preferably less than 5.0, and further, 3.0 or more and less than 5.0, 3.6 or more and 5.0. Less than, 4.0 or more and less than 5.0 are preferable, and among them, the range of 4.0 or more and 4.9 or less can be most preferably exemplified, and the range is 4.7 or more and 4.9 or less. You can also do it.
The pH of the aqueous pharmaceutical preparation according to the present invention can be adjusted by a known method, for example, using a buffer or a pH adjuster.
（１４）本発明の態様３
本発明の第３の態様（態様３と称することもある）として、水性医薬製剤の粘度を特定の範囲内にする方法が挙げられる。本態様の方法では、驚くべきことに、水性医薬製剤の粘度が特定範囲内である場合に振盪安定性に優れることを新たに見出した。 (14) Aspect 3 of the present invention
As a third aspect (sometimes referred to as aspect 3) of the present invention, there is a method of keeping the viscosity of the aqueous pharmaceutical preparation within a specific range. Surprisingly, it has been newly found that the method of this embodiment is excellent in shaking stability when the viscosity of the aqueous pharmaceutical preparation is within a specific range.
水性医薬製剤の粘度を特定範囲内にすることで優れた振盪安定性を示すメカニズムは明らかではないが、本発明者らは、水溶液の粘度を調節することで溶質であるテリパラチドの拡散係数が変わることが関係していると考えている。すなわち、水溶液中においてテリパラチドはブラウン運動しているが、このブラウン運動における溶質の拡散係数Ｄは、以下のStokes-Einstein式（式（５））にて表される。
式（５）に表されるように溶質の拡散係数は溶液の粘度に反比例し、粘度が高くなると拡散係数は小さくなる。拡散係数が小さくなることにより溶質同士の接近頻度が低下し、ファンデルワールス相互作用や疎水性相互作用による凝集が抑制されるだろうと推察する。Although the mechanism of exhibiting excellent shaking stability by keeping the viscosity of the aqueous pharmaceutical preparation within a specific range is not clear, the present inventors change the diffusion coefficient of teriparatide, which is a solute, by adjusting the viscosity of the aqueous solution. I think that is related. That is, teriparatide has a Brownian motion in an aqueous solution, and the diffusion coefficient D of the solute in this Brownian motion is expressed by the following Stokes-Einstein equation (formula (5)).
As represented by the formula (5), the diffusion coefficient of the solute is inversely proportional to the viscosity of the solution, and the diffusion coefficient decreases as the viscosity increases. It is speculated that the smaller the diffusion coefficient, the lower the frequency of solutes approaching each other, and the less agglutination due to van der Waals interaction and hydrophobic interaction.
なお本発明においては、上記の第１の態様及び／または第２の態様と第３の態様を組み合わせることもできる。従って、態様３においても、電解質を配合することができ、イオン強度及び活量イオン強度は、前記した第１の態様や第２の態様での数値範囲をそのまま好適な範囲として選択することもできる。 In the present invention, the first aspect and / or the second aspect and the third aspect described above can be combined. Therefore, even in the third aspect, the electrolyte can be blended, and the ionic strength and the activity ionic strength can be selected as they are from the numerical ranges in the first aspect and the second aspect described above as suitable ranges. ..
粘度を特定範囲内にする場合、水性製剤における活量イオン強度が多少高めであっても、白濁を抑制することができ、活量イオン強度を０．１４Ｍ以下とすることができる。従って、態様３における活量イオン強度は、例えば０．１４Ｍ以下、０．１２Ｍ以下、０．１０Ｍ以下、０．０９Ｍ以下、０．０８Ｍ以下、または０．０７Ｍ以下とすることが好ましい。下限としては例えば０．００５Ｍ以上、０．０１Ｍ以上、０．０２Ｍ以上、または０．０３Ｍ以上とすることが好ましい。 When the viscosity is within a specific range, cloudiness can be suppressed even if the activity ionic strength in the aqueous preparation is slightly higher, and the activity ionic strength can be set to 0.14 M or less. Therefore, the activity ionic strength in Aspect 3 is preferably, for example, 0.14 M or less, 0.12 M or less, 0.10 M or less, 0.09 M or less, 0.08 M or less, or 0.07 M or less. The lower limit is preferably, for example, 0.005M or more, 0.01M or more, 0.02M or more, or 0.03M or more.
