MXPA99005030A - Device for local administration of solid and semisolid formulations, sustained-release formulations for parenteral administration and method of preparation - Google Patents

Abstract

The invention concerns the use, for implanting or inserting a solid (1, 9) or semisolid (18) formulation, for being set in a precise receptor site (T) of the system, containing at least one active principle, said formulation being of a solid or semisolid consistency such that it can remain for some time in the site, and containing a limited dose of active principle for treatment in a targeted zone of the body, a device comprising one part set inside the body of the patient with means for conditioning the solid or semisolid form, positioning means for bringing these conditioning means to the deposit site, means for injecting or inserting in this deposit site, means for removal after injection or insertion, and one part remaining outside with means for activating the functions of the device. The invention also concerns a sustained-release solid formulation for parenteral administration containing a homogeneous mixture of an active principle in non-dispersed state and of a biologically compatible and biodegradable excipient, in which the amount of active principle is at least 50%by weight.

Description

LOCAL FORMULATION ADMINISTRATION DEVICE SOLID OR SEMI-SOLID, FORMULATIONS OF RELEASE DELAYED FOR PARENTERAL ADMINISTRATION AND PREPARATION PROCEDURE.

Description of the invention The present invention has as its objective a therapeutic method to allow the targeted treatment of non-liquid medical formulations as well as the preparation and the device conceived for the start-up of the process. The advantages of using a treatment or of a local administration are known when the active principle (PA) is thus preferably oriented towards its site of action. It has been proved, on the other hand, that the oral or parenteral administration of a drug and its systemic diffusion may, in certain cases, not give a satisfactory result. On the other hand, even in the case where a general or systemic treatment is considered, mainly in the case of delayed-release formulations, it is Ref .: 30389 interesting to insert the formulation in an adapted site. Apart from the improvement of local efficacy, the local treatment in relation to a general treatment allows first of all to diminish the doses and side effects mainly linked to P.A., in the sites of the organism where its presence is either useless or harmful. The local administration of a drug thus makes it possible to improve the therapeutic index of the product, always decreasing, depending on the case, its general toxicity and the risks of sys- temic effects. Topical skin, ocular, naso-sinus, pulmonary or even gastric or rectal forms have been the first non-parenteral forms to use local administration. When the site of the deposit of the formulation is more difficult to access or needs an invasive form, and when the treatment must be repeated, or even more, chronic, even if the advantage of a selection or screening is known, in practice, its use it faces the difficulty if not the discomfort of a repeated therapeutic action.

On the other hand, the advantages of using a prolonged or delayed treatment are known, which allows, in a single administration, to give the patient his medication for several days, several weeks or several days. months This form of delayed release improves compliance since the observation of treatment does not depend on the patient or the assigned personnel but on the preparation. This prolonged effect therefore improves the comfort of the patient who does not obligate him more to his treatment, and who thus receives a regular and permanent dose that does not vary depending on the doses of medication. The des.ax.X-allo rie J._a_s .fnpna ^ xle 1 ih r-aci-ó-n retarded has led specialists to consider their local uses mainly in the case mentioned above, where the site of the deposit is more hardly accessible. The delayed release form thus avoids having to repeat the administrations or, even more, the surgical action. Important local concentrations of the drug can then be expected over a prolonged period, without significant systemic doses, and with fewer side effects. This solution is more particularly useful for rapidly metabolized products or products that have a short half-life when they are administered systemically. In the interior of the organism, the directed and prolonged treatments are considered, such as intra-or peri-articular injections of delay corticosteroids. Cancers, and mainly solid tumors, are candidates of choice for these local forms that allow to reduce the total injected doses of the cytotoxic or antineoplastic compound, always increasing the concentration in the tumor area to be treated. This is therefore likely to avoid the serious side effects of this type of treatment. Matrix Pharmaceutical proposes a delay preparation based on collagen that can be injected intratumorally (Intra Dose CDDP-Cisplatin). This formulation is administered in cancers or skin lesions with the help of a 3 cc syringe and eventually a biopsy needle for less accessible areas. Under a viscous liquid volume that can reach 2 ml, it is therefore limited to relatively easy (peripheral) start sites or post-surgical treatments.

One can thus cite the MITSUI patent (FR 2 497 661, JP 562 737) which describes a form of polylactide-polyglycolide (PLGA) in bar or needle for local activity, which allows its direct implantation in an area or an organ in the interior of the organism, and for example a tumor zone before or after the removal. The Gliadel form (Guildord) describes a formulation based on polyanhydride in the form of a wafer or a wafer containing the Carmostina and which can, for example, be deposited at the time of surgery at the level of a brain tumor (glioblastoma). In the current state of medical technology, these treatments directed to the interior of the organism are even frequently linked to heavy surgical interventions. These benefit from the prolonged effect of the formulation but can not be easily repeated. There are also chemoembolization interventions that consist of injecting into the vessels, suspensions (microspheres), of gels or of tails with their solvent, which can obstruct a nutritive vascular path and release an active principle at the level of a tumor. The occlusion is obtained by deposit after the start of the injection vehicle. This technique uses transluminal percutaneous angioplasty catheters to introduce fluid into the vessels. The local use of delayed release forms is also considered in certain body cavities and in more accessible sites of the organism. The © Ocusert (Alza) system is a flexible and oval eyepiece that forms a delay deposition device that includes an ethylene-vinyl acetate copolymer membrane and may contain, for example, pilocarpi? A. This device is placed in the bottom of the conjunctive sac and releases its product according to a zero-order profile. The form of delay allows to significantly reduce the dose necessary for the same effect on intraocular pressure. The therapeutic efficacy of pilocarpine in the treatment of glaucoma is thus 8 to 10 times improved thanks to the use of a delay form compared to local drops. U.S. Patent No. 3,545,439 where the content is incorporated by reference discloses a form of intravaginal retardation consisting of a ring made of a silicone elastomer and releasing a medicament for several weeks. In this case, the administration of local delay on the vaginal mucosa ... also allows, according to the active principle, to obtain a general effect (contraception). The medical device described by Bu h Meditee (PCT International Patent Application No. WO89 / 03232 where the content is incorporated by reference) allows the introduction into a body cavity of an elaborate matrix delay form of a substance which is weakly penetrable by water and which contains an active substance . The form of delay associated with the device thus distributes the active ingredient locally and for the entire duration of the insertion of said device. It describes, for example, a catheter for the urethra that opens into the bladder, associated with a form of antibiotic delay capable of preventing urinary tract infections. For large-volume liquid forms, certain existing local injection procedures could be used. From intraurethral techniques, CRBARD, for example, has developed a formulation (Transurethral Distribution Equipment) that is a syringe containing a collagen solution in glutaraldehyde., Which can be easily injected submucosally under volumes of 2.5 to 7.5 ml that constitute implants without active principle in the framework of an anti-incontinence plasty. The development of intraluminal vascular systems has led to the realization of catheters that allow the release of an active principle at the local level. Nil - CoLtr-a i-aaeite - to the catheter simply open to release the fluid, local administration can be obtained with a double bayonet or porous catheter with multiple perforations. This local solution is however limited by the time of insertion of the catheter. The pressure of the solution necessary to penetrate the wall also imposes a tolerance problem. For liquid solutions, a true local injection can be obtained on the wall with the help of an injection system associated with a bayonet (Interventional Technologies) or a retractable needle catheter (Bavarian Medical Technologies). The application of the medication is not however very prolonged with these immediate liquid forms. A part of the device can sometimes be left locally and then be associated with a form of delay. This is the case of the "stents" used, for example in angioplasty, to avoid restenosis, which can be coated with a layer containing an active ingredient, sometimes with a delay effect. Two essential problems are imposed then, the first is the adequacy of the drug intended for the specific procedure of 'coating.' The second is the limitation of the total dose by space and the surface offered by the stent.With heparin, for example, Certain studies mention the importance of local treatment to avoid systemic side effects According to these studies, heparin inhibits the proliferation of muscle cells used after the endothelial lesion, its systemic administration, in the form of a subcutaneous or delayed release. local adjacent to the vessels, always leads to a decrease in neointima proliferation, but the local form is the only one that does not involve systemic disturbances of coagulation, including osmotic pumps that are used to validate prolonged local administrations with their surgical implant as a major drawback, for this reason, These are not currently used in man. All these cases show very well the interest and the advantages provided by a directed treatment, especially that this can be prolonged. However, these technical solutions present certain drawbacks, the most important of which are the lack of versatility of the solution in question, the association with a specific device that is totally or partially inserted over the duration of the release of the drug, and finally , the limit of the injectable volume, and therefore of the dose of the active principle. Each of these solutions allows to treat only one or several particular cases in a very precise place of the organism. Vectorization by local administration is sometimes qualified as a first generation in relation to the formulations of 'prodrugs' and vectors (liposomes) ... denoted as second generation or to macromolecular recognition or activation systems *. This solution, even more than the current local administration techniques, is nonetheless very specific, not always applicable and some p >oco precise. The object of the invention is to propose a method that remedies the current main drawbacks of local administration or vectorization by flexible endoscopic surgery techniques (fibroscopy) or rigid (endoscopy) and interventional radiology icatter active or not). The solid and semi-solid dispersed formulations have the advantage of offering a minimum volume for an amount of active principle corresponding to a treatment dose. The delayed, solid and semi-solid release forms can, thus, allow several days of treatment in a volume of a few microliters.

