FR2748934A1 - SYSTEM FOR THE CONTROLLED RELEASE OF A SUBSTANCE SOLUBLE IN A SURROUNDING LIQUID, NON-WOVEN MEMBRANE FOR THE REALIZATION OF SUCH A SYSTEM AND METHOD FOR OBTAINING THIS MEMBRANE - Google Patents

Abstract

The invention features a nonwoven membrane comprising thermoplastic polymer filaments and/or fibres, with controlled diffusion properties, i.e. through which can diffuse in controlled manner a substance soluble in a liquid such as water or an aqueous medium, when a solution of this substance in this liquid is in contact with one of the surfaces of the said membrane, the other surface being in contact with the said liquid. It is characterised in that it comprises further a polymer film on at least one of its surfaces or in the proximity of at least one of them, this polymer film totally or partially coating at least part of the surface filaments and/or fibres of the said nonwoven material and providing the membrane with the desired diffusion properties.

Description

System for the controlled release of a substance soluble in a surrounding liquid, nonwoven membrane for the reallsatlon of such a system and method for obtaining this membrane
The present invention relates to a nonwoven membrane comprising filaments and / or fibers of thermoplastic polymer, having properties of controlled diffusion, that is to say through which can diffuse in a controlled manner a substance soluble in a liquid such as water or an aqueous medium, when a solution of this substance in this liquid is in contact with one of the faces of said membrane, the other face being in contact with said liquid; it also relates to a process for obtaining such a membrane, as well as a system for the controlled release of a substance soluble in a surrounding liquid, produced from this membrane.

 In many fields, it is desired to have materials through which a liquid can diffuse according to a determined diffusion profile. In this perspective, two approaches are possible, one consisting in designing entirely new materials, the other in modifying existing materials, inexpensive and readily available, to give them the desired diffusion profile.

 In the context of this latter approach, it has already been proposed in European patent application No. 0 536 087, a closed reservoir system containing a water-soluble active principle which, when in contact with an external aqueous medium, allows a slow and constant release of said active ingredient towards said external aqueous medium. This reservoir system is constituted by an envelope closed on itself to define an interior space receiving said active principle, this envelope being produced from a basic nonwoven treated in an appropriate manner.

It is indicated in this European patent application that when the basic nonwoven is of hydrophobic nature, it is not wettable by water or an aqueous liquid and therefore completely shields water, which prevents any diffusion of water and therefore of active principle through this nonwoven. In this case, the aforementioned suitable treatment consists in impregnating the basic nonwoven either with polysiloxanes or polymers based on polysiloxane, these being hydrophobic by nature, or with quaternary ammonium salts of amphoteric type, those these being hydrophilic by nature. The main characteristic of the substances used in the patent application
No. () 53 (087 resides in their amphoteric nature; they are essentially surfactants used to modify the hydrophobicity of nonwoven membranes.

 It has therefore been observed by the authors of the present invention that even a reservoir system made of a nonwoven of hydrophobic nature ends up after a certain period of time by being completely impregnated with the liquid, at which point it generally occurs a rapid and uncontrolled release of the active ingredient present within said reservoir system.

 On the other hand, when the base nonwoven is hydrophilic in nature, it is wettable with water or an aqueous solvent, so that the water or the aqueous medium can diffuse freely through the nonwoven with very high release. active ingredient. In this case, the above-mentioned suitable treatment consists in impregnating the hydrophilic nonwoven base with a water repellent agent to reduce its hydrophilicity.

 The aforementioned European patent application further specifies that it is the chemical nature and not the quantity used of the impregnating substances which is decisive for obtaining the slow and constant release sought. The use of these substances therefore does not make it possible, by varying their quantity, to modify the release profile of the active ingredient as desired. The known reservoir system has the drawback of lacking flexibility and therefore of being limited in its applications.

