U.S. patent application number 12/583219 was filed with the patent office on 2009-12-17 for urogenital or anorectal transmucosal vaccine delivery system.
This patent application is currently assigned to Protein Express, Inc.. Invention is credited to Zsolt Istvan Hertelendy, Michael Howell, Joseph Thomas, Murray Weiner.
Application Number | 20090311290 12/583219 |
Document ID | / |
Family ID | 24054035 |
Filed Date | 2009-12-17 |
United States Patent
Application |
20090311290 |
Kind Code |
A1 |
Hertelendy; Zsolt Istvan ;
et al. |
December 17, 2009 |
Urogenital or anorectal transmucosal vaccine delivery system
Abstract
The invention is directed to a suppository based vaccine
delivery system for immunizing against urogenital and anorectally
transmitted infectious disease in humans and animals and a method
for treating the same. More particularly, this invention is
directed to a suppository based vaccine delivery system for the
prophylaxis against or treatment of urogenital or anorectal
transmitted infectious diseases, such as from viral or microbial
pathogens. The suppository based delivery system comprises vaccine
and/or vaccine adjuvant(s) comprised of whole or fractionated viral
or other microbial pathogens, or their purified cellular
constituents, whether native, mutated, synthetic, cloned or
recombinantly expressed, that consists of nucleic acids, proteins,
lipids or other antigenic determinants capable of producing humoral
or cellular-mediated immunity in humans or animals; and a
polyethylene glycol base; wherein the suppository is adapted to be
inserted into a bodily orifice of a human or animal so as to allow
the suppository to be in contact with tissue of the bodily orifice
to facilitate transfer of vaccine or vaccine adjuvant(s) material
therethrough.
Inventors: |
Hertelendy; Zsolt Istvan;
(Cincinnati, OH) ; Weiner; Murray; (Cincinatti,
OH) ; Howell; Michael; (Mason, OH) ; Thomas;
Joseph; (Hebron, KY) |
Correspondence
Address: |
Davidson, Davidson & Kappel, LLC
485 7th Avenue, 14th Floor
New York
NY
10018
US
|
Assignee: |
Protein Express, Inc.
Cincinnati
OH
|
Family ID: |
24054035 |
Appl. No.: |
12/583219 |
Filed: |
August 17, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11580258 |
Oct 12, 2006 |
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12583219 |
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09516078 |
Mar 1, 2000 |
7135191 |
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11580258 |
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08923813 |
Sep 4, 1997 |
6099853 |
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09516078 |
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Current U.S.
Class: |
424/231.1 |
Current CPC
Class: |
A61K 39/12 20130101;
A61K 2039/53 20130101; A61K 9/0034 20130101; C12N 2710/16622
20130101; A61K 39/245 20130101; A61P 31/22 20180101; C12N
2710/16634 20130101; A61K 9/0031 20130101; A61K 9/02 20130101; A61K
2039/541 20130101 |
Class at
Publication: |
424/231.1 |
International
Class: |
A61K 39/245 20060101
A61K039/245; A61P 31/22 20060101 A61P031/22 |
Claims
1. A suppository based vaccine delivery system for prophylaxis
against or treatment of urogenitally and anorectally transmitted
infectious disease in humans and animals, said suppository
comprising: (a) a vaccine or vaccine adjuvant(s) selected from the
group consisting of whole or fractionated viral or other microbial
pathogens, or their purified cellular constituents, whether native,
mutated, synthetic, cloned or recombinantly-expressed and
combinations thereof, that consists of nucleic acids, proteins,
lipids, other antigenic determinants or combinations thereof
capable of producing humoral- or cellular-mediated immunity in
humans or animals; and (b) a suppository base, selected from the
group consisting of polyethylene glycol, polysorbate and
combinations thereof; wherein the suppository is adapted to be
inserted into a bodily orifice of a human or animal so as to allow
the suppository to be in contact with tissue of the bodily orifice
to facilitate transfer of suppository material therethrough.
2. A suppository based vaccine delivery system for prophylaxis
against urogenital tract infections in humans, said suppository
comprising: (a) a vaccine or vaccine adjuvant(s) selected from the
group consisting of whole or fractionated viral or other microbial
pathogens, or their purified cellular constituents, whether native,
mutated, synthetic, cloned or recombinantly-expressed and
combinations thereof, that consists of nucleic acids, proteins,
lipids, other antigenic determinants or combinations thereof
capable of producing humoral or cellular-mediated immunity in
humans; and (b) a suppository base, selected from the group
consisting of polyethylene glycol, polysorbate and combinations
thereof; wherein the suppository is adapted to be inserted
vaginally so as to allow the suppository to be in contact with
vaginal mucous membrane to facilitate transfer of suppository
material therethrough.
