Drug delivery system

Abstract

The present invention particularly relates to a drug delivery system for the controlled administration of one or more active pharmaceutical ingredients to the body, more preferably for oral administration of one or more active pharmaceutical ingredients to the body. The system comprises a base component soluble in body fluids and a separate first component soluble in body fluids. The first component comprises a therapeutically effective amount of the first active pharmaceutical ingredient. [Selected Figure] Figure 1

Description

Technical Field

[0001] The present invention relates to a drug delivery system for the controlled administration, preferably systemic administration, of one or more pharmaceutical active ingredients to the body, particularly for oral administration (but not limited to).

Background Art

[0002] Drugs or pharmaceuticals are generally used for the diagnosis, treatment, management, or prevention of diseases. A pharmaceutical active ingredient (API) is a part of the drug that produces its effect. Some drugs contain various APIs that treat various symptoms and act in various ways. Thus, one or more APIs can be delivered by a drug. Drug delivery, or pharmaceutical delivery, may refer to the transport of a pharmaceutical compound into a patient's body as needed to safely achieve the desired (therapeutic) effect. The delivery or administration of a drug into a patient's body is performed in various ways. Routes of administration include the intravenous route (penetration into the blood compartment by venipuncture) and the oral route (penetration from the patient's mouth, e.g., through the oral mucosa, or passing through the gastrointestinal tract and reaching the blood compartment through the mucosa of the stomach or intestine). Also, drugs can be administered by injection into tissues (subcutaneous injection, intramuscular injection, etc.) or by inhalation with topical application (e.g., skin cream). Drugs can be provided in various dosage forms. Dosage forms include tablets, capsules, solutions, dispersions, emulsions, implants, and the like.

[0003] A tablet is a pharmaceutical dosage form. A tablet is a solid unit dosage form of a pharmaceutical product containing an API and optionally an appropriate excipient. Tablets can be prepared by molding or compression. When manufacturing tablets, it is usually the main guideline that an appropriate amount of the pharmaceutical active ingredient is contained in each tablet. For this reason, it is necessary to mix all the components well. Thereby, a homogeneous mixture of the components is obtained. Then, to obtain a tablet, for example, a specific amount of the mixture is compressed. Thereby, the API is usually homogeneously dispersed throughout the tablet or a part thereof.

[0004] When a tablet is administered, e.g., orally, the tablet dissolves and the API is released. Thereafter, the tablet passes through the intestinal mucosa to reach the blood compartment and finally reaches the target tissue. In a typical drug delivery system, the concentration of the API in the blood compartment usually exceeds the efficacy threshold of the API only for a predetermined period. During this period, the amount of API released from the drug delivery system into the gastrointestinal tract is usually much more than the actual required amount. Therefore, an excessive amount of API may (i) not be able to pass through the membrane sufficiently and may be recovered by the body and excreted, or (ii) reach the blood compartment or tissue and cause toxic effects.

[0005] The release profile of the API desirably has a specific profile depending on the respective background of drug administration or a particular treatment program. For example, it may be desirable to release the API at a constant rate over a long period. Also, it may be desirable to gently release the API into the body at a release rate slightly exceeding the efficacy threshold of the API, and the release rate may be substantially independent of time. Further, it may be desirable to release the API intermittently at specific intervals, e.g., over time. Additionally, depending on the release profile specific to the API, it may be desirable to release multiple APIs sequentially or simultaneously at their respective release rates.

[0006] The release of the API from a typical tablet, characterized by the homogeneous distribution of the API due to the requirements and limitations of conventional manufacturing techniques, is mainly determined by the size of the disintegrating tablet, particularly the surface exposed to the surrounding fluid. Thus, the release profile of the API is predetermined and fixed by the shape and size of the tablet, e.g., releasing a large amount first and decreasing over time. As a result, the blood / tissue concentration of the API can greatly exceed the threshold so that a desired concentration period above their respective efficacy thresholds can be obtained.

[0007] Such release profiles are particularly disadvantageous for APIs with a narrow therapeutic concentration range (little difference between therapeutic and toxic doses). Examples of APIs with a narrow therapeutic index (NTI) include aminoglycosides, cyclosporine, carbamazepine, digoxin, digitoxin, flecainide, lithium, phenytoin, phenobarbital, rifampicin, theophylline, warfarin, and others.

[0008] U.S. Patent No. 3,854,480 describes a drug delivery system for releasing a pharmaceutical active ingredient at a controlled rate over a long period. This drug delivery system includes a solid internal matrix material with solid particles of the drug distributed therein, and an external polymeric membrane that is permeable and insoluble in body fluids and covers the internal matrix. The external polymeric membrane continuously measures the flow of the drug from the internal matrix material to the outside of the system at a controlled, constant rate over a long period. However, with the drug delivery system according to U.S. Patent No. 3,854,480, complex release profiles cannot be used. Also, the administration of an insoluble polymeric membrane to a patient's body is undesirable.

[0009] U.S. Patent No. 5,674,530 relates to a drug delivery system in which half of a first water-permeable capsule is filled with a drug and an osmotic agent. U.S. Patent Application Publication No. 2010 / 0068271 relates to an osmotic delivery system used in tablets that can be divided into two usable half-strength tablets. Release by osmotic pressure effects depends on the environment of the drug delivery system in the patient, and accurate drug release at a desired target is difficult. Therefore, it is difficult to achieve controlled and accurate drug release with such a system. Furthermore, complex release profiles cannot be used with this system.

[0010] International Publication No. 1993 / 007861 relates to a drug delivery system comprising microcapsules or microspheres, and it is described that the multiphase microspheres contain molecular compounds included in a fixed oil within a polymer matrix. The molecular compounds need to pass through a water-oil barrier and a polymer barrier of the polymer matrix before diffusing out of the microspheres. Thereby, a constant and fixed delivery rate of the molecular compounds can be obtained without sacrificing the high drug loading efficiency of the microspheres. However, in this conventional system, a more complex release profile cannot be used.