また、態様３においても、界面活性剤を配合することができ、界面活性剤の種類や添加量は、前記した態様２での数値範囲をそのまま好適な範囲として選択することができる。 Further, also in the third aspect, the surfactant can be blended, and the type and the amount of the surfactant added can be selected from the numerical range in the above-mentioned aspect 2 as it is as a suitable range.
（１５）粘度：
第３の態様に係る水性医薬製剤の粘度は、２５℃、０．１ＭＰａ環境下における値である。本態様に係る水性医薬製剤の粘度は、好適には以下を例示できる。なお、即ち、上限としては例えば２０ｍPa・ｓ以下、１０ｍPa・ｓ以下、５．０ｍPa・ｓ以下、２．０ｍPa・ｓ以下、１．４０ｍPa・ｓ以下、１．２０ｍPa・ｓ以下とすることが好ましい。下限としては例えば０．９０ｍPa・ｓより大、０．９４ｍPa・ｓ以上、１．０ｍPa・ｓ以上、１．１ｍPa・ｓ以上とすることが好ましい。 (15) Viscosity:
The viscosity of the aqueous pharmaceutical preparation according to the third aspect is a value under an environment of 25 ° C. and 0.1 MPa. The viscosity of the aqueous pharmaceutical preparation according to this embodiment can preferably be exemplified as follows. That is, the upper limit is preferably, for example, 20 mPa · s or less, 10 mPa · s or less, 5.0 mPa · s or less, 2.0 mPa · s or less, 1.40 mPa · s or less, 1.20 mPa · s or less. .. The lower limit is preferably, for example, larger than 0.90 mPa · s, 0.94 mPa · s or more, 1.0 mPa · s or more, and 1.1 mPa · s or more.
本発明に係る水性医薬製剤の粘度は、またJ. Chem. Eng. Data （2013）, 58, "Densities and Viscosities of Erythritol, Xylitol, and Mannitol in L■ascorbic Acid Aqueous Solutions at T = (293.15 to 323.15) K" pp2970?2978（非特許文献５）に基づき算出することができる。具体的な算出方法は後述する。また本発明に係る水性医薬製剤の粘度は、JIS Z 8803：2011にしたがって測定することもできる。 The viscosity of the aqueous pharmaceutical preparation according to the present invention is also determined by J. Chem. Eng. Data (2013), 58, "Densities and Viscosities of Erythritol, Xylitol, and Mannitol in L ■ ascorbic Acid Aqueous Solutions at T = (293.15 to 323.15). ) K "pp2970-2978 (Non-Patent Document 5) can be calculated. The specific calculation method will be described later. The viscosity of the aqueous pharmaceutical preparation according to the present invention can also be measured according to JIS Z 8803: 2011.
本発明に係る水性医薬製剤の粘度は、公知の方法により、例えば、添加剤により調整することができる。粘度の調整に用いる添加剤としては、限定されないが、例えば糖アルコールがある。糖アルコールとしては、マンニトール、キシリトール、ソルビトール、エリスリトール、ガラクチトール、マルチトール、ラクチトール、グリセロール、イノシトールなどを例示できる。マンニトール、キシリトール、ソルビトール、エリスリトールを好ましく例示でき、マンニトールを最も好ましく例示できる。 The viscosity of the aqueous pharmaceutical preparation according to the present invention can be adjusted by a known method, for example, with an additive. Additives used for adjusting the viscosity include, but are not limited to, sugar alcohols, for example. Examples of sugar alcohols include mannitol, xylitol, sorbitol, erythritol, galactitol, maltitol, lactitol, glycerol, and inositol. Mannitol, xylitol, sorbitol, and erythritol can be preferably exemplified, and mannitol can be most preferably exemplified.
態様３における水性医薬製剤の粘度は、前述の通りに例示され得るが、２５℃、０．１ＭＰａ環境下、０．９０ｍPa・ｓより大とすることが、以下の表のとおり、好ましく例示される。 The viscosity of the aqueous pharmaceutical preparation according to the third aspect can be exemplified as described above, but it is preferably more than 0.90 mPa · s in an environment of 25 ° C. and 0.1 MPa, as shown in the table below. ..