3. A suppository based vaccine delivery system for prophylaxis
against anorectally transmitted infectious disease in humans or
animals, said suppository comprising: (a) a vaccine or vaccine
adjuvant(s) elected from the group consisting of whole or
fractionated viral or other microbial pathogens, or their purified
cellular constituents, whether native, mutated, synthetic, cloned
or recombinantly expressed and combinations thereof, that consists
of nucleic acids, proteins, lipids, other antigenic determinants or
combinations thereof capable of producing humoral or
cellular-mediated immunity in humans or animals; and (b)
suppository base, selected from the group consisting of
polyethylene glycol, polysorbate and combinations thereof; wherein
the suppository is adapted to be inserted rectally so as to allow
the suppository to be in contact with the anorectal mucous membrane
to facilitate transfer of vaccine or vaccine adjuvant material
therethrough.
4. The suppository based vaccine delivery system of claim 1 wherein
the vaccine content or vaccine adjuvant(s) is selected from the
group consisting of whole cells, purified constituents or is
generated from known genetic information of urogenital or
anorectally transmittable pathogens.
5. The suppository based vaccine delivery system of claim 1 wherein
the vaccine or vaccine adjuvant(s) contents are present in the
total amount of 10 to 1000 micrograms.
6. The suppository based vaccine delivery system of claim 1 wherein
the suppository base is comprised of polyethylene glycol and
polysorbate.
7. The suppository based vaccine delivery system of claim 6 wherein
the polyethylene glycol suppository base is comprised of about 75%
to about 98% by weight polyethylene glycol and about 2% to about
25% by weight polysorbate.
8. The suppository based vaccine delivery system of claim 6 wherein
the polyethylene glycol has an average molecular weight of about
950 to about 3700.
9. The suppository based vaccine delivery system of claim 6 wherein
the polyethylene glycol suppository base comprises from about 70%
to greater than 99% by weight of the suppository.
10. The suppository based vaccine delivery system of claim 1
wherein the suppository is further comprised of a preservative
selected from the group consisting of thimersal, benzoic acid,
benzylkonium, benzylkonium chloride, sulfites, quaternary ammonium
salts, chlorobutanol and combinations thereof.
11. The suppository based vaccine delivery system of claim 10
wherein the suppository is further comprised of an emulsifying
agent selected from the group consisting of gelatin, methyl
cellulose, alginic acid, sodium lauryl sulfate and combinations
thereof.
12. A suppository-based vaccine delivery system for prophylaxis
against urogenital or anorectally transmitted infections in humans
or animals, said suppository comprising: (a) a vaccine or vaccine
adjuvant(s) comprising purified mutated, synthetic or genetically
engineered constituents of known pathogens selected from the group
consisting of urogenital pathogens, anorectally pathogens and
combinations thereof; and (b) a suppository base, selected from the
group consisting of polyethylene glycol, polysorbate and
combinations thereof; wherein the polyethylene glycol suppository
base is comprised of about 75% to about 98% by weight polyethylene
glycol and about 2% to about 25% by weight polysorbate, wherein the
polyethylene glycol has an average molecular weight of about 950 to
about 3700, and wherein the polyethylene glycol suppository base
comprises from about 70% to about 99% by weight of the suppository;
wherein the suppository is adapted to be inserted vaginally or
rectally so as to allow the suppository to be in contact with
mucous membrane to facilitate transfer of vaccine or vaccine
adjuvant(s) material therethrough.
13. A suppository-based vaccine delivery system for prophylaxis
against genitourinary or anorectal tract infections in humans or
animals, said suppository resulting from the mixture of: (a) a
vaccine or vaccine adjuvant selected from the group consisting of
whole or fractionated viral or other microbial pathogens, or their
purified cellular constituents, whether native, mutated, synthetic,
cloned or recombinantly expressed, that consists of nucleic acids,
proteins, lipids, other antigenic determinants or combinations
thereof capable of producing humoral or cellular-mediated immunity
in humans or animals; and (b) a suppository base, selected from the
group consisting of polyethylene glycol, polysorbate and
combinations thereof; wherein the polyethylene glycol suppository
base is comprised of about 75% to about 98% by weight polyethylene
glycol and about 2% to about 25% by weight polysorbate, wherein the
polyethylene glycol has an average molecular weight of about 750 to
about 3700, and wherein the polyethylene glycol suppository base
comprises from about 70% to greater than 99% by weight of the
suppository base; wherein the suppository is adapted to be inserted
vaginally or rectally so as to allow the suppository to be in
contact with mucous membrane to facilitate transfer of vaccine or
vaccine adjuvant(s) material therethrough.
