Solid pharmaceutical form prolonged action for parenteral administration and its preparation
The invention relates to pharmaceutical industry and relates to solid dosage forms prolongirovannogo steps and method of receipt. The invention consists in that the solid preparation of the deferred action for parenteral administration includes a homogeneous mixture of the active principle in non-dispersible condition and biocompatible biorazlagaemykh excipient. Proposed also a method of obtaining a pharmaceutical form prolonged action. The invention provides improved local performance of local treatment, you can reduce the dose and side effects. 4 C. and 66 C.p. f-crystals, 39 ill. The object of the present invention is a therapeutic method of the target non-cryogenic treatment galenovye drugs, as well as receipt and a device for implementing this method.In practice, the known benefits of treatment or local administration of medication, in which the active principle (an) mainly goes to the range. On the other hand, it is proved that oral or parenteral administration of the drug and its diffusion system in some cases may not give satisfactory results. In addition,giovannoli actions it is preferable to introduce the drug into the appropriate area.In addition to improving local performance of local treatment compared with the overall treatment allows first of all to reduce the dose and side effects, in particular related to the Academy of Sciences in the areas of the body, where its presence does not bring any benefit or harm.Local injection of medication allows, therefore, to improve therapeutic index of the drug in a possible reduction of its overall toxicity and risk of systemic effects.Dosage forms for topical use, such as skin, eye, Polotno-nasal, lung, and gastric or rectal, became the first aparentally forms for local administration. In cases when the area of drug inaccessible or require invasive forms and when treatment should be repeated or, moreover, be carried out continuously, even if the advantage of local treatment obviously, in practice, its application is hindered by the complexity and even the inconvenience of multiple therapeutic interventions.On the other hand, the well-known advantages of application of preparations of prolonged or delayed action, allowing zjazev.This form of deferred action contributes to the compliance process, as well as adherence to treatment thus depends not on the patient, not from the medical staff, and the method of preparation. This prolonged effect increases comfort for the patient who is no longer associated procedures and thus acquires a regular constant dose, independent of medication doses.The development of dosage forms of deferred action has led experts to the need to study their local applications, in particular, in the above case, when the injection difficult. Form of deferred action allows you to avoid having to repeat the administration of medication or, more importantly, the surgical intervention. You can search for achieving high local drug concentrations for a long period without application of significant systemic doses and, consequently, with fewer side effects. This solution is particularly useful as applied to quickly split drugs or have a short half-life, when they entered the system path.Thus, there may be course local target treatment prolonger istia. Cancer and, in particular, solid tumors may first be treated with the use of local forms, allowing to reduce the total injected dose cytotoxic or antitumor compounds and simultaneously to increase the concentration in the tumor area, which is the object of treatment. This enables you to avoid severe side effects with this type of treatment.Matrix Pharmaceutical offers the drug delayed action on the basis of collagen, which may be injected into the tumor by injection (IntraDose CDDP-Cisplatin). This drug is injected into the cancerous area or in place of skin lesions by means of the syringe 3 CC, and, if necessary, needle biopsy for less accessible areas. When the volume of viscous liquid to 2 ml he, therefore, restricted to use only in relatively accessible (peripheral) areas and treatment.You can also call the MITSUI patent (FR 2497661; JP 562737), which describes polylactid-polyglycolide form (PLGA) in the form of sticks or needles for local use, enabling direct implantation in the area or organ within the body, for example in the tumor area before or after entereza.In the case of forms of Gliadel (Guilford) describes prema surgery on brain tumors (glioblastomas).In modern medical technology such targeted treatment inside the body yet is often associated with complex surgical interventions. It uses a prolonged action of the drug, but it is more difficult again.Practice operations associated with oily chemo-embolization, which consists in injecting into vessels suspensions (microspheres), gels or adhesives together with the solvent, which can occlude the vascular supply path and to release an on the level of the tumor. The blockage is achieved by a sediment after removal of the injection medium. With this method for introduction of fluid into the vessel using a catheter for percutaneous transluminal angioplasty.Local application of forms of deferred action also provides for certain body cavities and more accessible areas of the body.SystemOcusent (Alza) is an oval, and flexible eye insertat forming a reservoir device of deferred action, which includes the membrane of ethylene-vinyl acetate copolymer, and which may contain, for example, pilocarpine.The specified device is placed in the fornix of the conjunctiva and visualjockey to achieve the same effect on intraocular pressure. Therapeutic efficacy of pilocarpine in the treatment of glaucoma increases 8-10 times compared to local drops through the use of a form of deferred action.In U.S. patent 3545439 listed as links described intravaginal form of deferred action, representing a ring, made of silicone elastomer, which releases the drug in a few weeks.In this case, the local drug delayed action on the mucous membrane of the vagina also allows, thanks to an, to ensure the overall effect (contraception).Medical device described "Bukh Meditee" (international patent application PCT WO 89/03232 listed as a reference), can be entered into the body cavity of the matrix form of deferred action, made on the basis of substance, almost impervious to water and containing an.Form of deferred action in conjunction with the device thus provides a local an admission during the entire time that the specified device. Such a device may represent, for example, a catheter for the urethra, introduced into the bladder and connected to antibiotico volume you can use some existing methods of local injection. Based intraurethral methods, C. R. BARD, for example, has developed a form (Transuretral delivery Kit), which is a syringe with a solution of collagen in glutaraldehyde that can easily inetservices in sizes from 2.5 to 7.5 ml of forming implants without active principle in the framework of plastics against incontinence of urine.The development of fiber optic systems have made these catheters, releasing an from his end right at the point of destination. Unlike just open catheter is used to release the fluid, the local administration can be achieved using a catheter with dual spray or porous catheter with multiple holes. This solution topical application, however, is limited by the time of introduction of the catheter. The pressure required for penetration of the liquid through the wall, also creates a problem of endurance.For liquid forms of effective local injection at the wall can be made using injection system that is connected to the canister (Interventional Technologies), or catheter with a tapered needle (Bavarian Medical Technologies). However, the period of use of the drug may not be long when such liquid forms of immediate action.Part of the device may remain in the locale which which shunts, used, for example, in angioplasty for prevention of restenosis, which may be coated with a layer containing the active principle, sometimes with the effect of deferred action. In this case, two problems arise: the first is to achieve the adequacy of the used drug specific way to "cover" ("coating"). The second problem is the limited total dose of space and surface, provided by the shunt.When using heparin, for example, in some of the developments mentioned the importance of local treatment for the prevention of systemic side effects. In accordance with these studies, heparin inhibits the proliferation of smooth muscle cells after endothelial injury. The use of the system in the form of subcutaneous forms or local forms of deferred action entered in the immediate vicinity of the vessel, always leads to a decrease neointimal proliferation, but the local form is the only one that does not entail systemic clotting disorders.You can also give an example of osmotic pumps, used to facilitate the local delivery of drugs, prolonged action, while VI is the more shall not apply to the people.All these examples demonstrate the use and benefits of local treatment, especially if it can be prolonged.However, all these solutions have some drawbacks, among which the most significant are the lack of polivalentes each of this solution, the need of combining with a specific device, which remains fully or partially implemented during the introduction of the drug, and, finally, the limitations of the injection volume, and consequently, dose EN.Each of these solutions enables the treatment of only one or a few particular cases in a precisely defined region of the body.Vectorization using local injection is sometimes called the first generation in relation to drugs preventive actions "prodrugs" and the vectors (liposomes...), called the second generation, or in relation to macromolecular systems diagnosis or activate a specific area, called the third generation. These decisions, however, even more than modern methods of local administration, are very specific, not used in all cases and sometimes not differ accuracy.The purpose of this image is Oribatei through the introduction of endoscopic techniques are flexible (fibroscopy) or hard (endoscopic) surgery and operating room radiology (active or inactive catheters).The advantage of non-dispersive solid or semi-solid preparations is that they occupy a minimum volume while maintaining the quantity of an appropriate therapeutic dose. Thus, solid and semi-solid forms of deferred actions allow a few days of treatment when the size of a few microlitres.Local injection of a drug can significantly reduce the total therapeutic dose while maintaining the desired effect.The combination of solid or semi-solid form of deferred action with the local introduction allows microdosimetry, adapted for local insertion through a sufficiently large time intervals.Modern development of the television, optical