WO2016071814A1 - Promoteur pour l'absorption cutanée d'ingrédients actifs ayant une structure peptidique - Google Patents

Promoteur pour l'absorption cutanée d'ingrédients actifs ayant une structure peptidique Download PDF

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Publication number
WO2016071814A1
WO2016071814A1 PCT/IB2015/058400 IB2015058400W WO2016071814A1 WO 2016071814 A1 WO2016071814 A1 WO 2016071814A1 IB 2015058400 W IB2015058400 W IB 2015058400W WO 2016071814 A1 WO2016071814 A1 WO 2016071814A1
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WIPO (PCT)
Prior art keywords
peptide
peptides
family
active ingredient
identified
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PCT/IB2015/058400
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English (en)
Inventor
Paola Minghetti
Chiara GENNARI
Francesco Cilurzo
Sara PELLEGRINO
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Università Degli Studi Di Milano
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Publication of WO2016071814A1 publication Critical patent/WO2016071814A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • 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
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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

Definitions

  • the present invention concerns a family of peptides to be used as cutaneous absorption promoters of active ingredients, said peptides being selected through "phage displaying” technique starting from human epidermis.
  • the present invention also concerns compositions suitable for cutaneous administration containing an active ingredient and at least one of the aforementioned peptides, wherein said peptide is or is not conjugated with said active ingredient.
  • the alteration of the barrier properties of the stratum corneum can promote the absorption of the drug.
  • non-invasive chemical as absorption promoters
  • physical iontophoresis, electroporation or sonophoresis
  • absorption promoters are frequently associated with phenomena of irritation and/or sensitivity that limit the prolonged use thereof.
  • panning This creates a physical bond between each variant of protein sequence and the DNA encoding it, allowing rapid division based on the binding affinity to a certain target molecule (anti-bodies, enzymes, cell surface receptors) with an in vitro selection process called "panning" (Whaley et al 2000, Nature 405,665).
  • the panning is carried out by incubating a library of peptides of phages in the presence of a plate (or ball) covered with the target molecule. Thereafter, the phage not bonded to said plate is eliminated and the specifically bonded phage is eluted, amplified and passed through further bond amplification cycles. After 3-4 bond amplification cycles, the clones are characterised through DNA sequencing and ELISA.
  • oligopeptides capable of : considerably increasing cutaneous absorption of active ingredients also with high molecular weight, not only at the stratum corneum but also in the deeper layers of the skin, and of being used at neutral, therefore at not an acidic pH, without the need to be positively charged.
  • GSSKPAM identified with SEQ ID. NO.2,
  • ILPYAWT identified with SEQ. ID. NO.3,
  • NLLPTRG identified with SEQ. ID NO.6.
  • peptides were selected in particular through the phage display technique using human epidermis and Ph.D_7 phages library.
  • the object of the present invention is a peptide selected from the aforementioned family (A) of peptides, for use as a cutaneous permeation enhancer of an active ingredient.
  • a further object of the present invention is a composition comprising at least one active ingredient and at least one peptide selected from the aforementioned family (A) of peptides as cutaneous permeation enhancer of said at least one active ingredient in combination with suitable excipients and/or diluents.
  • Figure 1 displays a block diagram showing the stages of the phage display technique used to identify the family of peptides (A) object of the present invention, as described in example 1.
  • Figure 2 represents the graph of the quantity permeated in vitro expressed in (%) weight of the peptide DRTTLTN at different concentrations through the stratum corneum as a function of time expressed in hours as described in example 2.
  • Figure 3 represents the graph of the quantity permeated in vitro expressed in ⁇ g/cm 2 of the propranolol hydrochloride in the presence and in the absence of the peptide DRTTLTN as described in example 4.
