Two-part rotary mold encapsulation system and process for manufacturing capsules

Abstract

This invention provides a rotary mold encapsulation system and process for the manufacture and use of capsules. [Solution] The rotary mold encapsulation system and process can be used to improve the uniformity of the content of the multiphase filling composition within the capsule. The rotary mold encapsulation system and process can also be used to adjust the dosing strength of the filling composition within the capsule.

Description

Technical Field

[0001] The present invention generally relates to a two-part rotary die encapsulation system and process for manufacturing capsules.

Background Art

[0002] The standard rotary die encapsulation process has conventionally involved a single dispensing pump injecting a predetermined amount of a filling composition into a ribbon of gel trapped between a die and a wedge, distorting the ribbon into the shape of the die, whereby capsules are formed when the edges of the ribbon are fused by the heat of the wedge. This process is effective when the filling composition is a solution or homogeneous multiphase system that is resistant to phase separation. However, when the filling system is composed of multiple phases that may settle or separate before being injected between the ribbons, content uniformity problems typically occur that render the capsules unsuitable for their intended use. Currently, content uniformity problems are addressed by finely tuning the formulation to prevent phase separation or segregation. The most common approach is to adjust the rheology of the formulation so that gravitational settling is minimized, but in the process of moving or mixing a liquid system containing multiple phases with different phase densities, the movement of the liquid can impart a centrifugal force that may otherwise separate a homogeneous system. The centrifugal force can exceed gravity and may segregate an otherwise stable suspension. This problem can be very difficult to address for the liquid systems used in the rotary die process. Preventing phase segregation and ensuring content uniformity remain significant challenges in the art. and ensuring content uniformity remain significant challenges in the art.

[0003] However, if the filling system consists of multiple phases that may settle or separate before being injected between the ribbons, content uniformity problems typically occur, making the capsules unsuitable for their intended use. Currently, content uniformity problems are addressed by finely tuning the formulation to prevent phase separation or segregation. The most common approach is to adjust the rheology of the formulation so that gravitational settling is minimized, but in the process of moving or mixing a liquid system containing multiple phases with different phase densities, the movement of the liquid can impart a centrifugal force that may otherwise separate a homogeneous system. The centrifugal force can exceed gravity and may segregate an otherwise stable suspension. This problem can be very difficult to address for the liquid systems used in the rotary die process. This typically results in content uniformity problems that render the capsules unsuitable for their intended use.

[0004] Currently, content uniformity problems are addressed by finely tuning the formulation to prevent phase separation or segregation. The most common approach is to adjust the rheology of the formulation so that gravitational settling is minimized, but in the process of moving or mixing a liquid system containing multiple phases with different phase densities, the movement of the liquid can impart a centrifugal force that may otherwise separate a homogeneous system. The centrifugal force can exceed gravity and may segregate an otherwise stable suspension. This problem can be very difficult to address for the liquid systems used in the rotary die process. The most common approach is to adjust the rheology of the formulation so that gravitational settling is minimized, but in the process of moving or mixing a liquid system containing multiple phases with different phase densities, the movement of the liquid can impart a centrifugal force that may otherwise separate a homogeneous system. The centrifugal force can exceed gravity and may segregate an otherwise stable suspension. This problem can be very difficult to address for the liquid systems used in the rotary die process. The centrifugal force can exceed gravity and may segregate an otherwise stable suspension. This problem can be very difficult to address for the liquid systems used in the rotary die process. In the process of moving or mixing a liquid system containing multiple phases with different phase densities, the movement of the liquid can impart a centrifugal force that may otherwise separate a homogeneous system. The centrifugal force can exceed gravity and may segregate an otherwise stable suspension. This problem can be very difficult to address for the liquid systems used in the rotary die process. This problem can be very difficult to address for the liquid systems used in the rotary die process. Preventing phase segregation The viscosity required for this is a manufacturing issue, for example, the high viscosity of the viscous material that adheres to the walls of the transfer line. Line loss, and problems with the standard pump used to meter the formulation into the wedge. The risk of causing this is high. In addition, the added excipients, once ingested, can affect the formulation. Do not delay or interfere with the dispersion, or adversely affect the stability profile of the formulation. However, this can impart undesirable properties to the formulation.

[0005] For formulations (e.g., the physical and / or chemical stability of the formulation, the release profile of the formulation) File and / or dissolution profile, bioavailability and / or clinical performance of the formulation. , with minimal impact (on the physical and / or chemical properties of the formulation), and processing the formulation. With minimal impact on the hardware used (e.g., pumps), multiphase systems There is a need for rotary mold processes and equipment to address the issue of uniform content in this context. . [Overview of the project]

[0006] The objective of certain embodiments of the present invention is a rotating mold capsule for encapsulating multiphase formulations. The objective is to provide a chemical system and method.

[0007] The objective of certain embodiments of the present invention is to minimize phase segregation of a multiphase formulation during the filling process. The objective is to provide a rotary mold encapsulation system and method.

[0008] The objective of certain embodiments of the present invention is to enable rheological formulation when compounding multiphase formulations that are prone to phase segregation. - Provides a rotary mold encapsulation system and method that minimizes the use of modifying excipients. That is the case.

[0009] The objective of certain embodiments of the present invention is to produce multiphase dosage forms with minimal API content variation between dosage forms. The objective is to provide a rotary mold encapsulation system and method for this purpose.

[0010] The objective of certain embodiments of the present invention is to encapsulate a low-viscosity multiphase system using a rotary mold. The objective is to provide a system and method.

[0011] The objective of a particular embodiment of the present invention is to provide a multiphase system in which one of the phases (e.g., a small-volume phase) has a low concentration. The objective is to provide a rotary mold encapsulation system and method for processing pharmaceutical products.

[0012] The objective of certain embodiments of the present invention is to process multiphase formulations having large density differences between different phases. The objective is to provide a rotary mold encapsulation system and method for this purpose.

[0013] The objective of a particular embodiment of the present invention is to provide for one of the phases (for example, a phase from large particle size) Processing multiphase formulations that have a high separation rate (for small phases) due to the resulting issue. The objective is to provide a rotary mold encapsulation system and method for this purpose.

[0014] The objective of certain embodiments of the present invention is to minimize damage to the processing apparatus (e.g., pump, (Minimum blockage or damage to wedges or piping) and / or formulations (e.g.) For example, a rotary mold for processing multiphase formulations with minimal damage to fragile solid particles. The objective is to provide an encapsulation system and method.

[0015] The objective of certain embodiments of the present invention is to compare with other components (e.g., the amount of high-potency API) , multi-component formulations where the amount of one component needs to be controlled with greater precision (multi-component formulations) A rotary die capsule for manufacturing a dosage form, whether miscible, immiscible, or partially miscible To provide a cell encapsulation system and method

[0016] An object of a particular embodiment of the present invention is to provide a rotary die encapsulation system and method for adjusting the dosage administration intensity in-situ system and method

[0017] The above and other objects of the present invention, in some embodiments, are a rotary die encapsulation system, a method for improving the content uniformity of a multiphase filling composition, and a method for adjusting the administration intensity of a capsule filling composition, and / or a dosage form prepared according to any method or by any system disclosed herein, which can be achieved by the present invention In one embodiment, the rotary die encapsulation system comprises a first rotary encapsulation die having a first set of die cavities, a second rotary encapsulation die having a second set of die cavities, a wedge disposed between the first rotary encapsulation die and the second rotary encapsulation die, and one or more dispensing tubes integrated within the wedge and aligned with at least one cavity within the first set of die cavities and / or within the second set of die cavities, the one or more dispensing tubes being configured to inject a first filling composition and a second filling composition into at least one cavity, a first mechanical dispensing mechanism for dispensing a first quantity of the first filling composition to the one or more dispensing tubes via a first supply tube, and a second quantity of the second filling composition via a second supply tube and / or a method for adjusting the administration intensity of a capsule filling composition, and / or a dosage form prepared according to any method or by any system disclosed herein, which can be achieved by the present invention The present invention is directed to a dosage form prepared according to any method or by any system disclosed herein can be achieved by the present invention

[0018] In one embodiment, the rotary die encapsulation system includes a first rotary encapsulation die having a first set of die cavities, a second rotary encapsulation die having a second set of die cavities, a wedge disposed between the first rotary encapsulation die and the second rotary encapsulation die, and one or more dispensing tubes integrated within the wedge and aligned with at least one cavity within the first set of die cavities and / or within the second set of die cavities, the one or more dispensing tubes being configured to inject a first filling composition and a second filling composition into at least one cavity a second rotary encapsulation die having a second set of die cavities, a wedge disposed between the first rotary encapsulation die and the second rotary encapsulation die, and one or more dispensing tubes integrated within the wedge and aligned with at least one cavity within the first set of die cavities and / or within the second set of die cavities, the one or more dispensing tubes being configured to inject a first filling composition and a second filling composition into at least one cavity a wedge disposed between the first rotary encapsulation die and the second rotary encapsulation die, and one or more dispensing tubes integrated within the wedge and aligned with at least one cavity within the first set of die cavities and / or within the second set of die cavities, the one or more dispensing tubes being configured to inject a first filling composition and a second filling composition into at least one cavity a wedge disposed between the first rotary encapsulation die and the second rotary encapsulation die, and one or more dispensing tubes integrated within the wedge and aligned with at least one cavity within the first set of die cavities and / or within the second set of die cavities, the one or more dispensing tubes being configured to inject a first filling composition and a second filling composition into at least one cavity and one or more dispensing tubes integrated within the wedge and aligned with at least one cavity within the first set of die cavities and / or within the second set of die cavities, the one or more dispensing tubes being configured to inject a first filling composition and a second filling composition into at least one cavity one or more dispensing tubes integrated within the wedge and aligned with at least one cavity within the first set of die cavities and / or within the second set of die cavities, the one or more dispensing tubes being configured to inject a first filling composition and a second filling composition into at least one cavity a first filling composition and a second filling composition into at least one cavity A first mechanical dispensing mechanism for dispensing a first quantity of the first filling composition to the one or more dispensing tubes via a first supply tube and a second quantity of the second filling composition via a second supply tube Includes a second mechanical distribution mechanism for distributing to one or more distribution tubes via the same. The rotary mold encapsulation system is a continuous first fill on the first rotary encapsulation mold. The material may also include a continuous second film on a second rotating encapsulation mold.