14. A method for preventing urogenital or anorectal disease in
humans or animals, said method comprising the steps of: (a)
inserting a suppository-based vaccine delivery system into a bodily
orifice of a human, wherein said suppository comprises a vaccine or
vaccine adjuvant(s) material comprised of whole, fractionated viral
or other microbial pathogens, or their purified cellular
constituents, whether native, mutated, synthetic, cloned or
recombinantly expressed, that consists of nucleic acids, proteins,
other antigenic determinants or combinations thereof capable of
producing humoral or cellular-mediated immunity in humans or
animals; and (b) contacting the suppository with mucosal tissue at
and internal to the bodily orifice to facilitate transfer of the
vaccine or vaccine adjuvant material therethrough and induce an
immune response in the human.
15. The method of claim 14 wherein the protein or nucleic acid
originate from the genetic constituents of pathogenic urogenital or
anorectally transmissible viruses, other microbes or combination
thereof.
16. The method of claim 14 wherein the amount of protein, nucleic
acids, lipids, other antigenic determinants and combinations
thereof are present in the total amount of about 10 to about 1000
micrograms.
17. The method of claim 14 wherein the polyethylene glycol
suppository base is selected from the group consisting of
polyethylene glycol, polysorbate and combination thereof.
18. The method of claim 17 wherein the polyethylene glycol
suppository base is comprised of about 75% to about 98% by weight
polyethylene glycol and about 2% to about 25% by weight
polysorbate.
19. The method of claim 18 wherein the polyethylene glycol has an
average molecular weight of about 750 to about 3700.
20. The method of claim 14 wherein the suppository base comprises
from about 80% to greater than 99% by weight of the suppository
base.
Description
FIELD OF INVENTION
[0001] The present invention relates generally to a system and
method for treating disease in humans and animals, specifically a
prophylactic treatment of viral or microbial infections in humans
or animals. More particularly, the invention relates to a
suppository-based, vaccine delivery system for prophylaxis against
or therapy for viral or microbial infections in humans or animals,
wherein the suppository is intended for transmucosal immunization
and is comprised of a vaccine or vaccine adjuvant(s) that is
derived from whole or fractionated viral or other microbial
pathogens, or their purified cellular constituents or derivatives,
whether native, synthetic, cloned or recombinantly expressed, that
consists of nucleotide sequences, proteins or other antigenic
determinants capable of producing humoral or cellular-mediated
immunity in humans or animals. Still more particularly, the present
invention relates to a suppository-based, vaccine delivery system
for prophylaxis against or therapy for viral or microbial
infections in humans or animals, wherein the suppository is used
for transmucosal immunization and is comprised of a vaccine or
vaccine adjuvant(s) intended for mucosal immunization that is
derived from whole or fractionated viral or other microbial
pathogens, or their purified cellular constituents, whether native,
synthetic, cloned or recombinantly expressed, that consists of
nucleotide sequences, proteins or other antigenic determinants
capable of producing humoral or cellular-mediated immunity in
humans or animals, and wherein the suppository is comprised of a
suitable base that liquefies or becomes water miscible at body
temperature in order to deliver vaccine components and/or vaccine
adjuvant components to the urogenital or anorectal mucosa so as to
cause or enhance the development of a desired immune response.
BACKGROUND OF THE INVENTION
[0002] Viral and microbial pathogens transmitted through or
originating from exposure of the urogenital or anorectal epithelium
or mucosa are a major problem in medicine. Urogenital and anorectal
structures and systemic tissues beyond may be affected. Such
infectious disease can result from mucosal exposure during sexual
contact or other contact or from opportunistic growth of the
urogenital or anorectal flora.
[0003] A tendency for recurrence, reinfection and chronic
progression is characteristic of many urogenital or anorectal tract
infections. Viral or microbial adherence to the mucosal epithelium
is frequently a key precondition for the colonization or infection
of these tissues. In-vitro studies have shown that the adherence
phenomenon is often accomplished via the pili of bacteria or other
outer membrane constituents of infecting viruses or microbes. Such
adherence can be prevented by the development of antibodies and/or
enhancement of cell-mediated immunity against antigenic components
of the invading organisms, which include viruses, bacteria,
protozoa, fungi and the like.
