AU742061B2

AU742061B2 - Device for local administration of solid and semisolid formulations, sustained-release formulations for parenteral administration and method of preparation

Info

Publication number: AU742061B2
Application number: AU76232/98A
Authority: AU
Inventors: Roland Cherif-Cheikh
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1996-12-02
Filing date: 1997-12-02
Publication date: 2001-12-13
Anticipated expiration: 2017-12-02
Also published as: KR20000069264A; EP0952867B1; CZ301103B6; BR9713675A; CN1244132A; HUP9904601A3; DE69738048T2; DE69738048D1; IL130211A; CZ191999A3; DK0952867T3; NZ336074A; WO1998024504A3; EP0952867A2; HU228236B1; RU2207845C2; NO992610L; HUP9904601A2; IL130211A0; JP2001506144A

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 The device is withdrawn after (A) has been so placed.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

P:OPER\ArI\2183272 r 178.doc-03/07/01 -1- Device for local administration of solid or semi-solid formulations and delayed-release formulations for parenteral administration and preparation process The present invention relates to a device and method for the targeted treatment of non-liquid pharmaceutical formulations.

The advantages of the use of a local treatment or administration when the active principle (AP) is in this way 0 10 preferentially directed towards its side of action are known. It is proved, on the other hand, that oral or S0 parenteral administration of a medicament and its systemic

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diffusion can, in certain cases, not give a satisfactory result. In addition, even in the case where a general or 15 systemic treatment is aimed at, especially in the case of delayed-release formulations, it is of interest to insert the formulation into a suitable site.

Apart from the improvements in the local efficacy, the local treatment with respect to a general treatment above S 20 all allows the doses and the secondary effects, especially 5 linked to the AP, to be decreased in the sites of the body where its presence is either useless or harmful.

The local administration of a medicament thus allows the therapeutic index of the product to be improved while 25 decreasing, if need be its general toxicity and the risk of systemic effects.

The cutaneous, ocular, naso-sinusal, pulmonary or even gastric or rectal topical forms were the first nonparenteral forms to use local administration. When the deposit site of the formulation is accessible with relative difficulty or necessitates an invasive form and when the treatment must be repeated, or even more chronic, use of the advantage of targeting in practice comes up against the difficulty or even the discomfort of a repeated therapeutic action.

P:\OPERrI\2183272 re 178.doc.-0310701 -2- On the other hand, there is advantage in the use of a sustained-release or delayed-release formulation as this allows, in a single administration, the sick person to be given his/her medicament for several days, several weeks or several months.

This delayed-release form improves compliance when the observance of the treatment does not depend on the sick person or the care personnel but on the preparation. This sustained-release in fact thus improves the comfort of the Se 10 patient who is no longer constrained by his/her treatment and who thus continuously receives a regular and non- e• variable dose as a function of taking the medication.

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The development of delayed-release forms has led 5ooo specialists to consider their local use, especially in the 15 case mentioned above where the deposit site is accessible with relative difficulty. The delayed-release form thus avoids having to repeat the administrations or, even more, surgery. In this way, it is possible to hope for significant local concentrations of medicament over a S 20 prolonged period without significant systemic doses, thus

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with fewer secondary effects. This solution is more particularly useful for products which are rapidly metabolized or have a short half-life when they are administered by, the systemic route.

25 Inside the body, targeted and prolonged treatments such as intra- or peri-articular injections of delayedrelease corticoids are thus envisaged. Cancers and especially solid tumours are candidates of choice for these local forms which allow the total injected doses of cytotoxic or antineoplastic compound to be decreased, whilst increasing the concentration in the tumour zone to be treated. This is thus capable of avoiding the serious secondary effects of this type of treatment.

Matrix Pharmaceutical proposes a delayed-release preparation based on collagen which will be able to be injected intra-tumorally (IntraDose CDDP- 3 Cisplatin). This formulation is administered in cancers or cutaneous lesions with the aid of a 3 cc syringe and possibly a biopsy needle for the less accessible zones.

In a viscous liquid volume which can reach 2 ml, it is thus limited to the initially relatively easy (peripheral) sites or to post-surgical treatments.

