U.S. patent application number 15/103656 was filed with the patent office on 2016-12-01 for pulse photodynamic treatment of skin conditions.
The applicant listed for this patent is GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Hans Christian WULF.
Application Number | 20160346392 15/103656 |
Document ID | / |
Family ID | 52007045 |
Filed Date | 2016-12-01 |
United States Patent
Application |
20160346392 |
Kind Code |
A1 |
WULF; Hans Christian |
December 1, 2016 |
PULSE PHOTODYNAMIC TREATMENT OF SKIN CONDITIONS
Abstract
A pulse photodynamic therapy (or pulse PDT) treatment of skin
complaints is described herein. The skin complaint being treated
can be actinic keratosis (AK) or a basal cell carcinoma (BCC).
Inventors: |
WULF; Hans Christian;
(Espergaerde, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA RESEARCH & DEVELOPMENT |
Biot |
|
FR |
|
|
Family ID: |
52007045 |
Appl. No.: |
15/103656 |
Filed: |
December 19, 2014 |
PCT Filed: |
December 19, 2014 |
PCT NO: |
PCT/EP2014/078923 |
371 Date: |
June 10, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 5/062 20130101;
A61N 2005/0652 20130101; A61P 17/00 20180101; A61P 17/16 20180101;
A61N 2005/0657 20130101; A61K 41/0061 20130101; A61M 2037/0061
20130101; A61N 2005/0663 20130101; A61P 43/00 20180101; A61K 31/197
20130101; A61M 2037/0007 20130101; A61P 35/00 20180101; A61K 31/22
20130101; A61P 17/02 20180101; A61M 2037/0023 20130101; A61M 37/00
20130101; A61P 17/10 20180101; A61N 2005/0653 20130101; A61M
37/0015 20130101 |
International
Class: |
A61K 41/00 20060101
A61K041/00; A61M 37/00 20060101 A61M037/00; A61N 5/06 20060101
A61N005/06 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2013 |
EP |
13306826.2 |
Mar 28, 2014 |
EP |
14162516.0 |
Claims
1. A method of treating a skin condition in an animal the method
comprising adminisering a photosensitizer to the animal skin,
wherein the photosensitizer treats the skin condition with
photodynamic therapy (PDT), and wherein the photosensitizer is
applied to the skin of the animal for a short period of time, and
the skin condition is actinic keratosis or basal cell
carcinoma.
2. The method according to claim 1, wherein the method reduces side
effects associated with PDT.
3. The method according to claim 1, further comprising applying the
photosensitizer to the skin of the animal for a period of from 5
minutes to 120 minutes.
4. The method according to claim 1, wherein the PDT includes a
photoactivation achieved by artificial or natural light source.
5. The method according to claim 1, wherein the PDT comprises: a)
administering to the animal a composition comprising the
photosensitizer for a duration of from 5 minutes to 120 minutes;
and b) photoactivating the photosensitizer for a duration of from 1
minute to 15 minutes with artificial light or from 0.5 hour to 3
hours with natural light.
6. The method according to claim 5, wherein the PDT comprises: a)
administering to the animal a composition comprising the
photosensitizer for a duration of from 15 minutes to 60 minutes;
and b) photoactivating the photosensitizer for a duration of from 5
minutes to 10 minutes with artificial light or from 0.5 hour to 2
hours with natural light.
7. The method according to claim 6, wherein PDT comprises: a)
administering to the animal a composition comprising the
photosensitizer for a duration of 30 minutes; and b) removing the
photosensitizer; and c) photoactivating the photosensitizer 2.5
hours later for a duration of 9 minutes with artificial light or of
at least 2 hours with natural light.
8. The method according to claim 1, wherein the photosensitizer is
selected from the group consisting of 5-ALA, 5-ALA derivatives,
5-MAL, 5-MAL derivatives, and compounds covered by general formula
I: R.sup.2.sub.2N--CH.sub.2COCH.sub.2--CH.sub.2CO--OR.sup.1 (I)
wherein: R.sup.1 represents a substituted or unsubstituted
straight, branched or cyclic alkyl group; and each R.sup.2
independently represents a hydrogen atom or an optionally
substituted alkyl group; and pharmaceutically acceptable salts
thereof.
9. The method according to claim 1, wherein the photosensitizer is
5-ALA or 5-methyl ALA ester.
10. The method according to claim 1, wherein administering the
photosensitizer to the animal is carried out with or without
occlusion.
11. The method according to claim 1, wherein the photosensitizer is
used in combination with a glucocorticosteroid.
12. The method according to claim 3, wherein the period of time is
from 15 minutes to 60 minutes.
13. The method according to claim 4, wherein the artificial or
natural light source is a LED or sunlight.
14. The method according to claim 8, wherein the alkyl group is a
substituted or unsubstituted straight-chained alkyl group.
15. The method according to claim 10, wherein the administration of
the photosensitizer is carried out with occlusion.
Description
FIELD OF THE INVENTION
[0001] The present invention is related to a pulse photodynamic
therapy (or pulse PDT) treatment of skin complaints, wherein the
skin complaint is selected in the group consisting of actinic
keratosis (AK) and a basal cell carcinoma (BCC).
BACKGROUND OF THE INVENTION
[0002] Actinic keratosis (AK) is a hyperkeratotic pre-cancerous
epidermal lesion that is known to be caused by frequent and chronic
exposure of the skin to sunlight. The condition typically presents
as small, rough patches of skin approximately 2 mm to 7 mm in
diameter. The patches are usually reddish in color, with rough
texture and whitish or yellow hyperkeratosis. Actinic keratosis
maybe unpleasant or even painful, and untreated may develop to a
malignant tumor (squamous cell carcinoma) Actinic keratosis is most
commonly treated with topical treatments such photodynamic therapy
(ALA, 5-MAL and HAL as photosensitizers)), imiquimod, diclofenac,
or 5-fluorouracil, especially when patients present with multiple
lesions or so called field cancerisation. Alternatively, the
condition may be treated by cryosurgery with liquid nitrogen or
even curettage especially when patients present with few lesions.
