Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Patent
1998-01-09
1999-10-12
Rose, Shep K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
424463, 424490, 514 3, 514 9, 514938, 514943, 252312, 252358, A61K 9107, A61K 9113, A61K 948, A61K 956
Patent
active
059651601
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention concerns a self-emulsifying essentially hydrophobic formulation, namely, a formulation which upon mixture with water, spontaneously disintegrates to form an oil-in-water emulsion. The present invention also concerns the pharmaceutical use of such a formulation both (i) as a drug delivery vehicle of a lipophilic drug or (ii) as a precursor for the preparation of an oil-in-water emulsion useful in turn as a drug delivery vehicle of hydrophobic drugs.
One application of the inventive formulation is in the oral administration of a drug intended to be absorbed in the gastro intestinal (GI) tract and then reach the target organ via the blood or lymphatic system. Such a form of administration will be referred to herein as "oral systemic administration".
A particular application of the above preferred embodiment is in the oral systemic administration of a drug such as physostigmine, probucol, cyclosporin A, morphine base, penclomedine, and others.
The acknowledgement herein of the above prior art should not be interpreted as an admission that this art is in any way relevant to the issue of patentability of the invention as defined herein.
BACKGROUND OF THE INVENTION
Oral systemic administration of drugs, in general, is the preferred mode of administration in ambulatory treatment regimens which require repetitive drug administration over periods of time. While oral systemic administration is very effective with respect to water soluble drugs, it proves to be a problematic administration route for hydrophobic drugs or drugs with limited aqueous solubility such as physostigmine base, isradipine, virginiamycine, cyclosporin A, morphin, buprenorphine, nalorphine, methorfan, probucol and others.
The poor systemic effect achieved with orally-administered hydrophobic drugs results from a number of factors. For one, hydrophobic drugs do not dissolve in water and form a separate phase in aqueous solutions and are thus not readily available for absorption through the walls of the GI tract. Furthermore, some hydrophobic drugs, which are absorbed primarily through the walls of the small intestine, particularly through the jejunum, may undergo a so-called "first pass effect", i.e passage of the drugs in the liver prior to reaching the blood system. The overall effect of these factors is that only low, often non effective, amounts of orally administered hydrophobic drugs eventually reach the target organ(s), i.e orally administered hydrophobic drugs have generally a low bioavailability. This may be overcome by increasing the dose of the drug, but such an increase may, however, result in increased incidence of side-effects owing to erratic and variable inter subject absorption.
There have been various proposals for increasing bioavailability of hydrophobic drugs. For example, previous studies using oleic acid containing a dissolved lipophilic drug, have demonstrated a beneficial effect on drug bioavailability (Stella et al, 1978, J. Pharm. Sci, 67, 1375-1377). Recently, it was shown that the bioavailability of propranolol following oral administration, can be improved by dissolving the drug in a lipid formulation containing mainly oleic acid and packing it into a sealed and entero-coated hard gelatine capsule (Barnwell et al, 1992, Int. J. Pharmaceutics, 88, 423-432).
Emulsions have been proposed as carriers in oral formulations of hydrophobic drugs in general (Pal et al, 1984, J. Int. Pharm, 33. 99-104; Myers et al, 1992, Int. J. Pharm. 78, 217-226) and for drugs such as physostigmine in particular (Rubinstein et al, 1991, J. Pharm. Res, 80, 643-647; Friedman et al, 1989, Drug Design and Delivery, 4, 135-142; Benita et al, 1989, Drug Delivery Design, 4, 143-153). Colloid particles of the emulsion which carry the drug are absorbed in the jejunum and are presumably carried away mainly by the lymph through the thoracic duct, thus bypassing the liver and greatly reducing the first pass effect. Indeed, the oral bioavailability of several lipophilic drugs was shown to be somewhat improv
REFERENCES:
patent: 4464288 (1984-08-01), Sanders
patent: 4592859 (1986-06-01), Smith-Johannsen
patent: 4741872 (1988-05-01), De Luca et al.
patent: 5160745 (1992-11-01), DeLuca et al.
patent: 5256422 (1993-10-01), Albert et al.
patent: 5476660 (1995-12-01), Somasundaran et al.
patent: 5547677 (1996-08-01), Wright
patent: 5549901 (1996-08-01), Wright
patent: 5618840 (1997-04-01), Wright
patent: 5677341 (1997-10-01), Lyons
patent: 5744155 (1998-04-01), Friedman et al.
patent: 5753264 (1998-05-01), Magdassi et al.
