Method for designing oral pharmaceutical dosage forms based on target PK profile and said dosage forms

Abstract

In some aspects, the present disclosure relates to methods of designing oral pharmaceutical dosage forms, which are formulated and configured to provide any desired efficacy-based pharmacokinetic (PK) profile by optimizing drug concentration-permeability interactions at any time and / or location in the gastrointestinal tract. In other aspects, the present disclosure relates to oral pharmaceutical dosage forms with desired PK profiles, and methods of preparing such oral pharmaceutical dosage forms, such as three-dimensional printing, to release precise amounts of drug (and any functional excipients) at precise times and locations.

Description

[Technical Field]

[0001] In some aspects, the present disclosure relates to methods for designing oral pharmaceutical dosage forms, which are formulated and configured to provide a desired pharmacokinetic (PK) profile. In other aspects, the present disclosure relates to oral pharmaceutical dosage forms having desired pharmacokinetic characteristics, and methods for preparing such oral pharmaceutical dosage forms, e.g., three-dimensional printing. [Background technology]

[0002] The increasing complexity of drug and reagent treatments and mechanisms of action, coupled with the recognition that different patients respond differently to drugs and reagents, has increasingly highlighted the importance of precise in vivo drug delivery to ensure that drugs or reagents reach the desired location at the desired time and in the desired amount, thereby achieving a pharmacokinetic profile that maximizes the efficacy and safety of the drug, drug candidate, or reagent. To achieve a desired therapeutic outcome, some drugs and reagents may require the realization of a drug or reagent pharmacokinetic profile that can only be manufactured with specific formulations that facilitate the production of complex release profiles and / or unique dosing regimens. For all but a select few drugs and reagents, the design of pharmaceutical dosage forms that can achieve these unique pharmacokinetic profiles in individuals can be difficult, as the biopharmaceutical properties of many drugs and reagents preclude the use of traditional modeling and simulation design and testing methods. Furthermore, using traditional tablet or capsule manufacturing methods, it is often impossible to achieve the manufacturing processes necessary to produce these complex release profiles and facilitate the dosing regimens of these unique oral dosage forms.

[0003] All references cited herein, including patent applications and publications, are incorporated by reference in their entirety. Summary of the Invention

[0004] In some aspects, the present disclosure provides a method for designing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form being formulated and configured to provide a desired pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: (a) determining a simulated drug release profile configured to obtain the desired PK profile, wherein the simulated drug release profile includes an amount of the pharmaceutical agent released from the oral pharmaceutical dosage form at a plurality of time points over a predetermined time course, and wherein each time point in the simulated drug release profile is determined based on the amount of the pharmaceutical agent absorbed at that time point, a permeability value of the pharmaceutical agent at a specific gastrointestinal (GI) location associated with that time point (where the oral pharmaceutical dosage form is expected to be present after ingestion), and a volume of fluid in the GI tract in which the pharmaceutical agent is soluble at the desired location associated with that time point; and (b) designing the oral pharmaceutical dosage form to release the pharmaceutical agent based on the simulated drug release profile, thereby designing the oral pharmaceutical dosage form formulated and configured to provide the desired PK profile.

[0005] In some embodiments, the method further comprises determining the amount of drug absorbed from the oral pharmaceutical dosage form at each time point. In some embodiments, the amount of drug absorbed from the oral pharmaceutical dosage form at each time point is based on a drug absorption rate profile, wherein the drug absorption rate profile includes drug uptake rates at multiple time points to obtain a target PK profile. In some embodiments, the amount of drug absorbed from the oral pharmaceutical dosage form is based on Formula IV:

number

[0006] In some embodiments, the method further comprises determining a drug absorption rate profile. In some embodiments, the drug absorption rate profile is based on deconvolution, e.g., mathematical deconvolution, of the target PK profile with the drug treatment profile. In some embodiments, the deconvolution is based on the Laplacian domain, e.g., as shown in Formula I. In some embodiments, the drug absorption rate profile is based on deconvolution of the target PK profile according to Formula I with the drug treatment profile:

number

[0007] In some embodiments, the treatment profile of the pharmaceutical agent comprises the plasma concentration of the pharmaceutical agent at each of a plurality of time points when the pharmaceutical agent is administered parenterally. In some embodiments, the parenteral route is intravenous administration. In some embodiments, the method further comprises deconvolving the target PK profile using the treatment profile of the pharmaceutical agent. In some embodiments, the treatment profile of the pharmaceutical agent is a known profile. In some embodiments, the method further comprises obtaining the treatment profile of the pharmaceutical agent.

[0008] In some embodiments, the method further comprises determining the amount of medicinal agent required at a location in the GI tract from the oral pharmaceutical dosage form at the time point, wherein the amount of medicinal agent required for absorption from the oral pharmaceutical dosage form at the GI tract location at the time point is based on a permeability value of the medicinal agent at a desired location in the (GI) tract associated with the time point and a fluid volume in the GI tract at the location associated with the time point.

[0009] In some embodiments, the method further comprises determining a drug concentration time or position profile. In some embodiments, the drug concentration time or position profile is based on the drug absorption rate profile and the drug permeation rate time or position profile, wherein the drug permeation rate time or position profile includes permeation rate values ​​of the drug at positions in the (GI) tract associated with each of the plurality of time points. In some embodiments, the drug concentration time or position profile is based on Formula II:

number

[0010] In some embodiments, the amount of drug required for absorption from the oral pharmaceutical dosage form at that location in the GI tract at that time is based on a time or location profile of drug concentration and a time or location profile of GI fluid volume. In some embodiments, the amount of drug required at that location in the GI tract from the oral pharmaceutical dosage form is based on Formula III:

number

[0011] In some embodiments, the time or location profile of GI fluid volume is a known profile. In some embodiments, the method further comprises obtaining the time or location profile of GI fluid volume. In some embodiments, the time or location profile of GI fluid volume can reflect the fed or fasted state of the individual when the oral pharmaceutical dosage form is administered.

[0012] In some embodiments, the time or position profile of pharmaceutical agent permeation rate is a known profile. In some embodiments, the method further comprises obtaining the time or position profile of pharmaceutical agent permeation rate.