The local administration of a rat can significantly reduce the total therapeutic dose for the same effect. The combination of a delayed, solid or semi-solid release form and a local administration thus leads to the realization of microdoses particularly adapted for a local deposit at spaced time intervals. The current development of imaging, optics and micromechanics technologies applied to medicine in the field of intravascular or cavity instrumentation, and minimally invasive surgery, has led to the conception of more or less fine tools and more or less precise that allow to intervene locally in a very deep way in the organism with a minimum traumatism and multiply the accessible sites. The invention thus proposes a method, a device and a formulation adapted to the progress and miniaturization of pharmaceutical and medical technologies. The method considered by the invention for the implant or the insertion of an active ingredient contained in a solid or semisolid formulation in a precise deposit site of the organism, is characterized in that it consists of obtaining the solid or semi-solid formulation, to load this formulation in a device that can be operated from the outside of the organism, and provide said device to the deposition site inside classical intervention tools at this level, and insert or implant said formulation by actuating the device. According to other features of the invention: the deposit site is not accessible with a syringe or a classic hypodermic device, the solid or semi-solid formulation has a thin and elongated shape once loaded in said device, the device is thin and elongated to be able to circulate in the classic intervention tools, - the solid or semi-solid formulation is a delayed release formulation, the thin and elongated form offers a minimum length-to-diameter ratio of 10, the device is the container of the formulation, just adapted for this form, - the shape and the device are cylindrical, - the implant takes place in a tissue, in a mucosa or in an internal wall of the organism via the cavity, - the implant takes place in a tissue, in a mucosa or in an internal wall of the organism by vascular, arterial or venous route , - the implant takes place in a tissue., in a tumor or in a. pathogenic zone by surgical route, - the insertion takes place in a body cavity or in an organ via the cavity, - the insertion takes place in a body cavity or in an organ or tissue, by invasive or surgical route, - the principle active is an anti-inflammatory, - the active principle is a peptide or a peptide analog, the active substance is an anti-cancer product, - the active substance is a mixture of 2 or more active substances. The invention also has for its object: a method of therapeutic treatment in which an active ingredient in a solid or semi-solid formulation is inserted into a body cavity, so that said active principle is released into the fluids on the surface of the body. cavity, and can act locally towards drainage sites of bodily fluids, - a method of therapeutic treatment in which an active ingredient in a solid or semi-solid formulation is implanted in a mucosa or in an internal secretory tissue of the body, so that said active principle is released and excreted with natural fluids and can act locally or towards the drainage sites, - a method of treatment in which the active ingredient has a local and / or systemic action from the implant deposit site, a method of therapeutic treatment of ENT pathologies in which the active ingredient in a s formulation or Semis is introduced into a cavity of the face or into the mucosa that covers it, - a method of therapeutic treatment in which the active ingredient is a corticoid, a method of therapeutic treatment of vascular or enamel conditions or treatments. or arterial, in which the active ingredient in the s or semis formulation is introduced into or around the vascular wall by intraluminal injection. The pharmaceutical and medical aspects of the invention are combined in the search of a fine and miniaturized system that can be easily placed and activated in all areas of the body from percutaneous transluminal angioplasty catheters, endoscopes or any other invasive device sufficiently fine and long to access the deposit area. The shape (fine and elongated) of the formulation in the administration device facilitates its local deposit. This characteristic of the system under its pharmaceutical and medical aspect will allow its general use. If it is understood by insertion, a form deposited on the surface and by implant, an injection in a tissue, the directed or prolonged treatment may be inserted inside a natural cavity of the organism if it is capable of doing the same. Sometimes it is a natural deposit, that is, if the shape of the drug reservoir allows it to remain in the body cavity for at least the duration of its re-stretching. This form can be either the elongated form studied to facilitate its deposit with the device, or its evolution once deposited. The shape of the device and the formulation is not a priori adapted to the insertion area such as Ocusert, the vaginal ring or the stents. The shape of the formulation can nevertheless evolve after the deposit to facilitate its local maintenance. After its deposit, the formulation is not associated with all or part of the deposit device but is left alone at the deposit site. If by necessity and a specific therapeutic duration, an insertion in a natural cavity of the organism is not desirable, the directed or prolonged treatment may also be implanted inside an objective tissue of the organism, to allow its deposit for the duration of the treatment. rethinking This implant can be performed with the device associated with the classic tools, transcutaneously, by vascular or cavitary route in a mucosa or in a wall of the organism or by the surgical route in a target tissue.

The insertion of the delay form will allow a local, superficial or external treatment, but also a direction to the target for effect in depth, or for systemic effect, for example with a deposit on the mucous membranes. The same implant of the delayed release form will allow a general treatment but also a treatment directed by local hyperconcentration or by excretion. In this way, according to the therapeutic applications and the area, the insertion as the implant may be a systemic solution, an internal local solution or, finally, an external objective solution. The immediate or delayed release solid or semi-solid formulations used in the process of the invention may be of any type of solid or semi-solid formulations capable of being manufactured or conditioned in the form and volume compatible with the injection method and device. . From this node, the solid or semi-solid forms may preferably be formulations made from biodegradable excipients such as, for example, inorganic salts (calcium, magnesium, bismuth, zinc); the lipids; carbohydrates (polysaccharides, sucrose, glucose, agarose, dextrin, cyclodextrin and mixtures thereof); proteins (gelatin, modified collagen, albumin, casein, derivatives and mixtures thereof); natural and synthetic polymers (polyisobutyric acid, polylactic acid, polyglycolic acid, polylactide-polyglycolide copolymer (PLGA), polyester, polycaplanctone, polyethylene glycol, polypropylene glycol, Pluronics®, polyanhydrides and mixtures thereof). Solid or semi-solid formulations may be made without excipient or structured with small amounts of injectable excipients such as mannitol, hyaluronic acid, cellulose derivatives, etc. The semi-solid formulations can be made by mixing the active principle with or without excipient, with water, an organic solvent, oil or any other injectable liquid capable of giving the semi-solid form. The solid or semi-solid formulations will be either the immediate formulations or the delayed-release formulations.

The solid immediate formulations can be carried out as indicated in the patent SCRAS (Distribution of Solid Pharmaceutical Pharmaceutical Composition O96 / 07397). The solid and delayed release formulations can be made according to the formulation and the procedure claimed by the SCRAS patent (Sustained Release of Peptides from Strong and Semisolid Compositions a.cé.uti.cas. WO96 / 07398 whose content is incorporated by reference). The solid or semisolid formulations will be advantageously carried out according to the processes that allow a high concentration of active principle, higher than 20%, or higher than 40%, preferably higher than 50% and up to 100% active principle. Before being deposited, the solid non-dispersed formulations according to the invention will have a thin and elongated shape: spike, implant, pellet, cane or needle, in order to be introduced into the interior of the implant device which may, if necessary depending on the depth of injection in the body, be inside an endoscope or a catheter.Solid dispersed formulations (powders, spheres) should be able to be accommodated longitudinally in the device. solid formulations in the device will thus preferably have a maximum diameter of 3 mm and advantageously a lower diameter of 2.5 mm or a diameter of less than 2 mm, preferably less than 1 mm, depending on the total dose and on all for immediate forms or forms of short duration or small dose (less than 0.1 mg / day), the diameter of the solid forms may be even smaller and up to 0.1 mm The smaller diameters may, in certain cases, present a technical advantage to facilitate the deep local implant; However, with catheters and endoscopes, a larger diameter will not have the same disadvantages (mainly in terms of comfort for the patient) as in the case of hollow needle-type superficial injections (Zoladex, brand deposited by the company Zeneca ) or hollow mini-needles (auto-injector, retro-injector: Parenteral Introduction Device without Needle WO96 / 08289 whose content is incorporated by reference) or because the use of the medicinal devices needs, on the other hand, a local anesthetic or general, or else because the deep implant zone is less sensitive than the skin. The solid forms may have a length of a few centimeters, generally less than 3 cm and preferably less than 2 cm, and adapted to the space in the deposit area. The solid forms will preferably be cylindrical and obtained by extrusion techniques. The semisolid forms, according to the invention, will have a sufficiently high viscosity to contain a high concentration of active principle (preferably greater than 20%) and remain homogeneous, always allowing deep injections through the needle of the device of the invention. The semi-solid forms may be gels, oils, pastes or any other semi-solid dispersion of an active ingredient in a liquid vehicle. The semi-solid forms will have a small overall volume of less than 300 μl, and preferably less than 100 μl if not less than 50 μl. The process and devices according to the invention will preferably use injectable excipients biodegradable, or normally eliminated or solubilized in body fluids. However, the procedure may use devices or formulations based on biocompatible, non-biodegradable biomaterials, when the site or the deposition tools easily allow the retraction of said device or of the "formulation after its operation, ie rather for the inserts for implants The device or formulation should have a thin and elongated shape, like the other solid forms compatible with deep local administration, such as the Norplant silicone implants, the PHEMA reservoir systems of the Hidromed company, or or the hard osmotic pumps of the company Alza. The devices according to the invention correspond to the solid or semi-solid formulations associated with the insertion device or deep localized implant.

The device according to the invention, for the implantation or the insertion of an active ingredient in a solid or semisolid formulation in a precise deposit site of the organism, is characterized in that it comprises a part placed inside the body of the patient with means of conditioning of the solid or semi-solid form, placement means to the deposit site, injection or insertion means in this deposit site, and retraction means after injection or insertion, and a portion left on the outside with the means of activating the functions of the device. According to other features: - the means for conditioning the solid or semi-solid forms are also the means for positioning and injection, - the device comprises a piston inside a guide that can be driven in a hollow needle or in a catheter, - the conditioning, placement or injection means is a needle, the needle once actuated can be oriented relative to the device by elastic pre-compression or elastic constraint or by mechanical means, the external activation means of the device allow, sequentially, the injection of the needle, the advance of the piston to the bevel of the needle to deposit the solid or semi-solid form, the retraction of the needle around the piston, the combined retraction of the needle and the piston, - the sequential actions of the device to from the external means are controlled remotely and in order, with the help of two stirrups or removable stops The first is placed on a handle coaxial to the piston, and the second is a tubular piece sandwiched between the guide and the pusher. The devices may be used directly or associated with local therapy medical instruments (endoscope, fibroscope, tube, catheter, boil, aerator, cannula, perforator, hollow needle, etc ...). The devices will be introduced locally and will allow the insertion or implanting of solid or semi-solid forms. These will be removed immediately after this deposit.

As the formulations, the devices used, according to the method of the invention of deep local administration of the solid or semi-solid formulations, will be polyvalent and of small volume, with an adapted, thin and elongated shape. The devices will thus preferably have a maximum diameter of 3 mm, and advantageously a diameter of less than 2.5 mm, even less than 2 mm. Depending on the formulation, the diameter of the device may be even smaller and up to 0.3 mm. In a fibroscope or in a carried endoscope, for example 4 channels (video, instruments, introduction and retraction of fluid, light optical fibers), the insertion or implant device may, as a classic tool (style biopsy forceps) occupy the channel of the instruments, which releases the fluid introduction channel or allows its elimination. In this case, the devices may have a diameter of less than 2 mm and, for example, of 1.7 mm as certain instruments. In a catheter, the insertion or implant device may, as in the device for inserting the stents, occupy the channel and be activated from the outside ix¡. if you . In this case, the device may have a diameter of less than 2.5 mm and, for example, of 2 mm as certain stents. In a hollow needle, the insertion or implant device may, like the piercing device, occupy the light or internal diameter of the hollow needle. The device may have a diameter of less than 3 mm and, for example, 2.5 mm as certain perforators. Other features and advantages of the invention will appear in the course of the following description, made with reference to the accompanying drawings which illustrate various embodiments by way of non-limiting examples.

Figure 1 is a view in longitudinal elevation of a first embodiment of the device for administering the solid formulations according to the invention, in the case of depositing the formulation inside a natural cavity of the body, used as a reservoir of rethinking the formulation.

Figures 2, 3 and 4 illustrate a sequence of putting into operation the device of Figure 1, to administer a solid formulation locally in the organism.

Figure 5 is a half-longitudinal longitudinal elevation view of a second embodiment of the device for administering formulations according to the invention, represented partially introduced in the body of a patient, ready for the administration of the solid formulation.

Figure 6 is a cross-sectional view according to line 6/6 of the figure .

Figure 7 is a view analogous to the figure , which shows the device after being pushed out of the solid form on the outside by a guide of the device, ready to be deposited in the organism of a patient.

Fig. 8 is a cross-sectional view according to line 8/8 of Fig. 7. Fig. 9 is a view in elevation analogous to Fig. 5 and lj showing the device after partial retraction of the needle, leaving the solid form in place in the body.

