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Long acting injectable crystal formulations of estradiol metabolites and methods of using same

A technology of estradiol and metabolites, applied in the field of sustained release formulations of estradiol metabolites, which can solve the problems of short half-life, low oral bioavailability, and sensitivity to chemical degradation.

Inactive Publication Date: 2007-10-17
PR药品有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is particularly disadvantageous in cases where long-term treatment is required
Second, the increased volume of the formulation that the device enables may constrain the amount of active pharmaceutical ingredient that can be administered without undue discomfort to the patient
Third, the physical form of estradiol metabolites encapsulated within the device may be unstable and susceptible to chemical degradation, limiting the type of device that can be used to formulate drugs
Unfortunately, naturally occurring estradiol metabolites have low oral bioavailability, short half-lives, and beneficial effects appear to be tied to long-term treatment

Method used

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  • Long acting injectable crystal formulations of estradiol metabolites and methods of using same
  • Long acting injectable crystal formulations of estradiol metabolites and methods of using same
  • Long acting injectable crystal formulations of estradiol metabolites and methods of using same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1. Preparation of Estradiol Metabolite Crystals

[0065] A 4% w / v solution of 2ME was prepared in a solvent consisting of 9.2% tetrahydrofuran, 61% methanol, and 28% 6M hydrochloric acid. This solution was added dropwise to an equal volume of vigorously stirred water. The resulting solid was isolated by suction filtration, washed with water and dried under vacuum. The resulting 2ME crystals are a mixture of large hollow prisms greater than 500 μm in length and up to about 200 μm in width, and cubic particles falling from about 50 μm down to about 500 nm square. The broad particle size range is used to generate a complex, biphasic pharmacokinetic profile upon injection.

Embodiment 2

[0066] Example 2. In vivo pharmacokinetics of crystal formulations of estradiol metabolites

[0067] The material produced in Example 1 was ground in a mortar and pestle, sieved through a 180 μm sieve, and the particle size distribution of the sieved material was measured on a Coulter LS13320 particle size analyzer. The measured volume average particle diameter is 48.98±36.95 μm.

[0068] On day 0, animals in all treatment groups were administered subcutaneously with 5 mg / rat of 0.25 ml of Tween 80 and 0.1% w / v Tween 80 and 0.1% w / v using a 1cc syringe and a 1″ 20-gauge needle. 2ME in an injection vehicle consisting of 2.0% w / v sodium carboxymethylcellulose of SDS. On day 3, blood was collected from all rats via the tail vein. On days 1, 3, 7, 21, 28, And 35 days, make all rats bleed through lateral tail vein.Extract plasma sample, derivatization, and utilize qualified gas chromatography-mass detection method to measure 2ME concentration.Pharmacokinetic characteristics are as...

Embodiment 3

[0069] Example 3. Esterification of Estradiol Metabolites to Change Water Solubility

[0070]2-Methoxyestradiol is esterified to form 3-benzoyl-2-methoxyestradiol. The water solubility of 2ME is about 0.002 mg / ml at room temperature. The water solubility of the esterified compound is about 3 times lower under the same conditions. 2-Hydroxyestradiol is esterified to form 3-hydroxyestradiol-1,3,5(10)-triene-2,17β-diol diacetate. The water solubility of 2-hydroxyestradiol is about 0.155 mg / ml at room temperature. The water solubility of the esterified compound is about 25 times lower under the same conditions.

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Abstract

The present invention provides sustained release formulations of estradiol metabolites whereby the in vivo pharmacokinetics are manipulated by a method selected from the group consisting of chemical modification, crystal packing formation, particle size or a combination thereof. Such compositions are useful in the long-term treatment of a wide variety of diseases.

Description

technical field [0001] The present invention generally relates to sustained release formulations of estradiol metabolites in crystalline form in which pharmacokinetics are controlled by crystal structure and particle size. Background technique [0002] Estradiol is converted into different derivatives through metabolic processes in the body. Two specific metabolite classes are catecholestrogens and methoxyestradiol. The catechol estrogens 2-hydroxyestradiol and 4-hydroxyestradiol are produced by the hydroxylation reaction of estrogen through cytochrome P450 enzymes. The catecholestrogens can be methylated by catechol-O-methyltransferase to produce the methoxyestradiol 2-methoxyestradiol and 4-methoxyestradiol diol. [0003] Estradiol metabolites have been reported to act on many cellular processes. Estradiol metabolites significantly inhibit angiogenesis and tubulin polymerization and organization in actively growing cells (Brueggemeier, R.W., et al., 2001: Pribluda, V.S...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/566
CPCA61K31/56A61P13/12A61P3/04A61P9/12A61P3/10A61K31/566
Inventor S·迪安·阿利森
Owner PR药品有限公司
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