WO2006012667A1 - Methods of inducing melanogenesis in a subject. - Google Patents
Methods of inducing melanogenesis in a subject. Download PDFInfo
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- WO2006012667A1 WO2006012667A1 PCT/AU2005/000181 AU2005000181W WO2006012667A1 WO 2006012667 A1 WO2006012667 A1 WO 2006012667A1 AU 2005000181 W AU2005000181 W AU 2005000181W WO 2006012667 A1 WO2006012667 A1 WO 2006012667A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/04—Preparations for care of the skin for chemically tanning the skin
Definitions
- the melanocortins include a family of peptide hormones that induce pigmentation by interaction with melanocortin-1 receptors (MClR) in the epidermis.
- MlR melanocortin-1 receptors
- alpha-MSH alpha melanocyte stimulating hormone
- This 13 amino acid peptide binds to MClR to induce cyclic AMP-mediated signal transduction, which leads to the synthesis of melanin polymers from DOPA precursors.
- Two types of melanins can be expressed in humans.
- brownish-black pigment eumelanin is believed to convey protection from sun damage, whereas the reddish, sulfur-containing pigment, pheomelanin, is often expressed in light-skinned human populations that report a poor tanning response to sunlight. 2
- These poorly-tanning, easily-burning populations often possess defects in the MC IR gene 3 and are generally thought to be at a greater risk of developing both melanoma and non-melanoma skin cancers. 4 ' 5
- Melanotan Nle 4 -D-Phe 7 -alpha MSH, also referred to herein as "Melanotan-1" or “MTl"
- MTl a super-potent derivative of alpha-MSH
- Melanotan contains two amino acid substitutions and is approximately 100 to 1, 000-fold more potent than the native hormone at inducing pigmentation in experimental systems such as the frog skin bioassay or in cultured human keratinocytes.
- Melanotan primarily induces eumelanin synthesis in the skin in concert with its tanning effect.
- melanotropins have been postulated to affect immunologic changes, 9 ' 10>11 all of the prior trials reported only minimal side effects such as facial flushing and transient GI upset, unless doses greater than those needed for tanning were administered. 12
- melanotropic peptides may provide a potential for increasing melanin pigmentation of human skin.
- Synthetic MSH may be used to enhance skin pigmentation of normal or light-skinned individuals to protect them from the hazards of solar radiation.
- individuals whose skin tends to burn easily on exposure to the sun and does not tan readily are at higher risk of both nonmelanoma skin tumors and of cutaneous melanoma. 16>17>18
- UV radiation is responsible for skin cancer in humans. In the face of increased deterioration of the ozone layer and the increasing incidence of and mortality from skin cancer, the ability to stimulate the skin's own "protective mechanism" of tanning may prove extremely important as photoprotective strategy.
- described herein are methods for inducing melanogenesis in a human subject by administering alpha-MSH analogues to the subject at greatly reduced plasma levels, which surprisingly leads to increased melanin density levels in the subject.
- By increasing melanin levels in a subject it is possible to reduce or prevent the occurrence of UV radiation-induced skin damage in the subject.
- the reduced amount of alpha-MSH analogue that is required in the methods described herein avoids undesirable side effects associated with higher doses.
- Figure 1 shows the in vitro release of Melanotan from implants treated with ethyl acetate.
- Figure 2 shows the in vitro release of Melanotan from implant formulations made from 85:15 poly-(D,L-lactide-co-glycolide) copolymers.
- Figure 3 shows the in vitro release of Melanotan from implant formulations made from 84:16 poly-(D,L-lactide-co-glycolide) copolymers.
- Figure 4 shows the pharmacokinetic data from Study 1 described herein.
- Figure 5 shows the pharmacokinetic data from Study 3 described herein.
- Figure 6 shows the pharmacokinetic data from Study 4 described herein.
- Figure 7 shows the comparison of melanin density change (MD%) in the subjects in Studies 1, 2, 3 and 4 described herein.
- 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 is based on the total weight of the formulation or composition in which the component is included.
- contacting is meant an instance of exposure by close physical contact of at least one substance to another substance.
