[go: up one dir, main page]

WO1995034318A1 - Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation - Google Patents

Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation Download PDF

Info

Publication number
WO1995034318A1
WO1995034318A1 PCT/SE1995/000685 SE9500685W WO9534318A1 WO 1995034318 A1 WO1995034318 A1 WO 1995034318A1 SE 9500685 W SE9500685 W SE 9500685W WO 9534318 A1 WO9534318 A1 WO 9534318A1
Authority
WO
WIPO (PCT)
Prior art keywords
igf
solution
drug product
final drug
product according
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.)
Ceased
Application number
PCT/SE1995/000685
Other languages
English (en)
Inventor
Jonas Fransson
Ulf Nilsson
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.)
Pfizer Health AB
Original Assignee
Pharmacia and Upjohn AB
Pharmacia AB
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 Pharmacia and Upjohn AB, Pharmacia AB filed Critical Pharmacia and Upjohn AB
Priority to AU27576/95A priority Critical patent/AU2757695A/en
Publication of WO1995034318A1 publication Critical patent/WO1995034318A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • the present invention relates to a final drug product comprising IGF-I or any functional analogue thereof in an aqueous solution with a reduced concentration of oxygen.
  • the IGF-I purity can be retained during storage to a surprisingly high degree.
  • the IGF-I purity can be retained for a prolonged period of time, if the final drug product further comprises an inert gas and/or an antioxidant.
  • the present invention also relates to processes for reducing the oxygen concentration of the aqueous solution, and a method for improving the stability of IGF-I in an aqueous solution by storing the solution under an inert gas atmosphere.
  • IGF-I Insulin-like Growth Factor I
  • IGF-I Insulin-like Growth Factor I
  • Human IGF-I has been purified from plasma and its complete amino acid sequence is established. (Rinderknecht E et al. "The amino acid sequence of human insulin-like growth factor I and its structural homology with proinsulin” J. Biol. Chem 253; 2769-76, 1978) Sequences with extensive homologies to human IGF-I are present in IGF-I purified from plasma of other species.
  • IGF-I Because of the scarcity of purified plasma IGF-I there was a great necessity to develop methodology for the commercial scale production of IGF-I. Recently, such large scale production can readily be achieved by using recombinant DNA techniques. As a result of studies with preparations of recombinant DNA IGF-I it has been demonstrated that it promotes skeletal growth and skeletal muscle protein synthesis. IGF-I has been shown to act both as an endocrine factor as well as a paracrine/autocrine factor. (Skottner et al, Endocrinology, Vol.
  • IGF-I is also effective for the treatment or prevention of catabolic states in patients (Swedish patent application SE 9002731-9) and improves the regeneration of transected peripheral nerves (EP 0308386). It has previously been demonstrated in vitro that IGF-I also can promote actin synthesis in myocytes in culture (Florini, J R, Muscle and Nerve 10 (1987) 577-598 and contractility of neonatal rat cardiocytes in vitro (Vetter, U et al, Basic Res. Cardiol. 83 (1988)647-654).
  • the stability of proteins is generally a problem in the pharmaceutical industry.
  • a formulation with a low amount of protein will generally lose activity during purification, sterile manufacturing, storage and during the administration.
  • freeze-drying process is also a costly and time consuming process step, and it would be of great advantage if this step could be avoided, when preparing a commercial product of a protein.
  • Proteins are different with regard to physiological properties. When preparing a pharmaceutical preparation which should be physiologically acceptable, and stable for a long time, consideration can not only be taken to the physiological properties of the protein but also other aspects must be considered such as the industrial manufacture, easy handling for the patient and safety for the patient. The results of these aspects are not predictable when testing different formulations and each protein has often a unique solution regarding stability.
  • EP 35204 discloses a method for imparting thermal stability to a protein composition in the presence of a polyol.
  • EP 381345 discloses an aqueous liquid of a peptide, desmopressin, in the presence of carboxymethylcellulose.
  • WO 89/09614 Genentech
  • a stabilized formulation of human growth hormone containing glycine, mannitol, optionally a non-ionic surfactant and a buffer at pH 4-8 is disclosed.
  • the non-ionic surfactant is added for reduced aggregation and denaturation.
  • the formulation has an increased stability in lyophilized form and as a solution obtained after reconstitution.
  • EP 303 746 International Minerals and Chemical corporation discloses growth hormone (GH) stabilized in aqueous environment by mixing the growth hormone with polyol, amino acid, polymer of amino acid or choline derivative.
