Controlled release filling composition and capsule containing the same

Abstract

[Solution] The present invention provides a controlled-release fill composition for use in soft or hard capsules, a soft or hard capsule encapsulated with the controlled-release fill composition, and a method for producing soft gel capsules having the controlled-release fill composition encapsulated in a soft gel capsule shell. The controlled-release fill composition comprises an active pharmaceutical ingredient, polyethylene oxide having a number-average molecular weight of 0.05 M Daltons to 15 M Daltons, and at least one of water and a hydrophilic carrier having a number-average molecular weight of 200 Daltons to 5000 Daltons. In the controlled-release fill composition, the polyethylene oxide is present in an amount of at least 21.5% by weight, based on the total weight of the controlled-release fill composition, or the hydrophilic carrier is present in an amount of up to 65% by weight, based on the total weight of the controlled-release fill composition.

Description

Technical Field

[0001] The present disclosure relates to a controlled-release filling composition for encapsulation in a capsule, the filling composition incorporating different types and amounts of controlled-release materials (e.g., polyethylene oxide) to control or modify the drug release rate. The present disclosure also relates to capsules containing the controlled-release filling composition, as well as methods for manufacturing the capsules and the controlled-release filling composition.

Background Art

[0002] Capsules are a well-known dosage form, usually comprising a shell filled with a filling composition containing one or more active pharmaceutical ingredients or other excipients. Soft gelatin capsules (softgels) have long been used in the pharmaceutical industry as an important medical dosage form. A softgel capsule may refer to a solid capsule / shell surrounding a liquid or semi-solid internal filling composition having an active ingredient incorporated therein.

[0003] Compared to other medical dosage forms, softgel capsules offer advantages such as ease of swallowing, masking of taste / odor, enabling various administration routes, convenience of unit dosage, tamper resistance, a variety of colors, shapes and sizes, the ability to accommodate various active ingredients, use for immediate or delayed drug delivery, and potentially favorable effects on the bioavailability of the active ingredients incorporated therein.

[0004] In some instances, controlled-release softgel capsules are necessary to deliver drug substances over a long period (typically 8 to 24 hours).) Current controlled-release soft capsule products utilize waxy matrix formulations. The filling material must be kept at a high temperature during encapsulation in order to maintain a sufficiently low viscosity to facilitate encapsulation. High temperatures can affect heat-sensitive drug substances, and the high-temperature filling can have an adverse effect on the gelatin shell, potentially affecting one or both of the capsule's seal integrity and shape, particularly when the encapsulation temperature exceeds 35 - 40°C.

[0005] Polyethylene oxide (PEO) resins have been used in the development of pharmaceutical products as an alternative to waxy matrix formulations in release-controlled and abuse-inhibiting compositions. The use of polyethylene oxide resins avoids the need for high temperatures required for material preparation and encapsulation of waxy matrix materials, as PEO resins can be encapsulated at low temperatures of approximately 20-35°C.

[0006] For example, U.S. Patent No. 9,861,629 discloses a controlled-release oral dosage form of an abuse deterrent and a method for producing the same, partly employing PEO resin. However, attempts to control the release rate using PEO have increased the difficulty of the processing steps required to create the capsules in this patent, resulting in compositions that require the inclusion of flow enhancers such as glyceryl monolinoleate.

[0007] U.S. Patent No. 8,101,630 also discloses a dosage form of an abuse deterrent that provides an extended release of a pharmacopoeia. The dosage form of this disclosure includes a PEO resin for increasing the viscosity of the solution in situations where the dosage form is altered by crushing or dissolving. The dosage form of this disclosure also requires the inclusion of magnesium stearate to facilitate processing.

[0008] For many active pharmaceutical ingredients, controlled release of the drug from the capsule filling composition is desirable. Existing controlled-release filling compositions for softgel capsules present processing challenges, which are sometimes addressed by incorporating excipients to facilitate processing. Such excipients may be undesirable and may occupy volume in the filling composition that could otherwise be occupied by a larger dose of the active ingredient. Alternatively, such excipients can be completely eliminated, thereby allowing for the production of smaller capsules per unit dose that are easier to swallow.

[0009] Therefore, there is a need for a controlled-release capsule-filled composition that can be easily encapsulated while minimizing the use of excipients to facilitate processing. The following are prior art documents related to the invention of this application (including documents cited in the international phase after the international filing date and documents cited when the application entered the national phase in other countries): (Prior art document) (Patent Document) (Patent Document 1) U.S. Patent Application Publication No. 2020 / 0093749 Specification (Patent Document 2) U.S. Patent Application Publication No. 2007 / 0098783 (Patent Document 3) U.S. Patent Application Publication No. 2018 / 0055837 (Patent Document 4) U.S. Patent Application Publication No. 2018 / 0071221 (Patent Document 5) U.S. Patent Application Publication No. 2015 / 0366814 (Patent Document 6) U.S. Patent No. 6,753,009 (Patent Document 7) U.S. Patent No. 8,101,630 (Patent Document 8) U.S. Patent No. 8,333,989 (Patent Document 9) U.S. Patent No. 9,078,827 (Patent Document 10) U.S. Patent No. 9,492,444 (Patent Document 11) U.S. Patent No. 9,504,656 (Patent Document 12) U.S. Patent No. 9,861,629 (Patent Document 13) U.S. Patent Application Publication No. 2014 / 0227357 (Patent Document 14) U.S. Patent Application Publication No. 2015 / 0010622 (Patent Document 15) International Publication No. 2009 / 069139 (Patent Document 16) International Publication No. 2014 / 002015 (Patent Document 17) U.S. Patent No. 10,478,429 (Patent Document 18) International Publication No. 2020 / 068510 (Patent Document 19) International Publication No. 2007 / 131357 (Non-patent literature) (Non-Patent Literature 1) International Search Report and Written Opinion for corresponding International application no. PCT / US2021 / 054991; dated 2022-02-03 (12 pages) (Non-Patent Document 2) OH, Ching Mien, et al. "A Study on the Impact of Hydroxypropyl Methylcellulose on the Viscosity of PEG Melt Suspensions Using Surface Plots and Principal Component Analysis." AAPS PharmSciTech 16.2 (2015): 466-477. (Non-Patent Literature 3) Official Letter No. 16207, Notice of Opposition by PROCAPS SA for corresponding Colombian application no. NC2023 / 0005368; dated 2023-10-05 (16 pages) MACHINE TRANSLATION (Non-Patent Literature 4) Official Letter No. 16208, Notice of Opposition by LABORATORIOS LEGRAND SA for corresponding Colombian application no. NC2023 / 0005368; dated 2023-10-05 (30 pages) MACHINE TRANSLATION (Non-patent document 5) Search report for corresponding European application no. 21881089.3-1109; dated 2024-09-04 (8 pages) (Non-patent document 6) Office action for corresponding US application no. 18 / 248,415; dated 2025-06-12 (8 pages) (Non-Patent Document 7) Office action for corresponding Chinese application no. 202180070429.6; dated 2025-06-30 (21 pages). MACHINE TRANSLATION (Non-Patent Literature 8) Office action for corresponding Taiwanese application no. 11420745580; dated 2025-07-16 (16 pages). Machine Translation (Non-Patent Document 9) Vervaeck, Anouk, et al. "Prilling as manufacturing technique for multiparticulate lipid / PEG fixed-dose combinations." European Journal of Pharmaceutics and Biopharmaceutics 88.2 (2014): 472-482 (Non-Patent Document 10) Li, Hongtao, Robert J. Hardy, and Xiaochen Gu. "Effect of drug solubility on polymer hydration and drug dissolution from polyethylene oxide (PEO) matrix tablets." AAPS PharmSciTech 9.2 (2008): 437-443 (Non-Patent Document 11) Non-final office action for corresponding US application no. 18 / 248,415; dated 2025-08-26 (29 pages) (Non-patent document 12) Office action for corresponding Australian application no. 2021360905; dated 2025-08-23 (4 pages) (Non-patent document 13) Office action for corresponding New Zealand application no. 799086; dated 2026-06-09 (5 pages) (Non-Patent Document 14) Abd Mutalib, M., "Towards high performance perovskite solar cells: A review of morphological control and HTM development." (2018) Applied Materials Today, 13, 69-82. https:doi.org / 10.1016 / ja

Summary of the Invention

Means for Solving the Problems

[0010] In a first embodiment, the present disclosure relates to a controlled-release capsule filling composition comprising (i) an active pharmaceutical ingredient, (ii) polyethylene oxide having a number average molecular weight of 0.05 to 15 million daltons, and (iii) at least one of water or a hydrophilic carrier having a number average molecular weight of 200 daltons to 5000 daltons, and any of the following: (I) the polyethylene oxide is present in an amount of at least 21.5% by weight based on the total weight of the controlled-release capsule filling composition, or (II) the hydrophilic carrier is present in an amount of up to 65% by weight based on the total weight of the controlled-release capsule filling composition.

[0011] In the controlled-release capsule filling composition of each of the above embodiments, the polyethylene oxide may contain from about 1% to about 60% by weight of the controlled-release capsule filling composition based on the total weight of the controlled-release filling composition.

[0012] In the controlled-release capsule filling composition of each of the above embodiments, the polyethylene oxide may contain from 10% to 65% by weight of the controlled-release filling composition based on the total weight of the controlled-release filling composition.

[0013] In the controlled-release capsule filling composition of each of the above embodiments, water and / or the hydrophilic carrier may contain from about 30% to about 70% by weight based on the total weight of the controlled-release filling composition.

[0014] In the controlled-release capsule filling composition of each of the above embodiments, the number average molecular weight of the polyethylene oxide is from 900,000 to 7,000,000 daltons.

[0015] In the controlled-release capsule-filled compositions of each embodiment described above, the hydrophilic carrier may be present in an amount of 40 to 60 wt% of the total weight of the controlled-release-filled composition.

[0016] In the controlled-release capsule-filled compositions of each of the embodiments described above, the hydrophilic carrier may be selected from the group consisting of polyethylene glycol, polypropylene glycol, and other hydrophilic solvents.

[0017] In the controlled-release capsule filling compositions of each embodiment described above, polyethylene oxide may be present in an amount of 25 to 40% by weight of the filling composition, based on the total weight of the filling composition.

[0018] In one embodiment, the disclosure relates to a controlled-release capsule filling composition comprising (i) an active pharmaceutical ingredient that is less prone to abuse, (ii) polyethylene oxide, and (iii) water or a hydrophilic carrier.

[0019] In one embodiment, the disclosure relates to a controlled-release capsule filling composition comprising (i) an active pharmaceutical ingredient, (ii) polyethylene oxide, and (iii) water or a hydrophilic carrier, wherein the weight-to-weight ratio of (ii) to (iii) is in the range of approximately 10:1 to 1:3.

[0020] In another embodiment, the present invention comprises a capsule comprising (a) a soft gel capsule shell or a hard capsule shell, and (b) a controlled-release filling composition from any of the aforementioned embodiments encapsulated in the soft gel capsule shell or hard capsule shell.

[0021] In embodiments, the present invention comprises a capsule comprising (a) a soft gel gelatin capsule shell and (b) a controlled-release filling composition of any of the above embodiments encapsulated in the soft gel gelatin capsule shell.

[0022] In embodiments, the present invention comprises an annealing capsule comprising (a) a soft gel capsule shell or a hard capsule shell, and (b) a controlled-release filling composition from any of the above embodiments encapsulated in a soft gel gelatin capsule shell.

[0023] In the capsules of the above-described embodiment, less than 80% of the active pharmaceutical ingredient can be released after 0.5 hours in a fiber optical dissolution test using a USP apparatus II at 37°C and a paddle speed of 100 rpm in 500 ml of 0.1 N HCl or water.

