JP-7854982-B2 - Peptides for therapeutic use in dermatology

Inventors

• パブロ ペレグリーニ

Assignees

• ドンペ ファーマスーチシ ソシエタ ペル アチオニ

Dates

Publication Date

20260507

Application Date

20210819

Priority Date

20200820

Claims (12)

1. A pharmaceutical composition for use in the treatment and/or prevention of abnormal skin discoloration and/or denervation of the skin, A 14-amino acid peptide having SEQ ID NO: 1, Alternatively, a peptide of up to 16 amino acids having a sequence that is at least 85 % identical to Sequence ID No. 1, A pharmaceutical composition comprising or derivatives thereof and/or salts thereof, wherein the derivative contains the N-terminus and/or C-terminus of the peptide, which is chemically modified or protected with an organic compound .
2. The pharmaceutical composition according to claim 1, wherein the peptide has a sequence that is at least 85% identical to Sequence ID No. 1, and the peptide has a length of up to 15 amino acids .
3. The pharmaceutical composition according to claim 1 , wherein the organic compound is selected from the group consisting of phosphoryl, glycosyl, acyl, alkyl, carboxyl, hydroxyl, biotinyl, ubiquitinyl, and amide.
4. A pharmaceutical composition, A 14-amino acid peptide having SEQ ID NO: 1, Alternatively, a peptide of up to 16 amino acids having a sequence that is at least 85 % identical to Sequence ID No. 1, or derivatives and/or salts thereof , wherein the derivative contains the N-terminus and/or C-terminus of the peptide, which has been chemically modified or protected with an organic compound , At least one pharmaceutically acceptable excipient, It consists of, The pharmaceutical composition according to claim 1, for use in the treatment and/or prevention of abnormal skin discoloration and/or denervation of the skin.
5. The pharmaceutical composition according to claim 4 , wherein the composition comprises 10 to 10,000 μg/mL of the peptide.
6. A pharmaceutical composition according to claim 4 or 5 for topical administration.
7. The pharmaceutical composition according to claim 6, in the form of a lotion, cream, gel, stick, spray, ointment, paste, or mousse.
8. The pharmaceutical composition according to any one of claims 4 to 7, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of pharmaceutically acceptable vehicles, volatile and non-volatile solvents, water, surfactants, preservatives, absorbents, chelating agents, lubricants, humectants, water repellents, antioxidants, UV absorbers, anti-irritants, vitamins, trace metals, antibacterial agents, fragrances, colorants and color components, and/or structuring agents .
9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the abnormal skin discoloration is selected from vitiligo, bilateral vitiligo, vitiligo of the limbs and face, generalized vitiligo, focal vitiligo, segmental vitiligo, universal vitiligo, perinevus or Sutton's nevus vitiligo, leukoderma, abnormal skin discoloration, mottled leukoderma, white pityriasis, tinea versicolor, idiopathic and post-inflammatory guttate melanopenia, depigmentation or depigmentation of a nevus, progressive macular melanopenia, melanopenia resulting from metabolic, nutritional or endocrine diseases, melanopenia resulting from chemicals, physical factors or pharmaceuticals, infectious and post-infectious melanopenia, and inflammatory edipomelanosis.
10. The pharmaceutical composition according to claim 9, which can be combined with a steroid-based or calcitriol-based compound or composition.
11. The pharmaceutical composition according to any one of claims 1 to 8, wherein the denervation disorder of the skin is selected from trigeminal neurotrophic syndrome, postherpetic pruritus, scalp paresthesia, back paresthesia, brachioradial itching, paresthesia femoral neuralgia, pruritus associated with keloids or burn scars, and small-diameter fiber neuropathy in the course of a systemic disease.
12. The pharmaceutical composition according to claim 11, which can be combined with an antiviral compound or composition.

