U.S. patent application number 13/254715 was filed with the patent office on 2012-03-08 for treatment of infection.
Invention is credited to Jenny Colleen McCloskey.
Application Number | 20120058149 13/254715 |
Document ID | / |
Family ID | 42709152 |
Filed Date | 2012-03-08 |
United States Patent
Application |
20120058149 |
Kind Code |
A1 |
McCloskey; Jenny Colleen |
March 8, 2012 |
TREATMENT OF INFECTION
Abstract
The invention relates to compositions including a substance
useful as an adjuvant for potentiating an immune response, and
methods of using the composition in individuals with infections of
tissue within or adjacent to a transformation zone, such as the
transformation zone of the cervix or anal canal.
Inventors: |
McCloskey; Jenny Colleen;
(Western Australia, AU) |
Family ID: |
42709152 |
Appl. No.: |
13/254715 |
Filed: |
March 5, 2010 |
PCT Filed: |
March 5, 2010 |
PCT NO: |
PCT/AU2010/000255 |
371 Date: |
November 21, 2011 |
Current U.S.
Class: |
424/283.1 ;
604/514 |
Current CPC
Class: |
A61K 31/661 20130101;
A61K 2039/55572 20130101; A61P 31/20 20180101; A61P 37/04 20180101;
A61M 31/00 20130101; C12N 7/00 20130101; A61K 9/0014 20130101; A61K
2039/55505 20130101; A61K 45/06 20130101; A61K 39/12 20130101; A61K
9/0031 20130101; A61M 2210/14 20130101; C12N 2710/00034 20130101;
A61K 31/683 20130101; A61P 31/12 20180101; A61K 39/39 20130101;
A61K 33/08 20130101; A61K 9/0034 20130101; A61K 2039/54 20130101;
A61P 31/00 20180101; C12N 2710/20034 20130101; A61K 31/683
20130101; A61K 2300/00 20130101; A61K 33/08 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
424/283.1 ;
604/514 |
International
Class: |
A61K 33/08 20060101
A61K033/08; A61M 31/00 20060101 A61M031/00; A61P 31/20 20060101
A61P031/20; A61P 37/04 20060101 A61P037/04; A61P 31/00 20060101
A61P031/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 5, 2009 |
AU |
2009900969 |
Claims
1. A therapeutic or pharmaceutical composition including a
substance useful as an adjuvant for potentiating an immune
response, the substance being comprised of a combination of a
therapeutically effective amount of aluminium hydroxide and
3-deacylated monophospholipid A (MPL); and a pharmaceutically
acceptable diluent or carrier the composition being characterised
in that the composition does not include an immunogen for invoking
an immune response.
2. The therapeutic or pharmaceutical composition of claim 1,
wherein the therapeutically effective amount of aluminium hydroxide
is between 0.1 to 1 mg per unit dosage, and the therapeutically
effective amount of MPL is between 1 to 100 .mu.g.
3. (canceled)
4. The therapeutic or pharmaceutical composition of claim 1,
formulated for topical administration.
5. The therapeutic or pharmaceutical composition of claim 1 further
comprising one or more of the following: sodium chloride,
L-histidine, sodium borate, lactic acid, sodium phosphate
monobasic, sorbitan monostearate, polysorbate 60, cetyl esters wax,
benzyl alcohol, glycerol, cetostearyl alcohol, isopropyl myristate,
propylene glycol, purified water, chlorohexidine hydrochloride
octyldodecanol, sodium hydroxide, stearic acid and paraffin
liquid.
6. The therapeutic or pharmaceutical composition of claim 1,
further comprising sodium chloride and sodium phosphate monobasic,
and one or more of L-histidine, sodium borate, lactic acid,
sorbitan monostearate, polysorbate 60, cetyl esters wax, benzyl
alcohol, glycerol, cetostearyl alcohol, isopropyl myristate,
propylene glycol, purified water, chlorohexidine hydrochloride and
paraffin liquid.
7. The therapeutic or pharmaceutical composition of claim 1 further
comprising sodium chloride, L-histidine, Polysorbate 60 and sodium
borate, and one or more of lactic acid, sodium phosphate monobasic,
sorbitan monostearate, cetyl esters wax, benzyl alcohol, glycerol,
cetostearyl alcohol, isopropyl myristate, propylene glycol,
purified water, chlorohexidine hydrochloride octyldodecanol, sodium
hydroxide, stearic acid and paraffin liquid.
8. (canceled)
9. A method for treating an infection in an individual including
the steps of selecting an individual having an infection of tissue
within or adjacent to a transformation zone; and contacting the
tissue with a therapeutically effective amount of a composition
including a substance useful as an adjuvant for potentiating an
immune response and which is a combination of aluminium hydroxide
and 3-deacylated monophospholipid A.
10. The method of claim 9 wherein the infection is a HPV
infection.
11. A method of minimising the incidence of a complication of a
cervical or anal HPV infection in an individual including the step
of selecting an individual having a cervical or anal HPV infection
and contacting infected tissue in or adjacent to a transformation
zone in the individual with a therapeutically effected amount of a
composition including a substance useful as an adjuvant for
potentiating an immune response and which is a combination of
aluminium hydroxide and 3-deacylated monophospholipid A.
12. The method of claim 9, wherein the individual having an
infection of tissue is selected on the basis of cellular changes in
a sample from the transformation zone of the individual, physical
examination or by detection of nucleic acid of an agent causing the
infection.
13. The method of claim 9, wherein the transformation zone is the
cervical or the anal transformation zone.
14. (canceled)
15. A method for treating an individual having a cervical or anal
HPV infection including the step of contacting infected tissue
within or adjacent to the cervical or anal transformation zone in
the individual with a therapeutically effective amount of a
composition including a substance useful as an adjuvant for
potentiating an immune response and which is a combination of
aluminium hydroxide and 3-deacylated monophospholipid A.
16. The method of claim 15, wherein the individual has a
co-infection of viral, bacterial, fungal or protozoan origin.
17. The method of claim 9, wherein the transformation zone is
abraded or ruptured prior to contacting the infected tissue within
or adjacent to the transformation zone.