  • Figure 4 represents the graph of the quantity permeated in vitro expressed in ⁇ g/cm 2 of the lidocaine in the presence and in the absence of the peptide DRTTLTN as described in example 4.
  • Figure 5 represents the graph of the quantity permeated in vitro expressed in ⁇ g/cm 2 of the conjugated
  • Figure 6 represents the spectrum of the circular dichroism of the peptide Ac- NHDRTTLTN-CONH2 prepared as described in example 7.
  • active ingredient is meant to indicate a pharmaceutically effective or dermatologically-cosmetically effective substance consisting of a small molecule, i.e. a molecule characterised by low molecular weight in general not greater than 2000 Da, or a macromolecule like for example polysaccharides, polypeptides, proteins, antisense oligonucleotides, RNA and DNA.
  • the term "pharmaceutically effective substance” is meant to indicate a substance capable of treating, diagnosing and/or preventing, by systemic or topical administration, a possible ailment or illness.
  • the term "dermatologically-cosmetically effective substance” is meant to indicate a substance capable of preventing, diagnosing and/or treating, only topically, skin ailments not associated with a cutaneous pathology, for example a dermoprotective active ingredient for preventing/treating redness of the skin, or an active ingredient capable of treating/preventing the formation of wrinkles like for example botulin or analogous substances.
  • composition comprising at least one active ingredient and at least one peptide selected from the aforementioned family (A) of peptides as cutaneous permeation enhancer of said at least one active ingredient in combination with suitable excipients and/or diluents
  • A family of peptides as cutaneous permeation enhancer of said at least one active ingredient in combination with suitable excipients and/or diluents
  • the term essentially topical administration of an active ingredient is meant to indicate that said active ingredient is absorbed topically in the first layers of the skin.
  • essentially systemic administration of an active ingredient is meant to indicate that said active ingredient is absorbed in the deeper layers of the skin.
  • peptide of class (A) conjugated with the active ingredient is meant to indicate a peptide belonging to the aforementioned family, bonded with covalent bond to the carbon-terminal atom or to the nitrogen-terminal of said peptide at the active ingredient.
  • protected peptide of class (A) is meant to indicate a peptide belonging to the family (A), protected at the C-terminal or at the N-terminal or at both the terminal groups with the conventional protective groups specific for the terminal carboxyl group and for the terminal ammine group of the peptides.
  • the protective group for the N-terminal is the acetyl group.
  • GSSKPAM identified with SEQ ID. NO.2
  • ILPYAWT identified with SEQ. ID. NO.3
  • SAFNIVL identified with SEQ. ID NO. 4
  • LYASNHH identified with SEQ. ID. NO. 5
  • NLLPTRG identified with SEQ. ID NO.6.
  • the peptides of class (A) can be used according to the present invention in conjugated or non-conjugated form.
  • the conjugated form is used when the active ingredient consists of a macromolecule.
  • the active ingredient is a small- sized molecule.
  • the peptides according to the present invention can possibly be conjugated to nanoparticle systems of metallic, polymeric, peptide (peptide based nanoparticles device-PBND) or lipid (liposomes, etosomes and transferosomes) nature.
  • the peptide DRTTLTN is used.
  • this peptide is used in conjugated form to the N-terminal, when, for example, the active ingredient is heparin.
  • This peptide is used in conjugated form to the N-terminal in the case it must be bonded to a carbonyl group when for example the active ingredient is heparin.
  • This peptide is used in conjugated form to the carbonyl in case it must be bonded to an aminic group when for example the active ingredient is heparin.
  • the peptide can be conjugated to the active ingredient using biodegradable spacers so that the active ingredient can be regenerated in vivo.
  • the peptide is first conjugated to the lipid component through classical reactions of formation of amide bonds in the presence of condensing agents like carbodiimides, or through "click chemistry” reactions [Sletten E.M., Acc. Chem. Res. 2011; 44: 666-676].