Description

This invention relates to peptides that can promote skin pigmentation and/or nerve innervation in skin dyschromia and/or de-innervation diseases. Pharmaceutical compositions comprising such peptides and at least one pharmaceutically acceptable excipient are further subjects of this invention. Nerve growth factor (NGF) is a neurotrophic and neuropeptide factor primarily involved in regulating the growth, maintenance, proliferation, and survival of specific target neurons. NGF was discovered by Professor Rita Levi-Montalcini of the Institute of Zoology, Washington University in St. Louis (Non-Patent Literature 1). Because NGF can influence the development and protection of the biological function of neurons, as well as their regeneration, her discovery represents a significant advance in the study of the mechanisms of nerve cell growth and differentiation. Numerous in vitro and in vivo studies have demonstrated the pathophysiological importance of NGF in preventing surgical, chemical, mechanical, and ischemic nerve damage, making it an ideal candidate for the treatment of various conditions of the central and peripheral nervous systems (Non-Patent Literature 2, Non-Patent Literature 3). Indeed, for many years, clinical trials have been conducted on patients with Parkinson's disease and Alzheimer's disease using intracerebral administration of mouse NGF (e.g., Non-Patent Literature 4). The results of these studies supported observations from animal models and demonstrated the absence of potential side effects after administration of mouse NGF. This characteristic was later confirmed with human recombinant NGF (Non-Patent Literature 5). Immune cells, nerve cells, and skin cells play crucial roles in the development of various skin pathologies associated with abnormal discoloration, such as psoriasis, atopic dermatitis, vitiligo, and herpes. NGF receptors are expressed on sensory nerves, keratinocytes, melanocytes, fibroblasts, hair follicles, and various immune cells, playing a crucial role in skin homeostasis. Keratinocytes are crucial cellular components in both homeostatic and pathophysiological processes in the skin, producing numerous cytokines and being stimulated by various growth factors. NGF mRNA has been shown to be maximal when keratinocytes are in the logarithmic growth phase in vitro (Non-Patent Literature 6). In various species of keratinocytes, NGF controls proliferation and differentiation, and while exhibiting known anti-aging and skin regeneration activities (Non-Patent Literature 7), it protects human keratinocytes from apoptosis by activating high-affinity receptors (trkA) to maintain epidermal integrity. In fact, Trka plays a crucial role in activating signaling pathways that promote growth and survival and are also involved in skin innervation processes. In melanocytes, survival and dendritic formation increase after UV irradiation by NGF (Non-Patent Literature 8). Conventional technologies have shown how controlling NGF can be beneficial in the treatment of both skin diseases associated with abnormal discoloration and diseases associated with denervation, such as viral rashes like herpes and rare syndromes like trigeminal neurotrophic syndrome, which often occur in areas previously affected by herpes zoster. Treatment for vitiligo currently relies on therapies with significant side effects (Non-Patent Literature 9). In particular, treatment with corticosteroids, whether topical or oral, cannot be prolonged beyond three weeks. Despite the average quality of the results obtained (over 75% repigmentation in 63% of cases), even the optimal treatment, represented by narrowband phototherapy (NB-UVB phototherapy), can cause acute undesirable effects such as itching, erythema, burns, and xerosis. Patent Document 1 revealed that topical administration of a formulation containing NGF to the skin is effective in enhancing skin color, i.e., increasing pigmentation, in healthy skin not affected by pigment disorders, and similarly, is effective in improving skin conditions including depigmentation or hemoglobin deficiency, such as in vitiligo. Despite advancements in research, the problem of improving the treatment of skin discoloration and skin denervation remains. International Publication No. 2013/065078 Levi-Montalcini R., Harvey Lect., 60: 217, 1966Hefti F., J. Neurobiol., 25: 1418, 1994Fricker J., Lancet, 349:480, 1997Olson L. et al., J. Neural Transm, (Parkinson's Disease and Dementia Section), 4: 79-95, 1992Petty BG et al., Annals of Neurology, 36:244-246, 1994Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes.J Biol Chem 1991; 266: 21718-21722Nerve growth factor: its significance in cutaneous biology. J Invest Dermatol Symp Proc 2: 31-36, 1997The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes J. Clin. Invest.94: 1550-1562, 1994Am.J. Clin. Dermatol., 2017, 18:733-744 The graph shows the leg r