U.S. patent application number 11/833862 was filed with the patent office on 2008-03-06 for photodynamic therapy for the treatment of hair loss.
Invention is credited to Ronald Erwin Boch, Jean-Marie Houle, David W.C. Hunt, Peter Lutwyche, John Robert North, Anna M. Richter, Guillermo O. Simkim.
Application Number | 20080056996 11/833862 |
Document ID | / |
Family ID | 46123441 |
Filed Date | 2008-03-06 |
United States Patent
Application |
20080056996 |
Kind Code |
A1 |
Simkim; Guillermo O. ; et
al. |
March 6, 2008 |
PHOTODYNAMIC THERAPY FOR THE TREATMENT OF HAIR LOSS
Abstract
Photodynamic therapy (PDT) is used to stimulate and/or restore
hair growth in areas of hair loss. Methods and compositions
relating to PDT treatment for alopecia are disclosed. In light of
PDT use to remove unwanted hair by inactivating or destroying hair
follicles or destroying the tissue feeding the hair follicles, such
methods and compositions relate to a surprising and unexpected
discovery. PDT permits a means to treat conditions relating to hair
loss such as androgenic alopecia, alopecia areata and drug-induced
alopecia.
Inventors: |
Simkim; Guillermo O.; (North
Vancouver, CA) ; Richter; Anna M.; (Vancouver,
CA) ; Hunt; David W.C.; (Surrey, CA) ; North;
John Robert; (Vancouver, CA) ; Lutwyche; Peter;
(Vancouver, CA) ; Boch; Ronald Erwin; (North
Vancouver, CA) ; Houle; Jean-Marie; (Ste-Adele,
CA) |
Correspondence
Address: |
MORRISON & FOERSTER LLP
12531 HIGH BLUFF DRIVE
SUITE 100
SAN DIEGO
CA
92130-2040
US
|
Family ID: |
46123441 |
Appl. No.: |
11/833862 |
Filed: |
August 3, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10422363 |
Apr 23, 2003 |
7264629 |
|
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11833862 |
Aug 3, 2007 |
|
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10291795 |
Nov 8, 2002 |
7090691 |
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10422363 |
Apr 23, 2003 |
|
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60338295 |
Nov 9, 2001 |
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Current U.S.
Class: |
424/9.2 ;
514/185 |
Current CPC
Class: |
A61K 2800/434 20130101;
A61K 8/4913 20130101; A61K 9/0014 20130101; A61K 9/0019 20130101;
A61K 2300/00 20130101; A61K 41/0071 20130101; A61Q 7/00 20130101;
A61K 45/06 20130101; A61K 31/409 20130101; A61K 2800/81 20130101;
A61P 17/14 20180101; A61N 5/062 20130101; A61N 5/0617 20130101;
A61K 31/409 20130101; A61K 41/0076 20130101; A61K 41/0061 20130101;
A61K 47/10 20130101 |
Class at
Publication: |
424/009.2 ;
514/185 |
International
Class: |
A61K 49/00 20060101
A61K049/00; A61K 31/555 20060101 A61K031/555; A61P 17/14 20060101
A61P017/14 |
Claims
1. A pharmaceutical composition to treat, prevent, or inhibit the
development of, hair growth reduction or hair loss, said
composition comprising an effective amount of photosensitizer and a
pharmaceutically acceptable carrier or excipient for directing the
photosensitizer to the sites of hair growth reduction or hair
loss.
2. A method of preparing an area of skin for photodynamic therapy
to increase the number of terminal hairs in said area, said method
comprising administering the pharmaceutical composition of claim 1
to said area.
3. A method of preparing an area of skin for photodynamic therapy
to treat androgenetic alopecia, said method comprising
administering the pharmaceutical composition of claim 1 to said
area.
4. A method of determining the increase in hair growth in a
subject's skin exhibiting hair growth reduction or hair loss, said
method comprising a) administering a photosensitizer to said skin;
b) irradiating said skin with electromagnetic energy containing a
wavelength absorbed by said photosensitizer to activate it; and c)
measuring the increase in hair growth, wherein an increase in hair
growth in comparison to skin that has not been treated with both a)
and b) can be determined.
5. The method of claim 4 wherein said photosensitizer is one which
absorbs activating radiation in the range of about 400 nm to about
800 nm.
6. The method of claim 4 wherein said administering is by topical
application.
7. The method of claim 4 wherein said electromagnetic energy is
visible light.
8. The method of claim 4, wherein said skin that has not been
treated has not been administered said photosensitizer.
9. The method of claim 4, wherein said skin that has not been
treated has not been irradiated.
10. The method of claim 4, wherein said measuring is selected from
counting the number of terminal hairs, measuring hair weight,
measuring hair density, and/or measuring hair shaft diameter.
Description
RELATED APPLICATIONS
[0001] This application is a divisional application of U.S. patent
Ser. No. 10/422,363, filed Apr. 23, 2003, which is a
continuation-in-part of U.S. patent Ser. No. 10/291,795, filed Nov.
8, 2002, and claims priority to U.S. Provisional Ser. No.
60/338,295, filed Nov. 9, 2001, each of which are both hereby
incorporated in their entireties as if fully set forth.
FIELD OF THE INVENTION
[0002] This invention relates to the use of photodynamic therapy
(PDT) and the use of PDT with appropriate photosensitizers to
stimulate hair growth. In particular, the use of photosensitizers
and PDT for treating conditions relating to hair loss, such as
androgenetic alopecia and alopecia areata, is described. The
present invention further relates to increases in proinflammatory
cytokines induced by PDT, which stimulates hair growth, as well as
to methods of determining the level of hair growth stimulation
mediated by PDT.
BACKGROUND OF THE INVENTION
[0003] Alopecia is the general term referring to any disease or
condition involving hair loss. There are several different types of
hair loss, the most common being androgenetic alopecia (AGA; see
Sawaya, M. E. Seminars in Cutaneous Medicine and Surgery
17(4):276-283, 1998), alopecia areata (AA; see Fiedler &
Alaiti, Dermatologic Clinics 14(4): 733-738, 1996, as well as
chemotherapy and drug-induced alopecia.
[0004] Androgenetic alopecia (AGA) is by far the most common type
of alopecia. AGA is a patterned, progressive loss of an excessive
amount of hair from the scalp. Significant AGA occurs in 50% of men
by the age of fifty and 50% of women by the age of sixty. AGA is
believed to be a result of both genetic predisposition and the
presence of a sufficient level of circulating androgens. It is
thought that the enzyme 5 alpha reductase present in dermal papilla
cells converts testosterone to dihydrotestosterone (DHT). DHT binds
to androgen receptors, also localized in the dermal papilla cells,
triggering changes in the hair follicle that result in (1)
shortening of the anagen or growth phase of the hair cycle, (2)
development of a latent phase in the hair cycle following shedding
of the telogen hair, and (3) follicular miniaturization process
that reduces the caliber of the anagen hairs produced. It is
thought that differential expression of 5-alpha reductase and/or
androgen receptors in various types of hair follicles accounts for
patterned hair growth and loss.
[0005] Currently approved treatments for AGA include minoxidil
(Rogaine.TM.), an anti-hypertensive drug for which the mechanism of
action in promoting hair growth is unknown. Minoxidil must be
applied topically on a twice daily basis, and is therefore somewhat
inconvenient to use. Studies have shown that 2% Minoxidil can
provide an increase in the numbers of terminal hairs after 4-12
months (De Villez et al, Journal of the American Academy of
Dermatology, Vol. 16, No. 3, Part 2 (March 1987) 669-672). However,
this benefit disappears over time or once the treatment is stopped.
Another drug used in the treatment of AGA is finasteride
(Propecia.TM.), a selective inhibitor of the type 2 isoenzyme
5-alpha reductase. This treatment has marginal efficacy, requires
daily oral administration and can have some anti-androgenic side
effects such as alteration of libido. Hair transplants and scalp
reduction are also performed on patients with hair loss associated
with AGA. These procedures are too expensive or time consuming for
many people. In addition, many people are put off by the surgical
nature of the treatment.
[0006] Alopecia areata (AA) has been reported to account for 2% of
new outpatients in dermatology clinics (Fiedler & Alaiti
supra). AA is a nonscarring form of hair loss which occurs in
humans and other species and is thought to be due to an
inflammatory reaction caused by autoimmune response directed
against the anagen stage hair follicle structure (McElwee et al.
Pathobiology 66(2): 90-107, 1998).
[0007] A number of therapeutic modalities have been tested for the
treatment of AA, with variable results ranging from no effect to
partial or full hair regrowth. In some cases chronic maintenance
treatment is required. Major drawbacks of these treatments are side
effects, which can be local or systemic in nature. Fiedler &
Alaiti (supra) and Shapiro (Dermatological Clinics 11(1): 35-46,
1993) have reviewed the various treatments available for AA,
including steroids (topical, intralesional and systemic),
minoxidil, anthralin, photochemotherapy, cyclosporin A and other
agents, as well as combination treatments.
[0008] Photochemotherapy therapy for AA using psoralen and high
energy UVA (PUVA) treatment has met with very limited success and
its effectiveness for AA is in doubt (Lebwohl, M. Lancet
349:222-223, 1997). Side effects of PUVA treatment such as nausea,
pigmentary changes, risk of skin cancer formation, and cataracts
have been reported (Fiedler & Alaiti, supra). Antioxidants have
been used to ameliorate the side-effects of PUVA therapy (Ptapenko
& Kyagova, Membr. Cell Biol. 12(2): 269-278, 1998). The use of
2% khellin, a compound with a chemical structure that resembles
psoralen, and UVA for alopecia areata was found to be successful in
5 of the 10 patients tested (Orasa et al. Int. J. Dermatol. 32(9):
690, 1993). Since khellin did not cause phototoxicity, the authors
have suggested its use as an alternative to psoralen.
