Dosage form for dissolving an active ingredient in the oral cavity, method of production and use.
Patent Information
- Application Number
- BR112020008892
- Authority / Receiving Office
- BR · BR
- Patent Type
- Patents
- Current Assignee / Owner
- Publication Date
- 2026-09-01
Smart Images
Figure 00000026_0000
Abstract
Description
Descriptive Report of the Invention Patent for a DOSAGE FORM FOR DISSOLVING AN ACTIVE INGREDIENT IN THE ORAL CAVITY, METHOD OF PRODUCTION AND USE. Description
[001] The present invention relates to a dosage form for an active ingredient that has a cavity in which the active ingredient is present, wherein the dosage form is water-soluble so that it dissolves rapidly and releases the active ingredient when placed in the mouth. The fact that the active ingredient can be introduced into a cavity in the dosage form means that the technical limitations regarding the inclusion of larger quantities of the active ingredient in typical thin-film formulations are circumvented and, therefore, larger quantities of the active ingredient can also be included in the dosage form without any problem. The present invention also relates to methods for producing corresponding dosage forms.
[002] Oral or sublingual tablets are generally used to administer active ingredients through the oral mucosa and to release the active ingredient into the oral cavity. Reabsorption of the active ingredient through the oral mucosa offers a number of advantages over other oral dosage forms, for example, the fact that the onset of action is rapid due to bypassing the gastrointestinal tract and the fact that the utilization of the active ingredient is high.
[003] Another problem with tablets or capsules is that they are normally swallowed, meaning the patient has to ingest a liquid with which to take this dosage form. Sometimes, however, older patients or children have difficulty swallowing and therefore refuse to take tablets or capsules, or are reluctant to take them. Furthermore, it is possible Petition 870220102720, dated 07 / 11 / 2022, page 8 / 37 2 / 21 that tablets and capsules are kept in the mouth for too long and then spat out by the patient. This often results in complacency, which is detrimental to the progress of healing or the success of therapy.
[004] An alternative dosage form to known oral tablets and sublingual tablets is known in the form of flattened oblate-type dosage forms, also known as lozenges. For example, US patent document 5,529,782 describes a rapidly soluble film product made of soluble polymer material or complex polysaccharides, which is mainly used for the administration of contraceptives. The film product should have a thickness of 3 to 4 mm and its solubility should be adjustable so that it dissolves within 5 to 60 seconds after administration. The film product may also be in the form of a laminate having gas-foamed cavities.
[005] Patent document EP 0 450 141 B1 describes a carrier material for the administration of pharmaceutical products that dissolve rapidly upon contact with saliva. This carrier material is a dehydrated porous skeleton carrier material, especially based on proteins and polysaccharides. The cavities created by dehydration are used for the introduction of liquid active ingredients.
[006] Patent document WO 00 / 18365 proposes an edible film that dissolves quickly but can also adhere well to the oral mucosa in order to release antimicrobial substances and reduce the number of unwanted microorganisms in the oral flora. The antimicrobial substances are, for example, essential oils that are preferably mixed as a lipophilic phase with pullulan as a matrix material in the aqueous phase.
[007] Patent document WO 02 / 02085 describes forms of Petition 870220102720, dated 07 / 11 / 2022, page 9 / 37 3 / 21 Rapidly disintegrating dosage form for the release of active ingredients into the oral cavity or other body openings, wherein the dosage form has a matrix containing at least one water-soluble polymer as the base substance and is provided with cavities.
[008] Oral films (OTF systems (= oral thin film)) that dissolve rapidly in the oral cavity must be formulated so that the film fulfills certain physical requirements. For example, such films must have a certain minimum strength so that they do not break when held by the patient. Another problem with OTF formulations is that the films cannot be produced in any thickness, since the essential property of films is that they dissolve rapidly in the mouth. However, this is no longer guaranteed in the case of relatively thick films, since the entry of water or saliva into the inner area of the film is more difficult with a greater thickness.
[009] Furthermore, OTF systems are limited not only in terms of their thickness, but also in terms of their maximum size, since the user must be able to place the film in their mouth and over their tongue without any problem; this should no longer be possible with very large films. Due to these general conditions, the amount of active ingredient to be applied is limited to about 20 mg for normal film-type OTF formulations.
