AU2009228664B2 - Therapy for vitiligo - Google Patents
Therapy for vitiligoInfo
- Publication number
- AU2009228664B2 AU2009228664B2 AU2009228664A AU2009228664A AU2009228664B2 AU 2009228664 B2 AU2009228664 B2 AU 2009228664B2 AU 2009228664 A AU2009228664 A AU 2009228664A AU 2009228664 A AU2009228664 A AU 2009228664A AU 2009228664 B2 AU2009228664 B2 AU 2009228664B2
- Authority
- AU
- Australia
- Prior art keywords
- phe
- msh
- alpha
- arg
- trp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 206010047642 Vitiligo Diseases 0.000 title claims description 37
- 238000002560 therapeutic procedure Methods 0.000 title description 7
- -1 n-Pentadecanoyl Chemical group 0.000 claims description 64
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- 239000000203 mixture Substances 0.000 claims description 46
- 239000008194 pharmaceutical composition Substances 0.000 claims description 38
- 238000012384 transportation and delivery Methods 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 25
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 21
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 21
- 229960003444 immunosuppressant agent Drugs 0.000 claims description 21
- 239000003018 immunosuppressive agent Substances 0.000 claims description 21
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Description
Therapy for vitiligo FIELD OF THE INVENTION
The present invention relates to a therapy for vitiligo. In particular the present invention provides a pharmaceutical composition comprising an alpha melanocyte stimulating hormone (alpha-MSH) analogue either alone or in combination with one or more corticosteroid, immunosuppressant, anti-inflammatory agent and/or photochemotherapeutic agent for the treatment or prevention of vitiligo.
BACKGROUND OF THE INVENTION
Vitiligo is a chronic skin condition that causes loss of pigment, including melanin, resulting in irregular pale patches of skin. The precise etiology of vitiligo is complex and not fully understood although there is some evidence to suggest it is caused by a combination of auto-immune, genetic and environmental factors.
As many as 50% of people with vitiligo develop patches of de-pigmentεd skin appearing on extremities before their 20s. The patches may grow or remain constant in size and often occur symmetrically across both sides on the body. Occasionally small areas may repigment as they are "recolonised" by melanocytes and following melanin production and release. The location of vitiligo affected skin changes over time, with some patches re- pigmenting and others becoming affected. In some cases, mild trauma to an area of skin seems to cause new patches, for example, around the ankles (caused by friction with shoes or sneakers). Vitiligo may also be caused by stress factors that affect the immune system, causing the body to react or respond by "eliminating" or gradually loose the ability to produce and release melanin, skin pigment. Further, Vitiligo on the scalp may also affect the colour of the hair leaving white patches or streaks, with similar effects observed for facial and body hair.
There, are a number of ways to alter the appearance of vitiligo without addressing its underlying cause. In mild cases, vitiligo patches can be hidden with makeup or other cosmetic solutions. If the affected person is pale-skinned, the patches can be made less visible by avoiding sunlight and the sun tanning of unaffected skin. However, exposure to
sunlight may also cause the melanocytes to regenerate to allow the pigmentation to come back to its original colour.
Treatment options include medical treatments, surgical therapies and adjunctive treatments. Pharmaceuticals include topical steroid therapy, topical or oral psoralen phototherapy and depigmentation. Surgical therapies include skin grafts, melanocyte transplantations and micropigmentation or tattooing, while adjunctive therapies include sunscreens and cosmetics.
Despite the fact that many treatment options are available, each suffers from its own disadvantages and inherent limitations. For example, phototherapy involves exposing an individual to narrow band UV-B light (NB-UVB) resulting in skin re-pigmentation. Although phototherapy provides an effective short-term treatment option, repeiitive exposure to NB-UVB light is needed to achieve continuous re-pigmentation. Further, while the frequency of exposure to NB-UVB light varies from individual to individual, repetitive exposure may result in unwanted side-effects including mild burning, blistering and skin irritations. Foremost, the repetitive treatment by LIV-B increases the risk of inducing skin malignancies, e.g squamous cell carcinomas and basal cell carcinomas [Journal of Investigative Dermatology (2005) 124, 505-513; High Levels of Ultraviolet B Exposure Increase the Risk of Non-Melanoma Skin Cancer in Psoralen and Ultraviolet A- Treated Patients] [Mayo Clinics update].
Topical corticosteroid therapy has a reported success rate of up to 56%, however, long- term use of corticosteroids can result in thinning of the skin, stretch marks, and dilation of blood vessels. Further, treatment with oral or topical psoralen plus UVA (PUVA) has proven successful, however, patients need to ingest or apply psoralen before receiving the light treatment, and long term use of oral PUVA for the treatment of psoriasis has been associated with an increased incidence of skin cancer.
While immunomodulator creams are believed to cause repigmentation there is little or no scientific support to back this claim.
A need therefore exists to develop more effective treatments for vitiligo.
SUMMARY OF THE INVENTION
In a first aspect of the present invention there is provided a method for treating or preventing vitiligo in a subject comprising administering to the subject a therapeutically or prophyiactically effective amount of an alpha-MSH analogue.
In a second aspect of the present invention there is provided the use of an alpha-MSH analogue for the manufacture of a prophylactic or therapeutic agent for the treatment or prevention of vitiligo in a subject.
