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WO2012001641A1 - Stable pharmaceutical compositions - Google Patents

Stable pharmaceutical compositions 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
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WO
WIPO (PCT)
Prior art keywords
enzyme
pharmaceutical composition
miglustat
composition according
glucocerebrosidase
Prior art date
Application number
PCT/IB2011/052864
Other languages
French (fr)
Inventor
Olga Abian
Pilar Alfonso
Pilar Giraldo
Miguel Pocovi
Javier Sancho
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Actelion Pharmaceuticals Ltd
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Publication of WO2012001641A1 publication Critical patent/WO2012001641A1/en

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    • 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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Abstract

The invention relates to stable pharmaceutical compositions comprising a human β-glucocerebrosidase or an analogue thereof and miglustat.

Description

STABLE PHARMACEUTICAL COMPOSITIONS
The present invention relates to stable pharmaceutical compositions comprising a human β-glucocerebrosidase or an analogue thereof and miglustat. Human β-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.
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 β-glucocerebrosidase or an analogue thereof) for simultaneous, sequential or separate use in the treatment of, among others, Gaucher disease. Data about the use of the combination of miglustat and β-glucocerebrosidase are reported in WO 00/62779 as well as in an article by Priestman et al. {Glycobiology (2000), 10(l l), iv-ix).
No concrete pharmaceutical composition comprising miglustat and an ERT enzyme together is however described in these documents. A reason for the absence of pharmaceutical compositions comprising both miglustat and an ERT enzyme is that miglustat can be administered orally whereas the ERT enzyme has to be administered by infusion (because it would be degraded if it went through the gastrointestinal tract). As a result, to offer a combined treatment with an ERT enzyme and miglustat, one skilled in the art would not combine miglustat and an ERT enzyme in the same formulation; instead, he would provide the two components separately, namely miglustat in the form of capsules for oral administration and the ERT enzyme in the form of a solid composition to be reconstituted with water for intravenous administration. It has now been surprisingly found that, under certain conditions, miglustat has the ability to stabilise solid and liquid pharmaceutical compositions comprising human β-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. Various embodiments of the invention are presented hereafter:
1) The invention thus firstly relates to the use of miglustat to stabilise a pharmaceutical composition comprising an enzyme selected from human β-glucocerebrosidase and synthetic analogues of human β-glucocerebrosidase.
The following paragraphs provide definitions of various terms used herein and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition:
♦♦♦ A "synthetic analogue of human β-glucocerebrosidase" refers to an analogue of human β-glucocerebrosidase either obtained by recombinant technology or to a modified form of human β-glucocerebrosidase where the non-reducing ends of the oligosaccharide chains have been terminated with mannose residues. Representative examples of synthetic analogues of human β-glucocerebrosidase include imiglucerase, velaglucerase alfa, taliglucerase alfa and alglucerase. Preferred are imiglucerase and velaglucerase alfa.
♦♦♦ A "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.
❖ Unless used regarding temperatures or pH values, 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. In the particular case of temperatures, 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. Furthermore, in the case of pH values, 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.
2) According to a sub-embodiment of embodiment 1), the enzyme will be imiglucerase. 3) According to another sub-embodiment of embodiment 1), the enzyme will be velaglucerase alfa.
4) According to a further sub-embodiment of embodiment 1), the enzyme will be taliglucerase alfa.
5) According to yet a further sub-embodiment of embodiment 1), the enzyme will be alglucerase.
6) According to one main variant of this invention, the use according to embodiments 1) to 5) will be to stabilise a liquid composition.
7) According to the other main variant of this invention, the use according to embodiments 1) to 5) will be to stabilise a solid composition. 8) Preferably, for the use according to embodiments 1) to 7), 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. 9) The invention also relates to a liquid pharmaceutical composition, comprising:
a) an enzyme selected from human β-glucocerebrosidase and synthetic analogues thereof and
b) miglustat,
wherein the pH of said liquid pharmaceutical composition is a pH of from 6 to 8.
10) Preferably, 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).
11) According to more specific sub-embodiments of embodiments 9) or 10), 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. 12) In particular, the liquid pharmaceutical composition according to embodiment 11) will be a normal saline solution to which the enzyme and miglustat have been added.
13) According to particular sub-embodiments of embodiments 9) to 12), the enzyme will be imiglucerase.
14) According to other particular sub-embodiments of embodiments 9) to 12), the enzyme will be velaglucerase alfa.
15) According to further particular sub-embodiments of embodiments 9) to 12), the enzyme will be taliglucerase alfa.
16) According to yet further particular sub-embodiments of embodiments 9) to 12), the enzyme will be alglucerase. 17) Preferably, 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.
18) The invention furthermore relates to a solid pharmaceutical composition, comprising: a) an enzyme selected from human β-glucocerebrosidase and synthetic analogues thereof and
b) miglustat,
wherein the pH of the solution obtained after adding water to said solid pharmaceutical composition is a pH of from 6 to 8.
19) Preferably, 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).
20) According to a sub-embodiment of embodiment 18) or 19), the enzyme will be imiglucerase.
21) According to another sub-embodiment of embodiment 18) or 19), the enzyme will be velaglucerase alfa.
22) According to a further sub-embodiment of embodiment 18) or 19), the enzyme will be taliglucerase alfa.
23) According to yet a further sub-embodiment of embodiment 18) or 19), the enzyme will be alglucerase.
24) Preferably, 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.
25) 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). 26) 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). 27) 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).
The production of the pharmaceutical 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.
The 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.
EXAMPLES
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:
Figure imgf000008_0001
The pH measured for this water solution is 7.2.
Example 2: solid composition containing imiglucerase and miglustat:
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:
Figure imgf000008_0002
The pH measured for this water solution Example 4: solid composition containing velaglucerase alfa and miglustat:
The water solution of Example 4 may be freeze-dried to give a solid composition.
Experimental results
The stability of the 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.
Reference compositions:
Reference liquid composition RE1:
A water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
Figure imgf000009_0001
The pH measured for this reference liquid composition was 7.2. Reference liquid composition RE2:
A water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
Component Concentration
Sodium chloride 178 mM
Sodium acetate 10 mM
Imiglucerase 4 μΜ The pH measured for this reference liquid composition was 5. Reference liquid composition RE3:
A water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
Figure imgf000010_0001
The pH measured for this reference liquid composition was 5. Reference liquid composition RE4:
A water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
Figure imgf000010_0002
The pH measured for this reference liquid composition was 7.2. Reference liquid composition RE5:
A water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
Figure imgf000011_0001
The pH measured for this reference liquid composition was 5. Reference liquid composition RE6:
A water solution was prepared (using distilled water) which contains the components listed in the table hereafter:
Figure imgf000011_0002
The pH measured for this reference liquid composition was 5. Differential Scanning Calorimetry test:
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).
In the case of imiglucerase, a thermodynamic model could not be applied to analyze the data because severe aggregation upon denaturation occurred. This phenomenon had been previously reported (Lieberman et al, Biochemistry (2009), 48, 4816-4827). In this case, the analysis was limited to differences in the temperature at maximum heat capacity Tm of the normalized data.
Differential Scanning Calorimetry results: The temperatures at maximum heat capacity Tm obtained by performing the Differential Scanning Calorimetry test described in the preceding section regarding the compositions containing imiglucerase are summarised in Table 1 hereafter. Those obtained regarding the compositions containing velaglucerase alfa are summarised in Table 2 hereafter.
Figure imgf000012_0001
Table 1
Composition Tm
RE3 50.2
Example 2 50.6
RE4 55.5
RE6 55.5
Table 2 can be seen from Tables 1 and 2:
There is no difference in Tm between the reference compositions RE2 and RE3 or between the reference compositions RE5 and RE6. Thus, miglustat does not stabilise imiglucerase or velaglucerase alfa at pH 5.
There is a difference of 0.4 °C in Tm between the composition of Example 1 and the reference composition REl . This significant Tm difference shows that miglustat stabilises imiglucerase at pH 7.2.
There is also a difference of 0.4 °C in Tm between the composition of Example 2 and the reference composition RE4. This significant Tm difference shows that miglustat stabilises velaglucerase alfa at pH 7.2.