[0004] Bacteria and viruses are the most frequent causative agents
of genitourinary or anorectal tract infections. The
genitourinary/anorectal tracts can also be infected by other
microorganisms, such as protozoa, fungi and the like. Recurrence
and chronicity are characteristic of many genitourinary/anorectal
tract infections. Recurrence may be due to either relapse or
reinfection.
[0005] In spite of a great deal of progress in the treatment of
infectious disease, the morbidity and mortality of
genitourinary/anorectal tract infections remains unchanged. The
reasons for this are myriad and depend on the host susceptibility,
heightened sexual exposure and on viral or microbial factors.
[0006] Recurrences of infections with a previously infecting
organism may result from inadequacy of the treatment administered
because of incorrect choice of medicine, emergence of resistance
strains, insufficient treatment duration, insufficient
concentration of chemotherapeutic agents, the existence of
bacterial L-forms, and persistence or survival of viral or microbes
in urinary calculi or epithelium of the vaginal or anorectal mucosa
and surrounding tissues. Recurrent urogenital/anorectal infections
can be reinfections with different strains of organisms responsible
for prior infections and generally having a greater capacity to
adhere to the epithelial cells of the vagina, urethra or rectum.
The reinfecting bacteria can originate in the intestinal flora.
Frequently, viruses and chlamydia pathogens may lay dormant in
epithelial cells and revert to an active state through mechanisms
not fully understood.
[0007] The composition of the urogenital or anorectal flora may be
altered by chemotherapeutic agents that are used in the treatment
and prophylaxis of genitourinary or intestinal infections. The
flora frequently develop antibiotic resistance and cause a
reinfection or primary opportunistic infection. Such infections may
be a consequence of the eradication of normal, harmless flora, such
as lactobacilli, allowing other pathogenic microbes, resistant to
the antibiotics, to flourish.
[0008] Studies have revealed that low levels of secretory IgA
(sIgA) in urine indicate a defective local immune response of the
urinary tract and favor urogenital tract infections. An important
property of sIgA is the prevention of interaction of bacterial pili
or outer membrane constituents of viruses or other microbes with
the specific receptors found on the epithelium of the
vaginal/anorectal mucosa or urinary tract. Pili-mediated
adhesiveness is an important virulence factor of the bacteria
involved. In the case of viruses and non-piliated microbes, other
outer membrane constituents are involved in host-attachment
phenomena, prior to propagation to infection. For the defense
against infection it is important to reduce the adhesion of the
pathogens to the epithelium or to prevent the attachment of the
pathogen altogether.
[0009] Normally, the host organism forms specific local antibodies
against the invading bacteria and secretes these antibodies as
sIgA. In patients with persisting or frequently relapsing urinary
tract infections this natural mechanism of local immunological
infection defense is apparently disturbed. Therefore, enhancement
of immune defense is a rational means of eliminating the cause of
recurrent urinary tract infections.
[0010] A vaccination strategy that stimulates the production of
antibodies to a spectrum of antigens that are present in several
types of pathogens is desirable. Vaccination of the urogenital or
anorectal epithelium with nucleic acids encoding specific proteins
involved in pathogen-host attachment phenomena presents a novel
method of stimulating cell-mediated immunity.
[0011] Previously, vaccines against urogenital infections have been
administered parenterally or orally and have resulted in enhanced
resistance to urogenital infections. However, patients suffer from
side effects such as malaise, fever, and muscle soreness. Oral
vaccines are subject to the destructive influences of gastric
acidity and digestive enzymes. A necessary retention at a local
surface for extended transmucosal contact may be difficult to
achieve. Prior art concerning mucosal vaccination through the
vaginal route using whole cell lysates has taught enhanced
resistance to recurrent infection, but there is no mention of
transmucosal immunization by the anorectal route and the production
of transmucosal immunity against local infection at the site of
delivery system target. No specifically therapeutic local immune
response to a delivery system is presented. The efficacy presented
is confined to non-specific vaccine materials that present a
complex potential to produce complex reactions by poorly understood
mechanisms.