In a preferred embodiment the method further comprises administering to the subject one or more agents selected from the group consisting of corticosteroids, immunosuppressants, anti-inflammatory agents and a photochemotherapeutic agents.
In a third aspect of the present invention there is provided a pharmaceutical composition for treating or preventing vitiligo comprising an alpha-MSH analogue and one or more agents selected from the group consisting of corticosteroids, immunosuppressants, anti-inflammatory agents and a photochemotherapeutic agents together with a pharmaceutically acceptable carrier or diluent.
In a fourth aspect of the present invention there is provided a method for treating or preventing vitiligo in a subject comprising administering to the subject a therapeutically or prophyiactically effective amount of a pharmaceutical composition according to the third aspect of the invention.
In a fifth aspect of the present invention there is provided the use of an effective amount of a pharmaceutical composition according to the third aspect of the invention for the manufacture of a prophylactic or therapeutic medicament for the treatment or prevention of vitiligo in a subject.
DETAILED DESCRIPTION OF THE INVENTION
Before the present methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific methods or uses as such may, of course, vary It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.
In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:
It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.
The terms "optional" or "optionally" as used herein means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about" it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
References in the specification and concluding claims to parts by weight, of a particular element or component in a composition or article, denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.
The term "contacting" as used herein is meant an instance of exposure by close physical contact of at least one substance to another substance. For example, contacting can include contacting a substance, such as a pharmacologic agent, with a cell. A cell can be contacted with a test compound, for example, an analogue of alpha-MSH, by adding the agent to the
culture medium (by continuous infusion, by bolus delivery, or by changing the medium to a medium that contains the agent) or by adding the agent to the extracellular fluid in vivo (by local delivery, systemic delivery, intravenous injection, bolus delivery, or continuous infusion). The duration of contact with a cell or group of cells is determined by the time the test compound is present at physiologically effective levels or at presumed physiologically effective levels in the medium or extracellular fluid bathing the cell.
The teπns "prophylactic treatment", "prevention" or "preventing" as used herein mean the administration of an active compound or composition to a subject at risk for an undesirable condition. The condition can include a disease, disorder or reaction, or a predisposition to a disease, disorder or reaction. Prophylactic treatment can range from a reduction in the risk for the condition or of the severity of the condition to the complete prevention of the condition.
The terms "therapeutic treatment" and "treating" mean the administration of an active compound or composition to a subject having an undesirable condition such as a disease, disorder or reaction. Therapeutic treatment can range from reduction in the severity of the condition in the subject to the complete recovery of the subject from the condition.
The term "effective amount and time" as used herein means a therapeutic amount and time needed to achieve the desired result or results, e.g., preventing or treating photosensitivity associated with UVR exposure in a subject.
The term "induce" as used herein means initiating a desired response or result that was not present prior to the induction step. The term "induce" also includes the term "potentiate".
The term "intermittent" as used herein means administering an active compound or composition in a series of discreet doses over a determined period, e.g., a period of sustained release comprising of greater than 24 hours of an alpha-MSH analogue for up to 3 months.
The term "potentiate" as used herein means sustaining a desired response at the same level prior to the potentiating step or increasing the desired response over a period of time.
The term '"melanogenesis" as used herein is defined as the ability of a subject to produce melanins by melanin-producing cells, or melanocytes.
The term "epidermal tissue" as used herein includes in particular the skin of a subject.
The Invention
The invention pertains to methods and compositions for treatment of vitiligo utilising an alpha-MSH analogue.
In a first aspect of the present invention there is provided a method for treating or preventing vitiligo in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of an alpha-MSH analogue.
In a second aspect of the present invention there is provided the use of an alpha-MSH analogue for the manufacture of a prophylactic or therapeutic agent for the treatment or prevention of vitiligo in a subject.
In a preferred embodiment the method further comprises administering to the subject one or more agents selected from the group consisting of corticosteroids, immunosuppressants, anti-inflammatory agents and a photochemotherapeutic agents.
In a third aspect of the present invention there is provided a pharmaceutical composition for treating or preventing vitiligo comprising an alpha-MSH analogue and one or more agents selected from the group consisting of corticosteroids, immunosuppressants, anti-inflammatory agents and a photochemotherapeutic agents together with a pharmaceutically acceptable carrier or diluent.
In a fourth aspect of the present invention there is provided a method for treating or preventing vitiligo in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a pharmaceutical composition according to the third aspect of the invention.
In a fifth aspect of the present invention there is provided the use of an effective amount of a pharmaceutical composition according to the third aspect of the invention for the manufacture of a prophylactic or therapeutic medicament for the treatment or prevention of vitiligo in a subject.
Preferably the subject is a human or domestic animal subject. Most preferably the subject is a human subject.
It is also preferred that treatment with the alpha-MSH analogue commences as early as possible following appearance of the condition.
Alpha-MSH is released from UVR exposed keratinocytes in human skin following exposure to ultraviolet radiation. It is understood to act on the melanocortin- 1 -receptors (MClR) to, exclusively in melanocytes, induce synthesis of the brownish-black melanin pigment. MClR are expressed on keratinocytes as well as number of other cells including, but not exclusively, immunological cells such as dendritic / Langerhans cells, neutrophils, microglia and monocytes as well as astrocytes, and endothelial cells.