[010] On the one hand, this is a problem with active ingredients that have to be applied in larger quantities, but on the other hand, it is also a problem with bitter ingredients or other active ingredients that are perceived as having an unpleasant taste, since these generally have to be formulated with significant amounts of flavor-masking agents. Even in this case, however, the total amount of the active ingredient and any additional flavor-masking agents in a Petition 870220102720, dated 07 / 11 / 2022, page 10 / 37 The 4 / 21 OTF formulation is limited to approximately 20 mg.
[011] Against this backdrop, there is a need for a dosage form of active ingredients that offers the same advantages as known OTF formulations, namely, in particular rapid absorption and release of the active ingredient in the oral cavity, but which is not subject to such severe limitations in terms of the possible amount of active ingredient to be administered.
[012] Another problem with known OTF systems is that, in order to produce the films, the active ingredients have to be mixed with the matrix material used, for which purpose a solvent can be used or the mixing is carried out within the scope of an extrusion process. When processing is carried out with the aid of solvents, this solvent must be removed from the system during the further course of the process, for which purpose the system is normally heated. This entails a problem for the active ingredients which are unstable at high temperatures, since the active ingredients integrated into the OTF decompose during the evaporation of the solvent. Alternatively, the solvent can also be removed under a slight vacuum. However, this requires appropriate equipment and, from a technical point of view, can only be carried out at a higher expense, which involves cost disadvantages.
[013] In an extrusion process, the active ingredients are also exposed to a higher temperature, which can lead to a partial decomposition of the active ingredient.
[014] Against this backdrop, there is also a need for a dosage form for an active ingredient that can be produced without having to expose the active ingredient to high temperatures. The objective is to produce dosage forms that can also be loaded with temperature-labile active ingredients.
[015] The present invention satisfies that need. Petition 870220102720, dated 07 / 11 / 2022, p. 11 / 37 5 / 21
[016] To achieve the objective described above, the present invention proposes, according to claim 1, a dosage form for which an active ingredient is dissolved in the oral cavity, which comprises a first film layer and a second film layer that is disposed over the first film layer, wherein the composition of the first film layer may be identical to that of the second layer and comprises a water-soluble polymer, and the first and second film layers are interconnected by their overlapping edges so as to form at least one cavity, and the cavity is filled with an active ingredient.
[017] Therefore, the dosage form according to the invention substantially comprises a pouch or bag, which is formed by two layers of film arranged one over the other and which is formed by connecting the film layers in the edge area. An active ingredient can then be introduced into the cavity of the pouch or bag. Since the two film layers comprise water-soluble polymers similarly to normal OTF formulations, they exhibit similar dissolution properties compared to normal OTF formulations. Compared to these, however, the dosage forms according to the invention offer the advantage that the active ingredient can be introduced only after the films have dried, so that direct thermal stress on the active ingredient, for example, as a consequence of the drying of the films, is avoided.
[018] The terms bag and sack have synonymous meanings in the context of the following description.
[019] The expression two layers of film arranged one on top of the other includes both embodiments in which two separate layers of film are arranged one on top of the other, as well as embodiments that are created by positioning two Petition 870220102720, dated 07 / 11 / 2022, page 12 / 37 6 / 21 layers of film on top of each other when folding a single film.
[020] An example of a dosing form according to the invention is shown in Figure 1, wherein 1 denotes the edge region by which the two film layers are interconnected, while 2 shows the cavity filled with the active ingredient.
[021] The fact that the dosage form is formed as a water-soluble pouch means that much larger quantities of the active ingredient and / or additional excipients can also be introduced into the cavity. A final seal of the pouch after the insertion of the active ingredient can be performed on only one edge of the dosage form, for which purpose only a seal has to be performed in the area of the edge of the dosage form, in such a way that the active ingredient located in the middle of the dosage form does not have to be exposed to any direct thermal stress.
[022] In the context of the present invention, a water-soluble polymer refers to water-soluble and / or water-swellable polymers that rapidly dissolve and disintegrate in moist, aqueous environments, such as the oral cavity, thereby releasing an active ingredient incorporated in the dosage form.
[023] The statement that the first and second film layers are interconnected by their overlapping edges to form at least one cavity should be understood as meaning that the first and second film layers are in contact with each other in the region of their surface (provided the cavity is not filled), but are not joined to each other in this region, so that the two film layers can be separated from each other in this region by the introduction of a material (especially the active ingredient) without effort. The statement also includes successive embodiments of the film layers, although in this case only one overlapping edge is present, which, however, is not connected. Petition 870220102720, dated 07 / 11 / 2022, page 13 / 37 7 / 21 across its entire circumference to facilitate filling with an active ingredient.
