Improved API stability in soft capsules

Abstract

The invention relates to improved API stability in soft capsules. A soft capsule having improved stability of an active pharmaceutical ingredient and a method for preparing the same are provided. In some embodiments, a soft capsule comprises a filler material composition and a soft capsule shell. In some embodiments, the filler material composition of the soft capsule comprises one or more active pharmaceutical ingredients (APIs); from 2 to 15 wt.% of povidone; 30 to 60 wt.% of a polyethylene glycol; and 0.5 to 5 wt.% of propylene glycol, wherein the filler material composition has a pH of 3.75 or less. In some embodiments, the soft capsule shell is made from a soft capsule shell composition comprising an acidic component.

Description

This application is a divisional application of the invention patent application with the application date of March 11, 2020, application number 202080035260.6, and invention name “Improved API stability in soft capsules”.

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 816,621, filed on March 11, 2019, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] The present invention relates to soft gelatin capsules, and more particularly to soft gelatin capsules having improved active pharmaceutical compound (API) stability and minimal instability over time. Background Art

[0003] Soft capsules are a common dosage form for pharmaceutical compounds. In particular, soft capsules are oral dosage forms for medications that are generally easier to swallow, tamper-resistant, and often cause less stomach discomfort than alternative dosage forms such as liquids and tablets. Soft capsules comprise two main components: a shell and a filler. Some soft capsule shells may include gelatin, water, an opacifier, and a plasticizer. The filler comprises an active pharmaceutical ingredient (API) and any of a number of inactive ingredients.

[0004] Sometimes, undesirable reactions can occur between the soft capsule shell and the filling material of a soft capsule. For example, water in the soft capsule shell can migrate into the filling material, changing the physical and chemical properties of the filling material and the soft capsule shell. Similarly, components of the filling material can migrate into the soft capsule shell, also changing the physical and chemical properties of the filling material and the soft capsule shell. In addition, excipients and excipient degradation products can interact with the API in a negative manner. These reactions can adversely affect API efficacy, stability, etc., depending on the chemical components that migrate and participate in the adverse reactions. Summary of the Invention

[0005] Filling material compositions, soft capsule shell compositions, soft capsule compositions, and methods for preparing the same are described. The provided compositions and methods for preparing the filling material compositions, soft capsule shell compositions, and soft capsule compositions provide improved stability of one or more APIs by addressing the problem of interactions between the soft capsule shell and the filling material of the soft capsule. These adverse reactions can occur between the soft capsule shell and the filling material of the soft capsule, adversely affecting the stability of one or more components of the soft capsule.

[0006] When exposed to certain inactive ingredients of a softgel, one or more APIs may degrade. For example, phenylephrine may react with inactive ingredients of the filler material (such as povidone or PEG), causing the phenylephrine to decompose. In some embodiments, degradation products of the inactive material (such as povidone or PEG) may react with the phenylephrine and cause it to decompose. When an API such as phenylephrine decomposes in a softgel, the stability of the phenylephrine is compromised. API instability can affect the shelf life, strength, and / or effectiveness of the softgel.

[0007] Therefore, filler material compositions, soft capsule shell compositions, soft capsule compositions, and methods for preparing the same relate to improving the stability of one or more APIs in soft capsules. In some embodiments, the filler material composition may comprise an acidic solution. In some embodiments, the filler material composition may comprise an antioxidant. In some embodiments, the soft capsule shell composition may comprise an acidic solution. In some embodiments, controlling the pH of the filler material to be lower than the pKa of one or more degradation materials can improve the API stability of the soft capsule.

[0008] In some embodiments, a pharmaceutical soft capsule is provided, comprising a fill material composition and a soft capsule shell, wherein the fill material composition comprises: 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 fill material composition has a pH of 3.75 or less.

[0009] In some embodiments of the soft capsule, the soft capsule shell is made of a soft capsule shell composition comprising an acidic component.

[0010] In some embodiments of the soft capsule, the acidic component comprises hydrochloric acid.

[0011] In some embodiments of the soft capsule, the one or more APIs comprise ibuprofen, phenylephrine, dextromethorphan, acetaminophen, or guaifenesin.

[0012] In some embodiments of the soft capsule, the API comprises phenylephrine.

[0013] In some embodiments of the soft capsule, the fill material composition comprises 30 wt. % or more total API.

[0014] In some embodiments of the soft capsule, the soft capsule comprises 60 wt. % or less of total API.

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

[0016] In some embodiments of the soft capsule, the povidone comprises povidone K-30.

[0017] In some embodiments of the soft capsule, the polyethylene glycol comprises PEG 400.

[0018] In some embodiments of the soft capsule, the filling material composition comprises 0.5 wt.% to 1.0 wt.% of 0.5N hydrochloric acid.

[0019] In some embodiments of the soft capsule, the soft capsule comprises from 1 wt.% to 2 wt.% of 25% potassium iodide.

[0020] In some embodiments, a fill material composition for a soft capsule is provided, the 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 fill material composition has a pH of 3.75 or less.

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

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

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

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

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

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

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

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

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

[0030] In some embodiments, there is provided a method for preparing a filling material composition for soft capsules, the method comprising: combining 30 to 60 wt.% polyethylene glycol, 0.5 to 5 wt.% propylene glycol, 2 to 15 wt.% polyvinylpyrrolidone, one or more active pharmaceutical ingredients (API) and an acidic component to achieve a pH of 3.75 or less for the filling material composition.

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

[0032] In some embodiments of the method, the API comprises phenylephrine.

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

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

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

[0036] In some embodiments of the method, the polyvinylpyrrolidone comprises polyvinylpyrrolidone K-30.

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

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

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

[0040] In some embodiments, there is provided a method for preparing soft capsules, the method comprising: combining 30 to 60 wt.% polyethylene glycol, 0.5 to 5 wt.% propylene glycol, 2 to 15 wt.% polyvinylpyrrolidone, one or more active pharmaceutical ingredients (API) and an acidic component to form a filling material having a pH of 3.75 or less; and encapsulating the filling material into a soft capsule shell to form a soft capsule.

[0041] In some embodiments of the method, the soft capsule shell is made of a soft capsule shell composition comprising an acidic component.

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

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

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

[0045] In some embodiments of the method, the method includes 30 wt.% or more of the API.

[0046] In some embodiments of the method, the method includes 60 wt.% or less of the API.

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

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

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

[0050] In some embodiments of the method, the method includes adding an acid comprising 0.5 wt.% to 1.0 wt.% of 0.5 N hydrochloric acid.

[0051] In some embodiments of the method, preparing the filling material composition includes adding 1 wt.% to 2 wt.% of 25% potassium iodide. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] The present invention will now be described by way of example only with reference to the accompanying drawings, in which: Figure 1 Shows chromatogram overlays of PE measured under stress at 70°C according to some embodiments, showing a peak at about 21.6 minutes; Figure 2 Shows the change of povidone K-30 in the presence of PE according to some embodiments; Figure 3 Shows the change of the povidone K-30 spectrum over time due to the presence of PE according to some embodiments; Figure 4 Shows the effect of KI in the filling material composition on the formation of the PE-povidone peak; Figure 5 Shows the effect of KI in the filling material composition on the formation of total PE-related degradation products according to some embodiments; Figure 6 Shows the effect of various conditions on the formation of the PE-povidone peak according to some embodiments; Figure 7 Shows the effect of the pH of the filler composition on the formation of the PE-povidone peak according to some embodiments; Figure 8 Shows the effect of various concentrations of HCl on the formation of the PE-povidone peak according to some embodiments; Figure 9 Shows the effect of HCl, KI, and additional antioxidants on the stability of PE in the filler composition according to some embodiments; Figure 10 Shows the effect of HCl, KI, and additional antioxidants on the formation of PERS-1 in the filler composition according to some embodiments; Figure 11 Shows the effect of HCl, KI, and additional antioxidants on the formation of 4-aminophenol in the filler composition according to some embodiments; Figure 12 Shows the effect of encapsulation on the stability of PE for a filler composition containing HCl and KI according to some embodiments; Figure 13 Shows the effect of moisture in the filler composition on the degradation of PE according to some embodiments; Figure 14 Provides the effect of air exposure on the degradation of PE for soft gelatin capsules with and without HCl and KI according to some embodiments; Figure 15 Shows the analysis of a 25 mM buffered filler composition according to some embodiments; Figure 16 Shows the comparison of a 50 mM buffered filler composition according to some embodiments; and Figure 17 Shows the effect of various levels of HCl in gelatin on the stability of PE according to some embodiments. Detailed Description