and micromechanical technologies applied to medicine in the field of development of intravascular or abdominal instrumentation and surgery with minimal intervention led to the creation of a more subtle and precise tools that allow local deep surgical intervention in the body with minimal surgical trauma and, consequently, to increase the number available for such intervention zones.The present invention Ave is practical and medical technologies.Which is the subject of the present invention, the method of implantation or introduction of the active agent contained in the solid or semisolid preparation, in a specific area of the body is that receive solid or semi-solid product, enter it in the device that can operate remotely, to deliver this unit in the specified location of the introduction, placing it inside the classic surgical instruments and to implement or to implant such medication by actuation of the specified device.In accordance with other features of the invention: - the place of introduction is not available for syringe or classical subcutaneous trocar; - the specified solid or semi-solid drug after its introduction into the device gets thin and elongated shape; - the specified device is thin and elongated so that it could easily move to classic surgical instruments; - the specified solid or semi-solid drug is a drug of deferred action; - the specified thin and elongated shape is different minimum ratio of length to diameter equal to 10; - the specified device is the capacity for the specified is Jindrisska; is this implantation is carried out in the tissue in the mucous membrane or the inner wall of the body through the cavity; - this implantation is carried out in the tissue in the mucous membrane or the inner wall of the body through the vessel, arterial or venous;
is this implantation is carried out in tissue, tumor or pathogen zone surgically;
- the specified implementation is carried out in a body cavity or organ by intracavitary;
- the specified implementation is carried out in a body cavity or organ or tissue invasive or surgically;
- the specified active principle is an anti-inflammatory agent;
- the specified active principle is a peptide or analogue of the peptide;
- the specified active principle is an antitumor agent;
- the specified active principle is a mixture of two or more active principles.The object of the present invention is:
a method of therapeutic treatment in which the active principle contained in a solid or semi-solid preparation is introduced into the body cavity so that the specified active principle released in the liquid on the surface of the specified cavity and could act locally is aculo, contained in solid or semi-solid preparation, is implanted in the lining or internal secretory tissue of the body so that the specified active principle released and allocated together with the natural fluids and can act locally or in the direction of the drainage areas;
a method of therapeutic treatment in which the specified active principle has a local and/or systemic action, starting with the area where you have placed the implant;
- a method of therapeutic treatment of otorhinolaryngological disorders, in which the active principle in solid or semi-solid drug is injected into the facial cavity or covering mucosa;
a method of therapeutic treatment in which the specified active principle is corticoids;
a method of therapeutic treatment of diseases of the blood vessels, veins or arteries, in which the active principle contained in the solid and semi-solid drug is introduced into the vessel wall or around it by intraluminal injection.Pharmaceutical and medical aspects of the invention are closely intertwined with the development of thin and miniature systems, which can easily fit and be active in all areas of the body the aqueous instrument quite long and thin in order to achieve implementation. Shape (long and thin) of the drug in the device for introducing facilitates its local introduction. This characteristic of the system in its pharmaceutical and medical aspect will provide its General application.If the implementation is understood as a form, put on the surface and under the implantation injection into the tissue, the tool target, and prolonged treatment is embedded inside natural cavities of the body, if it can play the role of the natural reservoir, that is, if the form of the introduction of the drug allows him to remain in the cavity at least during the period of its release. This form can be either elongated, designed to facilitate its introduction together with the device or after changing its introduction.Consequently, the shape of the device and the drug does not necessarily have to be a priori adapted to the area of implementation, as Ocusert, vaginal ring or shunts. However, the form of the drug may change after the introduction to make it easier to hold in the introduction. After the introduction of the drug is not connected fully or even partially with the device, and remains alone in the place IHC introduction into a natural cavity of the body is undesirable, medication and even prolonged action may also be implanted accurately to the required tissue of the body to allow its introduction for the entire period of release.This implantation may be carried out using a device connected with classical instruments, dermal, vascular or abdominal by in the lining or wall of the body, or surgically in a given tissue.The introduction of a form of deferred action will provide local, superficial or external treatment, as well as preconceived treatment for deep, even for systemic effects, for example with the introduction of the mucous membrane.Similarly, implantation forms of deferred action will allow for General treatment, as well as local specified treatment by local hyperconcentration or by selection.Thus, depending on therapeutic application and region, implementation as well as implantation, can solve problems of the appointment system, local domestic destination or finally specified external destination.Solid or semi-solid preparations immediate or delayed steps used in the method in accordance with this is acouchi in the manner and to the extent compatible with the method and apparatus for injection.Thus, solid and semi-solid preparations are mainly to be products manufactured on the basis of biodegrading of excipients such as inorganic salts (calcium, magnesium, bismuth, zinc); lipids; carbohydrates (polysaccharides, sucrose, glucose, agar, dextrin, cyclodextrin, and mixtures thereof), proteins (gelatin, modified collagen, albumin, casein, derivatives and mixtures); natural or synthetic polymers (polyisobutylene acid, polylactic acid, polyglycolic acid, polylactic-polyglycolide copolymer (PLGA), polyester, polycaprolactone, polyethylene glycol, polypropyleneglycol,Pluronics, polyanhydride and mixtures thereof).Solid or semi-solid preparations can be made without excipient or be structured with a small amount of injectable excipient type mannitol, hialuronowy acid, cellulose derivatives, etc.Semi-solid preparations can be manufactured by mixing an with or without excipient with water, an organic solvent, oil or any other suitable for injection fluid, contributing about and deferred action.Solid preparations immediate action can be manufactured in accordance with the patent SCRAS (Delivery of Solid Drug Compositions WO 96/07397). Semi-solid and solid dosage forms of deferred action can be manufactured in accordance with the formula and method described in the patent SCRAS (Sustained Release of Peptides from Solid and Semisolid pharmaceutical compositions WO 96/07398) that are listed as references.In an advantageous embodiment, the solid or semi-solid preparations should be made in accordance with the methods, providing greater concentration of the active agent in excess of 20% and even 40%, and in the preferred embodiment, greater than 50% and up to 100% EN.Before the introduction of solid non-dispersible preparations in accordance with the present invention should have a thin and elongated shape; a rod implant, spatula, stick or needle placed in the device for implantation, which in turn in case of need and depending on the insertion depth in the body can fit inside of an endoscope or catheter. Dispersed solid dosage forms (powders, pellets) should be placed in the device in the longitudinal direction.In this regard, solid preparations that are placed in the device should have a maximum diameter of 3 mm, awns of the total dose and especially for forms immediate action or for forms of short term or low-dose (less than 0.1 mg per day) diameter solid forms must be even less up to 0.1 mmIn some cases, the minimum diameter has a technical advantage to facilitate deep local implantation, however, in the case of the use of catheters and endoscopes larger diameter will have the same disadvantage (in particular, in relation to the comfort of the patient), as at surface injection type trocar (Zoladex registered trademark of "Zeneca") or minirouter (autoinjector, retronectin: Needle-less Parenteral Intrudction Device WO 96/08289 cited references), because the use of medical devices requires, inter alia, local or General anesthesia, either because deep implant region is less sensitive than the skin.Solid forms may be several centimeters in length, generally less than 3 cm, and preferably less than 2 cm, and can be adapted for the area of introduction.Solid forms should preferably have a cylindrical shape; get them using extrusion technique.Semi-solid form in accordance with the present invention should have a sufficiently high viscosity to have a high concentration of NA (preferably above 20%), and remain homogeneous, while allowing him which may be a gel, oil, pasta or any other semi-solid dispersion in an liquid medium.Semi-solid forms must be small the total amount, generally less than 300 μl, and preferably less than 100 μl, and even less than 50 μl.In the method and device in accordance with the present invention in a preferred variant should be used injectable excipients - biodegradable, or naturally flushed out of the body, or dissolving in the inner fluids of the body.However, the method can be applied to devices or preparations made on the basis of neiderberger biocompatible biomaterials, if the injection and tools introduction make it easy to display the specified device or specified form after completion of the action that is to be applied is likely to insertitem than for implants. The device or the drug should have a thin and elongated shape, as well as other solid forms, adapted to the deep local introduction. Examples include silicone implants "bullet added" system-tanks "MAMA" company "Hydromed", as well as osmotic pumps "Duros'" firm "Alza".The device in accordance with the present invention correspond to the solid or protosovitskiy with the present invention for implantation or introduction of the active agent, contained in solid or semisolid preparation, in the specified area of the body differs in that it includes a one piece injected into the patient's body together with the means of packaging solid or semi-solid form, means of delivery to the place of introduction, by means of injection or introduction into the specified location of the injection means and return after the injection or introduction, and one part remaining outside together with the means of activation functions of the device.In accordance with other characteristics:
- packaging tools solid or semi-solid forms are also means of delivery and injection;
- the specified device includes a piston inside the guide tube, which is able to operate within a trocar or catheter;
- means of packaging, delivery and injections is the needle;
- after activating this needle can be oriented with respect to the device by reformowania or pre elastic tension or mechanical means;
- external activation device allow you to consistently carry out the injection needle, the forward movement of the piston to gazetki needle for removing solid or semi-solid, FWA using external funds are managed at a distance and in a certain order by using two removable lugs, the first of which is located on the pusher installed coaxially to the piston, and the second is a tubular part, which is placed between the guide tube and pusher.The device can be used directly or in conjunction with the medical instruments of local therapy (endoscope, fiberscope, tubes, catheters, nails, aerators, cannulas, punches, trocars...).Device is connected to the place, and they help carry out the introduction or implantation of a semi-solid or solid forms. After this, they immediately retrieved.As well as dosage forms used in accordance with the present invention the device for implementing the method of introduction of solid or semi-solid preparations are polyvalent and have a small volume, and the corresponding thin and elongated shape.Therefore, the device should have a maximum diameter of 3 mm, and in the preferred embodiment, the diameter less than 2.5 mm and even less than 2 mm, depending on the dosage form, the diameter of the device may be even less, up to 0.3 mmThe fiberscope or the endoscope, for example 4-channel video channel, channel injection and extraction fluid, the instrument channel and optical svetovolokna), astrologically channel, that frees up a channel for introducing the liquid and even allows you to clean it up. In this case, the device can have a diameter of less than 2 mm, for example, 1.7 mm, as some tools.The catheter device for the introduction or implantation, as a device for the implementation of shunts, to take the channel to be activated after its delivery to the place. In this case, the device may have a diameter of less than 2.5 mm, for example 2 mm, as some shunts.The trocar device introduction or implantation, as a device for punching, to occupy the cavity of the trocar. The device may have a diameter of less than 3 mm, for example 2.5 mm, as some punchers.Other characteristics and advantages of the invention evident from the following description given with reference to the drawings applications that illustrate the different ways of implementation as examples, without limiting their opportunities of the invention.Fig. 1 - the main view in longitudinal section of a first variant of the device for the introduction of solid preparations in accordance with the present invention in the case of the introduction of the drug into a natural cavity of the body, used as a reservoir for the drug.In Fig.2, 3 and 4 show the sequence Rainie half-foreign, half a longitudinal section of a second variant of the device for the introduction of drugs in accordance with the present invention, shown partially introduced into the patient's body and prepared for the introduction of solid drug.Fig.6 - the image in the cross section along the line 6-6 of Fig. 5.Fig.7 is an image similar to Fig. 5, showing the device while pulling the solid form of the guide tube of the device in the ready position to its introduction into the patient.Fig.8 - the image in the cross section along the line 8-8 of Fig. 7.Fig. 9 is an image similar to Fig.5 and 7, the device after partial extraction of the needle, this solid form remains in the body.Fig.10 is an image similar to Fig.9, showing the needle and located inside the piston after their return to the device.Fig. 11-16 - image that is similar to, respectively, Fig.5-10, which shows the use of the device for the introduction of semi-solid form.Fig. 17, 18 and 19 of the image release in vitro of insertitem dexamethasone at a concentration of respectively 10, 15 and 20%.Fig. 20, 21 and 22 - a picture of the results of pharmacokinetic studies in the rat of insertitem dexamethasone, respectively, with the concentration CI research solid forms of 12.8 mg lanreotide respectively dog intramuscular injection and voluntary healthy patient after subcutaneous and intramuscular (C) injection.Fig.25 image pharmacokinetic studies in healthy voluntary patient semi-solid form 40 mg lanreotide intramuscular injection.Fig.26 - the profile picture release in vitro matrix preparation of the acetate of triptorelin/PLGA (75:25) at 20% of the active agent.Fig.27 - the profile picture release in vitro drug in accordance with the present invention acetate of triptorelin/PLGA (75:25) with 52% of the active agent.Fig. 28 - the profile picture release in vitro drug of pamoate of triptorelin (active principle) and PLGA (50:50) at 40% of the active agent.Fig. 29 - the profile picture release in vitro drug of pamoate of triptorelin (active principle) and PLGA (50:50) with 52% of the active agent.Fig. 30 - the photographic image of the preparation of the acetate of triptorelin and PLGA (75:25) at 20% of the active agent, placed in a physiological environment (in vitro) after one hour, 1 day, 2 days, 3 days, 7 days and 10 days.Fig. 31 is a photographic image of the preparation of the acetate of triptorelin and PLGA (75:25) with 52% of the active agent, placed in a physiological environment (in vitro) after one hour, 1 day, 2 days, 3 days, 7 days and 10 days.Fig. 32 - the profile picture release in vitro three forms in accordance with the present invention, with 52%, 70% of the Vuh forms in accordance with the present invention, with 52% of the active principle (acetate of triptorelin) for doses of 9 mg and 6 mgFig.34 - the image changes according to the time level of the active agent remaining in the implant injected rat for drugs at 52%, 70% and 80% of the active principle (acetate of triptorelin).Fig. 35 image changes over time of the absolute residual amount of the active agent remaining in the implant injected rat for drugs at 52%, 70% and 80% of the active principle (acetate of triptorelin).Fig. 36 - image kinetics in dog plasma concentrations for preparation of the acetate of triptorelin/PLGA (75:25) at 20% of active principle and at the dose of 3 mg with tracking pharmaceutical effect on testosterone levels.Fig. 37 - the image of the kinetics of the dog in the plasmatic concentrations for preparation of the acetate of triptorelin/PLGA (75:25) with 52% of active principle and at a dose of 6 mg with tracking pharmaceutical effect on the level of testerone.Fig. 38 profile picture release in vivo in dogs drug acetate of triptorelin/PLGA (75:25) at 70% of the active agent to the dose of 9 mg (a) tracking pharmaceutical effect on testosterone levels ().Fig. 39 - the profile picture release in vivo in dogs drug acetate of triptorelin/PLGA, with 52% of the active agent to the dose of 6 mg and 70% Akti is abused tube 2 with a piston 3, able to push out from the guide tube 2 which is in solid form 1. Tube 2 and the piston 3 have at their opposite ends the respective flanges 4, 5 for manual manipulation.In Fig.2 shows a possible example of invasive system introduction into the patient to actuate the device for introducing solid form 1 shown in Fig.1. In the example of Fig.2 invasive system is a trocar 6 with mandrel-punch 7, if for penetration into a natural cavity of the body, used as a reservoir for solid preparation 1, the desired perforation of internal tissues. In Fig.2 invasive system shown partially inserted into the body part on the right side of the plane L at that time, as it is located on the left part remains outside.If for penetration into a natural cavity of the body does not require perforation of internal tissues, invasive system can be an endoscope, fiberscope, or catheter (not shown). Used invasive introduced into the body cavity (facial sinus, esophagus, trachea, vessel...) using mandrel-punch 7 in the case of the system shown in Fig.2. Then the rod 7 remove the e in Fig.1, until the flange 4 of the tube 2 abuts the annular curved end 8 of the trocar 6.After that just press on the plunger 3 to push solid form 1 of the tube 2, as its promotion meets with no resistance from the tissue (Fig.4).In the second variant of the device for introducing solid form 9, as shown in Fig. 5-10, the specified device is provided for its introduction into the tissue wall or mucosa of the inner invasive system that is already in the cavity, as shown on the drawings, as well as from invasive system introduced in the internal tissue.Invasive system includes a tubular part 50, is partially introduced into the tissue through the surface of P', and the guide tube 11, which may be a fiberscope or endoscope, which can be installed catheter 12. The latter serves as a guide device for the introduction, consisting of needle 13 and piston 14 to propel the solid form 9 in the fabric 17.The device includes two removable support (10, 15), the first of which is a nut in the plunger 20, which is located coaxially to the piston 14, with the specified stop 10 and the pusher truncated in length (Fig. 8), and the second tubular part 15, also truncated (Fig whom the promise by moving the guide tube back however, in the preferred embodiment, it is produced, as shown in Fig.7-10, as follows: pull the stop 15, the plunger 20 with the stop 10 move the needle 13 (Fig.7). If necessary, as shown in Fig.7, in particular, when introduced into the vessel, the needle 13 can have on the end of a curved shape 13A obtained by releasing the needle 13 from a predefined elastic stresses in the guide tube. After his release from elastic stresses the curved end 13A facilitates the introduction of solid forms 9 at an angle to the wall or mucous membrane 17. The angle between the needle and the guide tube can be obtained and be governed by any other mechanism, commonly used in such devices.After the introduction of solid forms 9 and a bent end 13A of the plunger 20 is removed, the stop 10 and pull the needle 13 with the projections 16, not moving the piston 14 to lay a solid form 9 in the fabric 17 (Fig.9). As soon as faceto 13b needle 13 will reach the end of