[0013] In some embodiments, the method further comprises designing an oral pharmaceutical dosage form based on the modulation of pharmaceutical solubility.

[0014] In some embodiments, the method further comprises designing an oral pharmaceutical dosage form based on modulating the time or position profile of pharmaceutical permeation rate.

[0015] In some embodiments, the method further comprises optimizing the simulated drug release profile.

[0016] In some embodiments, the method further comprises determining a cumulative drug release profile based on the simulated drug release profile.

[0017] In some embodiments, the method further comprises obtaining a target PK profile.

[0018] In some embodiments, the AUC of the oral pharmaceutical dosage form dosing regimen versus the reference dosing regimen 0-t The target PK profile has at least a 90% confidence interval that falls within a range of about 80% to about 125% for the ratio of t, where t is based on a predetermined time course. In some embodiments, the AUC 0-t The target PK profile has at least a 90% confidence interval that falls within a range of about 80% to about 125% for the relative mean ratio of t, where t is based on a predetermined time course. In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen is max The target PK profile has at least a 90% confidence interval that falls within a range of about 80% to about 125% for the ratio of the C of the oral pharmaceutical dosage form to the reference dosage regimen. max The target PK profile has at least a 90% confidence interval that falls within a range of about 80% to about 125% for the relative mean ratio of the C of the oral pharmaceutical dosage form to the reference dosage regimen. 24h The target PK profile has at least a 90% confidence interval that falls within a range of about 80% to about 125%, where 24 h is 24 hours after administration of the oral pharmaceutical dosage form. In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen is 24h For the relative mean value of the ratio, the target PK profile has at least a 90% confidence interval that falls within a range of about 80% to about 125%, where 24 h is 24 hours after administration of the oral pharmaceutical dosage form. In some embodiments, the AUC of the target PK profile 0-t , C max and C t is within the accepted threshold of the reference PK profile of the reference dosing regimen, where t is based on a pre-defined time course.

[0019] In some embodiments, the target PK profile is bioequivalent to a reference PK profile of a reference dosing regimen.

[0020] In another aspect, the present specification provides a method for designing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form being formulated and configured to provide a target pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: (a) determining a drug absorption rate profile based on deconvolution of the target PK profile with a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form; (b) determining a drug absorption amount profile based on the drug absorption rate profile; (c) determining a time or position profile of the pharmaceutical agent concentration based on the drug absorption rate profile and a time or position profile of the pharmaceutical agent permeability; and (d) determining a time or position profile of the pharmaceutical agent concentration. (e) determining a simulated drug release time or location profile based on the drug absorption profile and the GI fluid volume time or location profile, configured to obtain a target PK profile, wherein the simulated drug release profile includes an amount of drug released from the oral pharmaceutical dosage form to obtain the target PK profile; and (f) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release drug based on the simulated drug release profile.

[0021] In some embodiments, determining the pharmaceutical absorption rate profile comprises deconvoluting the target PK profile with the pharmaceutical's treatment profile.

[0022] In another aspect, the present specification provides an oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, wherein the oral pharmaceutical dosage form is formulated and configured to release the pharmaceutical agent based on a design obtained from any of the methods described herein.

[0023] In another aspect, the description provides a method for preparing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, the method comprising three-dimensionally (3D) printing the oral pharmaceutical dosage form based on a design of the oral pharmaceutical dosage form obtained from any of the methods described herein.

[0024] In another aspect, the description provides a method for preparing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, the method comprising: (a) determining a drug absorption rate profile based on deconvolution of the desired PK profile with a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form; (b) determining a drug absorption amount profile based on the drug absorption rate profile; (c) determining a drug concentration time or location profile based on the drug absorption rate profile and the drug permeability time or location profile; and (d) determining a drug concentration time or location profile and a GI fluid volume time or location profile. (e) determining a simulated drug release profile configured to obtain a target PK profile based on the drug absorption profile and the GI drug demand profile, wherein the simulated drug release profile comprises an amount of drug to be released from the oral pharmaceutical dosage form to obtain the target PK profile; and (f) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile.

[0025] Those skilled in the art will also appreciate that changes in form and detail of the embodiments described herein may be made without departing from the scope of the present disclosure. Also, while various advantages, aspects, and objectives have been described with reference to various embodiments, the scope of the present disclosure should not be limited by reference to these advantages, aspects, and objectives. [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 illustrates an exemplary workflow of a design method for designing an oral pharmaceutical dosage form formulated and configured to provide a desired pharmacokinetic (PK) profile, as disclosed herein. [Figure 2] FIG. 1 shows the overlay of the PK profile of a reference immediate-release oral pharmaceutical dosage form containing 5 mg Drug A administered twice daily (BID) and the target PK profile of a sustained-release oral pharmaceutical dosage form containing 10 mg Drug A administered once daily. [Figure 3] FIG. 1 illustrates exemplary steps and profiles utilized in deriving a drug absorption rate profile based on information regarding the target PK profile, the drug's treatment profile, and the total amount of drug in an oral pharmaceutical dosage form. [Figure 4] FIG. 1 illustrates exemplary steps and profiles utilized in deriving a drug absorption dose profile from a drug absorption rate profile. [Figure 5A] FIG. 1 illustrates exemplary steps and profiles utilized in deriving a time or position profile of drug concentration based on a drug absorption rate profile and a time or position profile of drug permeability. [Figure 5B] FIG. 10 shows an exemplary pharmaceutical permeation rate time or position profile with associated time and position information. [Figure 6] FIG. 1 illustrates exemplary steps and profiles utilized in deriving a GI drug requirement profile based on a time or location profile of drug concentration and a time or location profile of GI fluid volume. [Figure 7]FIG. 1 shows exemplary cumulative drug release profiles. [Figure 8A-8B] Figures 8A and 8B show the effect of optimizing absorption by techniques on the time or location profile of an exemplary pharmaceutical drug concentration. Figure 8A shows the effect of increasing the solubility of an exemplary pharmaceutical drug. Figure 8B shows the effect of increasing the permeability of an exemplary pharmaceutical drug at different times after administration and the subsequent effect on the concentration profile. DETAILED DESCRIPTION OF THE INVENTION