It is also possible to mention the MITSUI Patent (FR 2 497 661; JP 562 737) which describes a small rod or needle polylactide-polyglycolide

(PLGA)

form for local activity, allowing its direct implantation into a zone or an organ inside the body, and, for example, a tumour zone before or after exeresis.

The Gliadel form (Guildford) for its part describes a formulation based on polyanhydride in host form containing carmustine and which can, for example, be deposited at the time of surgery on a cerebral tumour (glioblastoma).

In the present state of medical technology, these targeted treatments inside the body are more often linked to serious surgical operations. They benefit from the prolonged effect of the formulation but cannot be easily repeated.

Chemo-embolization operations are also carried out which consist in injecting, into vessels, suspensions (microspheres), gels or glues with their solvent, which will be able to obstruct a nutrient vascular tract and liberate an AP in a tumour. The occlusion is obtained by deposition after the injection vehicle has left. This technique uses transluminal percutaneous angioplasty catheters to introduce the fluid into the vessel.

The local use of delayed-release forms is also envisaged in certain body cavities and in more accessible sites of the body.

The ®Ocusert system (Alza) is a flexible and oval ocular insert which forms a delayed-release reservoir device comprising an ethylene/vinyl acetate 4 copolymer membrane and which can contain, for example, pilocarpine.

This device is placed in the conjunctival sac and liberates its product according to a zero-order profile. The delayed-release form allows the dose necessary for the same effect on the intraocular pressure to be decreased significantly. The therapeutic efficacy of pilocarpine in the treatment of glaucoma is thus 8 to 10 times better owing to the use of a delayed-release form compared with local drops.

American Patent No. 3,545,439 whose contents are incorporated by reference describes an intravaginal delayed-release form formed of a ring made using a silicone elastomer and which liberates a medicament for several weeks.

In this case, the local delayed-release administration on the vaginal mucous membrane also allows, according to the AP, a general effect (contraception) to be obtained.

The medical device described by Bukh Meditee (International Patent Application PCT No. WO 89/03232 whose contents are incorporated by reference) allows the introduction into a body cavity of a matrix delayed-release form made of a substance which is poorly penetrable by water and containing an AP The delayed-release form combined with the device thus delivers the AP at the local level and during the period of the insertion of the said device.

It describes, for example, a catheter for the urethra opening into the bladder combined with an antibiotic delayed-release form capable of preventing infections of the urinary tracts.

For large-volume liquid forms, certain existing processes of local injection could be used. Starting from intraurethral techniques, C.R. BARD, for example, has developed a formulation (Transurethral delivery Kit) which is a syringe containing a solution of collagen in glutaraldehyde which can be easily injected submucosally in volumes of 2.5 to 7.5 ml which form 5 implants without active principle in the context of plastic surgery against incontinence.

The development of intraluminal vascular systems has led to the production of catheters allowing an AP to be liberated locally at their end. Contrary to the catheter which is simply open for liberating fluid, local administration can be obtained with a doubleballoon or porous catheter with multiple perforations.

This local solution, however, is limited by the time of insertion of the catheter. The pressure of the solution necessary to penetrate the wall also poses a tolerance problem.

For liquid solutions, a true local injection can be obtained in the wall with the aid of an injection system combined with a balloon (Interventional Technologies) or a catheter with a retractable needle (Bavarian Medical Technologies). The administration of the medicament, however, is not prolonged much with these immediate liquid forms.

A part of the device can sometimes be left locally and thus be associated with a delayed-release form. This is the case of the "stents" used, for example, in angioplasty to avoid restenosis, which can be covered by a layer containing an active principle, sometimes with a delayed-release effect. Two essential problems are then posed, the first is the suitability of the released medicament for the specific process of "coating". The second is the limitation of the total dose by the space and the surface offered by the stent.

With heparin, for example, certain studies mention the significance of local treatment to avoid the systemic secondary effects. According to these studies, heparin inhibits the proliferation of smooth muscle cells after endothelial damage. Its systemic administration, in adjacent subcutaneous or local delayed-release form external to the vessel, always leads to a decrease in the neointimal proliferation but the local form is the only one not to involve systemic perturbations of coagulation.

-6- It would-even be possible to cite osmotic pumps which are used to validate prolonged local administrations with, as a major disadvantage, their surgical implantation. For this reason, they are not presently used in man.

