Improved API stability in softgels

Abstract

To provide softgels, and in particular, softgels having improved active pharmaceutical compound (API) stability with minimal instability over time.SOLUTION: Softgels having improved stability of active pharmaceutical ingredients and methods of preparing the same are provided. In some embodiments, a softgel comprises a fill material composition and a softgel shell. In some embodiments, the fill material composition of the softgel comprises: one or more active pharmaceutical ingredients (APIs); 2 to 15 mass% of povidone; 30 to 60 mass% of polyethylene glycol; and 0.5 to 5 mass% of propylene glycol, where the fill material composition has a pH of 3.75 or less. In some embodiments, the softgel shell is made of a softgel shell composition comprising an acidic component.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 816,621, filed March 11, 2019, the entire contents of which are incorporated herein by reference.

[0002] This relates to softgels, and in particular to softgels that minimize instability over time and improve the stability of the active pharmaceutical compound (API). [Background technology]

[0003] Softgels are a common dosage form for pharmaceutical compounds. Specifically, softgels are pharmaceutical oral dosage forms that are generally easy to swallow, prevent contamination, and often cause less gastric discomfort than alternative dosage forms such as liquids, tablets, etc. Softgels contain two main components: a shell and a fill material. Some softgel shells may contain gelatin, water, opacifiers, and plasticizers. The fill material contains the active pharmaceutical ingredient (API) and any of a number of non-active ingredients.

[0004] Sometimes, undesirable reactions can occur between the softgel shell and the fill material of the softgel. For example, water from the softgel shell can migrate into the fill material, altering the physical and chemical properties of both the fill material and the softgel shell. Similarly, components of the fill material can migrate into the softgel shell, altering the physical and chemical properties of both the fill material and the softgel shell. In addition to this, excipients and excipient degradants can interact negatively with the API. These reactions can adversely affect the efficacy, stability, etc. of the API depending on the chemical components that migrate and are involved in the adverse reaction. Summary of the Invention [Problem to be solved by the invention]

[0005] Fill material compositions, softgel shell compositions, softgel compositions, and methods for preparing the same are described. The provided compositions, and methods for preparing the fill material compositions, softgel shell compositions, and softgel compositions, improve the stability of one or more APIs by addressing issues related to interactions between the softgel shell and the fill material of the softgel. These adverse reactions can occur between the softgel shell and the fill material of the softgel, adversely affecting the stability of one or more components of the softgel.

[0006] One or more APIs may degrade when exposed to certain non-active ingredients of the softgel. For example, phenylephrine may react with non-active ingredients of the filler material, such as povidone or PEG, causing the degradation of phenylephrine. In some embodiments, degradants of non-active materials, such as povidone or PEG, may react with phenylephrine, causing the degradation of phenylephrine. When an API, such as phenylephrine, degrades in a softgel, the stability of phenylephrine is compromised. The instability of the API may affect the shelf life, strength, and / or efficacy of the softgel. [Means for solving the problem]

[0007] Thus, the fill material composition, softgel shell composition, softgel composition, and methods of making the same relate to improving the stability of one or more APIs in a softgel. In some embodiments, the fill material composition can include an acidic solution. In some embodiments, the fill material composition can include an antioxidant. In some embodiments, the softgel shell composition can include an acidic solution. In some embodiments, the API stability of the softgel can be improved by controlling the pH of the fill material to be less than the pKa of one or more degradant materials.

[0008] In some embodiments, a pharmaceutical softgel is provided that includes a fill material composition comprising one or more active pharmaceutical ingredients (APIs), 2-15% by weight povidone, 30-60% by weight polyethylene glycol, and 0.5-5% by weight propylene glycol, and having a pH of 3.75 or less, and a softgel shell.

[0009] In some embodiments of the softgel, the softgel shell is made from a softgel shell composition that includes an acidic component.

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

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

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

[0013] In some softgel embodiments, the fill material composition comprises 30% or more of the total API by weight.

[0014] In some embodiments of the softgel, the softgel comprises 60% or less of the total API by weight.

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

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

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

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

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

[0020] In some embodiments, a softgel fill material composition is provided that includes one or more active pharmaceutical ingredients (APIs), 2-15% by weight povidone, 30-60% by weight polyethylene glycol, and 0.5-5% by weight propylene glycol, and has a pH of 3.75 or less.

[0021] In some embodiments of the composition, the one or more APIs include 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% or more of the total API by weight.

[0024] In some embodiments of the composition, the composition comprises no greater than 60% by weight of the 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, a pH of 3.75 or less is achieved by incorporating hydrochloric acid into the fill material composition.

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

[0030] In some embodiments, a method of preparing a softgel fill material composition is provided, the method comprising combining 30-60% by weight polyethylene glycol, 0.5-5% by weight propylene glycol, 2-15% by weight povidone, one or more active pharmaceutical ingredients (APIs), and an acidic component to achieve a pH of the fill material composition of 3.75 or less.

[0031] In some embodiments of the method, the one or more APIs include 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 includes 30% or more by weight of the API.

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

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

[0036] In some embodiments of the method, the povidone comprises povidone 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% to 1.0% by weight of 0.5 N hydrochloric acid.

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

[0040] In some embodiments, a method of preparing a softgel is provided, the method comprising combining 30-60% by weight polyethylene glycol, 0.5-5% by weight propylene glycol, 2-15% by weight povidone, one or more active pharmaceutical ingredients (APIs), and an acidic component to form a fill material having a pH of 3.75 or less, and encapsulating the fill material in a softgel shell to form the softgel.

[0041] In some embodiments of the method, the softgel shell is made from a softgel shell composition that includes 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 comprises phenylephrine.

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

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

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

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

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

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

[0051] In some embodiments of the method, preparing the fill material composition includes adding 1% to 2% by weight of 25% potassium iodide.

[0052] The invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0053] [Figure 1] FIG. 1 shows that a peak according to some embodiments appears at about 21.6 minutes in an overlaid chromatogram of a PE assay stressed at 70° C. [Diagram 2] FIG. 1 shows the change in Povidone K-30 in the presence of PE according to some embodiments. [Diagram 3] FIG. 1 shows the change in the spectrum of Povidone K-30 over time due to the presence of PE according to some embodiments. [Figure 4] FIG. 13 shows the effect of KI in the fill material composition on the formation of PE-povidone peaks. [Diagram 5] FIG. 13 shows the effect of KI in the fill material composition on the formation of total PE-related degradants according to some embodiments. [Figure 6] FIG. 1 illustrates the effect of various conditions on the formation of PE-Povidone peaks according to some embodiments. [Figure 7] FIG. 1 illustrates the effect of pH of a fill material composition on the formation of PE-povidone peaks according to some embodiments. [Figure 8] FIG. 1 illustrates the effect of various concentrations of HCl on the formation of PE-povidone peaks according to some embodiments. [Figure 9] FIG. 1 illustrates the effect of HCl, KI, and additional antioxidants on the stability of PE in a filler material composition according to some embodiments. [Figure 10] FIG. 1 shows the effect of HCl, KI, and additional antioxidants on the formation of PE RS-1 in a filler material composition according to some embodiments. [Figure 11] FIG. 1 illustrates the effect of HCl, KI, and additional antioxidants on the formation of 4-aminophenol in a fill material composition according to some embodiments. [Figure 12] FIG. 1 illustrates the effect of encapsulation on the PE stability of a fill material composition comprising HCl and KI according to some embodiments. [Figure 13] FIG. 1 illustrates the effect of moisture in the fill material composition on the degradation of PE according to some embodiments. [Figure 14] FIG. 13 shows the effect of air exposure on the degradation of PE for softgels with and without HCl and KI according to some embodiments. [Figure 15] FIG. 1 shows an analysis of a 25 mM buffered fill material composition according to some embodiments. [Figure 16] FIG. 1 shows a comparison of 50 mM buffered fill material compositions according to some embodiments. [Figure 17] FIG. 1 illustrates the effect of various levels of HCl in gelatin on PE stability according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] Exemplary embodiments of fill material compositions, softgel shell compositions, and softgel compositions with improved API stability, as well as methods of making fill materials, softgel shells, and softgels with improved API stability are described. As discussed above, fill materials can interact with each other and with the softgel shell of the formed softgel, causing instability of one or more components of the softgel shell and / or fill material. The embodiments described herein are directed to stabilizing one or more APIs of the fill material in the prepared softgel.