[0027] In some aspects, the present disclosure provides a method for designing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form being formulated and configured to provide a target pharmacokinetic (PK) profile of a pharmaceutical drug in an individual. The disclosure of the present application is based, at least in part, on the inventors' discoveries and unique insights, which relate to a method for designing an oral pharmaceutical dosage form to provide a desired target PK profile based on physiological gastrointestinal (GI) model simulations. Using the method described herein, an oral pharmaceutical dosage form can be accurately designed with an optimal total drug amount in the oral pharmaceutical dosage form to achieve a desired effect as measured by the target PK profile by accurately calculating the amount of drug released in a specific GI tract segment based on the associated drug absorption in each GI tract segment. The method disclosed herein can achieve the three essential Rs in designing oral pharmaceutical dosage forms, which achieve the desired target PK profile—the right amount, the right time, and the right location—through accurate drug release. Such a method provides a significant advance in the field of oral pharmaceutical dosage form design and enables, for example, accurate, tunable, and rapid formulation design. In addition to other advantages, the design method described herein is suitable for drugs belonging to any Biopharmaceutical Classification System (BCS) drug class because it resolves the interplay between GI location-dependent solubility and permeability, enabling optimization of drug absorption through modifications based on drug solubility and / or permeability. In contrast, the use of known in vitro in vivo correlation (IVIVC) techniques is highly limited to BCS Class II drugs. The ability to design oral pharmaceutical dosage forms by determining the required drug release profile further enables the rapid manufacture of oral pharmaceutical dosage forms that can provide the desired target PK profile using technologies capable of generating precise drug release (e.g., three-dimensional (3D) printing of oral pharmaceutical dosage forms).Such innovative methods, for example, provide a means to conduct preclinical and clinical trial formulation development on a predictable and accelerated timeline.

[0028] Thus, in some aspects, the present specification provides a method for designing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form being formulated and configured to provide a desired pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: (a) determining a simulated drug release profile configured to obtain the desired PK profile, wherein the simulated drug release profile includes an amount of the pharmaceutical agent released from the oral pharmaceutical dosage form at a plurality of time points over a predetermined time course, and wherein each time point in the simulated drug release profile is determined based on the amount of the pharmaceutical agent absorbed at that time point, a permeability value of the pharmaceutical agent at a gastrointestinal (GI) location associated with that time point, and a fluid volume in the GI tract at that location associated with that time point; and (b) designing the oral pharmaceutical dosage form to release the pharmaceutical agent based on the simulated drug release profile, thereby designing the oral pharmaceutical dosage form formulated and configured to provide the desired PK profile.

[0029] In another aspect, the present specification provides a method for designing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form being formulated and configured to provide a target pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: (a) determining a drug absorption rate profile based on mathematical deconvolution of the target PK profile using a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form; (b) determining a drug absorption amount profile based on the drug absorption rate profile; (c) determining a time or position profile of the pharmaceutical agent concentration based on the drug absorption rate profile and a time or position profile of the pharmaceutical agent permeability; and (d) determining a time or position profile of the pharmaceutical agent concentration. (e) determining a simulated drug release profile configured to obtain a target PK profile based on the drug absorption profile and the GI drug demand profile, wherein the simulated drug release profile includes an amount of drug released from the oral pharmaceutical dosage form to obtain the target PK profile; and (f) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release drug based on the simulated drug release profile.

[0030] In another aspect, the present specification provides an oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, wherein the oral pharmaceutical dosage form is formulated and configured to release the pharmaceutical agent based on a design obtained from any of the design methods taught herein.

[0031] In another aspect, the present specification provides an oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, wherein the oral pharmaceutical dosage form is formulated and configured to release the pharmaceutical agent based on a simulated pharmaceutical agent release profile designed to achieve the desired PK profile.

[0032] In another aspect, the description provides a method for preparing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, the method comprising three-dimensionally (3D) printing the oral pharmaceutical dosage form based on a design of the oral pharmaceutical dosage form obtained from any of the design methods described herein.

[0033] In another aspect, the description provides a method for preparing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, the method comprising: (a) determining a drug absorption rate profile based on deconvolution of the desired PK profile with a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form; (b) determining a drug absorption amount profile based on the drug absorption rate profile; (c) determining a drug concentration time or location profile based on the drug absorption rate profile and the drug permeability time or location profile; and (d) determining a drug concentration time or location profile and a GI fluid volume time or location profile. (e) determining a simulated drug release profile configured to obtain a target PK profile based on the drug absorption profile and the GI drug demand profile, wherein the simulated drug release profile comprises an amount of drug to be released from the oral pharmaceutical dosage form to obtain the target PK profile; and (f) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile.

[0034] While most of the content of this application discusses oral pharmaceutical dosage forms containing pharmaceutical agents, those skilled in the art will readily appreciate that the present disclosure is also applicable to and relates to other oral dosage forms, such as dosage forms containing reagents (e.g., oral reagent dosage forms), that are configured and formulated to provide the desired PK profile of any compound.

[0035] Those skilled in the art will also appreciate that changes in form and detail of the embodiments described herein may be made without departing from the scope of the present disclosure. Also, while various advantages, aspects, and objectives have been described with reference to various embodiments, the scope of the present disclosure should not be limited by reference to these advantages, aspects, and objectives.

[0036] I. Definition For the purposes of interpreting this specification, the following definitions apply, and where appropriate, terms used in the singular include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the set forth definition shall control.

[0037] As used herein, the term "individual" refers to a mammal, and includes, but is not limited to, a human, cow, horse, cat, dog, rodent, rat, mouse, canine, or primate. In some embodiments, the individual is a human.