the piston 14, the latter is extruded together with the needle 13, leaving a solid form 9 when this operation is performed by moving the back of the pusher 20 and the lugs 16 (Fig.10).The device shown in Fig.5-10 may also ispolzovaniya in Fig.5-10, and differs from it only in that the piston 14 acts on the unsteady form 18, according to the principle of microspace, until the end of the injector.In this case, invasive system 9, 11, 12 can also be introduced into the inner fabric 17.Route of administration in this case is the introduction, by pushing of the guide tube 9, 11, 12, the device for introducing consisting of needle 13, a piston 14 and a semi-solid form 18. The needle 13 may be curved, as in the embodiment shown in Fig.5-10. The piston 14 is moved to the needle 13 to eject semi-solid form 18 (Fig.14) is the same as in the previous embodiment.The piston 14 and the needle 13 pull together through the guide tube 11, 12 with the projections 16 and the plunger 20 (Fig.15 and 16), while left in the tissue of the 17 semi-solid form 18 may take a spherical or ellipsoidal shape.Schematic image shown in Fig. 1-16, will illustrate the ways in these different specific types of treatment. These various specific kinds of treatment using the method of local introduction of solid or semi-solid preparation in accordance with the present invention require an appropriate way p the invention. Various examples illustrate the scope of possible applications of the present invention, but they are not an exhaustive list of applications of the method and, therefore, are not restrictive.Among the possible treatments in the framework of the method according to the present invention it is possible to specify such kinds of therapeutic effects, as anaesthesia, analgesic, anti-inflammatory, enterological, cardiology, endocrinology, rheumatology, etc. and their associated treatments. Among endoscopic or radiological technology, allowing you to apply this method of local treatment, you can call the urology, gynaecology, arthroscopy, ENT, bronchoscopy, gastrology, surgery with minimal intervention, and Waterlily.Such methods are new, as they use herbal solid or semi-solid preparation is deferred or immediate action small volume (Microlitre). Specified drug differs from existing local treatment that are used in specific solid form or liquid form, or suspensions of large volume.In accordance with this SPO is Noah vectorization. On the contrary, the drug is being developed for the instrument or device, adapted for local internal administration and allows you to manage at a distance of local injection or introduction of drugs.In the specified galenical form and with the use of these tools allows you to use the classical Academy of Sciences, in particular, those who have already proven their applicability in the local introduction or such local applicability of which is derived from the image of an action, even if it is not used in this form, in particular, because such use could not be easily feasible without implementation of the present invention. The following examples illustrate the possibilities of this method.Method, forms and devices allow for intracavitary and interstitial introduction. Whatever
the cavity or tissue, an advantage of the invention is that the drug may be injected into the zone without damage or with minimal tissue damage.These natural cavities can be used as a reservoir for a therapeutic agent, in particular when their anatomy allows you to "conclude" the drug. The method allows, on the way, a number of previously defined goals (increase local efficiency, reduction in dose, increased time steps, reducing the pain and frequency of procedures, reduction of side effects).Vnutrishkolnye or okaloosae insertat or implants deliver an in mucus due to the movement of the cilia of the mucous membrane or provide a system of local diffusion contact means. You can also consider the General steps by the progressive diffusion in the direction of the digestive tract medication requiring daily administration in small doses.Corticoide local actions are a good example of drugs local action, although there are deficiencies in the overall action. However, treatment with the use of existing local forms (drops, sprays...) hits the complexity of the anatomical nature, impede the achievement of specific needed areas, such as the middle passage, single-groove). In addition, when existing treatments have a permanent presence in an area action requires frequent repetition of the procedure.Specified therapeutic method in accordance with the present invention allows to achieve a given key field with rhinosinusal Pato is linolenic and frontal sinuses, the tympanic cavity. Planted or introduced solid or semi-solid form of deferred action will be in contact with the mucous membrane, which allocates and covered with mucus flowing from the gutter into the nasal cavity, resulting in the posterior nasal cavity and come into contact with the tab in Evstafieva the pipe and with Evstafieva pipe.The method allows, for example, to increase and to maintain the concentration of drugs in unicellular groove, which is the center of pathology, in particular, inflammatory processes. If non-liquid form of deferred action is introduced into the sinus, it is necessary to apply the device shown in Fig.1, which can be entered by using the classical drainage of the instruments used in otorhinolaryngology (ENT; trocars, pipes). It is also possible to introduce the drug into the mucous membrane of the nasal cavity, nasal turbinates and the ledge Evstafieva pipe by means of the device shown in Fig.5-16. Depending on the area of administration and dosage form action will be mainly external, interstitial or system.Otolaryngology thus using corticosteroid therapy can be treated, such is the ITA's, etc. In addition to anti-inflammatory treatment can be practiced antibiotic, antiallergic, immunostimulatory and other treatments. Treatments can also be combined. These treatments are based on local action.You can, for example, to produce rods of matrix dexamethasone-phosphate with a level of 15% in PLGA in accordance with the following stages: the weighing of the raw materials, mixing the two powders, extrusion, proportioning, air-conditioning and sterilization. Received the implant can have an average diameter of 2.4 mm at a length of 12.5 mm, It may be injected into the maxillary sinus with the help of the device shown in Fig.1. It may also be implanted in the lining of the nasal shell with the help of the device shown in Fig. 5-10.Specified solid drug is a drug of deferred action for 1 month, containing 7.5 mg of dexamethasone and releasing on average 0.5 mg / day in the presence of the implant in each sinus. For long-term care can be provided vnutripuzarnoe the application of a polymeric forms (PLGA 75-25) with a validity of three months and even tank shape (type Hydromed) with a validity of one year.These funds deferred action p is shatelstve for vnutripuzarnogo introduction will be the same as conventional techniques used in otorhinolaryngology and practiced in the doctor's office: puncture using a trocar with anesthesia or without it. It is possible to prepare the way, if without it you cannot do (meatotomy, nails, drainage and so on).Deep localized injection into the nose at the sink or in the mucous membranes of the nasal cavities can be also simplified thanks to the use of the device in combination with conventional instruments endoscopic examination or independently of them. Introduction into the nasal cavity has a small depth. Depending on the body cavity or space endoscopic surgery the distance between the outer region and inner region of the introduction may be less or much more.In rheumatology already applied corticoide deferred action. In accordance with the specified method can, for example, local intra-articular or periarticular the form of deferred action small volume (corticoide, anti-inflammatory drugs) at the site of inflammation (infectious tendonitis, bursitis, arthritis, arthrosis, and so on). In accordance with the method can also be the treatment of eye diseases by introducing injection into the lining of abalonetti will contribute simultaneously to the effect of deferred action and local maintenance of therapeutic action is better than the introduction to the code of the conjunctiva, which is subjected to intensive drainage. This approach is especially preferred in long-term care, for example, glaucoma with pilocarpine.In this case, the injection is virtually surface and requires no tools other than the device for the introduction of semi-solid or solid preparations in the microvolume.Thanks to the method in accordance with the present invention can also treat some superficial tumors or skin disorders by local intradermal or subcutaneous injection.For example, dermopathy (BIM 23014C) can be used as a semi-solid form of deferred action in 20% aqueous solution and in the amount of 20 microlitres, giving a total dose of 4 mg of somatuline. The drug can inetservices level keloids or melanomas, thus creating an increased and prolonged local concentration of the zone of diffusion gradient to the site of injection.In the case of some solid tumors, the treatment may be combined with the introduction of cytotoxic substances (Type 5FU or cisplatin), the diffusion of which will be governed by the same local form and a local concentration of which is so very you the application, and in this case they are used in conjunction with the type tool active catheter SMA (Shape memory Alloy) or fiberscope and method such as operating radiology or endoscopic or robotic surgery.For example, through access to the cranial box, you can produce intracerebral implantation forms of deferred action BIM23014 WITH plus a cytotoxic agent.Solid or semi-solid form in accordance with the present invention have an advantage in relation to local treatment by type of Gliadel, because they can be used without trephination as at the surface level and deep divisions due to radiographic, endoscopic and robotic surgery.For example, solid tumors, for which treatment is used collagen Matrix form, it is also possible to treat these microdoses. Whatever solid or semi-solid form, the advantage of volume allows vectorization all areas and prevents the risk of proliferation, which may occur during the injection of liquid volume of a few milliliters.Using the same solid or semi-solid form, located at a greater depth in the body after percutaneous transluminal angioplasty can is the treatment according to the method according to the invention has the advantage of that it is not impeded by the lack of space of the vessel and the surface of the device, and that the drug is not in direct contact with the affected vessel wall, while providing a high local concentration in all layers of the vessel and around him, and, if necessary, systemic