18. The method of claim 9, wherein the composition is brought into
contact with the infected tissue by means of an apparatus, the
apparatus comprising a stem means adapted for insertion along an
orifice or canal to access the transformation zone; means carried
by the stem means for occluding a distal restriction; and means to
deliver an effective amount of the composition to the infected
tissue.
19. The method of claim 9, wherein the composition is brought into
contact with the surface of the infected tissue by direct
application to the surface or injection of the composition into
cells at the surface of the infected tissue.
20. (canceled)
21. (canceled)
22. The method of claim 11, wherein the transformation zone is
abraded or ruptured prior to contacting the infected tissue within
or adjacent to the transformation zone.
23. The method of claim 15, wherein the transformation zone is
abraded or ruptured prior to contacting the infected tissue within
or adjacent to the transformation zone.
24. The method of claim 11, wherein the composition is brought into
contact with the infected tissue by means of an apparatus, the
apparatus comprising a stem means adapted for insertion along an
orifice or canal to access the transformation zone; means carried
by the stem means for occluding a distal restriction; and means to
deliver an effective amount of the composition to the infected
tissue.
25. The method of claim 15, wherein the composition is brought into
contact with the infected tissue by means of an apparatus, the
apparatus comprising a stem means adapted for insertion along an
orifice or canal to access the transformation zone; means carried
by the stem means for occluding a distal restriction; and means to
deliver an effective amount of the composition to the infected
tissue.
26. The method of claim 11, wherein the composition is brought into
contact with the surface of the infected tissue by direct
application to the surface or injection of the composition into
cells at the surface of the infected tissue.
27. The method of claim 15, wherein the composition is brought into
contact with the surface of the infected tissue by direct
application to the surface or injection of the composition into
cells at the surface of the infected tissue.
Description
FIELD OF THE INVENTION
[0001] The invention relates generally to infections of tissue
within or adjacent to a transformation zone, such as the
transformation zones of the cervix and anus, especially infections
by human papillomavirus (HPV). The invention also relates to
adjuvants that have been used in vaccines against HPV including,
but not limited to, AS04.
BACKGROUND OF THE INVENTION
[0002] Reference to any prior art in the specification is not, and
should not be taken as, an acknowledgment or any form of suggestion
that this prior art forms part of the common general knowledge in
Australia or any other jurisdiction or that this prior art could
reasonably be expected to be ascertained, understood and regarded
as relevant by a person skilled in the art.
[0003] The cervix is the lower, narrower portion of the uterus
where it joins with the top end of the vagina. The exposed portion
of the cervix that projects into the vagina is called the exocervix
or ectocervix. The opening of the ectocervix is called the external
os. Between the uterine cavity and the external os is a passageway
known as the endocervical canal or the endocervix.
[0004] Generally two types of epithelium occur along the cervix.
The position or location of these types may change due to cervical
remodelling that occurs, for example, during puberty, menopause,
pregnancy and child birth and the normal menstrual cycle.
[0005] In general, the ectocervix is covered by stratified squamous
epithelium, whereas the endocervix is covered by simple columnar
epithelium. The "squamocolumnar junction" is a region where the
squamous epithelium is juxtaposed with the columnar epithelium.
During times of cervical remodelling, the columnar epithelium of
the endocervix may extend into the harsh acidic environment of the
vagina and undergo metaplasia to hardier squamous epithelium. In
turn, when the squamous epithelium regresses into the endocervical
canal, the squamous epithelium is replaced by simple columnar
epithelium. The area between the original squamocolumnar junction
and the new squamocolumnar junction is termed the "transformation
zone" (Rubin and Farber "Pathology". J.B. Lippincott Company 1988.
Page 956). In teenage girls, the transformation zone is on the
immature cervix's outer surface and is more susceptible to
infection than in adult women. In older women, the transformation
zone may be higher in the cervical canal.
[0006] Ectocervical epithelium consists of 4 layers: basal cells on
the basal membrane; parabasal cells between the basal cell layer
and the mature cell layers; a layer of intermediate, polygonal and
mature cells; and superficial cells. A layer of exfoliating cells
may also be seen in histological sections. Underneath the basal
membrane is the connective tissue. The endocervical epithelium in
contrast is a layer of columnar epithelium composed of mucin
secreting cells on top of the connective tissue. The endocervical
canal may contain crypt or crypt-like structures.
[0007] The transformation zone is itself particularly vulnerable to
the effects of infections, the most well known one being infection
with human papillomavirus (HPV). It has been estimated that 325
million women have either subclinical HPV or HPV-related clinical
lesions. The presence of persistent HPV infection is thought to be
a prerequisite for the development and maintenance of second and
third stage cervical intraepithelial neoplasia (CIN II-III), i.e.
severe or precancerous dysplasia. Cervical intraepithelial
neoplasia (CIN) can be either squamous or glandular in origin, but
squamous intraepithelial neoplasia (IN) is more common. CIN I
represents mild IN and the cell abnormalities are confined to the
basal 1/3 of the epithelium. CIN II is moderate IN confined to the
basal 2/3 of the epithelium and CIN III is severe IN that spans
more than 2/3 of the epithelium, possibly the full thickness.
[0008] Of the genital types affecting humans, the high-risk types
such as HPV 16, HPV 18, HPV 45 and HPV 31 are linked to the
development of low and high-grade dysplasia and cervical cancer.
Oncogenic strains of HPV have been found in 99.7% of cervical
cancers. They are also associated with vulval, anal and penile
carcinoma. Low risk types such as HPV 6 and HPV 11 are associated
with genital warts and low-grade IN.
[0009] Current treatment of severe uterine cervical IN is by
surgically removing the areas of the uterine cervix that may
possibly be involved. Treatment initially requires cytology,
colposcopy and biopsy, and then a surgical treatment such as laser
excision, loop excision or cold coagulation of the uterine cervix.
These more radical treatments however are associated with increased
risk of complications including cervical stenosis, constriction and
complete sealing of the os, pelvic endometriosis following
hematometra, painful and prolonged menstruation, excessive eversion
of columnar epithelium, infection, bleeding, pain, psychological
morbidity, infertility, and an incompetent cervix. And even after
treatment, disease may recur and even progress to invasive cancer.