[0055] In some embodiments, phenylephrine may directly interact with non-active ingredients of the fill material or may possibly interact with degradants of the non-active ingredients. This interaction may cause phenylephrine to degrade within the softgel, resulting in a shortened shelf life, reduced strength, and / or reduced efficacy of the softgel. In some embodiments, other APIs such as ibuprofen, guaifenesin, dextromethorphan, acetaminophen, and / or benzonatate may become unstable due to interaction with non-active ingredients of the fill material. In some embodiments, one or more APIs (e.g., phenylephrine) may degrade by interacting with non-active ingredients such as povidone or PEG. In some embodiments, one or more APIs (e.g., phenylephrine) may degrade by interacting with degradants of one or more non-active ingredients such as povidone or PEG.

[0056] Therefore, some embodiments provided herein are directed to improving API (e.g., phenylephrine) stability in softgels by controlling the pH of the fill material. In particular, it has been determined that phenylephrine can be inhibited from reacting with the decomposition products of povidone and PEG by controlling the pH of the fill material below the pKa of the decomposition products of povidone and / or PEG. For example, the fill material can be controlled at a pH of 3.75 or less. By inhibiting the reaction between phenylephrine and the decomposition products of povidone and / or PEG, the stability of phenylephrine is improved. The improved stability of phenylephrine may improve the shelf life, strength, and / or efficacy of the softgel.

[0057] In some embodiments, the pH of the fill material is controlled by adding an acidic solution to the fill material. In some embodiments, the pH of the fill material is controlled by adding an acidic solution to the softgel shell. In some embodiments, antioxidants are added to the fill material to minimize the degradation of non-active ingredients (e.g., povidone, PEG). Controlling the degradation of non-active ingredients such as povidone and PEG may improve the stability of the API (e.g., phenylephrine) by limiting the amount of degradants with which the API can react.

[0058] Below is a discussion of (1) API instability in softgels in general, (2) fill material compositions specifically including phenylephrine (PE) as the API, (3) softgel shell compositions, and (4) methods of preparing fill material compositions and softgels. Each of these is discussed in turn below.

[0059] Instability of Active Pharmaceutical Ingredients (API) in Softgels Below, we discuss API instability in softgels. API stability is a more common issue with softgel compositions than with other pharmaceutical forms (e.g., tablets, liquids, etc.). Examples of APIs and causes of API instability in softgels are provided.

[0060] A variety of APIs are suitable for use in softgel.For example, common APIs that are prepared into softgel dosage forms, 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 easily identify other suitable APIs for use in the disclosed embodiments.

[0061] One example of an API that can be used in a softgel is phenylephrine (PE). PE is a vasoconstrictor and decongestant. Most commonly, PE can be used to treat common cold symptoms (i.e., stuffy nose), sinus problems, and hemorrhoids. The instability of various APIs, especially PE, in softgels is a well-known problem.

[0062] The instability of PE is believed to result from the degradation of one or more non-active ingredients (i.e., excipients) in the softgel fill material and / or the softgel shell. Non-active ingredients that may degrade and potentially react adversely with APIs such as PE include polyethylene glycol (PEG) and povidone (also "polyvinylpyrrolidone" or "PVP"). For example, PEG is a common excipient used in softgel fill materials. When PEG degrades, the PEG degradants interact with PE, causing the degradation of PE. For example, PEG may degrade into aldehydes and / or short-chain organic acids, both of which readily react with PE.

[0063] PEG is known to degrade easily in the presence of oxygen and / or water into several short-chain organic acids and aldehydes (impurities). Short-chain organic acids can include formic acid, acetic acid, and / or glycolic acid. Aldehydes can include formaldehyde and / or acetaldehyde. These PEG decomposition products are known to easily interact with PE, causing the degradation of PE in the softgel fill material.

[0064] Similarly, povidone may degrade into compounds containing peroxides and short-chain acids such as formic acid. Similar to the decomposition products of PEG, the decomposition products of povidone may also react with APIs such as PE to cause adverse effects. In particular, some povidones may interact with PE more easily than others. For example, povidone K-30 reacts more readily with PE than povidone K-12. This may be due in part to the difference in the end groups of povidone K-12 and povidone K-30. In particular, povidone K-12 uses isopropanol during synthesis to produce propyl end groups, while povidone K-30 uses water during synthesis to produce hydroxyl end groups. PE reacts more readily with hydroxyl groups, such as the hydroxyl end groups of povidone K-30. Thus, 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 shown below.

[0065] Povidone K-12 (povidone synthesized with isopropanol):

[0066] [ka]

[0067] Povidone K-30 (Povidone synthesized with water):

[0068] [ka]

[0069] Phenylephrine (PE):

[0070] [ka]

[0071] PE degrades within the softgel when it reacts with PEG and / or povidone degradants. This degradation indicates instability of PE, which can lead to reduced shelf life, reduced strength, increased levels of potentially harmful impurities, and / or reduced efficacy of the softgel.

[0072] Therefore, to reduce the instability of PE in softgels, a method of reducing the interaction between PE and PEG and / or povidone can be used. Conventional methods of reducing the instability of PE include using antioxidants to reduce the amount of degradation of PEG and / or povidone. However, the method of improving the stability of PE according to the embodiments disclosed herein includes preventing the interaction between PE and PEG / povidone degradants, but does not necessarily include inhibiting the degradation of PEG and / or povidone. Some embodiments may include minimizing the interaction between PE and PEG / povidone degradants, as well as minimizing the degradation of PEG / povidone.

[0073] Below are described various embodiments directed to limiting various interactions between one or more APIs (e.g., PE) and degradants such as those formed from the degradation of PEG and / or povidone. In some embodiments, the stability of the API can be improved by introducing an acidic solution into the fill material and / or softgel shell. Some embodiments can include an antioxidant such as potassium iodide (KI) in the fill material to improve the stability of the API. In some embodiments, the pH of the fill material can be maintained below the pKa of the PEG and / or povidone degradants to inhibit interactions between PEG and / or povidone degradants and PE.

[0074] Filling material composition with improved stability of phenylephrine (PE) The following is a description of fill material compositions developed to improve the stability of APIs. The fill material compositions provided herein can be encapsulated with a softgel shell to form an administrable pharmaceutical composition. In some embodiments, the fill material composition can include an acidic solution to improve the stability of the API (e.g., improve the stability of PE). In some embodiments, the fill material composition can include an antioxidant that inhibits the degradation of one or more non-active ingredients to improve the stability of the API.

