WO2013112488A2 - Dermal filling compositions and methods - Google Patents
Dermal filling compositions and methods Download PDFInfo
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- WO2013112488A2 WO2013112488A2 PCT/US2013/022592 US2013022592W WO2013112488A2 WO 2013112488 A2 WO2013112488 A2 WO 2013112488A2 US 2013022592 W US2013022592 W US 2013022592W WO 2013112488 A2 WO2013112488 A2 WO 2013112488A2
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- penetrating peptide
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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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/001—Preparations for care of the lips
-
- 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
- A61Q19/08—Anti-ageing preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/91—Injection
Definitions
- compositions and methods for filling cells with non-pharmacological agents such as dermal fillers, which can result in, e.g., smoothening of skin wrinkles and augmentation of lips.
- Skin is the largest organ and its surface provides an amenable large area to deliver molecules for localized or systemic effects.
- the permeability of foreign molecules, especially large hydrophilic molecules, across the stratum corneum (the outer skin surface) is extremely low. It would be therefore be of great interest to develop modalities to permit the efficient transport of a broad range of molecules across the stratum corneum and into the skin (epidermis and dermis). Because some important components of the skin (such as hair follicles and sebaceous glands) are found deep in the dermis (up to 5 mm below the skin surface) the technology needs go significantly beyond the ability of breaking through the stratum corneum which is a thin layer ( ⁇ 10 ⁇ ) of dead keratinocytes.
- the present disclosure provides a composition comprising a non-pharmacological dermal filler and optionally a pharmaceutically acceptable excipient, the dermal filler being covalently or non-covalently bound to a cell penetrating peptide that is capable to penetrate a dermal cell.
- the cell penetrating peptide is not longer than about 10 amino acids in length.
- the cell penetrating peptide is about 7 amino acids in length.
- the cell penetrating peptide is capable to deliver the dermal filler across a stratum corneum.
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of TGSTQHQ, XiGSTQHQ, TX 2 STQHQ, TGX 3 TQHQ, TGSX 4 QHQ, TGSTXjHQ, TGSTQXgQ and TGSTQHX 7 , wherein X X 7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of HSALTKH, XiSALTKH, HX 2 ALTKH, HSX 3 LTKH, HSAX 4 TKH, HSALX 5 KH, HSALTX 6 H and HSALTKX 7 , wherein X 1 -X 7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of STHFIDT, XiTHFIDT, SX 2 HFIDT, STX 3 FIDT, STHX 4 IDT, STHFX 5 DT, STHFIX 6 T and STHFIDX 7 , wherein X 1 -X 7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of KTGSHNQ, XiTGSHNQ, KX 2 GSHNQ, KTX 3 SHNQ, KTGX 4 HNQ, KTGSX5NQ, KTGSHXgQ and KTGSHNX7, wherein X 1 -X7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of MGPSSML, XiGPSSML, MX 2 PSSML, MGX 3 SSML, MGPX 4 SML, MGPSXjML, MGPSSX 6 L and MGPSSMX 7 , wherein X X 7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of TDPNQLQ, XiDPNQLQ, TX 2 PNQLQ, TDX 3 NQLQ, TDPX 4 QLQ, TDPNX 5 LQ, TDPNQX 6 Q and TDPNQLX 7 , wherein X X 7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SSSPSKH, XiSSPSKH, SX 2 SPSKH, SSX 3 PSKH, SSSX 4 SKH, SSSPXjKH, SSSPSX 6 H and SSSPSKX ? , wherein X 1 -X 7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of GLHPAFQ, XiLHPAFQ, GX 2 HPAFQ, GLX 3 PAFQ, GLHX 4 AFQ, GLHPX 5 FQ, GLHPAX 6 Q and GLHPAFX 7 , wherein X 1 -X 7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SMNQPTA, XiMNQPTA, SX 2 NQPTA, SMX 3 QPTA, SMNX 4 PTA, SMNQX 5 TA, SMNQPX 6 A and SMNQPTX 7 , wherein X X 7 are: Position Amino Acid
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of PHNTTAS, XiHNTTAS, PX 2 NTTAS, PHX 3 TTAS, PHNX 4 TAS, PHNTXjAS, PHNTTX 6 S and PHNTTAX7, wherein X 1 -X7 are:
- the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SSHLSSS, XiSHLSSS, SX 2 HLSSS, SSX 3 LSSS, SSHX 4 SSS, SSHLXsSS, SSHLSX 6 S and SSHLSSX7, wherein X 1 -X7 are:
- the dermal filler can be biodegradable.
- the non-pharmacological agent is selected from the group consisting of hyaluronic acid (HA), collagen, collagen mimetic, elastin, fibrin, fibronectin, tenascin, vitamin A, polysaccharide, amino acid homocopolymer, melanin, melanin derivatives, natural or synthetic pigment, and combinations thereof.
- the polysaccharide is chitosan, chondroitin, glycosaminoglycan, proteoglycan or combinations thereof.
- the amino acid homocopolymer is poly-Lysine, polyacrylamide, polyethyleneglycol, polylactic acid, or combinations thereof.
- the pharmaceutically acceptable excipient provides a composition in the form of a lotion, a cream, a patch or an injectable.
- a method of smoothening the skin of a subject in need thereof comprising contacting the skin with an effective amount of a composition of the present disclosure.
- a method of treating wrinkles for a subject in need thereof comprising contacting the wrinkles with an effective amount of a
- composition of the present disclosure is a composition of the present disclosure.
- Another embodiment provides a method for lip augmentation for a subject in need thereof, comprising contacting the lip with an effective amount of a composition of the present disclosure.
- the contacting can be applying the composition on a skin, or injecting the composition under the epidermis of a skin, without limitation.
- the composition can be injected between the epidermis and the dermis, in one aspect.
- Still another embodiment provides a method of delivering a non-pharmacological dermal filler to a cell, comprising contacting the cell with a composition of the present disclosure.
- a cell includes a plurality of cells, including mixtures thereof.
- compositions and methods include the recited elements, but not excluding others.
- Consisting essentially of when used to define compositions and methods shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention.
- Consisting of shall mean excluding more than trace amount of other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.
- compositions comprising a dermal filler bound to a cell penetrating peptide that facilitates skin penetration.
- the compositions can optionally include a pharmaceutically acceptable excipient.
- the cell penetrating peptide is capable to deliver the dermal filler across a stratum corneum.