 The object of the present invention is to remedy the above-mentioned drawbacks and for CC f; lilC it provides a membrane as defined in the first paragraph of This description and which characterizes in that it comprises a polymer film on at least the one of its surfaces or in the vicinity of at least one of these, this polymer film partially or totally coating at least part of said filaments and / or surface fibers of the nonwoven and conferring on the membrane the properties desired distribution.

The membrane thus defined basically departs from the teachings of the aforementioned curopean patent application since it is characterized by the presence of a
film which does not exist in the nonwoven treated as described in said application.

 It should also be pointed out that according to the present invention, there is a superficial film, which is not the case in the European patent application cited above.

 Furthermore, according to the present invention, the film is somehow embedded in the nonwoven, that is to say that it is not simply glued to the surface or surfaces of the membrane, but designed so at least partially wrapping part or all of the filaments and / or surface fibers of the nonwoven, so that there is no discontinuity between the film and the nonwoven of the membrane.

 It is this polymer film which will impart the desired diffusion properties to the membrane.

 These diffusion properties can be adjusted as desired by varying the specific diffusion properties of the film, that is to say in fact by varying the chemical nature of the polymer constituting said film and / or the physical nature of the latter.

 More specifically, the polymer constituting the film can be hydrophobic or hydrophilic in nature; it may be soluble or insoluble in the liquid intended to pass through the membrane; and it may be permeable or impermeable to said liquid.

 As for the film, it can be continuous or discontinuous and more or less thick.

 By combining the above-mentioned features, it is easy to make films with the most diverse diffusion properties. Thus, a film through which an aqueous liquid can easily diffuse will for example be discontinuous and thin and made of a hydrophilic polymer, while on the other hand a film through which this liquid can only diffuse with difficulty will preferably be continuous. and made of a hydrophobic, permeable and thick polymer.

 It therefore appears that thanks to the present invention, that is to say thanks to the use of a film having determined diffusion characteristics, on the surface or in the vicinity of the surface of a non-absorbent membrane. woven, it is possible to easily control the diffusion of a liquid through this membrane. The invention is moreover very flexible since by varying certain parameters of the film, it is possible to provide nonwoven membranes having the most diverse diffusion profiles.

 The polymer constituting the filaments and / or fibers of the nonwoven can in particular be chosen from the group consisting of polyolefins, polyesters and polyamides, and by way of examples, polyethylene is mentioned as hydrophobic polymers, polypropylene and polybutylene therephthalate, and as hydrophilic polymers, polyhexamethylene-adipamide, PLA and PGA.

 As for the polymer constituting the film, it can in particular be chosen from the group consisting of cellulose, a cellulose derivative, a vinyl derivative, a polyamide, polyethylene, poly (vinyl acetate), an ethylene-acetate copolymer dc vinyl, a high molecular weight polyoxyethylene glycol (PEG) of the order of 1000 to 8000, a (meth) acrylic polymer and mixtures of at least two of them.

 Mention may in particular be made, as cellulose derivative, of ethylcellulose, hydroxypropylmethylcellulose and cellulose acetate phthalate; as vinyl derivative, In particular, polyvinylpyrrolidonc is mentioned; and as the (meth) acrylic polymer, mention may be made in particular of a polymethacrylate.

A particularly preferred polymethacrylate is that sold by the company
RÖHM PHARMA under the trade name EUDRAGIT NE30D which is a 30% aqueous dispersion of EUDAGIT NE which is itself a copolymer of ethyl acrylate and methyl methacrylate.

 We can usefully refer to Handbook of Pharmaceutical Excipients, 2nd edition, The Pharmaccutical Press for all useful information on the above polymers that can be used to make the film.

 The above-mentioned nonwoven membrane can be obtained by a process which comprises treating a nonwoven membrane comprising filaments and / or fibers of a thermoplastic polymer with a solution or dispersion in a suitable solvent of a polymer. film-forming, then removing said solvent, the film-forming polymer and its concentration in said solution or dispersion being chosen to form a polymer film capable of regulating the diffusion properties of said membrane.