[0075] In some embodiments, APAP may be in an unstable form in the fill 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 fill material composition may affect the precipitation of APAP. Therefore, some embodiments of the fill material composition provided herein may include an optimal amount of a specific type of povidone and / or propylene glycol to control the stability of APAP. The recommended amounts of povidone and propylene glycol to be included in the fill material composition are shown below.

[0076] The following Example 1A 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 level of povidone K-30 and / or propylene glycol in the fill material composition. In some embodiments, APAP precipitation can be minimized by increasing the level of both povidone K-30 and propylene glycol. In some embodiments, APAP precipitation can also be minimized by decreasing the level of plasticizer in the softgel shell.

[0077] 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 behave similarly to the APAP described above. In some embodiments, other types of non-active ingredients such as PEG (i.e., PEG400, PEG600, PEG1200, PEG2400) may also affect the stability of one or more APIs in solution.

[0078] For example, as discussed above, povidone K-30 tends to interact with PE, and the interaction between povidone K-30 (including any povidone K-30 degradants) and PE can cause instability of PE (i.e., when the amount of PE in the fill material composition decreases over time).

[0079] However, it has been determined that controlling the pH of the fill material composition can minimize the interaction between povidone K-30 (and / or povidone K-30 degradants) and PE, and therefore improve the PE stability of the fill material composition. In some embodiments, the fill material composition can include an acidic solution to control the pH of the fill material composition. In some embodiments, the acidic solution can include citric acid, formic acid, acetic acid, and / or hydrochloric acid (HCl). As described in the Examples section below, some tests were performed to introduce HCl into the fill material composition. The acidic solution should not be limited to materials that include HCl. Those skilled in the art will recognize that any suitable acidic solution can be used to control the pH of the fill material composition.

[0080] In some embodiments, antioxidants can also be included in the fill material composition. For example, antioxidants can help control the formation of species that correspond to the instability of PE. Thus, KI has little effect on the interaction between PE and povidone / PEG degradants, but when present in the fill material composition, it can help control the formation of other PE-related substances, APAP-related substances, and / or dextromethorphan-related substances. For example, the presence of KI in the fill material composition can also have a beneficial effect on controlling the formation of PE RS-3, an example of a PE-related degradant. PE RS-3 increases under acidic conditions. Thus, when an acidic solution is added to the fill material composition, the level of PE RS-3 can increase. Adding an antioxidant such as KI can help control the level of PE RS-3. The addition of KI can also help reduce the formation of 4-aminophenol from APAP and prevent the formation of N-oxide degradants of dextromethorphan and doxylamine. Examples of antioxidants include potassium iodide, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, and other suitable antioxidants.

[0081] Thus, some embodiments provided herein can include an acid to minimize the interaction between PE and degradants of one or more non-active ingredients. Some embodiments can also include an antioxidant, such as KI, to reduce the degradation of one or more non-active ingredients and thus reduce the presence of some degradants that may otherwise contribute to the instability of the API.

[0082] Below are listed the various ingredients and amounts of ingredients that may comprise the fill material composition to form a softgel according to embodiments provided herein.

[0083] As used herein, "active pharmaceutical ingredient" or "API" refers to a drug product that can be used to diagnose, cure, mitigate, treat, or prevent disease. Any API can be used for the purposes of this disclosure. Suitable APIs include analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigouts, antihypertensives, antimalarials, antimigraine, antimuscarinics, antineoplastics and immunosuppressants, antiprotozoal agents, antirheumatics, antithyroids, antivirals, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropics, and the like. The APIs include, but are not limited to, steroids, cough suppressants, cytotoxic drugs, decongestants, diuretics, enzymes, anti-Parkinson's agents, gastrointestinal agents, histamine receptor antagonists, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and anti-anginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, and stimulants, and combinations thereof. The APIs, if present, are present in the pharmaceutical composition in an amount necessary to exhibit the required physiological effect established by clinical studies. One of ordinary skill in the art can readily determine the appropriate amount of API to be included in a dosage form made according to the present disclosure.

[0084] In some embodiments, the fill material composition can comprise 15-70% total API, 20-65% total API, 25-60% total API, 30-55% total API, 35-55% total API, or 40-50% total API by weight. In some embodiments, the fill material composition can comprise less than 70% total API, less than 65% total API, less than 60% total API, less than 55% total API, less than 50% total API, less than 45% total API, less than 40% total API, less than 35% total API, less than 30% total API, less than 25% total API, or less than 20% total API. In some embodiments, the fill material composition can comprise greater than 15% total API by weight, greater than 20% total API by weight, greater than 25% total API by weight, greater than 30% total API by weight, greater than 35% total API by weight, greater than 40% total API by weight, greater than 45% total API by weight, greater than 50% total API by weight, greater than 55% total API by weight, greater than 60% total API by weight, or greater than 65% total API by weight.

[0085] In some embodiments, the filler material composition can include PE. For example, the filler material composition can include 0.1-15% by weight PE, 0.2-10% by weight PE, 0.3-5% by weight PE, or 0.3-1% by weight PE. In some embodiments, the filler material composition can include less than 15% by weight PE, less than 12% by weight PE, less than 10% by weight PE, less than 8% by weight PE, less than 5% by weight PE, less than 4% by weight PE, less than 3% by weight PE, less than 2% by weight PE, less than 1.0% by weight PE, less than 0.9% by weight PE, less than 0.8% by weight PE, less than 0.7% by weight PE, less than 0.6% by weight PE, less than 0.5% by weight PE, less than 0.4% by weight PE, less than 0.3% by weight PE, or less than 0.2% by weight PE. In some embodiments, the filler material composition can include greater than 0.1% by weight PE, greater than 0.2% by weight PE, greater than 0.3% by weight PE, greater than 0.4% by weight PE, greater than 0.5% by weight PE, greater than 0.6% by weight PE, greater than 0.7% by weight PE, greater than 0.8% by weight PE, greater than 0.9% by weight PE, greater than 1.0% by weight PE, greater than 2% by weight PE, greater than 3% by weight PE, greater than 4% by weight PE, greater than 5% by weight PE, greater than 8% by weight PE, greater than 10% by weight PE, or greater than 12% by weight PE.

[0086] In some embodiments, the filler material composition can include APAP. For example, the filler material composition can include 10-50% by weight APAP, 15-45% by weight APAP, 20-40% by weight APAP, or 25-35% by weight APAP. In some embodiments, the filler material composition can include less than 50% by weight APAP, less than 45% by weight APAP, less than 40% by weight APAP, less than 35% by weight APAP, less than 30% by weight APAP, less than 25% by weight APAP, less than 20% by weight APAP, or less than 15% by weight APAP. In some embodiments, the filler material composition can include more than 10% by weight APAP, more than 15% by weight APAP, more than 20% by weight APAP, more than 25% by weight APAP, more than 30% by weight APAP, more than 35% by weight APAP, more than 40% by weight APAP, or more than 45% by weight APAP.