[0053] Describes exemplary embodiments of filler compositions, soft gelatin capsule shell compositions, and soft gelatin capsule compositions with improved API stability, as well as methods for preparing fillers, soft gelatin capsule shells, and soft gelatin capsules with improved API stability. As described above, the fillers can interact with each other and with the soft gelatin capsule shell of the formed soft gelatin capsule, and cause instability of one or more components of the soft gelatin capsule shell and / or the filler. The embodiments described herein relate to stabilizing one or more APIs of the filler in the prepared soft gelatin capsule.

[0054] In some embodiments, phenylephrine may interact directly with the inactive ingredients of the filling material or may interact with the degradation products of the inactive ingredients. This interaction can cause phenylephrine to decompose in the soft gelatin capsule, resulting in a shorter shelf life, lower strength, and / or lower effectiveness of the soft gelatin capsule. In some embodiments, other APIs such as ibuprofen, guaifenesin, dextromethorphan, acetaminophen, and / or benzonatate may experience instability due to interaction with the inactive ingredients of the filling material. In some embodiments, one or more APIs (such as phenylephrine) may decompose by interacting with inactive ingredients such as povidone or PEG. In some embodiments, one or more APIs (such as phenylephrine) may decompose by interacting with the degradation products of one or more inactive ingredients such as povidone or PEG.

[0055] Accordingly, some embodiments provided herein relate to improving the stability of APIs (such as phenylephrine) in soft gelatin capsules by controlling the pH of the filling material. In particular, it has been determined that controlling the pH of the filling material below 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 filling material can be controlled to a pH of 3.75 or less. By inhibiting the reaction between phenylephrine and the degradation products of povidone and / or PEG, the stability of phenylephrine is improved. The improved stability of phenylephrine can improve the shelf life, strength, and / or effectiveness of the soft gelatin capsule.

[0056] In some embodiments, the pH of the filling material is controlled by adding an acidic solution to the filling material. In some embodiments, the pH of the filling material is controlled by adding an acidic solution to the soft gelatin capsule shell. In some embodiments, the degradation of inactive ingredients (such as povidone, PEG) is minimized by adding an antioxidant to the filling material. Controlling the degradation of inactive ingredients such as povidone and PEG can improve API stability by limiting the amount of degradation products with which the API (such as phenylephrine) can react.

[0057] Discussed below are: (1) the instability of APIs in soft gelatin capsules generally; (2) specific filling material compositions containing the API phenylephrine (PE); (3) soft gelatin capsule shell compositions; and (4) methods of preparing the filling material compositions and soft gelatin capsules. Each of these is discussed in turn below.

[0058] Drug Active Ingredient (API) Instability in Soft Gelatin Capsules A description of API instability in soft gelatin capsules is provided below. Compared to other drug forms (such as tablets, liquids, etc.), API stability in soft gelatin capsule compositions is a more common problem. Examples of APIs and the reasons for API instability in soft gelatin capsules are discussed.

[0059] A variety of APIs are suitable for use in soft capsules. For example, common APIs prepared in soft capsule form, alone or in combination, include ibuprofen, phenylephrine, guaifenesin, dextromethorphan, acetaminophen, naproxen, diphenhydramine, docusate sodium, loratadine, cetirizine, pseudoephedrine, doxylamine, chlorpheniramine, diclofenac, and benzonatate. Those skilled in the art can readily identify other suitable APIs for use in the disclosed embodiments.

[0060] An example of an API that can be used in softgels is phenylephrine (PE). PE is a vasoconstrictor and decongestant. Most commonly, PE is used to treat common cold symptoms (i.e., nasal congestion), sinus problems, and hemorrhoids. The instability of various APIs in softgels, and particularly PE, is a well-known problem.

[0061] The instability of PE is believed to be due to the degradation of one or more inactive ingredients (i.e., excipients) in the filling material of the soft capsule and / or the soft capsule shell. Degradable and inactive ingredients that react unfavorably with API, such as PE, include polyethylene glycol (PEG) and polyvinyl pyrrolidone (also referred to as "polyvinyl pyrrolidone" or "PVP"). For example, PEG is a common excipient used in the filling material of soft capsules. When PEG degrades, PEG degradation products interact with PE, causing PE degradation. For example, PEG can be decomposed into aldehydes and / or short-chain organic acids, which are all easily reacted with PE.

[0062] Known PEG is easily degraded into several 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. Known these PEG degradation products easily interact with PE, causing the PE in the filling material of soft capsules to degrade.

[0063] Similarly, polyvidone can also degrade into compounds containing peroxides and short-chain acids such as formic acid. Like PEG degradation products, polyvidone degradation products can also react adversely with APIs such as PE. In particular, certain types of polyvidone may be more likely to interact with PE than other types. For example, polyvidone K-30 is more likely to react with PE than polyvidone K-12. This is believed to be partly due to the different end groups between polyvidone K-12 and polyvidone K-30. In particular, polyvidone K-12 uses isopropyl alcohol during synthesis, producing propyl end groups, while polyvidone K-30 uses water during synthesis, producing hydroxyl end groups. PE easily reacts with hydroxyl groups, such as the hydroxyl end groups of polyvidone K-30. Therefore, PE interacts more easily with polyvidone K-30 than polyvidone K-12. The chemical structures of polyvidone K-12, polyvidone K-30, and PE are provided below.

[0064] Povidone K-12 (povidone synthesized with isopropyl alcohol): Povidone K-30 (povidone synthesized with water): Phenylephrine (PE): When PE reacts with the degradation products of PEG and / or povidone, it decomposes in the soft gelatin capsule. This decomposition indicates the instability of PE. The instability of PE can lead to a shorter shelf life of the soft gelatin capsule, lower strength, an increase in potentially harmful impurities, and / or lower effectiveness.

[0065] Therefore, to reduce the instability of PE in the soft gelatin capsule, methods can be employed to reduce the interaction between PE and PEG and / or povidone. Conventional methods for reducing the instability of PE include using antioxidants to reduce the amount of PEG and / or povidone degradation. However, according to the embodiments disclosed herein, the methods for improving the stability of PE include preventing the interaction between PE and the PEG / povidone degradation products, without necessarily inhibiting the degradation of PEG and / or povidone. Some embodiments may include methods for minimizing the interaction between PE and the PEG / povidone degradation products and for minimizing the degradation of PEG / povidone.

[0066] Various embodiments involving restricting the various interactions between one or more APIs (such as PE) and degradation products (such as those formed by the degradation of PEG and / or povidone) are described below. In some embodiments, introducing an acidic solution into the filling material and / or the soft gelatin capsule shell can improve API stability. Some embodiments may include an antioxidant such as potassium iodide (KI) in the filling material to improve API stability. In some embodiments, maintaining the pH of the filling material below the pKa of the PEG and / or povidone degradation products can inhibit the interaction between the PEG and / or povidone degradation products and PE.

