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WO2018104874A1 - Composition coadjuvante d'un facteur de croissance et d'un neuropeptide pour accélérer la cicatrisation de plaies et la réépithélialisation d'organes - Google Patents

Composition coadjuvante d'un facteur de croissance et d'un neuropeptide pour accélérer la cicatrisation de plaies et la réépithélialisation d'organes Download PDF

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Publication number
WO2018104874A1
WO2018104874A1 PCT/IB2017/057673 IB2017057673W WO2018104874A1 WO 2018104874 A1 WO2018104874 A1 WO 2018104874A1 IB 2017057673 W IB2017057673 W IB 2017057673W WO 2018104874 A1 WO2018104874 A1 WO 2018104874A1
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WO
WIPO (PCT)
Prior art keywords
growth factor
composition according
epidermal growth
neurotensin
pharmaceutical composition
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Application number
PCT/IB2017/057673
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English (en)
Spanish (es)
Inventor
Rafael RODRÍGUEZ ROJAS
Original Assignee
Desarrolladora Y Comercializadora De Tecnologías Biomédicas Decotecbio S.A.S. De C.V.
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Application filed by Desarrolladora Y Comercializadora De Tecnologías Biomédicas Decotecbio S.A.S. De C.V. filed Critical Desarrolladora Y Comercializadora De Tecnologías Biomédicas Decotecbio S.A.S. De C.V.
Publication of WO2018104874A1 publication Critical patent/WO2018104874A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • Adjuvant composition of a growth factor and a neuropeptide to accelerate wound healing and organ repetition
  • the present invention relates to the pharmaceutical and biotechnology industry in general and to the pharmaceutical and biotechnology manufacturing industry for the treatment of wound healing and organ repetition.
  • a wound is a loss of integrity and normal continuity in the tissues.
  • the tissue generated in the healing process is not similar to that of the injured organ, but it will be a tissue of fibrous predominance, with a high content of collagen, which will interpose in the injured tissue area.
  • Wounds can be classified as simple, involving only the skin and complexes which involve damage to levels of blood vessels, nerves, cartilage and / or muscles. Within the first ones you can find scrapes and abrasions which have little blood loss and generally do not present danger.
  • healing is a biological process in which the skin and other organs repair their wounds after a destructive stimulus (Nguyen et al. 2009). This biological process is divided into three phases: inflammation, proliferation and remodeling (Schilling 1976; Serhan et al. 2004).
  • the proliferation phase the balance between the proliferation of fibroblasts and keratinocytes (epithelial cells of the skin) is essential for proper repetition.
  • Fibroblasts are primarily responsible for producing an appropriate extracellular matrix (ECM) so that keratinocytes, which are the predominant cell type of the epidermis, can migrate conveniently and thus establish a better quality skin epithelium, thus improving the organ functionality after an injury (Butler et al. 2008; Pastar et al.
  • growth factors are proteins that have the ability to modulate morphogenetic behaviors, such as: survival, proliferation, migration and cell differentiation (Mitchell et al. 2016).
  • growth factors used they are: platelet-derived growth factor, epidermal growth factor, insulin growth factors type 1 and 2, insulin, among others (Jones et al. 1995; Ralpham et al. 2002; Demidova-Rice et al. 2012; Hrynyk et al. 2014).
  • FDA Drug and Drug Agency
  • epidermal growth factor has been shown to be the most effective for healing wounds (EP1466617).
  • the combination of growth factors with adjuvants can be a key combination therapy strategy to accelerate the healing process.
  • the present invention relates to the use of a combination of a growth factor and a peptide for the treatment of wounds and thus accelerate the healing process.
  • the first agent is the epidermal growth factor, which is a 53-amino acid protein that promotes wound healing, its main role in The skin is to stimulate the proliferation and migration of different cell types, favoring healing and timely repetition (Rheinwald et al. 1977; Barrandon et al. 1987; Tanaka et al. 2005).
  • Epidermal growth factor exerts its effects by binding to the epidermal growth factor receptor, also known as EGFR / ERBBl / HERl, for its acronym in English (Singh et al. 2016).
  • epidermal growth factor family which includes the following proteins: epidermal growth factor, alpha transforming growth factor, binding epidermal growth factor to heparin, betacellulin, anfiregulin and epiregulin (Demidova-Rice et al. 2012, -Singh et al. 2016). It has been shown in several studies that epidermal growth factor is able to promote and promote wound healing of different organs in both animal and human models (Itoh et al. 1994; Tanaka et al. 2005; Berlanga-Acosta et al . 2009; Dogan et al. 2009; Aktas et al.
  • the second agent of the present invention falls within the classification of neuropeptides, which are small molecules of a peptide nature that are widely distributed in the organism but particularly in the nervous system (Woll 1991). The union of these neuropeptides with their receptors triggers the activation of different cellular processes, such as: favoring innervation (Ashrafi et al. 2016) and exercising functions similar to growth factors (Rozengurt 2002); Examples of these neuropeptides are: neuropeptide Y, bombesin, substance P and neurotensin.
  • neurotensin which is composed of 13 amino acids and is widely distributed in the nervous system (Carraway et al. 1973), different works have documented that this neuropeptide can exert powerful effects on the cell growth (Mustain et al. 2011). Recently it has been reported that neurotensin promotes healing of the skin in both healthy and diabetic rodents (Moura et al. 2014; Moura et al. 2014).
  • in vitro models differ greatly from in vivo models, since in vivo models are much more complex and integrative. That said, it is difficult to predict whether there is an adjuvant effect between epidermal growth factor and neurotensin to promote wound healing in vivo.
  • neurotensin separately does not favor the proliferation of skin cells at least in in vitro models (Moura et al. 2014), so it is unknown whether neurotensin alone or in conjunction with the factor of Epidermal growth promotes the repetition of organs in vivo and thus improve their functionality after a destructive stimulus.
  • One of the objectives of the invention is to provide a pharmaceutical combination that accelerates wound healing.
  • Another objective of the present invention is to provide a pharmaceutical composition that accelerates wound healing.
  • Another objective of the present invention is to provide a pharmaceutical combination that accelerates the repetition of damaged organs and thus improve their appearance and functionality after a destructive stimulus.
  • Another objective is to provide a pharmaceutical composition that accelerates the repetition of damaged organs and thus improve their appearance and functionality after a destructive stimulus.
  • the present invention relates to a combination and pharmaceutical composition that accelerate wound healing.
  • the composition comprises the combination of a growth factor belonging to the family of epidermal growth factors specifically the epidermal growth factor with a neuropeptide, specifically neurotensin and one or more pharmaceutically acceptable excipients.
  • the present invention is also useful for the treatment of repeating damaged organs.
  • the preferred embodiment of the pharmaceutical composition is selected from the combination of epidermal growth factor and neurotensin. This combination makes it possible to accelerate the process of repeating damaged organs without causing epithelial hyperplasia, therefore, the combination of epidermal growth factor with neurotensin would have an adjunctive effect on wound healing and the repetition of damaged organs.
  • the combination therapy composition consists of epidermal growth factor and neurotensin where the concentration of epidermal growth factor is present between 0.00001 and 10 mg / ml and the concentration of neurotensin from 0.00001 to 10 mg / ml. .