[0011] International Publication No. 1999 / 008662 relates to a drug delivery system suitable for oral administration that promotes two-stage release of an active ingredient. This drug delivery system includes a first drug compartment, a first polymer compartment substantially encapsulating the first drug compartment, a second drug compartment encapsulating the first polymer compartment, and a second polymer compartment encapsulating the second drug compartment. The second polymer compartment consists of, for example, one or more water-insoluble polymers and controls the release of the active ingredient from the second drug compartment. However, in this conventional system, a more complex release profile cannot be used.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Summary of the Invention

Problems to be Solved by the Invention

[0013] The present invention aims to solve the above problems. That is, one of the problems in the present invention is to provide a more efficient drug delivery system that enables controlled administration of one or more pharmaceutical active ingredients (APIs) to the body using a release profile tailored to the use, the treatment, and / or specific to the API. A further object of the present invention is to provide a drug delivery system that enables controlled administration of APIs to the body such that multiple APIs are each released in a predetermined manner, preferably with a desired API-specific release profile. The object of the present invention is configured to optimize pharmacokinetics and pharmacodynamics.

[0014] These and other objects, which will be apparent to those skilled in the art from the following description, are achieved by the drug delivery system according to claim 1 and its use according to claim 31.

Means for Solving the Problems

[0015] The present invention relates to a drug delivery system. The drug delivery system is, for example, a drug and enables the transport of pharmaceutical active ingredients (APIs) in a patient's body as necessary to safely achieve a desired therapeutic effect. The drug delivery system may contain one API, or multiple APIs, or other components such as vitamins and minerals. The drug delivery system is, for example, a bioerodible drug delivery system. That is, the drug delivery system may erode when applied to a patient's body, for example, dissolve in the patient's oral cavity. The drug delivery system of the present invention is particularly suitable for the controlled administration of one or more APIs to the body. The body is, for example, the body of a patient such as a human or an animal. In particular, the drug delivery system is used for the oral administration of one or more APIs to the body, and the system may dissolve in the patient's oral cavity. Therefore, according to the drug delivery system of the present invention, APIs can be administered in a controlled manner according to specific treatment or application cases.

[0016] The drug delivery system of the present invention contains a base component soluble in body fluids. Body fluids include, for example, blood or tissue fluid. The body fluid encountered varies depending on the administration route. In the case of oral ingestion, depending on the composition of the outer layer, it is determined whether the dissolution of the drug delivery system starts in the mouth (dissolution in saliva) or during the process of the system passing through the gastrointestinal tract, particularly the stomach (acidic environment), ileum, jejunum, etc. Also, the drug delivery system can be placed directly in a tissue (e.g., subcutaneous, intramuscular) or body cavity (e.g., pleural cavity) or cerebrospinal fluid cavity. When placed in the ventricle, the drug delivery system dissolves in the cerebrospinal fluid, and the released API can reach the brain tissue. Placement in a body cavity (e.g., pleural cavity, peritoneal cavity) means that a large amount of API reaches these locations. Another possibility is that it may dissolve in the airway during inhalation. Those skilled in the art will understand that the dissolution characteristics of the drug delivery system can be selected so that appropriate release of the API is obtained according to each treatment or application. Thus, immediate dissolution or delayed dissolution can be selected.

[0017] Furthermore, the drug delivery system of the present invention contains a separate first component soluble in body fluids. Therefore, the first component can dissolve in the same way as the base component. The base component and the first component are preferably soluble in the same body fluid. The first component is provided as a separate component from the base component, rather than being mixed with the base component in a classical way to form a homogeneous mixture. Therefore, in the drug delivery system, the base component and the first component can be distinguished.

[0018] Furthermore, according to the present invention, the first component contains a therapeutically effective amount of a first pharmaceutical active ingredient. Therefore, the first component contains the API to be delivered or administered by the drug delivery system. The first API may be homogeneously distributed within the first component. Those skilled in the art will understand that the first component may contain several APIs that are homogeneously distributed within the first component. Also, the base component may contain a pharmaceutical active ingredient.

[0019] Furthermore, according to the present invention, the first component is heterogeneously arranged in the base component. Thus, the base component and the separate first component are not provided as a homogeneous mixture in the drug delivery system, but rather, preferably in a specific manner, the first component is provided as a separate component heterogeneously arranged in the base component. The first component is arranged heterogeneously or discontinuously in the base component along one, two, and most preferably three spatial or orthogonal directions. By arranging the components in this way, the first component is arranged in the system in a controlled and desirable manner, and the first component (the first API) is not homogeneously distributed throughout the system. Instead, heterogeneity is constituted by a specific arrangement of the components. The base component and the first component are provided as separate components, but the first component can be heterogeneously arranged within a matrix composed of the base component. For example, the amount of the first component arranged in the base component gradually increases along a specific direction throughout the system.

[0020] The base component is a three-dimensional body, and the separate first component may be heterogeneously arranged over the base component. Thus, the body of the drug delivery system may be composed of the base component, and for example, one or more parts of a drug delivery system of a predetermined size may be composed of the first component. The base component and the first component may be arranged on a virtual two-dimensional or three-dimensional grid, and each pixel of the grid may be occupied by the base component or the first component. Thus, since the first component is heterogeneously arranged in the base component, it is also heterogeneously arranged in the drug delivery system itself. The size or volume of each such pixel ranges from 1 μm 3 to 1 cm 3 preferably from 10 μm 3 to 100 mm 3 preferably from 100 μm 3 to 10 mm 3 most preferably about 1 mm 3It is as follows. The first component and the base component are preferably arranged so that the two-dimensional or three-dimensional structure composed of the components of the drug delivery system has a resolution in the range of 10 dpi to 10,000 dpi, more preferably 100 dpi to 5,000 dpi, still more preferably 200 dpi to 2,000 dpi, and even more preferably 500 dpi to 1,000 dpi.

