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Pulsatile release histamine H2 antagonist dosage form

a pulsatile release and histamine technology, applied in the field of pulsatile release histamine h2 antagonist dosage form, can solve the problems of limited size or material, few orally applicable pulsatile release systems, and inability to maintain a constant blood level of drugs

Inactive Publication Date: 2008-12-25
APTALIS PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]In embodiments, this invention is directed to a histamine H2 antagonist pharmaceutical dosage form providing a bi-modal pulsatile release profile comprising immediate release (IR) beads comprising an active-containing core particle and timed pulsatile release (TPR) beads, wherein said TPR beads comprise an a

Problems solved by technology

However, there are instances where maintaining a constant blood level of a drug is not desirable.
However, there are only a few such orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms.

Method used

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  • Pulsatile release histamine H2 antagonist dosage form
  • Pulsatile release histamine H2 antagonist dosage form
  • Pulsatile release histamine H2 antagonist dosage form

Examples

Experimental program
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Effect test

example 1

[0089]Nizatidine (5787.7 g) was slowly added to an aqueous solution of hydroxypropylcellulose such as KLUCEL LF (hydroxypropyl cellulose) (643.1 g) and mixed well. #25-30 mesh sugar spheres (3700 g) were coated with the drug suspension in a Glatt fluid bed coater. The drug containing particles were dried, and a seal coat of Opadry Clear (2% w / w) was first applied. These drug containing IR Beads were provided with an outer membrane by spraying a solution of 1:1 blend of ethylcellulose and HPMCP plasticized with diethyl phthalate in 98 / 2 acetone / water in a fluid bed coater for a weight gain of approximately 39-40%. The coated particles are cured at 60° C. until the polymers were coalesced to produce TPR Beads. Pulsatile Release Nizatidine Capsules, 150 mg, were manufactured by filling 75 mg IR Beads and 75 mg TPR Beads into size 0 hard gelatin capsules using a MG Futura capsule filling equipment. The drug release testing was performed using USP Apparatus 2 (Paddles @ 50 rpm) in 0.1N H...

example 2

[0090]Nizatidine (168 kg) was slowly added to an aqueous solution of hydroxypropylcellulose such as KLUCEL LF (hydroxypropyl cellulose) (18.6 kg) and mixed well. #25-30 mesh sugar spheres (107.4 kg) were coated with the drug suspension in a Glatt fluid bed coater, equipped with a 32″ bottom spray Wurster insert. The drug containing particles were dried, and a seal coat of Opadry Clear (2% w / w) was first applied and dried in the Glatt fluid bed unit as a precautionary measure to drive off excessive surface moisture. These drug containing IR Beads were provided with an outer membrane by spraying a solution of 1:1 blend of ethylcellulose and HPMCP plasticized with diethyl phthalate in 98 / 2 acetone / water in a fluid bed coater for a weight gain of approximately 39-40%. The coated particles are cured at 60° C. for 4 hours to produce TPR Beads (batch size: 300 kg). Pulsatile Release Nizatidine Capsules, 150 mg, were manufactured by filling 75 mg IR Beads and 75 mg TPR beads into size 0 har...

example 3

[0091]In order to assess the type of in vitro release profile needed to achieve a circadian rhythm effect under in vivo conditions, a modeling exercise was performed using the pharmacokinetic parameters for nizatidine. A diurnal variation in the pharmaco-kinetics of nizatidine has been reported by Jamali, A. et al., Journal of Clinical Pharmacology 35: 1071-1075 (1995), is incorporated in its entirety). A pharmaco-kinetic modeling was done separately to try to mimic both evening and day time results individually. Mean serum concentrations of nizatidine achieved in healthy volunteers were taken from the same literature. Theoretical in vitro dissolution profile (FIG. 4) as well as in vivo serum levels achieved during evening and daytime dosing, were simulated using the pharmaco-kinetic models developed. The advantages of a pulsatile dosage form are evident in attached FIG. 5 that compares simulated serum levels achieved with an immediate release dose of nizatidine versus the proposed ...

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Abstract

A unit dosage form, such as a capsule or the like, for delivering drugs into the body in a circadian release fashion comprising one or more populations of drug-containing particles (beads, pellets, granules, etc.) is disclosed. Each bead population exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag time of 3 to 5 hours. Such a circadian rhythm release drug delivery system is designed to provide a plasma concentration-time profile, which varies according to physiological need at different times during the dosing period, i.e., mimicking the circadian rhythm and severity / manifestation of gastric acid secretion (and / or midnight gerd), predicted based on pharmaco-kinetic and pharmaco-dynamic considerations and in vitro / in vivo correlations.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This is a Continuation application of U.S. patent application Ser. No. 10 / 875,627, filed Jun. 25, 2004, which is a Continuation-in-Part application of U.S. patent application Ser. No. 10 / 689,566, filed Oct. 20, 2003, which is a Continuation application of U.S. patent application Ser. No. 10 / 057,759, filed Jan. 25, 2002, now U.S. Pat. No. 6,663,888, issued Dec. 16, 2003, which is a Non-Provisional patent application that claims the benefit of U.S. Provisional Patent Application No. 60 / 340,419, filed Dec. 14, 2001. The disclosures of the prior applications are hereby incorporated herein in their entirety by reference.TECHNICAL FIELD[0002]A major objective of chronotherapy for indications such as asthma, gastric acid secretion, gastro-intestinal disorders, such as acid peptic disease, and cardiovascular diseases is to deliver the drug in higher concentrations during the time of greatest need and in lesser concentrations when the need is less...

Claims

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Application Information

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IPC IPC(8): A61K9/58A61K9/14A61K31/426A61K9/62A61K31/4164A61K31/341A61K9/26A61K9/50A61K9/52A61K9/54A61K9/60
CPCA61K9/5026A61K9/5042A61K9/5047A61K9/5078A61K9/5084Y10S514/965
Inventor PERCEL, PHILLIP J.VYAS, NEHAL H.VISHNUPAD, KRISHNA S.VENKATESH, GOPI M.
Owner APTALIS PHARMATECH
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