  • the concentration of epidermal growth factor and neurotensin is 0.02 mg / ml and 0.05 mg / ml, respectively.
  • Figure 2. Graph of cutaneous repetition.
  • the subject matter of the present invention in its broadest form consists of a combination and a pharmaceutical composition for the treatment of wound healing and organ repetition, comprising a combination of a growth factor and a neuropeptide.
  • growth factors we have, in the family of epidermal growth factors, in one of its modalities corresponds to the epidermal growth factor.
  • the neuropeptide in one of its modalities corresponds to the neurotensin.
  • the epidermal growth factor is a 53-amino acid protein that exerts its effects by binding to the epidermal growth factor receptor, also known as EGFR / ERBB1 / HER1 (Singh et al. 2016). This growth factor was first isolated from the mouse submaxillary glands (Cohen 1962) and can now be generated by recombinant DNA technology (Esquirol Caussa et al. 2015).
  • the epidermal growth factor favors the healing of wounds of different organs (Itoh et al. 1994; Berlanga-Acosta et al. 2009; Demidova-Rice et al. 2012), this is due to the proliferation and migration of different cell types (Bodnar 2013).
  • the epidermal growth factor favors hair growth (Alexandrescu et al. 2009) and protects it from chemotherapies (Paik et al. 2013).
  • the epidermal growth factor improves skin elasticity by reducing wrinkles and favoring the removal of dark spots on the skin (Schouest et al. 2012).
  • Neurotensin is a 13 amino acid neuropeptide that is naturally synthesized in neurons of the nervous system and endocrine cells of the small intestine (Evers 2006; St-Gelais et al. 2006). There are six functional amino acids (8-13), which are needed so that neurotensin can carry out its effects through neurotensin receptors type 1, 2, 3 and / or sorLA / LRl 1 (Vincent et al. 1999; Mustain et al. 2011). Currently, neurotensins can be synthesized, which include 13 amino acid (1-13) and 6 amino acid (8-13) neurotensin, neurotensin analogues and neurotensin receptor agonists (Boules et al. 2013 ).
  • neurotensin The general effects with which neurotensin is related, are to act as a neuromodulator of dopaminergic transmission, exert potent analgesic effects and have effects similar to those of a growth factor (Vincent et al. 1999; Evers 2006; St- Gelais et al. 2006). Recent studies have shown a favorable effect of neurotensin on the healing of skin wounds in in vivo models of healthy and diabetic rodents (Moura et al. 2014; Moura et al. 2014).
  • Healing is a biological process by which the organs are repaired after a destructive stimulus, this biological process can be compromised in cases of ischemia, infection, edema, elevated pressure, hypothyroidism, poisoning, diabetes, among others.
  • One of the strategies to favor the wound healing process is the use of growth factors.
  • the present invention relates to a composition for the treatment of wound healing and organ repetition.
  • Said composition consists of the combination of a growth factor belonging to the family of epidermal growth factors; and a neuropeptide, specifically neurotensin.
  • the epidermal growth factor is selected from the group comprising the transforming growth factor alpha, epidermal growth factor binding to heparin, betacellulin, anfiregulin, epiregulin, epidermal growth factor and other compounds with similar activity such as: factor analogues of epidermal growth and receptor agonists to epidermal growth factors.
  • the epidermal growth factor is selected from the group of epidermal growth factor of other non-human animal species, more preferably the epidermal growth factor is the human epidermal growth factor.
  • the neuropeptide is selected from the group consisting of neurotensins of 13 amino acids (1-13), 6 amino acids (8-13) and other compounds with similar activity such as: neurotensin analogs, neurotensin receptor agonists, neurotensin branched peptides, neurotensin branched molecules; the other compounds with similar activity are selected from substance P, analogues of substance P and receptor agonists to substance P.
  • the neuropeptide is the 13 amino acid neurotensin (1-13).
  • the quantitative composition consists of epidermal growth factor and neurotensin in various concentrations formed from 0.00001 to 10 mg / ml for both molecules, in addition to one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients for each pharmaceutical form are those known and widely used in the industry, which include diluents, disintegrants, binders, lubricants, glidants, flow improvers, among others.
  • composition can be presented in the form of a gel, cream, ointment, solution, suspension, injection, patch, tablet, capsule, that is, in any pharmaceutical form.
  • each dose of the composition has 0.02 mg / ml, epidermal growth factor and 0.05 mg / ml neurotensin.
  • Example 1 Evaluation of the efficiency of the combination of epidermal growth factor and neurotensin in wound healing.
  • the rats were anesthetized with an intraperitoneal injection of xylazine and ketamine, then a biopsy was done on the back at the level of the dermis and epidermis.
  • the wounds made by the biopsies were treated with different treatments. The size of the wound was monitored at different times. In the graph, wound healing was expressed as a percentage of the area of the wound (area of the wound on any day after surgery, divided by the area of the initial wound).
  • a pH 7 saline phosphate buffer was used to solubilize both epidermal growth factor and neurotensin.
  • Four experimental groups were included and the solutions were administered directly on the wound, according to table 1.
  • Neurotensin (N) 0.05 mg / ml for 10 days
  • Figure 1 shows the effect of treatments on wound healing.
  • the three treatment groups reduce the size of the wound when compared with the control, the reduction of the wound being greater in less time the group that received the combined growth factor treatment Epidermal with neurotensin.
  • This demonstrates the adjuvant effect of the combination of epidermal growth factor with neurotensin on acceleration in wound healing.
  • Example 2 Evaluation of the efficiency of the combined treatment of epidermal growth factor and neurotensin in skin repetition.
  • Immunoblot Total proteins were loaded on gels for electrophoresis separation and transfer in nitrocellulose membranes.
  • the membranes were stained with Ponceau Red to visualize the proteins and thus function as a load control.
  • the membranes were blocked and incubated with a primary anti-Claudin 1 antibody, a protein that is expressed in the epidermis (Furuse et al. 2002) and in the hair follicles of the skin (Brandner et al. 2003). Then, the membranes were re-incubated but with a secondary antibody. Finally, the membranes were revealed to perform densitometric analysis.
  • Figure 2 shows the effect of the treatments on the skin repetition on the sixth day.
  • the combined treatment of epidermal growth factor with neurotensin has the highest expression of Claudin 1, that is, the greatest cutaneous repeating.
  • the treatment of neurotensin alone has no effect on repeating when compared to the PBS control, this indicates that neurotensin has an important adjuvant effect on repeating when co-administered with the growth factor.
  • Figure 3 shows the effect of the treatments on skin repeating at the tenth day. The graph in Figure 3 shows that on the tenth day after treatment there is no significant difference between the different treatments.
  • Demidova-Rice TN et al. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 2: role of growth factors in normal and pathological wound healing: therapeutic potential and methods of delivery. Advances in skin & wound care. (2012). 25: 349-370. Dogan S., et al. Epidermal growth factor-containing wound closure enhances wound healing in non-diabetic and diabetic rats. International wound journal. (2009). 6: 107-115.
  • Moura LI et al. The effect of neurotensin in human keratinocytes - implication on impaired wound healing in diabetes. Experimental biology and medicine. (2014) . 239: 6-12.
  • Moura LI et al. Chitosan-based dressings loaded with neurotensin - an efficient strategy to improve early diabetic wound healing. Biomaterialia Act. (2014) . 10: 843-857.
  • EP1466617 Berlanga J., et al. Use of a pharmaceutical composition containing epidermal growth factor (EGF) for diabetic foot amputation prevention.
  • EGF epidermal growth factor