（１６）水性医薬製剤の製造方法：(16) Method for producing aqueous pharmaceutical preparation:
本発明に係る水性医薬製剤に含有されるテリパラチド又はその塩は、公知の方法（例えば特許文献１、非特許文献１等に記載の方法）により製造され得る。本発明に係る水性医薬製剤は、公知の種々の製法により製造可能である。例えば、本発明に係る水性医薬製剤を構成する前述の各種の成分を適宜選択し、適切な水性溶媒と混合して溶解させればよい。 The teriparatide or a salt thereof contained in the aqueous pharmaceutical preparation according to the present invention can be produced by a known method (for example, the method described in Patent Document 1, Non-Patent Document 1, etc.). The aqueous pharmaceutical preparation according to the present invention can be produced by various known production methods. For example, the above-mentioned various components constituting the aqueous pharmaceutical preparation according to the present invention may be appropriately selected and mixed with an appropriate aqueous solvent to dissolve them.
本発明に係る水性医薬製剤は、投与前に無菌処理されたものであることが好ましい。無菌処理として無菌操作法を採用する場合には、秤量した各原料を注射用水などに溶解させ、溶解液を濾過滅菌することにより水性医薬製剤を製造することができる。注射用水は、一般的に、発熱性物質（エンドトキシン）試験に適合した滅菌精製水として理解され、蒸留法により製造された注射用水は、注射用蒸留水と称呼される場合もある。 The aqueous pharmaceutical preparation according to the present invention is preferably aseptically treated before administration. When an aseptic technique is adopted as the aseptic treatment, an aqueous pharmaceutical preparation can be produced by dissolving each of the weighed raw materials in water for injection or the like and filtering and sterilizing the dissolved solution. Water for injection is generally understood as sterile purified water that meets the exothermic substance (endotoxin) test, and water for injection produced by the distillation method is sometimes referred to as distilled water for injection.
この注射用水性医薬製剤を、更に洗浄・滅菌処理されたシリンジまたはカートリッジに充填・密封し、場合によってオートインジェクターなどの２次容器に適合させ、検査・包装等を経て、本発明のプレフィルドシリンジまたはカートリッジ充填製剤を製造することができる。シリンジまたはカートリッジの材質は、ガラスやプラスチックを挙げることができる。強度、取扱い容易さ、安全性などの観点から、容器の材質としてプラスチックを好ましく例示できる。 This aqueous pharmaceutical preparation for injection is further filled and sealed in a cleaned and sterilized syringe or cartridge, and in some cases, adapted to a secondary container such as an autoinjector, inspected, packaged, etc., and then the prefilled syringe of the present invention or A cartridge-filled formulation can be produced. The material of the syringe or cartridge may be glass or plastic. From the viewpoint of strength, ease of handling, safety and the like, plastic can be preferably exemplified as the material of the container.
以下、実施例を挙げて本発明を更に詳細に説明する。但し、本発明は以下の実施例にも束縛されるものではなく、本発明の趣旨を逸脱しない範囲において、任意の形態で実施することが可能である。 Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not bound by the following examples, and can be carried out in any form as long as the gist of the present invention is not deviated.
なお、以下の実施例において、「処方」及び「処方製剤」を本発明の「水性医薬製剤」に相当する文言として表記する場合もある。 In the following examples, "prescription" and "prescription product" may be expressed as words corresponding to the "aqueous pharmaceutical product" of the present invention.
実施例１（振盪安定性試験に供した水性医薬製剤の調製）：
下記表５、６に従って処方１〜１５を調製した。 Example 1 (Preparation of an aqueous pharmaceutical preparation for a shaking stability test):
Formulations 1 to 15 were prepared according to Tables 5 and 6 below.