effect.You can, for example, in accordance with the scheme shown in Fig.5-16, to be injected angiopeptin alone or in combination with heparin. Of course, it is possible to be injected every other an, individually or in combination, can prevent the risk of restenosis and to contribute to a better result.In respect of the said okolososudistoe therapy can also mention the possible use of semi-solid forms for intravascular injection with the same purpose as the oily chemo-embolization using suspension, glue or gel. In this case, the advantage consists in the application form of deferred action, the volume of which (and hence the area of injection) pre-installed, which allows you to better localize the obstruction in the vessel.Method and device in accordance with the present invention in combination with a fiberscope or by any other means, direct or indirect image transfer call the OC through the urethra, you can include the implantation of a drug (preventive medication, antibiotics...) to the thickness of the urethra.You can enter the trachea and bronchi (tubes). Therefore, in accordance with the method according to the invention can provide for the treatment of lung or through the introduction of solid or semi-solid form in the lung, or by implantation in the lining of the bronchi or trachea depending on local tolerability at the introduction of intra-lungs, while the solid form may be dispersed (powder or sphere).For example, to replace preventive treatment by inhalation of corticosteroids in mild or moderate asthma early diagnosis in the lung through the bronchi or in the overlying wall or in the wall of the trachea, you can enter the form of deferred action with a daily dose of 0.4 mg budezonida that will secretariats in the thread, if the form is implanted, and which will be delivered by means of a moisture deep into the lung alveoli. At the specified preventive treatment with small doses without side effect issues no longer occur strict surveillance, in particular, in the treatment of children. This form may have a period of from 1 to 3 months and if necessary even more. For the treatment of p. the present invention.In the esophagus and in the stomach treatment of varicose veins can be provided using local forms, injectable into the wall. Similarly, tumors at this level, bearing an individual character and curable at the present time, for example, using PDT (photochemotherapy), after injection of a photosensitive substances require lighting by controlled introduction of the light diffuser at the local level. Therefore, it is also possible to directly injected anti-cancer tools at this level in solid or semisolid form by means of the device according to the invention. In this case, we can further localize the area of treatment and to avoid unnecessary damage of peripheral tissues.The way the local introduction of solid or semi-solid form requires prolonged presence of an in the introduction. If necessary you can add to the drug means of improving the tolerability at the injection site. For example, you can add a weak concentration of dexamethasone, indomethacin, heparin, or any other EN help eliminate unwanted local effects.Mucous membranes or walls achieve better penetration than the skin, and sumauma system penetration, anal. The disadvantage is sometimes insufficient resistance form in contact with the mucous membrane. The prolonged character introduction in accordance with the method according to the invention at the local level, mucous membranes or internal walls may therefore have an advantage in the development of local forms of systemic action. Depending on the form of local treatment to the drug, you can add a small amount of any excipient that can act as vectors for interstitial infiltration with adapting to an (organic solvents, surfactants, and so on). Thus, local deep form in an advantageous embodiment may be a system of diffusion in relation to the mucous membrane of the mouth or nose, for example, which is not possible topical application of prolonged action.The method in accordance with the present invention will also find application during surgical procedures with minimal invasive endoscopic (laparoscopy, arthroscopy, and so on). Applied Sciences (local anesthetics, anticoagulants. . . ) can be entered in the form of a solid or semi-solid form; it also has the advantage microvolume in accordance with the OTF is mo-naturally because of the way you can implant any other solid or semi-solid form of deferred action, in particular, the PLGA implants. They can be used together with other peptides, recombinant proteins (interferon), polyclonal or monoclonal antibodies, oligonucleotides or antimuslim polynucleotide etc.Hard drugs or implants that can be used for the local introduction of the active agent, as described above, are suitable because of their long and thin shape and a small diameter to the other classical types of introduction, for example, for systemic treatment by skin or intramuscular injection.Unexpectedly, it was also discovered that these solid shapes or implants, in particular, together with excipients PLGA with a high concentration of the active agent, as described above, soluble or insoluble, in particular, compounds having a concentration of between 40 and 100% and preferably above 50% allow in vivo is extremely long periods of release from one to three months and more, and very uniform, even constant levels of release, they performed in the elongated and thin shape, with a diameter the Troy solubility in vitro, regardless of whether they apply for local action or not.In a classic application of such levels of active principle provided for drugs instantaneous or rapid release.The inventors also found that for some forms at uniform distribution of excipient, in particular PLGA, it was possible to obtain the drug delayed action namatratsnik way in which excipient played a different role; this has resulted in better products with other characteristics that clearly distinguishes them from the existing matrix form.These amatrixia forms can be qualified as the matrix form of the active agent, which is dispersed excipient.Apply now and using PLGA matrix form can be either dispersed forms (microparticles) or non-dispersible form (implants).Among the already developed drugs deferred action mainly distinguish forms, called reservoir and matrix forms.In the "tank" forms are used diffusion barriers or membranes between the specified active early and environment, which should serve as a regulator wiswedel or liquid form. It can be in solution or dispersed in excipiente. Due to its porosity membrane provides adjustable output active start out. Among the "tank" systems for soluble active principles can be called hydrophilic mesh membrane from polymethacrylate of hydroxyethyl (pHEMA, Hydro Med Services). "Tank" can be used to obtain a relatively constant release rate of the order of 0. The main disadvantage of tank technology is necessary withdrawal biocompatible implant that is not biorazlagaemykh after the release of the active principle.In matrix form is used, the matrix or polymer base, which contains the active principle released by diffusion, erosion or a combination of these two phenomena.Matrix Nabereznaya form, for example, the implants of the hydrophobic polymer type silicone PDMS (bullet added, progestational hormones act only through diffusion. This type of action may entail decreasing the release of order 1, when the distance of diffusion increases. The disadvantage here is the need to extract a silicone implant after the release of the active h is raised by the body. In addition, such destruction or destruction may participate in the regulation of release of the active agent to achieve a constant release.In the most common currently biorazlagaemykh matrix forms polymers of lactic acid or glycolic acid, copolymers of lactic acid and glycolic acid (PLGA), or a mixture thereof.So, in the European patent 52510 given as reference, describes the preparation PLGA encapsulated with LHRH or its analog, which can be dispersed form of microcapsules produced using koatservatsii, and which feature is the distribution of active beginning in the center of the microcapsules with a peripheral layer of PLGA.From European patent 58481 listed as references, known preparations of peptides and PLGA, dispersed or non-dispersible, such as implants, in which the active principle is distributed homogeneously to the surface and using specific PLGA with the possibility of mutual overlapping of the two phases of release (diffusion and degradation) without a break in the release of the active agent.Many other documents relate to the use of PLGA in drugs deferred actions of human growth hormone, the stability of which is provided in the matrix and in the organic solvents used for microencapsulation, and the release of which is provided by the PLGA matrix. The regulatory process is based on the destruction of the polymer and the next opening of pores in the structure.All made to date development agree that the way the regulation of deferred action with PLGA may entail up to three phases of the release. The initial phase, releasing the active principle by diffusion, latent phase, during which there was no release, and phase release of related forms, correlated with the mass loss of the polymer.In all preparations, using PLGA, the regulation of deferred action is achieved by mixing PLGA and the active agent so that the polymer matrix acted as a barrier to the release of the active principle, and even participated in the physico-chemical interaction between the beginning and the polymer matrix.In all cases, this liberation requires dispersion of the active agent in the polymer borisloseso matrix in such a way as to isolate the load active beginning from outside the lo, which can then diffusivity out.This type of matrix forms of deferred action can easily be distinguished by adding water, which hydrates the dispersed zone of active start and will lead to swelling of the drug under osmotic forces, as the active principle may not be emitted from the matrix structure.These phases in more or less mixed, depending on the drugs PLGA, and the destruction of the polymer leads, for example, to increase the size of the cavities through which can diffusivity active principle.In addition to the PLGA and the above-mentioned polylactic acid, there are quite a few of injectable excipients to form a delayed action. However, you can call some polymers, gels and oils. Polyanhydride, for example, are polymers, the process of surface erosion which provides a release profile that is different from the profile obtained with PLGA and more dependent forms of introduction, than PLGA, which is exposed to global destruction.Some drugs deferred action apply collagen or gelatin to achieve release, stretched in time. Other drugs used gels or hydrogels. For example , Itradose).
