Method for producing orally disintegrating tablet
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutics, namely represents a method for producing an orally disintegrating tablet. The tablet is prepared by the method involving the stages of providing a liquid containing a drug substance, presenting a solid element having an at least one cavity formed thereof, cooling the solid element down to a temperature below a chilling temperature of the liquid, filling the cavity with the liquid, hardening the liquid in the cavity, rejecting heat from the liquid through a cavity wall by conductive heat transfer to form a solid granule containing a drug substance, with no active profiling along the whole surface of the granule, removing the granule from the cavity and drying the granule in vacuum.
EFFECT: developing the method for producing the orally disintegrating tablet.
15 cl, 4 ex, 6 tbl, 9 dwg
The SCOPE TO WHICH the INVENTION RELATES
The present invention relates to a method for producing tablets, disintegrating in the oral cavity for the introduction of man, and the tablet contains the medicinal substance for the treatment of disorders in humans.
Tablets, disintegrating in the oral cavity (ODT), also called melt in your mouth, quickly melting, dissolving in the mouth, melts quickly, orodispersible or rapidly dissolving tablets are solid dosage forms which rapidly disintegrate in the oral cavity of a person without zapivaniya water. Thus, for example, they allow to overcome the problems associated with swallowing (especially in patients of elderly and children's age) and can improve patients ' adherence to prescribed treatment. When ODT is placed in the oral cavity, saliva causes rapid destruction (usually within 60 seconds, preferably within 30 seconds, and preferably within 10 seconds) and dispersion of the dosage form so that saliva contains a medicinal substance. The patient swallows the mixture of saliva and medicinal substance so that it has reached the stomach, or ỏ part (if not all of the medicinal substance) is absorbed through the oral cavity, pharynx and/or food industry�, before it reaches the stomach, thus preventing first pass metabolism of the drug substance, and thus enhancing its bioavailability.
Various medicinal substances and/or combinations may be used as the active ingredient ODT, such as, for example, analgesics and anti-inflammatories, antacids, Anthelmintics, antiarrhythmic agents, antibacterial agents, anticoagulants, antidepressants, antidiabetic remedies, anti-diarrhea, anti-epileptic agents, antifungal agents, anti-gout, antihistamines, antihypertensives, anti-malaria, anti-migraine, antimuscarinic funds, funds and antineoplastic immunosuppressive agents, anti-psychotics, Antiprotozoal funds, Antirheumatic agents, antithyroid drugs, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropic funds, corticosteroids, suppressant cough, cytotoxic tools, decongestants, diuretics, enzymes, anti-parkinsonism, gastrointestinal agents, antagonists of histamine receptors, means regulating lipid metabolism, m�local anesthetics, neuromuscular means, nitrates and anti-angina, opioid analgesics, proteins, peptides and recombinant drugs, sex hormones, contraceptives, spermicides, stimulants, etc.
A method of producing ODT (in this description referred to as "tablets, disintegrating in the oral cavity") is known, among other sources, from U.S. patent No. 5384124 that is owned by a company Farmalyoc. In the known method, the result is a paste containing one or more medicinal substances, and the paste is mechanically divided into standard doses, having a well defined shape and volume, by distribution of the paste in the cavity of predetermined shape and size, and the cavity present in the element as a carrier of polyvinyl chloride. After spreading the paste, the carrier is placed in a freeze dryer, and the pasta is sublimated. Thus, each standard dose is formed into a tablet. An advantage of the method of lyophilization consists not only in that the medicinal substance is attached to a very stable form, but also that it turns solid dosage form that disintegrates after contact with liquid. In particular, if the paste was originally based on water as a carrier solvent (the term "solvent" includes any liquid medium that can�with as a carrier for other substances), this tablet typically disintegrates after contact with water or water-base liquid, such as saliva.
The known method is widely used in the biomedical industry (see, for example, a review of Deepak from Kaushik, Harish Dureja and T. R. Saini "Orally disintegrating tablets: an overview of melt-mouth tablet technologies and techniques", Maharishi dayanand came University and Shri G. S. Institute of Technology and Science, published in the Handbook "Tablets and Capsules", July 30, 2004). In certain technologies such as Zydis (Catalent Pharma Solutions, Somerset, NJ, USA) and Lyoc (Laboratoires Farmalyoc, Maisons-Alfort, France), used the data of a specific technology. Usually receive initial composition in the form of a paste or liquid and placed into pre-formed blister packs. Then this container, i.e., the material present in the packaging, frozen and subjected to lyophilization to remove water. The resulting structures are characterized by a high porosity and rapid decomposition upon contact with saliva. Indeed, this method has many advantages that can be obtained tablets, which quickly disintegrate, exhibit acceptable pharmacokinetic characteristics, provide better patient compliance with the prescribed treatment and higher bioavailability relative to solid compositions and reduction of side effects (see article Luca Dobetti "Fast-Melting Tablets: Developments and Technologies" in the journal Pharmaceutical Technology Drug Delivery 2001, pp. 44-50).The disadvantages are what tablets have a relatively low mechanical stability and high production costs. However, it is believed that these drawbacks are inherent to the method used lyophilization: Lyophilization requires the use of expensive equipment and results in tablets that are characterized by lower mechanical stability, compared to, for example, with conventional extrusion techniques. In view of this known method is carried out by using finite packing of tablets (i.e., blister packs) as a carrier during the manufacturing process. This essentially means that should govern each stage of receiving so that it can be used in combination with this particular package. This limits the freedom of operating at various stages of manufacture and, thus, further increases costs. However, given the advantages of lyophilized products in the form of disintegrating tablets, the manufacturer accepts inherent to this method of production the high cost.
It should be noted that in the prior art there are other ways of obtaining ODT. For example, in patent applications WO 93/12770 and US 2006/0057207 (the rights to which are owned by Pfizer Inc.) the described method, where the pill is actively profiled essentially along their entire surface� pressing frozen pellets pressing in a closed form. Thus, the known method is different from the passive receipt of form of tablets, for example, by using passively receive the form, which occurs just under the influence of gravity and surface tension. In this way, an easily adjustable way to obtain a predetermined shape. However, this method has the disadvantage that it requires a rather complicated extrusion and stamping plant, which is prone to leakage of the liquid composition from the cavity (i.e., closed molds). Frozen pellets also have a tendency of sticking to the head of the extruder or to the stamp due to the use of compression forces. The actual advantage is that due to the compression of the frozen pellets are provided with good mechanical properties, which allows us to extract the frozen pellets in an integral way.
From U.S. patent No. 5382437 and European patent EP 0450141 another known method, where the liquid composition is introduced into the open cavity of the solid element, which is at room temperature, after which this element is placed in the freezer for 30-60 min. it Seems that it has the advantage of being a liquid composition effectively fills the cavity, leading, thus, to obtain frozen pellets having a size and shape corresponding to the size and shape of the p�hygiene, and, thus, causing the projected shape of the pellets. However, the disadvantages are that this method should be a cycle of cooling-heating, and also that the whole process is relatively slow. Also, there is the risk of loss of fluid from the cavity after the filling liquid (low viscosity) composition.
The ESSENCE of the INVENTION
The aim of the present invention is to provide a method of producing disintegrating in the mouth tablets for administration to a person that uses lyophilization as the main technology, the method is characterized by a greatly reduced cost per tablet, at the same time providing excellent disintegration properties and adequate mechanical stability. This method was developed in accordance with the preamble, which includes the stage of providing a liquid composition containing the medicinal substance; providing a solid element having formed therein at least one cavity; cooling the solid element to a temperature below the freezing point of the composition; filling the cavity of the liquid composition; curing the composition contained in the cavity by heat from the structure through the wall cavity through conductive heat transfer with the formation of strongly� pellets, containing the medicinal substance, without active profiling of the entire surface of the granules; retrieve pellets from the cavity; and drying the granules in a vacuum to obtain tablets.
The applicant unexpectedly found that can be obtained adequate disintegration and mechanical properties of ODT, while a significant increase in the choice of manufacturing methods, and, thus, significant opportunities to reduce costs in the calculation of the pill, by, first, fill an open cavity with a liquid composition containing the medicinal substance (which also includes filling the cavity of two or more separate subcomposition, which together form a liquid composition containing a drug substance), and then freeze the liquid composition in said cavity with the formation of solid pellets simply by leaving the liquid composition in a pre-cooled cavity, without using any active profiling tools, so that was not received compressed frozen pellets having the form (at the open end of the cavity), which is formed simply by gravitational forces and surface tension (meniscus), removing the frozen pellets from the cavity and, thereafter, drying the granules (for example, in lyophilizers the device). It was also found that is especially�e the advantage of maintaining the temperature of the solid element at a temperature below the freezing point of the composition after filling the cavity. At first glance, this seems undesirable. A liquid composition needs to start curing immediately after contact with the cavity wall, theoretically leading to obtain frozen pellets having a size and shape that does not match the size and shape of the cavity, thus leading to uncontrolled freezing process, and thus, unpredictable form of pellets. However, the applicant found that for temperatures below the freezing point of the liquid composition can be found fill rate, which is high enough to counteract the immediate freezing of the fluid, simply because the amount of heat present in the flow of the liquid composition, may simply oppose the extraction of heat cold solid element, or at least an adequate portion of the heat extraction. Overall, the new method is easier to control: the temperature of the solid element can stay on the same level, whereas the methods of the prior art must be cycle cooling-heating. Furthermore, the method is faster. Heat is removed after filling of the cavity. Also, there is less risk of loss of fluid from the cavity, since the liquid is cooled very quickly after entering the cavity and, thus, will exhibit enhanced visco�you.