[0019] In another embodiment, a method for improving the content uniformity of a multiphase filling composition is a first filling composition The steps include preparing a first and second filling composition containing an active pharmaceutical ingredient (API). A first rotating encapsulating mold having a top and a first set of mold cavities, with a continuous second A step of forming a film and a second rotating cup with a second set of mold cavities The steps include forming a continuous second film on a cellular mold and a first mechanical distribution mechanism. Using this, a first amount of the first filling composition is dispensed through a first supply tube into a first distribution tube. A step of mechanically distributing to a tube, wherein the first distribution tube is a first rotating capsule It is integrated into a wedge positioned between the first mold and the second rotating encapsulation mold. Also, at least one in the first set of mold cavities or in the second set of mold cavities Using a step aligned with two cavities and a second mechanical distribution mechanism, A second amount of the second filling composition is mechanically supplied to the second distribution tube via the second supply tube. This is a step of distributing the contents, where the second distribution tube is the same as the first distribution tube. Alternatively, a step separated from the first distribution tube and the first rotary encapsulation mold Then rotate the second rotary encapsulation mold in the opposite direction, and the first rotary encapsulation mold and the second A continuous first film and a continuous second film are brought into contact between the rotating encapsulation mold. This forms a closed capsule, creating a continuous first film and a continuous second film. Inside the closed capsule between the two, a first amount of the first filling composition and a second amount of the second filling composition are placed. The process includes the step of capturing the resulting material.

[0020] In yet another embodiment, a method for adjusting the dosage strength of the capsule filling composition is a first filling The steps of preparing a filling composition, preparing a second filling composition, and the first set A continuous first film is formed on a first rotating encapsulation mold equipped with a mold cavity. The steps include continuously moving the second rotating encapsulating mold, which has a second set of mold cavities, onto the second rotating encapsulating mold. The steps of forming a second film and using a first mechanical distribution mechanism to divide the first amount The first filling composition is mechanically distributed to the first distribution tube via the first supply tube. The step involves the first distribution tube connecting the first rotating encapsulation mold and the second rotating tube. It is integrated into the wedge positioned between the capsule mold and the first set of mold caps. At least one cavity and position within the bitty and / or within the second set of mold cavities The steps involve placing the materials together and using a second mechanical distribution mechanism to fill the second packing batch of a second quantity. The step involves mechanically distributing the product to a second distribution tube via a second supply tube. So, the second distribution tube is the same as the first distribution tube, or the first distribution tube A step separate from the tube, and a first rotary encapsulation mold and a second rotary encapsulation mold. Rotate it in the opposite direction between the first rotating encapsulation mold and the second rotating encapsulation mold. The continuous first film and the continuous second film are brought into contact, and the closed capsule is formed. Formed within a closed capsule between a continuous first film and a continuous second film A step of capturing a first amount of a first filling composition and a second amount of a second filling composition in a part. This includes, in this case, the administration strength of the capsule filling composition is the first amount of the first filling composition and Determined by a second amount of the filling composition.

[0021] In one embodiment, according to the method described herein and / or the system described herein A dosage form prepared by any of the TEMs is disclosed.

[0022] The above and other features, their properties, and various advantages of this disclosure are described in conjunction with the attached drawings. This will become clearer when you consider the following detailed explanation. [Brief explanation of the drawing]

[0023] [Figure 1] This figure shows a rotary mold apparatus according to an embodiment disclosed herein. [Figure 2] This figure shows a rotary mold apparatus according to an embodiment disclosed herein. [Figure 3] This figure shows a method for preparing any of the dosage forms described herein. [Modes for carrying out the invention]

[0024] As used herein, the singular forms "a," "an," and "the" are used when the context is such. Unless explicitly stated otherwise, it includes multiple references. Therefore, for example, "activator (an a The term "active agent" refers to a single activator, a mixture of two or more activators, and others. It includes.

[0025] When used in this specification, the term "approximately" relating to a measured quantity means that the measurement is performed and When performing maintenance at a level appropriate to the purpose of measurement and the accuracy of the measuring instrument, by a person skilled in the art This refers to the normal variation in the measured quantity that is expected. In certain embodiments, the term "about" means "about 1 The number listed is ±10%, so that "0" includes 9-11.

[0026] As used herein, the terms “activator,” “active ingredient,” “active pharmaceutical ingredient,” and “A” are used in this specification. The terms "PI" and "drug" refer to whether or not they have been approved by a government agency for that purpose. This refers to any material intended to produce a therapeutic, preventative, or other intended effect. These terms, concerning specific drugs, refer to all pharmaceutical active agents, all of their pharmaceutical Acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, ethers, esters, hydrates, This includes solvates and mixtures thereof, which are pharmaceutically active in their respective forms. In the embodiments, the term "active ingredient" is an ingredient approved by a government agency for that purpose. Regardless of whether it has a therapeutic effect or not, materials intended to produce a cosmetic effect (with or without therapeutic effect) It can refer to a fee.

[0027] As used herein, the term “stereoisomer” means a difference between the atoms of those atoms in space. This term is a general term for all isomers of individual molecules that differ only in orientation. , enantiomers, and differentiating compounds having one or more chiral centers that are not mirror images of each other. Contains diastereomers.

[0028] The terms "enantiomer" or "of an enantiomer" refer to non-superimposable mirror images of each other. This refers to molecules that are optically active, and in this case, enantiomers have a different plane of polarization. By rotating it to a certain extent in one direction, its mirror image rotates the plane of polarization by the same degree, but in the opposite direction.

[0029] The term "chiral center" refers to a carbon atom bonded to four different groups.

[0030] While not limited to "pharmaceutically acceptable salts," hydrochloride salts, hydrobromide salts, and sulfate salts are also acceptable. , inorganic salts such as phosphates; formate, acetate, trifluoroacetate, maleate, tartrate Organic acid salts such as salts; methanesulfonate, benzenesulfonate, p-toluenesulfonate Sulfonates such as phosphates; alginates, aspartates, glutamine Amino acid salts such as salts; metal salts such as sodium salts, potassium salts, and cesium salts; calcium Alkaline earth metals such as magnesium salts, triethylamine salts, pyridine salts, pico Phosphate salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N Examples include organic amine salts such as N'-dibenzylethylenediamine salt.

[0031] In this specification, ranges of values ​​are described as being within the specified range unless otherwise indicated. It is simply intended to serve as a shorthand way to refer to each distinct value individually, The individual values ​​are incorporated herein as if they were individually stated herein. All methods described herein are, unless otherwise indicated herein, or written The procedures can be carried out in any appropriate order, as long as they do not clearly contradict each other. Any and all embodiments or illustrative language provided in this document (e.g., "such as (s) The use of "such as" simply indicates specific materials and methods, and does not limit the scope. It is not. No language in this specification is essential to the implementation of the disclosed materials and methods. It should not be interpreted as indicating an element of non-claim.

[0032] The present invention relates to a two-part rotary mold encapsulation system and a for manufacturing capsules. This applies to processes and their use. The systems and processes described herein are multifaceted. It advantageously minimizes the problem of phase segregation in phase-packed systems and APIs across multiple capsules. To improve dosage uniformity, reduce the use of rheological modifiers, and enable single-batch (e.g., in -In situ) adjust the API administration strength within the capsule and achieve better control of the filling composition. It can be used to provide high precision.

[0033] The above advantages and other benefits are due to the system and process described herein, which divides the formulation into two parts. This is achieved through [method / synthesis]. Each part is formulated separately. Furthermore, the way each part is introduced is: To achieve target characteristics (e.g., phase homogeneity, dosage, etc.), it is possible to control independently. can.

[0034] Embodiments of a two-part rotary mold encapsulation system and process are described in detail with respect to the drawings. I will explain it to them.

[0035] Figure 1 shows a rotary mold apparatus according to an embodiment disclosed herein. The system comprises a first rotary encapsulation mold 100A and a second rotary encapsulation mold 1 Includes 00B. The first rotating capsule mold 100A is the first set of mold cavities 110A The second rotating capsule mold 100B includes the second set of mold cavities 110B. The continuous first film 120A and the continuous second film 120B are, respectively , which may be formed on the first and second drums (not shown), and then the first rotating couple Even if passed over the cellular mold 100A and the second rotary encapsulation mold 100B, good.

