ES2387658B1 - THERMOSENSIBLE COMPOUND FOR THE CONTROLLED RELEASE OF ACTIVE SUBSTANCES OR INDICATOR. - Google Patents

Abstract

Thermosensitive compound for the controlled release of active substances or indicator # The present invention relates to a thermosensitive compound for the controlled release of at least one active substance or indicator, characterized in that it comprises: (a) a porous support comprising a set of pores containing said active substance or indicator; and (b) an interface layer comprising lipophilic nature molecules, wherein said molecules comprise a first end covalently bonded to the porous support and a second end consisting of lipophilic organic chains linked by non-covalent interactions to a heat sensitive surface layer located on the surface of the porous support, covering the pores, where said heat-sensitive surface layer comprises organic substances of non-polymeric lipophilic nature that, above a threshold temperature, decrease their interaction with the interface layer, unblocking the entrance of the pores of the porous support and releasing the active substance or indicator # It is also the object of the invention to obtain and use said compound for the controlled release of active substances and indicator.

Description

Heat sensitive compound for controlled release of active substances or indicator

Field of the Invention

The invention describes a new controlled release system of active substances in response to temperature variations as a specific stimulus. The nature of the union of the temperature sensitive part with that containing the active substance also falls within the scope of the invention. In addition, the methodology for its preparation and use has been developed.

Background of the invention

Controlled release systems with response to environmental stimuli are of interest to a wide variety of fields of application, including biotechnology, medicine, agriculture, environment, etc. The stimuli studied so far include among other physical stimuli such as variations in temperature, electric current, pressure, ultrasound, and magnetic fields. A wide range of systems that respond to chemical stimuli such as pH, solvent, the presence of ions, or certain organic molecules are also described.

Among them, systems with a response to temperature variations in biological or pharmaceutical applications are of special interest, since in general living organisms show a constant temperature, so that the variation of only a few degrees may be indicative of symptoms or require A certain answer. Likewise, living organisms that do not maintain their constant temperature are influenced by this factor.

So far, most of the temperature-stimulated controlled release systems are based on the use of organic polymers that vary in size, porosity and polarity depending on phase transitions, the most important being those based on chitosan and in polyacrylamide derivatives or policaprolactam. These systems show as main defects that not in all cases they can operate at physiological temperatures or can be controlled by design the temperature at which the change is desired. Its properties are defined by polymerization processes, in some complicated cases, that generate waste and by-products and can give rise to different structures with their effect on the properties of the system. In addition, they usually have wide temperature ranges with partial releases between the release and non-release ends, which decreases their specificity and leads to generally slow release processes. Finally, due to its chemical composition, the response not only occurs in the face of temperature variations, but another series of stimuli present in solution can lead to the transition acting as interferents. It would be the case for example of variations in pH.

Therefore, the present invention has focused on the development of temperature controlled release systems that are simple to prepare and reproducible, in which the release occurs in a narrow temperature range and in which the presence of the species Chemicals found in the environment do not cause uncontrolled releases.

In recent decades, the combination of materials with temperature response for controlled release with inorganic supports has led to the development of functional organic-inorganic hybrid materials, based on supramolecular type interactions and acting according to the rules of molecular recognition. One of the most promising combinations is with three-dimensional matrices that provide "warehouse" gaps and that can accommodate a large variety and quantity of molecules or even macromolecules inside. The resulting structures of these hybrid materials are interesting since their properties can significantly transcend those of their component parts. The development of materials with dimensions (particle size and pore size) controllable on a nanoscopic scale and with a homogeneous distribution, has allowed the obtaining of new materials with “on-demand properties”, applicable in various areas of science such as biochemistry, Analytical chemistry (sensor development) or materials engineering.

