Apomorphine Buccal Formulation Kit for Parkinson's Disease

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Solution Overview

Problem

Current pharmaceutical formulations of apomorphine for buccal administration are not optimized for rapid absorption and are prone to spontaneous oxidation, leading to suboptimal efficacy and discomfort due to acidic pH, which affects absorption and patient experience in treating Parkinson's disease and sexual dysfunction.

Innovation Solution

A kit comprising apomorphine or its acid addition salt combined with a pH modifying agent and diluent, adjusted to a pH of 5 to 10 for buccal administration, optimizing absorption and stability by maintaining a sufficient proportion of un-ionized apomorphine for rapid absorption and preventing oxidation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If apomorphine is formulated at acidic pH for stability, then oxidation is prevented, but absorption is reduced and patient comfort deteriorates

Engineering Contradiction:

ImprovestabilityVSAvoidabsorption

Core Design Contradiction:

Stability of the object's compositionVSEase of operation

Solution Approach 1:

The formulation is divided into two separate compartments: an acidic compartment containing apomorphine hydrochloride for stability, and an alkaline compartment containing pH modifying agents for absorption enhancement. At the moment of administration, these compartments are mixed, allowing the drug to transition from a stable acidic state to an absorbable alkaline state in the buccal cavity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The apomorphine is pre-formulated in acidic conditions to ensure stability during storage. The alkaline environment required for absorption is prepared separately and added at the moment of administration, ensuring the drug remains stable until use while enabling rapid absorption when needed.

Inventive Principle:

Principle #10Preliminary action

2Speed

If apomorphine is administered subcutaneously for rapid onset, then therapeutic speed is improved, but patient comfort and ease of administration deteriorates

Engineering Contradiction:

Improveonset of actionVSAvoidease of administration

Core Design Contradiction:

SpeedVSEase of operation

Solution Approach 1:

The invasive mechanical injection method is replaced with a non-invasive buccal administration system. The formulation uses pH-modified dissolution to achieve rapid absorption through the buccal mucosa, eliminating the need for needles and injection procedures while maintaining rapid onset of action.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Reliability

If oral doses are increased to improve therapeutic effect, then efficacy is improved, but nephrotoxicity increases

Engineering Contradiction:

Improvetherapeutic effectVSAvoidnephrotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The buccal mucosa serves as an intermediary absorption pathway that bypasses first-pass hepatic metabolism. By absorbing apomorphine directly through the buccal membrane into systemic circulation, the drug avoids liver metabolism that produces nephrotoxic metabolites, allowing effective doses without the associated kidney damage.

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The formulation achieves immediate and effective buccal absorption of apomorphine, enhancing its therapeutic speed and duration for managing Parkinson's disease symptoms and sexual dysfunction, while preventing auto-oxidation and minimizing side effects.

Implementation Method 1

The components being presented such that they can be combined at the point of use into a formulation which is adjusted to a pH of from 5 to 10

Methodology Applied

Scientific EffectpH modification:

Implementation Method 2

For optimal buccal absorption the apomorphine used should ideally be un-ionised at physiological pH. The pKa of apomorphine is 8.9 so, above a pH of about 9, significant amounts of the drug exist as free base.

Methodology Applied

Scientific EffectIonization: Ionisation

Implementation Method 3

Methodology Applied

Scientific EffectOxidation prevention: Oxidation

Data Source

PatentEP1885333B1Pharmaceutical formulation of apomorphine for buccal administration

Publication Date: 2012.02.15 AMARIN PHARMACEUTICALS IRELAND LIMITED(IE)

Figure 1

AI summary

The present invention provides a kit comprising, in separate compartments of a container, the following components (a) and (b): (a) a combination of apomorphine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable excipient or carrier; and (b) a solution which comprises a diluent and a pH modifying agent; the components being presented such that they can be combined at the point of use into a formulation which is adjusted to a pH ranging from mildly acidic to alkaline and which is suitable for buccal administration. The formulation is useful in treating Parkinson's disease and in promoting sexual function.