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WO2012001641A1 - Compositions pharmaceutiques stables - Google Patents

Compositions pharmaceutiques stables Download PDF

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Publication number
WO2012001641A1
WO2012001641A1 PCT/IB2011/052864 IB2011052864W WO2012001641A1 WO 2012001641 A1 WO2012001641 A1 WO 2012001641A1 IB 2011052864 W IB2011052864 W IB 2011052864W WO 2012001641 A1 WO2012001641 A1 WO 2012001641A1
Authority
WO
WIPO (PCT)
Prior art keywords
enzyme
pharmaceutical composition
miglustat
composition according
glucocerebrosidase
Prior art date
Application number
PCT/IB2011/052864
Other languages
English (en)
Inventor
Olga Abian
Pilar Alfonso
Pilar Giraldo
Miguel Pocovi
Javier Sancho
Original Assignee
Actelion Pharmaceuticals Ltd
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 Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2012001641A1 publication Critical patent/WO2012001641A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
    • C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
    • C12N9/2405—Glucanases
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01045—Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to stable pharmaceutical compositions comprising a human ⁇ -glucocerebrosidase or an analogue thereof and miglustat.
  • Human ⁇ -glucocerebrosidase and/or synthetic analogues thereof such as imiglucerase (commercially available under the trademark Cerezyme ® ) or velaglucerase alfa (commercially available under the trademark Vpriv ® ), are enzymes used in the Enzyme Replacement Therapy (hereafter ERT) treatment of Gaucher disease.
  • ERT enzymes A major drawback of the ERT enzymes is their relatively low stability. Thus pharmaceutical products containing such enzymes are provided as freeze-dried formulations that must be stored in a refrigerator. Similarly, the liquid formulations obtained after reconstitution with water are to be used right away as the ERT enzyme is unstable.
  • An alternative treatment to the ERT treatment of Gaucher disease is a substrate replacement therapy using the iminosugar miglustat (N-butyl-deoxynojirimycin), commercially available under the trademark Zavesca ® .
  • WO 00/62779 discloses the synergistic effect of the combined use of an inhibitor of glycolipid synthesis (such as miglustat) and an agent capable of increasing the rate of glycolipid degradation (such as human ⁇ -glucocerebrosidase or an analogue thereof) for simultaneous, sequential or separate use in the treatment of, among others, Gaucher disease.
  • an inhibitor of glycolipid synthesis such as miglustat
  • an agent capable of increasing the rate of glycolipid degradation such as human ⁇ -glucocerebrosidase or an analogue thereof
  • miglustat has the ability to stabilise solid and liquid pharmaceutical compositions comprising human ⁇ -glucocerebrosidase or a synthetic analogue thereof.
  • the quantity of miglustat required to obtain this stabilising effect can be much lower than the dose that would be used to obtain a therapeutic effect of miglustat itself.
  • the invention thus firstly relates to the use of miglustat to stabilise a pharmaceutical composition
  • a pharmaceutical composition comprising an enzyme selected from human ⁇ -glucocerebrosidase and synthetic analogues of human ⁇ -glucocerebrosidase.
  • synthetic analogue of human ⁇ -glucocerebrosidase refers to an analogue of human ⁇ -glucocerebrosidase either obtained by recombinant technology or to a modified form of human ⁇ -glucocerebrosidase where the non-reducing ends of the oligosaccharide chains have been terminated with mannose residues.
  • Representative examples of synthetic analogues of human ⁇ -glucocerebrosidase include imiglucerase, velaglucerase alfa, taliglucerase alfa and alglucerase. Preferred are imiglucerase and velaglucerase alfa.
  • normal saline solution refers to a sodium chloride solution obtained by dissolving about 9 grams of sodium chloride (NaCl) in 1 liter of distilled water.