It has previously been disclosed that a super-potent derivative of alpha-MSH, Nle4-D-Phe'-α- MSH, can induce melanin synthesis in human volunteers. Nle4-D-Phe7-α- MSH contains two amino acid substitutions and is approximately 10 to 1 , 000-fold more potent than the native hormone at inducing pigmentation in experimental systems such as the frog skin bioassayor in cultured human keratinocytes.
The term "alpha-MSH analogue" as used herein is defined as a derivative of alpha-MSH which exhibits agonist activity for the melanocortin- 1 receptor (MClR), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte. Such derivatives include derivatives in which (i) one or more amino acid residues are deleted from the native alpha-MSH molecule at the N-tenninal end, the C-terminal end, or both; and/or (ii) one or more amino acid residues of the native alpha-MSH molecule are replaced by another natural, non-natural or synthetic amino acid residue; and/or (iii) an intramolecular interaction forms as a cyclic derivative
The use of any alpha-MSH analogue is contemplated in the methods described herein. Several derivatives of alpha-MSH have been synthesized. In one aspect of the present invention, the alpha-MSH analogues described in US Patents Nos. 4,457,864, 4,485,039, 4,866,038, 4,918,055, 5,049,547, 5,674,839 and 5,714,576 and Australian Patents Nos. 597630 and 618733, which are herein incorporated by reference for their teachings with respect to alpha-MSH analogues and their synthesis thereof, can be used herein.
In one aspect of the present invention, the alpha-MSH analogue may be a compound as disclosed in Australian Patent No. 597630, selected from compounds of the formula:
R1-W-X-Y-Z-R2
wherein
R1 is absent; n-Pentadecanoyl, Ac, 4-phenylbutyryl; Ac-GIy-, Ac-Met-Glu, Ac-NIe-GIu-, or Ac-T>τ-Glu-;
W is -His- or -D-HiS-;
X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO2)D-Phe7-;
Y is -Arg- or -D-Arg-;
Z is -Tip- or -D-Trp-; and
R2 is -NH2; -GIy-NH2; or -GIy-LyS-NH2.
In another aspect, the alpha-MSH analogue maybe selected from cyclic analogues which are disclosed in Australian Patent No. 618733 where an intramolecular interaction (such as a disulfide or other covalent bond) exists (1) between the amino acid residue at position 4 and an amino acid residue at position 10 or 115 and/or (2) between the amino acid residue at position 5 and the amino acid residue at position 10 or 11.
The alpha-MSH analogue may be a linear analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:
Ac-Ser-T>τ-Ser-Nle-G!u-His-D-Phε-Arg-Trp-Lys-Gly-Pro-Val-NH2
Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Giy-Pro-Val-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro- VaI-NH2
Ac-NIe- Asp-His-D-Phe-Arg-Trp-Gly-NH2
Ac-Nle-Glu-His-D-Phε-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-D-Phε-Arg-Trp-Lys-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH2
Ac-Nle-Asp-His-D-Phε-Arg-Trp-Orn-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dab-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dab-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dpr-NH2
Ac-Nle-Glu-His-L-Phe-Aτg-Trp-Lys-NH2
Ac-Nle-Asp-His-L-Phe-Arg-Trp-Lys-NH2
The alpha-MSH analogue may also be a cyclic analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NHz
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-D-Phε-Arg-Trp-Lys-NH2
Ac-NIe- Asp-His-D-Phε-Arg-Trp-Om-NH2
Ac-Nle-Asp-Kis-D-Phe-Arg-Trp-Dab-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dpr-NH2
I I
Ac-Ser-Tyr-Ser-Nlc-Asp-His-D-Phe-Arg-Trp-Lys-Gly-PiO-Val-NH2
Ac-Ser-Try-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-NH2
Ac-Nie-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro- VaI-NH2
Ac-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2
wherein Ala = alanine, Arg = arginine, Dab — 2,4-diaminobutyric acid, Dpr = 2,3- diaminopropionic acid, GIu = glutamic acid, GIy = glycine, His = histidine, Lys = lysine, Met = methionine, NIe = norleucine, Orn = ornithine, Phe ~ phenylalanine, (pNO2)Phe = paranitrophenylalanine, PIg = phenylglycine, Pro = proline, Ser = serine, Trp = tryptophan, TrpFor = N1" formyl-tryptophan, Tyr = tyrosine, VaI = valine.
All peptides are written with the acyl-terminal end at the left and the amino terminal end to the right; the prefix "D" before an amino acid designates the D-isomer configuration, and unless specifically designated otherwise, all amino acids are in the L-isomer configuration.
In one aspect of the present invention, the alpha-MSH analogue can be
[D-Phe7]-alpha-MSH,
gue is:
r
In a particularly preferred aspect, the alpha-MSH analogue is [NIe4, D-Phe7]-alpha-MSH.
The pharmaceutical composition according to the first aspect of the invention further comprises one or more agents selected from the group consisting of corticosteroids, immunosuppressants, anti-inflammatory agents and photochemotherapeutic agents.