Surgery is recommended when there is a suspicion of invasive
SCC.
[0003] Basal cell carcinoma is the most common form of skin cancer
and accounts for more than 90% of all skin cancer in the U.S. These
cancers almost never spread (metastasize) to other parts of the
body, although they can cause damage by growing and invading
surrounding tissue.
[0004] Basal cell carcinomas usually present initially as a small,
dome-shaped nodule often pearl like shiny and translucent and with
superficial blood vessels. Some basal cell carcinomas contain
melanin pigment, making them look dark rather than shiny.
[0005] Photodynamic therapy (PDT), is a technique for the treatment
of various abnormalities or disorders of the skin or other
epithelial organs or mucosa, especially cancers or pre-cancerous
lesions, as well as certain non-malignant lesions (e.g. skin
complaints such as psoriasis, actinic keratosis (AK) and acne). PDT
involves the application of photosensitizing
(photochemotherapeutic) agents to the affected area of the body,
followed by exposure to photoactivating light in order to activate
the photosensitizing agents and convert them into cytotoxic form,
whereby the affected cells are killed (necrosis, apoptosis).
[0006] A range of photosensitizing agents is known, including the
psoralens, the porphyrins (e.g. Photofrin (Registered trademark)),
the chlorins and the phthalocyanins. Amongst the most clinically
useful photosensitizing agents known in the art, however, are
5-aminolevulinic acid and its derivatives, for example esters such
as 5-ALA esters.
[0007] The mechanism of action of PDT relies on intracellular
porphyrins (including PpIX) that are photoactive, fluorescing
compounds and, upon light activation in the presence of oxygen,
singlet oxygen is formed which causes damage to cellular
compartments, in particular the mitochondria. Light activation of
accumulated porphyrins leads to a photochemical reaction and
thereby phototoxicity to the light-exposed target cells.
[0008] Although PDT is clinically useful in the treatment of a wide
range of diseases, a major drawback of such treatment is the
concomitant side-effects, particularly at the treatment site. These
often include inflammation such as erythema, swelling, edema,
burning, itching, exfoliation, hyperpigmentation and prolonged
irritation and hypersensitivity after treatment. Such side-effects
are particularly undesirable when the treatment site is the face,
scalp or neck. This is frequently the case when the PDT is for the
treatment of lesions (e.g. acne, basal cell carcinoma, actinic
keratosis, photodamage and Bowen's disease (BD)).
[0009] The occurrence of such side effects is recognized in
WO2006/051269 which discloses use of 5-ALA esters in PDT for the
treatment of acne. WO2006/051269 describes a study wherein a cream
comprising 16% wt. methyl ALA ester is applied to the faces of
subjects for 3 hours followed by exposure of the subjects' faces to
non-coherent red light (light dose 37 Jkm-2). The treatment was
then repeated 2 weeks later. Although the results confirmed that
PDT with methyl ALA ester is effective in the treatment of acne,
the subjects also indicated that the treatment caused pain and
induced severe inflammation.
[0010] WO02/13788 discloses a similar study on use of ALA acid in
PDT for the treatment of acne. In this case 20% ALA acid was
applied to the backs of the subjects for 3 hours and then the
subjects were exposed to 150 J/cm2 broad band light. Again the
results confirmed that PDT with ALA is effective for the treatment
of acne, but the subjects also reported a plethora of undesirable
side effects. For example, WO02/13788 reports that erythema,
hyperpigmentation and exfoliation were often seen after PDT
treatment and states that in some cases a subsequent treatment even
had to be postponed. Reports of pain, burning and itching during
and after treatment were also common. WO02/13788 discloses the
above-described treatment regime as a "high dose, high energy"
regime and it is said to provide a permanent improvement to acne.
WO02/13788 additionally discloses a "low dose, low energy" regime
that is said to be designed to provide relief from acne. In this
treatment 0.1 to 10% wt. ALA acid is applied, and after waiting for
the ALA acid to penetrate the skin, is followed by irradiation with
a light dose of 1 to 20 J/cm.sup.2. WO02/13788 suggests that this
regime be used in occasional multiple treatments to alleviate acne
and be repeated as necessary to maintain diminishment thereof.
Although it is recognized that use of such a regime may be pain
free, the implication in WO02/13788 is that the therapeutic effect
of this treatment regime is less than the high dose, high energy
regime it describes and exemplifies.
[0011] A need still therefore exists for alternative PDT methods
that are free from undesirable side effects (e.g. inflammation) but
which have high therapeutic efficacy.
[0012] Inflammation and/or erythema is one of the main problems
associated with PDT treatment. It is generally believed that
inflammation is a necessary element/prerequisite in the cure of
AK/BCC/BD by PDT but is not a so big issue for BCCs and BD as the
lesions are often small and hidden by clothes. On the opposite AK
is located on the face mainly where the need to decrease the
downtime is key. A previous, unpublished relation between
inflammation and efficacy of PDT is shown in FIG. 1.
[0013] A need therefore exists for less inflammatory and still
effective methods for treating actinic keratosis and basal cell
carcinoma. The present invention addresses that need.
SUMMARY OF THE INVENTION
[0014] As is described above, the prior art teaches that
inflammation is severe adverse event in the cure of AK and BCC by
PDT. However, the present inventors have surprisingly found that
application of a photosensitizer for a shorter time period that is
classically implemented in a PDT, allows the implementation of a
PDT as efficient as in the case where the photosensitizer is used
for a longer period of time, greatly reduced side effects usually
observed in the prior art PDT protocols, especially
inflammation.
[0015] Therefore, the invention relates to a PDT treatment,
comprising administering to a subject in need thereof a
photosensitizer, in particular 5-MAL, for a short duration and then
removing the photosensitizer from the skin surface. This PDT
protocol is alternatively designated pulse-PDT herein.