[0009] Hematoporphyrin and high energy UVA has been used in a very
limited study by Monfrcola et al. (Photodermatology 4:305-306,
1987). Two patients were treated with topical hematoporphyrin
(0.5%, HP) and UVA irradiation with three times a week for eight
weeks. In the first week of treatment there was significant
erythema and mild scaling followed by hyperpigmentation in the HP
treated sites. Side effects included unpleasant reddish skin
coloration for several hours and sometimes burning sensations
during the irradiation phase. The authors point out that severe
phototoxic reactions could occur with the use of HP concentrations
greater than 1%. They also state that more work is needed before
this approach can be subject to routine clinical use.
[0010] Photodynamic therapy (PDT) has been utilized for the removal
of unwanted hair in human subjects. Briefly the treatment involves
a topical application of a photosensitizer on a selected area of
the skin, a period for absorption of the photosensitizer, followed
by a pulse or continuous irradiation or vibration of the area. The
process involves inactivating or destroying the hair follicles or
destroying the tissue feeding the hair follicles (see U.S. Pat.
Nos. 5,669,916; 5,871,480; WO 97/32046).
[0011] Photodynamic therapy is a minimally invasive two-step
medical procedure that uses photoactivatable drugs called
photosensitizers to treat a range of diseases. First, a
photosensitizer is administered and, once it has permeated the
target tissue, the photosensitizer is then activated by exposure to
a dose of electromagnetic (usually light) radiation at a particular
wavelength. Photodynamic therapies have been approved for a number
of indications including the treatment of non-small cell lung
cancer (Photofrin.TM.), age-related macular degeneration
(Visudyne.TM.), actinic keratosis (Metvix.TM., Levulan.TM.), and
basal cell carcinoma (Metvix.TM.).
[0012] There continues to be a need for an effective, non-surgical
procedure that results in a rapid increase in the number of
terminal hairs but has minimal side effects.
[0013] Citation of the above documents is not intended as an
admission that any of the foregoing is pertinent prior art. All
statements as to the date or representation as to the contents of
these documents is based on the information available to the
applicant and does not constitute any admission as to the
correctness of the dates or contents of these documents.
SUMMARY OF THE INVENTION
[0014] It has been discovered that photodynamic therapy (PDT) can
stimulate hair growth and restore hair growth in areas of hair
loss. The discovery includes the ability to use a variety of
photosensitizers in PDT to treat hair growth reduction or hair
loss. In light of the use of PDT to remove unwanted hair by
inactivating or destroying hair follicles or destroying the tissue
feeding the hair follicles, as discussed above, the instant
invention relates to a surprising and unexpected discovery.
[0015] The instant invention provides methods and compositions for
treating lack of hair growth or a reduction or loss of existing
hair by stimulating and/or restoring hair growth with PDT. Thus one
aspect of the invention relates to methods for stimulating,
inducing, restoring, reviving, renewing, replacing or otherwise
activating hair growth in animals characterized by a lack of hair
growth or a reduction in the amount of, or loss of, hair. In
particular, the treatment methods of the invention comprise i)
administering an effective and/or sufficient amount of
photosensitizer resulting in an effective or desired degree of
biodistribution; ii) irradiating at least a portion of the external
surface of the animal with light including one or more wavelengths
capable of activating said photosensitizer for a time period
sufficient to activate the photosensitizer. The administrating and
irradiating acts of (i) and (ii) may be repeated as necessary or
desired to result in a desired level of hair growth.
[0016] The desired therapeutic response of hair growth can also be
accomplished by the irradiation of skin, which has been treated
with an effective amount of a photosensitizer, with light including
one or more wavelengths capable of activating said photosensitizer
for a time period sufficient to activate the photosensitizer and
result in a desired level of hair growth. Moreover, the methods of
the invention may be practiced with any photosensitizer, which may
be delivered systemically or locally.
[0017] Thus in one application of the invention, the invention
provide for the use of photodynamic therapy (PDT) to stimulate an
increase in hair count numbers and restore hair growth in areas of
hair loss. One embodiment of this application comprises:
[0018] (a) administering an effective and/or sufficient amount of a
photosensitizer to an area of a subject's skin where hair growth is
desired; and
[0019] (b) irradiating the area with electromagnetic energy
containing a wavelength capable of activating, or appropriate to
activate, said photosensitizer for a time period sufficient to
activate the photosensitizer; and optionally
[0020] (c) repeating (a) and (b)
[0021] wherein there is an increase in hair count numbers in the
treated area.
[0022] Preferably, the increase in hair count is an increase in
terminal hairs, which are long, pigmented hairs that are produced
by follicles with sebaceous (oil) glands. They are found on the
scalp, beard, armpits and pubic areas and are in contrast to vellus
hairs, which are short hairs, often only a centimetre or two long,
that contain little or no pigment. The follicles that produce
vellus hairs do not have sebaceous and never produce any other kind
of hairs. Terminal hairs also differ from Lanugo hair, which
develops on an unborn baby. In people who have inherited a tendency
to baldness terminal hairs may gradually become thinner and shorter
until they look like vellus hairs. This may be due to the growth of
terminal hairs being influenced by hormones (e.g. androgens) while
vellus hairs are not so influenced.
[0023] The progression of conditions such as AGA is for a gradual
decrease in the number of terminal hairs over time. The terminal
hairs may also gradually become thinner and shorter until they look
like vellus hairs. It is surprising, therefore, that the current
method can actually increase the number of hairs after 3 months. In
addition to treatment of hair loss, the method of the present
invention may be used for the stimulation of hair growth in areas
not recognized as experiencing hair loss. As used herein, the term
"hair growth" refers to an increase in number of terminal hairs
present. Terminal hair counts can be conducted in a number of ways
as known in the art. A non-limiting example is where the terminal
hair is counted by trained and validated technicians who perform a
computer-assisted count on macrophotographs. In brief, a target
area on the scalp is chosen, the hair clipped and the scalp
permanently marked with a single dot tattoo in the center in order
to facilitate the exact positioning at each subsequent photo
session. The macrophotography is performed using a preset camera
with a macro lens and a stand that provides a constant reproduction
ratio and electronic flashes that reproducibly illuminate the area
to photograph. The images are taken in triplicate, centering the
camera using the tattoo and the color slide films are processed at
a central facility. The quality of the images is assessed and large
transparencies are made of the best images. The terminal hairs on
the target circle of the transparencies are then counted by the
trained technicians.
[0024] In all embodiments of the invention, the disclosed PDT
mediated methods may be repeated over time and preferably result in
a 2% or more increase in the number of terminal hairs within 3
months.
[0025] In another aspect, the invention is directed to formulations
or compositions comprising photosensitizers for treating lack of
hair growth or a reduction or loss of existing hair with the
methods of the invention. These compositions comprise an effective
amount of photosensitizer, optionally with a pharmaceutically
acceptable carrier or excipient, and may also be used to prevent or
inhibit the development of hair growth reduction or hair loss. The
invention includes pharmaceutical compositions targeted to hair
follicles, the surrounding tissue, or tissues which feed hair
follicles. In particular, formulations comprising photosensitizers
conjugated to agents, which specifically target or bind appropriate
scalp or skin tissues, hair follicles, or tissues and cells
surrounding said hair follicles, are preferred for use in the
methods of the invention. Compositions comprising conjugated or
unconjugated photosensitizers are optionally formulated with agents
suitable or preferred for application to the scalp, or other skin
where hair growth is desired. Examples of such agents include
pharmaceutically acceptable carriers or excipients.
[0026] The invention also provides for methods of using
photosensitizer formulations and compositions in preparing an area
of skin for PDT to increase the number of terminal hairs in said
area, or to treat AGA, said methods comprising administering,
preferably by topical administration, such formulations and
compositions to said area.
[0027] In one set of preferred embodiments, the invention is
practiced with a photosensitizer that is photoactivated by light of
a wavelength from about 400 to about 900 nm. In another set of
preferred embodiments of the invention, the treatment methods and
compositions comprise the use of a particularly potent group of
photosensitizers known as green porphyrins, which are described in
detail in Levy et al., U.S. Pat. No. 5,171,749 issued 15 Dec. 1992,
which is incorporated herein by reference. The term "green
porphyrins" refers to porphyrin derivatives obtained by reacting a
porphyrin nucleus with an alkyne in a Diels-Alder type reaction to
obtain a mono-hydrobenzoporphyrin. In particular, green porphyrin
compounds such as benzoporphyrin derivative mono-acid (BPD-MA),
EA6, and B3 may be used in the invention. Two preferred members of
the green porphyrin family are verteporfin (comprising the 4
enantiomers shown below) and QLT 0074. ##STR1## ##STR2##
[0028] Additionally, the methods of the invention preferably
comprise irradiation with visible light containing a wavelength
absorbed by Gp.
[0029] The invention also provides methods of stimulating an
increase in tissue levels of one or more growth factors or
cytokines in cells present within skin tissue by the use of PDT.
More particularly, the cytokines include, but are not limited to,
interleukin-1-.alpha., interleukin-1-.beta., and
granulocyte-macrophage colony stimulating factor (GM-CSF). Without
being bound by theory, it is believed that PDT mediated increases
in pro-inflammatory cytokines play a role in inducing hair,
particularly terminal hair, growth as described herein. The
invention also provides for the use of such increases in the
treatment of other conditions.
[0030] In another aspect, the invention provides for methods to
determine the amount of increase in hair growth mediated by PDT.
These methods may be practiced with any photosensitizer in various
amounts or concentrations and with use of various irradiation
regimens, including, but not limited to, those with variations in
timing, radiation energy dose and/or rate, and wavelength of
radiation. In one embodiment, such methods comprise
[0031] (a) administering a photosensitizer to skin exhibiting hair
growth reduction or hair loss;
[0032] (b) irradiating said skin with electromagnetic energy
containing a wavelength absorbed by said photosensitizer to
activate it; and
[0033] (c) measuring the increase in hair growth,
[0034] wherein an increase in hair growth in comparison to skin
that has not been treated with both a) and b) can be determined.
Preferably, the photosensitizer is one which absorbs activating
radiation in the range of about 400 nm to about 800 nm and is
administered by topical application. Said measuring can be by any
means known to the skilled person, including, but not limited to,
counting the number of terminal hairs, measuring hair weight,
measuring hair density, and/or measuring hair shaft diameter, most
preferably by counting the number of terminal hairs. Preferably,
the skin that has not been treated has not been treated with one of
a) and b).