[0036] In the illustrated embodiment, the system comprises a first rotary encapsulation mold 100A and a second rotary encapsulation mold The system further includes a wedge 300 positioned between the capsule mold 100B and the other element.

[0037] In certain embodiments, the system is integrated within the wedge and the first set of mold cavities Positioned within and / or at least one cavity in the second set of mold cavities The distribution may further include one or more connected distribution tubes, for example, as shown in Figure 1. In this embodiment, one distribution tube 130 is integrated into the center of the wedge 300. The center of the wedge 300 in Figure 1 is shown along the vertical axis Y. The distribution tube 130 is , the first set of mold cavities 110A of the first rotating encapsulating mold 100A The second set of molds of the center cavity 111A and the second rotating encapsulating mold 100B The first center cavity 111B is aligned with the second center cavity 110B. Center cavity 111A and the second center cavity 111B are combined, ultimately A first pair of mold cavities 111 are formed to form a complete capsule. ru.

[0038] Although not shown in the illustration, a single co-distribution tube 130 is also eccentrically located within the wedge 300. They are integrated and also have off-center cavities (for example, the first rotary capsule mold) First off-center cavity 112 in the first set of mold cavities 110A of 100A A, or the second set of mold cavities 110B of the second rotating capsule mold 100B The first off-center cavity (112B) may be aligned with the second off-center cavity (112B). Cavity 112A and the second off-center cavity 112B are both mold cavities. The second pair 112 is formed. Similarly, the single co-distribution tube is in the wedge 300. Integrated into the off-center position, and any other suitable off-center cavity (e.g., 1 It may also be aligned with 13A, 113B, etc.

[0039] In certain embodiments, the system further includes a first mechanical distribution mechanism 140A. The mechanical dispensing mechanism 140A is a first reservoir / container 15 filled with the first filling composition. It may be connected to 0A. The first mechanical distribution mechanism 140A is also connected to the first supply tube 1 It may be connected to 60A. The first mechanical distribution mechanism 140A is the first filling set of the first quantity. The product is distributed from the first reservoir / container 150A through the first supply tube 160A. It is configured to distribute to unit 130.

[0040] Similarly, the system further includes a second mechanical distribution mechanism 140B. Mechanism 140B is connected to a second reservoir / container 150B filled with a second filling composition. The second mechanical distribution mechanism 140B is also connected to the second supply tube 160B. The second mechanical dispensing mechanism 140B dispenses a second amount of the second filling composition. From reservoir / container 150B, via second supply tube 160B, distribution tube 130 It is configured to distribute to [the specified number / group].

[0041] In the embodiment shown in Figure 1, the first supply tube 160A and the second supply tube 16 0B converges together into a single co-distribution tube 130.

[0042] The first supply tube 160A transitions to the distribution tube 130, and the distribution tube 130 It may be an integrated continuum. Alternatively, the first supply tube 160A may be a distribution tube. It may be a separate component from B130, and the two may be combined / linked to form the first reservoir From container 150A to distribution tube 130 via first supply tube 160A, and Ultimately, less than one of the first set of mold cavities or the second set of mold cavities Both are one cavity (for example, the first center cavity 111A and the second center - Cavity 111B, or any other such as 112A, 112B, 113A, and 113B Entering the off-center cavity, a continuous path is formed for the first filling composition. That's good too.

[0043] Similarly, the second supply tube 160B transitions to the distribution tube 130, and the distribution tube 130 may be an integrated continuum. Alternatively, the second supply tube 160B is divided The distribution tube 130 may be a separate component, and the two may be joined / connected to form the second The second filling composition is supplied from the reservoir / container 150B through the second supply tube 160B. To form a continuous path for the distribution tube, via the second supply tube 160B, B130, and ultimately within the first set of mold cavities or the second set of mold cavities At least one cavity within the tee (for example, the first center cavity 111A and and the second center cavity 111B, or 112A, 112B, 113A and 11 Continuous filling composition for a second filling composition that enters any off-center cavity such as 3B A path may be formed.

[0044] In certain embodiments, the system rotates the first and second rotary molds to fill the first assembly. The distribution of a first amount from the product and / or a second amount from the second filling composition is precisely timed. The system further includes a synchronization mechanism (not shown) configured to set a first amount The first filling composition and a second amount of the second filling composition are placed in the first set of mold cavities. and / or consecutive third in at least one cavity in the second set of mold cavities It is timely captured between film 120A and wedge 300, (for example, the first In the center cavity 111A and in the second center cavity 111B, or 112 One half cavity (inside off-center cavities such as A, 112B, 113A, or 113B) To form a capsule or a complete capsule, the first rotary encapsulation mold 100A The first mechanical distribution mechanism 1 rotates at least one of the second rotating encapsulation molds 100B. This may be useful for synchronizing with 40A and the second mechanical distribution mechanism 140B, as shown in Figure 1. In this embodiment, the first cavity 111A and the second cavity 111B are co-filled. , forming a complete capsule (i.e., both halves) at once.

[0045] Synchronization is not limited to maintaining the mechanical connection between the mechanical distribution mechanism and the rotary encapsulation mold. via mechanical means such as gears, or by tracking the position of the encapsulation mold, mechanical This is achieved by encoding devices that send signals to a distribution mechanism, or through a combination thereof. It is possible.

[0046] Figure 1 shows the first center cavity 111A and the second center cavity 111B. The diagram illustrates a single distribution tube 310 aligned with the above, but the disclosure also illustrates additional This also includes the presence of distribution tubes. Two-part encapsulation with two separate distribution tubes. One exemplary embodiment of a rotary mold system is shown in Figure 2, which is described in more detail below. In certain embodiments, additional distribution tubes are used in the encapsulation process described herein. It can also be incorporated into a rolling type system (for example, 3 distribution tubes, 4 distributions) You should understand tubes, etc.

[0047] Figure 2 shows a rotary mold apparatus according to an embodiment disclosed herein. The capsule system has a similar relationship to that described in Figure 1 (i.e., connection and / (or arrangement) including similar components (for example, a first rotary mold 100A, a second Rotary mold 100B, first set of mold cavities 110A, second set of mold cavities 11 0B, continuous first film 120A, continuous second film 120B, wedge 1 30, First reservoir / container 150A, Second reservoir / container 150B, First mechanical unit Distribution mechanism 140A, second mechanical distribution mechanism 140B, first supply tube 160A and Two supply tubes (160B).

[0048] Figure 2 shows two separate distribution tubes, the first distribution tube 170A and the second distribution tube The Tube 170B is integrated with the Wedge 300, and they are positioned laterally relative to each other (for example, parallel to each other). It differs from Figure 1 in that it introduces embodiments that are arranged (or adjacent to each other).

[0049] In the embodiment shown in Figure 2, the first distribution tube 170A is located within the wedge 300. Eccentrically positioned, the first set of mold cavities 110A within the rotating mold 100A It is aligned with the off-center cavity 112A. The center of wedge 300 in Figure 1. This is shown along the vertical axis Y. In this configuration, the first supply tube 160A and The first mechanical distribution mechanism 140A, connected to the first reservoir / container 150A, is the first A quantity of the first filling composition is supplied from the first reservoir / container 150A to the first supply tube 160A. It is distributed to the first distribution tube 170A via and finally to the first off-center cavity It is injected into 112A to form the first half-capsule (this is the first rotating mold and the second During the timely reverse rotation of the rotary mold, the second half from the second off-center cavity 112B It is configured to form a complete capsule together with the capsule.

[0050] Furthermore, in the embodiment shown in Figure 2, the second distribution tube 17 0B is integrated into the center of the wedge 300 (illustrated along the vertical axis Y). The second distribution tube 170B is the first set of molds of the first rotary encapsulation mold 100A. The first center cavity 111A within cavity 110A and the second rotating encapsulated gold Second center cavity 111B within second set of mold cavity 110B of mold 100B They are aligned to the first center cavity 111A and the second center cavity Tee 111B together forms the first pair 111 of the mold cavity.

[0051] In this configuration, the second reservoir / container 150B and the second supply tube 160B are connected. The connected second mechanical dispensing mechanism 140B dispenses a second amount of the second filling composition into the second reservoir. From container 150B through second supply tube 160B to second distribution tube 170B It is distributed to the first center cavity 111A and the second center cavity Inject into 111B to form a complete capsule.

[0052] Although not shown in Figure 2, in certain embodiments, the first distribution tube 170A is Centered within the edge 300, the first center cavity 111A and the second center - It may be aligned with cavity 111B, and the second distribution tube 170B is wet Eccentric within the 300, off-center cavity (for example, (second pair of cavities 11) (together form 2) the first off-center cavity 112A or the second off-center - Cavity 112B, or the third pair of cavities 113 (together forming the third pair) Off-center cavity 113A or fourth off-center cavity 113B) This includes any other off-center elements, regardless of whether they are labeled in Figure 2. -Also align with the cavity. In this scenario, the first distribution tube 170 A provides a first amount of the first composition to the first center cavity 111A and the second center - Configured to co-inject into cavity 111B, the second distribution tube 170B is the A second composition in an amount of 2 is placed in one of the off-center cavities where it is aligned. (For example, 112A, 112B, 113A, or 113B, or any other off) It is configured to be injected into the center cavity.