Pillarisetti Sivaram et al.; An Amino-terminal Fragment of Apolipoprotein B Binds to Lipoprotein Lipase and May Faciliate Its Binding to Endothelial ells; The Journal of Biological Chemistry vol. 269, No.13 Issue of Apr. 1 pp. 9409-9412, 1994.
Wakerly, M.G. et al.;Evalutation of the Self-Emulsifying Performance of a Non-Ionic Surfactant-Vegetable Oil Mixture; (1986);p. 6P.
V. Stella et al.; Enhancement of Bioavailability of a Hydrophobic Amine Antimalarial by Formulation with Aleic Acid in a Soft Gelatin Capsule; Journal of Pharmaceutical Sciences vol.67 No. 10, Oct. 1978; pp. 1375-1377.
Susan A. Charman et al.;Self-Emulsifying Drug Delivery Systems: Formulation and Biopharmaceutic Evaluation of an Investigational Lipophilic Compound; Pharmaceutical Research, vol. 9, No.1, 1992.
K.J. Palin et al.; The oral absorption of cefoxitin from oil and emulsion vehicles in rats; International Journal Of Pharmaceutics 33 (1986)99-104.
Abraham Rubinstein et al.; In Vitro Release and Intestinal Absorption of Physostigmine salicylate from Submicron Emulsions; Journal of Pharmaceutical Sciences vol.80, No.7, Jul. 1991;pp. 643-647.
Robert A. Myers et al.; Systemic bioavailability of penclomedine (NSC-338720)from oil-in-water emulsions administered intraduodenally to rats; International Journal of Pharmaceutics, 78 (1992)217-226.
S.G.Barnwell et al.; Improved oral bioavailability of propranolol in healthy human volunteers using a liver bypass drug delivery system containing oleic acid; International Journal of Pharmaceutics, 88 (1992)423-432.
Efrat Elbaz et al.; Positively charged submicron emulsions--a new type of colloidal drug carrier; International Journal of Pharmaceutics, 96 (1993)R1-R6.
Ken Iseki et al.; The pH Dependent Uptake of Enoxacin by Rat Intestinal Brush-border Membrane Vesicles; J. Pharm. Pharmacol, 1992, 44; 722-726.
Hiroshi Saitoh et al.; Transport characteristics of [3H]-chlorpromazine across rat small intestinal brush border membrane; J. Pharm. Pharmacol, 1989,41: 200-202.
Colin W. Pouton et al.; Self-Emulsifying Systems for Oral Delivery Of Drugs; Proceed, Intern. Symp. Control.Ref. Bioact. Mater. 14 (1987); pp. 113-114.
Handbook of Emperimental Pharmacology;vol. 70/I; Germany, 1984 pp. 324-325.
S. Benita et al.; Micronized Emulsion for Controlled Release of Physostigmine After Oral Administratiom, Part II. Release Characteristics and Pharmacological Evaluation; Drug Design and Delivery, 1989, vol.4, pp. 143-153.
D. Friedman et al.; Micronized Emulsion For Controlled Release Of Physostigmine After Oral Administration. Part I. Formulation Design; Drug and Delivery, 1989, vol. 4, pp. 135-142.
C.W. Pouton; Effects of the Inclusion of a Model Drug on the Performance of Self Emulsifying Formulations; (1984) J. Pharm. Pharmac. 36: 51P.
Mark G. Wakerly et al.; Self-Emulsification of Vegetable Oil-Nonionic Surfactan Mixtures; 1986 American Chemical Society; pp. 242-255.
Colin W. Pouton; Self-emulsifying drug delivery systems; assessment of the efficiency of emulsification; International Journal of Pharmaceutics, 27 (1985) 335-348.
Benita Simon
Gershanik Tatyana
Kleinstern Jackie
Rose Shep K.
Yissum Research Development Company of the Hebrew University of
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