A new method has several important advantages relative to the most relevant methods of the prior art known from the company Farmalyoc. First, in this new method the final packaging of tablets should not participate in any of the stages of the method. Therefore, not only can be used the standard cheap packaging, but also each of the stages receiving may be performed using hardware that is optimized for a particular application. For example, when using the method of the prior art, where the blister pack is used as a carrier for tablets in the freeze dryer, drying conditions must adapt to a relatively low amount of heat that can be transmitted through the (plastic) packaging. It can greatly increase thermal load (e.g., high local temperature) per pill during the drying phase, and can also significantly increase the time required to complete the method. The applicant also found that the abstraction of heat from the composition through the wall cavity due to the conductive heat transfer (which means that at least the main part i.e., more than 50%, preferably more than 80% to 100% of the heat to be diverted to freeze the composition, is removed due to conductive heat transfer black�W wall cavity) has a significant positive effect. It not only overcomes or at least reduces the problem of prior art thermal load for pellets, but also can improve the mechanical strength of the final ODT. In the known methods, almost all heat is removed through convection heat transfer, in particular, with the use of gaseous nitrogen, which passes around a liquid composition for heat sinking until then, until the curing of the composition, and it is not transformed into frozen granules. Although convection can adequately be used for freezing liquid composition, the applicant found that the use of conductive heat transfer due to the presence of a thermally conductive material around at least part of the liquid composition, the cooling process can produce pellets with high mechanical resistance, for example, adequate mechanical strength and/or low fragility, at the same time maintaining a high level of its properties of rapid disintegration. The reason for this is unclear but may be related to the fact that the abstraction of heat by conductive heat transfer provides a more efficient and, thus, significantly faster the cooling process, which leads to a different arrangement of the molecules in the granule. It should be noted that in the methods of the prior art, �Bolshoe amount of heat can be abstracted from the liquid composition through the wall of the blister. However, this does not qualify as diverting heat conductive heat transfer in the sense of the present invention, since the material of the blister pack is a plastic, which typically has a conductivity of from 0.1 to 0.2 W/MK, and this inevitably means that the bulk of the heat is removed by other means than conductive heat transfer (e.g., convection through the flow of cold gaseous nitrogen).
Another important advantage of this method is that tablets in the finished Packed product does not remain in the mold in which they were formed. In the methods of the prior art, the pellets formed in a blister pack, which serves as the mold. However, the granules remain in their molds in the entire process as long as they are not converted into tablets contained in their final packaging. Therefore, there is a high risk that the tablets are more or less stuck to the wall of the blister, and can only be extracted by the application of considerable mechanical strength. This, in combination with the fact that the lyophilised tablets inherent not very large resistance (in comparison with classic extruded tablets), often leads to the destruction of the tablets before their admission. This can lead to the fact that such destroyed tab�ETCI will not be used or the patient will be put too little of the active ingredient.
Another important advantage of this method consists in the fact that the stage of freezing should not occur in the freeze dryer. In the method known from U.S. patent No. 5384124, the stage of freezing occurs in the freeze dryer, because pasta won't be in a blister pack. However, in the known method, the abstraction of heat from the pasta to freeze takes a relatively long time. In this way, by curing a liquid composition on a separate stage in the appropriate cavity, and then the extraction of the frozen pellets from the cavity and exposed to drying in an extra stage, initial freezing can be carried out much more effectively.
Another significant advantage of the present invention is that the step of producing frozen solid granules does not depend on the available equipment for drying. Since making frozen pellets completely independent of the drying step, the pellets can be obtained separately and, for example, be stored as long until it becomes available equipment for drying. In particular, when the medicinal substance is of a biological origin, it is important that the party liquid composition containing this substance, could be fully processed into frozen pellets, independently �t the currently available equipment for drying. Also, when using the present invention it is possible to get the pills (almost) spherical, oblong, "yaytsepodobny" or oval shapes in three dimensions without any flat surface. As you know, the forms that are closer to the spherical shape, the depravity inherent mechanical, although the form does not have a significant effect on the properties of rapid disintegration of standard dosage forms.
As regards means of extrusion and forging, known from the prior art, the present method has the important advantage that it is not associated with leakage of the liquid composition from the cavity. Since a liquid composition just left to freeze in an open cavity without the active profile of the entire surface of the granules by the application, for example, forces of compression or other technologies active forming, which profiles the surface of the pellets, there is no risk of squeezing of the liquid composition from the cavity. Also significantly reduced the risk of sticking of the pellets to any of the parts used for active profiling pellets. Suddenly, with a simple freezing of the liquid composition without the application of any compression forces, the pellet may still have sufficient mechanical strength to eject from the cavity for further processing, such as lyophilization.
It should be noted, h�of the present invention can be used in conjunction with any medicinal substance and/their combinations. Typical examples of such substances can be found in European patent EP 1 165 053 B1 from line 37 on page 5 (starting with "Analgesic and anti-inflammatory agents:"), and ending with line 25 on page 7 (ending with "...fenfluramine, mazindol, pumalin". Other examples are compounds of the type of Progestogens (such as desogestrel, etonogestrel, levonorgestrel, norgestimate, norelgestromin, gestoden, nomegestrol acetate, dienogest, drospirenone or any other steroid or non-steroidal compound with progestogen-based activity), estrogenic compounds type (such as estradiol, estriol, mestranol, ethinyl-estradiol or any other steroid or steroidal compound with estrogenic activity) and compounds acting on the Central nervous system (such as asenapine, mirtazapine, amirtization or other compounds with activity against CNS).
The present invention is based on several postulates, and the first of these is that the finished freeze-dried product can be mechanically not very stable, but the intermediate suddenly frozen product does not have this drawback, despite the fact that this frozen product is not pressed. This opens up opportunities for additional mechanical manipulation of the intermediate granules. However, such manipulirovanie� in the known method Farmalyoc doesn't make sense because of the frozen pellet is already present in the freeze dryer in its final blister package. However, the applicant came to the second conclusion, namely that the stage of drying in this known method is very inefficient, mostly due to the fact that when using the final packaging of tablets as a carrier in the freeze dryer, the drying space is not used adequately (each tablet takes a relatively large amount of space because the pill may not come into contact with the packaging). This is an inefficient use of the freeze dryer in the known method inherent, but can be overcome by separation of the stages of freezing and drying by the use of media for freezing stage, which is different from the carrier used in the drying step. The third conclusion was that in the known method, due to the relatively slow freezing stage, the initial liquid composition is frozen almost in equilibrium. This usually leads to a well-known end products are very fragile when dried. The applicant found that the significantly more rapid cooling process may lead to the curing process that produces the final product, more like an amorphous, leading to less vulnerable of the final product. �that can manifest in the form of higher ultimate strength in compression of tablets or to a lower fragility (as defined in the USP 24/NF19, 1999, p. 2148-2149).
It should be noted that the present invention also relates to disintegrating in the mouth tablet for administration to human, where the tablet has a curved surface preferably has a curvature K from 1 to 1.2. An important advantage of the method in accordance with the invention is that it can produce tablets with high mechanical strength, as compared with tablets made in accordance with existing technologies. This alleviates the disadvantages of the prior art, such as the need for individual packaging of each of the tablets in peelable blister pack. In the present invention, can be manufactured pills that are packaged in bulk or packaged in the usual pushed the blister pack.
The present invention also relates to a package containing disintegrating in the mouth tablet for administration to a human, wherein the tablet contains the medicinal substance for the treatment of disorders in humans, where the tablet is preferably, but not necessarily, separately Packed in the container and formed in the cavity using the method in accordance with the present invention, wherein the cavity is different from the container in which Packed tablet (e.g., a blister of the blister pack). As description�but above in the present application, the main advantage of the present invention is that tablets in the finished packaged product is not contained in the mold in which they were moulded, which almost eliminates the likelihood of sticking of the tablet to its container, for example, blister blister, ready in the package. This almost complete exclusion increases the convenience of the physician, veterinarian, patient and such persons during handling of the tablets.
Tablet is a solid dosage form, for example, for direct oral, rectal or parenteral administration or for indirect administration, for example, after mixing with the carrier material, in particular liquid, for administration in dissolved or dispersed form. The tablet may differ from that of a powder or small granules, the tablet can be separately manipulated manually. The minimum length of the tablet is 1 mm, preferably 2 mm, preferably 4 mm, and typically (but not necessarily) from 4 to 20 mm.
Disintegrating in the mouth tablet, which disintegrates after contact with saliva, for example, in the oral cavity within 60 seconds, preferably within 30 seconds, preferably within 10 seconds.
The freeze or lyophilization is a method used in �create the sustainable drug substance freezing liquid composition, containing the substance, and, in essence, removing the frozen liquid in a vacuum.
The vacuum is an air or other gas at low (below atmospheric) pressure.
Disintegration is a loss of integrity and disintegration into fragments. The term "disintegration" includes dissolution (the presence of fragments at the molecular level).
Rapidly disintegrating means disintegration, which begins after contact with a liquid, in particular water at 37°C, and is completed within 60 seconds, preferably within 30 seconds, preferably within 10 seconds.