All these examples indeed show the interest and the advantages brought by a targeted treatment, above all if it can be prolonged.

These technical solutions, however, all have certain disadvantages amongst which the most important are the lack of versatility of the solution retained, the association with a specific device which remains totally or partially inserted over the period of release of the medicament and, finally, the limits of the injectable volume, thus, of the dose of AP e Each of these solutions allows only one or several particular cases in a well-defined site of the body to be treated.

Vectorization by local administration is sometimes described as first generation with respect to the "prodrug" and vector (liposomes...) formulations called second generation or to macromolecular recognition systems or "site-specific" activation called third-generation. These solutions, even more than the present local administration techniques, however, are very specific, not always applicable and sometimes not very precise.

The aim of the invention is to propose a process to alleviate the present major disadvantages of local administration or vectorization by flexible endoscopic surgical techniques (fibroscopy) or rigid endoscopic surgical techniques (endoscopy) and of interventional radiology (active or non-active catheter), or to at least provide an alternative.

The non-dispersed solid and semi-solid formulations have the advantage of offering a minimal volume for a quantity of AP corresponding to a treatment dose. The solid and semi-solid delayed- P:\OPER\Ar IV 2 183272 rc 178.doc-O4/07/01 -7release forms can thus allow several days of treatment in a volume of a few microlitres.

The local administration of a treatment allows the total therapeutic dose for the same effect to be decreased significantly.

The combination of a solid or semi-solid delayedrelease form and of a local administration thus leads to the production of micro-dosages particularly adapted to local oeeo• deposition at spaced intervals of time.

0S 10 The present development of imaging, optical and micromechanical techniques applied to medicine in the field of intravascular or cavitary instrumentation and of minimally 96 "invasive surgery has led to the design of more and more fine and more and more precise tools allowing very deep local intervention in the body with minimal trauma and thus of multiplying the accessible sites.

@500 According to one aspect of the invention, there is 0o. provided a device for the implantation or insertion of a solid or semi-solid formulation, at a precise deposit site of a body, containing at least one active principle, said formulation being of solid or semi-solid consistency such that it is able to persist for a certain period in said deposit site, and containing a limited dose of active principle for a treatment in a targeted zone of the body, said device comprising a part placed inside the body of the patient with means for packaging said formulation, means for positioning said packaging means at said deposit site, means for injection or insertion of said formulation at said deposit site, and means for withdrawing said packaging means after injection or insertion, and a part being external of othe body during use with means for operating said device.

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000000 0 @000 @0 0 @0 :.:00 0 oo ooooo According to another aspect of the invention there is provided a method for the implantation or insertion of a solid or semi-solid formulation, at a precise deposit site of a body, containing at least one active principle, said formulation being of solid or semi-solid consistency such that it is able to persist for a certain period in said deposit site, and containing a limited dose of active principle for a treatment in a targeted zone of the body, said method comprising the steps of packaging said formulation into packaging means of an implantation device, placing a part of said device comprising said packaging means inside the body of the patient, positioning said packaging means at said deposit site through positioning means of said device, injecting or inserting said formulation at said deposit site by injection or insertion means of said device, and withdrawing said device after injection or insertion, wherein a part of said device, being external of the body during use, has means for operating said device.

Other preferable features of the invention include: the said solid or semi-solid formulation has a thin and elongated shape once filled into the said device, the said device is thin and elongated to be able to move in the said conventional tools of intervention, the said solid or semi-solid formulation is a delayed-release formulation, the said thin and elongated shape gives a minimum length to diameter ratio of the said device is that containing the said formulation exactly fitted to the said shape, the said shape and the said device are cylindrical, P:\OPER\ArlI 183272 r. 178.doc-03/07/01 -9the said implantation takes place in a tissue, in a mucous membrane or an internal wall of the body by the cavitary route, the said implantation takes place in a tissue, in a mucous membrane or an internal wall of the body by the vascular, arterial or venous route, a the said implantation takes place in a tissue, in a tumour or a pathogenic zone by the surgical route, the said insertion takes place in a body cavity or 10 in an organ by the cavitary route, e the said insertion takes place in a body cavity or in an organ or a tissue by the invasive or surgical route, the means of packaging of the solid or semi-solid forms are also the means of positioning and of injection, the said device comprises a piston inside a guide which can be operated in a trocar or a catheter, 0* 0 the means of packaging, positioning and injection is a needle, the said needle once operated can be orientated with respected to the device by elastic preshaping or preconstraint or by mechanical means, the external means of operation of the device allow, in a sequential fashion, the injection of the needle, the advancement of the piston as far as the bevel of the needle to deposit the solid or semi-solid form, the withdrawal of the needle around the piston and the combined withdrawal of the needle and of the piston, the sequential operations of the device from external means are controlled remotely and in order with the aid of two movable stops of which the first is arranged on a push button coaxial to the piston, and the second is a c A tubular piece inserted between the guide and the push P.\OPER\.AI\2 183272 rm 178.d-03/07/01 9abutton.