各処方の具体的調製法は次の通りである。
処方１，２，３，７，８，９，１０，１２：まず表５、６中の「添加剤」欄に記載の各添加剤を注射用水と共に混合し、これに主薬のテリパラチド酢酸塩を溶解させ、約８０ｍＬの薬液ａを調製した。さらに、その薬液ａに対して、表５、６中の「ｐＨ調節剤」欄に記載のｐＨ調節剤を添加することで、表５、６中の「ｐＨ」欄に記載のｐＨに調整し、注射用水を添加して１００ｍＬの薬液を調製した。
処方４，５，６：まず表５中の「添加剤」欄に記載の各添加剤のうち、ポリソルベート８０以外の添加剤を注射用水と共に混合し溶解液ｂを調製した。別途ポリソルベート８０を溶解液ｂで溶解して１０ｍｇ／ｍＬポリソルベート８０の溶解液ｃを調製した。表５中の主薬及び添加剤濃度となるように溶解液ｂ、溶解液ｃ及びテリパラチド酢酸塩を混合／溶解し、約８０ｍＬの薬液ｄを調製した。さらに、その薬液ｄに対して、表５中の「ｐＨ調節剤」欄に記載のｐＨ調節剤を添加することで、表５中の「ｐＨ」欄に記載のｐＨに調整し、溶解液ｂを添加して１００ｍＬの薬液を調製した。
処方１１：まず表６中の「添加剤」欄に記載の各添加剤のうち、氷酢酸と酢酸ナトリウム以外の添加剤を注射用水と共に混合し溶解液ｄを調製した。別途２ｍｇ／ｍＬ氷酢酸１０ｍＬと１ｍｇ／ｍＬ酢酸ナトリウム３．３ｍＬを溶解液ｄと溶解させ、溶解液ｅを２００ｍＬ調製した。溶解液ｅ５０ｍＬに主薬のテリパラチド酢酸塩を溶解させ、約１００ｍＬの薬液を調製した。
処方１３，１４，１５：まずテリパラチド酢酸塩を注射用水に溶解させ、これにｐＨ調節剤を添加することで、表６中の「ｐＨ」欄に記載のｐＨに調整した後、注射用水を添加して３００ｍＬの溶解液ｆを調製した。溶解液ｆ４５ｍＬと塩化ナトリウムを溶解させた後、さらに溶解液ｆを添加して５０ｍＬの薬液を調製した。The specific preparation method for each prescription is as follows.
Formulations 1, 2, 3, 7, 8, 9, 10, 12: First, each additive listed in the "Additives" column in Tables 5 and 6 is mixed with water for injection, and the main ingredient teriparatide acetate is added thereto. It was dissolved to prepare about 80 mL of the drug solution a. Further, by adding the pH adjusting agent described in the "pH adjusting agent" column in Tables 5 and 6 to the chemical solution a, the pH is adjusted to the pH described in the "pH" column in Tables 5 and 6. , Water for injection was added to prepare a 100 mL drug solution.
Formulations 4, 5 and 6: First, among the additives listed in the "Additives" column in Table 5, additives other than polysorbate 80 were mixed with water for injection to prepare a solution b. Separately, the polysorbate 80 was dissolved in the solution b to prepare a solution c of 10 mg / mL polysorbate 80. About 80 mL of the drug solution d was prepared by mixing / dissolving the solution b, the solution c and the teriparatide acetate so as to have the concentrations of the main drug and the additive in Table 5. Further, by adding the pH adjusting agent described in the "pH adjusting agent" column in Table 5 to the chemical solution d, the pH is adjusted to the pH described in the "pH" column in Table 5, and the solution b Was added to prepare a 100 mL drug solution.
Formulation 11: First, among the additives listed in the "Additives" column in Table 6, additives other than glacial acetic acid and sodium acetate were mixed with water for injection to prepare a solution d. Separately, 10 mL of 2 mg / mL glacial acetic acid and 3.3 mL of 1 mg / mL sodium acetate were dissolved with the solution d to prepare 200 mL of the solution e. Teriparatide acetate, the main ingredient, was dissolved in 50 mL of the solution e to prepare about 100 mL of the drug solution.
Formulations 13, 14, 15: First, teriparatide acetate is dissolved in water for injection, and a pH adjuster is added thereto to adjust the pH to the pH described in the "pH" column in Table 6, and then water for injection is added. A 300 mL solution f was prepared. After dissolving 45 mL of the solution f and sodium chloride, the solution f was further added to prepare 50 mL of the drug solution.
各処方を濾過滅菌処理した後に、プラスチック製シリンジに０．２ｇずつ充填することによって、各処方が充填された製剤を製造し、振盪安定性試験に供した。 After each formulation was sterilized by filtration, a plastic syringe was filled with 0.2 g each to produce a formulation filled with each formulation, which was subjected to a shaking stability test.
各処方の組成は表５、６中の「主薬」及び「添加剤」欄に記載の通りである。また、各処方のイオン強度および活量イオン強度を前述の方法にしたがって算出し、表５、６中に記載した。参考までに、処方８の計算過程を下記に示す。 The composition of each formulation is as described in the "Main agent" and "Additives" columns in Tables 5 and 6. In addition, the ionic strength and activity ionic strength of each formulation were calculated according to the above-mentioned method and are shown in Tables 5 and 6. For reference, the calculation process of Prescription 8 is shown below.