The medicinal substance is any substance that can be used for the treatment of disorders (including disease), i.e., to facilitate the prevention, relief or cure of disorders. Such a substance may be a chemical or biological compound, such as a natural or synthetic peptide or protein, (poly)saccharide, or any other organic or inorganic molecule, living or dead microorganism, dead or alive parasite, etc.
The freezing temperature of the liquid composition is a temperature at which the consistency of the composition is transformed from liquid to solid, i.e., consistency which can withstand the effects of externally� power without changing the shape.
thermally conductive material is a material having a heat transfer coefficient of at least 1 W/MK (Watts per meter Kelvin).
Adhesion refers to the ability to resist adhesion.
The crystalline material is a material which can form crystals after curing under conditions of equilibrium.
Gelling substance is an agent which is able to form a network of molecules within the liquid to provide the liquid with the consistency of the gel, i.e., having at least some ability to self-maintain (all conditions non-current freely liquid). The term gelling substance also covers agent containing two or more different compounds or material, each of which is able to form a network of molecules inside the liquid.
Forming the gel material is a material which at a concentration of 4% (wt./mass.) in the liquid composition, in particular water, at the temperature at which the liquid composition is used for administration (in this case, to fill cavities at room temperature, 20°C) to form a gel in the specified liquid composition while remaining in a stationary situation within 24 hours.
Not forming the gel material is a material that �concentratii 4% (wt./mass.) in the liquid composition, in particular, the water, when the temperature at which a liquid composition is used for administration (in this case, to fill cavities at room temperature, 20°C), does not form a gel in the specified liquid composition while remaining in a stationary situation within 24 hours.
Embodiments of the INVENTION
ODT should ideally conform to many requirements, for example, has sufficient mechanical strength for manual manipulation (to allow easy removal of the tablet from the packaging and placing the tablet in the oral cavity of the patient) may have mucoadhesive properties (e.g., so that the tablet disintegrated in the oral cavity and penetrated the stomach), at the same time is not sticky, so as not to interfere with the manipulation of the tablet, has an acceptable taste and provides a very fast disintegration (so that, for example, it was possible to obtain high levels of drug in the blood). A liquid composition used for the manufacture of tablets, may contain additives such as, for example, surface-active substances (surfactants) or other substances that may be used to give the final tablet properties that are useful for specific applications tablet. Such substances may be, for example, coloring agents, podslastiteli other modifier, or taste masking agents, preservatives, chelation, antioxidants, surfactants, coloring agents, pH modifiers, or any other substances that are compatible with the other ingredients of the pills, and, if necessary, pharmaceutically acceptable to the patient, who designed tablet.
In one embodiment of the present invention, the volume of the cavity is smaller than the volume of the granules. In the methods of the prior art selected cavity (or mold) that exactly matches the size and shape of the pills due to the formation. Unexpectedly, however, the applicant found that can be used cavity, which has a volume smaller than the volume due to the formation of pills. In this embodiment, the implementation, the granules protrude from the surface of the element from the cavity. The opportunity this provided, along with other aspects, since a liquid composition quickly cools conductive contact with the cold element. This helps to ensure that may be formed granule, which protrudes from the cavity. The advantage of this particular embodiment is that the pellet can be relatively easily removed from the cavity, since the contact surface between the pellet and the cavity is small compared to the pellets, which is fully placed or immersed in the cavity. Another advantage of this variationsummary is what can be achieved interruption of the physical appearance of the tablet corresponding to the transition between the cavity and the open space above the cavity. Because due to the formation of the bead protrudes from the cavity, can be provided such termination form pellets at the outlet of the cavity. This interrupt can be used to differentiate this tablet from other tablets (thus being, for example, the alternative for the logo, mark or color the company), or can be used for predominant mechanical properties.
In a preferred embodiment of the cavity volume is less than 50% of the volume of the pellet. In this embodiment, the implementation of more than half of the granules protrude from the element in which a cavity is formed. This greatly facilitates the removal of the pellets. The minimum amount to almost ensure adequate extraction of heat from a liquid composition is about 15%, preferably about 20%.
In a particular embodiment of the method according to the invention, the composition contains a crystalline material carrier which is solid at room temperature, and gelling agent. Crystalline carrier has the advantage that it can be easily incorporated in a liquid composition, and that it provides good mechanical St�an tablets. Gelling substance is included to further improve the mechanical properties of tablets. Examples of suitable materials media are sugars, such as mannitol, dextrose, lactose, galactose, trehalose and cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate, amino acids, typically having from 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine. Gelling agent can be any agent that is able to form a network of molecules within a fluid, for providing fluid consistency gel. Such agent may contain high molecular weight proteins or other polymers, but may also be based on low molecular weight compounds, which can form the network through recombination of low molecular weight compounds in a long chain (as it is known, among other sources, from U.S. patent No. 6471758). Gelling substance has the advantage that the high-molecular compounds provide additional mechanical stability of the finished tablet. Typical examples of gelling substances are gelatin, dextrins and proteins of soybean seeds, wheat and blatnoy herbs, resins, such�to gum, agar, acacia, xanthan gum and carrageenan, polysaccharides, alginates, carboxymethylcellulose, pectin, polyvinylpyrrolidone, etc.
In yet another variant implementation, the composition contains 3 or more % of the mass. crystalline material and about 4% of the mass. gelling substance. Usually, the amount of the crystalline carrier material in preparting the form below to get ODT is kept below 3% of the mass. For gelling substance is preferably used in the amount of about 4 wt%. The applicant found that when using 3 or more % of the mass. crystal media and at the same time using about 4% of the mass. gelling substances, it suddenly may cause high mechanical strength of the final tablet and very good disintegration properties.
In one embodiment, the implementation, the gelling substance contains not forming the gel material is preferably a material derived from collagen, such as gelatin. Although the gelling substance is in principle capable of forming a gel in the liquid, the applicants have found that it is preferable to choose gelling substance that does not form or at least don't fully form a gel in liquid composition during filling of the cavity (this can be simply accomplished by choosing gelling compound or material which dissolve�makes in the liquid composition at this temperature is the formation of a network of molecules of the gelling substance in a liquid). This simplifies the introduction of liquid composition with high viscosity and/or lower non-Newtonian behavior of the liquid composition. After the introduction, when the temperature gelling substance forms a gel. In a preferred embodiment of implementation, derived from the collagen material is a gelatin having a weighted mean molecular weight of 2×104g/mol (thus, having the actual weight of from 15000 to 25000 g/mol). The applicant found that the use of such gelling substances can lead to obtaining less sticky tablets and also tablets that have very good disintegration properties while maintaining adequate mechanical strength, despite the relatively low molecular weight gelling agents. Gelati Sol P (manufactured by Gelita, Eberbach Germany) is a good example of such gelling agents. It should be noted that the strength of the gelling substance is traditionally referred to as "Bloom". It is the force, expressed in grams, necessary for the pitting on 4 mm of the surface of the gel standard piston having a diameter of 0.5 inch (1.27 cm). For gelatins, gelling substance is used at a concentration of 6,67%, and the gel should be kept at 10°C for 17 hours before testing. Bloom is associated with mechanical elasticity of the gel and, along with other aspects, it is used for the� classification of types of gelatin. He generally is in the range from 10 to 300 Bloom. Gelati Sol P has a Bloom strength of about 15-25.
In yet another variant implementation, the volume of the granules is greater than the maximum amount of free droplets of the liquid composition at the temperature and pressure used to fill the cavity. In this embodiment, the implementation of the granule is more than one empty droplet of the liquid composition. This variant of implementation has the advantage in obtaining tablets with a size that is easy to manipulate manually, based on the liquid composition, one free drop which would have a size, e.g. 50 ál. For example, if the liquid composition is based on water as solvent (liquid media), one of the free droplet at a temperature of 20°C and a pressure of 1 atmosphere contains about 50 μl. After freezing and drying of such droplets, the diameter will be approximately 2.3 mm. It is a small enough size for manual manipulation. It is preferable to have obtained a larger tablet. In the prior art this is done by converting the liquid composition in such a composition, to obtain the droplet volume of 1 ml. However, this requires all kinds of additives for imparting a liquid composition consistency similar to a gel. These additives not only make the production process more complex, but they also d�should be considered when evaluating the suitability for use in a given patient. Although the freezing of single droplets has advantages regarding the production method, the merit of the applicant was the discovery that the preparation of pellets, of a volume that matches the volume of a plurality of single droplets, leads to less severe conditions for the ingredients of the liquid composition, simply because there are fewer links must be present in the composition.
In yet another variant implementation, the speed at which the cavity is filled with a liquid composition, is selected so that the surface of the granules, which is in the cavity before the pellets are extracted from the cavity, was an essentially negative imprint cavity surface. It was found that the fill rate can be selected so that the surface of the granules, at least part of which is adjacent to the cavity, was an essentially negative imprint cavity surface ("on the merits", meaning, at least as far as can be seen unaided by the human eye). When the fill rate is below this speed, will form the uneven surface of the granules, because the fluid that enters the cavity will be cured before she will be able to completely moisten the surface of the cavity. It is found that complete wetting is particularly suitable not only for the way�of neat and smooth pellets and thus, of tablets, but it also provides the opportunity to form a logo or any other identifying means in the tablet (for example, the logo of the business side of promoting tablet on the market, or any other print). For this, you should have a mirror image of the imprint in the wall cavity (or positive, that is, applied over walls, or negative, i.e., pressed into the wall).