Pre-term delivery is now also recognised as a complication.
[0010] In contrast, there is currently no reliable and effective
treatment available for women who have been diagnosed with an HPV
infection, usually during their routine Pap smears, but are
asymptomatic or only have low grade lesions. The routine practice
is to simply monitor the woman for signs of progression. This
approach however is unsatisfactory for at least two reasons:
1. Some women are distressed by having Pap smear abnormalities even
though they are not considered to be serious. In order to alleviate
their concerns, many women with low-grade lesions undergo
unnecessary treatment with the more radical methods reserved for
severe IN. 2. In the absence of treatment, it is more difficult to
ensure that the woman attends for further follow-up and monitoring
for possible progression to high-grade disease.
[0011] There is therefore a need for a treatment of early stage
infection before complications of infection occur. This treatment
needs to be less invasive and radical than those currently
available for the treatment of later stage disease.
[0012] In light of the vastness of the problem of HPV infection
world wide, research has focused on prevention. This focus has seen
the successful development of two vaccines--Cervarix.TM.,
manufactured by GlaxoSmithKline, and Gardasil.TM. by Merck &
Co. Cervarix.TM. is created using proteins of the HPV viral capsid,
which once administered, induces the formation of neutralizing
antibodies. In addition, Cervarix.TM. is formulated with AS04, a
proprietary adjuvant that has been reported to boost the immune
system response for a longer period of time by increasing the
humoral immune response and increasing the number of immune memory
B-cells (Vaccine 24, 14 Aug. 2006). AS04 is an adjuvant which is a
combination of standard aluminium hydroxide and 3'-deacylated
monophospholipid A (MPL--Corixa, Mo., USA), a derivative of the
lipid A molecule found in gram-negative bacteria and a potent
immune system stimulant.
[0013] Vaccines such as these however have two key limitations. The
first is that Cervarix.TM. and Gardasil.TM. are both preventative
vaccines, not therapeutic, and will therefore have no effect on
already established infections. The second limitation is that HPV
immunity is type-specific. So while these vaccines will block
infection with the most common cancer causing HPV strains,
vaccination with current vaccines will not completely block
infection from cervical cancer-causing HPV strains other than HPV
16, 18, and in the case of Cervarix.TM., HPV 31 and 45 as well.
[0014] An object of the invention therefore is to endeavour to
reduce the complications of HPV infection, the incidence of uterine
cervical dysplasia (all stages) and cervical cancers, and to avoid
more radical treatments by early treatment of infection.
[0015] It is understood that other tissues having transformation
zones may also be more vulnerable to infection and would benefit
from a treatment for early stage infection. The anus for example is
also particularly vulnerable to the effects of HPV infection at the
transformation zone where the stratified squamous cells of the anal
verge change over to the columnar epithelial cells of the rectum.
Current treatment for anal IN is either surgical removal or, in
many cases, observational if severe focal or multi quadrant
infection is present. It is observational in many cases where not
extensive. If the dysplasia is very severe and involves the whole
circumference of the anal canal, surgical treatment is to remove
the whole area and provide a colostomy. Because the operation is so
radical, and the duration of time to progress from anal dysplasia
to anal cancer is not known, an observational approach is usually
undertaken and the individual treated when cancer arises. This is
obviously an unsatisfactory approach for individuals with early
stage infection, who must simply sit back and wait to see if they
develop cancer or other complications of HPV infection.
[0016] Other tissues susceptible to metaplasia and having
transformation zones include the throat, where columnar epithelium
is replaced by squamous epithelium, the oesophagus, where squamous
epithelium is replaced by columnar epithelium, and the urinary
bladder, where transitional epithelium is replaced by squamous
epithelium.
[0017] It is also understood that infections of transformation
zones may be by micro-organisms other than HPV. Other infections
may include viral infection with herpes simplex virus (HSV),
bacterial infections with Chlamydia trachomatis, Haemophilus
ducreyi, Mycoplasma hominis, Mycoplasma genitalium, Streptococcus
Sp, Escherichia coli, Staphylococcus, and Neisseria gonorrhoeae,
fungal infections caused by an overgrowth of Candida albicans and
other Candida species, protozoan infections with Trichomonas
vaginalis.
[0018] In light of the different tissues that may require treatment
of infection of the transformation zone, and the different
micro-organisms that may be the infective agent, there is a need
for a treatment that has broad application.
SUMMARY OF THE INVENTION
[0019] The invention seeks to at least minimise one or more of the
above mentioned problems or limitations and in one embodiment
provides a method for treating an infection in an individual. The
method includes the steps of selecting an individual having an
infection of tissue within or adjacent to a transformation zone;
and contacting the tissue with a therapeutically effective amount
of a composition including a substance useful as an adjuvant for
potentiating an immune response, the substance being comprised of a
combination of aluminium hydroxide and 3'-deacylated
monophospholipid A, or aluminium hydroxide or 3'-deacylated
monophospholipid A.
[0020] In another embodiment there is provided a method for
treating an individual having a cervical HPV infection including
the step of contacting infected tissue within or adjacent to the
cervical transformation zone in the individual with a
therapeutically effective amount of a composition including a
substance useful as an adjuvant for potentiating an immune
response, the substance being comprised of a combination of
aluminium hydroxide and 3'-deacylated monophospholipid A.
[0021] In further embodiments there is provided a method of
minimising the incidence of a complication of a cervical HPV
infection in an individual including the step of selecting an
individual having a cervical HPV infection and contacting infected
tissue in or adjacent to a transformation zone in the individual
with a therapeutically effective amount of a composition including
a substance useful as an adjuvant for potentiating an immune
response, the substance being comprised of a combination of
aluminium hydroxide and 3'-deacylated monophospholipid A.
[0022] In other embodiments there is provided a therapeutic or
pharmaceutical composition including a substance useful as an
adjuvant for potentiating an immune response, the substance being
comprised of a combination of aluminium hydroxide and 3'-deacylated
monophospholipid A, the composition being characterised in that the
composition does not include an immunogen for invoking an immune
response.
