FIELD OF THE INVENTION

The present invention relates generally to abuse deterrent oral formulations.

BACKGROUND OF THE INVENTION

The design and development of an abuse deterrent formulation involves the balance of limiting the potential for manipulation and abuse while maintaining acceptable dissolution rates and bioavailability. At the same time, the formulation must have processing characteristics that enables commercial manufacturing of dosage units. Because of these challenges, there is a need for a suitable abuse deterrent formulation.

SUMMARY OF THE INVENTION

The application provides an abuse-deterrent formulation having a medicament; and at least two excipients. The medicament, is typically a controlled substance. The controlled substance may target the central nervous system and/or may be used to treat psychiatric disorders. A preferred medicament is an amphetamine such as dextroamphetamine, or a pharmaceutically acceptable salt thereof.

In specific embodiments, the medicament has a formula


or a pharmaceutically acceptable salt thereof. In further specific embodiments, the medicament is the S enantiomer, or a pharmaceutically acceptable salt thereof.

Excipients include for example, PEG ester, poloxamer, water-soluble anionic polysaccharide, and carboxymethylcellulose.

Preferably, the abuse deterrent formulation is in the form of a capsule.

The abuse-deterrent formulation is characterized as having at least one of the properties (a) having a dissolution profile wherein at least 80% of the medicament is released in solution within 45 minutes; (b) the peak force to expel the abuse-deterrent formulation through a 26 gauge needle is about an order of magnitude greater than the peak force to inject a non-abuse deterrent formulation through a 26 gauge needle; (c) the area under the force vs. time curve to expel the abuse-deterrent formulation through a 26 gauge needle is about 4 times greater than the area under the force vs. time curve to expel a non-abuse-deterrent formulation through a 26 gauge needle, wherein the non-abuse deterrent formulation is a filtered sample; (d) the viscosity of the abuse-deterrent formulation is about three orders of magnitude greater than an non-abuse-deterrent formulation, wherein the non-abuse-deterrent formulation is an unfiltered sample; (e) a mixture of the abuse-deterrent formulation and water is not syringeable; (f) less than 5 wt % of the abuse-deterrent formulation passes through a 1 mm sieve after grinding for about 5 minutes; and (g) less than 10% of the medicament is extracted with 10 mL of water from a unit dose of the abuse-deterrent formulation.

In some embodiments, the abuse-deterrent formulation is characterized as having at least three or more of the properties (a)-(g). In some embodiments, the abuse-deterrent formulation is characterized as having at least four or more of the properties (a)-(g). In some embodiments, the abuse-deterrent formulation is characterized as having at least five or more of the properties (a)-(g). In some embodiments, the abuse-deterrent formulation is characterized as having at least six or more of the properties (a)-(g)

The abuse deterrent formulation is orally bioavailable and can have a dissolution profile similar to the profile of a non-abuse deterrent formulation. In some embodiments, the abuse-abuse deterrent formulation has a dissolution profile wherein release of the medicament in solution is complete within 45 minutes.

In some embodiments, the abuse-abuse deterrent formulation has a dissolution profile wherein at least about 93% of the medicament is released in solution within 45 minutes. In some embodiments, the abuse-abuse deterrent formulation has a dissolution profile wherein at least about 80% of the medicament is released in solution within 20 minutes. In some embodiments, the abuse-abuse deterrent formulation has a dissolution profile wherein at least about 80% of the medicament is released in solution within 10 minutes. In particular embodiments, the application discloses a dextroamphetamine-containing formulation having a dissolution profile wherein at least about 80% of the medicament is released in solution within 45 minutes.

The abuse deterrent formulation is resistant to chemical extraction or injection. For example, the formulation is resistant to chemical extraction or injection wherein an abuser extracts the active ingredient of a dosage unit, sometimes in a heated solvent, then swallows or injects the resulting mixture. For instance, combining the formulation with a solvent results in a mixture that blocks a syringe or is otherwise uninjectable. In some embodiments, the formulation forms a viscous gel with a solvent making it difficult to draw up in a syringe or expel from a syringe. In other embodiments, the amount of filtrate obtained from the attempted extraction is very little, providing the abuser with an insufficient amount of the desired active ingredient.

In some embodiments, a mixture of the abuse-deterrent formulation and water is not syringeable. In some embodiments, combining a unit dose of the abuse-deterrent formulation and water forms a gel.

In other embodiments, less than 20% of volume can be syringed from a mixture of the abuse-deterrent formulation and water. In a further specific embodiment, less than 10% of volume can be syringed from a mixture of the abuse-deterrent formulation and water. In another embodiment, less than 10% of the medicament is extracted with 10 mL from a unit dose of the abuse-deterrent formulation. In specific embodiments, the temperature of the water is about 90° C. In other embodiments, the temperature of the water is ambient temperature.

