Long lasting drug formulations

• US 9,127,084 B2
• Filed: 06/15/2011
• Issued: 09/08/2015
• Est. Priority Date: 09/14/2006
• Status: Expired due to Fees

• Current Assignee: Medgenics Medical Israel Ltd.
• Original Assignee: Medgenics Medical Israel Ltd.
• Inventors: Pearlman, Andrew L., Stern, Baruch S.
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): Montanari, David A
• Application Number:
  US13/160,632
• Publication Number:
  US 20110286983A1
• Time in Patent Office: 1,546 Days
• Field of Search: 424/93.1
• US Class Current: 1/1
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• 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 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 47/6901 Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 14/505 Erythropoietin [EPO]
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/10343 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 7/00 Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00

Abstract

The present invention is directed to long-lasting erythropoietin therapeutic formulations and their methods of use wherein the formulation comprises a genetically modified micro-organ that comprises a vector which comprises a nucleic acid sequence operably linked to one or more regulatory sequences, wherein the nucleic acid sequence encodes erythropoietin.

Claims

1. A method of treating anemia in a human subject in need over a sustained time period comprising the steps of:

(a) providing at least one genetically modified autologous dermal micro-organ that expresses and secretes erythropoietin, wherein said dermal micro-organ is an intact explant of living tissue that maintains the micro-architecture and the three dimensional structure of the dermal tissue from which it was derived and consists essentially of a plurality of dermal components and lacking a complete epidermal layer, wherein said genetic modification of said dermal micro-organ comprises using a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding erythropoietin operably linked to one or more regulatory sequences, and wherein said dermal micro-organ or said genetically modified dermal micro-organ are maintained in vitro for at least between 1-7 days;

(b) determining erythropoietin secretion levels of said at least one genetically modified micro-organ in vitro; and

(c) implanting said at least one genetically modified autologous dermal micro-organ in said human subject at an effective dosage, wherein said method increases or maintains hemoglobin levels in said subject and said increased or maintained hemoglobin levels are maintained for at least three months.

2. The method of claim 1, further comprising a step of determining in vivo erythropoietin serum levels in said subject before and/or after said implanting step.

3. The method of claim 1, wherein said expression of erythropoietin is optimized for increased erythropoietin expression levels, increased duration of expression or a combination thereof.

4. The method of claim 1, wherein said effective dosage is 18-150 IU erythropoietin/Kg bodyweight of said subject/day.

5. The method of claim 4, wherein said effective dosage is 18-25 IU erythropoietin/Kg bodyweight of said subject/day.

6. The method of claim 4, wherein said effective dosage is 35-45 IU erythropoietin/Kg bodyweight of said subject/day.

7. The method of claim 4, wherein said effective dosage is 55-65 IU erythropoietin/Kg bodyweight of said subject/day.

8. The method of claim 1, wherein said increased hemoglobin levels are maintained within a range of 10-12 g/dl hemoglobin for at least 90% of said at least three months.

9. The method of claim 1, wherein said increased hemoglobin levels are maintained for at least 1 year.

10. The method of claim 1, further comprising a step of implanting at a later date to said subject, an additional at least one genetically modified autologous dermal micro-organ that expresses and secretes erythropoietin.

11. The method of claim 1, further comprising a step of maintaining said at least one genetically modified micro-organ in vitro for at least 9 days, prior to said implantation step.

12. The method of claim 1, wherein said implanting is subcutaneous or intradermal.

13. The method of claim 1, wherein said subject is suffering from chronic kidney disease (CKD) and is a pre-dialysis CKD subject.

14. The method of claim 1, wherein said subject is suffering from end stage renal disease.

16. The method of claim 4, wherein said effective dosage is 60-80 IU erythropoietin/Kg body weight of said subject/day.

15. A method of increasing or maintaining hemoglobin levels in a human subject over a sustained period of time comprising the steps of:

(a) providing at least one genetically modified autologous dermal micro-organ that expresses and secretes erythropoietin, wherein said dermal micro-organ is an intact explant of living tissue that maintains the micro-architecture and the three dimensional structure of the dermal tissue from which it was derived and consists essentially of a plurality of dermal components and lacking a complete epidermal layer, wherein said genetic modification of said dermal micro-organ comprises using a helper-dependent adenovirus vector comprising a nucleic acid sequence encoding erythropoietin operably linked to one or more regulatory sequences, and wherein said dermal micro-organ or said genetically modified dermal micro-organ are maintained in vitro for at least between 1-7 days;

(b) determining erythropoietin secretion levels of said at least one genetically modified micro-organ in vitro; and

(c) implanting said at least one genetically modified autologous dermal micro-organ in said human subject at an effective dosage, wherein said increased or maintained hemoglobin levels are maintained for at least three months.