[0021] Due to the specific arrangement of the base component and the first component, the first API can be released as desired. Since both the base component and the first component are soluble in body fluids, by adjusting the inhomogeneous arrangement of the first component with respect to the base component, the time and rate at which the first API is released from the drug delivery system can be controlled. Thereby, a drug delivery system capable of optimal API release for controlled administration of a given API to the body can be obtained. The release of the API is preferably determined only by the dissolution characteristics of the components and the form of the drug delivery system. No additional release agents such as osmotic agents for releasing the API are required.

[0022] Since there is no common principle of homogeneous distribution of the API in the drug delivery system, a drug delivery system having a drug delivery system in which the API is arranged in a specific form and having a customized API release profile can be obtained. The component containing the API may be arranged so that the API is stably released in a state where the blood / tissue concentration slightly exceeds the effectiveness threshold of the API. Thereby, in the drug delivery system of the present invention, compared with a general drug delivery system having a homogeneous API distribution, the required amount of the API is effectively smaller, and equivalent clinical results can be maintained with lower side effects.

[0023] According to the present invention, the non-uniform distribution of APIs in a drug delivery system is standardly utilized, whereby a specific arrangement of components is selected or set. Thereby, a drug delivery system having an advantageous release profile can be provided as described herein. By standardizing, determining, or normalizing the arrangement of components, i.e., the non-uniformity of APIs, such drug delivery systems can be mass-produced uniformly.

[0024] Any or all of the components of the drug delivery system include, for example, water, polyvinylpyrrolidone, citric acid, hypromellose, stearate, silicic acid, glycerol, hydroxypropylcellulose, hydroxypropylmethylcellulose, starch, croscarmellose sodium, glycol, crystalline gelatin, collagen, hydroxyapatite, hydrocarbon, lactide, lactic acid, silica, poloxamer, xylitol, erythritol, ethanol, isopropanol, triacetin, aspartame, sodium bicarbonate, and / or acetone.

[0025] In a preferred embodiment, the concentration of the first API varies across the drug delivery system, and more preferably, across the body consisting of the base component. For example, the first component is provided only in the central portion of the drug delivery system. Thus, a certain region of the drug delivery system may be identified as having a high concentration of the first API, and a certain region may be identified as having a low concentration of the first API (or none at all). Thereby, it is possible to accurately control exactly when and how the API is finally released while considering the form or shape of the drug delivery system, as well as the dissolution characteristics of the base component and the first component.

[0026] More preferably, the concentration of the first API is maximum at the center, end, or intermediate region of the system. Thus, for example, when the drug delivery system is in the form of a tablet, the first component may be arranged such that the peak concentration of the first API comes at the center or central part of the tablet. Thereby, depending on the shape of the drug delivery system, during the administration of the tablet and upon dissolution of the base component and the first component, the release of the first API can be increased over time or made substantially constant over time. This enables a specific release of the API.

[0027] More preferably, the concentration gradient of the first API increases towards or away from the center of the drug delivery system. For example, the amount of the first component may increase towards the center of the drug delivery system. For example, when the drug delivery system is in the form of a spherical tablet, if the first component, and thus the first API, has an increasing concentration towards the center of the tablet, the release rate can be made substantially constant upon application of the drug delivery system. By adjusting the concentration profile of the API in the drug delivery system, the release profile of the API can be appropriately controlled.

[0028] More preferably, the concentration profile of the first API in the system has a smooth transition to the high-concentration region. Thus, the concentration profile may have a smooth transition between a low-concentration (or zero-concentration) region and a high-concentration region. For example, the amount of the first component may gradually increase towards the center of the drug delivery system. Here, a smooth transition can be defined as the absence of sharp or discontinuous steps in the concentration profile. The concentration profile represents the profile of the concentration of the first API across the drug delivery system obliquely, for example from one end of the system to its center or across the entire drug delivery system. Such a smooth transition enables a smooth start of the release of the API upon dissolution of each component.

[0029] More preferably, the concentration profile of the first API in the system has a plurality of high-concentration regions. Thereby, using the drug delivery system, the API can be administered over time in multiple doses. In particular, the amount of the first API in the drug delivery system along the dissolution direction (for example, the direction from the end to the center) is preferably discontinuous and repetitive in an onion-skin pattern. In each shell of such a system, the first component is heterogeneously arranged so that the release of the first API does not start abruptly, and the release starts and / or ends gradually. Thereby, after an interval with a large release amount of the first API, a wave of API release occurs in which an interval with a small or no release amount follows. Furthermore, the API can be administered over time in multiple phases. These phases (especially their start) can be controlled by adjusting the arrangement of the high-concentration regions in the system.

[0030] More preferably, the amplitude of the concentration of the first API in the system is 5% or more, preferably 10% or more, more preferably 15% or more, more preferably 20% or more, more preferably 25% or more, more preferably 30% or more, more preferably 35% or more, more preferably 40% or more, more preferably 45% or more, more preferably 50% or more, more preferably 55% or more, more preferably 60% or more, more preferably 65% or more, more preferably 70% or more, more preferably 75% or more, more preferably 80% or more, more preferably 85% or more, more preferably 90% or more, more preferably 95% or more, more preferably almost 100%. More preferably, the amplitude of the concentration of the first API in the system is almost 100% or less, preferably 95% or less, more preferably 90% or less, more preferably 85% or less, more preferably 80% or less, more preferably 75% or less, more preferably 70% or less, more preferably 65% or less, more preferably 60% or less, more preferably 55% or less, more preferably 50% or less, more preferably 45% or less, more preferably 40% or less, more preferably 35% or less, more preferably 30% or less, more preferably 25% or less, more preferably 20% or less, more preferably 15% or less, more preferably 10% or less, more preferably 5% or less. The amplitude of the concentration can be controllably set by the local arrangement of the first component with respect to the base component, whereby it becomes possible to administer the first API as desired. Note that the amplitude of the concentration of the first API can be defined as the difference between the maximum concentration and the minimum concentration of the API in the system. Here, the concentration may be, for example, a mass concentration. Each sample volume for measuring the concentration may be any appropriate volume, for example, 1 μm 3 or the like. For example, when the highest concentration of the sample volume of the system is about 80% and the lowest concentration of the sample volume of the system is about 10%, the amplitude of the concentration is 70%. Therefore, for example, the concentration of the first API may be 10% or more throughout the entire drug delivery system, and the concentration of the first API may increase up to 80% at the central part of the drug delivery system.