- 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 alpha-MSH analogue, 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.
- prevent means the administration of a composition to a subject or a system at risk for an undesirable condition.
- the condition can include a disease or a predisposition to a disease. Prevention can range from a reduction in the severity of the condition to the complete ablation of the condition.
- an effective amount and time means a therapeutic amount and time needed to achieve the desired result or results, e.g., inducing melanogenesis in a subject.
- induce means initiating a desired response or result that was not present prior to the induction step.
- induce also includes the term “potentiate.”
- potentiate means sustaining a desired response at the same level prior to the potentiating step or increasing the desired response over a period of time.
- melanogenesis as referred to herein is defined as the ability of a subject to produce melanins by melanin-producing cells, or melanocytes.
- homologous desensitization as referred to herein is defined as the inhibition of a cellular response upon continuous exposure to an agonist.
- tissue includes in particular the skin of a subject.
- These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a number of different alpha-MSH analogues and biodegradable polymers are disclosed and discussed, each and every combination and permutation of the alpha-MSH analogue and biodegradable polymer are specifically contemplated unless specifically indicated to the contrary.
- the sub-group of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from disclosure of A, B, and C; D, E, and F; and the example combination A-D.
- This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions.
- steps in methods of making and using the disclosed compositions are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.
- the methods herein increase melanin production without inducing homologous desensitization of the melanocortin-1 -receptors of the subject. This is accomplished by administering alpha-MSH analogues to the subject so that low concentrations of the alpha-MSH analogue are present in the plasma of the subject.
- alpha-MSH analogue are administered to increase melanin production in a subject.
- undesirable side effects can occur when high doses of alpha-MSH analogue are administered.
- the method for inducing melanogenesis in a human subject comprises administering to the subject an alpha-MSH analogue in an effective amount and time to induce melanogenesis by the melanocytes in epidermal tissue of the subject without inducing homologous desensitization of the melanocortin-1 receptors of the subject.
- described herein are methods for inducing melanogenesis in a human subject, comprising administering to the subject an effective amount of an alpha- MSH analogue to induce melanogenesis by the melanocytes in epidermal tissue of the subject, wherein the alpha-MSH analogue is administered at a level not exceeding 10 ng/ml in the plasma of the subject for a period of at least 24 hours.
- the invention provides a composition for inducing melanogenesis in a human subject, wherein the composition administers an alpha-MSH analogue to the subject in an effective amount and time to induce melanogenesis by the melanocytes in epidermal tissue of the subject without inducing homologous densitization of the melanocortin-1 receptors of the subject.
- the invention also provides a composition for inducing melanogenesis in a human subject, wherein the composition administers an alpha-MSH analogue to the subject at a level not exceeding 10 ng/ml in the plasma of the subject for a period of at least 24 hours.
- alpha-MSH analogue referred to 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-terminal 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.
- alpha-MSH analogue may be a compound as disclosed 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.
- the alpha-MSH analogue may be a compound as disclosed 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.
- the alpha-MSH analogue may be a compound as disclosed in
- R 1 is Ac-GIy-, Ac-Met-Glu, Ac-NIe-GIu-, or Ac-Tyr-Glu-;
- W is -His- or -D-His-;
- X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO 2 )D-Phe 7 -;
- Y is -Arg- or -D-Arg-; Z is -Trp- or -D-Trp-; and R 2 is -NH 2 ; -GIy-NH 2 ; or -GIy-LyS-NH 2 .
- the alpha-MSH analogue may be 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 11, and/or (2) between the amino acid residue at position 5 and the amino acid residue at position 10 or 11.
- an intramolecular interaction such as a disulfide or other covalent bond
- the alpha-MSH analogue may be a linear analogue as disclosed in US Patent No.
- the alpha-MSH analogue may also be a cyclic analogue as disclosed in US Patent o. 5,674,839, selected from the group consisting of:
- 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
- (pNO 2 )Phe paranitrophenylalanine
- PIg phenylglycine
- Pro proline
- Ser serine
- Trp tryptophan
- TrpFor N 1" formyl-tryptophan
- Tyr tyrosine
- VaI valine.
