Improved api stability in softgels

Abstract

An improved stability of an active pharmaceutical ingredient and a method for manufacturing the same are provided. In some embodiments, the softgel comprises a filler composition and a softgel shell. In some embodiments, the filler composition of the softgel comprises one or more active pharmaceutical ingredients (APIs); 2 to 15 weight% povidone; 30 to 60 weight% polyethylene glycol; and 0.5 to 5 weight% propylene glycol, and the filler composition has a pH of 3.75 or lower. In some embodiments, the softgel shell is prepared from a softgel shell composition comprising an acidic ingredient.

Description

Technology Field

[0001] Cross-reference of related applications

[0002]

[0001] This application claims priority to U.S. Provisional Application No. 62 / 816,621 filed March 11, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0003] Field of invention

[0004]

[0002] The present invention relates to a soft gel, and specifically, to a soft gel in which the stability of an active pharmaceutical compound (API) is improved by minimizing instability over time. Background Technology

[0005]

[0003] Softgels are a common dosage form for pharmaceutical compounds. Specifically, softgels are pharmaceutical oral dosage forms that are generally easy to swallow, resistant to disturbance, and cause fewer gastrointestinal disturbances than alternative dosage forms such as liquids and tablets. Softgels consist of two main components: a shell and a filler. Some softgel shells may contain gelatin, water, opacifiers, and plasticizers. The filler contains an active pharmaceutical ingredient (API) and any number of inactive ingredients.

[0006]

[0004] Undesirable reactions can often occur between the softgel shell and the softgel filler. For example, water may migrate from the softgel shell to the filler, altering the physical and chemical properties of both the filler and the softgel shell. Similarly, components of the filler may migrate to the softgel shell, also altering the physical and chemical properties of both. In addition to the above, excipients and their degradation products may interact with the API in a negative manner. Depending on the chemical components that migrate and participate in adverse effects, these reactions may have adverse effects on the efficacy, safety, etc., of the API.

[0007]

[0005] A filler composition, a softgel shell composition, a softgel composition, and a method for manufacturing the same are described. The provided composition and the method for manufacturing the filler composition, the softgel shell composition, and the softgel composition improve the stability of one or more APIs by resolving issues related to the interaction between the softgel shell and the softgel filler. Such adverse effects occur between the softgel shell and the softgel filler and can have a detrimental effect on the stability of one or more components of the softgel.

[0008]

[0006] One or more APIs may degrade upon exposure to specific inactive components of the softgel. For example, phenylephrine may react with inactive components of the filler, such as povidone or PEG, causing the degradation of phenylephrine. In some embodiments, degradation products of inactive substances, such as povidone or PEG, may react with phenylephrine to cause degradation. If an API such as phenylephrine degrades in the softgel, the stability of phenylephrine is compromised. API instability may affect the shelf life, strength, and / or efficacy of the softgel.

[0009]

[0007] Accordingly, the filler composition, the softgel shell composition, the softgel composition, and the method for preparing the same are related to improving the stability of one or more APIs of the softgel. In some embodiments, the filler composition may include an acidic solution. In some embodiments, the filler composition may include an antioxidant. In some embodiments, the softgel shell composition may include an acidic solution. In some embodiments, controlling the pH of the filler to a value less than the pKa of one or more degradation substances can improve the stability of the API of the softgel.

[0010]

[0008] In some embodiments, a pharmaceutical softgel is provided, said softgel comprises a filler composition comprising: one or more active pharmaceutical ingredients (API); 2 to 15 wt% povidone; 30 to 60 wt% polyethylene glycol; and 0.5 to 5 wt% propylene glycol, (wherein the filler composition has a pH of 3.75 or less), and a softgel shell.

[0011]

[0009] In some embodiments of the softgel, the softgel shell is prepared from a softgel shell composition containing an acidic component.

[0012]

[0010] In some embodiments of the softgel, the acidic component contains hydrochloric acid.

[0013]

[0011] In some embodiments of the softgel, one or more APIs include ibuprofen, phenylephrine, dextromethorphan, acetaminophen, or guaifenesin.

[0014]

[0012] In some embodiments of the softgel, the API contains phenylephrine.

[0015]

[0013] In some embodiments of the softgel, the filler composition contains at least 30 weight percent of the total API.

[0016]

[0014] In some embodiments of the softgel, the softgel contains 60 weight percent or less of the total API.

[0017]

[0015] In some embodiments of the softgel, the povidone comprises one or more of povidone K-12 and povidone K-30.

[0018]

[0016] In some embodiments of the softgel, the povidone contains povidone K-30.

[0019]

[0017] In some embodiments of the softgel, the polyethylene glycol includes PEG 400.

[0020]

[0018] In some embodiments of the softgel, the filler composition comprises 0.5% by weight to 1.0% by weight of 0.5 N hydrochloric acid.

[0021]

[0019] In some embodiments of the softgel, the softgel contains 1% to 2% by weight of 25% potassium iodide.

[0022]

[0020] In some embodiments, a filler composition for softgels is provided, said composition comprising one or more active pharmaceutical ingredients (APIs), 2 to 15 weight% povidone, 30 to 60 weight% polyethylene glycol, and 0.5 to 5 weight% propylene glycol, and said filler composition has a pH of 3.75 or lower.

[0023]

[0021] In some embodiments of the composition, one or more APIs include at least one of ibuprofen, phenylephrine, dextromethorphan, acetaminophen, and guaifenesin.

[0024]

[0022] In some embodiments of the composition, one or more APIs include phenylephrine.

[0025]

[0023] In some embodiments of the composition, the composition comprises 30 weight percent or more of the total API.

[0026]

[0024] In some embodiments of the composition, the composition comprises 60 weight percent or less of the total API.

[0027]

[0025] In some embodiments of the composition, the povidone comprises at least one of povidone K-12 and povidone K-30.

[0028]

[0026] In some embodiments of the composition, the povidone includes povidone K-30.

[0029]

[0027] In some embodiments of the composition, the polyethylene glycol includes PEG 400.

[0030]

[0028] In some embodiments of the composition, a pH of 3.75 or lower is achieved by mixing hydrochloric acid into the filler composition.

[0031]

[0029] In some embodiments of the composition, the composition comprises 1% to 2% by weight of 25% potassium iodide.

[0032]

[0030] In some embodiments, a method for preparing a filler composition for softgels is provided, the method comprises the following steps: combining 30 to 60 weight% polyethylene glycol, 0.5 to 5 weight% propylene glycol, 2 to 15 weight% povidone, one or more active pharmaceutical ingredients (APIs), and an acidic ingredient to achieve a pH of 3.75 or lower of the filler composition.

[0033]

[0031] In some embodiments of the method, one or more APIs include ibuprofen, phenylephrine, dextromethorphan, acetaminophen, or guaifenesin.

[0034]

[0032] In some implementations of the method, the API includes phenylephrine.

[0035]

[0033] In some embodiments of the method, the method comprises 30 weight percent or more of API.

[0036]

[0034] In some embodiments of the method, the method comprises 60 weight percent or less of API.

[0037]

[0035] In some embodiments of the method, the povidone includes one or more of povidone K-12 and povidone K-30.

[0038]

[0036] In some embodiments of the method, the povidone includes povidone K-30.

[0039]

[0037] In some embodiments of the method, the polyethylene glycol includes PEG 400.

[0040]

[0038] In some embodiments of the method, the acidic component comprises 0.5 wt% to 1.0 wt% of 0.5 N hydrochloric acid.

[0041]

[0039] In some embodiments of the method, the method comprises 1 to 2 weight percent of 25% potassium iodide.

[0042]

[0040] In some embodiments, a method for manufacturing a softgel is provided, the method comprises the following steps: combining 30 to 60 weight% polyethylene glycol, 0.5 to 5 weight% propylene glycol, 2 to 15 weight% povidone, one or more active pharmaceutical ingredients (APIs), and an acidic ingredient for forming a filler having a pH of 3.75 or lower; and encapsulating the filler in a softgel shell to form a softgel.

[0043]

[0041] In some embodiments of the method, the softgel shell is prepared from a softgel shell composition containing an acidic component.

[0044]

[0042] In some embodiments of the method, the acidic component includes hydrochloric acid.

[0045]

[0043] In some embodiments of the method, one or more APIs include ibuprofen, phenylephrine, dextromethorphan, acetaminophen, or guaifenesin.

[0046]

[0044] In some implementations of the method, the API includes phenylephrine.

[0047]

[0045] In some embodiments of the method, the method comprises 30 weight percent or more of API.

[0048]

[0046] In some embodiments of the method, the method comprises 60 weight percent or less of API.

[0049]

[0047] In some embodiments of the method, the povidone includes one or more of povidone K-12 and povidone K-30.

[0050]

[0048] In some embodiments of the method, the povidone includes povidone K-30.