[0016] Representative photosensitizers include preferably
5-aminolevulinic acid (5-ALA) and derivatives (e.g. an ester) of
5-ALA, more preferably 5-ALA methyl ester (or 5-MAL), or a
pharmaceutically acceptable salt thereof. In the present uses and
methods, photactivation is achieved by natural or artificial light.
In a particular embodiment, the PDT comprises: [0017] (a)
optionally, preparing the area of skin to be treated with the
appropriate pre-treatment, for example a curettage or micro
perforation [0018] (b) administering to said animal a composition
comprising said photosensitizer for a short duration; and [0019]
(c) photoactivating said photosensitizer.
[0020] In a particular embodiment, the invention relates to a
pulse-PDT treatment, comprising administering to a subject in need
thereof a photosensitizer, in particular 5-MAL, for a short
duration and then removing the photosensitizer from the skin
surface. Photoactivation is then carried out as described
throughout the present application. The pulse-PDT treatment of the
invention ensures high intracellular PPIX and low extracellular
PPIX. Excess amounts of PPIX formation during and after the end of
the treatment are thus avoided. In particular, the inventors show
that the pulse-PDT treatment of the invention shows less
inflammation with unchanged efficacy.
[0021] According to an embodiment, the pulse time during which the
photosensitizer is let on the skin is comprised between 5 and 120
minutes. According to a preferred embodiment, the pulse time during
which the photosensitizer is let on the skin is comprised between
15 and 60 minutes, in particular between 20 and 40 minutes. In a
further particular embodiment, the photosensitizer is administered
for about 30 minutes (e.g. for 25, 26, 27, 28, 29, 30, 31, 32, 33,
34 or 35 minutes, more particularly during 30 minutes). With such a
short photosensitizer treatment, pain level is not changed and PPIX
concentration is clearly lower than for the conventional 3 hour
exposure to 5-MAL for example, but the treatment is as
efficient.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Skin Conditions Treated According to the Invention
[0023] By the term "animal" is meant herein any human or non-human
being. Preferred animals for treatment in accordance with the
invention are humans.
[0024] According to the present invention, a "skin condition"
denotes a disease that can be treated by PDT selected from the
group comprising AK and basal cell carcinoma (BCC).
[0025] Actinic keratoses (AK) are precancerous (premalignant) skin
lesions caused by and associated with chronic exposure to radiant
energy, such as sunlight. Actinic keratosis lesions are small, red,
rough hyperkeratotic lesions occurring on sun exposed areas of the
skin. Actinic keratosis lesions possess many of the same cellular
changes observed in a skin cancer called squamous cell carcinoma
(SCC). Research shows that a mutated version of the p53 gene is
found in sun-damaged cells in the body and is present in more than
about 90% of people who have AK and squamous cell carcinomas.
Although most actinic keratosis lesions do not actually become
cancerous, some lesions can become malignant.
[0026] Actinic keratosis develops in skin cells called
keratinocytes, which are the cells that constitute about 90% of the
epidermis, the outermost layer of skin. Chronic sun exposure, over
time, generates mutations in these cells and causes the cells to
change in size, shape, the way they are organized, and the way they
behave and proliferate. In addition, the proliferation of abnormal
cells can even extend to the dermis, the layer of skin beneath the
epidermis which is called invasive SCC.
[0027] Actinic keratoses (AKs) are common cutaneous lesions
associated with chronic exposure to solar ultraviolet radiation
(UVR). Frost CA and Green AC, Br J Dermatol 1994; 131:455-64. AKs
and squamous cell carcinomas (SCCs) share histologic and molecular
features; therefore, AKs are considered by some experts to be
incipient SCCs. Cockerell CJ, J Am Acad Dermatol 2000; 42(1 Pt2):
11-17. Although some AKs spontaneously regress and the risk of
progression of an individual AK to an invasive SCC is low, AKs tend
to be multifocal and recurrent. Since patients who present with
multiple AKs may be at higher risk for developing an SCC, treatment
of AKs is recommended. Glogau R G, J Am Acad Dermatol 2000; 42
(IPt2):23-24; Criscione V D et al., Cancer 2009:1 15:2523-30; Drake
L A et al., J Am Acad Dermatol 1995; 32:95-98.
[0028] Actinic keratosis lesions generally measure in size between
about 2 to about 7 millimeters in diameter. AK lesions can range in
color from skin-toned to reddish and is often hyperkeratotic. On
occasion, hyperkeratosis associated with AK lesions will form into
the shape of animal horns. When this occurs, the AKs are known as
"cutaneous horns". People who are at higher risk for developing
actinic keratosis tend to be fair-skinned and spend significant
time outdoors, e.g., at work or at play, over the course of many
years. AK lesions usually develop on those areas of the body that
have been constantly exposed to the sun for years. Additionally,
the skin often becomes wrinkled, mottled, and discolored from
chronic sun exposure. Common locations for actinic keratosis
include the face, ears, lips, balding scalp, back of the neck,
upper chest, the tops of the hands and forearms. When AK lesions
develop on the lips, the condition is known as actinic cheilitis.
Actinic cheilitis can be characterized by a diffuse scaling on the
lower lip that cracks and dries. In some cases, the lips will have
a whitish (hyperkeratotic) discoloration on the thickened lip.
[0029] Actinic keratosis is generally more common after age 40,
because actinic keratosis takes years to develop. However, even
younger adults may develop actinic keratosis when living in
geographic areas that are exposed to high-intensity sunlight year
round, such as Florida and Southern California. AK treatments can
be divided into lesion-directed versus field-directed, and
provider-administered and patient-administered treatments. In the
United States, cryosurgery is the most common provider-administered
treatment and is a lesion-directed therapy.
