FR2770134A1 - Device for accurate parenteral implantation of solid formulation - Google Patents

Abstract

The use of a specific device is claimed for implantation or insertion of a solid or semi-solid formulation (F), containing an active ingredient (A), into an organism at a precise receptor site. The device includes a component which is inserted into the body of the patient, can store (F) and can position (F) the precise site where it is required. The injection or insertion of (F) can be controlled externally. The device is withdrawn after (A) has been so placed. Formulations for use in the device are also claimed, specifically containing at least 50% of (A) mixed with a polylactide-glycolide copolymer (PGLA).

Description

 The advantages of the use of a treatment or of a local administration are known when the active principle (AP) is thus preferably oriented towards its site of action. It has been proven, on the other hand, that the oral or parenteral administration of a medicament and its systemic distribution may, in certain cases, not give a satisfactory result.

 Aside from improving local efficacy, local treatment compared to general treatment makes it possible above all to reduce the doses and side effects, in particular linked to PA, in sites of the body where its presence is either unnecessary or harmful.

 The local administration of a drug therefore makes it possible to improve the therapeutic index of the product while reducing, where appropriate, its general toxicity and the risks of systemic effects.

 Topical skin, eye, nasal sinus, pulmonary, gastric or rectal forms were the first non-parenteral forms to use local administration. When the site for depositing the formulation is more difficult to access or requires an invasive form and when the treatment must be repeated or even more chronic, even if the advantage of targeting is known, in practice, its use is hampered by the difficulty or even the discomfort of a repeated therapeutic gesture.

 We know, on the other hand, the advantages of using a prolonged or delayed formulation which allows, in a single administration, to give the patient his medicine for several days, several weeks or several months.

 This delayed form improves compliance since compliance with treatment no longer depends on the patient or the nursing staff but on preparation. This prolonged effect therefore improves the comfort of the patient who is no longer required to his treatment, and who thus receives a regular dose permanently and not variable depending on the medication taken.

 The development of late forms has led specialists to consider their local use, particularly in the case mentioned above where the depot site is more difficult to access. The delay form therefore avoids having to repeat administrations or, even more, the surgical gesture. We can then expect significant local concentrations of the drug over an extended period of time without significant systemic doses, therefore, with fewer side effects. This solution is more particularly useful for products that are rapidly metabolized or have a short half-life when administered systemically.

 Within the body, targeted and prolonged treatments are thus envisaged, such as intra or peri-articular injections of delayed corticosteroids. Cancers and in particular solid tumors are prime candidates for these local forms which make it possible to reduce the total injected doses of cytotoxic or antineoplastic, while 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 offers a collagen-based delayed preparation which can be injected intra-tumor (IntraDose CDDP
Cisplatin). This formulation is administered in cancers or skin lesions using a 3 cc syringe and possibly a biopsy needle for less accessible areas. Under a viscous liquid volume of up to 2 ml, it is therefore limited to sites that are relatively easy at first (peripheral) or to post-surgical treatments.

 We can, for example, cite the MITSUI patent (FR 2 497 661; JP 562 737) which describes a polyactide-coglycolide (PLGA) form in stick or needle for local activity, allowing its direct implantation in an area or an organ to inside the body, for example a tumor area before or after excision.

 The Gliadel form (Guilford) describes a formulation based on polyanhydride in the form of a host containing Carmustine 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 targeted treatments inside the body are still often linked to heavy surgical procedures. They benefit from the prolonged effect of the formulation but cannot be easily repeated.

 We also carry out chemo-embolization interventions which consist in injecting, into vessels, suspensions (microspheres), gels or glues with their solvent, which can obstruct a nourishing vascular path and release a PA at the level of a tumor. The occlusion is obtained by deposition after departure from the injection vehicle. This technique uses percutaneous transluminal angioplasty catheters to introduce the fluid into the vessel.

 The local use of delay forms is also envisaged in certain body cavities and in more accessible sites of the organism.

 The Ocusert system (Alza) is a flexible, oval ocular insert which constitutes a delay reservoir device comprising a membrane made of ethylene vinyl acetate polymer and which may contain, for example, pilocarpine.

 This device is placed in the conjunctival sac and releases its product according to a zero order profile. The delay form makes it possible 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 better thanks to the use of a delayed form compared to the drops locally.

 US Patent No. 3,545,439 describes an intravaginal delay form consisting of a ring made with a silicone elastomer and which releases a drug for several weeks.

 In this case, the local delay administration on the vaginal mucosa also makes it possible, according to the P.A., to obtain a general effect (contraception).

 The medical device described by Bukh Meditee (PCT international patent application no. W089 / 03232) allows the introduction into a body cavity of a matrixed delayed form made of a substance poorly penetrable by water and containing a P.A.