[0051]

[0049] In some embodiments of the method, the polyethylene glycol includes PEG 400.

[0052]

[0050] In some embodiments of the method, the method comprises adding an acid containing 0.5% to 1.0% by weight of 0.5 N hydrochloric acid.

[0053]

[0051] In some embodiments of the method, the preparation of the filler composition comprises adding 1% to 2% by weight of 25% potassium iodide. Brief explanation of the drawing

[0054]

[0052] The present invention will be described with reference to the accompanying drawings for illustrative purposes only, wherein:

[0053] FIG. 1 shows a chromatogram superposition of a stress-applied PE analysis at 70 °C according to some embodiments, showing a peak at approximately 21.6 min;

[0054] FIG. 2 illustrates the change of povidone K-30 in the presence of PE according to some embodiments;

[0055] FIG. 3 illustrates the change in the povidone K-30 spectrum over time in the presence of PE according to some embodiments;

[0056] Figure 4 illustrates the effect of KI in the filler composition on the formation of the PE-povidone peak;

[0057] FIG. 5 illustrates the effect of KI in a filler composition according to some embodiments on the formation of total PE-related degradation products;

[0058] FIG. 6 illustrates the effect of various conditions on the formation of the PE-povidone peak according to some embodiments;

[0059] FIG. 7 illustrates the effect of pH of the filler composition on the formation of the PE-povidone peak according to some embodiments;

[0060] FIG. 8 illustrates the effect of various HCl concentrations on the formation of PE-povidone peaks according to some embodiments;

[0061] FIG. 9 illustrates the effects of HCl, KI, and additional antioxidants on the stability of PE in a filler composition according to some embodiments;

[0062] FIG. 10 illustrates the effect of HCl, KI, and additional antioxidants on the formation of PE RS-1 in a filler composition according to some embodiments;

[0063] FIG. 10 illustrates the effect of HCl, KI, and additional antioxidants on the formation of 4-aminophenol in a filler composition according to some embodiments;

[0064] FIG. 12 illustrates the effect of encapsulation on PE stability for a filler composition containing HCl and KI according to some embodiments;

[0065] FIG. 13 illustrates the effect of moisture in the filler composition on PE decomposition according to some embodiments;

[0066] FIG. 14 illustrates the effect of air exposure on PE degradation for softgels having or not having HCl and KI according to some embodiments;

[0067] FIG. 15 illustrates the analysis of a filler composition buffered at 25 mM according to some embodiments;

[0068] FIG. 16 illustrates the analysis of a filler composition buffered at 50 mM according to some embodiments;

[0069] FIG. 17 illustrates the effect of various levels of HCl in gelatin on PE stability according to some embodiments. Specific details for implementing the invention

[0055]

[0070] A filler composition with improved API stability, a softgel shell composition, and exemplary embodiments of the softgel composition, as well as a method for manufacturing the filler with improved API stability, the softgel shell, and the softgel, are described. As described above, the fillers may interact with each other and with the softgel shell of the formed softgel, and may cause instability of one or more components of the softgel shell and / or fillers. The embodiments described herein relate to stabilizing one or more APIs of the filler in the manufactured softgel.

[0056]

[0071] In some embodiments, phenylephrine may interact directly with an inactive component of the filler or may interact with a degradation product of the inactive component. Such interactions may cause degradation of phenylephrine in the softgel, which may shorten shelf life, reduce strength, and / or degrade the effectiveness of the softgel. In some embodiments, other APIs, such as ibuprofen, guaifenesin, dextromethorphan, acetaminophen, and / or benzonatate, may experience instability due to interactions with an inactive component of the filler. In some embodiments, one or more APIs (e.g., phenylephrine) may be degraded by interacting with an inactive component such as povidone or PEG. In some embodiments, one or more APIs (e.g., phenylephrine) may be degraded by interacting with a degradation product of one or more inactive components such as povidone or PEG.

[0057]

[0072] Accordingly, some embodiments provided herein relate to improving the stability of an API (e.g., phenylephrine) in a softgel by controlling the pH of a filler. In particular, it has been found that controlling the pH of a filler to a value lower than the pKa of the degradation products of povidone and / or PEG can inhibit the reaction of phenylephrine with the degradation products of povidone and PEG. For example, the filler may be controlled to a pH of 3.75 or lower. By inhibiting the reaction between phenylephrine and the degradation products of povidone and / or PEG, the stability of phenylephrine is improved. Improved phenylephrine stability can improve the shelf life, strength, and / or efficacy of the softgel.

[0058]

[0073] In some embodiments, the pH of the filler is controlled by adding an acidic solution to the filler. In some embodiments, the pH of the filler is controlled by adding an acidic solution to the acidic solution. In some embodiments, the degradation of inactive components (e.g., povidone, PEG) is minimized by adding an antioxidant to the filler. Controlling the degradation of inactive components such as povidone and PEG can improve API stability by limiting the amount of degradation products to which the API (e.g., phenylephrine) can react.

[0059]

[0074] In the following, (1) the instability of API in softgels in general; (2) a filler composition specifically comprising API phenylephrine (PE); (3) a softgel shell composition; and (4) a method for manufacturing the filler composition and the softgel are discussed. Each of the above is discussed in turn below.

[0060] Instability of active pharmaceutical ingredients (APIs) in softgels

[0061]

[0075] The following describes the instability of APIs in softgels. API instability is a more common issue in softgel compositions than in other pharmaceutical formulations (e.g., tablets, liquids, etc.). Examples of APIs and the causes of API instability in softgels are discussed.

[0062]

[0076] Various APIs are suitable for use in softgels. For example, common APIs prepared in softgel form, either alone or in combination, include ibuprofen, phenylephrine, guaifenesin, dextromethorphan, acetaminophen, naproxen, diphenhydramine, sodium docusate, loratadine, cetirizine, pseudoephedrine, doxylamine, chlorpheniramine, diclofenac, and benzonatate. A person skilled in the art can easily identify other APIs suitable for use in the disclosed embodiments.

[0063]

[0077] One example of an API that can be used in softgels is phenylephrine (PE). PE is a vasoconstrictor and decongestant. Most commonly, PE can be used to treat common cold symptoms (i.e., nasal congestion), sinus problems, and hemorrhoids. The instability of various APIs in softgels, particularly PE, is a well-known problem.

[0064]

[0078] The instability of PE is believed to be caused by the degradation of one or more inactive components (i.e., excipients) in the softgel filler and / or softgel shell. Inactive components that can degrade and react adversely with APIs such as PE include polyethylene glycol (PEG) and povidone (also known as “polyvinylpyrrolidone” or “PVP”). For example, PEG is a common excipient used in softgel fillers. When PEG degrades, its degradation products can interact with PE, causing PE degradation. For example, PEG can degrade into aldehydes and / or short-chain organic acids, both of which react readily with PE.

[0065]

[0079] PEG is known to readily decompose into various short-chain organic acids and aldehydes (impurities) in the presence of oxygen and / or water. Short-chain organic acids may include formic acid, acetic acid, and / or glycolic acid. Aldehydes may include formaldehyde and / or acetaldehyde. These PEG degradation products are known to readily interact with PE, causing the degradation of PE within the softgel filler.

[0066]

[0080] Similarly, povidone can also decompose into compounds containing short-chain acids, such as peroxides and formic acid. Like the degradation products of PEG, the degradation products of povidone can also react adversely with APIs such as PE. In particular, certain types of povidone may interact with PE more readily than other types of PE. For example, povidone K-30 reacts more readily with PE than povidone K-12. This is believed to be partly due to the different terminal groups between povidone K-12 and povidone K-30. Specifically, povidone K-12 generates propyl terminal groups using isopropanol during synthesis, whereas povidone K-30 generates hydroxyl terminal groups using water during synthesis. PE readily reacts with hydroxyl groups, such as the hydroxyl terminal groups of povidone K-30. Consequently, PE interacts more readily with povidone K-30 than with povidone K-12. The chemical structures of povidone K-12, povidone K-30, and PE are provided below.

[0067]

[0081] Povidone K-12 (Povidone synthesized with isopropanol):

[0068]

[0069]

[0082] Povidone K-30 (Povidone synthesized with water):

[0070]

[0071]

[0083] Phenylephrine (PE):

[0072]

[0073]

[0084] When PE reacts with the degradation products of PEG and / or povidone, it degrades within the softgel. This degradation is an indicator of PE instability. PE instability can shorten the shelf life of the softgel, lower its strength, increase harmful impurities, and / or reduce its effectiveness.

[0074]

[0085] Accordingly, to reduce the instability of PE in softgels, a method to reduce the interaction between PE and PEG and / or povidone may be used. A conventional method to reduce the instability of PE is to use antioxidants to reduce the amount of PEG and / or povidone degradation products. However, the method for improving PE stability according to the embodiments disclosed herein includes preventing the interaction between PE and PEG / povidone degradation products, and does not necessarily include inhibiting the degradation of PEG and / or povidone. Some embodiments may include a method to minimize the interaction between PE and PEG / povidone degradation products, as well as a method to minimize the degradation of PEG / povidone.