[0053] Similarly, although not shown in Figure 2, the first distribution tube 170A is inside the wedge 300. In embodiments where it is eccentrically positioned, it is adjacent to any off Center cavity (e.g., 112A, 112B, 113A, 113B, or any) It may be aligned with other off-center cavities. In this scenario, the first minute The container tube 170A is used to dispense a first amount of the first composition, which is then aligned and off. One of the center cavities (for example, 112A, 112B, 113A, or 1 It is configured to be injected into 13B (or any other off-center cavity).

[0054] In addition, in certain embodiments, both distribution tubes, 170A and 170B, are wet The components may be eccentrically positioned in wedge 300, and each distribution tube is close to wedge 300. Any off-center cavity (e.g., 112A, 112B, 113A, or 1 13B (or any other off-center cavity) may be aligned. In Nario, the first distribution tube 170A and the second distribution tube 170B are each, A first composition in a first amount and a second composition in a second amount are each given a specific distribution tube. One of the off-center cavities where the bu is aligned (e.g., 112A, 112B) Inject into 113A, 113B, or any other off-center cavity. It is configured in such a way.

[0055] When a specific distribution tube is centered within the wedge 300, two halves of one capsule (For example, the first center cavity 111A and the second center cavity 111B) Co-filling is performed by co-filling with the other. A specific distribution tube is unevenly distributed within the wedge 300. When carefully positioned, half of the capsule (for example, the first off-center cavity) (By filling 112A or the third off-center cavity 113A) The half-capsule, when the first and second rotating molds rotate in the reverse direction in the appropriate time, the second half-capsule (For example, the second off-center cavity 112B or the fourth off-center cavity Together with 113B), it forms a complete capsule. In the embodiment shown in the figure, the first sensor The center cavity 111A and the second center cavity 111B form one complete cup Forms a first pair of mold cavities 111 that are joined to the cell, and a first off-center cavity The first 112A and the second off-center cavity 112B are joined together in one complete capsule. A second pair of mold cavities 112 join together, forming a third off-center cavity 113 A and the fourth off-center cavity 113B are joined together in one complete capsule. Three pairs of mold cavities 113 are formed.

[0056] In the embodiment shown in Figure 2, the first supply tube 160A is connected to the first distribution tube 1 Alternatively, it may be changed to 70A and made into an integrated continuum of the first distribution tube 170A. The first supply tube 160A is a separate component from the first distribution tube 170A. It is also possible that the two are joined / connected, and the first reservoir / container 150A receives the first supply Through the supply tube 160A, to the first distribution tube 170A, and finally to the first The distribution tube 170A enters at least one of the cavities that it is aligned with. This may form a continuous pathway for the first filling composition.

[0057] Similarly, the second supply tube 160B transitions to the second distribution tube 170B, and the second The distribution tube 170B may be an integrated continuum. Alternatively, the second supply tube 160B may be a separate component from the second distribution tube 170B, and the two may be, The second reservoir / container 150B is connected to the second supply tube 160B. Through this, to the second distribution tube 170B, and finally to the second distribution tube 170 A second filling, in which B enters at least one of the cavities aligned with it. A continuous pathway for the composition may be formed.

[0058] In certain embodiments, the system shown in Figure 2 (similar to the system in Figure 1) is a first The distribution of a first amount from the filling composition and / or a second amount from the second filling composition, The rotation of the first and second rotary molds and a synchronization mechanism configured to precisely synchronize the timing (Figure (Further includes "cannot be shown").

[0059] Various mechanical distribution mechanisms can be used in the systems described herein. The type of mechanical dispensing mechanism may depend on the filling composition. In a particular embodiment, the first filling The composition and the second filling composition are independently gases, solid particle suspensions, liquids, or so These are the combinations.

[0060] In a particular embodiment, the first mechanical distribution mechanism 140A and the second mechanical distribution mechanism 14 0B is a pump. A suitable pump dispenses a desired first amount of the first filling composition and a second This amount is required to distribute the second filling composition into the mold cavity (or mold pocket). Various positive displacement pumps (positi) offer sufficient accuracy and precision to deliver large volumes. You can choose from (ve displacement pump). Other mechanical distribution mechanisms include capsules. The composition of the contents (e.g., the volume of the filling composition in each capsule) is precisely and accurately controlled. As long as they are configured in this way, they can be used in the systems disclosed herein. It is possible.

[0061] In a particular embodiment, the pump is suitable for dispensing any number of other filling composition types. A positive displacement design may also be used. In certain embodiments, the pump may have a plunger or piston It may include a style (for example, a filling composition distributed by a distribution mechanism, for example (When composed of solid particles with large particle size). A suitable distribution mechanism is needed for distribution. It can be modified to adapt to the filling composition. For example, a mechanical distribution mechanism. The inlet and outlet orifices (for example, otherwise trapping particles and allowing particles to accumulate) This can cause blockages by shifting or eliminating constrictions in the flow path. The pump may be modified (for example, the plunger at the maximum injection position) Ensure sufficient clearance from the pump head and / or plunger surface. The profile is formed in a way that facilitates the removal of particles between the pump head wall and the wall. This means things like, "You may revise it," and so on.

[0062] The aforementioned two-part rotary mold encapsulation system improves the uniformity of the content of the multiphase filling composition. This approach can be used to make the final composition more prone to phase separation. Therefore, it is useful when conventional processing becomes difficult. This disclosure relates to a method for improving the content uniformity of a multiphase-filled composition. Figure 3 shows the method. Method 300 is shown below.

[0063] In a particular embodiment, method 300 prepares a first filling composition in block 310. Method 300 includes preparing a second filling composition in block 320. The following further includes: In certain embodiments, the first filling composition is a pharmaceutically acceptable excipient. (For example, medium-chain triglycerides) The second filling composition contains an active pharmaceutical ingredient (API) It contains (either alone or with additional pharmaceutically acceptable excipients).

[0064] In a particular embodiment, method 300 involves a first set of mold cabinets in block 330. On a first rotary encapsulation mold (e.g., 100A) equipped with a tee (e.g., 110A) , further comprising forming a continuous first film (e.g., 120A). In the application form, method 300 involves a second set of mold cavities (for example) in block 340. Then, on a second rotary encapsulation mold (e.g., 100B) equipped with 110B, The process further includes forming a second film (e.g., 120B).

[0065] In a particular embodiment, method 300 includes a first mechanical distribution mechanism in block 350. (For example, 140a) is used, (filled into the first reservoir / container, for example, 150A) A first amount of the first filling composition is supplied via a first supply tube (e.g., 160A). This further includes mechanically distributing the fluid into a distribution tube (e.g., 130 or 170A). The distribution tube (e.g., 130 or 170A) is related to the rotary mold encapsulation system. And, according to any of the embodiments described above, it is integrated into the wedge (e.g., 300) .

[0066] In a particular embodiment, method 300 includes a second mechanical distribution mechanism in block 360. Using (for example, 170B), a second amount of the second filling composition is supplied to the second supply tube. For example, mechanically through 160B) to a distribution tube (e.g., 130 or 170B) It further includes distribution.

[0067] Mechanical distribution can be done, for example, by using a distribution plunger or an actuator (for example) Batch By using a pump configuration, a pump configuration of continuous or semi-continuous type, etc., This can be done through various mechanical distribution mechanisms.

[0068] After block 360, method 300 varies depending on the design of the rotary mold encapsulation system. It can follow a route such as the first supply tube and the second supply tube co-distributing Method 3 uses a rotary mold encapsulation system that converges within a tube (as shown in Figure 1). In block 370, 00 is distributed via a co-distribution tube (e.g., 130) to the first A first filling composition in a certain amount and a second filling composition in a second amount are placed in at least one cavity This further includes co-injection into the wedge. For example, the co-distribution tube is eccentrically positioned within the wedge. If so, the first amount of the first filling composition and the second amount of the second filling composition are The distribution tube is aligned with the off-center cavity (e.g., 112 Co-injected in A or 112B or 113A or 113B). In another example, co The dispensing tube is located in the center of the wedge and dispenses a first amount of the first filling composition and a second amount The second filling composition is the first center cavity (e.g., 111A) and the second center - Simultaneously and / or co-injected into the cavity (e.g., 111B).

[0069] (As shown in Figure 2) It has two separate distribution tubes that are eccentrically offset from each other laterally. Using a rolling die encapsulation system, method 300 is described in blocks 380 and 390. It further includes two separate injection routes.

[0070] In block 380, method 300 provides a first amount of the first filling composition to a first distribution The tube includes injecting into at least one cavity that is aligned with it. For example, if the first distribution tube (e.g., 170A) is inside the wedge (e.g., 300) When centered, the first amount of the first filling composition is in the first center cavity 111A It is injected into the first part and into the second center cavity 111B. In another example, the first part When the distribution tube is eccentrically positioned within the wedge, the first amount of the first filling composition However, the first distribution tube is aligned with one off-center cavity It is injected into (for example, 112A or 112B or 113A or 113B).

[0071] In block 390, method 300 provides a second amount of the second filling composition to the second distribution The tube includes injecting into at least one cavity that is aligned with it. For example, when the second distribution tube is in the center within the wedge, the second filling of the second amount The composition is located in the first center cavity 111A and the second center cavity 111B It is injected into the inside as well. In another example, a second distribution tube (e.g., 170B) is a wedge When arranged eccentrically within (for example, 300), the second amount of the second filler composition is A second distribution tube is aligned with it, in one off-center cavity (e.g.) For example, it is injected into 112A or 112B or 113A or 113B.