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
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  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne l'industrie pharmaceutique et biotechnologique pour le traitement de cicatrisation de plaies et la réépithélialisation d'organes. Les avantages de l'invention par rapport aux compositions de l'état de la technique reposent sur le fait que la présente invention rend possible, outre l'accélération du processus de cicatrisation, une rapidité de la réépithélialisation d'organes sans produire d'hyperplasie, améliorant ainsi la qualité de ces derniers après une lésion. La composition est constituée d'un facteur de croissance et d'un neuropeptide. Le facteur de croissance est le facteur de croissance épidermique, tandis que le neuropeptide est la neurotensine. Le facteur de croissance épidermique est présent dans la composition suivant une concentration comprise entre 0,00001 et 10 mg/ml et la neurotensine entre 0,00001 et 10 mg/ml. La combinaison peut adopter n'importe quelle forme pharmaceutique et peut être administrée par n'importe quelle voie d'administration.
PCT/IB2017/057673 2016-12-09 2017-12-06 Composition coadjuvante d'un facteur de croissance et d'un neuropeptide pour accélérer la cicatrisation de plaies et la réépithélialisation d'organes WO2018104874A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MX2016016339A MX389934B (es) 2016-12-09 2016-12-09 Composición coadyuvante de un factor de crecimiento y un neuropéptido para acelerar la cicatrización de heridas y la repitelización de órganos.
MXMX/A/2016/016339 2016-12-09