These drugs, consisting of a matrix, to a lesser extent isolating the active principle from the environment or destroy faster, generally have weak percentage of active principle.Also apply to other injectable excipients, such as mannitol, polyethylene glycol, hyaluronic acid, often used as additives for the correction profile for deferred action.In addition to the matrix or reservoir technologies currently, there are few other solutions to achieve sufficiently long, uniform and accurate release.However, you can mention the case of the use of implants, fully or partially covered by the coating ("coating"), playing the role of the barrier in the diffusion of the active principle.In dispersed or non-dispersible matrix products a certain amount of the active agent does not fall into the polymer matrix as it appears on the surface of the drug.In the dispersion matrix forms for a given amount of surface active agent, the active principle is a relatively large number compared to the total calices filling or core-loading" (C. L.) active start is necessary, therefore, to be injected a large amount of polymeric matrix for a given amount of active principle.This disadvantage becomes even more evident in non-dispersible forms or implants, as their volume with a large amount of filler requires the use of a trocar for injection.Needless to say, there have been a lot of work to create drugs with a high C. L., but the experience convinced him of the existence of the phenomenon known as percolation, which is the rapid release of almost the entire amount of the active agent due to the fact that the loading zone are in contact with each other, and the polymer (PLGA) does not function matrix.In visual terms this phenomenon lies in the fact that after hydration of the drug the active principle is released in a very short period of time without swelling of the drug, while the active principle derived from the circulating drug in polymer matrix water.In matrix forms of the deferred action type PLGA and its physico-chemical parameters clearly outline and define the limits of feasibility. The immediate effect of PLGA on the release of its role as an extracellular matrix barrier, its role in the relationship (hydrophobic, hydrophilic, and so on) with an active early and the value of its destruction happened, for example, in the duration of the action matrix of the drug.In this drug, the duration of release depends on the time of the destruction of PLGA (second phase or second jump). Therefore, the choice of PLGA is carried out depending on the desired duration. For example, PLGA 50:50 in terms of depolymerization of one month should be used for the preparation of a drug with a period of prolonged action of one month, while for the preparation of a drug with a 3-month period will require the use of PLGA with later hydrolysis, for example PLGA 75:25.In the preparations according to the present invention excipient, in particular PLGA, does not affect the release, therefore, it becomes possible, for example, to achieve release for a period of three months with the use of PLGA 50:50, which is completely excreted from the body within 60 days, or to obtain forms from a period of one month with the use of PLGA 75: 25, the hydrolysis of which still will not start, while the active principle is already released. This became possible due to the fact that the weight content of PLGA is always lower than that of the active principle; that means that the role of the matrix does not already PLGA, as active principle, which will be subject to external influence, in particular the impact in the quantity.In this regard, the subject of the present invention are also these drugs systemic use or for local treatment with classical or reduced (local action) dosage.More specifically the object of this invention is the preparation of the deferred action for parenteral administration, comprising a homogeneous mixture of the active principle in non-dispersible condition constituting a continuous phase and at least one part of which is in direct contact with the surface of exchange between the drug and the external biological environment, and biocompatible biorazlagaemykh excipient, while in the product number of the active agent is at least 50% relative to the total weight of the drug, the drug has a profile of release of an independent composition excipient, from the molecular weight of excipient or from the weight ratio of the active principle/excipient" he (release profile) depends solely on the total number of active principle in the preparation.In contrast to the known matrix form, allowing the loading of the active agent within the above 30% of the active principle, to avoid the phenomenon pergola is lsit volume of administered funds 3-10 times in relation to the volume of matrix forms.Therefore, for solid forms of drugs in accordance with the present invention contain preferably, both before and after the introduction of at least 50%, in a preferred embodiment, at least 51%, in an even more preferred embodiment, at least 60% and even more preferred embodiment, at least 70% and up to 99,999% of the active agent relative to the total weight of the preparation, and excipient is less than 50%, preferably less than 49%, even more preferably less than 30% relative to the total weight of the preparation.As the excipients used traditional substances used in solid forms of a slow-release, in particular biorstwami polymers.As example can be mentioned polymers of polylactic or polyglycolic acid, or copolymers of polylactic and polyglycolic acids, or mixtures of these polymers and/or copolymers.The choice of biocompatible biorazlagaemykh polymer for forming excipient plays no role, as it does not affect the degree of diffusion of the active agent in the polymer.You can, for example, be used as excipient for preparations according to the invention injectable fatty substance, such as polymerized or nasi livingparrillas (PVP) or polyethylene glycol (PEG).The viscosity of the polymers can be very diverse. It has been shown that polymers with low viscosity can be suitable for so-called monophasic type of release of the active principle. In the above-mentioned European patent 58481 and 52510, as well as in the European patent 21234 and 26599 listed as references, there is an emphasis on polymers of low viscosity. Such polymers can be used in the present invention (for example, viscosity lower than 0.5 DL/g in chloroform). The applicant has already shown in my previously filed application FR 9704837 and in the following examples, which unexpectedly polymers of high viscosity, in particular above 0.5, 0.6 and even to 1.2 DL/g may be suitable and are preferred for obtaining monophasic release.You can use DL-PLGA or L-PLGA, preferably DL-PLGA obtained from 70-80% of DL-lactide and 20-30% of glycolide. PLGA is synthesized from 75% DL-lactide at 25% of glycolide fits especially well, but can also be used and other copolymers including PLGA 50-50. You can also use the D or DL-lactide polymers.PLGA can be hydrophilic or hydrophobic. The preparations in accordance with the present invention can be obtained with hydrophilic polymers.However, as biocombustibles embodiment, the viscosity in chloroform higher to 0.6 DL/g at 3 g/100 mlThe duration of drug action deferred action is determined solely by the total number contained in the active principle.Under the active beginning in non-dispersible condition is understood that the various particles of the active agent present in the product, most of them are in physical contact with each other until the surface of the drug.Therefore, it is clear that under the continuous phase understand this distribution, in which all or most of the internal parts of the active agent is separated from the surface only by active early or a mixture of the active principle and substance, not preventing diffusion or dissolution of the active principle.In a preferred embodiment, the mixture formed an active early and excipients must be homogeneous throughout its volume.Drugs deferred action in accordance with the present invention differ from each other by the duration of release in vitro and in vivo.Thus, the products in accordance with the present invention placed in an aqueous physiological environment, release of the active principle over a period of less than 7 days, while the duration of action in vivo significantly practicelink version at least three months.Matrix preparations containing the same active principle, on the contrary, freed is an in vitro longer with the same quantitative manner than in vivo.It is surprising that, despite the limited duration of release in vitro, the preparations according to the invention enable a much longer duration of release in vivo, regardless of the duration of precipitation in vitro.In addition, the release profile in vivo differs significantly from the profile of a two-phase matrix form and will be pseudopelade 0, which corresponds to the constant diffusion of the active agent over time.The specified profile release is another advantage, as it provides a constant release rate of the active agent in the body.The preparations in accordance with the present invention inherits directly in solid form without the presence of any liquid excipient; a high proportion of the active substance is therefore crucial advantage, allowing to significantly reduce the amount of the drug.So, compared to matrix form 20% of the active beginning of the new compounds according to the invention, for example, if 70% of the act is so where to start an active non-dispersible matrix form was required trocar for injection of the implant with a diameter larger than 1.8 mm, now fairly standard needle for intramuscular injection, to enter microimplants of the preparation according to the invention, having a diameter less than 1 mmIn addition, the nature of the release preparation according to the invention without fluid absorption and the initial swelling of the matrix has the advantage of stability of the active principle, which is stored in a controlled environment. In this regard, the form of deferred action according to the invention are particularly advantageous for unstable active principles, such as recombinant proteins.Because, given the nature of biocompatible biorazlagaemykh polymer forming excipient, constraints for the active there is no beginning, it is possible to make preparations in accordance with the present invention the active agent is a high molecular weight, which could not diffusivity in matrix form with the existing prior art, in particular synthetic or natural macromolecules, in particular proteins, or their equivalents.Thus, the present invention allows the release over a long period n be used for the purposes of the present invention, you can call the proteins, peptides, selected, for example, from the group consisting of acetate, triptorelin, acetate