JPH02111A - Physiologically active peptide preparation for nasotracheal - Google Patents
Physiologically active peptide preparation for nasotrachealInfo
- Publication number
- JPH02111A JPH02111A JP63144704A JP14470488A JPH02111A JP H02111 A JPH02111 A JP H02111A JP 63144704 A JP63144704 A JP 63144704A JP 14470488 A JP14470488 A JP 14470488A JP H02111 A JPH02111 A JP H02111A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- powder
- units
- formulation
- powder composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 238000002360 preparation method Methods 0.000 title abstract description 59
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 11
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- PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229940037525 nasal preparations Drugs 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 235000002949 phytic acid Nutrition 0.000 description 1
- 239000000467 phytic acid Substances 0.000 description 1
- 229940068041 phytic acid Drugs 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 108010094020 polyglycine Proteins 0.000 description 1
- 229920000232 polyglycine polymer Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 108010050934 polyleucine Proteins 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 230000002940 repellent Effects 0.000 description 1
- 239000005871 repellent Substances 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960002101 secretin Drugs 0.000 description 1
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 108010021724 tonin Proteins 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
【発明の詳細な説明】
［発明の目的］
（産業上の利用分野）
本発明は生理活性ペプチド類を有効成分とする経鼻投与
用粉末組成物であって、鼻粘膜より効率よく吸収される
ように改良した上記粉末組成物に関する。[Detailed Description of the Invention] [Object of the Invention] (Industrial Application Field) The present invention is a powder composition for nasal administration containing physiologically active peptides as an active ingredient, which is efficiently absorbed through the nasal mucosa. The present invention relates to the above-mentioned powder composition improved as described above.
（従来の技術） 現在臨床医薬として使われているインシュリン。(Conventional technology) Insulin is currently used as a clinical drug.
カルシトニン類などのペプチドホルモン類は消化管内あ
るいは潤化管壁の酵素により加水分解を受けやすいので
、消化管からの吸収は極めて困難でおる。したがって、
従来は注射剤投与に限られていた。Peptide hormones such as calcitonins are easily hydrolyzed by enzymes in the gastrointestinal tract or in the wall of the lubricating canal, and therefore absorption from the gastrointestinal tract is extremely difficult. therefore,
Previously, administration was limited to injections.
しかしながら、注射剤投与は苦痛を伴うので一般に好ま
れず、他の投与方法が種々試みられている。例えば、生
薬による直腸内投与法（Ｊ、Ｐｈａｒｍ。However, injection administration is generally not preferred because it is painful, and various other administration methods have been attempted. For example, rectal administration using crude drugs (J, Pharm.
Ｐｈａｒｍａｃｏｌ、、 ３３．３３４（１９８１）
） 、気管内投与法（Ｄｉａｂｅｔｅｓ、 ２０．５５
２（１９７１） ） 、点眼投与法（糖尿病学会抄集、
２３７（１９７４） ）などがあるが、何れの方法も
注射に比べ吸収率が低く、また吸収に変動が激しいので
、未だ実用化に至っていない。Pharmacol, 33.334 (1981)
), intratracheal administration method (Diabetes, 20.55
2 (1971)), Eye drop administration method (Abstracts of the Diabetes Society,
237 (1974)), but none of these methods has been put into practical use yet because the absorption rate is lower than that of injection and the absorption fluctuates widely.
＾孔内投与に関する試みも各種付われ、例えば吸収促進
剤として界面活性剤等を用いた経鼻投与法が知られてい
るが（例えば特開昭５９−８９６１９号公報、特開昭５
９−１３０８２０号公報、Ｄｉａｂｅｔｅｓ、 ２７．
２９６゜（１９７７）） 、剤型が液状であるため投与
後流出しやすく、また、界面活性剤の添加や微生物の混
入により安全性や薬剤の安定性が損なわれるという問題
もあり、満足すべきものではなかった。Various attempts have been made regarding intraforaminal administration; for example, nasal administration using a surfactant as an absorption enhancer is known (for example, Japanese Patent Application Laid-Open No. 59-89619, Japanese Patent Application Laid-open No. 59-89,
9-130820, Diabetes, 27.
296゜(1977)), because the dosage form is liquid, it tends to flow out after administration, and the addition of surfactants and the contamination of microorganisms impair the safety and stability of the drug, so it is not satisfactory. It wasn't.
これに対して粉末状の経鼻投与用製剤が提案された。粉
末状の経鼻投与製剤はインタール鼻炎用製剤において既
に昭和５０年には実用化されている。In response, a powdered formulation for nasal administration has been proposed. Powdered nasal preparations have already been put into practical use as preparations for intal rhinitis in 1975.
また、ペプチド製剤でも水吸収性の基剤とからなる経鼻
投与用の粉末状組成物が提案されたく特開昭５９−１６
３３１３号公報）。しかしながら、この製剤は鼻孔内よ
り薬効成分が充分に吸収されないため、実用的な面から
みると必ずしも優れているものとはいい難かった。In addition, for peptide preparations, a powder composition for nasal administration consisting of a water-absorbing base was proposed, and JP-A-59-16
Publication No. 3313). However, since the medicinal ingredients of this preparation are not sufficiently absorbed through the nasal passages, it is difficult to say that it is necessarily superior from a practical standpoint.
（発明が解決しようとする課題）
本発明は上記問題に対処してなされたもので、ペプチド
ホルモン類を有効成分とする鼻孔的投与製剤において、
安全性および製剤の安定性に優れ、また鼻孔内より薬効
成分を充分吸収させることのできる優れた粉末製剤を提
供することを目的とするものである。(Problems to be Solved by the Invention) The present invention has been made to address the above-mentioned problems.
The object of the present invention is to provide an excellent powder preparation which is excellent in safety and stability of the preparation, and which allows the medicinal ingredients to be sufficiently absorbed through the nasal passages.
［発明の構成］
（課題を解決するための手段および作用）本発明者らは
、先にカルシトニン類を有効成分とする経鼻投与用製剤
において、吸収促進剤として水溶性行ｖ１酸を添加し、
さらに増撥剤を加えることによって吸収性良好な経鼻投
与用粉末製剤を１ｑた。さらに研究の結果、他のペプチ
ドホルモンについても優れた吸収性を示す経鼻投与用粉
末製剤が得られることを見出だして本発明に至った。[Structure of the Invention] (Means and Effects for Solving the Problems) The present inventors have previously added a water-soluble acid as an absorption enhancer to a nasal preparation containing calcitonins as an active ingredient. ,
Furthermore, by adding a repellent agent, 1 q of a powder formulation for nasal administration with good absorption was obtained. As a result of further research, it was discovered that a powder preparation for nasal administration that exhibits excellent absorption properties for other peptide hormones can also be obtained, leading to the present invention.
すなわち本発明は、生理活性ペブヂド類を有効成分とす
る経の投与用粉末組成物において、吸収促進剤として水
溶性有機酸を○有し、さらに必要に応じて増■剤を含有
することを特徴とする経の投与用粉末組成物に関する。That is, the present invention is characterized in that a powder composition for oral administration containing physiologically active peptides as an active ingredient has (○) a water-soluble organic acid as an absorption enhancer, and further contains (■) an enhancer if necessary. The present invention relates to a powder composition for administration.
本発明の有効成分である生理活性ペプチド類としては、
生理活性を有するペプチドホルモン、蛋白質、酵素など
であって、例えば、カルシトニン。The physiologically active peptides that are the active ingredients of the present invention include:
Physiologically active peptide hormones, proteins, enzymes, etc., such as calcitonin.
０］甲状腺ホルモン（ＰＴＨ）、カルシ］〜ニン遺伝子
関連ペプヂド（ＣＧＲＰ）、インシュリン、ソマトスタ
ヂン、成艮ホル［ン、セクレヂン、ガストリン、パップ
レシン、オキシトシン、グルカゴン、副腎皮質刺激ホル
モン（ＡＣＴＨ）、甲状腺刺激ホルモン（ＴＳＨ）、プ
ロラクヂン、黄体形成ホルモン放出ホルモン（ＬＨ−Ｒ
Ｈ）、エンドルフィン、エンケファリン、ニューロテン
シンやインターフェロン、インターロイキンなどのリン
ホカインまたはモノ力イン、ならびにスーパーオキシド
ディスムターゼなどの酵素類およびそれらの誘導体、さ
らにそれらの塩類である。0] Thyroid hormone (PTH), calcinogen-related peptide (CGRP), insulin, somatostadin, growth hormone, secretin, gastrin, pappressin, oxytocin, glucagon, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), prolacdine, luteinizing hormone-releasing hormone (LH-R
H), lymphokines or monokines such as endorphins, enkephalins, neurotensins, interferons, and interleukins, enzymes such as superoxide dismutase, derivatives thereof, and salts thereof.
上記の他に、分子咄３万程度迄の公知のベプヂドホルモ
ン、蛋白質、）！素なども包含される。In addition to the above, there are also known peptide hormones and proteins with molecular weights up to about 30,000! Also included are elements.
上記の生理活性ペプチドのうち、好ましい例としては、
分子ｆｆ１１０００〜１００００の範囲に含まれるペプ
チドホルモンまたはその誘導体である。より好適な例と
してはカルシトニン類、副甲状腺ホルモン（Ｐ Ｔ Ｈ
）類、インシュリン類などが挙げられる。Among the above-mentioned physiologically active peptides, preferable examples include:
It is a peptide hormone or its derivative within the range of molecules ff11,000 to 10,000. More preferable examples include calcitonin, parathyroid hormone (PTH
), insulins, etc.
上記のカルシトニン類とは、血清カルシウム低下作用を
有するペプチドであればよく、種々の天然型カルシトニ
ンまたはそのペプチド類似体をいう。天然型カルシ１−
ニンの例としては、ウナギカルシｉ−ニン、ヒトカルシ
１〜ニン、サケ力ルシトニン、ブタカルシトニンまたは
ニワトリカルシトニン等が挙げられる。またそのペプチ
ド類似体の例としては、［ＡＳＵｌ・７］ウナギカルシ
トニン（ＷｆｌＯ−１８名： エルｈ トニン） 、
［ＡＳＵ” ］ サケカルシトニン、［ＡＳＵ１・７
］ヒトカルシトニンまたは［ＡＳｔＪｌ・７コニワトリ
カルシトニン等が挙げられる。特にエルカトニンは本発
明で用いる最も好適なカルシトニン類で市る。これらの
物質や合成法は、例えば英国特許箱１５１６９４７ ＠
明細書、日本化学会第５０春期年会１９８５年講演予稿
集■第９４７頁等に記載されている。さらに、上記以外
のカルシトニン様ペプチドで血清カルシウム低下作用を
有するペプチドであれば本発明に使用できるものであり
、広く骨疾患、内分泌代謝疾患、消化器疾患等に関与し
高カルシウム血症、骨粗髭症における疼痛、骨ベーチェ
ット病等の治療に用いられている。本発明の組成物中の
カルシトニン類の濃度としては、一般に０．１単位／！
１１９〜１００中位／ｍＨの濃度で、好ましくは１弔位
／ｍｌ〜５０単位／ｍｙである。投与量は１０〜５０ｍ
ｇ７回が好ましく、投与回数は一日１〜３回が好適であ
る。The above-mentioned calcitonins may be peptides having a serum calcium-lowering effect, and refer to various natural calcitonins or peptide analogs thereof. Natural calci 1-
Examples of the nin include eel calcitonin, human calcitonin, salmon calcitonin, pig calcitonin, or chicken calcitonin. Examples of its peptide analogues include [ASUl-7] eel calcitonin (WflO-18 name: Elh tonin),
[ASU”] Salmon calcitonin, [ASU1/7
] Human calcitonin or [AStJl/7-chicken calcitonin. In particular, elcatonin is the most preferred calcitonin for use in the present invention. These substances and synthetic methods are disclosed, for example, in British Patent Box 1516947 @
It is described in the specification, Proceedings of the 50th Spring Annual Meeting of the Chemical Society of Japan, 1985 ■, page 947, etc. Furthermore, calcitonin-like peptides other than those mentioned above that have a serum calcium-lowering effect can be used in the present invention, and are widely involved in bone diseases, endocrine metabolic diseases, gastrointestinal diseases, etc., and are associated with hypercalcemia and osteoporosis. It is used to treat pain in beard syndrome, bone Behcet's disease, etc. The concentration of calcitonins in the composition of the present invention is generally 0.1 unit/!