  • ⁇ ⁇ ⁇ A "half-normal saline solution” refers to a sodium chloride solution obtained by dissolving about 4.5 grams of sodium chloride (NaCl) and about 4.5 grams glucose in 1 liter of distilled water.
  • ⁇ ⁇ ⁇ A "lactated Ringer's solution” refers to a water solution containing about 130 mmol/L sodium ions, about 109 mmol/L chloride ions, about 28 mmol/L lactate ions, about 4 mmol/L potassium ions and about 1.5 mmol/L calcium ions.
  • the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.
  • the term "about” placed before a pH value "Z” refers in the current application to an interval extending from the pH Z minus 0.2 pH unit to Z plus 0.2 pH unit, and preferably to an interval extending from Z minus 0.1 pH unit to Z plus 0.1 pH unit.
  • the enzyme will be imiglucerase. 3) According to another sub-embodiment of embodiment 1), the enzyme will be velaglucerase alfa.
  • the enzyme will be taliglucerase alfa.
  • the enzyme will be alglucerase.
  • the use according to embodiments 1) to 5) will be to stabilise a solid composition.
  • the molar ratio of miglustat used with respect to the enzyme will be from 25 to 75 moles of miglustat per mole of enzyme, notably from 40 to 60 moles of miglustat per mole of enzyme, and in particular about 50 moles of miglustat per mole of enzyme.
  • the invention also relates to a liquid pharmaceutical composition, comprising:
  • pH of said liquid pharmaceutical composition is a pH of from 6 to 8.
  • the pH of the liquid pharmaceutical composition according to embodiment 9) will be from 6.5 to 7.5 (and in particular from 6.7 to 7.5 and notably about 7.2).
  • the liquid pharmaceutical composition according to embodiment 9) or 10 will be any water solution suitable for injection to which the enzyme and miglustat have been added, said liquid pharmaceutical composition being in particular selected from a normal saline solution, a half-normal saline solution and a lactated Ringer's solution, to which the enzyme and miglustat have been added.
  • the liquid pharmaceutical composition according to embodiment 11) will be a normal saline solution to which the enzyme and miglustat have been added.
  • the enzyme will be imiglucerase.
  • the enzyme will be velaglucerase alfa.
  • the enzyme will be taliglucerase alfa.
  • the enzyme will be alglucerase.
  • the molar ratio of miglustat with respect to the enzyme in the liquid composition according to one of embodiments 9) to 16) will be from 25 to 75 moles of miglustat per mole of enzyme, notably from 40 to 60 moles of miglustat per mole of enzyme, and in particular about 50 moles of miglustat per mole of enzyme.
  • the invention furthermore relates to a solid pharmaceutical composition, comprising: a) an enzyme selected from human ⁇ -glucocerebrosidase and synthetic analogues thereof and
  • pH of the solution obtained after adding water to said solid pharmaceutical composition is a pH of from 6 to 8.
  • the pH of the solution obtained after adding water to the solid pharmaceutical composition according to embodiment 18) will be from 6.5 to 7.5 (and in particular from 6.8 to 7.2).
  • the enzyme will be imiglucerase.
  • the enzyme will be velaglucerase alfa.
  • the enzyme will be taliglucerase alfa.
  • the enzyme will be alglucerase.
  • the molar ratio of miglustat with respect to the enzyme in the solid composition according to one of embodiments 18) to 23) will be from 25 to 75 moles of miglustat per mole of enzyme, notably from 40 to 60 moles of miglustat per mole of enzyme, and in particular about 50 moles of miglustat per mole of enzyme.
  • the invention also relates to a pharmaceutical composition according to one of embodiments 9) to 24) for use in the treatment of Gaucher disease (notably for use in the treatment of Gaucher disease type 1).
