WO2004002534A1 - Use of dimethyl sulfone as isotonicity agent - Google Patents

Use of dimethyl sulfone as isotonicity agent Download PDF

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Publication number
WO2004002534A1
WO2004002534A1 PCT/DK2003/000418 DK0300418W WO2004002534A1 WO 2004002534 A1 WO2004002534 A1 WO 2004002534A1 DK 0300418 W DK0300418 W DK 0300418W WO 2004002534 A1 WO2004002534 A1 WO 2004002534A1
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Prior art keywords
peptide
pharmaceutical composition
human insulin
administration
use according
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PCT/DK2003/000418
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French (fr)
Inventor
Svend Havelund
Per Balschmidt
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Novo Nordisk A/S
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Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to EP03729910A priority Critical patent/EP1539244A1/en
Priority to AU2003240437A priority patent/AU2003240437A1/en
Publication of WO2004002534A1 publication Critical patent/WO2004002534A1/en

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    • 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
    • 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
    • A61K38/26—Glucagons
    • 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
    • A61K38/28—Insulins
    • 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
    • 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

Definitions

  • the invention relates to a pharmaceutical composition for parenteral administration comprising a peptide and dimethyl sulfone and to the use of dimethyl sulfone as isotonicity agent in a pharmaceutical composition, especially a pharmaceutical composition comprising a peptide as the active ingredient.
  • compositions for parenteral administration comprise an isotonicity agent to provide tonicity or osmolarity close to the body fluids at the administration site.
  • isotonicity agents for parenteral peptide compositions are glycerol, dextrose, mannitol, lactose and salts such as sodium chloride.
  • isotonicity agent will affect the properties of the preparation as revealed by the chemical stability.
  • aldehyde impurities of glycerol may result in transformation of the peptide thus resulting in a product with deteriorated stability.
  • Dimethyl sulfone is a well known organic compound which has been disclosed for different applications.
  • US 4,863,748 and 4,616,039 disclose dimethyl sulfone for use as a dietary supplement.
  • US 4,973,605, US 4,559,329 and US 4,514,421 disclose dietary and pharmaceutical uses of dimethyl sulfone.
  • US 4,568,547 discloses the use of dimethyl sulfone as a tabletting and granulating aid for pharmaceutically active agents.
  • US 4,296,130 and US 4,477,469 disclose preparations containing dimethyl sulfone for softening skin and nails or for diluting blood.
  • CA 1988-568512 discloses a formulation for treating cancer comprising dimethyl sulfone for enhancing or altering the penetration of the active agent to the tumour.
  • WO 01/26642 discloses a method for treating neurobehavioral disorders by administering a composition comprising amino acids, neurotransmitter precursors, vitamins, inhibitors of neurotransmitter degradation and/or immune function enhancers.
  • a composition comprising amino acids, neurotransmitter precursors, vitamins, inhibitors of neurotransmitter degradation and/or immune function enhancers.
  • vitamins listed is dimethyl sulfone.
  • the present invention is based on the finding that dimethyl sulfone is useful as an isotonicity agent in pharmaceutical compositions for parenteral administration, especially pharmaceutical compositions for parenteral administration which comprise a peptide as the active ingredient.
  • peptide as used herein is intended to include a compound formed by linking at least two amino acids through a peptide bond.
  • the term comprises oligopeptides containing fewer than 10 amino acids as well as polypeptides containing at least 10 amino acids.
  • the term includes naturally occurring peptides, including proteins, as well as synthetic peptides.