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 shows photographs taken over time of a representative
untreated control C57BL/6 mouse from an experiment examining the
effect of photodynamic therapy (PDT) treatment of mice with
alopecia of unknown etiology (Example 1). FIGS. 1.1 to 1.4 shows a
control mouse with a worsening of the alopecic condition over the
experimental period of 28 days.
[0036] FIG. 2 shows photographs taken over time of a representative
PDT treated C57BL/6 mouse from the experiment examining the effect
of PDT treatment on mice with alopecia of unknown etiology (Example
1). FIGS. 2.1 to 2.4 demonstrate that the PDT treatment over the
experimental period of 28 days resulted in impressive hair growth
in the alopecic patches.
[0037] FIG. 3 is a photograph of a representative control Balb/c
mouse that was shaved to remove hair, and subjected to a placebo
PDT treatment (Example 2).
[0038] FIG. 4 is a photograph of a representative shaved Balb/c
mouse that was shaved to remove hair, and subjected to a PDT
treatment using the photosensitizer QLT 0074 (Example 2). Hair
re-growth was observed 17 days after PDT treatment.
DETAILED DESCRIPTION
[0039] Briefly stated, the invention provides methods and
compositions for stimulating hair growth utilizing photodynamic
therapy (PDT) treatment. For example, one aspect of the invention
includes methods for inducing or stimulating hair growth in animals
characterized by reduction or loss of hair. A sample method would
comprise: (a) administering an effective and/or sufficient amount
of a photosensitizer capable of penetrating into target skin to
result in an effective or desired degree of biodistribution; (b)
irradiating the target skin with light comprising one or more
wavelength capable of activating said photosensitizer for a time
period sufficient to activate the photosensitizer; and optionally
(c) repeating (a) and (b) as necessary or desired to elicit a
desired level of hair growth. Such hair growth would be the desired
therapeutic response in the majority of cases. PDT treatment of
hair loss has the advantage that it obviates the need for daily
administration of a drug.
[0040] The present invention may be used with any subject,
vertebrate or invertebrate, capable of hair growth. Preferably, the
invention is applied to skin tissue exhibiting, or suspected of,
hair growth reduction or hair loss. Preferred subjects include
mammals, with human subjects being particularly preferred. The
present invention is useful for treating subjects, particularly
humans, suffering from AGA.
[0041] After administration, the photosensitizer will be present in
hair follicles and the surrounding tissues and cells for
photoactivation. Irradiation with electromagnetic energy,
preferably with light of appropriate wavelength and intensity, will
be applied using an appropriate light source, thereby activating
the photosensitizer to stimulate and/or restore hair growth.
Appropriate activation energy sources can be any that is suitable.
For example, sunlight or other ambient sources may be used but
preferred for use are devices which allow a controlled energy dose
to be delivered. By "stimulating" or "restoring" hair growth, all
manner of inducing, reviving, renewing, replacing or otherwise
activating hair growth are included. Preferably, the irradiation is
with visible light or comprises a wavelength of visible light.
[0042] Any suitable photosensitizing agent or mixture of agents may
be used herein. Generally, these will absorb radiation in the range
of from about 380 nm to about 900 nm. Preferred are those which
absorb radiation in the range 400 nm to 800 nm. Those that absorb
radiation in the range of from 600 nm to 750 nm are even more
preferred. As used herein, "photosensitizer" or "photosensitizing
agent" preferably means a chemical compound which, when contacted
by radiation of a certain wavelength, forms singlet oxygen. More
preferred is a photosensitizer that is nontoxic to humans or is
capable of being formulated in a nontoxic composition. Even more
preferred is a chemical compound that is also nontoxic in its
photodegraded form after administration to a subject. A
photosensitizer may be defined as a substance that absorbs
electromagnetic radiation, most commonly in the visible spectrum,
and releases it as another for of energy, most commonly as reactive
oxygen species and/or as thermal energy.
[0043] The formulations and methods of the invention generally
relate to administering a photosensitizer, such as a green
porphyrin, to a subject undergoing PDT for alopecia. In one
embodiment, the methods of the invention are used to stimulate
and/or restore hair growth after initial diagnosis of a subject as
suffering from hair loss, such as that resulting from AGA. In
another embodiment, the methods of the invention follow other
treatments for alopecia, including PDT, as a form of maintenance
therapy to prevent appreciable hair loss and/or maintain hair
growth. The latter may be used to prevent or inhibit the
re-occurrence of alopecia.
[0044] The present invention also provides methods for causing an
increase in the number of terminal hairs by use of PDT in the area
in which an increase in the number of terminal hairs is desired and
administering at least one secondary treatment that causes an
increase in the number of terminal hairs within the treatment area,
wherein the secondary treatment is not photodynamic therapy. The
non-photodynamic treatment can be any suitable regimen, but is
preferably one that increases terminal hair numbers via a different
method of action from PDT treatment. For example, a local treatment
or a systemic treatment. Preferably, the secondary treatment is
selected from 5-alpha reductase inhibitors, minoxidil, hair
transplantation, scalp reduction, and combinations thereof. More
preferably, the secondary treatment is selected from 5-alpha
reductase inhibitors, minoxidil, and combinations thereof. For
example, Rogaine.TM. or Propecia.TM. maybe utilised in combination
with PDT treatment(s). For example, a patient may receive one or
several PDT treatments, but also use Rogaine.TM. or Propecia.TM. as
recommended.
[0045] One preferred method herein thus comprises:
[0046] (a) topically administering photosensitizer to a target skin
tissue,
[0047] (b) irradiating the target tissue with electromagnetic
radiation of a wavelength appropriate to activate the
photosensitizer, and
[0048] (c) administering at least one, non-photodynamic, treatment
that causes an increase in the number of terminal hairs within the
treatment area.
[0049] The non-photodynamic treatment can be administered at any
suitable time, before, concurrently or after the PDT. It is
preferred that the non-photodynamic treatment is selected from
5-alpha reductase inhibitors, minoxidil, and combinations
thereof.
[0050] If the non-photodynamic treatment is minoxidil it is
preferably used as a topical solution. Preferably the solution is
administered from 1 to 4 times daily, more preferably twice daily.
The solution can be any suitable strength but is preferably from
about 1% to about 10%, more preferably about 2% or about 5%.
[0051] If the non-photodynamic treatment is 5-alpha reductase
inhibitors it is preferably administered orally. Preferred 5-alpha
reductase inhibitor is finasteride. Finasteride is preferably
administered as a 1 mg oral table and is preferably taken once a
day.
[0052] The methods of the invention can be used to stimulate hair
growth in any situation in which additional hair growth is desired.
In particular, the methods of the invention will be useful when the
subject has experienced loss of hair associated with a variety of
conditions, including, but not limited to the following: anagen
effluvium, drug-induced alopecia, radiotherapy, poisoning, diffuse
alopecia areata, alopecia areata, loose anagen syndrome,
postoperative occipital alopecia, syphilis, traction alopecia,
tricholtillomania tinea capitis, telogen effluvium, telogen
gravidarum, chronic telogen effluvium, early androgenentic
alopecia, iron deficiency, malnutrition/malabsorption,
hypothyroidism, hyperthyroidism, systemic lupus erythematosus,
chronic renal failure, hepatic failure, advanced malignancy, viral
or bacterial infection and androgenetic alopecia. In particular,
the methods of the invention are useful for restoration of hair
loss in androgenetic alopecia, alopecia areata, drug-induced
alopecia (for example following chemotherapy treatment for cancer)
and hair loss due to radiation treatment.
[0053] If the condition being treated is alopecia areata,
preferably the photosensitizer pro-drug 5-ALA is not used for
topical administration unless combined with at least one
penetration enhancer that promotes the distribution of the drug
within the hair follicles.
[0054] After administration of the photosensitizer, sufficient time
is permitted to elapse for the compound to be taken up by the hair
follicles and/or the surrounding tissues and cells. This time for
uptake may be varied according to various parameters, including but
not limited to the photosensitizer administered, the route of
administration, the physiology of the subject and of the tumor
cells, and the artisan's skill and experience. With green
porphyrins, for example, the elapsed time may be from less than
about one minute to more than three hours, preferably from one
minute to three hours, and more preferably from 10 to 60 minutes.
The cells, or tissues containing them, are then irradiated at the
wavelength of maximum absorbance of the photosensitizer. In the
case of BPDs, the wavelength is usually between about 550 and 700
nm, as discussed above. In particular, red light is advantageous
because of its relatively lower energy and the resulting lack of
toxicity it poses to normal tissue.
[0055] Without being bound by theory, it is believed that the
methods of the invention stimulates an increase in tissue levels of
one or more growth factors and/or cytokines in the treated tissues
which then directly, or through other biochemical pathways,
stimulate resting hair follicles to enter the anagen (growth)
phase. In PDT-mediated hair growth it is believed that
pro-inflammatory cytokines, such as interleukin-1-alpha,
interleukin-1-beta, or granulocyte-macrophage colony stimulating
factor (GM-CSF), play a role in inducing hair, particularly
terminal hair, growth as described herein. Pro-inflammatory
cytokines, such as IL-1 and GM-CSF, are known to have a wide range
of effects within tissues. These actions may include stimulating
the production of various biochemical mediators, up-regulating the
expression of specific cell surface receptors and triggering the
activation and tissue infiltration of pro-inflammatory cell types
including neutrophils and macrophages. It is particularly
surprising that IL-1-.alpha. can cause an increase in the number of
terminal hairs since there is a body of evidence that suggests IL-1
induces hair loss rather than hair growth (see, for example,
Dermatology 1995;191:273-275 Hoffmann et al; Eur J Dermatol
1998;8:475-7 Hoffmann et al; Lymphokine & Cytokine Research
Vol. 12, Number 4, 1993 Harmon et al).
[0056] Cells capable of producing such cytokines include
keratinocytes, dermal fibroblasts, and dermal papilla cells.
Consequently, the present invention also relates to a method of
causing an increase in the number of terminal hairs with
photodynamic therapy said method comprising inducing
pro-inflammatory cytokines, particularly granulocyte-macrophage
colony stimulating factor and/or interleukin-1-.alpha.