The cross-section of a part of the granules, which is in the cavity may be smaller than the cross section of the cavity at its entrance. In this embodiment, the implementation of the granule can be easily removed from the cavity, for example, simply by pushing or pulling the pellets from the cavity using a mechanical force, air pressure, gravity, etc.
In one embodiment, the implementation of the measure taken to maintain the automatic detachment of the pellets from the wall cavity. Automatic deallocation, i.e., the mechanical interference of any kind, greatly reduces the probability that the bead will be damaged after removal from the cavity. In one embodiment, the implementation, the cavity formed in the solid element, the automatic undocking promotes the retention temperature of the solid element is adequately below the freezing point of the liquid composition. It was the DEA�hidden, for each liquid composition can be found temperature which is so low that it generates the rate of shrinkage of the pellets, sufficient to invoke the automatic detachment of the pellets from the wall cavity. For liquid water-based composition, the temperature should be at least 80 degrees (K) below the freezing point of the composition, thus, about -80°C. Preferably, the difference is approximately 100-120 degrees and even up to 196 degrees. The required difference depends on the composition, but can be simply found by increasing it from 0 to provide automatic checkout. Such detachment can be easily determined, because after the automatic checkout, the granule can be simply removed from the cavity using just gravity (turning the item upside down). In another embodiment, the implementation, the automatic undocking contributes to the provision of the cavity wall adhesive surface chemical and/or physical means to obtain the adhesive surface. Well-known chemical means for receiving the adhesive surface are, for example, coatings with a high content of fluorine (e.g., Teflon®) or a high content of silicone. Physical means are, for example, structures similar to the Lotus leaf, or obsesses�haunted nanosilica. Adhesively surface has the additional advantage that the pellet may be formed in a very shallow cavity. However, the inherent adhesive surface drawback is that a complete wetting of the surface for formation of a negative imprint of the cavity wall is elusive.
The pellet can be removed from the cavity by the application to the pellet propelling power. It was found that the application of the pushing force, despite the inherent risk of mechanical damage to frozen pellets, provides excellent results for the removal of granules from the cavity, at the same time keeping its shape intact. The advantage of a pushing force, for example, before the purge gas is that pushing may be a pure mechanical element, whereas the air flow inherent problems of sterility. In a preferred embodiment of implementation, the pellet is ejected from the cavity using a tangentially directed force. It was found that the tangential force, although less direct, has the advantage that there is less mechanical impact with the pellet, even though it improves the process of removal. By applying a tangential force, a granule may start to spin and turn in its cavity, which will lead to easy and reliable removal without damaging the pellets.
Mn�d's pellets can be placed in a compacted layer before drying of the pellets in a vacuum. In this embodiment, the implementation, the granules are not dried when placed in a single layer, but are compacted in order to become a part of multilayer formation. Thus, the stage of drying, which can occur in the freeze dryer, is carried out with a considerably higher efficiency. However, because the drying process, along with other aspects, depends on the heat transfer through the layer, the number of layers will be limited to 2 or 3. Therefore, in another embodiment, the pellets are arranged in a heat conducting container having a bottom and side walls, and the source of the body is located above the upper layer of compacted granules, wherein the heat source has a surface directed to a top layer of a layer, and this surface has a coefficient of relative emissivity of 0.4, after which the pellets are exposed to vacuum, and at the same time you are heating at least the bottom of the container and said surface for applying heat to the particles to facilitate drying of the granules. In this embodiment, the implementation, the number of layers in the reservoir can be increased to more than 3. However, also in the application of the monolayer of granules may advantageously be used an additional source of heat, for example, to ensure a more rapid drying process, but it is preferable, to ensure the best result�the drying. The relative emissivity coefficient (usually denoted as ε) in this respect is the ratio of energy radiated by the surface to energy radiated by a true black body at the same temperature. It is a measure of the ability to absorb and radiate energy. A true black body would have ε=1, then valid as any surface or object would have ε<1. The relative emissivity is a digital value and has no units. Having a relative emissivity coefficient of at least 0,4 heated surface emits a relatively large amount of heat on particles. Relative emissivity in the sense of the present invention is the average relative emissivity, as determined at four different temperatures of the surface, namely, 55, 60, 65 and 70°C. the Relative emissivity can be measured using specialized equipment to measure the relative emissivity, commercially available, such as the device model 205WB manufactured by Advanced Fuel Research Inc., East Hartford, CT USA. However, such equipment is very expensive. As is well known, very simple by measuring the relative emissivity is heating�their surface and a surface with a known relative emissivity to the same temperature, as determined by thermocouple. Then read the temperature of the two surfaces standard with an infrared pyrometer. The difference of the two infrared temperature measurements caused by the difference in the relative values of emissivity surfaces (see also the publication Applied Optics, Vol. 13, No. 9, September 1974).
As for the final tablet, in one embodiment of the tablet contains a crystalline carrier material which is solid at room temperature and gelling substance, as described above in the present application. Also, the tablet can be formed from a liquid composition containing 3 or more % of the mass. crystalline material and about 4% of the mass. gelling substance. Preferably, the tablet contains gelling substance containing at least 2% of the mass. forming a gel material, for example preferably of a material derived from collagen, such as gelatin. In addition, preferably, the addition of which does not form a gel material, for example preferably of a material derived from collagen, such as gelatin, to improve the disintegration properties. This is not forming a gelatin gel may be a gelatin, having a weighted mean molecular weight of 2×104g/mol.
SPECIFIC EXAMPLES of the INVENTION
Now the picture�Linux will be explained in more detail using the following non-limiting examples.
Fig. 1 schematically shows a tray with cavities and corresponding cooling element for use in the method to obtain frozen pellets.
Fig. 2 schematically shows the main parts of the device for producing frozen pellets.
Fig. 3 is a schematic top view of certain parts of the device shown in Fig. 2.
Fig. 4 schematically shows a filling needle coupled with the corresponding cavity.
Fig. 5 schematically shows a drying chamber for use in the present method and system.
Fig. 6 schematically shows the elasticity tester for determining the ultimate strength in compression of tablets.
Fig. 7 schematically shows a package containing a tablet in accordance with the invention.
Fig. 8 schematically shows a device for measuring the resistance of tablets during compression through the foil.
Fig. 9 schematically shows examples of tablets, compressible through the foil.
Example 1Obtaining ODT component of live vaccine
Example 2Obtaining ODT with chemical medicine
Example 3Establishing the mechanical stability of ODT
Example 4An alternative way of establishing the mechanical stability of ODT
Fig. 1A schematically shows a tray with cavities 100 and the corresponding cooling�ment element 105 for use in the method to obtain frozen pellets. Tray with cavities 100 is a solid steel plate (made of stainless steel, grade 316L) having a thickness of 6 mm. At the plate formed by three rows (102, 103 and 104) of the cavity 101. Fig.1B shows an example of the first type cavity. Shown cavity 101 has a spherical shape, the radius r of 2.9 mm and a depth of 2.1 mm. d In such a cavity may be formed in a spherical granule 30 volume approximately 100 ál (having a radius of approximately 2.9 mm). Another example that can be used for larger tablets, shown in Fig. 1B. This cavity 101' is also spherical, has a radius r of 4.9 mm and a depth of 4.0 mm. In such a cavity may be formed in a spherical granule 30' (approximately 500 µl (having a radius of about 4.9 mm). In fact, can also be provided with other dimensions (e.g., 50 ál and 1000 ál) and the form of, for example, to get flattened at the poles (also known as "M&M-" or having "elegant" form) granule, ovoid granules, oval (shaped airship) granules, etc. In particular, flattened at the poles, the pellet may be formed in tapered from the poles of the cavity having a length and a width of 6.0 mm and a depth of 3.3 mm by introducing a volume of about 300 μl.
The tray 100 by the gravitational force is on the cooling element 105 (in the alternative embodiment of the tray can be fixed for�Imam to the cooling element 105). This element is a hollow box made of stainless steel, having a height of about 6 cm Box 105 has an inlet 106 and release 107. Through the inlet 106 may be connected to liquid nitrogen (arrow A) at a temperature of about -196°C. After the release of 107 nitrogen (a mixture of liquid and gas) comes out of the box 105 (arrow B). This approach can provide adequate cooling tray 100 to get a very quick curing process, when the fluid composition is supplied in one (or more) of the cavity 101. Depending, among other factors, on the temperature, fluid composition, temperature of ambient air, nitrogen flux and the speed with which the solid granules, the equilibrium temperature from -85°C to -145°C for the tray 100 can be obtained as shown device.
Fig. 2 schematically shows the main parts of the device for producing frozen pellets. Seen the same tray 100 and the cooling element 105, as shown in Fig. 1. Front (below the tray 100) is shown black plastic container 15, the container has a handle 16 for manual manipulation of the container. The container 15 is placed with emphasis at the cooling element 105. The container is cooled to a temperature of about -45°C by cooling it to a stand (not shown) using liquid nitrogen. On the other side of the tray 100 (located above the side) showing� collecting element 120, moreover, this element is divided into three compartments 121, 122 and 123. This element is moved over the surface of the tray (with the gap of about 0.2 mm between the bottom of the element 120 and the surface of the tray 100) in the direction C and pushes the frozen pellets from their cavities. Then these granules are collected in each of the compartments 121, 122 and 123, and ultimately transferred to the container 15. To collecting element 120, by means of brackets 131 are attached to the feed unit 130. This block contains three needle 132, 133 and 134 corresponding to the rows of cavities 102, 103 and 104, respectively. The needle used to apply the liquid composition in each of the cavities. The liquid composition is supplied to each of the needles respectively through the tube 152, 153 and 154.