（１）酢酸イオン濃度の計算（全処方共通）
酢酸イオンの濃度は、下記の平衡を考慮して算出した。
The acetate ion concentration was calculated in consideration of the following equilibrium.
前述の平衡式より、ｐＨ４．１、４．８、５．０、各処方について、［ＡｃＯＨ］／［ＡｃＯ−］値としてそれぞれ４．５７、０．９１２、０．５５０を用いた。From the above equilibrium formula, pH 4.1, 4.8, 5.0 and 4.57, 0.912, 0.550 as [AcOH] / [AcO − ] values were used for each formulation, respectively.
［ＡｃＯＨ］／［ＡｃＯ−］値および下記式を用いて、酢酸イオン濃度［ＡｃＯ−］を算出した。
［ＡｃＯＨ］＋［ＡｃＯ−］＝［酢酸（テリパラチド酢酸塩由来）］＋［氷酢酸（添加）］＋［酢酸ナトリウム（添加）］ The acetate ion concentration [AcO − ] was calculated using the [AcOH] / [AcO − ] values and the following formula.
[AcOH] + [AcO − ] = [Acetic acid (derived from teriparatide acetate)] + [Glacial acetic acid (addition)] + [Sodium acetate (addition)]
（２）各イオンの半径（全処方共通）
各イオンの半径は、非特許文献３から、下記の値を用いた。
ＡｃＯ−：４．５Å
Ｎａ＋：４．０Å
Ｃｌ−：３．０Å(2) Radius of each ion (common to all prescriptions)
For the radius of each ion, the following values were used from Non-Patent Document 3.
AcO − : 4.5 Å
Na + : 4.0 Å
Cl − : 3.0 Å
（３）処方８のイオン強度および活量イオン強度算出過程
イオン強度Ｉの計算には、ナトリウムイオン（Ｎａ＋）、塩化物イオン（Ｃｌ−）および酢酸イオン（ＡｃＯ−）の３種のイオンを算入した。それぞれの濃度は下記のように計算した。
［Ｎａ＋］＝［塩化ナトリウム（添加）］＝０．１３９Ｍ
［Ｃｌ−］＝［塩化ナトリウム（添加）］＋［塩酸（Ｌ−アルギニン塩酸塩由来）］＋［塩酸（ｐＨ調節剤）］＝０．１３９＋０．１０４＋０．２３５ｘ１０−３＝０．２４３Ｍ
ｐＨ４．８における［ＡｃＯＨ］／［ＡｃＯ−］＝０．９１２、および
［ＡｃＯＨ］＋［ＡｃＯ−］＝［酢酸（テリパラチド酢酸塩由来）］＝０．１７１ｘ１０−３Ｍより
［ＡｃＯ−］＝０．１７１ｘ１０−３／（１＋０．９１２）＝０．０９００ｘ１０−３Ｍ
式（１）より、
Ｉ＝１／２ｘ（０．１３９ｘ１２＋０．２４３ｘ（−１）２＋０．０９００ｘ１０−３ｘ（−１）２））＝０．１９Ｍ(3) Ionic Strength and Activity Ionic Strength Calculation Process of Formulation 8 For the calculation of ionic strength I, three types of ions , sodium ion (Na + ), chloride ion (Cl − ) and acetate ion (AcO −), are used. It was included. Each concentration was calculated as follows.
[Na + ] = [sodium chloride (addition)] = 0.139M
[Cl -] = [sodium chloride (additive)] + [hydrochloride (from L- arginine hydrochloride)] + [HCl (pH adjusting agent)] = 0.139 + 0.104 + 0.235x10 -3 = 0.243M
[AcOH] / in pH4.8 [AcO -] = 0.912, and [AcOH] + [AcO -] = [ acid (derived teriparatide acetate)] = 0.171x10 -3 M than [AcO -] = 0 .171x10 -3 / (1 + 0.912) = 0.0900x10 -3 M
From equation (1)
I = 1 / 2x (0.139x1 2 + 0.243x (-1) 2 + 0.0900x10 -3 x (-1) 2 )) = 0.19M
式（２）より、各イオンの活量係数は下記のように計算した。
ｌｏｇγＮａ＋＝−０．５０９ｘ１２ｘＩ０．５／（１＋０．３２９ｘ４．０ｘＩ０．５）＝−０．１４２
γＮａ＋＝１０（−０．１４２）＝０．７２２
ｌｏｇγＣｌ−＝−０．５０９ｘ１２ｘＩ０．５／（１＋０．３２９ｘ３．０ｘＩ０．５）＝−０．１５５
γＣｌ−＝１０（−０．１５５）＝０．７００
ｌｏｇγＡｃＯ−＝−０．５０９ｘ１２ｘＩ０．５／（１＋０．３２９ｘ４．５ｘＩ０．５）＝−０．１３４
γＡｃＯ−＝１０（−０．１３４）＝０．７３４From the formula (2), the activity coefficient of each ion was calculated as follows.