  • US 4165370 discloses a gamma globulin solution and a process for the preparation thereof.
  • the solutions contains polyethylene glycol (PEG).
  • EP 440989 discloses a method for preparing a dried composition of IGF-I, which comprises drying a solution containing IGF-I together with a strong acid.
  • IGF-I in a citrate buffer at pH 6 is known from WO 91/18621, Genentech. None is mentioned regarding stability of IGF-I.
  • the patent application PCT /SE94/00010 relates to a stable solution containing Insulin-like Growth factor I (IGF-1) in a phosphate buffer in an amount of 50 mmol or less, giving a pH of 5.5 to 6.5, which is isotonic and suitable for injection.
  • IGF-1 Insulin-like Growth factor I
  • US 5272135 discloses a method for inhibiting oxidation by adding methionine to a polypeptide.
  • the oxidation process is reduced by the addition of a chemical compound.
  • the concentration of oxygen in the solution is thereby not reduced.
  • US 4727027, Diamond Scientific is directed to a method for photochemical decontamination of aqueous compositions containing biologically active proteins derived from blood or blood components, for minimizing loss in activity.
  • the method comprises adding at least one furocoumarin to the composition and irradiating the obtained composition with ultraviolet (UV) light.
  • UV ultraviolet
  • the oxygen concentration of the aqueaous composition can be reduced to inhibit denaturatione.g.
  • Aqueous solutions containing oxygen-sensitive chemical compounds including drugs other than proteins is normally deoxygenated as follows: Water for injection is bubbled with nitrogen to reduce the concentration of oxygen. The components are dissolved and the solution is bubbled with nitrogen and there-after kept under a nitrogen blanket. During filling, the bottles are flushed with nitrogen gas and the bottles are closed under a stream of nitrogen.
  • Figure 1 shows % of oxidized IGF-I during 18 months' storage at 7°C.
  • Figure 2 shows % of oxidized IGF-I during two months' storage at 25°C.
  • Figure 1 shows % of oxidized IGF-I during two months' storage at 50°C. Description of the invention
  • IGF-I can be deoxygenated without protein denaturation.
  • IGF-I can be in a stable solution, and that such an aqueous solution with a low oxygen content is very stable when stored even at e.g. 25°C.
  • the present invention relates to a final drug product comprising IGF-I or any functional analogue thereof in an aqueous solution with a reduced concentration of oxygen, for essentially retaining the IGF-I purity and activity during storage.
  • the oxygen content in the solution can be below 150 mmol/L, suitably below 100 mmol/L and preferably 50 mmol/L or below.
  • the final product can comprise an inert gas and the solution is suitably stored under the inert gas such as nitrogen, argon or helium, to essentially maintain the low content of oxygen.
  • inert gas such as nitrogen, argon or helium
  • the aqueous solution can also contain an antioxidant such as methionine. No concentration or amount can generally be given. It is, however, important that the amount of antioxidant, if used, is in a pharmaceutically acceptable amount For methionine the amount could be e.g. 2 - 50 mmol/L.
  • the concentration of IGF-I is only dependent of its solubility in the used buffer and the desired therapeutically amount for the given dose.
  • concentration of IGF-I is 1-100 mg/ml and more preferably 1-20 mg/ml.
  • the aqueous solution may contain a phosphate buffer, such as sodium phosphate buffer, in an amount of 50 mmol/L or less, e.g.5-20 mmol/L, preferably around 10 mmol/L, giving a pH of 5.5 to 6.5 , preferably 5.7 - 6.2.
  • the solution should be isotonic, which could easily be made by any of several excipients known for a person skilled in the art. E.g. NaCl, glycin, mannitol, glycerol and/or other carbohydrates can be added.
  • Benzyl alcohol could be chosen as preservative.
  • the final drug product has less than 2 % increase in oxidized IGF-I after 18 months 'storage at +7 ⁇ 1°C.
  • Example 2 we have shown that it is not enough to reduce oxygen content in the head space in order to retain purity of IGF-I when stored. Also the oxygen concentration in the solution should be reduced.
  • the invention also refers to a process for preparation of the claimed solution characterised by mixing IGF-I with an aqueous solution, and reducing the oxygen concentration in the solution by subjecting the aqueous solution to an inert gas atmosphere. It can first be done by reducing the pressure and thereafter introducing the inert gas. The latter process is preferably repeated in several cycles.
  • the invention also refers to a method for improving the stability of IGF-I or any functional analogue thereof in an aqueous solution characterised in that the solution is subjected to a process so that the solution has a reduced concentration of oxygen.