[0072] In a particular embodiment, a first amount of the first filling composition is injected by block 380. This involves injecting a second amount of the second filling composition by block 390. They will be performed sequentially or simultaneously.

[0073] As used herein, the term “sequentially” means that a first amount of the first filling composition is first This means that it is injected into, and then a second amount of the second filling composition is administered second. The subsequent injection of the second filling composition may occur during the injection of the first filling composition or the first filling composition It can be started after the injection of the substance is complete.

[0074] As used herein, the term “simultaneously” means that a first amount of the first filling composition is the This means that it is injected at the time of injection of the second filling composition in an amount of 2. In other words, both The injection of the filling composition begins simultaneously, regardless of whether it is completed at the same time.

[0075] As used herein, the term “joint” means a first filling composition in a first amount. and a second amount of the second filling composition, depending on whether the compositions are injected sequentially or simultaneously. Regardless, the same internal structure (for example, the first center cavity 111A and the second center cavity) This means that it is injected into the interior formed by the cavity 111B. The first amount of One filling composition is placed in one half-capsule (e.g., off-capsule such as 112A or 113A). A second amount of the second filling composition is injected into the turf cavity, and into the second half-capsule (for example) Then, the first half-capsule (each corresponding pair, such as 112B or 113B) is injected. In such cases, the term "co-injection" does not apply.

[0076] In a particular embodiment, method 300 performs a first rotational encapsulation in block 392. The mold (e.g., 100A) and the second rotary encapsulation mold (e.g., 100B) are in opposite directions. Rotate in the direction of the first rotating encapsulation mold (e.g., 100A) and the second rotating capsule A continuous first film (e.g., 120A) and a continuous mold (e.g., 100A) By bringing it into contact with a subsequent second film (e.g., 120B), a closed capsule is formed. A continuous first film (e.g., 120A) and a continuous second film (e.g., 120A) A first amount of the first filling composition and a second amount of the second filling are contained within a closed capsule between B and The further includes capturing the filler composition.

[0077] In a particular embodiment, block 350 mechanically dispenses a first amount of the first filling composition. Distributing involves mechanically distributing a second amount of the second filling composition by block 360. This involves the first rotary encapsulation mold and the second rotary encapsulation mold by block 392. It is synchronized with the rotation of the capsule mold. Furthermore, the first volume by block 370 The co-injection of the first filling composition and a second amount of the second filling composition is performed by the mechanical method of each filling composition. It can also be synchronized with the rotation of the distribution and rotational encapsulation mold. Similarly, block 38 Injecting a first amount of the first filling composition by 0, and second by block 390 Injecting the second filling composition in a certain amount means mechanical dispensing and rotating capping of each filling composition. It can also be synchronized with the rotation of the cell mold. Such synchronization is used for the first filling of a first quantity. The composition and a second amount of the second filling composition can be captured in a timely manner within a closed capsule. Make it Noh.

[0078] In a particular embodiment, method 300 uses block 395 to form a continuous first film A first pair of edges (for example, 120A) and a continuous second film (for example, 120B) The method further includes fusing the second pair of edges of the closed capsule with the second pair to hermetically seal the closed capsule. For example, the first center cavity 111A and the second center cavity 111B are Together, the first pair of edges ll1Atop and lllBtop, and the second pair of edges 111 By hermetically sealing Abottom and 111Bbottom, one closing The first pair of cavities can form a capsule. Similarly, together the second pair The pair of cavities are the first off-center cavity 112A and the second off-center Turk cavities 112B are the edges and bottom pairs of their corresponding top pairs. By hermetically sealing the edges of the ottom pair, another closed capsule can be formed. Yes, it is possible. Similarly, a third off-center cavity 1 can be formed together with the third pair of cavities. 13A and the fourth off-center cavity 113B are the edges of their corresponding top pair And by hermetically sealing the edges of the bottom pair, yet another closed capsule is formed. This is possible. When the first and second rotating molds are rotating in the opposite direction, any other pair of off-center The cavities come together, sealing the edges of the corresponding bottom pair and top pair of those pairs. By stopping the process, a closed capsule that can be hermetically sealed may be formed.

[0079] Blocks 350, 360, 370 (or 380-390), 392 of method 300 Step 395 may be repeated to form multiple closed capsules. Specific Embodiments Then, the first filling composition prepared in block 310 and / or prepared in block 320 The second filling composition and / or the continuous first f formed in block 330 Fully utilize the continuous second film formed by the film and / or block 340. When doing so, one of blocks 310, 320, 330, and / or 340 This process is repeated multiple times, and if necessary, additional first filling compositions are prepared and / or added. Prepare an additional second filling composition and / or form more continuous first films. And / or more continuous second films may be formed.

[0080] When forming multiple closed capsules having a multiphase filling composition, use Method 300 This minimizes variations in the multiphase filling composition between multiple closed capsules. In the embodiments, a plurality of closed-circuits prepared by the methods described herein (e.g., Method 300) are used. There is virtually no variation in the multiphase filling composition between the capsules. The term "substantially stable" means that each capsule has a substantially uniform composition in each phase. This means that it has. For example, a multiphase filling composition in one capsule is made using the same process. Another capsule prepared by [company name] has a weight of up to approximately 10% of each phase, and up to approximately 8%. It can fluctuate by up to approximately 5%, up to approximately 2%, or up to approximately 1%.

[0081] The “first” component in the systems and methods described herein (for example, the first (1 distribution tube, 1 supply tube, 1 container, 1 distribution mechanism, etc.), also is a second component (e.g., a second distribution tube, a second supply tube, a second container, the Any reference to the distribution mechanism (and others) is solely for the purpose of distinguishing the various components. This does not imply the order in which they are used, operated, or assembled. Specific Embodiments So, the first component is used first, and the second component is used second. This is possible. In certain embodiments, the "second" component is used first, and the "first" component is used first. The element can be used secondly. In certain embodiments, the "first" component and The "second" component can be used simultaneously.

[0082] The methods described herein (for example, method 300) involve dividing the formulation into two parts. This minimizes the problem of phase segregation in multiphase systems. One part (for example, the first phase) The filling composition may represent the main phase of the formulation. The second part (for example, the second filling composition) ) may represent the small phase of the formulation. The first and second parts of the formulation are weighed individually ( (or distributed and / or supplied) and proceed to the wedge, pass through the wedge, separate via an orifice (i.e., a separate distribution tube) or a common orifice (i.e., The contents are then injected into the cavity (which will eventually form a capsule) via a codistribution tube. It will be done.

[0083] In certain embodiments, the second part of the formulation has properties that minimize the segregation problem (for example, It is formulated to have a rheology. This controls the solid content ratio of the second formulation part. This can be done by doing so. This also allows for the desired rheology (as shown in Example 2). This can also be done by adding excipients designed to provide the second of the formulation. The composition of the part can be highly concentrated, so it is used to modify the rheology. The total amount of excipients added is, otherwise, in order to achieve the desired rheology (Examples) This will be used in formulations manufactured by conventional one-part methods (as shown in 2). The total amount will be less than the total amount of excipients.

[0084] The two-part formulation method described herein minimizes the impact on the composition of the formulation while encapsulating the capsule. This can facilitate the ability to improve the homogeneity of APIs within the system. This method, for example, When a small amount of low-concentration phase is present, when there is a large density difference between the phases, the separation rate of the small amount of phase When the viscosity is high (for example, large particle size), various flexes occur in low-viscosity multiphase systems. It is useful in O. The method described herein is useful in the case of phase segregation observed when viscosity increases. Since the amount is expected to decrease (though this is not limited to this case), its applicability to high-viscosity systems is low. There is a possibility that it will be decided.

[0085] For example, one application of a two-part rotary mold encapsulation system is to process low-viscosity multiphase formulations into first This involves dividing the first filling composition into a second filling composition, in this case the first filling composition The first has a viscosity, and the second filler composition has a viscosity. The viscosity of the first filling composition provides a uniform API distribution in the second filling composition. The viscosity may be designed to be higher than the first viscosity of the product. In this application, the first filling composition of the first amount To precisely and accurately incorporate a substance and a second quantity of a second filling composition into a single capsule. This makes it possible to achieve a final low-viscosity multiphase formulation with precise and accurate amounts for each phase. .

[0086] The methods described herein otherwise require a single mechanical distribution mechanism (e.g., a pump). To manufacture capsules having multiple phases that are difficult or impossible to encapsulate. This makes it possible. In part, there are multiple distribution mechanisms, and each distribution mechanism This is achieved by processing separate phases. The methods and systems described herein Furthermore, it enables the achievement of a uniform, accurate, and precise filling composition within each capsule.

[0087] The concept of distributing multiphase liquid formulations in relation to rotary mold processes involves liquids containing liquids, and liquids containing liquids. It can be extended to include multiphase systems composed of gases, liquids, and solids, and so on. Without it, it is difficult to maintain homogeneity during the conventional encapsulation process, each phase This can enable precise distribution. In a particular embodiment, the first filling composition The second filling composition may independently be a gas, a suspension of solid particles, a liquid, or a combination thereof. Selected from a combination. In certain embodiments, even if one phase (e.g., the main phase) is a liquid phase. Often, the second phase (for example, a small amount phase) may consist of solid inclusions.