- the alpha-MSH analogue can be [D-Phe 7 ]-alpha-MSH, [NIe 4 , D-Phe 7 ]-alpha-MSH, [D-Ser 1 , D-Phe 7 ]-alpha-MSH, [D-Tyr 2 , D-Phe 7 ]-alpha-MSH, [D-Ser 3 , D-Phe 7 ]-alpha-MSH, [D-Met 4 3 D-Phe 7 ]-alpha-MSH,
- the alpha-MSH analogue is [NIe 4 , D-Phe 7 ]-alpha-MSH.
- the actual preferred amounts of the alpha-MSH analogue in a specified case 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 formulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining doses for inducing melanogenesis by the methods described herein.
- the alpha-MSH analogue is administered in an amount to induce melanogenesis without inducing homologous desensitization of the melanocortin-1 receptors of the subject. In another aspect, the alpha-MSH analogue is administered at a level not exceeding 10 ng/ml in the plasma of the subject for a period of at least 24 hours.
- the alpha- MSH analogue is administered at a level not exceeding 9 ng/ml, 8 ng/ml, 7 ng/ml, 6 ng/ml, 5 ng/ml, 4 ng/ml, 3 ng/ml, 2 ng/ml, 1 ng/ml, 0.5 ng/ml, 0.2 ng/ml or 0.1 ng/ml, or lower, in the plasma of the subject for a period of at least 24 hours.
- 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.
- the mode of administration will depend upon the subject to be treated and the alpha-MSH analogue selected.
- the alpha-MSH analogues can be administered orally or parenterally.
- oral is used herein to encompass administration of the compounds via the digestive tract.
- 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, rectal, vaginal, transdermal, topical, buccal, sublingual, or mucosal administration.
- mucosal 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.
- transdermal 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.
- topical 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.
- delivery systems composed of devices or compositions containing an alpha-MSH analogue can be manufactured that allow for the controlled-release, extended- release, modified-release, sustained-release, pulsatile-release, or programmed-release delivery of the alpha-MSH analogue in order to maintain low concentrations of the alpha- MSH analogue in the plasma of the subject.
- 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 or non-biodegradable 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.
- polymeric delivery systems can be microparticles including, but not limited to microspheres, microcapsules, nanospheres and nanoparticles comprising biodegradable polymeric 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 poly(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(vinyl acetate) and the like; a poly(vinyl pyridine) such as poly(2-vinyl pyridine), poly(5-methyl-2-vinyl pyridine) and the like; a poly(styrene);
- the polymeric excipient 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(vinyl imidazole); a chlorosulphonate polyolefin; a polyethylene oxide; or a blend or copolymer thereof.
- 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(viny
- the polymeric excipient includes a biocompatible, biodegradable polymer such as, for example, a poly(lactide); a poly(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 poly(hydroxybutarate); a poly(lactide-co-caprolactone); 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
- the delivery system comprises an implant or rod, wherein the implant or rod comprises a biodegradable polymer, wherein the alpha-MSH analogue is imbedded within the implant or rod.
- the alpha-MSH analogue 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.
- 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.
- linear lactide/glycolide polymers are used; however star polymers can be used as well.
- high molecular weight polymers can be used for medical devices, for example, to meet strength requirements.
- 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.
- copolymers comprising glycolide and DL-lactide or L-lactide
- copolymers of L-lactide and DL-lactide are available.
- homopolymers of lactide or glycolide are available.
- the biodegradable polymer is poly(lactide-co-glycolide), poly(lactide), or poly(glycolide)
- the amount of lactide and glycolide in the polymer can vary.
- 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 % glycolide, wherein the amount of lactide and glycolide is 100 mole %.
- the biodegradable polymer can be poly(lactide), 85:15 poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), or 65:35 poly ⁇ actide-co-glycolide) where the ratios are mole ratios.
- the biodegradable polymer 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 dL/g, 0.25 to 1.0 dL/g, 0.25 to 0.8 dL/g, 0.25 to 0.6 dL/g, or 0.25 to 0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30 0 C.