 It will be specified that said treatment is preferably carried out by spraying said solution or dispersion of film-forming polymer onto the surface (s) of the nonwoven membrane or by dipping the latter in said solution or dispersion and in that the elimination of said solvent is produced by drying, for example in air or in an oven, the temperature of which depends in particular on the nature of said solvent.

 solvent used in this process will depend on the nature of the film-forming polymer used and will be chosen to dissolve or disperse said film-forming polymer.

It will preferably be chosen from water, a C1-C4 alkanol or a mixture of these, it being specified that the C1-C4 alkanol is advantageously ethanol or isopropanol as regards the film-forming polymer, it is as defined above.

 The present invention also relates to a system for the controlled release of a substance soluble in a surrounding liquid, comprising an envelope defining an interior space intended to contain said substance, this system being characterized in that at least part of said envelope is constituted by a membrane as defined above, the remaining part of the envelope being constituted by a material impermeable to said liquid and not soluble in the latter.

 This system finds its application in the most diverse fields where it is desired to release in a controlled manner a substance soluble in a surrounding liquid such as an aqueous medium.

 Thus, it can be used for controlling the diffusion of water-soluble active substances, for example an insecticide, a fertilizer or a drug. The latter may in particular be for veterinary use (antibiotic, antifungal, anti-inflammatory, antiparasitic, antiseptic or vitamin for example), in which case the said system may be absorbed orally by the animal or put in place at an appropriate point in the body of the body. animal to be treated, for example the belly of a cow.

 The production of the membrane and of the release system according to the invention will depend essentially on the nature of the nonwoven, on the nature of the substance to be released and on the desired release profile for this substance.

Consequently, after having chosen the nonwoven, the soluble substance and the desired release profile, it is necessary to determine which is the treatment solution or dispersion of this nonwoven which makes it possible to obtain the polymer film conferring said profile. release to the nonwoven membrane. This determination can be made - by carrying out a first series of treatment solutions or dispersions
each comprising a first film-forming polymer (PF), but at different
concentrations (Cl ,, Cl2, Cl3, etc ...), then a second series of solutions or
treatment dispersions each comprising a second film-forming polymer
(PF but at different concentrations (C21, C22, q, q, etc.) and so on, - by treating the nonwoven chosen respectively by the different solutions or
dispersions thus obtained, - by treating the resulting nonwovens to remove the solvent therefrom, - by making controlled release systems respectively from
each of the nonwovens thus obtained and by incorporating into each system the
same quantity of said soluble substance, - by subjecting each assembled system to an in vitro dissolution test to
establish a curve illustrating the release kinetics of said soluble substance,
and - by comparing the curves obtained with the desired release profile for
finally retain the controlled release system including the kinetics curve
closest to the desired release profile.

Nonwoven membranes: nature and structure
These membranes can in particular be simple systems formed of an elementary fleece of nonwoven or composite systems formed of at least two elementary veils of fleece assembled by an appropriate method such as hot calendering. By way of example, the internal veil (that is to say the closest to the water-soluble substance) is of the type obtained by the so-called melt-blown process (blowing of fibers) this veil is intended to control the diffusion of the water-soluble substance and has a relatively low mechanical resistance. The external veil is of the type obtained by the so-called spun process (spinning of monofilaments); its mechanical resistance is high and has no role in controlling diffusion. In what follows, the internal veil will be defined by the letters MB followed by the grammage expressed in g / m2 and the external veil will be defined by the term S-TEX followed by the grammage expressed in g / m2. It should be noted that a membrane may include one or more internal veils. A membrane constituted for example by an external veil with a grammage of 50 g / m2 and two internal veils each with a grammage of 40 g / m2 will be defined by S-TEX 50 g / m2 + 2MB 40 g / m2.

Rolling of nonwoven membranes by a solution or dispersion of a film-forming polymer
This treatment can for example be carried out by soaking the membranes in said solution or dispersion at room temperature and for a determined period, this soaking being followed by drying of said membranes for example for 2 hours at room temperature or at about 55 "C in an oven.