[0088] In an embodiment in which one of the phases is composed of solid particles, the solid particles range from submicron to... The size range can be limited to what the pump and wedge piping can handle. Examples of solid particles that can be encapsulated by the method described herein are, but are not limited to, However, beads, tablets, capsules, caplets, pellets, granules, and combinations thereof are not included. A combination of these can be used. The solid particles can be selected from circular, elliptical, oblong, and spherical shapes. It can have.

[0089] In a particular embodiment in which one of the phases consists of solid particles, encapsulation is very small Large-sized discrete particles within a capsule from a suspension containing solid particles of a certain particle size This can be transitioned to encapsulation of particles or beads. In contrast to conventional one-part suspensions, particles or beads are discretely injected into the capsule. It is possible to separate the particles as they move from smaller to larger sizes. Due to the tendency of particles to increase in velocity, such formulations can be handled without clogging. Grains that are vulnerable due to a decrease in pump capacity and / or, in some cases, are fragile. The challenge of minimizing damage to the offspring leads to the task of homogenizing the particles. This becomes more difficult. The systems and methods described herein address clogging and / Alternatively, to minimize damage to the particles, a mechanical distribution mechanism (e.g., a pump), a wedge By providing flexibility in modifying the piping, these challenges can be addressed. It is possible.

[0090] Another application of the method described herein is when filling a multi-component formulation into a capsule, The amount of one component in a formulation can be compared to other components in the formulation with greater precision and accuracy. This is a situation where measurement is necessary. This application requires higher accuracy and precision. Mechanical distribution mechanisms for components (e.g., distribution pumps) offer greater accuracy and precision. You may choose from a pump that dispenses the components, while the remaining components are dispensed using a standard mechanical distribution mechanism (for example). It can be dispensed using a standard performance pump. In this application, the multi-component composition of the formulation The substance is a miscible component, an immiscible component, or a capsule, which becomes a single phase within the capsule through diffusion. It can be composed of partially miscible components that form a multiphase system within it.

[0091] Such applications are also used to titrate patients to obtain a specific response. It can also be suitable for efficiently manufacturing multiple doses of potent APIs (Example 3). (As shown in [image]). This means that one stock solution is a diluent, and the other stock solution is a highly concentrated API. This can be achieved by using two types of undiluted solutions, including the two added to each capsule. By adjusting the ratio of the amounts of the two stock solutions, a range of different capsule strengths can be prepared. Yes, it is possible. In other words, a first amount from the first filling composition (which is a diluent) and (concentrated A Adjusting the ratio of the second amount from the second filling composition (which is a PI solution) is the most important aspect of capsules. It is configured to adjust the dosage strength of the final filling composition. For example, between a first amount and a second amount. Increasing the ratio (i.e., the rate of increase of the diluent relative to the concentrated API solution) will result in the most... The dosage strength of the final filling composition decreases. Similarly, the ratio of the first amount to the second amount decreases. In other words, reducing the ratio of the diluent to the concentrated API solution, and the final filling of the capsule. The administration strength of the composition increases.

[0092] In certain embodiments, this disclosure relates to any of the methods described herein, and rotary molds The target is dosage forms prepared by any of the capsule formation systems. The dosage forms are shell combinations. It can be a capsule having a compound and a filling composition.

[0093] The shell of a capsule (for example, a soft gelatin capsule) is usually made of liquid, fluid, or paper. Plasticized gelatin used for encapsulating syrup or other filling compositions It can be formed from other functional polymer materials.

[0094] The outer shell of the capsule may have an immediate-release coating, protective coating, enteric coating, or slow-release coating. Delayed emission coatings, sustained emission coatings, barrier coatings, and combinations thereof Coated with one or more coatings, including but not limited to these. It may also be the case that one or more coatings on the outer shell of the capsule control the capsule It releases the active ingredients, protects the shell from degradation, or contains one or more active ingredients in the dosage form. It may be useful for delivering minutes. Alternatively, the addition of pectin or synthetic polymers may be used. By incorporating the drug into a capsule shell, the dissolution during ingestion can be slowed down, or it can be removed. This can be a target. One or more coatings on the outer shell of the softgel capsule Coating is not limited to these, but also includes pan coating and fluidized bed coating. It can be applied by any conventional technique, including tinging or spray coating. .

[0095] The capsule filling composition includes liquid filler, gas filler, semi-solid filler, multiphase filler, and Other materials may also be used. The multiphase packing material (if present) may be layered, for example, within the softgel capsule. It may also contain different phases arranged in a row. Each layered phase may incorporate one or more active ingredients. It is possible.

[0096] The filling composition also contains dispersants, surfactants, plasticizers, antioxidants, flavoring agents, emulsions, and preservatives. Capsule encapsulation of agents, embrittlement inhibitors, colorants, dyes and pigments, and disintegrants. It may contain excipients known in the technical field.

[0097] Active ingredients suitable for encapsulation in the dosage forms described herein include APIs, nutritional supplements. Substances used in food, therapeutic or cosmetic purposes (e.g., non-pharmacological effects), functional excipients, Alternatively, control the release of the active ingredient into the gastrointestinal tract or absorption site, or by other means. It may contain a combination of active ingredients and functional excipients that have an effect. Different phases are capsules When present within (for example, solid inclusions and liquid or semi-solid fillers), each phase is It may contain one or more active ingredients. The active ingredients in different phases are the same. However, it's okay if they're different.

[0098] The present invention intends to use any active ingredient known in the art. Selecting a specific combination of drugs is well within the scope of the knowledge of those skilled in the art. In this embodiment, the active ingredient may be an API, a nutritional supplement, or any other active ingredient, although it is not limited to these. Nutritional supplements, therapeutic substances, beauty ingredients such as glycine and DHA (e.g., non-pharmacological agents) Examples include (for use) and functional excipients.

[0099] Appropriate APIs include, but are not limited to, analgesics, anti-inflammatory drugs, anti-helmintic drugs, and anti-inflammatory drugs. Antiarrhythmics, anti-asthmatics, antibacterials, antivirals, anticoagulants, antidementia agents, antidepressants, antidiabetics Disease medications, antiepileptic drugs, antifungal drugs, antigout drugs, antihypertensive drugs, antimalarial drugs, antimigraine drugs, antimuscle drugs Quince preparations, anti-cancer agents, immunosuppressants, antiparasitic agents, antipyretics, antithyroid agents, cough suppressants, anti-anxiety agents. Drugs, sedatives, hypnotics, nerve relaxants, neuroprotective drugs, beta-blockers, cardiac inotropes, cell adhesion inhibitors corticosteroids, cytokine receptor activators, diuretics, antiparkinson's disease drugs, Gastrointestinal drugs, histamine H receptor antagonists, HMG-CoA reductase inhibitors, keratolytic agents, lipids Regulatory agents, muscle relaxants, nitrates and other anti-anginal drugs, non-steroidal anti-asthmatic drugs, nutritional supplements, opioids Examples include iodide analgesics, sex hormones, stimulants, and erectile dysfunction medications.

[0100] Appropriate dietary supplements include, but are not limited to, 5-hydroxytryptophan, and Cetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutaric acid, bee products, betaine hydrochloride, bovine Cartilage, caffeine, cetyl myristic acid, charcoal, chitosan, choline, chondroitin sulfate, Coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 81) 2) Dimethylaminoethanol, fumaric acid, germanium sedative, glandular product Product) Glucosamine HCl, Glucosamine Sulfate, Hydroxymethyl Butyrate, Immunity Globulin, lactic acid, L-carnitine, liver products, malic acid, maltose-anhydrous, mannault (d-mannose), methylsulfonylmethane, phytosterol, picolinic acid, pill Bic acid, red yeast extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobro Examples include mine, vanadyl sulfate, and yeast.

[0101] Appropriate nutritional supplements include vitamins, minerals, fiber, fatty acids, amino acids, and herbal supplements. Prements, or combinations thereof, can be listed.

[0102] While not limited to those, ascorbic acid (vitamin C) is also a suitable vitamin. Vitamin B group, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol Mineral ascorates, mixed tocopherols, niacin (vitamin B3), orotin Acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyride hydrochloride Xyn (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B2) Vitamin B1, tocotrienol, vitamin A, vitamin D, vitamin E, vitamin F, Examples include vitamin K, vitamin oil, and fat-soluble vitamins.

[0103] Suitable herbal supplements include, but are not limited to, arnica and bilbe. Lee, black cohosh, cat's claw, chamomile, echinacea (echinacea), evening primrose oil, fenugreek, flaxseed, feverfew, ginseng Meat, ginger root, ginkgo, carrot, goldenrod, hawthorn, ka Bacaba, licorice, milk thistle, plantain, rauowolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, valerian Examples include valerian. Minerals include, but are not limited to, boron and calcium. Um, chelated minerals, chlorides, chromium, coated minerals, cobalt, copper, dolomite, yo Iodine, iron, magnesium, manganese, mineral premix, mineral product, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvic acid, zinc and other minerals can be mentioned.

[0104] The present invention can reduce problems such as time and cost associated with the adjusted administration of multi-component formulations and / or the formulation of multi-phase formulations. The methods and systems described herein provide the ability to adjust the administration of capsule filling compositions in-situ. In this way, an entire batch of one capsule filling composition dosage can be manufactured, and subsequently, various dosages can be manufactured in a single batch as needed without manufacturing another complete batch of another capsule filling composition dosage. Further, the methods and systems described herein provide the ability to control the content of multi-phase formulations in a safe and effective manner to ensure content uniformity across multiple capsules. The present invention can reduce the need to modify the rheology of excipients to achieve content uniformity across multiple capsules. Therefore, it is possible to use smaller and less expensive dosage forms.

