Increased permeability for pre-gastric absorption of active pharmaceutical ingredients

Abstract

A pharmaceutical composition comprising an osmotic enhancer for pre-gastric absorption of an active pharmaceutical ingredient (API) and a method for preparing such a pharmaceutical composition are provided. Specifically, the osmotic enhancer can be selected based on the API classification and subclassification of a particular biopharmaceutical classification system (BCS).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Patent Application No. 63 / 465,578, filed on 11 May 2023, the entire contents of which are incorporated herein by reference.

[0002] Field of Invention This disclosure relates to formulations and compositions containing osmotherapeutic agents for increasing the permeability of active pharmaceutical ingredients (APIs), and to methods for preparing them. More specifically, this disclosure relates to orally disintegrating dosage forms containing specific osmotherapeutic agents for a given API for aiding pregastric absorption of the API, and to methods for preparing them. [Background technology]

[0003] background Most drugs are absorbed through the gastrointestinal system. Some drugs may be absorbed before entering the gastrointestinal system via the buccal, sublingual, pharyngeal, and esophageal routes. For some pharmaceuticals, the use of the pregastric route is a preferred option because drug molecules can pass through mucosal tissue and diffuse directly into the circulatory system. As a result, the drug may have a faster onset of action and / or can avoid metabolism by the liver. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] U.S. Patent No. 6,316,027 [Patent Document 2] U.S. Patent No. 6,413,549 [Patent Document 3] U.S. Patent No. 6,509,040 [Non-patent literature]

[0005] [Non-Patent Document 1] Surfactant Self Assembling and Critical Micelle Concentration: One Approach Fits All?, by Diego Romano Perinelli et al., Langmuir 2020, 36, 5745-4753 [Overview of the project] [Problems that the invention aims to solve]

[0006] Drug development for pre-gastric delivery using lyophilized tablets can present challenges when the active pharmaceutical ingredient (API) has poor solubility and / or low permeability. API absorption can be strongly influenced by the API's physicochemical properties, such as molecular weight, solubility, hydrophilicity, and lipophilicity, as well as by factors such as drug load, mucosal contact time, drug formulation, and excipients used. APIs with poor solubility and / or low permeability may result in poor absorption and varying drug bioavailability.

[0007] To improve the absorption of low-permeability drugs, various formulation approaches have been used, including the addition of osmotic enhancers (PEs), also known as osmotic agents (PAs). In particular, PEs may be added to drug formulations to enhance the permeability of APIs in Biopharmaceutical Classification System (BCS) Class II and III. The BCS system classifies APIs according to their solubility and permeability properties; BCS Class II APIs are characterized by low solubility and high permeability, while BCS Class III APIs are characterized by high solubility and low permeability. While some PEs may help Class II and III APIs overcome the oral mucosal barrier, it is difficult to predict which PE will act with a given API. The selection of the appropriate PE for each type of API is largely based on empirical trial and error, and most research on PEs to date has focused on improving drug permeability to intestinal and skin tissues. The effect of PEs on pre-gastric absorption via oral mucosal tissue is not well established, especially in lyophilized orally disintegrating tablet (ODT) form. As a result, formulation often fails, and the necessary reformulation work prolongs drug development time, incurring additional development costs. [Means for solving the problem]

[0008] Pharmaceutical formulations and compositions utilizing appropriate PE for a given Class II and / or Class III API, as well as methods for producing them, are disclosed herein.

[0009] In some embodiments, the pharmaceutical composition comprises: a pharmaceutically effective amount of a biopharmaceutical classification system (BCS) class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof having a solubility of less than 0.1 mg / mL and a Log P value greater than 2.5; a penetration enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, micelles, or fatty acids; a matrix-forming agent; and a structure-forming agent. In some embodiments, the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance (HLB) greater than 10. In some embodiments, the molar ratio of API to surfactant is 5:1 to 1:5, and / or the pharmaceutical composition comprises 0.5 to 20 wt.% of the surfactant. In some embodiments, the pharmaceutical composition comprises a pH modifier. In some embodiments, the penetration enhancer comprises a bile salt. In some embodiments, the molar ratio of API to bile salt is 15:1 to 1:15, and / or the pharmaceutical composition comprises 1 to 20 wt.% of the bile salt. In some embodiments, the penetration enhancer contains fatty acids. In some embodiments, the molar ratio of the API to the fatty acid is 3:1 to 1:3, and / or the pharmaceutical composition contains 0.25 to 5 wt.% of fatty acids. In some embodiments, the penetration enhancer contains counterions. In some embodiments, the molar ratio of the API to the counterions is 6:1 to 1:6, and / or the pharmaceutical composition contains 0.1 to 25 wt.% of counterions. In some embodiments, the pharmaceutical composition contains a pH modifier. In some embodiments, the pharmaceutical composition contains 25 to 60 wt.% of a matrix-forming agent. In some embodiments, the matrix-forming agent includes gelatin, pullulan, starch, or a combination thereof. In some embodiments, the gelatin includes fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the pharmaceutical composition contains 20 to 45 wt.% of a structure-forming agent. In some embodiments, the structure-forming agent includes mannitol. In some embodiments, the pharmaceutical composition comprises 1 to 35 wt.% of a BCS class II API or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, the pharmaceutical composition comprises: a pharmaceutically effective amount of a Biopharmaceutical Classification System (BCS) Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof having a solubility of 0.1 to 1 mg / mL and a Log P value of 1 to 2.5; a penetration enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, or micelles; a matrix-forming agent; and a structure-forming agent. In some embodiments, the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance (HLB) greater than 10. In some embodiments, the molar ratio of API to surfactant is 5:1 to 1:5, and / or the pharmaceutical composition comprises 0.5 to 20 wt.% of the surfactant. In some embodiments, the penetration enhancer comprises a bile salt. In some embodiments, the molar ratio of API to bile salt is 15:1 to 1:15, and / or the pharmaceutical composition comprises 1 to 20 wt.% of the bile salt. In some embodiments, the penetration enhancer comprises a counterion. In some embodiments, the molar ratio of the API to the counterion is 6:1 to 1:6, and / or the pharmaceutical composition contains 0.1 to 25 wt.% of the counterion. In some embodiments, the pharmaceutical composition contains a pH modifier. In some embodiments, the pharmaceutical composition contains 1 to 35 wt.% of a pharmaceutically effective amount of a Biopharmaceutical Classification System (BCS) Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 0.1 to 1 mg / mL and a Log P value of 1 to 2.5. In some embodiments, the pharmaceutical composition contains 25 to 60 wt.% of a matrix-forming agent. In some embodiments, the matrix-forming agent includes gelatin, pullulan, starch, or a combination thereof. In some embodiments, the gelatin includes fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the pharmaceutical composition contains 20 to 45 wt.% of a structure-forming agent. In some embodiments, the structure-forming agent includes mannitol.

[0011] In some embodiments, the pharmaceutical composition comprises: a pharmaceutically effective amount of a Biopharmaceutical Classification System (BCS) Class III active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof having a solubility of 1 to 10 mg / mL and a Log P value of less than 1; a penetration enhancer comprising at least one selected from the group consisting of a counterion, a pH modifier, or a bile salt; a matrix-forming agent; and a structure-forming agent. In some embodiments, the penetration enhancer comprises a bile salt. In some embodiments, the molar ratio of the API to the bile salt is 15:1 to 1:15, and / or the pharmaceutical composition comprises 1 to 20 wt.% of the bile salt. In some embodiments, the penetration enhancer comprises a counterion. In some embodiments, the molar ratio of the API to the counterion is 6:1 to 1:6, and / or the pharmaceutical composition comprises 0.1 to 25 wt.% of the counterion. In some embodiments, the pharmaceutical composition comprises a pH modifier. In some embodiments, the pharmaceutical composition comprises 25 to 60 wt.% of the matrix-forming agent. In some embodiments, the matrix-forming agent includes gelatin, pullulan, starch, or a combination thereof. In some embodiments, the gelatin includes fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the pharmaceutical composition includes 20-45 wt.% of a structure-forming agent. In some embodiments, the structure-forming agent includes mannitol. In some embodiments, the pharmaceutical composition includes 1-35 wt.% of a BCS class III API or a pharmaceutically acceptable salt or solvate thereof.

[0012] In some embodiments, the pharmaceutical composition comprises: a pharmaceutically effective amount of a Biopharmaceutical Classification System (BCS) Class III active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof having a solubility of 10 to 33 mg / mL and a Log P value of less than 1; a penetration enhancer comprising at least one selected from the group consisting of counterions or pH modifiers; a matrix-forming agent; and a structure-forming agent. In some embodiments, the penetration enhancer comprises a counterion. In some embodiments, the molar ratio of the API to the counterion is 6:1 to 1:6, and / or the pharmaceutical composition comprises 0.1 to 25 wt.% of the counterion. In some embodiments, the pharmaceutical composition comprises 25 to 60 wt.% of the matrix-forming agent. In some embodiments, the matrix-forming agent comprises gelatin, pullulan, starch, or a combination thereof. In some embodiments, the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the pharmaceutical composition contains 20-45 wt.% of a structure-forming agent. In some embodiments, the structure-forming agent is mannitol. In some embodiments, the pharmaceutical composition contains 1-35 wt.% of a pharmaceutically effective amount of a Biopharmaceutical Classification System (BCS) Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 10-33 mg / mL and a Log P value of less than 1.

[0013] In some embodiments, the pharmaceutical composition is in solid dosage form. In some embodiments, a method of treating a patient includes the step of placing the solid dosage form in the oral cavity of a person in need of treatment. In some embodiments, the oral placement is on the tongue, sublingually, or in the buccal or pharyngeal region. In some embodiments, the pharmaceutical composition is provided for use in a therapeutic setting. In some embodiments, the pharmaceutical composition is provided for use in a method of treating a patient, which includes the step of placing the pharmaceutical composition in the oral cavity of a person in need of treatment. The oral placement may be on the tongue, sublingually, or in the buccal or pharyngeal region.

[0014] In some embodiments, the method for forming a solid dosage form includes: a step of placing a pharmaceutical formulation into a pre-formed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a biopharmaceutical classification system (BCS) class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof having a solubility of less than 0.1 mg / mL and a Log P value greater than 2.5; a penetration enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, micelles, or fatty acids; 1 to 10 wt.% of a matrix-forming agent; and 1 to 10 wt.% of a structure-forming agent; freezing the placed pharmaceutical formulation; and freeze-drying the frozen pharmaceutical formulation to form a dosage form. In some embodiments, the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance greater than 10. In some embodiments, the pharmaceutical formulation comprises 0.01 to 5 wt.% of a surfactant. In some embodiments, the surfactant has a concentration of 0.1 to 30 × its critical micelle concentration (CMC) in the pharmaceutical formulation. In some embodiments, the surfactant has a concentration of 0.5 to 3 × CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to surfactant of 5:1 to 1:5. In some embodiments, the penetration enhancer includes a bile salt. In some embodiments, the pharmaceutical formulation includes 0.25 to 5 wt.% of the bile salt. In some embodiments, the bile salt has a concentration of 0.5 to 5 × CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to bile salt of 15:1 to 1:15. In some embodiments, the molar ratio is 5:1 to 1:5. In some embodiments, the penetration enhancer includes a fatty acid. In some embodiments, the pharmaceutical formulation includes 0.03 to 0.15 wt.% of the fatty acid. In some embodiments, the pharmaceutical formulation has a molar ratio of API to fatty acid of 3:1 to 1:3. In some embodiments, the penetration enhancer includes a counterion. In some embodiments, the pharmaceutical formulation contains 0.025 to 5 wt.% of counterions. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:6. In some embodiments, the molar ratio is 3:1 to 1:3. In some embodiments, the pharmaceutical formulation contains a pH modifier.In some embodiments, the pharmaceutical formulation contains 0.1 to 5 wt.% of a BCS class II API or a pharmaceutically acceptable salt or solvate thereof.

[0015] In some embodiments, a method of forming a solid dosage form comprises: introducing a pharmaceutical formulation into a preformed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a Biopharmaceutics Classification System (BCS) Class II active pharmaceutical ingredient (API) having a solubility of 0.1 to 1 mg / mL and a Log P value of 1 to 2.5 or a pharmaceutically acceptable salt or solvate thereof; a penetration enhancer selected from the group consisting of a counter ion, a pH modifier, a surfactant having a hydrophilic-lipophilic balance (HLB) greater than 10, a bile salt, or a micelle; a matrix former in an amount of 1 to 10 wt.%; and a structure former in an amount of 1 to 10 wt.%; freezing the introduced pharmaceutical formulation; and lyophilizing the frozen pharmaceutical formulation to form the dosage form. In some embodiments, the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance greater than 10. In some embodiments, the pharmaceutical formulation comprises a surfactant in an amount of 0.01 to 5 wt.%. In some embodiments, the surfactant has a concentration in the pharmaceutical formulation of 0.1 to 30× its critical micelle concentration (CMC). In some embodiments, the surfactant has a concentration in the pharmaceutical formulation of 0.5 to 3× CMC. In some embodiments, the pharmaceutical formulation has a molar ratio of API to surfactant of 5:1 to 1:5. In some embodiments, the penetration enhancer comprises a bile salt. In some embodiments, the pharmaceutical formulation comprises a bile salt in an amount of 0.25 to 5 wt.%. In some embodiments, the bile salt has a concentration in the pharmaceutical formulation of 0.5 to 5× CMC. In some embodiments, the pharmaceutical formulation has a molar ratio of API to bile salt of 15:1 to 1:15. In some embodiments, the molar ratio is 5:1 to 1:5. In some embodiments, the penetration enhancer comprises a counter ion. In some embodiments, the pharmaceutical formulation comprises a counter ion in an amount of 0.025 to 5 wt.%. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counter ion of 6:1 to 1:6. In some embodiments, the molar ratio is 3:1 to 1:3. In some embodiments, the pharmaceutical formulation comprises a pH modifier. In some embodiments, the pharmaceutical formulation comprises 0.1 to 5 wt.% of a BCS Class II API or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, a method for forming a solid dosage form includes the steps of: placing a pharmaceutical formulation into a pre-formed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a Biopharmaceutical Classification System (BCS) Class III active pharmaceutical ingredient (API) having a solubility of 1 to 10 mg / mL and a Log P value of less than 1, or a pharmaceutically acceptable salt or solvate thereof; an osmotic enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, or bile salts; 1 to 10 wt.% of a matrix-forming agent; and 1 to 10 wt.% of a structure-forming agent; freezing the placed pharmaceutical formulation; and freeze-drying the frozen pharmaceutical formulation to form a dosage form. In some embodiments, the osmotic enhancer comprises a bile salt. In some embodiments, the pharmaceutical formulation comprises 0.25 to 5 wt.% of a bile salt. In some embodiments, the bile salt has a concentration of 0.5 to 5 × CMC in the pharmaceutical formulation. In some embodiments, the pharmaceutical formulation has a molar ratio of API to bile salt of 15:1 to 1:15. In some embodiments, the molar ratio is 5:1 to 1:5. In some embodiments, the penetration enhancer includes a counterion. In some embodiments, the pharmaceutical formulation contains 0.025 to 5 wt.% of the counterion. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterion of 6:1 to 1:6. In some embodiments, the pharmaceutical formulation includes a pH modifier. In some embodiments, the molar ratio is 3:1 to 1:3. In some embodiments, the pharmaceutical formulation contains 0.1 to 5 wt.% of the BCS class III API or a pharmaceutically acceptable salt or solvate thereof.

[0017] In some embodiments, the method of forming a solid dosage form comprises: introducing a pharmaceutical formulation into a pre-formed mold, wherein the pharmaceutical formulation comprises: a pharmaceutically effective amount of a Biopharmaceutics Classification System (BCS) Class III active pharmaceutical ingredient (API) having a solubility of 10 to 33 mg / mL and a Log P value of less than 1, or a pharmaceutically acceptable salt or solvate thereof; a penetration enhancer comprising at least one selected from the group consisting of counterions or pH modifiers; a matrix former in an amount of 1 to 10 wt.%; and a structure former in an amount of 1 to 10 wt.%; freezing the introduced pharmaceutical formulation; and lyophilizing the frozen pharmaceutical formulation to form the dosage form. In some embodiments, the penetration enhancer comprises a counterion. In some embodiments, the pharmaceutical formulation comprises a counterion in an amount of 0.025 to 5 wt.%. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterion of from 6:1 to 1:6. In some embodiments, the molar ratio is from 3:1 to 1:3. In some embodiments, the pharmaceutical formulation comprises a pH modifier. In some embodiments, the pharmaceutical formulation comprises a BCS Class III API or a pharmaceutically acceptable salt or solvate thereof in an amount of 0.1 to 5 wt.%. In some embodiments, the matrix former comprises gelatin, pullulan, starch, or a combination thereof. In some embodiments, the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof. In some embodiments, the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin. In some embodiments, the structure former comprises mannitol.