The delay form associated with the device thus delivers the AP locally and over the duration of the insertion of said device. II describes, for example, a catheter for the urethra opening into the bladder associated with a delay form
antibiotic that can prevent urinary tract infections.

 For large volume liquid forms, some existing local injection methods could be used. From intraurethral techniques, CR BARD, for example, has developed a formulation (Transurethal delivery Kit) which is a syringe containing a solution of collagen in glutaraldehyde which can be easily injected in sub-musocal in volumes of 2.5 to 7.5 ml which constitute implants without active principle at the base of an incontinence plasty.

 The development of intra-luminal vascular systems has led to the creation of catheters allowing the release of a P.A. locally at their end. Unlike the catheter simply opened to release fluid, local administration can be obtained with a double balloon or porous catheter with multiple perforations. This local solution is however limited by the insertion time of the catheter. The pressure of the solution necessary to penetrate the wall also poses a tolerance problem.

For liquid solutions, a real local injection can be obtained in the wall using an injection system associated with a balloon (Interventional Technologies) or a retractable needle catheter (Bavarian
Medical Technologies). However, the application of the drug is not much longer with these immediate liquid forms.

 Part of the device can sometimes be left local and therefore be associated with a delay form. This is the case of "stents" used, for example in angioplasty, to avoid restenosis, which can be covered with a layer containing an active principle sometimes with a delay effect. Two essential problems arise then, the first is the adequacy of the drug released to the specific "coating" process. The second is the limitation of the total dose by the space and surface offered by the stent.

 With heparin, for example, some studies mention the importance of local treatment to avoid systemic side effects.

According to these studies, heparin inhibits the proliferation of smooth muscle cells after endothelial injury. Its systemic administration, subcutaneous delay or local delay adjacent external to the vessel, always leads to a decrease in neointimal proliferation but the local form is the only one not to cause systemic disturbances of the coagulation.

 We could also cite the osmotic pumps which are used to validate prolonged local administrations with their major drawback being their surgical implantation. For this reason, they are not currently used in humans.

 All these examples clearly show the interest and the advantages brought by a targeted treatment especially if it can be prolonged.

 However, all of these technical solutions have certain drawbacks, the most important of which are the lack of versatility of the solution chosen, the combination with a specific device which remains totally or partially inserted over the period of drug release and, finally, , the limit of the injectable volume, therefore, of the PA dose

Each of these solutions makes it possible to treat only one or more specific cases in a very specific site of the body.
vectorization by local administration is sometimes qualified as first generation compared to "prodnug" and vector formulations (liposomes ...) said to be second generation or to macromolecular recognition systems or "site specific" activation known as to third generation.

These solutions, even more than current local administration techniques, are however very specific, not always applicable and sometimes imprecise.

 The object of the invention is to propose a method which remedies the major current drawbacks of local administration or vectorization by the techniques of flexible (fibroscopy) or rigid (endoscope) endoscopic surgery and interventional radiology (active or inactive catheter).

 Solid and semi-solid non-dispersed formulations have the advantage of offering a minimum volume for an amount of P.A. corresponding to a treatment dose. The solid and semi-solid delay forms can thus contain several days of treatment in a volume of a few microliters.

 The local administration of a treatment makes it possible to significantly reduce the total therapeutic dose for the same effect.

 The combination of a solid or semi-solid retard form and a local administration therefore leads to the production of micro-dosages particularly suitable for local deposition at spaced time intervals.

The current development of imaging technologies, optics and micro-mechanics applied to medical in the field of intravascular or cavity instrumentation and minimally invasive surgery has led to the design of increasingly thinner and more and more precise allowing to intervene locally very deeply in
The organism with minimal trauma and therefore to multiply the accessible sites.

 The invention proposes a formulation adapted to the progress and to the miniaturization of pharmaceutical and medical technologies.

According to other features of the invention:
- said deposit site is not accessible with a conventional hypodermic syringe or trocar,
- said solid or semi-solid formulation has a fine and elongated shape once loaded into the insertion or implantation device,
- said device is thin and elongated in order to be able to circulate in said conventional intervention tools,
- the said solid or semi-solid formulation is a delay formulation,
- the said fine and elongated shape offers a minimum length to diameter ratio of 10,
- said device is the container of said formulation just adapted to said form,
- said shape and said device are cylindrical,
said implantation takes place in a tissue, in a mucous membrane or an internal wall of the organism by cavitary route,
- the said implantation takes place in a tissue, in a mucous membrane or an internal wall of the organism by vascular, arterial or venous route,
- the said implantation takes place in a tissue, in a tumor or in a pathogenic area by the surgical route,
- the said insertion takes place in a body cavity or in an organ through the cavity,
- the said insertion takes place in a body cavity or in an organ by invasive or surgical route,
- said active ingredient is an anti-inflammatory,
- said active ingredient is a peptide or a peptide analog,
- said active ingredient is an anticancer product,
- said active ingredient is a mixture of 2 or more active ingredients.