[0038] As used herein, the terms "comprise," "have," "contain," "include," and other similar forms and grammatical equivalents are intended to be semantically equivalent and open-ended, as the item or items following any of these terms do not imply an exhaustive list of such items or are limited to the listed item or items. For example, an article "comprising" components A, B, and C can consist of (i.e., contain only) components A, B, and C, or it may further include not only components A, B, and C, but one or more other components. Thus, "comprise" and its similar forms and grammatical equivalents are intended and understood to include disclosure of embodiments "consisting essentially of" or "consisting of."

[0039] Where a range of values ​​is provided, unless the context clearly dictates otherwise, it is understood that each intervening value (to the tenth of the unit of the lower limit) between the upper and lower limit of the stated range, and any other stated or intervening value within the stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0040] As used herein, references to "about" a value or parameter include (and describe) variations on that value or parameter itself. For example, a statement about "about X" includes a statement of "X."

[0041] As used herein, including in the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0042] II. Methods for Designing Oral Pharmaceutical Dosage Forms In some aspects, the present disclosure provides methods for designing an oral pharmaceutical dosage form, the oral pharmaceutical dosage form being formulated and configured to provide a desired pharmacokinetic (PK) profile for a pharmaceutical product in an individual. In some aspects, the methods herein allow for the design of an oral pharmaceutical dosage form based on a desired PK profile (e.g., designed to be bioequivalent to a reference dosing regimen) and additional information including drug disposition, drug permeability, and fluid volume at a location in the gastrointestinal (GI) tract. In some examples, the additional information including drug disposition, drug permeability, and fluid volume at a location in the GI tract is known, e.g., based on literature values.

[0043] When an oral pharmaceutical dosage form is orally administered, a drug is released from the oral pharmaceutical dosage form as it passes through the GI tract. After release, a portion of the released drug is absorbed, and the remaining portion accompanies the drug and travels downward along the GI tract, continuing downstream. As the oral pharmaceutical dosage form travels downward along the GI tract, the amount of newly released drug and the amount of unabsorbed drug at upstream locations can be used to determine the total amount of drug that can be absorbed from the oral pharmaceutical dosage form at downstream locations in the GI tract. As described herein, drug absorption rate positively correlates with drug concentration in the GI tract (based on the amount of drug at that location within the GI tract and the fluid volume associated with the GI tract) and drug permeability. As described herein, drug absorption in the GI tract can be represented by a drug absorption rate profile. After a drug is absorbed, biological processes affect the drug in vivo, such as drug distribution, metabolism, and excretion. Generally, these biological processes are consistent with the biological processes a drug undergoes in vivo after intravenous injection. The amount of drug remaining in the circulation can be represented by a pharmacokinetic (PK) profile. The methods described herein take into account all of these processes, including specific parameters associated with the processes, and can use the PK profile to determine the amount of drug to be released from the oral pharmaceutical dosage form over time as it travels through the GI tract.

[0044] FIG. 1 illustrates an exemplary workflow for designing an oral pharmaceutical dosage form, which is formulated and configured to provide a target pharmacokinetic (PK) profile as described herein. Briefly, in some embodiments, a simulated drug release and absorption rate profile is determined by processing the target profile using mathematical deconvolution of the drug's treatment profile and the total amount of drug in the oral pharmaceutical dosage form. The simulated drug release and absorption rate profile is then used in calculations performed on two parallel traces to determine a simulated drug release profile. Specifically, one trace involves determining a drug absorption rate profile based on the drug absorption rate profile. The parallel trace involves first determining a time or position profile of drug concentration using the drug absorption rate profile and a time or position profile of drug permeability. The time or position profile of drug concentration and the time or position profile of GI fluid volume are then used to determine a GI drug demand profile (a profile of the amount of soluble drug required for absorption from the oral pharmaceutical dosage form in the GI tract). A simulated drug release profile is then determined based on the drug absorption rate profile and the GI drug demand profile. The mimicked drug release profile allows for the design of oral pharmaceutical dosage forms that are formulated and configured to provide the desired PK profile.

[0045] In some embodiments, the method includes: (a) determining a simulated drug release profile configured to obtain the target PK profile, wherein the simulated drug release profile includes an amount of the drug released from the oral pharmaceutical dosage form at a plurality of time points over a predetermined time course, and wherein each time point in the simulated drug release profile is determined based on the amount of the drug absorbed at that time point, a permeability value of the drug at a gastrointestinal (GI) location associated with that time point, and a fluid volume in the GI tract at the location associated with that time point; and (b) designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile, thereby designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile.

[0046] In some embodiments, a method for designing an oral pharmaceutical dosage form is provided, the oral pharmaceutical dosage form being formulated and configured to provide a target pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: (a) determining a drug absorption rate profile based on deconvolution of the target PK profile with a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form; (b) determining a drug absorption amount profile based on the drug absorption rate profile; (c) determining a time or position profile of the pharmaceutical agent concentration based on the drug absorption rate profile and a time or position profile of the pharmaceutical agent permeability; and (d) determining a time or position profile of the pharmaceutical agent concentration. (e) determining a GI drug demand profile based on the drug absorption profile and the time or location profile of GI fluid volume; (e) determining a simulated drug release profile configured to obtain a target PK profile based on the drug absorption profile and the GI drug demand profile, wherein the simulated drug release profile includes an amount of drug released from the oral pharmaceutical dosage form to obtain the target PK profile; and (f) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile. In some embodiments, determining the drug absorption rate profile includes deconvolving the target PK profile with a treatment profile of the drug. In some embodiments, the method further includes determining a cumulative drug release profile based on the simulated drug release profile.

[0047] In some aspects of the features described herein, the oral pharmaceutical dosage form has a relationship between location and time (e.g., a determined time after administration of the oral pharmaceutical dosage form). In some embodiments, features of the invention, such as profiles, e.g., time or location profiles of drug concentration, can be described in terms of time or location, or both, based on the relationship between time and location as the oral pharmaceutical dosage form travels through the GI tract. In some embodiments, the description herein is directed to one of time or location, and is not intended to exclude that the described relationship between time and location can be used to convert time-based features to position-based features, or vice versa. For example, in some embodiments, the methods use time-based time or location profiles of drug permeability. In some embodiments, the methods use position-based time or location profiles of drug permeability. In some embodiments, the methods use time- and position-based time or location profiles of drug permeability.

