US20070254828A1 - Pharmaceutical composition with healing activity comprising at least one soluble dextran derivative and at least one platelet-derived growth factor - Google Patents

Pharmaceutical composition with healing activity comprising at least one soluble dextran derivative and at least one platelet-derived growth factor Download PDF

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US20070254828A1
US20070254828A1 US11/526,678 US52667806A US2007254828A1 US 20070254828 A1 US20070254828 A1 US 20070254828A1 US 52667806 A US52667806 A US 52667806A US 2007254828 A1 US2007254828 A1 US 2007254828A1
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composition according
formula
composition
pdgf
dextran derivatives
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Guy Dubreucq
Latifa Dahri-correia
Jose Correia
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Biodex SARL
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Biodex SARL
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Publication of US20070254828A1 publication Critical patent/US20070254828A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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
    • A61K38/1858—Platelet-derived growth factor [PDGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • composition with healing activity comprising at least one soluble dextran derivative and at least one platelet-derived growth factor
  • the present invention relates to a pharmaceutical composition with healing activity comprising at least one soluble dextran derivative and at least one platelet-derived growth factor, and also to the use thereof for the preparation of a medicament with healing action, in particular for the treatment of ulcers.
  • Growth factors are a category of polypeptides having properties that regulate numerous parameters of cell life (such as proliferation, differentiation, survival). These factors are secreted by many types of cells. The growth factors exert their various effects by binding and activating a distinct subfamily of surface cellular receptors that have an intrinsic tyrosine kinase activity.
  • PDGFs are growth factors released by platelets during blood clotting, capable of promoting the growth of various types of cells (Ross R. et al., Proc. Natl. Acad. Sci. USA, 1974, 71, 1207; Kohler N. & Lipton A., Exp. Cell Res., 1974, 87, 297). It is now known that PDGF is produced by a certain number of cells other than platelets and that it is mitogenic for most of the cells derived from the mesenchyma, i.e. blood, muscle, bone and cartilaginous cells, and also connective tissue cells (Raines E. W., in “ Biology of Platelet - Derivated Growth Factor”, 1993, Westermark, B. and C.
  • PDGF macrophage-derived PDGF behaves as a chemotactic and mitogenic agent with respect to smooth muscle cells, and that it contributes to the myointimal thickening of artery walls that is characteristic of arteriosclerosis (Ross R. et al., Science, 1990, 248, 1009).
  • the activities of PDGF also and in particular include stimulation of granule release by neutrophilic monocytes (Tzeng D. Y. et al., Blood, 1985, 66, 179), facilitation of steroid synthesis by Leydig cells (Risbridger G. P., Mol. Cell.
  • Ulcer healing just like healing in general, is a process that takes place mainly in three major phases.
  • the healing process begins with a first inflammatory phase during which blood flow and blood streaming in increase around the site of ulceration. If bleeding from damaged blood vessels occurs, platelets invade the site of ulceration and allow clotting in order to stop the bleeding. The platelets also release PDGFs which will send signals to the neighbouring cells triggering the proliferation thereof, i.e. the second phase of the healing process.
  • the third, final, phase of the healing process is the remodelling phase.
  • diabetic ulcers have the particularity of healing very slowly and sometimes incompletely because the healing process does not occur normally, certainly because blood flow in the skin is reduced in diabetics. This can lead to serious bacterial infections in the ulcers, that can spread and sometimes require amputation of the foot or of the leg.
  • PDGF-BB-based medicament corresponding to the international non-proprietary name “becaplermin”, sold under the trade name Regranex®.
  • This medicament is indicated for the treatment of lower limb ulcers in diabetics. It is in the form of a gel for topical application and makes it possible to promote ulcer healing. It makes it possible in particular, just like kendogenous PDGF, to promote cell proliferation and therefore the formation of new tissues.
  • the human recombinant PDGF-BB or becaplermin is obtained according to a method of preparation using recombinant DNA technology by insertion of the gene encoding the B chain of PDGF-BB into a yeast, Saccharomyces cerevisiae .
  • This technique is tricky, long and expensive and results in the production of a medicament which is itself expensive for the patients.