The subject of the invention is also
a method of therapeutic treatment in which an active principle in a solid or semi-solid formulation is inserted into a body cavity so that the said active principle is released into the fluids on the surface of said cavity and can act locally towards the drainage sites for said body fluids,
- a method of therapeutic treatment in which an active principle in a solid or semi-solid formulation is implanted in a mucous membrane or an internal secretory tissue of the organism so that the said active principle is released and excreted with natural fluids and can act locally or towards drainage sites,
- a treatment method in which the said active principle has a local and systemic action from the site of deposition of the implant,
a method of therapeutic treatment of ENT pathologies in which the active principle in a solid or semi-solid formulation is introduced into a cavity of the face or into the mucosa which covers it,
- a method of therapeutic treatment in which the said active ingredient is a corticosteroid,
- a method of therapeutic treatment of vascular, venous or arterial conditions or treatments, in which the active principle in the solid or semi-solid formulation is introduced into, or around, the vascular wall by intraluminal injection.

 The pharmaceutical and medical aspects of the invention come together in the search for a fine and miniaturized system which can be easily positioned and activated in all areas of the body from percutaneous tranlusminal angioplasty catheters, endoscopes or any other invasive device sufficiently thin and long to access the deposition area.

The form (fine and long) of the formulation in the administration device is, therefore, above all, studied to facilitate its local deposition. This characteristic of the system in its pharmaceutical and medical aspect will allow its general use.

 If we mean by insertion, a form deposited on the surface and by implantation, an injection into a tissue, the targeted treatment, or even prolonged, can be inserted inside a natural cavity of the organism if it is susceptible to act as a natural reservoir, that is to say if the form of the drug deposit allows it to remain in the body cavity at least for the duration of its release. This shape could be either the elongated shape studied to facilitate its deposition with the device, or its evolution once deposited.

 The form of the device and of the formulation is therefore not a priori adapted to the insertion area, as can be Ocusert, the vaginal ring or the stents. The form of the formulation can however evolve after deposition to facilitate its local maintenance. After its deposit, the formulation is not associated with all or part of the deposit device but left alone at the deposit site.

 If, for a specific therapeutic need and duration, an insertion solution in a natural cavity of the organism is not desirable, the targeted treatment, or even prolonged, can also be implanted inside a target tissue of the body to allow its deposit over the release period.

 This implantation can be carried out with the device associated with conventional tools, by transcutaneous route, by vascular or cavitary route in a mucosa or a wall of the organism or by surgical route in a target tissue.

 The insertion of the delay form will allow local, superficial or external treatment, but also targeting for a deep effect, or even for a systemic effect, for example with a deposit on the mucous membranes.

 Similarly, the implantation of the delay form will allow a general treatment but also a targeted treatment by local hyperconcentration or by excretion.

 Thus, depending on the therapeutic applications and the area, both the insertion and the implantation may be a systemic solution, a local internal solution or, finally, an external targeting solution.

 The immediate or retarded solid or semi-solid formulations used in the process of the invention may be any solid or semi-solid formulations capable of being able to be manufactured or packaged in the form and the volume compatible with the process and the device. injection.

 Thus, the solid or semi-solid formulations may preferably be formulations produced from biodegradable excipients such as the polylactide glycolide copolymer.

 Solid or semi-solid formulations can be produced without excipient or structured with small quantities of injectable excipient.

 The semi-solid formulations can be produced by mixing the P.A. with or without excipient, with water, an organic solvent, oil or any other injectable liquid capable of giving the semi-solid form.

 Solid or semi-solid formulations will either be immediate formulations or late formulations.

 The immediate solid formulations will be produced as indicated in the SCRAS patent (Delivery of Solin Drug Compositions USSN 08 / 300,713). Semi-solid and solid delay formulations may be produced according to the formulation and process claimed by the SCRAS patent (Sustained Release of Peptides from Solin and Semi-solid pharmaceutical compositions USSN 08 / 400,610).

 The solid or semi-solid formulations will advantageously be produced according to methods allowing a high concentration of active principle greater than 40% and up to 100% of P.A.

 Before their deposition, the non-dispersed solid formulations according to the invention will have a fine and elongated shape: rod, implant, pellet, rod or needle, so that they can be introduced inside the implantation device which can itself - even, if necessary depending on the depth of the injection in the body, be inside an endoscope or a catheter.