[0023] In still further embodiments there is provided a kit or
device including a composition described above.
[0024] In yet further embodiments there is provided a use of a
composition as described above in the manufacture of means for
treating an infection in an individual.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0025] Reference will now be made in detail to certain embodiments
of the invention. While the invention will be described in
conjunction with the embodiments, it will be understood that the
intention is not to limit the invention to those embodiments. On
the contrary, the invention is intended to cover all alternatives,
modifications, and equivalents, which may be included within the
scope of the present invention as defined by the claims.
[0026] One skilled in the art will recognize many methods and
materials similar or equivalent to those described herein, which
could be used in the practice of the present invention. The present
invention is in no way limited to the methods and materials
described.
[0027] It will be understood that the invention disclosed and
defined in this specification extends to all alternative
combinations of two or more of the individual features mentioned or
evident from the text or drawings. All of these different
combinations constitute various alternative aspects of the
invention.
[0028] As used herein, except where the context requires otherwise,
the term "comprise" and variations of the term, such as
"comprising", "comprises" and "comprised", are not intended to
exclude further additives, components, integers or steps.
[0029] As discussed herein, AS04 (which is composed of an aluminium
salt and an immunostimulant, 3'-deacylated monophospholipid) and
related compositions have been used in vaccines as an adjuvant for
potentiating immune responses invoked by an immunogen contained in
the vaccine to protect against viral infections. In these
applications, the individual is normally one not having an
infection.
[0030] The inventor has surprisingly found a new use for AS04 and
related compositions in the form of a chemotherapy for the
treatment of viral infections. Specifically, the inventor has found
that a HPV infection can be cleared by administering AS04 and
related compositions to tissue defining a cervical transformation
zone.
[0031] Further, the inventor has found that an immunogen for
invoking an immune response is not required. The finding is
unanticipated as to date AS04 and related compositions have been
administered simultaneously with an immunogen whereby the AS04 has
potentiated an immune response raised against the immunogen,
thereby preventing infection. Simply put, at the time of the
invention, the therapeutic benefit of AS04 and like compositions
had not been understood in the absence of an immunogen.
[0032] While not wanting to be bound by hypothesis, it is believed
that when applied to tissue that is particularly vulnerable to
infection, such as a transformation zone, AS04 or like compositions
potentiate the response of local elements of the immune system to
non-self antigen, leading to reduction or clearance of microbial
load in infected individuals.
[0033] One advantage of the therapeutic composition is that the
therapeutic benefit is not restricted to a particular organism,
strain or serotype thereof, as for example is the case with a
vaccine.
[0034] Further in combination with screening techniques for early
detection of infection, with this invention it now becomes possible
to effectively prevent complication of infection, such as cervical
cancer.
[0035] Still further, in certain embodiments the therapeutic
formulation does not include antigen, thereby minimising
deleterious immune responses including auto-reactivity.
I. DEFINITIONS
[0036] AS04 is an adjuvant composed of an aluminium salt and an
immunostimulant, 3'-deacylated monophospholipid A (MPL), and the
names may be used interchangeably in the specification. The
aluminium salt may be aluminium phosphate or preferably aluminium
hydroxide. MPL is a purified, non-toxic endotoxin derivative of the
lipopolysaccharide from a heptoseless mutant of Salmonella
minnesota. The MPL can take the form of a mixture of related
molecules, varying by their acylation. For example, the MPL may
have 3, 4, 5 or 6 acyl chains, which may be of different
length.
[0037] The skilled person will appreciate that the conventional
terms "aluminium hydroxide" and MPL encompass variant molecules,
and these are intended to be within the scope of the invention.
[0038] It will be understood that the term "transformation zone"
refers to an area between an "original junction" defined by
juxtaposed epithelial cells (juxtaposed in the sense of cells on
one side having one form of histology and cells on the other side
having another form) and a "new junction" (Rubin and Farber
"Pathology". J.B. Lippincott Company 1988. Page 956). In one
example, the junction is defined by squamous epithelial cells that
are juxtaposed to columnar epithelial cells, as is seen in the
cervix. With respect to the cervix, the "original junction" may be
located on the exocervix, as in prenatal life or infancy. The "new
junction" may be in the endocervical canal as in adult life.
[0039] The phrase "tissue within or adjacent to a transformation
zone" refers to tissues, cells or extracellular matrix that is
located at a region flanking a transformation zone, usually within
a distance of no more than about 3 cm from a squamocolumnar
junction, (or where a junction is formed from other epithelial
cellular types, from within about 6 cm of that junction) and to
tissues, cells or extracellular materials located in the epithelial
layer, the basement membrane, lamina propria or underlying tissue
in the immediate vicinity below the transformation zone. The tissue
may include elements of the immune system such as lymphocytes,
granulocytes antigen presenting cells and lymph nodes.
[0040] The phrase "contacting the tissue with a therapeutically
effective amount of a composition including a substance useful as
an adjuvant for potentiating an immune response" refers to a
specific mode of administration whereby the composition is directly
or locally applied or administered to tissue in or adjacent the
relevant transformation zone. Such direct or local application or
administration is to be distinguished from systemic administration
of vaccine (such as Gardasil and Cervarix) as these vaccines have
been generally used for preventing HPV infection.
[0041] A "therapeutic composition" or "pharmaceutical composition"
or "composition for treating HPV infection" refers to a composition
including a substance useful as an adjuvant for potentiating an
immune response and which is a combination of aluminium hydroxide
and 3'-deacylated monophospholipid A (the latter being a derivative
of lipid A molecule found in gram negative bacteria). AS04 is one
example.
[0042] The words "treat" or "treatment" refer to therapeutic
treatment wherein the object is to slow down (lessen) an undesired
physiological change or disorder. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, alleviation of symptoms, diminishment of extent of disease,
stabilized (i.e., not worsening) state of disease, delay or slowing
of disease progression, amelioration or palliation of the disease
state, and remission (whether partial or total), whether detectable
or undetectable. "Treatment" can also mean prolonging survival as
compared to expected survival if not receiving treatment. Treatment
may not necessarily result in the complete clearance of an
infection but may reduce or minimise complications and side effects
of infection and the progression of infection. The success or
otherwise of treatment may be monitored by physical examination of
the individual, cytopathological, DNA, or mRNA detection
techniques.