  • Regranex® is available as a gel sold in tubes of 2, 7.5 or 15 grams, each gram of gel containing 100 ⁇ g of becaplermin. The amount of gel to be applied depends, of course, on the surface area of the ulcer; however, the average cost of a treatment lasting twenty weeks is excessively high (of the order of 1400 American dollars).
  • the inventors have therefore given themselves the aim of finding an excipient for increasing the activity of PDGF-BB and reducing the doses administered and, consequently, the toxicological risks and thus obtaining treatments that are less expensive for diabetic patients suffering from ulcers of the lower limbs.
  • the latter make it possible to increase the activity of PDGF-BB, in particular in the context of the treatment of ulcers of the lower limbs in diabetic patients.
  • FIG. 1 represents the amount of tritiated thymidine incorporated by human dermal fibroblasts after stimulation of proliferation by PDGF-BB alone at a concentration ranging from 0.1 to 100 ⁇ g/ml or in the presence of a dextran derivative of formula (I) at a concentration of 1 ⁇ g/ml in Example 1.
  • FIG. 2 represents the amount of tritiated thymidine incorporated by human dermal fibroblasts after stimulation of proliferation by PDGF-BB alone at a concentration ranging from 0.1 to 100 ⁇ g/ml or in the presence of a dextran derivative of formula (I) at a concentration of 1 ⁇ g/ml in Example 2.
  • FIG. 3 represents the amount of tritiated thymidine incorporated by human dermal fibroblasts after stimulation of proliferation by PDGF-BB alone at a concentration ranging from 0.1 to 100 ⁇ g/ml or in the presence of a dextran derivative of formula (I) at a concentration of 1 ⁇ g/ml in Example 3.
  • a subject of the present invention is therefore a pharmaceutical composition, characterized in that it comprises, in a pharmaceutically acceptable support:
  • dextran derivatives of formula (I), and also the method for preparing them are described more generally in patent application WO 99/29734.
  • These dextran derivatives of formula (I) are trivially called DMCBSu and are considered to be copolymers consisting of R—OH and R—OX subunits, it being possible for X to be a methylcarboxylic (MC), benzylamide (B) or sulphate (Su) group.
  • a methylcarboxylic dextran (DMC) with a degree of substitution (ds) of 0.6 in terms of methylcarboxylic groups, contains 0.6 substituted group (R—MC) and 2.4 hydroxyl groups (R—OH), per unit.
  • D preferably has a molar mass of between 1000 and 2 000 000 Da, and even more particularly less than 70 000 Da.
  • the dextran derivatives are chosen from the compounds of formula (I) in which b is greater than or equal to 0.35.
  • the dextran derivatives are chosen from the compounds of formula (I) in which a is between 0.5 and 0.8, and c is between 0.1 and 0.5
  • the amount of dextran derivatives of formula (I) present in the pharmaceutical composition in accordance with the invention is preferably between 0.5 and 100 mg/g, and even more preferably between 5 and 50 mg/g of composition.
  • the PDGFs are preferably chosen from human recombinant PDGFs containing two B chains (rhPDGF-BB).
  • rhPDGF-BB human recombinant PDGFs containing two B chains
  • Such PDGFs can be obtained according to the conventional techniques known to those skilled in the art or else can be directly purchased commercially, for example from the company Research Diagnostic Inc. (USA).
  • the amount of PDGFs present in the pharmaceutical composition in accordance with the invention is preferably between 1 and 200 ⁇ g/g of composition, and even more preferably between 10 and 100 ⁇ g/g of composition.
  • the dextran derivatives of formula (I)/PDGFs weight ratio is between 100 and 1000, and even more preferably between 300 and 700.
  • composition in accordance with the invention is preferably a composition for topical application that may be in the form of gels, creams, sprays or patches, the presentation in the form of gels being particularly preferred.
  • composition in accordance with the invention is in the form of a gel
  • the latter is preferably a cellulose gel, such as, for example, a carboxymethylcellulose (CMC) gel.
  • CMC carboxymethylcellulose
  • the pharmaceutical composition in accordance with the invention may also contain one or more additives such as those chosen from fillers, preserving agents such as methyl para-hydroxybenzoate, propyl para-hydroxy-benzoate or m-cresol, anti-oxidants, stabilizers such as L-lysine hydrochloride, acidifying and basifying agents, opacifiers, etc.