Solid dispersed formulations (powders, spheres) must be able to be arranged longitudinally in the device.

 The solid formulations in the device will thus preferably have a maximum diameter of 3 mm and advantageously a diameter of less than 2.5 mm or even a diameter of less than 2 mm. Depending on the total dose and especially for the immediate forms or the short-term or low-dose forms (less than 0.1 mg per day), the diameter of the solid forms may be even smaller and up to 0.1 mm.

The smallest diameters may, in some cases, present a technical advantage to facilitate deep local implantation; however, with catheters and endoscopes, a larger diameter will not have the same drawbacks (especially in terms of patient comfort) as in the case of superficial trocar type injections (Zoladex, trademark registered by the company Zeneca) or mini -trocarts (Auto-injector, Retro-injector: Needle-less
Parenteral Introduction Device USSN 08 / 304,274) either because the use of medical devices also requires local or general anesthesia, or also because the deep implantation area is less sensitive than the skin.

 The solid forms may have a length of a few centimeters, in general, less than 3 cm and preferably less than 2 cm and adapted to the space in the deposition area.

 The solid forms will preferably be cylindrical and obtained by extrusion techniques.

 The semi-solid forms, according to the invention, will have a sufficiently high viscosity to contain a high concentration of PA and remain homogeneous while 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 AP in a liquid vehicle.

The semi-solid forms will have a low total volume generally less than 300 μl and preferably less than 100 Cll or even less than 50 ffi
The process and the devices according to the invention will preferably use biodegradable injectable excipients or normally eliminated or solubilized in body fluids.

 The devices according to the invention correspond to solid or semi-solid formulations associated with the localized deep insertion or implantation device.

 The device for implanting or inserting an active principle in a solid or semi-solid formulation at a precise site of deposition of the organism, is characterized in that it comprises a part placed inside the patient's body with means for conditioning the solid or semi-solid form, means for positioning to the deposition site, means for injection or insertion at this deposition site and means for withdrawal after injection or insertion ; and a part left outside with means for activating the functions of the device.

According to other particularities:
the means for packaging solid or semi-solid forms are also the means for positioning and injection,
said device comprises a piston inside a guide which can be actuated in a trocar or a catheter,
- the packaging, positioning, injection means is a needle,
said needle once actuated can be oriented relative to the device by preforming or elastic prestressing or by mechanical means,
- the external means of activating the device allow, sequentially, the injection of the needle, the advancement of the piston to the bevel of the needle to deposit the solid or semi-solid form, the withdrawal of the needle around the piston, the combined withdrawal of the needle and the piston,
the sequential actions of the device from the external means are controlled remotely and in order using two removable stops, the first of which is arranged on a pusher coaxial with the piston, and the second is a tubular piece interposed between the guide and the pusher,
The devices can be used directly or combined with local therapy medical instruments (endoscope, fibroscope, tube; catheter, nail, aerator, cannula, perforator, trocar ...).

 The devices will be introduced locally and will allow the insertion or implantation of semi-solid or solid forms. They will be removed immediately after this deposit.

Like the formulations, the devices used, according to the method of
The invention of deep local administration of solid or semisolid formulations, will be versatile and of small volume with a fine and elongated adapted form.

 The devices will therefore preferably have a maximum diameter of 3 mm and advantageously a diameter of less than 2.5 mm or 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 endoscope comprising, for example 4 channels (video, instruments, introduction and withdrawal of fluid, luminous optical fibers), the insertion or implantation device can, like a conventional tool (biopsy forceps style) occupy the instrument channel, which frees the fluid introduction channel or even allows its elimination. In this case, the devices may have a diameter of less than 2 mm and, for example, 1.7 mm like certain instruments.

 In a catheter, the insertion or implantation device may, like the stent insertion device, occupy the canal and be activated from the outside in situ. In this case, the device could have a diameter less than 2.5 mm and, for example, 2 mm like certain stents.

 In a trocar, the insertion or implantation device can, like the perforation device, occupy the lumen of the trocar. The device may have a diameter of less than 3 mm and, for example, 2.5 mm like certain perforators.

 Other characteristics and advantages of the invention will appear during the description which follows, given with reference to the appended drawings which illustrate several embodiments thereof by way of nonlimiting examples.

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

 Figures 2, 3 and 4 illustrate an implementation sequence of the device of Figure 1 for locally administering in the body a solid formulation.

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

 FIG. 6 is a cross-sectional view along 6/6 of FIG. 5.

 Figure 7 is a view similar to Figure 5 showing the device after pushing the solid form outside a guide of the device, ready to be deposited in the body of a patient.

