Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—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.

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• Health & Medical Sciences (AREA)
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• Engineering & Computer Science (AREA)
• Gastroenterology & Hepatology (AREA)
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• Endocrinology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Diabetes (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Oil, Petroleum & Natural Gas (AREA)
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• 2003
  • 2003-06-23 AU AU2003240437A patent/AU2003240437A1/en not_active Abandoned
  • 2003-06-23 EP EP03729910A patent/EP1539244A1/de not_active Withdrawn
  • 2003-06-23 WO PCT/DK2003/000418 patent/WO2004002534A1/en not_active Application Discontinuation

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