EP0855917A1 - Formes galeniques pharmaceutiques stables contenant de la parathormone - Google Patents

Formes galeniques pharmaceutiques stables contenant de la parathormone

Info

Publication number
EP0855917A1
EP0855917A1 EP96934715A EP96934715A EP0855917A1 EP 0855917 A1 EP0855917 A1 EP 0855917A1 EP 96934715 A EP96934715 A EP 96934715A EP 96934715 A EP96934715 A EP 96934715A EP 0855917 A1 EP0855917 A1 EP 0855917A1
Authority
EP
European Patent Office
Prior art keywords
acid
pharmaceutical preparation
preparation according
amino acids
solution
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.)
Withdrawn
Application number
EP96934715A
Other languages
German (de)
English (en)
Inventor
Hendrik Von Bueren
Rolf-Dieter Gabel
Wolfgang Rödel
Heinrich Woog
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0855917A1 publication Critical patent/EP0855917A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

  • the invention relates to pharmaceutical preparations which contain parathyroid hormone or its fragments as an active ingredient, and to corresponding pharmaceutical dosage forms in the form of lyophilisates or injection solutions
  • Parathomone is an eighty-four amino acid protein that is involved in regulating the calcium and phosphate levels in blood and tissue. From the literature (see also WO 90/10067; WO 91/06564; EP 0 301 484, WO 93/15109) it is known that N-terminal fragments of this hormone, but also peptides with corresponding modifications in the amino acid sequence via an analog have biological activity like PTH (1-84).
  • dimers can lead to a loss of activity of the protein in the dosage form, in particular if the dosage forms are stored for a longer period of time or at suboptimal temperatures.
  • lyophilization is problematic in the context of the production of appropriately dried pharmaceutical dosage forms.
  • Parathormone fragments in the sense of the invention are in particular the human N-terminal fragments of the intact protein, for example fragments (1-34), (1-35), (1-36), (1-37) or ( 1-38)
  • fragments of the parathyroid hormone which are shortened at the N- and C-terminal for example fragments which are shortened at the N-terminal by one or two amino acids.
  • corresponding variants or modifications of this hormone can also be used , in which one or more amino acids are replaced by other amino acids in the amino acid sequence of PTH (1-84). This also applies to the fragments shortened correspondingly at the N- and / or C-terminal produce pharmaceutical preparations containing the parathormone fragment hPTH 1-37.
  • the active substance content of parathyroid hormone or parathyroid hormone fragments in the liquid dosage forms is up to 10 mg / ml, in particular up to 5 mg / ml or up to 2 mg / ml.
  • the active substance content is preferably at least 0.01 mg / ml, 0.04 mg / ml or 0.1 mg / ml.
  • the active substance content is preferably, for example, 0.01-5 mg / ml, in particular 0.04-2 mg / ml.
  • the lyophilized dosage forms contain the active ingredient in such amounts that by adding a certain volume of a physiologically contractual reconstitution solution, corresponding infusion or injection solutions of the active ingredient are obtained with the concentration ranges mentioned.
  • the pharmaceutical dosage forms within the meaning of the present invention are essentially free from surfactants and customary physiologically compatible antioxidants, in particular from reagents containing sulfhydryl groups, such as methionine or cysteine, or ascorbic acid. Furthermore, they are preferably essentially free of chloride ions, since chloride ions are the Favor formation of dimers
  • the dosage forms according to the invention otherwise contain no further pharmaceutical additives or auxiliaries, such as, for example, sugar or physiologically compatible polymers.
  • the dosage forms within the meaning of the invention are distinguished in particular by the fact that they consist essentially only of amino acids and organic or inorganic acids exist, but at least one basic amino acid is contained
  • basic amino acids are all physiological, contractual amino acids with at least one basic side group.
  • Basic side groups are in particular amino groups, which may be replaced by other radicals, such as e.g. Ci-C ⁇ - alkyl groups, may be substituted.
  • Preferred basic amino acids are in particular histidine, lysine, arginine or ornithine.
  • the physiologically acceptable amino acids with side groups which have no sulfhydryl groups are suitable as neutral amino acids
  • the amino acids can in principle be used in the form of their racemates or the optically active forms (D- or L-amino acids).