[0030] Basal-cell carcinoma (BCC), a skin cancer, is the most
common cancer.[1] It rarely metastasizes or kills. However, because
it can cause significant destruction and disfigurement by invading
surrounding tissues, it is still considered malignant.
[0031] Basal-cell carcinomas are differentiated toward the
folliculo-sebaceous-apocrine germ, also known as the trichoblast.
Overexposure to sun leads to the formation of thymine dimers, a
form of DNA damage. While DNA repair removes most UV-induced
damage, not all crosslinks are excised. There is, therefore,
cumulative DNA damage leading to mutations. Apart from the
mutagenesis, overexposure to sunlight depresses the local immune
system, possibly decreasing immune surveillance for new tumor
cells.
[0032] Basal-cell carcinoma also develops as a result of Basal-Cell
Nevus Syndrome, or Gorlin Syndrome, which is also characterized by
keratocystic odontogenic tumors of the jaw, palmar or plantar (sole
of the foot) pits, calcification of the falx cerebri (in the center
line of the brain) and rib abnormalities. The cause of the syndrome
is a mutation in the PTCH1 tumor-suppressor gene at chromosome
9q22.3, which inhibits the hedgehog signaling pathway. A mutation
in the SMO gene, which is also on the hedgehog pathway, also causes
basal-cell carcinoma.
[0033] Basal-cell carcinomas may be divided into the following
types according to Freedberg, et al. (2003). Fitzpatrick's
Dermatology in General Medicine. (6th ed.) and James, William D.;
Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin:
clinical Dermatology. Saunders Elsevier:
[0034] Nodular basal-cell carcinoma (also known as "Classic
basal-cell carcinoma") is a cutaneous condition, a subtype of
basal-cell carcinoma, most commonly occurring on the sun-exposed
areas of the head and neck.
[0035] Cystic basal-cell carcinoma is a cutaneous condition
characterized by dome-shaped, blue-gray cystic nodules.
[0036] Cicatricial basal-cell carcinoma (also known as "Morpheaform
basal-cell carcinoma," and "Morphoeic basal-cell carcinoma") is a
cutaneous condition, a subtype of basal-cell carcinoma, and is an
aggressive variant with a distinct clinical and histologic
appearance.
[0037] Infiltrative basal-cell carcinoma is a cutaneous condition
which is an aggressive type of basal-cell carcinoma characterized
by deep infiltration.
[0038] Micronodular basal-cell carcinoma is a cutaneous condition
characterized by a micronodular growth pattern.
[0039] Superficial basal-cell carcinoma (also known as "Superficial
multicentric basal-cell carcinoma") is a cutaneous condition, a
subtype of basal-cell carcinoma, that occurs most commonly on the
trunk and appears as an erythematous patch.
[0040] Pigmented basal-cell carcinoma is a cutaneous condition, a
subtype of basal-cell carcinoma, that exhibits increased
melanization.
[0041] Rodent ulcer (also known as a "Jacobi ulcer") is a large
skin lesion of nodular basal cell carcinoma with central necrosis
and is a type of Basal cell carcinoma
[0042] Fibroepithelioma of Pinkus is a cutaneous condition, a
subtype of basal cell carcinoma, most commonly occurring on the
lower back.
[0043] Polypoid basal-cell carcinoma is a cutaneous condition
characterized by exophytic nodules (polyp-like structures) on the
head and neck.
[0044] Pore-like basal-cell carcinoma is a cutaneous condition
characterized by a basal-cell carcinoma that resembles an enlarged
pore or stellate pit.
[0045] Aberrant basal-cell carcinoma is a cutaneous condition
characterized by the formation of basal-cell carcinoma in the
absence of any apparent carcinogenic factor, occurring in odd sites
such as the scrotum, vulva, perineum, nipple, and axilla.
[0046] Inflammation is a protective response of cells or tissues to
pathogen and external stressful stimuli. During inflammation, the
cells or tissues at a site of injury will stimulate the expression
of specific genes through NF-kB, followed by an increased
expression of chemokines, thereby leading to the accumulation of
polynuclear leukocytes, monocytes, macrophages and mast cells at
the site of injury (i.e., infiltration). The recruited macrophages
will be activated by lipopolysaccharides (LPS) that are expressed
on a surface of a pathogen. The activated macrophages will induce
the expression of proinflammatory genes (inducing cylooxygenase-2
gene, COX-2, and inducible nitric oxide synthase gene, iNOS) to
reinforce inflammatory response. In addition, the activated
macrophages release ROS and free radicals to kill pathogens.
However, prolonged inflammatory response leads to oxidative stress
and damage due to excess accumulation of ROS and free radicals,
thereby resulting in chronic inflammation and ultimately
potentiating the possibility of chronic illnesses or cancer.
[0047] Photosensitizers
[0048] Use of 5-ALA (5-amino-4-oxo-pentanoic acid, otherwise known
as 5-aminolevulinic acid) and derivatives of 5-ALA in PDT is well
known in the scientific and patent literature (see, for example, J.
C. Kennedy et al., J. Clin. Laser Med. Surg. (1996)14:289-304, U.S.
Pat. No. 5,079,262, U.S. Pat. No. 5,211,938, U.S. Pat. No.
5,234,940, U.S. Pat. No. 5,422,093, U.S. Pat. No. 6,034,267,
W091/01727, W096/28412, W02005/092838 and W02006/051269). 5-ALA and
all such derivatives of 5-ALA, as well as their pharmaceutically
acceptable salts, are suitable for the uses and methods herein
described.