[0067] Filling material composition with improved phenylephrine (PE) stability The following is a description of the filling material composition developed to improve API stability. The filling material composition provided herein can be encapsulated with a soft gelatin capsule shell to form an administrable pharmaceutical composition. In some embodiments, the filling material composition may contain an acidic solution to improve API stability (such as improved PE stability). In some embodiments, the filling material composition may contain an antioxidant to inhibit the degradation of one or more inactive ingredients to improve API stability.

[0068] In some embodiments, APAP may experience unstable states in the filler material composition. For example, APAP may precipitate out of solution. However, it has been determined 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 material composition can affect APAP precipitation. Therefore, some embodiments of the filler material compositions provided herein may include optimized amounts of a specific type of povidone and / or propylene glycol to control the stability of APAP. Suggested amounts of povidone and propylene glycol to be included in the filler material composition are provided below.

[0069] Example 1A below describes in more detail the effects of povidone and / or PEG on APAP stability. For example, the amount of APAP precipitation can be correlated with the levels of povidone K-30 and / or propylene glycol in the filler composition. In some embodiments, increasing the levels of povidone K-30 and propylene glycol can minimize APAP precipitation. In some embodiments, reducing the level of plasticizer in the softgel shell can also minimize APAP precipitation.

[0070] In some embodiments, the type and / or amount of excipients may also affect the stability of other APIs in solution. For example, APIs such as ibuprofen, phenylephrine, guaifenesin, dextromethorphan, and benzonatate may also exhibit similar behavior to the APAP described above. In some embodiments, other inactive ingredients such as PEG variants (i.e., PEG400, PEG600, PEG1200, PEG2400) may similarly affect the stability of one or more APIs in solution.

[0071] For example, as described above, povidone K-30 has a tendency to interact with PE. The interaction between povidone K-30 (including any povidone K-30 degradation products) and PE can lead to instability of PE (ie, when the amount of PE in the filler material composition decreases over time).

[0072] However, it has been determined that controlling the pH of the filler material composition can minimize the interaction between povidone K-30 (and / or povidone K-30 degradation products) and PE, and thus improve the PE stability of the filler material composition. In some embodiments, the filler material composition may include an acidic solution to control the pH of the filler material composition. In some embodiments, the acidic solution may include citric acid, formic acid, acetic acid and / or hydrochloric acid (HCl). Several tests were performed in which HCl was introduced into the filler material composition, as described in the Examples section below. The acidic solution should not be limited to materials comprising HCl. Those of ordinary skill in the art will recognize that any suitable acidic solution can be used to control the pH of the filler material composition.

[0073] In some embodiments, an antioxidant may also be included in the filling material composition. For example, the antioxidant can help control the formation of species corresponding to PE instability. Thus, even though KI has little effect on the interaction between PE and the polyvinylpyrrolidone / PEG degradation products, it can still help control the formation of other PE-related, APAP-related, and / or dextromethorphan-related substances when present in the filling material composition. For example, the presence of KI in the filling material composition can also have a beneficial effect on controlling the formation of PERS-3 (an example of a PE-related degradation product). PE RS-3 increases under acidic conditions. Thus, if an acidic solution is added to the filling material composition, the level of PE RS-3 may increase. Adding an antioxidant such as KI can help control the level of PE RS-3. In addition, the addition of KI can help reduce the formation of 4-aminophenol from APAP and prevent 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.

[0074] Accordingly, some embodiments provided herein may include an acid to minimize the interaction between PE and the degradation products of one or more inactive ingredients. Some embodiments may also include an antioxidant such as KI to reduce the degradation of one or more inactive ingredients and thus reduce the presence of certain degradation products that may otherwise cause instability of the API.

[0075] The following provides the various components and amounts of the components that can constitute the filling material composition to form the soft capsules according to the embodiments provided herein.

[0076] As used herein, "active pharmaceutical ingredient" or "API" refers to a pharmaceutical product that can be used for the diagnosis, cure, mitigation, treatment, or prevention of a disease. Any API can be used for the purposes of the present disclosure. Suitable APIs include, but are not limited to: analgesics and anti-inflammatory agents, antacids, antihelmintics, antiarrhythmics, antibacterial agents, anticoagulants, antidepressants, antidiabetic agents, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarials, antimigraine agents, antimuscarinics, antineoplastic and immunosuppressive agents, antiprotozoals, antirheumatics, antithyroid agents, antivirals, anxiolytics, sedatives, hypnotics, and neuroleptics, beta-blockers, inotropes, corticosteroids, cough suppressants, cytotoxics, decongestants, diuretics, enzymes, antiparkinson agents, gastrointestinal agents, histamine receptor antagonists, lipid regulators, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutraceuticals, opioid analgesics, oral vaccines, proteins, peptides, and recombinant drugs, sex hormones and contraceptives, spermicides, and stimulants; and combinations thereof. When present, the API is present in the pharmaceutical composition in an amount necessary to achieve the physiological effect required for the performance determined in clinical studies. A person of ordinary skill in the art can readily determine the appropriate amount of the API to be included in a dosage form prepared according to the present disclosure.

[0077] In some embodiments, the filler material composition can comprise from 15 to 70 wt.% total API, from 20 to 65 wt.% total API, from 25 to 60 wt.% total API, from 30 to 55 wt.% total API, from 35 to 55 wt.% total API, or from 40 to 50 wt.% total API. In some embodiments, the filler material composition can comprise less than 70 wt.% total API, less than 65 wt.% total API, less than 60 wt.% total API, less than 55 wt.% total API, less than 50 wt.% total API, less than 45 wt.% total API, less than 40 wt.% total API, less than 35 wt.% total API, less than 30 wt.% total API, less than 25 wt.% total API, or less than 20 wt.% total API. In some embodiments, the filler material composition can comprise more than 15 wt.% total API, more than 20 wt.% total API, more than 25 wt.% total API, more than 30 wt.% total API, more than 35 wt.% total API, more than 40 wt.% total API, more than 45 wt.% total API, more than 50 wt.% total API, more than 55 wt.% total API, more than 60 wt.% total API, or more than 65 wt.% total API.

[0078] In some embodiments, the filler material composition may comprise PE. For example, the filler material composition may comprise from 0.1 to 15 wt.%, from 0.2 to 10 wt.%, from 0.3 to 5 wt.%, or from 0.3 to 1 wt.% of PE. In some embodiments, the filler material composition may comprise less than 15 wt.%, less than 12 wt.%, less than 10 wt.%, less than 8 wt.%, less than 5 wt.%, 4 wt.%, less than 3 wt.%, less than 2 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 PE. In some embodiments, the filler material composition may comprise more than 0.1 wt.%, more than 0.2 wt.%, more than 0.3 wt.%, more than 0.4 wt.%, more than 0.5 wt.%, more than 0.6 wt.%, more than 0.7 wt.%, more than 0.8 wt.%, more than 0.9 wt.%, more than 1.0 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.%, or more than 12 wt.% of PE.

[0079] In some embodiments, the filler material composition may comprise APAP. For example, the filler material composition may comprise from 10 to 50 wt.%, from 15 to 45 wt.%, from 20 to 40 wt.%, or from 25 to 35 wt.% of APAP. In some embodiments, the filler material composition may comprise less than 50 wt.%, less than 45 wt.%, less than 40 wt.%, less than 35 wt.%, less than 30 wt.%, less than 25 wt.%, less than 20 wt.%, or less than 15 wt.% of APAP. In some embodiments, the filler material composition may comprise more than 10 wt.%, more than 15 wt.%, more than 20 wt.%, more than 25 wt.%, more than 30 wt.%, more than 35 wt.%, more than 40 wt.%, or more than 45 wt.% of APAP.