logγ Na + = -0.509x1 2 xI 0.5 / ( 1 + 0.329x4.0xI 0.5) = -0.142
γ Na + = 10 (-0.142) = 0.722
logγ Cl- = -0.509x1 2 xI 0.5 / ( 1 + 0.329x3.0xI 0.5) = -0.155
γ Cl- = 10 (-0.155) = 0.700
logγ AcO- = -0.509x1 2 xI 0.5 /(1+0.329x4.5xI 0.5) = - 0.134
γ AcO- = 10 (-0.134) = 0.734
式（３）より、各イオンの活量は下記のように計算した。
ａＮａ＋＝γＮａ＋ｘ［Ｎａ＋］＝０．７２２ｘ０．１３９＝０．１００Ｍ
ａＣｌ−＝γＣｌ−ｘ［Ｃｌ−］＝０．７００ｘ０．２３４＝０．１７０Ｍ
ａＡｃＯ−＝γＡｃＯ−ｘ［ＡｃＯ−］＝０．７３４ｘ０．０９０００ｘ１０−３＝０．０６５８ｘ１０−３ＭFrom the formula (3), the activity of each ion was calculated as follows.
a Na + = γ Na + x [Na + ] = 0.722 x 0.139 = 0.100M
a Cl- = γ Cl- x [Cl -] = 0.700x0.234 = 0.170M
a AcO- = γ AcO- x [AcO -] = 0.734x0.09000x10 -3 = 0.0658x10 -3 M
式（４）より、活量イオン強度Ｉ（ａ）は下記のように計算した。
Ｉ（ａ）＝１／２ｘ（０．１００ｘ１２＋０．１７０ｘ（−１）２＋０．０６５８ｘ１０−３ｘ（−１）２））＝０．１３ＭFrom the formula (4), the activity ionic strength I (a) was calculated as follows.
I (a) = 1 / 2x (0.100x1 2 + 0.170x (-1) 2 + 0.0658x10 -3 x (-1) 2 )) = 0.13M
また、各処方の粘度を非特許文献５に基づいて算出し、表中に記載した。参考までに、処方１の計算過程を下記に示す。 In addition, the viscosity of each formulation was calculated based on Non-Patent Document 5 and described in the table. For reference, the calculation process of Prescription 1 is shown below.
非特許文献５のＴａｂｌｅ２の”Ｍａｎｎｉｔｏｌ＋０．００００ｍｏｌ・ｋｇ?１ ＶＣ”欄には、マンニトール添加時の０．１ＭＰａにおける溶液の粘度ηが記載されている。Table2に示される粘度ηは、マンニトール濃度および絶対温度に対して線形に相関している。温度：２９３．１５Ｋ，３０３．１５Ｋ、およびマンニトール濃度：０．００００，および０．１９５３ ｍｏｌ／Ｌにおける溶液の粘度η（ｍＰａ・ｓ）を抜粋すると以下のとおりである。In the "Mannitol + 0.0000 mol · kg ? 1 VC" column of Table 2 of Non-Patent Document 5, the viscosity η of the solution at 0.1 MPa when mannitol is added is described. The viscosity η shown in Table 2 is linearly correlated with mannitol concentration and absolute temperature. The following is an excerpt of the viscosity η (mPa · s) of the solution at temperatures: 293.15K, 303.15K, and mannitol concentrations: 0.0000, and 0.1953 mol / L.
上記表４より、293.15Kにおけるマンニトール濃度（mol/L）と粘度η（mPa・s）との関係は以下の式で表される。
粘度η（@293.15K）＝0.5325 x マンニトール濃度 ＋ 1.002 式（６）From Table 4 above, the relationship between the mannitol concentration (mol / L) and the viscosity η (mPa · s) at 293.15 K is expressed by the following formula.