[0049] The 5-ALA derivatives useful in accordance with the
invention may be any derivative of 5-ALA capable of forming
protoporphyrin IX (PpIX) or any other photosensitizer (e.g. a PpIX
derivative) in vivo. Typically, such derivatives will be a
precursor of PpIX or of a PpIX derivative (e.g. a PpIX ester) and
which are therefore capable of inducing an accumulation of PpIX at
the site to be treated following administration in vivo. Suitable
precursors of PpIX or PpIX derivatives include 5-ALA prodrugs which
might be able to form 5-ALA in vivo as an intermediate in the
biosynthesis of PpIX or which may be converted (e.g. enzymatically)
to porphyrins without forming 5-ALA as an intermediate. Esters of
5-aminolevulinic acid and N-substituted derivatives thereof are
preferred photosensitizers for use in the invention. Those
compounds in which the 5-amino group is unsubstituted (i.e. the ALA
esters) are particularly preferred. Such compounds are generally
known and described in the literature (see, for example,
W096/28412, W002/10120 and W02005/092838 to PhotoCure ASA). Esters
of 5-aminolevulinic acid with substituted or unsubstituted
alkanols, i.e. alkyl esters are especially preferred
photosensitizers for use in the invention. In particular, 5-MAL and
5-MAL derivatives are particularly preferred. Examples of useful
derivatives include those of general formula I:
R.sup.2.sub.2N--CH.sub.2COCH.sub.2--CH.sub.2CO--OR.sup.1 (I)
[0050] Wherein:
[0051] R.sup.1 represents a substituted or unsubstituted straight,
branched or cyclic alkyl group (e.g. a substituted or unsubstituted
straight-chained alkyl group); and each R.sup.2 independently
represents a hydrogen atom or an optionally substituted alkyl
group, e.g. a group R.sup.1; and pharmaceutically acceptable salts
thereof.
[0052] As used herein, the term "alkyl", unless stated otherwise,
includes any long or short chain, cyclic, straight-chained or
branched aliphatic saturated or unsaturated hydrocarbon group. The
unsaturated alkyl groups may be mono- or polyunsaturated and
include both alkenyl and alkynyl groups. Unless stated otherwise,
such groups may contain up to 40 atoms. However, alkyl groups
containing up to 30, preferably up to 10, particularly preferably
up to 8, especially preferably up to 6, e.g. up to 4 carbon atoms,
for example 1, 2, 3 or 4 carbon atoms, are preferred.
[0053] The substituted alkyl R.sup.1 and R.sup.2 groups may be mono
or poly-substituted.
[0054] Suitable substituents may be selected from hydroxy, alkoxy,
acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, --SR3,
--NR.sup.3.sub.2 and --PR.sup.3.sub.2 groups, and each alkyl group
may be optionally interrupted by one or more --O--, --NR.sup.3--,
--S-- or --PR.sup.3-- groups, in which R.sup.3 is a hydrogen atom
or a C.sub.1-6 alkyl group).
[0055] Preferred substituted alkyl R.sup.1 groups include those
carrying one or more oxo groups, preferably straight-chained
C.sub.4-12 alkyl (e.g. C.sub.8-10 alkyl) groups substituted by one,
two or three (preferably two or three) oxo groups. Examples of such
groups include 3,6-dioxa-1-octyl and 3,6,9-trioxa-1-decyl
groups.
[0056] Particularly preferred for use in the invention are those
compounds of formula I in which at least one R.sup.2 represents a
hydrogen atom. In especially preferred compounds each R.sup.2
represents a hydrogen atom.
[0057] Compounds of formula I in which R.sup.1 represents an
unsubstituted alkyl group (preferably C.sub.1-8 alkyl, e.g.
C.sub.1-6 alkyl) or an alkyl group (e.g. C.sub.1-2 alkyl,
especially C.sub.1 alkyl) substituted by a substituent as
hereinbefore defined (e.g. by an aryl group such as phenyl or by an
alkoxy group such as methoxy) are also preferred.
[0058] Unsubstituted alkyl groups which may be used in the
invention include both branched and straight-chained hydrocarbon
groups. Compounds of formula I in which R.sup.1 is a C.sub.4-8,
preferably a C.sub.5-8, straight chain alkyl group which is
branched by one or more C.sub.1-6 (e.g. C.sub.1-2 alkyl) groups are
preferred. Representative examples of suitable unsubstituted
branched alkyl groups include 2-methylpentyl, 4-methylpentyl,
1-ethylbutyl and 3,3-dimethyl-1-butyl. 4-methylpentyl is
particularly preferred.
[0059] Compounds of formula I in which R.sup.1 is a C.sub.1-10
straight-chained alkyl group are also preferred. Representative
examples of suitable unsubstituted alkyl groups include methyl,
ethyl, propyl, butyl, pentyl, hexyl and octyl (e.g. n-propyl,
n-butyl, n-pentyl, n-hexyl and n-octyl). Hexyl, especially n-hexyl,
is a particularly preferred group. Methyl is also particularly
preferred.
[0060] Also preferred for use in the invention are those compounds
of formula I in which R.sup.1 represents a C.sub.1-2alkyl group
(preferably a C.sub.1 alkyl group) optionally substituted by an
aryl group.
[0061] Still further preferred for use in the invention are those
compounds of formula I in which R.sup.1 represents an alkyl group
(e.g. C.sub.1-2 alkyl, especially C.sub.1 alkyl) substituted by an
aryl group (e.g. phenyl). Preferred substituted alkyl R.sup.1
groups which may be present in compounds of formula I include
C.sub.1-6 alkyl, preferably C.sub.1-4 alkyl, particularly
preferably C.sub.1 or C.sub.2 alkyl (e.g. C.sub.1 alkyl)
substituted (preferably terminally substituted) by an optionally
substituted aryl group.
[0062] By an "aryl group" is meant a group which is aromatic.
Preferred aryl groups comprise up to 20 carbon atoms, more
preferably up to 12 carbon atoms, for example, 10 or 6 carbon
atoms.
[0063] Aryl groups which may be present in the compounds of the
invention may be heteroaromatic (e.g. 5-7 membered heteroaromatics)
but are preferably nonheteroaromatic. By "non-heteroaromatic" is
meant an aryl group having an aromatic system comprising electrons
originating solely from carbon atoms. Preferred aryl groups include
phenyl and napthyl, especially phenyl. In preferred compounds for
use in the invention one or two aryl groups may be present,
preferably one.
