Pharmaceutical composition for treatment of duchenne muscular dystrophy

• US 6,653,466 B2
• Filed: 07/31/2001
• Issued: 11/25/2003
• Est. Priority Date: 05/21/1999
• Status: Expired due to Term

• Current Assignee: JCR Pharmaceuticals Co., Ltd., Masafumi Matsuo
• Original Assignee: JCR Pharmaceuticals Co., Ltd., Masafumi Matsuo
• Inventors: Matsuo, Masafumi
• Primary Examiner(s): LACOURCIERE, KAREN A
• Application Number:
  US09/917,907
• Publication Number:
  US 20010056077A1
• Time in Patent Office: 847 Days
• Field of Search: 435/6, 435/91.1, 435/325, 435/375, 536/24.3, 536/24.31, 536/24.33, 536/24.5, 514/44
• US Class Current: 536/24.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/315 Phosphorothioates

Abstract

A therapeutic pharmaceutical composition for patients of Duchenne muscular dystrophy with entire loss of exon 20 in dystrophin mature mRNA is provided. The composition comprise as an active principle an antisense oligonucleotide consisting of a 20 to 50-nucleotide sequence against exon 19 of the dystrophin pre-mRNA.

Claims

1. A method of manufacturing a composition, the method comprising:

forming an antisense oligonucleotide consisting of a nucleotide sequence fully complementary to the sequence represented by SEQ ID NO;

1;

dissolving the antisense oligonucleotide in a pharmaceutically acceptable injectable medium to form a solution; and

sterilizing the solution to form a composition for intravenous administration.

2. The method of claim 1, wherein the antisense oligonucleotide comprises oligoDNA, phosphorothioate oligoDNA, or phosphorothioate oligoRNA.

3. A method of manufacturing a composition comprising:

forming an antisense oligonucleotide consisting of a nucleotide sequence fully complementary to the sequence represented by SEQ ID NO;

2;

dissolving the antisense oligonucleotide in a pharmaceutically acceptable injectable medium to form a solution; and

sterilizing the solution to form a composition for intravenous administration.

4. The method of claim 3, wherein the antisense oligonucleotide comprises oligoDNA, phosphorothioate oligoDNA, or phosphorothioate oligoRNA.

5. A composition comprising:

in a pharmaceutically acceptable injectable medium,

an antisense oligonucleotide consisting of a nucleotide sequence fully complementary to the nucleotide sequence represented by SEQ ID NO;

1 or SEQ ID NO;

2.

6. The composition of claim 5, wherein the antisense oligonucleotide comprises oligoDNA, phosphorothioate oligoDNA, or phosphorothioate oligoRNA.

7. The composition of claim 5, comprising 0.05-5 μ

mol/mL of the oligonucleotide, 0.02-10 w/v % of at least one carbohydrate or polyalcohol, and 0.0 1-0.4 w/v % of at least one pharmaceutically acceptable surfactant.

8. The composition of claim 7, wherein the at least one of carbohydrate or polyalcohol comprises carbohydrate comprising monosaccharides or disaccharides.

9. The composition of claim 7, wherein the at least one of carbohydrate or polyalcohol comprises glucose, galactose, mannose, lactose, maltose, mannitol, or sorbitol.

10. The composition of claim 7, wherein the pharmaceutically acceptable surfactant comprises polyoxyethylene sorbitan mono- to tri-ester, alkyl phenyl polyoxyethylene, sodium taurocholate, sodium cholate, or polyalcohol ester.

11. The composition of claim 7, wherein the pharmaceutically acceptable surfactant comprises polyoxyethylene sorbitan ester comprising oleate, laurate, stearate, or palmitate.

12. The composition of claim 5, further comprising 0.03-0.09 M of at least one pharmaceutically neutral salt.

13. The composition of claim 12, wherein the neutral salt is selected from at least one of sodium chloride, potassium chloride, or calcium chloride.

14. The composition of claim 5, further comprising 0.002-0.05 M of a pharmaceutically acceptable buffering agent.

15. The composition of claim 14, wherein the buffering agent is selected from at least one of sodium citrate, sodium glycinate, sodium phosphate, or tris(hydroxymethyl) aminomethane.

16. The composition of claim 5, wherein the composition is in lyophilized form.