[0031] More preferably, the concentration profile of the first API is configured such that when the system is applied, the first API is released from the system with a predetermined release profile. More preferably, the release profile includes a portion that is released at a constant rate. Thus, the first component may be disposed within the base component such that when the base component and the first component dissolve upon application of the drug delivery system, a specific release profile of the API including a portion of constant rate release in a preferred embodiment is obtained.

[0032] Particularly preferably, the first component is disposed within the base component such that when the system or the component dissolves, the total amount of the first API on the outer surface of the system is substantially constant over a predetermined time. The predetermined time is preferably in the range of 1 second to 180 days. For example, the amount of the first component may increase towards the central portion of the drug delivery system. Those skilled in the art will understand that long-term or short-term release is applicable depending on each application and the form of the drug delivery system. For example, when the drug delivery system is in the form of an implant, the API may be released for a long period of up to 180 days. For example, when the drug delivery system is in the form of a tablet, the API may be released for a period of up to 12 hours. The time of constant release is preferably in the range of 5 seconds to 24 hours, more preferably 10 seconds to 12 hours, more preferably 1 minute to 6 hours, more preferably 10 minutes to 1 hour. In an example of a spherical tablet, if the concentration gradient of the first API is inward, the amount of the API on the surface of the system can be made constant even when the system dissolves, i.e., even when the volume or surface of the system shrinks. Thus, the first component can be disposed such that ultimately the concentration of the first API depends on the distance to the surface of the system. Thus, by disposing the first component heterogeneously in the base component, a constant release of the first API can be set.

[0033] More preferably, the concentration profile of the first API is configured such that when the system is applied, the first API is released at two or more dosages, and the release of the first API at one of the dosages preferably starts 1 second to 10 days (the upper limit value is applicable, for example, when the drug delivery system is an implant) before the release of the first API at the other dosage, more preferably 2 seconds to 1 day, more preferably 5 seconds to 12 hours, more preferably 10 seconds to 6 hours, more preferably 20 seconds to 2 hours, more preferably 1 minute to 1 hour, and most preferably 10 minutes to 30 minutes before. For example, the first component may be arranged at a plurality of discrete positions in the direction towards the center of the drug delivery system. Thereby, for example, when the drug delivery system is in the form of a tablet, upon oral administration of the tablet, the first API can be released at the first dosage immediately after administration, and then the first API can be released at the second dosage. These dosages may be uniform or different from each other. The release period of the API described herein can be measured by a dissolution test, for example, in accordance with the USP guideline "General Chapter <711> Dissolution".

[0034] More preferably, the base component wraps the system, and the first component is not disposed on the outer surface of the system. Therefore, the first component containing the first API may be arranged so as not to be externally contacted at least before the application of the system. Thereby, the first API can be effectively sealed from the environment, and the contamination risk can be reduced. Further, for example, when in the form of a tablet, since the base component needs to dissolve (at least partially) first, the dissolution of the first component is delayed upon oral administration. Thereby, delayed administration of the first API becomes possible. Preferably, after the application of the drug delivery system, the release of the first API is configured to start 1 second to 1 day, more preferably 10 seconds to 12 hours, further preferably 30 seconds to 6 hours, further preferably 1 minute to 4 hours, further preferably 10 minutes to 2 hours, and further preferably 30 minutes to 1 hour later.

[0035] In a more preferred embodiment, the drug delivery system further comprises a separate second component that is soluble in body fluids, and the second component comprises a therapeutically effective amount of a second API. Thereby, the drug delivery system enables the controlled administration of multiple APIs in a particular application. These APIs can interact with each other after dissolution of their respective components and bring about a synergistic effect on the body. The first and second APIs may have different shapes and concentrations from each other.

[0036] Those skilled in the art will understand that the description regarding the first component and the first API can be similarly applied to the second component and the second API. Also, those skilled in the art will understand that the drug delivery system may have additional components that include additional pharmaceutical active ingredients, such as a third component containing a third API or a fourth component containing a fourth API.

[0037] More preferably, the second component is heterogeneously disposed within the base component. Thereby, by controlling the heterogeneous disposition of the first and second components within the base component, the release of the first and second APIs from the drug delivery system can be relatively controlled. The above description is similarly applicable to heterogeneous disposition.

[0038] More preferably, the concentration profile of the first API in the system is different from the concentration profile of the second API in the system. For example, the amount of the first component may increase towards the center of the drug delivery system, and the amount of the second component may decrease towards the center of the drug delivery system. Thus, in the drug delivery system, it can be designed such that the first and second APIs are released into the body at different dosages.

[0039] More preferably, the first component and the second component are discontinuously arranged in the drug delivery system such that the first active substance is released for a period of time when the system starts to dissolve, typically starting from the end side. For example, like an onion skin - like arrangement, the layer containing the first component may be arranged adjacent to another layer that does not contain the API or contains a second API. By changing parameters such as the layer thickness, composition, and distribution of the API within the layer, the release of the API can be controlled.

