Deformable nano-scale vehicles (DNVS) for trans-blood brain barrier, trans-mucosal, and transdermal drug delivery

Inventors

John, VargheseNishimura, IchiroSubbiah, NarenCampagna, JesusSpilman, Patricia R.Alam, Mohammad Parvez

Assignees

University of California San Diego UCSD

Publication Number

US-12364661-B2

Publication Date

2025-07-22

Expiration Date

2036-11-17

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Abstract

In various embodiments deformable nano-scale vehicles (DNV) are provided that are useful for the delivery of therapeutic agents. In certain embodiments the DNVs are capable of transdermal delivery and can additionally cross the blood-brain barrier.

Core Innovation

The invention provides deformable nanoscale vehicles (DNVs) useful for delivering therapeutic agents with capabilities for transdermal delivery and crossing the blood-brain barrier. These vehicles consist of liposomes composed of amphipathic vesicle-forming lipids, cholesterol as a membrane regulator, and non-ionic detergents serving as edge activators to confer deformability to the lipid bilayer. The lipid components typically include phospholipids such as DPPC, DOTAP, and DOPE, combined in defined molar ratios to yield elastic nanoparticles of tunable size capable of encapsulating hydrophilic and hydrophobic drugs, proteins, RNA, and DNA.

The problem addressed is the difficulty in achieving localized drug delivery that minimizes systemic toxicity and overcomes biological barriers such as the blood-brain barrier and mucosal or epidermal membranes. Existing drug delivery systems often fail to enhance transport efficiency, safety, or efficacy, especially for central nervous system therapeutics where crossing the blood-brain barrier is a significant challenge. The disclosed DNVs solve this by being deformable, allowing penetration through small pores smaller than their diameter without rupturing, thereby enabling localized delivery to targets such as the brain or oral and dermal tissues without systemic payload leakage.

The invention further includes methods for manufacturing these DNVs using microfluidic reactors which provide precise control over nanoparticle size and homogeneity. The vehicles can be functionalized with targeting moieties such as transferrin or folic acid to enhance delivery specificity to cell types including tumor cells or to facilitate translocation through the blood-brain barrier. Pharmaceutical formulations incorporating these DNVs and various routes of administration, including transdermal patches, oral, parenteral, aerosol, and others, are also provided.

Claims Coverage

The patent includes one independent claim that defines the deformable nanoscale drug delivery vehicle and several dependent claims detailing its composition, charge, size, therapeutic use, formulation, and method of delivery.

Deformable nanoscale liposomal drug delivery vehicle composition

A liposome consisting of a lipid bilayer around an aqueous compartment containing a therapeutic agent for neurological disorders, where the lipid bilayer consists of at least two phospholipids or at least one phospholipid with DOTAP, cholesterol, and a non-ionic detergent with specified weight ratios; sized about 60 nm to 150 nm.

Specific phospholipid components selection

Use of phospholipids independently selected from DPPC, DHP, and DOPE, or a combination with DOTAP including DPPC, DHP, and DOPE.

Defined phospholipid ratios

The phospholipids comprise DPPC and a second phospholipid with the DPPC to second phospholipid ratio ranging from 2:1 to 1:2.

Specified lipid to cholesterol ratios

The total of phospholipids and DOTAP to cholesterol ratios ranges from about 10:2 to about 6:2.

Non-ionic detergent selection and content

The non-ionic detergent is selected from sorbitan monooleate, polysorbate 20, and specific polyoxyethylene ethers, with sorbitan monooleate present at 10% to 20% by weight.

Charge characteristics of nanoscale vehicle

The nanoscale drug delivery vehicle can be neutrally charged comprising DPPC and DOPE or cationic comprising DPPC and DOTAP or anionic comprising DPPC and DHP.

Inclusion of cytotoxic and/or cytostatic agents

The nanoscale drug delivery vehicle can contain cytotoxic and/or cytostatic therapeutic agents.

Capability to cross blood-brain barrier via intravenous administration

The liposome is able to cross the blood-brain barrier in a mammal when administered intravenously.

Pharmaceutical formulations with DNVs

Pharmaceutical formulations comprising the deformable nanoscale drug delivery vehicle and a pharmaceutically acceptable carrier.

Method of delivering therapeutic agents to the brain

Administering the deformable nanoscale drug delivery vehicle to a subject where the vehicle crosses the blood-brain barrier to deliver the therapeutic agent.

The claims cover a deformable nanoscale liposomal vehicle with specified lipid compositions and ratios, size, charge characteristics, and abilities to carry therapeutic agents for neurological disorders through the blood-brain barrier, including specific pharmaceutical formulations and methods of delivery.

Stated Advantages

Ability to increase localized drug delivery through oral mucosa, dermal layers, and transdermally.

Potential to deliver a wide variety of cargos including small molecules, proteins, RNAs, and antibodies across the blood-brain barrier for CNS disorders.

Capability to target specific cell types, such as tumor cells, to avoid off-target effects.

Non-toxic, biodegradable, and do not require external enhancers like ultrasound or electricity for skin application.

Manufacturing using microfluidic reactors allows high quality control, homogenous small particle size, reproducibility, and scalability.

Potential for improved patient compliance due to routes of administration such as transdermal patches.

Documented Applications

Transdermal delivery of therapeutic agents crossing the blood-brain barrier to treat neurological disorders such as Alzheimer's disease and Parkinson's disease.

Local drug delivery through oral mucosa and dermal layers targeting alveolar bone, skin, and calvarial bone for dental, cosmeceutical, or regenerative purposes.

Delivery of cytotoxic and cytostatic agents for treatment of glioblastoma multiforme and other tumors by targeting tumor markers.

Delivery of large biomolecules like sAPPalpha and microRNAs for Alzheimer's disease therapy.

Transdermal delivery of pramipexole for Parkinson's disease.

Delivery of Sirtuin 1 enhancers for treatment of Amyotrophic Lateral Sclerosis (ALS).

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