  • the term is also intended to include modified peptides, eg alkylated, acylated peptides, etc.
  • parenteral administration means that the administration is not through the alimentary canal but rather through some other route, such as via the subcutaneous, intramuscular, intrathecal, pulmonal, intravenous, intradermal, intraspinal or intraster- nal route.
  • the term also covers ophthalmic administration and topical administration.
  • analogue as used herein designates a peptide wherein one or more amino acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more amino acid residues have been added to the parent peptide. Such addition can take place either in the peptide, at the N-terminal end or at the C-terminal end of the parent peptide, or any combination thereof.
  • derivative designates a peptide in which one or more of the amino acid residues of the parent peptide or analogue of the parent peptide have been chemically modified, eg by alkylation, acylation, ester formation or amide formation.
  • the present invention relates to a pharmaceutical composition for parenteral administration, which comprises a peptide and dimethyl sulfone.
  • Dimethyl sulfone which is also designated methylsulfonylmethane or MSM may be prepared from dimethyl sulfoxide by oxidation. It can be obtained in highly purified form as crystals with a melting point at about 110 °C and has a well defined boiling point at 238 °C. It is commercially available at a low price. It is non-toxic and non-allergenic. Furthermore, it is very soluble in water. These properties make it very attractive for use in pharmaceutical compositions. Dimethyl sulfone is very stable and does not deteriorate the peptide in the pharmaceutical composition. Accordingly, very stable pharmaceutical compositions are provided. Dimethyl sulfone is used in an amount to make the pharmaceutical composition iso- tonic with the site of administration. The amount has to be adjusted based on the other ingredients of the pharmaceutical composition which may also contribute to isotonicity. In one embodiment, the amount of dimethyl sulfone is of from 40 to 400 mM, such as of from 25 to 350 mM.
  • the pharmaceutical composition is a solution.
  • the pharmaceutical composition is a suspension.
  • the pharmaceutical composition is intended for parenteral administration.
  • the pharmaceutical composition is adapted for administration by injection or infusion, such as subcutaneous administration, intramuscular administration or intravenous administration.
  • the pharmaceutical composition is adapted for pulmonal administration.
  • the pharmaceutical composition is adapted for ophthalmic administration or topical administration.
  • the pharmaceutical composition comprises a peptide as active ingredient.
  • the peptide is human growth hormone, GLP-1, GLP-2, insulin, Factor VII, Fac- tor VIII, erythropoeitin (EPO), glucagon, interleukin, such as interleukin-2 (IL-2), interferon- ⁇ or interferon- ⁇ , or an analogue thereof, or a derivative of any such peptide or analogue.
  • the peptide is human growth hormone, GLP-1, GLP-2, insulin, Factor VII, Fac- tor VIII, erythropoeitin (EPO), glucagon, interleukin, such as interleukin-2 (IL-2), interferon- ⁇ or interferon- ⁇ , or an analogue thereof, or a derivative of any such peptide or analogue.
  • the peptide is human insulin or an analogue thereof, or a derivative of human insulin or the human insulin analogue, such as human insulin, Asp(B28)- human insulin, Lys(B28) Pro(B29)-human insulin, Lys(B3) Glu(B29)-human insulin, N ⁇ B29 -tetradecanoyl des (B30)-human insulin, Gly(A21) Arg(B31) Arg(B32)-human insulin or N ⁇ B 9 -litocholoyl- ⁇ -glutamyl des (B30)-human insulin.
  • the peptide is Gly(8)-human GLP-1 , Arg(34), N- ⁇ -( ⁇ - Glu(N- ⁇ -hexadecanoyl))-Lys(26)-human GLP-1 (7-37)OH or Gly(2)-human GLP-2.
  • the invention relates to the use of dimethyl sulfone as an isotonic- ity agent in a pharmaceutical composition for parenteral administration.
  • the invention relates to the use of dimethyl sulfone as an isotonicity agent in a pharmaceutical composition for parenteral administration comprising a peptide as the active ingredient.