[0024] In a further embodiment, the disclosure relates to a method for manufacturing capsules. This method is (a) A step of mixing a liquid filling composition, (i) Active pharmaceutical ingredients, (ii) Polyethylene oxide having a number-average molecular weight of approximately 0.05 M Dalton to approximately 15 M Dalton, (iii) Optionally, one or more additional release rate control polymers, and (iv) water or at least one hydrophilic carrier having a number average molecular weight of 200 daltons to 5000 daltons, Here, one of the following: (I) The polyethylene oxide is present in an amount of at least 21.5 wt% based on the total weight of the filling composition, or (II) The mixing step, wherein the hydrophilic carrier is present in an amount up to 65% by weight based on the total weight of the filling composition, b) To manufacture the capsule, a step of encapsulating the mixed liquid filling composition from step (a) into a capsule shell, and (c) The step of heating the capsule (which may be dried after encapsulation in a particular embodiment) at a temperature of about 40°C to about 80°C for a period of about 10 minutes to about 180 minutes to form a solid or semi-solid filling composition inside the capsule.

[0025] In a further embodiment, this disclosure relates to a method for manufacturing capsules. (a) A step of mixing a liquid filling composition, (i) Active pharmaceutical ingredients that are less likely to be misused, (ii) Polyethylene oxide and (iii) one or more additional release rate control polymers, and (iv) The mixing step comprising water or at least one hydrophilic carrier, (b) A step of encapsulating the mixed liquid filling composition in a capsule shell in order to manufacture the capsule, and (c) The step of heating the capsule (which may be dried after encapsulation in a particular embodiment) at a temperature of about 40°C to about 80°C for a period of about 10 minutes to about 180 minutes to form a solid or semi-solid filling composition inside the capsule.

[0026] In a further embodiment, the present disclosure relates to a method for manufacturing capsules. (a) A step of mixing a liquid filling composition, (i) Active pharmaceutical ingredients, (ii) Polyethylene oxide and (iii) Optionally one or more additional release rate control polymers, and (iv) comprising at least one water or hydrophilic carrier, Here, the weight-to-weight ratio of (ii) to (iv) is in the range of approximately 10:1 to 1:3, and the mixing process is as described above. (b) A step of encapsulating the mixed liquid filling composition in a capsule shell in order to manufacture the capsule, (c) The step of heating the capsule (which may be dried after encapsulation in a particular embodiment) at a temperature of about 40°C to about 80°C for a period of about 10 minutes to about 180 minutes to form a solid or semi-solid filling composition inside the capsule.

[0027] In a further embodiment, the disclosure relates to a method for producing soft gel gelatin capsules. The method is (a) A step of mixing a liquid filling composition, (i) Active pharmaceutical ingredients, (ii) Polyethylene oxide and (iii) Optionally, one or more additional release rate control polymers, and (iv) The mixing step comprising at least one water or hydrophilic carrier, (b) A step of encapsulating the mixed liquid filling composition in a gelatin capsule shell in order to manufacture the capsule, and (c) The step of heating the soft gel gelatin capsule (which may be dried after encapsulation in certain embodiments) at a temperature of about 40°C to about 80°C for a period of about 10 minutes to about 180 minutes to form a solid or semi-solid filling composition inside the soft gel gelatin capsule.

[0028] In the above embodiment of the method, the active pharmaceutical ingredient may be present in an amount of about 1% to about 60% by weight of the controlled-release filling composition, based on the total weight of the controlled-release filling composition.

[0029] In each of the embodiments of the method described above, polyethylene oxide may be included in the controlled-release filling composition in an amount of 10% to 65% by weight of the controlled-release filling composition, based on the total weight of the controlled-release filling composition.

[0030] In each of the methods described above, the filling composition may further contain one or more release rate control polymers.

[0031] In each embodiment of the method described above, water and / or hydrophilic carriers may be included in the release-controlled fill composition in an amount of about 30 wt% to about 70 wt%, or about 40 wt% to about 60 wt%, based on the total weight of the release-controlled fill composition.

[0032] In each of the embodiments of the method described above, polyethylene oxide may be included in the controlled-release filling composition in an amount of about 25% to about 40% by weight of the filling composition, based on the total weight of the filling composition.

[0033] In each of the embodiments described above, the active pharmaceutical ingredient may be an active pharmaceutical ingredient classified into one of the biopharmaceutical classification systems classes I, II, III, and IV.

[0034] In another embodiment, the disclosure relates to a softgel capsule or hard capsule made by any of the methods described above. In this embodiment of the softgel capsule or hard capsule, less than 80% of the active pharmaceutical ingredient may be released after 0.5 hours in a fiber optical dissolution test using a USP apparatus II with a paddle speed of 100 rpm at 37°C in 500 ml of 0.1 N HCl or water. [Brief explanation of the drawing]

[0035] [Figure 1] Figure 1 is a flowchart showing the steps of the capsule manufacturing method disclosed. [Figure 2] Figure 2 illustrates the dissolution profile of the capsule according to the embodiment, obtained in a fiber optical dissolution test using a USP apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of water. [Figure 3] Figure 3 illustrates the capsule dissolution profile obtained in a fiber optical dissolution test of the capsule according to the embodiment using the USP apparatus II at 37°C and a paddle speed of 50 RPM in 500 ml of water. [Figure 4A] Figures 4A-4D and 5-6 show residual plots for 90% of time (hours) for statistical analysis of dissolution data for Examples 1-6. Figure 4A is a normal probability plot for 90% of release (hours). [Figure 4B] Figure 4B is a versus-fit plot for 90% of the emission time. [Figure 4C] Figure 4C is a histogram for 90% of the emission time. [Figure 4D] Figure 4D is a pair-order plot for 90% of the emission time. [Figure 5] Figure 5 shows the interaction plot for the time (hours) until 90% release. [Figure 6] Figure 6 shows the main effect plot for the time to 90% emission (hours). [Figure 7] Figure 7 illustrates the dissolution profiles of capsules filled with formulations 13-15, obtained from fiber optical dissolution tests using a USP apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of water. [Figure 8] Figure 8 shows the dissolution profile of the capsule according to the embodiment, obtained in a fiber optical dissolution test using a USP apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of water. [Figure 9] Figure 9 shows the dissolution profile of the capsule according to the embodiment, obtained by a fiber optical dissolution test using a USP apparatus II with a paddle speed of 50 RPM at 37°C in 500 ml of water. [Figure 10] Figure 10 shows the DSC curve of heat flow versus temperature for a capsule filling composition containing polyethylene oxide having a number-average molecular weight of 900,000 Da. [Figure 11] Figure 11 shows the DSC curve of heat flow versus temperature for a capsule filling composition containing the MC18-30 filling mixture. [Figure 12] Figure 12 shows the DSC curve of heat flow versus temperature for a capsule filling composition containing polyethylene oxide having a number-average molecular weight of 5,000,000 Da. [Figure 13] Figure 13 shows the DSC curve of heat flow versus temperature for a capsule filling composition containing the MC18-31 filling mix. [Figure 14] Figure 14 shows the DSC curve of heat flow versus temperature for a capsule filling composition containing polyethylene oxide having a number-average molecular weight of 7,000,000 Da. [Figure 15]Figure 15 shows the DSC curve of heat flow versus temperature for a capsule filling composition containing the MC18-32 filling mix. [Modes for carrying out the invention]

[0036] For illustrative purposes, the principles of the present invention will be described by reference to various exemplary embodiments. While specific embodiments of the present invention are described herein, those skilled in the art will readily recognize that the same principles can be similarly applied to and adopted in other systems and methods. Before describing in detail the disclosed embodiments of the present invention, it should be understood that the application of the present invention is not limited to the details of any given embodiment. Furthermore, the terms used herein are for illustrative purposes only and not to limit. Moreover, while specific methods are described by reference to the steps shown herein in a particular order, in many cases these steps can be performed in any order as can be understood by those skilled in the art; therefore, novel methods are not limited to the specific arrangement of steps disclosed herein.

[0037] Note that, as used herein and in the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural references. Furthermore, the terms “a” (or “an”), “one or more,” and “at least one” may be used interchangeably herein. The terms “comprising,” “including,” “having,” and “constructed from” may also be used interchangeably.

[0038] Unless otherwise indicated, all figures used in the specification and claims to represent properties such as amounts, molecular weights, percentages, ratios, and reaction conditions of components are understood to be modified in all instances by the term "about," regardless of whether the term "about" is present. Therefore, unless otherwise indicated, the numerical parameters described in the specification and claims are approximations that may vary depending on the desired properties sought by this disclosure. Each numerical parameter should be interpreted using common rounding techniques, at least in light of the reported number of significant figures, not as an attempt to limit the application of the doctrine of equivalents to the claims. Despite the approximations of the numerical ranges and parameters representing the broad scope of this disclosure, the figures described in the specific examples are reported as accurately as possible. However, any numerical value inherently contains a certain degree of error, which inevitably arises from the standard deviation observed in each test measurement. As used herein, "about" refers to any value within a ±10% variation, such that "about 10" includes 9–11.

[0039] It is understood that each component, compound, substituent, or parameter disclosed herein is disclosed for use alone or in combination with one or more other components, compounds, substituents, or parameters disclosed herein.

[0040] Furthermore, it shall be understood that each amount / value or range of each component, compound, substituent, or parameter disclosed herein shall be interpreted as also being disclosed in combination with any other component(s), substituent(s), or parameter(s) disclosed herein, and any combination of amounts / values ​​or ranges of amounts / values ​​for two or more components, compounds, substituent(s), or parameters disclosed herein shall therefore also be disclosed in combination with each other for the purposes of this description.

[0041] Furthermore, it is understood that each lower limit of each range disclosed herein is to be interpreted as being disclosed in combination with each upper limit of each range disclosed herein for the same component, compound, substituent, or parameter. Thus, a disclosure of two ranges should be interpreted as a disclosure of four ranges obtained by combining each lower limit and each upper limit of each range. Similarly, a disclosure of three ranges should be interpreted as a disclosure of nine ranges obtained by combining each lower limit and each upper limit of each range, and so on. Moreover, any specific amount / value of a component, compound, substituent, or parameter disclosed in the description or examples should be interpreted as a disclosure of either a lower or upper limit of a range, and thus can be combined with other lower or upper limits or specific amounts / values ​​of the range for the same component, compound, substituent, or parameter disclosed elsewhere in this application to form a range for that component, compound, substituent, or parameter.

[0042] In this specification, the term "molecular weight" refers to the number-average molecular weight unless otherwise specified.

[0043] In this specification, the term "ambient temperature" refers to a temperature of approximately 20 to 35°C.

[0044] The filling compositions and methods of the present invention are designed for use in both hard capsules and softgel capsules to provide controlled release and abuse resistance of active pharmaceutical ingredients. The filling compositions of the present invention are liquid at the time of encapsulation to facilitate handling of the filling compositions during the capsule filling process. Suitable liquids include solutions, suspensions, and dispersions of the components in water and / or a hydrophilic carrier.

[0045] The term “softgel capsule” refers to gelatin-containing soft capsules and other types of soft capsules that do not contain gelatin. Similar tests can be performed on gelatin-free capsules to determine the manufacturing parameters required for a particular capsule formulation. As used herein, “soft capsule,” “softgel capsule,” and “soft elastic capsule” refer to capsules containing gelatin, or other polymers in combination with an explicit plasticizer such as glycerin or PEG400, or an intrinsic plasticizer such as water.

