Formulation development for a zidovudine chemical delivery system 2. Towards oral and non-parenteral dosage forms

doi:10.1016/0378-5173(95)00108-U

International Journal of Pharmaceutics

Volume 125, Issue 1, 17 October 1995, Pages 31-43

https://doi.org/10.1016/0378-5173(95)00108-U Get rights and content

Abstract

Steps toward the development of an oral dosage form for a dihydronicotinate chemical delivery system for zidovudine (AZT-CDS) were examined. Administration of the AZT-CDS by gavage to rats indicated poor bioavailability consistent with the acid lability of the CDS. Furthermore, administration of the AZT-CDS in dimethyl sulfoxide (DMSO) intraintestinally did not result in therapeutically relevant brain or blood levels of the AZT-CDS or its metabolites. Use of a liposome formulation, however, did provide for significant uptake with administration to the jejunum more effective than AZT-CDS administration to the ileum or colo-caecum. Invasive administration of AZT-CDS complexed with various chemically modified cyclodextrins to the intestine also resulted in good bioavailability. Perfusion of a section of jejunum with a solution of AZT-CDS in 2-hydroxypropyl-β-cyclodextrin (HPβCD) resulted in demonstrable AZT-CDS uptake and pre-liver/post-liver blood concentration ratio of approx. 0.5. These results suggest that an enterically coated AZT-CDS tablet may provide for pharmacologically useful oral bioavailability. A second route of administration considered was rectal dosing. AZT was significantly bioavailable from prototype suppositories in the rat and although AZT-CDS could be detected after AZT-CDS treatment, the absolute bioavailability for AZT after such treatment was low.

References (39)

B. Aungst
Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism
J. Pharm. Sci.
(1993)
M. Brewster et al.
An intravenous toxicity study of 2-hydroxypropyl-β-cyclodextrin, a useful drug solubilizer, in rats and monkeys
Int. J. Pharm.
(1990)
M. Brewster et al.
Formulation development for a zidovudine chemical delivery system. 1. Parenteral dosage forms
Int. J. Pharm.
(1995)
J. Gallo et al.
Pump delivery of azidothymidine: potential for constant concentrations and improved brain delivery
J. Controlled Release
(1989)
A. Kamiya et al.
Rectal adsorption of nitroglycerin in the rat: avoidance of first-pass metabolism as a function of rectal length exposure
J. Pharm. Sci.
(1982)
A. Pajeau et al.
HIV encephalopathy and dementia
Psychiatr. Clin. North Am.
(1992)
B. Patel et al.
Pharmacokinetic and saturable renal tubular secretion of zidovudine in rats
J. Pharm. Sci.
(1989)
K. Uekama et al.
Improvement of dissolution and suppository release characteristics of flurbiprofen by inclusion complexation with heptakis(2,6-di-O-methyl)-β-cyclodextrin
J. Pharm. Sci.
(1985)
A. Yoshida et al.
Pharmaceutical evaluation of hydroxyalkyl ethers of β-cyclodextrin
Int. J. Pharm.
(1988)
N. Bodor et al.
Site-specific, sustained release of drugs to the brain
Science
(1981)

M. Brandl et al.

Liposome preparation using high-pressure homogenizers

M. Brewster et al.

Redox approaches to drug delivery to the central nervous system

NIDA Res. Monogr.

(1992)

M. Brewster et al.

Brain, blood and cerebrospinal fluid distribution of a zidovudine chemical delivery system in rabbits

J. Pharm. Sci.

(1991)

M. Brewster et al.

Chemical approaches to brain-targeting of biologically active compounds

M. Brewster et al.

The effect of dihydronicotinate N-substitution on the brain-targeting efficacy of a zidovudine chemical delivery system

Pharm. Res.

(1993)

C. Chu et al.

Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3′-azido-2',3′-dideoxyuridine and 3′-azido-3′-deoxythymidine

J. Med. Chem.

(1990)

O. Corrigan et al.

Dissolution properties of phenobarbitone-β-cyclodextrin systems

Pharm. Acta Heb.

(1981)

O. Corrigan et al.

Mechanism of drug dissolution rate enhancement from β-cyclodextrin-drug systems

J. Pharm. Pharmacol.

(1982)

S. Davis

Delivery systems for biopharmaceuticals

J. Pharm. Pharmacol.

(1992)

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Research paperFormulation development for a zidovudine chemical delivery system 2. Towards oral and non-parenteral dosage forms

Abstract

J. Pharm. Sci.

Int. J. Pharm.

Int. J. Pharm.

J. Controlled Release

J. Pharm. Sci.

Psychiatr. Clin. North Am.

J. Pharm. Sci.

J. Pharm. Sci.

Int. J. Pharm.

Site-specific, sustained release of drugs to the brain

Science

Liposome preparation using high-pressure homogenizers

Redox approaches to drug delivery to the central nervous system

NIDA Res. Monogr.

Brain, blood and cerebrospinal fluid distribution of a zidovudine chemical delivery system in rabbits

J. Pharm. Sci.

Chemical approaches to brain-targeting of biologically active compounds

The effect of dihydronicotinate N-substitution on the brain-targeting efficacy of a zidovudine chemical delivery system

Pharm. Res.

Brain targeting of anti-HIV nucleosides: synthesis and in vitro and in vivo studies of dihydropyridine derivatives of 3′-azido-2',3′-dideoxyuridine and 3′-azido-3′-deoxythymidine

J. Med. Chem.

Dissolution properties of phenobarbitone-β-cyclodextrin systems

Pharm. Acta Heb.

Mechanism of drug dissolution rate enhancement from β-cyclodextrin-drug systems

J. Pharm. Pharmacol.

Delivery systems for biopharmaceuticals

J. Pharm. Pharmacol.

Research paper
Formulation development for a zidovudine chemical delivery system 2. Towards oral and non-parenteral dosage forms