The concentration is between 119 and 100 units/mH, preferably between 1 unit/ml and 50 units/my. Dosage is 10-50m
It is preferable to administer the drug 7 times a day, and the number of administrations is preferably 1 to 3 times a day.
また、ＰＴＨ類としては血清カルシウム上背作用を有す
るペプチド類であって、３４〜８４個のアミノ酸配列を
有し、天然型Ｐ Ｔ Ｈまたはその類似体が知られてい
る。例えばヒト−ＰＴＨ（ｈ−ＰＴＨ） （１−８４
＞ ［８ｉｏｃｈｅｍｉｓｔｒｙ１７．５７２３（１
９７８）］、ｈ−ＰＴＨ（１−３８＞ ［特開昭５７
−８１４４８＠公報］、ｈ−ＰＴＨ（１−３４） ［
Ｈｏｐｐｅ ５ｅｙｌｅｒ’ｓ Ｚ、 Ｐｈｙｓｉ。PTHs are known to be peptides that act on serum calcium, have a sequence of 34 to 84 amino acids, and are natural PTH or its analogs. For example, human-PTH (h-PTH) (1-84
> [8iochemistry17.5723(1
978)], h-PTH (1-38>
-81448@publication], h-PTH (1-34) [
Hoppe 5eyler's Z, Physi.
１、Ｃｈｅｍ、、 ３５５．４１５（１９７４）］ 、
ｈ−ＰＴＨ（１−３４）ＮＨ２［特開昭５８−９６０５
２号公報］、［Ｎｌｅ’ １８］ｈ−ＰＴＨ（１−３４
）、［Ｎｌｅ”８． Ｔｙｒ３’］ ｈ −ＰＴＨ（１
−３４＞ ［特開昭５５−１１３７５３号公報］、［
Ｎｌｅ”８］ ｈ−ＰＴＨ（１−３４＞ ＮＨ２［特開
昭６１−２４５９８号公報］、［Ｎｌｅ”８． Ｔｙｒ
３４］ ｈ−ＰＴＨ（１−３４） Ｎ＋−１２［特開昭
６０−３４９９６号公報］、うｙ ｔ”−ＰＴＨ（１−
８４） 、 ［Ｊ、 Ｂ１１１． ｃｈｅｍ、。1, Chem, 355.415 (1974)],
h-PTH(1-34)NH2 [JP-A-58-9605
No. 2], [Nle' 18]h-PTH (1-34
), [Nle"8. Tyr3'] h -PTH(1
-34> [Unexamined Japanese Patent Publication No. 55-113753], [
Nle"8] h-PTH (1-34> NH2 [JP-A-61-24598], [Nle"8.Tyr
34] h-PTH(1-34) N+-12 [JP-A-60-34996], Uyt"-PTH(1-
84), [J, B111. chem.
２５９ （５） 、 ３３２０ （１９８４） 、ラッ
ト−ＰＴト１（１−３４＞［Ｅｎｄｏｃｒｉｎｏｌ、、
１１７（３） 、 １２３０ （１９８５） ］ 、
］ウシーＰＴ−１（１−８４） ［＾ｍ、 Ｊ、 ｌ
ｅｄ、、 ５０６３９（１９７１） ］ 、ウシＰＴＨ
（１−３４＞ 、ウシ−ＰＴＨ（１−３４） ＮＨ２等
「Ｐｔｈｏｂｉｏｌｏｇｙ ａｎｎｕａｌ １１ 、５
３（１９８１） ］等が挙げられる。259 (5), 3320 (1984), Rat-PT 1 (1-34>[Endocrinol,
117(3), 1230 (1985)],
] Ushi PT-1 (1-84) [^m, J, l
ed, 50639 (1971)], bovine PTH
(1-34>, bovine-PTH (1-34) NH2 etc. "Pthobiology annual 11, 5
3 (1981)].
インシュリン類の例としては、ヒトインシュリン、ブタ
インシュリン、ウシインシュリン、ウマインシュリン、
ヒツジインシュリン等が挙げられる。Examples of insulins include human insulin, porcine insulin, bovine insulin, horse insulin,
Examples include sheep insulin.
本発明に用いられる水溶性有機酸としては、コハク酸、
酒石酸、クエン酸、フマール酸、マレイン酸、マロン酸
、グルタル酸、アジピン酸、リンゴ酸、Ｌ−グルタミン
酸、し−アスパラギン酸。The water-soluble organic acids used in the present invention include succinic acid,
Tartaric acid, citric acid, fumaric acid, maleic acid, malonic acid, glutaric acid, adipic acid, malic acid, L-glutamic acid, and aspartic acid.
グルコン酸およびグルクロン酸等水溶性有機酸の１種ま
たは２種以上の混合物が挙げられる。Examples include one or a mixture of two or more water-soluble organic acids such as gluconic acid and glucuronic acid.
本発明では必要に応じて増量剤を用いる。本発明に用い
られる増量剤は、水溶性または難溶性のもので、例えば
ａ！類、多糖類、デキストリン類、セルロース類、合成
または半合成高分子類、アミノ酸類、ポリアミノ酸類、
タンパク質類、リン脂質類等である。In the present invention, an extender is used as necessary. The filler used in the present invention is water-soluble or poorly soluble, such as a! polysaccharides, dextrins, celluloses, synthetic or semi-synthetic polymers, amino acids, polyamino acids,
These include proteins and phospholipids.
糖類（単糖類、少糖類）としては、例えばＤ−マンニト
ール、ブドウ糖、乳糖、果糖、イノシ１〜−ル、シヨ糖
等が挙げられ、多糖類としてはデキストラン、プルラン
、アルギン酸、ヒアルロン酸。Examples of saccharides (monosaccharides and oligosaccharides) include D-mannitol, glucose, lactose, fructose, inosyl, and sucrose, and examples of polysaccharides include dextran, pullulan, alginic acid, and hyaluronic acid.
ペクヂン酸、フィチン酸、フィチン等が挙げられる。ま
たデキストリン類としてはα−サイクロデキストリン、
β−サイクロデキストリン、γ−サイクロデキストリン
、デキストリン、ヒドロキシプロピルスターチ、ヒドロ
キシエチルスターチ等が挙げられる。Examples include pectic acid, phytic acid, and phytin. In addition, as dextrins, α-cyclodextrin,
Examples include β-cyclodextrin, γ-cyclodextrin, dextrin, hydroxypropyl starch, hydroxyethyl starch, and the like.
さらに、セルロース類としてはメチルセルロース、エチ
ルセルロース、ヒドロキシエチルセルロース、ヒドロキ
シプロピルセルロース、ヒドロキシプロピルメチルセル
ロース、カルボキシメチルセルロースナトリウム等があ
げられる。Furthermore, examples of celluloses include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and the like.
合成および半合成高分子類としてはポリビニルアルコー
ル、カルボキシビニルポリマー、ポリエチレングリコー
ル、ポリビニルピロリドン（ＰＶＰ）、ポリアクリル酸
ナトリ１クム、ポリ乳酸等が挙げられる。Synthetic and semi-synthetic polymers include polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone (PVP), 1cum sodium polyacrylate, polylactic acid, and the like.
アミノ酸としてはグリシン、タウリン等があげられ、ポ
リアミノ酸類としてはポリグルタミン酸。Examples of amino acids include glycine and taurine, and examples of polyamino acids include polyglutamic acid.
ポリアスパラギン酸、ポリグリシン、ポリロイシン等が
挙げられる。Examples include polyaspartic acid, polyglycine, polyleucine, and the like.
タンパク質としては、Ｕラヂン等が挙げられる。Examples of the protein include Uradin and the like.
その他キチン、キトサン等が挙げられる。Other examples include chitin and chitosan.
これらの増量剤の中でも、特にα−サイクロデキストリ
ン、β−サイクロデキストリン、デキストリン、Ｄ−マ
ンニトール、イノシトール、乳糖。Among these bulking agents, in particular α-cyclodextrin, β-cyclodextrin, dextrin, D-mannitol, inositol, lactose.
デキストラン、メチルセルロース、ヒドロキシプロピル
セルロース、ポリビニルアルコール、プルランが好まし
い。Dextran, methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, and pullulan are preferred.
本発明の粉末組成物における各成分の割合は各成分の種
類によって異なるが、−１的にいえば、生理活性ペプヂ
ド約０．００５〜２０重但％、好ましくは約０．０１〜
１０重最％、水溶性有機酸的０．０５〜９９、９９５重
量％、好ましくは約０．５〜９９．９９重椿％であり、
増量剤は必要に応じて添加し、使用する場合は、増■剤
約０．０５〜９９．５重量％である。水溶性有機酸の使
用量は、少なくとも粉末製剤を水に溶解した場合に水溶
液が酸性を示す程度必要であり、臨床使用目的により適
宜きめればよい。The proportion of each component in the powder composition of the present invention varies depending on the type of each component, but in terms of −1, the bioactive peptide is about 0.005 to 20% by weight, preferably about 0.01 to 20% by weight.
10% by weight, 0.05 to 99.995% by weight of water-soluble organic acid, preferably about 0.5 to 99.99% by weight,
A filler is added as necessary, and when used, the amount of filler is about 0.05 to 99.5% by weight. The amount of the water-soluble organic acid used must be at least such that the aqueous solution exhibits acidity when the powder preparation is dissolved in water, and may be determined as appropriate depending on the purpose of clinical use.
この他に粉末製剤化に必要な添加物を必要に応じて添加
することができる。In addition, additives necessary for powder formulation can be added as necessary.
本発明の経鼻投与用粉末製剤物の調製は公知の方法に学
じて行なうことができる。The powder formulation for nasal administration of the present invention can be prepared using known methods.
例えば、ペプチド類に水溶性有機酸あＪ：び必要に応じ
て増量剤を加えて混合してもよく、あるいはペプヂド類
、水溶性有機酸あるいは必要に応じて増量剤からなる混
合物を蒸留水に一度溶解して凍結乾燥した後、粉砕して
均一な経鼻投与用組成物とすることができる。あるいは
ペプチド類と水溶性有機酸を蒸留水に一度溶解して凍結
乾燥した後、粉砕して粉末とし、これに必要に応じて増
量剤あるいは増量剤と水溶性有機酸の混合物を加えて組
成物を得ることもできる。あるいはペプチド類と増量剤
を蒸留水に一度溶解して凍結乾燥した後、粉砕して得た
凍屹扮末に水溶性有機酸または水溶性有機酸と増量剤を
加えて混合して均一な組成物を得ることもできる。For example, peptides may be mixed with a water-soluble organic acid and, if necessary, a filler. Alternatively, a mixture of peptides, a water-soluble organic acid, or a filler, if necessary, may be mixed with distilled water. Once dissolved and lyophilized, it can be pulverized to obtain a uniform composition for nasal administration. Alternatively, the peptides and water-soluble organic acid are once dissolved in distilled water, lyophilized, and then crushed to form a powder, and if necessary, a filler or a mixture of the filler and the water-soluble organic acid is added to form a composition. You can also get Alternatively, the peptides and bulking agent are dissolved in distilled water, freeze-dried, and then crushed to obtain a frozen powder, which is then mixed with a water-soluble organic acid or a water-soluble organic acid and a bulking agent to obtain a uniform composition. You can also get things.