[0046] The term "shell composition" may be used interchangeably with the terms "film composition," "shell," and "film" throughout this specification. These terms refer to the outer portion of the capsule that encapsulates the filler material.

[0047] The term “filling material” can be used interchangeably with the terms “filling composition” and “filling” throughout this specification. These terms refer to the inner portion of the capsule encapsulated by the shell composition.

[0048] The terms “controlled release” refer to “modified release,” “delayed release,” and “extended release,” indicating that the release of the active pharmaceutical ingredient from the filling composition or capsule is controlled to be delayed, modified, or extended. In one embodiment, “controlled release” refers to the drug release rate from the control-release filling composition or capsule such that less than 80% of the active pharmaceutical ingredient is released after 0.5 hours in a fiber optical dissolution test using a USP apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of biological, artificial, or simulated gastric fluid such as 0.1N HCl and / or pH 6.8 phosphate buffer and / or water. In one embodiment, “release control” refers to the active drug being released gradually over a period of time, for example, about 2 hours to about 24 hours, to provide a once-daily or twice-daily dosage form. Controlled release is important for potent, low-dose drugs, or drugs that function better when administered over time in a controlled manner rather than intermittently.

[0049] In one embodiment, the present invention relates to a controlled-release filling composition suitable for use in capsules (e.g., softgel capsules), the filling composition comprising a polyethylene oxide (PEO) resin. The polyethylene oxide polymer is used in the filling composition to form a solid or semi-solid matrix for controlling the release of active pharmaceutical ingredients (APIs) from capsules containing such filling compositions. Water and / or hydrophilic carriers may also be included in these filling compositions. The release rate of APIs in the filling composition can be controlled by manipulating the number-average molecular weight and / or the concentration of PEO in the filling composition.

[0050] The process used to manufacture the capsule (e.g., softgel capsule) can also affect the API release profile. Release-controlled materials that are solid or semi-solid at ambient temperature require heating to facilitate processing. However, gelatin-based shell materials are heat-sensitive. Therefore, including a release-controlled material that requires heating to facilitate processing is undesirable for use with a gelatin-based shell material. Instead, in certain embodiments, the present invention does not impair the integrity of the heat-sensitive gelatin-based shell material by filling such a gelatin-based capsule with a liquid filling composition at an ambient temperature of about 20–35°C, and then heating the filled capsule to solidify or semi-solidify the liquid filling composition (and form a polymer matrix).

[0051] In one embodiment, the filling composition is provided as a mixture comprising an active pharmaceutical ingredient, a hydrophilic carrier and / or water, and a PEO polymer. This mixture may then be encapsulated in a capsule (e.g., a softgel capsule) at an ambient temperature of about 20–35°C, which provides flexibility in using a wider variety of capsule shell materials.

[0052] The filling composition may optionally contain other components such as high molecular weight polyethylene oxides and cellulose derivatives. These optional components may be included for a variety of reasons, one of which is to alter the API release profile of the filling composition. The filling composition may also contain other additional components, including one or more additional APIs, release rate-controlling polymers, inert components (e.g., pharmaceutically acceptable excipients), or other components of the filling composition for capsules known in the art (e.g., softgel capsules). In certain embodiments, the filling composition may not contain, or substantially not contain, flow-enhancing materials such as glyceryl monolinoleate, glyceryl monocaprylate, monocaprylate, glyceryl monolinoleate, oleic acid, or processability-facilitating materials such as magnesium stearate. Materials that enhance the flowability or processability of the filling composition are simply optional in this instant disclosure, since the filling composition may be liquid during processing and, if desired, solidify into a solid or semi-solid state after already encapsulated within the capsule shell.

[0053] As used herein, "not containing or substantially not containing" a component means a composition containing less than about 1 wt%, less than about 0.5 wt%, less than about 0.25 wt%, less than about 0.1 wt%, less than about 0.05 wt%, less than about 0.01 wt%, or 0 wt% of the component.

[0054] APIs may be pharmaceutical ingredients for therapeutic use. APIs may be a single ingredient or a mixture of one or more active pharmaceutical ingredients, as known in the art, and may include, but are not limited to, any drug, therapeutically acceptable drug salt, drug derivative, drug analog, drug homolog, or polymorph. Preferably, APIs are classified into one of the biopharmaceutical classification systems classes I, II, III, or IV. APIs may include APIs that are prone to abuse and APIs that are not prone to abuse. In one embodiment, the API in the filling composition is prone to abuse. In one embodiment, the API in the filling composition is not prone to abuse.

[0055] Any pharmaceutically active ingredient, including both water-soluble and poorly water-soluble ingredients, may be used for the purposes of this disclosure. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents (e.g., ibuprofen, naproxen sodium, aspirin), antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarial agents, antimigraine agents, antimuscarinic agents, antineoplastic and immunosuppressant agents, antiparasitic agents, antirheumatic agents, antithyroid agents, antithyroid agents, antihistamines (e.g., antihistamines (such as diphenhydramine)),). These include drugs such as Viruses, anxiolytics, sedatives, hypnotics, nerve blockers, beta-blockers, cardiotonic agents, corticosteroids, antitussives, cytotoxins, analgesics, diuretics, enzymes, antiparkinson's disease drugs, gastrointestinal drugs, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular drugs, nitrates and antianginal drugs, nutritional supplements, opioid analgesics, anticonvulsants (e.g., valproic acid), oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants, and combinations thereof.

[0056] In some embodiments, the active pharmaceutical ingredient is, without limitation, dabigatran, doronedarone, ticagrelor, iloperidone, ibacaftol, midostaurin, asimadrine, beclomethasone, apremilast, sapacitabine, lincitib, abiraterone, vitamin D analogues (e.g., calcifediol, calcitriol, paricalcitol, doxelcalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

[0057] In one embodiment of the present invention, the active pharmaceutical ingredient is an analgesic such as ibuprofen or an opioid. The term “opioid” refers to a psychoactive compound that acts by binding to opioid receptors. Opioids are commonly used in the medical field due to their analgesic effects. Opioids are considered to be APIs that are easily abused. Examples of opioids include codeine, tramadol, anirelidine, prozine, pethidine, hylocodone, morphine, oxycodone, methadone, diamorphine, hydromorphone, oxymorphone, 7-hydroxymitragin, buprenorphine, fentanyl, sufentanyl, levorphanol, meperidine, tirizine, dihydrocodeine, dihydromorphine, and their pharmaceutically acceptable salts.

[0058] Examples of active pharmaceutical ingredients include N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide; alfentanil; 5,5-diallylbarbiturate; allobarbital; allylprozine; alphaprozine; 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine; alprazolam; 2-die Tylaminopropiophenone; Amphepramon, (+ / -)-α-methylphenethylamine; Amphetamine; 2-(α-methylphenethylamino)-2-phenylacetonitrile; Amphetamine yl; 5-ethyl-5-isopentylbarbiturate; Amobarbital; Anyllysine; Apocodeine; 5,5-diethylbarbiturate; Barbital; Benzylmorphine; Benzitramid; 7-Bromo-5-(2-pyridyl)-1H-1, 4-Benzodiazepine-2(3H)-1; Bromazepam; 2-Bromo-4-(2-chlorophenyl)-9-methyl-1-6H-thieno[3,2-f][1,2,4]triazolo[4,3a][1,4]diazepine; Brotizolam, 17-Cyclopropylmethyl-4,5a-Epoxy-7a[(S)-1-Hydroxy-1,2,2-trimethylpropyl]-6-Methoxy-6,14-Endoethanomorphinan-3-ol; Buprenorphine n; 5-butyl-5-ethylbarbiturate; butobarbital; butorphanol; (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)dimethylcarbamate; chamazepam; (1S,2S)-2-amino-1-phenyl-1-propanol; catin; d-norptoephedrine; 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepine-2-ylamine 4-oxide; chlordiazepoxide, 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; clobazam, 5-(2-chlorophenyl)-7-nitro-1H-1,4-benz-diazepine-2(3H)-one; clonazepam; clonitazen; 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid; clorazepate;5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepine-2(3H)-1; clotiazepam; 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydroxazole-o[3,2-d][1,4]benzodiazepine-6(5H)-one; cloxazolam; (-)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropanecarboxylate]; cocaine; (5α,6α)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorph Nan-6-ol; 4,5α-epoxy-3-methoxy-17-methyl-7-morphinan-6α-ol; codeine; 5-(1-cyclohexenyl)-5-ethylbarbiturate; cyclobarbital; cyclophane; cyprenorphine; 7-chloro-5-(2-chlorophenyl-1)-1H-1,4-benzodiazepine-2(3H)-one; delorazepam; dezorphine; dextromoramide; (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate; doxytropoxyfen; dezosin; diam Bromide; Diamorphone; 7-Chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-1; Diazepam; 4,5α-Epoxy-3-methoxy-17-methyl-6α-morphinanol; Dihydrocodeine; 4,5α-Epoxy-17-methyl-3,6α-morphinanediol; Dihydromorphine; Dimenoxadol; Dimephetamol; Dimethylthiambutene; Dioxafetyl butyrate; Dipipanone; (6aR,10aR)-6,6,9-trimethyl-3-pentia-6a,7,8,10a-tetra Hydro-6H-benzo[c]chromen-1-ol; dronabinol; eptazosine; 8-chloro-6-phenyl-4H-[1,2,4]-triazolo[4,3-(a)][1,4]benzodiazepine; estazolam; etoheptadine; ethylmethiabutene; ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylic acid]; ethyl loflazepate; 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinene-6α-ol; ethylmorphine; etonitazene;4,5α-Epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endoethenomorphinan-3-ol; etorphine; N-ethyl-3-phenyl-8,9,10-trilorbornan-2-ylamine; fencampamine; 7-[2-(α-methylphenethylamino)ethyl]-theophylline; phenethyline; 3-(α-methylphenethylamino)propionitrile; fenproporex; N-(1-phenethyl-4-piperidyl)propionanilide; fentanyl; 7-chloro-5-(2 -Fluorophenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one; Fludiazepam; 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepine-2(3H)-one; Flunitrazsepam; 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepine-2(3H)-one; Flurazepam; 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepine-2(3H)-one; Harazepam; 1 0-Bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolyl[3,2-d][1,4]benzodiazepine-6(5H)-one;haloxazolam;herio;4,5α-epoxy-3-methoxy-17-methyl-6-morphinanon;hydrocodone;4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanon;hydromorphone;hydroxypethidine;isomethadone;hydroxymethylmorphinan;11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4 H-[1,3]oxazino[3,2d][1,4]benzodiazepine-4,7(6H)-dione; ketazolam; 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone; ketobemidone; (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-ylacetate; levacatylmetadol; LAAM; (-)-6-dimethylamino-4,4-diphenol-3-heptanone; levemethadone; (-)-17-methyl-3-morphinol; levofenacilmorphan; lofentanil;6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepine-1(4H)-one; loprazolam; 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepine-2(3H)-one; lorazepam; 7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepine-2(3H)-one; lormetazepam; 5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1a] Isoindo-5-ol; mazindol; 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine; medazepam; N-(3-chloropropyl)-α-methylphenethylamine; mephenorex; meperidine; 2-methyl-2-propyl trimethylenedicarbamate; meprobamate; meptadinol; metazosin; methylmorphine; N,α-dimethylphenethylamine; metaphetamine; (±)-6-dimethylamino-4,4-diphenol-3-heptanone; methadone; 2-methyl-3-otryl-4( 3H)-Quinazolinone; Methakalon; Methyl[2-phenyl-2-(2-piperidyl)acetate]; Methylphenidate; 5-Ethyl-1-methyl-5-phenylbarbitrate; Methylphenobarbital; 3,3-Diethyl-5-methyl-2,4-piperidinedione; Metiprilone; Metopon; 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine; Midazolam; 2-(Benzhydroylsphenyl)acetamide; Modafinyl; (5α,6α)-7,8-didehydro-4,5-epo Xy-17-methyl-7-methylmorphinan-3,6-diol; morphine; mirofin; (±)-trans-3-(1,1-dimethylheptile)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6αH)one; nabilone; nalbufen; nalorphine; narcein; nicomorphine; 1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-1; nimetazepam; 7-nitro-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one;Nitrazepam; 7-Chlor-5-phenyl-1H-1,4-benzodiazepine-2(-3H)-1; Nordazepam; Norlevorphanol; 6-Dimethylamino-4,4-diphenyl-3-hexanone; Normethadone; Normorphine; Norpipanone; Opium; 7-Chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepine-2(3H)-1; Oxazepam; (cis- / trans-)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepine Azepine-6-(5H)-1; Oxazolam; 4,5α-Epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanon; Oxycodone; Oxymorphone; Papaveretam; 2-Imino-5-phenyl-4-oxazolidinone; Pernoline; 1,2,3,4,5,6-Hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazosin-8-ol; Pentazocine; 5-Ethyl-5-(1-methylbutyl)-barbiturate; Pentobarbital; Ethyl-(1-methyl -4-phenyl-4-piperidinecarboxylate); pethidine; phenadoxone; phenomorphan; phenazosin; fenoperidin; piminodin; folcodeine; 3-methyl-2-phenylmorsolin; phentrazine; 5-ethyl-5-phenylbarbital phosphate; phenobarbital; α-dimethylphenethylamine; phentermine; (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol; phenylephrine, 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepine- 2(3H)-one; pinasepam; α-(2-piperidyl)benzhydryl alcohol; piperadrol; 1α-(3-cyano-3,3-diphenylpropyl)[1,4'-bipiperidine]-4α-carboxamide; pyritramide; 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepine-2(3H)-one; prazepam; profadol; proheptadine; promedol; proparidin; propoxifene; N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide;Methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamide)piperidino]propanoic acid}.(S,S)-2-methylamino-1-phenylpropan-1-ol; pseudoephedrine, remifentanil; 5-sec-butyl-5-ethylbarbiturate; secobutabarbital; 5-allyl-5-(1-methylbutyl)-barbiturate; secobutal; N-{4-methoxymethyl-1-[2-; (2-thienyl)ethyl]-4-piperidyl}propianylanilide; sufentanyl; 7-chloro-2-hydroxymethyl-5-phenyl-1H-1,4-benzodiazepine-2(3H)-1; temazepam; 7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepine-2(3H)-one; tetrazepam; ethyl (2-dimethylamino-1-phenyl-3-cyclohexen-1-carboxylate; cis- / trans-thyridine; tramadol; 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine; triazolam; 5-(1-methylbutyl)-5-vinylbarbiturate; vinylvitan; (1R * ,2R * Examples include )-3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol; and (1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(methoxyphenyl)cyclohexanol.