The three-dimensional supports used in this type of systems can be synthesized in a wide variety of morphologies with a defined pore size, and have a high specific surface area. In general, different types of porous materials such as titanium oxides, organic polymers, porous carbons, etc., can be used, but it is noteworthy that the porous silicas of the MCM-n type (n = 41, 48) arouse , HMS, MSU-n, MSU-V, FSM-16, KSW-2, SBA-n (n = 1, 2, 3, 8, 11-16) UVM-7, UVM-8, M-UVM-7 or M-UVM-8, or the "silicohollow". These have a particle size generally between 10 nm and several micrometers, and a specific surface area of 200 to 1100 m2 / g. In this invention it has been decided to use as an example a porous silica of the MCM type. The mesoporous solids of the MCM family are aluminosilicates with a pore size between 20 and 500 Å and, depending on the synthesis conditions, different phases can be obtained within this family (from the hexagonal in the MCM-41, cubic in the MCM-48 and laminar on the MCM-50). One of the most studied is the MCM-41 because it can be prepared by controlling the pore size (it has a pore size between 2 and 3 nm), it is highly stable and easy to prepare.

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The use of three-dimensional mesoporous matrices, that is, with pores in the range between 2 and 50 nm is especially interesting, since they are suitable as support for the development of hybrid materials with functions such as controlled molecular motion. Likewise, the appearance of new hybrid materials with a nanoscopic molecular gate function can be highlighted. These types of devices are capable of controlling the entry and exit of molecules from the pores through the action of a given stimulus, allowing the control of mass transport. It is very interesting the possibility of releasing species of interest at a given time chosen by the user himself without spreading from the inside of the matrix until the moment chosen. This fact allows the encapsulation and controlled release of highly harmful species not only for the human being, such as drugs of high toxicity, but for the environment, such as biocides, which are harmless until the moment of their release, greatly facilitating for example its storage and transport to the point of action. In addition, encapsulation in three-dimensional matrices allows the storage of the active substance without having to chemically modify it, or subject it to highly aggressive media such as acidity, basicity or aggressive oxide-reduction conditions.

Recently some functionalized materials with molecular doors have been described by the use of organized nanoscopic solid structures (mesoporous of the MCM-41 type) in which functional organic molecules have been anchored on their outer surface. In this way, functionalized materials with molecular doors have been described whose opening / closing cycles are controlled by the presence of certain ions, changes in the pH of the medium, temperature, redox reactions, irradiation with light or in the presence of bio-molecules. One of the applications that has been given to this type of systems is its ability to transport active substances to a specific site of the organism and release them in a controlled way by external or provoked stimuli at the cellular level. Among the existing patented systems, such materials are used in the patents described by J. Zink, F. Stoddart et al. (WO 2009/094580 and WO 2009/097439) to produce controlled release using oxidation-reduction reactions or pH changes as stimuli for the opening / closing mechanism, while in other examples, such as those described by V. Lin et al. in US2006 / 154069 or US2009 / 0252811, use CdS nanoparticles or different polymers to coat the synthesized material .

Despite the wide range of examples of materials with response to external stimuli, in the field of controlled release there are few strategies to achieve temperature-dependent release. The most common is based on the use of polyacrylamide derivatives barriers or other polymers that vary in polarity as a function of temperature due to phase changes.

Against this, in the present invention a new controlled release system with temperature response based on surface modification, with materials with non-polymeric phase variation, of supports containing the dye or active substance to be released is described.

As an antecedent to this type of systems, the invention described in the application US2002169235, which refers to a thermosensitive compound for the controlled release of active substances formed by a porous support and a heat sensitive surface layer, is mentioned, so as to increase the temperature , there is a conformational change in the copolymer allowing the release of the occluded substances in the polymer matrix.

However, unlike the previous application, a fundamental point of the present invention is that the support containing the active substance and the part that shows variation of its properties with temperature are joined by a molecule covalently bound to the first and forming non-covalent interactions with the second.