  • the amount of dimethyl sulfone in the pharmaceutical composi- tion is of from 40 to 400 mM, such as of from 125 to 350 mM.
  • the pharmaceutical composition is a solution.
  • the pharmaceutical composition is a suspension.
  • the pharmaceutical composition is adapted for administration by injection or infusion, such as subcutaneous administration, intramuscular admini- stration or intravenous administration.
  • the pharmaceutical composition is adapted for pulmonal administration.
  • the pharmaceutical composition is adapted for ophthalmic administration or topical administration.
  • the peptide is human growth hormone, GLP-1 , GLP-2, insulin, Factor VII, Factor VIII, erythropoeitin (EPO), glucagon, interleukin, such as interleukin-2 (IL-2), interferon- ⁇ or interferon- ⁇ , or an analogue thereof, or a derivative of any such peptide or analogue.
  • the peptide is human insulin or an analogue thereof, or a derivative of human insulin or the human insulin analogue, such as human insulin,
  • the peptide is Gly(8)-human GLP-1, Arg(34), N- ⁇ -( ⁇ -Glu(N- ⁇ -hexadecanoyl))-Lys(26)-human GLP-1 (7-37)OH or Gly(2)-human GLP-2.
  • compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Reming- ton: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions according to the invention are intended for parenteral administration, such as subcutaneous, intramuscular, intrathecal, intravenous, in- tradermal, intraspinal or intrasternal administration.
  • parenteral administration such as subcutaneous, intramuscular, intrathecal, intravenous, in- tradermal, intraspinal or intrasternal administration.
  • Other suitable administration routes are ophthalmic administration or topical administration for treating open wounds, ulcers, bedsores, pressure sores and burns.
  • Suitable administration forms include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • Other suitable administration forms include ophthalmic preparations such as eye drops and eye ointments and topical preparations such as wound dressings.
  • Example 1 Formulation of dissolved human insulin preparation containing dimethyl sulfone
  • the pH is adjusted to 7.3 with diluted hydrochloric acid or sodium hydroxide and water is added to a total volume of 20.0 ml.
  • the resulting solution is finally sterilized by filtration.
  • Formulation I is prepared according to example 1.
  • Formulation II is prepared according to example 1 with the exception that the dimethyl sulfone is omitted.
  • Formulation III is prepared according to example 1 with the exception that the dimethyl sulfone is replaced by 368 mg of glycerol.
  • the formulations were stored in closed 1 ml HPLC vials at 4 °C and at 25 °C, re- spectively. After storage for 10 weeks the formulations were analyzed by reverse phase
  • the AUC for the side peaks in percentage of the total AUC for the insulin-related peaks was calculated as a measure of purity. Thus, a low number indicates a high degree of purity.
  • the difference in purity between the human insulin solutions stored at 4 °C and 25 °C, respectively, is shown in the table for each of the formulations.
  • Example 4 Formulation of a preparation of dissolved Asp(B28)-human insulin analogue containing dimethyl sulfone
  • Zn-free Asp(B28)-human insulin can be prepared as described in eg EP 214 826) is dispersed in 2 ml of water and dissolved by addition of 65 ⁇ l of 2N hydrochloric acid. Then the following excipients are added with gentle stirring: 78.4 ⁇ l of zinc chloride solution (10 mg Zn/ml)
  • the pH is adjusted to 7.3 with diluted hydrochloric acid or sodium hydroxide and water is added to a total volume of 40.0 ml.
  • the resulting solution is finally sterilized by filtration.
  • the pH is adjusted to 7.4 with diluted hydrochloric acid and water is added to a total volume of 20 ml.
  • the pH is adjusted to 6.2 with diluted hydrochloric acid and water is added to a total volume of 10 ml.
  • 67 mg of human growth hormone can be prepared as described in eg EP 217 814 or EP 218 651 is added and dissolved by gentle stirring.
  • the resulting solution is sterilized by filtration, if necessary, after readjustment of the pH to 6.2.
  • FVIIa may be produced as disclosed in EP patent No. 200,421.