[0080] In some embodiments, the filling material composition may comprise dextromethorphan. For example, the filling material composition may comprise from 0.2 to 12 wt.% dextromethorphan, from 0.4 to 10 wt.%, from 0.6 to 5 wt.% or from 0.7 to 1.0 wt.% dextromethorphan. In some embodiments, the filling material composition may comprise 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 filling material composition may comprise 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.% dextromethorphan.

[0081] In some embodiments, the filling material composition may comprise guaifenesin. For example, the filling material composition may comprise from 5 to 30 wt.% guaifenesin, from 10 to 25 wt.% or from 15 to 20 wt.% guaifenesin. In some embodiments, the filling material composition may comprise less than 30 wt.%, less than 25 wt.%, less than 20 wt.%, less than 15 wt.% or less than 10 wt.% guaifenesin. In some embodiments, the filling material composition may comprise more than 5 wt.%, more than 10 wt.%, more than 15 wt.%, more than 20 wt.% or more than 25 wt.% guaifenesin.

[0082] The filler material composition may comprise any of many types of inactive ingredients (i.e., excipients). In some embodiments, the filler material composition may comprise from 30 to 80 wt.% total inactive ingredients, from 35 to 75 wt.%, from 40 to 70 wt.%, from 45 to 65 wt.%, or from 50 to 60 wt.% total inactive ingredients. In some embodiments, the filler material composition may comprise less than 80 wt.%, less than 75 wt.%, less than 70 wt.%, less than 65 wt.%, less than 60 wt.%, less than 55 wt.%, less than 50 wt.%, less than 45 wt.%, or less than 40 wt.% total inactive ingredients. In some embodiments, the fill material composition may contain 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.% total inactive ingredients.

[0083] Some embodiments of the filler material composition may include specific inactive ingredients such as polyethylene glycol (PEG), propylene glycol, povidone and / or purified water. PEG may include any one of PEG400, PEG600, PEG1200 and / or PEG2400. In some embodiments, the filler material composition may include from 30 to 60 wt.% PEG, from 35 to 55 wt.% or from 40 to 50 wt.% PEG. In some embodiments, the filler material 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 material 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.

[0084] In some embodiments, the filling material composition may comprise povidone. For example, some embodiments may comprise povidone K-12 and / or povidone K-30. In some embodiments, the filling material composition may comprise from 2 to 30 wt.%, from 3 to 25 wt.%, from 4 to 20 wt.% or from 5 to 15 wt.% povidone. In some embodiments, the filling material composition may comprise less than 30 wt.%, less than 25 wt.%, less than 20 wt.%, less than 15 wt.%, less than 12 wt.%, less than 10 wt.%, less than 8 wt.%, less than 5 wt.% or less than 4 wt.% povidone. In some embodiments, the filling material composition may comprise 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.% povidone.

[0085] In some embodiments, the filling material composition may comprise propylene glycol. In some embodiments, the filling material composition may comprise from 0.25 to 10.0 wt.%, from 0.5 to 5.0 wt.% or from 0.75 to 3.0 wt.% propylene glycol. In some embodiments, the filling material composition may comprise 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 1.5 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.%, more than 4.5 wt.%, more than 5.0 wt.%, more than 5.5 wt.%, more than 6.0 wt.%, more than 6.5 wt.%, more than 7.0 wt.%, more than 8.0 wt.% or more than 9.0 wt.% propylene glycol. In some embodiments, the filling 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.% propylene glycol.

[0086] In some embodiments, the filling material composition may comprise 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 material. In some embodiments, the acidic solution may have a concentration ranging from 0.05 to 0.5 N, from 0.075 to 0.3 N, or from 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, less than 0.08 N, or less than 0.075 N. In some embodiments, the acidic solution may have a concentration 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 filling material composition may contain from 0.25 - 10.0 wt.%, from 0.5 - 8.0 wt.%, or from 1.0 - 5.0 wt.% acidic solution. In some embodiments, the filling material composition may comprise more than 0.25 wt.%, more than 0.50 wt.%, more than 0.75 wt.%, more than 1.0 wt.%, more than 1.5 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.%, more than 4.5 wt.%, more than 5.0 wt.%, more than 6.0 wt.%, more than 7.0 wt.%, more than 8.0 wt.%, or more than 9.0 wt.% acidic solution. In some embodiments, the filling material 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 6.0 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.%, less than 1.0 wt.%, less than 0.75 wt.%, or less than 0.50 wt.% acidic solution.

[0087] In some embodiments, the filling material composition may comprise an antioxidant. Examples of antioxidants may include potassium iodide, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, and other suitable antioxidants. In some embodiments, the filling material composition may comprise from 0.25 to 5.0 wt.%, 0.5 to 4.0 wt.%, or 1.0 to 2.0 wt.% antioxidant. In some embodiments, the filling material composition may comprise 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.% antioxidant. In some embodiments, the filling material composition may comprise 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.% antioxidant.

[0088] In some embodiments, the filling material composition may comprise one or more solvents. For example, the solvent may be water (i.e., pure water). In some embodiments, the filling material composition may comprise from 1 to 10 wt.%, from 1.5 to 9 wt.%, from 2 to 8 wt.%, from 2.5 to 7 wt.%, from 3 to 6 wt.%, or from 3.5 to 5 wt.% solvent. In some embodiments, the filling material composition may comprise 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 filling material composition may comprise 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.% solvent.

[0089] Soft gelatin capsule shell composition A description of a soft gelatin capsule shell formulated to improve the API stability of soft gelatin capsules is provided below. The soft gelatin capsule shell is often a gelatin-based shell that encloses the filling material composition (detailed above). The soft gelatin capsule shell generally comprises gelatin, an opacifying agent, a plasticizer, and water. In some embodiments, the soft gelatin capsule shell may comprise an acidic solution to improve the API stability of the soft gelatin capsule.

[0090] In some embodiments, once the filling material (i.e., the filling material according to any of the above composition embodiments) is encapsulated in a soft gelatin capsule shell, one or more APIs of the filling material may experience instability over time. In particular, the migration of components from the soft gelatin capsule shell to the filling material can change the pH of the filling material, resulting in the instability of one or more APIs (such as PE). Therefore, it has been found that including an acidic solution in the soft gelatin capsule shell of the soft gelatin capsule can help maintain the stability of the APIs in the filling material of the soft gelatin capsule. With an acidic soft gelatin capsule shell, the acidic solution of the filling material is less likely to migrate into the shell of the soft gelatin capsule. Thus, the acidic environment of the filling material can be maintained when encapsulated by the soft gelatin capsule shell to minimize the reaction between the APIs and the degradation products of one or more inactive ingredients. The components and amounts of the components of the soft gelatin capsule shell according to some embodiments provided herein are given below.

[0091] Although most soft gelatin capsule shells are gelatin-based, some examples of soft gelatin capsule shells can include other materials such as carrageenan, starch, or other suitable gelling agents. In some embodiments, the soft gelatin capsule shell can include from 15 wt.% to 70 wt.%, from 30 wt.% to 50 wt.%, or from 40 wt.% to 45 wt.% gelling agent. In some embodiments, the soft gelatin capsule shell can include less than 70 wt.%, less than 65 wt.%, less than 60 wt.%, less than 55 wt.%, less than 50 wt.%, less than 45 wt.%, less than 40 wt.%, less than 35 wt.%, less than 30 wt.%, less than 25 wt.%, or less than 20 wt.% gelling agent. In some embodiments, the soft gelatin capsule shell can include 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.% gelling agent.

[0092] As described above, the soft gelatin capsule shell may contain an opacifying agent to render the outer surface of the shell light - impermeable. Examples of opacifying agents include titanium dioxide, zinc oxide, and calcium carbonate. In some embodiments, the soft gelatin capsule shell may contain from 0.1 to 5 wt.%, from 0.3 to 3 wt.%, or from 0.5 to 1.0 wt.% of the opacifying agent. In some embodiments, the soft gelatin capsule shell may contain 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 the opacifying agent. In some embodiments, the soft gelatin capsule shell may contain more than 0.1 wt.%, more than 0.2 wt.%, more than 0.3 wt.%, more than 0.4 wt.%, more than 0.5 wt.%, more than 0.6 wt.%, more than 0.7 wt.%, more than 0.8 wt.%, more than 0.9 wt.%, more than 1.0 wt.%, more than 1.5 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 the opacifying agent.

