Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1990-04-09
1993-04-20
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
424435, 424436, 424489, 424490, 424491, 424492, 424494, 514718, A61K 914, A61K 916, A61K 950, A61K 31075
Patent
active
052041085
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to drug delivery compositions and more particularly to a composition which provides for the uptake of active drug material across mucosal surfaces, such as the vagina or the nasal cavity.
A major problem in drug delivery is the effective absorption of high molecular weight material such as proteins and peptides across biological membranes. Normally such molecules are not taken up by the body if administered to the gastrointestinal tract, to the buccal mucosa, to the rectal mucosa, the vaginal mucosa or given as an intranasal system. Recent studies with the material insulin have demonstrated that the absorption of such a compound can be increased if it is given together with a so-called absorption enhancer. These absorption enhancing materials have included surfactants of the non-ionic type as well as various bile salt derivatives. An increased permeability of membranes in the presence of these types of surfactant material is not unexpected, indeed the literature in the field of gastroenterology contains a wide range of such absorption promoters. (For a review see Davis et al. (editors), Delivery Systems for Peptide Drugs, Plenum Press, New York, 1987). However, such materials will probably not be acceptable for the chronic administration of pharmacological agents because of their irritant effects on membranes. This includes not only the non-ionic variety of surface active agents but also bile salts and bile salt derivatives (e.g. fusidic acid).
EP-A-023,359 and EP-A-122,023 describe a powdery pharmaceutical composition for application to the nasal mucosa and methods for administration thereof. The pharmaceutical composition allows polypeptides and derivatives thereof to be effectively absorbed through the nasal mucosa. Similarly, U.S. Pat. No. 4,250,163 describes a method for administering a medicament to the nasal mucosa where the preferred composition has mucoadhesive properties.
EP-A-230,264 describes an aqueous nasal drug delivery system for vaccines containing a high molecular weight drug, a gelling agent (e.g. hydroxyethylcellulose) and in some cases other additives (e.g. surfactants, glycerol and polyethyleneglycol).
None of the above patents and applications describes the use of microspheres for nasal administration.
A microsphere preparation for nasal delivery has been described in PCT/GB86/00721 (Fisons). This refers only to one specific drug (sodium cromoglycate) for local effect rather than delivery to the general circulation. (See also J. Controlled Release, 1, 15-22, 1984). Most importantly, the function of the ion exchange materials was to keep the drug in contact with the mucosal surface for longer periods not to enhance absorption.
Similarly, Morimoto and colleages (J. Pharm. Pharmacol. vol 37 pages 135-136 1985) have used a nasal gel (once again polyacrylic acid) as delivery system for insulin and calcitonin in rats. A significant decrease in plasma glucose levels was obtained as compared to the normal formulation, indicating an increase in the absorption efficiency.
At the present time the nose is being proposed as an alternative route for the delivery of drugs that will act within the systemic circulation. Particular attention is being focused on nature-identical peptides or proteins, or analogues or fragments thereof, produced by recombinant DNA techniques. Other drugs that are being are extensively metabolised either .in the gastrointestinal tract itself or are subject to first pass metabolism in the liver.
However, most polypeptide drugs show a low bioavailability when administered intranasally.
The rapid clearance of nasal sprays from the nose can probably be considered to be a major factor in influencing loss of drugs from potential absorption surfaces. In addition, in the case of peptides and proteins, enzymatic degradation of the drug and molecular size may also have a role in giving low bioavailabilities.
Our earlier co-pending application PCT/GB 88/00396 discloses intra-nasal microsphere formulations containing an enhancer. We have now found that,
REFERENCES:
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patent: 4613500 (1986-09-01), Suzuki et al.
patent: 4816443 (1989-03-01), Brady et al.
NATO ASI Series A: Life Sciences, vol., 1986, L. M. Sanders et al.: "Controlled delivery of Nafarelin, anantagonistic analougue of LHRH from microspheres of poly(D,L,lactic-co-Glycolic) acid", pp. 125-138.
Illum et al., J. Pharm. Sci., 72(9), pp. 1086-1089 (1983).
L. Illum, NATO ASI Symp., "Microspheres as a Potential Controlled Release Nasal Drug Delivery System", 205-210 (1986).
Illum et al., Int. J. Pharm., 39, 189-199 (1987).
Salzman et al., New Engl. J. Med., 312, pp. 1078-1084 (1985).
Hanson et al., Advanced Delivery Systems for Peptides & Proteins, 233-242 (1988).
L. Illum, Archiv for Pharmaci og Chemi, 94, 127 (1987).
J. Controlled Release, 1, 15-22 (1984).
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J. Pharm. Pharmacol., Morimoto et al., 37, 134-36 (1985).
Azpuru Carlos
Danbiosyst UK Ltd.
Page Thurman K.
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