ES2358403B2 - SYSTEM FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE SUBSTANCES THAT INCLUDES POLY-EPSILON-CAPROLACTONE, POLOXAMINE AND ONE OR VARIOUS ACTIVE SUBSTANCES. - Google Patents

Abstract

Substance Administration System biologically active comprising poly-ε-caprolactone, poloxamine and one or more active substances.

The present invention relates to a system for the administration of biologically active substances that
It comprises poly-epsilon-caprolactone, poloxamine and one or more active substances characterized by being a biodegradable matrix of solid or semi-solid consistency with a homogeneous appearance, a method of obtaining based on the fusion of the components and pharmaceutical compositions comprising said system.

Description

Substance Administration System biologically active comprising poly-ε-caprolactone, poloxamine and one or more active substances.

Technical sector

The invention is directed to a system for administration of biologically active substances comprising poly-ε-caprolactone, poloxamine and one or more active substances, a procedure for the preparation of said systems and use for the manufacture of medications or implants

State of the art

The development of systems suitable for the control of the transfer or release of drugs or active substances is of great interest. In this field, intelligent systems and biodegradable systems have received extensive attention. Intelligent systems, which respond to stimuli external to the organism or to physio (duck) logical variables, allow precise regulation of the moment and speed of release of the drug or active substance (Alvarez-Lorenzo C, Concheiro A. Intelligent drug delivery systems: polymeric micelles and hydrogels. Mini-Reviews in Medicinal Chemistry 8, 1065-1074, 2008). Poly (ethylene oxide) -polis (propylene oxide) block copolymers capable of undergoing micellization processes and, at sufficiently high concentrations, transitions from sun to gel have proved very useful as components of temperature sensitive systems (Kabanov AV, Batrakova EV, Alakhov VY. Pluronic (R) block copolymers as novel polymer therapeutics for drug and gene delivery. Journal of Controlled Release 82, 189-212, 2002). The aqueous dispersions of these polymers can be used to develop injectable liquid systems that give rise to implant formation in situ . The greatest limitation of these systems lies in the reduced capacity of implants formed in situ to withstand mechanical stress in vivo and in the reduced time spent in the place of application.

Biodegradable systems, consisting mainly of polyesters and polyanhydrides, undergo a slow chemical or enzymatic degradation and allow a release of drugs or active substances very prolonged over time (Fair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 32, 762-798, 2007). Although they are only available in a small number, materials of these characteristics already have interesting applications such as implant components and drug delivery systems or active substances. Poly-ε-caprolactone (PCL) exhibits excellent biocompatibility, but degrades in vivo with excessive slowness (Ponsart S, Coudane J, Saulnier B, Morgat JL, Vert M. Biodegradation of [3H] poly (e-caprolactone) in the presence of active sludge extracts, Biomacromolecules 2, 373-377, 2001), which limits its interest as a component of drug delivery systems and active substances (Peña J, Corrales T, Izquierdo-Beard I, Doadrio AL, Vallet -Regi M. Long term degradation of poly (3-caprolactone) films in biologically related fluids. Polymer Degradation and Stability 91, 1424-1432, 2006).