In this type of system, when the temperature rises above a certain threshold, the unblocking of the pores containing the active substance and its release into the environment occurs. The variation in the components allows to obtain systems with different load capacities, with practically zero release below the critical temperature and a rapid release above it. The critical temperature can also be modulated in a couple of degrees, allowing "on-off" systems with response in a narrow range.

Description of the invention

In a first object of the invention a thermosensitive compound for the controlled release of at least one active substance or indicator, characterized in that it comprises:

(to)

a porous support comprising a set of pores containing at least one active substance or indicator;

(b)

an interface layer comprising lipophilic nature molecules, wherein said molecules comprise a first end covalently bonded to the porous support and a second end consisting of lipophilic organic chains, preferably alkyl chains, joined by non-covalent interactions to a heat sensitive surface layer located on the surface of the porous support, covering the pores, where said thermosensitive surface layer comprises organic substances of non-polymeric lipophilic nature that, above a threshold temperature, decrease their interaction with the interface layer, unblocking the entrance of the pores of the porous support and releasing accordingly the active substance or indicator.

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Due to their nature, the molecules that comprise the interface layer and those that comprise the thermosensitive surface layer are mixed together, actually forming part of a single coating layer.

The presence of the interface layer is essential for the proper functioning of the controlled release system since, in the absence of said interface layer, precise control of the thickness of the coating layer that blocks the exit of the active substance or indicator would not be obtained. , nor would the binding of the temperature sensitive substance to the compound be achieved. In this way, the interface layer allows to obtain a thin and homogeneous coating, with a thickness preferably between 1 and 100 nm. This thickness may be heterogeneously distributed on the surface of the porous support, or part of the porous support may not be effectively coated, which may result in extemporaneous releases or responses at various temperatures and at varying intervals.

In particular, the porous support may consist of an inorganic matrix characterized by comprising at least one material preferably selected from a group consisting of metals, semiconductors, organic polymers, carbons or oxides of different inorganic species, such as carbon, titanium, zirconium. silicon magnesium

or boron, among other examples. Even more preferably, said material may comprise pores with a pore size preferably between 2 and 50 nm and a specific surface area of up to 1500 m2 / g.

In a particular embodiment of the invention, the porous support can be constituted by silica of high specific surface area, preferably, greater than 200 m2 / g and up to 1500 m2 / g, and more preferably, a porous silica of the MCM-n type (n = 41, 48), HMS, MSU-n, MSU-V, FSM-16, KSW-2, SBA-n (n = 1, 2, 3, 8, 11-16) UVM-7, UVM-8, M -UVM-7, M-UVM-8, or “hollow silica”. The mesoporous solids of the MCM family are aluminosilicates with a size between 20 and 500 Å. Depending on the synthesis conditions, different phases can be obtained within this family (from hexagonal in MCM-41, cubic in MCM-48 and laminar in MCM-50). Preferably, the porous solid may consist of MCM-41, with a pore size between 2-3 nm.

In a particular embodiment of the invention, the inorganic matrix of the porous support may comprise magnetic or gold nanoparticles occluded therein. These nanoparticles occluded in the inorganic matrix give the material magnetic or optical properties, which can be manipulated magnetically, monitored by nuclear magnetic resonance or can increase its temperature by magnetic fields or light pulses.

In a preferred embodiment of the invention, the lipophilic nature molecules of the interface layer may comprise organic chains, preferably, chains with more than 7 carbons, which may contain heteroatoms such as O, N, P and S. These chains may preferably consist of alkyl chains. In a particularly preferred embodiment of the invention, said molecule may consist of octadecyltrimethoxysilane.

The presence of the interface layer ensures the fixation of the heat sensitive surface layer and controls its proper distribution and thickness.

With respect to the substances comprising the thermosensitive surface layer, said substances consist of non-polymeric lipophilic organic substances that can modify their interaction with the interface layer as a function of temperature, preferably, in a temperature range between 0 and 100 ° C. In this way, once the threshold temperature is exceeded, they decrease their interaction with the interface layer, detaching and releasing the pores of the porous support.