[0043] The words "prevent" and "prevention" refer to prophylactic
or preventative measures for protecting or precluding an individual
not having a given infection related complication from progressing
to that complication. Individuals in which prevention is required
include those who have an infection.
[0044] The phrase "therapeutically effective amount" means an
amount of a compound of the present invention that (i) treats the
particular disease, condition, or disorder, (ii) attenuates,
ameliorates, or eliminates one or more symptoms of the particular
disease, condition, or disorder, or (iii) delays the onset of one
or more symptoms of the particular disease, condition, or disorder
described herein.
[0045] The term "package insert" is used to refer to instructions
customarily included in commercial packages of therapeutic
products, that contain information about the indications, usage,
dosage, administration, contraindications and/or warnings
concerning the use of such therapeutic products.
[0046] The phrase "pharmaceutically acceptable" indicates that the
substance or composition must be compatible chemically and/or
toxicologically, with the other ingredients comprising a
formulation, and/or the mammal being treated therewith.
II. METHODS OF TREATMENT
[0047] In one embodiment there is provided a method for treating an
infection in an individual.
[0048] The method includes the steps of selecting an individual
having an infection of tissue within or adjacent to a
transformation zone; and contacting the tissue with a
therapeutically effective amount of a composition including a
substance useful as an adjuvant for potentiating an immune
response, the substance being comprised of a combination of an
aluminium salt and 3-deacylated monophospholipid A. Preferably the
aluminium salt is aluminium hydroxide (AH).
[0049] According to the method, the individuals to be treated are
generally people having an infected tissue that defines a
transformation zone. The individual may have other infected
tissues, in the same organ or tissue containing the transformation
zone or otherwise. The individual may be asymptomatic for the
infection or present with sub clinical symptoms of infection.
[0050] Infection of tissue located in or adjacent to a
transformation zone may be diagnosed by routine cytopathological
techniques. Where the cervix is concerned, one example is pap smear
where a sample of cells from the transformation zone of the cervix
is taken, and the cells are reviewed for the presence of
characteristic cellular changes. An HPV infection may also be
diagnosed by detection of HPV DNA. This test may be done on its own
or as a complement to a pap smear, particularly when pap smear
results are inconclusive. The Hybrid Capture.TM. 2 High-Risk HPV
DNA Test.TM. by Digene.TM. for example if an in vitro nucleic acid
hybridisation assay for the qualitative detection of HPV 16, 18,
31, 33, 35, 45, 51, 52, 56, 58, 59 and 68 in cervical cell
specimens or biopsy samples. To date, HPV cannot be readily
cultured in vitro, and immunological tests are inadequate to
determine the presence of HPV cervical infection.
[0051] Generally where the cervix is concerned, the individual has
a microbial load according to the Digene Hybrid Capture 2 of at
least 0.8 RLU.
[0052] In relation to anal HPV infection, diagnosis may be done by
physical examination and by the presence of characteristic cellular
changes associated with viral replication in biopsy specimens.
[0053] The infection may be present in the transformation zone of
the cervix or the anus, or for female individuals, both.
[0054] The individual in need of treatment may have one or more
infections including opportunistic infections of viral, bacterial,
fungal and protozoan origin. For example, Chlamydia trachomatis is
frequently associated with benign proliferative, pre-neoplastic and
malignant changes in cervical epithelium, and may therefore be
present as a co-infection with HPV. Herpes simplex virus (HSV) is
also a common co-infection with HPV due to their similar means of
transmission. It is envisaged that the method of the invention will
be useful in treating both infections due to the non-organism
specific nature of the adjuvant. However other therapeutics may be
co-administered.
[0055] Immunosuppressed individuals such as those receiving
transplant therapy or those having HIV infection are contemplated
as individuals to whom the methods of the invention may be
applied.
[0056] The therapeutic or pharmaceutical composition for use in
these methods of treatment are described further below. In one
embodiment, the composition for use in these methods may contain
aluminium hydroxide and 3'-deacylated monophospholipid A as the
only active ingredients in which case the composition may not
include an immunogen for invoking an immune response against an
antigen that is associated with the disease or condition that is to
be treated by the composition. When the infected tissue is in the
cervix, the composition of the invention is preferably contacted
with the infected tissue of the endocervical canal of the
cervix.
[0057] In an alternative embodiment the composition may further
include a polypeptide provided in the form of an immunogen,
especially a polypeptide that defines, or is contained, or is
comprised in a microbial antigen such as a viral antigen, bacterial
antigen, fungal antigen or protozoan antigen. Examples of suitable
therapeutic compositions according to these embodiments include
Cevarix and Gardasil containing HPV antigens. In one embodiment,
the composition may also be formulated with an antigen derived from
HPV, provided that the antigen is not derived from HPV subtypes 6,
11, 16, 18, 45 and 31.
[0058] According to the invention, the tissue in or adjacent to the
transformation zone is contacted with the therapeutic or
pharmaceutical composition so that at least some, if not all of the
various elements of the zone are brought into contact with, or
exposed to the composition. In certain embodiments, elements of the
immune system, such as one or more of lymphocytes, granulocytes
and/or antigen presenting cells (APCs) that are localised about the
zone are brought into contact with the composition.
[0059] In other embodiments the therapeutic or pharmaceutical
composition is applied to the endocervical canal and/or the
transformation zone.
[0060] The composition may be applied to the apical surface of the
epithelial cells in conditions where the substance may infuse cell
junctures. Alternatively, the visceral surface of the
transformation zone may be slightly abraded or ruptured resulting
in the removal of some or all of the epithelial cells, basement
membrane and lamina propria. It is also envisaged that the
composition may be directly injected into the tissue of the
transformation zone.
