Osmotic enhancement of drug/therapeutic delivery to the brain following infusion or injection into the cerebrospinal fluid

10123,969

15/293925

October 14, 2016

A method of enhancing therapeutic/drug transport to the perivascular space of the brain of a patient is disclosed. In one embodiment, the method comprises the step of introducing a therapeutic/drug and an osmolyte of the present invention into a patient's cerebrospinal fluid (CSF), wherein the osmolyte is introduced to the CSF at a concentration of between 0.5 and 12.9 M (dependent on the solubility upper limit of the osmolyte), and wherein the therapeutic/drug delivery to the perivascular spaces of cerebral blood vessels and parenchyma of the central nervous system is facilitated by the presence of the osmolyte.

Wisconsin Alumni Research Foundation (Madison, WI, US)

Wisconsin Alumni Research Foundation (Madison, WI, US)

1. A method of enhancing therapeutic/drug transport to perivascular spaces of a patient's brain, the method comprising the step of: injecting or infusing a therapeutic/drug and an osmolyte into a patient's cerebrospinal fluid (CSF), wherein the osmolyte is introduced to the CSF at a concentration between 0.5 M and 12.9 M (dependent on the solubility upper limit of the osmolyte), and wherein the therapeutic/drug delivery to the perivascular spaces of cerebral blood vessels and parenchyma in the patient's brain includes passing the therapeutic/drug through lining cells positioned on an external surface of the cerebral blood vessels, and wherein passing the therapeutic/drug through the lining cells is facilitated by the presence of the osmolyte, and wherein the injecting or infusing step is by way of intracerebroventricular injection or infusion, intrathecal intracisternal injection or infusion, or intrathecal lumbar injection or infusion.

2. The method of claim 1 wherein the osmolyte is introduced to the CSF at an osmolality between 600 mOsm/kg and 13 Osm/kg.

3. The method of claim 1 wherein the injection or infusion of the osmolyte and the therapeutic/drug is simultaneous.

4. The method of claim 1 wherein the osmolyte is injected or infused into the CSF before the therapeutic/drug.

5. The method of claim 1 wherein the therapeutic/drug and the osmolyte are infused at a volumetric flow rate between 1-60 mL per hour.

6. The method of claim 1 wherein the patient is a human.

7. The method of claim 1 where the therapeutic/drug is a macromolecule or biopharmaceutical with a Stokes-Einstein hydrodynamic diameter in the range of 1 to 15 nm.

8. The method of claim 1 where the therapeutic/drug is a macromolecule or biopharmaceutical with a Stokes-Einstein hydrodynamic diameter in the range of 15 to 300 nm.

9. The method of claim 1 where the therapeutic/drug is a macromolecule or biopharmaceutical with a Stokes-Einstein hydrodynamic diameter in the range of 15 to 800 nm.

10. The method of claim 1 where the therapeutic/drug is a macromolecule or biopharmaceutical with a Stokes-Einstein hydrodynamic diameter in the range of 10,000 to 30,000 nm.

11. The method of claim 1 where the therapeutic/drug is a macromolecule or biopharmaceutical is selected from the group consisting of a peptide, protein, antibody, RNA, asRNA, siRNA, DNA, cDNA, and viral vector.

12. The method of claim 1 where the therapeutic/drug is a stem cell.

13. The method of claim 1 , where the therapeutic/drug is used to treat central nervous system diseases such as lysosomal storage disorders, primary and metastatic brain cancer, neurodegenerative disorders, stroke, multiple sclerosis, CNS infections, and traumatic injury of the brain or spinal cord.

14. The method of claim 1 , where the therapeutic/drug is used to treat neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's, amylotropic lateral sclerosis, and prion diseases.

15. The method of claim 1 wherein the therapeutic/drug is selected from a group consisting of those with a Stokes-Einstein hydrodynamic diameter of 1-10, 10-30, 30-100, 100-800, 800-10,000, and 10,000-30,000 nm.

16. A method of enhancing therapeutic/drug transport to perivascular spaces of a patient's brain, the method comprising the step of: injecting or infusing a therapeutic/drug and an osmolyte into a patient's cerebrospinal fluid (CSF), wherein the osmolyte is selected from the group of mannitol and sorbitol and wherein the osmolyte is introduced to the CSF at an osmolality between 850 mOsm/kg and 4,200 mOsm/kg, and wherein the therapeutic/drug delivery to the perivascular spaces of cerebral blood vessels and parenchyma in the patient's brain includes passing the therapeutic/drug through lining cells positioned on an external surface of the cerebral blood vessels, and wherein passing the therapeutic/drug through the lining cells is facilitated by the presence of the osmolyte, and wherein the injecting or infusing step is by way of intracerebroventricular injection or infusion, intrathecal intracisternal injection or infusion, or intrathecal lumbar injection or infusion.

17. The method of claim 16 where the osmolyte is injected or infused to the CSF at a concentration between 0.5 and 1M.

18. The method of claim 16 where the osmolyte is introduced injected or infused to the CSF at an osmolality between 850 mOsm/kg and 2100 mOsm/kg.

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