[0048] In some embodiments, features of the invention are described as profiles. In some embodiments, a profile includes one or more time- and / or location-based data points. For example, a simulated drug release profile includes information about the amount of drug released from an oral pharmaceutical dosage form and may be time-based (e.g., measured after administration) and / or location-based. Unless otherwise specified, the description of features of the invention in terms of profiles or data points is not intended to be limited to such characterization. As described herein, in some embodiments, based on the relationship between time and location as a function of the time course of an oral pharmaceutical dosage form's travel through the GI tract after administration, a time point can serve as a surrogate for GI location, and vice versa (time zero). In some embodiments, a profile includes time-based data points, where the time points occur at intervals, e.g., regular one-hour intervals. When the data points are time-based, the time interval can be any desired time interval. In some examples, a profile includes location-based data points, for example, data points based on anatomical portions of the GI tract, such as the stomach, duodenum, jejunum, ileum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. Thus, in the description herein, discussion of a time point (and its profile) can include or extend to time and / or location information, and discussion of a location point (and its profile) can include or extend to time and / or location information.

[0049] Some features of the method are described in more detail in the following sections, including determining a simulated drug release profile configured to achieve a target PK profile. The modular discussion of these features is not intended to limit the scope of the methods described herein, and using the teachings herein, various modularly described features can be readily combined to achieve the full scope of the methods herein.

[0050] A. Desired PK Profile In some embodiments, the method includes obtaining (e.g., determining) a target PK profile. The target PK profile includes the plasma concentration of the pharmaceutical agent over time, e.g., the plasma concentration after administration of an oral pharmaceutical dosage form. In some embodiments, the target PK profile may be based on any desired plasma concentration of the pharmaceutical agent as a function of time in an individual, e.g., to improve efficacy, safety, and convenience of administration. For example, in some embodiments, the target PK profile is based on the desired efficacy of the associated pharmaceutical agent, e.g., an efficacy-based target PK profile. The target PK profile may be for any predetermined amount of time. For example, in some embodiments, the target PK profile lasts for a period of about 6 hours to 1 week. In some embodiments, the target PK profile lasts for a period of about 24 hours.

[0051] In some embodiments, the target PK profile is designed based on a reference dosing regimen. In some embodiments, the target PK profile is bioequivalent to a reference PK profile of the reference dosing regimen. In some embodiments, bioequivalence is defined based on bioequivalence regulations, such as those established by the U.S. Food and Drug Administration (FDA). In some embodiments, the target PK profile is based on a reference PK profile, where one or more features of the target PK profile (e.g., AUC or C max ) to a desired level (e.g., a percent decrease or increase compared to a reference PK profile). Techniques for measuring PK curves (e.g., reference PK profiles) of pharmaceuticals are known in the art. See, e.g., Heller et al., Annu Rev Anal Chem, 11, 2018, and Ghandforoush-Sattari et al., J Amino Acids, Document ID 346237, Vol. 2010.

[0052] In some embodiments, the AUC of the oral pharmaceutical dosage form dosing regimen versus the reference dosing regimen 0-t The target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125% for the ratio of t, where t is based on a pre-defined time course.

[0053] In some embodiments, the AUC of the oral pharmaceutical dosage form dosing regimen versus the reference dosing regimen 0-t For the relative mean value of the ratio, the target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125%, where t is based on a predetermined time course.

[0054] In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen max For the ratio, the target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125%.

[0055] In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen max For the relative mean value of the ratio, the target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125%.

[0056] In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen t The target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125% for the ratio of t, where t is based on a pre-defined time course.

[0057] In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen t For the relative mean value of the ratio, the target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125%, where t is based on a predetermined time course.

[0058] In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen 24h The target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125% for the ratio of , where 24 h is 24 hours post-dose.

[0059] In some embodiments, the C between the dosing regimen of the oral pharmaceutical dosage form and the reference dosing regimen 24h For the relative mean value of the ratio, the target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125%, where 24 h is 24 hours post-dose.

[0060] In some embodiments, the AUC of the oral pharmaceutical dosage form dosing regimen versus the reference dosing regimen 0-∞ For the ratio, the target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125%.

[0061] In some embodiments, the AUC of the oral pharmaceutical dosage form dosing regimen versus the reference dosing regimen 0-∞ For the relative mean value of the ratio, the target PK profile has at least a 90% confidence interval that falls within the range of about 80% to about 125%.

[0062] In some embodiments, the AUC of the target PK profile 0-t , C max and C t is within the accepted threshold of the reference PK profile of the reference dosing regimen, where t is based on a pre-defined time course.

[0063] B. Drug Absorption Rate Profile In some embodiments, the method includes obtaining (e.g., determining) a drug absorption rate profile configured to obtain a target PK profile. In some examples, to obtain the target PK profile, the drug absorption rate profile includes, for example, a drug uptake rate over time after administration of an oral pharmaceutical dosage form. The drug absorption rate profile can be any predetermined amount of time. In some examples, the time length of the simulated drug absorption rate profile is based, for example, on a time length consistent with the target PK profile.

[0064] In some embodiments, the drug absorption rate profile is based on deconvolution of a target PK profile according to Formula I with a treatment profile of the drug,

number

[0065] In some embodiments, the drug absorption rate profile is based on deconvolution of the target PK profile with the drug's treatment profile and the total amount of drug in the oral pharmaceutical dosage form.

[0066] In some embodiments, the treatment profile of the pharmaceutical agent comprises the plasma concentration of the pharmaceutical agent over time. In some embodiments, the treatment profile of the pharmaceutical agent reflects the fate of the pharmaceutical agent after absorption from the GI tract. For example, in some embodiments, the treatment profile of the pharmaceutical agent reflects the amount of pharmaceutical agent remaining in plasma as a function of biological processes, such as distribution, metabolism, and excretion. In some embodiments, the treatment profile of the pharmaceutical agent comprises the plasma concentration of the pharmaceutical agent measured over time when the pharmaceutical agent is administered parenterally. In some embodiments, the treatment profile of the pharmaceutical agent comprises the plasma concentration of the pharmaceutical agent at multiple time points when the pharmaceutical agent is administered parenterally. In some embodiments, the parenteral route is intravenous bolus (IV) administration. In some embodiments, the treatment profile of the pharmaceutical agent is a known profile. In some embodiments, the method further comprises obtaining the treatment profile of the pharmaceutical agent, e.g., measuring the plasma concentration of the pharmaceutical agent over time after the pharmaceutical agent is administered IV.

