Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-12-14
2001-07-24
Nguyen, Daug Trong (Department: 1623)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C514S002600
Reexamination Certificate
active
06264990
ABSTRACT:
BACKGROUND OF THE INVENTION
References
The following references are referred to by numbers in brackets ([ ]) at the relevant portion of the specification.
1. Ahern and Manning, Eds., Stability of Protein Pharmaceuticals, A: Chemical and Physical Pathways of Protein Degradation, Plenum Press, New York, 1992.
2. Wang et al., 1 988, J. Parenteral Science and Technology 42: S4-S26
3. Deetz et al., 1988, Trends in Biotechnol. 6: 15-19
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5. Klibanov, 1989, TIBS 14: 141-144
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16. Singer et al., 1962, Adv. Prot. Chem. 1-68 entitled The Properties of Protein in Nonaqueous Solvents
17. Volkin et al., 1991, Biotechnol. Bioeng. 37: 843-853
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29. Meadows, 1996, U.S. Pat. No. 5,480,914
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The disclosure of each of the above publications, patents or patent applications is hereby incorporated by reference in its entirety to the same extent as if the language of each individual publication, patent and patent application were specifically and individually incorporated by reference.
BACKGROUND OF THE INVENTION
Peptides, polypeptides, proteins and other proteinaceous substances (e.g., viruses, antibodies), collectively referred to herein as proteins, have great utility as pharmaceuticals in the prevention, treatment and diagnosis of disease. Proteins are naturally active in aqueous environments, thus the preferred formulations of proteins have been in aqueous solutions. However, proteins are only marginally stable in aqueous solutions. Thus, protein pharmaceuticals often require refrigeration or have short shelf-lives under ambient conditions. Further, many proteins have only limited solubility in aqueous solutions. Even when they are soluble at high concentrations, they are prone to aggregation and precipitation.
Proteins can degrade via a number of chemical mechanisms, including deamidation of asparagine and glutamine; oxidation of methionine and, to a lesser degree, tryptophan, tyrosine and histidine; hydrolysis of peptide bonds; disulfide interchange; and racemization of chiral amino acid residues [1, 2 and 24-28]. Water is a reactant in nearly all of these degradation pathways. Further, water acts as a plasticizer which facilitates unfolding and irreversible aggregation of proteins. Since water is a participant in almost all protein degradation pathways, reduction of the aqueous protein solution to a dry powder provides an alternative formulation methodology to enhance the stability of protein pharmaceuticals. Proteins can be dried using various techniques, including freeze-drying, spray-drying and dessication. Aqueous solutions of proteins are thus dried and stored as dry powders until their use is required.
A serious drawback to drying of proteins is that often one would like to use proteins in some sort of liquid form. Parenteral injection and the use of drug delivery devices for sustained delivery of drug are two examples of applications where one would like to use proteins in a liquid form. For injection, dried proteins must be reconstituted, adding additional steps which are time-consuming and where contamination may occur, and exposing the protein to potentially destabilizing conditions [15].
The sustained parenteral delivery of drugs, in particular proteins and nucleic acids, provides many advantages. The use of implantable devices for sustained delivery of a wide variety of drugs or other beneficial agents is well known in the art. Typical devices are described, for example, in U.S. Pat. Nos. 5,034,229; 5,057,318; and 5,110,596. The disclosure of each of these patents is incorporated herein by reference.
Proteins are only marginally soluble in non-aqueous solvents, and such solvents typically unfold and denature proteins [4, 16]. Solubilization of native proteins in non-aqueous solvents typically requires derivatization or complexation of the protein [12]. In attempting to achieve enzymatic catalysis in organic media, Klibanov and others have shown that certain catalytic enzymes can be suspended in non-aqueous vehicles as powders, typically in hydrophilic organic solvents including alcohol ketones and esters [3, 5-11, 13 and 18-23]. With enzyme hydration levels ≧10% and/or the addition of low molecular weight protic compounds, these enzymes can have enough conformational mobility to exhibit appreciable enzymatic activity. Optimal activity levels are apparently achieved at enzyme hydration of approximately 30%. At a minimum, such enzymatic activity requires a level of “essential water” hydrating the protein. However, hydration levels (generally 10-40% w/w water/protein) and/or protic solvents, such as those used in these studies, typically result in unacceptable stability of proteins for pharmaceutical purposes. A further requirement for catalysis in non-aqueous solvents is that the enzyme be dried from a solution having a pH near the optimal pH for the enzymatic activity. This pH limitation is detrimental to storage of protein pharmaceuticals, because most protein degradation mechanisms are pH dependent, and it is often the case that proteins are most stable when dried at pH values far from the value where they exhibit bioactivity [1]. Further, such catalytic enzyme systems are not amenable to the addition of protein stabilizers, particularly those that function by hydrogen bonding to the protein and reducing enzyme hydration (e.g., carbohydrates) [14].
The use of perfluorocarbons as components of drug delivery vehicles for certain ophthalmic compositions has been disclosed [29, 30]. Similarly, suspensions of growth hormone in triacetin or polyethylene glycol has been published [31].
The field of gene therapy or gene transfer is advancing both experimentally and clinically. Nucleic acids have been transferred into cells using viral vectors such as adenovirus, retrovirus, adeno-associated virus, vaccinia virus, and sindbis virus, among others. Non-viral methods have also been used, including calcium phosphate precipitation, DEAE dextran, injection of naked DNA, electroporation, cochleates, cationic lipid complexes, liposomes, polymers (such as dendrimers and PLGA), virosomes, and the like.
DNA co
Huang Manley T.
Knepp Victoria Marie
Prestrelski Steven Joseph
Smith Jessica G.
ALZA Corporation
Clarke Pauline A.
Nguyen Daug Trong
Stone Steven F.
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