Figure 10 is a view analogous to Figure 9, showing the u u a and the piston interior thereto, completely reintroduced.

Figures 11 to 16 are similar views respectively to Figures 5 to 10, but in which the device is used to administer a semi-solid form.

Figures 17, 18 and 19 represent the in vitro re-smear of the dexamethasone inserts at a respective concentration of 10, 15 and 20%.

Figures 20, 21 and 22 represent the results of rat faxmacokinetic studies of dexamethasone inserts at a respective concentration of 10, 15 and 20% injected subcutaneously (A) and intraperitoneally (B).

Figures 23 and 24 represent the results of the pharmacokinetic studies of the solid form of 12.8 mg of lanreotide acetate respectively, on a dog, injected intramuscularly and on a healthy volunteer injected subcutaneously (A) and intramuscularly (B).

Figure 25 represents the pharmacokinetic study in the healthy volunteer, of the semisolid form of 40 mg of lanreotide injected intramuscularly.

Figure 26 represents the broadening profile of a formulation in the form of an acetate matrix of Triptorelin / PLGA (75:25) to 20% of the active principle.

Figure 27 shows the broadening profile of a formulation according to the invention of Triptorelin acetate / PLGA (75:25) 52 'of the active principle.

Figure 28 represents the profile of broadening of a mixture of Triptorelin pamoate (active ingredient) and PLGA (50:50) to 40% of the active principle.

Figure 29 represents the expansion profile ± n .vX.tr or a foxnuilación.do pamoat of triptorelin (active principle) and PLGA (50:50) to 52% of the active principle.

Figure 30 depicts photographs of triptorelin acetate formulations PLGA (75:25) to 20% of active principle, placed in a physiological medium in vi tro after one hour l.j., 2j, 3j, 7j and lOj; Figure 31 depicts photographs of triptorelin acetate formulations PLGA (75:25) to 52% active ingredient, placed in a physiological medium after a one-hour period, 2j, 3j, 7j and lOj; Figure 32 shows the re-stretching cuts in one of three ways according to the invention at 52%, 70% and 80% of active principle (Triptorelin acetate) at a dose of 9 mg; Figure 33 represents the re-shrinkage cuts in two ways according to the invention at 52% of active principle (Triptorelin acetate) at the dose of 9 mg and 6 mg; Figure 34 represents the evolution in the course of time of the rates or proportions of active principle that remain in the implants injected in the rat for the formulations at 52%, 70% and 80% of active principle (Triptorelin acetate); Figure 35 represents the evolution in the course of time of the absolute residual amount of active principle that remains in the implants injected in rat, for formulations at 52%, 70% and 80% active ingredient (Triptorelin acetate); Figure 36 represents the kinetics in the dog, of the plasma concentrations for an acetate formulation of Triptorelin / PLGA (75:25) at 20% of active principle and at the dose of 3 mg, and the monitoring of the therapeutic effect by the rate of testosterone Figure 37 shows the kinetics in the dog, of the plasma concentrations for an acetate formulation of Triptorelin / PLGA (75:25) at 52% of active principle and at the dose of 6 mg, and the monitoring of the therapeutic effect by the rate of testosterone Figure 38 represents the re-snipping cuts in vi ve in the dog, from an acetate formulation of Triptorelin / PLGA (75:25) to 70% active principle, and at a dose of 9 mg. { A) and the monitoring of the pharmaceutical effect by the rate of testosterone (B).

Figure 39 represents the re-stretching profiles in the dog, of a formulation of Triptorelin acetate / PLGA at 52% of active principle, and at a dose of 6 mg and at 70% of active principle and at a dose of 9 mg.

The device for administering a solid form 1 represented in FIG. 1 includes a tubular guide 2 containing a piston 3 which can push the solid form 1 contained in the end of the guide 2 towards the outside of the guide 2. The guide 2 and the piston 3 are provided, at their opposite ends, with respective collars 4, 5 for manual handling. Figure 2 illustrates a possible example of the invasive system in the body of a patient for putting into operation the delivery device of the solid form 1 of figure 1. The invasive system is in the example of figure 2, a needle hollow 6 containing a perforating mandrel 7, if access to the natural cavity of the organism used as a re-suspending reservoir of the solid formulation 1, requires a perforation of internal tissues. In figure 2 the invasive system is represented partially introduced in the internal part in the organism, in its part located to the right of the plane L, while its part located on the left is in the external part. If the access to the natural cavity of the organism does not require a perforation of the internal tissues, the invasive system can be an endoscope, a fibroscope or a catheter (not shown). The invasive system used is introduced into the body cavity (the breast of the face, esophagus, trachea, vessels, etc.), thanks to the drilling mandrel 7 in the case of a system such as that of figure 2. After that the mandrel 7 is withdrawn from the hollow needle 6 (or the endoscope, the catheter, etc.), and the administration device of figure 1 is inserted inside the hollow needle 6 (figure 3), until the collar 4 of the guide 2 is butted against the recurved annular end 8 of the hollow needle 6. It is then sufficient to push the piston 3 to eject the solid form 1 towards the exterior of the guide 2, since it does not oppose no tissue resistance to its movement (figure 4). In the second embodiment of the administration device of a solid form 9, illustrated in figures 5 to 10, this device is provided for the case of an injection of the device into a tissue, a wall or a mucosa from an internal invasive system already coupled in a cavity such as that shown in the drawings, but also from an invasive system coupled in an internal tissue. The invasive system comprises a tubular piece 50 partially engaged in the tissue through the surface P 'thereof, and a tubular guide 11 which can be a fibroscope or an endoscope, in which a catheter 12 can be mounted. The latter constitutes a guide of the administration device formed by a needle 13 and a piston 14 for extracting the solid form 9 in the tissue 17. The device includes two removable stops (10, 15) where the first 10 is a cap placed on the pusher 20 coaxial to the piston 14, this stop 10 and the pusher are truncated longitudinally (figure 8); the second is an equally truncated tubular part 15V (FIG. 6), interposed between the catheter 12 and the pusher 20. The injection of the administration device 13, 14, 9 can be obtained by moving the guide backwards, but is preferably carried out as it is illustrated in figures 7 to 10, in the following manner. The stop 15 is removed; the needle 13 is moved with the help of the pusher 20 containing the stop 10 (figure 7). If necessary and as illustrated in FIG. 7, especially in the case of the vessels, the needle 13 may have at its end a curved shape 13a obtained by releasing an elastic constraint of the needle 13 in the guide. Once released from the constraint of the guide, the curved end 13a facilitates the oblique injection of the solid form 9 into the wall or mucosa 17. This angle between the needle and the guide can be obtained or regulated, by any other commonly used mechanism. by these devices. Once the solid form 9 and the curved end 13 have been injected, the stop 10 of the pusher 20 is raised, and the needle 13 is retracted by pulling on the spurs 16 without displacement of the piston 14, in order to deposit the solid form 9 in the tissue 17 (figure 9). When the bevel 13b of the needle 13 reaches the end of the piston 14, the latter is withdrawn by the needle 13, leaving the solid form 9 in place, being maneuverable by traction on the pusher 20 and the spurs 16 (figure 10) .

The device of figures 5 to 10 may also allow the administration of a semi-solid. The administration device illustrated in Figures 11 to 16 is similar to that of Figures 5 to 10 and does not differ by the fact that the piston 14 acts on a non-solid form 18, resembling a microsyringe just in the tip of the injection device. Likewise, here the invasive system 9, 11, 12 can be coupled to an internal tissue 17. The method of administration consists here of injecting, by pushing out of the guide 9, 11, 12, the administration device consisting of the needle 13, the piston 14 and the semi-solid form 18. The needle 13 may optionally be curved as in the embodiment of FIGS. 5 through 10. The piston 14 is moved in the needle 13 to inject the semisolid 18 (fi gure 14) in the same manner as * in the embodiment of previous embodiment. The piston 14 and the needle 13 are finally removed together by reintroduction into the guide 11, 12 by pulling on the spurs 16 and on the pusher 20 (figures 15 and 16), the semi-solid form 18 is left in place in the tissue 17 which can then take a spherical or ellipsoid shape. The schemes of Figures 1 to 16 will allow to illustrate the administration procedures for different specific treatments described below. These different specific treatments according to the method of the invention, of solid or semi-solid local administration, involve the putting into operation of the procedure to be able to be applied and offer, in this way, certain novel therapeutic solutions which form part of the invention. These different examples illustrate the possible field of application of the invention, but do not constitute an exhaustive list of application of the procedure and are therefore not limiting. Among the possible treatments, according to the method of the invention, we can mention the anesthetic, analgesic, anti-inflammatory, cancer, cardiological, endocrinological, rheumatological treatments, etc., as well as the associated treatments. Among the endoscopic or radiological techniques capable of allowing this local treatment procedure, we can cite urology, gynecology, arthroscopy, ENT, bronchoscopy, gastrology, surgery with minimal invasion or even cardiovascular treatment. These procedures are novel because they use a medicinal formulation, delayed or not, solid or semisolid, of low volume (microliters). This formulation differs from existing local treatments in that it uses specific solid forms or liquid forms or suspension, in large volume. According to this procedure and with these non-liquid formulations, the formulation is not in its composition or in its form, studied for an accurate vectorization. On the contrary, the formulation is studied for a tool or device adapted for internal local administration, and that allows the injection or insertion at a distance i n if t u. The procedure may use, under this medical form and with these tools, the classic active principles, and mainly those that have already demonstrated their interest in local administration, or where local interest can be inferred from the action modality of the active principle, even if its use under this form does not yet exist, mainly because it could not be easily put into operation without the contribution of the invention. The following different examples illustrate the possibilities of this procedure. The procedure, the formulations and devices allow the administration in body cavities and intrat isular. Whatever the cavity or tissue, the advantage is being able to provide the formulation at the deposition site avoiding or diminishing the injuries to the tissues. These natural cavities can be used as reservoirs of the therapeutic product mainly if their anatomy allows the 'imprisonment' of the formulation., for example the administration in the natural cavities of the face and in the tissue. With certain active ingredients, all the objectives listed above are combined with this treatment (better local efficacy, dose reduction, increase in the duration of the action, improvement of comfort and compliance, reduction of side effects).

