Expanding gastroretentive therapeutic system with a long residence time in the stomach
The invention relates to a device for slowing the passage through the pylorus introduced oral dosage forms. The device includes a component, expanding upon contact with gastric juice, and the polymer membrane, permeable to liquids, but not gases. The device may contain a biologically active substance, the release of which in the gastric juice are regulated mainly by the dosage form, in which it is included. Unlike conventional dosage forms with delayed passage through the pylorus, the release of the active substance does not depend much on the type and structure of the polymer shell, but is primarily determined included dosage form. The device according to the invention can be easily rolled or folded and can be placed in capsules. 7 C.p. f-crystals, 5 Il.
The presented invention describes a device for slowing the passage through the pylorus of the input oral dosage forms with expanding upon contact with gastric juice component and permeable to liquids but impermeable polymeric membrane. The device may contain b is its dosage forms. Unlike conventional dosage forms with delayed passage through the pylorus, the release of the active substance less depends on the type and structure of the polymer shell and basically is determined by the enclosing form. The device according to the invention can be easily rolled or folded and can be placed in capsules.
In U.S. patent No. 4207890 describes a device for controlled release of biologically active substances that, when the extension undergo local retention in the stomach and because of this are characterized by a longer residence time in the stomach. The device has (a) a polymer shell, which before use is in a weakened state. Itself polymer shell has no holes and is composed of a material that is virtually hydrated, however, is permeable to contained in the body fluids. The device also has the (b) element, which regulates the supply of biologically active substances. This element can be according to p. 2 the formula of the invention the polymer film. As another element (in) the device has a component extending in contact with contained in the body of liquid the substance, which drives the water through the polymer membrane (a) and thereby causes the formation of the solution in the device. The device will contain, therefore, an aqueous solution in able to expand the state and make possible based on the ratio of the concentrations of the diffusion from the device biologically active substances, however, to meet its apparent density about the chyme. Due to this, the device is in the chyme, suspended or submerged. Holding the principle is determined solely by the size of the device. The possible mechanism of deflation does not describe in this regard, the device is removed from the stomach and recycling it after impact of biologically active substances not explain.
Modification of the restraint principle shown in the application for the European patent 0307904 and in U.S. patent No. 4996058. As the expanding components listed substances, which when accessed acid to form gaseous components such as carbon dioxide or nitrogen, which vspuchivajut polymer membrane (a) and, thus, form is able to float in the chyme device. The principle of retention is (see U.S. patent No. 4996058, page 3, lines 6-7) in the floating in the governmental shortcomings. Regulation of extraction of biologically active substances is carried out in both cases mainly through the polymer shell. Simultaneously the kinetics of swelling of the device is mainly limited to a polymer membrane as the water, as hydronium ions must diffuse through the polymer shell, but on the other hand, the molecules of biologically active substances must diffuse outward in the opposite direction. The constant of diffusion in the polymer shell is a crucial parameter. If the violation is relatively thin and therefore sensitive polymer shell by mechanical or chemical exposure hazard sudden release of biologically active substances of the type of dose dumping. The volume of biogas produced expanding the amount of gas strongly depends, among other things, from the acidity, but by the composition of the chyme and the secretion of acid by the stomach. In the case of a strongly acidic environment and therefore a higher production of gas, a mechanical load device does not reach the boundaries of the gap, on the other hand, when less acidic reaction medium must be reached sufficient production of gas. This dilemma leads to strongly Manaudou of the invention is to provide retention in the stomach system, which can avoid the disadvantages of the systems known from the state of the art.
The solution to this problem according to the invention is achieved by holding in the stomach of the device that contains the following elements:
(a) a polymer shell of the microporous membrane, or partially microporous membrane, or a combination of both with other non-porous planoaren polymer. Receive then you can implement according to the invention in any way, for example by extrusion of films, by applying a multiphase systems and evaporating part of the system, by means of polymerization, for example, in the form of ionomers, using mechanical methods, such as using needles, using thermal methods, such as lasers, by exposure to ionizing radiation and subsequent etching, etc. as materials for the microporous membrane according to the invention can be used polyurethanes, polypropylene, polyvinyl alcohol, polyvinyl acetate, polyacrylic acid and its derivatives, polimetilmetakrilata acid and its derivatives, polycarbonates, polyvinylidenedifluoride, polytetrafluoroethylene, and any other polymers which can be provided with pores of a suitable RNO preferably between 0.5 and 1 microns. The pores can do it better wetted, membranes according to the invention can be impregnated with wetting means or other hydrophilic components;
(b) expanding component, which upon contact with gastric juice, in particular, under the action of acid produces a gas, such as carbon dioxide or nitrogen. As examples according to the invention are suitable for use, for example, carbonates and bicarbonates of alkali and alkaline earth metals, cations of ammonium, or sodium azide, or mixtures thereof. These expanding components can be modified to change the kinetics of gas production, for example, by covering lipophilic components or the introduction of lipophilic components, such as waxes or fats or a suitable coating, such as, for example, polymethylacrylate or polymetylmetacrylate and derivative or similar, well-known specialist substance. The expanding component according to the invention can also be a foam, for example, with the introduction of polyvinyl alcohol or exist in the form of semi-buttery compositions to regulate the kinetics of deflation;
(C) contain biologically active substances is e song or foam. It is also possible that the composition, at least part of the expanding component and/or at least part containing the biologically active substance component is presented in a slowly soluble crystalline form. As biologically active substances mainly refers to all substances with physiological activity, in particular medicinal substances for the treatment of humans or animals, preferably those which are absorbed by the mucous membrane of the stomach or act on the surface of the mucous membrane of the stomach. Such pharmaceutical biologically active substances known to the specialist. Components (b) and (C) can also be represented in a single composition.