The combination of polymers with different benefits in a single release system is a very useful approach to adjust the physical and mechanical properties and the transfer profiles to specific needs. In this regard, the combination of poly-ε-caprolactone with poly (ethylene oxide) -poly (propylene oxide) block copolymers has been proposed for the development of biodegradable and moldable surgical material (EP 0 747 072 A3 "Biodegradable moldable surgical material "). The incidence of the incorporation of tricalcium phosphate and bioglass on the degradation rate of polyvinylcaprolactone implants obtained by fusion and on their functionality in bone repair (Lam CXF, Hutmacher DW, Schantz JT, Woodruff) has also been studied. MA, Teoh SH. Evaluation of polycaprolactone scaffold degradation for 6 months in vitro and in vivo . Journal of Biomedical Materials Research Part A 90, 906-919 2009; Chouzouri G, Santos M. In vitro bioactivity and degradation of polycaprolactone composites containing silicate fillers Biomaterialia Act 3, 745-756, 2007). The incorporation of polyethylene glycol has been seen as a useful means to accelerate the release of drugs from polyvinylcaprolactone matrices obtained by fusion (Sprockel OL, Sen M, Shivanand P, Prapaitrakul W. A melt-extrusion process for manufacturing matrix drug delivery systems Int. J. Pharm. 155, 191-199, 1997). Finally, poly-ε-caprolactone and Pluronic copolymers have been prepared by modifying the block copolymer with polyvare-caprolactone precursor monomers in order to obtain biodegradable in situ gelation systems (Liu CB, Gong CY, Pan YF , Zhang YD, Wang JW, Huang MJ, Wang YS, Wang K, Gou ML, Tu MJ, Wei YQ, Qian ZY Synthesis and characterization of a thermosensitive hydrogel based on biodegradable amphiphilic poly- \ varepsilon-caprolactone-Pluronic (L35) - poly-? -caprolactone block copolymers. Colloids Surf. A 302, 430-438, 2007).

Description of the invention

The invention provides a new system. constituted by a biocompatible material, the poly-ε-caprolactone, and another cytocompatible, poloxamine, which form a biodegradable matrix of solid or semi-solid consistency in which one or more biologically active substances are dispersed at the molecular level, which makes it suitable as a pellet or as an implant for a controlled release of said biologically active substances in the place of application without toxic effects. Additionally, the assignment profiles of biologically active substances incorporated into the system of the invention are modular, by means of the selection of one of the components of the matrix based on their features. The matrix of the invention is also sensitive to temperature.

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A procedure of obtaining based on the fusion of the matrix components, a simple procedure of few steps, since it does not require the previous modification of any of the components, and that is environmentally friendly as it avoids the use of organic solvents

Thus, in a first aspect the invention is directed towards a system for the administration of substances biologically active comprising poly-ε-caprolactone, poloxamine and one or more biologically active substances characterized by being a biodegradable matrix of consistency solid or semi-solid with homogeneous appearance.

In another aspect, the invention is directed to a procedure to obtain a system as defined above, which comprises: a) preparation of a physical mixture of poly-? -caprolactone (PCL), poloxamine and one or more biologically active substances; b) application of heat to melt the mixture; and c) cooling.

In another aspect the invention is directed towards the use of the system as defined above for the preparation of a medicine or implant for the treatment of pathological or physiological states in humans or animals.

In a further aspect, the invention is directed to a pharmaceutical composition comprising the system previously described

Detailed description of the invention

The invention relates to a system for administration of biologically active substances, as has been previously defined. This system is preferably sized between 0.5 mm and 50 mm. In a particular embodiment, the system of the invention can be obtained as a pellet or as an implant for controlled release at the place of application without effect Toxic

The present invention also relates to a procedure to prepare a system like the one described previously, which comprises the following stages: a) preparation of a physical mixture of poly-? -caprolactone (PCL), poloxamine and one or more biologically active substances; b) application of heat to melt the mixture; and c) cooling. This procedure does not require the incorporation of solvents in None of its stages.

In a particular embodiment, the proportion of poly-? -caprolactone (PCL) in the PCL mixture: poloxamine is between 1% and 99% In an even more particular embodiment, the proportion of PCL It is between 25% and 75%.

Poloxamines are four-arm block copolymers of poly (ethylene oxide) -poly (propylene oxide) (EO-PO) bonded to a central group of ethylenediamine, which have the ability to give rise to micellar solutions in aqueous medium. The poloxamines of the invention have a molecular weight of between 1000 and 25000 Daltons. The authors of the present invention demonstrate that the selection of the poloxamine allows modulating the mechanical properties of the system of the invention as defined above, and additionally, allows modulating the transfer profiles of the biologically active substances incorporated into the system. Thus, systems according to the invention can be obtained with assignment profiles adjusted to specific needs by selecting poloxamines of different characteristics.
Structural techniques and incorporating them in different proportions to modulate the erosion rate of the matrix.