- the cell penetrating peptide is not longer than about 10 amino acids in length, or alternatively not longer than about 9 amino acids, or 8 amino acids or 7 amino acids. In another aspect, the cell penetrating peptide is about 7 amino acids in length. In another aspect, the penetrating peptide is not shorter than about 4 amino acids in length, or alternatively not shorter than about 5 amino acids, or 6 amino acids or 7 amino acids.
- the peptide that facilitates skin penetration comprises an amino acid sequence selected from SSSPSKH (Chen et al., Nature Biotechnology (2006) 24:455- 60), TGSTQHQ, HSALTKH, KTGSHNQ, MGPSSML, TDPNQLQ, and STHFIDT (Hsu and Mitragotri PNAS (2011) 108(38): 15816-21) and GLHPAFQ, SMNQPTA, PHNTTAS and SSHLSSS (Lee et al., Journal of Drug Targeting (2011) 19(9): 805-13), and their derivatives.
- a derivative of a peptide includes peptides that have a substitution at one of the amino acid residues of the peptide. Specific and non-limiting examples of such substitutions are provided below.
- the derivatives of TGSTQHQ include XiGSTQHQ, TX 2 STQHQ, TGX 3 TQHQ, TGSX 4 QHQ, TGSTXjHQ, TGSTQXgQ and TGSTQHX 7 , wherein X X 7 are:
- the derivatives of HSALTKH include Xi SALTKH, HX 2 ALTKH, HSX 3 LTKH, HSAX 4 TKH, HSALX 5 KH, HSALTX 6 H and HSALTKX 7 , wherein X X 7 are:
- the derivatives of STHFIDT include XiTHFIDT, SX 2 HFIDT, STX 3 FIDT, STHX 4 IDT, STHFX 5 DT, STHFIX 6 T and STHFIDX 7 , wherein X 1 -X7 are:
- the derivatives of KTGSHNQ include XiTGSHNQ, KX 2 GSHNQ, KTX 3 SHNQ, KTGX 4 HNQ, KTGSX 5 NQ, KTGSHXgQ and KTGSHNX 7 , wherein X X 7 are:
- the derivatives of MGPSSML include XiGPSSML, MX 2 PSSML, MGX 3 SSML, MGPX 4 SML, MGPSXjML, MGPSSX 6 L and MGPSSMX 7 , wherein X X 7 are:
- the derivatives of TDPNQLQ include XiDPNQLQ, TX 2 PNQLQ, TDX 3 NQLQ, TDPX 4 QLQ, TDPNX 5 LQ, TDPNQX 6 Q and TDPNQLX 7 , wherein X 1 -X 7 are:
- the derivatives of SSSPSKH include XiSSPSKH, SX 2 SPSKH, SSX 3 PSKH, SSSX 4 SKH, SSSPXjKH, SSSPSX 6 H and SSSPSKX 7 , wherein X X 7 are:
- the derivatives of GLHPAFQ include XiLHPAFQ, GX 2 HPAFQ, GLX 3 PAFQ, GLHX 4 AFQ, GLHPX 5 FQ, GLHPAX 6 Q and GLHPAFX 7 , wherein X 1 -X 7 are: Position Amino Acid
- the derivatives of SMNQPTA include XiMNQPTA, SX 2 NQPTA, SMX 3 QPTA, SMNX 4 PTA, SMNQX 5 TA, SMNQPX 6 A and SMNQPTX 7 , wherein X X 7
- the derivatives of PHNTTAS include XiHNTTAS, PX 2 NTTAS, PHX 3 TTAS, PHNX 4 TAS, PHNTXjAS, PHNTTX 6 S and PHNTTAX 7 , wherein X 1 -X7 are:
- the derivatives of SSHLSSS include XiSHLSSS, SX 2 HLSSS, SSX 3 LSSS, SSHX 4 SSS, SSHLXjSS, SSHLSXeS and SSHLSSX 7 , wherein X X 7 are:
- more than one, or more than one type of, peptides can be bound to the dermal filler.
- a "dermal filler,” as used herein, refers to a substance that adds volume to cells under the skin resulting in augmented or smoothened skin surface.
- the dermal filler is non-pharmacological.
- non-pharmacological refers to a substance that does not directly target a pharmacological target in a cell, through which the substance effects a pharmacological benefit.
- non-pharmacological explicitly excludes any
- a non-pharmacological dermal filler is none of a dermatological agents, an anti-neoplastic agent, a cardiovascular agent, a renal agent, a gastrointestinal agent, a rheumatologic agent, an immunological agent, or a neurological agent.
- a non-pharmacological dermal filler does not include nucleic acids, nucleotides, nucleosides or analogues thereof.
- compositions of the present disclosure do not contain a pharmacologically active agent.
- the compositions do not contain nucleic acids, nucleotides, nucleosides or analogues thereof that possess pharmacological properties, that regulate the expression or activities of a molecule that possess pharmacological properties, or that encode a protein having pharmacological properties.
- Non-limiting examples of non pharmacological dermal fillers include Hyaluronic Acid (HA), in particular of sizes ranging between 5,000 and 2,000,000 Daltons, collagen, collagen mimetic, elastin, fibrin, fibronectin, tenascin, vitamin A, polysaccharides such as chitosan and chondroitin, glycosaminoglycans, proteoglycans, homocopolymers of amino acids such as poly-Lysine, polyacrylamide, polyethyleneglycol, polylactic acid, and other polymers, melanin and melanin derivatives, natural and synthetic pigments, or the mixture thereof.
- HA Hyaluronic Acid
- the non-pharmacological dermal filler includes a mixture of HA and collagen or collagen mimetics. It is contemplated that an appropriate ratio between HA and collagen (or its mimetics) can help achieve a desired viscosity for the composition, for instance, when the composition is applied, as a cream, to the skin of the subject. In one aspect, therefore, the mixture contains HA and collagen (or its mimetics) in a ratio that is from about 1 : 100 to about 100: 1.
- the ratio between HA and collagen is at least about 1:100, or 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1.9, 1:1.8, 1:1.7, 1:1.6, 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1, 1 : 1.05, or 1 : 1.01.
- the ratio between HA and collagen (or its mimetics) is not greater than about 100:1, or 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1,6:1,5:1,4:1,3:1,2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1.05, or 1:1.01.
- the non-pharmacological dermal filler includes from about 1% to about 99% HA, or alternatively at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% HA.
- the non- pharmacological dermal filler includes no more than 99%, or alternatively no more than about 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% HA.
- the non-pharmacological dermal filler includes from about 1% to about 99% collagen or collagen mimetics, or alternatively at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%), 90%), or 95% collagen or collagen mimetics.