If insertion is understood as meaning a form deposited in the surface and by implantation or an injection into a tissue, the targeted, even prolonged, treatment will be able to be inserted inside a natural 0 0 0 0 0 0%.

@0 00 0 0 0 00 1. 0.S 0 10 cavity of the body if this is capable of acting as a natural reservoir, that is to say if the form of the administration of medicament allows it to stay in the body cavity at least over the time of its release. It will be possible for this form to be the elongated form studied to facilitate its deposition with the device, or its production once deposited.

The shape of the device and of the formulation is thus not adapted a priori to the zone of insertion as the Ocusert, vaginal ring or the stents can be. The shape of the formulation, however, can develop after administration to facilitate its local maintenance.

After its administration, the formulation is not combined with all or part of the deposition device but left on its own at the depot site.

If, for a specific need and therapeutic period, insertion into a natural cavity of the body is not desirable, the targeted, or even prolonged, treatment will also be able to be implanted inside a target tissue of the body to allow its administration over the release period.

It will be possible to carry out this implantation with the device combined with conventional tools, by the transcutaneous route or by the vascular or cavitary route in a mucous membrane or a wall of the body or by the surgical route in a target tissue.

The insertion of the delayed-release form will allow a local, superficial or external treatment, but also targeting for a deep effect, or even for a systemic effect, for example with a deposition to the mucous membranes.

In the same way, the implantation of the delayed-release form will allow general treatment but also targeted treatment by local hyperconcentration or by excretion.

Thus, according to the therapeutic applications and the zone, insertion, like implantation, will be able to be a systemic solution, an internal local solution or, finally, an external targeting solution.

11 It will be possible for the immediate or delayed-release solid or semi-solid formulations used in the process of the invention to be any solid or semi-solid formulations whatsoever capable of being able to be made or packaged in the form and the volume compatible with the process and the injection device.

Thus, it will be possible for the solid or semi-solid formulations preferentially to be formulations produced from biodegradable excipients such as, for example, inorganic salts (calcium, magnesium, bismuth, zinc); lipids; carbohydrates (polysaccharides, sucrose, glucose, agarose, dextrin, cyclodextrin and mixtures); proteins (gelatin, modified collagen, albumin, casein, derivatives and mixtures); natural and synthetic polymers (polyisobutyric acid, polylactic acid, polyglycolic acid, polylactidepolyglycolide copolymer (PLGA), polyester, polycaprolactam, polyethylene glycol, polypropylene glycol, ®Pluronics, polyanhydrides and their mixtures).

It will be possible to produce the solid or semi-solid formulations without excipient or structured with small quantities of injectable excipient of manitol, hyaluronic acid, cellulose derivatives type etc.

It will be possible to produce the semi-solid formulations by mixing the AP with or without excipient, with water, an organic solvent, oil or any other injectable liquid capable of giving the semisolid form.

The solid or semi-solid formulations will be either immediate formulations or delayed-release formulations.

It will be possible to produce the solid immediate formulations as indicated in the SCRAS patent (Delivery of Solid Drug Compositions WO 96/07397). It may be possible to. produce the delayed-release semisolid and solid formulations according to the formulation and the process claimed by the SCRAS patent (Sustained Release of Peptides from Solid and Semi- 12 solid pharmaceutical compositions WO 96/07398 whose contents are incorporated by reference) The solid or semi-solid formulations will advantageously be produced according to processes allowing a high concentration of active principle of greater than 20% or even greater than 40%, preferably of greater than 50% and up to 100% of AP Before their deposition, the non-dispersed solid formulations according to the invention will have a thin and elongated shape: rod, implant, pellet, stick or needle, so as to be able to be introduced inside the implantation device which will itself be able, if necessary as a function of the depth of the injection into the body, to be inside an endoscope or a catheter.