In operation, the atmosphere is cooled to a temperature approximately 15°C using dry nitrogen gas. Due to this relatively high temperature of the surrounding atmosphere, liquid water-based composition can be manipulated in the device and around it without the risk that the composition will freeze in the pipes 152, 153, 154, or pins and needles 132, 133 and 134. The dry nitrogen gas is used to prevent crystallization of water into ice on various parts, which are held at temperatures below 0°C. In this design, the tray 100 will have an equilibrium temperature of about -125°C. Collecting element 120 has a temperature of approximately -35°C, and Conte�ner 15 will have a temperature of about -45°C.
The process begins with the moving element 120 in the direction C until then, until the needle aligns with the first (upstream downstream) cavities. Then the movement of the element 120 is temporarily stopped, and the first three cavities are filled with a liquid composition. Upon completion, the element 120 is shifted forward until the needle is in alignment with the following three cavities. Then, these cavities are filled with a liquid composition. The process continues until, until all the cavity is filled with a liquid composition. Then the element 120 rises (by about 25 mm) and returned to its original position in the upstream portion of the tray 100. Then 120 again moves forward in the direction C. At this time, the element will pass through the frozen pellets in each of the cavities. The pellets are pushed out of their cavities and are collected respectively in the compartments 121, 122 and 123. In this process, each granule may stay from 20 to 90 seconds in its cavity (from fill-up ejection, depending, among other factors, pellet size: the larger the granule, the more time it will take the curing process). At the same time, located upstream in the element 120 devastated cavity again filled, as described above in the present application. This process continues until, until�ntainer 15 will not be adequately filled with the frozen pellets.
Fig. 3 is a schematic view in top plan of the parts shown in Fig. 2. In this schematic view shows the internal arrangement of the collecting element 120. Each compartment 121, 122 and 123 has correspondingly inclined inner wall 141, 142 and 143. Each of these walls is inclined relative to the direction of movement C at an angle of 10°. The walls reach the frozen pellets and pushed them out of their cavities. Since each wall is inclined, the pellets are ejected tangentially directed force. This has the advantage that the pellets are turned out more or less from their cavities. It turned out that it greatly reduces the risk of damage to the granules. When the pellets are pushed out, they are going in the rear of the compartments, in this case, respectively in curves 161, 162 and 163. In the position of the downstream element 120 (adjacent to the container 15) pellets will automatically fall into the container 15.
Fig. 4 schematically shows a filling needle coupled with the corresponding cavity. The needle 132 has the tip 232. The tip 232 is to give it a vertical position relative to the surface of the tray 100 so that the tip was aligned with the top of the pellets 30 to be educated in the cavity 101. From this position, the cavity filled�makes liquid composition. Filling speed can be adjusted to obtain any desired filling process. For example, when you select a very low speed, it will be formed pellets of irregular shape, among other reasons, because the liquid will not wet the wall of the cavity. When you select a high enough speed, can be achieved a complete wetting. This rate depends, among other factors, from the actual temperature of the liquid during the filling of the cavity, the temperature of the walls of the cavity, fluid viscosity, etc. For each part of this rate can be found by routine experimentation. After filling the required quantity of liquid composition, the needle moves on to the next cavity. However, preferably, the wetting time, for example, about 0.1 seconds, was used from the time when the composition was applied to the point in time at which again starts moving the needle. It can prevent mechanical damage introduced pellets. It should be noted that in this particular example depicts a spherical pellet 30. However, there may be also formed of other shapes. In any case, the optimal position of the tip is just at the very top of the subject to the formation of granules.
Fig. 5 schematically illustrates �movilizador (device freeze-drying). This freeze dryer can, for example, be a Christ freeze dryer Epsilon 2-12D, manufactured by Salm en Kipp, Breukelen, The Netherlands. Freeze dryer 1 includes a housing 2 and a lot of shelves 3. The device is Epsilon 2-12D contains 4 + 1 shelves, for convenience, Fig. 1 shows three of these shelves (namely, shelves 3a, 3b, and 3c). Each of these shelves is provided with a heating element 5 (marked respectively 5a, 5b and 5c) for uniform heating of the shelves 3. Heating can also be adjusted using the processing unit 10. The housing is connected to the pump unit 11 to provide adequate low pressure inside the housing 2. The inner space of the housing can be cooled to temperatures reaching -60°C, using a cooling unit 12, in particular containing a capacitor (indeed, it is the temperature of the condenser is held at a temperature at about -60°C, which acts as a driving force for condensation of sublimated ice). Shelves 3a and 3b is provided with black plates made of PTFE (polyethylenterephtalate) 8 and 8' are fixed to their bottom. The coefficient of relative emissivity of these shelves is 0,78. By close contact between these black plates and shelves, these plates can be heated essentially to the same temperature as the temperature of the shelves themselves. Thus, the plate 8 can� be considered as a heat source, in addition to the 3 shelves.
On the shelves are placed in the container 15 and 15'. These containers are made of thermally conductive material, in this case, polyethylenterephtalate filled with soot. The containers are in heat conductive contact with shelves, on which they are placed. In the illustrated construction, the containers are filled with frozen pellets 30 which thus form a layer 29 of compacted pellets in each container. By heating the shelves of a particle can gain heat through the heated bottom and side walls of the containers and radiation respectively from heated plates 8 and 8'. It should be noted that each container 15 has a width and a length of about 20 to 30 cm and a height of about 4 cm Height of the compacted layer after filling of the container is usually from 1.5 to 3 cm. This leads to the typical values for the aspect ratio of the layer from 20/3≈7 to about 30/1,5=20. However, it can also be used single-layer arrangement of the granules.
Fig. 6 schematically shows the elasticity tester for determining the ultimate strength in compression of tablets. This drawing is a schematic side view of the tester of elasticity LR5K Plus (manufactured by Lloyd Instruments, UK) with a load cell 400 to test the limit of compressive strength of 30 tablets. To do this, the tablet 30 is subjected to a force load� terminal 401 when placed on the substrate 300.
Fig. 7 schematically shows a packaging 500 containing tablet in accordance with the invention. The package 500 includes a rectangular base and many blisters 501 having contained therein the pills 30. Blister packaging can be peelable type, where the layer (not shown), fixed to the rectangular base may crack open one of the blisters for withdrawal of the respective tablets. Also, in particular, when the mechanical stability of the tablets is sufficient, the layer may be more convenient to type (often in the form of aluminum foil), where each tablet is pushed through the layer.
Fig. 8 schematically shows an alternative device for establishing mechanical stability of ODT. With this unit examines the propensity of lyophilized tablets to remain intact after punching through the foil. Head extruders 3001 and 3002 represent nodes that contain a cylindrical hole 13 diameter. Aluminum foil 3005 thickness of 5 μm is placed between the heads of the extruder and coated with rubber ring 3003 to prevent displacement of the foil. Lyophilized tablet 30 is placed on the foil and can be compressed through the foil using a glass rod 4001 by application of force by hand pressure on with�Ergen. After punching the tablets through the foil, or whole tablets or fragments of tablets can be collected under the head of the extruder 3002.
Fig. 9 shows examples of tablets or fragments of tablets after the test to measure the propensity to remain intact after punching through the foil. Fig. 9a shows the 30 tablets that remain intact after pressing through a foil thickness of 5 μm. Fig. 9b shows 30 pills", which was fragmented when passing the same test.
To obtain tablets containing vaccine component, human infectious influenza virus is harvested from the eggs. Allantoic fluid containing the virus is mixed with a stabilizer. The stabilizer is known from the document WO2006/094974 A2, and, in particular, are described in table 5 of the patent application (with the content of glycine 160 g/l). The method of adding the stabilizer is also described in the patent application, namely, in General the main principles of the introductory part of the section "Examples" on page 24.
Use the plate with three rows of cavities according to Fig.1b. In each of these cavities serves about 100 μl of liquid composition in approximately 0.3 seconds. The composition starts to freeze immediately after contact with the cavity wall. However, essentially until frozen pellets, COH�and it can be distorted after about 15 seconds. The pellets (which have a diameter of approximately 5.7 mm) is pushed out of the cavities (as explained in relation to Fig. 2 and 3) and transferred to a container of freeze-drying 15.