- the non- pharmacological dermal filler includes no more than 99%, or alternatively no more than about 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%), 3%), 2%) or 1%) collagen or collagen mimetics.
- the peptide is covalently or non-covalently bound to the dermal filler.
- dermal filler can be modified by covalent attachment of multiple copies of the peptides of the present disclosure on different sites of the dermal filler.
- the bonding can take place at a reactive side chain of one or more amino acids in the peptide.
- the amino acid can also be modified. For example, lysine, cysteine, threonine, glutamic acid, aspartic acid, serine, histidine, arginine, tyrosine, proline and tryptophan may be readily modified using known processes and procedures.
- a reagent used to modify the protein will have at least one reactive group.
- reactive groups that are used to react with amino acid side chains include activated esters (such as acyl halides or N-hydroxysuccinimide esters) that react with amine (such as lysine) and hydroxy 1 (such as threonine or serine) containing residues; maleimides that react with thiol (such as cysteine) containing residues; and amines which react with carboxylic acid (such as glutamic acid and aspartic acid) containing residues when activated with certain coupling reagents.
- activated esters such as acyl halides or N-hydroxysuccinimide esters
- amine such as lysine
- hydroxy 1 such as threonine or serine
- maleimides that react with thiol (such as cysteine) containing residues
- amines which react with carboxylic acid (such as glutamic acid and aspartic acid) containing residues when activated with certain coupling reagents.
- a linker can be incorporated between the peptide and the site of attachments on the dermal filler.
- the linker can be a chemical compound having two or more polymerizable groups.
- any linking compound may be used, so long as the polymerizable groups on the linker are capable of forming a linked peptide-dermal filler complex.
- linkers include compounds having two vinyl, acryl, alkylacryl, or methacryl groups.
- Examples of specific linkers having two acryl groups include ⁇ , ⁇ '-methylenebisacrylamide and glycerol dimethacrylate.
- the linker is a degradable linker.
- a degradable linker is cleaved under certain conditions, resulting in decomposition or removal of the peptide from the dermal filler, which peptide can then be degraded safely within the cell.
- a degradable linker may hydrolyze at certain pH (high or low), may be cleaved by specific enzymes (such as esterases or peptidases), may be photolytically cleaved upon exposure to certain wavelengths, or be cleaved at certain temperatures.
- linkers which hydrolyze at reduced pH include glycerol dimethacrylate, which is stable at physiological pH (about 7.4), but hydrolyzes at lower pH (about 5.5).
- Other examples of degradable linkers include acetal linkers described in US 7,056,901, which is incorporated by reference in its entirety.
- degradable linking groups include ⁇ , ⁇ '- methylenebis(acrylamide), 1 ,4-bis(acryloyl)piperazine, ethylene glycol diacrylate, N,N'-(1,2- dihydroxy-ethylene)bisacrylamide, and poly(ethylene glycol)diacrylate.
- non-degradable linking groups include ⁇ , ⁇ '- bis(acryloyl)cystamine, glycerol dimethacrylate, bis[2-(methacryloyloxy)ethyl] phosphate, and bisacryloylated polypeptide.
- the peptide is non-covalently bound to the dermal filler.
- non-covalent bounding include hydrogen bond, ionic force, hydrophobic bonding, and Van der Wall force.
- Ionic bonds for instance, can be used to bound the peptide to the dermal filler by virtue of the presence of positive or negative charges of certain amino acids, such as arginine, aspartic acid, glutamic acid, histidine and lysine, and amino acids that are modified to have charges.
- amino acids such as arginine, aspartic acid, glutamic acid, histidine and lysine, and amino acids that are modified to have charges.
- the peptide and/or the dermal filler has a surface modification.
- Surface modifications are chemical moieties which are added to the surface of the dermal filler or the peptide.
- a surface modifying agent may be a small molecule, polymer, peptide, polypeptide, protein, oligonucleotide, polysaccharide, or antibody.
- the surface modification may alter the solubility of the dermal filler of the peptide, change the surface charge of the dermal filler of the peptide, or impart an additional function to the complex.
- Surface modifications that enhance cell targeting result in an increased transduction of the nanocomplex into targeted cells, when compared with non-targeted cells.
- Surface modifications that enhance cell penetration result in increased transduction of the complex into cells. More than one surface modification may be present on the dermal filler peptide complex. Examples of small molecule surface modifications include cell targeting
- Polymers include polyethylene glycol to increase solubility.
- Peptides may be used for cell targeting, such as antibodies to particular cell surface features, cell signaling proteins, or growth hormones. Other peptides may be used to increase cell penetration of the nanoparticles (such as TAT or antennepedia homeodomain).
- compositions of the present disclosure are useful for delivering a non- pharmacological dermal filler to a cell, by virtue of the peptide's cell penetrating capabilities.
- the delivery can be effected by contacting the cell with the composition.
- the contact is in vitro.
- the contact is in vivo.
- the cell is a dermal cell.
- the delivery is through a dermal layer.
- Cosmetic or therapeutic benefits can be achieved by such delivery.
- the delivery results in smoothening the skin of a subject in need thereof.
- the delivery results in treatment of wrinkles in a subject in need thereof.
- the delivery leads to lip augmentation for a subject in need thereof.
- the intended uses include improving the appearance of the skin, removing or treating a scar, or filling a hole on the skin for a subject.
- the methods entail applying the compositions to the skin of a subject as a cream, lotion, or on a patch.
- the compositions are injected.
- the composition is injected under the epidermis.
- the composition is injected at the junction between the epidermis and the dermis.
- the composition can be delivered through the dermis.
- the use of such a peptide in the composition would enable the delivery of the dermal filler, such as Hyaluronic Acid (HA), close to the skin surface and be therefore suitable for the treatment of superficial fine wrinkles, among other uses.
- the dermal filler such as Hyaluronic Acid (HA)
- compositions and methods of the present disclosure therefore, have advantages over the conventional technology.
- compositions for use in cosmetic or therapeutic treatment methods.
- the compositions ⁇ e.g. pharmaceutical compositions
- a pharmaceutical composition of the invention comprises an effective amount ⁇ e.g., a pharmaceutically effective amount) of a composition of the invention.
- the formulation comprises at least one excipient to aid in achieving a formulation with desired properties, such as increased solubility, preservability or to provide an isotonic solution.
- excipients are known in the art.
- a composition of the invention can be formulated as a pharmaceutical composition, which comprises a composition of the invention and pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
- the carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
- suitable pharmaceutical carriers will be evident to a skilled worker and include, e.g., water (including sterile and/or deionized water), suitable buffers (such as PBS), physiological saline, cell culture medium (such as DMEM), artificial cerebral spinal fluid, or the like.