The intra- or peri-sinusial inserts or implants can transport the active principle to the mucus thanks to the mucosal ciliary flows or allow their local systemic diffusion by contact. You can also consider a general action by progressive diffusion to the digestive tract for medicines that need daily doses in small doses. Local corticosteroids are a good example of the local action product that presents disadvantages in general. However, existing local treatments (drops, sprays, etc.) are faced with anatomical arrangements to reach a precise target area such as the middle meatus (unicellular canal). Furthermore, with these existing treatments, the necessary persistence of active ingredient locally implies frequent applications. This therapeutic procedure, according to the invention, allows reaching this key area of nasosinus pathology. In addition to the maxillary sinuses, according to the needs, the ethmoidal cells, the sphenoid and frontal sinuses, the eardrum may be treated locally. The solid or semi-solid delayed release form, implanted or inserted will be in contact with that mucosa that secretes, and is covered with mucus that circulates from the meatus to the nasal cavities, and evacuated towards the cavity passing in contact with the tubar rim and of the eustachian tube. The method will allow, for example, to increase and maintain the concentration of the therapeutic product in the unicellular channel of the pathologies, in particular inflammatory diseases. If the non-liquid form of delayed release is deposited inside the breasts, a device will be used according to the scheme of Figure 1 that can be placed thanks to the classic tools of drainage of otorhinolaryngology (ENT, hollow needles, tubes) . It will also be possible to inject the formulation into the mucosa of the. nostrils, in the turbinates or in the tubar rim thanks to the devices present in figures 5 to 16. According to the deposit area and the formulation, the action will therefore be preferably external, intratissular or systemic. In ENT, it will be possible to treat in this way, for example, by means of cortico-therapy, nasosinus polyposis, allergic rhinitis or not, certain non-infectious otitis or sinusitis, etc. Apart from the inflammatory treatments, antibiotic, antiallergic, immunostimulatory treatments, etc. may be practiced. The treatments can also be combined. These treatments will have a local intensity. For example, dexamethasone phosphate pins can be manufactured in matrix to a degree of 15% in PLGA 50-50 according to the following steps: the raw materials are weighed, the two powders are blended, the extrusion is carried out, the dosage, conditioning and sterilization. The obtained implant may have a diameter greater than 2.4 mm for a length of 12.5 mm. This can be introduced in the interspace of the maxillary teeth with the aid of the device schematized by figure 1. This can also be implanted in the mucosa of the turbinate with the help of the device outlined in figures 5 to 10. Solid formulation is a delayed release formulation for 1 month that contains 7.5 mg of dexamethasone and that is re-thinned on average 0.5 mg / day with an -implant in each breast. For a chronic treatment, the intrasinusial use of a polymeric form (PLGA 75-25) of three months duration of action, or a form of deposit (Hydromed type) of 1 year duration of action may be considered. These delayed-release preparations may be useful in outpatients suffering, for example, from chronic nasal obstruction. Medical intervention for intrasinusal administration will resemble current ENT interventions, which can be practiced in the doctor's office; puncture with hollow needle with or without anesthesia. The access road can be prepared or not (meatotomy, ears, drained or others). The deep injection located in the turbinate or mucous membranes of the nasal slabs will be equally easy thanks to the device associated or not to the usual tools of endoscopic exploration. In the nostrils, the local administration is shallow. According to the bodily activities or the endoscopic surgery site, the distance between the external zone and the internal deposit may be even shorter or much larger. Delayed-release corticosteroids are already used in rheumatology. For example, a local intra or peri-articular injection with low-volume depot in a delayed manner (corticosteroids, anti-inflammatories) at the site of inflammation may be considered, according to the procedure.

(Tendinitis, bursitis, non-infectious arthritis, osteoarthritis, e c,). According to the procedure, an acular treatment can also be considered by injection-deposit in the mucosa under the eyelid. The small volume of the solid or semi-insular forms insensitive to this deposit and the injection will at the same time favor the delay effect and the local maintenance of the treatment more effectively than the deposit at the bottom of the conjunctival sac that is abundantly drained. This access is above all advantageous for chronic treatment with, for example, glaucoma with pilocarpine. Here, the injection is practically superficial and does not need tools outside the delivery device for the semi-solids or solids in microvolume. Similarly, according to the method of the invention, certain superficial tumors or skin problems can be treated by local, intra or hypodermic deposit.

For example, der opeptin (BIM 23014C) may be used in a delayed release form, semi-solid 20% in water and under a volume of 20 microliters, or at a total dose of 4 mg of Somatulin. The formulation can be injected at the level of the keloids or melanomas, thus creating a high and prolonged local concentration from a diffusion gradient zone at the site of the injection. In the case of certain solid tumors, the treatment may be associated with a cytotoxic one (Type 5FU or cisplatin) where the diffusion will be regulated by the same local form, and where the local concentration will be very high, with a very low total dose. . The same formulations can also be used in applications that are too deep and then associated with tools such as an SMA active catheter (shape memory alloy) or a fibroscope, and specialties such as interventional radiology or endoscopic or robotic surgery. For example, a more cytotoxic BIM23014 C delayed release form may be implanted intracerebrally, thanks to a skull access. The solid or semisolid forms according to the invention have the advantage, in relation to the local treatment Gliadel type, of being able to be applied without trepanation at the superficial level, but also in depth thanks to the neurosurgery is tereotaxic, endoscopic and robotic. Solid tumors treated, for example, with the forms of collagens, of matrix, can be treated in the same way with microdoses. Whatever the solid or semisolid form, the volume advantage allows vectorization at all sites, and avoids the risk of propagation entailed by the injection of a liquid volume of a few milliliters. However, with a solid or semi-solid form located more deeply in the body, after percutaneous transluminal angioplasty, restenosis can be treated at the intravascular site. With regard to the local treatment associated with the stent, the advantage of a treatment according to the procedure is not to be confronted with the dose limit of the vascular space and the surface of the device, and not to come into direct contact with the injured vascular wall, always allowing a strong local concentration in all the layers of the vessels and around, and a systemic effect if necessary. For example, angiopeptin alone or associated with heparin may be injected according to the scheme of Figures 5 to 16. Of course, any other active ingredient alone or associated may be injected, capable of avoiding the risks of restenosis and of favoring the result. With regard to this perivascular therapy, it is also possible to mention the possible use of semisolid forms in intravascular form, with the same objective as guimio-embolization by suspension, glue or gel, etc. The advantage here is to use a delayed release form whose volume (where the deposit area) is preset; which allows a better location of the occlusion in the vessels. The method and the devices according to the invention, associated with the fibroscope or any other direct or indirect image formation solution, allow the administration in the organic walls.

For example, since it is intervened at the level of the bladder via the urethra, the implant of a treatment can be considered (prophylaxis, antibiotic), in the thickness of the urethra. The tracheal artery and the bronchi (stents) can be accessed. Thus, according to the procedure, lung treatment can be considered, either by depositing a solid or semi-solid form in the lung or by implanting it in the mucosa, in the bronchi or in the trachea, according to the needs of local tolerance in the lungs. Intrapulmonary form, the solid form may be dispersed (powder or spheres). For example, to replace the preventive treatment with glucocort inhaled icosteroids in the light or moderate asthma of the recent diagnosis. It can be administered in the lung, through the bronchi, or in the wall that covers them or in those of the trachea, a form of delayed release of 0.4 mg of Budesonide daily, which will be secreted in the flow if the form is implanted, and which will be transported by moisture to the bottom of the pulmonary alveoli. This preventive treatment at a low dose without a secondary effect does not impose the observation problem mainly on the infant. A form of this type may have a duration of 1 to 3 months, or even longer if necessary. In the digestive tract, devices are also placed that allow the local administration of the treatment according to the invention. In the esophagus and in the stomach, the treatment of varicose veins can be considered from a local and injected into the wall. Similarly, tumors at this level that are very well individualized and are currently treated, for example with PDT (photochemotherapy), need after the injection of the photosensitive product, lighting by controlled introduction of a light diffuser locally. It is thus equally possible to directly inject the anticancer agents at this level in the solid or semi-solid form with the devices of the invention. One can then go even more to the area to be treated and avoid unnecessary injury to the peripheral tissues. The process of local administration of solid or semi-solid forms implies the prolonged presence of a local deposit of active principle. If necessary, add products that favor local tolerance at the deposit site to the formulation. For example, a small percentage of dexamethasone, indomethacin, heparin or any other active substance capable of avoiding an undesirable local effect may be added. The mucous membranes or walls are more permeable than the skin and there are systems of patches or bioadhesives that are applied on the mucous membranes (mainly oral or nasal) and that allow a systemic step of active principle. The drawback, however, is the non-persistence of the formulation upon contact with the mucosa. The prolonged presence of the administration according to the procedure at the local level of the mucous membranes or the internal walls, may therefore present an advantage in the search for a topical form with systemic activity. It will then be possible, according to the local treatment, to add to the formulation a small amount of any excipient capable of being a tissue penetration vector adapted to the active principles (organic solvents, surfactants, etc.). In this way, a deep local shape may advantageously be the site of a systemic diffusion in relation to the buccal or nasal mucosa, for example, which will not allow a prolonged topical deposit. The method according to the invention will also find its application during operations in surgery with minimal endoscopic invasion (laparoscopic, arthroscopic, etc.). The active ingredients used (local anesthetics, anticoagulants), can be administered in a solid or semi-solid form even here with the advantage of a microvolume in accordance with the reduced space of intervention, and the possibility of administration by means of instrumental access. Of course, any other form of delayed release, solid or semi-solid, and mainly PLGA implants, can be implanted thanks to the procedure. They can be used with other peptides, recombinant proteins (interferon), polyclonal or monoclonal antibodies, oligonucleotides or antisense polynucleotides, etc. The solid formulations or implants that can be used for a local administration of the active principle as described above, also agree, by their long and thin shape and small diameter, to other types of classical administrations, for example for systemic treatment by injection cutaneous or intramuscular. It has also been found in an unexpected way, that said solid formulations or implants, mainly by a PLGA excipient, having a very important concentration of active principle, as described above, whether soluble or insoluble, and especially those having a concentration of active principle comprised between 40 and 100%, and preferably greater than 50%, allows to obtain in vi vo, extremely prolonged re-stretching periods, from one month to three months and much more, and very regular re-suspending rates; is that constants, being made in the thin elongated shape, of diameter or lower transverse volume equal to 3 mm, for example 2.5 or 2 mm, even 1 mm or less, while this dissolves very quickly in vi tro, and so that these are used for a local action or not. Classically, such rates or proportions of active principle would be provided for instant or rapid release formulations.

The inventors have further discovered that, under a certain form, in homogenous distribution of the container, mainly PLGA, it would be possible to obtain a delayed release formulation according to a non-matrix mode in which the role played by the excipient would be different, which leads to more advantageous formulations whose characteristics are different, which distinguishes them clearly from the existing matrix forms. These non-matrix forms can be qualified as matrix forms of active principle, in which the excipient is dispersed. The matrix forms that put into operation the PLGA, used for this role can be either the dispersed forms (microparticles) or the non-dispersed forms (implants). In general, among the delayed-release formulations that have been developed, there are the so-called deposit forms and the atxic forms. The forms of 'deposit' use a barrier or diffusion membrane between the active principle and the medium that will serve to regulate the re-raising of this active principle.The drug can be inside the deposit in a solid, semi-solid or liquid form. This can be in solution or be dispersed in an excipient The membrane ensures by its porosity the controlled passage of the active principle towards the outside .. Among the systems of "deposit" for the soluble active principles, mention may be made of the hydrophilic poly membranes. -hydroxyethyl methacrylate crosslinked (pHEMA Hydro Med Sciences). The forms of 'deposit' allow to obtain a constant relativity level of the order of 0. The main drawback of these deposit techniques is the need to remove the biocompatible but non-biodegradable implant, after the release of the active principle. Matrix or matrix forms use a matrix or polymeric grid in which the active principle is imprisoned, to be released by diffusion, by erosion or by a combination of two phenomena: Non-biodegradable matrix forms, for example hydrophobic polymer implants Silicone type PDMS (Norplant, progestoid hormones), work only by diffusion.This mode of operation may involve a decreasing reenhancing of the order of 1 when the diffusion distance increases.The drawback here is even the need to remove the implant from Once the active substance has been released, the biodegradable matrix forms they do not present, on the contrary, this inconvenience since the polymeric matrix is eliminated by the organism. In addition, this elimination or erosion can participate in the regulation of the re-stretching of the active principle to obtain a constant re-stretching. The most widespread biodegradable matrix forms today use the polymers of lactic acid or glycolic acid, the copolymers of lactic acid and glycolic acid (PLGA) or their mixtures. Thus, the European patent EP 52510, whose content is incorporated by reference herein, describes a PLGA formulation with encapsulation of LHRH or analog, which may be a dispersed form of microcapsules made by coacervation, whose particularity is the distribution of the active ingredient in the center of the microcapsule, with a capsule of peripheral PLGA.