[0018] In some embodiments, the pharmaceutical composition comprises: a pharmaceutically effective amount of a biopharmaceutical classification system (BCS) class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof having a solubility of 0.1 to 1 mg / mL and a Log P value of 1 to 2.5; a penetration inhibitor comprising at least one selected from the group of surfactants or fatty acids having a hydrophilic-lipophilic balance (HLB) of less than 10; a matrix-forming agent; and a structure-forming agent. In some embodiments, the penetration inhibitor comprises a fatty acid. In some embodiments, the pharmaceutical composition comprises 0.25 to 0.5 wt.% of the fatty acid. In some embodiments, the pharmaceutical composition has a molar ratio of API to fatty acid of 3:1 to 1:3. In some embodiments, the penetration inhibitor comprises a surfactant having an HLB of less than 10. In some embodiments, the molar ratio of API to surfactant is 5:1 to 1:5.

[0019] Additional advantages will be readily apparent to those skilled in the art from the following detailed description. The examples and descriptions herein should be construed as illustrative and not as limiting.

[0020] All publications, including patent documents, scientific papers, and databases, referenced in this application are incorporated by reference in whole for the same extent as each individual publication would be incorporated by reference individually. If any definition provided herein contradicts or is inconsistent with any definition provided herein in a patent, application, published application, or other publication incorporated herein by reference, the definition provided herein shall prevail over the definition incorporated herein by reference. [Brief explanation of the drawing]

[0021] [Figure 1A] This figure shows various pre-pharmaceutical formulations (two-component mixtures of API and penetration enhancer) and piroxicam pharmaceutical compositions (ODTs) that have been tested for penetration in this specification when surfactants are used as penetration agents. [Figure 1B]This figure shows various pre-pharmaceutical formulations (two-component mixtures of API and penetration enhancer) and piroxicam pharmaceutical compositions (ODTs) that have been tested for permeability in this specification when bile salts are used as permeation agents. [Figure 1C] This figure shows various pre-pharmaceutical formulations (two-component mixtures of API and penetration enhancers) that have been tested for penetration in this specification when fatty acids are used as penetration agents. [Figure 1D] This figure shows various pre-pharmaceutical formulations (a two-component mixture of API and a penetration enhancer) that have been tested for penetration in this specification when a pH modifier is used as a penetration agent. [Figure 1E] This figure shows various pre-pharmaceutical formulations (two-component mixtures of API and penetration enhancers) that have been tested for penetration in this specification when counterions are used as penetration agents. [Figure 2A] This figure shows two-component mixes of atenolol and various penetrating agents that have been tested for their permeability in this specification. [Figure 2B] This figure shows two-component mixes of carvedilol and various penetrating agents that have been tested for their penetrating properties in this specification. [Figure 2C] This figure shows two-component mixes of famotidine and various penetrating agents that have been tested for their permeability in this specification. [Figure 2D] This figure shows two-component mixes of piroxicam and various penetrating agents, and orally disintegrating tablets containing piroxicam and various penetrating agents, which have been tested for penetrating properties in this specification. [Figure 3] This figure shows a set of empirically derived examples of various combinations of API BCS information and sub-classification information, along with associated penetration enhancers. [Figure 4] This figure illustrates the physicochemical properties of various Class II and Class III APIs that were tested in this specification. [Figure 5]This is exemplary penetration data illustrating the effect of using a high molecular weight nonionic surfactant as a penetration enhancer for piroxicam. [Figure 6] This is exemplary penetration data illustrating the effects of using various nonionic and ionic surfactants, as well as fatty acids, as penetration enhancers for piroxicam. [Figure 7] This is exemplary permeability data illustrating the effect of using bile salts as permeability enhancers for piroxicam. [Figure 8] This is exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for piroxicam. [Figure 9] This is exemplary permeability data illustrating the effect of using a high molecular weight nonionic surfactant as a permeability enhancer for piroxicam as a freeze-dried orally disintegrating tablet. [Figure 10] This is exemplary permeability data illustrating the effects of using bile salts and anionic surfactants as permeability enhancers for piroxicam as a freeze-dried orally disintegrating tablet. [Figure 11] This is exemplary permeability data illustrating the effect of using a pH modifier as a permeability enhancer for carvedilol. [Figure 12] This is exemplary permeability data illustrating the effects of using nonionic surfactants as permeability enhancers for carvedilol, as well as combinations of nonionic surfactants and pH modifiers. [Figure 13] This is exemplary permeability data illustrating the effects of using various ionic and nonionic surfactants, as well as fatty acids, as permeability enhancers for carvedilol. [Figure 14] This is exemplary permeability data illustrating the effects of using bile salts and combinations of bile salts and pH modifiers as permeability enhancers for carvedilol. [Figure 15] This is exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for carvedilol. [Figure 16]This is exemplary permeability data illustrating the effects of using bile salts and nonionic surfactants as permeability enhancers for famotidine. [Figure 17] This is exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for famotidine. [Figure 18] This is exemplary permeability data illustrating the effects of using various ionic and nonionic surfactants and bile salts as permeability enhancers for atenolol. [Figure 19] This is exemplary permeability data illustrating the effect of using pH modifiers as permeability enhancers for atenolol. [Figure 20] This is exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for atenolol. [Figure 21] This flowchart shows an empirically derived decision-making model for selecting a suitable penetration enhancer based on various combinations of API BCS information and sub-classification information. [Figure 22A] This figure illustrates permeability data that shows the base matrix excipients do not have any effect on the permeability of carvedilol. [Figure 22B] This figure illustrates penetration data that shows the base matrix excipient has no effect on the penetration of carvedilol compared to the positive effect of the nonionic surfactant (PF127). [Figure 22C] This figure illustrates penetration data that shows the base matrix excipients have no effect on the penetration of piroxicam (low dose). [Figure 22D] This figure illustrates penetration data showing that the base matrix (without excipients) has no effect on the penetration of piroxicam (low dose) compared to the positive effect of the nonionic surfactant (PF127). [Figure 22E]This figure illustrates penetration data that shows the base matrix excipients have no effect on the penetration of piroxicam (high dose). [Figure 22F] This figure illustrates penetration data that shows the base matrix excipient has no effect on the penetration of piroxicam (high dose) compared to the positive effect of the nonionic surfactant (PF127). [Figure 22G] This figure illustrates permeability data that shows the base matrix excipient does not have a promoting effect on atenolol permeability. [Modes for carrying out the invention]

[0022] Detailed explanation This specification describes exemplary embodiments of pharmaceutical formulations and compositions utilizing appropriate PE for a given Class II and / or Class III API, as well as methods for preparing them. In particular, as will be described in detail in the examples herein, the applicant has discovered osmotic enhancers suitable for aiding pre-gastric absorption with respect to a given active pharmaceutical ingredient.

[0023] The combination of the penetration enhancer and the API can then be incorporated into a pharmaceutical composition (e.g., a dosage form). In some embodiments, a pharmaceutical composition containing a penetration enhancer with respect to a given API can be produced by a freeze-drying process.

[0024] In some embodiments, APIs and penetration enhancers may be added to the base matrix to form a pharmaceutical formulation. As used herein, "pharmaceutical formulation" refers to a pharmaceutical formulation before lyophilization, and "pharmaceutical composition" refers to a composition after lyophilization. The base matrix may help provide structure for the final dosage form. In some embodiments, the base matrix may contain at least a matrix-forming agent and a structure-forming agent. Examples of matrix-forming agents and structure-forming agents can be found in U.S. Patents 6,316,027; 6,413,549; and 6,509,040, all of which are incorporated herein by reference as a whole.

[0025] Matrix-forming agents can provide a network structure that gives strength and elasticity to the dosage form. In some embodiments, the matrix-forming agent may be gelatin, pullulan, starch, hydrolyzed dextran, dextrin, alginate, polyvinyl alcohol, polyvinylpyrrolidone, acacia, cellulose polymer (e.g., hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, and / or methylcellulose), soy, wheat, or a combination thereof. In some embodiments, the gelatin may be fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof. In some embodiments, the fish gelatin may be high molecular weight fish gelatin. In some embodiments, the fish gelatin may be high molecular weight fish gelatin, standard molecular weight fish gelatin, or a combination thereof. High molecular weight fish gelatin is defined as fish gelatin in which more than 50% of the molecular weight distribution is greater than 30,000 daltons. Standard molecular weight fish gelatin is defined as fish gelatin in which more than 50% of the molecular weight distribution is less than 30,000 daltons.

[0026] In some embodiments, the pharmaceutical formulation (before lyophilization) may contain at least about 1 wt.%, at least about 2 wt.%, at least about 3 wt.%, at least about 4 wt.%, at least about 5 wt.%, at least about 6 wt.%, at least about 7 wt.%, or at least about 8 wt.% of a matrix-forming agent. In some embodiments, the pharmaceutical formulation may contain up to about 15 wt.%, up to about 12 wt.%, up to about 10 wt.%, up to about 9 wt.%, up to about 8 wt.%, up to about 7 wt.%, up to about 6 wt.%, or up to about 5 wt.% of a matrix-forming agent. In some embodiments, the pharmaceutical formulation may contain about 1 to 15 wt.%, about 1 to 10 wt.%, about 3 to 7 wt.%, about 4 to 6 wt.%, or about 5 wt.% of a matrix-forming agent.

[0027] Structuring agents can provide structural robustness to the dosage form. In some embodiments, the structural agent may include, but is not limited to, sugars such as mannitol, dextrose, lactose, galactose, cyclodextrin, or some combination thereof. In some embodiments, the pharmaceutical formulation (before lyophilization) may contain at least about 1 wt.%, at least about 2 wt.%, at least about 3 wt.%, at least about 4 wt.%, at least about 5 wt.%, at least about 6 wt.%, at least about 7 wt.%, or at least about 8 wt.% of the structural agent. In some embodiments, the pharmaceutical formulation may contain up to about 15 wt.%, up to about 12 wt.%, up to about 10 wt.%, up to about 9 wt.%, up to about 8 wt.%, up to about 7 wt.%, up to about 6 wt.%, or up to about 5 wt.% of the structural agent. In some embodiments, the pharmaceutical formulation may contain about 1-15 wt.%, about 1-10 wt.%, about 2-6 wt.%, about 3-5 wt.%, or about 4 wt.% of a structural agent.

[0028] In some embodiments, the base matrix (and thus the pharmaceutical formulation) may contain pharmaceutically acceptable agents or excipients. Such additional pharmaceutically acceptable agents or excipients include, but are not limited to, sugars, e.g., mannitol, dextrose, and lactose; inorganic salts, e.g., sodium chloride and aluminum silicate; mammalian gelatin, fish gelatin; modified starch; preservatives; antioxidants; surfactants; viscosity enhancers; colorants; flavorings; pH modifiers; sweeteners; taste maskings; and combinations thereof. Suitable colorants may include red, black, and yellow iron oxides, and FD&C dyes, e.g., FD&C Blue 2 and FD&C Red 40, and combinations thereof. Suitable flavorings may include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavors, and combinations thereof. Suitable pH modifiers may include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid, sodium hydroxide (e.g., 3% w / w sodium hydroxide solution), and combinations thereof. Suitable sweeteners may include sucralose, aspartame, acesulfamethoxazole, and thaumatin, and combinations thereof. Suitable flavor masking agents may include various flavorings and combinations thereof. Those skilled in the art can easily determine suitable amounts of these various additional excipients as needed.

[0029] Furthermore, the base matrix (and therefore the pharmaceutical formulation) may contain a solvent. In some embodiments, the solvent may be water (e.g., purified water). In some embodiments, the pharmaceutical formulation contains a certain amount of solvent, for example, an appropriate amount of solvent to make up 100% of the pharmaceutical formulation.

[0030] In some embodiments, the base matrix can be prepared by dissolving a matrix-forming agent and a structure-forming agent in a solvent to form a premix. In some embodiments, the API, a penetrant, and additional excipients can be incorporated into the premix to form an (aqueous) pharmaceutical formulation of the API. A pH modifier may be added as needed. In some embodiments, the pharmaceutical formulation may then be scaled up to the desired batch size using a solvent, at which point it can be prepared for loading into a blister tray containing a pre-formed template or pocket.

[0031] In some embodiments, the pharmaceutical formulation may be prepared by dry mixing. In some embodiments, the API may be dry-mixed with a penetrant, and the dry mixture may be incorporated into the base matrix along with the remaining excipients to form the pharmaceutical formulation. In some embodiments, the API may be dry-mixed with a penetrant, and the dry blend may then be mixed with a portion of the base matrix to form an intermediate API suspension, which may then be incorporated into the remaining base matrix along with the remaining excipients to form the pharmaceutical formulation. In some embodiments, the API may be dry-mixed with a penetrant, and the dry blend may be mixed with an appropriate amount of solvent. A portion of the base matrix may be incorporated into the API mixture. The base matrix may then be added in multiple portions until all of the base matrix has been added.

[0032] As described in detail in the examples herein, the applicant has discovered a suitable osmotic enhancer for aiding pre-gastric absorption of a given BCS class active pharmaceutical component in a pharmaceutical composition / formulation. In some embodiments, the API may be a class II or class III API. In some embodiments, the BCS class II API may be a substantially insoluble class II API. In some embodiments, the substantially insoluble BCS class II API may have a solubility of less than 0.1 mg / mL and / or a lipophilic log P value greater than 2.5.

[0033] APIs belonging to BCS Class II and III were selected and analyzed. The BCS system was developed to provide a scientific approach to classifying APIs based on a combination of their water solubility, which relates to dose and enteric permeability, and the solubility characteristics of the oral immediate-release dosage form. Solubility and permeability are properties inherent to APIs, while solubility is product-specific. According to the BCS, APIs are classified into highly soluble and highly permeable classes and low soluble and low permeability classes. Class I APIs are highly permeable and highly soluble, Class II APIs are low soluble and highly permeable, Class III APIs are highly soluble and low permeability, and Class IV APIs are low soluble and low permeability. An API is considered highly soluble when dissolved in 250 ml or less of an aqueous medium at 37°C with a pH between 1 and 7.5 according to USFDA guidelines, between 1.2 and 6.8 according to WHO guidelines, and between 1 and 8 according to EMEA guidelines. The BCS definition of water solubility differs from that of "inherent solubility," as it reflects the water solubility of the API in equilibrium. With respect to acids and bases, intrinsic solubility represents the concentration of an unionized species in a saturated solution at a pH value where the compound is not completely ionized.

[0034] Examples of substantially insoluble BCS class II APIs include, but are not limited to, carvedilol, aripiprazole, asenapine, atorvastatin, benidipine HCl, bicalutamide, buspirone, cefditoren pivoxil, cilostazol, citalopram, clotrimazole, clozapine, danazol, digoxin, domperidone, ebastine, etomidate, felodipine, flufenamic acid, flunarizine, flurbiprofen, glibenclamide, glimepiride, and glibri. These include haloperidol, hydroxyzine, isradipine, ketoprofen, loratadine, lorazepam, lovastatin, nicergoline, nifedipine, nivaripin, nimodipine, nitrendipine, olanzapine, oxatomide, pentazocine, pioglitazone, raloxifene, selegiline, simvastatin, sirolimus, spironolactone, tacrolimus, tamoxifen, testosterone, torsemide, trepostinil, verapamil, or combinations thereof.

[0035] In some embodiments, the BCS class II API may be a very slightly soluble BCS class II API. In some embodiments, the very slightly soluble BCS class II API may have a solubility of 0.1 to 1 mg / mL and / or a lipophilic log P value of 1 to 2.5. Examples of very slightly soluble BCS class II APIs, but not limited to these, include piroxicam, allopurinol, apomorphine, cyclosporine, dapsone, diazoxide, diacumarol, diclofenac, meloxicam, ondansetron, phenazopyridine, prednisone, triamterene, trimetaprim, or combinations thereof.

[0036] In some embodiments, the BCS class III API may be a slightly soluble BCS class III API. In some embodiments, the slightly soluble BCS class III API may have a solubility of 1 to 10 mg / mL and / or a lipophilic log P value of less than 1. Examples of slightly soluble BCS class III APIs, but not limited to these, include famotidine, amlodipine, baclofen, ceftazidime, dacarbazine, gimeracil, oteracil potassium, tetracycline, or combinations thereof.

[0037] In some embodiments, the BCS class III API may be a slightly soluble BCS class III API. In some embodiments, the slightly soluble BCS class III API may have a solubility of 10 to 33 mg / mL and / or a lipophilic log P value of less than 1. Examples of slightly soluble BCS class III APIs, but not limited to these, include atenolol, acarbose, amiloride, azacitidine, benznidazole, carbidopa, cefazolin, cefoxitine, cefuroxime, desmopressin acetate hydrate, enalapril acetate, hydralazine, ketorolac, imidapril HCl, latamoxef, lisinopril, midodrine HCl, miglitol, minocycline HCl, morphine, penciclovir, pentostatin, pirenzepine, pramipexole, risedronate sodium hydrate, stabudine, terbutaline, zalcitabine, or combinations thereof.

[0038] In some embodiments, the API is included in the pharmaceutical formulations and compositions (e.g., dosage forms) disclosed herein in an amount sufficient to be pharmaceutically effective when provided as a pharmaceutical composition. Those skilled in the art can readily determine the pharmaceutically effective amount for a given disease or infection based, in particular, on information about the patient to whom the pharmaceutical composition will be administered, including age and weight. In some embodiments, the pharmaceutical formulation may contain at least about 0.05 wt.%, at least about 0.1 wt.%, at least about 0.25 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 2 wt.%, at least about 3 wt.%, at least about 4 wt.%, or at least about 5 wt.% of the API. In some embodiments, the pharmaceutical formulation may contain up to approximately 10 wt.%, up to approximately 7 wt.%, up to approximately 5 wt.%, up to approximately 4.5 wt.%, up to approximately 4 wt.%, up to approximately 3.5 wt.%, up to approximately 3 wt.%, up to approximately 2.5 wt.%, up to approximately 2 wt.%, up to approximately 1.5 wt.%, up to approximately 1 wt.%, up to approximately 0.75 wt.%, or up to approximately 0.5 wt.% of the API. In some embodiments, the pharmaceutical formulation may contain approximately 0.01 to 10 wt.% or approximately 0.1 to 5 wt.% of the API.

[0039] As described herein, the applicant has found that, with respect to substantially insoluble BCS class II APIs (e.g., solubility less than 0.1 mg / mL and Log P value greater than 2.5), the following penetration enhancers: counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, micelles, fatty acids, or combinations thereof, can effectively promote penetration of these given APIs. Therefore, at least one of these penetration enhancers can be added together with a substantially insoluble BCS class II API (and base matrix) to form a pharmaceutical formulation.

[0040] Furthermore, the applicant has discovered that, with respect to BCS class II APIs with very low solubility (solubility 0.1-1 mg / mL and log P value 1-2.5), the following penetration enhancers: counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, micelles, or combinations thereof, can effectively promote the penetration of these given APIs. Therefore, at least one of these penetration enhancers can be added together with a very low solubility BCS class II API (and base matrix) to form a pharmaceutical formulation. In addition, the applicant has also discovered that fatty acids and surfactants having a hydrophilic-lipophilic balance (HLB) less than 10 can inhibit the penetration of very low solubility BCS class II APIs.

[0041] The applicant also found that, with respect to slightly soluble BCS class III APIs (solubility 1-10 mg / mL and Log P value less than 1), the following penetration enhancers: counterions, bile salts, pH modifiers, or combinations thereof, can effectively promote penetration of these given APIs. Therefore, at least one of these penetration enhancers can be added together with a slightly soluble BCS class III API (and base matrix) to form a pharmaceutical formulation. Furthermore, the applicant found that surfactants having micelles and HLB greater than 10 may not promote the penetration of slightly soluble BCS class III APIs, or may only promote it slightly.

[0042] Finally, the applicant found that, with respect to slightly soluble (solubility 10-33 mg / mL and Log P <1) BCS class III APIs, the following penetration enhancers: counterions, pH modifiers, or combinations thereof can effectively promote penetration of these given APIs. Therefore, at least one of these penetration enhancers can be added together with a slightly soluble BCS class III API (and base matrix) to form a pharmaceutical formulation. Furthermore, the applicant found that surfactants (both HLB > 10 and HLB < 10), bile salts, and micelles cannot promote penetration of slightly soluble BCS class III APIs.

[0043] As described above, penetration enhancers for substantially or very slightly soluble BCS class II APIs may include surfactants. In some embodiments, the surfactants are cationic surfactants (e.g., cetyltrimethylammonium bromide (CTAB), decyltrimethylammonium bromide, benzyldimethyldodecylammonium chloride, myristyltrimethylammonium chloride, benzalkonium chloride, benzethonium chloride, and / or cetylpyridinium chloride), anionic surfactants (e.g., sodium lauryl sulfate, sodium dodecyl sulfate, sodium octyl sulfate), hydrophilic surfactants (e.g., polyoxyethylene-20 sorbitan monolaurate (Polysorbate 20 / Tween 20), polyoxyethylene-4 sorbitan monolaurate (Tween 21), polyoxyethylene-20 sorbitan monostearate (Polysorbate 60 / Tween 60), polyoxyethylene-4 sorbitan monostearate (Tween 61), polyoxyethylene-20 sorbitan monolaurate (Polysorbate 20 / Tween 20), polyoxyethylene-4 sorbitan monostearate (Tween 61), polyoxyethylene-20 sorbitan monolaurate (Polysorbate 60 / Tween 60), polyoxyethylene-4 sorbitan monostearate (Tween 61), polyoxyethylene-20 sorbitan monolaurate (Polysorbate 20 / Tween 20), polyoxyethylene-20 sorbitan monostearate (Polysorbate 60 / Tween 60), polyoxyethylene-4 sorbitan monostearate (Tween 61), polyoxyethylene-20 sorbitan monolaurate (Polysorbate 20 / Tween 21), polyoxyethylene-20 sorbitan monostearate (Polysorbate 60 / Tween 60), polyoxyethylene-4 sorbitan monostearate (Tween 61), The surfactant may be at least one of the following: ethylene-20 sorbitan monooleate (polysorbate 80 / tween 80), polyoxyethylene-5 sorbitan monooleate (tween 81)), lipophilic surfactants (e.g., sorbitan monooleate (span 80), sorbitan monostearate (span 60), sorbitan monopalmitate (span 40), and / or sorbitan monolaurate (span 20)), polymeric surfactants (e.g., polyoxyethylene (POE)-polyoxypropylene (POP) block copolymer (poloxamer 124, 188, 407 → Pluronic® L44, F68, F127)), glycoside surfactants (e.g., dodecyl-BD-maltoside, tetradecyl maltoside, tridecyl maltoside, decyl β-D-maltopyranoside / dodecyl maltoside (DDM)), or a combination thereof. In some embodiments, the surfactant may be a surfactant having a hydrophilic-lipophilic balance (HLB) greater than 10. The HLB value can be obtained from the material data sheet of various surfactants.

[0044] In some embodiments, the pharmaceutical formulation may contain at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.025 wt.%, at least about 0.05 wt.%, at least about 0.075 wt.%, at least about 0.1 wt.%, at least about 0.25 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 1.5 wt.%, at least about 2 wt.%, at least about 2.5 wt.%, at least about 3 wt.%, at least about 3.5 wt.%, or at least about 4 wt.% of a surfactant. In some embodiments, the pharmaceutical formulation may contain a surfactant up to approximately 5 wt.%, up to approximately 4.5 wt.%, up to approximately 4 wt.%, up to approximately 3.5 wt.%, up to approximately 3 wt.%, up to approximately 2.5 wt.%, up to approximately 2 wt.%, up to approximately 1.5 wt.%, up to approximately 1 wt.%, up to approximately 0.75 wt.%, up to approximately 0.5 wt.%, up to approximately 0.4 wt.%, up to approximately 0.3 wt.%, up to approximately 0.25 wt.%, up to approximately 0.1 wt.%, up to approximately 0.075 wt.%, up to approximately 0.05 wt.%, or up to approximately 0.025 wt.%. In some embodiments, the pharmaceutical formulation may contain a surfactant up to approximately 0.01 to 5 wt.%, up to approximately 0.01 to 4 wt.%, or up to approximately 0.025 to 3.5 wt.%. In some embodiments, the pharmaceutical formulation has a surfactant with a critical micelle concentration (CMC) (mg / mL) of at least about 0.1 × CMC (meaning 0.1 times that CMC), at least about 0.2 × CMC, at least about 0.5 × CMC, at least about 1 × CMC, at least about 1.5 × CMC, at least about 2 × CMC, at least about 5 × CMC, at least about 10 × CMC, at least about 15 × CMC, at least about 20 × CMC, or at least about 25 × CMC. In some embodiments, the pharmaceutical formulation has a surfactant with a CMC of up to about 30 × CMC, up to about 25 × CMC, up to about 20 × CMC, up to about 15 × CMC, up to about 10 × CMC, up to about 5 × CMC, up to about 3 × CMC, up to about 2 × CMC, up to about 1.5 × CMC, up to about 1 × CMC, up to about 0.5 × CMC, or up to about 0.2 × CMC.In some embodiments, the pharmaceutical formulation has a surfactant with a CMC of about 0.1 to 30 × CMC, about 0.5 to 2 × CMC, or about 0.5 to 1 × CMC. In some embodiments, the CMC can be determined according to the method described in the paper *Surfactant Self Assembling and Critical Micelle Concentration: One Approach Fits All?* by Diego Romano Perinelli et al., Langmuir 2020, 36, 5745-4753, which is incorporated herein by reference in its entirety.

[0045] In some embodiments, the pharmaceutical formulation has a molar ratio of API to surfactant of at least about 1:10, at least about 1:6, at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical formulation has a molar ratio of API to surfactant of up to about 10:1, up to about 6:1, up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1. In some embodiments, the pharmaceutical formulation has a molar ratio of API to surfactant of about 10:1 to 1:10, about 6:1 to 1:6, about 5:1 to 1:5, about 2:1 to 1:2, or about 1:1.

[0046] As described above, osmotic enhancers for substantially insoluble or slightly soluble BCS class II APIs, or for slightly soluble BCS class III APIs, may contain bile salts. Examples of bile salts, but not limited to these, include sodium cholate hydrate, sodium glycodeoxycholate, sodium deoxycholate, sodium taurocholate, sodium taurodeoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium cholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, glycol chenodeoxycholate, sodium cholylsarcosinate, sodium N-methyltaurocholate, sodium lithocholate, or combinations thereof. In some embodiments, the pharmaceutical formulation may contain at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.025 wt.%, at least about 0.05 wt.%, at least about 0.075 wt.%, at least about 0.1 wt.%, at least about 0.25 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 1.5 wt.%, at least about 2 wt.%, at least about 2.5 wt.%, at least about 3 wt.%, at least about 3.5 wt.%, or at least about 4 wt.% of bile salts. In some embodiments, the pharmaceutical formulation may contain up to approximately 5 wt.%, up to approximately 4.5 wt.%, up to approximately 4 wt.%, up to approximately 3.5 wt.%, up to approximately 3 wt.%, up to approximately 2.5 wt.%, up to approximately 2 wt.%, up to approximately 1.5 wt.%, up to approximately 1 wt.%, up to approximately 0.75 wt.%, up to approximately 0.5 wt.%, up to approximately 0.4 wt.%, up to approximately 0.3 wt.%, up to approximately 0.25 wt.%, up to approximately 0.1 wt.%, up to approximately 0.075 wt.%, up to approximately 0.05 wt.%, or up to approximately 0.025 wt.% of bile salts. In some embodiments, the pharmaceutical formulation may contain approximately 0.01 to 5 wt.%, approximately 0.1 to 4 wt.%, or approximately 0.3 to 3 wt.% of bile salts.In some embodiments, the pharmaceutical formulation has a bile salt with a critical micelle concentration (CMC) (mg / mL) of at least about 0.1 × CMC, at least about 0.2 × CMC, at least about 0.5 × CMC, at least about 1 × CMC, at least about 1.5 × CMC, at least about 2 × CMC, at least about 5 × CMC, or at least about 10 × CMC. In some embodiments, the pharmaceutical formulation has a bile salt of CMC with a maximum of about 15 × CMC, at a maximum of about 10 × CMC, at a maximum of about 5 × CMC, at a maximum of about 3 × CMC, at a maximum of about 2 × CMC, at a maximum of about 1.5 × CMC, at a maximum of about 1 × CMC, or at a maximum of about 0.5 × CMC. In some embodiments, the pharmaceutical formulation has a bile salt of CMC with a maximum of about 0.1 to 10 × CMC, at a maximum of about 0.2 to 8 × CMC, or at a maximum of about 0.5 to 4 × CMC. In some embodiments, the pharmaceutical formulation has a molar ratio of API to bile salt of at least about 1:20, at least about 1:15, at least about 1:10, at least about 1:6, at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical formulation has a molar ratio of API to bile salt of up to about 20:1, up to about 15:1, up to about 10:1, up to about 6:1, up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1. In some embodiments, the pharmaceutical formulation has a molar ratio of API to bile salt of about 15:1 to 1:15, about 10:1 to 1:10, about 5:1 to 1:5, about 2:1 to 1:2, or about 1:1.

[0047] As described above, the penetration enhancer for substantially insoluble BCS class II APIs may contain fatty acids. In some embodiments, the fatty acids may be saturated and / or unsaturated. Examples of fatty acids, but not limited to these, include capric acid, sucrose fatty acid esters (e.g., sucrose monopalmitate), caproic acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid, or combinations thereof. In some embodiments, the pharmaceutical formulation may contain at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.025 wt.%, at least about 0.03 wt.%, at least about 0.05 wt.%, at least about 0.075 wt.%, at least about 0.1 wt.%, at least about 0.25 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 1.5 wt.%, at least about 2 wt.%, at least about 2.5 wt.%, at least about 3 wt.%, at least about 3.5 wt.%, or at least about 4 wt.% of fatty acids. In some embodiments, the pharmaceutical formulation may contain fatty acids up to approximately 5 wt.%, 4.5 wt.%, 4 wt.%, 3.5 wt.%, 3 wt.%, 2.5 wt.%, 2 wt.%, 1.5 wt.%, 1 wt.%, 0.75 wt.%, 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.25 wt.%, 0.15 wt.%, 0.1 wt.%, 0.075 wt.%, 0.05 wt.%, or 0.025 wt.%. In some embodiments, the pharmaceutical formulation may contain about 0.01 to 5 wt.%, about 0.1 to 1 wt.%, or about 0.03 to 0.15 wt.% of fatty acids. In some embodiments, the pharmaceutical formulation has a molar ratio of API to fatty acids of at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical formulation has a molar ratio of API to fatty acids of up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1.In some embodiments, the pharmaceutical formulation has a molar ratio of API to fatty acid of about 5:1 to 1:5, about 2:1 to 1:2, or about 1:1.

[0048] As described above, penetration enhancers for substantially insoluble or slightly soluble BCS class II APIs or slightly soluble or moderately soluble BCS class III APIs may contain a counterion. In some embodiments, the ionized counterion can achieve complete ionization by retaining the opposite charge of the ionized drug molecule from the pKa of the counterion and the drug molecule by about 1 pH unit, about 1.5 pH unit, or 2 pH unit. In some embodiments, the difference in pKa (DpKa) between the API and the counterion may be greater than 5, greater than 6, or greater than 7. In some embodiments, the counterion may be an amino acid, such as a weakly basic, strongly basic, basic, acidic, and / or neutral amino acid. Examples of counterions, but not limited to, include arginine, histidine, lysine, leucine, glutamic acid, aspartic acid, benzoic acid, glycine, alanine, or combinations thereof. In some embodiments, the pharmaceutical formulation may contain at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.025 wt.%, at least about 0.03 wt.%, at least about 0.04 wt.%, at least about 0.05 wt.%, at least about 0.075 wt.%, at least about 0.1 wt.%, at least about 0.25 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 1.5 wt.%, at least about 2 wt.%, at least about 2.5 wt.%, at least about 3 wt.%, at least about 3.5 wt.%, or at least about 4 wt.% of counterions. In some embodiments, the pharmaceutical formulation may contain up to approximately 5 wt.%, up to approximately 4.5 wt.%, up to approximately 4 wt.%, up to approximately 3.5 wt.%, up to approximately 3 wt.%, up to approximately 2.5 wt.%, up to approximately 2 wt.%, up to approximately 1.5 wt.%, up to approximately 1 wt.%, up to approximately 0.75 wt.%, up to approximately 0.5 wt.%, up to approximately 0.4 wt.%, up to approximately 0.3 wt.%, up to approximately 0.25 wt.%, up to approximately 0.15 wt.%, up to approximately 0.1 wt.%, up to approximately 0.075 wt.%, up to approximately 0.05 wt.%, or up to approximately 0.025 wt.% of counterions.In some embodiments, the pharmaceutical formulation may contain about 0.01 to 5 wt.%, about 0.1 to 5 wt.%, or about 0.04 to 4 wt.% of counterions. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterions of at least about 1:10, at least about 1:6, at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterions of up to about 10:1, up to about 6:1, up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1. In some embodiments, the pharmaceutical formulation has a molar ratio of API to counterions of about 6:1 to 1:6, about 3:1 to 1:3, about 2:1 to 1:2, or about 1:1.

[0049] In some embodiments, the penetration enhancer may be a pH modifier. In some embodiments, the enhancement or inhibition of the enhancement by the pH modifier may depend on the effect of the non-ionization fraction of the API. In some embodiments, the pH modifier may be an acidifying agent and / or an alkalizing agent. Examples of pH modifiers, but not limited to these, include citric acid, malic acid, maleic acid, tartaric acid, lactic acid, fumaric acid, succinic acid, adipic acid, ascorbic acid, sodium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate, magnesium carbonate, potassium carbonate, calcium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, sodium citrate, sodium acetate, or combinations thereof. In some embodiments, the pharmaceutical formulation may contain at least about 0.005 wt.%, at least about 0.01 wt.%, at least about 0.02 wt.%, at least about 0.025 wt.%, at least about 0.03 wt.%, at least about 0.04 wt.%, at least about 0.05 wt.%, at least about 0.075 wt.%, at least about 0.1 wt.%, at least about 0.25 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 1.5 wt.%, at least about 2 wt.%, at least about 2.5 wt.%, at least about 3 wt.%, at least about 3.5 wt.%, or at least about 4 wt.% of a pH modifier. In some embodiments, the pharmaceutical formulation may contain up to approximately 5 wt.%, up to approximately 4.5 wt.%, up to approximately 4 wt.%, up to approximately 3.5 wt.%, up to approximately 3 wt.%, up to approximately 2.5 wt.%, up to approximately 2 wt.%, up to approximately 1.5 wt.%, up to approximately 1 wt.%, up to approximately 0.75 wt.%, up to approximately 0.5 wt.%, up to approximately 0.4 wt.%, up to approximately 0.3 wt.%, up to approximately 0.25 wt.%, up to approximately 0.15 wt.%, up to approximately 0.1 wt.%, up to approximately 0.075 wt.%, up to approximately 0.05 wt.%, and up to approximately 0.025 wt.% of a pH modifier. In some embodiments, the pharmaceutical formulation may contain approximately 0.005 to 2.5 wt.% of a pH modifier. In some embodiments, the pH of the pharmaceutical formulation may be about 3.5 to 9.5 or about 4 to 8.

[0050] Once a pharmaceutical formulation has been prepared, it may be placed into a pre-formed mold. As used herein, “placed” (or similar term) means that a predetermined aliquot solution or suspension is deposited. As used herein, “pre-formed mold” means any suitable container or compartment into which an aqueous solution or suspension may be deposited and subsequently freeze-dried. In some embodiments, the pre-formed mold is a blister pack having one or more blister pockets. In some embodiments, a predetermined aliquot of a pharmaceutical formulation with a wet-filled loading mass of about 150 to 1000 mg or about 500 mg may be weighed into the pre-formed mold. In some embodiments, the minimum unit size (e.g., wet-filled loading mass of 150 mg) may be selected so that the amount of API in the solution is minimized in proportion to the unit dose, and therefore its surface area and the possibility of oxidative degradation in the final dosage form are minimized.

[0051] The added pharmaceutical formulation may then be frozen in a pre-formed mold. The formulation placed in the pre-formed mold may be frozen by any means known in the art. For example, the formulation may be passed through a low-temperature storage chamber (e.g., a liquid nitrogen tunnel). In some embodiments, the freezing temperature and freezing time may be changed to ensure that the added pharmaceutical formulation is frozen.

[0052] Next, the frozen units may be collected and stored in a freezer at a sub-zero temperature suitable for the formulation before freeze-drying. Alternatively, the frozen units may be slowly cooled over a suitable period of time to crystallize the structure-forming agent. Crystallization of the structure-forming agent provides frozen units with structural strength, preventing disintegration during freeze-drying.

[0053] After maintaining the freeze, the freeze units may be freeze-dried into a pharmaceutical composition, such as a dosage form (e.g., a tablet). The freeze-drying cycle may be optimized for each individual formulation. During the freeze-drying process, water may be removed from the freeze units by sublimation, leaving porous freeze-dried units that can rapidly disintegrate when placed in the mouth.

[0054] Next, the freeze-dried pharmaceutical composition may be removed from the freeze-dryer and inspected for any defects. The inspected pharmaceutical composition may then be placed in a storage cabinet in a temperature and humidity controlled environment and prepared to be sealed in its pre-formed blister tray.

[0055] The blister tray may be sealed by placing a lidding foil on a pre-formed tray. The pre-formed tray may then be cut to form individual blisters containing the lyophilized pharmaceutical composition (e.g., ODT).

[0056] In some embodiments, the pharmaceutical composition (i.e., after lyophilization) may contain at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, at least about 35 wt.%, at least about 40 wt.%, or at least about 50 wt.% of a matrix-forming agent. In some embodiments, the pharmaceutical composition may contain up to about 65 wt.%, up to about 60 wt.%, up to about 55 wt.%, up to about 50 wt.%, up to about 45 wt.%, or up to about 40 wt.% of a matrix-forming agent. In some embodiments, the pharmaceutical composition (i.e., after lyophilization) may contain about 25–60 wt.%, about 30–60 wt.%, or about 33–56.25 wt.% of a matrix-forming agent. In some embodiments, the pharmaceutical composition may contain at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, at least about 35 wt.%, or at least about 40 wt.% of a structuring agent. In some embodiments, the pharmaceutical composition may contain up to about 50 wt.%, up to about 45 wt.%, up to about 40 wt.%, up to about 35 wt.%, or up to about 30 wt.% of a structuring agent. In some embodiments, the pharmaceutical composition may contain about 20-45 wt.% or about 29-42.4 wt.% of a structuring agent.

[0057] In some embodiments, the API is included in the pharmaceutical composition (e.g., dosage form) disclosed herein in an amount sufficient to be pharmaceutically effective when provided as a pharmaceutical composition. Those skilled in the art can readily determine the pharmaceutically effective amount for a given disease or infection based, in particular, on information about the patient to whom the pharmaceutical composition will be administered, including age and weight. In some embodiments, the pharmaceutical composition may contain at least about 1 wt.%, at least about 2 wt.%, at least about 3 wt.%, at least about 4 wt.%, at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 20 wt.%, at least about 25 wt.%, at least about 30 wt.%, or at least about 35 wt.% of the API. In some embodiments, the pharmaceutical composition may contain up to about 40 wt.%, up to about 35 wt.%, up to about 30 wt.%, up to about 25 wt.%, up to about 21 wt.%, up to about 20 wt.%, up to about 15 wt.%, up to about 10 wt.%, or up to about 5 wt.% of APIs. In some embodiments, the pharmaceutical composition may contain about 1 to 40 wt.% or about 1.41 to 21 wt.% of APIs.

[0058] As described herein, the applicant has discovered specific penetration enhancers specific to APIs for use in pharmaceutical compositions. Where a surfactant is included as a penetration enhancer, the pharmaceutical composition (i.e., after lyophilization) may contain at least about 0.1 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 17 wt.%, or at least about 20 wt.% of the surfactant. In some embodiments, the pharmaceutical composition may contain up to about 30 wt.%, up to about 25 wt.%, up to about 20 wt.%, up to about 17 wt.%, up to about 15 wt.%, up to about 10 wt.%, or up to about 5 wt.% of the surfactant. In some embodiments, the pharmaceutical composition may contain 0.8 to 21.2 wt.% or about 0.14 to 17 wt.% of a surfactant.

[0059] In some embodiments, the pharmaceutical composition has a molar ratio of API to surfactant of at least about 1:10, at least about 1:6, at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to surfactant of up to about 10:1, up to about 6:1, up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to surfactant of about 10:1 to 1:10, about 6:1 to 1:6, about 5:1 to 1:5, about 2:1 to 1:2, or about 1:1.

[0060] When bile salts are included as penetration enhancers, the pharmaceutical composition (i.e., after lyophilization) may contain at least about 0.1 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 2 wt.%, at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, or at least about 17 wt.% of bile salts. In some embodiments, the pharmaceutical composition may contain up to about 20 wt.%, up to about 17 wt.%, up to about 15 wt.%, up to about 10 wt.%, or up to about 5 wt.% of bile salts. In some embodiments, the pharmaceutical composition may contain about 0.14 to 17 wt.% or about 2.5 to 17.3 wt.% of bile salts.

[0061] In some embodiments, the pharmaceutical composition has a molar ratio of API to bile salt of at least about 1:20, at least about 1:15, at least about 1:10, at least about 1:6, at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to bile salt of up to about 20:1, up to about 15:1, up to about 10:1, up to about 6:1, up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to bile salt of about 15:1 to 1:15, about 10:1 to 1:10, about 5:1 to 1:5, about 2:1 to 1:2, or about 1:1.

[0062] When fatty acids are included as penetration enhancers, the pharmaceutical composition (i.e., after lyophilization) may contain at least about 0.1 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 2 wt.%, at least about 5 wt.%, at least about 10 wt.%, at least about 15 wt.%, or at least about 17 wt.% of fatty acids. In some embodiments, the pharmaceutical composition may contain up to about 20 wt.%, up to about 17 wt.%, up to about 15 wt.%, up to about 10 wt.%, or up to about 5 wt.% of fatty acids. In some embodiments, the pharmaceutical composition may contain about 0.15 to 17 wt.% of fatty acids. In some embodiments, the pharmaceutical composition has a molar ratio of API to fatty acids of at least about 1:6, at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to fatty acids of up to about 6:1, up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to fatty acids of about 5:1 to 1:5, about 3:1 to 1:3, about 2:1 to 1:2, or about 1:1.

[0063] When counterions are included as penetration enhancers, the pharmaceutical composition (i.e., after lyophilization) may contain at least about 0.1 wt.%, at least about 0.5 wt.%, at least about 0.75 wt.%, at least about 1 wt.%, at least about 5 wt.%, at least about 8 wt.%, at least about 10 wt.%, at least about 15 wt.%, at least about 17 wt.%, or at least about 20 wt.% of counterions. In some embodiments, the pharmaceutical composition may contain up to about 30 wt.%, up to about 25 wt.%, up to about 20 wt.%, up to about 17 wt.%, up to about 15 wt.%, up to about 10 wt.%, or up to about 5 wt.% of counterions. In some embodiments, the pharmaceutical composition may contain about 5 to 25 wt.%, about 8 to 22 wt.%, or about 0.1 to 20 wt.% of counterions. In some embodiments, the pharmaceutical composition has a molar ratio of API to counterion of at least about 1:10, at least about 1:6, at least about 1:5, at least about 1:3, at least about 1:2, or at least about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to counterion of up to about 10:1, up to about 6:1, up to about 5:1, up to about 3:1, up to about 2:1, or up to about 1:1. In some embodiments, the pharmaceutical composition has a molar ratio of API to counterion of about 6:1 to 1:6, about 3:1 to 1:3, about 2:1 to 1:2, or about 1:1.

[0064] As specified above, in some embodiments, the penetration enhancer may also be a pH modifier. In some embodiments, the pharmaceutical composition contains about 0.1-5 wt.%, about 0.1-3 wt.%, about 0.1-2 wt.%, about 0.1-1.5 wt.%, about 0.2-1.5 wt.%, about 0.3-1.2 wt.%, about 0.5-1.1 wt.%, or about 0.5-1 wt.% of a pH modifier. In some embodiments, the pharmaceutical composition may contain at least about 0.1 wt.%, at least about 0.2 wt.%, at least about 0.3 wt.%, at least about 0.4 wt.%, at least about 0.5 wt.%, at least about 0.58 wt.%, at least about 0.75 wt.%, or at least about 1 wt.% of a pH modifier. In some embodiments, the pharmaceutical composition may contain up to about 5 wt.%, up to about 3 wt.%, up to about 2 wt.%, up to about 1.5 wt.%, up to about 1.25 wt.%, up to about 1 wt.%, up to about 0.99 wt.%, or up to about 0.75 wt.% of a pH modifier. In some embodiments, the pharmaceutical composition contains 0.1 to 5 wt.% of a pH modifier. Even if the pH modifier is present in the solution in the pharmaceutical formulation, the pH modifier in the pharmaceutical composition is simply the pH modifier itself. Water can be removed from the pH modifier solution by a freeze-drying process.

[0065] The pharmaceutical composition (e.g., dosage form) may be a soluble dosage form, and therefore has the clear advantage of a fast disintegration time.

[0066] Permeability was evaluated by quantifying the amount of drug that had permeated into the receiver compartment at a given time point. Permeability % was calculated from the ratio of the permeated drug (i.e., the amount in the receiver compartment) to the total amount in the donor compartment (i.e., the amount of drug administered to the donor at the start of the study). The obtained value was then multiplied by 100 to obtain a percentage. In some embodiments, the percentage increase in permeability due to the addition of a permeator (compared to no permeator) may be at least about 0.1%, at least about 1%, at least about 5%, at least about 10 wt.%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%. In some embodiments, the percentage increase in permeability due to the addition of a permeator (compared to no permeator) may be up to about 100%, up to about 75%, or up to about 50%.

[0067] For the purposes of clarity and concise description, features are described herein as part of the same or individual embodiments; however, it will be understood that the scope of this disclosure includes embodiments having all or some combinations of the features described herein. [Examples]

[0068] The following examples are provided as model data representing combinations of API BCS information, subcategory information, and (solubility and permeability), and suitable permeability enhancers associated with each combination of API BCS information and subcategory information.

[0069] The following procedure is an example of a method for generating data representing combinations of API BCS information and sub-classification information, and suitable penetration enhancers associated with each combination of API BCS information and sub-classification information, as shown in Figures 3 and 21.

[0070] Model API Selection Several model mucosal penetration agents were evaluated for their ability to modulate the penetration of four models of BCS class II and class III APIs with respect to pre-gastric delivery (e.g., via oral cavity, pharynx, and / or esophagus) by lyophilized ODT.

[0071] An API is considered highly permeable if, based on mass balance assessment or comparison with an intravenous reference dose, the degree of systemic intestinal absorption of the parent drug and its metabolites in humans is determined to be 90% or more of the administered dose. Methods for estimating BCS permeability criteria are based on in vivo intestinal absorption or high-throughput systems available to investigate human intestinal permeability, such as CaCO2 cell and equilibrium artificial membrane permeability assay (PAMPA). Therefore, these cannot always be easily extrapolated to pregastric permeability. One of the objectives of this experiment was to establish an in vitro permeability testing approach that can be applied to pregastric absorption.

[0072] Two model APIs were selected from BCS class II and III, respectively. The BCS class II APIs used were piroxicam and carvedilol. The BCS class III APIs used were atenolol and famotidine. These APIs were selected because their properties, such as molecular size, solubility, lipophilicity (log P), and ionization properties (pKa), are well-characterized (shown in Figure 4). Pharmacokinetic data on gastrointestinal adsorption of these APIs when delivered through oral dosage forms, such as tablets and capsules, are also available. However, their pre-gastric absorption is not well established.

[0073] Selection of Penetrating Agents Penetrating agents containing surfactants, bile salts, counterions, fatty acids, and pH modifiers were evaluated. The selected model penetrating agents are listed in Table 1 below. Penetrating agents were selected based on their mode of action, compatibility with the formulation and manufacturing process of lyophilized ODT, toxicity to mucous membranes, solubilizing ability, drug release characteristics, and compatibility with numerous APIs and excipients.

[0074] Surfactants can be classified as ionic or nonionic according to their polar head group. Surfactants may exhibit a wide range of properties, such as hydrophilic-lipophilic balance (HLB) values, molecular weight, chain length, critical micelle concentration (CMC), and solubility parameters. Surfactants may promote solubility and can form micelles at or above the CMC concentration. Surfactants can also interact with the lipid bilayer of cell membranes and thus increase the permeability of APIs. Nonionic surfactants are considered preferable due to their low toxicity. In this experiment, sodium lauryl sulfate was selected as a model ionic surfactant, and Tween 21, Span 80, Pluronic® F127 and L44, as well as dodecyl-BD-maltoside, were selected as model nonionic surfactants.

[0075] Bile salts may increase drug permeability due to their amphiphilic properties. When their concentration exceeds the cell membrane complex (CMC), they can self-associate in water, forming supramolecular aggregates or micelles. To promote permeability to the epithelial barrier, bile salts may disrupt cell membranes, cause phospholipid leakage, loosen intercellular filaments, reduce epithelial integrity, and form micelles with the phospholipids (APIs). In this experiment, sodium cholate hydrate was selected as the model bile salt.

[0076] Fatty acids may increase drug permeability through several processes, such as drug solubilization, increased membrane fluidity, and intercellular transport. In this experiment, capric acid was selected as a model fatty acid.

[0077] Counterions can increase drug permeability by forming ion pairs. The ion pairing approach involves the complexation of a drug molecule with the opposite charge to the counterion, resulting in an overall neutral ion pair bound together as a single unit by Coulomb attraction. The choice of counterion depends on the pKa and charge of the ionized drug molecule required by the counterion to form an ion pair. In this experiment, arginine, lysine, aspartic acid, benzoic acid, glycine, and alanine were selected as model counterions.

[0078] [Table 1]

[0079] Cell culture settings The drug penetration of several APIs was evaluated using an in vitro cell culture method with the TR146 buccal mucosa cell line, a well-characterized cell culture model derived from cervical lymph node metastases of buccal carcinoma. TR146 cells were grown in nutrient-rich culture medium to generate a multilayer cell barrier mimicking buccal epithelium. Cells were seeded onto Transwell polymer inserts and stratified for 25 to 30 days. The medium was changed periodically to maintain optimal cell conditions at 37°C, 5% CO2, and 98% relative humidity. Transepithelial electrical resistance (TEER) was measured every 2 to 3 days during cell culture. TEER indicates the integrity of the cell layers in the Transwell insert. Consistent readings throughout the study suggest that cell integrity remains robust, enhancing the reliability of the results. Once TEER indicated complete cell stratification, the insert was ready for use in penetration studies.

[0080] Pre-formulation evaluation of APIs and penetrating agents. Before conducting penetration studies on the API using ODT, the penetrants were screened in pre-formulation penetration studies with respect to two-component mixes of the penetrant and the API. The compositions of these pre-formulation two-component mixtures can be seen in Figures 1A-1E and 2A-2D.

[0081] Appropriate aliquots (e.g., 0.5 ml) of a two-component mixture of the drug and the penetrating agent were added to a donor chamber in a Transwell polymer insert. The donor chamber was then placed in a receiver chamber containing culture medium. Samples were periodically taken from the receiver chamber, and the drug concentrations in these samples were determined. Drug penetration was calculated relative to the drug concentration in the donor chamber at the start of the experiment. The drug content measurements detected in these samples can be expressed as drug transport at a fixed point or as a temporal profile.

[0082] Formulation procedure for lyophilized ODT Formulation penetration studies for piroxicam were also conducted using ODT formulations containing selected penetrating agents. The pharmaceutical compositions (ODTs) were produced by a lyophilization process. The compositions of these pharmaceutical formulations can be shown in Figures 1A-1B and 2D. The lyophilized ODTs contain a base matrix formulation to help provide structure to the final lyophilized tablets. The base matrix formulation consists of a matrix-forming agent and a structure-forming agent. The matrix-forming agent provides a network structure that gives strength and elasticity to the lyophilized tablets. Suitable matrix-forming agents may be gelatin, starch, or several combinations thereof. The structure-forming agent is used to provide structural robustness to the lyophilized tablets. Suitable structure-forming agents may be sugars, including but not limited to mannitol, dextrose, lactose, galactose, cyclodextrin, or several combinations thereof. The base matrix formulation may also contain additional agents or excipients, such as penetrating agents.

[0083] The base matrix was prepared by dissolving a matrix-forming agent and a structure-forming agent in water to form a premix. Other suitable solvents may be used. The API, a penetrating agent, and additional excipients were incorporated into the premix to form an aqueous dispersion of the API. A pH modifier was added as needed. The aqueous API dispersion was then scaled up to the desired batch size using water, at which point it was ready to be placed in a blister tray containing pre-formed pockets.

[0084] Alternatively, an aqueous API dispersion may be prepared by preparing a dry mix. In some embodiments, the API may be dry-mixed with a penetrant, and the dry mixture may be incorporated into a premix along with the remaining excipients to form an aqueous dispersion of the API. In other embodiments, the API may be dry-mixed with a penetrant, and the dry blend may then be mixed with a portion of the premix to form an intermediate API suspension, which may then be incorporated into the remaining premix along with the remaining excipients to form an aqueous dispersion of the API. In yet another embodiment, the API may be dry-mixed with a penetrant, and the dry blend may be mixed with an appropriate amount of water. A portion of the premix may be incorporated into the API mixture. The premix may then be added in several portions until all of the premix has been added.

[0085] After preparing an aqueous API formulation, approximately 150 to 1200 mg (wet-filled mass) of the formulation in predetermined aliquots was placed into each pocket on a blister tray at approximately 10°C to 30°C (±5°C). The placed formulations were then frozen in the pockets of pre-formed blisters (hereinafter referred to as "freezing units") by passing the blister tray through various sub-zero temperature low-temperature storage chambers. The freezing temperature and freezing time were varied to ensure that the placed API formulations were frozen.

[0086] Next, the frozen units were collected and maintained in a freezer at a sub-zero temperature appropriate for the formulation before freeze-drying. Alternatively, the frozen units may be slowly cooled over a suitable period of time to crystallize the structure-forming agent. Crystallization of the structure-forming agent provides frozen units with structural strength, preventing disintegration during freeze-drying.

[0087] After maintaining the freeze, the frozen units were freeze-dried into pharmaceutical compositions (e.g., tablets). The freeze-drying cycle was optimized for each individual formulation. During the freeze-drying process, water was removed from the frozen units by sublimation, leaving porous freeze-dried units that could rapidly disintegrate when placed in the mouth. The freeze-dried tablets were then removed from the freeze-dryer and inspected for any defects. The inspected tablets were then placed in a storage cabinet in a temperature and humidity controlled environment and prepared for sealing in pre-formed blister trays. The blister trays were sealed by placing lidding foil on pre-formed trays. The pre-formed trays were then cut to form individual blisters containing freeze-dried ODT. After formulation of the ODT, the ODT was then re-dispersed in distilled water. Appropriate aliquots (e.g., 0.5 ml) of the dispersed formulations were sampled and subjected to permeability studies.

[0088] Procedure for evaluating permeability TR146 buccal mucosal cells seeded on Transwell plates were grown in growth medium for 25 to 28 days. Before starting the permeability evaluation, the TEER of each Transwell insert in the same growth medium was measured. The inserts were then washed twice with Hanks' Balance Salt solution (HBSS), and the TEER was measured again. Subsequently, the HBSS buffer in the Transwell was decanted.

[0089] Three types of samples were used in the permeability test: (a) an API control sample, (b) a two-component mixture of the penetrant and API in water, and (c) a reconfigured aqueous dispersion of ODT containing the penetrant and API. For each test sample, the permeability experiment was repeated three times. Each API control sample and each two-component mixture of API and penetrant were prepared in 20 ml of distilled water. Each ODT sample was dispersed in 5 ml of distilled water.

[0090] For each type of sample, 0.5 ml of the sample was added directly to each donor chamber in the Transwell. The donor chambers were cumulatively transferred to new receiving chambers at the following time points: 1, 2, 5, 15, 20, and 30 minutes later. Each receiving chamber contained 1.5 ml of HBSS. The test was performed at 36°C on an orbital plate shaker at 150 rpm. After all measurements were taken, the donor chambers were washed again with HBSS and the TEER was measured to ensure that the integrity of the cell lines was still within acceptable limits.

[0091] After the permeability test was completed, an appropriate amount of solvent was added to the receiving chamber containing 1.5 ml of HBSS buffer. The appropriate solvent depends on the type of sample in the receiving chamber (e.g., 0.25 ml methanol for piroxicam (API), 2.5 ml methanol for piroxicam ODT, 2.5 ml methanol for carvedilol (API), 1.5 ml acetonitrile for atenolol (API), 1.5 ml acetonitrile for atenolol ODT, and 2.5 ml methanol for famotidine (API)).

[0092] For the two-component mixture of API and penetrant, each receiving chamber was shaken at 150 rpm at room temperature for a minimum of 2 hours. The liquid sample in the receiving chamber was then filtered using a 0.45 μm filter, appropriately aliquoted, and subjected to HPLC analysis.

[0093] For the ODT formulations, after adding the appropriate solvent to the receiving chamber, the liquid sample in each receiving chamber was transferred to individual vials and then sonicated in a water bath for 15 to 20 minutes. The liquid sample in each vial was then filtered using a 0.45 μm filter, appropriately aliquoted, and subjected to HPLC analysis.

[0094] Next, the HPLC sample assay for each sample was evaluated. Based on the HPLC data, the cumulative concentration of the permeated API at each time point was converted to mass (mcg), and then used to calculate the cumulative permeability percentage at each time point according to the following formula:

[0095]

number

[0096] Regarding the temporal profile (time dependence), the cumulative penetration percentage at each time point was plotted against the individual time points.

[0097] (Example 1) Evaluation of piroxicam's permeability Piroxicam is a weakly acidic BCS class II drug. Its molecular weight is 331.4 g / mol, and its water solubility is 0.143 mg / ml. It exhibits a weak acid pKa of 5.1 and a log P value of 2.2.

[0098] The permeability of piroxicam was evaluated in combination with the following permeation agents: Pluronic® F127, Pluronic® L44, sodium cholate hydrate, Tween 21, Span 80, sodium lauryl sulfate, dodecyl-BD-maltoside, capric acid, arginine, and lysine.

[0099] For this evaluation, control samples (1) containing 0.7 mg / ml of piroxicam alone were prepared with and without pH adjustment. PXM and 3 PXMNineteen two-component mixtures of piroxicam and a penetrating agent were prepared in distilled water. Each mixture contained 0.7 mg / ml of piroxicam. The concentrations of the penetrating agents in the mixtures are summarized in Table 2. Samples were prepared at room temperature, stirred, and then sampled for testing. The pH of the mixtures was then measured, and the theoretical ionization and non-ionization percentages of piroxicam at each pH value were calculated using the Henderson-Hasselbach formula.

[0100] [Table 2A]

[0101] [Table 2B]

[0102] For permeability evaluation, the control samples and two-component mixture samples summarized in Table 2 were tested according to the procedure described in the permeability evaluation procedure above. For each test sample (repeated three times), 0.5 ml containing 0.35 mg of piroxicam was added to the donor chamber of the Transwell plate. Before starting the permeability evaluation, 1.5 ml of HBSS was added to each receiving chamber. After the permeability evaluation was completed, 0.25 ml of methanol was added to each receiving chamber. The Transwell plate was then placed on a plate shaker and shaken at room temperature, 150 rpm, for 2 hours. The samples were then prepared and subjected to HPLC analysis to assay the piroxicam content.

[0103] To determine the drug concentration of piroxicam in a sample, an HPLC method was developed and validated. The method was optimized under chromatographic conditions of 60 / 40 TFA / ACN (trifluoroacetic acid / acetonitrile), 0.1% TFA, Eclipse Plus HPLC column (3.5 μC18, 150 × 4.6 mm), injection volume of 10 μl, room temperature (25 °C), flow rate of 1 ml / min, and detection at 330 nm (UV spectroscopy). The linearity range was 0.19 to 100 mcg / ml of piroxicam in methanol, which is acceptable linearity (R 2 The LOD and LOQ were low (0.10 mcg / ml and 0.30 mcg / ml, respectively). The execution time was 8 minutes.

[0104] The results of the cumulative penetration percentage of piroxicam are summarized in Table 3.

[0105] [Table 3A]

[0106] [Table 3B]

[0107] Figure 5 shows exemplary penetration data illustrating the effect of using high molecular weight nonionic surfactants as penetration enhancers for piroxicam. Pluronic® F127 (PF127) and Pluronic® L44 (PL44) were used as model surfactants. The molecular weights of PF127 and PL44 are 12600 g / mol and 2200 g / mol, respectively. Each grade has a different hydrophilic-lipophilic balance (HLB) value; the HLB values ​​for PF127 and PL44 are 22 and 16, respectively. Both grades were investigated at a concentration of 2 × CMC. PF127 was also evaluated at 0.5 × CMC and 1 × CMC. All samples were prepared by mixing the surfactant solution with the piroxicam suspension for 1 minute, and then the penetration was evaluated. The results showed that the solubilizing and micelle-forming effects of PL44 and PF127 increased the penetration of piroxicam.

[0108] In the case of PL44, the penetration of piroxicam increased slightly upon addition of PL44, with increases of up to 1.7 times and 1.3 times at 15 minutes and 20 minutes, respectively. However, no difference was observed in the cumulative penetration percentage compared to the control sample at 30 minutes. In the case of PF127, the penetration of piroxicam increased significantly upon addition of PF127, starting from the first minute, compared to the control sample. With 0.5×CMC and 1×CMC, penetration increased rapidly, ranging from 7 to 12 times in the first 15 minutes, and then the rate of increase gradually decreased to approximately 4.5 times at 30 minutes, resulting in cumulative penetration percentages of 48.15% and 45.29%, respectively. With 2×CMC, the increase exceeded 3 times at all time points (p<0.001), resulting in a cumulative penetration percentage of 27.22% at 30 minutes. The difference in penetration effect between the two grades may be due to the difference in the length of the PPO and PEO polymer blockers. For PF127, the low penetration in 2×CMC may be due to increased encapsulation of the API within the micelle, which can reduce penetration.

[0109] Figure 6 shows exemplary permeability data illustrating the effects of various nonionic and ionic surfactants and fatty acids as permeability enhancers for piroxicam. Tween 21, Span 80, and blends of these surfactants in a 5:1 ratio of Tween 21 to Span 80, with HLB values ​​of 4.3, 13.3, and 11.8, respectively, were used as model nonionic surfactants. Sodium lauryl sulfate (SLS) with an HLB value of 40 was used as an anionic surfactant. Dodecyl-BD-maltoside (DDM) with an HLB value of 13.5 was used as a glycoside surfactant. All two-component mixtures were screened in a 1:1 molar ratio with respect to piroxicam. All samples were prepared by mixing the surfactant solution with the piroxicam suspension, and then allowed to stand with stirring for 1 to 1.5 hours before permeability evaluation.

[0110] Span 80 is a nonpolar lipophilic surfactant with a low HLB of 4.3. It was hypothesized that Span 80 primarily interferes with tissue integrity by forming hydrogen bonds with the polar head groups of membrane lipids. However, in this experiment, Span 80 was observed to significantly reduce the permeability of piroxicam. Since piroxicam was partially ionized at the sample's pH (4.2), it is possible that the polar head groups of the membrane lipids were replaced and interacted with Span 80. Furthermore, Span 80 may form lipophilic aggregates. Since piroxicam is virtually lipophilic, these lipophilic aggregates may delay its release.

[0111] In contrast, when hydrophilic surfactants with HLB values ​​exceeding 10 (SLS, Tween 21, and DDM) and a 5:1 blend of Tween 21 and Span 80 were used, the penetration of piroxicam increased. Surfactants with HLB values ​​in the range of 10–20 may promote drug penetration by inserting themselves between the lipophilic tails of the bilayer, and thus may interfere with the lipid arrangement within the cell membrane.

[0112] Tween 21, with an HLB value of 13.3, achieved a 3.5 to 5-fold increase in penetration over the first 15 minutes compared to the piroxicam control sample, with a cumulative penetration percentage reaching 20.82% at 30 minutes (a 2.1-fold increase compared to the control sample). A blend of Tween 21 with Span 80, with an HLB value of 11.8, also promoted piroxicam penetration compared to the control, showing a 1.4 to 3-fold increase in penetration within the first 15 minutes, with a cumulative penetration percentage of 12.03% at 30 minutes (a 1.2-fold increase).

[0113] DDM is a glycoside surfactant with an HLB value of 13.5. DDM showed a statistically significant improvement in piroxicam penetration, with a cumulative penetration percentage increase of 1.75 to 2.6 times. It was also shown that the maximum cumulative penetration percentage for all surfactants was 25.60% after 30 minutes (a 2.6-fold increase compared to the control sample).

[0114] SLS has an HLB value of 40. An increase in piroxicam penetration was only observed after 15 minutes, with a maximum increase of 2.2 times in cumulative penetration percentage observed at 30 minutes compared to the control sample. Although SLS has the highest HLB value among the tested surfactants, its effect on piroxicam penetration was statistically significantly lower than that of Tween 21 and DDM. This low penetration can be explained by the micelle lipid extraction effect and encapsulation within micelles of SLS.

[0115] Figure 6 also shows the effect of fatty acids on the permeability of piroxicam compared to a piroxicam control sample. Capric acid (CA) was used as a medium-chain fatty acid (MCFA) model with a C-10 carbon chain length. To prepare the sample using CA, the required mass of CA was melted at 50°C and then cooled to 25°C to 30°C. After cooling, but before it became solid, the CA was mixed with the piroxicam-water mixture and left to stand with stirring at room temperature until the permeability evaluation began.

[0116] It was hypothesized that fatty acids promote drug permeability through several processes, such as drug solubilization, increased membrane fluidity, and intercellular transport. It was also hypothesized that saturated fatty acids, particularly those with medium chain lengths (i.e., C10 or C12), would exhibit optimal activity when used for delivery via the buccal mucosa, which has a high content of polar lipids. However, in this experiment, the opposite effect was observed with respect to CA and piroxicam. CA significantly reduced piroxicam permeability after 20 and 30 minutes compared to the piroxicam control. In aqueous solutions, fatty acid molecules exceeding the CMC may self-associate or aggregate to form micelles of varying sizes and structures. These micelles may interfere with the efficiency of CA as transient permeability enhancers, reducing drug permeability. However, the aggregation behavior and CMC values ​​of different MCFAs are highly dependent on various system properties, such as pH, temperature, and ionic strength. Furthermore, lipophilic fatty acid aggregates may delay the release of lipophilic drugs, and piroxicam is a lipophilic drug with a log P value of 2.2.

[0117] Figure 7 shows exemplary permeability data illustrating the effect of using bile salts as permeability enhancers for piroxicam. Sodium cholate hydrate was used as a model bile salt, and its effect on piroxicam permeability was evaluated at 0.5 CMC, 1 CMC, and 2 CMC. The samples had higher pH values ​​compared to the control, at 6.63, 6.61, and 6.66, respectively. A 2 CMC sample with pH adjusted to 5.51 using citrate was also evaluated.

[0118] Samples prepared using 0.5 CMC showed a slight increase in piroxicam permeability compared to the control, but this was not statistically significant. With 1 CMC, permeability increased significantly 5 to 6 times in the first 15 minutes. A cumulative permeability percentage of 39.52% (a 4-fold increase compared to the control) was observed at 30 minutes. With 2 CMC, a slight but statistically significant 1.5-fold increase in cumulative permeability percentage was observed in the first minute. The cumulative permeability percentage reached 14.44% after 30 minutes. For 2 CMC samples pH-adjusted with citrate, the increase in permeability was slight and not statistically significant. These results can be explained by the dual effect of sodium cholate. The lipid bilayer packing is disrupted, promoting the solubility of piroxicam, which may then enhance its permeability through micelle formation. When citric acid is added, the percentage of non-ionized drugs increases (conveniently increasing permeability), but drug solubility may decrease, which can explain the low permeability of samples containing citric acid.

[0119] Figure 8 shows exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for piroxicam. Since piroxicam is a weak acid (pKa=5.1), basic amino acids, such as arginine and lysine, were used as counterions. Both arginine and lysine have two basic groups: pKa1=9.04 and pKa2=12.48 for arginine, and pKa1=8.95 and pKa2=10.53 for lysine. To ensure complete ionization of both piroxicam and the counterion, all samples were prepared at pH levels differing by 2 units from their pKa. Therefore, the sample pH was adjusted to a range of 6.5–7 using 0.1 M HCl.

[0120] Arginine was studied at molar ratios of piroxicam to arginine of 1:1, 1:3, and 1:6. A significant increase in cumulative permeability percentage was observed with both 1:1 and 1:3 molar ratios, with a 2- to 4-fold increase in cumulative permeability % observed mainly at the initial time points (over 1 to 5 minutes). At time points after 15 to 30 minutes, the increase was less pronounced and decreased from 1.7 to 1.2 times over this period. For the 1:6 molar ratio sample, no increase in permeability was observed. Amino acids as counterions may reduce the lipophilicity of a drug, and therefore the log P value of the drug decreases as the amino acid fraction increases. Thus, drug permeability may not increase as the ratio of counterions to API increases.

[0121] Lysine was studied at molar ratios of 1:3 and 1:6 for piroxicam relative to lysine. The results did not show a significant enhancement of piroxicam's permeability. This may be due to the lower difference in pKa values ​​(ΔpKa ≥ 5) between piroxicam and lysine compared to arginine (ΔpKa ≥ 7). Arginine also has more H bonds than lysine and may form strong ionic bonds with weakly acidic APIs, such as piroxicam.

[0122] Penetration was evaluated by preparing lyophilized ODT containing a two-component mixture of API and a penetrating agent, along with piroxicam and selected penetrating agents, namely PF127, sodium cholate hydrate, and SLS. Batches of ODT containing different concentrations of penetrating agents were prepared. The ODT was prepared using the procedure described in the section on formulation procedures for lyophilized ODT.

[0123] The aqueous dispersion of the ODT formulation contained a base matrix (containing a matrix-forming agent (e.g., gelatin) and a structural agent (e.g., mannitol)) and piroxicam. Batches with and without the penetrating agent were prepared. A 500 mg wet-filled aqueous dispersion was placed into each pre-formed pocket of a blister pack. The aqueous dispersion contained 4% w / w piroxicam, yielding a dose of 20 mg of piroxicam per tablet.

[0124] These selected batches were evaluated for piroxicam penetration. The compositions of the ODT formulations (aqueous dispersions before lyophilization and lyophilized tablets) of these batches are summarized in Table 4.

[0125] [Table 4]

[0126] To determine the concentration of piroxicam in the ODT sample, the same HPLC method was used to determine the concentrations of piroxicam in API alone and in the API-permeant mixture. As described above, the method was optimized under chromatographic conditions of 60 / 40 TFA / ACN (trifluoroacetic acid / acetonitrile), 0.1% TFA, Eclipse Plus HPLC column (3.5 μC18, 150 × 4.6 mm), injection volume of 10 μl, room temperature (25 °C), flow rate of 1 ml / min, and detection at 330 nm (UV spectroscopy). The linearity range was 0.19 to 100 mcg / ml of piroxicam in methanol, which is acceptable linearity (R 2 The LOD and LOQ were low (0.10 mcg / ml and 0.30 mcg / ml, respectively). The execution time was 8 minutes.

[0127] Prior to the permeability evaluation, each lyophilized ODT from each batch, containing a target dose of 20 mg of piroxicam, was dissolved in 5 ml of distilled water (i.e., 4 mg / ml piroxicam) and stirred on a magnetic stirrer for 5 minutes. The pH was then measured to ensure there were no abrupt changes in pH, which may result from different permeability due to the ratio of ionized molecules to non-ionized molecules.

[0128] The permeability evaluation was performed according to the process described in the section on permeability evaluation procedures. The results of the cumulative permeability percentage of piroxicam are summarized in Table 5.

[0129] [Table 5]

[0130] Figure 9 shows exemplary permeability data illustrating the effect of using a nonionic surfactant as a permeability enhancer for reconstituted piroxicam in lyophilized orally disintegrating tablets. PF127 was used as a model surfactant. Its effect on the permeability of piroxicam in lyophilized ODT was evaluated at concentrations of 0.1% w / w, 1% w / w, and 1.5% w / w in the aqueous dispersion. These concentrations correspond to 2 × CMC, 20 × CMC, and 30 × CMC, respectively. PF127 may form micelles in an aqueous environment when its concentration is equal to or greater than the concentration of CMC, and these micelles may promote the permeability of piroxicam by solubilizing and encapsulating it within the micelles. In this experiment, the permeability of piroxicam in lyophilized ODT tablets was enhanced in the presence of PF127. The percentage cumulative permeability of the three batches of tablets was comparable, showing a 1.3 to 2.3-fold increase in permeability, respectively. At these concentrations, sufficient solubilization and / or micelle formation may occur, resulting in the formation of similar amounts of micelles containing piroxicam, which then passed through the buccal mucosa cell line.

[0131] Figure 10 shows exemplary permeability data illustrating the effects of using bile salts and anionic surfactants as permeability enhancers for piroxicam reconstituted in lyophilized orally disintegrating tablets. Sodium cholate hydrate was used as a model bile salt. The effect of piroxicam on permeability in lyophilized ODTs was evaluated at concentrations of 0.34% w / w and 2.72% w / w in aqueous dispersions, corresponding to 0.5 × CMC and 4 × CMC, respectively. At 0.5 × CMC, the permeability of piroxicam increased only slightly. At 4 × CMC, permeability decreased, and the cumulative permeability percentage was similar to that of the control sample. The difference between the two concentrations may be due to micelle size. At CMC, sodium cholate micelles exist mainly as dimers. At concentrations above CMC, the dimers may interact to form larger secondary structures, which may make permeability more difficult.

[0132] Figure 10 also shows the effect of SLS on the permeability of piroxicam ODT compared to a piroxicam control sample. This effect was evaluated at concentrations of 0.69% w / w and 3.49% w / w in aqueous dispersions, corresponding to PXM:SLS in molar ratios of 5:1 and 1:1, respectively. The permeability of piroxicam ODT increased in the presence of SLS. The 3.49% w / w SLS sample showed a slightly higher, but statistically significant, increase in permeability compared to the 0.69% w / w SLS sample. The increase in percentage cumulative permeability was small in the first 5 minutes, followed by a significant increase in permeability from 15 minutes onward. Two-component mixtures containing PXM:SLS in a 1:1 molar ratio showed similar trends in their temporal profiles.

[0133] (Example 2) Evaluation of the permeability of carvedilol Carvedilol (CAV) is a weakly basic BCS class II API. Its molecular weight is 406.5 g / mol, its log P value is 3.05, its base pKa1 is 7.8, and its acid pKa2 is 15. Carvedilol exhibits pH-dependent solubility, with low solubility and ionization at high pH values ​​and high solubility and ionization at low pH values. Its water solubility is 4.44 μg / ml.

[0134] The permeability of carvedilol was evaluated in combination with the following penetrating agents: PF127, sodium cholate hydrate, Tween 21, Span 80, SLS, DDM, capric acid, citric acid, aspartic acid, and alanine.

[0135] Regarding this evaluation, a control sample containing carvedilol alone (1 CAV Fifteen two-component mixtures of carvedilol and a penetrant were prepared in water, with each mixture containing 1.74 mg / ml of carvedilol. The concentrations of the penetrants in the mixtures are summarized in Table 6. Samples were prepared at room temperature, stirred, and then sampled for testing. The pH of the mixtures was then measured, and the theoretical ionization and non-ionization percentages of carvedilol at each pH value were calculated using the Henderson-Hasselbach formula.

[0136] [Table 6A]

[0137] [Table 6B]

[0138] For permeability evaluation, the control samples and two-component mixture samples summarized in Table 6 were tested according to the procedure described in the section on permeability evaluation. For each test sample (repeated three times), 0.5 ml containing 0.87 mg of carvedilol was added to the donor chamber of the Transwell plate. Before starting the permeability evaluation, 1.5 ml of HBSS was added to each receiving chamber. After the permeability evaluation was completed, 2.5 ml of methanol was added to each receiving chamber. The Transwell plate was then placed on a plate shaker and shaken at room temperature, room temperature, 150 rpm, and room temperature for 2 hours. The samples were then prepared and subjected to HPLC analysis to assay the carvedilol content.

[0139] An HPLC method was developed and validated to determine the drug concentration of carvedilol in a sample. The method was optimized under the following chromatographic conditions: 55 / 45v / vTFA / ACN (trifluoroacetic acid; acetonitrile), 0.1% TFA, Eclipse Plus HPLC column (3.5μ C18, 150×4.6mm), injection volume of 20μl, room temperature (25℃) with a flow rate of 1ml / min, and detection at 240nm (UV spectroscopy). The linearity range was 0.19–100mcg / ml of carvedilol in a 2:1 methanol:HBSS mixture, which is acceptable linearity (R 2 The LOD and LOQ were low (0.014 mcg / ml and 0.042 mcg / ml, respectively). The execution time was 7 minutes.

[0140] The results of the permeability of cumulative percentage carvedilol are summarized in Table 7.

[0141] [Table 7A]

[0142] [Table 7B]

[0143] Figure 11 shows exemplary permeability data illustrating the effect of using pH modifiers as permeability enhancers for carvedilol. The effect of increasing the ionization fraction of carvedilol on permeability was evaluated by lowering the pH of the carvedilol solution using a weak acid, such as citric acid. Using citric acid lowered the pH from 7 (carvedilol control pH) to 5.9 and 4.2. As the pH decreased, the ionization fraction of carvedilol increased from 86.32% (control) to 98.76% and 99.97%, respectively. Despite the low non-ionized drug fraction (approximately 1%), the permeability evaluation showed a significant increase (up to 7 times) in cumulative permeability percentage compared to the carvedilol control (non-ionized drug was approximately 13.7%). However, if the percentage of non-ionized drug decreases further, the enhancement of permeability may be hindered. The drug molecule as a non-ionized state is preferable for permeability, and the drug also needs to be in a solubilized state for absorption. The results suggest that, due to the increased drug solubility resulting from the decrease in pH, combined with the high lipophilicity of carvedilol (log P3.05), even low pH levels are sufficient to compensate for the low percentage of non-ionized drugs and enable adequate drug penetration. In contrast, at high pH values, the proportion of solubilized drugs is low, and therefore, the amount of drug available for absorption decreases. Thus, pH modification to improve the solubility of highly lipophilic APIs may be sufficient to increase penetration despite the low percentage of non-ionized drugs.

[0144] Figure 12 shows exemplary permeability data illustrating the effects of using nonionic surfactants alone and in combination with pH modifiers as permeability enhancers for carvedilol. Mixing 2×CMC PF127 with carvedilol did not show a statistically significant difference in permeability. The lack of permeability enhancement in the initial stage may be due to the strong association between the lipophilic substance carvedilol and PF127 micelles. However, samples prepared with both PF127 and citric acid showed a significant increase in permeability compared to the control sample. A 2-fold increase in cumulative permeability percentage was achieved after the first minute, and a 31-fold increase was achieved at 30 minutes. Citric acid enhances the permeability of carvedilol by altering its ionization state and solubility. Therefore, the presence of citric acid reduces the association between carvedilol and PF127, thereby increasing the influence of PF127 on the membrane and potentially hindering lipid bilayer packing. This can explain the significant enhancement of carvedilol permeability at low pH values.

[0145] Figure 13 shows exemplary permeability data illustrating the effects of various ionic and nonionic surfactants and fatty acids as permeability enhancers for carvedilol. All surfactants (SLS, Tween 21, DDM, and Span 80) were evaluated in a 1:1 molar ratio to carvedilol. SLS significantly increased the permeability of carvedilol, achieving a twofold increase from 5 minutes to 30 minutes. Tween 21 significantly increased permeability only after 30 minutes. No significant effect on permeability was observed when using DDM. Span 80 inhibited the permeability of carvedilol.

[0146] Figure 13 also shows the effect of fatty acids on the permeability of carvedilol. Capric acid was used as a model medium-chain fatty acid (MCFA) with a C-10 carbon chain length. In the presence of capric acid, carvedilol showed more than a threefold increase in permeability after 30 minutes. It is hypothesized that fatty acids with C-10 or C-12 chain lengths exhibit optimal activity when used for delivery via the buccal mucosa, which has a high content of polar lipids. This can explain the enhancement of carvedilol permeability in the presence of capric acid.

[0147] Figure 14 shows exemplary permeability data illustrating the effects of using bile salts and combinations of bile salts and pH modifiers as permeability enhancers for carvedilol. Sodium cholate hydrate was used as a model bile salt. Sodium cholate hydrate significantly enhanced the permeability of carvedilol after 15 minutes and showed an almost twofold increase in cumulative permeability percentage after 30 minutes. Samples containing both sodium cholate hydrate and citrate showed a similar trend to samples containing a combination of PF127 and citrate, with a threefold increase in carvedilol permeability compared to the control. It is hypothesized that the main technique for improving the permeability of carvedilol with bile salts is to increase its water solubility by micellization and membrane fluidization, enabling passive drug penetration. Adding citrate enhances the solubility of carvedilol and further increases its permeability.

[0148] Figure 15 shows exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for carvedilol. Because carvedilol has basic properties (pKa=7.8), aspartic acid, an acidic amino acid with pKa1=1.88, pKa2=3.65, and pKa3=9.60, was used as a model counterion. The effect of aspartic acid on carvedilol permeability was evaluated at molar ratios of carvedilol to aspartic acid of 1:1, 1:3, and 1:6. Carvedilol permeability significantly increased when aspartic acid was used at all test molar ratios. The increase in cumulative permeability percentage ranged from 7 to 27 times from 1 to 30 minutes of the experiment. Increasing the molar ratio of aspartic acid to carvedilol did not further increase carvedilol permeability. It is possible that amino acids as counterions may reduce the lipophilicity of a drug, and the log P value of the drug may decrease as the amino acid ratio increases. Therefore, even if the counter-ion ratio increases, the permeability of the drug may not increase further.

[0149] Alanine (pKa1=2.34, pKa2=9.69) was also studied as a model counterion to carvedilol in a 1:1 molar ratio. The cumulative osmotic percentage of carvedilol increased 7 to 13 times from 1 minute to 30 minutes in the presence of alanine.

[0150] (Example 3) Evaluation of famotidine's permeability Famotidine (FAM) is a BCS class III drug with a molecular weight of 337.5 g / mol. It is a weak base with a pKa of 6.76, a water solubility of 1 mg / ml, and a log P value of -0.64.

[0151] The permeability of famotidine was evaluated in combination with the following permeation agents: PF127, sodium cholate hydrate, Tween 21, DDM, aspartic acid, benzoic acid, and glycine.

[0152] For this evaluation, control samples (1FAM) containing famotidine alone and 12 two-component mixtures (2 FAM ~13 FAM ) of famotidine and penetration enhancers, each mixture containing 1.4 mg / ml of famotidine, were prepared in distilled water. The concentrations of the penetration enhancers in the mixtures are summarized in Table 8. The samples were prepared at room temperature, stirred, and then sampled for testing. Next, the pH of the mixtures was measured, and the theoretical ionization percentage and theoretical non-ionization percentage of famotidine at each pH value were calculated using the Henderson-Hasselbalch equation.

[0153]

Table 8

[0154] For the permeability evaluation, the control samples and the samples of the two-component mixtures summarized in Table 8 were tested by the procedure described in the section on the procedure for permeability evaluation. Each sample was tested 3 times. Before starting the permeability evaluation, 1.5 ml of HBSS was added to each receiving chamber. After the permeability evaluation was completed, 2.5 ml of methanol was added to each receiving chamber. Then, the Transwell plate was placed on a plate shaker and shaken at 150 rpm at room temperature for 2 hours. Next, the samples were prepared for HPLC analysis and assayed for famotidine content.

[0155] [[ID=B]] To determine the drug concentration of famotidine in the samples, an HPLC method was developed and validated. The method was optimized with chromatographic conditions of 55 / 45 v / v MeOH:H2O (methanol; water, pH 3.3, adjusted with phosphoric acid), Eclipse Plus HPLC column (3.5 μ C18, 150×4.6 mm), injection volume of 10 μl, flow rate of 0.5 ml / min at room temperature (25 °C), and detection at 265 nm (UV spectroscopy). The linear range was 0.19~100 mcg / ml of famotidine in methanol, with acceptable linearity (R 2The LOD and LOQ were low (0.028 mcg / ml and 0.085 mcg / ml, respectively). The execution time was 6 minutes.

[0156] The results of the cumulative permeability percentage of famotidine are summarized in Table 9.

[0157] [Table 9A]

[0158] [Table 9B]

[0159] Figure 16 shows exemplary permeability data illustrating the effects of using bile salts and nonionic surfactants as permeability enhancers for famotidine. The model surfactants evaluated were PF127, DDM, Tween 21, and Span 80. The model bile salt evaluated was sodium cholate hydrate. All samples were prepared by mixing the surfactant or bile salt solution with the famotidine solution, allowing it to stand after stirring before permeability evaluation. Neither PF127 nor Tween 21 showed any enhancement of famotidine permeability. DDM in a 1:1 molar ratio with famotidine showed a significant increase in famotidine permeability. Permeability increased threefold compared to the control sample during the first 5 to 15 minutes, but no significant difference was observed at 20 and 30 minutes. Span 80 in a 1:1 molar ratio with famotidine showed a twofold increase in permeability compared to the control sample. 2×CMC sodium cholate hydrate showed a significant increase in famotidine permeability, with cumulative permeability percentages increasing 2 to 3.5 times compared to the famotidine control at all time points in the experiment.

[0160] Regarding sodium cholate hydrate and DDM, the findings differed from those achieved when tested with atenolol, another BCS class III drug. However, famotidine and atenolol have very different solubility and lipophilic properties. Famotidine is less hydrophilic (water solubility 1 mg / ml) and less permeable (log P value -0.64) compared to atenolol, which has a water solubility of 13.5 mg / ml and a log P value of 0.57. Permeabilis agents such as bile salts may promote drug permeability by disrupting cell membranes. Therefore, when using sodium cholate hydrate and DDM, the difference in water solubility between famotidine and atenolol may contribute to the difference in permeability.

[0161] No increase in famotidine permeability was observed for PF127 and Tween 21. When PF127 and Tween 21 exceeded their CMC, they spontaneously formed micelles with a hydrophilic exterior and a hydrophobic interior. PF127 and Tween 21 were unable to improve permeability because the hydrophilic famotidine molecules were not encapsulated within the hydrophobic micelle core. This also explains similar results achieved when PF127 and Tween 21 were used with atenolol.

[0162] Figure 17 shows exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for famotidine. Famotidine has basic properties, a pKa of 6.76, and four basic NH2 functional groups. Aspartic acid (pKa1=1.88, pKa2=3.65, pKa3=9.60), benzoic acid (pKa4.20), and glycine (pKa1=2.34, pKa2=9.60) were selected as counterions. Samples of aspartic acid in 1:1 and 1:3 molar ratios relative to famotidine (Sample 9) FAM and 10 FAM ), benzoic acid in a 1:1 molar ratio to famotidine (Sample 12 FAM ), and glycine in a molar ratio of 1:3 to famotidine (Sample 6 FAMThe samples were prepared at pH levels differing by 2 units from the pKa of both famotidine and the counterion to ensure that both were completely ionized. Consequently, the pH values ​​of the samples were in the range of 5.0 to 5.5. None of the four samples showed any increase in famotidine permeability. At pH 5, all four functional groups of famotidine may be ionized, and in the presence of an ionized counterion, ion pairs can be formed at all four groups, increasing the bulk structure of the drug-ion pair complex and decreasing its permeability. Therefore, if famotidine is only partially ionized, it may be possible to form a smaller drug-counterion ion pair complex, which may increase permeability. To test this hypothesis, samples of famotidine and aspartic acid in a 1:1 molar ratio (Sample 11) were prepared. FAM ) and 1:1 (Sample 7 FAM ) and 1:3 (sample 8 FAM Samples of famotidine and glycine in a molar ratio of ) were prepared at pH values ​​of 8–9. All three samples showed a significant (2–3 times) increase in famotidine permeability at all time points compared to the control. In this pH range, the number of ion pairs formed was small, interference by ionized functional groups was reduced, and famotidine permeability increased.

[0163] (Example 4) Evaluation of atenolol permeability Atenolol (ATL) is a BCS class III drug with a molecular weight of 266.34 g / mol. It is a weak base with a pKa of 9.6, a water solubility of 13.5 mg / ml, and a log P value of 0.57.

[0164] The permeability of atenolol was evaluated in combination with the following penetrating agents: PF127, SLS, Tween 21, DDM, Span 80, sodium cholate hydrate, citric acid, aspartic acid, and benzoic acid.

[0165] Regarding this evaluation, a control sample containing atenolol alone (1 ATL), and 13 two-component mixtures (2 ATL to 14 ATL) of atenolol and a penetrant were prepared in distilled water, with each mixture containing 1.74 mg / ml of atenolol. The concentrations of the penetrants in the mixtures are summarized in Table 10. Samples were prepared at room temperature, stirred, and then sampled for testing. The pH of the mixtures was then measured, and the theoretical ionization and non-ionization percentages of atenolol at each pH value were calculated using the Henderson-Hasselbach formula.

[0166] [Table 10]

[0167] For permeability evaluation, the control samples and two-component mixture samples summarized in Table 10 were tested according to the procedure described in the section on permeability evaluation. For each test sample (repeated three times), 0.5 ml of the sample was added to the donor chamber of the Transwell plate. Before starting the permeability evaluation, 1.5 ml of HBSS was added to each receiving chamber. After the permeability evaluation was completed, 1.5 ml of acetonitrile was added to each receiving chamber. The Transwell plate was then placed on a plate shaker and shaken at 150 rpm at room temperature for 2 hours. The samples were then prepared and subjected to HPLC analysis to assay the atenolol content.

[0168] To determine the drug concentration of atenolol in a sample, an HPLC method was developed and validated. The method was optimized under chromatographic conditions of 60 / 40 TFA / ACN (trifluoroacetic acid; acetonitrile), 0.1% TFA, Phenomenex HPLC column (Gemini 5μ C18, 150×4.6mm), injection volume 20μl, room temperature (25℃) flow rate 0.5ml / min, and detection by fluorescence at excitation 276nm and emission 296nm. The linearity range was 0.19–100 μg / ml of atenolol in CAN, which is acceptable linearity (R 2=1), LOD and LOQ were low (0.02 μg / ml and 0.05 μg / ml, respectively).

[0169] The results of the cumulative permeability percentage of atenolol are summarized in Table 11.

[0170] [Table 11]

[0171] Figure 18 shows exemplary permeability data illustrating the effects of various ionic and nonionic surfactants and bile salts as permeability enhancers for atenolol. Atenolol was evaluated with Span 80, Tween 21, SLS, and DDM in a 1:1 molar ratio. PF127 was evaluated at a concentration of 2 CMC. Surfactants may improve drug permeability by interfering with lipid membranes, solubilizing drugs, and subsequently micellizing them. However, in this experiment, neither lipophilic (HLB<10) nor hydrophilic (HLB>10) surfactants showed a significant increase in atenolol permeability. SLS showed a non-statistically significant increase in permeability compared to the control for the first 5 minutes, and no difference thereafter. PF127, DDM, Tween 21, and Span 80 all showed no statistically significant difference in drug permeability compared to the control. While surfactants may affect the packing of the lipid bilayer of a membrane, drugs with hydrophilic functional groups, such as atenolol, may still be unable to pass through lipophilic membranes. The hydrophilic nature of atenolol also makes it less likely to be encapsulated within the micelle core.

[0172] Figure 18 also shows the effect of bile salts on atenolol permeability compared to an atenolol control sample. Sodium cholate hydrate was used as a model bile salt. Its effect on atenolol permeability was evaluated at a concentration of 2 × CMC. Bile salts can improve drug permeability by increasing water solubility through micelle formation and membrane fluidization, thus allowing the drug to penetrate passively. However, in this experiment, no statistically significant difference was observed in the permeability of the bile salt-atenolol mixture compared to the atenolol control. Despite membrane fluidization, sodium cholate hydrate had no effect on atenolol permeability because hydrophilic drugs cannot pass through lipid-rich cell membranes.

[0173] Figure 19 shows exemplary permeability data illustrating the effect of using a pH modifier as a permeability enhancer for atenolol. Citric acid was used as a model pH modifier for atenolol as a weak base. Drug permeability may be affected by the relative fraction of ionized and non-ionized drugs, which may be manipulated by adjusting the pH of the API dispersion using a pH modifier, e.g., a weak acid, a weak base, or a buffer. The non-ionized drug is the one required for absorption. Citric acid was evaluated at concentrations of 0.37 mg / ml, 0.5 mg / ml, and 1 mg / ml, resulting in pH values ​​of 8.84, 6.66, and 4.45, respectively. The corresponding calculated percentages of the non-ionized drug at each pH were 14.81%, 0.11%, and 0%, respectively. For comparison, the pH of the atenolol control sample was 10.58, and the calculated percentage of the non-ionized drug was 90.52%. For samples containing citric acid, a statistically significant decrease in cumulative permeability percentage was observed compared to the atenolol control sample. For example, at pH 6.6 with 0.5 mg / ml citric acid and 0.11% non-ionized atenolol, the cumulative permeability percentage at 30 minutes decreased from 1.77% (control) to 1.23%. The decrease in permeability corresponded to samples containing 0.37 mg / ml and 0.5 mg / ml citric acid. For the 1 mg / ml citric acid sample, the decrease was only slightly apparent. Since atenolol is a weak base and a BCS class III API, permeability is the rate-limiting factor. Therefore, when the pH decreased, the decrease in the percentage of the non-ionized drug had a greater impact on the API's permeability than the increase in solubility. Depending on whether the drug is a weak acid or a base, and its pKa and solubility characteristics, pH modification may be used to improve or inhibit drug permeability.

[0174] Figure 20 shows exemplary permeability data illustrating the effects of using various counterions as permeability enhancers for atenolol. Since atenolol is a weak base (pKa=9.6), benzoic acid (pKa=4.20) and aspartic acid (pKa1=1.88, pKa2=3.65, and pKa3=9.60) were selected as counterions. All samples were prepared at pH levels differing by 2 units from the pKa of both the drug and the counterion, and both were fully ionized. The pH of the samples was adjusted to 5.5–6.5 for aspartic acid and to 7 for benzoic acid. Aspartic acid was studied in molar ratios of 3:1, 1:1, and 1:3 with atenolol. The 3:1 molar ratio, which yielded a pH of 10.56, was not pH adjusted. This pH was similar to that of the atenolol control sample at pH 10.58. The permeability of the 3:1 molar ratio sample was equivalent to that of the atenolol control sample, confirming the need to adjust the sample's pH to ensure ionization of the drug and counterion and obtain ion pairs. The pH of the 1:1 molar ratio sample was 5.7, which is within the acceptable range, and no pH adjustment was necessary. The 1:1 sample showed a 7-fold increase in atenolol permeability compared to the atenolol control sample. The 1:3 molar ratio sample at pH 3.3 required pH adjustment to 6.3 using 0.1 M NaOH. The 1:3 sample showed a 4-fold increase in atenolol permeability compared to the control sample. The lower permeability compared to the 1:1 sample may be due to the reduction of the drug's lipophilicity when amino acids are present at high concentrations. Furthermore, an increase in the size of the ion pair complex may also reduce permeability. Benzoic acid was evaluated at a 1:1 molar ratio with respect to atenolol, and pH adjustment from 5.4 to 7.5 was necessary using 0.1 M NaOH. The benzoic acid sample showed a 4 to 4.5-fold increase in permeability compared to the atenolol control sample.

[0175] The enhanced permeability observed in two-component mixture formulations may directly correlate with enhanced permeability in pharmaceutical compositions (lyophilized orally dissolvable tablets). This is because the base matrix has been shown to be inert to permeability, as shown in Figures 22A to 22G. In these examples, the base matrix added to the pharmaceutical formulations contained 5 wt.% gelatin and 4 wt.% mannitol for samples containing excipients. The control samples simply had water added. These samples also contained drugs (piroxicam 0.35 mg (low dose) and 2 mg (high dose); atenolol 0.87 mg; carvedilol 0.87 mg) in 0.5 mL.

[0176] Figure 22A shows exemplary penetration data illustrating that the base matrix excipient has no effect on the penetration of carvedilol. Figure 22B shows exemplary penetration data illustrating that the base matrix excipient has no effect on the penetration of carvedilol compared to the positive effect of the nonionic surfactant (PF127). Figure 22C illustrates penetration data illustrating that the base matrix excipient has no effect on the penetration of piroxicam (low dose). Figure 22D shows exemplary penetration data illustrating that the base matrix (without excipient) has no effect on the penetration of piroxicam (low dose) compared to the positive effect of the nonionic surfactant (PF127). Figure 22E shows exemplary penetration data illustrating that the base matrix excipient has no effect on the penetration of piroxicam (high dose). Figure 22F shows exemplary penetration data illustrating that the base matrix excipient has no effect on the penetration of piroxicam (low dose) compared to the positive effect of the nonionic surfactant (PF127). Figure 22G shows exemplary penetration data illustrating that the base matrix excipient has no promoting effect on atenolol penetration.

[0177] In other words, additional materials added to form the pharmaceutical formulation (e.g., structural agents (mannitol), matrix-forming agents (gelatin)) have no effect on permeability. Furthermore, as shown by the data herein, when the corresponding dosage forms were tested, the permeability of the two-component test formulations (API and permeability enhancer) was either enhanced, inhibited, or unchanged.

[0178] Figure 3 shows an exemplary dataset determined by the applicant, which can show combinations of API BCS information and subclassification information, and suitable PEs associated with each combination of API BCS information and subclassification information. The dataset shows the performance of various PEs, including hydrophilic surfactants, lipophilic surfactants, bile salts, micelles, fatty acids, counterions, and pH modifiers, when used with APIs having various BCS classifications and subclassifications. Column 1 shows the performance of the aforementioned PEs with substantially insoluble BCS class II APIs. Column 2 shows the performance of the aforementioned PEs with very slightly soluble BCS class II APIs. Column 3 shows the performance of the aforementioned PEs with slightly soluble BCS class III APIs. Column 4 shows the performance of the aforementioned PEs with moderately soluble BCS class III APIs.

[0179] Figure 21 is a decision-making flowchart that shows how a given API BCS information and subclassification information can be combined to identify suitable PEs for use with the associated API, using the dataset in Figure 3. Suitable PEs for combination with the API can be determined from left to right by the flowchart. For example, an API may be identified as BCS Class II. Class II APIs can be further subdivided into "substantially insoluble" with a solubility of less than 0.1 mg / mL and / or a log P value greater than 2.5, or "very slightly soluble" with a solubility between 0.1 and 1 mg / mL and / or a log P value between 1 and 2.5. If the subclassification of the API is "substantially insoluble," the flowchart shows that suitable PEs for promoting permeability include counterions, pH modifiers, surfactants with an HLB value greater than 10, bile salts, micelles, and fatty acids (and possibly pH adjustments to improve solubility). Alternatively, if the API is classified as "slightly soluble," suitable PEs to promote penetration include counterions, pH modifiers, surfactants with an HLB value greater than 10, bile salts, and micelles (and possibly pH adjustments to improve solubility). For slightly soluble APIs, the flowchart also shows PEs that may inhibit penetration, such as surfactants with an HLB value less than 10 and fatty acids. In another example, the API may be classified as BCS Class III. Class III APIs may be further classified as "slightly soluble" with solubility between 1 and 10 mg / ml and / or log P value less than 1, or "moderately soluble" with solubility between 10 and 33 mg / ml and / or log P value less than 1. If the API is classified as "slightly soluble," suitable PEs to promote penetration include counterions, bile salts, and pH modifiers (and possibly pH adjustments to improve solubility). The flowchart also shows PEs, including micelles and surfactants with an HLB value greater than 10, that may only slightly promote penetration or have no effect on penetration.Alternatively, if the API subcategory is "slightly soluble," suitable PEs to promote permeability include counterions and pH modifiers (and possibly adjusting the pH to improve solubility). The flowchart also shows PEs that may inhibit permeability, including surfactants (including both HLB values ​​greater than and less than 10), bile salts, and micelles.

[0180] Additional definitions Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art in which the claimed subject matter relates. In some cases, terms that have a commonly understood meaning are defined herein for clarity and / or for ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a substantially different meaning from that commonly understood in the art.

[0181] References to values ​​or parameters “about” in this specification include (and are described) variations relating to the value or parameter itself. For example, a description referring to “about X” includes a description of “X.” Furthermore, phrases such as “less than,” “greater than,” “maximum,” “at least,” “less than or equal to,” “greater than or equal to,” or other similar phrases, and the subsequent references to a set of values ​​or parameters, mean that the phrase applies to each value or parameter in the set of values ​​or parameters. For example, the statement that the solution has a concentration of at least about 10 mM, at least about 15 mM, or at least about 20 mM means that the solution has a concentration of at least about 10 mM, at least about 15 mM, or at least about 20 mM.

[0182] As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms unless the context clearly indicates otherwise. As used herein, the terms "and / or" are understood to refer to and include any and all possible combinations of one or more of the related enumerated items. As used herein, the terms "includes," "including," "comprises," and / or "comprising" identify the presence of the described features, integers, processes, operations, elements, components, and / or units, but are not intended to exclude the presence or addition of one or more other features, integers, processes, operations, elements, components, units, and / or groups thereof.

[0183] This application discloses several numerical ranges in the text and drawings. Since this disclosure can be implemented across the entire disclosed numerical range, the disclosed numerical ranges essentially support any range or value within the disclosed numerical range, including both ends, even though precise range limitations are not verbatim stated in the specification.

[0184] The above description is presented to enable those skilled in the art to prepare and use the disclosure, and is provided in the context of a particular application and its requirements. Various modifications to preferred embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments and applications without departing from the spirit and scope of this disclosure. Accordingly, this disclosure is not intended to be limited to the embodiments shown, but should provide the broadest scope consistent with the principles and features disclosed herein.

Claims

1. A pharmaceutically effective amount of a Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of less than 0.1 mg / mL and a log P value greater than 2.5; A penetration enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, micelles, or fatty acids; Matrix-forming agent and; Structuring agent and A pharmaceutical composition containing the following:

2. The pharmaceutical composition according to claim 1, wherein the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance (HLB) greater than 10.

3. The pharmaceutical composition according to claim 2, wherein the molar ratio of the API to the surfactant is 5:1 to 1:5, and / or the pharmaceutical composition contains 0.5 to 20 wt.% of the surfactant.

4. The pharmaceutical composition according to claim 2, further comprising a pH modifier.

5. The pharmaceutical composition according to claim 1, wherein the penetration enhancer contains a bile salt.

6. The pharmaceutical composition according to claim 5, wherein the molar ratio of the API to the bile salt is 15:1 to 1:15, and / or the pharmaceutical composition contains 1 to 20 wt.% of the bile salt.

7. The pharmaceutical composition according to claim 1, wherein the penetration enhancer contains a fatty acid.

8. The pharmaceutical composition according to claim 7, wherein the molar ratio of the API to the fatty acid is 3:1 to 1:3, and / or the pharmaceutical composition contains 0.25 to 5 wt.% of fatty acids.

9. The pharmaceutical composition according to claim 1, wherein the penetration enhancer contains a counterion.

10. The pharmaceutical composition according to claim 1, wherein the molar ratio of the API to the counterion is 6:1 to 1:6, and / or the pharmaceutical composition contains 0.1 to 25 wt.% of the counterion.

11. The pharmaceutical composition according to claim 9, further comprising a pH modifier.

12. A pharmaceutical composition according to any one of claims 1 to 11, further comprising 25 to 60 wt.% of a matrix-forming agent.

13. The pharmaceutical composition according to claim 12, wherein the matrix-forming agent comprises gelatin, pullulan, starch, or a combination thereof.

14. The pharmaceutical composition according to claim 13, wherein the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof.

15. The pharmaceutical composition according to claim 14, wherein the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin.

16. A pharmaceutical composition according to any one of claims 1 to 15, further comprising 20 to 45 wt.% of a structure-forming agent.

17. The pharmaceutical composition according to claim 16, wherein the structure-forming agent comprises mannitol.

18. A pharmaceutical composition according to any one of claims 1 to 17, comprising 1 to 35 wt.% of a BCS class II API or a pharmaceutically acceptable salt or solvate thereof.

19. A pharmaceutically effective amount of a Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 0.1–1 mg / mL and a log P value of 1–2.5; A penetration enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, or micelles; Matrix-forming agent and; Structuring agent and A pharmaceutical composition containing the following:

20. The pharmaceutical composition according to claim 19, wherein the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance (HLB) greater than 10.

21. The pharmaceutical composition according to claim 20, wherein the molar ratio of the API to the surfactant is 5:1 to 1:5, and / or the pharmaceutical composition contains 0.5 to 20 wt.% of the surfactant.

22. The pharmaceutical composition according to claim 19, wherein the penetration enhancer contains a bile salt.

23. The pharmaceutical composition according to claim 22, wherein the molar ratio of the API to the bile salt is 15:1 to 1:15, and / or the pharmaceutical composition contains 1 to 20 wt.% of the bile salt.

24. The pharmaceutical composition according to claim 19, wherein the penetration enhancer contains a counterion.

25. The pharmaceutical composition according to claim 24, wherein the molar ratio of the API to the counterion is 6:1 to 1:6, and / or the pharmaceutical composition contains 0.1 to 25 wt.% of the counterion.

26. The pharmaceutical composition according to claim 24, further comprising a pH modifier.

27. A pharmaceutical composition according to any one of claims 19 to 26, further comprising 1 to 35 wt.% of a pharmaceutically effective amount of a biopharmaceutical classification system (BCS) class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 0.1 to 1 mg / mL and a log P value of 1 to 2.

5.

28. A pharmaceutical composition according to any one of claims 19 to 27, further comprising 25 to 60 wt.% of a matrix-forming agent.

29. The pharmaceutical composition according to claim 28, wherein the matrix-forming agent comprises gelatin, pullulan, starch, or a combination thereof.

30. The pharmaceutical composition according to claim 29, wherein the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof.

31. The pharmaceutical composition according to claim 30, wherein the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin.

32. A pharmaceutical composition according to any one of claims 19 to 31, further comprising 20 to 45 wt.% of a structure-forming agent.

33. The pharmaceutical composition according to claim 32, wherein the structure-forming agent comprises mannitol.

34. A pharmaceutically effective amount of a Class III active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 1 to 10 mg / mL and a log P value of less than 1; An osmotic enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, or bile salts; Matrix-forming agent and; Structuring agent and A pharmaceutical composition containing the following:

35. The pharmaceutical composition according to claim 34, wherein the penetration enhancer contains a bile salt.

36. The pharmaceutical composition according to claim 34, wherein the molar ratio of the API to the bile salt is 15:1 to 1:15, and / or the pharmaceutical composition contains 1 to 20 wt.% of the bile salt.

37. The pharmaceutical composition according to claim 32, wherein the penetration enhancer contains a counterion.

38. The pharmaceutical composition according to claim 37, wherein the molar ratio of the API to the counterion is 6:1 to 1:6, and / or the pharmaceutical composition contains 0.1 to 25 wt.% of the counterion.

39. The pharmaceutical composition according to claim 37, further comprising a pH modifier.

40. A pharmaceutical composition according to any one of claims 34 to 39, further comprising 25 to 60 wt.% of a matrix-forming agent.

41. The pharmaceutical composition according to claim 40, wherein the matrix-forming agent comprises gelatin, pullulan, starch, or a combination thereof.

42. The pharmaceutical composition according to claim 41, wherein the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof.

43. The pharmaceutical composition according to claim 42, wherein the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin.

44. A pharmaceutical composition according to any one of claims 34 to 43, further comprising 20 to 45 wt.% of a structure-forming agent.

45. The pharmaceutical composition according to claim 41, wherein the structure-forming agent comprises mannitol.

46. A pharmaceutical composition according to any one of claims 34 to 45, comprising 1 to 35 wt.% of a BCS class III API or a pharmaceutically acceptable salt or solvate thereof.

47. A pharmaceutically effective amount of a Class III active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 10–33 mg / mL and a log P value of less than 1; A penetration enhancer comprising at least one selected from the group consisting of counterions or pH modifiers; Matrix-forming agent and; Structuring agent and A pharmaceutical composition containing the following:

48. The pharmaceutical composition according to claim 47, wherein the penetration enhancer contains a counterion.

49. The pharmaceutical composition according to claim 48, wherein the molar ratio of the API to the counterion is 6:1 to 1:6, and / or the pharmaceutical composition contains 0.1 to 25 wt.% of the counterion.

50. A pharmaceutical composition according to any one of claims 47 to 49, further comprising 25 to 60 wt.% of a matrix-forming agent.

51. The pharmaceutical composition according to claim 50, wherein the matrix-forming agent comprises gelatin, pullulan, starch, or a combination thereof.

52. The pharmaceutical composition according to claim 51, wherein the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof.

53. The pharmaceutical composition according to claim 52, wherein the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin.

54. A pharmaceutical composition according to any one of claims 47 to 53, further comprising 20 to 45 wt.% of a structure-forming agent.

55. The pharmaceutical composition according to claim 54, wherein the structure-forming agent comprises mannitol.

56. A pharmaceutical composition according to any one of claims 47 to 55, further comprising 1 to 35 wt.% of a pharmaceutically effective amount of a biopharmaceutical classification system (BCS) class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 10 to 33 mg / mL and a log P value of less than 1.

57. A pharmaceutical composition according to any one of claims 1 to 56, wherein the pharmaceutical composition is in solid dosage form.

58. A method for treating a patient, comprising the step of placing the dosage form described in claim 57 into the oral cavity of a person in need of treatment.

59. The method according to claim 58, wherein the placement within the oral cavity is on or under the tongue, or in the buccal region or pharyngeal region.

60. A pharmaceutical composition according to any one of claims 1 to 59, for use in a therapeutic setting.

61. A pharmaceutical composition according to any one of claims 1 to 59, for use in a method of treating a patient, comprising the step of placing the pharmaceutical composition in the oral cavity of a person in need of treatment.

62. A method for forming a solid dosage form: A process in which a pharmaceutical preparation is poured into a pre-formed mold, wherein the pharmaceutical preparation is: A pharmaceutically effective amount of a Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of less than 0.1 mg / mL and a log P value greater than 2.5; A penetration enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, micelles, or fatty acids; With 1-10 wt.% of a matrix-forming agent; 1-10 wt.% of a structural agent and Processes including; The process of freezing the added pharmaceutical preparation; The process of freeze-drying a frozen pharmaceutical preparation to form a dosage form and A method that includes this.

63. The method according to claim 62, wherein the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance of more than 10.

64. The method according to claim 63, wherein the pharmaceutical formulation contains 0.01 to 5 wt.% of a surfactant.

65. The method according to claim 63, wherein the surfactant has a concentration in the pharmaceutical formulation of 0.1 to 30 × its critical micelle concentration (CMC).

66. The method according to claim 65, wherein the surfactant has a concentration of 0.5 to 3 × CMC in the pharmaceutical formulation.

67. The method according to claim 63, wherein the pharmaceutical formulation has a molar ratio of API to surfactant of 5:1 to 1:

5.

68. The method according to claim 62, wherein the penetration enhancer comprises a bile salt.

69. The method according to claim 68, wherein the pharmaceutical preparation contains 0.25 to 5 wt.% of a bile salt.

70. The method according to claim 68, wherein the bile salt has a concentration of 0.5 to 5 × CMC in the pharmaceutical preparation.

71. The method according to claim 68, wherein the pharmaceutical formulation has a molar ratio of API to bile salt of 15:1 to 1:

15.

72. The method according to claim 71, wherein the molar ratio is from 5:1 to 1:

5.

73. The method according to claim 62, wherein the penetration enhancer contains a fatty acid.

74. The method according to claim 73, wherein the pharmaceutical preparation contains 0.03 to 0.15 wt.% of fatty acids.

75. The method according to claim 73, wherein the pharmaceutical formulation has a molar ratio of API to fatty acid of 3:1 to 1:

3.

76. The method according to claim 62, wherein the penetration enhancer contains a counterion.

77. The method according to claim 76, wherein the pharmaceutical formulation contains 0.025 to 5 wt.% of a counterion.

78. The method according to claim 76, wherein the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:

6.

79. The method according to claim 78, wherein the molar ratio is from 3:1 to 1:

3.

80. The method according to claim 76, wherein the pharmaceutical formulation includes a pH modifier.

81. The method according to any one of claims 62 to 80, wherein the pharmaceutical formulation comprises 0.1 to 5 wt.% of a BCS class II API or a pharmaceutically acceptable salt or solvate thereof.

82. A method for forming a solid dosage form: A process in which a pharmaceutical preparation is poured into a pre-formed mold, wherein the pharmaceutical preparation is: A pharmaceutically effective amount of a Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 0.1–1 mg / mL and a log P value of 1–2.5; A penetration enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, surfactants having a hydrophilic-lipophilic balance (HLB) greater than 10, bile salts, or micelles; With 1-10 wt.% of a matrix-forming agent; 1-10 wt.% of a structural agent and Processes including; The process of freezing the added pharmaceutical preparation; The process of freeze-drying a frozen pharmaceutical preparation to form a dosage form and A method that includes this.

83. The method according to claim 82, wherein the penetration enhancer comprises a surfactant having a hydrophilic-lipophilic balance of more than 10.

84. The method according to claim 83, wherein the pharmaceutical formulation contains 0.01 to 5 wt.% of a surfactant.

85. The method according to claim 83, wherein the surfactant has a concentration in the pharmaceutical formulation of 0.1 to 30 × its critical micelle concentration (CMC).

86. The method according to claim 85, wherein the surfactant has a concentration of 0.5 to 3 × CMC in the pharmaceutical formulation.

87. The method according to claim 83, wherein the pharmaceutical formulation has a molar ratio of API to surfactant of 5:1 to 1:

5.

88. The method according to claim 82, wherein the penetration enhancer comprises a bile salt.

89. The method according to claim 88, wherein the pharmaceutical preparation contains 0.25 to 5 wt.% of a bile salt.

90. The method according to claim 88, wherein the bile salt has a concentration of 0.5 to 5 × CMC in the pharmaceutical preparation.

91. The method according to claim 88, wherein the pharmaceutical formulation has a molar ratio of API to bile salt of 15:1 to 1:

15.

92. The method according to claim 91, wherein the molar ratio is from 5:1 to 1:

5.

93. The method according to claim 82, wherein the penetration enhancer contains a counterion.

94. The method according to claim 93, wherein the pharmaceutical formulation contains 0.025 to 5 wt.% of a counterion.

95. The method according to claim 93, wherein the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:

6.

96. The method according to claim 95, wherein the molar ratio is from 3:1 to 1:

3.

97. The method according to claim 93, wherein the pharmaceutical formulation includes a pH modifier.

98. The method according to any one of claims 82 to 97, wherein the pharmaceutical formulation comprises 0.1 to 5 wt.% of a BCS class II API or a pharmaceutically acceptable salt or solvate thereof.

99. A method for forming a solid dosage form: A process in which a pharmaceutical preparation is poured into a pre-formed mold, wherein the pharmaceutical preparation is: A pharmaceutically effective amount of a Class III active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 1 to 10 mg / mL and a log P value of less than 1; An osmotic enhancer comprising at least one selected from the group consisting of counterions, pH modifiers, or bile salts; With 1-10 wt.% of a matrix-forming agent; 1-10 wt.% of a structural agent and Processes including; The process of freezing the added pharmaceutical preparation; The process of freeze-drying a frozen pharmaceutical preparation to form a dosage form and A method that includes this.

100. The method according to claim 99, wherein the penetration enhancer comprises a bile salt.

101. The method according to claim 100, wherein the pharmaceutical preparation contains 0.25 to 5 wt.% of a bile salt.

102. The method according to claim 100, wherein the bile salt has a concentration of 0.5 to 5 × CMC in the pharmaceutical preparation.

103. The method according to claim 100, wherein the pharmaceutical preparation has a molar ratio of API to bile salt of 15:1 to 1:

15.

104. The method according to claim 103, wherein the molar ratio is from 5:1 to 1:

5.

105. The method according to claim 99, wherein the penetration enhancer contains a counterion.

106. The method according to claim 105, wherein the pharmaceutical formulation contains 0.025 to 5 wt.% of a counterion.

107. The method according to claim 105, wherein the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:

6.

108. The method according to claim 107, wherein the molar ratio is from 3:1 to 1:

3.

109. The method according to claim 105, wherein the pharmaceutical formulation includes a pH modifier.

110. The method according to any one of claims 99 to 109, wherein the pharmaceutical formulation comprises 0.1 to 5 wt.% of a BCS class III API or a pharmaceutically acceptable salt or solvate thereof.

111. A method for forming a solid dosage form: A process in which a pharmaceutical preparation is poured into a pre-formed mold, wherein the pharmaceutical preparation is: A pharmaceutically effective amount of a Class III active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 10–33 mg / mL and a Log P value of less than 1; A penetration enhancer comprising at least one selected from the group consisting of counterions or pH modifiers, With 1-10 wt.% of a matrix-forming agent; 1-10 wt.% of a structural agent and Processes including; The process of freezing the added pharmaceutical preparation; The process of freeze-drying a frozen pharmaceutical preparation to form a dosage form and A method that includes this.

112. The method according to claim 111, wherein the penetration enhancer contains a counterion.

113. The method according to claim 112, wherein the pharmaceutical formulation contains 0.025 to 5 wt.% of a counterion.

114. The method according to claim 112, wherein the pharmaceutical formulation has a molar ratio of API to counterions of 6:1 to 1:

6.

115. The method according to claim 114, wherein the molar ratio is from 3:1 to 1:

3.

116. The method according to claim 112, wherein the pharmaceutical formulation includes a pH modifier.

117. The method according to any one of claims 101 to 116, wherein the pharmaceutical preparation comprises 0.1 to 5 wt.% of a BCS class III API or a pharmaceutically acceptable salt or solvate thereof.

118. The method according to any one of claims 62 to 117, wherein the matrix-forming agent comprises gelatin, pullulan, starch, or a combination thereof.

119. The method according to claim 118, wherein the gelatin comprises fish gelatin, bovine gelatin, porcine gelatin, or a combination thereof.

120. The method according to claim 119, wherein the gelatin is fish gelatin, and the fish gelatin is high molecular weight fish gelatin.

121. The method according to any one of claims 62 to 120, wherein the structural agent comprises mannitol.

122. A pharmaceutically effective amount of a Class II active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt or solvate thereof, having a solubility of 0.1–1 mg / mL and a Log P value of 1–2.5; An optotoxicity inhibitor comprising at least one selected from the group of surfactants or fatty acids having a hydrophilic-lipophilic balance (HLB) of less than 10; Matrix-forming agent and; Structuring agent and A pharmaceutical composition containing the following:

123. The pharmaceutical composition according to claim 122, wherein the permeation inhibitor contains a fatty acid.

124. The pharmaceutical composition according to claim 123, wherein the pharmaceutical composition contains 0.25 to 0.5 wt.% of fatty acids.

125. The pharmaceutical composition according to claim 122, wherein the pharmaceutical composition has a molar ratio of API to fatty acids of 3:1 to 1:

3.

126. The pharmaceutical composition according to claim 122, wherein the penetration inhibitor comprises a surfactant having an HLB of less than 10.

127. The pharmaceutical composition according to claim 126, wherein the molar ratio of the API to the surfactant is 5:1 to 1:

5.

128. The pharmaceutical composition according to claim 120, further comprising a pH modifier.

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