  • the IGF-I solution at a pH of 5.5 to 6.5. shows less than 2 % increase in oxidized IGF-I after storage for at least 18 months at a temperature of 7 ⁇ l °C
  • Final drug product relates to the formulated drug in its final container.
  • Suitable containers in the present invention are e.g. vials, syringes and injection devices.
  • the low content of oxygen can be essentially maintained by adding an antioxidant to the aqueous solution.
  • the antioxidant must, however, be specifically chosen, as there are few of the known and normally used antioxidants which will function and give the wanted result.
  • Methionine is the preferred antioxidant. It has been found that glutathione, acetylcysteine, sodium bisulfite and ascorbic acid give a decreased stability and EDTA and tocopherol give no effect on stability for IGF-I, see Example 3.
  • IGF-I Insulin-like Growth Factor
  • rIGF-I recombinant IGF-I
  • rhIGF-I human
  • rbIGF-I bovine
  • rpIGF-I rpIGF-I
  • functional analogues compounds having the same therapeutic effect as IGF-I in animals and humans.
  • rhIGF-I The recombinant human IGF-I (rhIGF-I) used in the experiments was produced in yeast. rhIGF-I was initially synthesised as a hybrid protein fused to the yeast a mating factor pre-pro leader peptide. After expression the primary translation product was secreted out of the cell. During this process the pre-pro-leader was cleaved off. Correctly processed and secreted rhIGF-I could then be isolated from the fermentation media in its native form.
  • the media with rhIGF-I was then micro filtered and impurities were removed by several chromatographic techniques known within the field.
  • IGF-I pools from the final step in the purification process were dissolved in the formulation buffer and chromatographed on a Sephadex G-50 column.
  • This example presents the results from a stability study of a solution which has been stored at +7, +25 and +50°C, respectively.
  • Nitrogen protection of the solutions was performed by deoxygenation in a vacuum chamber and replacing the evaporated oxygen by nitrogen.
  • the oxygen content was 50 mmol/L.
  • This example presents the results from a stability study of solutions filled in glass vials with or without head space and then stored at +5°C ⁇ 3°C and +25°C ⁇ 3°C.
  • the head space contained 1.5 mL of sterile air.
  • composition as in example 1.
  • Table 1 Purity and percentage of oxidized IGF-I. 2 mg/mL IGF-I with or without head space stored at +5°C ⁇ 3°C.
  • Reducing the head space in the vials is not sufficient to improve the stability of IGF-I or to reduce oxidation.
  • This example presents the results from a stability study of solutions to which have been added different antioxidants.
  • This composition gives a concentration of 1 mg/mL IGF-I in 50 mmol/L sodium phosphate buffer, and a pH 6, with 110 mmol/L sodium chloride as tonicity adjuster.
  • To these solutions were added the following common antioxidants: Ascorbic acid, sodium bisulphite, reduced glutathione, acetylcyteine, methionine, tocopherol, EDTA, 1,4-dithiothreitol, sodium tiosulphate, n- propylgallat and L-tryptophan.
  • the oxidants sodium bisulphite, reduced glutathione, acetylcysteine, 1,4- dithiothreitol, sodium tiosulphate, n-propylgallat and L-tryptophan were all incompatible with IGF-I. as precipitates of IGF-I were formed after some hours of storage. Ascorbic acid and sodium tiosulphate did in fact increase oxidation rates. EDTA and tocopherol did not enhance the stability towards oxidation. The antioxidant methionine did reduce the oxidation rate during storage. The results after storage are shown in table 3.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un produit médicamenteux final comprenant un facteur de croissance de type I proche de l'insuline (IGF-I) ou tout autre analogue fonctionnel contenu dans une solution aqueuse à concentration réduite en oxygène. On peut ainsi maintenir la pureté de l'IGF-I pendant le stockage à un degré étonnament élevé. La pureté de l'IGF-I peut être maintenue pendant une période prolongée si le produit médicamenteux final comprend également un gaz inerte et/ou un antioxydant. L'invention concerne également des procédés de réduction de la concentration en oxygène de la solution aqueuse, ainsi qu'une méthode permettant d'améliorer la stabilité de l'IGF-I dans une solution aqueuse en stockant cette dernière dans une atmosphère de gaz inerte.
PCT/SE1995/000685 1994-06-16 1995-06-08 Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation Ceased WO1995034318A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27576/95A AU2757695A (en) 1994-06-16 1995-06-08 Solution comprising igf-i or any functional analogue thereof and method for its preparation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9402119A SE9402119D0 (sv) 1994-06-16 1994-06-16 Solution
SE9402119-3 1994-06-16