  • this peptide is used in protected form with acetyl at the N-terminal when the active ingredient is a small molecule, for example propranolol hydrochloride or lidocaine.
  • the preferred pharmaceutical formulations (I) indicated above and the dermatological-cosmetic ones (II) can for example be in the form of a patch, powder, solution, foam, emulsion, gel, ointment, paste, mask or filming dispersions in situ.
  • filming dispersions in situ is meant to indicate liquid or semisolid preparations containing a polymer capable of forming a film in situ on the skin and of ensuring the absorption of the active ingredient therein contained.
  • the permeability tests were carried out using, as membrane, skin of human origin obtained from patients subjected to abdominoplasty.
  • the skin was prepared following a protocol encompassing mechanical separation of the derma from the stratum corneum epidermis (SCE) complex, obtained following to immersion of the skin in distilled water at 60 ⁇ 1°C for 1 minute.
  • SCE stratum corneum epidermis
  • the pieces thus obtained were inspected by microscope to check for possible defects.
  • the samples were placed on teflon plates and dried in a silica drier at a temperature of 4° C. After drying the samples, identified by an internal code, they were kept at a temperature of -20°C until their use.
  • the layer of SCE was thawed, cut into sections suitable for the area of the cell of diameter equal to 25 mm and rehydrated in a physiological solution (NaCl 0.9% p/v) for lh at room temperature.
  • the phages (1x1011 pfu) of the peptide library were loaded into the donor compartment of the Franz diffusion cell.
  • the phages that permeated the SCE were recovered by the receiving compartment after 24 hours and amplified through infection in Escherichia coli.
  • the amplified phages were used for a second selection cycle. At the end of this second cycle, the phages were incubated with Escherichia coli and plated on agar gel. From each plate 20 colonies were taken, each representing a single phage clone, and the viral DNA was extracted, which was in turn sequenced.
  • Example 2 In vitro permeation of the peptide DRTTLTN through the human stratum corneum
  • the effect of the peptide on the organisation of the lipids of the stratum corneum was determined through Fourier transform infrared spectroscopy with attenuated total reflectance (Spectrum One, Perkin Elmer).
  • a sample of human epidermis was treated with a solution of DRTTLTN for 1 hour at room temperature. At the end of the incubation period the solution was removed, the sample was dried and the spectrum was obtained.
  • Each spectrum and the result of the average from 128 scans carried out with a resolution of 4cm "1 in the region of the spectrum with wavelength comprised between 4000 and 650 cm "1 .
  • the values of the bands of the symmetric and asymmetric stretching of the CH 2 groups were subjected to statistical analysis to evaluate whether there were significant variations in intensity of the bands. These intensity variations are an indication of a fluidizing effect of the peptide on the three-dimensional organisation of the lipids.
  • the spectra were normalised with respect to the amide I that is characteristics of keratin.
  • the values of the ratios between the heights of the peaks relative to the vibrations of the symmetric or asymmetric stretching of the CH 2 and of the amide I (respectively indicated as aCH 2 /A and sCH 2 /A) are given in the table below.
  • the fluidizing effect of the peptide is expressed by the ratio between the values of aCH 2 /A of the sample treated with DRTTLTN and of the sample of epidermis not treated that must be greater than one.
  • the experiment was carried out using propranolol and lidocaine as model molecules.
  • a physiological solution containing propranolol hydrochloride (0.2 % p/v) and peptide DRTTLTN (0.1 mg/mL) or lidocaine base (0.3 %) and peptide (0.2 mg/mL) were loaded into the donor compartment of a Franz diffusion cell using SCE as membrane.
  • Solutions of propranolol hydrochloride (0.2%) and lidocaine base (0.3%) without the addition of peptide (1, 3 and 6 hours) samples (0.2 mL) were taken from the receiving compartment and an equal volume of physiological solution was added. The samples taken were analysed by HPLC.