[0093] Examples of plasticizers in the soft gelatin capsule shell may include sorbitol, glycerol, and / or other pharmaceutically suitable plasticizers. In some embodiments, the soft gelatin capsule shell may contain from 10 to 40 wt.% or from 20 to 30 wt.% of the plasticizer. In some embodiments, the soft gelatin capsule shell may contain less than 40 wt.%, less than 35 wt.%, less than 30 wt.%, less than 25 wt.%, less than 20 wt.%, or less than 15 wt.% of the plasticizer. In some embodiments, the soft gelatin capsule shell may contain more than 10 wt.%, more than 15 wt.%, more than 20 wt.%, more than 25 wt.%, more than 30 wt.%, or more than 35 wt.% of the plasticizer.

[0094] In some embodiments, as described above, the soft capsule shell may include 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 soft capsule shell may include from 1wt.% to 20wt.%, from 2wt.% to 15wt.% or from 3wt.% to 8wt.% acidic solution. In some embodiments, the soft capsule shell may include less than 20wt.%, less than 18wt.%, less than 15wt.%, less than 12wt.%, less than 10wt.%, less than 8wt.%, less than 5wt.%, less than 4wt.%, less than 3wt.% or less than 2wt.% acidic solution. In some embodiments, the soft capsule shell may contain 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.% acidic solution.

[0095] In some embodiments, the soft capsule shell may contain water. For example, the soft capsule shell may contain 30 to 60 wt.%, 35 to 55 wt.%, or 40 to 50 wt.% water. In some embodiments, the soft capsule shell may contain 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.% water. In some embodiments, the soft capsule shell may contain 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.% water.

[0096] The soft gelatin capsule shell may also contain additional materials such as colorants, flavors, sugars, fragrances, and other sensates, etc. One skilled in the art can readily determine the appropriate type of colorant suitable for use with embodiments of the present invention.

[0097] Method for preparing filling material composition and soft capsule Provided below are descriptions of methods for preparing fill material compositions and soft gelatin capsules with improved API stability.In general, the fill material compositions and soft gelatin capsules described herein can be prepared using techniques readily discernible to one of ordinary skill in the art.

[0098] For example, the filler material composition can be prepared by mixing the necessary components described in detail above into a suitable mixing vessel. A suitable mixing vessel can be an OLSA200L mixing vessel, an OLSA2000L mixing vessel, or any other suitable closed system with high shear mixing, temperature control, and nitrogen blanketing capabilities. Some APIs, such as APAP, may need to be dissolved in a solution. After all components are properly mixed, the solution can be degassed and cooled.

[0099] To encapsulate the filling material composition with a soft gelatin capsule shell, an encapsulating machine can be used. For example, a 6-inch or 7.24-inch encapsulating machine or any other suitable encapsulating device can be used to encapsulate the filling material composition. After encapsulation, the soft gelatin capsules can be dried until they reach a predetermined hardness. Examples

[0100] Further details of some of the embodiments generally described above are provided below, including specific test data.

[0101] Example 1: Prepare and test a filling material composition to observe physical and chemical stability characteristics. Specifically, prepare a filling material composition comprising the API acetaminophen, guaifenesin, dextromethorphan, and phenylephrine, as well as inactive ingredients comprising PEG, propylene glycol, povidone, and water. The physical and chemical stability of the filling material composition is tested as described below.

[0102] Example 1A - Physical Properties: To evaluate the physical stability of the filling material composition, the filling material composition according to the embodiments was encapsulated in a conventional soft gelatin capsule shell (i.e., a soft gelatin capsule shell not specifically formulated to maintain an acidic pH in the filling material composition according to the above embodiments) and observed under ambient conditions. The components of the specific filling material compositions tested are provided in Table 1. In the initial trials, APAP readily precipitated out of solution.

[0103] The type and amount of povidone were varied to test its effect on APAP precipitation. Filling material 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 increase in povidone, but were kept relatively similar to the amounts in the original filling material composition. Filling material composition B contained povidone K-12 instead of povidone K-30. The specific amounts of the components of filling material composition A and filling material composition B are provided in Table 1 below. Component Composition A (wt.%) Composition B (wt.%) PEG 400 42.8 42.8 Propylene glycol 1.5 1.5 Povidone K-12 6.7 0 Povidone K-30 0 6.7 Paracetamol 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

[0104] Table 1. Two examples of filling material compositions.

[0105] The two filler material compositions shown in Table 1 (i.e., filler material composition A and filler material composition B) were prepared and encapsulated in conventional soft capsule shells and observed over time. For filler material composition A, which included povidone K-12, precipitation of APAP from solution was observed as early as one week after combination and encapsulation. However, for filler material composition B, which included povidone K-30, APAP did not precipitate from solution until nearly two weeks after combination and encapsulation. Similarly, other filler material compositions were tested to evaluate their effects on the physical stability of APAP. The lowest levels of APAP precipitation were observed for filler material compositions containing increasing amounts of povidone K-30 and propylene glycol and decreasing amounts of plasticizer in the soft capsule shell.

[0106] Example 1B - Chemical Stability: In addition to the physical stability of the fill material compositions described above, the chemical stability of the fill material compositions encapsulated in conventional softgel shells was also evaluated under accelerated conditions. The chemical stability of the fill material compositions observed under accelerated conditions revealed that all compositions encapsulated in conventional softgel shells exhibited unduly high levels of PE degradation. For example, some results showed PE losses of as much as 7-10% over a two-month period.

[0107] Furthermore, as PE degradation increased, the presence of unknown degradation products in the filler material also increased. To determine the identity of these unknown degradation products, the filler material compositions were encapsulated, stressed at 70°C, and measured over time. Figure 1 The resulting chromatograms are provided in to determine the identity of the peaks that intensify as the amount of PE decreases (i.e., due to the instability of PE).

[0108] Figure 1 Four overlapping chromatograms of a filler material composition stressed at 70°C according to some embodiments described above are shown. Specifically, chromatograms were obtained at 0, 5, 13, and 22 days to observe the effect of the filler material composition over time. As shown, the overlapping chromatograms show a peak that gradually intensifies over time (at approximately 21.6 minutes).

[0109] according to Figure 1 The enhanced peak of each filler material component evaluation showed that the peak corresponds to the retention time of polyvidone K-30. In addition, as the peak size increases, an ultraviolet (UV) maximum at about 276nm is revealed, indicating that the peak is Figure 1 The enhanced peaks in Figure 5 suggest the possibility that the unknown degradants represented by the peaks are directly related to PE degradation (explained in further detail below).

[0110] Example 2 - Determining the cause of PE instability: To confirm Figure 1The enhanced peak in the middle is related to the degradation of PE. Two separate samples of the filling material were prepared. Both samples contained all the inactive ingredients included in the composition of Table 1 (i.e., PEG, propylene glycol, povidone K-30, and water). The first sample additionally contained PE ("PE-only" sample). In addition to PEG, propylene glycol, povidone K-30, and water, the second sample additionally contained APAP, guaifenesin, and dextromethorphan, but no PE. Each sample was tested at 70 °C and analyzed chromatographically at different times over a 15-day period (plotted in Figure 2 ).

