Nanotechnology formulation of poorly soluble compounds
Inventors
Assignees
Publication Number
US-8703727-B2
Publication Date
2014-04-22
Expiration Date
2031-08-23
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Abstract
Embodiments of the present invention are directed to articles of manufacture, spheres having a diameter of 50 to 500 nanometers which contain poorly soluble drugs and methods of making such spheres. Embodiments of the present invention have particular application for the following drug candidates and closely related poorly soluble derivatives of such candidates: (i) indole hydrazinecarbothioamide [NSC 73306]; (ii) fenretinide (4HPR) [NSC 374551]; (iii) safingol [NSC 714503]; (iv) 17-allylamino demethoxygeldanamycin (17-AAG) [NSC 330507]; and (v) an aminoflavone drug [NSC 686288].
Core Innovation
Embodiments of the present invention are directed to articles of manufacture consisting of spheres having a diameter of 50 to 500 nanometers, which encapsulate poorly soluble drugs. These spheres are manufactured with shells comprising poly(D,L-lactide-coglycolide polymer) and polycaprolactone, and are designed to contain drugs such as indole hydrazinecarbothioamide, fenretinide, safingol, 17-allylamino demethoxygeldanamycin, and aminoflavone, as well as closely related poorly soluble derivatives.
The problem addressed by this invention is the difficulty in administering poorly soluble drug candidates. Such drugs pose challenges in intravenous administration, often requiring low concentrations and long infusion periods that are poorly tolerated and raise the risk of infection. Oral administration is also problematic due to poor absorption. There is a recognized need for drug formulations that facilitate the administration of poorly soluble drugs.
The invention includes not only the formulation of these nanospheres but also methods for their production. The method involves mixing at least one of the specified polymers with the poorly soluble drug in a supercritical, critical or near critical fluid, then injecting this mixture into a stream containing a cross-linking agent in a buffer to form spheres of the prescribed nanoscale size. Various process and formulation enhancements are disclosed, including the use of buffers with alcohols (such as ethanol), lyophilization steps for the resulting product, and the option for the spheres to hold a buffer whose volatile components are removed upon lyophilization. The process enables the creation of stable dosage forms, suitable for various routes of administration.
Claims Coverage
The patent contains one independent claim, covering the principal inventive method for producing nanospheres for encapsulation of poorly soluble drugs.
Method of making nanospheres containing poorly soluble drugs using supercritical, critical or near critical fluids
The invention relates to a method for producing one or more spheres with a diameter of about 50 to 500 nanometers, each having a shell made from at least one polymer selected from poly(D,L-lactide-coglycolide polymer) and polycaprolactone, and encapsulating a poorly soluble drug (from the group: indole hydrazinecarbothioamide, fenretinide, safingol, 17-allylamino demethoxygeldanamycin, aminoflavone, and poorly soluble derivatives thereof). The steps comprise: 1. Forming a mixture of at least one polymer and the poorly soluble drug in a supercritical, critical or near critical fluid selected from nitrogen, carbon dioxide, propane, nitrous oxide, and fluorinated hydrocarbons. 2. Injecting the mixture as a stream into a solution with a cross-linking agent in a buffer, to form nanospheres of the stated diameter; or, alternatively, 3. Forming a mixture of the polymer(s) in the supercritical, critical or near critical fluid, then injecting into a solution containing the poorly soluble drug and the cross-linking agent in a buffer, to form nanospheres as described. The features further include the possibility that: - The resulting nanospheres are lyophilized. - The polymer may be present in specific lactide to glycolide ratios (75:25 to 25:75; 60:40 to 40:60; or about 50:50). - The buffer may contain an alcohol (preferably ethanol) at concentrations from 1% to 50%. - The cross-linking agent may be polyvinyl alcohol.
In summary, the inventive feature lies in the method for forming nanoscale spheres of defined composition and drug content using supercritical or near critical fluids and specific process steps, to encapsulate poorly soluble drugs, with optional formulation variables such as lyophilization and specific excipients.
Stated Advantages
Facilitates the administration of poorly soluble drugs, overcoming challenges with intravenous and oral delivery due to solubility limitations.
Documented Applications
Formulation and delivery of specific poorly soluble anticancer drugs, including indole hydrazinecarbothioamide, fenretinide, safingol, 17-allylamino demethoxygeldanamycin, aminoflavone, and closely related derivatives.
Use of the spheres in a dosage form such as inhalers, capsules, gel caps, tablets, pills, powders, suspensions, and transdermal patches.
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