[024] The cavity contains the active ingredient, but is substantially free of the water-soluble polymer. In addition, preferably the cavity does not contain a continuous formulation of the active ingredient, which is in contact with the entire surface of the first and second film layers, but contains the active ingredient in a form in which distinct gas spaces are present between the individual particles of the active ingredient.
[025] The connection of the first film layer to the second film layer can be achieved by gluing or sealing. When gluing, for example, a suitable adhesive can be introduced into the gap between the first and second film layers, thus fixing the first film layer to the second film layer. For sealing, the first film layer and the second film layer can be heated and pressed against each other so that the first film layer adheres to the second film layer in the sealing area.
[026] An example of a water-soluble adhesive suitable for bonding adhesive layers is Plastoid E35H (Eudragit E100 softened; the added modifiers are lauric acid, adipic acid and glycerol).
[027] Another suitable water-soluble adhesive is an adhesive based on at least one water-soluble polymer and at least one plasticizer, wherein the water-soluble polymer is preferably shellac, a vinyl pyrrolidone / vinyl acetate copolymer, a polyvinyl caprolactam / polyvinyl acetate / polyethylene glycol copolymer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and / or polyvinyl pyrrolidone. Glycerol, polyethylene glycol, especially polyethylene glycol 200, sorbitol and / or tributyl citrate are plasticizers. Petition 870220102720, dated 07 / 11 / 2022, page 14 / 37 8 / 21 suitable for combination with the water-soluble polymer. The preferred plasticizer is preferably selected from glycerol, polyethylene glycol 200 and / or tributyl citrate.
[028] As regards the ratio of water-soluble polymer to plasticizer, the adhesive is not subject to any relevant limitation provided that the ratio is adjusted in such a way that the mixture is sufficiently tacky and workable. A favorable mixing ratio may be a ratio of water-soluble polymer to plasticizer of about 85 to 50 to about 15 to 50, preferably from 85 to 65 to about 15 to 35, more preferably from about 80 to 60 to about 20 to 40, even more preferably from about 80 to 50 to about 20 to 50, even more preferably from about 82 to 68 to about 18 to 32 and most preferably from about 80 to 70 to about 20 to 30.
[029] It has already been mentioned above that the composition of the first film layer can be identical to that of the second film layer. Since this leads to a simplification of the production of the dosing form according to the invention, within the scope of the present invention it is preferable that the composition of the first film layer and the second film layer be identical.
[030] On the other hand, in certain cases it may be useful if the first film layer and the second film layer are based on different compositions. For example, it may be desirable to form one of the film layers as a mucoadhesive layer, while the second layer is relatively rapidly soluble in an aqueous environment, thereby releasing the active ingredient. In another embodiment, it may be expedient if the first film layer is a mucoadhesive film layer and the second film layer dissolves more slowly in the oral cavity than the first film layer. Petition 870220102720, dated 07 / 11 / 2022, page 15 / 37 9 / 21
[031] With respect to the form of the active ingredient, the present invention is not subject to any significant limitations. Thus, the active ingredient may be in liquid or solid form, wherein powder, granular, micro or nanoparticulate, or micro or nanoencapsulated forms are particularly expedient as solid forms. If the active ingredient is in liquid form, it is primarily in aqueous solution or suspension, however, since this impairs the integrity of the surrounding film layers. If the active ingredient is in liquid form, this form should, to the greatest extent possible, not affect the adjacent film layers. Active ingredients in solid form are preferred, and for solid formulations, those based on lipophilic base materials, in which the active ingredient is dissolved or dispersed, should be excluded where possible.Therefore, in a preferred embodiment, the active ingredient is not present in the form of a lipophilic, oily, or cerulean formulation.
[032] The term microparticulate is understood in the context of the present invention to mean a material in which 90% by weight and preferably 95% by weight of the particles have a particle size in the range of less than 1 mm to 1 µm. The term nanoparticulate is understood in the context of the present invention to mean a material in which 90% by weight and preferably 95% by weight of the particles have a particle size in the range of less than 1 µm.
[033] In the terms micro or nanoencapsulated, the above statement refers to encapsulated particles.