[0064] Aryl groups which may be present in the compounds of the
invention may optionally be substituted by one or more (e.g. 1 to
5), more preferably one or two, groups (e.g. one group). Preferably
the aryl group is substituted at the meta or para position, most
preferably the para position. Suitable substituent groups may
include haloalkyl (e.g. trifluoromethyl), alkoxy (i.e. --OR groups
wherein R is preferably a C.sub.1-6 alkyl group), halo (e.g. iodo,
bromo, more especially chloro and fluoro), nitro and C.sub.1-6
alkyl (preferably C.sub.1-4 alkyl). Preferred C.sub.1-6 alkyl
groups include methyl, isopropyl and t-butyl, particularly methyl.
Particularly preferred substituent groups include chloro and nitro.
Still more preferably the aryl group is unsubstituted.
[0065] In a further preferred aspect the invention provides the use
of a photosensitiser which is a compound of formula I wherein
R.sup.1 represents an aryl substituted C.sub.1-4 alkyl group
(preferably C.sub.1-2, e.g. C.sub.1), preferably wherein said aryl
group comprises up to 20 carbon atoms (e.g. up to 12 carbon atoms,
especially 6 carbon atoms) and is itself optionally substituted,
and each R.sup.2 is as hereinbefore described.
[0066] Preferred compounds for use in the invention include methyl
ALA ester, ethyl ALA ester, propyl ALA ester, butyl ALA ester,
pentyl ALA ester, hexyl ALA ester, octyl ALA ester, 2-methoxyethyl
ALA ester, 2-methylpentyl ALA ester, 4-methylpentyl ALA ester,
1-ethylbutyl ALA ester, 3,3-dimethyl-1-butyl ALA ester, benzyl ALA
ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester,
2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester,
4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester,
4-methoxybenzyl ALA ester, 3,4-[dichloro]benzyl ALA ester,
4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl
ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl
ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester,
2-phenylethyl ALA ester, 4-phenylbutyl ALA ester,
3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and
benzyl-5-[(1-acetyloxyethoxy)-carbonyl]amino levulinate.
[0067] Still further preferred compounds for use in the invention
include methyl ALA ester, ethyl ALA ester, 2-methoxyethyl ALA
ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester,
4-methylbenzyl ALA ester, 2-methyl benzyl ALA ester, 3-methyl
benzyl ALA ester, 4[t-butyl]benzyl ALA ester,
4-[trifluoromethyl]benzyl ALA ester, 4-methoxybenzyl ALA ester,
3,4[di-chloro]benzyl ALA ester, 4-chlorobenzyl ALA ester,
4-fluorobenzyl ALA ester, 2-fluorobenzyl ALA ester, 3-fluorobenzyl
ALA ester, 4-nitrobenzyl ALA ester, 2-phenylethyl ALA ester,
4-phenylbutyl ALA ester, 3-pyridinyl-methyl ALA ester,
4-diphenyl-methyl ALA ester and
benzyl-5-[(1-acetyloxyethoxy)-carbonyl]amino levulinate.
[0068] Particularly preferred compounds for use in the invention
include methyl ALA ester, hexyl ALA ester and benzyl ALA ester,
especially methyl ALA ester.
[0069] The compounds for use in the invention may be prepared by
any conventional procedure available in the art (e.g. as described
in WO02/10120 to PhotoCure ASA). For example, esters of 5-ALA may
be prepared by reaction of 5-ALA with the appropriate alcohol in
the presence of acid. Alternatively compounds for use in the
invention may be available commercially (e.g. from Photocure ASA,
Norway).
[0070] Photoactivation
[0071] According to the present invention, photoactivation is
achieved by either an artificial or natural light source. In a
preferred embodiment, photoactivation of the photosensitizer is
achieve by LED or sunlight.
[0072] Light Sources--Artificial
[0073] Electroluminescence (EL) is an optical and electrical
phenomenon in which a material emits light in response to the
passage of an electric current or to a strong electric field. This
is distinct from black body light emission resulting from heat
(incandescence), from a chemical reaction (chemiluminescence),
sound (sonoluminescence), or other mechanical action
(mechanoluminescence).
[0074] Among the electroluminescence sources, LED (Light emitting
diodes) lamps are well known and preferred as artificial light
souce in the present invention. A LED lamp (LED light bulb) is a
solid-state lamp that uses light-emitting diodes (LEDs) as the
source of light. The LEDs involved may be conventional
semiconductor light-emitting diodes, organic LEDs (OLED), or
polymer light-emitting diodes (PLED) devices.
[0075] The LED lamps used in the examples hereafter are defined by
some characteristics like wavelength (in nm), power of the LED (in
mW/cm.sup.2) energy of the LED (in J/cm.sup.2). Such particular
features are provided below.
[0076] Light Sources--Natural
[0077] This aspect of the invention includes photoactivation with
either natural sunlight or any light source which provides
artificial sunlight (i.e. the entire range from UV to IR). Use of
natural sunlight as the light source has the advantage that the
animal being treated is free to leave the clinical environment
where treatment is normally conducted.
[0078] Light Sources--Intensity
[0079] In the uses and methods of the invention, photoactivation
may be achieved using light sources known in the art. Methods for
the irradiation of different areas of the body, e.g. by lamps or
lasers are well known in the art (see for example Van den Bergh,
Chemistry in Britain, May 1986 p. 430-439). The wavelength of light
used for irradiation may be selected to achieve a more efficacious
photosensitizing effect. The most effective light is light in the
wavelength range 300-800 nm, typically within the 400-700 nm range.
The irradiation will in general be applied at a dose level of 30 to
200 Joules/cm.sup.2, for example at 100 Joules/cm.sup.2. A light
source having a fluence rate of 1 to 100 mW/cm.sup.2 may be
used.