 FIG. 8 is a cross-sectional view along 8/8 of FIG. 7.

 Figure 9 is an elevational view similar to Figures 5 and 7 showing the device after partial withdrawal of the needle, the solid form remaining in place in the body.

 Figure 10 is a view similar to Figure 9 showing the needle and the inner piston therein completely retracted.

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

 The device for administering a solid form 1 shown in FIG. 1 comprises a tubular guide 2 containing a piston 3 capable of pushing outside the guide 2 the solid form 1 contained at the end of the latter. The guide 2 and the piston 3 are provided, at their opposite ends, with respective flanges 4, 5 for manual manipulation.

 FIG. 2 illustrates a possible example of an invasive system in the body of a patient for the implementation of the device for administering the solid form 1 of FIG. 1. The invasive system is in the example of FIG. 2 a trocar 6 containing a perforating mandrel 7, if access to the natural cavity of the organism used as a release reservoir for the solid formulation 1, requires perforation of internal tissues. In Figure 2 the invasive system is shown partially introduced internally into the body in its part located to the right of the plane L, while its part located to the left remains external.

 If access to the body's natural cavity does not require perforation of internal tissue, the invasive system may be an endoscope, a fibroscope or a catheter (not shown). The invasive system used is introduced into the body cavity (sinus of the face, esophagus, trachea, vessel, etc.), using the perforating mandrel 7 in the case of a system such as that of FIG. 2. Then the mandrel 7 is removed from the trocar engaged in an internal tissue.

 The invasive system comprises a tubular part 50 partially engaged in the tissue through the surface P ′ thereof, and a tubular guide II which can be a fibroscope or an endoscope, in which a catheter 12 can be mounted. This latter constitutes a guide of the administration device formed by a needle 13 and a piston 14 for extracting the solid form 9 from the tissue 17.

 The device comprises two removable stops (10, 15) of which the first 10 is a bushing disposed in a pusher 20 coaxial with the piston 14, this stop 10 and the pusher being truncated longitudinally (FIG. 8); the second is a tubular part 15, also truncated (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 back, but is preferably carried out as illustrated in FIGS. 7 to 10, in the following manner. The stop 15 is removed; the needle 13 is moved using the pusher 20 containing the stop 10. (FIG. 7). If necessary and as illustrated in FIG. 7, in particular in the case of vessels, the needle 13 can have at its end a curved shape 1 3a obtained by releasing an elastic preload from the needle 13 in the guide. Once freed from the constraint of the guide, the curved end 13a facilitates the oblique injection of the solid form 9 into the wall or the mucosa 17. This angle between the needle and the guide can be obtained or adjusted, by any another mechanism usually used by these devices.

 Once the solid form 9 and the curved end 13 have been injected, the stop 10 is removed from the pusher 20, and the needle 13 is retracted by pulling on the pins 16 without displacement of the piston 14, in order to deposit the solid form 9 in fabric 17 (Figure 9). When the bevel 13b of the needle 13 reaches the end of the piston 14, the latter is removed with the needle 13, leaving the solid form 9 in place, this maneuver being obtained by traction on the pusher 20 and the pins 16 (figure 10).

 The device of FIGS. 5 to 10 can also allow the administration of a semi-solid.

 The administration device illustrated in FIGS. 11 to 16 is similar to that of FIGS. 5 to 10 and differs from it only in that the piston 14 acts on a non-solid form 18, similar to a micro-syringe to the tip of the injection device.

 Here too, the invasive system 9, 11, 12 can be engaged in an internal tissue 17.

 The administration process here consists in injecting, by pushing it outside the guide 9, 11, 12, the administration device consisting of the needle 13, the piston 14 and the semi-solid form 18 L ' needle 13 can optionally be bent as in the embodiment of FIGS. 5 to 10. The piston 14 is moved in needle 13 to inject the semi-solid 18 (FIG. 14) in the same manner as in the previous embodiment.

 The piston 14 and the needle 13 are finally removed together by reintroduction into the guide 11, 12, by pulling on the pins 16 and on the pusher 20 (FIGS. 15 and 16), the semi-solid form 18 left in place in the fabric 17 can then take a spherical or ellipsoid shape.

 The diagrams of FIGS. 1 to 16 will make it possible to illustrate the methods of administration for different specific treatments described below. These different specific treatments according to the method of the invention of local solid or semi-solid administration imply the implementation of the method in order to be able to be applied and thus offer certain new 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 applications of the method and are therefore not limiting.

 Among the possible treatments, according to the method of the invention, mention may be made of anesthetic, analgesic, anti-inflammatory, cancer, cardiological, endocrinological, rheumatological treatments, etc., as well as associated treatments. Among the endoscopic or radiological techniques likely to allow this local treatment process, mention may be made of urology, gynecology, arthroscopy, ENT, bronchoscopy, gastrology, minimally invasive surgery or even cardiovascular.

