Baclofen solution for low-volume therapeutic delivery

Abstract

A high concentration baclofen solution is provided suitable for therapeutic use in a medical setting. A high concentration solution of baclofen in multivalent physiological ion solution such as artificial cerebrospinal fluid is provided with concentrations of baclofen of 10 mg / ml. Artificial cerebrospinal fluid is particularly advantageous as a baclofen solvent. A medical package is also provided for baclofen delivery to patients suffering from spasticity.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from U.S. Provisional Application Ser. No. 60 / 943,729, 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]This invention relates to the field of high concentration baclofen solutions in cerebrospinal fluid compatible solution suitable for clinical and research intrathecal administration and in particular to an artificial cerebrospinal fluid solution and medical package suitable for clinical delivery to patients and use in medical devices designed to deliver solution based baclofen to patients.BACKGROUND OF THE INVENTION[0003]Baclofen is a muscle relaxant and anti-spastic. Baclofen is useful for the alleviation of signs and symptoms of spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and concomitant pain, clonus, and muscular rigidity. Baclofen is an analog of the putat...

AI Technical Summary

Benefits of technology

[0017]A solution of baclofen is provided wherein baclofen is solubilized in a multivalent physiological ion solution such as artificial cerebrospinal fluid at a concentration at or above 2 mg / ml and to 10 mg / ml. The pH of the inventive baclofen solution is between 5 and 8. The high concentration baclofen solution is suitable for delivery to a patient by a route including intrathecal, intraventrical, oral, intravenous, intra-arterial, intraperitoneal, epidural, intramuscular, or subcutaneous routes of delivery.

[0018]The high concentration baclofen solution is suitable for treating a disease or injury. Common diseases or injuries that are treatable by the inventive solution are spasticity, brain injury, cerebral palsy, spinal cord injury, cervical injury, multiple sclerosis, thoracic injuries, and spinal pathology.

[0019]Further provided is a medical package including a single or multidose ampule or ampules of inventive high concentration baclofen solution along with instructions for the treatment of an injury or disease such as spasticity.

[0020]The inventive high concentration baclofen solution is provided in a solvent containing 130-160 mM NaCl, 2.7-3.9 mM KCl, 1-10 mM CaCl2.2H2O, 0.5-10 mM MgCl2.6H2O and a remainder water. Preferred concentrations of ingredients are 148 mM NaCl; 3 mM KCl; 1.4 mM CaCl2.2H2O; 0.8 mM MgCl2.6H2O; 0.8 mM Na2HPO4.7H2O; 0.2 mM NaH2PO4.H2O. The solution optionally also contains 0.5-1.0 mM Na2HPO4 and 0.1-0.5 mM NaH2PO4 and / or 15-35 mM HCO3. The pH of the inventive solutions is at or between 5 and 8.

[0021]The inventive high concentration baclofen solution is suitable to be used in combination with other therapeutics such as one or more pain regulating agents that illustratively include morphine, clondine, hydromorphine, hydrocodone, merperidine, celeroxib, tramadol, oxycodone, acetometaphen, ketaprofen, ibuprofen, naproxen sodium, aspirin, and combinations thereof.

Problems solved by technology

Spasticity is a debilitating complication that commonly leads to functional impairment, pain, and decreased personal independence.

However, the oral therapy is commonly insufficient to reduce spasticity, and many patients are unresponsive.

The high circulating concentrations of oral baclofen required for clinical efficacy produce numerous side effects including drowsiness, dizziness, weakness, ataxia, and confusion.

Administration of baclofen to patients with spinal or distal spasmodic conditions has proven to be a therapeutic challenge.

Oral administration of baclofen is limited in that the maximum concentration of neural fluid baclofen is commonly insufficient to alleviate the spastic result of underlying etiology.

Commonly, patients are unresponsive to oral baclofen administration or suffer intolerable side effects such as drowsiness, dizziness, weakness, ataxia, and confusion when efficacious levels of baclofen are present.

However, it is not without complications.

The most common complications include pump failure, infection, or migration of the catheter.

However, cerebrospinal fluid (CSF) leaks are common with intrathecal delivery, particularly in children with cerebral palsy where an incidence rate of 6-15% is observed.

The presence of the saline itself leads to toxicity and other complications.

Injection of baclofen / saline solutions suffer neurotoxic complications resulting from their differing pH, osmotic pressure, membrane-active ion concentration, and CO2.

However, baclofen has poor solubility in aqueous solutions necessitating high volumes of infused baclofen solution to achieve efficacious doses.

Further, the 2 mg / mL maximum saline concentration has been inadequate to control the spasticity, hypertonia and symptoms of some patients.

An additional difficulty is that mixing a 2 mg / mL baclofen injection with other drugs such as morphine or hydromorphone in “cocktails” to aid in control of pain can dilute the baclofen content to unacceptably low levels.

This was only achieved following long term dissolution of powder baclofen requiring weeks or months and merely represents an equilibrium suspension not suitable for intrathecal delivery.

The drawbacks of this method are that creating baclofen solutions is time consuming and requires instrumentation not commonly found in a clinical setting.

Unfortunately, saline solutions suffer neurotoxic complications resulting from their differing pH, osmotic pressure, membrane-active ion concentration, and CO2 making them unsuitable for intrathecal delivery directly into the CSF.