[034] As indicated above, the main advantage of the dosage form according to the invention is that it also allows the inclusion of relatively large fillers containing active ingredients. For example, it is preferable that the dosage form have an amount of filler containing active ingredient that is greater than Petition 870220102720, dated 07 / 11 / 2022, page 16 / 37 10 / 21 which is about 20 mg, and especially more than about 30 mg.
[035] An appropriate upper limit for the filler content containing active ingredient may be specified as an amount of 1,000 mg. An upper limit of 500 mg is preferred, 200 mg is more preferred, and 100 mg is even more preferred.
[036] In a form with thermoformed films or large pouches, the amount of active ingredient filler can also be even greater. The amounts then depend not only on the size of the pouch, but also on the depth of the cavity produced by thermoforming.
[037] An amount of about 50 to about 200 mg may be specified as a particularly favorable range for the filler containing the active ingredient.
[038] The size of the dosage form according to the invention is expediently dimensioned to receive an appropriate amount of filler containing active ingredient. As a rough guideline, a surface area in the range of about 1 to about 10 cm2, and preferably about 1.5 to about 6 cm2, may be specified. If the dosage form is, for example, in the form of a rectangular pouch, these dimensions may be about 2 x 2.5 cm or about 1 x 1.5 cm.
[039] The dosing form according to the invention is generally of a fine and smooth or slightly curved design, for example, in the form of pouches, bags, sachets, packages or wads. These pouches, bags, sachets, packages or wads may have various geometric shapes, for example, circular, elliptical, oblong or polygonal, such as especially rectangular or square.
[040] The thickness of the film layers is preferably from about 0.01 to about 2 mm, especially preferably in the range of about 0.02 to about 0.5 mm. Petition 870220102720, dated 07 / 11 / 2022, page 17 / 37 11 / 21
[041] With respect to the water-soluble polymer, the present invention is not subject to any relevant limitations, provided that the water-soluble polymer is a pharmaceutically acceptable material. Suitable water-soluble polymers are, for example, starch and starch derivatives, dextran; cellulose derivatives, such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, sodium carboxymethyl cellulose, ethyl or propyl cellulose; Polyacrylic acid, polyacrylates, polyvinylpyrrolidones, polyvinyl alcohol, polyethylene oxide polymers, polyacrylamides, polyethylene glycol, gelatin, collagen, alginates, pectins, pullulan, tragacanth, chitosan, alginic acid, arabinogalactan, galactomannan, agar, agarose, carrageenan and natural gums.In the context of the present invention, water-soluble polymers selected from the group comprising polyvinyl alcohol, polyethylene glycol, polyethylene oxide, cellulose derivatives, pullulan, gelatin, and agar are particularly preferred. Polyvinyl alcohol is most preferred in the context of the present invention as a water-soluble polymer.
[042] The proportion of water-soluble polymer in the first and second film layers is normally from about 85 to about 100% by weight, especially from about 90 to about 99.9% by weight and more preferably from about 95 to about 99.5% by weight. Since the polymer film does not have to contain any active ingredient, unlike conventional OTF systems, the proportion of water-soluble polymer can be very high. On the other hand, depending on the intended application result, additives such as flavor masking agents or part of the active ingredient can be incorporated into the first film layer and / or the second film layer. In this case, the proportion of water-soluble polymer in the first film layer and the second film layer Petition 870220102720, dated 07 / 11 / 2022, page 18 / 37 The 12 / 21 film thickness may be less than that indicated above, but should still be in the range of about 15 to about 75% by weight, and preferably about 50 to about 70% by weight.