かかる粉末組成物は溶解性に優れているので、各成分の
粒子径は特に限定しないが、８０％以上が３００ミクロ
ン以下であることが好ましい。特に、８０％以上が５〜
２００ミクロンの範囲に分散するようにすると、多少持
続性にすることができる。Since such a powder composition has excellent solubility, the particle size of each component is not particularly limited, but preferably 80% or more is 300 microns or less. In particular, more than 80% of
Dispersion in the 200 micron range allows for some persistence.
本発明の粉末組成物は例えばカプセルに充填して使用時
にこのカプセルを点０用スプレー容器に固定し、釘でカ
プセルの両端に小孔を聞けた後、スプレー容器でエアー
を送り込んで粉末組成物を鼻腔内に噴出させるという方
法で適用されるが、投与方法については特に限定されな
い。The powder composition of the present invention is filled into a capsule, for example, and when used, the capsule is fixed in a point 0 spray container, small holes are made at both ends of the capsule with a nail, and air is introduced into the powder composition using the spray container. It is applied by squirting it into the nasal cavity, but the method of administration is not particularly limited.
本発明の経の投与用粉末組成物は、従来のベプヂドホル
モン経鼻投与用液剤に比べて有効成分の安定性に優れて
いる。また従来のペプチドホルモン経鼻用液剤の場合に
は吸収促進剤として界面活性剤を使用するので鼻粘膜に
対して刺激性が強く、さらに微生物による汚染を防止す
るために防腐剤を加えるのでその副作用が問題となった
か、本発明の経０投与用粉末組成物からなる製剤ではこ
れらの問題がない。The powder composition for intranasal administration of the present invention has superior stability of active ingredients compared to conventional liquid preparations for intranasal administration of vepdide hormone. Furthermore, in the case of conventional peptide hormone nasal solutions, surfactants are used as absorption enhancers, which is highly irritating to the nasal mucosa, and preservatives are added to prevent contamination by microorganisms, resulting in side effects. However, the formulation consisting of the powder composition for oral administration of the present invention does not have these problems.
さらに本発明の経鼻投与用粉末組成物は従来の経鼻投与
用粉末製剤に比べて鼻粘膜からの吸収性が極めてよい。Furthermore, the powder composition for nasal administration of the present invention has extremely good absorbability through the nasal mucosa compared to conventional powder formulations for nasal administration.
（実施例）
以下に実施例および実験例を挙げて、本発明を更に詳し
く説明するが、本発明はこれらに限定されるものではな
い。(Example) The present invention will be explained in more detail with reference to Examples and Experimental Examples below, but the present invention is not limited thereto.
実施例 １
（ａ）エルカトニン（東洋醸造社製） １０，０００単
位とＤ−グルクロンｒ！ｉ２．０ｙに蒸留水５（７を加
え溶解した後、凍結乾燥して均一な凍乾品を（ｑだ。更
に凍屹晶を乳鉢中に取り粉砕して粉末製剤を得た。Example 1 (a) Elcatonin (manufactured by Toyo Jozo Co., Ltd.) 10,000 units and D-glucuronr! After adding 5 (7) of distilled water to i2.0y and dissolving it, it was freeze-dried to obtain a uniform freeze-dried product ((q).Furthermore, the frozen crystals were taken in a mortar and crushed to obtain a powder preparation.
このようにして１ｑられた粉末製剤はエルカトニン５単
位／／１７９を含有した。The powder formulation thus made 1q contained 5 units//179 units of elcatonin.
この粉末製剤は経の投与用粉末製剤として供するもので
ある。This powder preparation is provided as a powder preparation for oral administration.
（ｂ）エルカトニン１０．０００単位とコハク酸２，０
７に蒸留水５０ｄを加え溶解した後、凍結乾燥して均一
な凍吃品を１ｑた。史に凍屹晶を乳鉢中に取り粉砕して
粉末製剤を冑た。このようにして１ｑられた粉末製剤は
エルカトニン５単位／ｍｇを含イ１した。(b) Elcatonin 10,000 units and succinic acid 2,0
7 was dissolved by adding 50 d of distilled water, and then lyophilized to obtain 1 q of uniform frozen product. The frozen crystals were placed in a mortar and crushed to form a powder formulation. The powder formulation thus prepared contained 5 units/mg of elcatonin.
この粉末製剤は経の投与用粉末製剤として供するもので
ある。This powder preparation is provided as a powder preparation for oral administration.
実施例 ２
（ａ）エルカトニン（［ＡＳＵｌ・７］ウナギカルシト
ニン６．０００中位／ｍｙ） ５０，０００単位とＤ−
？ン二１〜−ル４９１．４ｍＦＩをビーカーに取り、蒸
留水２５ｒｎ１を加えて溶解した後、溶解液を凍結乾燥
し乳鉢で粉砕して均一なエルカトニン１００甲位／Ｉｒ
１Ｈを含有する凍屹粉末を得た。Example 2 (a) Elcatonin ([ASUl・7] eel calcitonin 6.000 medium/my) 50,000 units and D-
? Take 491.4mFI of Elcatonin in a beaker, add 25rn1 of distilled water to dissolve it, freeze-dry the solution, and grind it in a mortar to obtain a uniform elcatonin of 100 K/Ir.
A frozen powder containing 1H was obtained.
製剤 １
次いで得られたエルカ１〜ニン１００単位／覆含有した
凍乾扮末（Ｄ−マンニトール含有）２０１ｎｌとＤグル
クロン酸１００ｍｆｆを乳鉢中に取り、よく混合した後
、デキストラン（シグマ社製、平均分子和４０．２００
） ８８０ｍｇを徐々に加えながら混合することに
より均一な粉末製剤を得た。このようにして得られた粉
末製剤はエルカトニン２単位／ｍｇを含有した。Formulation 1 Next, 201 nl of the obtained freeze-dried powder (containing D-mannitol) containing 100 units of Eruca 1 to Nin and 100 mff of D-glucuronic acid were placed in a mortar, mixed well, and then dextran (manufactured by Sigma, average Molecular sum 40.200
) A homogeneous powder formulation was obtained by gradually adding and mixing 880 mg. The powder formulation thus obtained contained 2 units/mg of elcatonin.
本粉末製剤は後述の通り経鼻投与用粉末製剤として供す
るものである。This powder preparation is provided as a powder preparation for nasal administration as described below.
製剤 ２
上述の（ａ）で得られたＴルカトニン１００単位／ｍｙ
含有した凍乾扮末（Ｄ−マンニトール含有）２０Ｉｎ３
とＤ−グルクロンＭ ２ｏｏｍｇを乳鉢中に取り、よく
混合した後、デキストラン（シグマ社製、平均分子ｆｆ
ｉ ４０，２００ ） ７８０ｍｇを徐々に加えなが
ら混合することにより均一な粉末製剤を１ｑた。このよ
うにして１ｑた粉末製剤はエルカトニン２単位／Ｉｎ３
を含有し、経の投与用粉末製剤として供した。Formulation 2 T-katonin obtained in (a) above 100 units/my
Freeze-dried powder (containing D-mannitol) containing 20In3
and D-glucuron M 2 oomg in a mortar, mix well, and add dextran (manufactured by Sigma, average molecular weight ff
i 40,200 ) 780 mg was gradually added and mixed to give 1 q of homogeneous powder formulation. Thus, 1 q of powdered preparation contains 2 units of elcatonin/In3
It was provided as a powder preparation for oral administration.
製剤 ３
上述の（ａ）で得られたエルカトニンｉｏｏ弔位／ｍｙ
含有した凍乾粉末（Ｄ−マンニトール含有）２０Ｉｎ９
とＤ−グルクロン酸５００ｍｇを乳鉢中に取り、よく混
合した後、デキストラン（シグマ社製、平均分子量４０
，２００ ） ４８０ｍｇを徐々に加えながら混合す
ることにより均一な粉末製剤を得た。このようにして得
た粉末製剤はエルカトニン２単位／ｍｌを含有し、経鼻
投与用粉末製剤として供した。Formulation 3 Elcatonin ioo/my obtained in (a) above
Freeze-dried powder (containing D-mannitol) containing 20In9
and 500 mg of D-glucuronic acid in a mortar, mixed well, and then added dextran (manufactured by Sigma, average molecular weight 40
, 200 ) was gradually added and mixed to obtain a homogeneous powder formulation. The powder preparation thus obtained contained 2 units/ml of elcatonin and was used as a powder preparation for nasal administration.
製剤 ４（対照〉
上述の（ａ）で得られたエルカトニン１００単位／ｍｙ
含有した凍乾粉末２ａｎｇを、乳鉢中に取り、デキスト
ラン（シグマ社製、平均分子１４０，２００ ）９８０
ｍｇを徐々に加えながら混合することにより均一な粉末
製剤を得た。これは本発明の製剤と比較するための製剤
であって、有機酸を含有していない。このＪ：うにして
１りた粉末製剤はエルカトニン２単位／ｍ’Ｊを含有し
た。Formulation 4 (Control) Elcatonin 100 units/my obtained in (a) above
Take 2 ang of the contained freeze-dried powder in a mortar and add dextran (manufactured by Sigma, average molecular weight 140,200) 980
A homogeneous powder formulation was obtained by mixing while gradually adding mg. This is a formulation for comparison with the formulation of the present invention and does not contain organic acids. This J:1 powder formulation contained 2 units of elcatonin/m'J.
実験例 １
日本白色種雄性ウサギ（体重３Ｋｇ前後、１群５羽）を
１晩絶食させた後、麻酔下にて鼻腔内に、上記の実施例
２の製剤１および製剤２の各製剤（５単位／ ２．５ｍ
ｌ／ＫＦＩ＞を投与した。また上記比較例の製剤／１（
Ｄ−グルクロン酸無添加）を同様に投与した。Experimental Example 1 Japanese White male rabbits (body weight around 3 kg, 5 rabbits per group) were fasted overnight, and then each of the formulations 1 and 2 of Example 2 (5 lbs. Unit/2.5m
l/KFI> was administered. In addition, formulation/1 of the above comparative example (
(without addition of D-glucuronic acid) was administered in the same manner.
投与前および投与後１時間、２時間、３時間。Before administration and 1 hour, 2 hours, and 3 hours after administration.
４時間、６時間毎にウサギ耳動脈より２ｄづつ採血した
。採血後、３．００Ｏｒ、ｐ、ｍ、 １０分間遠心分離
して血漿を冑た。2 d of blood was collected from the rabbit ear artery every 4 and 6 hours. After blood collection, the blood was centrifuged at 3.00 Or, p, m for 10 minutes to remove plasma.
血漿中のカルシウム濃度の測定は原子吸光度計を用いて
行なった。Calcium concentration in plasma was measured using an atomic absorption spectrometer.