The dispersed solid formulations (powders, spheres) will have to be able to be arranged longitudinally in the device.

The solid formulations in the device will thus preferentially 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, preferably of less than 1 mm. As a function of the total dose and above all for the immediate forms or the short-duration or low-dose forms (less than 0.1 mg/day), it will be possible for the diameter of the solid forms to be even smaller and down to 0.1 mm.

It will be possible for the smallest diameters, in certain cases, to have a technical advantage to facilitate deep local implantation; however, with catheters and endoscopes, a greater diameter will not have the same disadvantages (especially in terms of comfort of the sick person) as in the case of trocartype, superficial injections (Zoladex, trademark registered by Zeneca) or mini-trocars (Auto-injector, Retro-injector: Needle-less Parenteral Introduction Device WO 96/08289 whose contents are incorporated by reference) or because the use of medical devices necessitates, in addition, local or general 13 anaesthesia, or alternatively because the deep implantation zone is less sensitive than the skin.

It will be possible for the solid forms to have a length of a few centimetres, in general of less than 3 cm and preferentially of less than 2 cm and suited to the space in the depot zone.

The solid forms will preferentially 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 AP (preferentially greater than 020%) and to remain homogeneous while allowing deep injections through the needle of the device of the invention.

S0 15 It will be possible for the semi-solid forms to be gels, oils, pastes or any other semi-solid dispersion of an AP in a liquid vehicle.

S"The semi-solid forms will have a low total volume, in general of less than 300 l and preferentially of less than 100 Al or even less than 50 Al.

The method and the devices according to the invention .00o will preferentially use injectable excipients which are biodegradable or normally eliminated or solubilized in the body fluids.

However, it will be possible for the method to use devices or formulations based on non-biodegradable biocompatible biomaterials when the site and the deposition tools will easily allow the withdrawal of the said device or of the said formulation after its action, that is to say rather for inserts than for implants. The device or the formulation will have to have a thin and elongated shape, like the other solid forms compatible with deep local administration like, for example, Norplant silicone implants,

PHEMA

reservoir systems from Hydromed, or even Duros osmotic pumps from Alza.

The devices according to the invention correspond to the solid or semi-solid formulations combined P.OPER\Arl\2183272 rc 178.doc-03/07/01 -14with the localized deep insertion or implantation device.

It will be possible for the devices to be used directly or combined with the medical instruments for local therapy (endoscope, fibroscope, tube, catheter, spike, aerator, cannula, perforator, trocar...).

The devices will be introduced at the local level and will allow the insertion or the implantation of the semisolid or solid forms. They will be withdrawn immediately after this deposition.

10 The devices are used for deep local administration of Ssolid or semi-solid formulations will be versatile and of low volume with a suited thin and elongated shape.

The devices will thus preferentially have a maximum diameter of 3mm and advantageously a diameter of less than 15 2.5mm or even of less than 2mm. As a function of the formulation, it will be possible for the diameter of the device to be even smaller and down to 0.3mm.

In a fibroscope or an endoscope comprising, for example, 4 channels (video, instruments, introduction and 20 withdrawal of fluid, illuminated optical fibres), it will be S possible for the insertion or implantation device, like a conventional tool (biopsy forceps style) to occupy the channel of the instruments, which frees the channel for introduction of fluids or even allows its elimination. In this case, it will be possible for the devices to have a diameter of less than 2mm and, for example, of 1.7mm like certain instruments.

P:'OPER\ArI2183272 re 78 doc-03107/01 In a catheter, it will be possible for the insertion or implantation device, like the device for insertion of stents, to occupy the channel and to be operated from the exterior in situ. In this case, it will be possible for the device to have a diameter of less than 2.5mm and, for example, of 2mm like certain stents.