Frozen pellets (having a temperature of about -45°C) is placed in the container 15 in the form of a compacted layer with an aspect ratio of about 15. Then the set of containers is placed in a freeze dryer (see Fig. 5), the temperature of which was previously increased to about -35°C. the freeze dryer is subjected to the next cycle of freeze-drying (table 1).
|Phase||Time [h:min]||Temperature [°C]||Vacuum [mbar]|
|The final stage||00:01||4||Of 0.021|
As can be seen from table 1, after loading the shelves filled with containers, the temperature of the shelves is first maintained at -35°C for 30 minutes (phase "Freezing"). Through this, the temperature of the frozen pellet was adjusted to a temperature of -35°C. Maintain atmospheric pressure. Then the temperature of the shelves is stabilized at the level of -35°C for 20 minutes, and the pressure remains atmospheric ("Preparation"). Then the pressure was reduced to 0,307 mbar for a period of 10 minutes, the temperature of the shelves is maintained at -35°C (Initial sublimation"). In these conditions, the frozen fluid is sublimated and heat in the granules of the two heat sources, respectively, via conduction and radiation. However, the sublimation rate under these conditions is relatively low. To increase the speed of sublimation, the temperature of the shelves is adjusted to 40°C over a 3 hour period ("Sublimation 1") and maintain at this temperature for 16 hours ("Sublimation 2"). The pressure is maintained at low� level when the value 0,370 mbar. Then, the pressure is further reduced to of 0.021 mbar, while the temperature of the shelves is adjusted to 4°C. the Latter stages takes 1 minute (the"Final stage"). After that, the sublimation process complete, and about 98% of the frozen liquid was removed from the pellets, thereby converting into fast disintegrating tablets. Then dry nitrogen gas with a temperature of about 20°C is introduced into the freeze dryer until then, until the pressure becomes approximately atmospheric. It takes about 2 minutes. Then the door can be opened to retrieve the pills. When using this method shows that it is possible to obtain a homogeneous lyophilization, visible as a homogeneous layer of lyophilized pellets. After the operation of the freeze dryer, tablet preferably not exposed to a moist environment to prevent condensation of water on the pill. In particular, the tablets are filled into containers in a closed room with the atmosphere of dried air or nitrogen. After filling the containers, close them and store in a cool place (4-8°C) until further use.
Thus, can be obtained lyophilized spherical pills with an average diameter of approximately 5.5 mm and having contained therein a vaccine ingredient.
The tablets can be used to produce pharmaceutical packaging. This�akovica consists of a container (such as glass or plastic bottle), containing one or more tablets and possibly other ingredients. Vaccine ingredient in tablets can be administered to man the premises of one tablet under the tongue of the patient and the abandonment of the tablets to melt. Live flu virus will enter the body of the patient through the mucosa.
To obtain tablets containing chemotherapeutic drug, you can use the plate with three rows of cavities, in accordance with Fig. 1C. In each of these cavities serves approximately 500 µl of the liquid composition within 2 seconds. At this speed the introduction, the cavity wall is completely wetted and, therefore, the surface of the granules, which is in the cavity (before removing the pellets from the cavity), is a negative imprint of the cavity surface, in this case, smooth surface without depressions or wrinkles. If the logo (positive or negative) is present in the cavity, the logo would be visible on the surface of the pellets. Examples of the liquid composition that can be used to obtain frozen pellets below in the present description:
Liquid composition 1:2% of the mass. asenapine ((3aS,12bS)-5-chloro-2,3,3 a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepin[4,5-c]pyrrole maleate (1:1); ORG 5222), 4% of the mass. hydrolyzed gelatin (manufactured by Croda, Yorkshire, England), 3% of the mass. �flakes (PEARLITOL®, type C160 manufactured by Roquette, Lestrem, France), and water QS (as needed, i.e. add up to the total 100 mass%).
A liquid composition 2:16% of the mass. receptor antagonist of thrombin SCH 530348 bisulfate (TRA; see U.S. patent No. 7235567), 3,5% of the mass. hydrolyzed gelatin, 3% of the mass. mannitol, 3.73% of the mass. dehydroacetate sodium, 1,41% of the mass. monohydrate citric acid and water QS (much needed).
A liquid composition 3:8% of the mass. TRA, 8% of the mass. gelatin (Sol P, manufactured by Gelita, Eberbach, Germany), 9% of the mass. mannitol, 3.73% of dehydroacetate sodium, 1,41% of the mass. monohydrate citric acid and water QS.
A liquid composition 4:8% of the mass. TRA, 8% of the mass. gelatin (Sol P, manufactured by Gelita, Eberbach, Germany), 9% of the mass. mannitol and water QS.
The composition will start to freeze immediately after contact with the cavity wall. However, after about 45 seconds before the pellet will essentially freeze so that it was possible to mechanically manipulate. After that, the pellets (which have a diameter of approximately 9.8 mm) are ejected from the cavities (as explained in connection with Fig. 2 and 3) and transferred to a container of freeze-drying 15.
Frozen pellets (having a temperature of about -45°C) is placed in the container 15 in the form of a densely Packed monolayer. Then the set of containers is placed in a freeze dryer (see Fig. 5), the temperature of which is adjusted in advance to a temperature of about -5°C. Freeze dryer is subjected to the next cycle of freeze-drying (table 2).
|Phase||Time [h:min]||Temperature [°C]||Vacuum [mbar]|
|Initial sublimation, part 1||00:10||-35||0,310|
|Initial sublimation, part 2||05:10||-15||0,310|
|The final stage||00:01||35||0,310|
As described above in the present application, after the "Final stage" process complete sublimation, and approximately 98% of the frozen liquid out of the granules, thereby converting the pellets into fast disintegrating tablets. Then, dry nitrogen gas with a temperature of about 20°C is introduced into the freeze dryer until then, until the pressure becomes approximately atmospheric. It takes about 2 minutes. Then the door can be opened to retrieve the pills. Tablets are filled into containers in a closed room with the atmosphere of dried air or nitrogen. After filling the containers, close them and store in a cool place (4-8°C) until further use.
The disintegration of the tablets obtained can be tested by placing in a beaker filled with water having a temperature of 37°C, and measuring how much time is essentially complete disintegration (when not visible to the naked human eye large pieces). It seems that all the tablets obtained from the liquid compositions 1, 2, 3, and 4 fall in the range of 5-10 seconds.
This example describes various methods of evaluation of mechanical stability of the tablets. The first test is a test of the fragility of the tablet, which is commonly used to test the vulnerability of the tablet for mechanical manipulate�the stripes. The known method an unambiguous assessment of the fragility and used for it device manufactured by DeltaLab, of Moirans France: the A41 13 Tablet Friability and Abrasion Tester. The industry has also produced other devices and methods are known with their application.
Method of assessment of other properties that can be used to characterize the mechanical stability of the tablets is a limit of compressive strength tablets. The principle of this method of testing is that the tablet is subjected to deformation, and the resulting force is measured as long as the tablet has to be crushed. This may be the tester of elasticity LR5K Plus manufactured by Llyod Instruments (Fareham, Hants, UK). In this example, applicants used the XLC load cell 50N (see Fig. 6). The speed of movement of the punch (also referred to as "elongation") was 10 mm/min force Profiles-bias was detected three times, and the failure modes were determined using the software Nexygen, which is supplied with the tester. It should be noted that alternatively, the limit of compressive strength can be measured by the device Pharmatest PTB 300/301 (manufactured by Pharmatest, Hainburg, Germany).
In the first experiment, a series of spherical placebo pills 250 ál (not containing medicinal substance) was obtained in the manner described above in �ustasha application (example 2), however, with the difference of the size of the cavity; the radius is 3.9 mm, and the depth is 3.0 mm. Used various liquid formulations, and each contained a different quantity of gelling substance Gelita Sol P (Gelita, Eberbach, Germany) and crystalline media mannitol (PEARLITOL®, type C160 manufactured by Roquette, Lestrem, France) to obtain a variety of pills. In addition to these compounds, the liquid composition contains water. Table 3 shows the different compositions.
|Party||gelatin (% wt.)||mannitol (% wt.)||water QS|
When an assessment is made of the limit of compressive elasticity tester Llyod Instruments LR5K, first load increases elongation. After some time, when the tablet does not stand (i.e., destroyed), increasing the load stops or even decreases. The maximum load at the time of dissolution of the tablet is called the limit of the compressive strength. The results of the measurement limit of the compressive strength of the tablets is presented in table 4.
|Composition||The average ultimate strength in compression (N)|
|Sol P7||To 5.89|
It is seen that the average ultimate strength in compression is relatively high for these pills (which are all based on a liquid composition containing 3 wt%. or more crystalline media and 4% of the mass. or more gelling agents).
In the second experiment, a series of flattened at the poles tablets volume of 500 µl, possibly containing TRA (as described in example 2) as a medicinal substance obtained in the manner described above in the present application (example 2), but with the difference consisting in the size of the cavity radius was 12.0 mm, and the depth was 3.0 mm. Used various liquid compositions, each containing a different amount of gelling substances Gelita Sol P (Gelita, Eberbach, Germany) and crystalline media are composed of various amounts of mannitol (PEARLITOL®, type C160, manufactured by Roquette, Lestrem, France) and sucrose (α-D-glucopyranosyl-β-D-fructofuranoside). To�ome of these compounds, liquid compositions contains water QS. Table 5 shows the different compositions.
|Party||gelatin (% wt.)||mannitol (% wt.)||sucrose (% wt.)||TRA (% wt.)|
It was found that the ultimate strength in compression tab�etok was the same, approximately 5N. This means that no additional sucrose or medicinal substance does not have a significant impact on the strength of the tablets in this experiment. Therefore, the amount of gelatin 8% of the mass. and mannitol, more than 9 wt.%, which, as observed, provides very good tensile strength in compression in the first experiment, it is very suitable for tablets, in particular tablets, which itself requires a high mechanical stability.
The tendency of tablets to remain intact after punching through the foil was determined using the device described in conjunction with Fig. 8. The test was referred to as a "test push" in this example.