In a particular embodiment of the invention, poloxamines are selected from Tetronic 304, 701, 901, 904, 908, 1107, 1301, 1304, 1307, 90R4 and 150R1, whose properties are collected in the following table.

one

The term "biologically substance active "refers to any substance that is used in the treatment, cure, prevention or diagnosis of a disease or that It is used to improve the physical and mental well-being of beings humans and animals, as well as that compound that is intended for destroy, prevent action, counteract or neutralize, any harmful organism. When one or more substances biologically active are incorporated into the system of the invention these are found dispersed at the molecular or particular level. The system is adequate to incorporate biologically active substances independently of the solubility characteristics thereof. But nevertheless, Due to the characteristics of the system components, this is especially suitable for incorporating substances biologically active low water solubility.

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In a particular embodiment, the substances biologically active are selected from hormones, anti-inflammatory, antineoplastic, antimicrobial agents and morphogenic substances for bone defect repair. In a more particular embodiment, the antimicrobial agent is intended to localized treatment of soft tissue infections or bones.

In a particular embodiment of the invention, the proportion of biologically active substance is comprised between 1% and 50% by weight of the PCL: poloxamine mixture.

The preparation of the physical mixture between the PCL, poloxamine and one or more biologically active substances, according to step a) of the procedure, it can be performed using usual mixing techniques, such as a mixer paddles a planetary mixer or a turbo mixer.

The application of heat to melt the mixture, according to step b) of the process of the invention, it can be carried carried out, for example, with a thermostatized bath of blanket or fluid to which a stirring system is coupled. At this stage, the biologically active substances can be found dissolved or in suspension.

The mixture of step b) is cooled to obtain the system of the invention described above with consistency solid or semi-solid and homogeneous appearance. Additionally, if this liquid is allowed to cool in molds the system is obtained with sizes predefined according to the mold. In another particular embodiment, the melting and molding processes are also carried out in a single stage using a hot melt extrusion system.

In a particular embodiment, the invention is refers to an additional step to the described procedure, which It includes the formation of implants or pellets: the cooled system is it can be divided into portions by cut and it is also possible to obtain spray pellets.

The systems obtained, in the form of pellets or with other morphology suitable for implantation, are suitable for administer biologically active substances by different routes with in order to provide a sustained, speed release Adjustable to specific requirements.

Consequently, an additional aspect of the invention refers to the use of a system as defined previously in the preparation of a medicine or implant.

In a preferred embodiment, the invention is directs the use of a system as defined above in the Implant preparation. In a more preferred embodiment, said implant is able to release a biologically active substance for the repair of bone defects.

In another aspect, the invention is directed to a pharmaceutical composition comprising the system previously described

Description of the figures

Figure 1. Ciprofloxacin assignment profiles in pH7.4 phosphate buffer medium from 1 gram matrices prepared from PCL mixtures: Tetronic 1107 75:25 and 25:75 weight / weight and 10 mg of ciprofloxacin.

Figure 2. Erosion profiles in half buffer pH7.4 phosphate of PCL matrices: Tetronic 1107 75:25 and 25:75 weight / weight

Figure 3. Ciprofloxacin assignment profiles in pH7.4 phosphate buffer medium from 1 gram matrices prepared from PCL mixtures: Tetronic 1307 75:25 and 25:75 weight / weight and 10 mg of ciprofloxacin.

Figure 4. Erosion profiles in half buffer Phosphate pH7.4 of PCL matrices: Tetronic 1307 75:25 and 25:75 weight / weight

Next, for a better understanding of the invention the following examples are provided, without these suppose a limitation on the invention.