From the European patent EP 58481, the content of which is incorporated by reference herein, known peptide and PLGA formulations, dispersed or non-dispersed, such as implants, in which the active principle is uniformly distributed to the surface and using a specific PLGA so that the two phases of re-stretching (diffusion and degradation) overlap without there being any interruption in the re-suspension of the active principle. Numerous other documents deal with the use of PLGA in 1 to 1 delayed release conditions for peptides, but also for proteins and genes. The international patent WO 96/40072, whose content is incorporated by reference herein, thus describes a preparation of human growth hormone whose stability in the matrix and in the organic solvents used for microencapsulation is favored, and whose re-stretching is regulated by the PLGA matrix. The control procedure is based on the degradation of the polymer and the opening of the pores in the structure that this involves.

All the works carried out today agree to say that the delayed control procedure with PLGA can involve up to three phases of release: an initial phase that releases the active principle by diffusion, a latency phase where no spreading is involved, and a phase of re-stretching of the bound forms, correlated with the mass loss of the polymer, in all the formulations that use the PLGA, the control of the delayed effect is obtained by matrix mixing of the PLGA and the active principle, in order to allow the polymer matrix to play its role of re-screening barrier of the active principle, or a role in the physico-chemical interactions between the principle active and the polymeric matrix- In all cases, this mode of re-stretching requires a dispersion of the active principle in the biodegradable polymer matrix, in order to isolate the loading zones of active principle to the external medium, and to retain them in the matrix until the biodegradation of it releases the active principle that can then spread outwards.

This type of matrix delayed release form can be easily characterized by penetrating the water that will hydrate the dispersed areas of active principle, and cause an inflation of the formulation under the effect of hydration by the osmotic forces, due to the fact that Impossibility of active principle to escape from the matrix structure. These phases are intermixed more or less according to the PLGA formulations, allowing the degradation of the polymer, for example, the increase in the size of the cavities by which the active principle can diffuse. Apart from the PLGA and the polylactic acids mentioned above, there are very few injectable delayed release excipients. However, for example, certain polymers, gels and fatty substances can be mentioned. Polyanhydrides are for example polymers where the surface erosion process gives a re-stretching profile different from that of PLGA and more dependent on the shape of the PLGA deposit, which undergoes a global degradation. There are also certain delayed release formulations that use collagen or gelatin to obtain a re-stretching over time. Other formulations that use gel.es or hydrogels. Matrix Pharmaceutical®, for example, uses a viscous injectable gel (AccuSite® Intradose®). These formulations consisting of a matrix less susceptible to isolating ... the active principle of the medium or more rapidly eliminated, contain in general a per cent active ingredient. Other injectable excipients such as mannitol, polyethylene glycols, hyaluronic acid are also used, more often as additives to adjust the delayed release profile. In addition to matrix or deposit techniques, * other procedures nowadays allow obtaining a sufficiently long, regular and precise re-stretching. However, the case may be mentioned of the implants, totally or partially coated with a coating that serves as a barrier for the diffusion of the active principle In matrix formulations dispersed or not, a certain quantity of active principle is found on the surface of the formulation and not included in the polymer matrix In the dispersed matrix forms, for a given quantity of active ingredient, the surface active ingredient represents a high relative quantity in relation to the total of the active principle, by virtue of the importance of the surface in relation to the total volume To increase the load or "core load" (CL) of the active principle, it is therefore essential to inject a large volume of polymer matrix for a given volume of active principle. This constraint is even more penalizing for non-dispersed forms or implants since the volume of these for a high load amount, it needs the use of a hollow needle for the injection of the formulation. Obviously it has been sought to obtain formulations that have a higher CL, but the experience has demonstrated the existence of a phenomenon known under the name of percolation that results in a rapid re-screening of almost all of the active principle, due to the fact that the polymeric matrix, the loading zones are in contact with each other, not ensuring more to the polymer (PLGA) its matrix function. On the visual plane, this phenomenon is translated after hydration of the formulation, in a very short time release of the active principle, without inflating the formulation, the active principle being dragged towards the exterior of the formulation by the water that circulates in the polymer matrix. In the matrix delayed release forms, the PLGA type and its physicochemical characteristics are clearly precise and determine a feasibility domain. The direct influence of the PLGA on the resensanchamiento by his paper of matrix barrier, his paper in the relations (hydrophobic, hidrofilico, etc.) with the active principle and the influence of his degradation, imply a precise election of the PLGA. This relationship between PLGA and re-screening clearly appears, for example, in the duration of action of a formulation in the form of a matrix. In a formulation of this type, the duration of the re-stretching depends directly on the degradation time of the PLGA (second phase or rebound). In this way, the PLGAs will be selected according to the duration sought. For example, PLGA 50:50, depolymerized in one month, will be used to make a one-month formulation, while necessarily the three-month formulations would involve PLGA whose hydrolysis is more delayed, for example, PLGA 75:25. In the non-matrix formulations of the invention, the excipient, mainly the PLGA, does not influence re-stretching and it is, for example, possible to obtain re-smears in about three months with a single PLGA 50:50, which completely disappears from the body in 60 days or even forms of a month with a PLGA 75:25 that will not have already begun its hydrolysis until all the active principle is released. This is made possible by the fact that the proportion of PLGA is always lower in weight to the proportion of the active principle; which means that the continuous matrix is no longer the PLGA but the active principle, which will then rise for the assembly of the load, the external and mainly aqueous influence. It is then the active principle, mainly by the total amount, which will determine the duration of action.

The invention also has mainly aimed at such formulations, which are for systemic use or for a local treatment, with a classical dose or decreased for a local action. The invention more particularly aims at a delayed formulation for parenteral administration, comprising a homogeneous mixture of an active principle in the non-dispersed state, forming a continuous phase, where at least a part is in direct contact with the exchange surface of the formulation, and the external biological medium, and of a biocompatible, biodegradable excipient, in which the quantity of active principle is at least 50% by weight relative to the total weight of the formulation, and which has a re-tightening profile which is independent of the composition of the excipient, the molecular weight of the excipient, or the weight ratio active ingredient / excipient, the re-tightening profile being essentially and exclusively, dependent on the total amount of the active principle present in the formulation. In contrast to the known matrix forms that allow a "loading of active principle" in a limit of more than 30% of active principle, in order to avoid the percolation phenomena, the formulations of the invention contain more than 50% of principle active, which represents a decrease in the volume of the deposit of the order of 3 to 10 times in relation to the volume of the matrix forms.Thus, under the solid form, the formulations of the -invention- advantageously contain, both before and after after deposit, at least 50%, preferably at least 51%, advantageously at least 60%, and more advantageously at least 60%, and up to 99.999% by weight relative to the total weight of the formulation, the excipient representing less than 50%, preferably less than 49%, and more preferably less than 30% by weight in relation to the total weight of the formulation.Excipients are those traditionally used in the sustained release forms only. , mainly biodegradable polymers. Mention may be made, by way of example, of the polymers of the polylactic or polyglycolic acid type, or of the copolymers of the polylactic-polyglycolic acid type, or mixtures of these polymers and / or copolymers. The choice of the biocompatible, biodegradable polymer that forms the excipient is indistinct, without influencing it on the diffusion capacity of the active principle in the polymer. However, an injectable fatty substance may be used as an excipient of the formulations of the invention, such as a polymerized or saturated fatty acid such as Compritol®, or even excipients such as polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG). The viscosity of the polymers can vary considerably. This has shown that the low viscosity copolymers can be suitable for a so-called monophasic re-raising mode of active principle. European patents EP 58481 and 52510 cited above, but also European patents EP 21234 and EP 26599 whose contents are incorporated by reference herein, for example, have emphasized low viscosity polymers. These polymers can be suitable for the present invention (for example, viscosity lower than 0.5 dl / g in chloroform) The applicant, on the other hand, has shown in a French patent application already filed, FR 97 04 837 and in the following examples, that unexpectedly, high viscosity polymers, mainly higher than 0.5 or even 0.6 and which can go up to 1.2 dl / g, can be used in a preferential way to obtain a monophasic release.The DL-PLGA or the L-PLGA can be used , more preferably a DL-PLGA made from 70 to 80% DL-lactide and from 20 to 30% glycolide A PLGA synthesized from 25% DL-lactide to 25% glycolide is particularly well suited, but other copolymers can also be used, including PLGA 50-50. Polymers D or DL-lactide can also be used. PLGA can be hydrophilic or hydrophobic. Formulations of the invention can be made with the hydrophilic polymers. As a biocompatible biodegradable polymer, however, PLGA is preferred, in particular a hydrophilic PLGA advantageously having a chloroform viscosity at 1 g / 100 ml, greater than 0.6 dl / g. The duration of action of the delayed release formulation will be determined exclusively by the total amount of active ingredient it contains. By active principle in the non-dispersed state, it is understood that the different particles of active principle, present in the formulation, are mostly physically in contact with each other, and up to the surface of the formulation. It is therefore understood that by continuous phase, a distribution is understood such that all or most of the internal portions of the active principle are not separated from the surface except by the active principle, or a mixture of the active principle and a substance that does not opposes the diffusion or dissolution of the active principle. Advantageously, the mixture formed by the active principle and the excipient is homogeneous at all points. The delayed-release formulations according to the invention are further characterized by their difference in re-sharpening duration in vi tro and in vi. Thus, the formulations according to the invention placed in a physiological aqueous medium reenhanchan the active principle in a period less than seven days while the duration of ..action? N ..vi vo .is substantially higher than this period, advantageously at least one month, and preferably at least three months. Matrix or matrix formulations that comprise the same amount of active principle would, on the other hand, have a more prolonged rescreening in the same order of amplitude as the duration of re-stretching in vi. Surprisingly, despite a restructuring with a limited duration, the formulations according to the invention make it possible to obtain a much longer re-sharpening duration without regard to the duration of the re-stretching in vi tro. In addition, the resynchronization profile in vi is clearly different from that of the matrix forms of two phases, and will be of pseudo-order 0, corresponding to a constant diffusion of the active principle in the course of time. This re-tightening profile also constitutes an advantage, since it allows a release of the active principle from a constant level in the organism.