ｂ）結果
エルカトニン経鼻投与製剤を投与後、血漿中力ルシウム
濃度を測定しエルカトニンの鼻粘膜からの吸収を調べた
結果を第１図に示す。この図から明らかなように、本発
明の各製剤は対照量である製剤４に比較して投与後着し
い血漿中力ルシウム濃度の低下を示した。b) Results After administering the nasal preparation of elcatonin, the plasma lucium concentration was measured and the absorption of elcatonin from the nasal mucosa was investigated. The results are shown in FIG. As is clear from this figure, each of the formulations of the present invention showed a decrease in plasma lucium concentration after administration compared to formulation 4, which was the control dose.
このことはエルカトニンに吸収促進剤としてＤ−グルク
ロン酸を添加することにより鼻粘膜からの吸収を著しく
増加することを示している。This indicates that the addition of D-glucuronic acid as an absorption enhancer to elcatonin significantly increases its absorption through the nasal mucosa.
実施例 ３
エルカトニン５，０００単位とアジピンＭ ５００ｍｇ
を蒸留水１０ｏ認に溶解して凍結乾燥して均一なエルカ
トニン１０ｍＦ１単位を含有するアジピン酸（凍乾粉末
）を得た。上記で得られたエルカ１ヘニン１０単位／ｍ
Ｆｌを含有するアジピン酸（凍乾粉末） １００ｍ１
を乳鉢中に取り、予め粉砕したアジピンＭ ４ｏｏｍｇ
を徐々に添加しながらよく混合することにより均一な粉
末製剤を１ワた。このＪ：うにして１ｑられた扮末製剤
はエルカトニン２単位／ＩＷｇを含有した。Example 3 Elcatonin 5,000 units and Adipine M 500mg
was dissolved in distilled water at 10° C. and lyophilized to obtain uniform adipic acid (lyophilized powder) containing 10 mF 1 unit of elcatonin. Elca 1 henin 10 units/m obtained above
Adipic acid containing Fl (lyophilized powder) 100ml
in a mortar and pre-pulverized Adipine M 4oomg
By gradually adding and mixing thoroughly, a uniform powder formulation was prepared. This J: 1q powder formulation contained 2 units/IWg of elcatonin.
本粉末製剤および以下に述べるいずれの粉末製剤も同様
に経鼻投与用粉末製剤として供するものである。This powder preparation and any of the powder preparations described below are similarly provided as powder preparations for nasal administration.
実施例 ４
エルカトニン５．０００１位と１−グルタミン酸２．０
７を蒸留水２００威に溶解して凍結乾燥し、エルカトニ
ン２．５単位／ｍｇを含有する［−グルタミン酸（凍乾
品）を得た。更に凍屹品を乳鉢に取り粉砕して、粉末製
剤を得た。Example 4 Elcatonin at position 5.0001 and 1-glutamic acid at position 2.0
7 was dissolved in 200 g of distilled water and lyophilized to obtain [-glutamic acid (lyophilized product)] containing 2.5 units/mg of elcatonin. Furthermore, the frozen product was placed in a mortar and ground to obtain a powder preparation.
実施例 ５
エルカトニン５ 、０００単位とＤ−マンニトール５０
ｍｇを蒸留水５ｍ！！に）ｄ解して凍結乾燥し、エルカ
トニン１００単位／ｍＦＩを含有するＤ−マンニトール
（凍乾粉末）を得た。Example 5 Elcatonin 5,000 units and D-mannitol 50
mg to 5m of distilled water! ! ) D-mannitol (lyophilized powder) containing 100 units of elcatonin/mFI was obtained by thawing and lyophilizing.
上記で１９られたエルカトニン１００甲位／ｍＦＩを含
有するＤ−マンニトール（凍乾粉末）ｉｏｍｙと予め微
粉砕した酒石酸１ｏｏｍｇを乳鉢中にとりＪ：り混合し
た後、微粉砕したプルラン（林原生物化学研究所社製、
ＰＩ−２０） ３９０ｍｙを徐々に添加しながら混
合して、均一な粉末製剤を得た。D-mannitol (freeze-dried powder) iomy containing elcatonin 100 K/mFI determined above and 1 oomg of tartaric acid that had been finely ground in advance were placed in a mortar and mixed, and then finely ground pullulan (Hayashibara Biochemical Research Manufactured by Shosha,
PI-20) 390my was gradually added and mixed to obtain a uniform powder formulation.
このようにして得られた粉末製剤はエルカトニン２単位
／ｍ！９を含有した。The powder formulation thus obtained contained 2 units of elcatonin/m! Contained 9.
実施例 ６
サケカルシトニン（４，０００単位／ｍｇ） ５，０
００単位と１−グルタミン酸１．０ｇを蒸留水１００ｄ
に溶解して凍結乾燥し、凍屹品を粉砕してナケカルシト
ニン５単位／ｍｌを含有する粉末製剤を得た。Example 6 Salmon calcitonin (4,000 units/mg) 5,0
0 units and 1.0 g of 1-glutamic acid in 100 d of distilled water.
The product was dissolved in water and freeze-dried, and the frozen product was pulverized to obtain a powder preparation containing 5 units/ml of Nana calcitonin.
Ｘ圧１ｉ
Ｄ−マンニトール（和光純桑、試薬特級）５０ｍｙとエ
ルカトニン（６，０００単位７ｍｇ） ５，０００単
位に蒸留水５ｍ！！を加え溶解した後、溶解液を凍結乾
燥して均一なエルカトニン１００弔位／ｍＦｌを含有す
る粉末を得た。X pressure 1i D-mannitol (Wako Pure Mulberry, special grade reagent) 50my and elcatonin (6,000 units 7mg) 5,000 units and distilled water 5m! ! After adding and dissolving the solution, the solution was freeze-dried to obtain a uniform powder containing 100 elcatonin/mFl.
更にコハク酸（和光紬薬、試桑特級） ５００ｍｇお
よびＤ−マンニトール５００ｍｇの各々に蒸留水５０＋
ｍを加え溶解した後凍結乾燥して１ｑだ粉末を、乳鉢に
て粉砕して、コハク酸の凍乾粉末およびＤ−マンニトー
ルの凍乾粉末をそれぞれ得た。Furthermore, 500 mg of succinic acid (Wako Tsumugi Yakuhin, Saikuwa Special Grade) and 500 mg of D-mannitol were added with 50+ distilled water.
After adding and dissolving m, the powder was freeze-dried and pulverized in a mortar to obtain a freeze-dried powder of succinic acid and a freeze-dried powder of D-mannitol, respectively.
上記の各凍乾粉末を使って以下に示す製剤５を調製した
。Formulation 5 shown below was prepared using each of the above-mentioned freeze-dried powders.
誓亙互■遷１
上記で得られたエルカトニン１００１位／ｍｇ含有した
Ｄ−マンニトール（凍乾粉末）１０ｍ７、同様に上記で
１ｑられた］ハク酸（凍乾粉末）５０ｍｇを乳鉢中にと
りよく混合した後、ヒドロキシプロピルセルロース（日
本曹達社製、トＩＰｃ −Ｌ ） ４４０ｍｇヲ徐々
に加えながら混合することにより均一な粉末製剤を得た
。このにうにして冑られた粉末製剤はエルカトニン２単
位／ｍｇを含有した。10ml of D-mannitol (freeze-dried powder) containing elcatonin 1001/mg obtained above and 50mg of succinic acid (freeze-dried powder) obtained above (1q) were mixed well in a mortar. After that, 440 mg of hydroxypropyl cellulose (IPc-L, manufactured by Nippon Soda Co., Ltd.) was gradually added and mixed to obtain a uniform powder preparation. This soured powder formulation contained 2 units/mg of elcatonin.
また対照としてコハク酸（凍９２粉末）の代りに上記で
得られたマンニトール（凍乾粉末）５０７７１ｇを用い
てブランク製剤を同様に調製した。As a control, a blank formulation was similarly prepared using 50,771 g of mannitol (freeze-dried powder) obtained above instead of succinic acid (freeze-dried powder).
実験例 ２
日本内色種雄性ウサギ（体重３ Ｋ１前後、１群５羽）
を１晩絶食させた後、麻酔下にて碍腔内に実施例７の製
剤５のエルカトニン経碍投与用粉末製剤（４単位／２ｍ
！ｊ／Ｋｇ）を投与した。Experimental example 2 Japanese domestic colored male rabbits (weight around 3K1, 5 rabbits per group)
After fasting overnight, a powdered formulation of elcatonin for oral administration (4 units/2 m
! j/Kg) was administered.
また実施例７で対照として調製した２単位／ｍｙのエル
カトニンを含有しコハク酸を含まないブランク製剤を製
剤５と同様に投与した。In addition, a blank formulation containing 2 units/my of elcatonin and no succinic acid prepared as a control in Example 7 was administered in the same manner as Formulation 5.
投与前および投与後１時間、２時間、３時間。Before administration and 1 hour, 2 hours, and 3 hours after administration.
４時間、６時間毎にウサギ■動脈より２ｄづつ採血した
。採血後３．００Ｏｒ、 Ｉ）、 ｍ、 １０分間遠心
分離して血漿を得た。Two days of blood was collected from the rabbit artery every 4 and 6 hours. After blood collection, the blood was centrifuged for 10 minutes at 3.00 Or, I) to obtain plasma.
血漿中のカルシウム濃度の測定は原子吸光光度削を用い
て行なった。Measurement of calcium concentration in plasma was performed using atomic absorption spectrophotometry.
なお、血中のカルシウム濃度の基準値（１００％）は投
与５分前に採血した値を示している。Note that the reference value (100%) of the calcium concentration in blood indicates the value obtained from blood collected 5 minutes before administration.
ｂ）結果
上記実験例２の結果を第２図に示す。すなわち第２図は
ブランク製剤（４単位／２ｍｇ／ＫＦＩ”）の碍粘膜投
与（−ロー）と製剤５（４単位／２ｍび／に３）の鼻粘
膜投与（−〇−）後の各々の血中カルシウム濃度の変化
を示すものである。b) Results The results of Experimental Example 2 above are shown in FIG. That is, Figure 2 shows the results of administration of the blank formulation (4 units/2 mg/KFI'') to the nasal mucosa (-low) and formulation 5 (4 units/2 mg/KFI'') to the nasal mucosa (-〇-). This shows changes in blood calcium concentration.
図面から明らかなように、水溶性有機酸の添加により血
中のカルシウム濃度はブランク製剤の結果と比較して有
意に低下していることがわかる。As is clear from the drawing, it can be seen that the addition of the water-soluble organic acid significantly lowers the calcium concentration in the blood compared to the results of the blank preparation.
実施例 ８
■ルカトニン５ 、０００単位とコハクＭ ２５ｈｙｇ
を蒸留水２５ｄに溶解して凍結乾燥し、エルカトニン２
０単位／ｍＦｌを含有するコハク酸（凍乾粉末）を）ｑ
だ。Example 8 ■ Lukatonin 5,000 units and Amber M 25hyg
was dissolved in 25 d of distilled water and lyophilized to obtain elcatonin 2.
Succinic acid (lyophilized powder) containing 0 units/mFl)
is.
上記で得られたエルカトニン２０９位／ｍぴを含有する
コハク酸（凍屹粉末）５０ｍｇを乳鉢中に取り、ヒドロ
キシプロピルセルロース（日本曹達社製。50 mg of succinic acid (frozen powder) containing ercatonin 209/mpi obtained above was placed in a mortar, and hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd.) was placed in a mortar.