[0075]

[0086] Various embodiments are described below regarding limiting various interactions between one or more APIs (e.g., PE) and degradation products, such as those formed from the degradation of PEG and / or povidone. In some embodiments, introducing an acidic solution into the filler and / or softgel shell may improve API stability. Some embodiments may include an antioxidant, such as potassium iodide (KI), in the filler to improve API stability. In some embodiments, maintaining the pH of the filler below the pKa of the PEG and / or povidone degradation products may inhibit interactions between the PEG and / or povidone degradation products and PE.

[0076] Phenylephrine (PE) Filler Composition with Improved Stability

[0077]

[0087] The following is a description of a filler composition developed to improve API stability. The filler composition provided herein may be encapsulated in a softgel shell to form an administerable pharmaceutical composition. In some embodiments, the filler composition may include an acidic solution for improved API stability (e.g., improved PE stability). In some embodiments, the filler composition may include an antioxidant that inhibits the degradation of one or more inactive components for improved API stability.

[0078]

[0088] In some embodiments, APAP may experience an unstable form in the filler composition. For example, APAP may precipitate in solution. However, it has been found that the type and amount of povidone (i.e., povidone K-12 and / or povidone K-30) and / or the amount of propylene glycol in the filler composition may affect APAP precipitation. Accordingly, some embodiments of the filler composition provided herein may include optimized amounts of specific types of povidone and / or propylene glycol to control the stability of APAP. The amounts of povidone and propylene glycol proposed to be included in the filler composition are provided below.

[0079]

[0089] Example 1A below describes in more detail the effect of povidone and / or PEG on the stability of APAP. For example, the amount of APAP precipitation may be related to the levels of povidone K-30 and / or propylene glycol in the filler composition. In some embodiments, increasing the levels of both povidone K-30 and propylene glycol can minimize APAP precipitation. In some embodiments, decreasing the level of plasticizer in the softgel shell can also minimize APAP precipitation.

[0080]

[0090] In some embodiments, the type and / or amount of excipients may also affect the stability of other APIs in the solution. For example, APIs such as ibuprofen, phenylephrine, guaifenesin, dextromethorphan, and benzonatate may also exhibit behavior similar to that of APAP as described above. In some embodiments, other types of inactive components such as PEG (i.e., PEG400, PEG600, PEG1200, PEG2400) may similarly affect the stability of one or more APIs in the solution.

[0081]

[0091] For example, as described above, povidone K-30 tends to interact with PE. Interactions between povidone K-30 (including any povidone K-30 degradation products) and PE can cause PE instability (i.e., when the amount of PE in the filler composition decreases over time).

[0082]

[0092] However, it has been found that controlling the pH of the filler composition can improve the stability of the PE in the filler composition by minimizing the interaction between povidone K-30 (and / or povidone K-30 degradation products) and PE. In some embodiments, the filler composition may include an acidic solution to control the pH of the filler composition. In some embodiments, the acidic solution may include citric acid, formic acid, acetic acid, and / or hydrochloric acid (HCl). Several tests were performed to introduce HCl into the filler composition, which are described in the following Examples section. The acidic solution should not be limited to a material containing HCl. Those skilled in the art will recognize that any suitable acidic solution may be used to control the pH of the filler composition.

[0083]

[0093] In some embodiments, an antioxidant may also be included in the filler composition. For example, the antioxidant may help control the formation of species corresponding to PE instability. Accordingly, even if KI has little effect on the interaction between PE and povidone / PEG degradation products, if it is present in the filler composition, it may still help control the formation of other PE-related, APAP-related, and / or dextromethorphan-related substances. For example, the presence of KI in the filler composition material may also have a favorable effect in controlling the formation of PE RS-3, an example of a PE-related degradation product. PE RS-3 increases under acidic conditions. Accordingly, the level of PE RS-3 may increase when an acidic solution is added to the filler composition. Adding an antioxidant such as KI may help control the level of PE RS-3. Additionally, the addition of KI may help not only reduce the formation of 4-aminophenol APAP but also stop the formation of N-oxide degradation products of dextromethorphan and doxylamine. Examples of antioxidants include potassium iodide, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, and other suitable antioxidants.

[0084]

[0094] Accordingly, some embodiments provided herein may include an acid to minimize the interaction between PE and the degradation products of one or more inactive components. Some embodiments may also include an antioxidant such as KI to reduce the degradation of one or more inactive components, thereby reducing the presence of certain degradation products that may contribute to the instability of the API.

[0085]

[0095] Various components and amounts of such components that may comprise a filler composition to form a softgel according to an embodiment provided in this specification are provided below.

[0086]

[0096] As used herein, “active pharmaceutical ingredient” or “API” refers to a drug that may be used for the diagnosis, cure, alleviation, treatment, or prevention of a disease. Any API may be used for the purposes of this disclosure. Suitable APIs include, but are not limited to: analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetic agents, antidiabetic agents, antiepileptic agents, antifungal agents, antigout agents, antihypertensive agents, antimalarial agents, antimigraine agents, antimuscarinic agents, antineoplastic agents and immunosuppressants, antinematodes, antirheumatic agents, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac contractility stimulants, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid modifiers, local anesthetics, neuromuscular blockers, nitrates and anti-anginal agents, nutritional preparations, opioid analgesics, oral vaccines, proteins, peptides, and recombinants Drugs, sex hormones and contraceptives, spermicides and stimulants; and combinations thereof. Where present, the API may be present in the pharmaceutical composition in an amount necessary to produce the required physiological effect established by clinical studies. A person skilled in the art can easily determine the amount of API suitable to include in the dosage form prepared according to the present disclosure.

[0087]

[0097] In some embodiments, the filler composition may comprise 15 to 70 weight% of the total API, 20 to 65 weight% of the total API, 25 to 60 weight% of the total API, 30 to 55 weight% of the total API, 35 to 55 weight% of the total API, or 40 to 50 weight% of the total API. In some embodiments, the filler composition may comprise less than 70 weight% of the total API, less than 65 weight% of the total API, less than 60 weight% of the total API, less than 55 weight% of the total API, less than 50 weight% of the total API, less than 45 weight% of the total API, less than 40 weight% of the total API, less than 35 weight% of the total API, less than 30 weight% of the total API, less than 25 weight% of the total API, or less than 20 weight% of the total API. In some embodiments, the filler composition may comprise more than 15 wt% of the total API, more than 20 wt% of the total API, more than 25 wt% of the total API, more than 30 wt% of the total API, more than 35 wt% of the total API, more than 40 wt% of the total API, more than 45 wt% of the total API, more than 50 wt% of the total API, more than 55 wt% of the total API, more than 60 wt% of the total API, or more than 65 wt% of the total API.

[0088]

[0098] In some embodiments, the filler composition may include PE. For example, the filler composition may include 0.1 to 15 wt% PE, 0.2 to 10 wt% PE, 0.3 to 5 wt% PE, or 0.3 to 1 wt% PE. In some embodiments, the filler composition may include less than 15 wt% PE, less than 12 wt% PE, less than 10 wt% PE, less than 8 wt% PE, 5 wt% PE, less than 4 wt% PE, less than 3 wt% PE, less than 2 wt% PE, less than 1.0 wt% PE, less than 0.9 wt% PE, less than 0.8 wt% PE, less than 0.7 wt% PE, less than 0.6 wt% PE, less than 0.5 wt% PE, less than 0.4 wt% PE, less than 0.3 wt% PE, or less than 0.2 wt% PE. In some embodiments, the filler composition may comprise more than 0.1 wt% PE, more than 0.2 wt% PE, more than 0.3 wt% PE, more than 0.4 wt% PE, more than 0.5 wt% PE, more than 0.6 wt% PE, more than 0.7 wt% PE, more than 0.8 wt% PE, more than 0.9 wt% PE, more than 1.0 wt% PE, more than 2 wt% PE, more than 3 wt% PE, more than 4 wt% PE, more than 5 wt% PE, more than 8 wt% PE, more than 10 wt% PE, or more than 12 wt% PE.

[0089]

[0099] In some embodiments, the filler composition may include APAP. For example, the filler composition may include 10 to 50 wt% APAP, 15 to 45 wt% APAP, 20 to 40 wt% APAP, or 25 to 35 wt% APAP. In some embodiments, the filler composition may include less than 50 wt% APAP, less than 45 wt% APAP, less than 40 wt% APAP, less than 35 wt% APAP, less than 30 wt% APAP, less than 25 wt% APAP, less than 20 wt% APAP, or less than 15 wt% APAP. In some embodiments, the filler composition may comprise more than 10 wt% APAP, more than 15 wt% APAP, more than 20 wt% APAP, more than 25 wt% APAP, more than 30 wt% APAP, more than 35 wt% APAP, more than 40 wt% APAP, or more than 45 wt% APAP.