Examples

[0105] To assist in understanding the present invention, the following predictive examples are described, but should not be construed as specifically limiting the invention described and claimed herein. Such variations of the present invention, including all equivalent substitutions, whether currently known or later developed, within the scope of the skilled person's vision, and minor changes in formulations or excipient designs fall within the scope of the present invention incorporated herein. It is considered to be.

[0106] [Example 1] Two-part rotary mold encapsulation to minimize phase segregation problems Comparative Example 1A 10 mg of medium-chain triglyceride (MCT) oil in 990 mg of medium-chain triglyceride (MCT) oil, with a filling volume of 1 g. A formulation containing an active pharmaceutical ingredient (API) is prepared. The viscosity of this composition is such that segregation is prevented. It is too low for the eye and would likely result in capsules containing a high and variable API content.

[0107] Invention Example 1B According to the process described herein, one way to prevent phase segregation in this formulation is The method involves dividing the formulation into two formulation parts as follows: a) Part 1 is b) Part 2 contains 975 mg of MCT, and 10 mg of API in 15 mg of MCT. It includes. Divided, the solid material load in Part 2 is 40%, which is sufficient to prevent segregation of the API. A fluid paste with a certain viscosity is obtained as a result. Two formulations are applied to the wedge. By weighing each part individually, it can be treated as a diluted one-part suspension. Accurate API dosage is more easily achieved than in other cases.

[0108] [Example 2] Two-part rotation to minimize phase segregation problems, involving the use of low-rheological-modifying excipients. Mold encapsulation Comparative example 2A For a total of 1000 mg, 10 mg of API, 740 mg of MCT oil, and the formulation A formulation containing 250 mg of excipients to adjust the rheology. The amount of excipients is per part. Excipients required to adjust the rheology of a formulation in order to obtain a formulation suitable for a filler. The concentration of the agent is selected assuming it is 25% by weight based on the total weight of the formulation.

[0109] Inventive Example 2B In the comparison, a two-part metering approach according to the process described herein is used where the part 2 portion can be concentrated and will require much less rheology modifying excipient. For comparison, assume the amount of rheology modifying excipient remains the same as in Comparative Example 2A (about 250:740).

[0110] Here, the two formulation parts are: a) Part 1 - 760 mg MCT, and b) Part 2 - 10 mg API, 170 mg MCT, and 60 mg rheology modifying excipient.

[0111] This results in a reduction in the amount of rheology modifying excipient per capsule from 250 mg in the single-part system of Comparative Example 2A to 60 mg in the two-part system of Inventive Example 2B.

[0112] [Example 3] Two-part rotary die encapsulation for adjusting the API dose in a capsule Products that require a 10 strength of a high-potency API can be formulated as a two-part formulation comprising a two-part formulation system where a) Part 1 is the high-concentration API part and b) Part 2 is the dilution part.

[0113] Using this approach, only two formulation parts are prepared as shown in Table 1 below, and during encapsulation, the ratio of the two formulation parts is adjusted to adjust the API dose in the capsule. This reduces the need to manufacture a unique batch for each API dose, as is done with the conventional single-part injection approach. ​​​

[0114] [Table 1]

[0115] [Example 4] Two-part rotary mold encapsulation to form gas / liquid / solid multiphase capsules The first filling composition comprises a concentrated solution of the API in alcohol.

[0116] The second filling composition contains nitrogen or air.

[0117] A first amount of the first filling composition (a concentrated solution of API in alcohol) (a gelatin chain) Gelatin (formed from a continuous first film and a continuous second film of gelatin) It is combined with a second amount of a second filler composition (nitrogen or air) in the shell composition. When dried, the alcohol passes through the shell and evaporates, leaving the API and nitrogen inside the capsule. The volume of alcohol / API is small compared to the total volume of nitrogen in the capsule, so The capsule does not disintegrate due to the loss of volume of alcohol.

[0118] For the sake of simplicity, embodiments of the methods of this disclosure are described as a series of actions. It is stated. However, the actions under this disclosure may occur in various orders and / or simultaneously. , as well as other actions not presented or described herein, which may result Furthermore, in order to implement this method in accordance with the disclosed subject matter, all illustrated actions This is not always necessary. In addition, those skilled in the art will see that the method can alternatively involve a state diagram or events. They will understand and recognize that these can be represented as a series of interconnected states.

[0119] In the above description, in order to provide a complete understanding of the present invention, specific materials, dimensions, and processes are not mentioned. Numerous specific details such as parameters are described. Specific features, structure, materials, or The characteristics can be combined in any suitable way in one or more embodiments. The words "example" or "exemplary" in this specification mean example, instance, or illustration. Used to fulfill the role of [specific function]. Described herein as "examples" or "exemplary." Any embodiment or design is not necessarily preferable to any other embodiment or design. It should not be interpreted as, or as being advantageous. Rather, it should be interpreted as, “example” or “exemplary.” The use of the word is intended to represent the concept in a concrete way. When used, the term "or" is not an exclusive "or" but an inclusive "or". It is intended to mean that; that is, unless otherwise specified or evident from the context. Otherwise, "X contains either A or B" means any of the naturally inclusive permutations. This is intended to mean that X includes A, X includes B, or X includes both A and B. If a person is included, the statement "X includes A or B" is satisfied in any of the aforementioned cases. Throughout this specification, the terms "embodiment," "specific embodiment," or "one embodiment" are used to describe a particular embodiment. The references contain specific features, structures, or characteristics described in relation to their embodiments, with respect to less than one. This means that both are included in one embodiment. Therefore, in various places in this specification The appearance of the words "embodiment," "specific embodiment," or "one embodiment" in this context does not necessarily mean Not all of these refer to the same embodiment.

[0120] The present invention has been described with reference to specific and exemplary embodiments thereof. The writings and drawings in this specification should be considered illustrative, not restrictive. In addition to those shown and described herein, various modifications of the present invention will be apparent to those skilled in the art. It is intended to fall within the scope of the attached claims. [Explanation of symbols]

[0121] 100A First Rotary Encapsulation Mold 100B Second Rotary Encapsulation Mold 110A First set of mold cavities 110B Second set of mold cavities 111A First Center Cavity 111B Second Center Cavity ll1Atop, lllBtop upper pair of edges 111Abottom, 111Bbottom: Edges of the bottom pair 112A First off-center cavity 112B Second off-center cavity 113A Third off-center cavity 113B Fourth off-center cavity 120A First film 120B Second film 300 Wedge 130 Co-distribution tubes 140A First Mechanical Distribution Mechanism 140B Second Mechanical Distribution Mechanism 150A First reservoir / container 150B Second reservoir / container 160A First supply tube 160B Second supply tube 170A First distribution tube 170B Second distribution tube

Claims

1. A first rotary encapsulating mold comprising a first set of mold cavities, A continuous first film on the first rotating encapsulation mold, A second rotary encapsulating mold having a second set of mold cavities, A continuous second film on the second rotating encapsulation mold, A wedged between the first rotary encapsulation mold and the second rotary encapsulation mold And, Integrated with the wedge, within the mold cavity of the first set or the second set Aligned to at least one cavity within the mold cavity, 1 or A distribution tube comprising a first filling composition and a second filling composition, the at least one of the above. One or more dispensing tubes configured to inject into the cavity, Distributing one or more of the first filling composition in a first amount via the first supply tube A first mechanical distribution mechanism for distributing into tubes, A second amount of the second filling composition is distributed via the second supply tube to the one or more distribution tubes. A second mechanical distribution mechanism for distributing into the tubes, A system equipped with these features.

2. A first amount of the first filling composition and a second amount of the second filling composition are continuous At least one of the first film or the continuous second film and the Between the edge, in the first set of mold cavities or the second set of mold cavities The first rotating capsule is to be captured in a timely manner within at least one cavity inside. The rotation of at least one of the encapsulation mold and the second rotary encapsulation mold is controlled by the first machine A mechanical distribution mechanism and at least one of the second mechanical distribution mechanism for synchronization The system according to claim 1, further comprising a periodic mechanism.

3. A first distribution tube and a second distribution tube separate from the first distribution tube The first distribution tube is provided to be offset laterally from the second distribution tube. The first supply tube is separate from or integrated with the first distribution tube. It is a continuum, and the second supply tube is a separate, and also a second distribution tube. The system according to claim 1 or 2, wherein is an integral continuum.

4. The first distribution tube is eccentrically positioned within the wedge, and the first In the first set of mold cavities within the rotary encapsulating mold, or the second rotary encapsulating mold The first off-center cavity and position within the second set of mold cavities in the cellular mold. The first dispensing tube is fitted together and dispenses the first amount of the first filling composition. The method according to claim 3, configured to be injected into the first off-center cavity. system.

5. The second distribution tube is positioned in the center of the wedge, and the first rotation The first center cavity in the first set of mold cavities within the encapsulating mold, and The second center cap in the second set of mold cavities in the second rotating encapsulating mold. Aligned with the bitty, the first distribution tube distributes the first amount of the first The filling composition is co-injected into the first center cavity and the second center cavity. It is configured to insert the first center cavity and the second center cavity A bitie is a pair of mold cavities that together form a complete capsule, as described in claim 4. The system.