[0087] In some embodiments, the fill material composition can include dextromethorphan. For example, the fill material composition can include 0.2-12% by weight dextromethorphan, 0.4-10% by weight, 0.6-5% by weight, or 0.7-1.0% by weight dextromethorphan. In some embodiments, the fill material composition can include less than 12% by weight, less than 10% by weight, less than 8% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1.8% by weight, less than 1.6% by weight, less than 1.4% by weight, less than 1.2% by weight, less than 1.0% by weight, less than 0.8% by weight, less than 0.6% by weight, or less than 0.4% by weight dextromethorphan. In some embodiments, the fill material composition can contain greater than 0.2%, greater than 0.4%, greater than 0.6%, greater than 0.8%, greater than 1.0%, greater than 1.2%, greater than 1.4%, greater than 1.6%, greater than 1.8%, greater than 2%, greater than 3%, greater than 4%, greater than 5%, greater than 8%, or greater than 10% by weight of dextromethorphan.

[0088] In some embodiments, the filler composition can include guaifenesin. For example, the filler composition can include 5-30% by weight guaifenesin, 10-25% by weight, or 15-20% by weight guaifenesin. In some embodiments, the filler composition can include less than 30% by weight, less than 25% by weight, less than 20% by weight, less than 15% by weight, or less than 10% by weight guaifenesin. In some embodiments, the filler composition can include more than 5% by weight, more than 10% by weight, more than 15% by weight, more than 20% by weight, or more than 25% by weight guaifenesin.

[0089] The fill material composition can include any of a number of types of non-active ingredients (i.e., excipients). In some embodiments, the fill material composition can include 30-80% by weight total non-active ingredients, 35-75% by weight, 40-70% by weight, 45-65% by weight, or 50-60% by weight total non-active ingredients. In some embodiments, the fill material composition can include less than 80% by weight, less than 75% by weight, 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, or less than 40% by weight total non-active ingredients. In some embodiments, the fill material composition can include more than 30% by weight, more than 35% by weight, more than 40% by weight, more than 45% by weight, more than 50% by weight, more than 55% by weight, more than 60% by weight, more than 65% by weight, or more than 70% by weight total non-active ingredients.

[0090] Some embodiments of the fill material composition may include certain non-active ingredients, such as polyethylene glycol (PEG), propylene glycol, povidone, and / or purified water. PEG may include any of PEG 400, PEG 600, PEG 1200, and / or PEG 2400. In some embodiments, the fill material composition may include 30-60% PEG, 35-55% or 40-50% PEG by weight. In some embodiments, the fill material composition may include less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% PEG by weight. In some embodiments, the fill material composition may include more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% PEG by weight.

[0091] In some embodiments, the fill material composition can include povidone. For example, some embodiments can include povidone K-12 and / or povidone K-30. In some embodiments, the fill material composition can include 2-30% povidone, 3-25%, 4-20%, or 5-15% by weight of povidone. In some embodiments, the fill material composition can include less than 30%, less than 25%, less than 20%, less than 15%, less than 12%, less than 10%, less than 8%, less than 5%, or less than 4% povidone by weight. In some embodiments, the fill material composition can include more than 2%, more than 3%, more than 4%, more than 5%, more than 8%, more than 10%, more than 12%, more than 15%, more than 20%, or more than 25% povidone by weight.

[0092] In some embodiments, the filler material composition can include propylene glycol. In some embodiments, the filler material composition can include 0.25 to 10.0% by weight, 0.5 to 5.0% by weight, or 0.75 to 3.0% by weight of propylene glycol. In some embodiments, the filler material composition can include more than 0.25% by weight, more than 0.5% by weight, more than 0.75% by weight, more than 1.0% by weight, more than 1.25% by weight, more than 1.5% by weight, more than 1.75% by weight, more than 2.0% by weight, more than 2.5% by weight, more than 3.0% by weight, more than 3.5% by weight, more than 4.0% by weight, more than 4.5% by weight, more than 5.0% by weight, more than 5.5% by weight, more than 6.0% by weight, more than 6.5% by weight, more than 7.0% by weight, more than 8.0% by weight, or more than 9.0% by weight of propylene glycol. In some embodiments, the fill composition can comprise less than 10.0%, less than 9.0%, less than 8.0%, less than 7.0%, less than 6.5%, less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.75%, less than 1.5%, less than 1.25%, less than 1.0%, less than 0.75%, or less than 0.50% by weight propylene glycol.

[0093] In some embodiments, the filler material composition can include an acidic solution. For example, the acidic solution can 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 can have a concentration of 0.05-0.5N, 0.075-0.3N, or 0.10-0.20N. In some embodiments, the concentration can be less than 0.5N, less than 0.4N, less than 0.3N, less than 0.25N, less than 0.20N, less than 0.15N, less than 0.10N, less than 0.08N, or less than 0.075N. In some embodiments, the acid solution can have a concentration of 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 fill material composition can include 0.25-10.0 wt. %, 0.5-8.0 wt. %, or 1.0-5.0 wt. % of the acid solution. In some embodiments, the filler material composition can comprise greater than 0.25%, greater than 0.50%, greater than 0.75%, greater than 1.0%, greater than 1.5%, greater than 2.0%, greater than 2.5%, greater than 3.0%, greater than 3.5%, greater than 4.0%, greater than 4.5%, greater than 5.0%, greater than 6.0%, greater than 7.0%, greater than 8.0%, or greater than 9.0% by weight of the acid solution. In some embodiments, the filler material composition can comprise less than 10.0%, less than 9.0%, less than 8.0%, less than 7.0%, less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.75%, less than 1.50%, less than 1.25%, less than 1.0%, less than 0.75%, or less than 0.50% by weight of the acidic solution.

[0094] In some embodiments, the filler material composition can include an antioxidant. Examples of antioxidants can include potassium iodide, propyl gallate, butylated hydroxytoluene, butylated hydroxyanisole, and other suitable antioxidants. In some embodiments, the filler material composition can include 0.25-5.0 wt%, 0.5-4.0 wt%, or 1.0-2.0 wt% of the antioxidant. In some embodiments, the filler material composition can 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 the antioxidant. In some embodiments, the filler material composition can comprise less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.75%, less than 1.5%, less than 1.25%, less than 1.0%, less than 0.75%, or less than 0.50% by weight of antioxidant.

[0095] In some embodiments, the filler material composition can include one or more solvents. For example, the solvent can be water (e.g., purified water). In some embodiments, the filler material composition can include 1-10% by weight of solvent, 1.5-9% by weight, 2-8% by weight, 2.5-7% by weight, 3-6% by weight, or 3.5-5% by weight of solvent. In some embodiments, the filler material composition can include less than 10% by weight, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, or less than 2% by weight of solvent. In some embodiments, the filler material composition can include more than 1% by weight, more than 2% by weight, more than 3% by weight, more than 4% by weight, more than 5% by weight, more than 6% by weight, more than 7% by weight, more than 8% by weight, or more than 9% by weight of solvent.

[0096] Softgel Shell Composition Below is a description of softgel shells formulated to improve the API stability of the softgel. Softgel shells are often gelatin-based shells that surround a fill material composition (described in detail above). Softgel shells typically include gelatin, an opacifier, a plasticizer, and water. In some embodiments, the softgel shell can include an acidic solution to improve the API stability of the softgel.