[0111] Figure 2 Overlapped chromatograms of the above two samples are shown. The PE-only sample was provided on the left-hand side of the figure, and the sample of APAP, guaifenesin, and dextromethorphan without PE was provided on the right-hand side of the figure. Chromatograms were obtained at days 0, 6, and 15. Figure 2 It is shown that the peak at approximately 21.6 minutes was enhanced only in the first sample containing PE. In contrast, for the sample containing APAP, guaifenesin, and dextromethorphan but no PE, the peak remained at approximately the same height. Therefore, Figure 2 the chromatograms confirm that the unknown degradation product represented by the 21.6-minute peak is generated by the interaction between PE and povidone K-30.

[0112] As described above, since the peak size increased over time, a UV maximum at approximately 276 nm was also generated, as shown in Figure 3 . The left-hand side of the figure shows the UV spectrum of the povidone K-30 peak in the filling material composition containing only PE (no other APIs). The right-hand side of the figure shows the UV spectrum of the povidone K-30 peak in the filling material composition containing APAP, guaifenesin, and dextromethorphan (but no PE). As plotted in Figure 3 , the UV spectrum of the povidone K-30 peak in the filling material composition containing PE changed to indicate a UV maximum of approximately 276 nm. However, for the composition without PE, the UV spectrum of the povidone K-30 peak remained unchanged. Therefore, this data further supports that the observed PE degradation is the result of the interaction between povidone K-30 and PE.

[0113] Similar tests were conducted on filling material compositions containing povidone K-12 instead of povidone K-30 (similar to those provided in Figures 1 - 3 ). However, no interaction between povidone K-12 and PE was observed in these tests, indicating that povidone K-12 does not significantly promote the degradation of PE.

[0114] Example 3 - Controlling the formation of degradation products using antioxidants: Samples of the filling material composition were prepared by adding potassium iodide (KI) to evaluate the effect of ionic strength and the presence of iodine on the formation of the PE-povidone peak. Figure 4 The results provided in Figure 4 indicate that the addition of KI has little effect on the formation of the PE-povidone peak.

[0115] Specifically, Figure 4 The results of two different samples of the filling material composition are shown. Each of the two samples contains PE, dextromethorphan, and 13% povidone K-30. In addition, one sample contains 5% KI while one sample contains 5% water. The two samples were tested at 70 °C over a 15-day period and showed relatively large PE-povidone peak formation. Thus, these results indicate that adding KI to the filling material composition has little effect on the formation of the PE-povidone peak compared to a filling material composition containing only water and no KI.

[0116] Although adding KI to the filling material composition has little effect on the formation of the PE-povidone peak, it does have an effect on the formation of other known PE-related substances (shown in Figure 5 ). Figure 5 Two samples of the filling material composition tested at 70 °C over a 15-day period are shown. Both samples contain PE, dextromethorphan, and 13% povidone K-30. One sample contains only water while the other sample contains KI. As shown, the sample of the filling material composition with KI shows less PE degradation product formation than the sample of the filling material composition containing only water.

[0117] Thus, not only does the presence of acid improve the stability of the API in the filling material composition of the soft gelatin capsule, but the presence of antioxidants such as KI is also necessary to reduce the presence of certain degradation products that could otherwise lead to API instability.

[0118] Example 4 - Inhibiting the interaction between an API (such as phenylephrine) and inactive ingredients: Various studies were conducted to evaluate the effect of pH, air, peroxides, water, and povidone concentration on the formation of PE (or "PE-PVP", "PE-povidone") degradation products. Some of the results of these tests are provided in Figure 6 .

[0119] Figure 6 Data on the effect of pH (upper left), air (upper right), peroxides (lower left), and water (lower right) on the change in the povidone K-30 peak at 70 °C are provided. As Figure 6As shown, pH has the greatest effect on the formation of the PE-povidone peak. Specifically, compared to the filler material composition containing sodium hydroxide (alkaline pH), samples of the filler material composition containing HCl (acidic pH) showed a decrease in the PE-povidone peak change of almost 400%. None of the other variables (air, peroxide, and / or water) had such a significant effect on the povidone K-30 peak.

[0120] Example 5 - Testing the effect of pH: Once it was determined that pH affects the stability of PE, various pH values were tested. Filler material compositions were prepared at various pH values using acetate buffer. Samples were tested at 70 °C over a 15-day period, and the results are provided in Figure 7 .

[0121] Figure 7 Data from three different filler material compositions were provided. One sample was tested at a pH of 3.6, one sample was tested at a pH of 4.6, and one sample was tested at a pH of 5.6. Based on the results provided in the figure, the PE-povidone peak is proportional to the pH of the filler material composition. Specifically, as the pH of the filler material composition decreases, the interaction between povidone and PE also decreases.

[0122] Example 6 - Adding acid to the filler material composition: Figure 7 The test results depicted in

[0123] showed that reducing the acidity of the filler material composition can reduce the degradation of PE. To reduce the acidity of the filler material composition, various amounts of 0.1 N HCl were added to the filler material composition and tested. Figure 8 Samples of various filler material compositions prepared with various amounts of HCl were stressed at 70 °C and tested over a 15-day period. Specifically, five different samples were prepared and tested over a 15-day period. All samples contained PE, dextromethorphan, and 13% povidone K-30. However, these five samples contained various amounts of HCl: 5% 1.0 N HCl, 3.75% 1.0 N HCl, 2.5% 1.0 N HCl, 0.5% 1.0 N HCl, and 5% water (no HCl). The results of these tests are provided in

[0124] As Figure 8 shown, the filler material composition containing only water (at approximately neutral pH) showed the highest effect on the povidone K-30 peak. In contrast, the filler material composition containing 0.5% 0.1 N HCl had a slightly smaller effect on the povidone K-30 peak, while the samples of the filler material compositions containing 2.5%, 3.75%, and 5.0% 0.1 N HCl had a significantly smaller effect on the povidone K-30 peak.

[0125] Examples 7 - 9 - PE Stability of Filling Material Compositions Containing Acid and Antioxidants: To monitor and evaluate the formation of all PE degradation products, the filling material composition additives were evaluated using a filling material composition containing only APIPE and dextromethorphan. In addition to various antioxidants, various amounts of HCl and KI were tested with Filling Material Composition A of Table 1 to monitor the effect on all APIs present in the combination. Composition A was also used because it showed the lowest amount of APAP precipitation (as described above).

[0126] These tests confirmed that the stability of PE was greatest in the presence of HCl. However, due to the addition of HCl, the high acidity of the composition increased the formation of 4 - aminophenol and PE - RS - 1 (other PE - related degradation products). Therefore, it was necessary to add KI as an antioxidant to help control the levels of these other degradation products. The addition of other antioxidants showed little effect on the stability of the composition. The results of this study are provided in Figures 9 - 11 and are described below.

[0127] Figure 9 shows the effect of HCl, KI, and additional antioxidants on the stability of PE in filling material compositions according to some embodiments. Specifically, 11 different samples were tested over a 20 - day period at 70°C. The filling material composition samples contained a filling material composition that included 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% butylhydroxyanisole (BHA); or 2.0% water and 0.02% BHT and 0.08% BHA.

[0128] Only the samples containing HCl exhibited suitable PE stability by maintaining at least 99% of the initial amount of PE during the test. In contrast, the samples without HCl exhibited insufficient PE stability by losing at least 8% of the initial amount of PE during the 20 - day test. These results confirmed that filling material compositions with a lower pH can help minimize PE degradation in soft gelatin capsules.

[0129] Figure 10The effects of HCl, KI, and additional antioxidants on the formation of PE RS-1 in filler material compositions according to some embodiments are shown. PE RS-1 is a degradation product of PE. Therefore, an increase in PE RS-1 levels indicates an increase in PE degradation levels. The 11 samples tested in this study were Figure 9 The 11 samples were tested at 70°C over a period of 20 days. Specifically, the filler material composition samples included a filler material 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 (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.