In a preferred embodiment of the invention, the thermosensitive surface layer may comprise hydrocarbons with more than 9 carbons, and preferably with more than 12 carbons, which may contain heteroatoms such as O, N, P and S.

In a further preferred embodiment of the invention, the heat sensitive surface layer may comprise alkanes of between 12 and 60 carbons, preferably between 16 and 30 carbons, more preferably, docosan.

The thermosensitive compound of the invention may be presented as a powder. However, the invention may also refer to a formulation in which the compound is in solution, on textile fibers, or embedded in polymers.

In a particular embodiment of the invention, the thermosensitive controlled release compound may have a submicron structure in the form of nanoparticulate material. The term nanoparticulate material refers to a material whose micrometric structure is formed by nanoparticles of a size, preferably between 0 and 750 nm.

One of the main advantages of the compound object of the invention is that it allows a practically zero release of the active substances below the critical temperature or threshold and a rapid release above it. The critical temperature can also be modulated in a couple of degrees, allowing "on-off" systems with response in a narrow range.

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A second aspect of the invention refers to a process for the preparation of the described compound, which may be based on porous supports that have previously been surface functionalized with the interface layer, preferably by common grafting or co-condensation techniques, widely known in the technique.

Thus, the process for the preparation of the thermosensitive compound for the controlled release of active substances object of the invention is characterized in that it comprises the following steps:

a) weigh an amount, preferably greater than 5 mg and more preferably between 5 mg and 10 g of surface-functionalized porous support with an interface layer comprising molecules of lipophilic nature, which is then suspended in a non-polar solvent, preferably a alkane with less than 10 carbons, and more preferably hexane;

b) on the suspension obtained in the previous stage, a suitable amount is added, preferably between 1 and 100 times the weight of the material obtained in the previous stage (a), of the non-polymeric lipophilic nature substances comprising the thermosensitive surface layer , and stirring to favor the formation of a supramolecular structure;

c) the solvent is removed, preferably by centrifugation, and the compound obtained is dried, preferably in vacuo.

In a preferred embodiment of the invention, the formation of the suspension in step (b) can be favored by sonication between 1 minute and 6 hours.

A third aspect of the invention refers to the use of the described compound for the controlled release of active substances or as indicators of temperature variation. For this, it is possible to raise the temperature of the compound until reaching the threshold temperature at which there is a decrease in the interactions between the interface layer and the surface layer, unblocking the pores of the porous layer and releasing the active substance or indicator into the medium. contained in said pores.

In a preferred embodiment of the invention, the active substance may consist of a substance preferably selected from a group consisting of drugs, biocides, perfumes, etc.

In a further particular embodiment of the invention, the active substances may consist of biologically active substances, with a size suitable to be introduced into the pores of the porous support, and characterized in that they do not react with the material constituting said support. porous.

Additionally, the active substances may consist of molecules used for cancer treatments, such as camptothecin, doxorubicin or paclitaxel, nucleic acids such as siRNA or DNA, antioxidant molecules such as n-acetylcysteine, vitamin E or vitamin C, molecules pharmacologically active that can be encapsulated, such as analgesics, hormones, steroids, antiepileptics, antihypertensives, antibiotics, antiviral agents, cardio-stimulants, polypeptides, moisturizers, hormones, contrast agents, biocides, enzymes or antibodies, among others. This controlled release of the active substance can be carried out in solution, in the air, on the skin or in biological or cellular systems.

Also, for the purposes of this patent, indicator substance is understood as a colored substance or with fluorescent or luminescent properties.

Brief description of the figures

Figure 1: The scheme of operation of a particular embodiment of the thermosensitive compound of the invention, called "material S1", is shown. The material inhibits the release of the active substance until it is subjected to the predefined temperature change;

Figure 2: Representative image of transmission electron microscopy of the "material S1", where both the porous structure of the material and the lipophilic layer that surrounds it and inhibits the release of the active load or substance can be appreciated;

Figure 3: Graph of the response of “material S1” as a function of temperature. The graph shows the absorbance variation of the indicator (dye) that has been released to the solution as a function of temperature.