[0040] More preferably, the first component and the second component are arranged in the system such that the release of the first API starts before the release of the second API when the system is applied. For example, the second component may be arranged on the central side of the drug delivery system, and the first component may be arranged on the end side of the drug delivery system. The release of the first API preferably starts 1 second to 10 days before the release of the second API (the upper limit value is applicable, for example, when the drug delivery system is an implant), more preferably 2 seconds to 1 day, more preferably 5 seconds to 12 hours, more preferably 10 seconds to 6 hours, more preferably 20 seconds to 2 hours, more preferably 1 minute to 1 hour, and most preferably 10 minutes to 30 minutes before. Therefore, preferably, by arranging the first and second components heterogeneously or discontinuously in the base component with respect to the dissolution direction, the release times of the first and second APIs can be relatively controlled. Depending on the spatial arrangement of the first and second APIs within each layer, the release of the two APIs may be separated by a predetermined time interval, or the release of the first API may be continued at the start of the release of the second API. Thereby, a synergistic effect of the APIs can be obtained. Usually, the API is released into the body within several hours, days, or months depending on the form of application.

[0041] Preferably, the first component and the second component are arranged in the system such that the release profile of the first API is different from the release profile of the second API when the system is applied. For example, the first API may be released at a constant rate, and the second API may be released intermittently. Thereby, a complex drug delivery system can be designed.

[0042] In a preferred embodiment, the total amount of the first API in the system is 1 μg to 100 g, preferably 10 μg to 10 g, more preferably 100 μg to 1 g, more preferably 500 μg to 500 mg, more preferably 1 mg to 100 mg, and even more preferably 10 mg to 50 mg. Those skilled in the art will understand that the description regarding the first API can also be applied to a second API or other APIs that may be included in the second component or other components of the drug delivery system.

[0043] In an even more preferred embodiment, one or more of the components include ceramics, metals, polymers (preferably polyacrylates), and / or minerals.

[0044] Also, in a preferred embodiment, one or more of the components include a disintegrant that promotes the dissolution of each component. Disintegrants include, for example, cellulose (preferably microcrystalline cellulose), croscarmellose sodium, crospovidone, starch (modified starch), crosslinked polyvinylpyrrolidone, sodium starch glycolate, and / or sodium carboxymethylcellulose.

[0045] Preferably, one or more of the components include one or more selected from coloring agents, sweeteners, flavors, antibacterial and preservative agents (e.g., sorbic acid, benzoic acid, parabens, sucrose, benzalkonium chloride), chemical stabilizers used to enhance the chemical stability of the API (e.g., antioxidants such as ascorbic acid and sodium metabisulfite, chelating agents such as ethylenediaminetetraacetic acid), viscosity modifiers used to suppress the sedimentation of particles (e.g., inorganic materials such as polymer materials and clays), and cellulose-based materials used as thickeners in suspensions (e.g., cellulose, cellulose ethers, alginic acid).

[0046] Preferably, one or more of the components comprise one or more excipients selected from fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, cellulose), wet binders (e.g., gelatin, polyvinylpyrrolidone, cellulose derivatives, polyethylene glycol), dry binders (e.g., cellulose, polyethylene glycol, methylcellulose), lubricants (e.g., silica, magnesium stearate, talc).

[0047] Preferably, the first component has a geometric shape. This shape is preferably tubular (hollow cylindrical), spot-shaped (local collection, mass), elliptical (e.g., open circle or oval), plate-shaped, and / or polygonal (e.g., square). Thereby, the first component can have a shape that enables the desired release of the first API. The same applies to other APIs arranged in other components of the system. In a specific geometric shape, the concentration of the API may vary.

[0048] In a preferred embodiment, the drug delivery system further comprises a marker component that is optically different from the base component. The marker component is arranged to form a two-dimensional pattern on the surface of the system, preferably visible from the outside. The marker component may have a color different from that of the base component. By attaching a desired two-dimensional pattern to the marker component, a predetermined symbol, logo, brand name, etc. can be provided on the drug delivery system. Thereby, a kind of security function can be provided that enables the user to confirm the origin of the drug delivery system.

[0049] In another preferred embodiment, the first component is optically different from the base component and is arranged to form a two-dimensional pattern on the surface of the system, preferably visible from the outside. The first component may have a color different from that of the base component. In this case, a logo or the like is formed by the first component, providing a security function.

[0050] More preferably, the two-dimensional pattern is a discontinuous pattern, for example, due to the non-uniform arrangement of each component within the base component. This can enhance the strength of the authentication level of the security function and increase the user's trust in the product.

[0051] In a preferred embodiment, the drug delivery system is in the form of a tablet, capsule, disk, film, implant, subcutaneous implant, patch, pellet, or granule. This enables the drug delivery system of the present invention to be provided in various forms, thereby allowing for the desired administration and desired release of the API according to specific therapeutic applications.

[0052] Preferably, the drug delivery system has a structured surface. For example, convex or concave portions may be formed on the surface of the drug delivery system. This can expand the surface of the drug delivery system, and as a result, increase the release amount of each API. It will be understood that the API in the drug delivery system of the present invention is not limited to a specific API. Generally, any suitable API provided to each component that is non-uniformly arranged within the base component can be used. For example, the API may be an anti-infective agent, anti-inflammatory agent, cardiac agent, nerve blocker, or nutrient agent. Those skilled in the art will understand that the API is not limited to these. Furthermore, the drug delivery system of the present invention may contain additional components or substances such as additives.

[0053] In a preferred embodiment, the first API includes any one selected from anthelmintics, narcotics and narcotic antagonists, antihistamines, adrenergic agents, adrenergic blockers, sedative-hypnotics, CNS agents, analgesics, anti-Parkinson's disease agents, steroids, coronary vasodilators, anticoagulants, antihypercholesterolemia agents, antibiotics, antifungal agents, antiviral agents, bone growth promoters, anti-cancer agents, vitamins, anti-inflammatory agents, and antihypertensive agents. Also, in a preferred embodiment, the first API includes pregabalin, lurasidone, fentanyl, rivaroxaban, sildenafil / tadalafil, dasatinib, sorafenib, varenicline, memantine, dexlansoprazole, sunitinib, nebivolol, zolmitriptan, sitagliptin, lacosamide, desvenlafaxine, lenalidomide, ledipasvir / sofosbuvir, aripiprazole, levodopa, or ondansetron / granisetron. Those skilled in the art will understand that it is not limited thereto.