- the amount of alpha-MSH analogue 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 alpha-MSH to be delivered to the subject.
- the amount of alpha-MSH analogue encapsulated in the microcapsule, implant, or rod can be up to 50% by weight of the delivery system.
- the amount of alpha-MSH analogue 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.
- the amount of alpha-MSH analogue in the formulation can be from 0.001 to 10%, or 0.05 to 5% by weight of the formulation.
- the pharmaceutically-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, polysacharride, 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.
- the delivery system comprises an implant or rod, wherein the alpha-MSH analogue is [NIe 4 , D-Phe 7 ]- 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).
- the delivery system can be administered subcutaneously to the subject.
- the duration of administration can vary depending upon the amount of alpha-MSH analogue that is encapsulated and the biodegradable polymer selected.
- the delivery system is administered subcutaneously to the subject and releases the alpha-MSH analogue for a period of at least 1, 2, 4, 6, 8, 10 or 12 days.
- the delivery system releases the alpha-MSH analogue in the subject for up to three months.
- the delivery system releases the alpha-MSH analogue in the subject for 5 days, 10 days, 15 days, 20 days, 25 days, or 30 days.
- any of the alpha-MSH analogues can be combined with at least one pharmaceutically-acceptable carrier to produce a pharmaceutical composition.
- the pharmaceutical compositions can be prepared using techniques known in the art.
- the composition is prepared by admixing the alpha-MSH analogue with a pharmaceutically-acceptable carrier.
- admixing is defined as mixing the two components together so that there is no chemical reaction or physical interaction.
- admixing also includes the chemical reaction or physical interaction between the alpha- MSH analogue and the pharmaceutically-acceptable carrier.
- Pharmaceutically-acceptable carriers are known to those skilled in the art. These most typically would be standard carriers for admim ' stration 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, antiinflammatory agents, anesthetics, and the like.
- Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- 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 replenishers, electrolyte replenishers (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 alpha-MSH analogue 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.
- compositions for topical applications e.g., viscous compositions that can be creams or ointments, as well as compositions for nasal and mucosal administration.
- 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 microparticulates, swelling mucoadhesive particulates, pH sensitive microparticulates, 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.
- the methods described herein induce melanogenesis in a subject (i.e, increase melanin production from melanin-producing cells).
- the methods herein increase melanin production without inducing homologous desensitization of the melanocortin-1 -receptors of the subject.
- By maintaining low concentrations of the alpha-MSH analogue in the plasma of the subject it is possible to increase melanin production without inducing homologous desensitization of the melanocortin-1 -receptors of the subject, which can prevent the occurrence of skin damage in a subject due to exposure to UV radiation.
- described herein are methods for preventing UV radiation-induced skin damage in a human subject comprising administering to the subject an alpha-MSH analogue, wherein the alpha-MSH analogue is administered at a level to induce melanogenesis in the subject without inducing homologous desensitization of the melanocortin-1 -receptors of the subject.
- methods for preventing UV radiation- induced skin damage in a human subject comprising administering to the subject an alpha- MSH analogue, wherein the alpha-MSH analogue is administered at a level not exceeding 10 ng/ml in the plasma of the subject for a period of at least 24 hours.
- compositions for preventing UV radiation-induced skin damage in a human subject wherein the composition administers an alpha-MSH analogue to the subject in an effective amount and time to induce melanogenesis by the melanocytes in epidermal tissue of the subject without inducing homologous desensitization of the melanocortin-1 receptors of the subject.
- compositions for preventing UV radiation-induced skin damage in a human subject wherein the composition administers an alpha-MSH analogue to the subject at a level not exceeding 10 ng/ml in the plasma of the subject for a period of at least 24 hours.
- an epidermal cell can be contacted with the alpha-MSH analogue in order to prevent UV radiation-induced skin damage in a subject.
- the epidermal cell can be contacted with the alpha-MSH analogue in vivo, in vitro, or ex vivo
- reaction conditions e.g., component concentrations, component mixtures, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.