lanreotide, connection with the activity of LH-RH, such as triptorelin, goserelin, leiprorelina, buserelin or their salts, antagonist LH-RH antagonist GPIIb/IIIa, a compound with activity similar to the antagonist GPIIb/IIIa, erythropoietin (EPO) or one of its analogues, various interferons, interferonor, somatostatin-derived somatostatin, described in European patent 215171 listed as a reference, an analog of somatostatin, is described in U.S. patent 5552520 (specified patent contains a list of other patents describing analogues somatostatin and incorporated into the present application by reference), insulin, growth hormone, factor, release growth hormone (GRF), epidermal growth factor (EGF), melanocytestimulating hormone (MSH), hormone releasing tireotropin (TRH), growth hormone, thyroid-stimulating (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), parathyroid hormone (PTH) or one of its derivatives, chloromethane connection lysozyme, N-terminal peptide fragment (position 1->34) chelovecheskogo similar acunett, glucagon, gastrin, secretin, pancreozymin, cholecystokinin, angiotensin, lactogenic human placenta, human chorionic gonadotropin (HCG), enkephalin, colony-stimulating factor (CSF) derived enkefalina, endorphin, kyotorphin, interleukins, such as interleukin 2, tuftsin, thymopoietin, thymostimulin, humoral timony factor (THF), serum timony factor (FTS), derived serum timusewo factor (FTS), thymosin, timony the X factor, tumor necrosis factor, motilin, bombezin or one of its derivatives, described in U.S. patent 5552520 (in this patent contains a list of other patents describing derivatives bombezin and incorporated into the present application by reference), prolactin, neurotensin, dynorphin, cerulein, substance P, urokinase, asparaginase, bradykinin, kallickrein, nerve growth factor, blood coagulation factor, polymyxin B, colistin, gramicid, bacitracin, peptide, stimulates protein synthesis, endothelin antagonist or one of its salts or derivatives, vasoactive intestinal polypeptide (VIP), adrenocorticotropic hormone (ACTH), growth factor, derived from platelets (PDGF), bone morphogenetic protein (BMP) and gastric polypeptide-inhibitor (gif). Specializedservices.Preferably, use a water-soluble substance obtained by salt formation in the form of a cation, for example, using acetic acid. However, it is possible to use insoluble salt, such as pamoat.Under the peptide and/or protein refers to both the peptide and/or protein, and fragments of these pharmacologically active peptides or proteins.Active water-soluble substance used for the preparation of drugs or implants in accordance with the present invention, may be acetate of triptorelin, acetate lanreotide, gecelerin, leiprorelina, buserelin or their salts.The advantage of these drugs is that they can be entered through the above-described device for the method according to the invention.Methods of obtaining drugs in accordance with the present invention is based on the technology mix, compression, extrusion in the molten state and shaping, usually used in the field of manufacturing of herbal forms of deferred action.The object of the present invention is also a method of obtaining the drug delayed action in accordance with the present invention, which includes the following the e less than 50%;
compression of this mixture; and
- extrusion of the specified compressed mixture in the molten state.An alternative method, used mainly for matrix and rematrixing compositions regardless of the content of active principle and excipients, in particular PLGA intended for local and non-local use and requires no solvent or heating the mixture comprises the following stages:
- obtaining a homogeneous mixture of the active principle and excipients;
compression of a homogeneous mixture, preferably in an effort to greater than 1000 kg;
- the fragmentation of the obtained compacts; and
- the production of a form corresponding to the form of the introduction.In accordance with the first method is carried out, for example, the following operations.Take a portion of the active principle (an) and PLGA in the required weight proportions (for example, 70% EN and 30% PLGA).Produce mixing to obtain a homogeneous mixture, for example, with the aid mixerTurbulat. The mixture is then loaded into a press form.Produce a seal which is actually appropriate for soft pressing, allowing to obtain extruded shapes, for example with a diameter of 13 mm and a thickness of 5 mm, the above-Mentioned operation Khujand the forms, which may be, for example, by screening, using the ball of crimeline or knife mill.This operation should help to improve the flow of powder mixture during extrusion, which is necessary especially in situations when the melted portion is less than 50% of the total number.Produce extrusion of the mixture through a die plate with a diameter equal to the diameter required microimplants. After checking the diameter using laser beams (Cheese) on twang tape device receive the extruded substance.In a preferred embodiment, the calibration microimplants is carried out by means of the extrusion nozzle, not the broaching device.Extruded matter is cut along the length of the necessary pieces, depending on the analytical control to obtain microimplants who will then be charged at the injectors before gamma radiation (25 kGy).The second method is carried out, for example, the following operations.After receiving a mixture of an and PLGA not produce a simple seal, and compressing under the high pressure of the mixture of the same components (excipient and the active principle).This hypergate can be achieved when primogeniture, for example, 13 mm or above, is the transformation of this thermoplastic capable of melting at the temperature) excipient in a structure similar to the structure obtained by hot processing, that is, transparent and glassy, very different from previous patterns obtained after a simple seal.This operation is carried out at ambient temperature, cold, or below the 0oC. During the specified hypergate at low temperature is achieved the transition to a plastic state excipient inside the mixture.Received hyperresonance form then crushed, as in the previous method, and condense to form microcompact similar to the above microimplants.This technology is specially adapted for receipt of forms of PLGA deferred action allows temperature, solvent, and special production media to get herbal form, is able to preserve the integrity of the active principle, in particular, unstable molecules, such as recombinant proteins.This method is also interesting for the manufacture of matrix forms (containing not more than 50% of the active principle), dispersed or non-dispersible. For matrix FA.Hyperresonance form after grinding can
directly applied in the form of a dispersion of microparticles.Dispersed form can inetservices directly after inserting the needle of the above devices or inetservices in suspension in a liquid medium (for example, in the case of microspheres).One of the possible aspects for solid shape is an elongated cylinder.The preparation described above can mainly be shapes and sizes, as defined above, corresponding to the described device for local administration.In a preferred embodiment, the drug has the shape of a cylinder with a diameter less than 3 mm, preferably less than 1 mm and a length of less than 50 mm, preferably less than 30 mm, the total volume should be less than 55 mm3preferably less than 20 mm3.The object of the present invention is also a method of therapeutic treatment comprising an injection to a patient in need of treatment, which requires release of the active agent over an extended period of time, the preparation according to the invention.The drug can be injected predominantly subcutaneous or intramuscular route.This can be done using any of the present invention is also the use of the above-described solid preparation for the delayed effect.The following examples illustrate the invention.EXAMPLE 1.Vnutrimatocny of insertat phosphate dexamethasone, form PLGA.The manufacturer insertitem dexamethasone phosphate is carried out in accordance with the following phases.The weighed raw materials, mixing, the first extrusion, the monumental aspect and screening, dosing and packaging, all under laminar flow class And in the white hall class D, and finally sterilization.For one party, for example, to weigh 38,25 g of a copolymer of lactide-coglycolide PLGA (50: 50) and add to 6.75 g of dexamethasone-21-disodium phosphate, crushed to a size less than 100 micrometers.The powder is mixed in the mixer with three-dimensional movement and when the first extrusion control the quality of the mixture (% EN).After the extrusion, the mixture is again ground and ekstragiruyut in the form of rods with a diameter of 2-2 .5 mm, with check its uniformity (% EN content EN/length). Then calculate the weight insertat required to obtain the dose equivalent to 7.5 mg of dexamethasone phosphate. The cylinders are cut along the length into segments corresponding to the required weight, and pack them individually in the container of the device under the influence of gamma radiation (25 kGy).The device may not is how to conduct a study of the effectiveness of these insertRow on the maxillary sinus, for example, in chronic blockage of the nose, check the release of an in vitro and in vivo on the object, giving the opportunity to make a forecast for the duration of insertat.In vitro, the release of observing, measuring an amount in HPLC in an isotonic environment, which is placed in insertat. In Fig. 17, 18 and 19 shows the values of release in vitro for three different concentrations of NA, respectively 10, 15 and 20%.In vivo studies carried out on the model rats. Insertat administered either by subcutaneous or intra-abdominal and by the release within one month estimated approximately by determining an amount remaining in incertae after slaughter animals and sampling after a certain period of time.In Fig. 20, 21 and 22 shows the results of this monitoring in-vivo for the three concentrations in subcutaneous and intraabdominal administration ().EXAMPLE 2.Transluminal implant acetate lanreotide, solid form.Manufactured implants or cylinders with a diameter of 0.75 mm and a length of 30 mm. They contain 12,80 mg lanreotide (BIM2301-4C) comprising 90% acetate lanreotide and 10% mannitol.For a party of 200 units or 4.5 g of solid product (acetate lanreotide-mannitol) obtaining consists of the following stages: usaasa corresponds to the volume of solution of water-mannitol, on the one hand, in the same syringe and powder acetate of somatuline in another syringe.Linking consists in connecting two syringes through ball, three-way valve.A vacuum is created inside the powder EN.The hydration is carried out by contact of the powder in vacuum with a solution of mannitol. The mixture is obtained by using