Preferred Description of the Invention

The following are a series of examples, illustrative and not limiting of the invention, and with reference to the figures accompanying this description:

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Example 1. Obtaining the “S1 material”

In a particular embodiment of the invention, 50 mg of a porous solid (1) of a silicon mesoporous nature of the nanoparticulate MCM-41 type and superficially modified with 18-carbon alkyl chains constituting an interface layer (3), was charged with an indicator ( 2), specifically [Ru (bipi) 3] Cl2 in 40 mL of hexane, subjecting the

5 mix to sonicated for 30 minutes. Next, 500 mg of docosan was added, subjecting the mixture to sonicated for an additional 15 minutes and forming the surface layer (4). Finally, the mixture was stirred for 15 minutes, centrifuging at 3500 rpm, for 3 min. The solid was resuspended in water and stirred for 2 hours, then filtered and dried. The resulting material, "material S1", was dried under vacuum. Figure 1 shows a scheme thereof.

10 The material was characterized using standard procedures. Figure 2 shows a representative image of electron transmission microscopy in which both the porous structure of the material and the lipophilic layer that surrounds it can be appreciated, and it can be estimated that the lipophilic layer has a thickness of about 15 nm.

Example 2. Activity as a controlled release system of S1 as a function of temperature

In this second example, 10 mg of the "S1 material" was added to 25 mL of water at the temperature of the

15 experiment The mixture was stirred for one hour in a glass with a thermostatted jacket at the temperature of the experiment. Next, the amount of dye released was measured by UV-vis spectroscopy at A = 454 nm (maximum absorption of the dye [Ru (bipi) 3) Cl2. The results obtained are shown in Figure 3, observing that the material does not release dye until the temperature corresponding to docosan is not exceeded (42.5 ° C).

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Claims (27)

1. Thermosensitive compound for the controlled release of at least one active substance or indicator, characterized in that it comprises:

(to)

a porous support comprising a set of pores containing said active substance or indicator;

(b)

an interface layer comprising lipophilic nature molecules, wherein said molecules comprise a first end covalently bonded to the porous support and a second end consisting of lipophilic organic chains linked by non-covalent interactions to a thermosensitive surface layer located on the surface of the porous support, covering the pores, where said heat-sensitive surface layer comprises organic substances of non-polymeric lipophilic nature that, above a threshold temperature, decrease their interaction with the interface layer, unblocking the entrance of the pores of the porous support and releasing the active substance or indicator.

2.

Compound according to claim 1, wherein the porous support is constituted by at least one material selected from a group consisting of metals, semiconductors, organic polymers, carbons and oxides of at least one inorganic species.

3.

Compound according to claim 2, wherein the inorganic spice is selected from a group consisting of carbon, titanium, zirconium, silicon, magnesium and boron, as well as any combination thereof.

Four.

Compound according to claim 1, wherein the porous support is silica with a specific surface area greater than 200 m2 / g.

5.

Compound according to claim 4, wherein the porous support is silica selected from a group consisting of MCM-41, MCM-48, HMS, MSU-n, MSU-V, FSM-16, KSW-2, SBA- 1, SBA-2, SBA-3, SBA-8, SBA-11, SBA12, SBA-13, SBA-14, SBA-15, SBA-16, UVM-7, UVM-8, M-UVM-7, M-UVM-8 and hollow silica, as well as any of its combinations.

6.

Compound, according to any one of the preceding claims, wherein the lipophilic nature molecules of the interface layer comprise lipophilic organic chains with more than 7 carbons.

7.

Compound according to claim 6, wherein the lipophilic organic chains additionally comprise at least one heteroatom selected from a group consisting of O, N, P and S.