6. The second distribution tube is eccentrically positioned within the wedge, and the first In the first set of mold cavities, which are different from the off-center cavities, or the It is aligned with the second off-center cavity within the two sets of mold cavities. The second distribution tube distributes the second amount of the second filling composition to the second off-center The system according to claim 4, configured to be injected into a turf cavity.

7. The system includes a co-distribution tube, and the first supply tube and the second supply tube are connected to the co-distribution tube. The system according to claim 1 or 2, wherein the distribution tube converges.

8. The co-distribution tube is eccentrically arranged within the wedge, and the first Off-center cavity within the first set of mold cavities or within the second set of mold cavities The co-distribution tube is aligned with the first amount of the first filling composition Co-distribute the material and the second amount of the second filling composition into the off-center cavity. The system according to claim 7, configured as described above.

9. The co-distribution tube is positioned in the center of the wedge and the first rotational cable The first center cavity in the first set of mold cavities within the capsule mold, and The second center cavity in the second set of mold cavities within the second rotating encapsulating mold Aligned to the tee, the co-distribution tube is the first amount of the first filling The composition and the second amount of the second filling composition are placed in the first center cavity and the front The first center is configured to be co-distributed to the second center cavity, and the first center - The cavity and the aforementioned second center cavity are configured to form a complete capsule. The system according to claim 7, for forming a pair of mold cavities together.

10. At least one of the first mechanical distribution mechanism and the second mechanical distribution mechanism A pump, the system according to any one of claims 1 to 9.

11. The first and second filling compositions are, independently, gases and solid particle suspensions. A liquid, a combination thereof, according to any one of claims 1 to 10. Tem.

12. A method for improving the content uniformity of a multiphase packed composition, The steps include preparing a first filling composition, The steps include preparing a second filling composition containing an active pharmaceutical ingredient (API), A continuous first fil The steps of forming a film, A second continuous second fill on a second rotary encapsulating mold with a second set of mold cavities The steps of forming a film, Using a first mechanical dispensing mechanism, a first amount of the first filling composition is dispensed through a first supply tube. A step of mechanically distributing to a first distribution tube via a tube, wherein the first distribution The tube is positioned between the first rotary encapsulation mold and the second rotary encapsulation mold. It is integrated with the placed wedge and within the mold cavity of the first set or Steps aligned with at least one cavity in the second set of mold cavities P and, Using a second mechanical distribution mechanism, a second amount of the second filling composition is dispensed through a second supply tube. A step of mechanically distributing to a second distribution tube via a tube, wherein the second distribution The tube is the same as the first distribution tube, or the first distribution tube and These are separate steps, The first rotary encapsulation mold and the second rotary encapsulation mold are rotated in opposite directions. Then, between the first rotary encapsulation mold and the second rotary encapsulation mold, the continuous The first film and the continuous second film are brought into contact to form a closed capsule. Then, the closed C between the continuous first film and the continuous second film The capsule contains the first amount of the first filling composition and the second amount of the second filling composition To capture an object, step and Methods that include...

13. The first pair of edges of the continuous first film and the edges of the continuous second film The step further includes fusing the second pair with the closed capsule to hermetically seal it. The method according to claim 12.

14. The first amount of the first filling composition and the second amount of the second filling composition are used in the process. The first amount of the first The mechanical distribution of the filling composition is the mechanical distribution of the second amount of the second filling composition. To distribute to, and to rotate the first encapsulation mold and the second encapsulation mold. The method according to claim 12 or 13, which is synchronized with the rotation.

15. The first supply tube is connected to the first distribution tube separately or integrally. The second supply tube is connected to the second distribution tube, either separately or integrally. The second distribution tube is connected, and the second distribution tube is separate from the first distribution tube. The distribution tube is eccentrically positioned laterally from the second distribution tube, claim 12. The method described in any one of items 14.

16. The first amount of the first filling composition is distributed through the first distribution tube. The first off-center key in the mold cavity of the first set or in the mold cavity of the second set The step further includes injecting into the cavity, wherein the first distribution tube is inside the wedge They are arranged eccentrically, and within the mold cavity of the first set or the second set The off-center cavity within the mold cavity is aligned with claim 15. Method of description.

17. The second amount of the second filling composition is distributed through the second dispensing tube to the first The first center cavity in the set of mold cavities and the second set of mold cavities The step further includes injecting into the second center cavity inside the second distribution tube The hub is located in the center of the wedge, and the first center cavity It is aligned with the second center cavity and the first center cavity The tee and the second center cavity are configured to together form a complete capsule. The method according to claim 16, wherein a pair of mold cavities are formed.

18. The second amount of the second filling composition is distributed through the second dispensing tube to the first Unlike the off-center cavity, within the first set of mold cavities or the second The step further includes injecting into a second off-center cavity within the mold cavity of the set. The second distribution tube is eccentrically positioned within the wedge, and The method according to claim 16, wherein the second off-center cavity is aligned with the method according to claim 16.

19. Injecting the first amount of the first filling composition, and the second amount of the second The injection of the filling composition is performed sequentially or simultaneously, as in claim 17 or 18. Methods used.

20. The first supply tube and the second supply tube converge into a co-distribution tube. The method according to any one of claims 12 to 14.

21. The co-distribution tube is eccentrically positioned within the wedge, and the first set Off-center cavity within the mold cavity of the first set of mold cavities or within the second set of mold cavities The method according to claim 20, which is aligned with the above.

22. The co-distribution tube is centrally located within the wedge and the first set of metals The first center cavity in the mold cavity and the second in the second set of mold cavities It is aligned with the center cavity, and the front of the first center cavity The second center cavity is configured to form a complete capsule together. The method according to claim 20, wherein the mold cavity is a pair.

23. Through the co-distribution tube, the first amount of the first filling composition and the second amount The claim further includes the step of co-injecting the second filling composition into a single cavity. The method described in any one of items 20 to 22.

24. At least one of the first mechanical distribution mechanism and the second mechanical distribution mechanism The method according to any one of claims 12 to 23, wherein the pump is...

25. The first and second filling compositions independently form a gas and a solid particle suspension. The method according to any one of claims 12 to 24, which is a liquid, a liquid, or a combination thereof. Law.

26. In order to ensure that there is substantially no variation in the multiphase-filled composition between multiple closed capsules, the multiple The claim further includes the step of forming a plurality of closed capsules having a phase-filled composition. The method described in any one of paragraphs 12 to 25.

27. A method for adjusting the dosage strength of a capsule-filled composition, The steps include preparing a first filling composition, The steps include preparing a second filling composition, A first rotating encapsulating mold having a first set of mold cavities, a continuous first f The steps of forming a film, A second rotating encapsulating mold having a second set of mold cavities, with a continuous second f The steps of forming a film, Using a first mechanical dispensing mechanism, a first amount of the first filling composition is dispensed through a first supply tube. A step of mechanically distributing to a first distribution tube via a tube, wherein the first distribution The tube is positioned between the first rotary encapsulation mold and the second rotary encapsulation mold. It is integrated with the placed wedge and within the mold cavity of the first set or Aligned with at least one cavity in the second set of mold cavities, Step and, Using a second mechanical distribution mechanism, a second amount of the second filling composition is dispensed through a second supply tube. A step of mechanically distributing to a second distribution tube via a tube, wherein the second distribution The tube is the same as the first distribution tube, or the first distribution tube and These are separate steps, The first rotary encapsulation mold and the second rotary encapsulation mold are rotated in opposite directions. Between the first rotary encapsulation mold and the second rotary encapsulation mold, the continuous The first film and the continuous second film are brought into contact to form a closed capsule. The closed cap between the continuous first film and the continuous second film The cell contains the first amount of the first filling composition and the second amount of the second filling composition. And to capture, step and Includes, The administration strength of the capsule filling composition is such that the amount of the first filling composition is equal to the amount of the first filling composition. A method determined by a second amount of the filling composition.

28. The first filling composition contains a diluent, and the second filling composition contains a concentrated active pharmaceutical ingredient ( The method according to claim 27, comprising an API solution.

29. To adjust the dosage strength of the filling composition, the first filling composition The claim further includes the step of adjusting the ratio of the amount to the second amount of the second filling composition. The method described in paragraph 27 or 28.

30. Increasing the ratio of the first amount to the second amount is the amount of the filling composition The method according to claim 29, which reduces the applied intensity.

31. Reducing the ratio of the first amount to the second amount is the amount of the filling composition The method according to claim 29, which increases the strength.

32. A first rotary encapsulating mold having a first set of mold cavities, A second rotary encapsulating mold having a second set of mold cavities, A U is placed between the first rotary encapsulation mold and the second rotary encapsulation mold. Edge and, It is integrated into the wedge and within the mold cavity of the first set and / or or aligned with at least one cavity in the second set of mold cavities , one or more dispensing tubes comprising a first filling composition and a second filling composition One or more dispensing units configured to be injected into the at least one cavity Tube and, A first amount of the first filling composition is supplied through the first supply tube to one or more of the above-mentioned components. A first mechanical distribution mechanism for distributing to distribution tubes, A second amount of the second filling composition is supplied through the second supply tube to one or more of the above-mentioned components. A second mechanical distribution mechanism for distributing to the distribution tubes, A system equipped with these features.

Images