Viscosity η (@ 293.15K) = 0.5325 x mannitol concentration + 1.002 Equation (6)
また、マンニトール濃度(mol/L) 0.1953Mの結果より、絶対温度(K)と粘度η（mPa・s）との関係は以下の式で表される。
粘度η= -0.0231 x 絶対温度 + 7.8778 式（７）
式（７）より、
粘度η（@298.15K）=粘度η（@293.15K）x 0.90 式（８）From the result of mannitol concentration (mol / L) 0.1953M, the relationship between absolute temperature (K) and viscosity η (mPa · s) is expressed by the following formula.
Viscosity η = -0.0231 x Absolute temperature + 7.8778 Equation (7)
From equation (7)
Viscosity η (@ 298.15K) = Viscosity η (@ 293.15K) x 0.90 Equation (8)
式（６）より、
粘度η（処方１、@293.15K）＝0.5325 x 0.078 + 1.002 =1.044
式（８）より、
粘度η（処方１、@298.15K）＝1.044 x 0.90 =0.94From equation (6)
Viscosity η (Prescription 1, @ 293.15K) = 0.5325 x 0.078 + 1.002 = 1.044
From equation (8)
Viscosity η (Prescription 1, @ 298.15K) = 1.044 x 0.90 = 0.94
実施例２（活量イオン強度が振盪安定性に与える影響の確認）：
実施例１で調製した処方２、３、６〜１５を用いて、振盪安定性試験を実施した。
（１）試験方法
各シリンジ製剤を、振とう試験機ＢＲ−３０００ＬＦ（タイテック）に供し、温度２５℃、震盪速度１８０回／分、振幅５ｃｍの条件で、震盪開始後２４時間、４８時間、７２時間、１４４時間および１６８時間後における白濁の有無を目視にて確認した。各試験に１０本ずつ供し、そのうち白濁した本数を表７に示す。 Example 2 (Confirmation of the effect of activity ionic strength on shaking stability):
Shaking stability tests were performed using Formulations 2, 3, 6-15 prepared in Example 1.
(1) Test method Each syringe preparation is subjected to a shaking tester BR-3000LF (Tietech), and under the conditions of a temperature of 25 ° C., a shaking speed of 180 times / minute, and an amplitude of 5 cm, 24 hours, 48 hours, and 72 after the start of shaking. The presence or absence of white turbidity was visually confirmed after hours, 144 hours and 168 hours. Ten of them were used for each test, and the number of white turbid ones is shown in Table 7.
実施例３（粘度が振盪安定性に与える影響の確認）：
実施例１で調製した処方１、２、５〜１５を用いて、振盪安定性試験を実施した。
（１）試験方法
各シリンジ製剤を、振とう試験機ＢＲ−３０００ＬＦ（タイテック）に供し、温度２５℃、震盪速度１８０回／分、振幅５ｃｍの条件で、震盪開始後２４時間、４８時間、７２時間、１４４時間および１６８時間後における白濁の有無を目視にて確認した。各試験に１０本ずつ供し、そのうち白濁した本数を表８に示す。 Example 3 (Confirmation of the effect of viscosity on shaking stability):
Shaking stability tests were performed using Formulations 1, 2, 5-15 prepared in Example 1.
(1) Test method Each syringe preparation is subjected to a shaking tester BR-3000LF (Tietech), and under the conditions of a temperature of 25 ° C., a shaking speed of 180 times / minute, and an amplitude of 5 cm, 24 hours, 48 hours, and 72 after the start of shaking. The presence or absence of white turbidity was visually confirmed after hours, 144 hours and 168 hours. Ten of them were used for each test, and the number of white turbid ones is shown in Table 8.
実施例４（非イオン性界面活性剤の添加が振盪安定性に与える影響の確認）：
実施例１で調製した処方４〜８、１２〜１５を用いて、振盪安定性試験を実施した。
（１）試験方法
各シリンジ製剤を、振とう試験機ＢＲ−３０００ＬＦ（タイテック）に供し、温度２５℃、震盪速度１８０回／分、振幅５ｃｍの条件で、震盪開始後２４時間、４８時間、７２時間、１４４時間および１６８時間後における白濁の有無を目視にて確認した。各試験に１０本ずつ供し、そのうち白濁した本数を表９に示す。 Example 4 (Confirmation of the effect of addition of nonionic surfactant on shaking stability):
Shaking stability tests were performed using Formulations 4-8 and 12-15 prepared in Example 1.