In a trocar, it will be possible for the insertion or implantation device, like the perforation device, to occupy Sthe lumen of the trocar. It will be possible for the device S 10 to have a diameter of less than 16 3 mm and, for example, of 2.5 mm like certain perforators.

Other characteristics and advantages of the invention will become clear from the description which will follow, made with reference to the annexed drawings which illustrate several embodiments by way of non-limiting examples.

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

Figures 2, 3 and 4 illustrate a sequence of employing the device of Figure 1 to administer a solid formulation locally in the body.

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

Figure 6 is a transverse sectional view along 6/6 of Figure Figure 7 is a view analogous to Figure showing the device after pushing of the solid form outside a guide of the device, ready to be deposited in the body of a patient.

Figure 8 is a transverse sectional view along 8/8 of Figure 7.

Figure 9 is a view in elevation analogous 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 analogous to Figure 9 showing the needle and the piston inside this completely returned.

P:'DPER\ArI\2183272 178 d.~.03107/01 17 Figures 11 to 16 are views similar to Figures 5 to respectively but in which the device is used to administer a semi-solid form.

The administration device of solid form 1 of formulation represented in Figure 1 comprises a tubular guide 2 containing a piston 3 which is able to push outside the 0 *0 00

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C SO OS 0 O 00 00 C C C 5505 0 OSS CO 0 O C 19 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 manual handling collars 4, Figure 2 illustrates a possible example of the invasive system in the body of a patient for the employment of the device for administration of the solid form 1 of Figure 1. The invasive system is, in the example of Figure 2, a trocar 6 containing a perforator mandrel 7, if the access to the natural cavity of the body used as a reservoir for release of the solid formulation 1 necessitates a perforation of internal tissues. In Figure 2, the invasive system is shown partially introduced inside the body in its part situated to the right of the plane L, while its part situated to the left remains external.

If the access to the natural cavity of the body does not necessitate a perforation of 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 (sinus of the face, oesophagus, trachea, vessel, etc.), with the aid of the perforator mandrel 7 in the case of a system such as that of Figure 2. The mandrel 7 is then withdrawn from the trocar 6 (or from the endoscope, from the catheter, etc.) and the administration device of Figure 1 is introduced inside the trocar 6 (Figure until the collar 4 of. the guide 2 comes up against the bent annular end 8 of the trocar 6.

It is then sufficient to push the piston 3 to eject the solid form 1 outside the guide 2, because no tissue resistance opposes its movement (Figure 4).

In the second embodiment of the device for administration of a solid form 9, illustrated in Figures 5 to 10, this device is intended for the case of an injection of the said device inside a tissue, a wall or a mucous membrane from an internal invasive system already inserted into a cavity as shown in the 20 drawings, but also from an invasive system inserted in an internal tissue.

The invasive system comprises a tubular piece 50 partially inserted in the tissue through the surface P' of the latter, and a tubular guide 11 which can be a fibroscope or an endoscope, in which a catheter 12 can be mounted. The latter forms a guide for the administration device formed by a needle 13 and a piston 14 for extraction of the solid form 9 in the tissue 17.

The device has two movable stops (10, 15) of which the first 10 is a sleeve arranged in a push button 20 coaxial to the piston 14, this stop 10 and the push button being longitudinally truncated (Figure the second is a tubular piece 15, likewise truncated (Figure interposed between the catheter 12 and the push button The injection of the administration device 13, 14, 9, can be obtained by moving the guide backwards, but is preferably carried out as illustrated in Figures 7 to 10, in the following manner. The stop 15 is withdrawn; the needle 13 is moved with the aid of the push button 20 containing the stop 10 (Figure If necessary and as illustrated in Figure 7, especially in the case of vessels, the needle 13 can have at its end a bent shape 13a obtained by liberation of an elastic preconstraint of the needle 13 in the guide. Once the constraint of the guide is liberated, the bent end 13a facilitates the oblique injection of the solid form 9 into the wall or the mucous membrane 17. It will be possible to obtain or set this angle between the needle and the guide by any other mechanism customarily used by these devices.