[0061] It will be clear that the intention is for treatment of
infected cells within and adjacent to the transformation zone, and
that in certain embodiments the methods of the invention include a
step of selecting an individual having an infection of tissue
within or adjacent to a transformation zone.
[0062] The step of contacting the tissue with a therapeutically
effective amount of the composition may be achieved in a number of
ways. In a preferred embodiment, the adjuvant is applied using the
apparatus described in WO2003/026681 (McCloskey), the contents of
which are herein incorporated in their entirety by reference. The
apparatus for treatment of early human papillomavirus infection of
an orifice of a human or animal body including any canal associated
with the orifice, comprises a stem means adapted for insertion
along the orifice or canal; means carried by the stem means for
occluding a distal restriction whereby to define a treatment cavity
in the orifice and/or canal; and means to deliver an effective
amount of an agent for inactivation of papillomavirus to said
treatment cavity for application to the surfaces of the orifice
and/or canal bounding said cavity.
[0063] The method of treatment described herein may conveniently be
implemented as a post surgical procedure.
[0064] The adjuvant is to be used in a therapeutically effective
amount. The therapeutically effect amount in certain embodiments is
about 0.1 to 1 mg of Al (OH).sub.3 or any amount within that range
including 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55,
0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95 and 1 mg and 1 to 100
.mu.g of MPL, or any amount within that range including 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,
40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,
57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,
74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,
91, 92, 93, 94, 95, 96, 97, 98, 99 and 100 .mu.g. Where Cevarix is
used the dose may be about 0.5 mL.
[0065] Generally the therapeutic composition is administered twice
daily, daily, once weekly or monthly until the infection has been
cleared.
[0066] Progress of treatment may be monitored using the same
techniques as diagnosis. That is, cytological examination of cells
from the transformation zone and/or detection of viral DNA in the
cells obtained by pap smear or biopsy, or in secretions from
infected tissue. Treatment may also be resumed in the event of
re-infection occurring.
[0067] In another embodiment there is provided a method for
treating an individual having a cervical HPV infection including
the step of contacting infected tissue within or adjacent to the
cervical transformation zone in the individual with a
therapeutically effective amount of a composition including a
substance useful as an adjuvant for potentiating an immune
response, the substance being comprised of a combination of
aluminium hydroxide and 3'-deacylated monophospholipid A.
[0068] In further embodiments there is provided a method of
minimising the incidence of a complication of a cervical HPV
infection in an individual including the step of selecting an
individual having a cervical HPV infection and contacting infected
tissue in or adjacent to a transformation zone in the individual
with a therapeutically effected amount of a composition including a
substance useful as an adjuvant for potentiating an immune
response, the substance being comprised of a combination of
aluminium hydroxide and 3'-deacylated monophospholipid A. The
aluminium hydroxide and 3'-deacylated monophospholipid A may
constitute the only active ingredients in the composition.
Alternatively, additional active ingredients may be included,
including immunogens such as viral antigens.
[0069] When the infected tissue is in the cervix, the composition
of the invention is preferably applied to the endocervical canal of
the cervix.
III. COMPOSITIONS AND FORMULATIONS
[0070] As described herein, the invention relates to a therapeutic
or pharmaceutical composition including a substance useful as an
adjuvant for potentiating an immune response, the substance being
comprised of a combination of aluminium hydroxide and 3'-deacylated
monophospholipid A. Typically, the composition is characterised in
that the composition does not include an immunogen for invoking an
immune response against the aetiological agent of the disease or
condition to be treated.
[0071] The composition may further comprises a pharmaceutically
acceptable diluent, carrier, excipient or like compound. Acceptable
diluents, carriers, excipients, and stabilizers are nontoxic to
recipients at the dosages and concentrations employed, and include
buffers such as phosphate, citrate, and other organic acids;
antioxidants including ascorbic acid and methionine; preservatives
(such as octadecyldimethylbenzyl ammonium chloride; hexamethonium
chloride; benzalkonium chloride, benzethonium chloride; phenol,
butyl or benzyl alcohol; alkyl parabens such as methyl or propyl
paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and
m-cresol); low molecular weight (less than about 10 residues)
polypeptides; proteins, such as plasma albumin, gelatin, or
immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;
amino acids such as glycine, glutamine, asparagine, histidine,
arginine, or lysine; monosaccharides, disaccharides, and other
carbohydrates including glucose, mannose, or dextrins; chelating
agents such as EDTA; sugars such as sucrose, mannitol, trehalose or
sorbitol; salt-forming counter-ions such as sodium; metal complexes
(e.g. Zn-protein complexes); and/or non-ionic surfactants such as
TWEEN.TM., PLURONICS.TM. or polyethylene glycol (PEG).
[0072] The composition may also be entrapped in microcapsules
prepared, for example, by coacervation techniques or by interfacial
polymerization, for example, hydroxymethylcellulose or
gelatin-microcapsules and poly-(methylmethacylate) microcapsules,
respectively, in colloidal drug delivery systems (for example,
liposomes, albumin microspheres, microemulsions, nano-particles and
nanocapsules) or in macroemulsions. Such techniques are disclosed
in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed.
(1980).
[0073] Sustained-release preparations may be prepared. Suitable,
examples of sustained-release preparations include semipermeable
matrices of solid hydrophobic polymers containing the N-acylated
dipeptide proline boronate compound, which matrices are in the form
of shaped articles, e.g. films, or microcapsules. Examples of
sustained-release matrices include polyesters, hydrogels (for
example, poly(2-hydroxyethyl-methacrylate), or polyCvinylalcohol)),
polylactides, copolymers of L-glutamic acid and
gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,
degradable lactic acid-glycolic acid copolymers such as the LUPRON
DEPOT.TM. (injectable microspheres composed of lactic acid-glycolic
acid copolymer and leuprolide acetate), and
poly-D-(-)-3-hydroxybutyric acid.
[0074] Compositions prepared for various routes and types of
administration may be in suitable or useful form for application to
the transformation zone in certain embodiments of the invention.