  • the invention furthermore relates to a method of treating a patient having Gaucher disease (notably Gaucher disease type 1), said method comprising administering by intravenous route to said patient an effective amount of a liquid pharmaceutical composition according to one of embodiments 9) to 17).
  • the invention moreover relates to a method of treating a patient having Gaucher disease (notably Gaucher disease type 1), said method comprising administering by intravenous route to said patient a solution obtained by adding water to a solid pharmaceutical composition according to one of embodiments 18) to 24).
  • compositions according to this invention can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described components, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • solid pharmaceutical solutions according to this invention can in particular be obtained by lyophilising water solutions containing the respective components in the appropriate proportions.
  • Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way.
  • Example 1 liquid composition containing imiglucerase and miglustat:
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • the pH measured for this water solution is 7.2.
  • Example 2 solid composition containing imiglucerase and miglustat:
  • Example 1 The water solution of Example 1 may be freeze-dried to give a solid composition.
  • Example 3 liquid composition containing velaglucerase alfa and miglustat:
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • Example 4 solid composition containing velaglucerase alfa and miglustat:
  • Example 4 The water solution of Example 4 may be freeze-dried to give a solid composition.
  • compositions of Examples 1 and 3 in comparison with reference compositions which contain the same enzyme but not miglustat or have a slightly acidic pH, has been studied thanks to the methods described hereafter.
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • Reference liquid composition RE2 The pH measured for this reference liquid composition was 7.2.
  • Reference liquid composition RE2 The pH measured for this reference liquid composition was 7.2.
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • Reference liquid composition RE4 The pH measured for this reference liquid composition was 5.
  • Reference liquid composition RE4 The pH measured for this reference liquid composition was 5.
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • Reference liquid composition RE5 The pH measured for this reference liquid composition was 7.2.
  • Reference liquid composition RE5 The pH measured for this reference liquid composition was 7.2.
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • Reference liquid composition RE6 The pH measured for this reference liquid composition was 5.
  • Reference liquid composition RE6 The pH measured for this reference liquid composition was 5.
  • a water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
  • the heat capacity of the proteins was measured as a function of temperature with a high precision differential scanning VP-DSC microcalorimeter (MicroCal, Northampton, MA). Protein samples and reference solutions were properly degassed and carefully loaded into the cells to avoid bubble formation. Thermal denaturation scans were performed with freshly prepared buffer-exchanged protein solutions. The baseline of the instrument was routinely recorded before the experiments. Experiments were performed in 164 mM NaCl, 10 mM sodium phosphate, pH 7.2 or 178 mM NaCl, 10 mM sodium acetate, pH 5, at a scanning rate of 1 °C/min. Data were analyzed using software developed in our laboratory implemented in Origin 7 (OriginLab).
  • Table 2 can be seen from Tables 1 and 2:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques stables comprenant une β-glucocérébrosidase humaine ou un analogue de celle-ci et du miglustat.
PCT/IB2011/052864 2010-06-30 2011-06-29 Compositions pharmaceutiques stables WO2012001641A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IB2010052983 2010-06-30
IBPCT/IB2010/052983 2010-06-30