[0012] In an attempt to overcome the defects associated with
parenteral and oral administrations of vaccines or in using
vaginally-delivered vaccines comprised of fractionated or whole
cell extracts, an intravaginal or intrarectal mucosal vaccine
delivery system against infections is proposed wherein the vaccine
is comprised of purified antigenic determinants capable of
stimulating an immune response to pathogenic factors involved in
attachment and disease. Administering a vaccine against urogenital
or anorectal infections intravaginally or intrarectally is that
there is a mucosal immune system wherein antigens are absorbed
through mucosal surfaces and processed by specialized local
lymphoid tissues, after which antibodies are secreted onto local
mucosal surfaces. In the case of nucleotide vaccines, epithelial
cells of the mucosa express the proteins to the cell surface
promoting cellular-mediated immune responses. As discussed above,
in the genitourinary tract, temporary or partial deficiencies in
local vaginal or urinary antibodies are an important factor in the
heightened susceptibility to urogenital infections shown in some
women. Immunization via the mucosal surface within the
genitourinary tract is preferable to parental or oral routes as it
has been discovered that vaccination via the intravaginal surface
creates a secretory immune response in the urogenital tract. With
nucleotide vaccines, such vaccination stimulates specific
cellular-mediated immune responses.
[0013] Advances in the identification of specific pathogenic
factors involved in infection attachment and propagation, the
elucidation of the mucosal immune system and the ability of the
mucosal tissue to participate in cellular-mediated immune response
via nucleotide vaccination suggest that vaccination of the
genitourinary/anorectal tract by a transvaginal or anal route is
preferable to oral or parenteral immunization. The specific method
of vaginal or rectal immunization may actually resolve infection
before disease ensues, preventing pathogen attachment or
neutralizing toxins prior to pathogen and host interaction.
[0014] For instance, in the past, urinary tract infections vaccines
were administered vaginally in the form of a liquid vaccine.
Several problems were associated with the intravaginal
administration of liquid urinary tract infections vaccine. The
major problem encountered was that the liquid vaccine flowed out of
the vagina soon after insertion. This severely limits the amount of
time that the liquid antigens are in contact with the mucosal
surface of the vagina, decreasing the effectiveness of the vaccine.
The antigens need sufficient contact with the vaginal mucous
membrane to elicit a secretory immunoglobin response. Patients
receiving the vaccination were required to lie in a supine position
for an extended time after receiving the vaccine to prevent the
vaccine from immediately flowing out of the vagina. However, often
the vaccine still leaked out of the vagina following the period of
time in the supine position, limiting the effectiveness of the
vaccine. In addition, the requirement that patients lie in a supine
position for an extended time after receiving the vaccine, is a
burden on the patient. Patients may receive several vaccinations
over the course of treatment and the patients must spend a
considerable amount of time after each vaccination immobile.
[0015] U.S. Ser. No. 08/923,813 entitled Vaginal Suppository
Vaccine For Urogenital Infections was filed Sep. 4, 1997 and
allowed. This application is owned by assignee herein and relates
to a suppository based vaccine delivery system for immunizing
against urogenital infectious diseases in humans.
[0016] It is apparent that improvements are necessary in optimizing
vaccine delivery to the urogenital mucosa for effective prophylaxis
against urogenital infectious diseases. Further, it is desirable to
have a rectally-administered vaccine for effective prophylaxis
against rectal tract infections involving transmission through the
anorectal tract.
[0017] The subject invention overcomes the above limitations and
others, and teaches a suppository-based vaccine delivery system for
prophylaxis against urogenital and anorectal tract infectious
diseases, such as bacterial, protozoal, fungi, viral infections and
the like, using fractionated, whole cell or purified protein,
nucleic acid or lipid constituents, whether native, mutated,
synthetic, cloned or recombinantly expressed, of
urogenital/anorectal pathogens that stimulate the generation of
humoral or cellular-mediated immune response.
SUMMARY OF THE INVENTION
[0018] According to the present invention, there is provided an
intravaginally or intrarectally administered suppository based
vaccine delivery system for prophylaxis against urogenital or
anorectal localized or transmitted infectious diseases.
[0019] Further according to the present invention, there is
provided a suppository based vaccine delivery system for the
prophylaxis against or treatment of urogenitally or rectally
transmitted or localized infectious diseases, such as bacterial,
protozoal, fungal or viral infections wherein the vaccine or
vaccine adjuvant is in contact with the vaginal or anorectal mucous
membrane for a sufficient period of time to enhance the immune
response.