The formulations according to the invention are injected directly under their solid form in the absence of any liquid excipient; the high proportion of active principle thus constitutes a determining advantage, allowing to reduce the volume in an important way. Thus, in relation to a matrix form at 20% of active principle, the novel formulations according to the invention for example at 70% of the active principle, allow to reduce the volume by a factor of 3.5, or even multiply the dose by 3.5 for an identical volume. This means "that where, for a given active ingredient with a non-dispersed matrix formulation, a hollow needle would be necessary to inject an implant with a diameter greater than 1.8 mm it is sufficient with a standard intramuscular needle to deposit a microimplant of a formulation of according to the invention having less than 1 mm in diameter In addition, the re-stretching mode of the formulation of the invention, without absorption of fluids, or initial inflation of a matrix, constitutes a stability advantage for the active principle, which is The delayed release forms according to the invention are thus particularly advantageous for fragile active ingredients such as recombinant proteins, insofar as there is no limitation for the active principle, taking into account the nature of the biocompatible, biodegradable polymer, which forms the excipient, is "possible to incorporate into the formulations according to the invention active ingredients of high molecular weight, which are not "capable of diffusing in the matrix forms of the state of the art, mainly synthetic or natural macromolecules, mainly proteins, or their analogues. The invention thus allows the release over a prolonged period of fragile molecules, mainly of peptides and proteins, or their analogs. Among the active substances which can be used for the invention, there may be mentioned, in particular, proteins, peptides chosen, for example, from the group consisting of triptorelin acetate, lanreotide acetate, of a compound having an LH-RH activity such as triptorelin, • goserelin, leuprorelin, buserelin or its salts, an LH-RH antagonist, a GPIIb / IIIa antagonist, a compound that has an activity similar to a GPIIb / IIIa antagonist, erythropoietin (EPO) or one of its analogues, the different interferons α, interferon β or α, somatostatin, a somatostatin derivative as described in European patent EP 216171 whose content is incorporated by reference, an analog of somatostatin, as described in US application 5,552,520 (this patent includes a list of other patents that describe the somatostatin analogues which are incorporated by reference in the present application), the sulin, a growth hormone, a growth hormone-releasing factor (GRF), an epidermal growth factor (EGF), a melanocyte-stimulating hormone (MSH), a thyrotropin-releasing hormone (TRH) or a of its salts or derivatives, a thyroid stimulating hormone (TSH), a luteinizing hormone (LH), a thyroid stimulating hormone (TSH), a luteinizing hormone (LH), a follicle-stimulating hormone (FSH) a parathyroid hormone (PTH) or one of its derivatives, a lysozyme hydrochloride, a peptide fragment with N-terminal end (position 1-34) of the human hormone PTH, vasopressin or one of its derivatives, oxytocin, calcitonin, or a calcitonin derivative that has activity similar to that of calcitonin, glucagon, gastrin, secretin, pancreozimine, cholesistocinin, angiotensin, lactogen of the human placenta, human chorionic gonadotropin (HCG) , enkephalin , the colony stimulating factor (CSF), a derivative of enkephalin, endorphin, quorphine interleukins, for example interleukin 2, tufsin, thymopoietin, thymoestimline, tumor thymic factor (THF), serum thymic factor (FTS), a derivative of serum thymic factor (FTS), thymosin, thymic factor X, tumor necrosis factor (TNF), motilin, bombesin or one of its derivatives such as described in US Pat. No. 5,552,520 (this patent includes a list of other patents that describe the bombesin derivatives that are incorporated for reference to the present application), prolactin, neurotensin, dynorphin, caerulein, substance P, urokinase, asparaginase, bradykinin, kallikrein, nerve growth factor, a blood coagulation factor, polymyxin B, colistin, gramicin, bacitracin, a peptide stimulator of protein synthesis, an antagonist of endothelin, or one of its salts or derivatives, a vasoactive intestinal polypeptide (VIP), the adrenocorticotropic mona (ACTH), a platelet derived growth factor (PDGF), a bone morphogenetic protein (BPM), and a gastric inhibitory polypeptide (GIP).

Any other water-soluble active substance, or one of its salts or precursors, may also be used by the person skilled in the art if it deems it useful. Preferably, a water-soluble product, obtained by salification in the form of a cation, for example with acetic acid, will be used. However, an insoluble salt such as pamoate can be used. By peptide and / or protein, it is also understood the peptide and / or the protein itself as well as the fragments of these peptides or proteins, pharmacologically active. The water-soluble active substance used to manufacture the formulations or implants according to the invention can be, in particular, triptorelin acetate, lanreotide acetate, goserelin, leuprorelin, buserelin or their salts. The formulations also have the advantage of being able to be administered thanks to the use of the above device for the process according to the invention. The manufacturing processes of the formulations according to the invention involve mixing techniques, compression techniques, extrusion techniques in the molten state and molding techniques, conventionally used in the field of manufacturing galenic forms of delayed release. Another subject of the invention is a process for the preparation of a delayed release formulation according to the invention which includes the steps consisting of: - preparing a homogeneous mixture of active principle and excipient, containing at least 50% of the active principle; - compacting said mixture; and - extruding the compacted mixture in the molten state. An alternative procedure that is generally applied to matrix and non-matrix compositions, whatever the proportion of active ingredient and excipient, mainly PLGA, and intended both for local and non-local application and which does not need solvent, nor heating the mixture, comprises the steps consisting of: - elaborating a homogeneous mixture of active principle and excipient; subjecting the homogeneous mixture to a high compression, preferably to a force exceeding 1000 kg; - crush the tablets obtained; and put in a form adapted for administration. According to the first process, for example, the following procedure is carried out: The active ingredient (PA) and the PLGA are weighed to the proportions by weight of the mixture (for example 70% of PA and 30% of PLGA). Mix to obtain a homogeneous mixture, for example with the help of a Turbulat® mixer. The mixture is immediately loaded into a compression die or die. Compaction is then carried out, which corresponds in fact to a 'soft' compression which makes it possible to form blocks or pieces, for example, 13 mm in diameter by 5 mm thick, advantageously with an angled lever press. crushing of the pieces that can, for example, be carried out by means of sieving, cricketing with balls or with a blade crusher.This operation aims to improve the flow quality of the powder mixture during extrusion, necessary in this particular situation where the molten part represents less than 50% of the total.The mixture is extruded through a tap of the same diameter as the desired microimplants, the extrudate is recovered after the control of the diameter by laser beams (Keyence) on a vehicle of Stretching Preferably, the microimplants are calibrated by the extrusion nozzle and not by stretching.The extrudate is cut to the desired length in of the analytical control to obtain the microimplants that are immediately loaded in the injection devices that have gamma radiation (25 kGy).

According to the second procedure, for example, as follows: From a mixture of PA and PLGA, no more than simple compaction is carried out, but at a very high compaction of the mixture from the same constituents (excipients and active principle). This hyper compression can be obtained with a minimum force of one ton. The consequence of this hypercompression performed at an important diameter, for example 13 mm or more, is the transformation of this thermoplastic excipient (capable of melting at temperature) into a structure similar to that obtained in hot, ie transparent or vitrea, very different from the one obtained after the simple compaction. This operation takes place at room temperature, cold or even below 0 ° C. During this hypercompression, the glass transition to the plastic state of the excipient in the mix is obtained at a lower temperature. These hypercompressed immediately ground as described above, can be recompacted in the form of microcomprimidos equivalent to the previous microimplants. This technique, particularly adapted to the forms of delayed release of PLGA, allows without temperature, neither solvent nor manufacturing vehicles, the obtaining of galenic forms particularly interesting to preserve the integrity of the active principle, mainly for fragile molecules such as proteins. recombinants. This procedure is equally interesting for the manufacture of matrix forms. { that do not comprise more than 50% of active principle) than those that are dispersed or not dispersed. For the matrix forms, PLGA compression leads to a matrix structure equivalent to that obtained by melting the excipient hot. Hypercomprimings after grinding can be used directly under a dispersed form of microparticles. The dispersed form may be injected directly after loading into a needle of a device as described above, or be injected in suspension in a liquid medium (as for microspheres, for example). One of the possible aspects for the solid form is that of an elongated cylinder. The formulation as defined above may, preferably, have the shapes and dimensions defined above in relation to the described local administration device. Advantageously, the formulation is in the form of a cylinder with a diameter of less than 3 mm, preferably less than 1 mm and less than 50 mm in length, preferably less than 30 m, the total volume being less than 50 mm3, preferably at 20 m?; . Another object of the invention is a method of therapeutic treatment comprising the injection to a patient in need of a treatment involving the release of an active ingredient, over a prolonged period of time, of a formulation according to the invention. The formulation can be advantageously injected by subcutaneous or intramuscular route.

This can be done by any adapted means, mainly a standard injection needle having a diameter of less than 1 mm. Another object of the invention is the use of a solid formulation as defined above for obtaining a delayed effect. The following examples illustrate the invention: EXAMPLE 1: Intra-sinusial insert of dexamethasone phosphate, PLGA form The manufacturing of dexamethasone phosphate inserts is carried out according to the following phases: - the raw materials are weighed, mixed, the first extrusion is carried out, crushed and sieved, dosing and conditioning are carried out, all under flows laminar class A in a class D white room, and finally, sterilization is performed.

For a batch, for example 38.25 g of lactide-coglycolide copolymer PLGA (50:50) can be weighed and 6.75 g disodium dexamethasone phosphate 21, crushed to less than 100 micrometers, added. The powder will be mixed thanks to the three-dimensional motion mixer and to the first extrusion, controlling the quality of the mixture (% PA). After extrusion, the mixture is crushed and extruded again in rings of 2 to 2.5 mm in diameter where the homogeneity is verified (% PA, PA content / length). The weight of the insert, necessary for the obtaining a dose equivalent to 7.5 mg of dexamethasone phosphate. The cylinders are cut to lengths corresponding to the necessary weight and individually conditioned in the devices that contain them, which will be irradiated with gamma rays (25 kGy). The device can be directly used inside a hollow needle 3 mm in diameter and 10 cm in length according to the schemes of figures 5 to 10. Before testing the maxillary sinus, the effectiveness of these inserts, by For example, in chronic nasal occlusion, resentment is verified in vi tro ein vi ve on a model capable of being predictive of the duration of the insert. In vi tro, re-tightening is followed by the dosage of PA in HPLC in an isoponic medium in which the insert is driven. Figures 17, 18 and 19 represent in vitro re-smears for very different concentrations of PA, respectively of 10, 15 and 20%. In vi voj a rat model is used.