 These processes are new because they use a dosage formulation, delayed or not, solid or semi-solid of low volume (micro-liters).

This formulation differs from existing local treatments which use specific solid forms or liquid or suspension forms, in large volume.

 According to this process and with these non-liquid formulations, the formulation is not, in its composition or in its form, studied for a precise vectorization. On the contrary, the formulation is studied for a tool or device adapted to internal local administration and which allows remote injection or insertion in situ.

 The method may use, in this dosage form and with these tools, conventional APs and in particular those having already demonstrated their interest in local administration1 or whose local interest can be deduced from the mode of action of the AP, even if its use under this form does not yet exist, in particular because it could not be easily implemented without the contribution of the invention. The various examples which follow illustrate the possibilities of this process.

 The method, the formulations and the devices allow the administration in cavities of the organism and intra-tissue. Whatever the cavity or the tissue, the advantage is to be able to bring the formulation to the deposition site while avoiding or reducing tissue damage.

These natural cavities can be used as reservoirs of therapeutic product, especially if their anatomy allows the "imprisonment" of the formulation. The process allows1 for example,
Administration in the natural cavities of the face and in its tissues. With certain APs, we find with this treatment all the objectives set out above (better local efficacy1 dose reduction, increase in duration of action, improvement in comfort and compliance, reduction in side effects).

The intra or peri-sinus inserts or implants may carry the
PA in the mucus thanks to the ciliary flows of the mucous membranes or allow its local systemic diffusion by contact. We can also consider a general action by progressive diffusion towards the digestive tract for drugs requiring daily doses at low doses.

 Local corticosteroids are a good example of a local action product with general drawbacks. However, existing local treatments (drops, spray, etc.) come up against anatomical arrangements to reach a precise target area such as the middle meatus (single-celled groove). In addition, with these existing treatments1, the necessary persistence of AP locally implies frequent applications.

This therapeutic process, according to the invention, makes it possible to reach this key area of naso-sinus pathology. In addition to the maxillary sinuses, as needed, we can locally treat the ethmoid cells, the sphenoid and frontal sinuses, the eardrum. The solid or semi-solid retarded form implanted or inserted will be in contact with this mucous membrane which secretes and is covered with a mucus circulating from the meatus to the nasal fossae, and evacuated towards the cavum by passing in contact with the tubal bead and the tube of Eustace
The process will, for example, increase and maintain the concentration of therapeutic product in the single-cell gutter where pathologies, in particular inflammatory diseases, occur. If the non-liquid retardant form is deposited inside the sinuses, a device will be used according to the diagram in FIG. 1 which can be positioned using conventional tools for otolaryngology drainage (ENT; trocars, tubes ). We can also inject the formulation into the mucosa of the nasal cavity, into the comets or into the tubular bead using the devices shown in Figures 5 to 16. Depending on the deposition area and the formulation, The action will therefore preferably be external, intra - tissue or systemic.

 In ENT, we can thus treat, for example, by corticosteroid therapy, nasosinus polyposis, rhinitis allergic or not, certain otitis or non-infectious sinusitis etc. Apart from anti-inflammatory treatments, we can practice antibiotic, anti-allergic, immunostimulant treatments, etc. We can also combine treatments. These treatments will have a local aim.

 For chronic treatment, one could imagine the intrasine use of a polymeric form (PLGA 75-25) with three months of duration of action.

 These delayed preparations may be used on an outpatient basis for patients suffering, for example, from chronic nasal obstruction. The medical procedure for intrasinus administration will be similar to the usual ENT procedures, which can be performed in the doctor's office: trocar puncture with or without anesthesia. The approach may be prepared or not (meatotomy, nails, drains or others).

The deep localized injection in the comet or the mucous membranes of the nasal cavities will also be easy thanks to the device associated or not with the usual tools of endoscopic exploration. In the nasal cavity,
Local government is shallow. Depending on the body cavities or the endoscopic surgery site, the distance between the external area and the internal deposit may be even shorter or much greater.

 Retard corticosteroids are already used in rheumatology. One can, for example, according to the method, imagine a local intra or peri-articular injection with deposition in low volume of delay form (corticoids, anti-inflammatory drugs) at the site of inflammation (tendinitis, bursitis, non-infectious arthritis, arthritis ...).

