Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1998-03-30
1999-12-14
Webman, Edward J.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424426, 424490, A61K 916, A61K 4734
Patent
active
060013958
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a composition for delivery of an active agent, and more particularly to a composition comprising lamellar polymeric particles.
BACKGROUND OF THE INVENTION
Systems for delivering pharmaceutically or therapeutically active agents, especially antigens, are of considerable interest.
Although the influence of factors such as the dose, formulation and frequency of administration of antigen on the immune response is recognised, optimal delivery and presentation have not in general been established (Khan et al 1994). In conventional liquid dosing regimens, several small doses of antigen are more effective than a single inoculation or a few large doses in stimulating a protective immune response. It is also known that protein concentrations as low as 0.001 .mu.g are sufficient to stimulate a secondary response and that immunological unresponsiveness (tolerance) can be induced by both high and low doses of antigen and by frequent administration.
Many purified, synthetic or inactivated antigens such as Tetanus toxoid are poorly immunogenic and usually require several parenteral doses to confer adequate protection. Adsorption of vaccine antigens onto adjuvants such as Alum is a common method for enhancing the immunogenicity. A wide variety of substances, both biological and synthetic, have been used as adjuvants including mycobacteria, oil emulsions, liposomes, polymer microparticles and mineral gels. A range of 24 different adjuvants was recently investigated by Stieneker et al (1995) for inactivated HIV virus encompassing many of the adjuvant systems currently under investigation. However, only Aluminium hydroxide "Alum" has been approved for administration in humans but its use is often associated with adverse reactions.
As well as protecting antigens, stimulating phagocytosis and activating lymphoid cells, some adjuvants function by retaining the antigen at the site of deposition. Antigen retention appears vital for repeated stimulation of the memory B-cell population and for maintaining antibody titres over long periods (Gray et al 1988). The adjuvant effect of water-in oil emulsions Freund's Complete Adjuvant (FCA)/Freund's Incomplete Adjuvant (FIA), for example, is considered to arise from creation of a short-term `depot effect` involving antigen retention as a result of granuloma formation. Malarial antigen has been detected at the injection site 80 days post-administration when formulated with liposomes and encapsulated in alginate poly(L-lysine) microparticles (Cohen et al 1991) suggesting that this system also provides a `depot-type` vaccine for sustained retention and presentation of antigens to the immune system.
The considerable research effort devoted to vaccine formulation has generated a multitude of strategies for optimising antigen release rates and achieving single dose delivery systems. Pulse release of antigen from biodegradable, biocompatible poly(lactide co-glycolide) [PLG] microparticles is considered advantageous for stimulating the conventional, multi-dose, schedule. However, most microparticulate delivery systems are considered to function on the principle of sustained, long term antigen release which presents a continuous trickle of antigen to the immune system to maintain proliferation of immune cells and antibody production. Raghuvanshi et al (1993) developed a single injection formulation for Tetanus toxoid (TT) based on this principle using PLG microparticles. The resultant immune response over 5 months in rats was comparable with the conventional 2-dose schedule of TT adsorbed on alum.
The lower primary response observed with TT adsorbed to Alum was considered due to rapid antigen depletion resulting in reduced proliferation of immune cells.
The ability of small antigen-loaded PLG microparticles (<5 .mu.m in size) to function as potent antigen delivery systems after sub-cutaneous administration is considered to arise from 2 mechanisms: 1) efficient phagocytosis resulting in transport to the lymph nodes where efficient antigen processing and prese
REFERENCES:
patent: 4492720 (1985-01-01), Mosier
patent: 5827531 (1998-10-01), Morrison et al.
patent: 5869103 (1999-02-01), Yeh et al.
Alpar, et al., "Identification of Some of the Physico-Chemical Characteristics of Microspheres which Influence the Induction of the Immune Response Following Mucosal Delivery," Eur. J. Pharm. Biopharm. 40(4):198-202 (1994).
Cohen, et al., "The pharmacokinetics of, and humoral responses to, antigen delivered by microencapsulated liposomes," Proc. Natl. Acad. Sci. USA 88:10440-44 (1991).
Eldridge, et al., "Biodegradable Microspheres as a Vaccine Delivery System," Mol. Immunol. 28(3):287-94 (1991).
Esparza, et al., "Parameters affecting the immunogenicity of microencapsulated tetanus toxoid," Vaccine 10(10):714-20 (1992).
Gray, et al., "B-cell memory is short lived in the absence of antigen," Nature 336:70-73 (1988).
Kalb, et al., "General crystalliazation behavior of poly(L-lactic acid)," Polymer 21(6):607-12; ACS Abstract No. 93:240075 (1980).
Khan, et al., "Immunopotentiation and Delivery Systems for Antigens for Single-Step Immunization: Recent Trends and Progress," Pharm. Res. 11(1):2-11 (1994).
Kreuter, et al., "Influence of hydrophobicity on the adjuvant effect of particulate polymeric adjuvants," Vaccine 6(3):253-56 (1988).
O'Hagan, et al., "Biodegradable microparticles as controlled release antigen delivery systems," Immunology 73(2):239-42 (1991); ACS Abstract No. 115:56995 (1991).
O'Hagan, et al., "Long term antibody responses in mice following subcutaneous immunization with ovalbumin entrapped in biodegradable microparticles," Vaccine 11(9):965-69 (1993).
Park, et al., "Importance of in vitro experimental conditions as protein release kinetics, stability and polymer degradation in protein encapsulated poly(D,L-lactic acid-co-glycolic acid) microspheres," J. Controlled Rel. 33:211-22 (1995).
Raghuvanshi, et al., "Biodegradable delivery system for single step immunization with tetanus toxoid," Int. J. Pharm. 93:R1-R5 (1993).
Sharif, et al., "Biodegradable microparticles as a delivery system for the allergens of Dermatophogoides pteronyssinus (house dust mite): I. Preparation and characterization of microparticles," Int. J. Pharm. 119(2):239-46; ACS Abstract No. 122:298951 (1995).
Stieneker, et al., "Comparison of 24 different adjuvants for inactivated HIV-2 split whole virus as antigen in mice: Induction of titres of binding antibodies and toxicity of the formulations," Vaccine 13(1):45-53 (1995).
Coombes Allan Gerald Arthur
Davis Stanley Stewart
Major Diane Lisa
Wood John Michael
Danbiosyst UK Limited
Webman Edward J.
LandOfFree
Polymeric lamellar substrate particles for drug delivery does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Polymeric lamellar substrate particles for drug delivery, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Polymeric lamellar substrate particles for drug delivery will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-860749