(IL-1-.alpha.).
[0057] Therefore, the present invention also relates to a method of
causing an increase in the number of terminal hairs by increasing
the levels of pro-inflammatory cytokines in the target area. The
method comprises treating the area with photodynamic therapy
wherein said photodynamic therapy causes an increase in the levels
of pro-inflammatory cytokines in the area where hair growth is
desired. Preferably the PDT treatment causes an increase in
granulocyte-macrophage colony stimulating factor,
interleukin-1-.beta. (IL-1-.beta.), and/or interleukin-1-.alpha.
(IL-1-.alpha.).
[0058] The present method provides at least 2% increase in the
numbers of terminal hairs within 3 months of the PDT treatment.
Preferably, the present invention provides a 3% or more increase,
more preferably a 4% or more increase, in the numbers of terminal
hairs within 3 months. The numbers of terminal hairs on a
particular subject can be assessed by any means known to the
skilled person, such as the validated method described in
"Photographic Documentation of Hair Growth in Androgenetic
Alopecia" (D. Canfield, Dermatologic Clinics, Vol. 14 No. 4
(October 1996)713-721).
[0059] In one embodiment, the method can comprise:
[0060] (a) assessing the numbers of terminal hairs in an area of
skin;
[0061] (b) administering an effective amount of a photosensitizer
to said area;
[0062] (c) irradiating the area with activation energy comprising
one or more wavelength capable of activating said photosensitizer
for a time period sufficient to activate the photosensitizer;
and
[0063] (d) optionally repeating (b) and (c);
[0064] (e) assessing the numbers of terminal hairs according to the
above mentioned method 3 months from the date of first
treatment.
[0065] The method preferably produces at least a 2%, more
preferably at least a 3%, and even more preferably at least a 4%
increase in the numbers of terminal hairs as assessed within 3
months.
[0066] The compositions and methods of the present invention
provide a useful PDT treatment to treat, and/or prevent or inhibit
re-occurrence of, alopecia. The following describes exemplary
photosensitizers, compositions and formulations of the present
invention and their clinical application. Experimental data also
are presented and described.
Photosensitizers
[0067] A listing of photosensitive chemicals for use in the present
invention may be found in Kreimer-Bimbaum, Sem. Hematol. 26:157-73,
1989 (incorporated herein by reference) and in Redmond and Gamlin,
Photochem. Photobiol. 70 (4): 391-475 (1999). The invention may be
practiced with a variety of synthetic and naturally occurring
photosensitizers, including, but not limited to, pro-drugs such as
the pro-porphyrin 5-aminolevulinic acid (ALA) and derivatives
thereof such as aminolevulinic acid esters, porphyrins and
porphyrin derivatives e.g. chlorins, bacteriochlorins,
isobacteriochlorins, phthalocyanine and naphthalocyanines and other
tetra- and poly-macrocyclic compounds, and related compounds (e.g.
pyropheophorbides, sapphyrins and texaphyrins) and metal complexes
such as, but not limited to, tin, aluminum, zinc, lutetium, tin
ethyl etiopurpurin (SnET2). Tetrahydrochlorins, purpurins,
porphycenes, and phenothiaziniums are also within the scope of the
invention. Some examples of suitable compounds include, but are not
limited to, those described in U.S. Pat. Nos. 6,462,192; 6,444,194;
6,376,483; WO-A-03/028628; WO-A-03/028629; WO-A-02/096417; and
WO-A-02/096366, all of which are herein incorporated by
reference.
[0068] Preferably the photosensitizers herein are selected from
pro-porphyrins, porphyrins, and mixtures thereof. Some examples
include aminolevulinic acid such as Levulan.TM., aminolevulinic
acid esters such as described in WO-A-02/10120 and available as
Metvix.TM., Hexvix.TM. and Benzvix.TM., di-hydro or tetra-hydro
porphyrins such as described in described in EP-A-337,601 or
WO-A-01/66550 and available as Foscan.TM. (temoporfin), porfimer
sodium (available as Photofrin.TM.), Visudyne.TM., benzoporphyrin
derivatives (which are described in more detail below), and
mixtures thereof.
[0069] In preferred embodiments of the invention, the
photosensitizer is selected from a particularly potent group of
photosensitizers known as green porphyrins, which are described in
detail in U.S. Pat. No. 5,171,749 (incorporated herein by
reference). The term "green porphyrins" refers to porphyrin
derivatives obtained by reacting a porphyrin nucleus with an alkyne
in a Diels-Alder type reaction to obtain a
mono-hydrobenzoporphyrin. Such resultant macropyrrolic compounds
are called benzoporphyrin derivatives (BPDs), which is a synthetic
chlorin-like porphyrin with various structural analogues, as shown
in U.S. Pat. No. 5,171,749. Typically, green porphyrins are
selected from a group of tetrapyrrolic porphyrin derivatives
obtained by Diels-Alder reactions of acetylene derivatives with
protoporphyrin under conditions that promote reaction at only one
of the two available conjugated, nonaromatic diene structures
present in the protoporphyrin-IX ring systems (rings A and B).
Metallated forms of a Gp, in which a metal cation replaces one or
two hydrogens in the center of the ring system, may also be used in
the practice of the invention. The preparation of the green
porphyrin compounds useful in this invention is described in detail
in U.S. Pat. No. 5,095,030 (hereby incorporated by reference).
[0070] Preferably, the BPD is a benzoporphyrin derivative diester
di-acid (BPD-DA), mono-acid ring A (BPD-MA), mono-acid ring B
(BPD-MB), or mixtures thereof. These compounds absorb light at
about 692 nm wavelength and have improved tissue penetration
properties. The compounds of formulas BPD-MA and BPD-MB may be
homogeneous, in which only the C ring carbalkoxyethyl or only the D
ring carbalkoxyethyl would be hydrolyzed, or may be mixtures of the
C and D ring substituent hydrolyzates. A number of other BPD B-ring
derivatives may also be used in the present methods. These
derivatives have the following general formula: ##STR3##
[0071] wherein; R.sup.5 is vinyl, R.sup.1 and R.sup.6 are methyl,
and n is 2. X.sub.1, X.sub.2, and X.sub.3 are listed in the tables
below: TABLE-US-00001 TABLE 1 Hydrophilic BPD B-ring analogs Drug
X.sub.1 X.sub.2 X.sub.3 QLT0061 COOH COOH COOH QLT0077
CONH(CH.sub.2).sub.2N.sup.+(CH.sub.3).sub.3I.sup.-
CONH(CH.sub.2).sub.2N.sup.+(CH.sub.3).sub.3I.sup.- COOCH.sub.3
QLT0079
CONH(CH.sub.2).sub.2N.sup.+(CH.sub.3).sub.2((CH.sub.2).sub.3CH.sub-
.3
CONH(CH.sub.2).sub.2N.sup.+(CH.sub.3).sub.2((CH.sub.2).sub.3CH.sub.3)
COOCH.sub.3 QLT0086 CONHCH(COOH)CH.sub.2COOH
CONHCH(COOH)CH.sub.2COOH COOCH.sub.3 QLT0092
CONH(CH.sub.2).sub.2NH(CH.sub.3).sub.2CF.sub.3COO.sup.-
CONH(CH.sub.2).sub.2NH(CH.sub.3).sub.2CF.sub.3COO-- COOCH.sub.3
QLT0094 CONHCH.sub.2COOH CONHCH.sub.2COOH CONHCH.sub.2COOH
[0072] TABLE-US-00002 TABLE 2 Lipophilic BPD B-ring analogs Drug X1
X2 X3 QLT0060 CO(O(CH.sub.2).sub.2)0H CO(O(CH.sub.2).sub.2)0H
COOCH.sub.3 QLT0069 COOCH.sub.3 COOCH.sub.3 COOH QLT0078
CO(O(CH.sub.2).sub.2).sub.20H CO(O(CH.sub.2).sub.2).sub.20H
COOCH.sub.3 QLT0080 CO(O(CH.sub.2).sub.2).sub.3OH
CO(O(CH.sub.2).sub.2).sub.3OH COOCH.sub.3 QLT0081
CO(O(CH.sub.2).sub.2).sub.2OCH.sub.3
CO(O(CH.sub.2).sub.2).sub.2OCH.sub.3
CO(O(CH.sub.2).sub.2).sub.2OCH.sub.3 QLT0082
CO(O(CH.sub.2).sub.2).sub.2OH CO(O(CH.sub.2).sub.2).sub.2OH
CO(O(CH.sub.2).sub.2).sub.2OH QLT0083 CO(O(CH.sub.2).sub.2).sub.3OH
CO(O(CH.sub.2).sub.2).sub.3OH CO(O(CH.sub.2).sub.2).sub.3OH QLT0087
CO(O(CH.sub.2).sub.2).sub.4OH CO(O(CH.sub.2).sub.2).sub.4OH
COOCH.sub.3 QLT0088 COOCH.sub.3 COOCH.sub.3
CONH(C.sub.6H.sub.4)(C.sub.5H.sub.10N) QLT0090
CO(O(CH.sub.2).sub.2).sub.5OH CO(O(CH.sub.2).sub.2).sub.5OH
COOCH.sub.3 QLT0093 CO(O(CH.sub.2).sub.2).sub.5OH
CO(O(CH.sub.2).sub.2).sub.5OH CO(O(CH.sub.2).sub.2).sub.5OH
[0073] Preferred photosensitizers are the benzoporphyrin derivative
mono-acid (BPD-MA), QLT0074 (as set forth in U.S. Pat. No.
5,929,105 referred to therein as A-EA6) and B3 (as set forth in
U.S. Pat. No. 5,990,149). Most preferably the photosensitizer is
QLT0074 which has the structure: ##STR4##
[0074] Additionally, the photosensitizers used in the invention may
be conjugated to various ligands to facilitate targeting. These
ligands include receptor-specific ligands as well as
immunoglobulins and fragments thereof. Preferred ligands include
antibodies in general and monoclonal antibodies, as well as
immunologically reactive fragments of both.