[0090]

[0100] In some embodiments, the filler composition may include dextromethorphan. For example, the filler composition may include 0.2 to 12 wt% dextromethorphan, 0.4 to 10 wt%, 0.6 to 5 wt%, or 0.7 to 1.0 wt% dextromethorphan. In some embodiments, the filler composition may include less than 12 wt%, less than 10 wt%, less than 8 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, less than 1.8 wt%, less than 1.6 wt%, less than 1.4 wt%, less than 1.2 wt%, less than 1.0 wt%, less than 0.8 wt%, less than 0.6 wt%, or less than 0.4 wt% dextromethorphan. In some embodiments, the filler composition may contain more than 0.2 wt%, more than 0.4 wt%, more than 0.6 wt%, more than 0.8 wt%, more than 1.0 wt%, more than 1.2 wt%, more than 1.4 wt%, more than 1.6 wt%, more than 1.8 wt%, more than 2 wt%, more than 3 wt%, more than 4 wt%, more than 5 wt%, more than 8 wt%, or more than 10 wt% of dextromethorphan.

[0091]

[0101] In some embodiments, the filler composition may contain guaifenesin. For example, the filler composition may contain 5 to 30 weight% guaifenesin, 10 to 25 weight%, or 15 to 20 weight% guaifenesin. In some embodiments, the filler composition may contain less than 30 weight%, less than 25 weight%, less than 20 weight%, less than 15 weight%, or less than 10 weight% guaifenesin. In some embodiments, the filler composition may contain more than 5 weight%, more than 10 weight%, more than 15 weight%, more than 20 weight%, or more than 25 weight% guaifenesin.

[0092]

[0102] The filler composition may include any number of types of inactive components (i.e., excipients). In some embodiments, the filler composition may include 30 to 80 weight% of total inactive components, 35 to 75 weight%, 40 to 70 weight%, 45 to 65 weight%, or 50 to 60 weight% of total inactive components. In some embodiments, the filler composition may include less than 80 weight%, less than 75 weight%, less than 70 weight%, less than 65 weight%, less than 60 weight%, less than 55 weight%, less than 50 weight%, less than 45 weight%, or less than 40 weight% of total inactive components. In some embodiments, the filler composition may comprise more than 30 wt%, more than 35 wt%, more than 40 wt%, more than 45 wt%, more than 50 wt%, more than 55 wt%, more than 60 wt%, more than 65 wt%, or more than 70 wt% of the total inactive component.

[0093]

[0103] Some embodiments of the filler composition may include specific inert components such as polyethylene glycol (PEG), propylene glycol, povidone, and / or purified water. The PEG may include any of PEG400, PEG600, PEG1200, and / or PEG2400. In some embodiments, the filler composition may include 30 to 60 wt% PEG, 35 to 55 wt%, or 40 to 50 wt% PEG. In some embodiments, the filler composition may include less than 60 wt%, less than 55 wt%, less than 50 wt%, less than 45 wt%, less than 40 wt%, or less than 35 wt% PEG. In some embodiments, the filler composition may include more than 30 wt%, more than 35 wt%, more than 40 wt%, more than 45 wt%, more than 50 wt%, or more than 55 wt% PEG.

[0094]

[0104] In some embodiments, the filler composition may contain povidone. For example, some embodiments may contain povidone K-12 and / or povidone K-30. In some embodiments, the filler composition may contain 2 to 30 weight% povidone, 3 to 25 weight%, 4 to 20 weight%, or 5 to 15 weight% povidone. In some embodiments, the filler composition may contain less than 30 weight%, less than 25 weight%, less than 20 weight%, less than 15 weight%, less than 12 weight%, less than 10 weight%, less than 8 weight%, less than 5 weight%, or less than 4 weight% povidone. In some embodiments, the filler composition may contain more than 2 wt%, more than 3 wt%, more than 4 wt%, more than 5 wt%, more than 8 wt%, more than 10 wt%, more than 12 wt%, more than 15 wt%, more than 20 wt%, or more than 25 wt% of povidone.

[0095]

[0105] In some embodiments, the filler composition may include propylene glycol. In some embodiments, the filler composition may include 0.25 to 10.0 weight%, 0.5 to 5.0 weight%, or 0.75 to 3.0 weight% of propylene glycol. In some embodiments, the filler composition may include propylene glycol in an amount greater than 0.25 wt%, greater than 0.5 wt%, greater than 0.75 wt%, greater than 1.0 wt%, greater than 1.25 wt%, greater than 1.5 wt%, greater than 1.75 wt%, greater than 2.0 wt%, greater than 2.5 wt%, greater than 3.0 wt%, greater than 3.5 wt%, greater than 4.0 wt%, greater than 4.5 wt%, greater than 5.0 wt%, greater than 5.5 wt%, greater than 6.0 wt%, greater than 6.5 wt%, greater than 7.0 wt%, greater than 8.0 wt%, or greater than 9.0 wt%. In some embodiments, the filler composition may comprise less than 10.0 wt%, less than 9.0 wt%, less than 8.0 wt%, less than 7.0 wt%, less than 6.5 wt%, less than 6.0 wt%, less than 5.5 wt%, less than 5.0 wt%, less than 4.5 wt%, less than 4.0 wt%, less than 3.5 wt%, less than 3.0 wt%, less than 2.5 wt%, less than 2.0 wt%, less than 1.75 wt%, less than 1.5 wt%, less than 1.25 wt%, less than 1.0 wt%, less than 0.75 wt%, or less than 0.50 wt% of propylene glycol.

[0096]

[0106] In some embodiments, the filler composition may include an acidic solution. For example, the acidic solution may include one or more of citric acid, formic acid, acetic acid, hydrochloric acid (HCl), or any other suitable acidic substance. In some embodiments, the acidic solution may have a concentration of 0.05 to 0.5 N, 0.075 to 0.3 N, or 0.10 to 0.20 N. In some embodiments, the concentration may be less than 0.5 N, less than 0.4 N, less than 0.3 N, less than 0.25 N, less than 0.20 N, less than 0.15 N, less than 0.10 N, 0.08 N, or less than 0.075 N. In some embodiments, the acidic solution concentration may be greater than 0.05 N, greater than 0.075 N, greater than 0.08 N, greater than 0.10 N, greater than 0.125 N, greater than 0.15 N, greater than 0.175 N, greater than 0.20 N, greater than 0.25 N, greater than 0.30 N, or greater than 0.40 N. In some embodiments, the filler composition may comprise 0.25-10.0 wt%, 0.5-8.0 wt%, or 1.0-5.0 wt% acidic solution. In some embodiments, the filler composition may include an acidic solution in an amount greater than 0.25 wt%, greater than 0.50 wt%, greater than 0.75 wt%, greater than 1.0 wt%, greater than 1.5 wt%, greater than 2.0 wt%, greater than 2.5 wt%, greater than 3.0 wt%, greater than 3.5 wt%, greater than 4.0 wt%, greater than 4.5 wt%, greater than 5.0 wt%, greater than 6.0 wt%, greater than 7.0 wt%, greater than 8.0 wt%, or greater than 9.0 wt%. In some embodiments, the filler composition is less than 10.0 wt%, less than 9.0 wt%, less than 8.0 wt%, less than 7.0 wt%, less than 6.0 wt%, less than 5.5 wt%, less than 5.0 wt%, less than 4.5 wt%, less than 4.0 wt%, less than 3.5 wt%, less than 3.0 wt%, less than 2.5 wt%, less than 2.0 wt%, less than 1.75 wt%, less than 1.50 wt%, less than 1.25 wt%, 1.It may contain an acidic solution of less than 0 wt%, less than 0.75 wt%, or less than 0.50 wt%.

[0097]

[0107] In some embodiments, the filler composition may include an antioxidant. Examples of antioxidants may include potassium iodide, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, and other suitable antioxidants. In some embodiments, the filler composition may include 0.25 to 5.0 wt%, 0.5 to 4.0 wt%, or 1.0 to 2.0 wt% of an antioxidant. In some embodiments, the filler composition may include more than 0.25 wt%, more than 0.5 wt%, more than 0.75 wt%, more than 1.0 wt%, more than 1.25 wt%, more than 1.50 wt%, more than 1.75 wt%, more than 2.0 wt%, more than 2.5 wt%, more than 3.0 wt%, more than 3.5 wt%, more than 4.0 wt%, or more than 4.5 wt% of an antioxidant. In some embodiments, the filler composition may include an antioxidant in an amount of less than 5.0 wt%, less than 4.5 wt%, less than 4.0 wt%, less than 3.5 wt%, less than 3.0 wt%, less than 2.5 wt%, less than 2.0 wt%, less than 1.75 wt%, less than 1.5 wt%, less than 1.25 wt%, less than 1.0 wt%, less than 0.75 wt%, or less than 0.50 wt%.