[0059] In addition to the compounds mentioned above, pharmaceutical active ingredients also include prodrugs of any of these compounds. The term "prodrug" refers to a compound that is a metabolite of the active ingredient of a pharmaceutical. This precursor is converted in vivo to provide the active ingredient of the pharmaceutical with the desired therapeutic effect.

[0060] The active ingredients of pharmaceuticals also include pharmaceutically acceptable salts of any of the above compounds. A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, and camphorsulfonic acid. Salic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthic acid, salicylic acid, stearic acid, muconic acid, etc.; and salts formed when the acidic protons present in the parent compound are substituted with metal ions, for example, alkali metal ions, alkaline earth ions, aluminum ions, etc., or with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, and benzoate, as well as lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthyl mesylate, glucoheptonate, lactobionate, and laurylsulfonate. These may contain cations based on alkali metals and alkaline earth metals such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, tetramethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0061] "Pharmacologically acceptable" means that it is generally safe, non-toxic, not biologically or otherwise undesirable, and useful in preparing pharmaceutical compositions that are acceptable for human medicinal use.

[0062] Furthermore, in addition to the compounds mentioned above, the active pharmaceutical ingredient may also be a solvate of any of the compounds mentioned above. The term "solvate" refers to an aggregate composed of one or more molecules of the active pharmaceutical ingredient with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. In one embodiment, "solvate" refers to the active pharmaceutical ingredient in its state before dissolution. Alternatively, the suspended solid particles of the active pharmaceutical ingredient may contain the co-precipitated solvent.

[0063] In certain embodiments, the filling composition may also include, in addition to or instead of the active pharmaceutical ingredient, nutritional supplements such as vitamins, minerals, or other supplements. Any reference to the API throughout this description (e.g., concentration) should also be understood to be appropriate for different activators such as nutritional supplements (i.e., vitamins, minerals, and / or other supplements).

[0064] In some embodiments, the lipids in the dosage form may be selected from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, colza oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, and lecithin, but are not limited to these. They may also be selected from the group consisting of linseed oil, macadamia oil, mango butter, manila oil, mongol nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, peppermint oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, walnut oil, and watermelon seed oil. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, garlic oil, animal or vegetable fats, for example their hydrogenated forms, free fatty acids and mono, di and triglycerides of C8-, C10-, C12-, C14-, C16-, C18-, C20- and C22- fatty acids, fatty acid esters such as EPA and DHA3 and combinations thereof.

[0065] According to certain embodiments, the activators include, but are not limited to, statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid chelating agents, ezetimibe, lomitapide, phytosterols, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof, mixtures of any of the foregoing, and similar.

[0066] Suitable dietary supplement activators include, but are not limited to, 5-hydroxytryptophan, acetyl L-carnitine, alpha-lipoic acid, alpha-ketoglutarate, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin 812), dimethylaminoethanol fumarate, germanium dioxide, glandular products, glucosamine hydrochloride, glucosamine sulfate, hydroxylmethylbutyrate, immunoglobulin, lactic acid, L-carnitine, liver products, malic acid, anhydrous maltose, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvic acid, red yeast rice extract, S-adenosylmethionine, selenium yeast, shark cartilage, theobromine, vanadyl sulfate, and yeast.

[0067] Suitable nutritional supplement activators may include vitamins, minerals, fiber, fatty acids, amino acids, herbal supplements, or combinations thereof.

[0068] Suitable vitamin activators, though not limited to these, may include ascorbic acid (vitamin C), B vitamins, biotin, fat-soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbate, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenate, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin oil, and fat-soluble vitamins.

[0069] Suitable herbal supplement activators may include, but are not limited to, arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic oil, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, psyllium, lauwolfia, senna, soybean, St. John's wort, soy palmetto, turmeric, and valerian.

[0070] Mineral activators may include, but are not limited to, boron, calcium, chelated minerals, chlorides, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pirubate, zinc, and other minerals.

[0071] Other possible activators include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, pyroprofen, carprofen, oxaprozin, pramprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, flupro, buclocate, indomethacin, sulindac, zomepirac, thiopinac, didomethacin, acemetacin, fenthiazac, cridanac, oxpinac, meclofenamic acid, flufenamic acid, niflum Acid, tolfenamic acid, diflurisal, fluphenisal, piroxicam, sudoxicam, isoxicam, aceclofenum, roxiprine, azapropazon, benolilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, facelamin, fenbufen, fenoprofen, fluviprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamisole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimeslide, oxyfenbutazone, parecoxib, phenylbutazone, salcin salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin.(These pharmaceutically acceptable salts and mixtures thereof) and acetaminophen, antiemetics (e.g., metoclopramide, methylnaltrexone), antiepileptics (e.g., pheniloin, meprobmate, nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem, nicardipine), cough and expectorant drugs (e.g., codeine phosphate), antiasthmatics (e.g., theophylline), antacids, anticonvulsants (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., ethacrine, bendroftiazide), antihypertensives (e.g., propranolol) The following may be included: norol (clonidine), antihypertensive agents (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisolone), antibiotics (e.g., tetracycline), antihemorrhoids, hypnotics, psychotropic agents, antidiarrheals, mucolytics, sedatives, nasal decongestants (e.g., pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine), and cannabinoids, as well as pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof.

[0072] Furthermore, the activators may be, but are not limited to, benzodiazepines, barbiturates, stimulants, or mixtures thereof. The term “benzodiazepine” refers to drugs that are benzodiazepines and benzodiazepine derivatives that can depress the central nervous system. Benzodiazepines include alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, harazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs and mixtures (but are not limited to these). Benzodiazepine antagonists that can be used as activators may include flumazenil, and their pharmaceutically acceptable salts, hydrates, solvates and mixtures.

[0073] The term "barbiturate" refers to sedatives and hypnotics derived from barbituric acids (2,4,6-trioxohexahydropyrimidine), but is not limited to these. Barbiturates include, but are not limited to, amobarbital, aprobarbital, butabarbital, methhexital, mefobarbital, metalbital, pentobarbital, phenobarbital, scobarbital, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures. Barbiturate antagonists that can be used as activators may include amphetamines, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures.

[0074] The term “stimulant” includes, but is not limited to, dextroamphetamine resin complexes, dextroamphetamine, methamphetamine, methylphenidate and other amphetamines, as well as pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof. Stimulant antagonists that can be used as activators may also include benzodiazepines and pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

[0075] The present invention is suitable for the delivery of abuse-sensitive active pharmaceutical ingredients because it can provide a certain degree of abuse deterrence by making it difficult to separate and purify the active pharmaceutical ingredient from the filling composition. The filling composition of the present invention is also suitable for controlled-release delivery of APIs, and is preferably suitable for high-potency APIs that are released to the target substance in relatively small amounts over a long period of time (such as about 2 hours to about 24 hours).

[0076] Preferably, the API is present in the controlled-release-filled composition in an amount of about 5 wt% to about 60 wt% based on the total weight of the controlled-release-filled composition. More preferably, the API is present in the controlled-release-filled composition in an amount of about 10 wt% to about 30 wt% based on the total weight of the controlled-release-filled composition.

[0077] In certain embodiments, the API (or activator) is present in the controlled-release filling composition in an amount of at least about 1% by weight, at least about 5% by weight, at least about 10% by weight, at least about 15% by weight, or at least about 20% by weight. Based on the total weight of the controlled-release filling composition, this amount may be up to about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt%, or about 60 wt%. In certain embodiments, the API (or activator) is present in the controlled-release filling composition in an amount of about 12 wt% to about 18 wt%, about 19 wt% to about 25 wt%, about 24 wt% to about 32 wt%, about 4 wt% to about 10 wt%, or about 25 wt% to about 42 wt%, based on the total weight of the controlled-release filling composition. The concentration ranges of activators described herein may refer to the concentration of a single API (regardless of the number of APIs in the filling composition) or the cumulative concentration of all APIs in the filling composition (if multiple APIs are present in the filling composition). Similarly, the concentration of API(s) is applicable to activators that are not pharmaceutical ingredients, such as, but not limited to, dietary supplements and other activators as described above.