[0020] Still further according to the present invention, there is
provided a suppository based vaccine delivery system for the
prophylaxis against or treatment of urogenitally or rectally
transmitted or localized infectious diseases, such as bacterial,
protozoal, fungal or viral infections, wherein the vaccine or
vaccine adjuvant is easily administered, does not require the
patient to lie in a supine position for an extended period of time
after receiving the vaccination, and is suitably administered by
the patient for primary and routine booster requirements.
[0021] Still further according to the present invention, there is
provided a suppository based vaccine delivery system for
prophylaxis against urogenitally or rectally transmitted or
localized infectious diseases, such as bacterial, protozoal, fungal
or viral infections in humans or animals, said suppository
comprising: a vaccine or vaccine adjuvant containing whole or
fractionated viral or other microbial pathogens, or their purified
cellular constituents, whether native, synthetic, cloned or
recombinantly expressed, that consists of nucleic acids, proteins,
lipids or other antigenic determinants capable of producing
humoral- or cellular-mediated immunity in humans or animals,
wherein the suppository is comprised of a suitable base that
liquefies or becomes water miscible at body temperature in order to
deliver vaccine components to the urogenital or anorectal mucosa;
wherein the suppository is adapted to be inserted vaginally or
rectally so as to allow the suppository to be in contact with
mucous membrane to facilitate transfer of vaccine or vaccine
adjuvant material therethrough.
[0022] An advantage of the present invention is the provision of a
suppository based vaccine delivery system for the prophylaxis
against or treatment of urogenital and/or rectally transmitted or
localized infectious diseases, such as viral or other pathogenic
microbial infections, wherein the vaccine or vaccine adjuvant is in
contact with the vaginal or rectal mucous membrane for a sufficient
period of time to enhance the immune response.
[0023] Another advantage of the present invention is the provision
of a suppository based vaccine delivery system wherein humoral-
and/or cell-mediated stimulation from mucosal vaccination allows
immune responses to specifically keep viral or microbial shedding
or colonization from occurring or recurring, or prohibiting
pathogen-host attachment instead of fighting the infection after it
has colonized or has propagated.
[0024] Another advantage of the present invention is the provision
of a suppository based vaccine delivery system wherein the
suppository can be easily manufactured to allow incorporation of
vaccine or vaccine adjuvant(s) with preservatives, such as
thimersal; is a solid at or below room temperature for structure
and to allow ease of insertion; and becomes liquified or
water-miscible at body temperature so as to allow its components to
enhance an immune response.
[0025] Another advantage of the present invention is the provision
of a suppository based vaccine delivery system for the prophylaxis
against urogenitally or rectally transmitted or localized
infectious diseases, such as viral or other pathogenic
microorganism infections, wherein the vaccine is easily
administered, and does not require the patient to be in a supine
position for an extended period of time after receiving the
vaccination.
[0026] Another advantage of the present invention is the provision
of a suppository based vaccine delivery system wherein the vaccine
can be readily self-administered by the patient.
[0027] Another advantage of the present invention is the provision
of a suppository based vaccine delivery system wherein the
administration of the vaccine is relatively painless.
[0028] Yet another advantage of the present invention is the
provision of a suppository based vaccine delivery system wherein
the patient may self-administer booster vaccinations periodically.
Still other advantages of the invention will become apparent to
those skilled in the art upon a reading and understanding of the
following detailed description, and appended claims.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0029] This invention is directed to a suppository based vaccine
delivery system for immunizing against infectious disease in humans
and animals and a method for treating the same. More particularly,
this invention is directed to a suppository based vaccine delivery
system for the prophylaxis against or treatment of urogenitally and
anorectally localized or transmitted infectious diseases, such as
from viral or other pathogenic microbial infections including but
not limited to bacteria, protozoans, fungi and the like. The
suppository based vaccine delivery system comprises a vaccine
and/or vaccine adjuvant(s) comprising pathogenic microbial or viral
antigenic constituents and optionally a preservative and optionally
a buffer; wherein the suppository is adapted to be inserted into a
bodily orifice of a human or animal so as to allow the vaccine
and/or vaccine adjuvant to come in contact with the mucosal tissue
of the bodily orifice to facilitate transfer of the suppository
material therethrough.
[0030] The suppository comprises a vaccine and/or vaccine
adjuvant(s) comprising fractionated or whole cell or purified
cellular constituents whether native, mutated, synthetic, cloned or
recombinantly-expressed pathogenic microbial or viral protein
lipids or nucleic acid constituents that are capable of stimulating
humoral- or cellular-mediated immune responses against which the
pathogens or constituents correspond.