- Melanotan 36 g, where 78% is Melanotan peptide
- poly(DL-lactide) 44 g
- the Tinius Olsen is a solid block of steel about 80 mm in diameter and about 160 mm high/long with a hollow core about 13 mm in diameter.
- the discharge of the core has a shoulder that allows different size "dies" to be used based on the desired diameter of extruded rod.
- a 3.9-mm die was used, meaning that the core of the die was 3.9 mm in diameter.
- the main block of the Tinius Olsen has heater bands encased by insulation and a shroud that allow the Tinius Olsen to be heated to a desired temperature.
- a thermocouple was used to measure the temperature of the block.
- the control system then uses the thermocouple values to either turn the heater bands on or off. Throughout the extrusion process, the heater bands will switch off and on to maintain the desired temperature.
- a charging rod was placed in the core or the Tinius Olsen to compress the blend. Weights were placed on the end of the charging rod as appropriate. More specifically, the Tinius Olsen was equilibrated to 90 0 C. The compression load used, while the blend was melting, was 3,700 grams. The equilibration time for the blend to melt lasted for about 15 minutes. The plug was removed from the discharge area and the extrusion load of 12,360 grams was added, which included the compression load. An extruded rod of approximately 140 -180 cm was then made.
- Table 1 lists representative examples of the different implants prepared.
- the polymers for the above implants ranged from homopolymers (poly(DL-lacide)) to copolymers of lactide and glycolide. Therefore, polymers with 100 mole % lactide to 65 mole % lactide were used. The end groups of these polymers were capped (blocked) or were synthesized to have carboxylic acid end groups.
- the inherent viscosity of the polymers ranged from 0.36 to 1.09 dL/g.
- the inherent viscosities were determined with polymers dissolved in chloroform at a concentration of 0.5gm/dL.
- the viscosity measurements were made at 30 0 C.
- the Melanotan content of the implants ranged from 15 to 45 wt%.
- the typical in vitro release characteristics of the Melanotan implants made with 85:15 poly(DL-lactide-co-glycolide) in runs 4 and 5 are shown in Figure 2.
- An implant formulation was made with Melanotan and 84: 16 poly(DL-lactide-co- glycolide) with carboxylic acid end groups.
- the poly(DL-lactide-co-glycolide) had an inherent viscosity of 0.29 dL/g. The inherent viscosity was measured at 30 0 C with 0.5 gm/dL polymer concentration in chloroform.
- the desired Melanotan content in the implant was 17.3 wt % Melanotan peptide. Therefore, Melanotan (3 g) and the poly(DL-lactide) (12 g) were dry blended using a mortar and pestle to form a blended powder. The 3 gm of Melanotan comprised about 88% Melanotan peptide. Next a Tinius Olsen (MP 600) melt plastometer was used to melt extrude the blended powder.
- the Tinius Olsen is a solid block of steel about 80 mm in diameter and about 160 mm high/long with a hollow core about 13 mm in diameter. The discharge of the core has a shoulder that allows different size "dies" to be used based on the desired diameter of extruded rod.
- the main block of the Tinius Olsen has heater bands encased by insulation and a shroud that allow the Tinius Olsen to be heated to a desired temperature.
- a thermocouple was used to measure the temperature of the block. The control system then used the thermocouple values to either turn the heater bands on or off. Throughout the extrusion process the heater bands will switch off and on to maintain the desired temperature.
- the Tinius Olsen was equilibrated to 87 0 C.
- the compression load used, while the blend was melting, was 3,700 grams.
- the equilibration time for the blend to melt lasted for about 15 minutes.
- the plug was removed from the discharge area and the extrusion load of 10,300 grams was added (includes the compression load). An extruded rod approximately 600-700 cm was then made.
- Example 4 Clinical trials.
- MT- 1 Melanotan 1
- MT-I Melanotan 1
- MD melanin density
- Melanotan (MT-I) was administered at a fixed, subcutaneous daily dose for 30 days over a 70 day period to 59 subjects, and the remaining 20 subjects were administered the placebo (saline). Fourteen subjects did not complete the trial protocol (twelve Melanotan and two placebo). Average baseline melanin density (MD) and MD change (%) was measured in all 47 protocol completers. In the third clinical trial, a dose-escalation study of a single depot controlled release formulation was conducted with 3 human subjects. Melanotan (MT-I) was administered as a single, subcutaneous controlled release dose at day 1 only. Average baseline melanin density (MD) and MD change (%) was measured in these three subjects.