[0078] The polyethylene oxide (PEO) in the controlled-release filling composition has a number-average molecular weight of about 0.05 million daltons to about 15 million daltons, more preferably about 500 thousand daltons to about 10 million daltons, and most preferably about 1 million daltons to about 8 million daltons. In embodiments, the PEO that can be used has a number-average molecular weight in the range of any one of about 0.05 M, about 0.5 M daltons, about 1 M dalton, about 2 M daltons, about 3 M daltons, or about 4 M daltons to about 5 M, about 7 M daltons, about 10 M daltons, about 12 M daltons, about 15 M daltons, or about 20 M daltons, or any sub-range or single value therein. In one embodiment, the number-average molecular weight of the polyethylene oxide in the controlled-release filling composition is in the range of about 0.05 M daltons to about 15 M daltons. In one embodiment, the number-average molecular weight of the polyethylene oxide in the controlled-release filling composition is in the range of about 1 M daltons to about 10 M daltons. In one embodiment, the number-average molecular weight of polyethylene oxide in the controlled-release filling composition is in the range of about 1 M Dalton to about 8 M Daltons. In another embodiment, the number-average molecular weight of polyethylene oxide in the controlled-release filling composition is in the range of about 2 M Daltons to about 5 M Daltons.

[0079] PEO is incorporated into the controlled-release filling composition in an amount of at least 21.5 wt% based on the total weight of the controlled-release filling composition. In alternative embodiments, PEO is present in the controlled-release filling composition in an amount of about 10% to about 65% based on the total weight of the controlled-release filling composition. Most preferably, PEO is present in the controlled-release filling composition in an amount of about 25% to about 40% based on the total weight of the controlled-release filling composition.

[0080] In embodiments, the PEO is included in any lower range based on the total weight of the controlled-release filling composition, up to about 25% by weight, up to about 35% by weight, up to about 45% by weight, up to about 55% by weight, or up to about 65% by weight, based on the total weight of the controlled-release filling composition. In particular embodiments, the controlled-release filling composition contains about 8% to about 15% by weight, about 16% to about 20% by weight, about 22% to about 28% by weight, about 15% by weight, up to about 10 wt% to about 35 wt%, or about 11 wt% to about 40.5 wt% of the PEO based on the total weight of the controlled-release filling composition.

[0081] In alternative embodiments, if water and / or hydrophilic carriers are present in an amount of up to 65% by weight based on the total weight of the controlled-release filling composition, PEO may be present in any suitable amount in the controlled-release filling composition. In this embodiment, the minimum amount of water and / or hydrophilic carriers may optionally be at least about 30% by weight, or at least about 40% by weight, or at least about 55% by weight, based on the total weight of the controlled-release filling composition. In these alternative embodiments, the amount of PEO in the controlled-release filling composition may be about 5% to about 35% by weight, or about 20% by weight, based on the total weight of the controlled-release filling composition.

[0082] In certain embodiments, the weight ratio (individually or cumulatively) of PEO to water and / or hydrophilic carrier is approximately 10:1 to approximately 1:10, approximately 8:1 to approximately 1:8, approximately 5:1 to approximately 1:5, approximately 3:1 to approximately 1:3, approximately 2:1 to approximately 1:2, approximately 10:1 to approximately 1:3, approximately 8:1 to approximately 1:3, approximately 5:1 to approximately 1:3, approximately 3:1 to approximately 1:3, approximately 2:1 to approximately 1:3, approximately 1:1 to approximately 1:1 to approximately 3, approximately 10:1 to approximately 1:2, approximately 8:1 to approximately 1:2, approximately 5:1 to approximately 1:2, approximately 3:1 to approximately 1:2, approximately 1:1 to approximately 1:2, or any subrange or single weight ratio value within that range. In one embodiment, the weight ratio of PEO to water and / or hydrophilic carrier (individually or cumulatively) is in the range of approximately 2:1 to approximately 1:2. In another embodiment, the weight ratio of PEO to water and / or hydrophilic carrier (individually or cumulatively) is in the range of approximately 3:1 to 1:3.

[0083] Suitable polyethylene oxides are typically nonionic, high molecular weight, water-soluble polyethylene oxide resins. An exemplary PEO resin of this type is Polyox® water-soluble resin, available from DuPont Pharma Solutions. These PEO resins are commonly used as thickeners and rheology control agents. In the present invention, these water-soluble PEO resins may be employed to modify or control the release of APIs from softgel capsules and / or hard capsules and / or capsule filling compositions. PEO resins may also be employed in filling compositions to suppress the abuse of APIs contained in the filling composition.

[0084] The ratio of PEO to other components of the filling composition (such as API or other controlled-release materials, if present) may be adjusted to achieve the target release profile of the API. In certain embodiments, the wt:wt ratio of PEO to API may range from about 10:1 to about 1:10, about 8:1 to about 1:8, about 5:1 to about 1:5, about 3:1 to about 1:3, or about 1:1.

[0085] In certain embodiments, the hydrophilic carrier in the filling composition has a number average molecular weight of about 50 daltons to about 7000 daltons, about 200 daltons to 5000 daltons, more preferably about 300 daltons to about 3000 daltons, and most preferably about 400 daltons to about 1500 daltons. In certain embodiments, the hydrophilic carrier may include compounds having a number average molecular weight of less than 200 daltons.

[0086] Examples of suitable hydrophilic carriers include hydrophilic solvents, such as polyoxyethylene derivatives of sorbitan esters, e.g., sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan triolate (polysorbate 85), and other hydrophilic carriers such as polyethylene glycol, polypropylene glycol, propylene glycol, acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof.

[0087] The hydrophilic carrier is preferably selected from polyethylene glycol and polypropylene glycol. In addition, or as an alternative to these hydrophilic carriers, water may be added to the filling compositions described herein. Most preferably, the hydrophilic carrier is polyethylene glycol. Polyethylene glycol will typically have a number-average molecular weight of 300 to 7000 g / mol. As used herein, the term “high molecular weight polyethylene glycol” refers to polyethylene glycol having a number-average molecular weight higher than 1500 daltons, for example, 1500 to 7000 daltons. Combinations of two or more polyethylene glycols with different molecular weights can also be employed. Polypropylene glycol is a preferred additional component of the hydrophilic carrier when a reduction in the viscosity of the liquid filling composition is required.

[0088] In one embodiment, water and / or hydrophilic carriers are included in the controlled-release-filled composition in an amount of up to 65 wt% based on the total weight of the controlled-release-filled composition. In another embodiment, water and / or hydrophilic carriers are included in the controlled-release-filled composition in an amount of about 10% to about 75% by weight, or 30% to about 70% by weight, based on the total weight of the controlled-release-filled composition. Preferably, water and / or hydrophilic carriers are included in the controlled-release-filled composition in an amount of about 40% to about 60% by weight, based on the total weight of the controlled-release-filled composition.

[0089] In certain embodiments, water and / or hydrophilic carriers are included in the controlled-release-filled composition in amounts of 0% by weight or more, at least about 15% by weight or more, or at least about 30% by weight to about 45% by weight, up to about 60% by weight, up to about 70% by weight, or up to about 80% by weight, based on the total weight of the controlled-release-filled composition. In certain embodiments, the controlled-release-filled composition may include water and / or hydrophilic carriers in amounts of about 5% by weight to about 15% by weight, about 15% by weight to about 28% by weight, about 20% by weight to about 32% by weight, about 20% by weight to about 42% by weight, about 22% by weight to about 45% by weight, about 40% by weight to about 45% by weight, about 40% by weight to about 55% by weight, about 35% by weight to about 55% by weight, about 56% by weight to about 77% by weight, about 40% by weight to about 79% by weight, or about 29% by weight to about 66% by weight, based on the total weight of the controlled-release-filled composition. The concentration ranges of hydrophilic carriers described herein may refer to the concentration of a single hydrophilic carrier material (regardless of the number of hydrophilic carrier materials in the filler composition) or the cumulative concentration of all hydrophilic carrier materials in the filler composition (if multiple hydrophilic carrier materials are present in the filler composition).

[0090] In another embodiment, the hydrophilic carrier may be present in any amount in the controlled-release filling composition, as long as polyethylene oxide is present in an amount of at least 21.5% by weight of the controlled-release filling composition based on the total weight of the controlled-release filling composition. In this embodiment, the hydrophilic carrier is typically present in an amount of up to 65% by weight, or 10% to 65% by weight, or 30% to 60% by weight, or 30% to 55% by weight, based on the total weight of the controlled-release filling composition. The hydrophilic carrier is used to dissolve, disperse and / or suspend other components of the liquid filling composition in the liquid, and may also function to adjust the viscosity of the liquid filling composition to a desired viscosity for the encapsulation process.

[0091] The liquid-filled composition may have a viscosity in the range of 1,000 cP to 100,000 cP, 5,000 cP to 80,000 cP, or 10,000 cP to 60,000 cP at the time of capsule filling (or encapsulation). The viscosity of the liquid-filled composition was measured at 20°C using a HAAKE RheoStress 600 rheometer with a 40 mm flat plate geometry. The geometry was vibrated at 1 Hz with a 2 mm gap setting.

[0092] The filling compositions described herein provide the ability to control the release of the API from the dosage form. The amount of PEO and / or the molecular weight of the PEO component can be adjusted to optimize the release rate of the API from the capsule.

[0093] A key advantage of the filling composition being liquid during processing is that, in contrast to tablet formulations which generally require handling of powder throughout the entire formulation manufacturing process, it eliminates the need to handle powder in the formulation manufacturing process, except for the initial mixing step. Furthermore, the processing of liquid filling compositions described herein can reduce or eliminate the need to include flowability or processability enhancers to facilitate processing. Similarly, given that the filling composition is liquid at ambient temperature, there is no need to heat them before encapsulation, which can be detrimental to heat-sensitive materials, such as those used in the shell composition of certain softgel capsules. The ability to provide liquid fillings for encapsulation enables the use of softgel and hard-shell capsules to provide controlled-release formulations.

[0094] Another embodiment relates to capsules containing the above-described filling compositions. These capsules may be softgel capsules, soft capsules, or hard capsules. In the case of soft capsules, capsules of any size can be used. In one embodiment, a softgel gelatin capsule encapsulates one of the filling compositions described herein.

[0095] The dry shell accounts for approximately 30% to 60% by weight, based on the total weight of the filled soft capsule. In this case, the release-controlled filling composition accounts for approximately 40% to 70% by weight, based on the total weight of the filled soft capsule.

[0096] In the case of hard capsules, the capsule shell accounts for up to approximately 10% by weight, based on the total weight of the filled hard capsule. In this case, the controlled-release filling composition accounts for up to approximately 90% by weight, based on the total weight of the filled hard capsule. The hard capsule is sealed using conventional hard capsule sealing methods known in the art to prevent the liquid filling composition from leaking out of the capsule during encapsulation.

[0097] Softgel capsules can contain gelatin, but they do not have to be gelatin-based. Other suitable, conventional softgel capsules can also be used. The advantage of non-gelatin soft capsules is that high encapsulation temperatures up to 70°C can be used in the encapsulation process to ensure that the filling composition is sufficiently fluid, which allows for the use of high-viscosity fillers, such as those containing high molecular weight hydrophilic excipients.

[0098] Hard-shell capsules offer similar flexibility in the encapsulation process, as they allow for the use of high encapsulation temperatures up to 70°C.

[0099] For non-gelatin soft capsules or hard capsules that allow heating above the melting point of PEO (approximately 50°C), the liquid filler can be heated above the melting point of PEO after encapsulation to melt the PEO, and the molten filler composition can then be cooled and solidified to form the desired substantially homogeneous controlled-release filler composition. As a result of this melting process, a more uniform filler composition is formed in situ within the capsule. This uniformity of the filler composition is facilitated by the presence of a hydrophilic carrier that can also function as a plasticizer during this melting process.

[0100] A key advantage of using polyethylene oxide as the primary rate control component in liquid filling compositions is that it tends to be less tacky or sticky than other rate control polymers, thereby facilitating the encapsulation process and ensuring a more uniform filling composition. While other additional rate control polymers can also be employed, the amount of such polymers must be carefully selected to prevent this tackiness or stickiness from causing problems during the encapsulation process and leading to inferior products.