[0097] In some embodiments, when a fill material (i.e., a fill material according to any of the above-mentioned composition embodiments) is encapsulated by a softgel shell, one or more APIs of the fill material may become unstable over time. In particular, migration of components from the softgel shell to the fill material may change the pH of the fill material, causing instability of one or more APIs (e.g., PE). Therefore, it has been discovered that including an acidic solution in the softgel shell of a softgel may help maintain API stability of the fill material within the softgel. With an acidic softgel shell, the acidic solution of the fill material will be less likely to migrate to the shell of the softgel. Thus, encapsulation with a softgel shell may maintain an acidic environment of the fill material to minimize reactions between the API and degradants of one or more non-active ingredients. Below are the components and component amounts of the softgel shell according to some embodiments provided herein.

[0098] While most softgel shells are gelatin based, some embodiments of the softgel shell may include other materials such as carrageenan, starch, or another suitable gelling agent. In some embodiments, the softgel shell may include 15%-70%, 30%-50%, or 40%-45% of the gelling agent by weight. In some embodiments, the softgel shell may include less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, less than 35%, less than 30%, less than 25%, or less than 20% of the gelling agent by weight. In some embodiments, the softgel shell may include more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, or more than 65% of the gelling agent by weight.

[0099] As discussed above, the softgel shell may include an opacifying agent to impart an opaque appearance to the shell. Examples of opacifying agents include titanium dioxide, zinc oxide, and calcium carbonate. In some embodiments, the softgel shell may include 0.1-5%, 0.3-3%, or 0.5-1.0% by weight of an opacifying agent. In some embodiments, the softgel shell may include less than 5%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1.0%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, or less than 0.2% by weight of an opacifying agent. In some embodiments, the softgel shell can comprise greater than 0.1%, greater than 0.2%, greater than 0.3%, greater than 0.4%, greater than 0.5%, greater than 0.6%, greater than 0.7%, greater than 0.8%, greater than 0.9%, greater than 1.0%, greater than 1.5%, greater than 2.0%, greater than 2.5%, greater than 3.0%, greater than 3.5%, greater than 4.0%, or greater than 4.5% by weight of opacifying agent.

[0100] Examples of plasticizers in the softgel shell can include sorbitol, glycerin, and / or other plasticizers suitable for pharmaceutical use. In some embodiments, the softgel shell can include 10-40% or 20-30% plasticizer by weight. In some embodiments, the softgel shell can include less than 40%, less than 35%, less than 30%, less than 25%, less than 20%, or less than 15% plasticizer by weight. In some embodiments, the softgel shell can include more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, or more than 35% plasticizer by weight.

[0101] In some embodiments, the softgel shell can include an acidic solution, as described above. For example, the acidic solution can be one or more of citric acid, formic acid, acetic acid, and / or hydrochloric acid (HCl). In some embodiments, the softgel shell can include 1% to 20%, 2% to 15%, or 3% to 8% by weight of the acidic solution. In some embodiments, the softgel shell can include less than 20%, less than 18%, less than 15%, less than 12%, less than 10%, less than 8%, less than 5%, less than 4%, less than 3%, or less than 2% by weight of the acidic solution. In some embodiments, the softgel shell can include more than 1%, more than 2%, more than 3%, more than 4%, more than 5%, more than 8%, more than 10%, more than 12%, more than 15%, or more than 18% by weight of the acidic solution.

[0102] In some embodiments, the softgel shell can include water. For example, the softgel shell can include 30-60%, 35-55%, or 40-50% water by weight. In some embodiments, the softgel shell can include more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, or more than 55% water by weight. In some embodiments, the softgel shell can include less than 60%, less than 55%, less than 50%, less than 45%, less than 40%, or less than 35% water by weight.

[0103] The softgel shell may also include additional materials such as colorants, flavors, sugars, aromatic agents, and other sensory agents. One of ordinary skill in the art can readily determine the appropriate types of colorants suitable for embodiments of the present invention.

[0104] Filling material composition and method for preparing softgels Below is provided a description of methods for preparing the fill material compositions and softgels with improved API stability. In general, the fill material compositions and softgels described herein can be prepared using techniques that should be readily discernible to one of ordinary skill in the art.

[0105] For example, the fill material composition can be prepared by mixing the necessary ingredients detailed above in a suitable mixing vessel. A suitable mixing vessel can be an OLSA 200L mixing vessel, an OLSA 2000L mixing vessel, or 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 ingredients are properly mixed, the solution can be degassed and cooled.

[0106] An encapsulation machine can be used to encapsulate the fill material composition in a softgel shell. For example, a 6" or 7.24" encapsulation machine or other suitable encapsulation equipment can be used to encapsulate the fill material composition. After encapsulation, the softgel can be dried until a predefined hardness is achieved. EXAMPLES

[0107] Below are provided further details, including specific test data, for some of the embodiments broadly described above.

[0108] Example 1 Fill material compositions were prepared and tested to observe the physical and chemical stability characteristics. Specifically, fill material compositions were prepared that included the APIs acetaminophen, guaifenesin, dextromethorphan, and phenylephrine, and non-active ingredients that included PEG, propylene glycol, povidone, and water. The physical and chemical stability of the fill material compositions were tested as described below.

[0109] Example 1A physical stability To evaluate the physical stability of the fill material compositions, fill material compositions according to the described embodiments were encapsulated in conventional softgel shells (i.e., softgel shells not specifically formulated to maintain the acidic pH of the fill material compositions according to the above-described embodiments) and observed under ambient conditions. The ingredients of the specific fill material compositions tested are shown in Table 1. In initial demonstration experiments, APAP readily precipitated from solution.

[0110] The type and amount of povidone was varied to test the effect on APAP precipitation. Fill Material Composition A (per Table 1 below) had an increased amount of povidone K-30. The amounts of PEG 400, propylene glycol, and water were adjusted to account for the increased povidone, but remained relatively the same as in the original fill material composition. Fill Material Composition B contained povidone K-12 in place of povidone K-30. The specific amounts of the ingredients for both Fill Material Composition A and Fill Material Composition B are shown in Table 1 below.

[0111] [Table 1] Table 1. Examples of two filler material compositions.

[0112] Both fill material compositions in Table 1 (i.e., fill material composition A and fill material composition B) were prepared, encapsulated in conventional softgel shells, and observed over time. In fill material composition A containing povidone K-12, APAP was observed to precipitate out of solution as early as one week after compounding and encapsulation. However, in fill material composition B containing povidone K-30, APAP did not precipitate out of solution until nearly two weeks after compounding and encapsulation. Similarly, other fill material compositions were tested to evaluate their impact on the physical stability of APAP. The fill material compositions containing increasing amounts of povidone K-30 and propylene glycol, and decreasing amounts of plasticizer in the softgel shell, were observed to have the lowest levels of APAP precipitation.

[0113] Example 1B chemical stability In addition to the physical stability of the fill material compositions described above, the fill material compositions encapsulated in conventional softgel shells were also evaluated for chemical stability under accelerated conditions. The chemical stability of the fill material compositions observed under accelerated conditions showed inadequately large amounts of PE degradation for all compositions encapsulated in conventional softgel shells. For example, some results showed as much as 7-10% loss of PE over a two month period.

[0114] Furthermore, the increased degradation of PE also increased the occurrence of unknown degradants in the packing material. To determine the identity of these unknown degradants, packing material composition materials were encapsulated, stressed at 70°C, and analyzed over time. The resulting chromatograms shown in Figure 1 were compared to determine the identity of the peaks that increase as the amount of PE decreases (i.e., as a result of PE becoming unstable).