The physical properties of the abuse deterrent formulation deters abusers from grinding or cutting the formulation and then snorting the ground material. Upon grinding or a similar physical manipulation, the formulation may become sticky or have a waxy character that prevents forming an inhalable powder or snortable, even in the presence of a flow enhancer such as talc or sodium chloride.

In some embodiments, less than 5 wt % of the abuse-deterrent formulation passes through a 1 mm sieve after grinding for about 5 minutes. In specific embodiments, a flow enhancer is combined with the abuse-deterrent formulation during grinding.

In some embodiments, the abuse-deterrent formulation comprises a medicament, PEG ester, poloxamer, and water-soluble anionic polysaccharide. In specific embodiments, the PEG ester is polyoxyl stearate; the poloxamer is poloxamer 124; and the water-soluble anionic polysaccharide is gellan gum. In some embodiments, the ratio of poloxamer:polysaccharide:PEG ester is about 40:30:30.

In some embodiments, the abuse-deterrent formulation comprises medicament, PEG ester, and water-soluble anionic polysaccharide. In specific embodiments, the PEG ester is polyoxyl stearate; and the water-soluble anionic polysaccharide is gellan gum. In further specific embodiments, the ratio of PEG ester:water-soluble anionic polysaccharide is about 70:30.

In yet another embodiment, the abuse-deterrent formulation comprises medicament, PEG ester, and carboxymethylcellulose. In specific embodiments, the PEG ester is polyoxyl stearate. In further specific embodiments, the ratio of PEG ester and carboxymethylcellulose is about 70:30.

Specifically, the invention provides, an abuse-deterrent formulation, including a medicament, a poloxamer, a water-soluble anionic polysaccharide, and a PEG ester. The medicament is


or a pharmaceutically acceptable salt thereof.

Alternatively, is the S enantiomer of amphetamine, or a pharmaceutically acceptable salt thereof.

Preferably, the medicament is dextroamphetamine, or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salt is for example, a sulfate salt. The unit dose of the medicament in the formulation is from about 10 mg to about 50 mg. Preferably, the abuse deterrent formulation is in the form of a capsule. The capsule is for example gelatin,

The poloxamer is poloxamer 124. The water-soluble anionic polysaccharide is gellan gum.

The PEG ester is polyoxyl stearate. The ratio of poloxamer:water-soluble anionic polysaccharide:PEG ester is about 40:30:30.

The abuse-deterrent formulation included 33-43 wt % of poloxamer; 24-32 wt % of water-soluble anionic polysaccharide; and 24-32 wt % of PEG ester.The ratio of poloxamer 124:gellan gum:polyoxyl stearate is about 40:30:30.

The poloxamer is Kollisolv P124, the water-soluble anionic polysaccharide is Kelcogel CGHA, and the PEG ester is Gelucire 48/16.

A preferred formulation includes or the S enantiomer


(dextroamphetamine), or a pharmaceutically acceptable salt as thereof as the medicament, poloxamer 124, gellan gum, and polyoxyl stearate where the ratio of poloxamer 124:gellan gum:polyoxyl stearate is about 40:30:30. In some embodiments, the poloxamer 124 is Kollisolv P124, the gellan gum is Kelcogel CGHA, and the polyoxyl stearate is Gelucire 48/16.

In some embodiments, at least 80% of the medicament is released in solution within 45 minutes.

In some aspects when the abuse-deterrent formulation and water is combined a gel is formed.

In other aspects, at least 80% of the medicament is released in solution within 45 minutes.

In a further aspect, the peak force to expel the abuse-deterrent formulation through a 26 gauge needle is at least 8 times greater than a peak force to inject a non-abuse deterrent formulation through a 26 gauge needle.

The area under a force vs. time curve to expel the abuse-deterrent formulation through a 26 gauge needle is at least 3 times greater than the area under a force vs. time curve to expel a non-abuse-deterrent formulation through a 26 gauge needle, wherein the non-abuse deterrent formulation is a filtered sample.

In yet another aspect the viscosity of the abuse-deterrent formulation is at least about 2 orders of magnitude greater than a non-abuse-deterrent formulation.

In a further aspect, a mixture of the abuse-deterrent formulation and water is not syringeable.

In another aspect, less than 5 wt % of the abuse-deterrent formulation passes through a 1 mm sieve after grinding for about 5 minutes.

In some aspects, less than 10% of the medicament is extracted with 10 mL of water from a unit dose of the abuse-deterrent formulation.

Also included in the invention are methods of treating attention-deficit/hyperactivity disorder (ADHD) in a subject by administering an abuse deterrent formulation of the invention, where the medicament is an amphetamine such as dextroamphetamine.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety. In cases of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

Other features and advantages of the invention will be apparent from and encompassed by the following detailed description and claims.