[0098]

[0108] In some embodiments, the filler composition may include one or more solvents. For example, the solvent may be water (e.g., purified water). In some embodiments, the filler composition may include 1 to 10 wt% solvent, 1.5 to 9 wt%, 2 to 8 wt%, 2.5 to 7 wt%, 3 to 6 wt%, or 3.5 to 5 wt% solvent. In some embodiments, the filler composition may include less than 10 wt%, less than 9 wt%, less than 8 wt%, less than 7 wt%, less than 6 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, or less than 2 wt% solvent. In some embodiments, the filler composition may contain more than 1 wt%, more than 2 wt%, more than 3 wt%, more than 4 wt%, more than 5 wt%, more than 6 wt%, more than 7 wt%, more than 8 wt%, or more than 9 wt% of solvent.

[0099] softgel shell composition

[0100]

[0109] The following is a description of a softgel shell formulated to improve the API stability of the softgel. The softgel shell is typically a gelatin-based shell that surrounds a filler composition (described in detail above). The softgel shell generally comprises gelatin, an opacifying agent, a plasticizer, and water. In some embodiments, the softgel shell may contain an acidic solution to improve the API stability of the softgel.

[0101]

[0110] In some embodiments, when a filler (i.e., a filler according to any compositional embodiment described above) is encapsulated by a softgel shell, one or more APIs of the filler may experience instability over time. In particular, if a component migrates from the softgel shell to the filler, the pH of the filler changes, which can cause instability of one or more APIs (e.g., PE). Therefore, it has been found that including an acidic solution within the softgel shell of the softgel can help maintain the stability of the APIs of the filler within the softgel. By using an acidic softgel shell, the likelihood of the acidic solution of the filler migrating to the shell of the softgel will be reduced. Accordingly, the acidic environment of the filler can be maintained by encapsulating it in a softgel shell to minimize the reaction between the API and the degradation product(s) of one or more inactive components. The components of the softgel shell and the amounts of the components according to some embodiments provided herein are presented below.

[0102]

[0111] While most softgel shells are gelatin-based, some embodiments of the softgel shell may include other materials such as carrageenan, starch, or other suitable gelling agents. In some embodiments, the softgel shell may include 15% to 70% by weight, 30% to 50% by weight, or 40% to 45% by weight of a gelling agent. In some embodiments, the softgel shell may include less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 55% by weight, less than 50% by weight, less than 45% by weight, less than 40% by weight, less than 35% by weight, less than 30% by weight, less than 25% by weight, or less than 20% by weight of a gelling agent. In some embodiments, the softgel shell may contain more than 15 wt%, more than 20 wt%, more than 25 wt%, more than 30 wt%, more than 35 wt%, more than 40 wt%, more than 45 wt%, more than 50 wt%, more than 55 wt%, more than 60 wt%, or more than 65 wt% of a gelling agent.

[0103]

[0112] As described above, the softgel shell may include an opacifying agent so that the shell appears opaque. Examples of opacifying agents include titanium dioxide, zinc oxide, and calcium carbonate. In some embodiments, the softgel shell may include 0.1 to 5 wt%, 0.3 to 3 wt%, or 0.5 to 1.0 wt% of an opacifying agent. In some embodiments, the softgel shell may include less than 5 wt%, less than 4.5 wt%, less than 4.0 wt%, less than 3.5 wt%, less than 3.0 wt%, less than 2.5 wt%, less than 2.0 wt%, less than 1.5 wt%, less than 1.0 wt%, less than 0.9 wt%, less than 0.8 wt%, less than 0.7 wt%, less than 0.6 wt%, less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, or less than 0.2 wt% of an opacifying agent. In some embodiments, the softgel shell may contain an opacifying agent in an amount greater than 0.1 wt%, greater than 0.2 wt%, greater than 0.3 wt%, greater than 0.4 wt%, greater than 0.5 wt%, greater than 0.6 wt%, greater than 0.7 wt%, greater than 0.8 wt%, greater than 0.9 wt%, greater than 1.0 wt%, greater than 1.5 wt%, greater than 2.0 wt%, greater than 2.5 wt%, greater than 3.0 wt%, greater than 3.5 wt%, greater than 4.0 wt%, or greater than 4.5 wt%.

[0104]

[0113] Exemplary plasticizers in the softgel shell may include sorbitol, glycerin, and / or other plasticizers suitable for pharmaceutical use. In some embodiments, the softgel shell may contain 10 to 40 weight% or 20 to 30 weight% of a plasticizer. In some embodiments, the softgel shell may contain less than 40 weight%, less than 35 weight%, less than 30 weight%, less than 25 weight%, less than 20 weight%, or less than 15 weight% of a plasticizer. In some embodiments, the softgel shell may contain more than 10 weight%, more than 15 weight%, more than 20 weight%, more than 25 weight%, more than 30 weight%, or more than 35 weight% of a plasticizer.

[0105]

[0114] In some embodiments, as described above, the softgel shell may comprise an acidic solution. For example, the acidic solution may be one or more of citric acid, formic acid, acetic acid, and / or hydrochloric acid (HCl). In some embodiments, the softgel shell may comprise an acidic solution in an amount of 1 wt% to 20 wt%, 2 wt% to 15 wt%, or 3 wt% to 8 wt%. In some embodiments, the softgel shell may comprise an acidic solution in an amount of less than 20 wt%, less than 18 wt%, less than 15 wt%, less than 12 wt%, less than 10 wt%, less than 8 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, or less than 2 wt%. In some embodiments, the softgel shell may contain an acidic solution of more than 1 wt%, more than 2 wt%, more than 3 wt%, more than 4 wt%, more than 5 wt%, more than 8 wt%, more than 10 wt%, more than 12 wt%, more than 15 wt%, or more than 18 wt%.

[0106]

[0115] In some embodiments, the softgel shell may contain water. For example, the softgel shell may contain 30 to 60 weight%, 35 to 55 weight%, or 40 to 50 weight% of water. In some embodiments, the softgel shell may contain more than 30 weight%, more than 35 weight%, more than 40 weight%, more than 45 weight%, more than 50 weight%, or more than 55 weight% of water. In some embodiments, the softgel shell may contain less than 60 weight%, less than 55 weight%, less than 50 weight%, less than 45 weight%, less than 40 weight%, or less than 35 weight% of water.

[0107]

[0116] The softgel shell may also include additional substances, such as coloring agents, flavorings, sugars, fragrances, and other sensory agents. A person skilled in the art can easily determine a suitable type of coloring agent for an embodiment of the present invention.

[0108] Filler composition and method for manufacturing softgel

[0109]

[0117] The following describes a method for manufacturing a filler composition and a softgel with improved API stability. Generally, the filler composition and softgel described herein can be manufactured using techniques that can be easily identified by a person skilled in the art.

[0110]

[0118] For example, the filler composition may be prepared by mixing the essential components described in detail above in a suitable mixing vessel. The suitable mixing vessel may be an OLSA 200 L mixing vessel, an OLSA 2000 L mixing vessel, or any other suitable closed system having high-shear mixing, temperature control, and nitrogen-blanket functions. Some APIs, such as APAP, may need to be dissolved in the solution. After all components are properly mixed, the solution may be degassed and cooled.

[0111]

[0119] To encapsulate the filler composition into a softgel shell, an encapsulation device may be used. For example, a 6-inch or 7.24-inch encapsulation device or any other suitable encapsulation device may be used to encapsulate the filler composition. After encapsulation, the softgel may be dried until a predefined hardness is achieved.

[0112] Examples

[0113]

[0120] Additional details, including specific test data for some of the generally described embodiments above, are provided below.

[0114]

[0121] Example 1: A filler composition was prepared and tested to observe its physical and chemical stability characteristics. Specifically, a filler composition was prepared comprising APIs acetaminophen, guaifenesin, dextromethorphan, and phenylephrine, and inactive components including PEG, propylene glycol, povidone, and water. The physical and chemical stability of the filler composition was tested as described below.

[0115]

[0122] Example 1A—Physical Stability: To evaluate the physical stability of the filler composition, the filler composition according to the described embodiment was encapsulated in a conventional softgel shell (i.e., a softgel shell not specifically formulated to maintain an acidic pH within the filler composition according to the described embodiment) and observed under ambient conditions. The specific components of the tested filler composition are provided in Table 1. In the initial test, APAP precipitates easily in solution.

[0116]

[0123] The type and amount of povidone were varied to test the effect on APAP precipitation. Filler composition A (according to Table 1 below) contained an increased amount of povidone K-30. The amounts of PEG400, propylene glycol, and water were adjusted to account for the increased povidone, but were maintained to be relatively similar to the amounts in the original filler composition. Filler composition B contained povidone K-12 instead of povidone K-30. The specific amounts of the components for both filler composition A and filler composition B are provided in Table 1 below.