- MT-I Melanotan
- MD melanin density
- One of the primary objectives of this study was to determine the pharmacokinetics of 0.16 mg/kg/day of Melanotan administered by subcutaneous injection on 10 consecutive days to healthy adult subjects.
- Study 2 One of the primary objectives of this study was to compare the incidence of sunburn cells (defined as apoptotic cells) in all subjects elicited 24 hours after controlled solar irradiation (3x MED) to a small area of skin (2 x 2 cm) at baseline and 90 days after initiation of dosing with Melanotan or placebo.
- 3x MED controlled solar irradiation
- the target population was male and female Caucasian subjects.
- the following inclusion and exclusion criterion had to be met by each subject before enrollment in the study.
- the inclusion and exclusion criterion was similar for all three studies conducted.
- For Study 1 Active: Melanotan was provided in single-use, sterile 6 mL vials each containing 16 mg (+ 5%) of Melanotan in 1 mL sterile saline. A dose of 0.16 mg/kg/day was administered by subcutaneous injection to each subject receiving the Melanotan treatment, which is equivalent to a dose volume of 0.01 mL/kg/day.
- Placebo was provided as single-use, sterile 6 mL vials containing 1 mL sterile saline. A dose volume of 0.01 mL/kg/day was subcutaneously injected at each administration.
- the treatments were injected subcutaneously, using a 25-gauge needle (16 mm length) and 1 mL syringe, to the abdomen each day for 10 consecutive days. Each subject's body weight was determined at check-in and the same weight was used for all dose calculations for subsequent treatments. Each subject received, in total, 1.6 mg/kg of Melanotan, which equates to 112 mg of Melanotan for a 70 kg person.
- Melanotan was provided in single-use, sterile 6 mL vials each containing 16 mg (+ 5%) of Melanotan in 1 mL sterile saline. A dose of 0.16 mg/kg/day was administered by subcutaneous injection to each subject receiving the Melanotan treatment, which is equivalent to a dose volume of 0.01 mL/kg/day.
- Placebo was provided as single-use, sterile 6 mL vials containing 1 mL sterile saline. A dose volume of 0.01 mL/kg/day was subcutaneously injected at each administration. The treatments were injected subcutaneously, using a 25 gauge needle (16 mm length) and 1 mL syringe, to the abdomen each day for 5 days a week x 2 weeks. Each subject's body weight was determined at check-in and the same weight was used for all dose calculations for the first 10 days treatment. This cycle of treatment was repeated at Days 29 to 40 and Days 57 to 66. The subject was reweighed at the start of each dosing period for calculation of dose. Drag was given as nearly as possible at the same time each day (+/- 4 hours). Each subject received, in total, 4.8 mg/kg of Melanotan, which equates to 336 mg of Melanotan for a 70 kg person.
- the treatments were implanted subcutaneously, using a trocar delivery device (5.2 mm ID x 70 mm length), in the abdomen on Day 1 only.
- a trocar delivery device 5.2 mm ID x 70 mm length
- Each subject received, in total, 0.29 mg/kg of Melanotan, which equates to 20 mg of Melanotan for a 70 kg person.
- Melanotan was provided in a biodegradable poly(DL-lactide-co-glycolide) rod containing 5 mg (+ 10%) of Melanotan. Doses of 10 and 20 mg were administered by subcutaneous implantation to each subject.
- the treatments were implanted subcutaneously, using a SURFLO® LV. catheter with a 16G needle, in the inner upper arm on Day 1 only.
- Blood collection was performed at 0 hr (time of treatment) and 0.5, 1, 2, 3, 4, 6, 8, 10, 16 and 24 hr post-treatment on Day 1 and Day 10 of the study for pharmacokinetic analysis after dose administration.