ＨＰＣ−１） ４５０ｍｇを徐々に添加しながらよく
混合することにより均一な粉末製剤を得た。HPC-1) 450 mg was gradually added and mixed well to obtain a uniform powder formulation.
このようにして１ｑられた粉末製剤はエルカトニン２単
位／ηを含有した。The powder formulation thus made 1q contained 2 units/η of elcatonin.
得られた粉末製剤を経鼻用カプセルに１０〜５ｏｍｇ充
填することにより、ヒト用の経の投与用製剤を１ｑだ。By filling 10 to 5 omg of the obtained powder preparation into a nasal capsule, 1 q of the preparation for oral administration to humans is obtained.
実施例 ９
エルカトニン５ 、０００単位とＤ−マンニトール５０
ｍ３を蒸留水５ｍｌに溶解して凍結乾燥し、エルカトロ
ン１００単位／ＩＲ１Ｉを含有するＤ−マンニトール（
凍乾粉末）を得た。上記で得られたエルカトロン１００
単位／ｍＦＩを含有するＤ−マンニトール（凍乾粉末＞
１０＃１ｇと予め微粉砕したコハク酸５０ｍｇを乳鉢中
にとりよく混合した後、ヒドロキシプロビルセ／Ｌｚロ
ース（日本曹達社製、 ＮＰＣ−１＞ ４４０ｍｇを
徐々に添加しながら混合して、均一な粉末製剤を得た。Example 9 Elcatonin 5,000 units and D-mannitol 50
m3 was dissolved in 5 ml of distilled water and lyophilized to obtain D-mannitol (containing 100 units of elcatron/IR1I).
Freeze-dried powder) was obtained. Elcatron 100 obtained above
D-mannitol (lyophilized powder) containing units/mFI>
After thoroughly mixing 1 g of 10 #1 and 50 mg of succinic acid finely ground in a mortar in a mortar, 440 mg of hydroxyprovirce/Lz loin (manufactured by Nippon Soda Co., Ltd., NPC-1) was gradually added and mixed to form a homogeneous mixture. A powder formulation was obtained.
このようにして得られた粉末製剤はエルカトニン２単位
／ｍｌを含有した。゛
得られた粉末製剤を経鼻用カプセルに１０〜５ｏｍｇ充
填してヒト用の経の投与用製剤を得た。The powder formulation thus obtained contained 2 units/ml of elcatonin. 10 to 5 omg of the obtained powder preparation was filled into nasal capsules to obtain a preparation for oral administration to humans.
実施例 １０
サケカルシトニン（４，０００単位／ｍ’ｌ） ５，
０００威１位とＬ−グルタミン酸２５０ｍ１を蒸留水２
５ｒｎＩｌに溶解して凍結乾燥し、サケカルシトニン２
０中位／ｍｌを含有する［−−グルタミン酸（凍乾粉末
）を得た。Example 10 Salmon calcitonin (4,000 units/m'l) 5,
000 Wei1 and L-glutamic acid 250ml with distilled water 2
Salmon calcitonin 2 was dissolved in 5rnIl and lyophilized.
[--Glutamic acid (lyophilized powder) containing 0 medium/ml was obtained.
上記で得られたサケカルシトニン２０中位／ｍ３含有す
るし一グルタミン酸（凍乾粉末）５０４を乳鉢中にとり
、デキストラン（シグマ製、平均分子徂４０２００ ）
４５０ｒＩＩｇを徐々に添加しながらよく混合する
ことにより、均一な粉末製剤を得た。504 of salmon monoglutamic acid (lyophilized powder) containing salmon calcitonin 20 medium/m3 obtained above was placed in a mortar, and dextran (manufactured by Sigma, average molecular size 40200) was placed in a mortar.
A homogeneous powder formulation was obtained by gradually adding 450 rIIg and mixing well.
Ｘ匹叢−ユユ
リーグカルシトニン５，０００単位とアジピンｒｔｉ１
２５ｍｇオよびイノシトール８７５１ｆｔｇをビーカー
にとり、これに蒸留水１００威を加えて溶解し、凍結乾
燥して凍乾固形物を得た。これを乳鉢中にとり、粉砕し
てサケカルシトニン（５甲位／Ｉｎ！Ｊ）を含有する粉
末組成物を得た。X plexus - 5,000 units of yuri calcitonin and adipine rti1
25 mg of inositol and 8,751 ftg of inositol were placed in a beaker, 100 g of distilled water was added thereto to dissolve it, and the mixture was freeze-dried to obtain a freeze-dried solid. This was placed in a mortar and pulverized to obtain a powder composition containing salmon calcitonin (5th order/In!J).
実施例 １２
ｈ−Ｐ Ｔ Ｈ（１−３４） ５，０００単位とグリシ
ン２５０ｍｇを蒸留水２５ｍ１に溶解して凍結乾燥し、
ｈ−ＰＴＨ（１−３４） ２０中位を含有するグリシン
（凍乾粉末）を得た。Example 12 5,000 units of h-P T H (1-34) and 250 mg of glycine were dissolved in 25 ml of distilled water and lyophilized.
Glycine (lyophilized powder) containing about 20 h-PTH(1-34) was obtained.
上記で１ｑられたｈ−Ｐ Ｔ ｌ−１（１−３４）２０
単位／■を含有するグリシン（凍乾粉末＞ １ｏｏｍ
ｇを乳鉢中に取り、予め粉砕した酒石酸３００ｆｆｉＪ
を徐々に添加しながらよく混合することにより均一な粉
末製剤を得た。h-P T l-1 (1-34) 20 obtained by 1q above
Glycine (freeze-dried powder > 1oom) containing unit/■
Take g in a mortar and add 300ffiJ of pre-pulverized tartaric acid.
A uniform powder formulation was obtained by gradually adding and mixing thoroughly.
実施例 １３
（ａ）ブタインシュリンナトリウムＷ （ＣＡＬＢＩＯ
ＣＩ＋ＥＨ社￥Ａ２６．３ｕ／ｍｌ、水分９．８８％＞
１００ｍｇを乳鉢中にとり、Ｄ−グルクロン酸９０
０＃１ｇを徐々に加えながら混合することにより均一な
インシュリン粉末製剤を得た。このようにして得られた
粉末製剤はインシュリン２．３７ ｕ／ｍ！ｊ （実測
値）を含有した。Example 13 (a) Porcine insulin sodium W (CALBIO
CI+EH ￥A26.3u/ml, moisture 9.88%>
Take 100mg in a mortar and add 90mg of D-glucuronic acid.
A homogeneous insulin powder preparation was obtained by gradually adding and mixing 0#1g. The powder formulation thus obtained has an insulin content of 2.37 u/m! j (actually measured value).
（ｂ）ブタインシュリンナトリウム塩（ＣＡＬＢＩＯＣ
ＩＩＥＨ社製２６．３ｕ／＊、水分９．８８％） １
ｏｏｍｇを乳鉢中にとり、アジピン酸９００１ｆｔｇを
徐々に加えながら混合することにより均一なインシュリ
ン粉末製剤を得た。このようにして得られた粉末製剤は
インシュリン２．３７１Ｊ／ｍ’ｊ （実測値）を含有
した。(b) Porcine insulin sodium salt (CALBIOC
Made by IIEH 26.3u/*, moisture 9.88%) 1
oomg was placed in a mortar and mixed while gradually adding 9001 ftg of adipic acid to obtain a uniform insulin powder formulation. The powder formulation thus obtained contained 2.371 J/m'j (actual value) of insulin.
（Ｃ）ブタインシュリンナトリウム塩（ＣＡＬ８１０Ｃ
１ｌＥＭ社Ｍ ２６．３ｕ／ｍｙ、水分９．８８％＞
１ｏｏｍｇを乳鉢中にとり、無水クエンＭ ９００／
ｆｆｇを徐々に加えながら混合することにより均一なイ
ンシュリン粉末製剤を得た。このようにして得られた粉
末製剤はインシュリン２．３７ ｕ／ＩＩＩ！ｊ （実
測値）を含有シタ。(C) Porcine insulin sodium salt (CAL810C
1lEM M 26.3u/my, moisture 9.88%>
Take 1 oomg in a mortar and add anhydrous citric M 900/
A uniform insulin powder formulation was obtained by gradually adding and mixing ffg. The powder formulation thus obtained has an insulin content of 2.37 u/III! Contains j (actual value).
叉凰桝−ユＡ
（ａ）ブタインシュリンナトリウム塩（ＣＡＬＢＩＯＣ
ＩＩＥＭ社製２６．３１Ｊ ／ＩＱ、水分９．８８％＞
１ｏｏｍ３とＤ−グルクロンｌ １００ｍｇを乳鉢
中にとりよく混合した後、更に増量剤としてデキストラ
ン（シグマ社製。叉凰桝-Yu A (a) Porcine insulin sodium salt (CALBIOC
IIEM 26.31J/IQ, moisture 9.88%>
After thoroughly mixing 1oom3 and 100mg of D-glucuronin in a mortar, dextran (manufactured by Sigma) was added as a bulking agent.
平均分子量４０，２００） ８００ｍぴを徐々に加え
ながら混合することにより均一な粉末製剤６を得た。こ
のようにして得た粉末製剤はインシュリン２．３７ ｕ
／ｍ！？（実測値）を含有した。A uniform powder formulation 6 was obtained by mixing while gradually adding 800 mpi (average molecular weight: 40,200). The powder formulation thus obtained contained 2.37 u of insulin.
/m! ? (Actually measured value).
（ｂ）ブタインシュリンナトリウム塩（ＣＡＬＢＩＯＣ
Ｅｌ（社製２６．３ｕ／ｍｙ、水分９．８８％） １
ｏｏｍｇとＤ−グルクロン酸２００ｍｇを乳鉢中にとり
、よく混合した後、更に増量剤としてデキストラン（シ
グマ社製。(b) Porcine insulin sodium salt (CALBIOC
El (manufactured by 26.3u/my, moisture 9.88%) 1
oomg and 200 mg of D-glucuronic acid were placed in a mortar and mixed well, followed by dextran (manufactured by Sigma) as a bulking agent.
平均分子ａ ４０，２００ ） ７００ｍｇを徐々に
加えながら混合することにより均一な粉末製剤を１ｑた
。このようにして１ｑだ粉末製剤はインシュリン２．３
７１Ｊ／ｍ！Ｊ（実測値）を含有した。A homogeneous powder formulation of 1 q was prepared by gradually adding and mixing 700 mg of average molecular weight a 40,200 ). In this way, 1 q of powdered preparation has 2.3 ml of insulin.
71J/m! J (actually measured value).
（Ｃ）ブタインシュリンナトリウムＷ （ＣＡＬＢＩＯ
ＣＩＩ団礼装２６．３ｕ／ｍｙ、水分９．８８％）
１００ｍ７とＤ−グルクロン［３００ｍＦｌを乳鉢中に
とりよく混合した後、更に増量剤としてデキストラン（
シグマ社製、平均分子量４０，２００ ） ６００ｍ
ｇを徐々に加えながら混合することにより均一な粉末製
剤を冑た。このようにして１ｑた粉末製剤はインシュリ
ン２．３７ ｕ／ｍｙ（実測値）を含有した。(C) Porcine insulin sodium W (CALBIO
CII formal dress 26.3u/my, moisture 9.88%)
After thoroughly mixing 100 m7 and D-glucuron [300 mFl in a mortar, add dextran (
Manufactured by Sigma, average molecular weight 40,200) 600m
A homogeneous powder formulation was prepared by mixing while gradually adding g. 1 q of the powder formulation thus obtained contained 2.37 u/my (actual value) of insulin.