the forward-backward movement powered pistons of the two syringes. After checking HPLC to homogeneity is extrusion of the rod through the die plate configured to the desired diameter. Extrusion is also carried out by bringing into action of the plunger of the syringe by means of the engine.Drying produce before or after cutting cylinders. It is the evaporation of water from the paste-like mixture to obtain a dry cylinder.Packaging is to place the cylinder inside the injection needle into the device with a diameter of 1 mm, as shown in Fig.5.Sterilization irradiation after packaging of the device is performed at 25 kGy.The specified device can be injected at the local level for the introduction cylinder lanreotide before or after angioplasty, as a shunt, through the channel of the catheter.Local deferred action of this drug was predvaritelniy.In Fig.23 shows the result of pharmacokinetic studies in the dog solid forms of 12.8 mg lanreotide with intramuscular injection.In Fig. 24 shows the results of kinetic studies on a voluntary healthy patient after subcutaneous and intramuscular ().The obtained results allow to count on deferred action at the local level when angioplasty with high local concentration of the specified period.EXAMPLE 3.Semi-solid form acetate lanreotide.Acetate lanreotide forms together with water paste or injectable semi-solid form of deferred action.The effect of deferred action is achieved by deposition directly from the active agent. This effect depends on the percentage. The duration of action in this case is directly proportional to the erosion or destruction of the specified semi-solid fat. Therefore, the connection can participate any other active principle, the local effect which in combination with lanreotide will be of interest. The duration of action of the active principle or active principles are evaluated solely on the basis of the pharmacokinetics of lanreotide.Manufacturing of semi-solid forms of the m For example, for 200 units prepare 40 g of the acetate of lanreotide in the case of the form of monthly actions with 35% acetate lanreotide, 65% water and injected doses of 40 mg EN.The stages are getting the capture portions, binding, depression, hydration, mixing, distribution and exposure.Distribution is the volumetric filling of the injector (Fig.11-16), for example, using a rotary piston of the syringe-mixers. Specified semi-solid drug was clinically tested by intramuscular injection (Fig.25) voluntary healthy patient.Thus, you can obtain a form with a duration of local action in one month. The concentration and amount of toothpaste will determine the duration and intensity of local diffusion.EXAMPLE 4.Comparison matrix form 20% of the active agent with rematrixing form with 52%.Soluble acetate salt of triptorelin (AT) mixed with PLGA (75:25) with molecular weight of more than 100,000 and a viscosity of 1 DL/g in chloroform, which is only a month undergoes hydrolysis with weight loss, affecting the release of matrix.Thus is produced a mixture with 20% (up to percolation) and 52% by weight of the active principle in PLGA. The mixture ekstragiruyut in affect, the adjustable tap wrenches and without stirring.Implants with 20% of the active agent release only 4% of the total dose over two days and only 6,7% for 36 days before will be a loss of weight of the polymer, which entails the release of the active agent between 36 and 60 days (Fig.26). Implants with 52% of the active agent release 66% of the total dose over two days and more than 90% for one week (Fig.27).EXAMPLE 5.Comparison of matrix and rematrixing forms an insoluble salt of triptorelin (pamoat of triptorelin).Prepare two drugs of pamoate of triptorelin and PLGA (50:50), first with 40% and the second with 52% of the active agent.Compare to model in vitro release of these two drugs (low solubility active principles requires volume suspending in 100 ml).Despite the insolubility of the active principle, to celebrate the release of matrix type, with 40% (Fig.28). At 52% (Fig.29) the release is already largely independent of the matrix.Therefore, the effect of in vitro active agent relative to in PLGA matrix and rematrixing form does not depend on the solubility of its salts.EXAMPLE 6.Macroscopic difference in principle between the matrix and rematrixing forms.Matrix preparation is described in example 4, PLGA 75:25 - acetate triptonic almost all of the active principle; he has the appearance of translucent substances with increase in diameter and decrease in length relative to time 0 (Fig.30), which indicates that the deformation of the PLGA matrix.Amatrixy drug PLGA 75:25 - acetate of triptorelin (48%-52%) in the same conditions after ten days almost completely released from active principle. However, he did not change either in diameter or in length (Fig.31).Thus, the active principle is released from rematrixing structure of PLGA. In this case, the active principle is not exposed to any physico-chemical deformation effects together with the polymer. PLGA remains unchanged during the release of the active principle.EXAMPLE 7.Comparison between rematrixing form (52% acetate of triptorelin) and nesatricinami forms (70% and 80% of the acetate of triptorelin).At the same modules in vitro, as in example 4, made a comparison of three rematrixing forms of the same dose of 9 mg Results release an in a single day (Fig.32) show the similarity in the effects of these three drugs. Therefore, the value of release achieved in vitro, is not directly proportional to C. L. This shows the role of the active principle and its total number in action rematrixing of farata, using the same PLGA 75:25 with a molecular weight of more than 100000 made with C. L. 52% acetate of triptorelin (AT). Monitoring of these two drugs was carried out in vitro, the first drug with a dose of 9 mg (52% AT 9 mg), and the second dose 6 mg (52% AT 6 mg). The results (Fig.33) show the difference in the kinetics of release associated with the difference in the dose of active principle.EXAMPLE 9.Comparison matrix forms with 52%, 70% and 80% of the active principle (acetate of triptorelin) when tested in vivo in the rat.Two batches of implants with 52% of the active principle, one party with 70% of the active agent and one party with 80% of the active agent were injected by subcutaneous four groups of 12 rats each: four rats from each group were euthanized on day 1, on day 4 and on the 19th day. The implants were retrieved and occasioanly by HPLC to determine the residual amount of the active agent.In Fig.34 shows the results, reflecting the residual level implants as a percentage between 0 and 19-day.There is a clear parallelism in reducing this percentage between forms 52%, 70% and 80%.In Fig. 35 shows the variation in the residual amount of pure active principle in the mg Noted that the ex is positive and equivalent to the implant 52% and implants 70% and 80%.In living rats before killing samples were taken of the plasma, and this result was confirmed by analysis of the RIA.EXAMPLE 10.The results of pharmacokinetic studies of matrix preparation (20% active basis) and rematrixing drug (52% active basis) on the dog.Drugs 20% of the acetate of triptorelin and 52% were injected by intramuscular in two doses six dogs in total doses of 3 and 6 mg of pure triptorelin and using RIA analysis of plasma samples was monitored kinetics and dynamic efficiency of the active principle in comparison with testosterone levels (Fig.36 and 37).The results show the activity release for three months in both cases.The kinetics of forms 20% has a classic profile with a peak and re-jump). The kinetics of forms 52% incomparable to traditional forms of PLGA, but has a profile pseudopelade 0 without peaks and repeated jumps.EXAMPLE 11.The results of pharmacokinetic studies rematrixing shape with 70% of the active principle on the dog.The drug with the same PLGA and the same active early, as the drug with 52% of the active principle (example 10), was made with 70% and 30% PLGA.The specified medication was injected unutilised is on kinetics (Fig.38A), and dynamic efficiency of the active principle with testosterone levels (Fig.38B).The results show the activity release for at least three months, as and for the form 52% of the active principle, with the only difference consisting in a higher release rate when the change in the total dose.The change in load between 52% and 70% have no impact on the duration or profile, and the release rate depends on the total injected dose (Fig. 39).
1. Solid dosage form with prolonged action, containing at least one active principle and birthdaaay excipient, characterized in that excipients is polylactid-glycolide copolymer (PLGA), and the fact that the concentration of the active agent is at least 40%.2. Pharmaceutical form prolonged action under item 1, characterized in that the concentration of the active agent is at least 50%.3. Pharmaceutical form prolonged action on one of the PP.1 and 2, characterized in that it has a thin and elongated shape with a diameter not exceeding 3 mm4. Pharmaceutical form prolonged action on p. 3 distinguishing what the lasting themes its diameter is about 0.1 mm6. Pharmaceutical form prolonged action on one of the PP.1-5, characterized in that the minimum ratio of length/diameter is 10.7. Pharmaceutical form prolonged action on one of the PP.1-6, characterized in that it contains the active peptide or protein.8. Pharmaceutical form according to one of paragraphs.1-7, characterized in that it contains a low dose of the active agent compared with the usual dose is considered active principle for the treatment of systemic way.9. Pharmaceutical form according to one of paragraphs.1-8, which is the solid, which can be deformed pre-stress in the finishing device is elongated and restore the original form in situ.10. Pharmaceutical form according to one of paragraphs.1-9, characterized in that it is designed to release the active agent was in the anatomical cavity, in which the specified dosage form is introduced.11. Dosage form under item 10, characterized in that it has a pre-designed form, adapted to the anatomical cavity of the body in such a way as to prevent its displacement or destruction.
< / BR>its pharmaceutically acceptable salt and solvate, referred to as compounds of formula 1
FIELD: medicine, gastroenterology.
SUBSTANCE: one should apply food additives as tablets of oats, corn and cabbage by "Biophyt" company; moreover, to decrease motor system of biliary ducts one should apply tablets of oats, to increase motor system - tablets of corn and for total normalization of kinetics - tablets of cabbage. Treatment lasts for 10 d at the dosage of 1-2 tablets twice daily 30 min meals. The present innovation enables to normalize functional activity of biliary ducts at the background of shortened therapeutic terms.
EFFECT: higher efficiency of therapy.