[0101] Preferably, the API release rate from the controlled-release filling composition is such that less than 80% of the API is released in 0.5 hours in a fiber optical dissolution test using a USP apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of biological, artificial, or simulated gastric fluid, e.g., 0.1N HCl and / or biological, artificial, or simulated intestinal fluid, e.g., pH 6.8 phosphate buffer and / or water. More preferably, the API release rate from the controlled-release capsule is such that less than 80% of the API is released after 1 hour in a fiber optical dissolution test using a USP apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of biological, artificial, or simulated intestinal fluid, e.g., biological, artificial, or simulated gastric fluid such as 0.1N HCl and / or pH 6.8 phosphate buffer and / or water. The filling composition is a rate-controlled composition independent of the capsule shell, whether softgel or hard. In certain embodiments, the controlled-release filling composition releases approximately 10% to 30% by weight of the API in 1 hour, approximately 15% to 50% by weight of the API in 2 hours, approximately 20% to 80% by weight of the API in 4 hours, approximately 40 wt% to 95 wt% of the API in 8 hours, approximately 65 wt% to 100 wt% of the API in 12 hours, and over 90 wt% of the API in 24 hours, in each case measured in a fiber optic dissolution test using a USP apparatus II (paddle) at 37°C and 100 RPM in 500 ml of biological, artificial, or simulated gastric fluid such as 0.1N HCl and / or biological, artificial, or simulated intestinal fluid such as pH 6.8, for example, phosphate buffer and / or water.

[0102] The filling composition may contain one or more optional components, including one or more surfactants, one or more plasticizers, and one or more API release rate control polymers other than PEO. Any additional API release rate control polymers that may be included in the filling composition are preferably selected from one or more of the following: cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, or a combination thereof), chitosan, carnauba wax, carbomer, polysaccharides, gums (e.g., acacia, pectin, agar, tragacanth, guar gum, xanthan gum, locust bean gum, tara gum, karaya, gellan gum, welan gum, rumsang gum, or a combination thereof), or a combination thereof.

[0103] Examples of any surfactant include polyoxyl 40 hydrogenated castor oil, caprylocaproyl macrogol-8 glyceride, glycerol, macrogol glycerol hydroxystearate, Cremophor® RH40, macrogol glycerol ricinolate, Cremophor® EL, glycerol monooleate 40, peseol®, macrogol glycerol linoleate, and labrafil M2125. This includes CS, propylene monolaurate FCC, lauroglycol FCC, polyglycerin-6-dioleic acid, polyglycerin-3-dioleic acid, Plurol® oleic acid, propylene glycol monocaprylate, Capriol® 90, sorbitan monolaurate, Span® 20, sorbitan monooleate, Span® 80, vitamin E polyethylene glycol succinate, Labrasol®, macrogol-32-glycerol-laurate, Gelsia 44 / 14, glyceryl monocaprate / caprylate, Capmul MCM, and mixtures thereof.

[0104] Optional additional API-release controlled polymers may include cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose, biological gums, and other gelling agents. Biological gums may be selected from acacia, pectin, agar, tragacanth, guar gum, xanthan gum, locust bean gum, tara gum, karaya, gellan gum, welan gum, and rumsang gum, and other gelling agents include pectin, starch, carbomer, sodium alginate, gelatin, casein, carrageenan, collagen, dextran, succinoglucon, and polyvinyl alcohol clay.

[0105] Another embodiment relates to a method for producing controlled-release softgel capsules comprising a controlled-release filling composition containing polyethylene oxide resin. This process is designed to accommodate softgel capsules that are not suitable for high encapsulation temperatures due to the relatively low melting point of the capsule shell material. For example, gelatin-based softgels may begin to melt at temperatures of 33–45°C, depending to some extent on the water content of the capsule shell material at the time of encapsulation. For capsule shell materials with such low melting points, a method has been devised in which a liquid filling composition is filled into the capsule at a lower temperature. A major advantage of this method is that it can be used to provide a high-viscosity liquid, semi-solid, or solid filling composition that is ultimately encapsulated. In this method, a solid solution or semi-solid filling is formed in situ within the capsule as a result of a heating step carried out after encapsulation.

[0106] In this method, suspensions or dispersions may be used instead of solutions. A softgel capsule shell will typically contain up to 20% by weight of water, based on the total weight of the capsule shell, upon completion of the encapsulation process. During the encapsulation and subsequent drying processes, most of the water in the capsule shell, i.e., up to about 70%, migrates into the filling composition, solubilizing solid components in the suspension / dispersion of the filling composition, such as PEO, in situ to form the desired solution. In this method, the solubilization of solid components (e.g., PEO) in the filling composition occurs in situ. The water content in the filling composition before encapsulation can be sufficiently low to limit or avoid the solubilization of at least some of the components of the filling composition (such as PEO) before the encapsulation and drying processes. Premature solubilization of certain components in the filling composition (i.e., before encapsulation and drying) can increase the viscosity of the filling composition and impede processability. Typically, the initial filling composition has a water content of about 2% to about 10% by weight, based on the total weight of the filling composition, to avoid premature solubilization of the PEO component in the filling composition before encapsulation. After encapsulation of the filling composition, some of the water from the softgel capsule shell migrates into the filling composition, typically increasing its water content to about 15% to 20% by weight, based on the total weight of the encapsulated filling composition, thereby causing the solubilization of PEO in the encapsulated filling composition. During subsequent drying, water is gradually removed until the water content of the encapsulated filling composition is less than 10% by weight, based on the total weight of the encapsulated and dried filling composition. After the final heating step (also called the annealing step), the water content of the final encapsulated filling composition is further reduced to about 5% to 8% by weight, based on the total weight of the final encapsulated filling composition. The final encapsulated filling composition forms a solid solution of PEO in a hydrophilic carrier.

[0107] This process of forming a solid solution in situ is important because, unlike powder-filled capsules or other solid dosage forms, it provides a more uniform distribution of the API within the filling composition. Uniform distribution of the API is a crucial property for the delivery of high-potency and / or low-dose APIs, as such APIs should be delivered at a relatively constant rate over time to avoid over- or under-dosing. In certain embodiments, uniform distribution of the API within the filling composition enables zero-order release of the API from a controlled-release filling composition (where the API is delivered at a relatively constant rate over time, for example, from about 2 hours to about 12 hours, or from about 2 hours to about 24 hours).

[0108] Figure 1 shows a flowchart 100 of the steps and materials used in this method for manufacturing capsules. In this method, the filling composition 102 is mixed in a mixing step 104 using any suitable apparatus known in the art that can be used to mix the filling composition 102. The filling composition 102 comprises at least a pharmacokinetic active ingredient (API) 106, polyethylene oxide 108, and optionally one or more additional API release rate control polymers 110, as well as water and / or a hydrophilic carrier 112. The filling composition 102 may also include other additional components 114 such as inert components (e.g., pharmaceutically acceptable excipients), and other suitable components such as surfactants and plasticizers for use in filling compositions known in the art.

[0109] API 106 may be a pharmaceutical ingredient that is a single component or a mixture of one or more APIs, as is known in the art. Preferably, API 106 is selected from APIs classified in one of the Biopharmaceutics Classification System Classes I, II, III, or IV. In certain embodiments, nutritional supplements such as vitamins, minerals, or supplements are included instead of or in addition to API 106. In one embodiment, the API is a drug that is less likely to be abused. Preferably, API 106 is mixed into the filling composition 102 in an amount of about 5% to about 60% by weight, based on the total weight of the filling composition 102. More preferably, API 106 is mixed into the filling composition 102 in an amount of about 5% to about 40% by weight, or about 10% to about 30% by weight, based on the total weight of the filling composition 102.

[0110] Polyethylene oxide 108 may have a number average molecular weight of about 0.05 M Daltons to about 15 M Daltons, more preferably about 0.5 M Daltons to about 10 M Daltons, and most preferably about 1 million Daltons to about 8 million Daltons. In one embodiment of the method, polyethylene oxide 108 is mixed into the filling composition 102 in an amount of at least 21.5 wt% based on the total weight of the filling composition 102. In another embodiment, polyethylene oxide 108 is mixed into the filling composition 102 in an amount of about 10% to about 65% by weight based on the total weight of the filling composition 102, and most preferably polyethylene oxide 108 is mixed into the filling composition 102 in an amount of about 25% to about 40% by weight based on the total weight of the filling composition 102.

[0111] In another embodiment of this method, polyethylene oxide 108 can be mixed into the filler composition 102 in any amount, as long as the hydrophilic carrier 112 is present in an amount of up to 65% by weight based on the total weight of the filler composition 102. In this embodiment, the minimum amount of hydrophilic carrier 112 may optionally be at least 55% by weight based on the total weight of the filler composition 102. In this embodiment, the minimum amount of hydrophilic carrier 112 may optionally be at least about 30% by weight, or at least about 40% by weight, or at least about 55% by weight based on the total weight of the filler composition 102. In this alternative embodiment, the amount of PEO 108 may be about 5% to about 35% by weight, or about 20% by weight.

[0112] The hydrophilic carrier 112 mixed into the packing composition 102 may have a number average molecular weight of 50 to 7000 daltons, 200 to 5000 daltons, more preferably about 300 to 3000 daltons, and most preferably about 400 to 1500 daltons. In certain embodiments, the hydrophilic carrier 112 may have a number average molecular weight lower than 200 daltons.

[0113] The hydrophilic carrier 112 is preferably selected from polyethylene glycol, polypropylene glycol, or other known hydrophilic solvents. Most preferably, water and / or the hydrophilic carrier 112 is polyethylene glycol. The water and / or the hydrophilic carrier 112 is mixed into the filling composition 102 in an amount up to 65% by weight, based on the total weight of the filling composition 102. In alternative embodiments, the water and / or the hydrophilic carrier 112 is mixed into the filling composition 102 in an amount of about 30% to about 70% by weight, based on the total weight of the filling composition 102. Preferably, the water and / or the hydrophilic carrier 112 is mixed into the filling composition 102 in an amount of about 40% to about 60% by weight, based on the total weight of the filling composition 102.

[0114] In yet another embodiment, water and / or hydrophilic carrier 112 may be present in the filling composition 102 in any amount, provided that polyethylene oxide 108 is present in an amount of at least 21.5% by weight, based on the total weight of the filling composition 102.

[0115] In certain embodiments, the weight ratio (individually or cumulatively) of polyethylene oxide 108 to water and / or hydrophilic carrier 112 is approximately 10:1 to approximately 1:10, approximately 8:1 to approximately 1:8, approximately 5:1 to approximately 1:5, approximately 3.1 to approximately 1:3, approximately 2:1 to approximately 1:2, approximately 10:1 to approximately 1:3, approximately 8:1 to approximately 1:3, approximately 5:1 to approximately 1:3, approximately 3:1 to approximately 1:3, approximately 2:1 to approximately 1:3, approximately 1:1 to approximately 1:3, approximately 10:1 to approximately 1:2, approximately 8:1 to approximately 1:2, approximately 5:1 to approximately 1:2, approximately 3:1 to approximately 1:2, approximately 1:1 to approximately 1:2, or any subrange or single weight ratio value therein. In one embodiment, the weight ratio (individually or cumulatively) of PEO108 to water and / or hydrophilic carrier 112 in the filling composition 102 is in the range of about 2:1 to about 1:2. In one embodiment, the weight ratio of PEO108 to water and / or hydrophilic carrier 112 (individually or cumulatively) in the filling composition 102 is in the range of about 3:1 to 1:3.