Abstract

A pharmaceutical composition for parenteral administration comprising a peptide (insulin, human growth hormone, erythropoietin etc.) and dimethyl sulfone, and use of dimethyl sulfone as an isotonicity agent in a pharmaceutical composition for parenteral administration.

Description

USE OF DIMETHYL SULFONE AS ISOTONICITY AGENT
FIELD OF THE INVENTION
The invention relates to a pharmaceutical composition for parenteral administration comprising a peptide and dimethyl sulfone and to the use of dimethyl sulfone as isotonicity agent in a pharmaceutical composition, especially a pharmaceutical composition comprising a peptide as the active ingredient.
BACKGROUND OF THE INVENTION
To avoid pain or tissue damage, pharmaceutical compositions for parenteral administration comprise an isotonicity agent to provide tonicity or osmolarity close to the body fluids at the administration site. Conventional isotonicity agents for parenteral peptide compositions are glycerol, dextrose, mannitol, lactose and salts such as sodium chloride.
The choice of isotonicity agent will affect the properties of the preparation as revealed by the chemical stability. For example aldehyde impurities of glycerol may result in transformation of the peptide thus resulting in a product with deteriorated stability. Dimethyl sulfone is a well known organic compound which has been disclosed for different applications.
US 4,863,748 and 4,616,039 disclose dimethyl sulfone for use as a dietary supplement. US 4,973,605, US 4,559,329 and US 4,514,421 disclose dietary and pharmaceutical uses of dimethyl sulfone. US 4,568,547 discloses the use of dimethyl sulfone as a tabletting and granulating aid for pharmaceutically active agents. US 4,296,130 and US 4,477,469 disclose preparations containing dimethyl sulfone for softening skin and nails or for diluting blood. CA 1988-568512 discloses a formulation for treating cancer comprising dimethyl sulfone for enhancing or altering the penetration of the active agent to the tumour. WO 01/26642 discloses a method for treating neurobehavioral disorders by administering a composition comprising amino acids, neurotransmitter precursors, vitamins, inhibitors of neurotransmitter degradation and/or immune function enhancers. Among the vitamins listed is dimethyl sulfone.
The present invention is based on the finding that dimethyl sulfone is useful as an isotonicity agent in pharmaceutical compositions for parenteral administration, especially pharmaceutical compositions for parenteral administration which comprise a peptide as the active ingredient.
DEFINITIONS
The following is a detailed definition of the terms used in the specification: The term "peptide" as used herein is intended to include a compound formed by linking at least two amino acids through a peptide bond. The term comprises oligopeptides containing fewer than 10 amino acids as well as polypeptides containing at least 10 amino acids. The term includes naturally occurring peptides, including proteins, as well as synthetic peptides. The term is also intended to include modified peptides, eg alkylated, acylated peptides, etc.
The term "parenteral administration" as used herein means that the administration is not through the alimentary canal but rather through some other route, such as via the subcutaneous, intramuscular, intrathecal, pulmonal, intravenous, intradermal, intraspinal or intraster- nal route. The term also covers ophthalmic administration and topical administration. The term "analogue" as used herein designates a peptide wherein one or more amino acid residues of the parent peptide have been substituted by another amino acid residue and/or wherein one or more amino acid residues of the parent peptide have been deleted and/or wherein one or more amino acid residues have been added to the parent peptide. Such addition can take place either in the peptide, at the N-terminal end or at the C-terminal end of the parent peptide, or any combination thereof.
The term "derivative" as used herein designates a peptide in which one or more of the amino acid residues of the parent peptide or analogue of the parent peptide have been chemically modified, eg by alkylation, acylation, ester formation or amide formation.
DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition for parenteral administration, which comprises a peptide and dimethyl sulfone.
Dimethyl sulfone which is also designated methylsulfonylmethane or MSM may be prepared from dimethyl sulfoxide by oxidation. It can be obtained in highly purified form as crystals with a melting point at about 110 °C and has a well defined boiling point at 238 °C. It is commercially available at a low price. It is non-toxic and non-allergenic. Furthermore, it is very soluble in water. These properties make it very attractive for use in pharmaceutical compositions. Dimethyl sulfone is very stable and does not deteriorate the peptide in the pharmaceutical composition. Accordingly, very stable pharmaceutical compositions are provided. Dimethyl sulfone is used in an amount to make the pharmaceutical composition iso- tonic with the site of administration. The amount has to be adjusted based on the other ingredients of the pharmaceutical composition which may also contribute to isotonicity. In one embodiment, the amount of dimethyl sulfone is of from 40 to 400 mM, such as of from 25 to 350 mM.