The insert is administered either subcutaneously or intraperitoneally and re-stretching in * one month is evaluated by omission by dosing the amount of PA remaining in the insert after the animals are sacrificed, and taking samples at determined times. Figures 20, 21 and 22 represent the results of this in vivo control at three percentages subcutaneously. (A) and in 'intraperitoneal form (B) EXAMPLE 2: Transluminal implant of Lanreotide Acetate, solid form Implants or cylinders have been manufactured 0. 75 mm in diameter and 30 mm in length. These contain 12.80 mg of Lanreotide (BIM2301-4C) for a 90% composition of Lanreotide Acetate and 10% Mannitol. For a batch size of 200 units or 4.5 g of solid (Lanreotide-Mannitol Acetate), manufacturing includes the following stages: weighing, connection, vacuum, hydration, mixing, extrusion, drying, the conditioning and irradiation. The weighing corresponds to the volume of the water-toluene solution, on the one hand, in a syringe, and to the Somatulina acetate powder in another. The connection is the association of two syringes through a 3-way ball valve. The vacuum is then made inside the PA powder. Hydration is obtained by contacting the vacuum powder of the Mannitol solution.

The mixing is carried out by means of a drive to and from the pistons of two syringes. The extrusion corresponds subsequently to the control of homogeneity by HPLC to the realization of a ring through a die adapted to the desired diameter. This extrusion is obtained also by operating with a piston motor of the syringe. The drying is carried out after or before cutting the cylinders. This consists of evaporating the water from the paste mixture to obtain the dry cylinder. The conditioning consists in introducing the cylinder inside the injection needle in a device of 1 mm in diameter, as shown in figure 5. Radiation sterilization, after packaging of the device, is carried out with 25 kGy. This device can be injected at the local level to deposit the Lanreotide cylinder before or after the angioplasty, like a stent, by the lumen of the catheter. The local retardation effect of this formulation has been previously evaluated intramuscularly (i.m.) in the dog, and intramuscularly and subcutaneously (s.c.) in man.

Figure 23 represents the result of a pharmacokinetics in the dog, of the solid form of 12.8 mg of Lanreotide in intramuscular form. Figure 24 represents the results of a kinetics in a healthy volunteer, in subcutaneous ioxma (A) and in intramuscular form (B). The results obtained allow us to consider a delayed release effect, prolonged at the local level of the angioplasty, with a high local concentration over this period.

EXAMPLE 3- Semi-solid deposit of Lanreotide Acetate Lanreotide acetate forms a slow-release, injectable, slow-release paste or semi-solid with water. The delay effect is obtained by deposit, directly from the active principle. This delay effect is modulable depending on the percentage. The duration of action is therefore directly proportional to the erosion or elimination of this semi-solid deposit. It is possible to associate any other active principle where the combined local effect to the Lanreotide will be sought. The duration of action of the active ingredient (s) may be evaluated by the single pharmacokinetics of the Lanreotide. The semi-solid is manufactured according to a procedure similar to that of the solid of Example 2 without Mannitol. The extrusion, the drying and the rearrangement or conditioning, are replaced by a distribution. For example, for 200 units, 40 g of Lanreotide Acetate will be prepared in the form of a month 35% of Lanreotide Acetate, 65% of water and for the injected doses of 40 mg of PA. The manufacturing stages are weighing, connection, vacuum, hydration, mixing, distribution and irradiation. The distribution is given in a volumetric filling of the injection device (Figures 11 to 16), for example, by rotary piston from the mixing syringe. This semisolid formulation forms the object of a clinical trial in a healthy volunteer, intramuscularly (figure 25). Thus, a local form can be obtained in this way in a month. The concentration and amount of paste will determine the duration and intensity of local diffusion.

EXAMPLE 4: Comparison of a matrix form to 20% of active principle with a non-matrix form at 52% A very soluble salt of Triptorelin acetate (AT) is mixed with a PLGA (75:25) of molecular weight greater than 100,000 and of inherent viscosity equal to 1 dl / g in chloroform, which does not undergo hydrolysis due to mass loss, able to control a matrix release only after one month. 20% mixtures are prepared in this way (before percolation) and 52% by weight of the active ingredient in the PLGA. These mixtures are extruded in order to form implants where re-scaling is verified at 37 ° C in 10 ml of physiological saline and without agitation. The implants with 20% of active principle do not release more than 4% of the total dose in two days and only 6.7% in 36 days, before the loss of mass of the polymer that involves the release of the active principle between the day 36 and day 60 (figure 26). The implants with 52% of active principle release 66% of the total dose in two days, and more than 90% in a week (figure 27).

EXAMPLE 5: Comparison of a matrix and non-matrix form with an insoluble salt of Triptorelin (Triptorelin pamoate).

Two formulations of pamoate of Triptorelin and PLGA (50:50) are prepared, the first at 40% and the second at 52% of active principle. - The release of these two formulations is compared in a re-annealing model.

(The weak solubility of the active ingredients requires a suspension volume of 100 ml). In spite of the insolubility of the active principle, a re-expansion of the matrix type with 40% is observed (figure 28). At 52% (figure 29), the re-stretching is already essentially independent of the matrix.

The functioning in vi tro of the active principle in relation to PLGA in matrix and not matrix mode does not depend on the solubility of its salt.

EXAMPLE 6: Macroscopic difference of mode of action before the matrix formulation and the non-matrix form The matrix preparation of Example 4, PLGA 75: 25-acetate of Triptorelin (80% - ~ 20%) in a non-dispersed form after ten days in a physiological medium, contains practically all its active principle; it has a translucent appearance with an increase in diameter and a decrease in length in relation to time 0 (figure 30), which demonstrates a constraint of the PLGA matrix. The non-matrix preparation of PLGA 72:25 Triptorelin acetate (48% - 52%) under the same conditions after ten days, is practically completely empty of the active ingredient. This has not undergone a change in diameter or length (Figure 31).

The active principle is therefore free of the non-matrix skeleton of PLGA. The active principle is in this case, free of any physicochemical constraint with the polymer. The PLGA remains without change in the course of re-raising the active principle.

EXAMPLE 7: Comparison between the non-matrix form (52% Triptorelin acetate) and non-matrix forms at 70% and 80% Triptorelin acetate.

In the same re-anchoring model and in example 4, three matrix forms have been compared to the same dose of 9 mg. The results of re-stretching in one day (Figure 32) demonstrate a similarity of operation of these three formulations. The value of reenhancing achieved in vi tro is therefore not proportional to C.L. This demonstrates the role of the active principle and its total quantity in the functioning of non-matrix forms.

EXAMPLE 8: Comparison of the release of the non-matrix forms to 52% at the dose of 6 mg and 9 mg Two formulations have been developed using the same PLGA 75:25 molecular weight higher than 100,000, with a C.L. of 52% Triptorelin acetate (AT). These two formulations have been controlled in vi tro, the first at the dose of 9 mg (52% AT to 9 mg) and the second at the dose of 6 mg (52% AT at 6 mg). The results (figure 33) demonstrate a kinetic difference of .reensanda in relation to the dose difference of active principle.

EXAMPLE 9: Comparison of matrix forms to 52%, 70% and 80% of the active substance (Triptorelin acetate) in a rat in vitro test Two lots of implants with 52% of active principle, a batch of implant with 70% of active principle and an implant batch of 80% of active principle have been injected subcutaneously into four groups of 12 rats: 4 animals of each group have been slaughtered on days 1, 4 and 19. The implants have been recovered and dosed on HPLC to know the residual amounts of the active principle. The results of figure 34 express between day 0 and day 19 the residual rate of the implants, in percent. An evident parallelism is observed in the reduction of this percentage between the forms to 52%, 70% or 80%. Figure 35 represents the evolution of the residual amount of the pure active ingredient in mg. It is noted that, contrary to the results, after 19 days, there is an average of an important and equivalent amount of active principle in implants at 52% and in implants at 70% and 80%. Plasma samples of these animals have been taken before slaughter, and this result has been confirmed by an analysis of RIA (Radio. Immunoassay).

EXAMPLE 10: Pharmacokinetic result of a matrix formulation (20% of active principle) and of a non-matrix formulation (52% of active ingredient) in the dog The formulations at 20% Triptorelin acetate and at 52% have been injected intramuscularly in two series to six dogs, at respective total doses of 3 and 6 mg of pure Triptorelin and the kinetics have been followed by analysis of. plasma triglycosides, as well as the dynamic efficacy of the active principle with testosterone levels (figures 36 and 37). The results show a reenhancing activity over three months at least in both cases. The kinetics of the 20% form show a classic profile (with ico and rebound.). The kinetics of the form at 52% is not comparable to those of the classic PLGA forms, but of pseudo-ordinance at 0 without peak or bounce.

EXAMPLE 11 Pharmacokinetic results of a non-matrix formulation with 70% of active principle in dogs.

A formulation using the same PLGA has been prepared with the same active principle as the formulation with 52% of active principle (example 10), with 70% and 30% of PLGA. This formulation has been injected intramuscularly in dogs at the total dose of 9 mg of pure Triptorelin. The kinetics was followed by RIA analysis of the plasma samples (Figure 38A) as well as the dynamic efficacy of the active principle with the rate or proportion of testosterone (figure * 38B). The results show either a re-stretching activity on B I minus tx.es .meses as for the 52% form of active principle, with the only difference being a higher re-raising level by varying the total dose. The variation of the load between 52% and 70% does not influence either the duration or the profile and the level of re-tightening depends on the total dose injected (Figure 39).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (72)

1. The use, for the implant or insertion of a solid or semi-solid formulation, destined to be placed in a precise deposit site of an organism, containing at least one active principle, said formulation being of solid or semi-solid consistency, such that it can be persist for a certain period of time at the site, and containing a dose of active ingredient limited for a treatment in a target area of the organism, of a device comprising a part placed inside the body of the patient, with the means of conditioning of the solid or semi-solid form, positioning means allowing these conditioning means to be brought to the deposit site, injection or insertion means in this deposit site, and retraction means after injection or insertion, and a part left outside with the means of activating the functions of the device.

2. The use according to claim 1, characterized in that the means for conditioning the solid or semi-solid form are placed suddenly on the end of the device intended to be taken to the storage site.

3. The use according to any of claims 1 and 2, characterized in that the conditioning means are arranged to allow the solid or semi-solid formulation to have a thin and elongated shape, mainly cylindrical.

4. The use according to claim 3, wherein the form of 2.a. The formulation is substantially cylindrical, characterized in that the diameter of the conditioning means is such that the shape of the formulation has a diameter comprised between 0.1 and 2 to 3 millimeters.

5. The use according to claim 4, characterized in that the conditioning means are arranged to allow the solid or semi-solid formulation to have a minimum length / diameter ratio of 10.

6. Use according to any one of claims 1 to 5, characterized in that the means for conditioning the solid or semi-solid forms are also the means for positioning and injection.

7. The use according to any of claims 3 to 6, characterized in that the device comprises a piston inside a needle, which can be operated in a hollow needle and / or in a catheter.

8. The use according to any of claims 3 to 6, characterized in that the conditioning, placement, and injection means includes a needle.

9. The use according to claim 8, characterized in that the needle once actuated can be oriented relative to the device by pre-forming or pre-stretching or by mechanical means.