[0075] Dimeric forms of the green porphyrin and dimeric or
multimeric forms of green porphyrin/porphyrin combinations can be
used. The dimers and oligomeric compounds of the invention can be
prepared using reactions analogous to those for dimerization and
oligomerization of porphyrins per se. The green porphyrins or green
porphyrin/porphyrin linkages can be made directly, or porphyrins
may be coupled, followed by a Diels-Alder reaction of either or
both terminal porphyrins to convert them to the corresponding green
porphyrins. Combinations of two or more photosensitizers may also
be used in the practice of the invention.
[0076] In addition to the above mentioned preferred
photosensitizing agents, additional examples of photosensitizers
useful in the invention include, but are not limited to, green
porphyrins disclosed in U.S. Pat. Nos. 5,283,255, 4,920,143,
4,883,790, 5,095,030, and 5,171,749; and green porphyrin
derivatives, discussed in U.S. Pat. Nos. 5,880,145 and 5,990,149.
Several structures of typical green porphyrins are shown in the
above cited patents, which also provide details for the production
of the compounds.
[0077] A preferred photosensitizer for use in the present invention
will satisfy the following general criteria: 1) it is capable of
entry into the target hair follicles and/or the surrounding tissues
and cells; and 2) irradiation, preferably with light (and more
preferably with visible light), results in the stimulation of
and/or restoration of hair growth.
[0078] Suitable photosensitizer formulations for the practice of
the invention include those appropriate for administration of
therapeutic compounds in vivo. Additionally, other components may
be incorporated into such formulations. These include, for example,
visible dyes to facilitate visualization or imaging of the
formulation or various enzymes to facilitate the access of a
photosensitizing compound to target sites.
Formulations
[0079] The photosensitizers of the invention may be formulated into
a variety of compositions. These compositions may comprise any
component that is suitable for the intended purpose, such as
conventional delivery vehicles and excipients including isotonising
agents, pH regulators, solvents, solubilizers, dyes, gelling agents
and thickeners and buffers and combinations thereof. Pharmaceutical
formulations suitable for use with the instant photosensitizers can
be found, for instance, in Remington's Pharmaceutical Sciences.
Preferred formulations herein comprise pharmaceutical excipients or
carriers capable of directing the photosensitizer to the area of
hair growth reduction or hair loss. Suitable excipients for use
with photosensitizers include water, saline, dextrose, glycerol and
the like.
[0080] Typically, the photosensitizer is formulated by mixing it,
at an appropriate temperature, e.g., at ambient temperatures, and
at appropriate pHs, and the desired degree of purity, with one or
more physiologically acceptable carriers, i.e., carriers that are
nontoxic at the dosages and concentrations employed. Generally, the
pH of the formulation depends mainly on the particular use, and
concentration of photosensitizer, but preferably ranges anywhere
from about 3 to about 8. Preferably, the photosensitizer is
maintained at a pH in the physiological range (e.g., about 6.5 to
about 7.5). The presence of salts is not necessary, and, therefore
the formulation preferably is not an electrolyte solution.
[0081] The formulations herein preferably comprise a
skin-penetration enhancer. Any skin-penetration enhancer suitable
for aiding the delivery of the photosensitizing agent can be used
herein. A list of skin-penetration enhancers can be found in
"Pharmaceutical Skin Penetration Enhancement" (1993) Walters, K.
A., ed.; Hadgraft, J., ed--New York, N.Y. Marcel Dekker and in
"Skin Penetration Enhancers cited in the Technical Literature"
Osboume, D. W. Pharmaceutical Technology, November 1997, pp 59-65,
both of which are incorporated herein by reference. Preferred for
use in the formulations herein are hydrophobic skin-penetration
enhancers.
[0082] Preferred skin-penetration enhancers are selected from
glycol ethers, fatty acids, fatty acid esters, glycol esters,
glycerides, azones, polysorbates, alcohols, dimethylsulfoxide, and
mixtures thereof. Preferred skin-penetration enhancers for use
herein include, but are not limited to, diethylene glycol monoethyl
ether (Transcutol.RTM.), Oleyl alcohol, Oleic acid, Azone
(Laurocapram or 1-n-Dodecyl azacycloheptan-2-one), Propylene glycol
mono- and diesters of fats and fatty acids (e.g. propylene glycol
monocaprylate, propylene glycol monolaurate), Triglycerides and
lipids (e.g. linoleic acid), Macrogolglycerides or Polyethylene
glycol glycerides and fatty esters (e.g. stearoyl
macrogolglycerides, oleoyl macrogolglycerides, lauroyl
macrogolglycerides, Oleyl macrogol-6-glycerides, Lauroyl macrogol-6
glycerides), Glycerides and fatty acid esters of polyethylene
glycol (e.g. caprylocaproyl macrogolglycerides, capryl-caproyl
macrogolglycerides, oleoyl macrogol glycerides), Polyoxyl 40
Hydrogenated Castor Oil (Cremophor RH 40), Polysorbate 80 (Tween
80), Dodecylazacycloheptanone, SEPA.RTM. such as described in U.S.
Pat. No. 4,861,764 (e.g. 2-n-nonyl-1,3-dioxolane), and mixtures
thereof. More preferred is diethylene glycol monoethyl ether
(available from Gattefosse under the tradename Transcutol).
[0083] It is preferred that the formulations comprise from about
0.1% to about 99%, preferably from about 0.1% to about 90%, more
preferably from about 5% to about 90%, even more preferably from
about 15% to about 75%, by weight of skin penetration enhancer.
[0084] It is preferred that the ratio of photosensitizer to
skin-penetration enhancer is from about 1:20 to about 1:10000, more
preferably from about 1:60 to 1:300, on the basis of percentages by
weight of total composition.
[0085] It is preferred that the photosensitizer is solubilised,
especially when the photosensitizer is hydrophobic. One method of
solubilising certain photosensitizers, including green porphyrins,
is by formulation in liposomes. An alternative may be to solubilise
the photosensitizer in cyclodextrins or cyclodextrin derivatives.
Preferred are partially etherified cyclodextrin, the ether
substituents of which are hydroxyethyl, hydroxypropyl or
dihydroxypropyl groups. However, appropriate cyclodextrins should
be of a size and conformation appropriate for use with the
photosensitizing agents disclosed herein.
[0086] Other methods suitable for solubilising certain
photosensitizers include the use of a solvent acceptable for use in
the treatment of skin tissues and cells such as, but are not
limited to, DMSO (dimethylsulfoxide), polyethylene glycol (PEG) or
any other solvent. It is preferred that the formulations herein
comprise a solubilizer. Some solubilizers are also penetration
enhancers and it is preferred that the formulations herein comprise
a penetration enhancer that is also a solubilizer for the
photosensitizer. Preferably the solubilizer is selected from glycol
ethers, polyethylene glycol, polyethylene glycol derivatives,
propylene glycol, propylene glycol derivatives, polysorbates (e.g.
Tween.TM.), fatty alcohols, aromatic alcohols, propylene glycol,
glycerols, oils, surfactants, glucosides, and mixtures thereof.
More preferably the solubilizer is selected from diethylene glycol
monoethyl ether (Transcutol.RTM.), polyethylene glycol of average
molecular weight from 100 to 5000, triethylene glycol,
tetraethylene glycol, pentaethylene glycol, hexaethylene glycol,
septaethylene glycol, octaethylene glycol, propylene glycol,
propylene glycol mono- and diesters of fats and fatty acids (e.g.
propylene glycol monocaprylate, propylene glycol monolaurate),
benzyl alcohol, glycerol, oleyl alcohol, mineral oil,
lanolin/lanolin derivatives, petrolatum or other petroleum products
suitable for application to the skin, propylene glycol mono- and
diesters of fats and fatty acids, macrogols, macrogolglycerides or
polyethylene glycol glycerides and fatty esters (e.g. stearoyl
macrogolglycerides, oleoyl macrogolglycerides, lauroyl
macrogolglycerides, linoleoyl macrogolglycerides), ethoxylated
castor oil (e.g. Cremophor--a polyoxyl hydrogenated castor oil),
C6-C30 triglycerides, natural oils, glucosides (e.g. cetearyl
glucoside), surfactants, and mixtures thereof. More preferable the
solubilizer is selected from diethylene glycol monoethyl ether
(Transcutol.RTM.), oleyl alcohol, and mixtures thereof.
[0087] It is preferred that the formulations herein comprise from
about 0.1% to about 99%, more preferably from about 1% to about
75%, by weight of solubilizer.
[0088] It is preferred that the formulations have a viscosity at
20.degree. C. of from about 50 cps to about 50000 cps, more
preferably from about 500 cps to about 40000 cps, even more
preferably from about 5000 cps to about 30000 cps. Should the
viscosity need to be adjusted it can be done by means of a
viscosity modifying agent. Preferred viscosity modifiers are
selected from polyethylene glycols, acrylic acid-based polymers
(carbopol polymers or carbomers), polymers of acrylic acid
crosslinked with allyl sucrose or allylpentaerythritol (carbopol
homopolymers), polymers of acrylic acid modified by long chain
(C10-C30) alkyl acrylates and crosslinked with allylpentaerythritol
(carbopol copolymers), poloxamers also known as pluronics (block
polymers; e.g. Poloxamer 124, 188, 237, 338, 407), waxes (paraffin,
glyceryl monostearate, diethylene glycol monostearate, propylene
glycol monostearate, ethylene glycol monosterate, glycol stearate),
hard fats (e.g. Saturated C8-C18 fatty acid glycerides), xantham
gum, polyvinyl alcohol, solid alcohols, and mixtures thereof.
[0089] In preferred embodiments the formulation contain one or more
PEGs. It is preferred that the formulation comprises at least one
PEG of average molecular weight about 2000 or less, preferably
about 1500 or less, preferably about 1000 or less, preferably about
800 or less, preferably about 600 or less, preferably about 500 or
less, preferably about 400 or less. It is preferred that the
formulation comprises at least one PEG of average molecular weight
about 3000 or more, preferably about 3350 or more, preferably about
3500 or more. It is preferred that the formulation comprises a
mixture of PEG's. More preferably, one PEG has an average molecular
weight of about 800 or less and one PEG has an average molecular
weight of 3000 or more.