Once the solid form 9 and the bent end 13 a have been injected, the stop 10 of the push button is removed, and the needle 13 is withdrawn by traction on the lugs 16 without moving 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 -21 the piston 14, the latter is withdrawn with the needle 13, leaving the solid form 9 in place, this movement being obtained by traction on the push button and the lugs 16 (Figure The device of Figures 5 to 10 can likewise allow the administration of a semi-solid formulation.

The administration device illustrated in Figures 11 to 16 is similar to that of Figures 5 to and only differs from it by the fact that the piston 14 acts on a non-solid form 18, in appertaining to a microsyringe up to the point of the injection device.

S"Here also, the invasive system 9, 11, 12 can be inserted in an internal tissue 17.

The administration process here consists in °0 15 injecting by pushing it outside the guide 9, 11, 12 the administration device formed of the needle 13, the piston 14 and the semi-solid form 18. The needle 13 can possibly be bent as in the embodiment of Figures 5 to The piston 14 is moved in the needle 13 to inject the semi-solid 18 (Figure 14) in the same manner as in the preceding embodiment.

o The piston 14 and the needle 13 are finally withdrawn together by reintroduction into the guide 11, 0. 12 by traction on the lugs 16 and on the push button (Figures 15 and 16), the semi-solid form 18 left in place in the tissue 17 then being able to assume a spherical or ellipsoidal form.

S.The drawings of Figures 1 to 16 are to allow the administration processes for different specific treatments described further on to be illustrated.

These different specific treatments according- to the process of the invention of solid or semi-solid local administration involve the employment of the method in order that it can be carried out and thus offer certain therapeutic solutions. These different examples illustrate the possible field of application of the invention, but do not form an exhaustive list of applications of the process 3and are thus not limiting.

P:'OPER\Arl\2183272 res 178.doc-04/07/01 -22- Of the number of possible treatments, according to the method of the invention, it is possible to mention anaesthetic, analgesic, anti-inflammatory, cancerological, cardiological, endocrinological, rheumatological etc...

treatments as well as the combined treatments. Of the number of endoscopic or radiological techniques capable of allowing this local treatment process, it is possible to S* mention urology, gynaecology, arthroscopy, ORL, bronchoscopy, gastrology, minimal invasion or even 0 10 cardiovascular surgery.

These methods use a low volume (microlitres) solid or 0 semi-solid, delayed-release or non-delayed-release pharmaceutical formulation. This formulation differs from existing local treatments which use large-volume specific solid forms or liquid or suspension forms.

The foregoing describes only one embodiment of the invention and modifications can be made without departing Sfrom the scope of the invention.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