The corticoseriod according to the invention may be selected from the group consisting of mometasone furoate, betamethasone, dexamethasone, hydrocortisone, methylprednisolone. prednisolone and cortisone. It is particularly preferred that the corticosteroid is mometasone furoate or betamethasone.
The immunosuppressant according to the invention may be selected from the group consisting of cytostatics including cytotoxic antibiotics, alkylating agents and antimetabolites, antibodies, glucocorticoids, drugs acting on immunophilins including cyciosporine, tacrolimus and sirolimus, interferons, azathioprine, 5-fluorouracil and opioids. It is particularly preferred that the immunosuppressant is selected from the group consisting of tacrolimus, betamethasone, azathioprine and levamisole.
The anti-inflammatory agent according to the invention may be selected from the group consisting of betamethasone, cortisone. It is particularly preferred that the antiinflammatory agent is betamethasone or cortisone.
It is preferred that the photochemotherapeutic agent according to the invention is psoralen.
As will be appreciated by a person skilled in the art, corticosteroids according to the invention may act as an immunosuppressant and/or anti-inflammatory agent. For example, the dipropionate salt of betamethasone (trade name Diprosone) is a glucocorticoid which acts as both an immunosuppressant and an anti-inflammatory agent.
In a second aspect of the present invention there is provided a method for treating or preventing vitiligo in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a pharmaceutical composition according to the first aspect of the invention.
In a preferred embodiment, the method according to the second aspect of the invention further comprises the step of exposing the subject to an effective amount of ultra-violet A light (UVA) when the pharmaceutical composition administered to the subject comprises one or more photochemotherapeutic agents.
It is know to persons skilled in the art that photochemotherapeutic agents such as psoralens make the skin sensitive to ultra-violet (TJV) light, particularly the long wavelength UVA light. Administration of psoralen prior to UVA exposure is known to be effective for treating vitiligo.
Accordingly in a preferred aspect of the present invention the pharmaceutical composition is administered to the subject prior to exposure to UVA light.
The pharmaceutical composition according to the invention may be administered in a sustained-release delivery system as disclosed in International Patent Application No. PCT/AU2005/000181 (WO 2006/012667), or topically using a transdermal delivery system as disclosed in International Patent Application No. PCT/AU2005/001 552 (WO 2006/037188).
It will be appreciated that the actual preferred amounts of the alpha-MSH analogue and corticosteroid, immunosuppressant, anti-inflammatory agent and/or photochemotherapeutic agent (hereinafter referred to as the "active pharmaceutical ingredients") will vary according to the specific compounds being utilized, the particular compositions formulated, the mode of application, and the particular situs and subject being treated. Dosages for a given host can be determined using conventional considerations, e.g. by customary comparison of the differential activities of the subject compounds and of a known agent, e.g. by means of an appropriate conventional pharmacological protocol. Physicians and fonnulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining doses for prophylactically or therapeutically treating vitiligo by administration of an amount of a pharmaceutical composition of the invention by the methods described herein. In one aspect of the present invention, the pharmaceutical composition is administered in an amount which is effective to prophylactically or therapeutically treat vitiligo.
Any of the alpha-MSH analogues useful herein can be administered to a subject using a variety of administration or delivery techniques known in the art. It is desirable to maintain low concentrations (eg concentrations of O.OOlng to 10ng/ml) of the alpha-MSH analogue in the plasma of the subject in the treatment υf vitiligo. In one preferred embodiment the alpha-MSH analogue is administered in a prolonged release formulation such as described in WO 2006/012667, the disclosure of which is included herein by cross reference. Therefore, the mode of administration will depend upon the subject to be treated and the alpha-MSH analogue selected. In various aspects, the alpha-MSH analogues can be administered orally or parenterally. The term "oral" is used herein to encompass administration of the compounds via the digestive tract. The term "parenteral" is used herein to encompass any route of administration, other than oral administration, by which the alpha-MSH analogue is introduced into the systemic circulation which includes, but is not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal, ocular, inhalable, iectai, vaginal, transdermal, topical, buccal, sublingual, or mucosal administration. The term "mucosal" as used herein encompasses the administration of the compounds by methods that employ the mucosa (mucous membranes) of the human body such as, but not limited to, buccal, intranasal, gingival, vaginal, sublingual, pulmonary, or rectal tissue. The term "transdermal" as used herein encompasses the administration of the
compounds that go into the skin or go through the skin using formulations such as, but not limited to, transdermal formulations, buccal patches, skin patches, or transdermal patches. The term "topical" as used herein encompasses administration by applying conventional topical preparations such as creams, gels, or solutions for localized percutaneous delivery and/or by solution for systemic and/or localized delivery to areas such as, but not limited to the eye, skin, rectum, and vagina.
In one aspect of the present invention, delivery systems composed of devices or compositions containing an alpha-MSH analogue together with one or more corticosteroid, immunosuppressant, anti-inflammatory agent or photochemotherapeutic agent can be manufactured that allow for the controlled-release, extended-release, modified-release, sustained-release, pulsatile-release, or programmed-release delivery of the active components in order to maintain concentration of the active components in the plasma of the subject.