[0090] A preferred formulation for use in the present invention
comprises photosensitizer (especially green-porphyrins), low
molecular weight PEG such as PEG200, diethylene glycol monoethyl
ether (Transcutol.RTM.), high molecular weight PEG such as PEG3350
and fatty alcohol such as oleyl alcohol.
[0091] The formulation herein may comprise a variety of other
components. Any suitable ingredient may be used herein but
typically these optional component will render the formulations
more cosmetically acceptable or provide additional usage benefits.
Some examples of preferred optional ingredients include, but are
not limited to, emulsifiers, humectants, emollients, surfactants,
oils, waxes, fatty alcohols, dispersants, skin-benefit agents, pH
adjusters, dyes/colourants, analgesics, perfumes, preservatives,
and mixtures thereof.
[0092] Examples of suitable preservatives include but are not
limited to parabens, benzyl alcohol, quaternium 15, imidazolidyl
urea, disodium EDTA, methylisothiazoline, alcohols, and mixtures
thereof. Examples of suitable emulsifiers include but are not
limited to waxes, sorbitan esters, polysorbates, ethoxylated castor
oil, ethoxylated fatty alcohols, macrogolglycerides or polyethylene
glycol glycerides and fatty esters (e.g. stearoyl
macrogolglycerides, oleoyl macrogolglycerides, lauroyl
macrogolglycerides), esters of saturated fatty acids (e.g.
diethylene glycol parmitostearate), macrogols of cetostearyl ether
(e.g. macrogol-6-cetostearyl ether), polymers of high molecular
weight, crosslinked acrylic acid-based polymers (carbopols or
carbomers), and mixtures thereof. Examples of suitable emollients
include but are not limited to propylene glycol dipelargonate,
2-octyldodecyl myristate, non-polar esters, triglycerides and
esters (animal and vegetable oils), lanolin, lanolin derivatives,
cholesterol, glucosides (e.g. cetearyl glucoside), pegylated
lanolin, ethoxylated glycerides, and mixtures thereof. Examples of
suitable surfactants include but are not limited to sorbitan
esters, polysorbates, sarcosinates, taurate, ethoxylated castor
oil, ethoxylated fatty alcohols, ethoxylated glycerides,
caprylocaproyl macrogol-8 glycerides, polyglyceryl-6 dioleate, and
mixtures thereof. Examples of suitable oils include but are not
limited to propylene glycol monocaprylate, medium chain
triglycerides (MCT), 2-octyl-dodecyl myristate, cetearyl
ethylhexanoate, and mixtures thereof. Examples of suitable fatty
alcohols include but are not limited to cetostearyl alcohol, cetyl
alcohol, stearyl alcohol, and mixtures thereof. Also useful in the
formulations herein are lipids and triglycerides (e.g. concentrates
of Seed Oil Lipids, Concentrates of Marine Oil Lipids, high purity
triglycerides and esters), alkyl ether sulfates, alkyl
polyglycosides, alkylsulfates, amphoterics cream bases, and
mixtures thereof.
[0093] Preparation of dry formulations that are reconstituted
immediately before use also is contemplated. The preparation of dry
or lyophilized formulations can be effected in a known manner,
conveniently from the solutions of the invention. The dry
formulations of this invention are also storable. By conventional
techniques, a solution can be evaporated to dryness under mild
conditions, especially after the addition of solvents for
azeotropic removal of water, typically a mixture of toluene and
ethanol. The residue is thereafter conveniently dried, e.g. for
some hours in a drying oven.
[0094] The method herein is targeted to hair follicles and/or
surrounding tissues and cells as a treatment for alopecia. The
photosensitizer containing preparations of the invention may be
administered systemically or locally and may be used alone or as
components of mixtures. Preferably the administration is local. The
route of administration for the photosensitizer may be topical,
intradermal, intravenous, oral, or by use of an implant. Preferably
the route of administration is topical. For example, green
porphyrins may be administered by means including, but not limited
to, topical lotions, topical creams, topical pastes, topical
suspensions, intravenous injection or infusion, oral intake, or
local administration in the form of intradermal injection or an
implant. Additional routes of administration are subcutaneous,
intramuscular, or intraperitoneal injections of the
photosensitizers in conventional or convenient forms.
[0095] For topical formulations (such as ointments) to be applied
to the surface of the skin, the concentration of the
photosensitizer in the excipient preferably ranges from about 0.001
to about 10% w/w, and more preferably from about 0.005 to about 5%
w/w, and even more preferably between about 0.01 to about 1% w/w.
Particularly preferred is the use of about a 0.2% w/w topical
formulation.
[0096] When administered topically, it is preferred that the area
to be treated be massaged after application of the photosensitizer.
While not wishing to be bound by theory, it is believed that the
massage aids in the penetration and distribution of photosensitizer
in the target tissue.
[0097] The particular concentration of a given photosensitizer
should be adjusted according to its photosensitizing potency.
[0098] Suitable isotonising agents are preferably nonionic
isotonising agents such as urea, glycerol, sorbitol, mannitol,
aminoethanol or propylene glycol as well as ionic isotonising
agents such as sodium chloride. The solutions of this invention
will contain the isotonising agent, if present, in an amount
sufficient to bring about the formation of an approximately
isotonic solution. The expression "an approximately isotonic
solution" will be taken to mean in this context a solution that has
an osmolarity of about 300 milliosmol (mOsm), conveniently 300+10%
mOsm. It should be borne in mind that all components of the
solution contribute to the osmolarity. The nonionic isotonising
agent, if present, is added in customary amounts, i.e., preferably
in amounts of about 1 to about 3.5 percent by weight, preferably in
amounts of about 1.5 to 3 percent by weight.
Administration of Photosensitizers
[0099] As noted above, the treatment methods of the invention are
targeted to hair follicles and/or surrounding tissues and cells as
a treatment for alopecia. The photosensitizer containing
preparations of the invention may be administered systemically or
locally and may be used alone or as components of mixtures. The
route of administration for the photosensitizer may be topical,
intravenous, oral, or by use of an implant. For example green
porphyrins may be administered by means including, but not limited
to, topical preparations, intravenous injection or infusion, oral
intake, or local administration in the form of intradermal
injection or an implant. Additional routes of administration are
subcutaneous, intramuscular, or intraperitoneal injections of the
photosensitizers in conventional or convenient forms.
[0100] In particular, topical delivery of photosensitizers is
preferred, while injection may also be used when desired. For
topical administration, the photosensitizers may be in standard
topical formulations and compositions including lotions,
suspensions or pastes. Oral administration of suitable formulations
may also be appropriate in those instances where the
photosensitizer may be readily administered to the hair follicle
and/or surrounding tissues or cells via this route. A preferred
method of administration is to apply the photosensitizer topically
in an excipient containing solubilizing agent, such as Cremophor or
corn glycerides, and to wash the treatment area within about an
hour (such as, but not limited to, after about 10, about 15, about
20, about 30, about 45, or about 60 minutes) with the excipient to
remove excess drug from the surface of the skin.
[0101] The dose of photosensitizers may be optimized by the skilled
artisan depending on factors such as, but not limited to, the
photosensitizer chosen, the physical delivery system in which it is
carried, the individual subject, and the judgment of the skilled
practitioner. It should be noted that the various parameters used
for effective PDT in the invention are interrelated. Therefore, the
dose should also be adjusted with respect to other parameters, for
example, fluence, irradiance, duration of the light used in PDT,
and time interval between administration of the dose and the
therapeutic irradiation. All of these parameters may be readily
adjusted using routine experimentation to produce a desired level
of alopecia treatment without causing significant damage to the
surrounding tissue. With photosensitizers, for example, the form of
administration, such as in liposomes or when coupled to a
target-specific ligand, such as an antibody or an immunologically
active fragment thereof, is one factor considered by a skilled
artisan.
[0102] Depending on the specificity of the preparation, smaller or
larger doses of photosensitizers may be needed. For compositions
which are highly specific to the target skin tissues and cells,
such as those with the photosensitizer conjugated to a highly
specific monoclonal antibody preparation or specific receptor
ligand, dosages in the range of 0.005-10 mg/kg of body weight are
suggested for systemic administration. For compositions which are
less specific to the target, larger dosages, up to 1-20 mg/kg, may
be desirable. The potency of the photosensitizer also determines
the dosage, with less required for highly potent photosensitizers,
and more for photosensitizers with less potency. The preferred
range for use in mice is from about 0.05 mg/kg to about 20 mg/kg.
The useful range in humans for the photosensitizer will be lower
than mice, such as from about 0.005 mg/kg to about 4 mg/kg, and
preferably from about 0.05 to about 2.0 mg/kg.
[0103] For topical formulations (such as ointments) to be applied
to the surface of the skin, the concentration of the
photosensitizer in the excipient can range from about 0.001 to
about 10% w/w, and more preferably from about 0.005 to about 5% w/w
(or about 0.05 to about 1% w/w), and even more preferably between
about 0.1 to about 1% w/w. Particularly preferred is the use of a
0.2% (or about 0.2) w/w topical formulation. The foregoing ranges
are merely suggestive in that the number of variables with regard
to an individual treatment regime is large and considerable
deviation from these values may be expected.
[0104] The skilled artisan is free to vary the foregoing
concentrations so that the uptake and stimulation/restoration
parameters are consistent with the therapeutic objectives disclosed
above. The concentration of a particular photosensitizer to use in
a topical formulation can easily be determined by performing a dose
ranging study similar to the one outlined in the Examples
below.
[0105] Each photosensitizer requires activation with an appropriate
wavelength(s) of electromagnetic radiation. As such, the methods of
the invention may be conducted with any irradiation, preferably
with light, which activates the photosensitizer used. Preferably,
the irradiation contains one or more wavelength which is capable of
penetrating the skin to activate the photosensitizer used. The
wavelength(s) of radiation or light useful in the invention depends
on the activation range of the photosensitizer used as part of the
treatment method. Wavelengths of about 380-900 nanometers (nm) are
preferred, depending upon the photosensitizer and upon the depth of
tissue penetration desired. More preferred are wavelengths from
about 400 to about 900 nm, most preferred from about 400 to about
700 nm. For example, BPD-MA, a green porphyrin derivative, can be
activated by red and blue light as well as ambient light containing
wavelengths from 400-900 nm. Light having a wavelength shorter than
400 nm is acceptable, but not preferred because of the potentially
damaging effects of UVA light.