0 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

Claims

2. A device according to Claim 1, wherein said packaging e* means are initially placed at the end of the device intended to be placed at the deposit site.
3. A device according to Claim 1 or 2, wherein said packaging means are arranged to allow said formulation to have a thin and elongated, or cylindrical, form.
4. A device according to Claim 3, in which said formulation is approximately cylindrical in form wherein the diameter of said packaging means is such that said formulation has a diameter of between 0.1 and 2 to 3 millimetres. P:\OPERArl\2I t3272 rs 17S.doc-407/01 -24- A device according to Claim 4, wherein said packaging means are arranged to allow said formulation to have a minimum length/diameter ratio of
6. A device according to any one of Claims 1 to 5, wherein packaging means, said positioning means and said injection means are the same.
7. A device according to any one of Claims 3 to 6, wherein said device comprises a piston inside a needle which can be operated in a trocar and/or a catheter.
8. A device according to any one of Claims 3 to 6, wherein said packaging means, said positioning means and said injection means comprises a needle. oooo 9. A device according to Claim 8, wherein said needle is operable by said operating means to be orientated with respect to said device by elastic preshaping or preconstraint or by mechanical means. A device according to Claim 8, wherein said operating means provides, in a sequential fashion, the injection of said needle, the advancement of said piston as far as the bevel of said needle, to deposit said formulation, the withdrawal of said needle around said piston and the combined withdrawal of said needle and of said piston.
11. A device according to Claim 10, wherein the sequential operations of the device by said operating means are R remotely controlled and with the aid of two movable stops, the first stop being arranged on a push button coaxial to P:\OPERU'A\2183272 rm 17S.do-4/O7/01 said piston, and the second stop is a tubular piece inserted between a guide and said push button.
12. A method for the implantation or insertion of a solid or semi-solid formulation, at a precise deposit site of a body, containing at least one active principle, said formulation being of solid or semi-solid consistency such that it is able to persist for a certain period in said deposit site, and containing a limited dose of active principle for a treatment in a targeted zone of the body, said method comprising the steps of packaging said formulation into packaging means of an implantation device, placing a part of said device comprising said packaging means inside the body of the patient, positioning said packaging means at said deposit site through positioning oo oo Smeans of said device, injecting or inserting said @000 "0000 formulation at said deposit site by injection or insertion 00o0. means of said device, and withdrawing said device after 0 0. injection or insertion, wherein a part of said device, being external of the body during use, has means of operating said device. S
13. A method according to claim 12, wherein said packaging means are initially placed at the end of said device intended to be placed at said deposit site.
14. A method according to claim 12 or 13, wherein said packaging means are arranged to allow said formulation to have a thin and elongated, or cylindrical, form. A method according to claim 14 in which said formulation is approximately cylindrical in form, wherein P:AOPERWI\2 183272 -m 178.doc-19/07/01 -26- the diameter of said packaging means is such that said formulation has a diameter of between 0.1 and 2 to 3mm.
16. A method according to claim 15, wherein said packaging means are arranged to allow said formulation to have a minimum length to diameter ratio of
17. A method according to any one of claims 12 to 16, S* wherein said packaging step, said positioning step and said injection step are performed by the same integer of said :device. *o
18. A method according to any one of claims 14 to 17, wherein said device comprises a piston, inside a needle which can be operated in a trocar and/or a catheter. 0 "0000" 19. A method according to any one of claims 14 to 17, 00 0 wherein said packaging step, said positioning step and said injection step are performed by a needle.
20. A method according to claim 19, wherein said needle is operable by said operating means to be oriented with respect to said device by elastic preshaping or preconstraint or by mechanical means.
21. A method according to claim 19 wherein said operation means provides said injection step and said withdrawal step to be performed in a sequential fashion, said injection step comprises injection of said needle, the advancement of said piston as far as the bevel of said needle, to deposit said formulation, and said withdrawal step comprises the withdrawal of said needle around said piston and the ?.\OPERAr2 183272 r 178.do.-4/07/01 -27- combined withdrawal of said needle and of said piston.
22. A method according to claim 21, wherein the sequential operations of said device by said operation means are remotely controlled with the aid of two movable stages, the first stop being arranged on a push button coaxial to said S. piston, and the second stop is a tubular piece inserted between a guide and push button.
23. An assembly for the implantation and insertion of a Ssolid or semi-solid formulation containing an active principle, at a precise deposit site of the body, wherein said assembly comprises a device defined in any one of Claims 1 to 11 and, in said device, said formulation to be delivered is contained in said packaging means. oooo• oooo
24. An assembly according to Claim 23, wherein said assembly is arranged to be inserted inside a trocar. *o S An assembly according to Claim 23, wherein said assembly is arranged to be inserted inside a catheter. o••o•
26. An assembly according to Claim 23, wherein said assembly is arranged to be inserted inside an endoscope.
27. An assembly according to Claim 23, wherein said assembly is arranged to be inserted inside an instrument adapted for surgical route of approach.
28. A device for the implantation or insertion of a solid or semi-solid formulation, at a precise deposit site of a body, containing at least one active principle, said P:OPER\ArlU 183272 r 178 doc.-1510SOI @0 0 0 0 0 0 0 0 0 0@ 0 @0 0 S 0 @0 0 -28- formulation being of solid or semi-solid consistency such that it is able to persist for a certain period in said deposit site, and containing a limited dose of active principle for a treatment in a targeted zone of the body, substantially as described with reference to the drawings and/or examples.
29. A method for the implantation or insertion of a solid or semi-solid formulation, at a precise deposit site of a body, containing at least one active principle, said formulation being of solid or semi-solid consistency such that it is able to persist for a certain period in said deposit site, and containing a limited dose of active principle for a treatment in a targeted zone of the body, substantially as described with reference to the drawings and/or examples. DATED this 15th day of August, 2001 Societe de Conseils de Recherches et D'Application Scientifiques Scras By DAVIES COLLISON CAVE Patent Attorneys for the applicant