[0067] In some embodiments, the treatment profile of a pharmaceutical agent is obtained after parenteral administration (e.g., IV administration) of a certain amount of the pharmaceutical agent, where the amount of the pharmaceutical agent in the IV formulation is based on the amount of the pharmaceutical agent absorbed from the GI tract when the pharmaceutical agent is administered orally. For example, the known bioavailability of an orally administered pharmaceutical agent can be used to estimate the amount of the pharmaceutical agent absorbed from an oral dosage form containing a certain amount of the pharmaceutical agent, whereby the amount of the pharmaceutical agent administered parenterally approximates and mimics the amount of the pharmaceutical agent absorbed from an orally administered pharmaceutical dosage form. In some embodiments, the amount of the pharmaceutical agent in the IV formulation is bioequivalent to the amount of the pharmaceutical agent in an orally administered pharmaceutical dosage form.

[0068] In some embodiments, the method further comprises deconvolving the target PK profile with the treatment profile of the pharmaceutical agent. Techniques used for deconvolution are known in the art and include Wagner-Nelson methods, numerical methods, and mathematical deconvolution.

[0069] C. Drug Absorption Profile In some embodiments, the method includes obtaining (e.g., determining) a drug absorption profile. In some examples, the drug absorption profile includes the amount of drug absorbed from the oral pharmaceutical dosage form over time. The drug absorption profile can be any predetermined amount of time. In some examples, the time length of the drug absorption profile is based, for example, on a time length consistent with a target PK profile and / or a drug absorption kinetic profile. In some examples, the method includes obtaining (e.g., determining) the amount of drug absorbed from the oral pharmaceutical dosage form at a time point (e.g., a time point after administration).

[0070] In some embodiments, the amount of drug absorbed from the oral pharmaceutical dosage form at a time point is based on a drug absorption rate profile and a time interval. In some embodiments, the amount of drug absorbed from the oral pharmaceutical dosage form is based on Formula IV:

number

[0071] D. Time or location profile of drug concentration and GI drug requirement profile In some embodiments, the method includes obtaining (e.g., determining) an amount of pharmaceutical agent required for absorption from the oral pharmaceutical dosage form at a time and / or location in the GI tract. In some examples, the amount of pharmaceutical agent required for absorption from the oral pharmaceutical dosage form at the time and / or location is based on a permeability value of the pharmaceutical agent at the desired location of the pharmaceutical agent in the GI tract at the time or location, and the fluid volume in the GI tract associated with the time or location. As described herein, oral pharmaceutical dosage forms have a relationship between time and location in the GI tract and can translate information provided based on time and GI tract location measured after administration.

[0072] In some embodiments, determining the amount of drug required for absorption from the oral pharmaceutical dosage form at a time and / or location in the GI tract includes using a time or position profile of drug concentration. As described herein, the amount of drug required for absorption from the oral pharmaceutical dosage form at a time and / or location is based on a portion of the amount of drug released upstream from the oral pharmaceutical dosage form and the amount of drug newly released from the oral pharmaceutical dosage form. In some embodiments, the method includes obtaining (e.g., determining) a time or position profile of drug concentration. The time or position profile of drug concentration is necessary to obtain a drug absorption rate profile, which includes time- and / or position-dependent drug concentration from the oral pharmaceutical dosage form in the GI tract. In the methods described herein, the drug concentration from the oral pharmaceutical dosage form at a location in the GI tract interacts with the permeation rate of the drug at that location. For example, a given absorption rate profile can have various concentration-permeation rate combinations. In some embodiments, the time or position profile of drug concentration is a time or position profile of drug concentration selected, for example, based on permeation rate. The time or position profile of drug concentration can be any predetermined amount of time. In some embodiments, the time length of the drug concentration time or location profile is based on, for example, a time length consistent with a target PK profile and / or a drug absorption rate profile and / or a drug absorption dose profile. In some embodiments, the drug concentration time or location profile includes time post-administration based drug concentration information or location-based drug concentration information in the GI tract. In some embodiments, the drug concentration time or location profile includes time and location-based concentration information in the GI tract.

[0073] In some embodiments, the drug concentration time or position profile is based on a drug absorption rate profile and a drug permeability time or position profile. In some embodiments, the drug permeability time or position profile includes permeability values ​​at the drug's locations (e.g., relevant time points) in the GI tract. In some embodiments, the drug concentration or position profile is based on Equation II:

number

[0074] In some embodiments, the time or position profile of drug permeability is a known profile, e.g., based on known literature profiles. In some embodiments, the method further includes obtaining the time or position profile of drug permeability, e.g., via drug absorption studies in the GI tract region. In some embodiments, the permeability values ​​of the time or position profile of drug permeability indicate the intestinal surface area of ​​the GI tract region associated with the permeability value.

[0075] In some embodiments, the method includes obtaining (e.g., determining) an amount of drug required for absorption from the oral pharmaceutical dosage form at a location in the GI tract and / or absorption at a time point based on a drug concentration time or position profile. In some examples, the absorption from the oral pharmaceutical dosage form at a location in the GI tract, e.g., the amount of drug required for absorption at a time point, is based on a drug concentration time or position profile and a GI fluid volume time or position profile. In some examples, the amount of drug required for absorption at a location in the GI tract and / or at a time point after administration is represented by a GI drug demand profile. In some examples, the GI drug demand profile, or the amount of drug required for absorption at a location in the GI tract and / or at a time point from the oral pharmaceutical dosage form, is based on Formula III:

number

[0076] In some embodiments, the time or position profile of GI liquid volume is a known profile. In some embodiments, the method includes obtaining the time or position profile of GI liquid volume. In some embodiments, the time or position profile of GI liquid volume reflects the state or condition of an individual. For example, in some embodiments, the time or position profile of GI liquid volume can reflect a food state, e.g., the fed or fasted state of an individual, when the oral pharmaceutical dosage form is administered.

[0077] E. Simulated Drug Release Profiles and Cumulative Drug Release Profiles In some embodiments, the method includes obtaining (e.g., determining) a simulated drug release profile and / or a simulated cumulative drug release profile. The simulated drug release profile and simulated cumulative drug release profile are based on the amount of drug released from the oral pharmaceutical dosage form over time and may be related to a location in the GI tract, as described herein. Specifically, in some embodiments, the simulated drug release profile is based on the amount of drug released from the oral pharmaceutical dosage form at a given time, and the simulated cumulative drug release profile is based on the cumulative amount of drug released from the oral pharmaceutical dosage form at a given time.

[0078] In some embodiments, a simulated drug release profile is determined based on the drug absorption profile and the GI drug demand profile. In some embodiments, the simulated drug release profile is determined using Formula V, which is:

number

[0079] In some examples, Formula VI is used to determine the simulated cumulative drug release profile. Formula VI is:

number

[0080] In some examples, Formula VII is used to determine a simulated cumulative drug release profile. Formula VII is:

number

[0081] F. Methods for Optimizing Absorption In some aspects, the present disclosure provides techniques for optimizing absorption that can be used in combination with the design methods and oral pharmaceutical dosage forms described herein. In some embodiments, the optimization techniques include adjusting the permeability of the pharmaceutical agent. In some embodiments, the optimization techniques include adjusting the solubility of the pharmaceutical agent. In some embodiments, the optimization techniques include adjusting the release of the pharmaceutical agent based on time and / or location in the GI tract.

[0082] In some examples, a time or location profile of drug concentration, based on data obtained from artificially simulated conditions using, for example, gastric, intestinal, or colonic fluids, indicates that the drug concentration in the GI tract required to achieve the target PK profile exceeds the drug solubility. See FIG. 8A. In some examples, if the drug concentration in the GI tract required to achieve a desired absorption rate profile exceeds the drug solubility, the drug solubility may be adjusted, e.g., increased. In some examples, the drug solubility is adjusted (e.g., increased) by using a different form and / or formulation of the drug (e.g., an amorphous solid dispersion (ASD) of the drug). In some examples, the drug solubility is adjusted (e.g., increased) by using a solubility enhancer, e.g., an excipient. In some examples, the solubility enhancer is included in the oral pharmaceutical dosage form. In some examples, the solubility enhancer is released from the oral pharmaceutical dosage form in a controlled manner (e.g., in a controlled amount at a controlled location).

[0083] In some embodiments, the time or location profile of drug concentration may be adjusted to account for the indicated consistency between drug concentration and drug solubility required to achieve the desired PK profile in the GI tract. In some embodiments, the permeability of the drug may also be adjusted to adjust the absorption rate, with or without adjusting the drug concentration. As described herein, in the provided methods, the drug concentration from the oral pharmaceutical dosage form at a location in the GI tract and the permeability of the drug at that location interact. In some embodiments, the permeability of the drug may be enhanced to adjust the time or location profile of the drug concentration. In some embodiments, the permeability of the drug is adjusted by inhibiting an efflux pump, e.g., by using an efflux pump inhibitor (e.g., a P-gp inhibitor). In some embodiments, the permeability of the drug is adjusted by enhancing drug permeation, e.g., by using a permeability enhancer. In some embodiments, an efflux pump inhibitor and / or a permeability enhancer is included in the oral pharmaceutical dosage form. In some embodiments, the efflux pump inhibitor and / or permeability enhancer is released from the oral pharmaceutical dosage form in a controlled manner (e.g., in a controlled amount at a controlled location).

[0084] Adjusting the drug permeability values ​​can alter the time or location profile of drug concentration, as shown in Figure 8B. Figure 8B shows the effect on the time or location profile of drug concentration when (a) the permeability value from 0 to 24 hours post-dose is 1.4 times the original permeability value, (b) the permeability value from 3 (jejunum) to 24 hours post-dose is 1.4 times the original permeability value, (c) the permeability value from 8 (colon) to 24 hours post-dose is 1.4 times the original permeability value, and (d) the permeability value from 8 (colon) to 24 hours post-dose is 1.8 times the original permeability value.

[0085] In some embodiments, the oral pharmaceutical dosage form is GIT (t / x), where Q GIT(t / x) is the amount of drug required for absorption from the oral pharmaceutical dosage form as a function of location and / or time. In some embodiments, optimization of drug release from the oral pharmaceutical dosage form as a function of time and location at which the drug is released from the oral pharmaceutical dosage form is based on improving drug permeability and / or drug solubility and the interaction therebetween.

[0086] In some embodiments, the methods described herein employ one or more optimization techniques, for example, in some embodiments, modulating any one or more of the solubility, permeability, and release of a pharmaceutical agent.

[0087] In some embodiments, these methods involve selecting an optimized design for an oral pharmaceutical dosage form that is formulated and configured to provide a desired PK profile for the pharmaceutical agent in an individual.

[0088] G. Exemplary Methods for Designing Oral Pharmaceutical Dosage Forms In some embodiments, a method for designing an oral pharmaceutical dosage form is provided, the oral pharmaceutical dosage form being formulated and configured to provide a target pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: (a) determining a drug absorption rate profile based on deconvolution of the target PK profile with a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form; (b) determining a drug absorption amount profile based on the drug absorption rate profile; (c) determining a time or location profile of the pharmaceutical agent concentration based on the simulated drug absorption rate profile and the time or location profile of the pharmaceutical agent permeability; and (d) determining a time or location profile of the pharmaceutical agent concentration. (e) determining a simulated drug release profile based on the drug absorption profile and the GI drug demand profile, configured to obtain a target PK profile, wherein the simulated drug release profile includes an amount of drug released from the oral pharmaceutical dosage form to obtain the target PK profile; and (f) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile. In some embodiments, determining the drug absorption rate profile includes deconvolving the target PK profile with a treatment profile of the drug. In some embodiments, the method further includes determining a cumulative drug release profile based on the simulated drug release profile.