（ｄ＞ブタインシュリンナトリウムＷ （ＣＡＬＢＩＯ
ＣＨＥＭ社製２６．３ ｕ ７ｍｇ、水分９．８８％＞
１００ｍｇとコハクＷ ２００ｍｇを乳鉢中にとり
よく混合した後、さらに増量剤としてデキストラン（シ
グマ社製、平均分子ＩＭ ４０，２００ ＞ ７００
ｒｔｖ）を徐々に加えながら混合することにより均一な
粉末製剤を冑た。このようにして冑た粉末製剤はインシ
ュリン２．３７ｕ／ｍ！Ｊ（実測値）を含有した。(d>Porcine insulin sodium W (CALBIO
CHEM 26.3 u 7mg, moisture 9.88%>
After thoroughly mixing 100 mg of Amber W and 200 mg of Amber W in a mortar, dextran (manufactured by Sigma, average molecular weight IM 40,200 > 700) was added as a bulking agent.
A homogeneous powder formulation was prepared by gradually adding and mixing the mixture (rtv). The powder formulation prepared in this way has an insulin level of 2.37 u/m! J (actually measured value).
（ｅ）ブタインシュリンナトリウム塩（ＣＡＬＢＩＯＣ
ＩＩ［Ｈ社製２Ｂ、３ｕ ７ｍ３．水分９．８８％）
１００ｍｇと酒石酸２００ｍｙを乳鉢中にとりよく混
合した後、さらに増量剤としてデキストラン（シグマ社
製、平均分子量４０□２００ ） ７００ｍｇを徐々
に加えながら混合することにより均一な粉末製剤を得た
。このようにして冑た粉末製剤はインシュリン２．３７
ｕ／ｍｙ （実測値）を含有した。(e) Porcine insulin sodium salt (CALBIOC
II [H Company 2B, 3u 7m3. moisture 9.88%)
After thoroughly mixing 100 mg of tartaric acid and 200 my of tartaric acid in a mortar, 700 mg of dextran (manufactured by Sigma, average molecular weight: 40□200) as a bulking agent was gradually added and mixed to obtain a uniform powder preparation. The powder preparation prepared in this way has an insulin concentration of 2.37
u/my (actual value).
（ｆ）ブタインシュリンナトリウム塩（ＣＡＬＢＩＯＣ
ＩＩ［８社Ｍ ２６．３ Ｕ ／ｍＦＩ、水分９．８８
％＞ １００＃ｌ！Ｊと無水クエン酸２００ｍｇを乳
鉢中にとりに ＜ ｆ１合した後、さらに増量剤として
デキストラン（シグマ社製。(f) Porcine insulin sodium salt (CALBIOC
II [8 companies M 26.3 U/mFI, moisture 9.88
%＞100#l! After combining J and 200 mg of anhydrous citric acid in a mortar, add dextran (manufactured by Sigma) as a bulking agent.
平均分子ｆｊｊｒ ４０，２００ ） ７００ｍｇを
徐々に加えながら混合することにより均一な粉末製剤を
得た。このようにして１ｑだ粉末製剤はインシュリン２
．３７ ｕ／ｍｓ ＜実測値）を含有した。A uniform powder formulation was obtained by gradually adding and mixing 700 mg of the average molecular weight fjjr 40,200. In this way, 1 q of powdered preparation can be converted into 2 q of insulin.
．． 37 u/ms <actual value).
（ｇ）ブタインシュリンナトリウム塩（ＣＡＬＢ ｌｏ
ＣＩＩＥＨ社’１２６．３ Ｌｌ ７ｍｇ、水分９．８
８％） １ｏｏｍｇを乳鉢中にとり、デキストラン（
シグマ社製、平均分子量４０，２００ ＞ ９００ｍ
ｇを徐々に加えながら混合することにより均一な粉末製
剤を冑た。このＪ、うにして得た粉末製剤はインシュリ
ン２．３７ ｕ／ｍｇ （実測値）を含有した。これは
本発明の製剤と比較するための有機酸を含有しない対照
量である。(g) Porcine insulin sodium salt (CALB lo
CIIEH '126.3 Ll 7mg, moisture 9.8
8%) Take 10mg in a mortar and add dextran (
Manufactured by Sigma, average molecular weight 40,200 > 900m
A homogeneous powder formulation was prepared by mixing while gradually adding g. The powder preparation obtained in this manner contained 2.37 u/mg (actual value) of insulin. This is a control amount containing no organic acid for comparison with the formulation of the invention.
実験例 ３
日水白色種７ｊｔ性ｒクサキ（体重３ Ｋ’ｊ前後、ｌ
’ｌ’５羽）を投与前１７時間絶食させた後、ベンドパ
ルビタール＜２５ｍ！ｊ／Ｋｌ’）麻酔下にて獅腔内に
実施例１４の製剤６および比較のため調製した実施例１
４の対照量のインシュリンＳ有扮末製剤を５単位／２．
１ｍｇ／ Ｋｇ投与した。Experimental example 3 Nissui white species 7jt sex r Kusaki (weight around 3 K'j, l
'l' 5 birds) after fasting for 17 hours before administration, bentoparbital <25 m! j/Kl') Formulation 6 of Example 14 and Example 1 prepared for comparison into the lion cavity under anesthesia.
5 units/2.4 control amount of insulin S supplement powder preparation.
1 mg/Kg was administered.
投与前５分おＪ：び投与後３０分、１時間、２時間。5 minutes before administration and 30 minutes, 1 hour, and 2 hours after administration.
３時間、４時間、６時間にウサギ耳動脈より２７！づつ
採血した。採血後３．ｏｏｏｒ、ｐ、ｍ、 １０分間遠
心分離して血漿を得た。27 from the rabbit ear artery at 3, 4 and 6 hours! Blood was drawn one by one. After blood collection 3. ooor, p, m, centrifuged for 10 minutes to obtain plasma.
インシュリン製剤の鼻粘膜からの吸収性の評価は血漿中
のグルコース濃度の低下を測定することにより行ない、
和光ＨＡ薬（Ｇｌｕｃｏｓｅ−Ｔｅｓｔ ＷＡＫＯ）の
臨床検査薬キットを用いて血漿中のグルコース濃度を測
定した。The absorption of insulin preparations through the nasal mucosa is evaluated by measuring the decrease in plasma glucose concentration.
Glucose concentration in plasma was measured using a clinical test kit from Wako HA Pharmaceuticals (Glucose-Test WAKO).
なお、血漿中グルコース濃度の基準値（１００％）は投
与前に採血した値を示している。Note that the reference value (100%) of plasma glucose concentration indicates the value obtained by blood collection before administration.
ｂ）結果
上記実験の結果を第３図に示す。Ｊなわち第３図は粉末
製剤６（−〇＝）および対照量（−ロー）のウサギの嬶
腔内投与後の血漿中のグルコース濃度の変化を示すもの
である。b) Results The results of the above experiment are shown in FIG. FIG. 3 shows changes in plasma glucose concentration after intraluminal administration of powder formulation 6 (-0=) and control amount (-low) to rabbits.
図面から明らかなように、吸収促進剤としてのＤ−グル
クロン酸を添加することにより、対照量に比較してイン
シュリンが鼻粘膜より効率よく吸収されたことを示して
いる。As is clear from the drawing, by adding D-glucuronic acid as an absorption enhancer, insulin was absorbed more efficiently through the nasal mucosa compared to the control amount.
実施例 １５
■ルカトニン５０，０００単位とＤ−マンニトール１９
０ｍｇをビーカーにとり、蒸留水ｉｏｍ１を加えて溶解
した侵、溶解液を凍結乾燥し、乳鉢で粉砕した均一なエ
ルカトニン２５０単位／ｍｇを含有する凍乾扮末を１ｑ
だ。Example 15 ■ 50,000 units of lucatonin and D-mannitol 19
Take 0mg of elcatonin in a beaker, add ioml of distilled water to dissolve it, freeze-dry the solution, and grind in a mortar to obtain 1q of lyophilized powder containing uniform 250 units/mg of elcatonin.
is.
（ａ）上記で冑られたエルカトニン２５０単位／ｍ’Ｊ
を含有した凍乾（分末２０ｍｇとＤ−グルクロン１２０
０ｍｇを乳鉢中にとり、よく混合した後、デキストラン
（シグマ社製、平均分子Ｅｉ ６６．３００ ） ７
８０ｍｇを徐々に加えながら混合することにより均一な
粉末製剤を１ｑだ。さらに２０ｍｇを２号カプセルに充
填した。この様にして１ｑられたカプセル剤は１カプセ
ル当りエルカトニン１ｏ ｏ ｉ、ｐ位を含有した。実
際の投与はカプセルをスプレーに固定した後、カプセル
の両端に孔を開け、空気を送り先端より粉末を鼻腔内に
投与する。(a) 250 units of elcatonin/m'J as obtained above
Freeze-dried (20 mg fraction and D-glucuron 120
After placing 0 mg in a mortar and mixing well, add dextran (manufactured by Sigma, average molecular Ei 66.300) 7
By gradually adding 80 mg and mixing, 1 q of a homogeneous powder preparation is obtained. An additional 20 mg was filled into No. 2 capsules. The capsules prepared in this manner contained 1 o o i, p of elcatonin per capsule. For actual administration, after fixing the capsule to the sprayer, holes are made at both ends of the capsule, air is sent through the tip, and the powder is administered into the nasal cavity.
（ｂ＞上記で得られたエルカトニン２５０弔位／Ｉｎ！
ｊ含有した凍乾粉末４ｏｍｇとＤ−グルクロン酸２００
ｍ３を乳鉢中にとり、よく混合した後、プルラン（ＰＩ
−２０） ７６０ｍｇを徐々に加えながら混合する
ことにより均一な粉末製剤を得た。さらに１ｑられた粉
末製剤を経鼻用２号カプセルに１０〜５０ｍ３充填する
ことにより、ヒト用の経内投与用製剤を得た。この様に
して得られたカプセル剤は１カプセル当りエルカトニン
１００〜５００単位を含有した。(b>250 elcatonin obtained above/In!
4 omg of freeze-dried powder containing j and 200 g of D-glucuronic acid
m3 in a mortar, mix well, and add pullulan (PI).
-20) A uniform powder formulation was obtained by gradually adding and mixing 760 mg. Furthermore, by filling 10 to 50 m3 of the powdered preparation into nasal No. 2 capsules, a preparation for intranasal administration for humans was obtained. The capsules thus obtained contained 100-500 units of elcatonin per capsule.
丈厖叢−ユ１
ｈ−ＰＴＨ（１−３４） ４０，０００中位とＤ−マン
ニトール１９０ｍ！ｊをビーカーにとり、蒸留水１０ｒ
ＩＩｌを加えて溶解した後、溶解液を凍結乾燥し、乳鉢
で粉砕して均一なｈ−ＰＴＨ（１−３４） ２００中位
／ＩｎＦｌヲ含有スル凍乾粉末を得た。Length Kusou-Yu 1 h-PTH (1-34) 40,000 medium and D-Mannitol 190m! Take j in a beaker and add 10 liters of distilled water.