The substance useful as an adjuvant for potentiating an immune
response being comprised of a combination of aluminium hydroxide
and 3'-deacylated monophospholipid A and having the desired degree
of purity is optionally mixed with pharmaceutically acceptable
diluents, carriers, excipients or stabilizers (Remington's
Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.), in the
form of a lyophilized formulation, milled powder, or an aqueous
solution. In general the formulations are prepared by uniformly and
intimately bringing into association the active ingredient with
liquid carriers or finely divided solid carriers or both, and if
necessary, shaping the product. Formulation may be conducted by
mixing at ambient temperature at the appropriate pH, and at the
desired degree of purity, with physiologically acceptable carriers,
i.e., carriers that are non-toxic to recipients at the dosages and
concentrations employed. The pH of the formulation depends mainly
on the particular use and the concentration of compound, but may
range from about 3 to about 8. Formulation in an acetate buffer at
pH 5 is a suitable embodiment. The inhibitory compound for use
herein is preferably sterile. The compound ordinarily will be
stored as a solid composition, although lyophilized formulations or
aqueous solutions are acceptable. Thus in certain embodiments there
is provided a use of a composition as described above in the
manufacture of a composition for treating an infection in an
individual.
[0075] The composition may be packaged in a variety of ways
depending upon the method used for administering the drug.
Generally, a kit or article for distribution includes a container
having deposited therein the pharmaceutical formulation in an
appropriate form. Suitable containers are well-known to those
skilled in the art and include materials such as bottles (plastic
and glass), sachets, ampoules, plastic bags, metal cylinders, and
the like. The container may also include a tamper-proof assemblage
to prevent indiscreet access to the contents of the package. In
addition, the container has deposited thereon a label that
describes the contents of the container. The label may also include
appropriate warnings.
[0076] In certain embodiments, the therapeutic composition consists
essentially of a substance useful as an adjuvant for potentiating
an immune response and which is a combination of aluminium
hydroxide and 3'-deacylated monophospholipid A. By "consists
essentially of" it is meant that the composition does not include
any other active ingredient or principal. In these embodiments, the
therapeutic composition may contain diluents, excipients, fillers
and the like as described above.
[0077] In other embodiments, the therapeutic composition does not
contain a molecule provided in the form of an immunogen. Thus for
example, in these embodiments, the therapeutic composition does not
contain a polypeptide forming an antigen on a microorganism such as
a virus or bacteria.
[0078] In other embodiments, the therapeutic composition further
includes a further active pharmaceutical or principle. These may be
incorporated into the therapeutic composition, depending on the
anticipated route of administration and the stage of the infection
or related complications. In the case of co-infections, the
therapeutic composition may include one or more anti-viral,
anti-bacterial, anti-fungal and anti-protozoan agents. As well as
treating the infection in the transformation zone itself, treatment
of side effects from infection may be undertaken. For example, the
therapeutic composition may further include an anti-inflammatory to
treat inflammation as the site of infection. In the event that
there is mild irritation or discomfort associated with the lesions
associated with the HPV infection, or the procedure by which the
therapeutic composition is to be applied, the composition may
further include an analgesic.
[0079] The pharmaceutical composition may be in the form of a
sterile injectable preparation, such as a sterile injectable
aqueous or oleaginous suspension. This suspension may be formulated
according to the known art using those suitable dispersing or
wetting agents and suspending agents which have been mentioned
above. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, such as a solution in
1,3-butane-diol or prepared as a lyophilized powder. Among the
acceptable vehicles and solvents that may be employed are water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile fixed oils may conventionally be employed as a
solvent or suspending medium. For this purpose any bland fixed oil
may be employed including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid may likewise be used in
the preparation of injectables.
[0080] The amount of active ingredient that may be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans may contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which may vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion may contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0081] The composition of the invention may be formulated as an
ointment, cream, gel or lotion. Ointments and creams may, for
example, be formulated with an aqueous or oily base with the
addition of suitable thickening and/or gelling agents. Lotions and
gels may be formulated with an aqueous or oily base, and will in
general also contain one or more emulsifying agents, stabilising
agents, dispersing agents, suspending agents, thickening agents, or
colouring agents.
[0082] Compositions of the invention formulated for vaginal
administration may be presented as pessaries, tampons, creams,
gels, pastes, foams, injectable solution or sprays containing in
addition to the adjuvant such carriers as are known in the art to
be appropriate. Accordingly the invention provides a topical
composition including a substance useful as an adjuvant for
potentiating an immune response, the substance being comprised of a
combination of a therapeutically effective amount of aluminium
hydroxide and 3'-deacylated monophospholipid A (MPL); and a
pharmaceutically acceptable diluent or carrier, the composition
being characterised in that the composition does not include an
immunogen for invoking an immune response. The topical composition
of the invention may be contacted with infected tissue within or
adjacent to a transformation zone of an individual. In a preferred
embodiment, the tissue is infected with HPV.
[0083] Formulations for topical administration include one or more
of the following ingredients together with the therapeutically
effective amount of aluminium hydroxide and 3'-deacylated
monophospholipid A (MPL); sodium chloride, L-histidine, sodium
borate, lactic acid, sodium phosphate monobasic, sorbitan
monostearate, polysorbate 60, cetyl esters wax, benzyl alcohol,
glycerol, cetostearyl alcohol, isopropyl myristate, propylene
glycol, purified water, chlorohexidine hydrochloride
octyldodecanol, sodium hydroxide, stearic acid and paraffin
liquid.
[0084] Compositions of the invention formulated for rectal
administration wherein the carrier is a solid are most preferably
presented as unit dosage suppositories. Suitable carriers include
cocoa butter, water soluble based carriers such as polyethylene
glycol, and glycerin and other materials commonly used in the art.
The suppositories may be conveniently formed by admixture of the
adjuvant with the softened or melted carrier(s) followed by
chilling and shaping moulds.
[0085] It is especially advantageous to formulate the compositions
of the present invention in unit dosage form for ease of
administration and uniformity of dosage. The specifications for the
dosage unit forms of the present invention may be determined by a
person skilled in the art depending on, for example (a) the
characteristics of the adjuvant and the particular therapeutic
effect to be achieved, and (b) the limitations inherent in the art
of compounding such an active ingredient for the particular
treatment.
