Multi-spike release formulation for oral drug delivery

Details Multi-spike release formulation for oral drug delivery Multi-spike release formulation for oral drug delivery

2001-01-19

2003-04-29

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Food or edible as carrier for pharmaceutical

C424S400000, C424S441000, C424S468000, C424S474000, C424S490000, C424S464000, C514S937000, C514S944000, C514S974000

Reexamination Certificate

active

06555127

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention is generally in the field of pharmaceutical formulations, and more particularly related to methods and compositions for controlling the pharmacokinetic profile of drugs, such as methylphenidate, which are used in pharmaceutical applications.
Methylphenidate (trade name RITALIN™) is used to treat hyperactivity and attention deficit disorder (ADD) in children. While it is very effective when administered orally, the effects only last for only about three to four hours. It would be desirable to have a dose form that could be administered in the morning and maintain the child throughout the school day. Typical slow release formulations are not suitable because they produce a continuous slow release, approaching a zero order kinetic release profile. Methylphenidate, however, requires a spike or “saw tooth” (i.e. multi-spike) kinetic profile to be effective in the treatment of ADD.
Methylphenidate is currently being used to treat young children who differ widely in their body weight and hence their dose requirement. A desirable formulation would allow for convenient manipulation of dose by the parent. A more accurate dosing regimen could be achieved if it was provided in a formulation that was amenable to apportionment.
Methylphenidate is currently administered in pill form. It is not administered in an aqueous solution since it is so bitter. Young children frequently have difficulty swallowing pills. It would be advantageous to provide methylphenidate in a form that is easily swallowed by children and that masks the unpleasant taste of the drug.
Methylphenidate is known to be abused by individuals who inject it intravenously to achieve a “high”. A desirable formulation would be difficult to inject intravenously and hence would reduce the drug's abuse liability.
It is therefore an object of the present invention to provide a composition for the oral administration of methylphenidate or other drugs that require a multi-spike release.
It is another object of the present invention to provide a composition for the oral administration of methylphenidate or other drugs in an easy to swallow, preferably pleasant tasting, dosage form.
It is a further object of the present invention to provide a composition for oral administration of methylphenidate or other drugs in a form in which the dose of the drug is conveniently manipulated, but which preferably reduces the likelihood of abuse of the drug.
SUMMARY OF THE INVENTION
Methylphenidate or other drugs are provided in a formulation for oral administration that releases the drug in two or more pharmacokinetic spikes, by combining different release forms in a single formulation. In a preferred embodiment for methylphenidate, the first pharmacokinetic spike is achieved by the release of taste-masked methylphenidate which is not enterically coated, while a second pharmacokinetic spike is achieved by the release of methylphenidate in a finely divided form from enterically coated pellets or microparticles formulated for rapid release following dissolution of the enteric coating (i.e., delayed release particles). A critical aspect of the formulation is the inclusion of excipients that create a burst release following the initial rapid release and uptake.
The formulation can be administered as a paste, jelly, suspension, or fast dissolving wafer. The drug can be in the form of drug particles, microencapsulated particles, or drug-polymer particles. In one embodiment, both delayed release and the unprotected methylphenidate are thoroughly mixed and suspended in an appropriate medium to form a paste or a gel. Peanut butter or alginate, flavored with raspberry and a sweetener are examples of the many suitable taste masking agents.
To manipulate the dose, the formulation can be provided, for example, as a paste packaged in a tube similar to those used to dispense toothpaste. The paste can be squeezed out of an orifice of a fixed size such that a given length of paste contains a specified dose of methylphenidate, e.g., one inch contains 5 mg of methylphenidate, two inches contain 10 mg of methylphenidate. An alternative approach is to package the paste in a hypodermic syringe-like dispenser that is calibrated for dose. Yet another alternative approach is to package the formulation as a gelatinous solid, for example, a jelly candy bar. The bar can be scored or marked in units of methylphenidate for convenient dosing. Furthermore, the potential for intravenous abuse of the methylphenidate is markedly reduced when in the form of a semi-solid suspension of particles in a fat based substrate, such as in peanut butter, or a suspension of solid particles in a semi-solid gel.


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