In another embodiment, the pharmaceutical composition is a solution.
In yet another embodiment, the pharmaceutical composition is a suspension. The pharmaceutical composition is intended for parenteral administration. In one embodiment, the pharmaceutical composition is adapted for administration by injection or infusion, such as subcutaneous administration, intramuscular administration or intravenous administration.
In another embodiment, the pharmaceutical composition is adapted for pulmonal administration.
In yet her embodiment, the pharmaceutical composition is adapted for ophthalmic administration or topical administration.
The pharmaceutical composition comprises a peptide as active ingredient. In one embodiment, the peptide is human growth hormone, GLP-1, GLP-2, insulin, Factor VII, Fac- tor VIII, erythropoeitin (EPO), glucagon, interleukin, such as interleukin-2 (IL-2), interferon-α or interferon-β, or an analogue thereof, or a derivative of any such peptide or analogue.
In another embodiment, the peptide is human insulin or an analogue thereof, or a derivative of human insulin or the human insulin analogue, such as human insulin, Asp(B28)- human insulin, Lys(B28) Pro(B29)-human insulin, Lys(B3) Glu(B29)-human insulin, NεB29-tetradecanoyl des (B30)-human insulin, Gly(A21) Arg(B31) Arg(B32)-human insulin or NεB 9-litocholoyl-γ-glutamyl des (B30)-human insulin.
In yet another embodiment, the peptide is Gly(8)-human GLP-1 , Arg(34), N-ε-(γ- Glu(N-α-hexadecanoyl))-Lys(26)-human GLP-1 (7-37)OH or Gly(2)-human GLP-2.
In a further aspect the invention relates to the use of dimethyl sulfone as an isotonic- ity agent in a pharmaceutical composition for parenteral administration.
In yet a further aspect, the invention relates to the use of dimethyl sulfone as an isotonicity agent in a pharmaceutical composition for parenteral administration comprising a peptide as the active ingredient.
In one embodiment, the amount of dimethyl sulfone in the pharmaceutical composi- tion is of from 40 to 400 mM, such as of from 125 to 350 mM.
In another embodiment, the pharmaceutical composition is a solution.
In yet another embodiment, the pharmaceutical composition is a suspension.
In still another embodiment, the pharmaceutical composition is adapted for administration by injection or infusion, such as subcutaneous administration, intramuscular admini- stration or intravenous administration. In a further embodiment, the pharmaceutical composition is adapted for pulmonal administration.
In a further embodiment, the pharmaceutical composition is adapted for ophthalmic administration or topical administration. In yet a further embodiment, the peptide is human growth hormone, GLP-1 , GLP-2, insulin, Factor VII, Factor VIII, erythropoeitin (EPO), glucagon, interleukin, such as interleukin-2 (IL-2), interferon-α or interferon-β, or an analogue thereof, or a derivative of any such peptide or analogue.
In still a further embodiment, the peptide is human insulin or an analogue thereof, or a derivative of human insulin or the human insulin analogue, such as human insulin,
Asp(B28)-human insulin, Lys(B28) Pro(B29)-human insulin, Lys(B3) Glu(B29)-human insulin, NεB29-tetradecanoyl des (B30)-human insulin, Gly(A21) Arg(B31) Arg(B32)-human insulin or NεB29-litocholoyl-γ-glutamyl des (B30)-human insulin.
In another embodiment, the peptide is Gly(8)-human GLP-1, Arg(34), N-ε-(γ-Glu(N- α-hexadecanoyl))-Lys(26)-human GLP-1 (7-37)OH or Gly(2)-human GLP-2.
PHARMACEUTICAL COMPOSITIONS
The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Reming- ton: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical compositions according to the invention are intended for parenteral administration, such as subcutaneous, intramuscular, intrathecal, intravenous, in- tradermal, intraspinal or intrasternal administration. Other suitable administration routes are ophthalmic administration or topical administration for treating open wounds, ulcers, bedsores, pressure sores and burns.
It will be appreciated that the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen. Suitable administration forms include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. Other suitable administration forms include ophthalmic preparations such as eye drops and eye ointments and topical preparations such as wound dressings.
EXAMPLES
Example 1 Formulation of dissolved human insulin preparation containing dimethyl sulfone
74.9 mg of Zn-crystallized human insulin is dispersed in 2 ml of water and dissolved by addition of 32.5 μl of 2N hydrochloric acid. Then the following ingredients are added: 2.0 ml of 160 mM m-cresol solution 2.0 ml of 160 mM phenol solution 376 mg of dimethyl sulfone
1.0 ml of 140 mM disodium hydrogen phosphate solution 1.0 ml of 200 mM sodium chloride solution 10 ml of water