[0031] The suppository comprises a vaccine and/or vaccine
adjuvant(s) that is prepared by either purifying native pathogen
constituents, by synthesis or recombinant expression of protein or
genetic components of native pathogens or by purifying synthetic,
mutated or cloned pathogen-derived nucleic acid sequences.
[0032] The suppository of the present invention comprises any
suitable suppository base known in the art. More particularly, the
suppository base comprises material that is solid or semi-solid at
or below room temperature but liquefies or becomes water-miscible
at body temperature. The suppository base includes but is not
limited to polyethylene glycol, triglycerides, fatty acids, fatty
alcohols, glycerin and the like. Preferably the suppository base is
polyethylene glycol. The suppository base optionally includes
emulsifying agents such as polysorbate, gelatin, methylcellulose,
alginic acid, sodium lauryl sulfate, and the like.
[0033] The suppository base is present in the delivery system in
any suitable amount so as to allow the incorporation of the vaccine
or vaccine adjuvant(s) in a solid or semi-solid form so that the
structural integrity is maintained or that insertion into a body
orifice can be easily performed. When inserted, the suppository
base liquefies or becomes water-miscible at body temperature so as
to allow the vaccine and/or vaccine adjuvant components to become
in contact with the mucous membrane for a sufficient period of time
to enhance the immune response. The weight percent of the
suppository base is dependent upon the size of the bodily orifice
of the human and/or the animal, the dosage of vaccine and/or
vaccine adjuvant(s) necessary to elicit an immune response and its
physiochemical characteristics that allow it to remain solid at or
below room temperature. The suppository comprises from about 50% to
greater than 99%, preferably about 75% to greater than 99% by
weight of the suppository base. Preferably the suppository
comprises about 75% to about 98% by weight polyethylene glycol.
Preferably the suppository comprises about 2% to about 25% by
weight polysorbate. The suppository base has a molecular weight in
the range of about 400 to about 5000, preferably about 950 to about
3700. In a more preferred embodiment, the polyethylene glycol
suppository base is comprised of about 39% by weight of
polyethylene glycol having a molecular weight of about (3000) and
about 59% by weight of polyethylene glycol having a molecular
weight of about 400. A suitable commercially available polyethylene
glycol suppository base is POLYBASE, available from Paddock
Laboratories, Inc.
[0034] The suppository base optionally includes either or both of a
preservative(s) and a buffer(s). The preservative is selected from
the group consisting of thimersal, benzoic acid, benzoic acid
derivatives, benzylkonium, benzylkonium chloride sulfites,
quaternary ammonium salts, chlorobutanol and combinations thereof
at concentrations ranging from about 0.01% to about 0.5%. The
buffers are employed so that the pH of the suppository vaccine
remains the same. The buffers used are those known in the art and
include, but are not limited to citrate, phosphate, hepes (or their
salts) and combinations thereof at a concentration in the range of
about 5 milimolar to about 0.5 molar.
[0035] The suppository base confers a degree of miscibleness with
the mucous membrane surfaces of the vagina or rectum, wherein
suspended particles of the vaccine and/or vaccine adjuvant(s) are
in contact with such mucous membrane surfaces for a sufficient
amount of time to elicit a humoral- or cell-mediated immune
response. The suppository base has an adjuvant effect that enhances
the immune response by allowing the vaccine to facilitate contact
time with the vaginal or anorectal tract mucous membranes, serving
as a depot that slowly releases antigen, and by localizing and
delivering antigens to immunocompetent cells. The suppository base
possesses properties that allow the suppository to be molded in a
desirable form and further function as a structural necessity that
keeps the suppository in its desired molded form at or below room
temperature.
[0036] The suppository is allowed to harden in a suppository shell
or a mold that forms the desired shape. The suppository is
generally stored in the shell until used or is removed from the
mold and repackaged. The suppository shell or mold is any shell or
mold known in the art suitable for molding or packaging of the
suppository. A suitable commercially available laminate suppository
shell is a polyvinylchloride polyethylene laminate suppository
shell available from Paddock Laboratories, Inc.
[0037] The suppository based vaccine delivery system of the present
invention is prepared by general techniques known in the art.
Typically, the suppository base vaccine delivery system is prepared
under a sterile environment. The suppository base is heated in a
sterile environment to a temperature in the range of its melting
point to liquefy the base. The suppository base is heated for a
time sufficient to liquefy it without degrading it.
