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Zwitterion solution for low-volume therapeutic delivery

a zwitterion solution and low-volume technology, applied in the field of high-concentration therapeutic zwitterion solutions, can solve the problems of poor solubility of zwitterion therapeutic agents in saline solution, limited pharmokinetics of agents, low dose, etc., and achieve the effect of increasing concentration or ease of solution and/or storag

Inactive Publication Date: 2010-08-19
WAYNE STATE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, the low solubility of zwitterionic compounds at physiological pH has resulted in low dose—high volume administration that limits the pharmokinetics of the agent.
Here as well, poor solubility of the zwitterionic therapeutic agent in saline solution necessitates multiple intrathecal pumping cycles to achieve an efficacious dose.
The resulting suspension, however, is not suitable for intrathecal delivery.
The drawbacks of this method are that it is time consuming and requires instrumentation not commonly found in a clinical setting.
Further, saline solutions suffer neurotoxic complications resulting from their differing pH, osmotic pressure, membrane-active ion concentration, and CO2.
As with baclofen, the poor solubility of these therapeutic zwitterions has limited therapeutic efficacy owing to the large carrier volumes needed to solubilize needed doses.

Method used

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  • Zwitterion solution for low-volume therapeutic delivery
  • Zwitterion solution for low-volume therapeutic delivery
  • Zwitterion solution for low-volume therapeutic delivery

Examples

Experimental program
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example 1

[0035]Multivalent physiologic ion solution formation. A solution (A) is produced with 8.66 g NaCl, 0.224 g KCl, 0.206 g CaCl2.2H20 and 0.163 g MgCl2.6H20 dissolving in 500 mL of deionized water. A solution (B) is produced with 0.214 g Na2HPO4.7H20 and 0.027 g NaH2PO4.H20 dissolving in 450 mL of water. The pH is adjusted to 6.0, 6.5, 7.0, 7.3, 7.6 and 8.0 as necessary with either NaOH or H3PO4 and dilution to final volume of 500 mL with deionized water. A final multivalent physiologic ion solution is obtained by mixing equal parts of Solution A and B. pH is tested and adjusted to the desired final pH if necessary. All reagents are available from sources known in the art. Illustratively, reagents are available from Sigma-Aldrich Corp., St. Louis, Mo.

example 2

[0036]Ofloxacin solubilization in multivalent physiologic ion solution. Ofloxacin powder, or ground tablets, are weighed and added to accurately measured volumes of MPI solution composed of 20 mM sodium carbonate, 8 mM MgCl2.6H2O, 5 mM CaCl2, 150 mM NaCl titrated to pH 7.0. Solutions are warmed to 37° C. in a water bath. Each solution is manually mixed every minute during the first five minutes and at five minute intervals thereafter for an entire 30 minute aliquot pull period. Visually clear solutions are immediately obtained, but gentle stirring or vortexing is applied to the samples for several seconds to ensure complete solubilization of the ofloxacin. Clear solutions are achieved with no visual particulate matter remaining. Approximate 5 mL aliquots are pulled at 2, 5 and 30 minutes of incubation using a syringe equipped with a 10 micron filter tip. The aliquots are analyzed by high performance liquid chromatography (HPLC). For analyses, 2.0 mL of each aliquot is transferred to...

example 3

[0037]Ofloxacin solubilization in artificial cerebrospinal fluid. Ofloxacin powder, or ground tablets, are weighed and added to accurately measured volumes of aCSF. Visually clear solutions are immediately obtained, but gentle stirring or vortexing is applied to the samples for several seconds to ensure complete solubilization of the ofloxacin. Ofloxacin concentrations are achieved in aCSF at 10 mg / ml. Solutions with greater than 7 mg / ml final concentrations required gentle agitation for 2 minutes or less. Clear solutions are achieved with no visual particulate matter remaining.

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Abstract

A formulation is provided that includes a volume of an aqueous multivalent physiological ion solution compatible with cerebrospinal fluid containing at least one divalent cation of magnesium or calcium, and at least one anion of carbonate or phosphate, and having a pH between 6.5 and 8.0. A zwitterionic therapeutic agent other than baclofen is dissolved the solution to achieve higher concentration or ease of solution and / or storage relative to therapeutic saline solutions of the same agent. A process of delivering a zwitterionic therapeutic agent into a subject is provided that includes dissolving a therapeutic amount of the zwitterionic therapeutic agent in a volume of artificial cerebrospinal fluid to form a stable formulation. The solution is then administered to the subject using an intrathecal pump.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Application Ser. No. 60 / 943,732, filed on Jun. 13, 2007, the entire contents of which are incorporated herein by reference as if explicitly stated herein.FIELD OF THE INVENTION[0002]The invention relates to the field of high concentration therapeutic zwitterion solutions in cerebrospinal fluid compatible solution suitable for clinical and research intrathecal administration, more particular, in an artificial cerebrospinal fluid solution, and medical package suitable for clinical delivery to patients and use in medical devices designed to deliver solution based the therapeutic zwitterions to patients.BACKGROUND OF THE INVENTION[0003]A zwitterion is a chemical compound that is electrically neutral through a net cancellation of formal positive and negative charges within the compound. Zwitterions are polar and usually have a higher solubility at acid and basic pH values where a net charg...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/616A61K31/60A61K31/5383A61K31/445A61K31/426A61K31/4375A61K31/4709A61K31/4418A61K31/546A61K31/485A61P25/00A61P29/00
CPCA61K47/02A61K9/0085A61P11/00A61P25/00A61P29/00
Inventor MEYTHALER, JAY M.
Owner WAYNE STATE UNIV
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