8.

Compound according to claim 6 or 7, wherein the lipophilic organic chains are alkyl chains.

9.

Compound, according to any one of the preceding claims, wherein the substances comprising the heat sensitive surface layer consist of hydrocarbons with more than 9 carbons.

10.

Compound according to claim 9, wherein hydrocarbons with more than 9 carbons comprise at least one heteroatom selected from a group consisting of O, N, P and S.

eleven.

Compound, according to any one of the preceding claims, wherein the heat sensitive surface layer comprises alkanes of between 12 and 60 carbons.

12.

Compound, according to any one of the preceding claims, wherein the porous support has a submicron structure, in the form of nanoparticulate material formed by nanoparticles of a size between 0 and 750 nm.

13.

Compound, according to any one of the preceding claims, wherein the porous support comprises magnetic or gold nanoparticles occluded in said porous support.

14.

Compound, according to any one of the preceding claims, characterized in that it is suspended in solution, in powder form, on textile fibers or embedded in polymers.

fifteen.

Compound, according to any one of the preceding claims, characterized in that the active substances consist of biologically active substances with a suitable size to be introduced inside the pores of the porous support, said active substances being also inert with respect to the material that It constitutes the porous support.

16.

Compound according to any one of claims 1 to 14, wherein the active substances are selected from a group consisting of cancer treatment molecules, nucleic acids, antioxidant molecules, pharmacologically active encapsulated molecules and biocides, as well as any of their combinations.

17.

Compound according to claim 16, wherein the pharmacologically active encapsulated molecules are selected from a group consisting of analgesics, hormones, steroids, antiepileptics, antihypertensives,

ES 2 387 658 Al antibiotics, antiviral agents, cardio-stimulants, polypeptides, moisturizers, hormones, contrast agents, enzymes and antibodies, as well as any of their combinations. 18. Method for the preparation of a compound according to any one of claims 1 to 17, characterized in that it comprises: a) suspending a surface functionalized porous support with an interface layer comprising lipophilic nature molecules in an apolar solvent; b) add to the suspension obtained in the previous stage, substances of non-polymeric lipophilic nature comprising the thermosensitive surface layer, and stir to favor the formation of a supramolecular structure; c) remove the solvent and dry the compound obtained.

19.

Process according to claim 18, wherein the apolar solvent is an alkane with less than 10 carbons.

twenty.

Process according to claim 19, wherein the apolar solvent is hexane.

twenty-one.

Procedure, according to any one of claims 18 to 20, wherein the suspension is achieved by sonication between 1 minute and 6 hours.

22

Process according to any one of claims 18 to 21, wherein the solvent is removed by centrifugation.

2. 3.

Use of a compound according to any one of claims 1 to 17 for the controlled release of the active substance or indicator contained in the pores of the porous support.

24.

Use according to claim 23, wherein the controlled release of the active substance is carried out in solution, in the air, on the skin or in biological or cellular systems.

25.

Use, according to claim 23 or 24, characterized in that it comprises raising the temperature of the described system until reaching the threshold temperature at which a decrease in the interactions between the interface layer and the thermosensitive surface layer occurs, unblocking the pores of the porous support and releasing the active substance or indicator contained in said pores into the medium.

ES 2 387 658 Al ES 2 387 658 Al SPANISH OFFICE OF THE PATENTS AND BRAND Application no .: 201130265 SPAIN Date of submission of the application: 01.03.2011 Priority Date: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: A61K9 / 00 (2006.01) A61K47 / 00 (2006.01) RELEVANT DOCUMENTS

Category

56 Documents cited Claims Affected

TO

ZHENGYANG ZHOU, SHEMIN ZHU and DI ZHANG. "Grafting of thermo-responsive polymer inside mesoporous silica with large pore size using ATRP and investigation of its use in drug release" Journal of Materials Chemistry 2007 Vol. 17 pages 2428-2433; Section 1, Table 1. 1-25