- a pharmaceutical composition or kit of the invention can contain other pharmaceuticals, in addition to the compositions of the invention.
- the other agent(s) can be administered at any suitable time during the treatment of the patient, either concurrently or sequentially.
- compositions of the present invention will depend, in part, upon the particular agent that is employed, and the chosen route of administration. Accordingly, there is a wide variety of suitable formulations of compositions of the present invention.
- the pharmaceutically acceptable excipient and/or the carrier provides a composition in the form of a lotion, a cream, a patch or an injectable, with methods known in the art.
- compositions of the invention can be in unit dosage form.
- unit dosage form refers to physically discrete units suitable as unitary dosages for animal (e.g. human) subjects, each unit containing a predetermined quantity of an agent of the invention, alone or in combination with other therapeutic agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
- the dose of a composition of the invention, administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect at least a detectable amount of a diagnostic or therapeutic response in the individual over a reasonable time frame.
- the dose used to achieve a desired effect will be determined by a variety of factors, including the potency of the particular agent being administered, the
- the size of the dose also will be determined by the existence of any adverse side effects that may accompany the particular agent, or composition thereof, employed. It is generally desirable, whenever possible, to keep adverse side effects to a minimum.
- the dose of the biologically active material will vary; suitable amounts for each particular agent will be evident to a skilled worker.
- kits useful for any of the methods disclosed herein can comprise one or more of the compositions of the invention.
- the kits comprise instructions for performing the method.
- Optional elements of a kit of the invention include suitable buffers, pharmaceutically acceptable carriers, or the like, containers, or packaging materials.
- the reagents of the kit may be in containers in which the reagents are stable, e.g. , in lyophilized form or stabilized liquids.
- the reagents may also be in single use form, e.g., in single dosage form.
Abstract
Provided are compositions and methods for filling cells with non-pharmacological dermal fillers leading to smoothened skin wrinkles, augmented lips, improved skin appearance, or treated scars.
Description
DERMAL FILLING COMPOSITIONS AND METHODS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application Serial Numbers 61/589,775, filed January 23, 2012 and 61/604,396, filed February 28, 2012, the contents of both of which are incorporated by reference in their entirety.
FIELD OF THE DISCLOSURE
[0002] This disclosure generally relates to compositions and methods for filling cells with non-pharmacological agents, such as dermal fillers, which can result in, e.g., smoothening of skin wrinkles and augmentation of lips.
BACKGROUND
[0003] Skin is the largest organ and its surface provides an amenable large area to deliver molecules for localized or systemic effects. Unfortunately, the permeability of foreign molecules, especially large hydrophilic molecules, across the stratum corneum (the outer skin surface) is extremely low. It would be therefore be of great interest to develop modalities to permit the efficient transport of a broad range of molecules across the stratum corneum and into the skin (epidermis and dermis). Because some important components of the skin (such as hair follicles and sebaceous glands) are found deep in the dermis (up to 5 mm below the skin surface) the technology needs go significantly beyond the ability of breaking through the stratum corneum which is a thin layer (~ 10 μιη) of dead keratinocytes.
SUMMARY
[0004] The present disclosure provides a composition comprising a non-pharmacological dermal filler and optionally a pharmaceutically acceptable excipient, the dermal filler being covalently or non-covalently bound to a cell penetrating peptide that is capable to penetrate a dermal cell. In one aspect, the cell penetrating peptide is not longer than about 10 amino acids in length. In another aspect, the cell penetrating peptide is about 7 amino acids in length. In
some aspects, the cell penetrating peptide is capable to deliver the dermal filler across a stratum corneum.
[0005] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of TGSTQHQ, XiGSTQHQ, TX2STQHQ, TGX3TQHQ, TGSX4QHQ, TGSTXjHQ, TGSTQXgQ and TGSTQHX7, wherein X X7 are:
[0006] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of HSALTKH, XiSALTKH, HX2ALTKH, HSX3LTKH, HSAX4TKH, HSALX5KH, HSALTX6H and HSALTKX7, wherein X1-X7 are:
[0007] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of STHFIDT, XiTHFIDT, SX2HFIDT, STX3FIDT, STHX4IDT, STHFX5DT, STHFIX6T and STHFIDX7, wherein X1-X7 are:
[0008] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of KTGSHNQ, XiTGSHNQ, KX2GSHNQ, KTX3SHNQ, KTGX4HNQ, KTGSX5NQ, KTGSHXgQ and KTGSHNX7, wherein X1-X7 are:
[0009] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of MGPSSML, XiGPSSML, MX2PSSML, MGX3SSML, MGPX4SML, MGPSXjML, MGPSSX6L and MGPSSMX7, wherein X X7 are:
[0010] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of TDPNQLQ, XiDPNQLQ, TX2PNQLQ, TDX3NQLQ, TDPX4QLQ, TDPNX5LQ, TDPNQX6Q and TDPNQLX7, wherein X X7 are:
[0011] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SSSPSKH, XiSSPSKH, SX2SPSKH, SSX3PSKH, SSSX4SKH, SSSPXjKH, SSSPSX6H and SSSPSKX?, wherein X1-X7 are:
[0012] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of GLHPAFQ, XiLHPAFQ, GX2HPAFQ, GLX3PAFQ, GLHX4AFQ, GLHPX5FQ, GLHPAX6Q and GLHPAFX7, wherein X1-X7 are:
[0013] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SMNQPTA, XiMNQPTA, SX2NQPTA, SMX3QPTA, SMNX4PTA, SMNQX5TA, SMNQPX6A and SMNQPTX7, wherein X X7 are:
Position Amino Acid
Xl G, P, A or T
X2 L, I or V
X3 H or D
X4 D, E or H
X5 A or S
X6 S or A
X7 G, P, S or T
[0014] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of PHNTTAS, XiHNTTAS, PX2NTTAS, PHX3TTAS, PHNX4TAS, PHNTXjAS, PHNTTX6S and PHNTTAX7, wherein X1-X7 are:
[0015] In one embodiment, the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SSHLSSS, XiSHLSSS, SX2HLSSS, SSX3LSSS, SSHX4SSS, SSHLXsSS, SSHLSX6S and SSHLSSX7, wherein X1-X7 are:
[0016] In any of the above embodiments, the dermal filler can be biodegradable.
