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CA-3209594-C - PHARMACEUTICAL COMPOSITION CONTAINING GHRP-6

CA3209594CCA 3209594 CCA3209594 CCA 3209594CCA-3209594-C

Abstract

The present invention relates to a pharmaceutical composition comprising growth-hormone releasing peptide 6 (GHRP- 6), tartrate buffer at pH 5.0 - 6.0, and trehalose as stabilizing agent, as well as to the use of said composition for the manufacture of a medicament. The invention also provides a kit of parts comprising said pharmaceutical composition and a method for treating an individual in need thereof, which entails the administration of a therapeutically effective amount of the pharmaceutical composition comprising of GHRP-6, tartrate buffer at pH 5.0 - 6.0 and trehalose.

Inventors

  • HECTOR JESUS SANTANA MILIAN
  • Gerardo Enrique Guillen Nieto
  • Juan VALIENTE MUSTELIER
  • Francisco HERNANDEZ BERNAL
  • Sonia Gonzalez Blanco
  • Yasser ZARATE RIVERA
  • DANIA MERCEDES BACARDI FERNANDEZ
  • Diana Garcia Del Barco Herrera
  • YAIMA GONZALEZ GONZALEZ
  • FIDEL RAUL CASTRO ODIO
  • Jorge Amador Berlanga Acosta

Assignees

  • CENTRO DE INGENIERIA GENETICA Y BIOTECNOLOGIA

Dates

Publication Date
20260505
Application Date
20220127
Priority Date
20210129

Claims (11)

  1. CLAIMS 1. A pharmaceutical composition comprising growth-hormone releasing peptide 6 (GHRP-6) at a concentration between 1.0 mg/ml and 10.0 mg/ml, 5 tartrate buffer at pH 5.0 - 6.0, and trehalose.
  2. 2. The composition according to claim 1 wherein the buffer has a concentration between 10 mmol/L and 100 mmol/L.
  3. 3. The composition according to claim 1 wherein the tartrate buffer is formed by a sodium salt, potassium salt, or a mixture of both. 10
  4. 4. The composition according to claim 1 wherein trehalose is in the range between 2% and 10% (w/v).
  5. 5. The composition according to claim 1 wherein the composition is in liquid form or is a suspension of a lyophilisate.
  6. 6. Use of the pharmaceutical composition as defined in any one of claims 1 to 5 15 for the manufacture of a medicament.
  7. 7. The use of the composition according to claim 6 wherein the medicament is a kit of parts that additionally comprises a second pharmaceutical composition.
  8. 8. The use of the composition according to claim 6 wherein the medicament is used as a cytoprotective, cardio-protective, cardio-restorer agent, 20 neuroprotective agent, or restorer of cerebral damage.
  9. 9. A kit comprising the pharmaceutical composition as defined in any one of claims 1 to 5.
  10. 10. The pharmaceutical composition according to any one of claims 1 to 5 for use as a cytoprotective, cardio-protective, cardio-restorer agent, neuroprotective 25 agent, or restorer of cerebral damage. 26
  11. 11. The ,pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is for administration by intravenous, subcutaneous or intramuscular routes. 27

