Pharmaceutical formulation of apomorphine for buccal administration

Abstract

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.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to pharmaceutical formulations of apomorphine, a drug used in the management of Parkinson's disease and in the treatment of sexual dysfunction. More specifically the invention relates to pharmaceutical formulations of apomorphine which are for buccal administration.BACKGROUND OF THE INVENTION

[0002] Parkinson's disease is a chronic, progressive neurological disorder affecting approximately 20 in every 100,000 people. The disease is typically characterised by resting tremor, muscle rigidity, bradykinesia and postural instability. Although the exact pathological course of Parkinson's disease is unknown, the dopaminergic neurones in the substantia nigra are progressively destroyed which leads to a net decrease in the amount of dopamine in the basal ganglia. Dopamine replacement with levodopa is the current primary therapy for Parkinson's disease.

[0003] After a three to five year period of control, 25% of Parkinson's disease suffere...

Examples

example 1

Preparation of a Formulation of the Invention

[0059]A commercially available injectable solution of apomorphine in hydrochloric acid with a pH of 3.5 (trade name “APO-go”, supplied by Britannia Pharmaceuticals) was employed as component (a). A solution of sodium hydroxide was employed as component (b).

[0060]A pre-calculated amount of sodium hydroxide was added to a solution of APO-go in order to bring the pH of the solution up to 6. The resulting mixture was put into a vortex blender. Subsequently, the blended mixture was drawn up into a syringe ready for squirting onto a patient's tongue.

example 2

Pharmacokinetic Study

[0061]The objective of this study was to investigate the bioavailability of apomorphine hydrochloride following administration, to 12 healthy volunteers by the oral route, of a formulation which could be prepared using a two-compartment kit of the present invention. Formulation 1 was used, which was prepared, according to Example 1, individually for each volunteer in turn.

[0062]Due to the emetic properties of apomorphine, subjects were pre-treated with the anti-emetic domperidone. Following 2 days of domperidone pre-treatment, Formulation 1 was prepared as described in Example 1 for each volunteer in turn. Subjects received a 2.5 mg dose of apomorphine by administration of Formulation 1 by the sub-lingual route: in each case the solution was made up and drawn into a syringe as described in Example 1, and then squirted onto the volunteer's tongue. Blood samples for pharmacokinetic analysis were taken pre-dose and at intervals for 6 hours after each dose of apomor...

FIELD OF THE INVENTION

[0001] The present invention relates to pharmaceutical formulations of apomorphine, a drug used in the management of Parkinson's disease and in the treatment of sexual dysfunction. More specifically the invention relates to pharmaceutical formulations of apomorphine which are for buccal administration.BACKGROUND OF THE INVENTION

[0002] Parkinson's disease is a chronic, progressive neurological disorder affecting approximately 20 in every 100,000 people. The disease is typically characterised by resting tremor, muscle rigidity, bradykinesia and postural instability. Although the exact pathological course of Parkinson's disease is unknown, the dopaminergic neurones in the substantia nigra are progressively destroyed which leads to a net decrease in the amount of dopamine in the basal ganglia. Dopamine replacement with levodopa is the current primary therapy for Parkinson's disease.

[0003] After a three to five year period of control, 25% of Parkinson's disease suffere...

Examples

example 1

Preparation of a Formulation of the Invention

[0059]A commercially available injectable solution of apomorphine in hydrochloric acid with a pH of 3.5 (trade name “APO-go”, supplied by Britannia Pharmaceuticals) was employed as component (a). A solution of sodium hydroxide was employed as component (b).

[0060]A pre-calculated amount of sodium hydroxide was added to a solution of APO-go in order to bring the pH of the solution up to 6. The resulting mixture was put into a vortex blender. Subsequently, the blended mixture was drawn up into a syringe ready for squirting onto a patient's tongue.

example 2

Pharmacokinetic Study

[0061]The objective of this study was to investigate the bioavailability of apomorphine hydrochloride following administration, to 12 healthy volunteers by the oral route, of a formulation which could be prepared using a two-compartment kit of the present invention. Formulation 1 was used, which was prepared, according to Example 1, individually for each volunteer in turn.

[0062]Due to the emetic properties of apomorphine, subjects were pre-treated with the anti-emetic domperidone. Following 2 days of domperidone pre-treatment, Formulation 1 was prepared as described in Example 1 for each volunteer in turn. Subjects received a 2.5 mg dose of apomorphine by administration of Formulation 1 by the sub-lingual route: in each case the solution was made up and drawn into a syringe as described in Example 1, and then squirted onto the volunteer's tongue. Blood samples for pharmacokinetic analysis were taken pre-dose and at intervals for 6 hours after each dose of apomor...

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