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Methods and Compositions for the Delivery of a Therapeutic Agent

a therapeutic agent and composition technology, applied in the direction of biocide, heterocyclic compound active ingredients, aerosol delivery, etc., can solve the problems of pain and/or irritation, injection cannot be administered by untrained personnel, and sterile syringes must be used, so as to reduce irritation and reduce viscosity , the effect of less viscosity

Inactive Publication Date: 2008-11-06
HANANJA EHF +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]The invention is based, in part, upon the discovery that the inclusion of one or more alkoxy-polyethylene glycols in a formulation provides certain advantages when the resulting composition is to be applied, for example, to a mucosal surface. For example, it has been discovered that when alkoxy-polyethylene glycol is used in such formulations, the therapeutic agent can be still be solubilized (which is especially useful for poorly soluble therapeutic agents) but the resulting formulations are less viscous and cause less irritation to mucosal membranes because the amount of other potentially viscous and irritable excipients, for example, polyethylene glycol or propylene glucol, can be reduced or eliminated altogether. As a result, the lower viscosity formulations, when converted into droplets, for example, by a nasal sprayer during intranasal delivery, can produce a spray pattern optimized for delivering the therapeutic agent to the mucosal membrane. In addition, formulations containing alkoxy-polyethylene glycols create less irritation (burning sensation) when applied to a mucosal surface, for example, a nasal membrane following nasal administration. In addition, when administered intranasally, the compositions of the invention minimize undesirable after taste (for example, a petroleum-like after taste) that can be associated with certain other excipients.

Problems solved by technology

However, administration by injection presents a range of disadvantages.
For example, sterile syringes must be used and injections cannot be administered by untrained personnel.
Furthermore, this mode of administration may cause pain and / or irritation, especially in the case of repeated injections at the same site.
It has been hypothesized that the usefulness of nasal administration can be limited if the therapeutic agent has limited solubility in water (Proctor, D. F. (1985) Nasal Physiology in Intranasal Drug Administrations, in Chien, Y. W. (Ed.)
As a result, this hypothesis, if correct, may limit the delivery of certain therapeutic agents that are sparingly soluble in water.
As a result, if large volumes are administered, a portion of the therapeutic agent can be lost from the absorption site, and it can be difficult if not impossible to reproducibly administer the correct dose of the therapeutic agent.
The authors concluded that the intranasal route of administration had limited potential for the acute treatment of epileptic seizures.
However, the volumes used were impractical and exceeded the maximal volume required for efficient administration.
This resulted in coughing and sneezing with expulsion of at least part of the dose.

Method used

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  • Methods and Compositions for the Delivery of a Therapeutic Agent

Examples

Experimental program
Comparison scheme
Effect test

example 1

Exemplary Lorazapam Containing Formulation

[0079]In this Example, 10 mg lorazepam is dissolved in 2 mL of mPEG 350 using ultrasound to obtain a solution containing 5 mg / mL of lorazepam. 50 μL of the resulting composition is administered into each nasal cavity of male New Zealand White rabbits held in a supine position during, and then one minute after application. An Eppendorf pipette is used for each application. After administration, blood samples then are harvested from a marginal ear vein at 0, 2, 5, 10, 15, 30 and 60 minutes, and the lorazepam concentration determined by high performance liquid chromatography (HPLC). The pharmacokinetics of lorazepam delivery via intranasal administration can then be compared with the pharmacokinetics of lorazepam delivery by intravenous administration. It is contemplated that the pharmacokinetics of the intranasally administered lorazepam will be comparable to those of the intravenously administered lorazepam.

example 2

Exemplary Midazolam Containing Formulation

[0080]In this Example, 10 mg of midazolam is dissolved in 2 mL of mPEG 350 using ultrasound to obtain a solution containing 5 mg / mL midazolam. 50 μL of the resulting composition is then administered into each nasal cavity of male New Zealand White rabbits, held in a supine position during, and then one minute after application. After administration, blood samples then are harvested from a marginal ear vein at 0, 2, 5, 10, 15, 30 and 60 minutes, and the midazolam concentration determined by HPLC. The pharmacokinetics of midazolam delivery via intranasal administration can then be compared with the pharmacokinetics of midazolam delivery by intravenous administration. It is contemplated that the pharmacokinetics of the intranasally administered midazolam will be comparable to those of the intravenously administered midazolam.

example 3

Pharmacokinetics of Exemplary Midazolam Formulations

[0081]This Example describes a variety of formulations containing methoxy-polyethylene glycol that demonstrate comparable pharmacokinetic properties to a control formulation containing polyethylene glycol and propylene. In addition to having comparable pharmacokinetic properties, the methoxy-polyethylene glycol formulations had a lower viscosity than the control formulation.

[0082]Table 1 lists the composition of a first test formulation, Table 2 lists the composition of a second test formulation, and Table 3 lists the composition of a control formulation.

TABLE 1Test Formulation 1 Containing 50 mg / mL Midazolam basePercent of FinalComponent(% v / v)mPEG 35047PEG 40018Propylene Glycol5Ethanol7Water21

TABLE 2Test Formulation 2 Containing 50 mg / mL Midazolam basePercent of FinalComponent(% v / v)mPEG 35047PEG 40018Propylene Glycol10Polysorbate 800.1Water22

TABLE 3Control Containing 50 mg / mL Midazolam basePercent of FinalComponent(% v / v)PEG 400...

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Abstract

The present invention provides a liquid pharmaceutical composition comprising a therapeutic agent and an alkoxy-polyethylene glycol, for example, methoxy-polyethylene glycol, for administration of the therapeutic agent to the mammal. The compositions can be applied to a membrane, for example, a nasal membrane during intranasal administration. The invention also provides methods of administering such compositions to a mammal.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of and priority to Icelandic Patent Application Serial No. 8593 / 2007, filed Jan. 19, 2007, the entire disclosure of which is incorporated by reference herein for all purposes.FIELD OF THE INVENTION[0002]This invention relates generally to compositions for the delivery of a therapeutic agent and to related methods, and more particularly relates to compositions containing one or more alkoxy-polyethylene glycols for the delivery of a therapeutic agent and to related methods.BACKGROUND[0003]The administration of a therapeutic agent by injection (e.g., intravenous, intramuscular or subcutaneous injection) typically is regarded as the most convenient way of administration when the purpose is to achieve a rapid and strong systemic effect, for example, within 3-10 minutes, when the agent is not absorbed by the gastrointestinal tract, or when the agent is inactivated in the gastrointestinal tract or by first-pass hepatic metabolis...

Claims

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Application Information

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IPC IPC(8): A61K47/30A61K31/5513A61K31/5517
CPCA61K9/0043A61K9/12A61K47/10A61K31/5517A61K31/5513Y02A50/30
Inventor GIZURARSON, SVEINBJORNARP, JAMESGHADERI, RAOUFLUSTY, MICHAEL E.PLUCINSKI, GREGORY G.YAZDI, MEHDI
Owner HANANJA EHF