The device may be placed in the tank of a physiologically acceptable material, for example in a hard gelatin capsule, for ease of application and use.
The convex shape of the device preferably is in the form of a convex triangle to provide planar, the maximum volumetric structure. Due to the planarity sustainable in the floating state in the chyme two preferred positions, both of which allow the passage of chyme by gastroretentive device, so that the chyme is not m the ary forms of dimensions and stiffness of the structure in the convex condition and it is therefore proposed to restraint. In the stomach three-dimensional structure "jams" between the walls of the stomach and allows chyme to go through the pylorus, jamming in the lumen should stand just in front of the hydraulic resistance in the chyme. The more spherical device is, the earlier it is possible colobinae seal the exit of the stomach, with the consequence that the pressure discharge will force the device through the pylorus. According to the invention can, however, also be applied to rectangular and polygonal patterns, as well as those with rounded corners.
By applying a microporous or porous polymer membranes is possible according to the invention to solve many problems. Due to the surface tension of the liquid, in particular water, systems need a certain pressure for discharging fluid-filled pores, which mainly depends on the pore size, surface tension and surface tension at the phase boundary and the boundary angle. Through suitable choice of the diameter of pores for this system is set to a certain pressure, below which the pores can not be emptied. When this membrane is gas-tight. The fluid can, however, easily flow through the membrane, the thread sets the pore size can thus according to the invention to realize a device highly permeable to liquids but impermeable to gases below a certain pressure. As a consequence, the internal pressure of the device is limited to a predefined value. When exceeding the limit pressure, the membrane becomes permeable and prevent being non-destructive protection, increased mechanical load device above the maximum allowable podavlyayushego efforts. Thus, using the device according to the invention it is possible to achieve almost constant internal pressure during the period of use of the device. Duration of use of the device is governed by the kind and amount of the expanding component. Due to capillarity is located on the inner side of the membrane particles are wetted and release the biologically active substance through the microporous membrane with only minor slowdown.
The system according to the invention can be used for the treatment of humans and in veterinary medicine.
Fig.1 is a system construction according to the invention, the view from the top.
Fig.2 represents the construction of another system according to the invention, the view from the top.
Fig.3 is a side view of the system of Fig.1.
Fig.4 is a side view of the system of Fig.2.
Phi is the area correspond to the microporous membrane, where there's no shading regions correspond to non-porous polymer film. Components (b) and (C) are not visible because they are enclosed in the device.
1. Gastroretentive device containing component, expanding upon contact with gastric juice due to gas generation, and the component containing the biologically active substance, characterized in that these components are completely covered with the polymer membrane of microporous or partially microporous membrane.
2. Gastroretentive device under item 1, characterized in that the shape of the device is approximately planar triangular, or planar trichlorbenzene star, or tetrahedral.
3. Gastroretentive device under item 1 or 2, characterized in that the composition of at least part of the expanding component, or at least the part containing the biologically active substance component, or both is semi-buttery.
4. Gastroretentive device under item 1 or 2, characterized in that the composition of at least part of the expanding component and/or at least part containing the biologically active substance component is presented in the form of compositions is at least part of the expanding component, or at least the part containing the biologically active substance component, or both is presented in the form of foam or foaming of the composition.
6. Gastroretentive device under item 1 or 2, characterized in that the composition of at least part of the expanding component and/or at least part containing the biologically active substance component is presented in a slowly soluble crystalline form.
7. Gastroretentive the device according to one of the above paragraphs, characterized in that it contains in bystrorasshiryayuscheysya in the gastric juice of the shell, preferably in a hard gelatin capsule.
8. Gastroretentive the device according to one of the above paragraphs, characterized in that it is formed and fixed in the folded form soluble in the gastric juice of the polymer shell.
or its pharmaceutically acceptable salts, where R1- H, CH3or CH2OH; R2- CH3CH2CH3; R3- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; R6, R7are the same or different and mean H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or C1-C6alkoxy-substituted C1-C6alkyl; X represents NH or O, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases
which have the properties of receptor antagonists neirokinina-1(NK-1)