[0080] In particularly preferred uses and methods of the invention,
side effects of PDT are further prevented or reduced by
photoactivating with a light source having a fluence rate of less
than 50 mW/cm.sup.2.
[0081] Still more preferably the irradiation is applied at a dose
of 10 to 100 J/cm.sup.2, more preferably 20 to 60 J/cm.sup.2, e.g.
about 37 Joules/cm.sup.2. Penetration of light into tissues depends
on the wavelength used and is deeper for red light than for blue
light.
[0082] Irradiation with an artificial light is preferably performed
for 1 to 30 minutes, preferably for 1 to 15 minutes, more
preferably from 5 to 10 minutes, preferably for 5 minutes,
depending on the light dose and fluence rate. A single irradiation
may be used or alternatively a light split dose in which the light
dose is delivered in a number of fractions, e.g. a 1 to 10 minutes
between irradiations, may be used.
[0083] Photoactivation with natural light is preferably done for a
duration between 30 minutes and 3 hours.
[0084] Treatment of the Skin According to the Invention
[0085] The methods and uses of the invention may involve
pretreatment of the skin. For example, the pretreatment may
comprise curettage, dermoabrasion (e.g. with sandpaper) or
micro-perforation before application of the photosensitizer. In a
particular embodiment, the pretreatment includes perforation of the
skin using an adapted device such as a micro-needling device, for
example a dermaroller.
[0086] The methods and uses of the invention may also be carried
out with or without occlusion, more preferably with occlusion.
[0087] The photosensitizer is applied as a pulse therapy for the
time periods provided above, for example for a duration of about 30
minutes. The inventors herein show that such a pulse therapy has
the advantage of being as efficient as therapy with longer
exposures, but with less PPIX produced, thereby preventing side
effects associated with PPIX.
[0088] Photoactivation is performed after application of the
photosensitizer, preferably after having removed the
photosensitizer from the skin.
[0089] In a particular embodiment, the treatment comprises: [0090]
(a) optionally, preparing the area of skin to be treated with the
appropriate pre-treatment, for example a curettage or micro
perforation, in particular a perforation with an adapted device
micro-needling device such as a dermaroller; [0091] (b)
administering to said animal a composition comprising said
photosensitizer for a short period of time; [0092] (c) optionally,
removing the photosensitizer; an [0093] (c) photoactivating said
photosensitizer.
[0094] In an embodiment of the invention, the pulse photodynamic
therapy (PDT) on an animal comprises: [0095] a) administering to
said animal a composition comprising said photosensitizer for a
duration between 5 min to 120 minutes; [0096] b) optionally,
removing the photosensitizer; and [0097] c) photoactivating said
photosensitizer for a duration between 1 to 15 minutes with
artificial light or 0.5 hour to 3 hours with natural light.
[0098] In a more preferred embodiment of the invention the use of a
photosensitizer in photodynamic therapy (PDT) on an animal
comprises: [0099] a) administering to said animal a composition
comprising said photosensitizer for a duration between 15 min to 60
minutes; [0100] b) optionally, removing the photosensitizer; and
[0101] c) photoactivating said photosensitizer for a duration
between 5 to 10 minutes with artificial light or 0.5 hour to 2
hours with natural light.
[0102] In a more preferred embodiment of the invention the
photosensitizer for use in photodynamic therapy (PDT) on an animal
comprises [0103] a) administering to said animal a composition
comprising said photosensitizer for a duration of 30 minutes; and
[0104] b) optionally, removing the photosensitizer; and [0105] c)
photoactivating said photosensitizer 2.5 hours later for a duration
of 9 minutes with artificial light or of at least 2 hours with
natural light.
[0106] Any of the above particular or preferred embodiments may
comprise a step of pretreating the skin as described above, before
the step of applying the photosensitizer on the skin.
[0107] Furthermore, in a particular embodiment, the PDT according
to the invention also comprises applying to the skin of the subject
a glucocorticosteroid. According to this embodiment, the
glucocorticosteroid is administered for further preventing or
reducing the side effects associated with PDT. The
glucocorticosteroid may be applied either simultaneously, before,
after or both before and after administration of the
photosensitizer. In a particular embodiment, the
glucocorticosteroid is selected from the group consisting of
Clobetasol propionate, Betamethasone dipropionate, Halobetasol
proprionate, Diflorasone diacetate, Diflucortolone valerate,
Hydrocortisone 17-butyrate, Mometasone furoate, Methylprednisolone
aceponate and Halometasone. In a further particular embodiment, the
glucocorticosteroid is Clobetasol propionate or Betamethasone.
BRIEF DESCRIPTION OF THE DRAWINGS
[0108] FIG. 1 is a graph showing the inflammation vs. response rate
(3 months) of AK on the face.
[0109] FIG. 2 is a graph showing the mean increased redness the day
after PDT.
[0110] FIG. 3 is a graph reporting the visual redness 1 day after
PDT with different treatment protocols.
[0111] FIG. 4 is a graph showing the pain scale after different
treatments.
[0112] FIG. 5 is a graph showing the cure rate after different
treatments.
[0113] FIG. 6 is a graph showing the increase in erythema
percentage one day after treatment with different protocols.
[0114] FIG. 7 s a graph showing erythema scale after treatment with
different protocols.
[0115] FIG. 8 is a graph showing the mean photobleaching in the
standard treatment and a different "pulse" treatment.
[0116] FIG. 9 is a graph showing the inflammation (erythema)/PpIX
formation relationship
EXAMPLES
Example 1
PDT Procedure Change to Minimize Inflammation in PDT
[0117] According to the just mentioned theory it would be
preferable to keep PPIX and cellular enzymes away from the
extracellular compartment, thereby avoiding inflammation.
[0118] The purpose of this project is therefore to keep the PPIX
formation within the mitochondria and avoid excess amounts of PPIX
to be formed. Simultaneously PPIX should be allowed to be formed
for such a long time that most unnormal cells will be affected.