[0115] Figure 1 shows four overlapping chromatograms of packing material compositions stressed at 70°C according to some embodiments described above. In particular, chromatograms were obtained at days 0, 5, 13, and 22 to observe the effect of the packing material composition over time. As shown, the overlapping chromatograms show a peak (at about 21.6 minutes) that gradually increases over time.

[0116] Evaluation of each of the fill material components in light of the growing peak in Figure 1 revealed a peak corresponding to the retention time of Povidone K-30. Additionally, the increasing size of the peak reveals an ultraviolet (UV) maximum at approximately 276 nm, suggesting that the unknown degradant represented by the growing peak in Figure 1 may be directly related to the degradation of PE (discussed in further detail below).

[0117] Example 2 Identifying the cause of PE instability To confirm that the increasing peak in Figure 1 is associated with the degradation of PE, two separate samples of the fill material were prepared. Both samples contained all of the inactive ingredients included in the composition of Table 1 (i.e., PEG, propylene glycol, povidone K-30, and water). The first sample also contained PE (the "PE only" sample). The second sample, in addition to PEG, propylene glycol, povidone K-30, and water, also contained APAP, guaifenesin, and dextromethorphan, but no PE. Each sample was tested at 70°C and analyzed using chromatography at various time points over a 15-day period (as shown in Figure 2).

[0118] FIG. 2 shows overlapping chromatograms of both samples. The PE only sample is shown on the left side of the figure, and the APAP, guaifenesin, and dextromethorphan sample without PE is shown on the right side of the figure. Chromatograms were taken on days 0, 6, and 15. FIG. 2 demonstrates that the peak at about 21.6 minutes was increased only in the first sample with PE. In contrast, in the sample with APAP, guaifenesin, and dextromethorphan but without PE, the peak remains at about the same height. Thus, the chromatogram in FIG. 2 confirms that the unknown degradant represented by the peak at 21.6 minutes resulted from the interaction between PE and povidone K-30.

[0119] As previously mentioned, when the size of the peak increases over time, a UV maximum also occurs at about 276 nm, as shown in FIG. 3. The left side of the figure shows the UV spectrum of the povidone K-30 peak in a fill material composition containing only PE (no other APIs). The right side of the figure shows the UV spectrum of the povidone K-30 peak in a fill material composition containing APAP, guaifenesin, and dextromethorphan (but no PE). As shown in FIG. 3, the UV spectrum of the povidone K-30 peak in the fill material composition containing PE changed to show a UV maximum at about 276 nm. However, the UV spectrum of the povidone K-30 peak did not change in the composition without PE. Thus, this data further supports that the observed degradation of PE is the result of an interaction between povidone K-30 and PE.

[0120] Similar tests (shown in Figures 1-3) were performed on fill material compositions containing povidone K-12 instead of povidone K-30. However, no interaction between povidone K-12 and PE was observed in these tests, suggesting that povidone K-12 does not contribute significantly to the degradation of PE.

[0121] Example 3 Use antioxidants to control the formation of degradants To evaluate the effect of both ionic strength and the presence of iodine on the formation of the PE-povidone peak, fill material composition samples were prepared with the addition of potassium iodide (KI). The results, shown in Figure 4, indicate that the addition of KI had little effect on the formation of the PE-povidone peak.

[0122] In particular, Figure 4 shows the results of two different samples of the fill material composition. The two samples contained PE, dextromethorphan, and 13% povidone K-30, respectively. Additionally, one sample contained 5% KI and one sample contained 5% water. Both samples were tested at 70°C for 15 days and showed the formation of a relatively large PE-povidone peak. Thus, these results suggest that the addition of KI to the fill material composition had little effect on the formation of the PE-povidone peak compared to the fill material composition containing only water and no KI.

[0123] The addition of KI to the fill material composition had little effect on the formation of the PE-povidone peak, but did affect the formation of other known PE related substances (as shown in FIG. 5). FIG. 5 shows two samples of fill material composition tested at 70° C. for 15 days. Both samples contained PE, dextromethorphan, and 13% povidone K-30. One sample contained only water and the other sample contained KI. As shown, the fill material composition sample containing KI showed less formation of PE degradants than the water only fill material composition sample.

[0124] Therefore, it appears that not only the presence of an acid improves the stability of the API in the softgel fill material composition, but the presence of an antioxidant such as KI is also necessary to reduce the presence of some degradants that may otherwise contribute to the instability of the API.

[0125] Example 4 Inhibits interactions between APIs (e.g., phenylephrine) and non-active ingredients Various studies were conducted to evaluate the effect of pH, air, peroxide, water, and povidone concentration on the formation of PE (or "PE-PVP", "PE-povidone") degradants. The results of some of these tests are shown in Figure 6.

[0126] Figure 6 presents data showing the effect of pH (top left), air (top right), peroxide (bottom left), and water (bottom right) on the peak shift of Povidone K-30 at 70°C. As shown in Figure 6, pH has the greatest effect on the formation of the PE-Povidone peak. In particular, samples of fill material compositions containing HCl (acidic pH) showed nearly a 400% reduction in the PE-Povidone peak shift compared to fill material compositions containing sodium hydroxide (basic pH). None of the other variables (air, peroxide, and / or water) had such a dramatic effect on the Povidone K-30 peak.

[0127] Example 5 Testing the effect of pH After 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 for 15 days, and the results are shown in Figure 7.

[0128] Figure 7 shows data from three different fill material compositions. One sample was tested at pH 3.6, one sample was tested at pH 4.6, and one sample was tested at pH 5.6. Based on the results shown in the figure, the PE-povidone peak is directly proportional to the pH of the fill material composition. In particular, as the pH of the fill material composition decreases, the interaction between povidone and PE also decreases.

[0129] Example 6 Adding an Acid to the Filler Material Composition The results of the tests, shown in Figure 7, indicate that reducing the acidity of the fill material composition can reduce the degradation of PE. To reduce the acidity of the fill material composition, various amounts of 0.1N HCl were added to the fill material composition and tested.

[0130] Various fill material composition samples prepared with various amounts of HCl were stressed at 70° C. and tested for 15 days. In particular, five different samples were prepared and tested for 15 days. All samples contained PE, dextromethorphan, and 13% povidone K-30. However, the 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 shown in FIG. 8 and are discussed below.

[0131] As shown in Figure 8, the fill material composition containing only water (near neutral pH) showed the highest impact on the povidone K-30 peak. In contrast, the fill material composition containing 0.5% 0.1 N HCl showed slightly less impact on the povidone K-30 peak, and the fill material composition samples containing 2.5%, 3.75%, and 5.0% 0.1 N HCl showed significantly less impact on the povidone K-30 peak.

[0132] (Examples 7 to 9) PE Stability of Filler Material Compositions Containing Acids and Antioxidants To monitor and evaluate the formation of all PE degradants, fill material composition excipients were evaluated using a fill material composition containing only the APIs PE and dextromethorphan. To monitor the effect on all APIs present in combination, various antioxidants, as well as various amounts of HCl and KI, were tested in fill material composition A of Table 1. Composition A was also used because it produced the least amount of APAP precipitation (as discussed above).