Claims

Claims
1. Use of miglustat to stabilise a pharmaceutical composition comprising an enzyme selected from human β-glucocerebrosidase and synthetic analogues thereof.
2. Use according to claim 1, wherein the enzyme is imiglucerase.
3. Use according to claim 1, wherein the enzyme is velaglucerase alfa.
4. Use according to claim 1, wherein the enzyme is taliglucerase alfa.
5. Use according to claim 1, wherein the enzyme is alglucerase.
6. A liquid pharmaceutical composition, comprising:
c) an enzyme selected from human β-glucocerebrosidase and synthetic analogues thereof and
d) miglustat,
wherein the pH of said liquid pharmaceutical composition is a pH of from 6 to 8.
7. A liquid pharmaceutical composition according to claim 6, which has a pH of from 6.5 to 7.5.
8. A liquid pharmaceutical composition according to claim 6 or 7, wherein the enzyme is imiglucerase.
9. A liquid pharmaceutical composition according to claim 6 or 7, wherein the enzyme is velaglucerase alfa.
10. A liquid pharmaceutical composition according to claim 6 or 7, wherein the enzyme is taliglucerase alfa.
11. A liquid pharmaceutical composition according to claim 6 or 7, wherein the enzyme is alglucerase.
12. A solid pharmaceutical composition, comprising:
a) an enzyme selected from human β-glucocerebrosidase and synthetic analogues thereof and
b) miglustat,
wherein the pH of the solution obtained after adding water to said solid pharmaceutical composition is a pH of from 6 to 8.
13. A solid pharmaceutical composition according to claim 12, wherein the pH of the solution obtained after adding water to said solid pharmaceutical composition is a pH of from 6.5 to 7.5.
14. A solid pharmaceutical composition according to claim 12 or 13, wherein the enzyme is imiglucerase.
15. A solid pharmaceutical composition according to claim 12 or 13, wherein the enzyme is velaglucerase alfa.
16. A solid pharmaceutical composition according to claim 12 or 13, wherein the enzyme is taliglucerase alfa.
17. A solid pharmaceutical composition according to claim 12 or 13, wherein the enzyme is alglucerase.
18. A pharmaceutical composition according to one of claims 6 to 17 for use in the treatment of Gaucher disease.
PCT/IB2011/052864 2010-06-30 2011-06-29 Stable pharmaceutical compositions WO2012001641A1 (en)

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