[043] The active ingredient can, in principle, be any active ingredient suitable for oral administration, wherein pharmaceutical active ingredients are preferred. Pharmaceutical active ingredients that are suitable for oral applications in the context of the present invention are, for example, antiallergic agents, antiarrhythmic agents, antibiotics, antidiabetic agents, antiepileptic agents, antihistamines, antitussives, cardiotonic agents, diuretics, antihypertensive agents, anesthetics, nerve muscle blockers and sex hormones, such as vasopressors. Specific examples include acetaminophen, adrenaline, alprazolam, amlodipine, anastrozole, apomorphine, aripiprazole, atorvastatin, baclofen, benzocaine, benzocaine / menthol, benzydamine, buprenorphine, buprenorphine / naloxone, buprenorphine / naloxone / cetirizine, cetirizine, chlorpheniramine, clomipramine, dexamethasone, dextromethorphan, dextromethorphan / phenylephrine, diclofenac, diphenhydramine,diphenhydramine / phenylephrine, donepezil, dronabinol, epinephrine, escitalopram, famotidine, fentanyl, glimepiride, GLP-1 peptides, granisetron, insulin, insulin nanoparticles, insulin / GLP-1 nanoparticles, ketoprofen, ketotifen, caffeine, levocetirizine, loperamide, loratadine, meclizine, methylphenidate, midazolam, mirodenafil, montelukast, multimeric-001, naloxone, nicotine, nitroglycerin, olanzapine, olopatadine, ondansetron, oxybutynin, pectin, pectin / menthol, pectin / ascorbic acid, PediaSUNAT (artesunate and amodiaquine), piroxicam, phenylephrine, prednisolone, pseudoephedrine, risperidone, rivastigmine, rizatriptan, selegiline, senna glycosides, sildenafil citrate, simethicone, sumatriptan, tadalafil, testosterone, triamcinolone acetonide, triptan, tropicamide, voglibose, zolmitriptan, zolpidem, or, Petition 870220102720, dated 07 / 11 / 2022, page 19 / 37 13 / 21 the pharmaceutically acceptable salts of these compounds. As non-pharmaceutical active ingredients, the dosage form according to the invention may contain, for example, active ingredients for oral hygiene, such as menthol. The pharmaceutically active ingredient may also be a mixture of different active ingredients.
[044] The dosage form according to the invention may contain, in addition to the water-soluble polymer already mentioned as a component of the first and second film layers and an active ingredient located in the cavity between the first and second film layers, other ingredients, especially adjuvants, which are selected from the group comprising colorants, aromatic substances, especially flavorings and / or odorous substances, sweeteners, flavor masking agents, surfactants, enhancers, pH regulators, preservatives and / or antioxidants. The aforementioned adjuvants may be a component of one or both film layers and / or may be introduced together with the active ingredient into the cavity between the two film layers.
[045] The addition of flavorings, odorous substances and aromatic substances, individually or in combination, is especially advantageous.
[046] A flavor-masking agent is an ion-exchange resin.
[047] The ion exchange resins that are preferred for use in the dosage form according to the invention are insoluble in water and consist of a pharmacologically inert organic or inorganic matrix containing covalently linked functional groups that are ionic or can be ionized under appropriate pH value conditions. The organic matrix may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic acid, styrene sulfonate, divinylbenzene sulfonate) or partially synthetic (e.g., Petition 870220102720, dated 07 / 11 / 2022, page 20 / 37 14 / 21 cellulose and modified dextrans). The matrix can also be inorganic, for example, silica gel, modified by the addition of ionic groups.
[048] Covalently bonded ion groups can be strongly acidic (e.g., sulfonic acid), weakly acidic (e.g., carboxylic acid), strongly basic (e.g., quaternary ammonium), weakly basic (e.g., primary amine), or a combination of acidic and basic groups. In general, the types of ion exchangers that are suitable for use in ion-exchange chromatography and for applications such as water deionization are suitable for use in the dosing forms according to the invention.
[049] The ion exchange resin is preferably a crosslinked polystyrene-based resin. The polystyrene is crosslinked with a crosslinking agent selected from difunctional compounds capable of crosslinking polystyrenes. The crosslinking agent is preferably a divinyl or polyvinyl compound. The most preferred is the divinylbenzene crosslinking agent.
[050] Generally, polystyrene is expediently crosslinked to an extent of about 3 to about 20%, preferably about 4 to about 16%, more preferably about 6 to about 10%, and even more preferably about 8% by weight, based on the total polystyrene. The polystyrene is crosslinked with the crosslinking agent by known means.
[051] Ion exchange resins particularly suitable as flavor masking agents within the scope of the present invention have exchange capacities below about 6 milliequivalents per gram (meq / g) and preferably below about 5.5 meq / g.
[052] The particle size of ion exchange resin should preferably fall within the range of about 20 to about 200 Petition 870220102720, dated 07 / 11 / 2022, page 21 / 37 15 / 21 micrometers. Particle sizes well below the lower limit are difficult to handle in foreign processing steps. Particle sizes above the upper limit, for example, of commercially available ion exchange resins with spherical shapes and diameters up to about 1,000 micrometers, are granular in liquid dosage forms and have a stronger tendency to break down when exposed to dry hydration cycles.