(1) Test method Each syringe preparation is subjected to a shaking tester BR-3000LF (Tietech), and under the conditions of a temperature of 25 ° C., a shaking speed of 180 times / minute, and an amplitude of 5 cm, 24 hours, 48 hours, and 72 after the start of shaking. The presence or absence of white turbidity was visually confirmed after hours, 144 hours and 168 hours. Ten of them were used for each test, and the number of white turbid ones is shown in Table 9.
表７〜９は、水性製剤の活量イオン強度が０．０７Ｍ以下であれば、震盪ストレスによる白濁が抑制されることを示している。また、処方Ｎｏ．４に示されるように、活量イオン強度が０．０７Ｍより大きくても、ポリソルベート８０を共存させることで、震盪ストレスによる白濁が抑制されることが分かる。さらに、処方Ｎｏ．１、２、５、６、９、１０、１１に示されるように、粘度が０．９０ｍＰａ・ｓより大であれば、活量イオン強度の大きさやポリソルベートの添加有無にかかわらず、振盪ストレスによる白濁が抑制されることが分かる。 Tables 7 to 9 show that when the activity ionic strength of the aqueous preparation is 0.07 M or less, the white turbidity due to shaking stress is suppressed. In addition, the prescription No. As shown in 4, even if the activity ionic strength is larger than 0.07 M, it can be seen that the coexistence of polysorbate 80 suppresses cloudiness due to shaking stress. Furthermore, the prescription No. As shown in 1, 2, 5, 6, 9, 10 and 11, if the viscosity is larger than 0.90 mPa · s, it depends on the shaking stress regardless of the magnitude of the activity ionic strength and the addition or absence of polysorbate. It can be seen that cloudiness is suppressed.
本発明の方法により、優れた振盪安定性を有する液状医薬製剤を提供するものであり、医薬品産業において極めて有用である。 The method of the present invention provides a liquid pharmaceutical preparation having excellent shaking stability, which is extremely useful in the pharmaceutical industry.
Claims (3)
I(a)：活量イオン強度、ai:各イオンの活量、ｚｉ：各イオンの電荷（ただし、各イオンとは、前記水性医薬製剤に溶解し、電離している各イオンを意味する） A method for suppressing cloudiness due to shaking stress on a prefilled syringe or cartridge-filled preparation filled with an aqueous pharmaceutical preparation containing teriparatide or a salt thereof and one or more kinds of electrolytes, wherein the prefilled syringe or cartridge is made of plastic. There, the water and the pH of the pharmaceutical formulation teriparatide or isoelectric point of the salt is less than (pI), wherein the ionic strength of the aqueous pharmaceutical formulation to less than 0.20 M, and the activity of the following formula in said aqueous pharmaceutical formulation The electrolyte is blended so that the ionic strength is 0.07 M or less, whereby the ionic strength and the active ionic strength are adjusted, and the prefilled syringe or the cartridge-filled preparation is shaken. How to suppress.
I (a): activity ionic strength, a i: activity of each ion, z i: charge of each ion (where the respective ions, the dissolved in an aqueous pharmaceutical formulation, means the ions are ionized do)
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| JP2008543839A (en) * | 2005-06-14 | 2008-12-04 | アムジェン インコーポレーテッド | Self-buffering protein formulation |
| WO2019059302A1 (en) * | 2017-09-22 | 2019-03-28 | 旭化成ファーマ株式会社 | Teriparatide-containing liquid pharmaceutical composition having excellent stability |
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| JP2008543839A (en) * | 2005-06-14 | 2008-12-04 | アムジェン インコーポレーテッド | Self-buffering protein formulation |
| WO2019059302A1 (en) * | 2017-09-22 | 2019-03-28 | 旭化成ファーマ株式会社 | Teriparatide-containing liquid pharmaceutical composition having excellent stability |
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| Title |
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| 医薬品インタビューフォーム「テリパラチドＢＳ皮下注キット６００ΜＧ「モチダ」, vol. 第１版, JPN6021002382, November 2019 (2019-11-01), ISSN: 0004536414 * |
| 骨粗鬆症治療剤 テリパラチドＢＳ皮下注キット６００ΜＧ 「モチダ」 添付文書, JPN6021002378, September 2019 (2019-09-01), ISSN: 0004536413 * |
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