The pH is adjusted to 7.3 with diluted hydrochloric acid or sodium hydroxide and water is added to a total volume of 20.0 ml. The resulting solution is finally sterilized by filtration.
Example 2
Comparison of the chemical stability of 3 formulations of dissolved human insulin
Formulation I is prepared according to example 1. Formulation II is prepared according to example 1 with the exception that the dimethyl sulfone is omitted.
Formulation III is prepared according to example 1 with the exception that the dimethyl sulfone is replaced by 368 mg of glycerol.
The formulations were stored in closed 1 ml HPLC vials at 4 °C and at 25 °C, re- spectively. After storage for 10 weeks the formulations were analyzed by reverse phase
HPLC on a 4.6 mm X 150 mm Waters SymmetryShield RP8 (3.5 μm) column eluted at 30 °C by a buffer system A (0.2 M sodium sulphate, 0.04 M sodium phosphate, pH 7.2 in 10% (v/v) acetonitrile) with 19% B (70% (v/v) acetonitrile ) for 21 min, then with 24% B for 30 min and finally with a linear gradient from 24% B to 39% B over 30 min.
The AUC for the side peaks in percentage of the total AUC for the insulin-related peaks was calculated as a measure of purity. Thus, a low number indicates a high degree of purity. The difference in purity between the human insulin solutions stored at 4 °C and 25 °C, respectively, is shown in the table for each of the formulations.
Figure imgf000007_0001
The results show that the content of dimethyl sulfone does not impair the chemical stability of the insulin in the formulation and that the insulin is substantially less stable when dimethyl sulfone is replaced by glycerol in the formulation.
Example 3
Formulation of NPH-crystallized human insulin preparation containing dimethyl sulfone Solution A:
74.5 mg of Zn-crystallized human insulin is dispersed in 2 ml of water and dissolved by addition of 34 μl of 2N hydrochloric acid. Then the following ingredients are added:
650 μl of 160 mM m-cresol solution
430 μl of 160 mM phenol solution 176 mg of dimethyl sulfone
35.8 μl of zinc chloride solution (10 mg Zn/ml)
750 μl of protamine sulphate solution (10 mg/ml)
Water is added to a total volume of 10 ml. Solution B:
The following ingredients are mixed:
2.0 ml of 140 mM disodium hydrogen phosphate
650 μl of 160 mM m-cresol
430 μl of 160 mM phenol 176 mg of dimethyl sulfone
8 μl of 2N sodium hydroxide Water is added to a total volume of 10 ml. Solution A and solution B are sterilized by filtration and then mixed. The resulting suspension is left at 23°C and after overnight standing the crystallization is complete.
Example 4 Formulation of a preparation of dissolved Asp(B28)-human insulin analogue containing dimethyl sulfone
151.9 mg of Zn-free Asp(B28)-human insulin (can be prepared as described in eg EP 214 826) is dispersed in 2 ml of water and dissolved by addition of 65 μl of 2N hydrochloric acid. Then the following excipients are added with gentle stirring: 78.4 μl of zinc chloride solution (10 mg Zn/ml)
4.0 ml of 160 mM m-cresol solution 4.0 ml of 160 M phenol solution 752 mg of dimethyl sulfone 50 mg of disodium hydrogen phosphate, dihydrate 23.5 mg of sodium chloride
25 ml of water
The pH is adjusted to 7.3 with diluted hydrochloric acid or sodium hydroxide and water is added to a total volume of 40.0 ml. The resulting solution is finally sterilized by filtration.
Example 5
Formulation of a dissolved preparation of Arg(34), N-ε-(γ-Glu(N-α-hexadecanoyl))-Lys(26)- human GLP-1 (7-37)OH containing dimethyl sulfone
The following ingredients are mixed:
3.2 ml of 50 mM disodium hydrogen phosphate solution 0.6 ml of 100 mM phenol solution
382 mg of dimethyl sulfone
5 ml of water
The pH is adjusted to 7.4 with diluted hydrochloric acid and water is added to a total volume of 20 ml.
40 mg of Arg(34), N-ε-(γ-Glu(N-α-hexadecanoyl))-Lys(26)-human GLP-1 (7-37)OH (can be prepared as described in eg WO 98/08871) is added and dissolved by gentle stirring. The resulting solution is sterilized by filtration, if necessary, after readjustment of the pH to 7.4.
Example 6
Formulation of a dissolved preparation of human growth hormone containing dimethyl sul- fone
The following ingredients are mixed: 6.8 mg of L-histidine 30 mg of poloxamer 188 207 mg of dimethyl sulfone 3.2 ml of 100 mM phenol solution
5 ml of water
The pH is adjusted to 6.2 with diluted hydrochloric acid and water is added to a total volume of 10 ml. 67 mg of human growth hormone (can be prepared as described in eg EP 217 814 or EP 218 651) is added and dissolved by gentle stirring. The resulting solution is sterilized by filtration, if necessary, after readjustment of the pH to 6.2.
Example 7
Formulation of a freeze-dried preparation of human FVIIa containing dimethyl sul- phon
The following ingredients are mixed:
FVIIa 0.6 mg/ml
CaCI2 10 mM
Glycylglycine 10 mM
Dimethyl sulphone 8.3 mg/ml
Tween 80 0.07 mg/ml
Mannitol 30 mg/ml pH 5.5
The pH is adjusted to 5.5 with NaOH/HCI. The solution is sterilized by filtration and filled into sterile glass vials. The vials are freeze-dried, closed with rubber stoppers and sealed with aluminum flip-off type caps. FVIIa may be produced as disclosed in EP patent No. 200,421.