[053] The representative resins useful in the present invention comprise AMBERLITE IRP-69 (available from Dow Chemical) and Dow XYS-40010.00 (available from Dow Chemical). Both are sulfonated polystyrene polymers, crosslinked with 8% divinylbenzene, with an ion exchange capacity of about 4.5 to 5.5 meq / g of dry resin (H ± form). Their main difference is their physical form. AMBERLITE IRP-69 comprises irregularly shaped particles with a size range of 47 to 149 micrometers, produced by grinding larger area spheres of AMBERLITE IRP-120. The Dow XYS 40010.00 product comprises spherical particles with a size range of 45 to 150 micrometers. Another useful exchange resin, Dow XYS-40013.00, is a polystyrene consisting of a polymer crosslinked with 8% divinylbenzene and functionalized with a quaternary ammonium group. Its exchange capacity is typically in the range of about 3 to 4 meq / g of dry resin.Another suitable resin is AMBERLITE IRP-64.
[054] A flavor-masking agent may be present as a component of the first and / or second film layer, but it may also be introduced into the cavity of the dosing form according to the invention, as shown above. If the flavor-masking agent is an ion-exchange resin, it should be noted that it is only effective if the active ingredient is dissolved in the presence of the ion-exchange resin. Therefore, it is not possible to obtain, by Petition 870220102720, dated 07 / 11 / 2022, page 22 / 37 16 / 21 For example, a flavor-masking effect with formulations in which an ion-exchange resin is formulated as a component of the first or second film layer, while the active ingredient is introduced into the cavity of the dosage form according to the invention. The ion-exchange resins as flavor-masking agents must therefore be formulated in the same component of the dosage form according to the invention as the active ingredient, and the active ingredient is expediently linked to the ion-exchange resin by an ionic bond.
[055] If the dosage form according to the invention contains a flavor-masking agent, this can be incorporated into one or more of the film layers or, in the case of a multi-layer film structure, into one or more outer layers of the film. This allows, for example, an earlier release of the flavor-masking agent from an outer layer of the polymer compared to the release of the active ingredient, so that the flavor receptors, for example, for bitter-tasting active ingredients within the dosage form according to the invention, can already be blocked before the active ingredient is released.
[056] In addition, the first and / or second film layer may contain at least one pigment or UV radiation absorbing agent that protects a light-sensitive active ingredient introduced into the dosage form cavity against UV light. Furthermore, it is expedient if the first and / or second film layer contains one or more colorants, flavorings, or sweeteners.
[057] In addition to the adjuvants already mentioned above, the first film layer and / or the second film layer may also contain other components to optimize its flexibility, or other physical properties, such as at least one plasticizer and / or a humectant. The preferred plasticizers and / or humectants in the context of Petition 870220102720, dated 07 / 11 / 2022, page 23 / 37 17 / 21 of the present invention are selected, for example, from the group comprising glycerol, propylene glycol, polyethylene glycol and citric acid esters.
[058] Furthermore, the first film layer and / or the second film layer may be incorporated as a foam, i.e., they may contain an introduced gas, such as air, nitrogen or CO2, or another gas.
[059] As indicated above, the first film layer and the second film layer can be formed with one or more layers in the form of dosage according to the invention, and it is also possible that the first film layer and / or the second film layer be constructed of several layers of the same composition, for example, by producing the first film layer or the second film layer by applying the composition to the layers one above the other. On the other hand, the layers may differ in their composition, for example, by introducing a pigment or a UV radiation absorbing agent into a layer of the first layer or the second layer, or by superimposing or sub-posing a composition without pigments or UV radiation absorbing agent.
[060] In a multi-layered construction, one or more of the layers may be incorporated as a foam, that is, they may contain an introduced gas, such as air, nitrogen or CO2, or another gas.
[061] Furthermore, the dosing form according to the invention can also be designed in such a way that it has two spatially separated cavities. Thus, for example, the first film layer can be connected to the second film layer by an additional seal in the region of its surface. In this way, two or more cavities that have the same filling or fillings Petition 870220102720, dated 07 / 11 / 2022, page 24 / 37 18 / 21 different patterns can be formed between the film layers.
[062] This is especially advantageous when a base that is not stable under storage in this manner, but is compatible with the mucosa, is used as the active ingredient, whereas the salt of the active ingredient has greater stability under storage, but is not compatible with the mucosa. In this case, it is possible to introduce the salt of the active ingredient into a first cavity of the dosage form according to the invention and introduce an auxiliary base into a second cavity of the dosage form according to the invention, wherein, with the introduction of the dosage form into the oral cavity, the auxiliary base and the salt of the active ingredient are released so that the base of the active ingredient, which is not stable under storage, but is compatible with the mucosa, can be formed.A connection between the first and second film layers in the surface region can also be made by a seam in the cover that is separated by massaging the dosing form before use, thus allowing the filling from the first cavity to be mixed with the filling from the second cavity.
[063] Furthermore, in order to increase the volume between the two film layers of the dispensing form according to the invention, it is possible that the first film layer and / or the second film layer have a non-planar shape. For this purpose, the first film layer or the second film layer may preferably be thermoformed to obtain more filling volume with the same base area.
[064] Furthermore, it is possible that the dosage form according to the invention contains not only the active ingredient introduced into the cavity, but also the active ingredient introduced into the film layer. Finally, it is possible that the active ingredient introduced into the cavity is introduced in various modifications, for example, a Petition 870220102720, dated 07 / 11 / 2022, page 25 / 37 19 / 21 part is possible in a direct-release form, while another part is introduced in granular form or in a delayed-release form, in order to produce mixed kinetics of the active ingredient release.
[065] The dosage form according to the invention is particularly suitable for the oral administration of active ingredients, including oral, gingival or sublingual administration, or administration to the palate.
[066] Finally, another aspect of the present invention relates to a method for producing a dosing form of the type described above, wherein the method comprises the following steps:
[067] a) positioning a first and a second film layer one on top of the other,
[068] b) fixing the first film layer to the second film layer in such a way that at least one pocket is formed between the first film layer and the second film layer,
[069] c) if necessary, cutting the double film layers obtained in b) to obtain individual pockets,
[070] d) the filling of at least one pouch with an active ingredient, and
[071] e) the closing of the stock exchange(s).
[072] The fixing in step b) and / or the closing of the bag (in step e)) is / are preferably obtained by gluing or sealing within the scope of this method.
[073] Positioning a first layer of film and a second layer of film on top of each other in step a) can be done by positioning two individual films on top of each other or by folding a film in half so that two layers of film are formed that are placed on top of each other and connected at an edge. Petition 870220102720, dated 07 / 11 / 2022, page 26 / 37 20 / 21
[074] The present invention will be illustrated more closely by means of some examples, which, however, should not be interpreted as definitive for the scope of protection of the patent application. Example 1
[075] Polymer films with the compositions given in Table 1 were formulated and provided with a filler, as shown in Table 1. For this purpose, the various polymer films were first coated with solutions of the listed ingredients using a coating box, which were then dried into a film. Next, the corresponding film pieces were perforated, and a double layer with the dimensions given in Table 1 was created by folding. The double layer thus produced was then heat-sealed together at two of the film edges to create a pocket. The filler was then inserted, and the resulting pocket was also heat-sealed at the open edge. Table 1 ABC Polymer film 1 Polyvinyl alcohol 96.9% 96.9% 96.9% Colorant 0.1% 0.1% 0.1% Flavoring 1% 1% 1% Sweetener 2% 2% 2% Weight per unit area . _ . 2 48 g / m . _ . 2 48 g / m . _ . 2 48 g / m Polymer film 2 As polymer film 1 As polymer film 1 As polymer film 1 Filler Amberlite IPR-64 96% Flavoring 1% Sweetener 3% Migliol 100% 33% Lactose 66% Filler quantity 100 mg 70 pl 150 mg Pouch size 20 x 25 mm 20 x 25 mm 20 x 25 mm
[076] In example C, migliol was formulated as an ingredient Active liquid model with lactose as a binder. This facilitates the Petition 870220102720, dated 07 / 11 / 2022, page 27 / 37 21 / 21 sealing to form a completely closed pocket, since the binder prevents liquid material from penetrating the sealing area. The binder can thus prevent liquid material from weakening the seal. Example 2
[077] The following dosage forms containing dextromethorphan were produced in the same manner as described in Example 1. The compositions of these dosage forms are shown in Table 2 below. Table 2 ABC Polymer film 1 Polyvinyl alcohol 96.9% Polyol N10 95.9% Pullulan 95.6% Xanthan gum 0.3% Colorant 0.1% 0.1% 0.1% Flavoring 1% 1% 1% Sweetener 2% 3% 3% Weight per unit area _ ,2 45 g / m _ ,2 45 g / m _ ,2 45 g / m Polymer film 2 As polymer film 1 As polymer film 1 As polymer film 1 Filler Dextromethorphan / Amberlite 64 1:1 96% 96% 96% Flavoring 1% 1% 1% Sweetener 3% 3% 3% Filler quantity 52 mg 52 mg 52 mg Pouch size 20 x 25 mm 20 x 25 mm 20 x 25 mm
Claims
1. A dosage form for dissolving a pharmaceutically active ingredient in the oral cavity, characterized in that it comprises a first film layer and a second film layer that is disposed over the first film layer, wherein the composition of the first film layer may be identical to that of the second film layer and comprises a water-soluble polymer, and the first and second film layers are interconnected by their overlapping edges to form at least one cavity, and the cavity is filled with a pharmaceutically active ingredient, wherein nicotine is excluded as the pharmaceutically active ingredient, and wherein the pharmaceutically active ingredient is present in the form of a powder, granules, micro or nanoparticulate, or micro or nanoencapsulated in the cavity of the dosage form.
2. Dosing form, according to claim 1, characterized in that the first and second film layers are glued or sealed to each other by their overlapping edges.
3. Dosage form, according to claim 1 or 2, characterized in that the compositions of the first and second film layers are identical.
4. Dosage form, according to claim 1 or 2, characterized in that the first film layer is formed as a mucoadhesive film layer and the second film layer dissolves more slowly in the oral cavity than the first film layer.
5. Dosage form, according to any one of claims 1 to 4, characterized in that the dosage form contains a filler containing the pharmaceutically active ingredient in an amount of 50 to 1,000 mg.
6. Dosage form, according to any of claims 1 to 5, characterized in that the water-soluble polymer in the first and second film layers is selected from the group comprising polyvinyl alcohol, polyethylene glycol, polyethylene oxide, celluloses, pullulan, gelatin and agar.
7. Dosage form, according to any one of claims 1 to 6, characterized in that it comprises at least one adjuvant selected from the group comprising colorants, flavorings, sweeteners, flavor masking agents, surfactants, enhancers, pH regulators, preservatives and / or antioxidants, as a component of one or both layers of the film or cavity.
8. Dosage form according to claim 7, characterized in that it contains a flavor-masking agent as part of the first and / or second film layer.
9. Dosage form, according to any one of claims 1 to 8, characterized in that the first and / or second film layer contains at least one pigment and / or a UV radiation absorbing agent.
10. Dosage form, according to any one of claims 1 to 9, characterized in that the first and / or second film layer is formed with one or more layers.
11. Dosage form, according to any one of claims 1 to 10, characterized in that the first and / or second film layer contains at least one plasticizer and / or a humectant, preferably selected from the group comprising glycerol, propylene glycol, polyethylene glycol and citric acid ester.
12. Dosing form, according to any one of claims 1 to 11, characterized in that the first and / or second film layer is interconnected in the region of its surface by means of an additional seal, so that at least two cavities are formed between the film layers, and in which the cavities have identical or different fillings.
13. Dosing form, according to any one of claims 1 to 12, characterized in that the first and / or second film layer has a non-planar shape and is preferably in the form of a deep-printed film.
14. Method for producing a dosage form, as defined in any one of claims 1 to 13, said method being characterized in that it comprises the following steps: a) positioning a first and a second film layer one on top of the other, b) fixing the first film layer to the second film layer in such a way that at least one pouch is formed between the first film layer and the second film layer, c) if necessary, cutting the double film layers obtained in b) to obtain individual pouches, d) filling at least one pouch with a pharmaceutically active ingredient, and e) closing the pouch(s).
15. Method according to claim 14, characterized in that the fixation in step b) and / or the closure of the pouch(s) in step e) is / are obtained by gluing or sealing.
16. Use of a first film layer and a second film layer that is disposed over the first film layer, wherein the composition of the first film layer may be identical to that of the second film layer and comprises a water-soluble polymer, and the first and second film layers are interconnected by their overlapping edges to form at least one cavity, and the cavity is filled with an active ingredient, Petition 870220102720, dated 07 / 11 / 2022, page 31 / 37 4 / 4, said use being characterized in that it is in the preparation of a dosage form for oral administration of a pharmaceutically active ingredient to an individual.