  • additives such as those chosen from fillers, preserving agents such as methyl para-hydroxybenzoate, propyl para-hydroxy-benzoate or m-cresol, anti-oxidants, stabilizers such as L-lysine hydrochloride, acidifying and basifying agents, opacifiers, etc.
  • the pharmaceutical compositions in accordance with the invention are most particularly for use in the treatment of ulcers, preferably for ulcers of the lower limbs in diabetic patients.
  • the inventors have in fact noted that the use of such a composition makes it possible to improve and accelerate the healing of ulcers, with compositions containing amounts of PDGFs that are lower than in the compositions currently available on the market (such as, for example, the medicament sold under the name Regranex®).
  • another subject of the invention is therefore the use of at least one pharmaceutical composition as described above, i.e. containing at least one dextran derivative of formula (I) as described above and at least one platelet-derived growth factor, for the preparation of a medicament with healing action, for use in the treatment of ulcers by topical application, and in particular in the treatment of ulcers of the lower limbs in diabetic patients.
  • said medicament is preferably intended to be administered as a treatment of 2 to 10 weeks at a rate of 1 or 2 applications a day on the lesioned portion.
  • the invention also comprises other arrangements that will emerge from the description that follows, which refers to an example of demonstration of the increase in the proliferative effect of a PDGF-BB with a dextran derivative of formula (I) and also to the attached FIG. 1 which represents the amount of tritiated thymidine incorporated by human dermal fibroblasts (in Dpm ⁇ 10 3 ), after stimulation of proliferation by PDGF-BB alone at a concentration ranging from 0.1 to 100 ⁇ g/ml (dashed-line curve) or in the presence of a dextran derivative of formula (I) (solid-line curve) at a concentration of 1 ⁇ g/ml.
  • a primary culture of human dermal fibroblasts (Human Dermal Fibroblast adult (HDFa), the company Cascade Biologics) was realized at a temperature of 37° C. in ⁇ MEM medium (Minimum Essential Medium, the company Gibco) with Glutamax, without ribo/deoxyribo-nucleotides, supplemented with 10% of foetal calf serum (FCS, the company Dutscher) and 1% of penicillin-streptomycin (the company Gibco) in an atmosphere saturated with humidity and enriched in CO 2 (5%). The medium was renewed every 4 days. The human fibroblasts were used between passages 1 and 5. A dilution of the cell suspension in the culture medium was then realized in order to seed culture dishes at a density of 5000 cells/well for 96-well plates (the company Nunc).
  • the tritiated thymidine incorporation (at 52 Ci/mmol, the company Amersham Biosciences) was carried out 18 hours after the stimulation with PDGF-BB in the absence or presence of the dextran derivative, by adding a solution at 50 ⁇ Ci/ml, i.e. 0.5 ⁇ Ci/well.
  • the culture medium was suctioned off, and the cells were fixed for one hour at 4° C. by adding 100 ⁇ l/well of 10% trichloroacetic acid (TCA).
  • TCA trichloroacetic acid
  • the wells were then rinsed three times with 100 ⁇ l of ultrapure water and the cells were lysed overnight at 4° C. with 100 ⁇ l of 100 mM NaOH.
  • the radioactivity was recovered in counting vials, the wells were rinsed with 100 ⁇ l of 100 mM NaOH and the radioactivity was counted after the addition of 1 ml of scintillation fluid (Zinsser Analytic), on an automatic counter sold by the company Beckman (LS 6000 TA).
  • each stimulation condition was carried out in triplicate.
  • results obtained are represented in the attached FIG. 1 in which the amount of tritiated thymidine incorporated by the fibroblasts (in Dpm ⁇ 10 3 ) is expressed as a function of the concentration of PDGF-BB in ⁇ g/ml.
  • the solid-line curve represents the results in the presence of the dextran derivative at a concentration of 1 ⁇ g/ml and the dashed-line curve represents the results in the absence of the dextran derivative.
  • the ED 50 corresponds to the concentration of PDGF-BB to obtain 50% proliferation of the human fibroblasts.