Claims

1. A pharmaceutical composition for parenteral administration, which comprises a peptide and dimethyl sulfone.
2. A pharmaceutical composition according to claim 1 , wherein the amount of dimethyl sulfone is of from 40 to 400 mM.
3. A pharmaceutical composition according to claim 2, wherein amount of dimethyl sulfone is of from 125 to 350 mM.
4. A pharmaceutical composition according to any one of the claims 1 to 3, wherein the composition is a solution.
5. A pharmaceutical composition according to any one of the claims 1 to 3, wherein the composition is a suspension.
6. A pharmaceutical composition according to any one of the preceding claims, which is suitable for administration by injection or infusion.
7. A pharmaceutical composition according to claim 6, which is suitable for subcutaneous administration.
8. A pharmaceutical composition according to claim 6, which is suitable for intramuscular administration.
9. A pharmaceutical composition according to claim 6, which is suitable for intravenous administration.
10. A pharmaceutical composition according to any one of the preceding claims 1 to 5, which is suitable for pulmonal administration.
11. A pharmaceutical composition according to any one of the preceding claims 1 to 5, which is suitable for ophthalmic administration or topical administration.
12. A pharmaceutical composition according to any one of the preceding claims, wherein the peptide is human growth hormone, GLP-1 , GLP-2, insulin, Factor Vila, Factor VIII, erythropoeitin (EPO), glucagon, interleukin, such as interleukin-2 (IL-2), interferon-α or interferon-β, or an analogue thereof, or a derivative of any such peptide or analogue.
13. A pharmaceutical composition according to claim 12, wherein the peptide is human insulin or an analogue thereof, or a derivative of human insulin or the human insulin analogue.
14. A pharmaceutical composition according to claim 13, wherein the peptide is human insu- lin.
15. A pharmaceutical composition according to claim 13, wherein the peptide is Asp(B28)- human insulin.
16. A pharmaceutical composition according to claim 13, wherein the peptide is Lys(B28) Pro(B29)-human insulin.
17. A pharmaceutical composition according to claim 13, wherein the peptide is Lys(B3) Glu(B29)-human insulin.
18. A pharmaceutical composition according to claim 13, wherein the peptide is NεB29-tetra- decanoyl des (B30)-human insulin.
19. A pharmaceutical composition according to claim 13, wherein the peptide is Gly(A21 ) Arg(B31 ) Arg(B32)-human insulin.
20. A pharmaceutical composition according to claim 13, wherein the peptide is NεB29-lito- choloyl-γ-glutamyl des (B30)-human insulin.
21. A pharmaceutical composition according to claim 12, wherein the peptide is Gly(8)- human GLP-1.
22. A pharmaceutical composition according to claim 12, wherein the peptide is Arg(34), N-ε- (γ-Glu(N-α-hexadecanoyl))-Lys(26)-human GLP-1 (7-37)OH.
23. A pharmaceutical composition according to claim 12, wherein the peptide is Gly(2)- human GLP-2.
24. Use of dimethyl sulfone as an isotonicity agent in a pharmaceutical composition for par- enteral administration.
25. Use of dimethyl sulfone as an isotonicity agent in a pharmaceutical composition for parenteral administration comprising a peptide.
26. Use according to claims 24 or 25, wherein the amount of dimethyl sulfone in the pharmaceutical composition is of from 40 to 400 mM.
27. Use according to claim 26, wherein the amount of dimethyl sulfone in the pharmaceutical composition is of from 125 to 350 mM.
28. Use according to any one of the claims 24 to 27, wherein the composition is a solution.
29. Use according to any one of the claims 24 to 27, wherein the composition is a suspension.
30. Use according to any one of the claims 24 to 29, wherein the composition is suitable for administration by injection or infusion.
31. Use according to claim 30, wherein the composition is suitable for subcutaneous admini- stration.
32. Use according to claim 30, wherein the composition is suitable for intramuscular administration.
33. Use according to claim 30, wherein the composition is suitable for intravenous administration.
34. Use according to any one of the claims 24 to 29, wherein the composition is suitable for pul onal administration.
35. Use according to any one of the claims 24 to 29, wherein the composition is suitable for ophthalmic administration or topical administration.
36. Use according to any one of the preceding claims 24 to 35, wherein the peptide is human growth hormone, GLP-1 , GLP-2, insulin, Factor VII, Factor VIII, erythropoeitin (EPO), glucagon, interleukin, such as interleukin-2 (IL-2), interferon-α or interferon-β, or an analogue thereof, or a derivative of any such peptide or analogue.
37. Use according to claim 36, wherein the peptide is human insulin or an analogue thereof, or a derivative of human insulin or the human insulin analogue.
38. Use according to claim 37, wherein the peptide is human insulin.
39. Use according to claim 37, wherein the peptide is Asp(B28)-human insulin.
40. Use according to claim 37, wherein the peptide is Lys(B28) Pro(B29)-human insulin.
41. Use according to claim 37, wherein the peptide is Lys(B3) Glu(B29)-human insulin.
42. Use according to claim 37, wherein the peptide is NεB29-tetradecanoyl des (B30)-human insulin.
43. Use according to claim 37, wherein the peptide is Gly(A21) Arg(B31) Arg(B32)-human insulin.
44. Use according to claim 37, wherein the peptide is NεB29-litocholoyl-γ-glutamyl des (B30)- human insulin.
45. Use according to claim 36, wherein the peptide is Gly(8)-human GLP-1.
46. Use according to claim 36, wherein the peptide is Arg(34), N-ε-(γ-Glu(N-α-hexadecan- oyl))-Lys(26)-human GLP-1 (7-37)OH.
47. Use according to claim 36, wherein the peptide is Gly(2)-human GLP-2.
PCT/DK2003/000418 2002-06-27 2003-06-23 Use of dimethyl sulfone as isotonicity agent WO2004002534A1 (en)