[0117] ingredient Composition A (weight%) Composition B (weight%) PEG 400 42.8 42.8 Propylene glycol 1.5 1.5 Povidone K-12 6.7 0 Povidone K-30 0 6.7 Acetaminophen 27.1 27.1 Phenylephrine 0.4 0.4 Dextromethorphan 0.8 0.8 Guaifenesin 16.7 16.7 purified water 4.0 4.0

[0118] Table 1. Two exemplary filler compositions.

[0124] Both of the two filler compositions in Table 1 (i.e., filler composition A and filler composition B) were prepared, encapsulated in conventional softgel shells, and observed over time. In the case of filler composition A containing povidone K-12, APAP was observed to precipitate from the solution one week after composition and encapsulation. However, in the case of filler composition B containing povidone K-30, APAP did not precipitate from the solution until nearly two weeks after composition and encapsulation. Similarly, other filler compositions were tested to evaluate the effect on the physical stability of APAP. The lowest level of APAP precipitation was observed in filler compositions containing increased amounts of povidone K-30 and propylene glycol, and in softgel shells with reduced amounts of plasticizer.

[0119]

[0125] Example 1B—Chemical Stability: In addition to the physical stability of the filler compositions described above, the chemical stability of filler compositions encapsulated in conventional softgel shells was also evaluated under accelerated conditions. The chemical stability of the filler compositions observed under accelerated conditions showed an inappropriately large amount of PE degradation for all compositions encapsulated in conventional softgel shells. For example, some results showed a PE loss of 7–10% over a period of two months.

[0120]

[0126] In addition, as PE degradation increased, the appearance of unknown degradation products within the filler also increased. To identify the identity of these unknown degradation products, the filler composition material was encapsulated, stress was applied at 70°C, and analyzed over time. By comparing the chromatograms of the results provided in Figure 1, the identity of the peaks that increased as the amount of PE decreased (i.e., as a result of PE instability) was determined.

[0121]

[0127] Figure 1 illustrates four superimposed chromatograms of a filler composition subjected to stress at 70°C according to some embodiments described above. Specifically, chromatograms were obtained on day 0, day 5, day 13, and day 22 to observe the effect on the filler composition over time. As shown in the figure, superimposed chromatography demonstrates a gradually increasing peak over time (approximately at 21.6 minutes).

[0122]

[0128] Based on the increasing peak in Fig. 1, the evaluation of each filler component revealed that the peak corresponds to the residence time of povidone K-30. Additionally, as the peak size increases, the maximum ultraviolet (UV) radiation appears at ~276 nm, which suggests the possibility that the unknown degradation product indicated by the increasing peak in Fig. 1 is directly related to PE degradation (explained in more detail below).

[0123]

[0129] Example 2—Identification of the cause of PE instability:To confirm that the increasing peak in Figure 1 is associated with PE degradation, two separate filler samples were prepared. Both samples contained all inactive components included in the compositions of Table 1 (i.e., PEG, propylene glycol, povidone K-30, and water). The first sample additionally contained PE (“PE-alone” sample). The second sample, in addition to PEG, propylene glycol, povidone K-30, and water, additionally contained APAP, guaifenesin, and dextromethorphan, but did not contain PE. Each sample was tested at 70 °C and analyzed using chromatography at various time points over a period of 15 days (see Figure 2).

[0124]

[0130] Figure 2 illustrates the superimposed chromatograms for the two samples described above. The PE-alone sample is provided on the left side of the figure, and the APAP, guaifenesin, and dextromethorphan samples, which do not contain PE, are provided on the right side of the figure. Chromatograms were obtained on Day 0, Day 6, and Day 15. Figure 2 demonstrates that the peak at approximately 21.6 min increases only for the first sample containing PE. In contrast, the peak for the sample containing APAP, guaifenesin, and dextromethorphan, but not PE, maintained approximately the same height. Thus, the chromatogram in Figure 2 confirmed that the unknown degradation product represented by the 21.6 min peak is due to the interaction between PE and povidone K-30.

[0125]

[0131] As mentioned above, just as the peak size increases over time, a maximum UV at ~276 nm also occurs, as illustrated in Fig. 3. The left figure shows the UV spectrum for the povidone K-30 peak in a filler composition containing only PE (not containing other APIs). The right figure shows the UV spectrum for the povidone K-30 peak in a filler composition containing APAP, guaifenesin, and dextromethorphan (not containing PE). As shown in Fig. 3, the UV spectrum of the povidone K-30 peak for the filler composition containing PE changed to exhibit a maximum UV at approximately 276 nm. However, the UV spectrum of the povidone K-30 peak remained unchanged for the composition without PE. Therefore, these data further support the conclusion that the observed PE degradation is a result of the interaction between povidone K-30 and PE.

[0126]

[0132] A test similar to the one provided in FIG. 1-3 was performed on a filler composition containing povidone K-12 instead of povidone K-30. However, no interaction was observed between povidone K-12 and PE in the test, which suggests that povidone K-12 does not significantly contribute to the degradation of PE.

[0127]

[0133] Example 3—Use of an antioxidant to control the formation of decomposition products: Filler composition samples were prepared by adding potassium iodide (KI), and the effects of both ionic strength and the presence of iodine on the formation of the PE-povidone peak were evaluated. The results provided in Figure 5 indicate that the addition of KI has little effect on the formation of the PE-povidone peak.

[0128]

[0134] Specifically, Figure 4 shows the results of two different samples of the filler composition. Each of the two samples contained PE, dextromethorphan, and 13% povidone K-30. Additionally, one sample contained 5% KI, and the other sample contained 5% water. Both samples were tested at 70 °C over a period of 15 days and showed the formation of a relatively large PE-povidone peak. Accordingly, these results indicate that the addition of KI to the filler composition has little effect on the formation of the PE-povidone peak compared to a filler composition containing only water and not KI.

[0129]

[0135] Adding KI to the filler composition had little effect on the formation of the PE-povidone peak, but it did affect the formation of other known PE-related substances (as shown in Fig. 5). Fig. 5 shows two samples of filler compositions tested over a period of 15 days at 70 °C. Both samples contained PE, dextromethorphan, and 13% povidone K-30. One sample contained only water, and the other sample contained KI. As shown, the filler composition sample containing KI showed less formation of PE degradation products than the filler composition sample containing only water.

[0130]

[0136] Therefore, the presence of acid is essential not only to improve the stability of the API within the softgel filler composition, but also to reduce the presence of certain degradation products that can contribute to the instability of the API.

[0131]

[0137] Example 4—Inhibition of interaction between API (e.g., phenylephrine) and inactive ingredient: Various studies were conducted to evaluate the effects of pH, air, peroxide, water, and povidone concentrations on the formation of PE (or “PE-PVP” “PE-Povidone”) degradation products. Some of the results of the above tests are shown in Fig. 6.

[0132]

[0138] Figure 6 provides data illustrating the effects of pH (top left), air (top right), peroxide (bottom left), and water (bottom right) on the change in the povidone K-30 peak at 70 °C. As shown in Figure 6, pH has the greatest influence on the formation of the PE-povidone peak. Specifically, samples of a filler composition containing HCl (acidic pH) caused a nearly 400% reduction in the change of the PE-povidone peak compared to a filler composition containing sodium hydroxide (basic pH). Other variables (air, peroxide, and / or water) did not cause such a dramatic effect on the povidone K-30 peak.

[0133]

[0139] Example 5—Test of pH effect: It was determined that pH affects PE stability, so tests were conducted at various pH values. Filler compositions of various pH values ​​were prepared using the prepared acetate buffer. Both samples were tested at 70°C over a period of 15 days, and the results are provided in Fig. 7.

[0134]

[0140] Figure 7 provides data from three different filler compositions. One sample was tested at pH 3.6, another at pH 4.6, and yet another at pH 5.6. Based on the results provided in the figure, the PE-povidone peak is directly proportional to the pH of the filler composition. In particular, as the pH of the filler composition decreases, the interaction between povidone and PE also decreases.

[0135]

[0141] Example 6—Addition of acid to filler composition: The results of the test shown in Figure 7 indicate that lowering the acidity of the filler composition can reduce the decomposition of PE. To lower the acidity of the filler composition, various amounts of 0.1 N HCl were added to the filler composition and tested.

[0136]

[0142] Samples of various filler compositions prepared with varying amounts of HCl were subjected to stress at 70°C and tested over a period of 15 days. Specifically, five different samples were prepared and tested over a period of 15 days. All samples contained PE, dextromethorphan, and 13% povidone K-30. However, the five samples contained varying amounts of HCl as follows: 5% 1.0N HCl, 3.75% 1.0N HCl, 2.5% 1.0N HCl, 0.5% 1.0N HCl, and 5% water (without HCl). The results of the above tests are shown in Fig. 8 and described below.