Depending on the delivery system or composition of a formulation or route of administration chosen, drugs or active pharmaceutical ingredients can be delivered for hours, weeks, or months following a single administration. Drug-delivery devices include, but are not limited to pumps, needle-free injectors, metered-dose inhalers, and the like. Transdermal compositions with or without penetration enhancers include but are not limited to transdermal patches, microneedles, and transdermal formulations that achieve drug delivery using inotophoresis, sonophoresis, electroporation, thermoporation, perfusion, adsorption and absorption. Other delivery systems include, but are not limited to, biodegradable of ncn-biodεgradable rods or other shaped implants, fibers, microparticles, microspheres, microcapsules, nanospheres, nanocapsules, porous silicon nanoparticles, in situ gelling formulations, in situ bolus forming compositions, quick dissolving tablets and the like, buccal patches, films, tablets, capsules, osmotic pressure driven formulations, liquid filled capsules, liposomes and other lipid based compositions and the like, pegalation and the like, hydrogel formulations, emulsions, microemulsions, and suspensions.
In one aspect of the present invention, polymeric delivery systems can be microparticles including, but not limited to microspheres, microcapsules, nanospheres and nanoparticles comprising biodegradable pol ymeric excipients, non-biodegradable polymeric excipients,
or mixtures of polymeric excipients thereof, or the polymeric delivery systems can be, but not limited to rods or other various shaped implants, wafers, fibers, films, in situ forming boluses and the like comprising biodegradable polymeric excipients, non-biodegradable polymeric excipients, or mixtures thereof. These systems can be made from a single polymeric excipient or a mixture or blend of two or more polymeric excipients.
A suitable polymeric excipient includes, but is not limited to, a poly(diene) such as poly(butadiene) and the like; a poly(alkene) such as polyethylene, polypropylene, and the like; a poly(acrylic) such as poly(acrylic acid) and the like; a poly(methacrylic) such as poly(methyl methacrylate), a poly(hydroxyethyl methacrylate), and the like; a poiy(vinyl ether); a poly(vinyl alcohol); a poly(vinyl ketone); a poly(vinyl halide) such as poly( vinyl chloride) and the like; a poly(vinyl nitrile), a poly(vinyl ester) such as poly(vinyi acetate) and the like; a poly(vinyl pyridine) such as poly(2-vinyl pyridine), poly(5-mεthyl-2-vinyl pyridine) and the like; a poly(styrene); a poly(carbonate); a poly(ester); a poly(orthoester) including a copolymer; a poly(esteramide); a poly( anhydride); a poly(urethane); a poly(amide); a cellulose ether such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and the like; a cellulose ester such as cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, and the like; a poly(saccharide), a protein, gelatin, starch, gum, a resin, and the like. These materials may be used alone, as physical mixtures (blends), or as co-polymers. Derivatives of any of the polymers listed above are also contemplated.
In one aspect of the present invention, the polymeric excipieni of the delivery system includes a biocompatible, non-biodegradable polymer such as, for example, a silicone, a polyacrylate; a polymer of ethylene- vinyl acetate; an acyl substituted cellulose acetate; a non-degradable polyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl fluoride; a poly(vinyi imidazole); a chlorosulphonate polyolefm; a polyethylene oxide; or a blend or copolymer thereof.
In another aspect, the polymeric excipient includes a biocompatible, biodegradable polymer such as, for example, a poly(lactide); a ρoly(glycolide); a poly(lactide-co- glycolide); a poly(lactic acid); a poly(glycolic acid); a poly(lactic acid-co-glycolic acid); a poly(caprolactone); a poly(orthoester); a poly(phosphazene); a poly(hydroxybutyrate) or a copolymer containing a ρoly(hydroxybuiarate); a poly(laciide-co-caproiactone); a
polycarbonate; a polyesteramide; a polyanhydride; a poly(dioxanone); a poly(alkylene alkylate); a copolymer of polyethylene glycol and a polyorthoester; a biodegradable polyurethane; a poly(amino acid); a polyetherester; a polyacetal; a polycyanoacrylate; a poly(oxyethylene)/poly(oxypropylene) copolymer, or a blend or copolymer thereof.
In one aspect of the present invention, the delivery system comprises an implant or rod, wherein the implant or rod comprises a biodegradable polymer, wherein the pharmaceutical composition of the invention is embedded within the implant or rod. In another aspect of the present invention, the pharmaceutical composition of the invention is encapsulated in an implant or rod composed of poly(lactide-co-glycolide), poly(lactide), poly(glycolide), or a mixture thereof. Lactide/glycolide polymers for drug-delivery formulations are typically made by melt polymerization through the ring opening of lactide and glycolide monomers. Some polymers are available with or without carboxylic acid end groups. When the end group of the poly(lactide-co-glycolide), poly(lactide), or poly(glycolide) is not a carboxylic acid, for example, an ester, then the resultant polymer is referred to herein as blocked or capped. The unblocked polymer, conversely, has a terminal carboxylic group. In another aspect of the present invention, linear lactide/glycolide polymers are used; however star polymers can be used as well. In certain aspects, high molecular weight polymers can be used for medical devices, for example, to meet strength requirements. In other aspects, low molecular weight polymers can be used for drug-delivery and vaccine delivery products where resorption time and not material strength is as important. The lactide portion of the polymer has an asymmetric carbon. Commercially racemic DL-, L-, and D-polymers are available. The L-polymers are more crystalline and resorb slower than DL- polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are available. Additionally, homopolymers of lactide or glycolide are available.