 One can also, according to the method, imagine an ocular treatment by injection-deposition in the mucous membrane under the eyelid. The small volume of the solid or semi-solid forms will render this deposit insensitive and the injection will promote both the delay effect and the local maintenance of the treatment more effectively than the deposit in the conjunctival sac which is abundantly drained. This approach is especially advantageous for chronic treatment such as, for example, glaucoma with pilocarpine.

 Here, the injection is practically superficial and does not require tools outside the administration device for semi-solids or solids in micro-volume.

 Similarly, it is possible according to the method of the invention to treat certain superficial tumors or skin problems by local, intra or hypodermic deposition.

 In the case of certain solid tumors, the treatment may be combined with a cytotoxic agent (Type 5FU or cisplatin) whose diffusion will be regulated by the same local form and whose local concentration will thus be very high with a very low total dose.

 The same formulations can also be used in much deeper applications and then associated with tools such as an active SMA (Shape memory Alloy) or fibroscope catheter, and specialties such as interventional radiology or endoscopic or robotic surgery.

 We could, for example, implant intra-cerebral, a delayed form BIM23014 C more cytotoxic thanks to an access in the skull.

 The solid or semi-solid forms according to the invention1 have the advantage, compared to the local treatment type Gliadel, of being able to be applied without trepanation at the surface level, but also in depth thanks to stereotaxic, endoscopic and robotic neurosurgery.

 We can of course implant any other solid or semi-solid retardation form, and in particular PLGA implants, using the process. It can be treated with other peptides, recombinant proteins (interferon), antibodies or monoclonal antisense, etc.

 Solid tumors treated, for example, with the collagenous forms of Matrix can be treated in the same way with these microdoses.

Whatever the solid or semi-solid form, the advantage of volume allows vectorization in all sites and avoids the risk of propagation caused by the injection of a liquid volume of a few milliliters.

 Still with a solid or semi-solid form located deeper in the body, after percutaneous transluminal angioplasty, restenosis can be treated locally intravascularly. Compared to the local treatment associated with the stent, the advantage of a treatment according to the method 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, while allowing a high local concentration in all the layers of the vessel and around, and a systemic effect if necessary.

 We can, for example, inject according to the diagram of Figures 5 to 16, Angiopeptin alone or associated with Heparin. We can of course inject any other AP alone or associated likely to avoid the risks of restenosis and, to favor the result.

 Compared to this perivascular therapy, we can also mention the possible use of semi-solid forms in the intravascular with the same objective as chemoembolization by suspension, glue or gel.

The advantage here is to use a delay form whose volume (therefore the deposit area) is prefixed; which allows a better localization of the occlusion in the vessel.

 The method and the devices according to the invention, associated with the fibroscope or any other direct or indirect imaging solution, allow administration into the organic walls.

 For example, since we intervene in the urinary bladder, we can imagine the implementation of a treatment (prophylaxis, antibiotic ...) in the thickness of the urethra.

 You can access the windpipe and bronchi (stents). We can therefore consider, according to the method, a pulmonary treatment either by depositing a solid or semi-solid form in the lung or by implantation in the mucosa, bronchi or trachea, according to the needs of local tolerance intra- pulmonary, the solid form may be dispersed (powder or sphere).

For example, to replace preventive treatment with glucocorti costeroids inhaled in mild or moderate asthma recently diagnosed. We can administer in the lungs, through the bronchi, or in the wall that covers them or in those of the trachea, a delayed form of 0.4 mg of
Daily budesonide which will be secreted into 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 low dose, without side effect, no longer poses a problem of compliance, especially in children. Such a form may have a duration of 1 to 3 months, or even longer if necessary.

 In the digestive tract, devices are also available for the local administration of treatment according to the invention.

 In the esophagus and in the stomach, the treatment of varicose veins can be considered from a local form and injected into the wall. Likewise, tumors at this level which are well individualized and are currently treated, for example by PDT (photochemotherapy), require, after injection of the photosensitive product, illumination by controlled introduction of a light diffuser locally. It is therefore also possible to directly inject the anticancer agents at this level in solid or semi-solid form with the devices of the invention. We can then target even more the area to be treated and avoid unnecessary damage to the peripheral tissues.

 The method of local administration of solid or semisolid forms implies the prolonged presence of a local deposit of PA. We can, if necessary, consider adding to the formulation of products promoting local tolerance at the depot site. We can, for example, add a very small percentage of Dexamethasone, lndomethacin, Heparin or any other AP likely to avoid an undesirable local effect.

 The mucous membranes or the walls are more permeable than the skin and there are systems of patches or bioadhesives which are applied to the mucous membranes (in particular buccal or nasal) and which allow a systemic passage of the AP. The disadvantage is sometimes the non-persistence of the formulation in contact with the mucosa. The prolonged presence of the administration according to the process at the local level of the mucous membranes or the internal walls could therefore present an advantage in the search for a topical form with systemic activity. It is therefore possible, depending on the local treatment, to add to the formulation in a small amount any excipient capable of being a vector of tissue penetration adapted to PA (organic solvents, surfactants, etc.).