[0130] Figure 10 The results showed that PE RS-1 levels increased in filler compositions containing only HCl. However, in filler compositions containing KI (with or without HCl), PE RS-1 levels remained relatively low. Therefore, this study demonstrates that the presence of KI in filler compositions can help control the production of PE RS-1, an undesirable PE degradation product.

[0131] Figure 11 The effects of HCl, KI, and additional antioxidants on the formation of 4-aminophenol in filler material compositions according to some embodiments are provided. 4-aminophenol is another example of a PE degradation product. These 11 samples were compared with Figure 9 and 10 Specifically, the filler material composition samples included a filler material 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.

[0132] based onFigure 11 In the results provided in, the formation of 4-aminophenol increases with the composition containing HCl rather than KI. However, in the composition with a higher pH and containing KI, the level of 4-aminophenol remains low. Thus, like PERS-1 in, the presence of KI can help control the production of 4-aminophenol as well as PERS-1. Figure 10 In the same way as PERS-1 in, the presence of KI can help control the production of 4-aminophenol as well as PERS-1.

[0133] Example 10 - Encapsulated Filling Materials: Gelatin of type A (pig skin) and type B (animal bone) is used to encapsulate the filling material compositions according to various embodiments. The filling material compositions encapsulated with these soft capsule shells correspond to the above embodiments. In particular, in some embodiments, filling material compositions that exhibit suitable API stability in the presence of HCl and KI are tested. Various soft capsule samples are tested at room temperature and accelerated conditions (50 °C and 70 °C). In addition, soft capsule samples stressed at 50 °C are tested in two different ways: stressed when intact and stressed when cut to allow air exposure. In some embodiments, filling material compositions stressed at 70 °C before encapsulation are also used.

[0134] Figure 12 It shows that regardless of the type of filling material composition, the soft capsules stressed at 70 °C underwent rapid PE degradation. Figure 12 Data on the PE stability in the filling material compositions tested over a 20-day period at 70 °C (left hand side) and data on the PE stability in the finished soft capsules tested over a 20-day period at 70 °C (right hand side) are provided. As shown in the figure on the left hand side, three different samples of filling material compositions were tested: one containing 2.6 mM HCl / 0.26% KI; one containing 2.6 mM HCl (0% KI); and one containing 2.6 mM HCl / 0.38% KI. The PE stability of each of the three samples was almost the same. This data supports the above tests, which determined that PE stability is pH-dependent (and inversely proportional to pH). In addition, the PE stability of the filling material composition (unencapsulated) does not depend on the presence of KI.

[0135] In Figure 12 On the right hand side of, four different soft capsule samples were tested: one containing a filling material composition containing 2.6 mM HCl / 0.26% KI; one containing a filling material composition containing 2.6 mM HCl (no KI); one containing a filling material composition containing 2.6 mM HCl / 0.38% KI; and one containing a filling material composition without HCl or KI. All four samples underwent significant PE degradation. Interestingly, the two samples containing KI experienced slightly worse PE stability than the two samples without KI.

[0136] Therefore, Figure 12 the results in indicate that the filling material composition containing HCl and KI undergoes significant PE degradation during encapsulation, even though such compositions exhibit excellent stability prior to encapsulation, as discussed above. Therefore, Figure 12 the results provided in indicate that the encapsulation of the filling material composition somehow alters the filling material composition, resulting in PE instability / degradation.

[0137] Examples 11 - 13 - Investigating the cause of PE degradation during encapsulation: Based on the nature of the encapsulation process and the chemical components involved, there are three main factors that can potentially cause PE degradation due to encapsulation - water flowing from the shell into the filling material composition, air exposure of the filling material composition, and migration of components from the filling material composition into the soft gelatin capsule shell. Each of these possible causes was tested, and the details are provided below.

[0138] The first possible cause, water flowing from the soft gelatin capsule shell into the filling material composition, was investigated by increasing the moisture content of the filling material composition and applying stress at 70°C. Figure 13 shows the effect of the moisture content of the filling material composition on PE degradation. Specifically, two different samples of the filling material composition were tested - one containing 2% water and the other containing 10% water. Both samples were tested at 70°C over a 15 - day period. As shown, Figure 13 the results in indicate that PE stability is independent of the moisture content of the filling material composition, as there is little difference in PE stability between the two samples.

[0139] The second possible cause, air exposure of the filling material composition, was investigated by applying stress to intact and cut soft gelatin capsules at 50°C. Specifically, Figure 14 shows the effect of air exposure on PE degradation for soft gelatin capsules with and without HCl and KI. Four different soft gelatin capsules were tested: the filling material composition without HCl / KI from an unopened soft gelatin capsule; the filling material composition without HCl / KI from an opened soft gelatin capsule; the filling material composition with HCl and KI from an unopened soft gelatin capsule; and the filling material composition with HCl and KI from an opened soft gelatin capsule. The results of this study are provided in Figure 14 and indicate no significant correlation between PE stability and air exposure. Additionally, this study shows that the degradation rate of soft gelatin capsules containing HCl and KI is essentially the same as that of soft gelatin capsules not containing HCl or KI.

[0140] A third possible cause was investigated by specifically observing the migration of HCl from the filling material composition into the soft gelatin capsule shell: the migration of components of the filling material composition into the soft gelatin capsule shell. It is known that hydrophilic components such as acids can migrate rapidly into the soft gelatin capsule shell. In addition, based on the above research, it is also known that the degradation of PE is not dependent on KI. Note that the migration of other APIs and inactive ingredients is not considered, because the degradation rate of PE in the filling material composition without HCl and KI before encapsulation is the same as that in the filling material composition without HCl and KI in the finished soft gelatin capsule (after encapsulation).

[0141] Therefore, by comparing the pH of the filling material composition before encapsulation and the pH of the filling material composition after encapsulation (once removed from the soft gelatin capsule shell), the migration of HCl from the components of the filling material composition into the soft gelatin capsule shell and its effect on the degradation of PE were studied. The tests showed that the pH of the filling material composition increased by approximately 2 full units (see Examples for details). In addition, the maximum degradation product observed in the filling material composition (with HCl and KI) after encapsulation was the PE-formic acid conjugate. However, the results showed that if the pH of the filling material composition was kept below the pKa of the degradation product (formic acid), the stability of PE was improved. Therefore, since the pKa of formic acid is approximately 3.75, the results indicate that the pH of the filling material composition should be controlled at a level below 3.75 to improve the stability of PE.

[0142] Examples 14 and 15: Controlling the pH of the filling material composition below the pKa of the degradation product: Based on the above results, various tests were conducted to control the pH of the filling material composition and study the effect of various pH levels on the stability of PE. To stabilize the pH of the filling material composition, various buffers with different pH values (from 2.4 to 4.4) and concentrations of 25 mM and 50 mM were added to the filling material composition without HCl or KI and tested. Figure 15 and 16 All samples in were tested at 70 °C for a period of 15 days.

[0143] Figure 15 A comparison of filling material compositions buffered at different pH values of 25 mM is provided. Specifically, seven different samples of the filling material composition 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, the results were significantly different. However, in terms of the stability of PE, none of the buffers performed as well as HCl.

[0144] Figure 16Shows a comparison of the filling material compositions buffered at different pH values of 50 mM. This time, eight different samples of the filling material compositions 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 described above Figure 15 results, the results here are also different. However, although HCl has the best effect on the stability of PE, as Figure 15 studies, 50 mM citrate also shows suitable results.

[0145] Therefore, introducing various acidic solutions into the filling material composition can improve the stability of the API in the soft capsule. However, the key is to maintain the pH of the filling material composition below the pKa of the degradation products of the inactive ingredients that may interact with one or more APIs. In particular, it has been found that adding HCl and KI to the filling material composition of the soft capsule can improve the stability of APIs such as PE in the soft capsule. Maintaining the pH of the filling material below the pKa of the degradation products of PEG and / or povidone can inhibit the interaction between the degradation products of PEG and / or povidone and the API, thereby improving the stability of the API.