10. The use according to claim 8, characterized in that the external activation means of the device allow, sequentially, the injection of the needle, the advance of the piston, h.as the bevel of the needle, to deposit the solid form or semisolid, the retraction of the needle around the piston, the combined retraction of the needle and the piston.

11. The use according to claim 10, characterized in that the sequential actions of the device from the external means are controlled remotely and in order with the help of two removable stops where the first is placed on a pusher coaxial to the piston, and the second is a tubular piece sandwiched between the guide and the pusher.

12. A formulation "intended to be placed in a precise deposition site in an organism, containing at least one active ingredient, the formulation is of solid or semi-solid consistency, such that it may persist for a certain length of time at the site, and containing a dose of active ingredient limited for a treatment in the target area of the organism, and having a shape that makes it susceptible to being placed by a device according to any of claims 1 to 11.

13. The formulation according to claim 12, characterized in that this is a delayed release formulation.

14. The iormulation according to any of claims 12 and 13, characterized in that it contains a low dose of active principle in relation to the usual dose for a systemic treatment of the active principle considered.

15. The formulation according to any of claims 12 to 14, characterized in that it has a thin and elongated shape, mainly cylindrical.

16. The formulation according to claim 15, characterized in that it has a diameter comprised between 0.1 and 2 to 3 mm.

17. The formulation according to any of claims 15 and 16, characterized in that the shape has a minimum length / diameter ratio of 10.

18. The formulation according to any of claims 12 to 17, characterized in that it is solid in nature, capable of being deformed by being constrained in a device according to any of claims 1 to 11, to recover its shape i n if t u.

19. The formulation according to any of claims 12 to 18, characterized in that it is placed for the re-stretching of the active principle at the site, in an anatomical cavity in which it has been introduced.

20. The formulation according to claim 19, characterized in that it has a studied form to be able to be imprisoned in an anatomical cavity of the organism avoiding the displacement or elimination of the formulation.

21. The formulation * according to claim 20, characterized in that it is pre-constrained in the conditioning means and recovers a non-rectilinear shape once placed in its deposit site.

22. The formulation according to claim 20, characterized in that the length and diameter of the formulation are proportioned to prevent its elimination or displacement.

23. The formulation according to any of claims 12 to 22, characterized in that the formulation and the active principle that it contains are provided so that the re-smearing of active principle takes place in the secretions of a mucosa.

24. The formulation according to any of claims 19 to 23, characterized in that the cavity or mucosa is a cavity or mucosa of the facial or ENT-

25. The formulation according to claim 23, characterized in that the mucosa is a tracheo-pulmonary mucosa.

26. The formulation according to claim 23, characterized in that the mucosa is the bucco-esophageal mucosa.

27. The formulation according to any of claims 23 to 26, characterized in that the formulation is provided to be placed on the mucosal surface, so that the active principle is transported by the mucus.

28. The formulation according to any of claims 23 to 26, characterized in that the formulation is provided to be placed inside the mucosa.

29. The formulation according to claim 28, characterized in that the formulation and the active principle that it contains are provided for an injection into the subpalpebral mucosa.

30. The formulation according to any of claims 19 to 29, characterized in that it comprises a corticoid adapted to the treatment, in a cavity, cavity or mucous wall, of nasosinus polyposis, allergic rhinitis or not, otitis or sinusitis not infectious, by introduction into the maxillary, phenoid or frontal sinus, the nasal mucosa, the ethmoidal cells or the eardrum.

31. The formulation according to any of claims 12 to 18, characterized in that the formulation and the active principle that it contains are provided for an introduction in or around the vascular wall by intra or trans-luminal injection.

32. The formulation according to claim 31, characterized in that it is usable mainly after transluminal percutaneous angioplasty, which comprises an active principle for the prevention or treatment of restenosis.

33. The formulation according to claim 32, characterized in that it contains angiopeptin alone. or associated with another active principle, mainly heparin.

34. The formulation according to any of claims 12 to 18, characterized in that the formulation and the active principle that it contains are provided to be introduced into or under a tumor tissue for an antitumor action.

35. The formulation according to claim 34, characterized in that the active principle comprises a photosensitive product.

36 / The formulation according to any of claims 12 to 18, characterized in that the formulation and the active principle that it contains are provided for an intra or peri-articular injection.

37. The formulation according to any of the claims. 12 to * 37, characterized in that it contains an anti-inflammatory active principle.

38. The formulation according to any of claims 12 to 36, characterized in that it contains a high concentration of active principle comprised between 20% and 100%.

39. The formulation according to claim 38, characterized by a concentration of active principle comprised between 40 and 100%.

40. The formulation according to claim 39, characterized by a concentration of active principle comprised between 50 and 100%.

41. - The delayed release formulation according to any of claims 12 to 40, characterized in that the active principle is associated with a copolymeric excipient of polylactic ido-glycolide (PLGA).

42. The solid formulation according to claim 41, characterized in that it is prepared in the form of an implant.

43. The formulation according to any of claims 12 to 42, characterized in that it contains an active principle of a peptide or protein nature.

. 44. The solid formulation of delayed release, intended to be placed in an organism, containing at least one active ingredient and a biodegradable excipient, characterized in that the excipient is a copolymer of polylactide-glycolide (PLGA) and because the concentration of active is between 40% and 100%.

45. The delayed release formulation according to claim 44, characterized in that the concentration of active principle is between 50 and 100%.

46. The delayed release formulation according to any of claims 44 and 45, characterized in that it has a thin and elongated shape with a diameter not exceeding 3 mm.

47. The formulation of delayed release of. according to claim 46, characterized by • having a diameter not exceeding 2 mm.

48. The delayed release formulation according to claim 46, characterized in that it has a diameter of the order of 0.1 mm.

49. The delayed release formulation according to any of claims 44 to 48, characterized in that it has a minimum length / diameter ratio of 10,

50. The delayed release formulation according to any of claims 44 to 49, characterized in that it contains an active ingredient of peptide or protein nature.

51. A set for the implant and the insertion of a solid or semi-solid formulation, containing an active ingredient, according to any of claims 12 to 50, in a precise deposit site of the organism, characterized in that it comprises a device defined in accordance with with any of claims 1 to 11 and, in said device, a formulation to be administered, contained in the conditioning means.

52. The assembly according to claim 51, characterized in that it is provided to be inserted inside a hollow needle.

53. The assembly according to claim 51, characterized in that it is provided to be inserted inside a catheter.

54. The assembly according to claim 51, characterized in that it is provided to be inserted inside an endoscope

55. The assembly according to claim 51, characterized in that it is provided to be inserted into an instrument adapted for a surgical approach.

56. The use of an active ingredient for the realization of a formulation according to any of claims 12 'to 50.

57. A solid delayed release formulation for parenteral administration, characterized in that it comprises a homogeneous mixture of an active principle in the non-dispersed state, which forms a continuous phase where at least a part is in direct contact with the exchange surface of the formulation and of the external biological medium, and of a biocompatible biodegradable excipient, in which the quantity of active principle is at least 50% by weight relative to the total weight of the formulation, and which has a re-stretching profile independent of the composition of the excipient , of the molecular weight of the excipient or of the weight ratio active ingredient / excipient, the re-tightening profile being essentially exclusively dependent on the total amount of the active principle present in the formulation.

58. The delayed release formulation according to claim 57, characterized in that the biocompatible, biodegradable excipient is a polymer or copolymer of lactic and / or glycolic acid or a mixture of polymers and / or copolymers of lactic and / or glycolic acid .

59. The delayed release formulation according to claim 58, characterized in that the biodegradable biocompatible polymer is a copolymer of lactic acid and glycolic acid (PLGA).

60. The delayed release formulation according to any of claims 57 to 59, characterized in that the biodegradable biocompatible polymer is a copolymer of lactic and glycolic acid having "an intrinsic viscosity in chloroform at 1 g .. for 100 ml, higher than 0.6 gl / g.

61. The delayed release formulation according to claim 59 or claim 60, characterized in that the copolymer of lactic acid and glycolic acid is hydrophilic in nature.

62. The delayed release formulation according to any one of claims 57 to 60, characterized in that, when it is placed in a liquid physiological medium, it releases almost all of the active principle in less than a week and, when it is placed in vi subcutaneously or intramuscularly, it presents a re-raising of the active principle in a period substantially longer than one week.

63. The delayed release formulation according to any of claims 57 to 62, characterized in that it comprises a homogeneous mixture of active principle and excipient at all points.

64. The delayed release formulation according to any of claims 57 to 63, characterized in that the re-stretching is carried out in a single phase of diffusion of the active principle

65. The delayed release formulation according to any of claims 57 to 64, characterized in that the active principle represents at least 51%, advantageously at least 60%, preferably at least 70% and up to 99.999% by weight relative to the weight total of the formulation, the excipient representing less than 50%, preferably less than 49%, and more advantageously less than 30% by weight relative to the total weight of the formulation.

66. The delayed release formulation according to any of claims 57 to 67, characterized in that the active principle is a peptide, a peptide analog or a protein, mainly LHRH or an analogue of LHRH, mainly Triptorelin.

67. The delayed release formulation according to any of claims 57 to 66, characterized in that it is in the cylindrical form and has a diameter less than or equal to 3 mm, preferably less than 1 mm.

68. The delayed release formulation according to any of claims 57 to 67, characterized in that it is for injection by intramuscular or subcutaneous route.

69. The delayed release formulation according to any of claims 57 to 68, characterized in that it is in the form of an implant.

70. The use of a delayed-release formulation according to any of claims 57 to 69, for the preparation of a medicament intended for a parenteral injection under the anhydrous form.

71. The method of preparing a delayed release formulation according to any of claims 57 to 69 ,. characterized in that it includes' the steps consisting of: - preparing a homogeneous mixture of active principle and excipient, containing at least 50% of active principle; - compacting said mixture; and - extruding the compacted mixture in the molten state.

72. The process for preparing a formulation according to any of claims 12 to 50 and 57 to 69, characterized in that it includes the steps * consisting of: - preparing a homogeneous mixture of active principle and excipient, which contains at least 50% active ingredient; subjecting the homogeneous mixture to a high compression; - crush the tablets obtained; and put it in a form adapted to the administration. SUMMARY OF THE INVENTION The object of the invention is the use, for the implant or the insertion of a solid (1, 9) or semi-solid (18) formulation, intended to be placed in a precise deposit site (T) of an organism, containing at least an active ingredient, said formulation being of solid or semi-solid consistency, such that it may persist for a certain duration at the site, and that it contains a dose of active substance limited for a treatment in a target area in the organism, of a device that comprises a part placed inside the body of the patient, with means for conditioning the solid or semi-solid form, positioning means allowing these conditioning means to be brought to the deposit site, injection or insertion means in this deposit site, and means of retraction after injection or insertion, and a part left outside with the means for activating the functions of the device. The invention also aims at a solid delayed release formulation for parenteral administration, comprising a homogeneous mixture of an active principle in the non-dispersed state, and a biocompatible, biodegradable excipient, in which the quantity of active principle is less than 50% by weight.