[0119] So the purpose of PDT is to kill unnormal cells, preferably
by apoptosis. The ideal situation would be to keep PPIX inside the
cell and to destroy the mitochondria only, thereby inhibiting the
ATP formation necessary for cell functions. That should result in
cell death by apoptosis.
[0120] One possible way to achieve this would be to give a short
5-MAL pulse treatment to get a high concentration of 5-MAL in the
cells initially and then diminish further access to 5-MAL by
removing 5-MAL from the skin surface.
[0121] This could be done by only exposing the skin to 5-MAL for a
short time, after which all 5-MAL is removed from the skin surface.
If the right "pulse time" can be found it might ensure high
cellular PPIX and low extracellular PPIX. Excess amounts of PPIX
formation during and after the end of the treatment would thus be
avoided.
[0122] The result shows less inflammation with unchanged efficacy
and thus mitochondria destruction seems to be the most important
factor in PDT.
[0123] To estimate the preferable Metvix "pulse time" a separate
investigation was performed (Method B) on 24 healthy volunteers.
The pulse time was 20 min., 40 min., 60 min., and the conventional
180 min, after which excess amounts of Metvix was removed from the
skin.
[0124] The formation of PPIX after 3 hours is seen in FIG. 8, and
the relation to inflammation is seen in FIG. 9. It is seen that
PPIX concentration speeds up between 20-40 min. of "pulse
exposure", and so we have chosen 30 min. as the minimum "pulse
exposure" time in the following (Method A) investigation of
efficacy and inflammation by this method change. The results are
illustrated in Column 3 in FIGS. 4, 5, 6, and 7. The procedure
change clearly diminishes inflammation (erythema), without
affecting the cure rate (FIG. 5). Pain level is not changed. PPIX
concentration is clearly lower than for the conventional 3-hour
exposure to Metvix (Table 1 and FIG. 8).
[0125] Methods
[0126] Healthy Volunteers
[0127] Twenty-four healthy male volunteers of Scandinavian ancestry
were included in the study (mean age 30 years, range 20-51). A
treatment area was selected on the inside of both forearms of the
volunteer. Each treatment area was divided into four minor
treatment fields of the size 2.times.5 cm with at least 3 cm
between each field using a prefabricated flexible template. In
order to imitate skin lesions all fields were tape stripped 10
times with occlusive dressing before treatment (Tegaderm.TM. Roll,
3M, Glostrup, Denmark).
[0128] On the left forearm vehicle Unguentum M was applied to the
treatment field.
[0129] On the right forearm excess amounts of 5-MAL 16 %
(Metvix.RTM., Photocure, Oslo, Norway) were applied to all four
fields of treatment. All fields were covered with
light-impermeable, occlusive dressing. After 20 minutes the
dressing was removed from the first field and the excess cream
gently wiped off. The field was covered again with a thin piece of
gauze and light impermeable dressing. After additional 20 and 40
min same procedure was followed with the second and third field.
180 min after application of 5-MAL and vehicle was removed from all
five fields, and the excess cream was gently wiped of the last
field. All fields were illuminated with red light. Illumination was
performed with red LED light 630 nm peak (Aktilite.TM. 128;
Photocure ASA, Oslo Norway) using a total light dose of 37
J/cm.sup.2 given over 9 min. During and after illumination pain was
recorded. The volunteers were equipped with a special diary for
recording pain in the days after treatment. Four follow-up visits
were performed at day 1,2,3 and 8 after treatment.
[0130] PpIX Fluorescence
[0131] 5-MAL-induced PpIX fluorescence was depicted non-invasively
using a fluorescence camera (Medeikonos AB, Gothenburg, Sweden).
The amount of PpIX fluorescence was calculated from the photographs
by the program MatLab.RTM. (MatLab.RTM., MathWorks, Natic, US). The
amount of fluorescence was measured before tape stripping and cream
application (baseline) and before and after illumination.
[0132] The photo bleaching is then the difference in PpIX
fluorescence (AU) calculated from the pre and post illumination
images.
[0133] Erythema and Pigmentation
[0134] As an indicator of inflammation erythema was measured. The
erythema was assessed by an expert evaluator and measured
objectively.
[0135] The objective measurements of erythema and pigmentation were
performed using a skin reflectance meter (Optimize Scientific 558,
Chromo-Light, Espergaerde, Denmark).
[0136] Erythema % and pigmentation % were measured before
treatment, immediately before illumination, immediately after
illumination, and at the four follow-up visits.
[0137] Pain Score
[0138] The volunteers scored their pain every minute during
illumination, and recorded their pain in the diary every hour after
illumination on the treatment day, twice per day the next three
days and once a day on the following five days. Since PDT was
performed at different times of the day the number of evaluations
differed from 3 to 11 the first day. Pain was assessed using a
numerical scale ranging from 0 to 10, where 0 is no pain and 10 is
worst imaginable pain. To make it easier for the patients to
identify the different treated fields, the dairy was supplied with
numbered drawings of the fields.
[0139] Randomizing
[0140] The study was designed as an open randomised trial. A
statistical adviser made the randomisation. Since the sequence of
treatment duration was predefined, randomization was only
determining which of the four treatment fields should be the
first.
[0141] Statistics
[0142] The sample size was calculated on the bases of data from the
literature. We set the minimal clinical relevant difference to 8.8
% (50% of the earlier found 17.6%) and choose a power of 0.80 and a
significance level of 0.05, 22 volunteers should be included.
[0143] To identify differences in pain score, erythema% and
pigmentation% between the treatment fields we used Wilcoxon Signed
Ranked Test, since all results were paired.
[0144] For all calculations a p-value <0.05 was considered
statistical significant. All analyses were performed with PASW
Statistics 19.0 for Windows (SPSS Inc, Chicago, Ill., USA).
* * * * *