[0054] In a preferred embodiment, the drug delivery system is manufactured by screen printing technology. By using such screen printing technology, the arrangement of the first component in the base component of the drug delivery system can be accurately controlled. To arrange the components of the drug delivery system by screen printing technology, a mesh can be used. Thereby, the components can be in the form of a paste, and these pastes can be relatively arranged by screen printing technology. In this case, the API may be soluble in each paste.

[0055] More preferably, the system is manufactured by alternately performing a step of screen printing and curing a base paste containing a base component and a step of screen printing and curing a first paste containing a first component. Those skilled in the art will understand that, for example, additional pastes can be used to obtain a second component containing a second API.

[0056] The present invention further relates to the use of a drug delivery system for the controlled administration of one or more APIs to the body.

[0057] Hereinafter, exemplary embodiments of the present invention will be described with reference to the drawings.

Brief Description of the Drawings

[0058]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Modes for Carrying Out the Invention

[0059] Figure 1 shows nine design examples of the drug delivery system of the present invention. As shown in the figure, all of these designs include a base component as a matrix forming the main body of each drug delivery system (DDS), and additional components are arranged in this base material component. These components are represented as Component A, Component B, Component C, and Component D, each of which may contain a therapeutically effective amount of a separate pharmaceutical active ingredient (API). Therefore, Components A to D can all be regarded as the first components in the present invention. The base component and Components A to D are soluble in body fluids.

[0060] The design of DDS(a) in Figure 1 has a round shape. DDS(a) may be in the form of tablets, disks, etc., and for example, has a diameter D of 15 mm. Inside the base component of DDS(a), a first component A containing a first API, a second component B containing a second API, and a third component C containing a third API are arranged. As shown in the figure, each API is not evenly distributed across the drug delivery system, and by placing components A, B, and C at specific positions within the drug delivery system, they are unevenly arranged within the base component. Components A, B, and C are polygonal with a hexagonal cross-section.

[0061] When applying and dissolving DDS(a), since dissolution starts from the edge side of the system, first the base component dissolves. After a predetermined time, component C and component B start to dissolve, thereby releasing their respective APIs. Then, component A starts to dissolve last, thereby releasing the first API. In this way, due to the specific arrangement of the components in the drug delivery system, after applying the drug delivery system, different APIs are released at different dosages and at different stages. Also, due to the specific arrangement of the different components within DDS(a), each API is released at a predetermined time after applying the drug delivery system with an individual API-specific release profile.

[0062] The design of DDS(b) in Figure 1 is formed as a tablet, for example, with a height of 2.5 mm and a diameter of 15 mm. According to the present invention, two components B and C each containing an API are unevenly arranged within the base component. When applying the system, a specific release profile of the APIs contained in components B and C is obtained, which is characterized by a smooth transition between the release increase phases.

[0063] The design of DDS(c) in Figure 1 is similar to the design of DDS(a), but in addition to the base component, it only contains two components B and C each containing an API. When applying the system, a specific release profile of the APIs contained in components B and C is obtained, which is characterized by a smooth transition between the release increase phases.

[0064] In the design of DDS(d) in FIG. 1, two components with an API are formed in a tubular shape. Also, these components may be formed in a laminated state.

[0065] DDS(e) in FIG. 7 is designed such that the component containing the API is arranged in a spot shape within the base component. When the system is applied, a specific release profile of the API contained in components B and C, which is characterized by a smooth transition between the release enhancement phases, is obtained.

[0066] DDS(f) in FIG. 1 has, for example, a design with a height of 25 mm, and only one component containing the API is heterogeneously arranged in a tubular shape within the base component. Also, this component may be arranged in a plate shape.

[0067] DDS(g) in FIG. 1 is similar to DDS(e), but the component containing the API is arranged more randomly. When the system is applied, a specific release profile of the API contained in components B and C, which is characterized by a smooth transition between the release enhancement phases, is obtained.

[0068] DDS(h) in FIG. 1 has a design in which the component containing the API is arranged in a circular shape within the base component. When the drug delivery system is applied, the base component and the first component dissolve alternately, and the first API is released intermittently, for example, periodically. After the first API is completely released, the second component begins to dissolve and the second API is released. As shown in the figure, the circles of component A are not concentric and the thickness is not uniform. This heterogeneous arrangement results in a specific release profile that is characterized by a smooth transition between the release enhancement phases.

[0069] DDS(i) in FIG. 1 has a design in which the component containing the API is arranged in a specific pattern within the matrix of the additive arranged in the base component.

[0070] One skilled in the art will understand that each system described with reference to FIG. 1 has specific release characteristics with respect to the APIs disposed therein. Also, depending on the therapeutic use, one skilled in the art will understand to select an appropriate design having a non-uniform arrangement of the APIs in the base component according to the present invention.

[0071] FIG. 2 shows a further design of the drug delivery system of the present invention. Here, the component containing the API and the base component are arranged in a grid structure in which each “pixel” is defined by either the API component or the base component. As shown in the figure, these two components are arranged such that the density of the “API pixels” is high in the central part of the drug delivery system. This is also clear from the API concentration profile shown in FIG. 2. In this profile, the API concentration peaks high at the center of the system and is low at the edges of the system. The transition from the low API concentration at the edges to the high API concentration at the center is smooth without a sharp step. With such a drug delivery system, the release profile of the system when the two components dissolve can be adjusted or configured in a desired manner.

[0072] FIG. 3 shows the release profile of a general drug delivery system in which the API is uniformly distributed (graph (1) in FIG. 3) and the two release profiles of the drug delivery system according to the present invention (graphs (2) and (3) in FIG. 3). The design of each drug delivery system is shown horizontally in the graph. The drug delivery system is in a round shape and is, for example, a tablet that dissolves by oral administration. Each graph shows the release of the API of each drug delivery system over time.