[0133] These demonstration experiments confirm that the stability of PE is greatest in the presence of HCl. However, the high acidity of the composition resulting from the addition of HCl increases the formation of both 4-aminophenol and PE-RS-1 (another PE-related degradant). Thus, the addition of KI as an antioxidant is necessary to help control the levels of these other degradants mentioned above. The addition of other antioxidants showed little effect on the stability of the composition. The results of this study are shown in Figures 9-11 and are discussed below.

[0134] 9 shows the effect of HCl, KI, and additional antioxidants on the stability of PE in a filler material composition according to some embodiments. Specifically, 11 different samples were tested at 70° C. for 20 days. The fill material composition samples included fill material compositions containing one of: 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.

[0135] Only the samples containing HCl demonstrated adequate PE stability by maintaining at least 99% of the original PE amount throughout the demonstration experiment. In contrast, the samples without HCl demonstrated insufficient PE stability by losing at least 8% of the original PE amount throughout the 20 day test period. These results confirm that a lower pH fill material composition can minimize PE degradation in softgels.

[0136] FIG. 10 shows the effect of HCl, KI, and additional antioxidants on the formation of PE RS-1 in filler material compositions according to some embodiments. PE RS-1 is a decomposition product of PE. Thus, increasing levels of PE RS-1 indicate increasing levels of PE decomposition. The eleven samples tested in this study were the same as those tested in FIG. 9. The eleven samples were tested at 70° C. for 20 days. In particular, the fill material composition samples included one of the following fill material compositions: 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.

[0137] The results in Figure 10 show that PE RS-1 levels are increased in the fill material composition containing only HCl. However, in the fill material composition containing KI (with or without HCl), PE RS-1 levels remain relatively low. Thus, this study confirms that the presence of KI in the fill material composition may help control the formation of PE RS-1, an undesirable PE decomposition product.

[0138] Figure 11 shows the effect of HCl, KI, and additional antioxidants on the formation of 4-aminophenol in a filler material composition according to some embodiments. 4-aminophenol is another example of a PE decomposition product. The 11 samples were the same as those tested in Figures 9 and 10. In particular, the fill material composition samples included one of the following fill material compositions: 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.

[0139] Based on the results shown in Figure 11, the formation of 4-aminophenol increases when the composition contains HCl and does not contain KI. However, the level of 4-aminophenol remains lower in the composition with a higher pH and containing KI. Thus, like PE RS-1 in Figure 10, the presence of KI may help control the formation of 4-aminophenol in a similar manner to PE RS-1.

[0140] Example 10 Encapsulating the fill material Fill material compositions according to various embodiments were encapsulated using type A (pigskin) and type B (animal bone) gelatin. These softgel shell encapsulated fill material compositions correspond to the embodiments described above. In particular, fill material compositions that showed suitable API stability in the presence of HCl and KI were tested in some embodiments. Various softgel samples were tested both at room temperature and under accelerated conditions (50°C and 70°C). In addition, softgel samples stressed at 50°C were tested in two different ways: when stressed as is and when stressed cut open to expose to air. In some embodiments, fill material compositions stressed at 70°C prior to encapsulation were also used.

[0141] FIG. 12 demonstrates that PE degrades rapidly in softgels stressed at 70° C., regardless of the type of fill material composition. FIG. 12 shows data on the stability of PE in fill material compositions tested over 20 days at 70° C. (left) and in finished softgels tested over 20 days at 70° C. (right). As shown in the graph on the left, three different fill material 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 of each of the three samples was nearly the same. This data supports the studies described above which confirmed that PE stability is pH dependent (inversely proportional to pH). Furthermore, PE stability in the fill material compositions (not encapsulated) is not dependent on the presence of KI.

[0142] On the right side of Figure 12, four different softgel samples were tested: one with a fill material composition containing 2.6 mM HCl / 0.26% KI; one with a fill material composition containing 2.6 mM HCl (no KI); one with a fill material composition containing 2.6 mM HCl / 0.38% KI; and one with a fill material composition without HCL or KI. PE degraded significantly in all four samples. Interestingly, the two samples with KI had slightly less PE stability than the two samples without KI.

[0143] Thus, the results in Figure 12 demonstrate that the fill material composition containing HCl and KI exhibited excellent stability prior to encapsulation as described above, yet experienced significant PE degradation after encapsulation. Thus, the results shown in Figure 12 suggest that encapsulation of the fill material composition somehow alters the fill material composition, resulting in PE instability / degradation.

[0144] (Examples 11 to 13) Investigating the cause of PE decomposition after encapsulation Based on the nature of the encapsulation process and the chemical components involved, there are three primary factors that can cause PE degradation as a result of encapsulation - water ingress from the shell into the fill material composition, air exposure of the fill material composition, and migration of components from the fill material composition into the softgel shell. Each of these potential causes was tested and is detailed below.

[0145] The first possible cause, i.e., water ingress from the softgel shell into the fill material composition, was investigated by increasing the water content of the fill material composition and stressing it at 70° C. FIG. 13 shows the effect of moisture in the fill material composition on PE degradation. Two different samples of the fill material composition were tested, one with 2% water and one with 10% water. Both samples were tested at 70° C. for 15 days. As shown, the results in FIG. 13 suggest that PE stability is independent of the water content of the fill material composition, as there is little difference in PE stability between the two samples.

[0146] The second possible cause, i.e., air exposure of the fill material composition, was investigated by stressing both intact and cut-open softgels at 50° C. In particular, FIG. 14 shows the effect of air exposure on PE degradation of softgels with and without HCl and KI. Four different softgels were tested: fill material composition without HCl / KI from uncut softgels; fill material composition without HCl / KI from cut softgels; fill material composition with HCl and KI from uncut softgels; and fill material composition with HCl and KI from cut softgels. The results of this study are shown in FIG. 14 and show that there is no obvious correlation between PE stability and air exposure. Furthermore, this study shows that the degradation rate of the softgels with HCl and KI is substantially the same as the softgels without HCl or KI.

[0147] The third possible cause, i.e., migration of fill material composition components into the softgel shell, was investigated by specifically examining the migration of HCl from the fill material composition into the softgel shell. It is known that hydrophilic components such as acids can migrate quickly into the softgel shell. Furthermore, based on the above-mentioned investigations, it is also known that the degradation of PE is independent of KI. It is noted that the migration of other APIs and non-active ingredients was not considered, since the degradation rate of PE in the fill material composition without HCl and KI compared to the degradation rate of PE in the fill material composition without HCl and KI after encapsulation (in the finished softgel) is the same as before encapsulation.

[0148] Therefore, the migration of HCl from the fill material composition to the softgel shell and its effect on the degradation of PE was investigated by comparing the pH of the fill material composition before encapsulation with the pH of the fill material composition after encapsulation (after removal from the softgel). Testing showed that the pH of the fill material composition increased by about 2 full units. (See Examples for more details.) Furthermore, the largest degradant observed in the fill material composition after encapsulation (containing HCl and KI) was the PE-formic acid complex. However, the results show that maintaining the pH of the fill material composition below the pKa of the degradant (formic acid) improves the stability of PE. Thus, since the pKa of formic acid is about 3.75, the results suggest that the pH of the fill material composition should be controlled at a level below 3.75 to improve the stability of PE.