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WO2005037304A1 (en) * 2003-10-17 2005-04-28 Crucell Holland B.V. Treatment and prevention of decubitus
EP1941901A1 (en) * 2005-09-27 2008-07-09 Genescience Pharmaceuticals Co. Ltd. An exterior-applied formulation and its preparation methods and uses
EP1997505A1 (en) * 2006-03-22 2008-12-03 Chugai Seiyaku Kabushiki Kaisha Erythropoietin solution preparation
WO2010019276A3 (en) * 2008-08-15 2010-06-03 Livionex Inc. Method and formulation for treating adverse biological conditions
US9101607B2 (en) 2010-03-31 2015-08-11 Stabilitech Ltd. Method for preserving alum adjuvants and alum-adjuvanted vaccines
US10029007B2 (en) 2011-10-05 2018-07-24 Stabilitech Biopharma Ltd Stabilisation of polypeptides
US10206960B2 (en) 2010-03-31 2019-02-19 Stabilitech Biopharma Ltd Stabilisation of viral particles
US10716859B2 (en) 2010-03-31 2020-07-21 Stabilitech Biopharma Ltd Excipients for stabilising viral particles, polypeptides or biological material
US10806783B2 (en) 2014-04-11 2020-10-20 Stabilitech Biopharma Ltd Vaccine compositions
US10980871B2 (en) 2017-05-08 2021-04-20 Iosbio Ltd Vaccine compositions

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EP1254961A1 (en) * 1998-05-06 2002-11-06 Transgene S.A. Improvments in gene therapy using compositions comprising a polynucleotide and interleukin-10
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EP1254961A1 (en) * 1998-05-06 2002-11-06 Transgene S.A. Improvments in gene therapy using compositions comprising a polynucleotide and interleukin-10
EP1052288A1 (en) * 1999-05-10 2000-11-15 Transgene S.A. Complex for transferring an anionic substance of interest into a cell
WO2003048195A2 (en) * 2001-12-02 2003-06-12 Novo Nordisk A/S Glucose dependant release of insulin from glucose sensing insulin derivatives

Cited By (14)

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Publication number Priority date Publication date Assignee Title
WO2005037304A1 (en) * 2003-10-17 2005-04-28 Crucell Holland B.V. Treatment and prevention of decubitus
CN1939534B (en) * 2005-09-27 2010-12-01 长春金赛药业股份有限公司 Externally-applied preparation containing human growth incretion or human granular leukocyte macrophage stimulus factor for treating injury ulceration
EP1941901A1 (en) * 2005-09-27 2008-07-09 Genescience Pharmaceuticals Co. Ltd. An exterior-applied formulation and its preparation methods and uses
EP1941901A4 (en) * 2005-09-27 2009-08-05 Genescience Pharmaceuticals Co An exterior-applied formulation and its preparation methods and uses
EP1997505A4 (en) * 2006-03-22 2013-02-13 Chugai Pharmaceutical Co Ltd Erythropoietin solution preparation
EP1997505A1 (en) * 2006-03-22 2008-12-03 Chugai Seiyaku Kabushiki Kaisha Erythropoietin solution preparation
US8546329B2 (en) 2006-03-22 2013-10-01 Chugai Seiyaku Kabushiki Kaisha Erythropoietin solution preparation
WO2010019276A3 (en) * 2008-08-15 2010-06-03 Livionex Inc. Method and formulation for treating adverse biological conditions
US9101607B2 (en) 2010-03-31 2015-08-11 Stabilitech Ltd. Method for preserving alum adjuvants and alum-adjuvanted vaccines
US10206960B2 (en) 2010-03-31 2019-02-19 Stabilitech Biopharma Ltd Stabilisation of viral particles
US10716859B2 (en) 2010-03-31 2020-07-21 Stabilitech Biopharma Ltd Excipients for stabilising viral particles, polypeptides or biological material
US10029007B2 (en) 2011-10-05 2018-07-24 Stabilitech Biopharma Ltd Stabilisation of polypeptides
US10806783B2 (en) 2014-04-11 2020-10-20 Stabilitech Biopharma Ltd Vaccine compositions
US10980871B2 (en) 2017-05-08 2021-04-20 Iosbio Ltd Vaccine compositions

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