[0073] Regarding the graph (1) in Figure 3, the drug delivery system is designed such that the API is uniformly distributed throughout the system. This uniformity, which is characteristic of a typical conventional drug delivery system, is derived from the corresponding manufacturing process. When a conventional drug delivery system decomposes, the API is released. Depending on the dissolution characteristics of the uniform system and the shape of the system, a specific, fixed release profile is obtained. As can be seen from the graph (1) in Figure 3, the release of the API gradually increases over time, reaches a maximum value, and then gradually decreases.

[0074] Due to the non-uniform placement of the API of the present invention, different release profiles can be obtained. The design regarding the graph (2) in Figure 3 is such that the API is placed at the end sides of the drug delivery system and is different from the design regarding the graph (1) in Figure 3. Thus, since the API is non-uniformly distributed within the system, here at a high concentration at the end sides of the system, the principle of uniform distribution of the API within the system does not apply. The concentration of the API smoothly decreases towards the center of the system. When the drug delivery system regarding the graph (2) in Figure 3 is applied, a large amount of the API is first released and then gradually decreases. As will be understood by those skilled in the art, such an initial large release of the API is beneficial for certain applications.

[0075] In the design regarding the graph (3) in Figure 3, the API is accumulated in the central part of the drug delivery system. Thus, the API concentration is maximum at the center of the system and the concentration gradient is from the ends of the system towards the center. As can be seen from the graph (3) in Figure 3, the release gradually increases over a long period of time and the maximum release rate is delayed compared to a typical design. Compared to a typical design, the release of the API is considered to be more constant over a long period. Such a release profile is beneficial for certain applications, as will be understood by those skilled in the art.

[0076] Figure 4 shows a further design example of the drug delivery system of the present invention. The overall shape of the system is a round disk shape with a diameter of 5 to 25 mm, preferably 20 mm or 15 mm, and a thickness of 0.5 to 15 mm, preferably 2 mm or 6 mm. The notch of the tablet is for visualizing the arrangement of the components within the tablet.

[0077] In the design of DDS(j) in Figure 4, the first component containing the first API is arranged at the central part of the tablet, surrounded by the base component, and the whole tablet is coated with a film. The film may be a hydrophilic film or, for example, enteric-soluble. The concentration of the API in the tablet is maximum at the center of the tablet. The concentration profile of the API is configured to have a smooth transition from the edge of the tablet towards the center of the tablet.

[0078] In the design of DDS(k) in Figure 4, the first component containing the first API and the second component containing the second API are arranged within the base component, and a film is also provided. The second component is arranged in a spherical shape, and the concentration of the second API is maximum at the surface of the sphere and smoothly decreases towards the center of the sphere. Inside the sphere composed of the second component, the first component is arranged. Thereby, when the tablet is applied and the components dissolve, the second API is released before the first API, and both APIs are released during the transition.

[0079] The design of DDS(l) in Figure 4 has two different APIs. The second API is located at the central part of the tablet, and the first API is located around the second API. In the interface region of these APIs, the APIs exist overlappingly so that both APIs are arranged. Thereby, a smooth crossover is obtained. Further, a layer extending within the system, for example, a hydrophobic layer, is provided.

[0080] The design of DDS(m) in Figure 4 does not include a film. The APIs are arranged heterogeneously within the tablet such that regions with different API concentrations are formed.

[0081] Figure 5 shows a further design example of the drug delivery system of the present invention. The overall shape of the system is a round disk shape with a specific thickness. As can be seen from the figure, one or more marks are provided on at least a part of the surface of the tablet. The marks form a two-dimensional pattern visible on the surface of the tablet. As shown in Figure 5, the pattern of the marks may be a discontinuous pattern. The pattern includes, for example, smooth curves and sharp edges. Therefore, the pattern can be arranged unevenly. The marks can be formed by a specific mark component or a component containing an API. By providing such a complex mark on the drug delivery system, a security function can be obtained that allows the user to confirm the origin of the drug delivery system.

[0082] Figure 6 shows a further design example of the drug delivery system of the present invention. This system is spherical and has a hydrophobic coating. The coating contains hydrophilic pores with a size of 1 μm to 500 μm. Inside the drug delivery system, a base component and three different pharmaceutical active ingredients, API A, API B, and API C, are provided. API C is located at the central part of the system and has an edge pattern. The other two APIs, A and B, surround API C. API B is provided as a hollow sphere in which the API is uniformly distributed. Also, API A is distributed unevenly surrounding API C. Therefore, the concentration of API A decreases towards the end of the illustrated drug delivery system.

[0083] Figure 7 shows a cross-section of the drug delivery system of the present invention. As shown, the surface of the drug delivery system is structured, with six convex portions and recesses formed therebetween on one side. By increasing the surface area in this way, the dissolution of the drug delivery system, that is, the release of the API, can be enhanced. A person skilled in the art will understand that the entire surface of the drug delivery system, or only a part or multiple parts thereof, can be structured.

[0084] Thus, one skilled in the art would understand that, with the drug delivery system of the present invention, in order to achieve the desired release of the API, it is necessary to adjust the specific inhomogeneous distribution of one or more APIs within the system. Also, one skilled in the art would understand that it is possible to obtain immediate release or delayed release of the API. Furthermore, it is possible to release a specific single API, for example intermittently, at different dosages over a long period of time, thereby enabling the stepwise release of the API.

[0085] Furthermore, by using a single new drug delivery system, different APIs can be released at different stages. For example, the system can be designed such that the first API is released before the release of the second API. Examples of systems combining two or more APIs include combinations of gastroprotective agents such as proton pump inhibitors and antihistamines, and non-steroidal anti-inflammatory substances such as ibuprofen and diclofenac. Another example is the combination of antiemetics (such as ondansetron and domperidone) and analgesics, particularly those acting on the structures of the central nervous system (such as tramadol hydrochloride). Another example is the combination of carbidopa and levodopa, i.e., a combination of agents that prevent the degradation of pharmaceutically active ingredients. One skilled in the art would understand that the release of these two APIs may result in a specific synergistic effect. Furthermore, controlled release may mean, for example, physiological mimicking such as cortisone therapy, where the drug delivery system is administered at 10 p.m. and preferably releases the steroid 6 hours later. Since it is desirable to administer the steroid at 4 a.m., the steroid can be administered using the drug delivery system of the present invention designed to release the API at the desired time at night, taken the previous night. Similarly, according to the drug delivery system of the present invention, for example, it is possible to ensure the appropriate administration of antibiotics stepwise over a long period (e.g., several days). This can reduce the adverse effects on patients who ignore the prescribed dosing routine.