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Example 1 Preparation of PCL matrices: Tetronic 1107 75:25 and 25:75 with ciprofloxacin, and drug assignment and erosion assays

Mixtures of PCL and Tetronic 1107 were prepared in proportions 75:25 p / p and 25:75 p / p and ciprofloxacin was incorporated into the 1% in relation to the PCL mix weight: Tetronic 1107. The Mix in an oil bath at 150 ° C by applying magnetic stirring. TO Then, the mixture was poured into molds cooled to 0 ° C.

To perform the assignment essay, matrices of 1 gram were taken to test tubes and contacted 10 ml of pH 7.4 phosphate buffer at 37 ° C, exposing 1.57 cm 2 to dissolution medium The tubes were subjected to oscillating agitation (50 osc / min). At pre-established times, 1 ml aliquots were taken of the dissolution medium and the spectrophotometrically determined amount of ciprofloxacin transferred. The extracted medium was replaced with an equal volume of buffer. As a control a matrix was used of PCL without poloxamine prepared by the same procedure. The Assignment profiles obtained are shown in Figure 1.

The erosion rate of the matrices is evaluated by recording the evolution of its weight over the course of weather. The profiles obtained are shown in Figure 2.

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Example 2 Preparation of PCL matrices: Tetronic 1307 75:25 and 25:75 with ciprofloxacin, and drug assignment and erosion assays

Mixtures of PCL and Tetronic 1307 were prepared in proportions 75:25 p / p and 25:75 p / p and ciprofloxacin was incorporated into the 1% in relation to the PCL mix weight: Tetronic 1307. The Mix in an oil bath at 150 ° C by applying magnetic stirring. TO Then, the mixture was poured into molds cooled to 0 ° C.

To perform the assignment essay, matrices of 1 gram were taken to test tubes and contacted 10 ml of pH 7.4 phosphate buffer at 37 ° C, exposing 1.57 cm 2 to dissolution medium The tubes were subjected to oscillating agitation (50 osc / min). At pre-established times, 1 ml aliquots were taken of the dissolution medium and the spectrophotometrically determined amount of ciprofloxacin transferred. The extracted medium was replaced with an equal volume of buffer. As a control a matrix was used of PCL without poloxamine prepared by the same procedure. The Profiles obtained are shown in Figure 3.

The erosion rate of the matrices is evaluated by recording the evolution of its weight over the course of weather. The profiles obtained are shown in Figure 4.

Claims (10)

1. System for the administration of biologically active substances comprising poly-epsilon-caprolactone, poloxamine and one or more active substances, characterized by being a biodegradable matrix of solid or semi-solid consistency with a homogeneous appearance and whose size is between 0.5 and 50 mm 2. System according to claim 1 wherein one or more active substances are dispersed at the level molecular. 3. Procedure for obtaining a system according to claim 1, comprising:

to)

preparation of a physical mixture of poly-? -caprolactone (PCL), poloxamine and one or more substances biologically active;

b)

application of heat to melt the mixture; Y

C)

cooling.

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4. Method according to claim 3, which It also includes the formation of pellets or implants. 5. Method according to claim 3 or 4, characterized in that the poloxamine is selected from Tetronic® 304, 701, 901, 904, 908, 1107, 1301, 1304, 1307, 90R4 and 150R1. Method according to claims 3 to 5, characterized in that the proportion of PCL in the PCL: poloxamine mixture is between 1% and 99%. 7. Method according to claim 6, characterized in that the proportion of PCL in the PCL mixture: poloxa-
mine is preferably between 25% and 75%. Method according to claims 3 to 7, characterized in that the active substance ratio is between 1% and 50% by weight of the PCL: poloxamine mixture. 9. Use of the systems described in the claim 1, for the manufacture of a medicament or implant for the treatment of pathological or physiological states in humans or animals 10. Pharmaceutical composition comprising the system described in claim 1.