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020227642A1 (fr) * 2019-05-08 2020-11-12 Modernatx, Inc. Compositions pour peau et plaies et leurs méthodes d'utilisation
US11696892B2 (en) 2017-10-31 2023-07-11 Modernatx, Inc. Lipid nanoparticles for delivering modified RNA encoding a VEGF-A polypeptide
US11866475B2 (en) 2016-06-07 2024-01-09 Modernatx, Inc. Modified RNA encoding VEGF-A polypeptides, formulations, and uses relating thereto

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003053458A1 (fr) * 2001-12-20 2003-07-03 Centro De Ingenieria Genetica Y Biotecnologia Utilisation d'une composition pharmaceutique contenant le facteur de croissance epidermique (egf) pour la prevention de l'amputation du pied diabetique
ES2210727T3 (es) * 1998-03-07 2004-07-01 Daewoong Pharmaceutical Co., Ltd. Composicion topica que contiene factor de crecimiento epidermico humano.
ES2330688T3 (es) * 2006-01-31 2009-12-14 Centro De Ingenieria Genetica Y Biotecnologia Composicion farmaceutica de microesferas para prevenir la amputacion de pie diabetico.
US7776815B2 (en) * 2004-02-24 2010-08-17 Wisconsin Alumni Research Foundation Use of neuropeptides for ligament healing

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2210727T3 (es) * 1998-03-07 2004-07-01 Daewoong Pharmaceutical Co., Ltd. Composicion topica que contiene factor de crecimiento epidermico humano.
WO2003053458A1 (fr) * 2001-12-20 2003-07-03 Centro De Ingenieria Genetica Y Biotecnologia Utilisation d'une composition pharmaceutique contenant le facteur de croissance epidermique (egf) pour la prevention de l'amputation du pied diabetique
US7776815B2 (en) * 2004-02-24 2010-08-17 Wisconsin Alumni Research Foundation Use of neuropeptides for ligament healing
ES2330688T3 (es) * 2006-01-31 2009-12-14 Centro De Ingenieria Genetica Y Biotecnologia Composicion farmaceutica de microesferas para prevenir la amputacion de pie diabetico.

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11866475B2 (en) 2016-06-07 2024-01-09 Modernatx, Inc. Modified RNA encoding VEGF-A polypeptides, formulations, and uses relating thereto
US11696892B2 (en) 2017-10-31 2023-07-11 Modernatx, Inc. Lipid nanoparticles for delivering modified RNA encoding a VEGF-A polypeptide
WO2020227642A1 (fr) * 2019-05-08 2020-11-12 Modernatx, Inc. Compositions pour peau et plaies et leurs méthodes d'utilisation
CN114375190A (zh) * 2019-05-08 2022-04-19 阿斯利康(瑞典)有限公司 用于皮肤和伤口的组合物及其使用方法

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MX389934B (es) 2025-03-20

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