- Subject plasma samples were analysed for Melanotan using a validated LC/MS/MS method.
- Blood collection was performed at Day 0 (time of treatment) and Day 2, 4, 6, 8, 10, 12, 15, 18, 21 and 25 post-implantation for pharmacokinetic analysis after dose administration.
- Subject plasma samples were analysed for Melanotan using a validated LC/MS/MS method.
- Blood collection was performed at Day 0 (time of treatment) and Day 1, 2, 3, 4, 6, 8, 10, 12, 15, 20 and 25 post-implantation for pharmacokinetic analysis after dose administration.
- Subject plasma samples were analysed for Melanotan using a validated LC/MS/MS method.
- MD 100 x (0.035307 + 0.009974(R 420 - R 400 )) where MD is an estimate of the percentage of the epidermis of the skin that contains melanin, R 4O0 and R 420 denote reflectance at 400nm and 420nm, respectively. These MD measurements were calculated at the analysis stage.
- MD 100 x (0.035307 + 0.009974(R 420 - R 400 )) where MD is an estimate of the percentage of the epidermis of the skin that contains melanin, R 400 and R 420 denote reflectance at 400nm and 420nm, respectively. These MD measurements were calculated at the analysis stage.
- MD 100 x (0.035307 + 0.009974(R 420 - R400)) where MD is an estimate of the percentage of the epidermis of the skin that contains melanin, R 400 and R 42O denote reflectance at 400nm and 420nm, respectively. These MD measurements were calculated at the analysis stage.
- Tables 2, 3 and 4 list the responses of the protocol completers in Studies 1, 3 and 4 respectively in terms of the measured concentration of Melanotan in their plasma.
- Tables 5, 6, 7 and 8 list the responses of the subjects for each of the studies following the different dosing regimes of Melanotan in terms of the change in melanin density (MD) measured at the inner upper arm after 30, 90 and 60 days for Studies 1, 2, 3 and 4 respectively.
- the inner upper arm generally denotes a person's constitutive skin melanin since environmental exposure appears to be least in this area.
- Figure 7 shows that the melanin density change of the subjects in Studies 3 and 4 was dramatically higher and quicker than for Studies 1 and 2. This unexpected result is to be viewed with the fact that the subjects in both Studies 3 and 4 received no more than a 1/15 of the dose of Melanotan overall, when compared with subjects in Study 2.
- various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the compounds, compositions and methods described herein.
- Thody AJ et al. Pheomelanin as well as eumelanin are present in human epidermis. J. Invest. Dermatol. (1991), 97:340-44.
- Valverde P et al. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nature Genet. (1995), 11:328-30.
- Ceriani G et al.
- the neuropeptide alpha-melanocyte-stimulating hormone inhibits experimental arthritis in rats. Neuroimmunomodulation (1994), 1:28-32.
- Fitzpatrick TB The validity and practicality of sun-reactive skin types I through VI. Arch. Dermatol. (1988), 124: 869-871.
- Stenback F Life history and histopathology of ultraviolet light-induced skin tumours. National Cancer Institute Monograph (1978), 50: 57-70.
