Oromucosal Liquid Estradiol Compositions

• US 20140371191A1
• Filed: 01/04/2013
• Published: 12/18/2014
• Est. Priority Date: 01/04/2012
• Status: Active Grant

• Current Assignee: Innotesto Bvba
• Original Assignee: Innotesto Bvba
• Inventors: Merkus, Franciscus Wilhelmus Henricus Maria
• Granted Patent: US 9,402,811 B2
• Time in Patent Office: Days
• US Class Current: 514/182
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

The present invention relates to low dose estradiol solutions for oromucosal administration suitable in replacement therapy or suppletion of low estradiol levels and also for preventing, alleviating or treating symptoms associated with low endogenous levels of estradiol in female subjects.

Claims

1. A non-aqueous (or substantially non-aqueous) solution containing 0.01-0.9% (w/v) of estradiol, or an equivalent amount of a pharmaceutically acceptable hydrate or ester thereof, 5-30% (v/v) of a C₂-C₅ alcohol and 70-95% (v/v) of an ester of a C₂-C₆ alcohol and a C₈-C₂₂ fatty acid, for use in the treatment of a human female with reduced estradiol levels, by oromucosal administration of a dose of said solution, said dose containing 0.01-0.3 mg of estradiol or an equivalent amount of a pharmaceutically acceptable hydrate, or an ester thereof, by single or multiple administration, at one or more points in time.

2. The solution according to claim 1, wherein the dose comprises about 10-500 μ

l of the estradiol solution.

3. The solution according to claim 1 or claim 2, wherein said dose is administered 1-6 times per day.

4. The solution according to any one of claims 1-3, wherein said dose is administered intermittently at an interval in the range 1 to 4 hours.

5. The solution according to any one of claims 1-4, for use in treating, preventing or relieving symptoms caused by insufficient endogenous production of estrogen, such as headaches, nausea, vasomotor symptoms (hot flushes), symptoms of urogenital atrophy, decrease in bone mineral density, osteoporosis and increased risk or incidence of bone fractures.

11. The solution according to any one of claims 1-10 wherein the solution is administered per spray, per drops or by a dosage pen in a volume between 10 μ

l to 500 μ

l.

18. The method according to claim 1, wherein 1-6 dose are administered per day.

20. The method according to claim 1, wherein the elevation and control of the estradiol levels in the female patient results in treating, preventing or relieving symptoms caused by insufficient endogenous production of estrogen, such as headaches;

nausea, vasomotor symptoms (hot flushes), symptoms of urogenital atrophy, decrease in bone mineral density, osteoporosis and increased risk or incidence of bone fractures.

6. A non-aqueous (or substantially non-aqueous) solution containing 0.01-0.9% (w/v) of estradiol, or an equivalent amount of a pharmaceutically acceptable hydrate or ester thereof, 10-30% (v/v) of a C₂-C₅ alcohol and 70-90% (v/v) of an ester of a C₂-C₆ alcohol and a C₈-C₂₂ fatty acid.

7. The solution of claim 6, wherein the ester of the C₈-C₂₂ fatty acid and C₂-C₆ alcohol is isopropyl myristate and the C₂-C₅ alcohol is ethanol.

8. The solution according to claim 6 or claim 7, wherein the solution contains 10-30% ethanol (v/v).

9. The solution of claim 8, comprising 0.01- 0.9% of estradiol (w/v), 10-30% (v/v) ethanol (v/v) and 70-90% (v/v) isopropyl myristate.

10. The solution according to any one of claims 6-9, wherein the ratio of the volumes of the C₂-C₅ alcohol and the ester of a C₂-C₆ alcohol and a C₈-C₂₂ fatty acid is 30:

70, 25;

75, 20;

80, 15;

85, or 10-90 (v/v %).

12. A method of treatment of a female having reduced estradiol levels, said method comprising administering oromucosally to a human female patient in need thereof, at one or more points in time, a dose of a solution containing 0.01-0.9% (w/v) of estradiol, or an equivalent amount of a pharmaceutically acceptable hydrate or ester thereof, 5-30% (v/v) of a C₂-C₅ alcohol and 70-95% (v/v) of an ester of a C₂-C₆ alcohol and a C₈-C₂₂ fatty acid;

wherein said dose is given by single or multiple administration and comprises 0.01-0.3 mg of estradiol, or an equivalent amount of a pharmaceutically acceptable hydrate or ester thereof.

13. The method according to claim 12, wherein the dose of said solution and the number of administrations are selected such that the patient'"'"'s resulting estradiol serum level is in the range of 10-500 pg/ml.

14. The method according to claim 12, wherein the dose of said solution and the number of administrations are selected such that the patient'"'"'s resulting estradiol serum level is higher than 20 pg/ml for more than 3 hours.

15. The method according to claim 12, wherein for each 0.05 mg of estradiol administered, a controlled increase in the patient'"'"'s estradiol serum level of between about 150-300 pg/ml is obtained.

16. The method according to claim 12, wherein for each 0.025 mg estradiol administered, a controlled increase in the patient'"'"'s estradiol serum level of between about 75-150 pg/ml is obtained.

17. The method according to claim 12, wherein a quantity of about 10-500 μ

l of the estradiol solution is administered per dose.

19. The method according to claim 12, wherein said dose is administer intermittently in a time period in the range 1 to 4 hours.