 The higher the concentration of said polymer solution or dispersions, the higher the quantity of polymer fixed on the membranes, that is to say the more continuous and thick the film formed.

Reallsatlon of a controlled release system
Two strips of determined dimensions are cut from a membrane treated as indicated above. These two strips are superimposed and joined, for example by welding (in particular by ultrasound or heat sealing) at three of their sides. After introduction of a determined quantity of water-soluble substance into the pocket thus formed, the latter is closed by joining by heat sealing the last sides of the two strips to thereby obtain said controlled release system.

Soluble substance
It is usually used in pure form or in combination with substances which can modify its dissolution (gel, microgranule, coating) and in an amount depending on the desired duration of action.

In vitro dissolution test
For this test, use can be made of the standardized dissolution device,
DISSOLUTEST PROLABO, based on the so-called rotating paddle method, described in the Xth Edition of the French Pharmacopoeia.

 The controlled release system is fixed on the pallets of the dissolution device.

 - Pallet rotation speed: 15 revolutions per minute.

 - Volume and temperature of the dissolution medium: 1000 ml, 37 C.

- Composition of the dissolution medium: phosphate buffer at pH = 6.4,
- Interval of withdrawal of the dissolution medium: 24 hours,
- Determination of the water-soluble substance released in the dissolution medium: by
spectrophotometry at a wavelength depending on the substance.

 In order to avoid possible saturation of the dissolution medium with said substance and to comply with the SINK conditions, the dissolution medium is preferably replaced after each assay.

 The present invention will now be illustrated by a number of examples given without implied limitation.

Example 1
Controlled release systems are made as described above, each using two strips (10 cm x 10 cm) of polypropylene nonwoven. Each strip is of the S-TEX 50 g / m2 + 2 MB 30 g / m2 type and has been treated as indicated above under the following conditions - solution of film-forming polymer: ethanolic solution at 5, 12.5, 15, 20 or 25 %
in volume of EUDRAGIT NE 30D, - soaking time: 1 () min.

We find cn annex to illustrate the invention
- uiic figure 1 which is a photograph of the section of the nonwoven treated with an ethanolic solution at 20 C,! cn volume of EUDAGIT NE 30D; this photograph shows that the treatment of this solution leads to the formation of films located in the vicinity of the surfaces of the nonwoven;
FIGS. 2 and 3 which are photographs of the S-TEX face and of the MB face respectively, of an untreated nonwoven,
- Figures 4 and 2 which are photographs of the S-TEX side and dc the MB side respectively, of a nonwoven treated with an ethanolic solution of EUDAGIT NE 30D; they show the presence of a discontinuous polymer film on these faces, a film which coats the surface fibers of the nonwoven, and
- Figure 6 which is a photograph of the S-TEX face of a nonwoven treated with an ethanolic solution at 20% by volume of EUDAGIT NE 30D; it highlights the effect of concentration of the treatment solution on the uniformity and the thickness of the film obtained.

 Note that these photographs were taken using a scanning electron microscope.

 In each system are introduced 10 g or 23 g of morantel citrate powder (anthelmintic for veterinary use).

 The systems thus produced are subjected to the in vitro dissolution test described above, the assay of morantel citrate being carried out by spectrophotometry at a wavelength of 320 nm.

 The results obtained are illustrated by the graphs which are the subject of appended FIGS. 7 to 11 which represent the kinetics of release of morantel citrate, FIG. 7 corresponding to the system containing 10 g of morantel citrate and FIGS. 8 to 11 to the system containing 23 g morantel citrate; the abscissa scale gives the time expressed in days and the ordinate scale the cumulative amount of released morantel citrate expressed in mg.

It should be noted that a treatment of nonwovens with a pure solution of EUDAGIT
NE 30D or with a 50% by volume aqueous solution of EUDRAGIT NE 30D did not lead to any release of morantel citrate; this corresponds to the case of a continuous polymer film and of a thickness such that no diffusion of liquid takes place through this film.