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Priority Applications (10)
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EP05706231.7A EP1789076B1 (en) | 2004-08-04 | 2005-02-11 | Methods of inducing melanogenesis in a subject. |
CA2575866A CA2575866C (en) | 2004-08-04 | 2005-02-11 | Methods for inducing melanogenesis in a subject |
AU2005269244A AU2005269244B2 (en) | 2004-08-04 | 2005-02-11 | Methods of inducing melanogenesis in a subject. |
DK05706231.7T DK1789076T3 (en) | 2004-08-04 | 2005-02-11 | METHODS for inducing melanogenesis in a subject |
SI200532052A SI1789076T1 (en) | 2004-08-04 | 2005-02-11 | Methods of inducing melanogenesis in a subject. |
JP2007524126A JP5208504B2 (en) | 2004-08-04 | 2005-02-11 | Method for inducing melanogenesis in a subject |
US11/659,178 US9345911B2 (en) | 2004-08-04 | 2005-02-11 | Methods of inducing melanogenesis in a subject |
ES05706231.7T ES2566801T3 (en) | 2004-08-04 | 2005-02-11 | Methods of induction of melanogenesis in a subject |
US15/135,241 US10076555B2 (en) | 2004-08-04 | 2016-04-21 | Methods of inducing melanogenesis in a subject |
US16/113,580 US10857208B2 (en) | 2004-08-04 | 2018-08-27 | Methods of inducing melanogenesis in a subject |
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US59914304P | 2004-08-04 | 2004-08-04 | |
US60/599,143 | 2004-08-04 |
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US11/659,178 A-371-Of-International US9345911B2 (en) | 2004-08-04 | 2005-02-11 | Methods of inducing melanogenesis in a subject |
US15/135,241 Division US10076555B2 (en) | 2004-08-04 | 2016-04-21 | Methods of inducing melanogenesis in a subject |
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EP (1) | EP1789076B1 (en) |
JP (1) | JP5208504B2 (en) |
CN (1) | CN101076314A (en) |
AU (1) | AU2005269244B2 (en) |
CA (1) | CA2575866C (en) |
DK (1) | DK1789076T3 (en) |
ES (1) | ES2566801T3 (en) |
NZ (1) | NZ582130A (en) |
SI (1) | SI1789076T1 (en) |
WO (1) | WO2006012667A1 (en) |
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EP1812034A1 (en) * | 2004-10-08 | 2007-08-01 | Clinuvel Pharmaceuticals Limited | Compositions and methods for inducing melanogenesis in a subject |
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CA2575866C (en) * | 2004-08-04 | 2018-07-10 | Clinuvel Pharmaceuticals Limited | Methods for inducing melanogenesis in a subject |
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- 2005-02-11 WO PCT/AU2005/000181 patent/WO2006012667A1/en active Application Filing
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WO2016066700A1 (en) | 2014-10-28 | 2016-05-06 | Clinuvel Ag | New indication for alpha-msh analogues |
WO2016066702A1 (en) | 2014-10-28 | 2016-05-06 | Clinuvel Ag | Inflammatory disease |
WO2016174610A1 (en) | 2015-04-28 | 2016-11-03 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
EP3088418A1 (en) | 2015-04-28 | 2016-11-02 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
US10508142B2 (en) | 2015-04-28 | 2019-12-17 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
EP3581583A1 (en) | 2015-04-28 | 2019-12-18 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
EP3581582A1 (en) | 2015-04-28 | 2019-12-18 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
WO2016174611A1 (en) | 2015-04-28 | 2016-11-03 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
US11286288B2 (en) | 2015-04-28 | 2022-03-29 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
EP3088417A1 (en) | 2015-04-28 | 2016-11-02 | Vallaurix Pte. Ltd. | Pharmaceutical compound |
WO2018142318A1 (en) | 2017-02-01 | 2018-08-09 | Clinuvel Pharmaceuticals Ltd | Alpha-msh analogues used in the treatment of xeroderma pigmentosum |
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SI1789076T1 (en) | 2016-07-29 |
US20080305152A1 (en) | 2008-12-11 |
US20180360919A1 (en) | 2018-12-20 |
AU2005269244B2 (en) | 2010-12-09 |
CA2575866A1 (en) | 2006-02-09 |
US10857208B2 (en) | 2020-12-08 |
EP1789076A1 (en) | 2007-05-30 |
NZ582130A (en) | 2011-11-25 |
US9345911B2 (en) | 2016-05-24 |
CN101076314A (en) | 2007-11-21 |
ES2566801T3 (en) | 2016-04-15 |
EP1789076A4 (en) | 2011-08-10 |
US10076555B2 (en) | 2018-09-18 |
JP2008508324A (en) | 2008-03-21 |
DK1789076T3 (en) | 2016-04-11 |
US20160235819A1 (en) | 2016-08-18 |
JP5208504B2 (en) | 2013-06-12 |
EP1789076B1 (en) | 2016-01-20 |
AU2005269244A1 (en) | 2006-02-09 |
CA2575866C (en) | 2018-07-10 |
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