[0017] In one aspect, the non-pharmacological agent is selected from the group consisting of hyaluronic acid (HA), collagen, collagen mimetic, elastin, fibrin, fibronectin, tenascin, vitamin A, polysaccharide, amino acid homocopolymer, melanin, melanin derivatives, natural
or synthetic pigment, and combinations thereof. In one aspect, the polysaccharide is chitosan, chondroitin, glycosaminoglycan, proteoglycan or combinations thereof. In one aspect, the amino acid homocopolymer is poly-Lysine, polyacrylamide, polyethyleneglycol, polylactic acid, or combinations thereof.
[0018] In one aspect, the pharmaceutically acceptable excipient provides a composition in the form of a lotion, a cream, a patch or an injectable.
[0019] Also provided, in one embodiment, is a method of smoothening the skin of a subject in need thereof, comprising contacting the skin with an effective amount of a composition of the present disclosure.
[0020] Further provided, in one embodiment, is a method of treating wrinkles for a subject in need thereof, comprising contacting the wrinkles with an effective amount of a
composition of the present disclosure.
[0021] Another embodiment provides a method for lip augmentation for a subject in need thereof, comprising contacting the lip with an effective amount of a composition of the present disclosure.
[0022] In any of these methods, the contacting can be applying the composition on a skin, or injecting the composition under the epidermis of a skin, without limitation. When injected, the composition can be injected between the epidermis and the dermis, in one aspect.
[0023] Still another embodiment provides a method of delivering a non-pharmacological dermal filler to a cell, comprising contacting the cell with a composition of the present disclosure.
DETAILED DESCRIPTION
[0024] Before the compositions and methods are described, it is to be understood that the invention is not limited to the particular methodologies, protocols, cell lines, assays, and reagents described, as these may vary. It is also to be understood that the terminology used
herein is intended to describe particular embodiments of the present invention, and is in no way intended to limit the scope of the present invention as set forth in the appended claims.
[0025] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
[0026] When a numerical designation is preceded by the term "about", it varies by ( + ) or ( - ) 10 %, 5 % or 1 %. When "about" is used before an amount, for example, in mg, it indicates that the weight value may vary ( + ) or ( - ) 10 %, 5 % or 1 %.
Definitions
[0027] In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
[0028] As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof.
[0029] As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of shall mean excluding more than trace amount of other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this invention.
Compositions
[0030] Provided, in some embodiments, are compositions comprising a dermal filler bound to a cell penetrating peptide that facilitates skin penetration. The compositions can optionally include a pharmaceutically acceptable excipient. In some aspects, the cell penetrating peptide is capable to deliver the dermal filler across a stratum corneum.
[0031] In one embodiment, the cell penetrating peptide is not longer than about 10 amino acids in length, or alternatively not longer than about 9 amino acids, or 8 amino acids or 7 amino acids. In another aspect, the cell penetrating peptide is about 7 amino acids in length. In another aspect, the penetrating peptide is not shorter than about 4 amino acids in length, or alternatively not shorter than about 5 amino acids, or 6 amino acids or 7 amino acids.
[0032] In one embodiment, the peptide that facilitates skin penetration comprises an amino acid sequence selected from SSSPSKH (Chen et al., Nature Biotechnology (2006) 24:455- 60), TGSTQHQ, HSALTKH, KTGSHNQ, MGPSSML, TDPNQLQ, and STHFIDT (Hsu and Mitragotri PNAS (2011) 108(38): 15816-21) and GLHPAFQ, SMNQPTA, PHNTTAS and SSHLSSS (Lee et al., Journal of Drug Targeting (2011) 19(9): 805-13), and their derivatives.
[0033] The peptides described in the above references have not been shown to be able to deliver significant amounts of cargoes at dermal depths that would enable them to affect the biology of the hair follicles or sebaceous glands. The present inventors have the insight, however, that these peptides and their derivatives are effective in delivering dermal fillers across the stratum corneum and into the skin.
[0034] In some embodiments, a derivative of a peptide includes peptides that have a substitution at one of the amino acid residues of the peptide. Specific and non-limiting examples of such substitutions are provided below.
[0035] In one aspect, the derivatives of TGSTQHQ include XiGSTQHQ, TX2STQHQ, TGX3TQHQ, TGSX4QHQ, TGSTXjHQ, TGSTQXgQ and TGSTQHX7, wherein X X7 are:
[0036] In one aspect, the derivatives of HSALTKH include Xi SALTKH, HX2ALTKH, HSX3LTKH, HSAX4TKH, HSALX5KH, HSALTX6H and HSALTKX7, wherein X X7 are:
[0037] In one aspect, the derivatives of STHFIDT include XiTHFIDT, SX2HFIDT, STX3FIDT, STHX4IDT, STHFX5DT, STHFIX6T and STHFIDX7, wherein X1-X7 are:
[0038] In one aspect, the derivatives of KTGSHNQ include XiTGSHNQ, KX2GSHNQ, KTX3SHNQ, KTGX4HNQ, KTGSX5NQ, KTGSHXgQ and KTGSHNX7, wherein X X7 are:
[0039] In one aspect, the derivatives of MGPSSML include XiGPSSML, MX2PSSML, MGX3SSML, MGPX4SML, MGPSXjML, MGPSSX6L and MGPSSMX7, wherein X X7 are:
[0040] In one aspect, the derivatives of TDPNQLQ include XiDPNQLQ, TX2PNQLQ, TDX3NQLQ, TDPX4QLQ, TDPNX5LQ, TDPNQX6Q and TDPNQLX7, wherein X1-X7 are:
[0041] In one aspect, the derivatives of SSSPSKH include XiSSPSKH, SX2SPSKH, SSX3PSKH, SSSX4SKH, SSSPXjKH, SSSPSX6H and SSSPSKX7, wherein X X7 are:
[0042] In one aspect, the derivatives of GLHPAFQ include XiLHPAFQ, GX2HPAFQ, GLX3PAFQ, GLHX4AFQ, GLHPX5FQ, GLHPAX6Q and GLHPAFX7, wherein X1-X7 are:
Position Amino Acid
Xl S, A or D
X2 V, M, I or L
X3 R, N or Q
X4 A or S
X5 G, P, S or T
X6 Y, I or L
X7 D, E or H
[0043] In one aspect, the derivatives of SMNQPTA include XiMNQPTA, SX2NQPTA, SMX3QPTA, SMNX4PTA, SMNQX5TA, SMNQPX6A and SMNQPTX7, wherein X X7
[0044] In one aspect, the derivatives of PHNTTAS include XiHNTTAS, PX2NTTAS, PHX3TTAS, PHNX4TAS, PHNTXjAS, PHNTTX6S and PHNTTAX7, wherein X1-X7 are:
[0045] In one aspect, the derivatives of SSHLSSS include XiSHLSSS, SX2HLSSS, SSX3LSSS, SSHX4SSS, SSHLXjSS, SSHLSXeS and SSHLSSX7, wherein X X7 are:
X7 G, P, A or T
[0046] In some aspects, more than one, or more than one type of, peptides can be bound to the dermal filler.