Publications (1)

Publication Number Publication Date
WO1995034318A1 true WO1995034318A1 (fr) 1995-12-21

Family

ID=20394415

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1995/000685 Ceased WO1995034318A1 (fr) 1994-06-16 1995-06-08 Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation

Country Status (4)

Country Link
AU (1) AU2757695A (fr)
IL (1) IL114063A0 (fr)
SE (1) SE9402119D0 (fr)
WO (1) WO1995034318A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5783556A (en) * 1996-08-13 1998-07-21 Genentech, Inc. Formulated insulin-containing composition
US6559122B1 (en) 1999-04-08 2003-05-06 Genentech, Inc. Formulated composition
US6884083B2 (en) 2001-04-20 2005-04-26 Kettle Solutions Limited Electrical connector
EP2952203B1 (fr) * 2014-05-29 2016-10-26 Grifols, S.A. Méthode pour la préparation de albumine humaine avec niveau réduit d'oxygène dissous

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727027A (en) * 1983-05-02 1988-02-23 Diamond Scientific Co. Photochemical decontamination treatment of whole blood or blood components
US5272135A (en) * 1991-03-01 1993-12-21 Chiron Ophthalmics, Inc. Method for the stabilization of methionine-containing polypeptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4727027A (en) * 1983-05-02 1988-02-23 Diamond Scientific Co. Photochemical decontamination treatment of whole blood or blood components
US5272135A (en) * 1991-03-01 1993-12-21 Chiron Ophthalmics, Inc. Method for the stabilization of methionine-containing polypeptides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5783556A (en) * 1996-08-13 1998-07-21 Genentech, Inc. Formulated insulin-containing composition
US6559122B1 (en) 1999-04-08 2003-05-06 Genentech, Inc. Formulated composition
US7186686B2 (en) 1999-04-08 2007-03-06 Genentech, Inc. Formulated composition
US6884083B2 (en) 2001-04-20 2005-04-26 Kettle Solutions Limited Electrical connector
EP2952203B1 (fr) * 2014-05-29 2016-10-26 Grifols, S.A. Méthode pour la préparation de albumine humaine avec niveau réduit d'oxygène dissous

Also Published As

Publication number Publication date
AU2757695A (en) 1996-01-05
SE9402119D0 (sv) 1994-06-16
IL114063A0 (en) 1995-11-27

Similar Documents

Publication Publication Date Title
CA2252535C (fr) Formulation pharmaceutique contenant une hormone de croissance, un acide amine et un detergent non ionique
KR100304143B1 (ko) 산소가감소된인자viii의수용액
AU738413B2 (en) Human growth hormone-containing aqueous pharmaceutical composition
EP0785796B1 (fr) Formulation pharmaceutique comportant une hormone de croissance et de l'isoleucine
US8841252B2 (en) Pharmaceutical formulation
EP0785795B1 (fr) Formulation pharmaceutique comportant une hormone de croissance et de la valine
JP2002512973A (ja) タンパク質製剤
AU676882B2 (en) Solution containing IGF-1
EP1034007B1 (fr) METHODE DE PRODUCTION D'UNE SERINGUE MONODOSE COMPORTANT UNE COMPOSITION PROTEINIQUE LYOPHILISEE ET SERVANT A ADMINISTRER UN VOLUME INFERIEUR A 0,5 ml
CN100518819C (zh) 含有人甲状旁腺激素的药物成分及含有该成分的用于鼻内给药的药物组合物
WO1995034318A1 (fr) Solution comprenant un facteur de croissance de type i proche de l'insuline ou tout autre analogue fonctionnel et methode de preparation
EP0785797B1 (fr) Formulation pharmaceutique comportant une hormone de croissance et de la leucine
US5552385A (en) Pharmaceutical formulation
AU4329596A (en) A stabilized pharmaceutical formulation comprising a growth hormone and x-lys
US20030162711A1 (en) Pharmaceutical formulation
WO1997007816A1 (fr) Solution contenant l'igf-i
IL147413A (en) Pharmaceutical preparations containing GRF
CA2153787C (fr) Solution renfermant igf-1

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA