Method for producing soft tablets

Abstract

The present invention relates to a method for producing a soft tablet with organoleptic characteristics such as a smooth texture, good palatability, and deformation resistance. The invention further relates to equipment for producing the soft tablet, said equipment forming tablets by means of extrusion and cold moulding, enabling the production of soft tablets that contain temperature-sensitive pharmaceutically active ingredients.

Description

PROCEDURE FOR THE MANUFACTURE OF SOFT TABLETS TECHNICAL FIELD

[0001] The present invention is framed within the technical field of the pharmaceutical industry, mainly with the veterinary pharmaceutical products industry. STATE OF THE ART

[0002] In the field of patents, tablet manufacturing processes in general are known, such as document US2014141055 which refers to a process for the manufacture of semi-plastic pharmaceutical unit doses, through the use of a rotary molding machine and semi-plastic pharmaceutical dosage units obtained through said process, where the process temperature must be between 35°C and 45°C to ensure the formation process in the rotary molding machine.

[0003] Also known is document US2018169008 which discloses a product and a manufacturing process for an edible soft chewable pharmaceutical form for the administration of pharmaceutically active ingredients or nutritional agents orally to an animal or a human, forming a granulated soft chewable mass by appropriate mixing and sieving steps, and forming tablets with a compression press. The process for manufacturing said soft chewable tablets employs conventional compression pressing equipment to produce soft chewable tablets of consistent weight and texture, wherein the granulated mass can be heated by direct application of heat on a static solid bed and then dried at temperatures between 25 ° C and 50 ° C.

[0004] For its part, document DE19815327 teaches the production of chewable tablets containing medicaments, using specific additives and dissolution conditions to provide a homogeneous distribution of the medicament and a constant release, where the preparation of chewable tablets containing a water-soluble polymer (I), active agent(s) (A) and additives / auxiliaries, involves the pre-dissolution of various components in water under specific temperature conditions prior to the addition of (A). The production of chewable tablets involves: (a) contacting partially or completely water-soluble natural and / or synthetic polymers (I), as well as alginates, carrageenans, starch, pectin and gelatin, with water and additives and adjuvants to form a viscous solution as a base mixture; and (b) emulsifying, suspending or dissolving active agent(s) (A) in the base mixture.The process involves: (i) pre-dissolving additives and auxiliaries, including isomaltol as a sugar substitute, at speed. of constant stirring for at least 5-20 minutes at 90°C-130°C; (i) boiling the obtained solution at 100-140°C for at least 15-45 minutes; (iii) pre-dissolving (I) at constant stirring speed for at least 30-90 minutes at 85-110°C; (iv) forming the base mixture by mixing the products of (i) and (iii) at constant stirring speed; and (v) cooling and incorporating (A) with stirring at constant speed. This process in its different stages requires high temperatures which makes it impractical for the production of soft tablets with heat-sensitive active agents such as, for example, vitamins and other active ingredients sensitive to high temperatures.

[0005] Another document, patent CN109330891, teaches a device for preparing chewable tablets from Dendrobium candidum. The device comprises a support, a mixing device, a feeding device, a tableting device, and a discharging device; the mixing device, the feeding device, the tableting device, and the discharging device are all installed on a support; the mixing device, the feeding device, and the tableting device are arranged in sequence from top to bottom, and the discharging device is connected to the tableting device.Using the mixing device, the raw materials prepared in proportion are mixed until uniform and then poured into the feeding device; using the feeding device, the uniformly mixed raw materials collected are injected into the tableting device; the injected raw materials are pressed into sheets by the tableting device; and finally, the pressed sheets are ejected through the discharging device. However, this device can generate heat due to the pressing action of the sheet, which can affect the nature of the temperature-sensitive active ingredients.

[0006] Document CN109676996 teaches an all-in-one machine that is a tabletting machine and a dryer for the production of chewable tablets, wherein the machine comprises a tableting device and a drying device; the tableting device comprises a cylindrical cavity, an upper punching mechanism, a lower punching mechanism, a discharge mechanism and a tablet-forming mold cavity mechanism; three upper punches are uniformly arranged on the bottom surface of a disk I of the upper punch mechanism; three mold cavities I and three mold cavities II are arranged on a disk II of the tablet-forming mold cavity mechanism; the outer periphery of a disk III of the lower punch mechanism is fixedly connected to the inner wall of the cylindrical cavity; three lower punches and three collecting cavities are uniformly arranged on the upper surface;A discharge tube of the discharge mechanism is divided into three branches; the lower end of each; branch is arranged above the three mold cavities II; the drying device comprises a rotating drum and a wave-shaped drying cylinder; a feed port and a dehumidifying port are arranged at the upper end of the rotating drum, and a discharge port and an air supply port are arranged at the lower end; a water pipe is arranged outside the drying cylinder; and a microwave generator is arranged on the inner wall of the rotating drum. However, this device comprises an electric heating device for drying the tablets.

[0007] Finally, document CN219360401 is known, which discloses a device for forming chewable tablets comprising a base, support columns that are fixedly connected to the periphery of the upper part of the base, an upper plate that is fixedly connected between the upper ends of the four support columns, and an electric hydraulic tablet press. The press is fixedly installed at the bottom of the upper plate. A lower case is fixedly connected to the position, below the electric hydraulic tablet press, of the upper part of the base, and a tablet pressing module is fixedly connected to the top of the lower case. The electric hydraulic tablet press is used to extrude and form the powdered medicine placed in the die cavity, and the support plate is pulled to the left through the pull rod and extracted from inside the die plate into the tablet.However, this device may present drawbacks related to the heat produced by the tablet pressing stage, which may affect the active ingredient(s) that may be temperature-sensitive.

[0008] Therefore, there is still a need to provide a method for manufacturing a soft tablet with organoleptic characteristics such as soft texture, good palatability and resistance to deformation and for cold extrusion and molding tablet forming equipment to produce soft tablets comprising temperature-sensitive pharmaceutically active ingredients. BRIEF DESCRIPTION OF THE INVENTION

[0009] The present invention relates to a process for manufacturing a soft tablet to obtain organoleptic characteristics that distinguish it from other similar inventions to date, such as a smooth texture, good palatability, and resistance to deformation. Another important aspect of the invention relates to the equipment used to manufacture the soft tablet, which is a tablet-forming device by extrusion and cold molding, allowing the manufacture of soft tablets containing temperature-sensitive pharmaceutically active ingredients. BRIEF DESCRIPTION OF THE FIGURES

[0010] Figure 1 shows a side diagram of the soft tablet forming equipment, where (A) indicates the feed hopper and (B) indicates the conveyor screw.

[0011] Figure 2 shows a frontal diagram of the soft tablet forming equipment, where (C) indicates the extrusion screws, (D) indicates the weighing and cutting system, (E) indicates the rotary molding system and (F) indicates the ejection system. DETAILED DESCRIPTION OF THE INVENTION

[0012] A first aspect of the present invention relates to the process for manufacturing soft tablets which meet the following organoleptic characteristics: soft texture, good palatability and resistance to deformation.

[0013] A soft tablet has semi-plastic elasticity, lower hardness, and high wettability compared to a conventional hard tablet. Due to their semi-plastic characteristics, which give them resistance to deformation, these masses can be molded into various formats.

[0014] A soft tablet, having a smooth consistency, can be easily chewed and ingested by human or animal patients, and having a high percentage of moisturizing agents, can include a large percentage of flavorings that improve acceptance by the end consumer.

[0015] The proposed process for manufacturing soft tablets involves at least the following steps: a) Mix one or more active pharmaceutical ingredients with at least one solid excipient, prepare a premix, b) Mix the premix from the previous step with the selected wetting agents, proceed with kneading, c) Heat the forming agent until it melts, and incorporate it into the mixture until a homogeneous mass is obtained. d) Transfer the mass to soft tablet forming equipment.

[0016] An active pharmaceutical ingredient (API) is a substance that produces pharmacological activity for the treatment, mitigation, or prevention of a disease, or for the modification of physiological functions in humans or animals. These can be selected alone or in combination with antibiotics, analgesics, antivirals, antifungals, antiparasitics, hormones, anti-inflammatories, anticonvulsants, sedatives, tranquilizers, antitussives, antihistamines, decongestants, expectorants, probiotics, natural extracts, amino acids, minerals, vitamins, among others, including those that are temperature-sensitive.

[0017] The solid excipient can be selected alone or in combination with diluents, binders, flavorings, sweeteners, and disintegrants, among others.

[0018] The diluent can be selected from natural starch sources, such as flours or byproducts from the milling process of corn, oats, wheat, millet, barley, or rice. Pharmaceutical-grade diluents such as corn starch, pregelatinized starch, lactose, and maltodextrin, among others, can also be used, alone or in combination. The present invention proposes using corn starch as the primary diluent, as it also functions as a disintegrant in the formulation.

[0019] The described soft tablet could also contain a binder that allows the formation of granules within the formulation in order to improve the masking of active pharmaceutical ingredients with unpleasant taste, it can be selected from cellulose, carboxymethylcellulose, povidone, crospovidone, hydroxypropylmethylcellulose, or similar, alone or in combination.

[0020] The flavoring may be selected from natural or artificial sources based on meat flavors, such as beef, pork, chicken, turkey, fish, lamb, pork liver, chicken liver, among others, or combinations thereof; non-animal flavorings such as fruit flavors, herbs, or combinations thereof may also be included.

[0021] The sweetener may be selected from sugar, corn syrup, sorbitol, mannitol, fructose, lactose, glucose, xylitol, mannitol, sucrose and the like, and mixtures thereof, or artificial sweeteners such as saccharin, aspartame and sucralose, among others and mixtures thereof.

[0022] The disintegrating agent can be selected from microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, sodium starch glycolate, among others and mixtures thereof, which facilitates the decomposition of the tablet in order to ensure the release of the pharmaceutically active ingredient.

[0023] In addition to the above, the soft tablet may contain antioxidants, preservatives and lubricants, and mixtures thereof.

[0024] The wetting agent may be selected from vegetable oils such as corn, soybean, olive, peanut, and similar oils; glycerin, sorbitol, and mannitol, among others; and mixtures thereof.

[0025] The forming agent that confers semi-plastic properties can be selected from polyethylene glycol, polyvinylpyrrolidone, polymethacrylate, and similar materials, or mixtures thereof. The forming agent is solid at room temperature and has a melting point between 45 and 100°C. It is included in the manufacturing process in its molten form and is important for providing the soft tablet with resistance to deformation.

[0026] For the industrial-scale manufacture of soft tablets, the inventors identified the need for tablet-forming equipment capable of producing a large volume of soft tablets that meet established quality attributes. Quality attributes are understood to mean obtaining a uniform weight, dimensions within the permissible range, and a conforming appearance that is free of breaks, cracks, or deformations.

[0027] Molding equipment is commonly used in the manufacture of candy and chocolate, among other industries. The general mechanism of this equipment is the pressing of the dough through a system of rollers, which feed it into molds for the formation of the manufacturing units.

[0028] In a second aspect of the present invention, a soft tablet forming device is described. Although the use of this device is not limited to the formation of soft tablets, it could be used for the manufacture of other pharmaceutical forms that have semi-plastic behaviors such as suppositories, ovules, and orodispersible tablets, among others.

[0029] Unlike conventional molding equipment, the equipment described in the present invention has a mass extrusion mechanism that does not require the application of temperature to any of its components, which is why it allows including active pharmaceutical ingredients that are thermolabile or thermosensitive in the formulations. This aspect of the invention is of utmost importance because it is known that many active ingredients are sensitive to temperature, which would limit the production of soft tablets containing them under the currently known mechanisms.

[0030] The soft tablet forming equipment described in the present invention, as shown in Figures 1 and 2, consists or comprises a feed hopper (A) where the previously manufactured mass is loaded, this hopper is communicated with a first auger (B), also known as a conveyor screw, which has a variable step system, which exerts pressure on the mass without generating heating of the same, allowing it to be transported, softened by the pressure mechanism and more moldable, the mass is transported by the auger screw (B) towards a compartment where a vertical extrusion system is located composed of two auger screws (C) which extrude the mass and push it perpendicularly towards a weighing and cutting system (D) where thanks to a high precision sensor, the mass is cut when it reaches the weight established by a programmable logic controller (PLC),The already weighed mass enters a rotary molding system (E) where multiple nests with the desired format are located, where the shape is finished by a pressure mechanism, subsequently the tablet already formed in the nests enters an ejection system (F) where by applying a slight pressure the soft tablets are expelled from the nest without deforming.

[0031] It is noteworthy that the equipment described in the present invention allows for the manufacture of soft tablets weighing less than one gram, while maintaining established quality attributes. Furthermore, the molding mechanism allows for the addition of design features to the tablet, such as the inclusion of a groove to facilitate dosing, and the engraving of numbers, letters, or logos that enable product differentiation in the market.

Claims

1. A procedure for the manufacture of soft tablets, wherein the procedure includes at least the following steps:a) Mixing one or more active pharmaceutical ingredients (APIs) with at least one solid excipient, preparing a premix,b) Mixing the premix from the previous step with the selected wetting agents and proceed with kneading,c) Heating the forming agent until it melts, incorporate over the kneading until a homogeneous mass is obtained; andd) Taking the mass to a soft tablet forming equipment.

2. The process for the manufacture of soft tablets in accordance with claim 1, wherein the active pharmaceutical ingredient(s) are selected from antibiotics, analgesics, antivirals, antifungals, antiparasitics, hormones, anti-inflammatories, anticonvulsants, sedatives, tranquilizers, antitussives, antihistamines, decongestants, expectorants, probiotics, natural extracts, amino acids, minerals, vitamins alone or in combination, including those that are sensitive to temperature.

3. The process for the manufacture of soft tablets in accordance with claim 1, wherein wetting agents are selected from vegetable oil such as corn, soybean, olive, peanut, and similar oil; glycerin, sorbitol, and mannitol or mixtures thereof.

4. The process for the manufacture of soft tablets in accordance with claim 1, wherein the forming agent is selected from polyethylene glycol, polyvinylpyrrolidone, polymethacrylate and mixtures thereof.

5. The process for the manufacture of soft tablets in accordance with claim 1, wherein a solid excipient is added, selected from diluents, binders, flavorings, sweeteners, disintegrants and mixtures thereof.

6. The process for the manufacture of soft tablets in accordance with claim 5, wherein the diluent is selected from natural sources of starch.

7. The process for the manufacture of soft tablets in accordance with claim 6, natural sources of starch are selected from flours or by-products of the milling process of corn, oats, wheat, millet, barley, rice; and pharmaceutical-grade diluents selected from corn starch, pregelatinized starch, lactose and maltodextrin and / or mixtures thereof.

8. The process for the manufacture of soft tablets in accordance with claim 1, wherein a binder for granule formation is added within the formulation and is selected from cellulose, carboxymethylcellulose, povidone, crospovidone, hydroxypropyl methylcellulose and / or mixtures thereof.

9. The process for the manufacture of soft tablets in accordance with claim 1, wherein a flavoring selected from natural or artificial sources based on meat flavors is added, such as beef, pork, chicken, turkey, fish, lamb, pork liver, chicken liver, or combinations thereof; and flavorings of non-animal origin such as fruit flavors, herbs, or combinations thereof.

10. The process for the manufacture of soft tablets in accordance with claim 1, wherein a sweetener selected from sugar, corn syrup, sorbitol, mannitol, fructose, lactose, glucose, xylitol, mannitol and sucrose or mixtures thereof, or artificial sweeteners such as saccharin, aspartame and sucralose or mixtures thereof, is added.

11. The process for the manufacture of soft tablets in accordance with claim 1, wherein a disintegrating agent selected from microcrystalline cellulose, croscarmellose sodium, crospovidone, povidone, starch sodium glycolate or mixtures thereof is added.

12. The process for the manufacture of soft tablets in accordance with claim 1, wherein antioxidant agents, preservative and lubricating agents or mixtures thereof are added.

13. A soft tablet forming equipment for a soft tablet manufacturing process in accordance with claim 1, wherein the equipment comprises a feeding hopper (A), a first auger screw (B), a vertical extrusion system consisting of two auger screws (C), and a weighing and cutting system (D) and a rotary molding system (E) comprising multiple nests and an ejection system (F), wherein the previously manufactured mass is loaded into the feeding hopper (A), which is connected to the first auger screw (B) that has a variable step system and that exerts pressure on the mass without heating it and transported to a compartment, where the vertical extrusion system composed of two auger screws is located (C), which extrude the mass and push it perpendicularly to the weighing and cutting system (D), wherein the mass is cut when it reaches the weight established by means of a programmable logic controller, the already weighed mass enters the rotary molding system (E), where multiple nests with the desired format are located, where the shape is finished by a pressure mechanism, and then the tablet already formed in the nests enters the ejection system (F) where by exerting light pressure the soft tablets are expelled from the nest without deforming.

14. The soft tablet forming equipment in accordance with claim 13, where the equipment does not require the application of temperature to obtain the soft tablets, so it allows working with temperature-sensitive active pharmaceutical ingredients.

15. The soft tablet forming equipment in accordance with claim 13, where the equipment allows manufacturing soft tablets from weights less than one gram and to include a groove, numbers, letters and logos on their surface, in such a way that the product is differentiated from others.

Images