[0047] A "dermal filler," as used herein, refers to a substance that adds volume to cells under the skin resulting in augmented or smoothened skin surface.
[0048] In some aspects, the dermal filler is non-pharmacological. The term "non- pharmacological" refers to a substance that does not directly target a pharmacological target in a cell, through which the substance effects a pharmacological benefit.
[0049] In one aspect, the term "non-pharmacological" explicitly excludes any
"pharmaceutically active agents." As used herein, the term "pharmaceutically active agent" or simply "active agent" refers to an agent that, upon administration to a human or non-human animal subject, provides a desired pharmaceutical effect. In one aspect, therefore, a non- pharmacological dermal filler is none of a dermatological agents, an anti-neoplastic agent, a cardiovascular agent, a renal agent, a gastrointestinal agent, a rheumatologic agent, an immunological agent, or a neurological agent. In a particular aspect, a non-pharmacological dermal filler does not include nucleic acids, nucleotides, nucleosides or analogues thereof.
[0050] In some aspects, the compositions of the present disclosure do not contain a pharmacologically active agent. In one aspect, the compositions do not contain nucleic acids, nucleotides, nucleosides or analogues thereof that possess pharmacological properties, that regulate the expression or activities of a molecule that possess pharmacological properties, or that encode a protein having pharmacological properties.
[0051] Non-limiting examples of non pharmacological dermal fillers include Hyaluronic Acid (HA), in particular of sizes ranging between 5,000 and 2,000,000 Daltons, collagen, collagen mimetic, elastin, fibrin, fibronectin, tenascin, vitamin A, polysaccharides such as chitosan and chondroitin, glycosaminoglycans, proteoglycans, homocopolymers of amino acids such as poly-Lysine, polyacrylamide, polyethyleneglycol, polylactic acid, and other
polymers, melanin and melanin derivatives, natural and synthetic pigments, or the mixture thereof.
[0052] In a particular aspect, the non-pharmacological dermal filler includes a mixture of HA and collagen or collagen mimetics. It is contemplated that an appropriate ratio between HA and collagen (or its mimetics) can help achieve a desired viscosity for the composition, for instance, when the composition is applied, as a cream, to the skin of the subject. In one aspect, therefore, the mixture contains HA and collagen (or its mimetics) in a ratio that is from about 1 : 100 to about 100: 1. In another aspect, the ratio between HA and collagen (or its mimetics) is at least about 1:100, or 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1:20, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1.9, 1:1.8, 1:1.7, 1:1.6, 1:1.5, 1:1.4, 1:1.3, 1:1.2, 1:1.1, 1 : 1.05, or 1 : 1.01. In yet another aspect, the ratio between HA and collagen (or its mimetics) is not greater than about 100:1, or 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, 10:1, 9:1, 8:1, 7:1,6:1,5:1,4:1,3:1,2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1.05, or 1:1.01.
[0053] In one aspect, the non-pharmacological dermal filler includes from about 1% to about 99% HA, or alternatively at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% HA. In another aspect, the non- pharmacological dermal filler includes no more than 99%, or alternatively no more than about 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% HA. In yet another aspect, the non-pharmacological dermal filler includes from about 1% to about 99% collagen or collagen mimetics, or alternatively at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%), 90%), or 95% collagen or collagen mimetics. In still another aspect, the non- pharmacological dermal filler includes no more than 99%, or alternatively no more than about 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%), 3%), 2%) or 1%) collagen or collagen mimetics.
[0054] In some aspects, the peptide is covalently or non-covalently bound to the dermal filler. For covalent binding, for instance, dermal filler can be modified by covalent attachment of multiple copies of the peptides of the present disclosure on different sites of the dermal filler.
[0055] When bound directly, the bonding can take place at a reactive side chain of one or more amino acids in the peptide. The amino acid can also be modified. For example, lysine, cysteine, threonine, glutamic acid, aspartic acid, serine, histidine, arginine, tyrosine, proline and tryptophan may be readily modified using known processes and procedures. A reagent used to modify the protein will have at least one reactive group. Examples of reactive groups that are used to react with amino acid side chains include activated esters (such as acyl halides or N-hydroxysuccinimide esters) that react with amine (such as lysine) and hydroxy 1 (such as threonine or serine) containing residues; maleimides that react with thiol (such as cysteine) containing residues; and amines which react with carboxylic acid (such as glutamic acid and aspartic acid) containing residues when activated with certain coupling reagents.
[0056] To prevent possible steric issues, in some aspects, a linker can be incorporated between the peptide and the site of attachments on the dermal filler. The linker can be a chemical compound having two or more polymerizable groups. In general, any linking compound may be used, so long as the polymerizable groups on the linker are capable of forming a linked peptide-dermal filler complex. Examples of linkers include compounds having two vinyl, acryl, alkylacryl, or methacryl groups. Examples of specific linkers having two acryl groups include Ν,Ν'-methylenebisacrylamide and glycerol dimethacrylate.
[0057] In some embodiments, the linker is a degradable linker. A degradable linker is cleaved under certain conditions, resulting in decomposition or removal of the peptide from the dermal filler, which peptide can then be degraded safely within the cell. For example, a degradable linker may hydrolyze at certain pH (high or low), may be cleaved by specific enzymes (such as esterases or peptidases), may be photolytically cleaved upon exposure to certain wavelengths, or be cleaved at certain temperatures. Examples of linkers which hydrolyze at reduced pH include glycerol dimethacrylate, which is stable at physiological pH (about 7.4), but hydrolyzes at lower pH (about 5.5). Other examples of degradable linkers include acetal linkers described in US 7,056,901, which is incorporated by reference in its entirety.
[0058] Further specific examples of degradable linking groups include Ν,Ν'- methylenebis(acrylamide), 1 ,4-bis(acryloyl)piperazine, ethylene glycol diacrylate, N,N'-(1,2- dihydroxy-ethylene)bisacrylamide, and poly(ethylene glycol)diacrylate.
[0059] Further examples of non-degradable linking groups include Ν,Ν'- bis(acryloyl)cystamine, glycerol dimethacrylate, bis[2-(methacryloyloxy)ethyl] phosphate, and bisacryloylated polypeptide.