[0106] Any appropriate activation energy source, depending on the
absorption spectrum of the photosensitizer, may be used for
photosensitizer activation. Preferred sources include, but are not
limited to, lasers, light emitting diodes (LED), incandescent
lamps, arc lamps, standard fluorescent lamps, U.V. lamps, and
combinations thereof. More preferred are lasers, light emitting
diodes, and combinations thereof
[0107] Alternatively any convenient source of activation energy
having a component of wavelengths that are absorbed by the
photosensitizer may be used, for example, an operating room lamp,
or any bright light source, including sunlight. Wavelengths in the
ultraviolet range should, however, may be avoided because of their
mutagenic potential. Therefore, and in some embodiments of the
invention, the activation energy used for the methods herein is not
in the ultraviolet range. Commercially available activation energy
sources include CureLight.TM. (available from Photocure ASA, Oslo,
Norway), BLU-U.TM. (available from DUSA, Wilmington, Mass., USA),
PDT Laser (available from Diomed, Andover, Mass., USA), Ceralas.TM.
(available from Biolitec AG, Jena, Germany), and Q-Beam &
Quanta-med (Quantum Devices Inc., Barneveld, Wis., USA).
[0108] The activation energy dose administered during the PDT
treatment contemplated herein can vary as necessary. Preferably,
for photosensitizers of high potency, such as green porphyrins, the
dosage of the light is about 5-50 J/cm.sup.2 for
systemically-delivered drug and about 25-200 J/cm.sup.2 for
topically-delivered photosensitizers. It is generally preferred
that the total dose of the irradiation should generally not exceed
200 J/cm.sup.2, or more preferably not exceed 100 J/cm.sup.2.
Preferred doses can range between about 0.01 J/cm.sup.2 to about
200 J/cm.sup.2, more preferably 0.1 J/cm.sup.2 to about 100
J/cm.sup.2. For example, about 25, about 50, about 75, about 100,
about 125, about 150, or about 175 J/cm.sup.2. More preferred doses
range from about 25 J/cm.sup.2 to about 100 J/cm.sup.2. Even more
preferred doses range from about 40 J/cm.sup.2 to about 80
J/cm.sup.2, especially about 50 J/cm.sup.2 to about 75 J/cm.sup.2.
Increases in irradiance will generally decrease the light exposure
times. Generally, a higher dose of photosensitizer will decrease
the light dose required to exert a therapeutic effect.
[0109] Normally, the intensity of the light source should not
exceed about 600-1000 mW/cm.sup.2. Irradiances between about 10 and
about 400 mW/cm.sup.2, and more preferably between about 25 and
about 100 mW/cm.sup.2 are preferred.
[0110] Normally, the irradiation lasts from about 10 seconds to
about 4 hours, and preferably between about 5 minutes and 1 hour.
Irradiation times of about 10, about 15, about 20, about 30, about
45, about 60, about 75, about 90, about 105, about 120, about 135,
about 150, about 165 and about 180 minutes may be used.
[0111] While not wishing to be bound by theory, it is believed that
different photosensitizers, different formulations, and different
activation energies will require different parameters in order to
cause hair growth. Such parameters can be determined by simple
dose-ranging studies. For example, a suitable method could involve:
[0112] (a) taking a terminal hair count, [0113] (b) applying the
photosensitizing composition at various strengths, [0114] (c)
waiting for varying lengths of time, [0115] (d) treating with
various activation energy doses, and [0116] (e) reassessing hair
counts.
[0117] Alternatively, the study might involve some other methods of
assessing hair growth such as (visual) assessment of the hair
density, hair weight, and/or hair shaft diameter.
[0118] It is preferred that the present invention not involve a PDT
dose that results in extensive cell death in the treatment area.
PDT dose is determined by two factors, the amount of
photosensitizer present and the amount of activation energy
delivered. While not wishing to be bound by theory, it is believed
that the mechanism by which PDT stimulates hair growth is through
increasing the levels of pro-inflammatory cytokines. It is thought
that these cytokines act through biochemical pathways to cause
susceptible hair follicles to grow terminal hair. It is possible
that there is a specific dose range where the PDT dose is high
enough to increase the level of these pro-inflammatory cytokines
but low enough to avoid unwarranted side-effects such as extensive
cell death and the resultant tissue damage. In addition, as
discussed above, it has been suggested that PDT could be used for
hair removal and, while the inventors have not found that PDT aids
hair removal and not wishing to be bound by theory, it is possible
that at higher doses of PDT may affect the hair follicle in such a
way that hair removal is aided while lower doses of PDT stimulates
an increase in terminal hair numbers. As used herein, the term "low
dose of PDT" refers to dose of PDT that don't result in extensive
cell death.
[0119] It is preferred that the area to be treated have minimal
hair coverage when the activation energy is applied. Therefore, if
there is significant hair coverage of the area to be treated, it is
preferred that the hair is cut short or shaved prior to energy
application. While not wishing to be bound by theory, it is
believed that, due to the fact that hair has a light shielding
function, hair coverage can affect the energy dose that is
delivered to the target area. Consequently, in order to more
accurately deliver the correct light does it is preferred that
there be little or no hair coverage. Alternatively, the shielding
effect of the hair may be compensated for by changes to delivery of
the activation energy.
[0120] The irradiation or light exposure used in the invention may
be directed to a small or large area of the body or scalp depending
on the patch to be treated. Treatment may be preceded with an
assessment of the time of light exposure for the patient's minimal
erythemal dose (MED) occurrence in order to avoid potential burning
of the exposed skin.
[0121] The PDT may be a single treatment but it is preferred that
the treatment is repeated. The frequency may vary. For example, the
treatments could be daily, every two days, twice weekly, weekly,
ever two weeks, twice monthly, every four weeks, monthly, every six
weeks, every eight weeks, every two months, quarterly, twice
annually, or annually, or other suitable time interval to stimulate
hair growth or to maintain the prevailing condition. Preferably,
the treatment is repeated at least once every six months. More
preferably at least once every three months. Even more preferably
at least once every two months.
[0122] The total number of treatments can range from one to as many
as required. In cases where hair loss is observed, maintenance
treatment on a regular basis may be initiated and sustained. It is
preferred that the total number of treatments in any 3 month period
be from 1 to 12, more preferably from 1 to 6, even more preferably
from 2 to 3. Frequencies of 1, 2, 3, 4, 5, 6, or 12 times per 3
month period may also be used.
[0123] The time between administration of photosensitizer and
administration of activation energy will vary depending on a number
of factors. Activation energy delivery can take place at any
suitable time following administration of photosensitizer as long
as there is still photosensitizer present at the skin. Activation
energy treatment within a period of about five minutes to about 6
hours after administration of the photosensitizer is preferred,
with a range of 30 minutes to 4 hours being more preferred. Even
more preferably the light is administered within a period of about
2 hours after administration of the photosensitizer.
Photosensitizers that rapidly accumulate in target tissues can be
activated soon after administration. Photosensitizers that are
cleared from tissues quickly should be activated soon after
accumulation in the target tissues.
[0124] Having now generally described the invention, the same will
be more readily understood through reference to the following
examples which are provided by way of illustration, and are not
intended to be limiting of the present invention, unless
specified.
EXAMPLE 1
Photodynamic Therapy Treatment of C57BL/6 Mice with Alopecia of
Unknown Etiology
[0125] C57BL/6 mice used in this example were purchased from
Jackson Laboratories (Bar Harbor, Me.). After 4 weeks of housing
some of the C57BL/6 mice spontaneously developed a hair loss
condition which resulted in large bald patches (see FIG. 1.1) at 12
to 14 weeks of age. One of these animals was sacrificed and skin
samples were sent for histopathological evaluation. The skin sample
showed no evidence of infection according to a veterinarian's
histopathological examination. The condition was diagnosed as
alopecia of unknown etiology. The presence of an undefined
"mononuclear cell infiltrate" was noted within the affected skin
and, without being bound by theory, may indicate an autoimmune
etiology for alopecia in the mouse.
[0126] Eight mice that were developing hair loss were chosen. Four
mice were randomly picked for the PDT treatment while the remaining
four served as untreated controls. PDT consisted of intravenously
injecting vertporfin in a lipid-based formulation (Visudyne.RTM.,
Novartis Opthalmics, Duluth, Ga.) at a dosage of 1 mg/kg of body
weight per mouse, followed by exposure to 690 nm wavelength red
light at 15 J/cm.sup.2, delivered by an array of light emitting
diode (LED) panels, at 1 hour post-injection. (see Simkin G. et Al.
1997. Inhibition of contact hypersensitivity with different analogs
of benzoporphyrin derivative. Immunopharmacology 37:221-230, which
is incorporated by reference as if fully set forth). This was
followed by two additional PDT treatments on days 7 and 14.
[0127] The mice were observed and photographed on days 0, 13, 21
and 28. FIGS. 1 and 2 show a representative untreated control and a
PDT treated mouse photographed at day 0, day 13, day 21 and day 28.
There was no improvement in the alopecic patches in the untreated
control group of mice (n=4) and in fact, these patches worsened
over the time course of the experiment (FIGS. 1.1 to 1.4). In the
PDT treated group (n=4) there was a startling and impressive hair
growth observed in the alopecic patches after the first and second
treatments as demonstrated in FIGS. 2-2 and 2-3. By day 28, the
previously alopecic patches were covered with what appeared to be a
full complement of hair.