Thus, a deep local form may advantageously be the site of a systemic diffusion in relation to the oral or nasal mucosa, for example, which would not allow prolonged topical deposition.

 The method according to the invention will also find its application during surgery for minimally invasive endoscopic surgery (laparoscopic, arthroscopic, etc.). The APs used (local anticoagulant anesthetics, etc.) can be administered in a solid or semi-solid form, here again with the advantage of a micro-volume in adequacy with the reduced intervention space, and the possibility of administration via the instrumental access route.

Claims (26)

 1. Solid retardation formulation, intended to be placed in a precise deposition site of an organism, containing at least one active principle and a biodegradable excipient, characterized in that the excipient is a polylactide-glycolide copolymer (PLGA) , and in that the concentration of active principle is greater than 40%.  2. Delay formulation according to claim 1, characterized in that the concentration of active principle is between 40% and 100%.  3. Delay formulation according to one of claims 1 and 2, characterized in that it has a fine and elongated shape with a diameter not exceeding 3 mm.  4. Delay formulation according to claim 3, characterized by a diameter not exceeding 2 mm.  5. Delay formulation according to claim 3, characterized by a diameter of the order of 0.1 mm.  6. Delay formulation according to one of claims 1 to 5 characterized by a minimum length-diameter ratio of 10.  7. Delay formulation according to one of claims 1 to 6, characterized in that it contains an active principle of peptide or protein nature.  8. Formulation according to one of claims 1 to 7, said formulation being of solid or semi-solid consistency such that it persists for a certain period of time on the site, and containing a dose of active ingredient limited for treatment in an area targeted to the organism, and having a shape allowing its implementation by a device comprising a part capable of being placed inside the patient's body, with conditioning means (2, 13), means (6 , 11, 13) of injection or insertion and withdrawal means (4, 16) after injection or insertion, and a part left outside with means (5, 14) for activating the functions of the device , the device comprising positioning means (13) enabling these packaging means to be brought to the depot site.  9. Formulation according to one of claims 1 to 8, characterized in that it contains a dose of active ingredient low compared to the usual dose for a systemic treatment of the active ingredient considered.  10. Semi-solid formulation according to one of claims 1 to 9, characterized by a form which evolves after deposition in the site (T) to facilitate its local maintenance.  11. Formulation according to one of claims 1 to 10, characterized in that it contains an anti-inflammatory active principle.  12. Use of a formulation according to one of claims 1 to 11, for the preparation of a drug which can be released into an anatomical cavity into which it has been introduced.  13. Use of a formulation according to one of claims 1 to 11, for the preparation of a drug which can be released into the secretions of a mucosa.  14. Use according to one of claims 12 and 13, wherein said cavity or mucosa is a cavity or mucosa of the facial sphere or ENT.  15. Use according to claim 13, wherein said mucosa is a tracheo-pulmonary mucosa.  16. Use according to claim 13, in which said mucosa is the buco-esophageal mucosa.  17. Use according to one of claims 13 to 16, for the preparation of a medicament intended to be placed at. the surface of said mucosa, so that the active ingredient is carried by the mucus.  18. Use according to one of claims 13 to 16, for the preparation of a medicament intended to be placed inside the mucosa.  19. Use according to claim 18, for the preparation of a medicament intended for injection into the subpalpebral mucosa.  20. Formulation for use according to one of claims 12 to 19, characterized in that it comprises a corticosteroid suitable for the treatment, in a cavity, cavity or mucous wall, of nasal sinus polyposis, allergic rhinitis or no, non-infectious otitis or sinusitis, by introduction into the maxillary, phenoidal or frontal sinus, the nasal mucosa, ethmoid cells or the eardrum.  21. Use of a formulation according to one of claims 1 to 11, for the preparation of a drug which can be released into or around the vascular wall by intra or trans-luminal injection.  22. Use according to claim 21, for the preparation of a drug which can be released after percutaneous transluminal angioplasty, comprising an active principle for the prevention or treatment of restenosis.  23. Formulation for a use according to claim 22 containing angiopeptin alone or associated with another active principle, in particular heparin.  24. Use of a formulation according to one of claims 1 to 11, for the preparation of a medicament intended to be introduced into or under a tumor tissue for an anti-tumor action.  25. A formulation for use according to claim 24, in which the active principle comprises a photosensitive product.  26. Use of a formulation according to one of claims 1 to 11, for the preparation of a medicament intended for intra or peri-articular injection.