[0149] (Examples 14 and 15) Controlling the pH of the filler composition below the pKa of the degradants Considering the above results, various tests were performed to control the pH of the fill material composition and test the effect of different pH levels on the stability of PE. To stabilize the pH of the fill material composition, various buffer solutions with different pH values ​​from 2.4 to 4.4 and concentrations of 25 mM and 50 mM were added to the fill material composition without HCl or KI and tested. All samples in Figures 15 and 16 were tested at 70°C for 15 days.

[0150] Figure 15 shows a comparison of filler composition buffered 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 were significantly different. However, none of the buffers performed similarly to HCl with respect to PE stability.

[0151] FIG. 16 shows a comparison of filler material compositions buffered at various pH values ​​at 50 mM. Eight different filler material composition samples were tested, this time 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); 50 mM acetate (pH 4.4); and 50 mM citrate (pH 4.4). As with the results in FIG. 15 above, the results here are mixed. However, as with the FIG. 15 study, HCl had the most effect on PE stability, although 50 mM citrate also showed suitable results.

[0152] Therefore, the stability of APIs in softgels can be improved by introducing various acidic solutions into the fill material composition. However, it is important to maintain the pH of the fill material composition below the pKa of the degradants of non-active ingredients that may interact with one or more APIs. In particular, it has been found that the addition of HCl and KI to the fill material composition of the softgel can improve the stability of APIs such as PE in the softgel. By maintaining the pH of the fill material below the pKa of the degradants of PEG and / or povidone, the interaction between the degradants of PEG and / or povidone and the API can be inhibited, improving the stability of the API.

[0153] (Example 16) Migration of acids from traditional softgel shells into the fill material As discussed above and shown in Figures 15 and 16, it is believed that encapsulated samples under certain circumstances experienced HCl migration from the fill material to the softgel shell. Therefore, the pH of the fill material compositions was compared before and after encapsulation to quantify the extent of this HCl migration. Details of this demonstration are shown in Table 2 below. The pH values ​​of two different fill material compositions, one without HCl or KI, and one with HCl, are shown.

[0154] [Table 2]

[0155] (Example 17) Migration of acid from a softgel shell containing an acidic solution into the filling material The effect of pH equilibration on the control of the pH of the fill material composition was evaluated with four separate fill material compositions, each containing 0, 3.75, 7.5, or 15 mM HCl. Each of the four samples was dispensed into a 20 mL vial (approximately 2 g per vial) and allowed to settle and dry. Approximately 5 g of the fill material composition (containing both HCL and KI) was added on top of the gelatin mixture in the vial and all vials were placed in a water bath at 45° C. The vials were analyzed at predetermined times and the results are shown in FIG. 17. As shown in the figure, the PE degradation of each sample is directly correlated to the amount of acid in the gelatin. Specifically, the more HCl present in the gelatin of the gelatin mixture, the greater the PE stability of the fill material composition on the gelatin mixture. Furthermore, the pH of the fill material composition in the vial is inversely proportional to the level of HCl in the gelatin.

[0156] The foregoing specification has been described with reference to specific embodiments for purposes of illustration. However, the illustrative discussion above is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of the above teachings. The embodiments have been chosen and described in order to best explain the principles of the techniques and their practical application, thereby enabling those skilled in the art to best utilize the techniques and various embodiments with various modifications as suited to the particular use contemplated.

[0157] 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, and such changes and modifications are to be understood as falling within the scope of the disclosure and embodiments as defined by the claims.

Claims

1. one or more active pharmaceutical ingredients (APIs); 2 to 15% by weight of povidone, 30 to 60% by weight of polyethylene glycol, 0.5 to 5% by weight of propylene glycol, and a filler material composition comprising 0.5 to 8% by weight of citric acid, formic acid, acetic acid, and / or hydrochloric acid; Soft gel shell 1. A pharmaceutical softgel comprising:

2. 10. The softgel of claim 1, wherein the softgel shell is made from a softgel shell composition that includes an acidic component.

3. 3. The softgel of claim 2, wherein the acidic component comprises hydrochloric acid.

4. 4. The softgel of claim 1, wherein the one or more APIs comprise ibuprofen, phenylephrine, dextromethorphan, acetaminophen, and / or guaifenesin.

5. 5. The softgel of any one of claims 1 to 4, wherein the fill material composition comprises 15-70% by weight of the total API.

6. 6. The softgel of claim 1, wherein the fill material composition comprises an antioxidant.

7. 7. The softgel of claim 6, wherein the fill material composition comprises 0.25 to 5% by weight of an antioxidant.

8. 8. The softgel of claim 6 or 7, wherein the antioxidant comprises potassium iodide.

9. one or more active pharmaceutical ingredients (APIs); 2 to 15% by weight of povidone, 30 to 60% by weight of polyethylene glycol, 0.5 to 5% by weight of propylene glycol, and A fill material composition for a softgel comprising 0.5 to 8% by weight of citric acid, formic acid, acetic acid, and / or hydrochloric acid.

10. 10. The composition of claim 9, comprising 15 to 70% by weight of the one or more APIs.

11. 11. The composition of claim 9 or 10, wherein the one or more APIs comprise ibuprofen, phenylephrine, dextromethorphan, acetaminophen, and / or guaifenesin.

12. 12. The composition of claim 9, further comprising an antioxidant.

13. 13. The composition of claim 12, comprising 0.25 to 5% by weight of an antioxidant.

14. 14. The composition of claim 12 or 13, wherein the antioxidant comprises potassium iodide.

15. 1. A method for preparing a softgel fill material composition, comprising:

1. A method comprising combining 30-60% by weight polyethylene glycol, 0.5-5% by weight propylene glycol, 2-15% by weight povidone, one or more active pharmaceutical ingredients (APIs), and 0.5-8% by weight citric acid, formic acid, acetic acid, and / or hydrochloric acid.

16. 16. The method of claim 15, comprising 15 to 70% by weight of the one or more APIs.

17. 17. The method of claim 15 or 16, wherein the one or more APIs comprise ibuprofen, phenylephrine, dextromethorphan, acetaminophen, and / or guaifenesin.

18. 18. The method of any one of claims 15 to 17, further comprising combining an antioxidant.

19. 19. The method of claim 18, comprising combining 0.25 to 5% by weight of an antioxidant.

20. 20. The method of claim 18 or 19, wherein the antioxidant comprises potassium iodide.

21. 1. A method for preparing a softgel, comprising: combining 30-60% by weight polyethylene glycol, 0.5-5% by weight propylene glycol, 2-15% by weight povidone, one or more active pharmaceutical ingredients (APIs), and 0.5-8% by weight citric acid, formic acid, acetic acid, and / or hydrochloric acid; and c. encapsulating the fill material composition in a softgel shell to form a softgel.

22. 22. The method of claim 21, wherein the softgel shell is made from a softgel shell composition that includes an acidic component.

23. 23. The method of claim 22, wherein the acidic component comprises hydrochloric acid.

24. 24. The method of any one of claims 21 to 23, comprising 15 to 70% by weight of the one or more APIs.

25. 25. The method of any one of claims 21 to 24, wherein the one or more APIs comprise ibuprofen, phenylephrine, dextromethorphan, acetaminophen, and / or guaifenesin.

26. 26. The method of any one of claims 21 to 25, further comprising combining an antioxidant.

27. 27. The method of claim 26, comprising combining 0.25 to 5% by weight of an antioxidant.

28. 28. The method of claim 26 or 27, wherein the antioxidant comprises potassium iodide.

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