  • the experiment was carried out by loading a solution of heparin (2 mg/mL) and of peptide DRTTLTN (0.5 mg/mL) in the donor compartment of a Franz diffusion cell using SCE as membrane. At predetermined times, an aliquot of the receiving phase was taken and the heparin content was determined using the Kit COATEST ® (Chromogenix). 0.3 mL of a physiological solution containing 100 ⁇ g/ml of sodium azide and 6.7 mg/mL of conjugate or heparin were loaded into the donor compartment. A solution containing 2 mg/mL of heparin was used as reference.
  • the receiving phase (Tris 0.05 mol/L, pH 7.4) was taken and the samples were analysed with the Kit COATEST ® (Chromogenix) which allows the heparin to be dosed in terms of activity against the factor Xa.
  • the quantities permeated after 24 hours were about 0.03 UI/cm 2 in the case of only heparin and about 0.05 UI/cm 2 in the case of co-administration of heparin and DRTTLTN.
  • the ability of the peptide to promote the percutaneous passage of macromolecules was studied by directly bonding the peptide DRTTLTN to the heparin (according to the synthetic scheme given below) and by evaluating the cutaneous permeability properties in vitro using Franz cells human epidermis as membrane. The permeation of the conjugate heparin-DRTTLTN was studied in comparison with a solution of heparin as such.
  • the conjugate was purified of the possible unreacted peptide through centrifugal ultra-filtration (six passages through Microcon/Amicon filters, cut-off 3KDa, centrifuging at 5000 g per 10 minutes). Cutaneous permeation study - 0.3 mL of a physiological solution containing 100 ⁇ g/ml of sodium azide and 6.7 mg/mL of conjugate or heparin were loaded into the donor compartment. After 7 and 24 hours from the start of the experiment, samples of 0.2 mL of receiving phase (Tris 0,05 mol/L, pH 7.4) were taken by the sampling arm.
  • D aspartic acid
  • DCM Dichloromethane
  • DIPEA Diisopropylethylamine
  • DMF ⁇ , ⁇ -dimethylformamide
  • Fmoc 9-Fluorenylmethyloxycarbonyl
  • FIBTU O- benzotriazole-N,N,NO,NO-tetramethyluronium-hexafluoro-phosphate
  • HOBT 1 - Hydroxybenzotriazole
  • L leucine
  • N asparagine
  • NMP 1 -Methyl -2-pyrrolidinone
  • Pbf 2,2,4,6,7-Pentamethyldihydrobenzofuran-5-sulfonyl
  • R arginine T: threonine
  • RP-HPLC reverse phase HPLC
  • tBu ter-butyl
  • TFA trifluoroacetic acid
  • Trt Trityl
  • Trityl The peptide was prepared by solid phase peptide synthesis
  • the amidated peptide at C-terminal was prepared using Rink amide resin with a loading of 0.5 mmol g-1 and e on a scale 0.2 mM.
  • the carboxylated peptide at C-terminal was prepared using chlorotrityl resin with a loading of 1.0 mmol g-1 and e on a scale 0.2 mM.
  • the protections of the lateral chains of the amino acids used are: tBu per D and T, Pbf for R, Trt for N.
  • Solutions 0.2 M of Fmoc amino acids in DMF or NMP were used.
  • As coupling reactant a mixture HOBT/HBTU 0.45M in DMF was used and as base a solution of DIPEA 2 M in NMP (Fmoc amino acid/HOBT/HBTU/DIPEA 5/5/5/10 equivalent with respect to the loading resin) was used.
  • DIPEA 2 M in NMP Fmoc amino acid/HOBT/HBTU/DIPEA 5/5/5/10 equivalent with respect to the loading resin
  • For the deprotection reaction of the Fmoc group a solution of piperidine 20% in DMF was used.
  • the coupling reaction was carried out for 90 min at room temperature.
  • the deprotection is carried out with 2 cycles of 30 min and 10 min respectively.
  • Automated synthesis with the help of microwaves (CEM Liberty instrument) The coupling reaction was carried out for 5 min at 40 W with a maximum temperature of 75 °C.
  • the deprotection is carried out with 2 cycles of 5 min and 10 min respectively (75 °C, 40 W)
  • the acetylation reaction was carried out manually in solid phase, using acetic anhydride (10 eq), DIPEA (10 eq) in DCM for 30 min at room temperature.
  • the detachment from the resin was carried out using the K reactant (TFA/phenol/thioanisole/triisopropylsilane/water, 82.5:5:5:5:2.5 v/v) for 5h.
  • the peptide was precipitated by cold ethyl ether and purified through RP-HPLC with a gradient 5-70% of the solvent B (solvent A: water/acetonitrile/TFA 95/5/0.1; solvent B: water/acetonitrile/TFA 5/95/0.1) in 20 min with a flow of 20 ml/min.
  • solvent B solvent B
  • the peptide was lyophilised and kept at 0°C.
  • Figure 6 shows the spectrum of the circular dichroism of the peptide Ac- HDRTTLTN-C O H 2 carried out in water concentration 500 ⁇ .
  • P05SI2 SEQUENCE L ⁇ ST ⁇ SiG ST25