Description

PHARMACEUTICAL COMPOSITION CONTAINING GHRP-6 Technical Field The current invention is related to the pharmaceutical and biomedical industry, with the pharmaceutical formulation of peptides and proteins for improving its safety 5 profile. In particular, the invention is related to pharmaceutical compositions of growth-hormone releasing peptide 6 (GHRP-6). It reveals pharmaceutical formulations of the peptide, suitable for its administration by parenteral route. Previous Art 10 GHRP-6 is one of the most studied molecules in the family of secretagogues of growth hormone (Casanueva and Dieguez, Trends Endocrinol. Metab., 1999, 10: 30- 38). Its amino acid sequence is His-Trp-Ala-Trp-Phe-Lys-NH2, where the second and fifth amino acids are D amino acids. It is a synthetic peptide, analogue of intestinal met-encephalin and gastric ghrelin, and it also competes with these agents for the 15 somatrotroph adenohypophyseal receptors. These peptides act through the receptor coupled to protein G, known as receptor of the growth hormone secretagogues (GHSR1a), whose natural ligand is ghrelin (Kojima et al., Nature, 1999, 402: 656-660). It has been demonstrated there are additional binding sites for GHRP-6 in nonendocrine tissues, through its association to receptor CD36, which belongs to the 20 family of scavenger or type B remover receptors (Bodart et al., Gire. Res., 1999, 85: 796-802). In studies conducted in animal models of ischemia/reperfusion, GHRP-6 has exhibited a potent cytoprotective effect (Murriel and Mochly, Arch. Biochem. Brophys., 2003, 420: 246-254). Preliminary pieces of evidence suggest the possibility 25 that the mechanism by means of which tissue damages are lessened relates to the control of the cellular redox environment. Another form of cell death, like apoptosis, seems to be also prevented by GHRP-6 (Colonna et al., EUR. J. Pharmacol., 1997, 334: 201-207; Cibrian et al., Clin. Sci., 2006, 110: 563-573). Its beneficial effect on the cardiovascular function has been evidenced in diseases like myocardial infarction 30 and ischemic cardiopathology (Berlanga et al., Clin. Sci., 2007, 112: 241-250; Berlanga et al., Clin. Med. Insights Cardiol., 2017, 11: 1-9). On the other hand, the 1 combination of GHRP-6 with the epidermal growth factor (EGF) has turned out to be a promising therapy in the treatment of ischemic cerebral infarction (Subir6s et al., Neural. Res., 2016, 38 (3): 187-195). GHRP-6 has been administered in humans by parenteral route, mainly by 5 intravenous route, with the purpose of inducing the release of the growth hormone. The dosage applied by intravenous route in humans oscillated between 1 and 2 μg/kg of weight (Leal-Cerro et al., EUR. J. Endocrinol., 1995, 132 (6): 712-715); Loche et al., J. Clin. Endocrinol. Metab., 1995, 80 (2): 674-678). For new applications in humans, by parenteral route, pharmacological studies suggest that the therapeutic 10 dosage of GHRP-6 is 100 times higher. The therapeutic dosage reported in a model of acute myocardial infarction in pigs was of 400 μg/kg (Berlanga et al., Clin. Sci., 2007, 112: 241-250), which represents a dosage between 200 and 400 times higher than the one used in humans, during the nineties. On the other hand, the therapeutic dosage of GHRP-6 reported in a model of ischemic cerebral infarction, in Mongolia 15 gerbil (Meriones unguiculatus) was around 600 μg/kg (Subir6s et al., Neural. Res., 2016, 38 (3): 187-195). In this last case, GHRP-6 was used in combination with EGF. As to the safety in humans, during the administration of GHRP-6 by intravenous route, there are referred as safe the doses equal to or lower than 2 μg/kg. However, to attain an efficacious use of the peptide in the treatment of acute myocardial infarction and 20 ischemic cerebral infarction, there are required much higher doses, in a range between 50 to 600 μg/kg. Likewise, for the said purpose, it is necessary to obtain a GHRP-6 formulation at a high concentration (from 1.0 to 10.0 mg/ml), which maintains the quality, stability and therapeutic properties, while minimizing the adverse and/or toxic effects. A high safety profile of the product is particularly 25 necessary in the treatment of patients with acute myocardial infarction and stroke. A particular problem of the formulations that include peptides or proteins at high concentrations is posed by its tendency towards aggregation. As result of aggregation, there may occur the precipitation of the product during storage, which may have an impact on the reproducibility of the dosage administered to the patients. 30 Also, embolism may occur during the parenteral administration of particle-containing solutions. 2 Another general problem of pharmaceutical products is that adverse effects and/or toxicity might be found during the treatment of patients. These undesired events may be of different varieties, depending on characteristics of the active ingredient (metabolism, binding to proteins, etc.), formulation, route of