Example 2
Release systems are made (dimensions of 5 cm × 5 cm; containing 3 g of morantel citrate) in the same manner as in Example 1, except that the strips of nonwoven are treated respectively by the following film-forming polymer solutions
(a) aqueous solution at 8% by weight of cellulose acetate phthalate (CAP),
(b) ethanolic solution at 7% by weight of ethylcellulose,
(c) 20% by weight ethanolic solution of polyvinylpyrrolidone (PVP),
(d) aqueous solution at 15% by weight of hydroxypropylmethylcellulose (HPMC).

 The results obtained are illustrated respectively by the graphs which are the subject of Figures In to 15, which give the cumulative amount of morantel citrate released (in mg) as a function of time (in days or in hours depending on the treatment solution used).

 The above examples therefore show that by varying the chemical nature of the film integrated in the nonwoven membrane, its continuous nature and its thickness (these two last parameters being a function of the concentration of the treatment solutions), it is possible to obtain treated membranes having the most diverse release profiles.

Claims (12)

 1. Nonwoven membrane comprising filaments and / or fibers of thermoplastic polymer, having controlled diffusion properties, that is to say through which can diffuse in a controlled manner a substance soluble in a liquid such as l water or an aqueous medium, when a solution of this substance in this liquid is in contact with one of the faces of said membrane, the other face being in contact with said liquid, characterized in that it further comprises a polymer film on at least one of its surfaces or in the vicinity of at least one of these, this polymer film completely or partially coating at least part of said filaments and / or surface fibers of said non -woven and giving the membrane the desired diffusion properties.  2. Membrane according to claim 1, characterized in that said polymer film is continuous or discontinuous.  3. Membrane according to claim 1 or 2, characterized in that the polymer constituting said film is hydrophobic or hydrophilic in nature.  4. Membrane according to claim 1, 2 or 3, characterized in that the polymer constituting said film is soluble in said liquid or insoluble in this liquid and permeable to the latter.  5. Membrane according to one of the preceding claims, characterized in that the polymer constituting said filaments and / or fibers is chosen from the group consisting of polyolefins, polyesters and polyamides.  6. Membrane according to one of the preceding claims, characterized in that the polymer constituting said film is chosen from the group consisting of cellulose, a cellulose derivative, a vinyl derivative, a polyamide, polyethylene, poly (vinyl acetate ), an ethylene-vinyl acetate copolymer, a high molecular weight polyoxyethylene glycol from 1,000 to 8,000, (meth) acrylic polymers and mixtures of at least two of them.  7. Membrane according to claim 6, characterized in that said cellulose derivative is ethylcellulose, hydroxypropylmetylcellulose and cellulose acetate phthalate and in that the vinyl derivative is polyvinylpyrrolidone.  8. Membrane according to claim 6, characterized in that said (meth) acrylic polymer consists of a polymethacrylate.  9. A method of obtaining a nonwoven membrane according to any one of claims 1 to 8, characterized in that it comprises the treatment of a nonwoven membrane comprising filaments and / or fibers. in thermoplastic polymer, by a solution or dispersion in a suitable solvent of a film-forming polymer, then elimination of said solvent, said film-forming polymer and its concentration in said solution or dispersion being chosen to form a polymer film capable of regulating the diffusion properties of said membrane.  10. The method as claimed in claim 9, characterized in that said treatment is carried out by spraying said solution or dispersion onto the surface (s) of said nonwoven membrane or by dipping the latter in said solution or dispersion and in that said solvent is removed by drying.  11. System for the controlled release of a substance soluble in a surrounding liquid, comprising an envelope defining an interior space intended to contain said substance, characterized in that at least part of said envelope consists of a membrane according to the one of claims 1 to 8, the remaining part of the envelope consisting of a material impermeable to said liquid and not soluble in the latter.  12. System according to claim 11, characterized in that said substance is a water-soluble active substance.