[0116] One or more additional API release rate control polymers 110 that can be mixed with the filling composition 102 can be selected from one or more of the following polymers, hydroxypropyl methylcellulose, cellulose derivatives, chitosan, carnauba wax, carbomers and polysaccharides, or any other release rate control polymers described herein, or combinations thereof. After mixing the filling composition 102 (step 104), the filling composition 102 is encapsulated in a capsule shell (step 116) to produce capsules. After the encapsulation step 116, the softgel capsules are preferably dried (step 118), although this step is optional. In certain embodiments, if a drying step 118 is present, not too much water should be removed from the capsule shell, as water in the capsule shell that migrates into the filling composition during a subsequent heating step acts as a solubilizer that solubilizes the filling composition in situ.

[0117] Next, the softgel capsules are heated to a temperature of about 40°C to about 80°C for a period of about 10 minutes to about 180 minutes (step 120). More preferably, the softgel capsules are heated to a temperature of about 45°C to about 70°C (step 120). Most preferably, the softgel capsules are heated to a temperature of about 50°C to about 60°C (step 120). More preferably, the softgel capsules are heated for a period of about 20 minutes to 120 minutes, most preferably for a period of about 30 minutes to 90 minutes (step 120). After the softgel capsules have been heated (step 120), the final capsule 122 is formed. The purpose of this heating step (which may also be called annealing or curing) is to solubilize particles in the suspension or dispersion type liquid filler using water that migrates from the capsule shell into the filler composition during the heating step. As a result, the filler composition forms a homogeneous solution which solidifies upon cooling to form a homogeneous solid or semi-solid solution in the filler composition that provides at least partially controlled release properties. Typically, a water content of approximately 10% to 15% by weight in the capsule shell (e.g., softgel capsule shell) is used at the start of the heating process to provide sufficient water transfer to the filling composition to form the filling composition solution. If the water content of the capsule shell is too high after encapsulation, an optional drying process can be employed before the heating (or annealing) process to reach the desired water content of the softgel capsule shell.

[0118] In this method, the capsule is prepared by a process (step 120) which includes heating a capsule 122 containing a filling composition. The API release profile exhibited by capsule 122 can be adjusted by selecting the molecular weight and / or concentration of PEO108 in the filling composition. In some embodiments, the API release rate is such that 10-80% of API106 is released after 0.5 hours in a fiber optical dissolution test using a USP apparatus II with a paddle speed of 100 RPM at 37°C in 500 ml of biological, artificial, or simulated gastric fluid such as 0.1 N HCl and / or pH 6.8 phosphate buffer and / or water. More preferably, the release rate can be determined in a fiber microscopy dissolution test using a USP apparatus II with 500 ml of biological, artificial, or simulated gastric fluid, such as 0.8N hydrochloric acid and / or water, at 37°C and a paddle speed of 100 rpm, where 20-100% of the API is released after 1 hour, 30-100% after 6 hours, 50-100% after 12 hours, 70-100% after 18 hours, or 80-100% after 24 hours.

[0119] In a particular embodiment, the method provides capsules for encapsulating a controlled-release-filled composition that releases approximately 10 wt% to approximately 30 wt% of the API. In each case, the controlled-release-filled composition is encapsulated to release approximately 10 wt% to approximately 30 wt% of the API after 1 hour, approximately 15 wt% to approximately 50 wt% of the API after 2 hours, approximately 20 wt% to approximately 80 wt% of the API after 4 hours, approximately 40 wt% to approximately 95 wt% of the API after 8 hours, approximately 65 wt% to approximately 100 wt% of the API after 12 hours, and more than 90 wt% of the API after 24 hours. The results were measured in vitro by optical fiber dissolution test using a USP instrument II (paddle) at 37°C and 100 RPM in biological, artificial, or simulated gastric fluid such as 500 ml of 0.1N HCl and / or biological, artificial, or simulated intestinal fluid such as pH 6.8 phosphate buffer and / or water.

[0120] The method of the present invention may include an optional step of drying the capsules 122 (step 118) before the heating step 120. The drying step 118 may be carried out at a temperature of 20-30°C for a period of 24-240 hours under mild temperature and humidity conditions (20-35°C and 10-50% or 20-40% or 30% relative humidity).

[0121] In certain embodiments, the immediate disclosure also relates to a method of treating a condition, which includes administering one of the capsules described herein to a subject in need of it. The term “condition” or “condition” refers to those medical conditions that can be treated or prevented by administering an effective amount of the active pharmaceutical ingredient to a subject.

[0122] In certain embodiments, the immediate disclosure relates to a method for adjusting the dissolution profile of a controlled-release filling composition, the method adjusting at least one of i) to v) to achieve a target dissolution profile of the API, comprising: i) the number-average molecular weight of polyethylene oxide in the controlled-release filling composition; ii) the concentration of polyethylene oxide in the controlled-release filling composition; iii) the water or hydrophilic carrier content of the controlled-release filling composition; iv) the annealing temperature; and v) the annealing time.

[0123] The following embodiments illustrate, but do not limit, the present disclosure. Various conditions and parameters commonly encountered in the art, and other suitable modifications and adaptations that are obvious to those skilled in the art, are within the scope of the present disclosure. The following embodiments illustrate the practice of the present disclosure in some preferred embodiments.

[0124] Examples Examples 1-6 Dissolution Profile of Filling Composition As shown in Table 1 below, a 2x3 full factorial design of experiment with overlap was used to design the six (6) filling compositions used in Samples 1–12. Each composition was prepared twice to evaluate the variability of the compositions. Diphenhydramine hydrochloride was used as a model drug for the active pharmaceutical ingredient in the filling compositions. "PEG 400" is an abbreviation for polyethylene glycol with a number average molecular weight of 400, "PEO" is an abbreviation for polyethylene oxide, "M" is an abbreviation for "million", "HCl" is an abbreviation for hydrogen chloride, and "Mn" is an abbreviation for number average molecular weight. All PEOs used in Examples 1–12 were nonionic and water-soluble, and were Polyox® products available from DuPont Pharma Solutions. [Table 1]

[0125] Diphenhydramine capsules for samples 1-12, using the filling compositions shown in Table 1, were prepared as follows. First, diphenhydramine HCl (DHP) was solubilized in 2 ml of water, and PEG400 was mixed with PEO to form a two-component filling composition. Subsequently, an aqueous DPH solution was added to the PEG / PEO mixture. 0.55 g of the filling composition was filled into each size 0 capsule, providing a dose of 50 mg of diphenhydramine per capsule. Next, the capsules were annealed in an oven at 60°C for 1 hour.

[0126] Dissolution tests were performed using pre-filled size 0 gelatin hard-shell capsules containing the filling composition, with a USP apparatus II, at paddle speeds of 50 rpm and 100 rpm, by optical fiber dissolution at 37α in 500 ml of water as the dissolution medium. The filling compositions used in the dissolution tests are shown in Table 2. [Table 2]

[0127] Figure 2 shows the dissolution profiles of the six types of filling compositions listed in Table 2 at a paddle speed of 100 RPM. Figure 3 shows the dissolution profiles of the six (6) filling compositions listed in Table 2 at a paddle speed of 50 RPM.

[0128] The dissolution profiles were similar for each filler composition at paddle speeds of 50 RPM and 100 RPM, indicating that the drug release mechanism is primarily by diffusion. The dissolution results show that higher molecular weight PEO and higher PEO concentrations resulted in slower drug release, respectively. Filler compositions 5 and 6, prepared from 0.1 M PEO, had immediate release profiles, while all other filler compositions exhibited variable drug release rates, as shown in Figures 2-3.

[0129] The Minitab 16 software package was used to analyze the collected lysis dataset. The time to reach 90% drug release was used as the dependent variable. The effects of PEO content and PEO molecular weight on the dependent variable were analyzed using the General Linear Model module of the Minitab 16 software package. The results are summarized in Table 3-4-6 below. [Table 3] [Table 4] [Table 5] [Table 6]

[0130] The following abbreviations were used in the table above: DF - degrees of freedom. Seq refers to the continuous square root sum, which is a measure of the variation of different components of a SS model. The adjusted sum of squares for the Adj SS term is the increase in the regression sum of squares compared to the model with only the other terms. AdjMS (Adjusted Mean Sum of Squares) measures how much variation a term or model explains. The FF value is a test statistic used to determine whether a model lacks higher-order terms that include predictors of the current model. P - probability. A P < 0.05 indicates a statistically significant result; otherwise, it is not significant. N - the number of data points.

[0131] Figure 4 shows the residual plot for 90% of time (hours). Figure 4A is the normal probability plot, Figure 4B is the paired fit, Figure 4C is the histogram, and Figure 4D is the paired rank. Figure 5 is the interaction plot for time (hours) up to 90% of release. Figure 6 is a graph showing the main effects plot for 90% of time (hours) up to release.

[0132] Based on these statistical analyses, an interaction exists between the time to release and the molecular weight and concentration of PEO. The higher the PEO molecular weight and the higher the PEO concentration, the slower the API release.

[0133] Example 7 - Immediate-release composition of PEO polymer, high-Mn polyethylene glycol, and HPMC polymer Immediate-release compositions based on PEO resin, high molecular weight polyethylene glycol, and low viscosity hydroxypropyl methylcellulose (HPMC) were developed for potential applications in abuse-deterrent softgel capsules. Three (3) formulations were prepared, as shown in Table 7 below. Formulation 13 contained PEO and PEG3350 with a number average molecular weight of 100,000 Da. Formulation 14 contained PEO and HPMC. Formulation 15 contained PEO, PEG3350, and HPMC. [Table 7]

[0134] Size 0 diphenhydramine (DPH) capsules were prepared by mixing PEG400 and PEO with PEG 3350 and / or HPMC. DPH was solubilized in water, and the DPH solution was added to the PEG / PEO mixture, HPMC / PEO mixture, or PEO / PEG / HPMC mixture. Each capsule was filled with 0.5 g of the filling mixture (25 mg of diphenhydramine per capsule). Finally, the capsules were annealed in an oven at 60°C for 1 hour.

[0135] For dissolution studies, fiber optical dissolution was performed using a USP apparatus II at a paddle speed of 100 RPM. The dissolution profiles of formulations 13-15 at 37°C in 500 ml of water as the dissolution medium are shown in Figure 7.

[0136] Formulations 13-15 were shown to be immediate-release formulations. Diphenhydramine release reached 100% from these formulations in approximately one hour. Formulation 15 had the fastest drug release rate among the three formulations. While not bound by theory, this is likely due to the higher amount of PEG3350 in formulation 15.

[0137] Examples 8-10: Controlled-release PEO softgel capsules Three batches of softgel capsules containing filling compositions made of PEO resins with various number-average molecular weights (900,000 Da, 5,000,000 Da, and 7,000,000 Da) were manufactured using a softgel capsule encapsulation machine. The filling compositions used in the batches are shown in Tables 8-10 below. [Table 8] [Table 9] [Table 10]

[0138] After encapsulation, the softgel capsules were sealed in aluminum bags for 5 days to allow moisture to migrate from the moist capsule shell to the filler. This moisture migration was utilized to solubilize the PEO in the filler composition, form a gel, and provide a sustained release profile. After 5 days, the filler moisture content of each capsule was tested, and the results are shown in Table 11 below. [Table 11]

[0139] Although the filling moisture content was sufficiently high, the results indicated that the PEO resin particles inside the softgel capsules were not completely dissolved. Without being bound by theory, it seems that PEG400 was binding to the filling moisture, preventing the complete solubilization of the PEO resin particles. Therefore, the softgel capsules were annealed in an oven at 60°C for 1 hour to melt and solubilize the PEO resin particles. Using 500 ml of aqueous solvent, optical fiber dissolution was performed at 37°C at paddle speeds of 50 RPM and 100 RPM using a USP apparatus II, and the in vitro drug release rate was evaluated. The comparative dissolution results of capsules prepared with three (3)PEO resins with different number-average molecular weights are shown in Figures 8-9.