  • the concentration of the amino acids in the liquid dosage form is in the range of up to 100 mg / ml. Concentrations of up to are particularly advantageous 80 mg / ml, in particular up to 60 mg / ml, or up to 50 mg / ml or 40 mg / ml.
  • the concentration of the amino acids is advantageously at least 1 mg / ml, in particular at least 5 mg / ml
  • organic acids which are physiologically acceptable are carboxylic acids, hydroxycarboxylic acids or amino acids, and their salts, in particular alkali salts.
  • carboxylic acids hydroxycarboxylic acids or amino acids
  • salts in particular alkali salts.
  • Advantageous in the context of the invention are, for example, lactic acid, acetic acid, citric acid or aspartic acid. the racemates or the optically active derivatives can be used
  • Suitable inorganic acids are physiologically acceptable acids, for example phosphoric acid or sulfuric acid, or their salts, which can also be used as a buffer in aqueous solution, such as sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen sulfate, etc.
  • the organic or inorganic acids can also be used in combination with one another.
  • the amount of acid is chosen such that the aqueous solution has a pH of 4-8, preferably 6-8.
  • the concentration of the acid in the solution is up to 100 mg / ml, in particular up to 50 mg / ml or up to 40 mg / ml.
  • the concentration of the acid is at least 1 mg / ml, preferably at least 5 mg / ml or 10 mg / ml
  • the following combinations of additives are used as physiologically contractual auxiliaries in particular: a) arginine and phosphoric acid (argininium phosphate), b) arginine, phosphoric acid and aspartic acid or c) arginine, phosphoric acid, aspartic acid and isoleucine
  • arginine and phosphoric acid argininium phosphate
  • arginine, phosphoric acid and aspartic acid or c) arginine, phosphoric acid, aspartic acid and isoleucine
  • the pharmaceutical dosage forms can be made available as ready-to-use injection or infusion solutions in corresponding ampoules.
  • it is also possible to provide appropriate lyophilisates which are converted into the aqueous form shortly before application to the patient by adding isotonic solvents can be
  • the dosage forms are expediently prepared by preparing an aqueous solution of all the ingredients and transferring them to corresponding ampoules or glass vials.
  • the drying is preferably carried out directly from the glass containers into which the solution was filled
  • PTH (1-37), 15 mg, arginine 3.0 g, aspartic acid 1.0 g and isoleucine 1.0 g were dissolved in 100 ml of water for injections and the pH was adjusted to pH with 85% phosphoric acid 7.4 set. This solution was sterile filtered and each with N 2 gassing
  • Example 2 the formulation from Example 2 is produced with different pH values.
  • the amount of arginine is varied at the same time
  • PTH and arginine were dissolved in 100 ml of water for injections and the pH was adjusted to the respective pH with 85% phosphoric acid.
  • the solutions were sterile filtered and 1 ml of the solution was filled into vials with N2 gassing. These vials were lyophilized, sealed and bound
  • Example 9 The recipes in Example 9 were prepared analogously to the recipe in Example 2. 10 mg of methionine were used in formulation 9 a). 10 mg of ascorbic acid were added in formulation 9 b). Both solutions were adjusted to pH 7.4. The solutions were sterile filtered and 1 ml of this solution was poured into vials each under N2 gassing, and these vials were lyophilized, sealed and sealed
  • Example 10 In Example 10, the recipe from Example 2 was used with the addition of 10 mg of Tween 20. PTH (1-84), arginine and Tween 20 were dissolved in water for injection purposes and the pH was raised to 85% phosphoric acid pH 7.4 set. This solution was sterile filtered and filled with 1 ml of the solution in vials each with N2 gassing. These vials were lyophilized, sealed and sealed
  • PTH 1-3-7
  • 15 mg and 3.5 g of histidine were dissolved in 100 ml of water for injections and the pH was adjusted to 7.4 with 85% phosphoric acid.
  • This solution was sterile filtered and under N2 Fumigation filled with 1 ml of the solution in vials. This vial was lyophilized, sealed and sealed
  • PTH (1-84) (manufacturer Sigma Corporation), 15 mg and 5.5 g of L-arginine were dissolved in 100 ml of water for injections and the pH was adjusted to pH 7.4 with 85% phosphoric acid The solution was filtered st ⁇ l and filled with 1 ml of the solution in vials under gassing with N2. These vials were lyophilized, sealed and sealed