[0060] In some aspects, the peptide is non-covalently bound to the dermal filler. Non- limiting examples of non-covalent bounding include hydrogen bond, ionic force, hydrophobic bonding, and Van der Wall force.
[0061] Ionic bonds, for instance, can be used to bound the peptide to the dermal filler by virtue of the presence of positive or negative charges of certain amino acids, such as arginine, aspartic acid, glutamic acid, histidine and lysine, and amino acids that are modified to have charges.
[0062] In certain embodiments, the peptide and/or the dermal filler has a surface modification. Surface modifications are chemical moieties which are added to the surface of the dermal filler or the peptide. A surface modifying agent may be a small molecule, polymer, peptide, polypeptide, protein, oligonucleotide, polysaccharide, or antibody. The surface modification may alter the solubility of the dermal filler of the peptide, change the surface charge of the dermal filler of the peptide, or impart an additional function to the complex. Surface modifications that enhance cell targeting result in an increased transduction of the nanocomplex into targeted cells, when compared with non-targeted cells. Surface modifications that enhance cell penetration result in increased transduction of the complex into cells. More than one surface modification may be present on the dermal filler peptide complex. Examples of small molecule surface modifications include cell targeting
compounds such as folic acid. Polymers include polyethylene glycol to increase solubility. Peptides may be used for cell targeting, such as antibodies to particular cell surface features, cell signaling proteins, or growth hormones. Other peptides may be used to increase cell penetration of the nanoparticles (such as TAT or antennepedia homeodomain).
Uses
[0063] Compositions of the present disclosure are useful for delivering a non- pharmacological dermal filler to a cell, by virtue of the peptide's cell penetrating capabilities. The delivery can be effected by contacting the cell with the composition. In one aspect, the
contact is in vitro. In another aspect, the contact is in vivo. In one aspect, the cell is a dermal cell. In another aspect, the delivery is through a dermal layer.
[0064] Cosmetic or therapeutic benefits can be achieved by such delivery. In one embodiment, the delivery results in smoothening the skin of a subject in need thereof. In another embodiment, the delivery results in treatment of wrinkles in a subject in need thereof. In yet another embodiment, the delivery leads to lip augmentation for a subject in need thereof. In yet other embodiments, the intended uses include improving the appearance of the skin, removing or treating a scar, or filling a hole on the skin for a subject.
[0065] In some embodiments, the methods entail applying the compositions to the skin of a subject as a cream, lotion, or on a patch. In some embodiments, the compositions are injected. In one aspect, the composition is injected under the epidermis. In some aspects, the composition is injected at the junction between the epidermis and the dermis. By virtue of the peptide's ability to penetrate the dermis, it is contemplated that the composition can be delivered through the dermis. The use of such a peptide in the composition would enable the delivery of the dermal filler, such as Hyaluronic Acid (HA), close to the skin surface and be therefore suitable for the treatment of superficial fine wrinkles, among other uses. Current methods to deliver hyaluronic acids, for instance, are based on dermal and subcutaneous injections via needles of varied bore sizes. HA injections methods are therefore not adapted to inject close to the skins surface (epidermis). The compositions and methods of the present disclosure, therefore, have advantages over the conventional technology.
Formulations
[0066] The peptide-dermal filler complexes discussed herein can be formulated into various compositions, for use in cosmetic or therapeutic treatment methods. The compositions {e.g. pharmaceutical compositions) can be assembled as a kit. Generally, a pharmaceutical composition of the invention comprises an effective amount {e.g., a pharmaceutically effective amount) of a composition of the invention.
[0067] In some embodiments, the formulation comprises at least one excipient to aid in achieving a formulation with desired properties, such as increased solubility, preservability or to provide an isotonic solution. Such excipients are known in the art.
[0068] A composition of the invention can be formulated as a pharmaceutical composition, which comprises a composition of the invention and pharmaceutically acceptable carrier. By a "pharmaceutically acceptable carrier" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The carrier would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. For a discussion of pharmaceutically acceptable carriers and other components of pharmaceutical compositions, see, e.g., Remington's Pharmaceutical Sciences, 184εά., Mack Publishing Company, 1990. Some suitable pharmaceutical carriers will be evident to a skilled worker and include, e.g., water (including sterile and/or deionized water), suitable buffers (such as PBS), physiological saline, cell culture medium (such as DMEM), artificial cerebral spinal fluid, or the like. A pharmaceutical composition or kit of the invention can contain other pharmaceuticals, in addition to the compositions of the invention. The other agent(s) can be administered at any suitable time during the treatment of the patient, either concurrently or sequentially.
[0069] One skilled in the art will appreciate that the particular formulation will depend, in part, upon the particular agent that is employed, and the chosen route of administration. Accordingly, there is a wide variety of suitable formulations of compositions of the present invention.
[0070] In some aspects, the pharmaceutically acceptable excipient and/or the carrier provides a composition in the form of a lotion, a cream, a patch or an injectable, with methods known in the art.
[0071] One skilled in the art will appreciate that a suitable or appropriate formulation can be selected, adapted or developed based upon the particular application at hand. Dosages for compositions of the invention can be in unit dosage form. The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for animal (e.g. human) subjects, each unit containing a predetermined quantity of an agent of the invention, alone or in combination with other therapeutic agents, calculated in an amount sufficient to
produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
[0072] One skilled in the art can easily determine the appropriate dose, schedule, and method of administration for the exact formulation of the composition being used, in order to achieve the desired effective amount or effective concentration of the agent in the individual patient.
[0073] The dose of a composition of the invention, administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect at least a detectable amount of a diagnostic or therapeutic response in the individual over a reasonable time frame. The dose used to achieve a desired effect will be determined by a variety of factors, including the potency of the particular agent being administered, the
pharmacodynamics associated with the agent in the host, the severity of the disease state of infected individuals, other medications being administered to the subject, etc. The size of the dose also will be determined by the existence of any adverse side effects that may accompany the particular agent, or composition thereof, employed. It is generally desirable, whenever possible, to keep adverse side effects to a minimum. The dose of the biologically active material will vary; suitable amounts for each particular agent will be evident to a skilled worker.
[0074] Another embodiment of the invention is a kit useful for any of the methods disclosed herein, either in vitro or in vivo. Such a kit can comprise one or more of the compositions of the invention. Optionally, the kits comprise instructions for performing the method. Optional elements of a kit of the invention include suitable buffers, pharmaceutically acceptable carriers, or the like, containers, or packaging materials. The reagents of the kit may be in containers in which the reagents are stable, e.g. , in lyophilized form or stabilized liquids. The reagents may also be in single use form, e.g., in single dosage form.