After adding and dissolving IIl, the solution was freeze-dried and ground in a mortar to obtain a uniform freeze-dried powder containing h-PTH(1-34) 200 medium/InFl.
（ａ）上記で）？られたｈ−ＰＴＨ（１−３４） ２０
０１位／ｍｇを含有した凍乾扮末を２ｏｍｇとＤ−グル
クロン酸２００ｍｇを乳鉢中にとり、よく混合した後デ
キストラン（シグマ社製、平均分子ｍ ４０，２００
＞ ７８０ｍ１を徐々に加えながら混合することによ
り均一な粉末製剤を得た。さらに２５ｍｇを２＠カプセ
ルに充填することにより、１カプセル当りｈ−Ｐ Ｔ
Ｈ（１−３４）１００中位を含有するヒト用の経鼻投与
用粉末製剤を得た。(a) above)? h-PTH(1-34) 20
01/mg of lyophilized powder and 200 mg of D-glucuronic acid were placed in a mortar and mixed well.
> 780 ml was gradually added and mixed to obtain a homogeneous powder formulation. Furthermore, by filling 2@capsules with 25 mg, h-P T per capsule
A powder preparation for intranasal administration for humans containing H(1-34) of about 100 was obtained.
（ｂ）上記で得られたｈ−Ｐ Ｔ Ｈ（１−３４） ２
００中位／ｍｇを含有した凍乾粉末４ｏｍｇとＤ−グル
クロン酸２００ｍＦＩを乳鉢中にとり、よく混合した後
、ヒドロキシプロピルセルロース（日本曹達社製、ＨＰ
Ｃ−１） ７６０ｍ１を徐々に加えながら混合して均
一な粉末製剤を得た。さらに２５ｍｔ）、 ５０ｍｇを
２号カプセルにそれぞれ充填することにより、１カプセ
ル当りｈ−Ｐ Ｔ ｌ−１（１−３４） ２００中位、
４００単位のヒト用の経鼻投与用粉末製剤を得た。(b) h-P T H(1-34) 2 obtained above
4 omg of freeze-dried powder containing 00 medium/mg and 200 mFI of D-glucuronic acid were placed in a mortar, mixed well, and then hydroxypropyl cellulose (manufactured by Nippon Soda Co., Ltd., HP
C-1) 760ml was gradually added and mixed to obtain a uniform powder formulation. Furthermore, by filling 25 mt) and 50 mg into No. 2 capsules, h-P T l-1 (1-34) 200 medium per capsule,
A powder formulation for nasal administration of 400 units for humans was obtained.
実施例 １７
製剤７の調製
エルカトニン５，０００単位とＤ−グルクロン酸２．０
ｇに蒸留水５０ｍを加え溶解した後凍結乾燥して均一な
乾燥品を）ｑた。さらに凍屹品を乳鉢中に取り粉砕して
粉末製剤を得た。このＪ：うにして得られたう）末製剤
はエルカトニン２゜５弔位／ｍＦｌを含有した。Example 17 Preparation of Formulation 7 5,000 units of elcatonin and 2.0 units of D-glucuronic acid
After dissolving 50 ml of distilled water in g, the mixture was freeze-dried to obtain a uniform dried product. Further, the frozen product was placed in a mortar and ground to obtain a powder preparation. The powder preparation obtained in this manner contained elcatonin at 2.5 mF/mFl.
また対照としてＤ−グルクロン酸の代りにＤマンニトー
ルを用いて同様に調製して対照品（エルカトニン２．５
ψ位／ｍｌ’）を得た。In addition, as a control, a control product (elcatonin 2.5
ψ position/ml') was obtained.
艮赳旦五遷ｌ
エルカトニン５，０００単位とコハク１２．０９に蒸留
水５０ｄを加え溶解した後、凍結乾燥して均一な乾燥品
を得た。さらに凍吃品を乳鉢中に取り粉砕して粉末製剤
を冑た。このようにして得られた粉末製剤はエルカトニ
ン２．５単位／ｍｇを含有した。5000 units of elcatonin and 12.09 units of amber were dissolved in 50 d of distilled water, and then freeze-dried to obtain a uniform dried product. Furthermore, the frozen product was placed in a mortar and ground to form a powder formulation. The powder formulation thus obtained contained 2.5 units/mg of elcatonin.
実験例 ４
日本白色種雄性ウサギ（体重３ Ｋ’ｊ前後、１群５羽
）を１晩絶食した後、麻酔下にて鼻腔内に実施例１７の
製剤７および製剤８（５単位／２ｍｙ／Ｋｙ＞を投与し
た。Experimental Example 4 Japanese White male rabbits (body weight around 3 K'j, 5 rabbits per group) were fasted overnight, and then Formulation 7 and Formulation 8 of Example 17 (5 units/2my/ Ky> was administered.
また実施例１７て対照として調製した対照品（有機酸の
代りにマンニトールを用いた）を同様に投与した。In addition, a control product prepared as a control in Example 17 (using mannitol instead of the organic acid) was administered in the same manner.
投与前および投与後１時間、２時間、３時間。Before administration and 1 hour, 2 hours, and 3 hours after administration.
４時間、６時間毎にウサギ耳動脈より２ｍｆ！づつ採面
した。採血後、３．０００ｒ、 ｐ、 ｍ、１０分間遠
心分離して血漿を得た。2mf from the rabbit ear artery every 4 to 6 hours! I interviewed them one by one. After blood collection, plasma was obtained by centrifugation at 3,000 r, p, m for 10 minutes.
血漿中のカルシウム濃度の測定は原子吸光度計を用いて
行った。なお、血中のカルシウム濃度の基準値（１００
％）は投与前５分前に採血した値を示している。Calcium concentration in plasma was measured using an atomic absorption spectrometer. In addition, the standard value of blood calcium concentration (100
%) indicates the value of blood collected 5 minutes before administration.
ｂ）結果
第４図に対照品（５単位／２ｍｙ／Ｋｇ）の鼻粘膜投与
（−Ａ−）と製剤７（５単位／２ｍＦｌ／に’ｌ）の鼻
粘膜投与（−・−）および製剤８（５単位／２ｍＦＩ
／ Ｋｇ）の鼻粘膜投与（−画一）後の各々の血中カル
シウム濃度の変化を示した。b) Results Figure 4 shows nasal mucosal administration of control product (5 units/2 my/Kg) (-A-), nasal mucosal administration of Formulation 7 (5 units/2 mFl/'l) (-・-), and formulation. 8 (5 units/2mFI
/ Kg) was administered to the nasal mucosa (-). Changes in blood calcium concentration were shown.
図面から明らかなように、水溶性有機酸の添加により血
中のカルシウム濃度は対照品の結果と比較して有意に低
下していることがわかる。As is clear from the drawing, it can be seen that the addition of the water-soluble organic acid significantly lowers the calcium concentration in the blood compared to the results for the control product.
実施例 １８
に逍旦悶遷１
ヒｉ〜副甲状腺ホルモン１−３／ｌ （ｈ−Ｐ Ｔ ｌ
−（（１−３４））５．０００単位とＤ−グルクロン酸
１．０ｇに蒸留水２５ｄを加えて溶解した後、溶解液を
凍結乾燥して均一なｈ−Ｐ Ｔ Ｈ（１−３４）５単位
／ｍｇを含有する凍屹品を１ｑた。さらに上記で得られ
た凍屹品を乳鉢に取り粉砕して粉末製剤を得た。Example 18 Parathyroid hormone 1-3/l (h-P T l
-((1-34)) 5.000 units and 1.0 g of D-glucuronic acid were dissolved by adding 25 d of distilled water, and the solution was freeze-dried to obtain a uniform h-P T H(1-34) 1 q of frozen product containing 5 units/mg was collected. Further, the frozen product obtained above was placed in a mortar and ground to obtain a powder preparation.
日本画色種雄性ウサギ（体重３ Ｋｇ前後、’！！′１
′５羽）を１晩絶食した後、麻酔下にて動脈圧測定のた
めにあらかじめ一側総頚動脈内へチューブをカニュレー
ションして実験に供した。動脈圧はトランジューサーを
介して記録した。麻酔下、実施例１８の製剤９のｈ−Ｐ
Ｔ Ｈ（１−３４）経の投与用粉末製剤（１０単位／
２ｍｇ／Ｋｌ＞を鼻腔内投与した。投与後１時間までの
血圧を観察した。比較のためｈ−Ｐ Ｔ ｌ−１（１−
３４）の注射剤を３単位／ ０．１ｒｎｌｌ／Ｋｌ静脈
内注射して同様に動脈圧を測定した。Nihonga color male rabbit (weighing around 3 kg, '!!'1
After fasting overnight, the animals were subjected to experiments by cannulating a tube into one side of the common carotid artery in order to measure arterial pressure under anesthesia. Arterial pressure was recorded via transducer. h-P of Formulation 9 of Example 18 under anesthesia
Powder preparation for administration of T H(1-34) route (10 units/
2 mg/Kl> was administered intranasally. Blood pressure was observed for up to 1 hour after administration. For comparison, h-P T l-1(1-
34) was intravenously injected at 3 units/0.1 rnll/Kl, and the arterial pressure was measured in the same manner.
ｂ）結果 その結果を第１表に示す。b) Results The results are shown in Table 1.
第 １ 表
第１表から明らかなように、吸収促進剤としての水溶性
有機酸を添加することによりｈ−ＰＴＩ−（（１，−３
４）が鼻粘膜より効率よく吸収されることがわかった。Table 1 As is clear from Table 1, by adding a water-soluble organic acid as an absorption enhancer, h-PTI-((1,-3
4) was found to be absorbed more efficiently than through the nasal mucosa.
［発明の効果コ
本発明の生理活性ペプチド類の経鼻投与用粉末組成物は
、有機酸を吸収促進剤として添加したことにより、鼻腔
粘膜より安全に生理活性ペプチド類を効率よく吸収せし
めることができる。また粉末製剤であるので有効成分の
安定性に優れている。[Effects of the Invention] The powder composition for nasal administration of physiologically active peptides of the present invention has the ability to safely and efficiently absorb physiologically active peptides through the nasal mucosa by adding an organic acid as an absorption enhancer. can. Also, since it is a powder formulation, the stability of the active ingredient is excellent.
したがって本発明により、生理活性ペプチド類の経鼻投
与用粉末製剤の実用化が可能となった。Therefore, the present invention has made it possible to put into practical use a powder preparation for nasal administration of physiologically active peptides.
第１図は本発明の実施例２で得られた製剤１および製剤
２とその対照品である水溶性有機酸を含有しない製剤４
との各々をウサギに投与したときの血中カルシウム濃度
の変化を示すグラフでおり、第２図は本発明の実施例７
で１ｑられた製剤５とその対照品とをウサギに投与した
ときのカルシウム濃度の変化を示すグラフであり、第３
図は本発明の実施例１４で得られた製剤６とその対照品
とをウサギに投与した時の血中グルコース濃度の変化を
示すグラフであり、第４図は本発明の実施例１７で得ら
れた製剤７おＪ：び８を用いて実験例４の方法に基いて
ウナギに投与したときのカルシウム濃度の変化を示すグ
ラフである。
（８７３３）代理人 弁理士 猪 股 祥 晃（ほか
１名）
時開（Ｈｒ）
期用（Ｈｒ）
手
続
補
正
占（自発）
持訂庁長官 殿
１、事件の表示
特願昭６３−１４４７０４号
２、発明の名称
経鼻投与用生理活性ペプチド製剤
３、補正をする者
第
閃聞（Ｈｒ）
４ 図
東京都港区虎ノ門１丁目９番１０号
港電設ビル 猪股特許事務所内
１゜
明細書の発明の詳細な説明の摺
６、補正の内容
（１）明細書第１３頁第４行の［本発明の粉末組成物は
例えば」を以下のように訂正する。
１本発明の粉末組成物は経鼻投与し１ｑる手段を用いる
製剤となせばよく、例えば窒素ガス、炭酸ガスやフロン
ガス等の噴出剤を用いる密封型経鼻投与剤としてもよく
、またフロン液に懸濁したエアゾール化した経鼻投与剤
としてもよく、さらに例えば」
以上Figure 1 shows Formulation 1 and Formulation 2 obtained in Example 2 of the present invention, and Formulation 4, which is a control product, and does not contain a water-soluble organic acid.