[0146] Example 16 - Migration of acid from the conventional soft capsule shell to the filling material: As described above and Figure 15 and 16 depicted in, in some cases, the encapsulated sample may experience migration of HCl from the filling material to the soft capsule shell. Therefore, the pH of the filling material composition before and after encapsulation was compared to quantify the severity of this HCl migration. The details of this test are provided in Table 2 below. The pH values of two different filling material compositions are provided - one without HCl or KI, and one with HCl.

[0147] Example 17 - Migration of acid from the soft capsule shell containing acidic solution to the filling: The effect of pH balance on controlling the pH of the filling material composition was evaluated using four separate filling material compositions each containing 0, 3.75, 7.5, or 15 mM of HCl. Each of the four samples was dispensed into 20 mL vials (approximately 2 g per vial) and allowed to solidify and dry. Approximately 5 g of the filling material composition (containing HCl and KI) was added on top of the gel mixture in the vials, and all vials were placed in a water bath at 45 °C. The vials were analyzed at predetermined times, and the results are provided in Figure 17As shown in the figure, the PE degradation of each sample was directly correlated with the amount of acid in the gelatin. Specifically, the more HCl present in the gelatin of the gelatin mixture, the better the PE stability of the filler material composition on top of the gelatin mixture. Furthermore, the pH of the filler material composition in the vial was inversely proportional to the level of HCl in the gelatin.

[0148] For purposes of explanation, the foregoing description has been described with reference to specific embodiments. However, the foregoing illustrative discussion is not intended to be exhaustive or to limit the invention to the precise forms disclosed. In light of the foregoing teachings, numerous modifications and variations are possible. The embodiments were chosen and described in order to best explain the principles of the technology and its practical application. Thus, others skilled in the art will be able to best utilize the technology and various embodiments with various modifications as are suitable for the particular application contemplated.

[0149] Although the present disclosure and embodiments have been fully described with reference to the accompanying drawings, it should be noted that various changes and modifications will become apparent to those skilled in the art. Such changes and modifications should be understood to be included within the scope of the present disclosure and embodiments defined by the claims.

Claims

1. A pharmaceutical soft capsule, comprising: a filling material composition and a soft capsule shell, the filling material composition comprising: one or more active pharmaceutical ingredients (APIs), including ibuprofen, phenylephrine, dextromethorphan, acetaminophen or guaifenesin; 2 to 15 wt.% of povidone, including one or more of povidone K-12 and povidone K-30; 30 to 60 wt.% of polyethylene glycol; 0.5 to 5 wt.% of propylene glycol; and 0.25 to 5 wt.% of potassium iodide, wherein the filling material composition has a pH of 3.75 or less.

2. The soft capsule according to claim 1, wherein the soft capsule shell is made of a soft capsule shell composition comprising an acidic component.

3. The soft capsule according to claim 2, wherein the acidic component comprises hydrochloric acid.

4. The soft capsule according to any one of claims 1-3, wherein the filling material composition comprises 30 wt.% or more total API.

5. The soft capsule according to any one of claims 1-4, which comprises 60 wt.% or less total API.

6. The soft capsule according to any one of claims 1-5, wherein the povidone comprises povidone K-30.

7. The soft capsule according to any one of claims 1-6, wherein the polyethylene glycol comprises PEG 400.

8. The soft capsule according to any one of claims 1-7, wherein the filling material composition comprises 0.5 wt.% to 1.0 wt.% of 0.5N hydrochloric acid.

9. The soft capsule according to any one of claims 1-8, wherein the antioxidant comprises potassium iodide, and the filling material composition comprises 1 wt.% to 2 wt.% of 25% potassium iodide.

10. A filling material composition for a soft capsule, comprising: one or more active pharmaceutical ingredients (APIs), including ibuprofen, phenylephrine, dextromethorphan, acetaminophen or guaifenesin, 2 to 15 wt.% of povidone, including one or more of povidone K-12 and povidone K-30, 30 to 60 wt.% of polyethylene glycol, 0.5 to 5 wt.% of propylene glycol, and 0.25 to 5 wt.% of potassium iodide, wherein the filling material composition has a pH of 3.75 or less.

11. The composition according to claim 10, which comprises 30 wt.% or more total API.

12. The composition according to any one of claims 10-11, which comprises 60 wt.% or less total API.

13. The composition according to any one of claims 10-12, wherein the povidone comprises povidone K-30.

14. The composition according to any one of claims 10-13, wherein the polyethylene glycol comprises PEG 400.

15. The composition according to any one of claims 10-14, wherein a pH of 3.75 or less is achieved by mixing hydrochloric acid into the filling material composition.

16. The composition according to any one of claims 10 - 15, wherein the antioxidant comprises potassium iodide, and the filling material composition comprises 1 wt.% to 2 wt.% of 25% potassium iodide.

17. A method for preparing a filling material composition for soft capsules, comprising: Combining 30 to 60 wt.% polyethylene glycol, 0.5 to 5 wt.% propylene glycol, 2 to 15 wt.% povidone, one or more active pharmaceutical ingredients (API), 0.25 to 5 wt.% potassium iodide, and an acidic component to achieve a pH of 3.75 or less for the filling material composition, wherein the povidone comprises one or more of povidone K - 12 and povidone K - 30, and the one or more active pharmaceutical ingredients (API) comprise ibuprofen, phenylephrine, dextromethorphan, acetaminophen, or guaifenesin.

18. The method according to claim 17, which comprises 30 wt.% or more API.

19. The method according to any one of claims 17 - 18, which comprises 60 wt.% or less API.

20. The method according to any one of claims 17 - 19, wherein the povidone comprises povidone K - 30.

21. The method according to any one of claims 17 - 20, wherein the polyethylene glycol comprises PEG 400.

22. The method according to any one of claims 17 - 21, wherein the acidic component comprises 0.5 wt.% to 1.0 wt.% of 0.5N hydrochloric acid.

23. The method according to any one of claims 17 - 22, wherein the antioxidant comprises potassium iodide, and the filling material composition comprises 1 wt.% to 2 wt.% of 25% potassium iodide.

24. A method for preparing soft capsules, comprising: Combining 30 to 60 wt.% polyethylene glycol, 0.5 to 5 wt.% propylene glycol, 2 to 15 wt.% povidone, one or more active pharmaceutical ingredients (API), 0.25 to 5 wt.% potassium iodide, and an acidic component to form a filling material having a pH of 3.75 or less; and Encapsulating the filling material into a soft capsule shell to form soft capsules, wherein the povidone comprises one or more of povidone K - 12 and povidone K - 30, and the one or more active pharmaceutical ingredients (API) comprise ibuprofen, phenylephrine, dextromethorphan, acetaminophen, or guaifenesin.

25. The method according to claim 24, wherein the soft capsule shell is made from a soft capsule shell composition comprising an acidic component.

26. The method according to claim 25, wherein the acidic component comprises hydrochloric acid.

27. The method according to any one of claims 24 - 26, which comprises 30 wt.% or more API.

28. The method according to any one of claims 24 - 27, which comprises 60 wt.% or less API.

29. The method according to any one of claims 24 - 28, wherein the povidone comprises povidone K - 30.

30. The method according to any one of claims 24-29, wherein the polyethylene glycol comprises PEG 400.

31. The method according to any one of claims 24-30, wherein adding an acid comprises 0.5 wt.% to 1.0 wt.% of 0.5N hydrochloric acid.

32. The method according to any one of claims 24-31, wherein the antioxidant comprises potassium iodide, and the filler composition comprises 1 wt.% to 2 wt.% of 25% potassium iodide.

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