[0075] It is to be understood that while the invention has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and
modifications within the scope of the invention will be apparent to those skilled in the art to
which the invention pertains.
Claims
1. A composition comprising a non-pharmacological dermal filler and optionally a pharmaceutically acceptable excipient, the dermal filler being covalently or non-covalently bound to a cell penetrating peptide that is capable to penetrate a dermal cell.
2. The composition of claim 1, wherein the cell penetrating peptide is not longer than about 10 amino acids in length.
3. The composition of claim 1, wherein the cell penetrating peptide is about 7 amino acids in length.
4. The composition of any one of claims 1-3, wherein the cell penetrating peptide is capable to deliver the dermal filler across a stratum corneum.
5. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of TGSTQHQ, XiGSTQHQ, TX2STQHQ, TGX3TQHQ, TGSX4QHQ, TGSTXjHQ, TGSTQXgQ and TGSTQHX7, wherein X X7 are:
6. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of HSALTKH, XiSALTKH, HX2ALTKH, HSX3LTKH, HSAX4TKH, HSALX5KH, HSALTX6H and HSALTKX7, wherein X1-X7 are:
X7 R, N or Q
7. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of STHFIDT, XiTHFIDT, SX2HFIDT, STX3FIDT, STHX4IDT, STHFX5DT, STHFIX6T and STHFIDX7, wherein X X7 are:
8. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of KTGSHNQ, XiTGSHNQ, KX2GSHNQ, KTX3SHNQ, KTGX4HNQ, KTGSX5NQ, KTGSHXgQ and KTGSHNX?, wherein X1-X7 are:
9. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of MGPSSML, XiGPSSML, MX2PSSML, MGX3SSML, MGPX4SML, MGPSX5ML, MGPSSX6L and MGPSSMX7, wherein X1-X7 are:
10. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of TDPNQLQ, XiDPNQLQ, TX2PNQLQ, TDX3NQLQ, TDPX4QLQ, TDPNX5LQ, TDPNQX6Q and TDPNQLX?, wherein X1-X7 are:
11. The composition of claim 1 , wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SSSPSKH, XiSSPSKH, SX2SPSKH, SSX3PSKH, SSSX4SKH, SSSPXjKH, SSSPSX6H and SSSPSKX7, wherein X X7 are:
12. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of GLHPAFQ, XiLHPAFQ, GX2HPAFQ, GLX3PAFQ, GLHX4AFQ, GLHPXjFQ, GLHPAXgQ and GLHPAFX7, wherein X X7 are:
13. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SMNQPTA, XiMNQPTA, SX2NQPTA, SMX3QPTA, SMNX4PTA, SMNQX5TA, SMNQPX6A and SMNQPTX7, wherein X1-X7 are: Position Amino Acid
Xl G, P, A or T
X2 L, I or V
X3 H or D
X4 D, E or H
X5 A or S
X6 S or A
X7 G, P, S or T
14. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of PHNTTAS, XiHNTTAS, PX2NTTAS, PHX3TTAS, PHNX4TAS, PHNTXjAS, PHNTTX6S and PHNTTAX7, wherein X1-X7 are:
15. The composition of claim 1, wherein the cell penetrating peptide comprises an amino acid sequence selected from the group consisting of SSHLSSS, XiSHLSSS, SX2HLSSS, SSX3LSSS, SSHX4SSS, SSHLXjSS, SSHLSXeS and SSHLSSX?, wherein X X7 are:
16. The composition of any one of claims 1-15, wherein the dermal filler is
biodegradable.
17. The composition of any one of claims 1-16, wherein the non-pharmacological agent is selected from the group consisting of hyaluronic acid (HA), collagen, collagen mimetic, elastin, fibrin, fibronectin, tenascin, vitamin A, polysaccharide, amino acid homocopolymer, melanin, melanin derivatives, natural or synthetic pigment, and combinations thereof.
18. The composition of claim 17, wherein the polysaccharide is chitosan, chondroitin, glycosaminoglycan, proteoglycan or combinations thereof.
19. The composition of claim 17, wherein the amino acid homocopolymer is poly-Lysine, polyacrylamide, polyethyleneglycol, polylactic acid, or combinations thereof.
20. The composition of any one of claims 1-19, wherein the pharmaceutically acceptable excipient provides a composition in the form of a lotion, a cream, a patch or an injectable.
21. A method of smoothening the skin of a subject in need thereof, comprising contacting the skin with an effective amount of a composition of any one of claims 1-20.
22. A method of treating wrinkles for a subject in need thereof, comprising contacting the wrinkles with an effective amount of a composition of any one of claims 1-20.
23. A method for lip augmentation for a subject in need thereof, comprising contacting the lip with an effective amount of a composition of any one of claims 1-20.
24. The method of any one of claims 21-23, wherein the contacting comprises applying the composition on a skin.
25. The method of any one of claims 21-23, wherein the contacting comprises injecting the composition under the epidermis of a skin.
26. The method of claim 25, wherein the composition is injected between the epidermis and the dermis.
27. A method of delivering a non-pharmacological dermal filler to a cell, comprising contacting the cell with a composition of any one of claims 1-20.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015023649A2 (en) | 2013-08-12 | 2015-02-19 | 3M Innovative Properties Company | Peptides for enhancing transdermal delivery |
WO2017048812A1 (en) * | 2015-09-15 | 2017-03-23 | The Regents Of The University Of California | Skin-penetrating peptides and compositions and methods of use thereof |
CN114470329A (en) * | 2022-03-11 | 2022-05-13 | 上海医妃医药科技有限公司 | Human albumin dermal filler |
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WO2010115052A2 (en) * | 2009-04-03 | 2010-10-07 | The Mclean Hospital Corporation | Induced pluripotent stem cells |
CN103201386A (en) * | 2010-11-09 | 2013-07-10 | 加利福尼亚大学董事会 | Skin permeating and cell entering (SPACE) peptides and methods of use thereof |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015023649A2 (en) | 2013-08-12 | 2015-02-19 | 3M Innovative Properties Company | Peptides for enhancing transdermal delivery |
US9642895B2 (en) | 2013-08-12 | 2017-05-09 | 3M Innovative Properties Company | Peptides for enhancing transdermal delivery |
WO2017048812A1 (en) * | 2015-09-15 | 2017-03-23 | The Regents Of The University Of California | Skin-penetrating peptides and compositions and methods of use thereof |
CN114470329A (en) * | 2022-03-11 | 2022-05-13 | 上海医妃医药科技有限公司 | Human albumin dermal filler |
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