Publications (1)

Publication Number Publication Date
WO2012001641A1 true WO2012001641A1 (fr) 2012-01-05

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062779A1 (fr) 1999-04-20 2000-10-26 Oxford Glycosciences (Uk) Limited Combinaison d'inhibiteurs de synthese de glucosylceramide et d'enzyme degradant les glycolipides utilisee en therapie
WO2001007078A1 (fr) * 1999-07-26 2001-02-01 G.D. Searle & Co. Utilisation de derives n-alkyle de deoxynojirimycine a chaine longue et d'enzyme glucocerebro-sidase pour fabriquer un medicament permettant de traiter des maladies provoquees par le stockage de glycolipides
WO2004037373A2 (fr) * 2002-10-21 2004-05-06 The Scripps Research Institute Chaperons moleculaires chimiques et leur effet sur l'activite cellulaire de $g(b)-glucosidase
US20060204487A1 (en) * 2003-04-27 2006-09-14 Protalix Ltd. Production of high mannose proteins in plant culture

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062779A1 (fr) 1999-04-20 2000-10-26 Oxford Glycosciences (Uk) Limited Combinaison d'inhibiteurs de synthese de glucosylceramide et d'enzyme degradant les glycolipides utilisee en therapie
EP1321143A1 (fr) * 1999-04-20 2003-06-25 Oxford GlycoSciences (UK) Limited Combinaison de n-butyldéoxygalactonojirimycine et de enzyme de la dégradation de glycolipide en thérapie
WO2001007078A1 (fr) * 1999-07-26 2001-02-01 G.D. Searle & Co. Utilisation de derives n-alkyle de deoxynojirimycine a chaine longue et d'enzyme glucocerebro-sidase pour fabriquer un medicament permettant de traiter des maladies provoquees par le stockage de glycolipides
WO2004037373A2 (fr) * 2002-10-21 2004-05-06 The Scripps Research Institute Chaperons moleculaires chimiques et leur effet sur l'activite cellulaire de $g(b)-glucosidase
US20060204487A1 (en) * 2003-04-27 2006-09-14 Protalix Ltd. Production of high mannose proteins in plant culture

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
A. ZIMRAN ET AL: "Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience", BLOOD, vol. 115, no. 23, 18 March 2010 (2010-03-18), pages 4651 - 4656, XP055010530, ISSN: 0006-4971, DOI: 10.1182/blood-2010-02-268649 *
ALFONSO ET AL: "Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in cells transfected with several Gaucher disease mutations", BLOOD CELLS, MOLECULES AND DISEASES, LAJOLLA, US, vol. 35, no. 2, 1 September 2005 (2005-09-01), pages 268 - 276, XP005074539, ISSN: 1079-9796, DOI: 10.1016/J.BCMD.2005.05.007 *
ANONYMOUS: "Cerezyme/imiglucerase product data sheet", 25 October 2011 (2011-10-25), XP055010420, Retrieved from the Internet <URL:http://www.cerezyme.com/~/media/Files/CerezymeUS/pdf/cerezyme_pi.pdf> [retrieved on 20111025] *
JOSE L. CAPABLO ET AL: "Neurologic Improvement in a Type 3 Gaucher Disease Patient Treated with Imiglucerase/Miglustat Combination", EPILEPSIA, vol. 48, no. 7, 1 July 2007 (2007-07-01), pages 1406 - 1408, XP055010307, ISSN: 0013-9580, DOI: 10.1111/j.1528-1167.2007.01074.x *
LIEBERMAN ET AL., BIOCHEMISTRY, vol. 48, 2009, pages 4816 - 4827
PRIESTMAN ET AL., GLYCOBIOLOGY, vol. 10, no. 11, 2000, pages IV - IX
REMINGTON: "The Science and Practice of Phannacy", 2005, LIPPINCOTT WILLIAMS & WILKINS, article "Pharmaceutical Manufacturing"
SANCHEZ-OLLE G ET AL: "Promising results of the chaperone effect caused by iminosugars and aminocyclitol derivatives on mutant glucocerebrosidases causing Gaucher disease", BLOOD CELLS, MOLECULES AND DISEASES, LAJOLLA, US, vol. 42, no. 2, 1 March 2009 (2009-03-01), pages 159 - 166, XP025915574, ISSN: 1079-9796, [retrieved on 20090122], DOI: 10.1016/J.BCMD.2008.11.002 *
WEINREB NEAL J ET AL: "Guidance on the use of miglustat for treating patients with type 1 Gaucher disease", AMERICAN JOURNAL OF HEMATOLOGY, vol. 80, no. 3, November 2005 (2005-11-01), pages 223 - 229, XP009153444, ISSN: 0361-8609 *
ZIMRAN ARI ET AL: "Gaucher disease and the clinical experience with substrate reduction therapy.", PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON B BIOLOGICAL SCIENCES, vol. 358, no. 1433, 29 May 2003 (2003-05-29), pages 961 - 966, XP009153443, ISSN: 0962-8436 *

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