[0140] At a paddle speed of 100 RPM, capsules containing PEO with a number-average molecular weight of 900,000 Da showed a faster drug release rate compared to capsules prepared with PEO with a number-average molecular weight of 5,000,000 or 7,000,000 Da. Capsules prepared with PEO with number-average molecular weights of 5,000,000 and 7,000,000 Da showed similar drug release rates. At 50 RPM, the dissolution profiles were similar for all three capsules in Examples 8-10.

[0141] As shown in Figures 10-15, differential scanning colorimetric (DSC) analysis was performed on the PEO resins and filler compositions used for soft encapsulation. The blue curve represents the initial heating at 10°C per minute. The green curve represents the cooling at 10 cycles per minute. The red curve represents the heating at 10 cycles per minute. The three PEO resins reached a melting temperature of 60°C or less in the first heating cycle. Without being constrained by theory, this low melting temperature of the filler compositions is considered to be due to the plasticizing effect of PEG400 on the PEO resins. DSC analysis can be employed to select appropriate processing and annealing temperatures for specific filler compositions.

[0142] Controlled-release softgel-filled compositions based on polyethylene oxide resin were developed according to the experimental design. The effects of PEO concentration and molecular weight on drug release rate were investigated. Drug release rate was significantly affected by both PEO molecular weight and PEO polymer concentration. Higher PEO molecular weight or PEO polymer concentration resulted in slower drug release rate. Dissolution profiles were similar for the same compositions at either 50 rpm or 100 rpm paddle speeds, indicating that the drug release mechanism is primarily due to diffusion through the polymer matrix.

[0143] Compositions containing low molecular weight PEO, PEG3350, and low viscosity HPMC have also been developed for immediate-release softgel capsules. These compositions exhibited an immediate-release profile when subjected to dissolution tests.

[0144] Three batches of softgel capsules containing various MnPEO resins were manufactured. The softgel capsules were subjected to dissolution testing. All three batches of softgel capsules showed extended release profiles. DSC analysis was performed on the PEO resins and the three compositions. PEG400 in the compositions appears to act as a plasticizer for the PEO resins, resulting in a lower melting point (<60°C) of the PEO resins, which is advantageous for product manufacturing.

[0145] To demonstrate how the viscosity of a filler composition can be controlled by varying the amounts of polyethylene oxide and polyethylene glycol in the filler composition, three compositions containing only polyethylene oxide (Polyox®) and polyethylene glycol 400 were prepared. The filler compositions and their viscosities are shown in Table 12 below. [Table 12]

[0146] However, although numerous features and advantages of the present disclosure are described above, along with details of the structure and function of the present disclosure, it should be understood that the present disclosure is merely illustrative and that details, particularly of shape, size and arrangement of parts, may be modified within the principles of the disclosure to the maximum extent indicated by the broad general meaning of the terms used in the appended claims.

Claims

1. A controlled-release capsule-filled composition, (i) Active pharmaceutical ingredients, (ii) Based on the total weight of the controlled-release capsule filling composition, 10 wt% to 65 wt% of polyethylene oxide having a number average molecular weight of 0.05 M Dalton to 15 M Dalton, (iii) 30% to 65% by weight of polyethylene glycol having a number average molecular weight of 50 Daltons to 3000 Daltons, based on the total weight of the controlled-release capsule filling composition, and (iv) Optionally, a controlled-release capsule filling composition comprising water.

2. A controlled-release capsule-filled composition according to claim 1, wherein the active pharmaceutical ingredient is present in an amount of 5% to 60% by weight based on the total weight of the controlled-release capsule-filled composition.

3. A controlled-release capsule-filled composition according to any one of claims 1 to 2, wherein the polyethylene oxide is present in an amount of 21.5 wt% to 65 wt% based on the total weight of the controlled-release capsule-filled composition.

4. A controlled-release capsule-filled composition according to any one of claims 1 to 3, wherein the combination of polyethylene glycol and water is present in an amount greater than 30% by weight and up to 75% by weight, based on the total weight of the controlled-release capsule-filled composition.

5. A controlled-release capsule-filled composition according to any one of claims 1 to 4, wherein the number-average molecular weight of the polyethylene oxide is 500,000 daltons to 10,000,000 daltons.

6. A controlled-release capsule-filled composition according to any one of claims 1 to 5, wherein the combination of polyethylene glycol and water is present in an amount of 40 to 60% by weight based on the total weight of the controlled-release capsule-filled composition.

7. A controlled-release capsule-filled composition according to any one of claims 1 to 6, further comprising a hydrophilic carrier selected from polypropylene glycol, acetic acid, formic acid, other hydrophilic solvents, and combinations thereof.

8. A controlled-release capsule-filled composition according to any one of claims 1 to 7, wherein the polyethylene oxide is present in an amount of 25 to 40% by weight based on the total weight of the controlled-release capsule-filled composition.

9. It is a capsule, (c) soft capsule shell or hard capsule shell, and (d) The controlled release filling composition according to any one of claims 1 to 8, encapsulated in the soft capsule shell or hard capsule shell, A capsule containing [this ingredient].

10. A capsule according to claim 9, wherein, in a fiber optical dissolution test using a USP apparatus II at a paddle speed of 100 rpm at 37°C in 500 ml of 0.1 N HCl or water, less than 80% of the active pharmaceutical ingredient is released after 0.5 hours.

11. A method for manufacturing soft capsules, (a) A step of mixing liquid filling compositions, (i) Active pharmaceutical ingredients, (ii) 10 wt% to 65 wt% polyethylene oxide having a number average molecular weight of 0.05 M Dalton to 15 M Dalton, (iii) Based on the total weight of the liquid filling composition, 30% to 65% by weight of polyethylene glycol having a number average molecular weight of 200 Daltons to 3000 Daltons, (iv) optionally, the mixing step including water, (b) A step of encapsulating the mixed liquid filling composition from step (a) into a soft gel capsule shell in order to provide the soft gel capsule, and (c) A method comprising the step of annealing the softgel capsule at a temperature of 40°C to 80°C for a period of 10 to 180 minutes to form a solid or semi-solid solution-filled composition inside the softgel capsule shell.

12. The method according to claim 11, wherein the active pharmaceutical ingredient is present in an amount of 5% to 60% by weight based on the total weight of the filling composition, and the active pharmaceutical ingredient is classified into one of the biopharmaceutical classification systems classes I, II, III, and IV.

13. A method according to any one of claims 11 to 12, wherein the polyethylene oxide is present in an amount of 31.5 wt% to 65 wt% based on the total weight of the filling composition.

14. A method according to any one of claims 11 to 13, wherein the combination of polyethylene glycol and water is present in an amount greater than 30 wt% and up to 75 wt% based on the total weight of the filling composition.

15. A method according to any one of claims 11 to 14, wherein the number average molecular weight of the polyethylene oxide is 1,000,000 to 8,000,000 daltons.

16. A method according to any one of claims 11 to 15, wherein the combination of polyethylene glycol and water is present in an amount of 40 to 60% by weight based on the total weight of the filling composition.

17. A method according to any one of claims 11 to 16, wherein the polyethylene oxide is present in an amount of 25 to 40% by weight based on the total weight of the filling composition.

18. A method according to any one of claims 11 to 17, further comprising the step of drying the softgel capsule before step (c).

19. A method according to any one of claims 11 to 18, wherein the liquid-filled composition mixed in step (a) further comprises an additional release rate-controlling polymer.

20. A soft gel capsule, (a) A liquid-filled composition, (i) Active pharmaceutical ingredients, (ii) 10 wt% to 65 wt% polyethylene oxide having a number average molecular weight of 0.05 M Dalton to 15 M Dalton, (iii) 30% to 65% by weight of polyethylene glycol having a number average molecular weight of 200 Daltons to 3000 Daltons, based on the total weight of the liquid filling composition, and (iv) Optionally, the liquid filling composition comprising water, (b) A softgel capsule for encapsulating the liquid-filled composition, wherein the softgel capsule for encapsulating the liquid-filled composition is annealed at a temperature of 40°C to 80°C for a period of 10 to 180 minutes to form a solid or semi-solid solution-filled composition within the softgel capsule shell, and the softgel capsule releases 10% to less than 80% of the active pharmaceutical ingredient after 0.5 hours in a fiber optical dissolution test using a USP apparatus II at a paddle speed of 100 rpm at 37°C in 500 ml of 0.1 N HCl or water.

21. It is a capsule, Shell composition and, A controlled release filling composition, (i) Active pharmaceutical ingredients, (ii) 10 wt% to 65 wt% polyethylene oxide having a number average molecular weight of 0.05 M Dalton to 15 M Dalton, based on the total weight of the controlled release filling composition, and (iii) Based on the total weight of the controlled release filling composition, 30% to 65% by weight of polyethylene glycol having a number average molecular weight of 200 Daltons to 3000 Daltons, (iv) optionally, the controlled release filling composition comprising water, Herein, the capsule substantially contains no fluidity enhancer selected from glyceryl monocaprylate, glyceryl monocaprylcaprate, glyceryl monolinoleate, oleic acid, magnesium stearate, or combinations thereof.

22. A capsule according to claim 21, wherein the controlled-release filling composition is a liquid, a solid, or a semi-solid.

23. A method for adjusting the dissolution profile of a controlled release filling composition, wherein the method is: A step of adjusting at least one of i) to iii) to achieve a targeted lysis profile of the API, i) The number average molecular weight of polyethylene oxide in the release-controlled filling composition, ii) Annealing temperature and, iii) Annealing time, including, The controlled release filling composition is (a) Active pharmaceutical ingredients, (b) Based on the total weight of the controlled-release capsule filling composition, 10 wt% to 65 wt% of polyethylene oxide, (c) A method comprising 30% to 65% by weight of polyethylene glycol having a number average molecular weight of 50 daltons to 3000 daltons, based on the total weight of the controlled-release capsule filling composition.

24. A release-controlled capsule-filled composition according to any one of claims 1 to 8, wherein the weight ratio of the weight of (ii) to the weight of the combination of (iii) to (iv) is in the range of 10:1 to 1:

3.

25. It is a capsule, Shell composition and, A capsule comprising a controlled-release capsule filling composition according to any one of claims 1 to 8, wherein the active pharmaceutical ingredient is less likely to be abused.

26. It is a capsule, Shell composition and, A capsule comprising a release-controlled capsule filling composition according to any one of claims 1 to 8.

27. It is a capsule, A shell composition containing gelatin, and A capsule comprising a release-controlled capsule-filled composition according to any one of claims 1 to 8, wherein the capsule is annealed.

28. A method for manufacturing capsules, wherein the method is (a) A step of mixing the liquid form of the release control capsule filling composition according to any one of claims 1 to 8, Here, the mixing step is such that the weight ratio of the weight of (ii) and the weight of the combination of (iii) and (iv) is in the range of 10:1 to 1:3, and (b) A method comprising the step of encapsulating the mixed liquid release control capsule filling composition from step (a) within a capsule shell composition in order to provide the capsule.

29. A method for producing a softgel capsule according to claim 28, wherein the method is: A method wherein the liquid release control capsule filling composition mixed in step (a) further comprises an additional release rate control polymer.

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