[0137]

[0143] As shown in Figure 8, a filler composition containing only water (approximately neutral pH) was found to have the greatest effect on the povidone K-30 peak. In contrast, a filler composition containing 0.5% 0.1N HCl was found to have a slightly smaller effect on the povidone K-30 peak, and filler composition samples containing 2.5%, 3.75%, and 5.0% 0.1N HCl were found to have a much smaller effect on the povidone K-30 peak.

[0138]

[0144] Example 7-9—PE Stability of Filler Composition Containing Acid and Antioxidant: To monitor and evaluate the formation of all PE degradation products, filler composition additives were evaluated using a filler composition containing only PE and dextromethorphan as APIs. To monitor the effects on all APIs present in combination, various amounts of HCl and KI, in addition to various antioxidants, were evaluated using filler composition A of Table 1. Composition A was also used because it exhibited the lowest amount of APAP precipitation (as stated above).

[0139]

[0145] These tests confirm that the stability of PE is maximum in the presence of HCl. However, the high acidity of the composition due to the addition of HCl increases the formation of both 4-aminophenol and PE-RS-1 (another PE-related degradation product). Accordingly, the addition of KI as an antioxidant helps control the levels of these other degradation products mentioned above. The addition of other antioxidants was shown to have little effect on the stability of the composition. The results of these studies are illustrated in Figures 9-11 and described below.

[0140]

[0146] Figure 9 illustrates the effect of HCl, KI, and additional antioxidants on the stability of PE in a filler composition according to some embodiments. Specifically, 11 different samples were tested at 70 °C over a period of 20 days. The filler composition samples included a filler composition comprising one of the following: 2.1% water; 2.1% HCl (0.25 N); 2.1% KI (25%); 2.1% HCl:KI (0.25 N:25%); 2.1% HCl (0.125 N); 2.1% KI (12.5%); 2.1% HCl:KI (0.125 N:12.5%); 2.0% water and 0.16% propyl gallate (PG); 2.1% water and 0.02% butylated hydroxytoluene (BHT); 2.0% water and 0.08% butylated hydroxyanisole (BHA); or 2.0% water and 0.02% BHT and 0.08% BHA.

[0141]

[0147] Only the sample containing HCl demonstrated adequate PE stability by maintaining more than 99% of the original amount of PE during the test period. In contrast, the sample not containing HCl showed insufficient PE stability by losing at least 8% of the original amount of PE during the 20-day test period. These results confirm that filler compositions containing a lower pH can help minimize PE degradation within softgels.

[0142]

[0148] Figure 10 illustrates the effect of HCl, KI, and additional antioxidants on the formation of PE RS-1 in the filler composition according to some embodiments. PE RS-1 is a degradation product of PE. Accordingly, an increase in the level of PE RS-1 indicates an increase in the level of PE degradation. The 11 samples tested in the above study were identical to the samples tested in Figure 9. The 11 samples were tested at 70 °C over a period of 20 days. Specifically, the filler composition samples contained a filler composition comprising one of the following: 2.1% water; 2.1% HCl (0.25 N); 2.1% KI (25%); 2.1% HCl:KI (0.25 N:25%); 2.1% HCl (0.125 N); 2.1% KI (12.5%); 2.1% HCl:KI (0.125 N:12.5%); 2.0% water and 0.16% propyl gallate (PG); 2.1% water and 0.02% butylated hydroxytoluene (BHT); 2.0% water and 0.08% butylated hydroxyanisole (BHA); or 2.0% water and 0.02% BHT and 0.08% BHA.

[0143]

[0149] The results of Figure 10 indicate that PE RS-1 levels increase in filler compositions containing only HCl. However, in filler compositions containing KI (regardless of whether HCl is included), PE RS-1 levels remain relatively low. Accordingly, the study confirms that the presence of KI in filler compositions can help control the formation of PE RS-1, an undesirable PE degradation product.

[0144]

[0150] Figure 11 illustrates the effect of HCl, KI, and additional antioxidants on the formation of 4-aminophenol in the filler composition according to some embodiments. 4-aminophenol is another example of PE degradation products. The 11 samples were identical to the samples tested in Figures 9 and 10. Specifically, the filler composition samples contained a filler composition comprising one of the following: 2.1% water; 2.1% HCl (0.25N); 2.1% KI (25%); 2.1% HCl:KI (0.25N:25%); 2.1% HCl (0.125N); 2.1% KI (12.5%); 2.1% HCl:KI (0.125N:12.5%); 2.0% water and 0.16% propyl gallate; 2.1% water and 0.02% butylated hydroxytoluene (BHT); 2.0% water and 0.08% butylated hydroxyanisole (BHA); or 2.0% water and 0.02% BHT and 0.08% BHA.

[0145]

[0151] Based on the results provided in Fig. 11, the formation of 4-aminophenol increases with compositions containing HCl rather than KI. However, the level of 4-aminophenol remains low in compositions containing KI at high pH. Accordingly, as with PE RS-1 in Fig. 10, the presence of KI can help control the formation of PE RS-1 as well as 4-aminophenol.

[0146]

[0152] Example 10—Encapsulation of filler:Filler compositions according to various embodiments were encapsulated using Type A (pig skin) and Type B (animal bone) gelatin. Filler compositions encapsulated with such softgel shells correspond to the embodiments described above. In particular, in some embodiments, filler compositions exhibiting suitable API stability in the presence of HCl and KI were tested. Various softgel samples were tested at both room temperature and accelerated conditions (50 °C and 70 °C). Additionally, softgel samples subjected to stress at 50 °C were tested in two different ways: stressing when undamaged and stressing when cut to expose to air. In some embodiments, filler compositions subjected to stress at 70 °C prior to encapsulation were also used.

[0147]

[0153] Figure 12 demonstrates that softgels subjected to stress at 70 °C experienced rapid PE degradation regardless of the type of filler composition. Figure 12 provides data on the stability of PE in the filler composition tested over a period of 20 days at 70 °C (left) and the stability of PE in the finished softgels tested over a period of 20 days at 70 °C (right). As shown in the graph on the left, three different filler composition samples were tested: a sample containing 2.6 mM HCl / 0.26% KI; a sample containing 2.6 mM HCl (0% KI); and a sample containing 2.6 mM HCl / 0.38% KI. The PE stability for each of the three samples was nearly identical. These data support the aforementioned tests, which confirmed that PE stability is pH-dependent (and inversely proportional to pH). Furthermore, the PE stability of the (unencapsulated) filler composition does not depend on the presence of KI.

[0148]

[0154] On the right side of Fig. 12, four different softgel samples were tested: a sample containing a filler composition containing 2.6 mM HCl / 0.26% KI; a sample containing a filler composition containing 2.6 mM HCl (without KI); a sample containing a filler composition containing 2.6 mM HCl / 0.38% KI; and a sample containing a filler composition not containing HCl or KI. All four samples experienced significant PE degradation. Interestingly, the two samples containing KI experienced slightly worse PE stability than the two samples not containing KI.

[0149]

[0155] Accordingly, the results of FIG. 12 demonstrate that although the filler composition containing HCl and KI exhibited excellent stability prior to encapsulation as discussed above, it experienced significant PE degradation upon encapsulation. Thus, the results provided in FIG. 12 indicate that the encapsulation of the filler composition alters the filler composition in some way, causing PE instability / degradation.

[0150]

[0156] Examples 11-13—Investigation of the Cause of PE Degradation During Encapsulation Based on the characteristics of the encapsulation process and the associated chemical components, the three major factors that could potentially cause PE degradation as a result of encapsulation are as follows: water ingress from the shell into the filler composition, exposure of the filler composition to air, and migration of components from the filler composition into the softgel shell. Each of these three possible causes was tested, and details are provided below.

[0151]

[0157] The first possible cause, water ingress from the shell into the filler composition, was investigated by increasing the moisture content of the filler composition and applying stress at 70°C. Figure 13 illustrates the effect of moisture in the filler composition on PE degradation. Specifically, two different samples of the filler composition were tested: one containing 2% water and the other containing 10% water. Both samples were tested at 70°C over a period of 15 days. As shown, the results in Figure 13 indicate that PE stability is independent of the moisture content of the filler composition, as there is almost no difference in PE stability between the two samples.

[0152]

[0158] A second possible cause, air exposure of the filler composition, was investigated by applying stress at 50 °C to both undamaged and cut-opened softgels. Specifically, Figure 14 illustrates the effect of air exposure on PE degradation for softgels containing or not containing HCl and KI. The following four different softgels were tested: a filler composition without HCl / KI from unopened softgels; a filler composition without HCl / KI from opened softgels; a filler composition containing HCl / KI from unopened softgels; and a filler composition containing HCl / KI from opened softgels. The results from these investigations are provided in Figure 14, demonstrating that there is no apparent correlation between PE stability and air exposure. Furthermore, these investigations indicate that the degradation rate of softgels containing HCl and KI is substantially the same as that of softgels not containing HCl or KI.

