Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-12-22
2003-10-07
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S426000, C424S434000, C424S450000, C424S490000
Reexamination Certificate
active
06630169
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to compositions and methods for the administration of particulates comprising at least one bioactive agent which, in selected embodiments, may comprise an immunoactive agent. In this respect, the invention provides for both topical and systemic delivery of the bioactive agent using, for example, the respiratory, gastrointestinal or urogenital tracts. In particularly preferred embodiments, the disclosed compositions will be used in conjunction with inhalation devices such as metered dose inhalers, dry powder inhalers, atomizers or nebulizers for targeted delivery to mucosal surfaces.
BACKGROUND OF THE INVENTION
Vertebrates possess the ability to mount an immune response as a defense against pathogens from the environment as well as against aberrant cells, such as tumor cells, which develop internally. This can take the form of innate or passive immunity, which is mediated by neutrophils and cells of the monocyte/macrophage lineage, or the form of acquired or active immunity mediated by lymphocytes against a specific antigenic sequence. Active immune responses can themselves be further subdivided into two arms, the humoral response which entails the production of specific antibodies which serve to neutralize antigens exposed to the systemic circulation and aid in their uptake by professional phagocytic cells, and the cellular arm which is required for recognition of infected or aberrant cells within the body.
In both cases the specific response is triggered by the intracellular processing of antigen. When the antigen is processed through the cytoplasmic route, the resultant peptides are bound to nascent MHC class I molecules which facilitates appropriate presentation to effector T-cells. MHC class I presentation favors recognition by cytotoxic T lymphocytes. In contrast, intracellular processing via the endocytic route results in presentation on MHC class II molecules which favors T helper responses involved in stimulation of the humoral arm. The goal of vaccination is to prime both responses and generate memory T cells, such that the immune system is primed to react to a pathogenic infection. Such a response is promoted by the coadministration of signals that promote costimulatory molecule expression, so called “adjuvants.” Engagement of both the humoral and cellular immune responses leads to broad based immunity and is the preferred goal for intracellular pathogens. The absence of appropriate costimulatory molecule expression can lead to a state of T cell unresponsiveness.
In this regard, modulation of an immune response can take one of two directions; either to elicit an immune response directed against a foreign pathogenic agent or antigen thereof, or to suppress an inappropriate reaction mounted against a self-epitope that leads to chronic inflammation. Such chronic reactions against self-epitopes are associated with various autoimmune diseases such as diabetes, typically type I, multiple sclerosis, rheumatoid arthritis or lupus erythrematosis. In either case, the active agent frequently takes the form of a relatively complex peptide, protein, RNA or DNA-based entity or other macromolecular structure rather than small chemical entities typical of classical pharmaceutical agents. These complex bioactive agents generally exhibit poor bioavailability when administered orally, and therefore have traditionally been administered by invasive parenteral injection. Recently however, it has been suggested that relatively large biomolecules may be delivered via mucosal routes, e.g. by inhalation. Delivery of these agents into systemic circulation through inhalation is particularly attractive since administration via the respiratory mucosa bypasses the digestive enzymes of the GI tract. Furthermore, it offers the potential for increased bioavailability for peptides and proteins because of the large surface area available for exchange with systemic circulation. While the molecular weight cut-off for oral bioavailability is generally regarded to be in the range of 500 Daltons, peptide hormones or analogues of larger molecular weight (e.g., 1.8 kD desmopressin, 5.8 kD insulin, 9.5 kD parathyroid hormone), have been shown to be absorbed across the nasal or pulmonary mucosa intact into the systemic circulation.
Besides allowing for the effective delivery of protein, peptide, viral and DNA formulations without degradation, targeted delivery to the mucosal surface itself may offer a benefit if it elicits a local immune response within the MALT (mucosa-associated lymphoid tissue) lymphoid system. Mucosal vaccination is of particular interest for vaccines designed against pathogens whose port of entry is typically at one of the mucosal surfaces interfacing the body with the external environment. The MALT lymphoid system resides within the lamina propria of the mucosa. When foreign antigen is presented to local dendritic cells, there is a local amplification and maturation of B-cell precursors, which produce IgA and IgM antibodies in addition to the IgG antibodies typically induced by systemic delivery of antigen. The former are secreted through specialized transport receptors by a process known as transcytosis across the mucosal surface into the lumen. There, they provide a first line of defense against invading pathogens at the mucosal surface. Recent evidence indicates that, in addition to binding pathogenic antigens, the resultant formation of immune complexes may in and of itself inhibit viral transmission occurring via the transcytotic route. By priming this first line immune response to antigens derived from pathogens, mucosal immunization should greatly enhance the efficiency with which the organism first intercepts an invading pathogen.
Several previous attempts have been made to exploit this uptake mechanism and provide for the effective delivery of peptides or proteins. For example, U.S. Pat. No. 5,756,104 describes the use of liposome formulations for intranasal vaccine formulations. These formulations appear to comprise aqueous carriers having liposomes and free antigenic material dispersed therein. While the compositions were found to elicit an immune response, they appear to be extremely labile and susceptible to degradation over time. In a practical sense this is a substantial drawback.
Attempts to overcome such limitations and further increase delivery efficiency have resulted in the development of dry powders for the administration of relatively large biomolecules. Unfortunately, conventional powdered preparations (i.e. micronized) often fail to provide accurate, reproducible dosing over extended periods. In part, this is because the powders tend to aggregate due to hydrophobic or electrostatic interactions between the fine particles. Such cohesion may be partially overcome through the use of larger carrier particles (i.e. lactose) to inhibit aggregation. However, these larger particles and associated drug often fail to reach the targeted cells resulting in uneven delivery profiles. Further, crude mixtures comprising carrier molecules provide little, if any, protection for the incorporated biomolecule. Accordingly, as with the aqueous compositions described above, such preparations are subject to degradation and loss of activity over time.
More recently, improved formulation methods have been undertaken in order to overcome the limitations associated with conventional prior art powders and aqueous preparations. In this regard, U.S. patent applications Ser. Nos. 09/218,209 and 09/219,736, incorporated herein by reference, describe methods and processes for generating preparations comprising bioactive agents in microparticulate form. The resultant powders, which preferably exhibit a hollow, porous morphology, are suitable for use in inhalation devices such as dry powder inhalers (DPIs) or, when suspended in a nonaqueous liquid (i.e. a hydrofluoroalkane or fluorocarbon), metered dose inhalers (MDIs) and nebulizers. Moreover, the mild conditions used during the formulation process support retention of biological activi
Bot Adrian I.
Dellamary Luis A.
Kabalnov Alexev
Schutt Ernest G.
Tarara Thomas E.
Cagan Felissa H.
Evans Susan T.
Nektar Therapeutics
Page Thurman K.
Tran S.
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