In the case when the biodegradable polymer is poly(lactide-co-glycolide), poly(lactide), or poly(glycolide), the amount of lactide and glycolide in the polymer can vary. In one aspect of the present invention, the biodegradable polymer contains 0 to 100 mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100 mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to 60 mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40 mole % glycolidc, wherein the amount of lactide and glycolide is 100 mole %. In another aspect of the present invention, the biodegradable polymer can be poly(Iactide),
85:15 poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), or 65:35 poly(lactide- co-glycolide) where the ratios are mole ratios.
In one aspect of the present invention, when the biodegradable polymer is poly(lactide-co- glycolide), poly(lactide), or poly(glycolide), the polymer has an intrinsic viscosity of from 0.15 to 1.5 dL/g, 0.25 to 1.5 dLVg, 0.25 to 1.0 dL/g, 0.25 to 0.8 dlVg, 0.25 to 0.6 dlVg, or 0.25 to 0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30 0C.
The amount of alpha-MSH analogue, corticosteroid, immunosuppressant, antiinflammatory agent and/or photochemotherapeutic agent that is encapsulated or incorporated in the biodegradable polymer will vary depending upon the selection of the biodegradable polymer, the encapsulation or incorporation technique, and the amount of active pharmaceutical ingredients to be delivered to the subject. In one aspect of the present invention, the amount of active pharmaceutical ingredients encapsulated in the microcapsule, implant, or rod can be up to 50% by weight of the delivery system. In other aspects, the amount of active pharmaceutical ingredients encapsulated in the microcapsule, implant, or rod can be from 5 to 60, 10 to 50%, 15 to 40%, or 15 to 30% by weight of the delivery system.
In another aspect, where the alpha-MSH analogue in combination with one or more corticosteroid, immunosuppressant, anti-inflammatory agent or photochemotheapeutic agent is delivered by another delivery system such as a transdermal formulation, the amount of active pharmaceutical ingredients in the formulation can be from 0.001 to 10%, or 0.05 to 5% by weight of the formulation.
Other pharmaceutical! y-acceptable components can be encapsulated or incorporated in the delivery system in combination with the alpha-MSH analogue, corticosteroid, immunosuppressant and/or anti-inflammatory agent. For example, the pharmaceutical Iy- acceptable component can include, but is not limited to, a fatty acid, a sugar, a salt, a water-soluble polymer such as polyethylene glycol, a protein, polysaccharide, or carboxmethyl cellulose, a surfactant, a plasticizer, a high- or low-molecular-weight porosigen such as polymer or a salt or sugar, or a hydrophobic low-molecular-weight compound such as cholesterol or a wax. In another aspect, the delivery system comprises an implant or rod, wherein the alpha-MSH analogue is [NIe4, D-Phe7]-alpha-MSH in the
amount from 15% to 45% by weight of the implant or rod, wherein the rod or implant comprises poly(lactide) or poly(lactide-co-glycolide) such as, for example, 85: 15 poly(lactide-co-glycolide).
Any of the delivery systems described herein can be administered using techniques known in the art. In one aspect of the present invention, the delivery system can be administered subcutaneously to the subject. In this aspect, the duration of administration can vary depending upon the amount of active pharmaceutical ingredients that are encapsulated and the biodegradable polymer selected. In another aspect of the present invention, the delivery system is administered subcutaneously to the subject and releases the active pharmaceutical ingredients for a period of at least 2, 4, 6, 8, 10 or 12 days. In another aspect of the present invention, the delivery system releases the active pharmaceutical ingredients in the subject for at least 1, 2 or 3 months. In various other aspects, the delivery system releases the active pharmaceutical ingredients in the subject for 10 days, 15 days, 20 days, 25 days, or 30 days.
In a preferred embodiment of the present invention the pharmaceutical composition is administered to a subject when skin lesions are active. The term "active lesion" as used herein means incipient vitiligo lesions of the skin, or incipient loss of pigmentation of the skin, migrating areas of depigmentation of the skin. Active lesions show clinically daily, weekly and monthly pigmentation ('disclolouring') changes over time.
The pharmaceutical compositions can be prepared using techniques known in the art. In one aspect of the present invention, the composition is prepared by admixing the alpha- MSH analogue and corticosteroid, immunosuppressant and/or anti-inflammatory agent with a pharmaceutically-acceptable carrier. The term "admixing" is defined as mixing the two components together so that there is no chemical reaction or physical interaction. The term "admixing" also includes the chemical reaction or physical interaction between the alpha-MSH analogue, corticosteroid, immunosuppressant and/or anti-inflammatory agent and the pharmaceutically-acceptable carrier.
Pharmaceutically-acceptable carriers are known to those skilled in the art. These most typically would be standard earners for administration to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.
Molecules intended for pharmaceutical delivery may be formulated in a pharmaceutical composition. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles, if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles, if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishεrs, electrolyte replenishεrs (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
Formulations for topical administration may include, ointments, lotions, creams, gels, drops, ointments, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The active pharmaceutical ingredients can be admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, propellants, or absorption enhancers as may be required or desired. Reference is made to documents cited herein, e.g., U.S. Patent No. 5,990,091, WO 98/00166, and WO 99/60164, for the preparation of compositions for topical applications, e.g., viscous compositions that can be creams or ointments, as well as compositions for nasal and mucosal administration.