[0086] Design examples resulting from the concept of heterogeneous placement of one or more APIs in a drug delivery system are diverse. Those skilled in the art will understand that by combining the above examples, more complex designs with release profiles optimized for a particular use or treatment can be obtained.

Claims

1. A drug delivery system in the form of a tablet for the controlled administration of one or more pharmaceutical active ingredients (APIs), comprising: a base component soluble in body fluids; a separate first component soluble in body fluids; a separate second component soluble in body fluids; wherein the first component contains a therapeutically effective amount of a first API; the second component contains a therapeutically effective amount of a second API; the first component is arranged such that the first API has a concentration gradient in the base component, and the second component is arranged such that the second API has a concentration gradient in the base component, whereby the first API and the second API are each non-uniformly arranged in the base component; the first component and the second component are arranged in the drug delivery system such that the release of the first API starts before the release of the second API when the drug delivery system is applied; the base component is a three-dimensional body, and the first component and the second component are arranged such that the concentrations of the first API and the second API each have a concentration gradient that varies three-dimensionally within the base component; The drug delivery system, wherein the first component and the second component are plate-shaped and formed in a laminated manner.

2. The drug delivery system according to claim 1, wherein the concentration of the first API is maximum at the center, end, or intermediate region of the drug delivery system.

3. The drug delivery system according to claim 1 or 2, wherein the concentration gradient of the first API increases towards the center of the drug delivery system or away from the center of the drug delivery system.

4. The drug delivery system according to any one of claims 1 to 3, wherein the concentration profile of the first API in the drug delivery system has a smooth transition to a high-concentration region.

5. The drug delivery system according to any one of claims 1 to 4, wherein the concentration profile of the first API in the drug delivery system has a plurality of high-concentration regions.

6. The drug delivery system according to any one of claims 1 to 5, wherein, when the change in the concentration of the first API in the drug delivery system is defined as the difference between the maximum and minimum concentrations of the first API in the drug delivery system, the change in the concentration of the first API is 5% or more.

7. When the change in the concentration of the first API in the drug delivery system is defined as the difference between the maximum concentration and the minimum concentration of the first API in the drug delivery system, the change in the concentration of the first API is 100% or less. The drug delivery system according to any one of claims 1 to 6.

8. The concentration profile of the first API is configured such that when the drug delivery system is applied, the first API is released from the drug delivery system with a predetermined release profile. The drug delivery system according to any one of claims 1 to 7.

9. The concentration profile of the first API is configured such that when the drug delivery system is applied, the first API is released in two or more dosages, and the release of the first API in one of the dosages starts 1 second to 10 days before the release of the first API in the other dosage. The drug delivery system according to any one of claims 1 to 8.

10. The base component wraps the first component, and the first component is not disposed on the outer surface of the drug delivery system. The drug delivery system according to any one of claims 1 to 9.

11. The concentration profile of the first API in the drug delivery system is different from the concentration profile of the second API in the drug delivery system. The drug delivery system according to any one of claims 1 to 10.

12. The release of the first API starts 1 second to 10 days before the release of the second API. The drug delivery system according to any one of claims 1 to 11.

13. The first component and the second component are disposed in the drug delivery system such that when the drug delivery system is applied, the release profile of the first API is different from the release profile of the second API. The drug delivery system according to any one of claims 1 to 12.

14. The total amount of the first API in the drug delivery system is 1 μg to 100 g. The drug delivery system according to any one of claims 1 to 13.

15. One or more of the first component or the second component include ceramic, metal, polymer, mineral, filler, wet binder, dry binder, and / or lubricant. The drug delivery system according to any one of claims 1 to 14.

16. The drug delivery system according to any one of claims 1 to 15, wherein one or more of the first component and the second component contain a disintegrant.

17. The disintegrant is cellulose, croscarmellose sodium, crospovidone, starch, crosslinked polyvinylpyrrolidone, sodium starch glycolate, and / or sodium carboxymethyl cellulose, and the drug delivery system according to claim 16.

18. The drug delivery system according to any one of claims 1 to 17, further comprising a marker component optically different from the base component, wherein the marker component is arranged on the surface of the drug delivery system so as to form a two-dimensional pattern.

19. The drug delivery system according to any one of claims 1 to 18, wherein the first component is optically different from the base component and is arranged on the surface of the drug delivery system so as to form a two-dimensional pattern.

20. The drug delivery system according to claim 18 or 19, wherein the two-dimensional pattern is a discontinuous pattern.

21. The drug delivery system according to any one of claims 1 to 20, wherein the first API contains any one selected from anthelmintics, narcotics and narcotic antagonists, antihistamines, adrenergic agents, adrenergic blockers, sedative-hypnotics, CNS agents, analgesics, anti-Parkinson's disease agents, steroids, coronary vasodilators, anticoagulants, antihypercholesterolemic agents, antibiotics, antifungal agents, antiviral agents, bone growth promoters, anti-cancer agents, vitamins, anti-inflammatory agents, antihypertensive agents.

22. The drug delivery system according to any one of claims 1 to 21, wherein the first API contains any one selected from pregabalin, lurasidone, fentanyl, rivaroxaban, sildenafil / tadalafil, desatinib, sorafenib, varenicline, memantine, dexlansoprazole, sunitinib, nebivolol, zolmitriptan, sitagliptin, lacosamide, desvenlafaxine, lenalidomide, ledipasvir / sofosbuvir, aripiprazole, levodopa, or ondansetron / granisetron.

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