Received tablets of different compositions. The number and ratio of the two types of gelatin was varied to obtain gelling substances, in accordance with data published Chandrasekhar, R., Hassan, Z., AIHusban, F, Smith, A. M. and Mohammed, A. R. Eur. J. Pharm. Biopharm 72 (2009) 119-129. Used two types of gelatin: Sol P (which does not form gel gelatin) and BS100 (forming a gelatin gel). The latter of these gelatins produced by the company Gelita, Eberbach Germany. The amount of mannitol (PEARLITOL®, type C160) supported on two levels. All tablets contained 2% (wt./about.) drugs, in this case, asenapine (see example 2). Received splume�exercises with poles, spherical and dense tablets volume of 250 µl and tested in the test push. For comparison, also used the manufactured tablet volume of 250 µl ("the Pill"). This tablet contained 2% drugs 4% gelling substances of unknown type and 3% mannitol. After testing, the tablets were either intact, or broke into numerous pieces, as illustrated by the schematic drawings in Fig. 9. Table 6 summarizes the results and presents the percentage of intact tablets, when tested 10 tablets of each composition and the specific shape and volume. It should be noted that ODT in General is so fragile that it is usually assumed that in the structure of the experiment none of the tablet will remain intact. However, unexpectedly it was found that when using the present invention can be obtained tablets that remain intact when punching through aluminum foil with a thickness of 5 μm.
The results presented in table 6, also implies the impact of the tablet form for her safety after the test push. In General, it appears that with tapered poles and spherical tablets have the advantage in comparison with flat tablets. Can be expressed also by the curvature of the upper or lower surface relative to the diameter standard�Oh dosage forms. The principle of the introduction of the method in accordance with the invention, however, that the liquid has a surface tension implies that the surface pills can be described in the form of two hemispheres in the case of spherical pellets and two connected spherical caps in the case of tablets with tapered poles. For the reason that the pellets shrink during drying or during storage or when both of these effects, the injection volume is not adequately predict future sizes of tablets. It is possible to calculate the radius of curvature of the cap and its correlation with the diameter of the tablet using the dimensions of the tablets using widely available information that correlates with the size of the cap with its volume. For example, the relative curvature K of the tablets is determined by the ratio of the radius of curvature (R) of the cap to the half of the tablet diameter (D):
Higher values of relative curvature correlated with flatter surfaces. The spheres used in this test had a relative curvature K of about 1.0. The wafer had a relative curvature K of about 1.2, and the "pill" had curvature K uncertain quantities. We can conclude that the value of K from 1 to 1.2 is optimal.
|Form||The percentage of intact tablets|
|*type of gelatin is unknown|
Overall, it appears that tablets containing about 4% gelling substances, have good resistance against fracture while pushing through the aluminum foil. It was also found that the presence of at least 2% of the mass. clicks�realizes the gelatin gel (such as BS100) can result in tablets with a very good score rating during the test push. This can be caused by a higher degree of "network" in these pills. However, the preferred tablet having not forming a gel gelatin (such as Sol (P) as additional connections to the gelling substance is due to best properties of disintegration.
1. A method of producing disintegrating in the mouth tablets for administration to a human, wherein the tablet contains the medicinal substance for the treatment of disorders in humans, which includes stages:
- providing a liquid composition containing the medicinal substance,
- providing a solid element having formed therein at least one cavity,
- cooling of the solid element to a temperature below the freezing point of the composition,
- fill the cavity of the liquid mixture,
curing of the composition, is present in the cavity, the heat dissipation from the structure through the wall cavity through conductive heat transfer with formation of solid granules containing the medicinal substance, without active profiling of the entire surface of the granules,
- extract the pellet from the cavity and
- drying the pellets under vacuum to obtain tablets,
characterized in that the volume of the cavity is smaller than the volume of the granules.
2. A method according to claim 1, characterized in that the volume of the cavity is less than 50% of the volume of the pellet.
3. A method according to any one of claims.1-2, characterized in that the composition of ODS�REIT crystalline material of the carrier, which is a solid at room temperature selected from sugars, cyclic sugars, inorganic salts and amino acids, and gelling substance selected from gelatin, dextrin and protein of soybean seeds, wheat and blatnoy herbs, resins, such as gum, agar, acacia, xanthan gum and carrageenan, polysaccharides, alginates, carboxymethylcellulose, pectin, polyvinylpyrrolidone.
4. A method according to claim 3, characterized in that the composition contains 3% by weight. or more of a crystalline material and about 4% of the mass. gelling agents.
5. A method according to claim 3, characterized in that the gelling substance contains material derived from collagen.
6. A method according to claim 5, characterized in that the material derived from collagen, is a gelatin having a weighted mean molecular weight of 2×104g/mol.
7. A method according to claim 1, characterized in that the volume of the granules is greater than the maximum amount of free droplets of liquid composition, temperature and pressure used to fill the cavity.
8. A method according to claim 7, characterized in that the speed at which the cavity is filled with a liquid composition, is selected so that the surface of the granules, which is in the cavity before removing the pellets from the cavity, is essentially a negative imprint of the cavity surface.
9. A method according to claim 1, wherein �then take steps to facilitate the automatic detach the pellet from the wall of the cavity.
10. A method according to claim 9, where the cavity is formed in the solid element, characterized in that the automatic undocking contributes to maintaining the temperature of the solid element below the freezing point of the liquid composition.
11. A method according to claim 1, characterized in that the pellets are arranged in a heat conducting container having a bottom and side walls, and that the heat source is above the upper layer of compacted granules, wherein the heat source has a surface directed to a top layer of the reservoir, wherein the surface has a coefficient of relative emissivity of at least 0,4, after which the granules are subjected to a vacuum while heating at least the bottom of the container and said surface for applying heat to the particles to facilitate drying of the granules.
12. Disintegrating in the mouth tablet for administration to a human, wherein the tablet contains the medicinal substance for the treatment of disorders in humans, where the tablet can be obtained by a method according to any one of claims.1-11, characterized in that the tablet has a curved surface.
13. Disintegrating in the mouth tablet according to claim 12, characterized in that the tablet has a relative curvature To 1 to 1.2.
14. Tablet according to any of claims.12 and 13, characterized in that it comprises a gelling substance, including, for men�her least 2% of the mass. forming the gel material is preferably a material derived from collagen.
15. Tablet according to claim 12, characterized in that the gelling substance contains no gel forming material, preferably a material derived from collagen.
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to the pharmaceutical industry, namely, represents a delivery system for the application in the oral cavity, application and method of obtaining the said delivery system. The delivery system includes a carrier, which includes a cellulose-based or starch-based material and has a surface, including oxygen-binding sites and one binding unit, bound to the carrier, where the said binding unit includes a sugar chain of the following formula: xylose-galactose-galactose-glucosamine.
EFFECT: realisation of the invention provides the possibility of the improved and simplified delivery of a wide range of biologically active substances, simultaneously providing a precise dose of the biologically active substance.
14 cl, 4 dwg, 3 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed invention relates to a method of manufacturing a tablet by pressing a powder mixture in a press-mould plate with the formation of a tablet form, with the powder mixture including a pharmaceutically active substance and hydrated sugars, as well as exposure of the tablet form to radiation for a period of time, sufficient for heating the hydrogen-containing material in the tablet form to a temperature higher than its dehydration temperature with the tablet formation.
EFFECT: increase of production efficiency.
21 cl, 14 dwg, 3 ex, 3 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a tabletted oral dosage form containing desloratadine in an amount of 3 to 15%, processing additives and a pharmaceutically acceptable excipient. The processing additives consist of sodium croscarmellose, magnesium stearate and povidone. The excipient represents a mixture of lactose disaccharide and microcrystalline cellulose polysaccharide in ratio from 2:1 to 8:1. Lactose and microcrystalline cellulose have an average particle size from 30 to 200 mcm. Producing the table involves granulating desloratadine, lactose and microcrystalline cellulose.
EFFECT: invention provides reducing granulate compression force, increasing process capability and maintaining the high quality of the tablets.
9 cl, 4 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to the pharmaceutical industry, namely to a formulation of a cough medical composition. The formulation of the cough medical composition contains an active substance presented by thermopsis herb powder or a dry extract of thermopsis and sodium hydrocarbonate, as well as an excipient, a granulating agent and a lubricant taken in certain relations (versions).
EFFECT: composition of the cough medical composition possesses improved pharmaceutical (appearance, taste) and technological characteristics (hardness, disintegration).
11 cl, 7 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a storage-stable pharmaceutical composition and a pharmaceutical formulation containing at least one active pharmaceutical ingredient presenting a nitrocatechol derivative, 2,5-dichlor-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide, at least one excipients and at least one binding agent, wherein at least one excipient is other than a phosphate derivative, wherein at least one binding ingredient is other than a polyvinylpyrrolidone compound, and wherein the above active pharmaceutical ingredient is present in the granulated form.
EFFECT: compositions and/or formulations according to the invention are stable for a long period of time and show a high stability if stored in the high temperature and moisture environment.
26 cl, 8 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: amlodipine base or its pharmaceutically acceptable salt, preferentially amlodipine besylate, bisoprolol fumarate, a disintegrating agent, a wetting agent, and if necessary additional excipients are homogenised; an antiadhesion agent is added, and the homogenisation procedure is continued; the homogenate is then tabletted by direct compression, or solid gelatine capsule is filled in; the prepared tablets or capsules are packed in moisture-proof protective packaging. The prepared tablets or capsules contain less than 0.5 wt % of active ingredients of compounds of formula
EFFECT: what is described is a method for preparing the stable solid pack dosage form containing the amlodipine base or its pharmaceutically acceptable salt and bisoprolol fumarate.