In the case when the composition is administered mucosally, ocularly, intranasally, or by inhalation, the formulation can be in the form of a drop, a spray, an aerosol, or a sustained release format. The spray and the aerosol can be achieved through use of the appropriate dispenser. The sustained release format can be an ocular insert, erodible microparticuiates, swelling mucoadhesive particulates, pH sensitive microparticuiates, nanoparticles/latex systems, ion-exchange resins and other polymeric gels and implants (Ocusert, Alza Corp. , California; Joshi, A., S. Ping and K. J. Himmelstein, Patent Application WO 91/19481).
These systems maintain prolonged drug contact with the absorptive surface preventing washout and nonproductive drug loss.
In a preferred embodiment of the present invention the pharmaceutical composition according is administered to a human or domestic animal subject. Most preferably the subject is a human subject.
Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia or elsewhere before ihe priority date of each claim of this application.
It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
Claims
1. A pharmaceutical composition for treating or preventing vitiligo comprising an alpha-MSH analogue selected from compounds of the formula:
R1-W-X-Y-Z-R2
wherein
Ri is absent; n-Pentadecanoyl Ac, 4-phenyIburyryl; Ac-GIy-, Ac-Met-Glu, Ac-NIe-GIu-, orAc-Tyr-Glu-;
W is -His- or -D-His-;
X is -Pbe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO2)D-Phe7-;
Y is -Arg- or -D- Arg- ;
Z is -Tip- or -D-Trp-; and
R2 is -NH2; -GIy-NH2; or -GIy-LyS-NH2.
2. A pharmaceutical composition for treating or preventing vitiligo comprising a linear alpha-MSH analogue selected from the group consisting of:
Ac-Ser-Tyr-Ser-Nle-G!υ-His-D-Plie-Arg-Trp-LyS'Gly-Pro-Vat-NH2 Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro- VaI-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Giy-Pro-Val-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro- VaI-NH2
Ac-Nle-Asρ-His-D-Phe-Arg-Trp-Gly-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH2
Ac-NIe- Asρ-His-D-Phe-Arg-Trρ-Lys-NH2
Ac-NIe-G!u-Hιs-D-Phe-Arg-Trp-Orn-NH2
Ac-Nle-Glu-His-D-Phe-Ai^-Trp-Lys-NHz
Ac-Nle-Asp-H!S-D-Phe-Arg-Trp-Lys-NH2
Ac-NIe-GIu-His-D-Phe-Arg-Trp-Om-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Om-NH2
Ac-Nle-G!u-His-D-Phe-Arg-Trp-Dab-NH2
Ac-Nle-A^>.His-D>Phe-Arg-Trp-Dab-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dpr-NH2
Ac-Nle-Glu-His-L-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-L-Phe-Arg-Trp-Lys-NH2
or a cyclic alpha-MSH analogue selected from the group consisting of: Ac-Nle-Gto-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2
Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nte-Asρ-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Om-HH2
Ac-NIe- Asρ-His-D-Phe-Arg-Trp-Dab-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dpr-NH2
Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2
Ac-Ser-Try-Ser-Nle-Asp-Hϊs-D-Phe-Arg-Trp-Lys-NH2
Ac-Tyr-Ser-Nle-Asρ-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2 Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-NKb
Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-NHa
Ac-NIe- Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro- VaI-NH2
Ac-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH2
wherein Ala = alanine, Arg = arginine, Dab = 2,4-diaminobutyricacid, Dpr = 2,3-diaminopropionicacid, GIu = glutamic acid, GIy = glycine, His = histidine, Lys = lysine, Met = methionine, NIe = norleucine, Om = ornithine, Phe = phenylalanine, (pNO2)Phe = paranitrophenylalanine, PIg = phenylglycine, Pro = proline, Ser = serine, Trp = tryptophan, TrpFor = N1"-formyl-tryptophan, Tyr = tyrosine, VaI = valine.