[0038] The vaccine or vaccine adjuvant(s) comprising the whole or
fractionated viral or other microbial pathogen, or their purified
cellular constituents or derivatives, whether native, mutated,
synthetic, cloned or recombinantly expressed, that consist of
nucleic acids, proteins, lipids or other antigenic determinants
capable of producing humoral or cullular-mediated immunity is
placed in a container containing the liquified suppository base.
The vaccine and/or vaccine adjuvant(s) are stirred with the liquid
suppository base until a homogeneous suspension is produced. A
preservative or adjuvant is added and stirred until a homogeneous
suspension is again attained. The suspension comprising the
suppository base and the vaccine and/or vaccine adjuvant(s) and
preservative is placed into individual laminate suppository shells.
The suppository is then cooled at room temperature to allow it to
harden. The suppositories are then heat-sealed and stored at
refrigerated temperature.
[0039] The suppository based vaccine delivery system according to
the present invention when inserted into a bodily orifice and
allowed to liquify or become water-miscible allows the vaccine to
be in contact with the vaginal or rectal tract mucous membrane for
a sufficient period of time to enhance the immune response.
Further, the suppository based vaccine delivery system according to
the present invention allows the incorporation of vaccine, vaccine
adjuvant(s) and preservative and is easily administered, does not
require the patient to lie in a supine position for an extended
period of time after receiving the vaccination, is suitably
administered by the patient, is painless, is amenable to routine
booster vaccinations and allows a favorable method of antigen
delivery to immunocompetent cells through the mucosa.
[0040] The present invention is further exemplified in the
following example. The example illustrates the effectiveness of the
suppository based vaccine delivery system of the present invention.
It is understood that the example is only illustrative of preferred
embodiments according to the present invention wherein the claims
set forth the scope of the present invention.
Example
[0041] In this example, the HSV-2 gD2 and its complementary DNA are
used as representative vaccine candidates for mucosal immunization.
This protein is specific to the herpes simplex-2 (HSV-2) virus and
represents a major outer membrane constituent of the virus that is
implicated in the host-attachment phenomena. Others have
demonstrated that this protein is a candidate vaccine to prevent
transmission or recurrence of HSV-2. This is based on its
antigenicity and, that following parenteral vaccination, it elicits
satisfactory immune response based on protection against HSV-2
challenge in animal models. The DNA of HSV-2 gD2 is the cloned
complementary DNA encoding this protein. Its use as a DNA vaccine
is intended to stimulate the production of cellular-mediated immune
response. Both the protein and cDNA is manufactured by Protein
Express, Inc., Cincinnati, Ohio.
[0042] POLYBASE, a polyethylene glycol polysorbate suppository base
manufactured by and available from Paddock Laboratories, Inc., in
an amount sufficient to manufacture 50 two-gram suppositories, was
heated in a sterile flask atop a magnetic stirrer/heater to a
temperature of about 60.degree. C. for about one hour to liquefy
the suppository base. Recombinant HSV gD2 protein and/or its
complementary DNA, 500 micrograms each (enough to manufacture about
50 suppositories) was aseptically placed in the liquefied
suppository base suppository. A sterile magnetic stir bar was
placed in the flask, and the vaccine and suppository base were
stirred for about 10 minutes at about 60.degree. C. in a
temperature-controlled water bath to form a homogeneous suspension.
Thimersal, as a preservative, was added to a final concentration of
about 0.1% and stirred until a homogeneous suspension was achieved.
The suspension comprised of the suppository base, the vaccine and
the preservative was then placed into individual polyvinyl
chloride-polyethylene laminate suppository shell using a sterile
pipette. Approximately 2.0 ml of the suspension was placed into
each shell.
[0043] The suppository base was cooled at a temperature of about
24.degree. C. for about 30 minutes to harden the suppository base.
The top of each shell was heat-sealed and the suppositories were
then stored at about 4.degree. C. When used, the suppositories are
removed from the shell and inserted vaginally or rectally.
[0044] While various embodiments of a suppository based vaccine
delivery system for treating or prophylaxes against urogenitally
and/or anorectally transmitted or localized infectious diseases and
a method for treating or prophylaxes against urogenitally and/or
anorectally transmitted infections in humans and animals have been
disclosed, it should be understood that modifications and
adaptations thereof will occur to persons skilled in the art. Other
features and aspects of this invention will be appreciated by those
skilled in the art upon reading and comprehending this disclosure.
Such features, aspects, and variations and modifications of the
reported results and examples are clearly within the scope of the
invention where the invention is limited solely by the scope of the
following claims.
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