TO

ANDREZA DE SOUSA et al. "Synthesis and characterization of mesoporous silica / poly (Nisopropylacrylamide) functional hybrid useful for drug delivery" J. Mater. Sci. 22.12.2009 [online] Vol. 45 pages 1478-1486; Section 1 Table 1. 1-25

TO

SEHNMIN ZHU et al. "Thermo-responsive polymer-functionalized mesoporous carbon for controlled drug release" Materials Chemistry and Physics 04.12.2009 [online] Vol. 126 pages 357-363; Paragraph 1. 1-25

TO

YUAN GAO et al. "Temperature-sensitive and highly water-soluble titanate nanotubes" Polymer 21.04.2009 [online] Vol. 50 pages 2572-2577; Paragraph 1. 1-25

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims • for claims no:

Date of realization of the report 27.01.2012

Examiner V. Balmaseda Valencia Page 1/4

REPORT OF THE STATE OF THE TECHNIQUE Application number: 201130265 Minimum documentation sought (classification system followed by classification symbols) A61K Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, XPESP, NPL, HCAPLUS State of the Art Report Page 2/4  WRITTEN OPINION Application number: 201130265 Date of Written Opinion: 27.01.2012 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1-25 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 1-25 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published. State of the Art Report Page 3/4  WRITTEN OPINION Application number: 201130265  1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

ZHENGYANG ZHOU, SHEMIN ZHU and DI ZHANG. Journal of Materials Chemistry 2007 Vol. 17 pages 2428-2433.

D02

ANDREZA DE SOUSA et al. J. Mater. Sci. 22.12.2009 [online] Vol. 45 pages 1478-1486.

D03

SEHNMIN ZHU et al. Materials Chemistry and Physics 04.12.2009 [online] Vol. 126 pages 357-363.

D04

YUAN GAO et al. "Polymer 04/21/2009 [online] Vol. 50 pages 2572-2577; section 1.

 2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement The object of the present invention is a thermos sensitive compound for the controlled release of at least one active substance or indicator comprising a porous support and an interface layer with molecules of lipophilic nature. Document D01 studies the design and synthesis of a thermosensitive system for the controlled release of ibuprofen based on a poly (N-isopropylacrylamide) inside a mesoporous support (SBA-15) via atomic radical transfer polymerization. The specific surface area of the support is 443.5 m2g-1 (section 1, Table 1). In D02 a comparative study of the temperature-controlled release of atenolol between a mesoporous silica support (SBA-15) and a hybrid silica-poly (N-isopropylacrylamide) nanosystem is obtained using a surfactant. neutral (section 1). The specific surfaces of these systems are 672m2g-2 and 326m2g-1 respectively (section 1, Table 1). Document D03 studies the response as a function of the temperature of a mesoporous carbon functionalized with a polymer for the controlled release of ibuprofen. The functionalization of the mesoporous carbon is carried out by means of a superficial modification of the carbon and the polymerization inside of the poly (N-isopropylacrylamide) (section 1). Document D04 describes a method of obtaining water-soluble and thermosensitive titanate nanotubes. Said method comprises the functionalization of the surface of the nanotubes with poly (N-isopropylacrylamide) via polymerization by atomic radical transfer (section 1). The difference between the object of the present invention and the cited documents is that none of said documents discloses a thermosensitive compound for the controlled release of at least one active substance or indicator comprising a porous support and an interface layer comprising organic molecules of lipophilic nature covalently bonded to the porous support at one end and by non-covalent interactions to a heat sensitive surface layer located on the surface of the porous support, at the other end. In this way, the controlled release of the active substance or indicator is improved. In addition, it would not be obvious to a person skilled in the art said compound from the cited documents. Consequently, the object of claims 1-25 is considered to be new and involves inventive activity (Articles 6.1 and 8.1 of the L.P.) State of the Art Report Page 4/4