3. A pharmaceutical composition for treating or preventing vitiligo comprising an alpha-MSH analogue selected from the group consisting of:
[D-Phe7]-alpha-MSH,
[NIe4, D-Phβ7J-alpha-MSH,
[D-Ser!, D-Phe7]-alpha-MSH,
[D-TyT2, D-Phe7]-alpha-MSH,
[D-Ser3, D-Phe73-alpha-MSH,
[D-Met4, D-Phe73-alpha-MSH, ' [D-GIu5, D-Phe7]-alpha-MSH, [D-His6, D-Phe7]-alpha-MSH, [D-Phe7, D-Arg8]-alpha-MSH, [D-Phe7, D-Trp9]-alpha-MSH,
[D-Plie7, D-Lys11]-alpha-MSH, [D-Phe-7, D-Pro12]-a!pha-MSH,
[D-Phe7, D-Val13]-alpha-MSH, [D-Ser1, Nle4, D-Phe7]-alpha-MSH, [D-Tyr2, NIe4, D-Phe7J-alpha-MSH, [D-SerJ, NIe4, D-Phe7]-alpha-MSH, [NIs4, D-GIu5 ,D-Phe7]-aIpha-MSH, [NIe4, D-His6, D-Phe7}-alpha-MSH, [NIe4, D-Phe7, D-Arg8]-alpha-MSH, [NIe4, D-Phe7, D-Trp9]-alpha-MSH, [NIe4, D-Phe7, D-Lys11]-aIpha-MSH, [NIe4, D-Phe7, D-Pro12]-aIpha-MSH,
[NIe4, D-Phe7, D-VaI13]-alpha-MSH,
[Cys4, Cys10]-alpha-MSH [Cys4, D-Phe7, Cysl0]-alpha-MSH
I 1
[Cys4, Cys11]-alpha-MSH
[Cys5, Cys!0]-alpha-MSH
[Cyss, Cys11 ]-aIpha-MSH
[Cys4, Cysl0]-alpha-MSH4-13
[Cys4, Cys10]-alpha-MSH4-12
[NIe4, D-Phe7]-alpha-MSH4-10,
[NIe4, D-Phe7]-aIpha-MSH4-11,
[D-Phe7]-alpha-MSH5-11 ,
[NIe4, D-Tyr7]-alpha-MSH4-11,
[(pNO2)D-Phe7]-alpha-MSH4-11,
[Tyr4, D-Fhe7]-aϊpha-MSH4-10,
[Tyr4, D-Phe7]-alpha-MSH4-11,
[Nle4]-alpha-MSH4-11,
[NIe4, (pNO2)D-Phe7]-alpha-MSH4-11,
[NIe4, D-His6]-alpha-MSH4-11,
[NIe4, D-His5, D-Phe7]-alpha-MSH4-11,
[NIe4, D-Arg8]-alpha-MSH4-11,
4. A pharmaceutical composition for treating or preventing vitiligo comprising an alpha-MSH analogue selected from the group consisting of:
[ , ] p
5. A pharmaceutical composition for treating or preventing vitiligo comprising an alpha-MSH analogue selected from the group consisting of:
[NIe4, D-Phe7]-alpha-MSH.
6. The pharmaceutical composition according to claims 1 to 5, further comprising one or more agents selected from the group consisting of corticosteroids, immunosuppressants, anti-inflammatory agents and photochemotherapeutic agents together with a pharmaceutically acceptable carrier or diluent.
7. The pharmaceutical composition according to claim 6, wherein the corticosteroid is selected from mometasone furoate, betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone and cortisone.
8. The pharmaceutical composition according to claim 6, wherein the corticosteroid is selected from mometasone furoate and betamethasone.
9. The pharmaceutical composition according to claim 6, wherein the immunosuppressant is selected from cytostatics including cytotoxic antibiotics, alkylating agents and antimetabolites, antibodies, glucocorticoids, drugs acting on immunophilins including cyclosporine, tacrolimus and sirolimus, interferons, azathioprine, 5-fluorouracil and opioids.
10. The pharmaceutical composition according to claim 6, wherein the immunosuppressant is selected from tacrolimus, betamethasone, azathioprine and levamisole.
11. The pharmaceutical composition according to claim 6, wherein the antiinflammatory agent is selected from betamethasone and cortisone.
12. The pharmaceutical composition according to claim 6, wherein the photochemotherapeutic agent is psoralen.
13. A method for treating or preventing vitiligo in a subject comprising administering to the subject a therapeutically or prophylactically effective amount of a pharmaceutical composition comprising an alpha-MSH analogue according to claims 1 to 12.
14. The method according to claim 13, further comprising the step of exposing the subject to an effective amount of ultra-violet light (UV)1 in particular ultra-violet A light (UVA), when the pharmaceutical composition administered to the subject comprises one or more photochemotherapeutic agents.
15. The method according to claims 13 or 14, wherein the pharmaceutical composition is administered in a sustained-release delivery system, topically using a transdermal delivery system or in a prolonged release formulation.
16. The method according to claims 13 to 15, wherein the concentration of the alpha-MSH analogue in the plasma of the subject in the treatment of vitiligo is maintained in a low concentration range of 0.001 ng/ml to 10 ng/ml.
17. The method according to claims 13 to 16, wherein the pharmaceutical composition is administered orally or parenterally.
18. A delivery system composed of devices or compositions containing an alpha-MSH analogue together with one or more corticosteroids, immunosuppressants, anti-inflammatory agents or photochemotherapeutic agents according to claims 1 to 12, wherein the delivery system allows for the controlled-release, extended-release, modified-release, sustained-release, pulsatile-release, or programmed-release delivery of the active components in order to maintain concentration of the active components in the plasma of the subject.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2009228664A AU2009228664B2 (en) | 2008-03-27 | 2009-03-27 | Therapy for vitiligo |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2008901461 | 2008-03-27 | ||
| AU2008901461A AU2008901461A0 (en) | 2008-03-27 | Therapy for vitiligo | |
| AU2009228664A AU2009228664B2 (en) | 2008-03-27 | 2009-03-27 | Therapy for vitiligo |
| PCT/EP2009/002265 WO2009118191A2 (en) | 2008-03-27 | 2009-03-27 | Therapy for vitiligo |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2009228664A1 AU2009228664A1 (en) | 2009-10-01 |
| AU2009228664B2 true AU2009228664B2 (en) | 2013-08-08 |
Family
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