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US11/526,678 2005-09-26 2006-09-26 Pharmaceutical composition with healing activity comprising at least one soluble dextran derivative and at least one platelet-derived growth factor Abandoned US20070254828A1 (en)

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FR05.09803 2005-09-26
FR0509803A FR2891149B1 (fr) 2005-09-26 2005-09-26 Composition pharmaceutique a action cicatrisante comprenant un derive de dextrane soluble et un facteur de croissance derive des plaquettes.

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US11/526,735 Abandoned US20090221805A1 (en) 2005-09-26 2006-09-26 Complex polymere amphiphile-PDGF
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US (3) US20070254828A1 (enrdf_load_stackoverflow)
EP (2) EP1940449A2 (enrdf_load_stackoverflow)
JP (1) JP5438968B2 (enrdf_load_stackoverflow)
KR (1) KR101506593B1 (enrdf_load_stackoverflow)
CN (3) CN101316607A (enrdf_load_stackoverflow)
AU (1) AU2006293613B2 (enrdf_load_stackoverflow)
BR (1) BRPI0616439A2 (enrdf_load_stackoverflow)
CA (1) CA2623529C (enrdf_load_stackoverflow)
DK (1) DK1940448T3 (enrdf_load_stackoverflow)
ES (1) ES2406229T3 (enrdf_load_stackoverflow)
FR (1) FR2891149B1 (enrdf_load_stackoverflow)
IL (1) IL190400A (enrdf_load_stackoverflow)
PL (1) PL1940448T3 (enrdf_load_stackoverflow)
PT (1) PT1940448E (enrdf_load_stackoverflow)
RU (1) RU2424824C2 (enrdf_load_stackoverflow)
WO (2) WO2007034321A2 (enrdf_load_stackoverflow)
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US20070265192A1 (en) * 2003-10-03 2007-11-15 Soula Remi Telechelic Homopolyamino Acids Functionalized with Hydrophobic Groups, and Their Applications, Especially Therapeutic Applications
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FR2936800B1 (fr) * 2008-10-06 2010-12-31 Adocia Polysaccharide comportant des groupes fonctionnels carboxyles substitues par un derive d'alcool hydrophobe
US8426382B2 (en) * 2008-10-06 2013-04-23 Adocia Polysaccharides comprising carboxyl functional groups substituted by a hydrophobic alcohol derivative
US9018190B2 (en) 2009-03-27 2015-04-28 Adocia Functionalized oligosaccharides
FR2943538B1 (fr) * 2009-03-27 2011-05-20 Adocia Formulation a action rapide d'insuline recombinante humaine
FR2958646B1 (fr) * 2010-04-07 2012-05-18 Adocia Polysaccharides comportant des groupes fonctionnels carboxyles substitues par un derive d'acide hydrophobe.
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JP6322642B2 (ja) 2012-11-13 2018-05-09 アドシア 置換されたアニオン性化合物を含有する速効型インスリン製剤
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FR3025428A1 (fr) * 2014-09-08 2016-03-11 Adocia Composition pharmaceutique stable comprenant du pdgf
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US8084045B2 (en) 2003-11-21 2011-12-27 Flamel Technologies Pharmaceutical formulations for the prolonged release of active principle(s) and their applications
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US10406174B2 (en) 2006-11-15 2019-09-10 Ocunexus Therapeutics, Inc. Methods and compositions for wound healing
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WO2007034320A2 (fr) 2007-03-29
CN101316607A (zh) 2008-12-03
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US8241620B2 (en) 2012-08-14
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CN101631804B (zh) 2012-11-28
US20110301086A1 (en) 2011-12-08
KR20080080278A (ko) 2008-09-03
CN103203023A (zh) 2013-07-17
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AU2006293613B2 (en) 2012-05-17
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US20090221805A1 (en) 2009-09-03
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AU2006293613A1 (en) 2007-03-29
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JP5438968B2 (ja) 2014-03-12
KR101506593B1 (ko) 2015-03-30
EP1940448B1 (fr) 2013-03-06
IL190400A (en) 2015-08-31
JP2009509952A (ja) 2009-03-12
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BRPI0616439A2 (pt) 2011-06-21
FR2891149A1 (fr) 2007-03-30

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