Oral pulsed dose drug delivery system

Abstract

A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising an immediate-release component and an enteric delayed-release component wherein (1) the enteric release coating has a defined minimum thickness and / or (2) there is a protective layer between the pharmaceutically active amphetamine salt and the enteric release coating and / or (3) there is a protective layer over the enteric release coating. The product can be composed of either one of a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.

Description

[0001]This invention pertains to a multiple dosage form delivery system comprising one or more amphetamine salts for administering the amphetamine salts to a recipient.BACKGROUND OF THE INVENTION[0002]Traditionally, drug delivery systems have focused on constant / sustained drug output with the objective of minimizing peaks and valleys of drug concentrations in the body to optimize drug efficacy and to reduce adverse effects. A reduced dosing frequency and improved patient compliance can also be expected for the controlled / sustained release drug delivery systems, compared to immediate release preparations. However, for certain drugs, sustained release delivery is not suitable and is affected by the following factors:[0003]First pass metabolism: Some drugs, such as β blockers, β-estradiol, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant / sustained oral me...

AI Technical Summary

Benefits of technology

[0027]The enteric release coating layer retards or delays the release of the pharmaceutical active or drug for a specified time period (“lag time”) until a predetermined time, at which time the release of the drug is rapid and complete, i.e., the entire dose is released within about 30-60 minutes under predetermined environmental conditions, i.e. a particular location within the gastrointestinal tract.

[0033]Surprisingly, applicants found that using a thicker application of enteric coating on the formulation allowed for the second pulsed dose to be released only and completely at the appropriate time in the desired predetermined area of the gastrointestinal tract, i.e., in the intestine.

[0046]In one aspect of this embodiment, a semi-permeable polymer, which may comprise a low water-permeable pH-insensitive polymer, is layered onto the outer surface of the enteric layer, in order to obtain prolonged delayed release time. This semi-permeable polymer coating controls the erosion of the pH-sensitive enteric polymer in an alkaline pH environment in which a pH-sensitive polymer will dissolve rapidly. Another pH-sensitive layer may be applied onto the surface of a low water-permeability layer to further delay the release time.

[0047]In a still further aspect of the invention, in addition to a protective layer, the composition comprises an acid which is incorporated into the pharmaceutical active layer or coated onto the surface of the active layer to reduce the pH value of the environment around the enteric polymer layer. The acid layer may also be applied on the outer layer of the pH-sensitive enteric polymer layer, followed by a layer of low water-permeability polymer. The release of the active thus may be delayed and the dissolution rate may be increased in an alkaline environment.

Problems solved by technology

First pass metabolism: Some drugs, such as β blockers, β-estradiol, and salicylamide, undergo extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant / sustained oral method of delivery would result in reduced oral bioavailability.

Gastric irritation or drug instability in gastric fluid: For compounds with gastric irritation or chemical instability in gastric fluid, the use of a sustained release preparation may exacerbate gastric irritation and chemical instability in gastric fluid.

These same factors are also problematic in pulsed dose formulation development.

Additionally, drug layering or core making for multiple unit systems is a time-consuming and hard-to-optimize process.

Particularly challenging for formulation scientists has been overcoming two conflicting hurdles for pulsatile formulation development, i.e., lag time and rapid release.

Due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performance as well as inter- and intra-subject variability are major issues for using enteric coated systems as a time-controlled release of drugs.

However, in the majority of subjects, no measurable amounts of the drug were observed in the blood, possibly due to instability of the drug in the distal intestine.

One disadvantage of current treatment is that a tablet form is commonly used which many young children have difficulty in swallowing.

Another disadvantage of current treatments is that two separate doses are administered, one in the morning and one approximately 4-6 hours later, commonly away from home under other than parental supervision.

This current form of treatment, therefore, requires a second treatment which is time-consuming, inconvenient and may be problematic for those children having difficulties in swallowing table t formulations.

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