Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1998-07-09
2003-02-04
Zeman, Mary K. (Department: 1631)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S234100, C424S184100, C514S002600
Reexamination Certificate
active
06514503
ABSTRACT:
RELATED APPLICATION
This application is a continuation-in-part of Icelandic patent application 4518, filed Jul. 9, 1997, the entire teachings of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Parenteral administration (intramuscular and subcutaneous) of antigens or vaccines is normally regarded as the most effective route of administration. However, administration by injection has a number of disadvantages. Injection of an antigen or vaccine requires the use of sterile syringes and administration by trained personnel, and may cause pain and irritation, particularly in the case of repeated injections. This route of administration also poses a risk of infection. More significantly, intramuscular injections are often poorly tolerated by the individual, and may possibly cause an induration (hardening of tissue), hemorrhage (bleeding) and/or necrosis (local death of tissue) at the injection site.
The mucosal membrane contains numerous dendritic cells which are excellent antigen-presenting cells. The mucosal membranes are also connected to lymphoid organs, called mucosal-associated lymphoid tissue, which are able to potentiate an immune response to other mucosal areas. One example of such a mucosal membrane is the nasal epithelial membrane, which consists essentially of a single layer of epithelial cells (pseudostratified epithelium); the mucosal membrane is connected to two lymphoid tissues, the adenoids and the tonsils. The extensive network of blood capillaries under the nasal mucosa and the high density of T and B cells are particularly suited to provide rapid recognition of the antigen and to provide a quick immunological response.
Intranasal administration of attenuated viruses, bacteria and parasites has been attempted, along with administration through other mucosal surfaces, for particular pathogens which normally infect a host by this route. The elicitation of an immune response by these antigens through mucosal surfaces is expected in such cases, because the modified live pathogen of the vaccine is following the natural route of infection of the wild-type pathogen, creating immunity through a sub-clinical infection. Mucosal administration of immunogenic compositions is of particular interest since this route is able to stimulate locally-produced antibodies (secretory IgA antibodies) and avoids the problems caused by parenteral administration. Furthermore, mucosal administration can typically be performed by an untrained person, including the individual to be treated, and young children are typically not as averse to mucosal administration as to parenteral administration. Due to the risk associated with administration of live, attenuated, modified pathogens, it is often desirable to utilize a subunit vaccine. However, the mucosal administration of purified antigens in a subunit vaccine is normally associated with a poor immune response.
A variety of vehicle systems for the delivery of antigens have been developed. One of the problems encountered in using such vehicle systems, e.g., for intranasal or mucosal administration, is that the antigen and/or the vaccine is absorbed and degraded without recognition and, therefore, without stimulating an immunological response, partially due to the short contact-time inside the nasal cavity. A mixture of polyethylene glycol substituted caprylic/capric acid glycerides and Tween 20® has been described for use as a mucosal adjuvant (Gizurarson et al.,
Toxicology
107:61-68 (1996); Gizurarson et al.,
Vaccine Research
5:69-75 (1996); Gizurarson et al.,
Vaccine Research
6:41-47 (1997)); however, this formulation produces an uncomfortable stinging sensation in the recipient at the site of administration. Thus, there is a need for an effective formulation for mucosal administration of antigens to produce an acceptable immune response.
EP Patent No. 0544612A2 discloses a composition comprising an immunogen and a triglyceride that can be orally or nasally administered. The composition can enhance the effect of the immunogen.
In one reference (U.S. Pat. No. 4,610,868; issued Sep. 9, 1986) a lipid matrix carrier is described for parenteral administration of drugs. This system requires a lipid matrix carrier comprising a hydrophobic compound, an amphipathic compound and a bioactive agent with a globular structure with 500-100000 nm in diameter. Here the hydrophobic compound may comprise a mixture of glycerides, and the amphipathic compound may comprise a sphingolipid. Furthermore, this formulation may be administered into the nasal area. This system may not be acceptable as nasal formulation, due to the rapid clearance inside the nose and the large globular structure. Therefore, this system will be removed, into the stomach, by the cilia before the bioactive agent is released. This patent does not describe the use of the adjuvant substance according to the invention.
In JP 309347/91 (priority Nov. 25, 1991) an orally or nasally administered immunogen composition comprising an immunogen capable of immunizing mammals using an adjuvant comprising of triglycerides with C
6-26
residue of saturated or unsaturated fatty acid. The use of saturated fatty acids does not induce the immune response according to the invention, and the use of triglycerides does not give the possibilities of having one hydrophilic group able to solubilize the adjuvant or having the possibility to connect the antigen to the adjuvant.
WO 94/17827 (priority Feb. 15, 1993) describes a pharmaceutical preparation for topical administration of antigens to mammals via mucosal membranes. The adjuvant/vehicle preparation is selected from (a) polyoxyethylene sorbitan monoesters, (b) polyoxyethylene castor oil, (c) caprylic/capric glycerides, and (d) gangliosides.
SUMMARY OF THE INVENTION
The present invention provides a composition which can be used as an adjuvant for the administration of antigens and vaccines, particularly for mucosal administration. The compositions of the present invention provide enhanced adhesion of the antigen to the mucosal membrane, as well as enhanced absorption of the antigen through the mucus membrane. Use of the compositions of the invention provides the ability to elicit both a systemic (e.g., antibodies of the IgG isotype) and a local (e.g., secretory antibodies of the IgA isotype) immune response in the recipients of the composition without causing unacceptable irritation of the epithelial membrane. The compositions of the invention can also be used in plants as an adjuvant to stimulate the plant immune defense system. The invention also provides a controlled delivery system for intranasal application, which is biocompatible with the mucus membrane and which is capable of administering required amounts of antigens in small volumes.
The present invention pertains to compositions which comprise an antigen and an adjuvant containing 0.01-70% v/v of glycerides selected from the group consisting of monoglycerides, diglycerides, and mixtures thereof, said glycerides having the formula (I):
wherein R
1
, R
2
, and R
3
are independently selected from the group consisting of saturated or unsaturated C
6-24
fatty acids, water soluble polymers, and mixtures thereof, provided that the glyceride contains at least one water soluble polymer at R
1
, R
2
, or R
3
. The adjuvant can also contain small amounts of triglycerides. In a particular embodiment, the water soluble polymers consist of PEG
2-30
residues of polyoxyethylene, or derivatives thereof, having 2-30 polyoxyethylene units. In another embodiment, one or two of the groups R
1
, R
2
, and R
3
are replaced by bound antigen.
In a further embodiment of the invention, the water soluble polymer is a PEG
3-6
residue of polyoxyethylene having 3 to 6 polyoxyethylene units. In another embodiment of the invention, the glycerides have a structure selected from the group consisting of:
wherein in each formula, R
1
, and R
2
are defined above.
In particular embodiments of the invention, R
1
, R
2
, and R
3
are selected from saturated C
6-4
fatty acids, more preferably saturated C
8-1
Gizurarson Sveinbjörn
Gudmundsdottir Vera
Hamilton Brook Smith & Reynolds P.C.
Lyfjathoun HF
Zeman Mary K.
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