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Abstract

La présente invention concerne une famille de peptides à utiliser en tant que promoteurs d'absorption cutanée d'ingrédients actifs, lesdits promoteurs étant sélectionnés par la technique "d'exposition sur phage" à partir d'épiderme humain. La présente invention concerne également des compositions convenant à l'administration cutanée, contenant au moins un ingrédient actif et au moins l'un des peptides mentionnés ci-dessus.
PCT/IB2015/058400 2014-11-04 2015-10-30 Promoteur pour l'absorption cutanée d'ingrédients actifs ayant une structure peptidique WO2016071814A1 (fr)

Applications Claiming Priority (2)

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ITMI2014A001882 2014-11-04
ITMI20141882 2014-11-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006094193A2 (fr) 2005-03-03 2006-09-08 Revance Therapeutics, Inc. Compositions et procedes d'application topique et d'administration transdermique d'un oligopeptide
US7659252B2 (en) 2005-09-15 2010-02-09 Novomed Technologies, Inc. (Shanghai) Transdermal delivery peptides and method of use thereof
WO2012064429A2 (fr) 2010-11-09 2012-05-18 The Regents Of The University Of California Peptides entrant dans les cellules et traversant la peau (space) et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006094193A2 (fr) 2005-03-03 2006-09-08 Revance Therapeutics, Inc. Compositions et procedes d'application topique et d'administration transdermique d'un oligopeptide
US7659252B2 (en) 2005-09-15 2010-02-09 Novomed Technologies, Inc. (Shanghai) Transdermal delivery peptides and method of use thereof
WO2012064429A2 (fr) 2010-11-09 2012-05-18 The Regents Of The University Of California Peptides entrant dans les cellules et traversant la peau (space) et leurs procédés d'utilisation

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
BIOU HAMDAN ET AL., J. BIOL.CHEM, vol. 273, 1998, pages 8009
C G M GENNARI ET AL.: "Skin penetrating peptide as a tool to enhance the permeation of heparin through human epidermis", BIOMACROMOLECULES, vol. 17, no. 1, January 2016 (2016-01-01), AMERICAN CHEMICAL SOCIETY, pages 46 - 55, XP002754063, ISSN: 1525-7797 *
FERRE ET AL., J. PEPT. RES., vol. 54, 1999, pages 32
PELLEGRINO ET AL., AMINO ACIDS, vol. 43, 2012, pages 1995 - 2003
S KUMAR ET AL.: "Identification of a novel skin penetration enhancement peptide by phage display peptide library screening", MOLECULAR PHARMACEUTICS, vol. 9, 2012, American Chemical Society, pages 1320 - 1330, XP002742349, ISSN: 1543-8384 *
SIDHU ET AL., CHEM BIOCHEM., vol. 4, 2003, pages 14
SLETTEN E.M., ACC. CHEM. RES., vol. 44, 2011, pages 666 - 676
SUNNY KUMAR ET AL.: "Identification of a Novel Skin Penetration Enhancement Peptide by Phage Display Peptide Library Screening", MOL. PHARMACEUTICS, vol. 9, 2012, pages 1320 - 1330
TRACY HSU ET AL.: "Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer", PNAS, vol. 108, no. 38, 2011, pages 15816 - 15821
WHALEY ET AL., NATURE, vol. 405, 2000, pages 665
YONGPING CHEN: "Transdermal protein delivery by a coadministered peptide identified via phage display", NATURE BIOTECHNOLOGY, vol. 24, no. 4, 2006, pages 455 - 460

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