[0153]

[0159] The third possible factor, the migration of components of the filler composition into the softgel shell, was investigated by specifically examining the migration of HCl from the filler composition into the softgel shell. It is known that hydrophilic components, such as acids, can migrate rapidly into the softgel shell. Furthermore, based on the investigation discussed above, it is also known that the degradation of PE is independent of KI. It should be noted that the migration of other APIs and inactive components was not considered because the degradation rate of PE in the filler composition not containing HCl and KI is the same before encapsulation as the degradation rate of PE in the filler composition not containing HCl and KI after encapsulation (in the finished softgel).

[0154]

[0160] Therefore, the effect of HCl migration from the filler composition components to the softgel shell on PE degradation was evaluated by comparing the pH of the filler composition before encapsulation with the pH of the filler composition after encapsulation (after removal from the softgel shell). The test indicated that the pH of the filler composition increased by approximately 2 full units. (See Examples for details.) Furthermore, the largest degradation product observed in the filler composition (containing HCl and KI) after encapsulation was the PE-formic acid conjugate. However, the results indicate that PE stability improves when the pH of the filler composition is maintained below the pKa of the degradation product (formic acid). Thus, since the pKa of formic acid is approximately 3.75, the results indicate that the pH of the filler composition must be controlled to a level below 3.75 to improve PE stability.

[0155]

[0161] Examples 14 & 15: pH control of filler composition to less than decomposition product pKa:In light of the above results, various tests were performed to control the pH of the filler composition and to study the effect of various pH levels on PE stability. To stabilize the pH of the filler composition, different pH values ​​of 2.4 to 4.4 and various buffer solutions of 25 mM and 50 mM were added to the filler compositions that did not contain HCl or KI and were tested. All samples in Figures 15 and 15 were tested at 70 °C over a period of 15 days.

[0156]

[0162] Figure 15 provides a comparison of buffered filler compositions at various pH values ​​at 25 mM. Specifically, seven different filler composition samples were tested, including: 5% water; 25 mM HCl; 25 mM phosphate (pH 2.4); 25 mM citrate (pH 3.0); 25 mM phosphate (pH 3.2); 25 mM acetate (pH 3.6); and 25 mM acetate (pH 4.4). As shown in the figure, the results varied considerably. However, regarding PE stability, no buffer performed as well as HCl.

[0157]

[0163] Figure 16 provides a comparison of buffered filler compositions at various pH values ​​at 50 mM. In this instance, eight different filler composition samples were tested, including: 5% water; 50 mM HCl; 50 mM phosphate (pH 2.4); 50 mM citrate (pH 3.0); 50 mM phosphate (pH 3.2); 50 mM acetate (pH 3.6); and 50 mM acetate (pH 4.4); and 50 mM citrate (pH 4.4). As with the results in Figure 15, the results here are also varied. However, while HCl has the best effect on PE stability, 50 mM citrate also showed suitable results, similar to the study in Figure 15.

[0158]

[0164] Therefore, introducing various acidic solutions into the filler composition can improve the stability of APIs within softgels. However, the key is to maintain the pH of the filler composition below the pKa of the degradation products of inactive components that may interact with one or more APIs. In particular, it has been found that adding HCl and KI to the filler composition of softgels can improve the stability of APIs such as PE within softgels. Maintaining the pH of the filler below the pKa of PEG and / or povidone degradation products inhibits the interaction between PEG and / or povidone degradation products and PE, thereby improving the stability of the API(s).

[0159]

[0165] Example 16—Movement of acid from a conventional softgel shell to a filler: As described above and illustrated in FIGS. 15 and 16, the encapsulated samples may have experienced HCl migration from the filler to the softgel shell under certain conditions. Therefore, to quantify the intensity of this HCl migration, the pH of the filler composition was compared before and after encapsulation. Details of this test are provided in Table 2 below. The pH values ​​for two different filler compositions are provided: a composition without HCl or KI, and a composition containing HCl.

[0160] composition pH before encapsulation pH after encapsulation Filler composition free of HCl or KI 4.6 N / A HCl-containing filler composition 3.6 5.6

[0161]

[0166] Example 17—Transfer of acid softgel shell containing acidic solution as filler:The effect of pH equilibrium on controlling the pH of the filler composition was evaluated using four individual filler compositions containing 0, 3.75, 7.5, or 15 mM HCl, respectively. Each of the four samples was dispensed into a 20 mL vial (approximately 2 g per vial), fixed, and dried. Approximately 5 g of the filler composition (containing both HCl and KI) was added to the top of the gel mix in the vial, and all vials were placed in a water bath at 45 °C. The vials were analyzed at predetermined time points, and the results are provided in Fig. 17. As illustrated in the figure, the PE degradation of each sample is directly related to the amount of acid in the gelatin. Specifically, the higher the amount of HCl present in the gelatin within the gelatin mix, the better the PE stability of the filler composition on top of the gel mix. Furthermore, the pH of the filler composition in the vial is inversely proportional to the level of HCl in the gel.

[0167] The foregoing description is provided with reference to specific embodiments for illustrative purposes. However, the exemplary description above is not intended to be complete or to limit the invention to the exact form disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments have been selected and described to best illustrate the principles of the technique and its practical application. Accordingly, those skilled in the art can best utilize the technique and various embodiments through various modifications suitable for the specific use being considered.

[0162]

[0168] Although the present specification and embodiments have been sufficiently described with reference to the accompanying drawings, it should be noted that various changes and modifications will be obvious to those skilled in the art. Such changes and modifications should be understood to be included within the scope of the specification and embodiments as defined by the claims.

Claims

Claim 1 A pharmaceutical softgel comprising a fill material composition and a softgel shell, wherein the fill material composition is: One or more active pharmaceutical ingredients (API); Povidone; Polyethylene glycol; and It comprises propylene glycol, wherein the filler composition has a pH of 3.75 or lower, and the softgel shell is: 15 to 70 weight% of a gelling agent; and A pharmaceutical softgel comprising 1 to 20 weight percent of an acidic component. Claim 2 In claim 1, the acidic component comprises citric acid, formic acid, acetic acid, hydrochloric acid, or a combination thereof, softgel Claim 3 In claim 1, the softgel shell comprises 3 to 8 weight percent of an acidic component. Claim 4 In claim 1, the gelling agent comprises gelatin, carrageenan, starch, or a combination thereof, a soft gel. Claim 5 In claim 1, the softgel shell further comprises 0.1 to 5 weight percent of an opacifying agent. Claim 6 In paragraph 5, the opacifying agent comprises titanium dioxide, zinc oxide, calcium carbonate, or a combination thereof, in a soft gel. Claim 7 In claim 1, the softgel shell further comprises 10 to 40 weight percent of a plasticizer. Claim 8 In claim 7, the plasticizer is a softgel comprising sorbitol, glycerin, or a combination thereof. Claim 9 In paragraph 1, the softgel shell is a softgel that additionally contains water. Claim 10 In claim 9, the softgel shell comprises 30 to 60 weight percent water. Claim 11 In claim 1, the softgel shell further comprises a coloring agent, a flavoring agent, sugar, or a combination thereof. Claim 12 A method for manufacturing a softgel, the method comprises: a step of forming a filler having a pH of 3.75 or lower by combining polyethylene glycol, propylene glycol, povidone, one or more active pharmaceutical ingredients (APIs), and a first acidic ingredient; and a step of forming a softgel by encapsulating the filler in a softgel shell, wherein the softgel shell is: 15 to 70 weight% of a gelling agent; and A method for manufacturing a softgel comprising 1 to 20 weight percent of a second acidic component. Claim 13 In paragraph 12, the second acidic component comprises citric acid, formic acid, acetic acid, hydrochloric acid, or a combination thereof. Claim 14 In claim 12, the method comprises a softgel shell containing 3 to 8 weight percent of a second acidic component. Claim 15 In paragraph 12, the method comprises a gelling agent comprising gelatin, carrageenan, starch, or a combination thereof. Claim 16 In claim 12, the method further comprises 0.1 to 5 weight percent of an opacifying agent in the softgel shell. Claim 17 In paragraph 16, the method comprises an opacifying agent comprising titanium dioxide, zinc oxide, calcium carbonate, or a combination thereof. Claim 18 In claim 12, the method further comprises 10 to 40 weight percent of a plasticizer in the softgel shell. Claim 19 In paragraph 18, the plasticizer comprises sorbitol, glycerin, or a combination thereof. Claim 20 In claim 12, the method further comprises 30 to 60 weight percent of water in the softgel shell.

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