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques de parathormone stables au stockage, qui contiennent un aminoacide basique et éventuellement un acide organique ou inorganique présentant une bonne tolérance sur le plan physiologique.
EP96934715A 1995-10-17 1996-10-17 Formes galeniques pharmaceutiques stables contenant de la parathormone Withdrawn EP0855917A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19538687 1995-10-17
DE19538687A DE19538687A1 (de) 1995-10-17 1995-10-17 Stabile pharmazeutische Darreichungsformen enthaltend Parathormon
PCT/EP1996/004503 WO1997014429A1 (fr) 1995-10-17 1996-10-17 Formes galeniques pharmaceutiques stables contenant de la parathormone

Publications (1)

Publication Number Publication Date
EP0855917A1 true EP0855917A1 (fr) 1998-08-05

Family

ID=7775105

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96934715A Withdrawn EP0855917A1 (fr) 1995-10-17 1996-10-17 Formes galeniques pharmaceutiques stables contenant de la parathormone

Country Status (14)

Country Link
EP (1) EP0855917A1 (fr)
JP (1) JPH11515002A (fr)
KR (1) KR19990064322A (fr)
AU (1) AU7294196A (fr)
BR (1) BR9610983A (fr)
CA (1) CA2234724A1 (fr)
CZ (1) CZ108398A3 (fr)
DE (1) DE19538687A1 (fr)
HU (1) HUP9900751A3 (fr)
NZ (1) NZ320237A (fr)
SK (1) SK47298A3 (fr)
TR (1) TR199800690T1 (fr)
WO (1) WO1997014429A1 (fr)
ZA (1) ZA968715B (fr)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19539574A1 (de) 1995-10-25 1997-04-30 Boehringer Mannheim Gmbh Zubereitungen und Verfahren zur Stabilisierung biologischer Materialien mittels Trocknungsverfahren ohne Einfrieren
DE19716154A1 (de) * 1997-04-18 1998-10-22 Boehringer Mannheim Gmbh Stabile pharmazeutische Darreichungsform für Peptide, Proteine und Nukleinsäuren
ZA9811127B (en) † 1997-12-09 2000-07-11 Lilly Co Eli Stabilized teriparatide solutions.
US6770623B1 (en) 1997-12-09 2004-08-03 Eli Lilly And Company Stabilized teriparatide solutions
SE9801495D0 (sv) * 1998-04-28 1998-04-28 Astra Ab Protein formulationa
AU1189301A (en) * 1999-10-29 2001-05-14 Eli Lilly And Company A pharmaceutical composition having high cell membrane permeability
EP1253932B1 (fr) * 2000-02-08 2005-04-27 Allergan, Inc. Compositions pharmaceutiques a base de toxine botulique
NZ523457A (en) * 2000-06-30 2004-11-26 Daiichi Suntory Pharma Co Composition for stimulating bone formation comprising hPTH in which the acetic acid component is low enough for administration to the nasal mucosa
JP4607010B2 (ja) 2003-02-28 2011-01-05 中外製薬株式会社 タンパク質含有安定化製剤
WO2005014034A1 (fr) * 2003-07-14 2005-02-17 Nps Allelix Corp. Preparations stabilisees d'hormone parathyroide
KR100700869B1 (ko) * 2005-06-03 2007-03-29 재단법인 목암생명공학연구소 Ｐｔｈ, 완충제 및 안정제를 포함하는 안정한 ｐｔｈ조성물
USRE49444E1 (en) 2006-10-03 2023-03-07 Radius Health, Inc. Method of treating osteoporosis comprising administration of PTHrP analog
FR2947181B1 (fr) * 2009-06-26 2012-05-04 Lfb Biotechnologies Composition de facteur vii
KR101792473B1 (ko) 2011-06-07 2017-10-31 아사히 가세이 파마 가부시키가이샤 고순도 ｐｔｈ 함유 동결 건조 제제 및 그의 제조 방법
IL310069A (en) 2015-04-29 2024-03-01 Radius Pharmaceuticals Inc Cancer treatment methods
JP6634758B2 (ja) * 2015-09-25 2020-01-22 ニプロ株式会社 液体組成物及び凍結乾燥製剤
WO2018129419A1 (fr) 2017-01-05 2018-07-12 Radius Pharmaceuticals, Inc. Formes polymorphes de rad1901-2hcl
US10996208B2 (en) 2017-04-28 2021-05-04 Radius Health, Inc. Abaloparatide formulations and methods of testing, storing, modifying, and using same
JP6577683B2 (ja) * 2017-09-22 2019-09-18 旭化成ファーマ株式会社 安定性に優れるテリパラチド含有液状医薬組成物
SG11202013177WA (en) 2018-07-04 2021-01-28 Radius Pharmaceuticals Inc Polymorphic forms of rad 1901-2hcl
WO2021229835A1 (fr) * 2020-05-11 2021-11-18 旭化成ファーマ株式会社 Préparation pharmaceutique liquide stable contenant du tériparatide ou un sel de celui-ci
JP6947946B1 (ja) * 2020-05-11 2021-10-13 旭化成ファーマ株式会社 テリパラチド又はその塩を含有する安定な液状医薬製剤

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US4816568A (en) * 1986-05-16 1989-03-28 International Minerals & Chemical Corp. Stabilization of growth hormones
JP2739482B2 (ja) * 1988-08-11 1998-04-15 バイオ・チバ株式会社 安定なカルシトニン注射液の製造方法
JPH0341033A (ja) * 1989-07-07 1991-02-21 Kyowa Hakko Kogyo Co Ltd 安定なモチリン類含有製剤
US5563122A (en) * 1991-12-09 1996-10-08 Asahi Kasei Kogyo Kabushiki Kaisha Stabilized parathyroid hormone composition
DE4203040A1 (de) * 1992-02-04 1993-08-05 Boehringer Mannheim Gmbh Neue parathormonfragmente, deren herstellung und diese enthaltende arzneimittel

Non-Patent Citations (1)

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Title
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Also Published As

Publication number Publication date
TR199800690T1 (xx) 1998-06-22
SK47298A3 (en) 1998-11-04
NZ320237A (en) 1999-11-29
KR19990064322A (ko) 1999-07-26
WO1997014429A1 (fr) 1997-04-24
AU7294196A (en) 1997-05-07
CZ108398A3 (cs) 1998-09-16
HUP9900751A2 (hu) 1999-07-28
DE19538687A1 (de) 1997-04-24
HUP9900751A3 (en) 2000-07-28
BR9610983A (pt) 1999-03-02
JPH11515002A (ja) 1999-12-21
CA2234724A1 (fr) 1997-04-24
ZA968715B (en) 1998-04-16

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