FIG. 2 is a graph showing changes in blood calcium concentration when rabbits were administered with each of the following.
1q is a graph showing changes in calcium concentration when preparation 5 and its control product were administered to rabbits.
The figure is a graph showing changes in blood glucose concentration when formulation 6 obtained in Example 14 of the present invention and its control product were administered to rabbits. 2 is a graph showing changes in calcium concentration when Formulations 7, J: and 8 were administered to eels according to the method of Experimental Example 4. (8733) Agent: Yoshiaki Inomata, patent attorney (and others)
1 person) Time opening (Hr) Period (Hr) Procedural amendment (voluntary) Director-General of the Office of Corrections Mr. 1, Indication of the case Patent Application No. 1983-144704 2, Name of the invention: Physiologically active peptide preparation for nasal administration 3 , Person making the amendment No. 4 (Hr) Figure 4 Inomata Patent Office Building, Minato Electric Construction Building, 1-9-10 Toranomon, Minato-ku, Tokyo 1゜Detailed explanation of the invention in the specification 6, Contents of the amendment (1) ) In the fourth line of page 13 of the specification, [the powder composition of the present invention includes, for example] is corrected as follows. 1. The powder composition of the present invention may be formulated into a preparation using a means for intranasal administration, for example, it may be a sealed nasal preparation using a propellant such as nitrogen gas, carbon dioxide gas or chlorofluorocarbon gas, or a fluorocarbon solution may be used. It may also be used as an aerosolized intranasal preparation suspended in, for example,
Claims (6)
粉末組成物において、吸収促進剤として水溶性有機酸を
含有し、さらに必要に応じて増量剤を含有することを特
徴とする経鼻投与用粉末組成物。(1) A powder composition for nasal administration containing physiologically active peptides as an active ingredient, which contains a water-soluble organic acid as an absorption enhancer and, if necessary, a filler. Powder composition for administration.
０の範囲に含まれるペプチドまたはその誘導体である特
許請求の範囲第１項記載の経鼻投与用粉末組成物。(2) Physiologically active peptides have a molecular weight of 1000 to 1000
The powder composition for nasal administration according to claim 1, which is a peptide or a derivative thereof falling within the range of 0.
フマール酸、マレイン酸、マロン酸、グルタル酸、アジ
ピン酸、リンゴ酸、Ｌ−グルタミン酸、Ｌ−アスパラギ
ン酸、グルコン酸およびグルクロン酸からなる群より選
ばれた１種または２種以上である特許請求の範囲第１項
記載の経鼻投与用粉末組成物。(3) The water-soluble organic acid is succinic acid, tartaric acid, citric acid,
One or more selected from the group consisting of fumaric acid, maleic acid, malonic acid, glutaric acid, adipic acid, malic acid, L-glutamic acid, L-aspartic acid, gluconic acid, and glucuronic acid. A powder composition for nasal administration according to Scope 1.
ロース類、合成または半合成高分子類、アミノ酸類、ポ
リアミノ酸類、タンパク類、リン脂質類からなる群より
選ばれた１種または２種以上である特許請求の範囲第１
項記載の経鼻投与用粉末組成物。(4) The filler is one or two selected from the group consisting of saccharides, polysaccharides, dextrins, celluloses, synthetic or semi-synthetic polymers, amino acids, polyamino acids, proteins, and phospholipids. Claim 1 that is more than one species
Powder composition for nasal administration as described in Section 3.
機酸がＤ−グルクロン酸またはコハク酸であって、必要
に応じて増量剤を添加してなる特許請求の範囲第１項記
載の経鼻投与用粉末組成物。(5) Nasal administration according to claim 1, wherein the physiologically active peptides are calcitonins, the water-soluble organic acid is D-glucuronic acid or succinic acid, and if necessary, a filler is added. Powder composition for use.
ンである特許請求の範囲第５項記載の経鼻投与用粉末組
成物。(6) The powder composition for nasal administration according to claim 5, wherein the bulking agent is mannitol or/and dextran.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63144704A JPH02111A (en) | 1987-08-03 | 1988-06-14 | Physiologically active peptide preparation for nasotracheal |
| US07/221,302 US5059587A (en) | 1987-08-03 | 1988-07-19 | Physiologically active peptide composition for nasal administration |
| EP88401904A EP0302772B1 (en) | 1987-08-03 | 1988-07-22 | Calcitonin composition for nasal administration |
| DE8888401904T DE3875025T2 (en) | 1987-08-03 | 1988-07-22 | COMPOSITION CONTAINING CALCITONIN FOR NASAL ADMINISTRATION. |
| KR1019880009634A KR890003400A (en) | 1987-08-03 | 1988-07-29 | Bioactive Peptide Powder Composition (Formulation) for Nasal Administration |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19265887 | 1987-08-03 | ||
| JP62-192658 | 1987-08-03 | ||
| JP62-296059 | 1987-11-26 | ||
| JP63144704A JPH02111A (en) | 1987-08-03 | 1988-06-14 | Physiologically active peptide preparation for nasotracheal |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02111A true JPH02111A (en) | 1990-01-05 |
Family
ID=26476039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63144704A Pending JPH02111A (en) | 1987-08-03 | 1988-06-14 | Physiologically active peptide preparation for nasotracheal |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02111A (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0352821A (en) * | 1989-07-21 | 1991-03-07 | Teijin Ltd | Stabilized powdery pharmaceutical composition of calcitonins |
| WO1994025017A1 (en) * | 1993-04-27 | 1994-11-10 | Sumitomo Pharmaceuticals Company, Limited | PERNASAL PREPARATION COMPRISING threo-3-(3,4-DIHYDROXYPHENYL)SERINE |
| EP0679088A1 (en) * | 1992-09-29 | 1995-11-02 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
| US5515015A (en) * | 1992-06-18 | 1996-05-07 | Mitsubishi Denki Kabushiki Kaisha | Transceiver duplex filter utilizing saw filter |
| JP2007536195A (en) * | 2003-06-24 | 2007-12-13 | ノバルティス アクチエンゲゼルシャフト | Pharmaceutical composition containing cyclic somatostatin analog |
| KR100794881B1 (en) * | 2005-02-03 | 2008-01-14 | 전진태 | PIK3C3 DNA marker Development of DNA markers derived from PIK3C3 gene available for the selection of backfat and carcass fat in pigs |
| JP2008019245A (en) * | 2006-06-15 | 2008-01-31 | Japan Science & Technology Agency | Intranasal agent for prevention and treatment of alzheimer's disease containing humanin derivative or fused peptide composed of humanin derivative and neurotropic peptide as active component |
| KR100816018B1 (en) * | 2007-01-19 | 2008-03-21 | 한국과학기술원 | Method for super-resolution reconstruction using focal underdetermined system solver algorithm |
| WO2008038644A1 (en) | 2006-09-27 | 2008-04-03 | Asahi Kasei Pharma Corporation | Agent for preventing development of reflex sympathetic dystrophy after stroke |
| WO2011062073A1 (en) | 2009-11-18 | 2011-05-26 | 旭化成ファーマ株式会社 | Preventative agent and/or therapeutic agent and/or exacerbation-suppressing agent for human knee osteoarthritis |
| WO2012169435A1 (en) | 2011-06-07 | 2012-12-13 | 旭化成ファーマ株式会社 | Freeze-dried preparation containing high-purity pth and method for producing same |
-
1988
- 1988-06-14 JP JP63144704A patent/JPH02111A/en active Pending
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0352821A (en) * | 1989-07-21 | 1991-03-07 | Teijin Ltd | Stabilized powdery pharmaceutical composition of calcitonins |
| US5515015A (en) * | 1992-06-18 | 1996-05-07 | Mitsubishi Denki Kabushiki Kaisha | Transceiver duplex filter utilizing saw filter |
| EP0679088A1 (en) * | 1992-09-29 | 1995-11-02 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
| EP0679088A4 (en) * | 1992-09-29 | 1996-02-28 | Inhale Therapeutic Syst | Pulmonary delivery of active fragments of parathyroid hormone. |
| US5607915A (en) * | 1992-09-29 | 1997-03-04 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
| WO1994025017A1 (en) * | 1993-04-27 | 1994-11-10 | Sumitomo Pharmaceuticals Company, Limited | PERNASAL PREPARATION COMPRISING threo-3-(3,4-DIHYDROXYPHENYL)SERINE |
| JP4746541B2 (en) * | 2003-06-24 | 2011-08-10 | ノバルティス アーゲー | Pharmaceutical composition containing cyclic somatostatin analog |
| JP2007536195A (en) * | 2003-06-24 | 2007-12-13 | ノバルティス アクチエンゲゼルシャフト | Pharmaceutical composition containing cyclic somatostatin analog |
| KR100794881B1 (en) * | 2005-02-03 | 2008-01-14 | 전진태 | PIK3C3 DNA marker Development of DNA markers derived from PIK3C3 gene available for the selection of backfat and carcass fat in pigs |
| JP2008019245A (en) * | 2006-06-15 | 2008-01-31 | Japan Science & Technology Agency | Intranasal agent for prevention and treatment of alzheimer's disease containing humanin derivative or fused peptide composed of humanin derivative and neurotropic peptide as active component |
| WO2008038644A1 (en) | 2006-09-27 | 2008-04-03 | Asahi Kasei Pharma Corporation | Agent for preventing development of reflex sympathetic dystrophy after stroke |
| KR100816018B1 (en) * | 2007-01-19 | 2008-03-21 | 한국과학기술원 | Method for super-resolution reconstruction using focal underdetermined system solver algorithm |
| WO2011062073A1 (en) | 2009-11-18 | 2011-05-26 | 旭化成ファーマ株式会社 | Preventative agent and/or therapeutic agent and/or exacerbation-suppressing agent for human knee osteoarthritis |
| WO2012169435A1 (en) | 2011-06-07 | 2012-12-13 | 旭化成ファーマ株式会社 | Freeze-dried preparation containing high-purity pth and method for producing same |
| EP3020409A1 (en) | 2011-06-07 | 2016-05-18 | Asahi Kasei Pharma Corporation | Freeze-dried preparation containing high-purity pth and method for producing same |
| EP3170493A1 (en) | 2011-06-07 | 2017-05-24 | Asahi Kasei Pharma Corporation | Freeze-dried preparation containing high-purity pth and method for producing same |
| US10011643B2 (en) | 2011-06-07 | 2018-07-03 | Asahi Kasei Pharma Corporation | Freeze-dried preparation containing high-purity PTH and method for producing same |
| US10683335B2 (en) | 2011-06-07 | 2020-06-16 | Asahi Kasei Pharma Corporation | Freeze-dried preparation containing high-purity PTH and method for producing same |
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