3 cl, 6 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: claimed invention relates to the pharmaceutical industry and provides a multilayered tablet, containing an effervescent layer, containing hydrochlorothiazide or amlodipine or its salt as an active ingredient, carbonate salt and organic acid, and a telmisartan-containing layer.
EFFECT: obtaining the multilayered tablet, containing the effervescent layer.
1 dwg, 9 tbl, 9 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention concerns a hot-melt extruded pharmaceutical dosage form with controlled-release pharmaceutically active ingredient (A) enclosed in a matrix containing polymer (C). A core of the pharmaceutical dosage form is morphologically oriented according to the holt-melt extrusion, which is substantially orthogonal to a long direction of the dosage form; and/or a release per a unit area of the pharmacologically active ingredient (A) through a front side and an opposite back side is faster than that through an annular ring.
EFFECT: dosage form shows min breaking strength 300 H; it has an oblong shape with the long direction and the cross direction orthogonal to the long one, with the front side opposite to the back side, and the annular rim between the above front and back sides.
11 cl, 20 tbl, 3 ex, 13 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions refers to medicine. What is described is a pharmaceutical composition containing licarbazepine acetate, preferentially eslicarbazepine acetate, in a combination with acceptable excipients, particularly a binding agent and a disintegrating agent. What is also described is a method for wet granulation for preparing the pharmaceutical composition.
EFFECT: composition is compacted as a tablet, which has reduced size and volume density.
79 cl, 10 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a method for producing a tablet by (i) compressing a powder mixture in a mould plate of one device for producing a tabletted form with the powder mixture comprising a pharmaceutically active substance and a fusible binding agent, and (ii) exposing the above tabletted form to radio-frequency radiation generated by the above device over a period of time adequate to soften or melt the binding agent inside the above tabletted form to produce a tablet. Oral absorption of the produced tablet placed on the tongue takes less than approximately 30 s.
EFFECT: more effective method for producing the tablet by (i) compression.
18 cl, 14 dwg, 7 tbl, 9 ex
SUBSTANCE: invention refers to medicine, namely represents a method for the therapy of respiratory symptom. The method involves administering a liquid composition containing a gel former and/or a mucoactive polymer, a non-menthol cooling substance; and contacting the oral mucosa with the liquid composition. The invention also describes liquid compositions applicable in the method for the therapy of a respiratory disease.
EFFECT: implementing the method provides improving the cooling properties of the cooling agent N-(4-cyanomethylphenyl)-n-menthane carboxamide in the liquid composition by combining the non-menthol cooling substance with the gel former.
14 cl, 2 tbl, 5 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to quinolines substituted by phosphorus-containing group of formula and applicable in medicine, wherein Z represents V1 and V2 are independently specified in hydrogen or halogen; one of R and R` represent phosphorus-containing substitute Q; the other one is specified in hydrogen or methoxyl; wherein the phosphorus-containing substitute Q represents A represents O; L represents C1-6alkyl; J represents NH or C3-6heterocycloalkyl and J is optionally substituted by G3; X is absent or represents -C(=O)-; X is absent or represents C1-6alkyl; each of R1 and R2 are independently specified in C1-6alkyl or C1-6alkoxy; G3 represents C1-6alkyl, R3S(=O)m-, R5C(=O)- or R3R4NC(=O)-; R3, R4 and R5 are independently specified in 3 or C1-6alkyl; m is equal to 0-2.
EFFECT: there are presented new protein kinase inhibitors effective for treating the diseases associated with abnormal protein kinase activity.
20 cl, 42 ex, 8 tbl, 3 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to field of pharmaceutics and deals with application of aqueous balanced solution of electrolytes as external washing solution, for washing and purification in case of surgery, for washing and purification of wounds and burns, for washing body cavities, for eye washing, for washing and purification of instruments and in servicing stomas or as carrier solution for compatible electrolytes, nutrients and medications. Aqueous balanced solution contains: 138-146 mmol/l of sodium, 4-5 mmol/l of potassium, 0.5-2.0 mmol/l calcium, 1.0-1.5 mmol/l of magnesium, 100-108 mmol/l of chloride, 0.5-1.5 mmol/l of phosphate, 18-26 mmol/l of gluconate, 20-28 mmol/l of acetate.
EFFECT: invention makes it possible to use aqueous balanced solution as effective means of external washing solution or as carrier solution for compatible electrolytes, nutrients and medications.
11 cl, 2 tbl, 4 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: pro-apoptotic solid dispersion contains a compound, e.g. ABT-263 taken in a substantially non-crystalline form to inhibit Bcl-2 proteins and dispersed in a solid binding substance containing (a) a pharmaceutically acceptable water-soluble polymer carrier and (b) a pharmaceutically acceptable surfactant. A method for preparing this solid dispersion involving dissolving the compound, polymer carrier and surfactant in an acceptable dissolution medium and removing the dissolution medium to form the solid binding substance containing the polymer carrier and surfactant and possessing a compound dispersed therein in the substantially non-crystalline form.
EFFECT: solid dispersion is orally applicable in the individual in need thereof for treating a disease characterised by the overexpression of one or more anti-apoptotic Bcl-2 proteins, eg a malignant new growth.
22 cl, 6 ex, 2 tbl, 3 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: group of inventions relates to medicine and deals with a method of obtaining an elongated implant, where the ratio of the diameter to the length on the implant axis constitutes between 1:20 and 1:40, for the controlled and delayed release of a GnRH analogue of triptorelin acetate. In addition, the group of inventions deals with the elongated implant, obtained in accordance with the said method.
EFFECT: group of inventions provides good control over triptorelin release from the implant.
11 cl, 26 ex, 6 dwg, 11 tbl
SUBSTANCE: group of inventions refers to medicine and concerns a method for the delivery of octreotide or its pharmaceutically acceptable salt into an individual, involving implanting the implanted device comprising a polyurethane polymer into the individual; the implanted drug delivery device for the octreotide acetate release by diffusion through a polyurethane polymer.
EFFECT: group of inventions provides high biocompatibility and biostability when used as an implant for the patients for the octreotide delivery to tissues or organs.
4 cl, 3 dwg, 5 tbl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention relates to medicine, in particular to a pharmaceutical composition in the form of the extrudate, containing at least one pharmaceutically active substance in the form of needles, characterised by the fact that the ratio of the particle size of the needle-like active substance to the diameter of strands constitutes at least 1:25.
EFFECT: invention makes it possible to obtain the more homogeneous extrudate.
11 cl, 13 ex, 10 dwg
FIELD: medicine, pharmaceutics.
SUBSTANCE: present invention refers to a pharmaceutical composition containing N-[3-chlor-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulphonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine or its pharmaceutically acceptable salt as an active pharmaceutical ingredient in an amount of more than 60 wt % to less than 85 wt % as related to total weight of the composition. The active pharmaceutical ingredient is characterised by a wetting angle of less than 55°.
EFFECT: method for preparing the pharmaceutical composition involves the stage of grinding or milling the above pharmaceutical ingredient in the presence of one or more excipients.
7 cl, 7 dwg, 5 tbl, 6 ex
SUBSTANCE: invention relates to a balanced fat composition, suitable for probe feeding. The fat composition, suitable for the probe feeding, contains from 8 to 15 wt % of linoleic acid (LA); from 3.0 to 6.0 wt % of a mixture, consisting of ω-3 polyunsaturated fatty acids, alpha-linolenic acid (ALA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), where the quantity of ALA>2.5 wt % and the mixed quantity of DHA and EPA≤2.5 wt %l from 10 to 20 wt % of at least one medium-chain fatty acid (MCFA); and from 35 to 79 wt % of one monounsaturated fatty acid (MUFA). Claimed is a liquid nutritional composition, containing the said fat composition. Claimed is a method of supplying enteral feeding to patients, which includes the introduction of an effective quantity of the said liquid nutritional composition, containing the balanced fat composition by the invention.
EFFECT: invention makes it possible to obtain the balanced nutritional composition for long enteral feeding.
27 cl, 1 dwg, 5 tbl
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to pharmaceutics, namely represents pharmaceutical formulations containing 9-cis-retinyl esters in a lipid excipient. The pharmaceutical formulations containing 9-cis-retinyl esters are described to be applicable in a retinoid replacement therapy for treating retinal degenerations in individuals.
EFFECT: using the formulations for the retinoid replacement therapy for treating retinal degenerations in individuals.
73 cl, 14 dwg, 2 tbl, 6 ex
SUBSTANCE: group of inventions relates to medical equipment. Medical infusion bag contains case of polyethylene film in form of bag for storing medical infusion solution and welded to case bottom tubular port, through which medical infusion solution is discharged from case. Multi-layered tube for medical application is used as tubular port. Tube contains external, internal and adhesive layers. External layer contains high-density polyethylene. Internal layer contains polymer material, which contains random polypropylene and/or block-polypropylene. Adhesive layer is placed between external and internal layers and contains adhesive resin. Tube can also contain external and internal layers. External layer contains polymer material, which contains high-density polyethylene and adhesive resin, where content of adhesive resin constitutes from 20 to 60 wt %. Internal layer contains polymer material which contains random polypropylene and/or block-polypropylene.
EFFECT: application of group of inventions will make it possible to increase adhesive ability of tube to polyethylene bag and polypropylene connector, as well as to increase thermal resistance.
3 cl, 3 dwg, 3 tbl, 16 ex