[0086] The adjuvant composition may also be formulated for
administration by injection directly in to the infected cells of
the tissue, for example bolus injection, or continuous infusion,
and may be presented in unit dosage form in ampoules, pre-filled
syringes, small volume infusion or in multi-dose containers with an
added preservative. The compositions may take such forms as
suspensions, solutions, or emulsions in oily or aqueous vehicles,
and may contain formulating agents such as suspending, stabilising
and/or dispersing agents.
[0087] Alternatively, the adjuvant may be in powder form, obtained
by aseptic isolation of sterile solid or by lyophilisation from
solution, for constitution with a suitable vehicle, e.g. sterile,
pyrogen-free water, before use.
IV. KITS
[0088] In other embodiments there is provided a kit for use in one
of the above described embodiments, the kit including: [0089] a
container holding a therapeutic composition; [0090] a label or
package insert with instructions for use.
[0091] In certain embodiments the kit may contain one or more
further active principles or ingredients for treatment or an
infection or for preventing an infection-related complication
described above.
[0092] The kit or "article of manufacture" may comprise a container
and a label or package insert on or associated with the container.
Suitable containers include, for example, bottles, vials, syringes,
blister pack, etc. The containers may be formed from a variety of
materials such as glass or plastic. The container holds a
therapeutic composition which is effective for treating the
condition and may have a sterile access port (for example the
container may be an intravenous solution bag or a vial having a
stopper pierceable by a hypodermic injection needle). The label or
package insert indicates that the therapeutic composition is used
for treating the condition of choice. In one embodiment, the label
or package insert includes instructions for use and indicates that
the therapeutic composition can be used to treat an infection or to
prevent a complication stemming from infection.
[0093] The kit may comprise (a) a therapeutic composition; and (b)
a second container with a second active principle or ingredient
contained therein. The kit in this embodiment of the invention may
further comprise a package insert indicating that the other active
principle can be used to treat a disorder or prevent a complication
stemming from infection. Alternatively, or additionally, the kit
may further comprise a second (or third) container comprising a
pharmaceutically-acceptable buffer, such as bacteriostatic water
for injection (BWFI), phosphate-buffered saline, Ringer's solution
and dextrose solution. It may further include other materials
desirable from a commercial and user standpoint, including other
buffers, diluents, filters, needles, and syringes.
V. DEVICES
[0094] In certain embodiments the therapeutic composition may be
provided in the form of a device, disposable or reusable, including
a receptacle for holding the therapeutic composition. In one
embodiment, the device is a syringe. The device may hold 1-2 mL of
the therapeutic composition. The therapeutic composition may be
provided in the device in a state that is ready for use or in a
state requiring mixing or addition of further components.
EXAMPLES
[0095] Exemplary compositions for formulation as a topical
composition.
TABLE-US-00001 Range Preferred (0.5 mL dose) Al(OH).sub.3 200-550
.mu.g 0.5 mg MPL 20-100 .mu.g 50 .mu.g NaCl 3-10 mg 4.4 mg
NaH.sub.2PO.sub.4.cndot.2H.sub.2O 500-700 .mu.g 624 .mu.g
i)
[0096] Adjusted to a pH of between 6 and 8 and to be formulated
into a cream for topical application.
TABLE-US-00002 Range Preferred (0.5 mL dose) Al(OH).sub.3 200-550
.mu.g 225 .mu.g MPL 20-100 .mu.g 50 .mu.g NaCl 3-10 mg 9.56 mg
L-histidine 0.5-1 mg 0.78 mg Polysorbate 60 20-100 .mu.g 50 .mu.g
NaBr 25-50 .mu.g 35 .mu.g
ii)
[0097] Adjusted to a pH of between 6 and 8 and to be formulated
into a cream for topical application.
iii)
TABLE-US-00003 Range Preferred (0.5 mL dose) HPV antigen 20-40
.mu.g 20 .mu.g of each different antigen Al(OH).sub.3 200-550 .mu.g
0.5 mg MPL 20-100 .mu.g 50 .mu.g NaCl 3-10 mg 4.4 mg
NaH.sub.2PO.sub.4.cndot.2H.sub.2O 500-700 .mu.g 624 .mu.g
[0098] The HPV antigen may be selected from one or more of 6, 11,
16, 18, 30, 31, 33, 35, 39, 42, 43, 44, 45, 51-56, 58, 59, 66 and
68, but usually one or more of 6, 11, 16, 18, 45 and 56. Adjusted
to a pH of between 6 and 8 and to be formulated into a cream for
topical application.
iv)
TABLE-US-00004 Range Preferred (0.5 mL dose) HPV antigen 20-40
.mu.g 20 .mu.g of each different antigen Al(OH).sub.3 200-550 .mu.g
225 .mu.g MPL 20-100 .mu.g 50 .mu.g NaCl 3-10 mg 9.56 mg
L-histidine 0.5-1 mg 0.78 mg Polysorbate 60 20-100 .mu.g 50 .mu.g
Na borate 25-50 .mu.g 35 .mu.g
[0099] The HPV antigen may be selected from one or more of 6, 11,
16, 18, 30, 31, 33, 35, 39, 42, 43, 44, 45, 51-56, 58, 59, 66 and
68, but usually one or more of 6, 11, 16, 18, 45 and 56. Adjusted
to a pH of between 6 and 8 and to be formulated into a cream for
topical application.
v) Exemplary topical composition ingredients selected from:
TABLE-US-00005 Lactic acid Sorbitan monostearate Polysorbate 60
Cetyl esters wax Cetostearyl alcohol Isopropyl myristate Benzyl
alcohol Purified water Octyldodecanol Glycerol Chlorohexidine
Sodium hydroxide hydrochloride Propylene glycol Paraffin liquid
Stearic acid
vi) Pessary formulations further include:
TABLE-US-00006 Lactose Calcium lactate pentahydrate Maize starch
Silica-colloidal anhydrous Magnesium stearate Cellulose
microcrystalline Crospovidone Hypermellose Lactic acid
* * * * *