EXAMPLE 2
PDT-Induced Stimulation of Hair Growth Using Topically-Applied
Photosensitizer
[0128] To prepare QLT 0074-containing ointment, QLT 0074
photosensitizer was dissolved in glacial acetic acid to solubilize
it. The solution was then frozen in a dry ice/isopropanol bath and
the acetic acid was removed by lyophilization. The resultant
material was a fine fluffy powder. Analytical testing of the
cryodessicated QLT 0074 indicated that the process did not cause
degradation. The ointment base was prepared by first warming
polyethylene glycol 200 (PEG 200) to 80-90.degree. C. with
stirring. Polyethylene glycol 3350 (PEG 3.35K) was then added with
stirring, followed by oleyl alcohol, and then diethylene glycol
monoethyl ether. Stirring was continued until the solution was
clear. The ointment base was cooled to approximately 50.degree. C.,
and the QLT 0074 was added with stirring. Stirring was continued as
the mixture cooled, until a homogenous paste was achieved. The
ointment contained the following proportions of the components on a
weight/weight basis.
[0129] QLT 0074 (1)
[0130] PEG-200 (108)
[0131] diethylene glycol monoethyl ether Transcutol.RTM. (40)
[0132] PEG-3.35K (32)
[0133] oleyl alcohol (20).
[0134] The concentration of QLT 0074 in the ointment was 0.5%
weight/weight. A placebo ointment was prepared which contained the
excipients, but lacked QLT 0074. The ointments were stored
refrigerated at 2 to 8.degree. C. until use.
[0135] Female Balb/C mice (8-14 weeks old) were supplied by Charles
River Canada (St. Constance, Quebec). Mice were acclimated to
laboratory conditions for seven days prior to release from
quarantine. Cages of animals were held in enclosed ventilated
animal racks in temperature and humidity controlled rooms. Mice
were kept on a standard diet and water ad libitum in a 12 hours
light/dark cycle. Mice were randomly assigned to PDT treatment and
controlled groups, and were monitored for pain or distress.
[0136] Eighteen mice were shaved to remove hair from the back and
both flanks. The right side of each mouse served as a control,
receiving no light and no photosensitizer. QLT 0074-containing
ointment was applied to a square spot on the left side of each of
mice 1-9 using a square template, with the same quantity of
ointment applied to each spot. Placebo formulation was applied to a
square spot on the left side of each of mice 10-18 in the same
manner. After 30 minutes, the excess ointment was removed from the
spots by washing with water using a sterile gauze pad, and then
placebo ointment was applied to the same spots on each of mice
1-18. After 15 minutes, the spots were irradiated with 50 J/cm of
light delivered at a fluence rate of 200 mW/cm.sup.2. Light (688
nm.+-.6 nm) was delivered from a light emitting diode (LED) unit
(Quantum, Model QB-Quanta-Med-688).
[0137] Out of the nine mice treated with QLT 0074, five developed
hair growth on the treated area by day 17. In contrast, none of the
placebo-treated mice developed hair regrowth on the area
corresponding to the treatment area during that period. A
photograph showing hair regrowth on the left side of a
representative QLT 0074-treated mouse at day 17 is shown in FIG. 4.
A mouse treated with placebo is shown in FIG. 3.
[0138] Similar results were obtained in another experiment in which
mice were treated with the same formulation of 0.5% (w/w) QLT 0074,
but a higher light dose of 150 J/ cm.sup.2 was used.
EXAMPLE 3
Optimization of Irradiation Dose and Timing for Photodynamic
Treatment of Alopecia Areata After Intravenous Injection of
Photosensitizer
[0139] This example examines the effect of different irradiation
protocols on PDT treatment of alopecic mice as described above.
[0140] Alopecic mice are divided into control and treatment groups.
The treatment mice are injected with verteporfin in a lipid-based
formulation at 1 mg/kg of body weight, and the control group are
mock injected. Mice from both groups are exposed to red light at
the following doses: 1, 2, 5, 10 and 20 J/cm.sup.2 light LED at 1
hour post-injection, in a manner as described above in Example 1.
Two additional PDT treatments are administered on days 7 and 14
post photosensitizer administration. All mice are monitored over a
5 week period, photographed pre-treatment and on days 6, 13, 20,
27, and 34 post irradiation, and with biopsies taken for
histopathological analysis.
[0141] In a separate experiment, alopecic mice are divided into
control and treatment groups. The treatment mice are injected with
verteporfin at 1 mg/kg of body weight, and the control group are
mock injected. Mice from both groups are exposed to red light at 15
J/cm.sup.2 light LED at 15, 30 and 60 120 and 180 minutes
post-injection, in a manner as described above in Example 1. Two
additional PDT treatments are administered on days 7 and 14 post
photosensitizer administration. All mice are monitored over a 5
week period, photographed pre-treatment and on days 6, 13, 20, 27,
and 34 post irradiation, and with biopsies taken for
histopathological analysis.
EXAMPLE 4
Optimization of Drug Concentration, Irradiation Dose and Light
Intensity on Hair Regrowth in Mice Using Topically-Applied
QLT-0074
[0142] A study was performed to assess the effect of drug
concentration (0.005, 0.05, or 0.5% QLT 0074 ointment), light dose
(50, 100 or 150 J/cm.sup.2 red light) and light intensity 50 or 200
mW/cm.sup.2) on hair regrowth in shaved female Balb/c mice. Mice
received QLT 0074 ointment applied to the skin for 30 minutes,
followed by a 15-minute treatment with placebo ointment and
exposure to red light (688 nm). One group received no QLT 0074
ointment, only the placebo ointment and light exposure. Preparation
of ointments and treatment procedure was as outlined in Example 2,
except that different amounts of QLT 0074 were added.
[0143] Hair regrowth at the treatment site was observed in mice
treated with a QLT 0074 ointment doses of 0.5% combined with light
doses of 50, 100 or 150 J/cm.sup.2 at 200 mW/cm.sup.2. Hair
regrowth at the treatment site was also observed for mice treated
with 0.5% QLT 0074 ointment combined with either 50 or 100
J/cm.sup.2 red light delivered at 50 mW/cm.sup.2. Animals treated
with 0.05% QLT 0074 ointment did not exhibit hair growth at any
light dose, but hair regrowth at the treatment site was observed
for one of three animals treated with 0.005% QLT 0074 ointment and
150 J/cm.sup.2 delivered at 200 mW/cm.sup.2. No hair regrowth
occurred in mice that received placebo ointment only and were
exposed to red light at 200mW/cm.sup.2.
[0144] Ointments were prepared as in Example 2, except that
different amounts of QLT 0074 (on a weight/weight basis) were
incorporated into the ointments. The treatment procedure was as
outlined in Example 2.
[0145] Mild skin reactions were evident following some treatments,
typically at the highest drug and light dose combinations, but no
moderate or severe skin photosensitivity reactions were
observed.
EXAMPLE 5
Stimulation of Hair Growth in Human Subjects with AGA
[0146] A total of 10 subjects were treated. All subjects were human
males over 18 years of age and had type II or III Vertex alopecia,
rated according to the modified Hamilton-Norwood scale.
[0147] All subjects received a single application of topical
QLT0074 ointment 0.2% weight in weight (w/w) to two of three
circular test sites on the vertex area of the scalp. The amount of
ointment applied to each test site was approximately 224 mg (about
0.44 mg of photosensitizer per test site). After 2 hours the excess
drug was removed and red light (LED's--690 nm) was administered to
two of the three sites. The other test site served as a control
with no drug or light administration.
[0148] Two light dose cohorts (50 and 75 J/cm.sup.2) were
investigated with each cohort having 5 subjects.
[0149] Safety was assessed by monitoring all adverse events during
and after the treatment. No serious adverse events were
reported.
[0150] The efficacy was assessed by hair counts 3 months after the
treatment and compared to baseline counts. These results are shown
in Table 3: TABLE-US-00003 TABLE 3 50 J/cm.sup.2 75 J/cm.sup.2 (%
change in terminal hair (% change in terminal hair count) count)
Drug +8% +4% Control -1.7%
[0151] These results show that a single PDT treatment can produce
an increase in hair count in subjects having AGA associated hair
loss.
EXAMPLE 6
Stimulation of Hair Growth in a Mouse Model of Alopecia Areata
[0152] A disease closely resembling human alopecia areata has been
observed in aging (over 6-month old) C3H/HeJ mice (see Sundberg, J.
P et al, Alopecia Areata in Aging C3H/HeJ Mice, Journal of
Investigative Dermatology 102(6): 847-856 [1994[). The C3H/HeJ
mouse model has become recognized as a good model for the study of
the etiology and pathogenesis of alopecia areata and for the
evaluation of treatments for the disease (McElwee, K. J. et al,
Comparison of Alopecia areata in Human and Nonhuman Mammalian
Species, Pathobiology 66:90-107 (1998). A study was carried out to
determine if topical application of QLT0074 ointment could
influence hair re-growth on C3H/HeJ female mice exhibiting hair
loss. The C3H/HeJ mice were obtained from the Jackson Laboratories,
Bar Harbor, Me. Three animals received QLT0074 ointment, prepared
as outlined in Example 2, at 0.2% (w/w) applied onto balding areas
of skin, 1.5.times.1.5 cm in area. All other areas outside of the
treatment site were left untreated.
[0153] Following this treatment, all 3 mice received a dose of 50
J/cm.sup.2 688 nm light delivered at a rate of 50 mw/cm.sup.2 in
the 1.5 square area. Mice were monitored for skin photosensitivity
reactions on Days 1 and 3 after light exposure and observed for
hair re-growth for up to 19 days post-treatment. With QLT0074
ointment and red light treatment, no skin photosensitivity
reactions were observed for mice treated with light. At day 7
post-treatment, an increased amount of hair was observed in the
treatment area of 2 of the 3 mice treated.
[0154] All references cited herein, including patents, patent
applications, and publications, are hereby incorporated by
reference in their entireties, whether previously specifically
incorporated or not.
[0155] Having now fully described this invention, it will be
appreciated by those skilled in the art that the same can be
performed within a wide range of equivalent parameters,
concentrations, and conditions without undue experimentation. This
application is intended to cover any variations, uses, or
adaptations of the invention, following in general the principles
of the invention, that include such departures from the present
disclosure as come within known or customary practice within the
art to which the invention pertains and as may be applied to the
essential features hereinbefore set forth.
* * * * *