[0089] In some embodiments, a method for designing an oral pharmaceutical dosage form is provided, the oral pharmaceutical dosage form being formulated and configured to provide a desired pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: designing the oral pharmaceutical dosage form by releasing the pharmaceutical agent based on a simulated drug release profile, thereby designing the oral pharmaceutical dosage form formulated and configured to provide the desired PK profile. In some embodiments, the method comprises determining a drug absorption rate profile based on deconvolution of the desired PK profile using a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form. In some embodiments, the method comprises determining a drug absorption amount profile based on the drug absorption rate profile. In some embodiments, the method comprises determining a time or position profile of drug concentration based on the simulated drug absorption rate profile and a time or position profile of drug permeability. In some embodiments, the method comprises determining a GI drug demand profile based on the time or position profile of drug concentration and a time or position profile of GI fluid volume. In some embodiments, the method includes determining a simulated drug release profile configured to obtain a target PK profile based on the drug absorption profile and the GI drug demand profile, wherein the simulated drug release profile includes an amount of drug released from the oral pharmaceutical dosage form to obtain the target PK profile. In some embodiments, determining the drug absorption rate profile includes deconvolving the target PK profile with a treatment profile of the drug. In some embodiments, the method further includes determining an estimated drug release profile based on the simulated drug release profile.

[0090] In some embodiments, a method for designing an oral pharmaceutical dosage form is provided, the oral pharmaceutical dosage form being formulated and configured to provide a target pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the method comprising: (a) generating a drug absorption rate profile of the pharmaceutical agent in the gastrointestinal (GI) tract based on mathematical deconvolution of the target PK profile to remove therefrom a treatment profile of the pharmaceutical agent (e.g., a treatment profile based on the PK profile of the pharmaceutical agent after intravenous bolus administration of the pharmaceutical agent); and (b) simulating drug concentration-permeability interactions as a function of time and / or location to generate a combination of drug concentration and permeability that satisfies the drug absorption rate profile. (c) determining a GI drug demand profile based on the drug concentration and permeability combinations that satisfy the drug absorption rate profile, the drug concentration time or location profile, and the GI fluid volume time or location profile, and (d) designing an oral pharmaceutical dosage form formulated and configured to provide a target PK profile for the drug in the individual by determining a cumulative drug release profile based on the GI drug demand profile. In some embodiments, the method further includes designing a multi-compartment oral pharmaceutical dosage form to release the drug (and any functional excipients, if desired) based on the cumulative drug release profile. In some embodiments, an optimization strategy is performed on the undesirable drug concentration and permeability value combinations to generate a drug concentration and permeability combination that satisfies the drug absorption rate profile. In some embodiments, the optimization strategy includes modulating (e.g., increasing) dissolution kinetics, modulating (e.g., enhancing) apparent permeability, or modulating (e.g., inhibiting) drug degradation, or any combination thereof. In some embodiments, the pharmaceutical agent is an ionizable pharmaceutical agent, for example, a weak acid or a weak base in the GI physiological pH range.In some embodiments, for ionizable pharmaceuticals, the total solubility is the sum of the solubilities of the ionized and non-ionized species balanced by the pH-pKa relationship (Henderson-Hasselbalch equation), where the non-ionized species has a much greater permeability than the ionized species of the pharmaceutical. In some embodiments, the pharmaceutical is a non-ionized pharmaceutical. In some embodiments, the pharmaceutical is a non-ionized pharmaceutical, where the total solubility is based on the non-ionized molecule. In some embodiments, the apparent permeability or net permeability may include a negative efflux pump effect. In some embodiments, the use of efflux inhibitors can improve the apparent permeability. In some embodiments, the method further includes conducting in vitro testing (e.g., by drug release studies in biorelevant media, e.g., simulating gastric and / or intestinal fluids) to optimize the oral pharmaceutical dosage form.

[0091] III. Oral Pharmaceutical Dosage Forms In some aspects, the present disclosure provides oral pharmaceutical dosage forms formulated and configured to have a desired pharmacokinetic (PK) profile for a pharmaceutical agent. In some embodiments, the present disclosure provides oral pharmaceutical dosage forms comprising a pharmaceutical agent formulated and configured to have a desired PK profile, wherein the oral pharmaceutical dosage form is formulated and configured to release the pharmaceutical agent based on a simulated pharmaceutical agent release profile to achieve the desired PK profile.

[0092] In some embodiments, an oral pharmaceutical dosage form is provided that includes a pharmaceutical agent formulated and configured to have a desired PK profile, wherein the oral pharmaceutical dosage form is formulated and configured to release the pharmaceutical agent based on a design obtained from any of the methods described herein.

[0093] In some embodiments, an oral pharmaceutical dosage form is provided that includes a pharmaceutical agent formulated and configured to have a target PK profile, wherein the oral pharmaceutical dosage form is prepared by: (a) determining a drug absorption rate profile based on deconvolution of the target PK profile with a treatment profile of the pharmaceutical agent and a total amount of the pharmaceutical agent in the oral pharmaceutical dosage form; (b) determining a drug absorption amount profile based on the drug absorption rate profile; (c) determining a drug concentration time or location profile based on the drug absorption rate profile and the drug permeability time or location profile; and (d) determining a drug concentration time or location profile and a GI fluid volume time or location profile. (e) determining a simulated drug release profile configured to obtain a desired PK profile based on the drug absorption profile and the GI drug demand profile, wherein the simulated drug release profile includes an amount of drug to be released from the oral pharmaceutical dosage form to obtain the desired PK profile; and (f) designing an oral pharmaceutical dosage form formulated and configured to provide the desired PK profile by designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile.

[0094] Oral pharmaceutical dosage forms according to the present disclosure may be of any design formulated and configured to release a pharmaceutical agent according to a simulated drug release profile, the simulated drug release profile configured to achieve a target PK profile. In some embodiments, the oral pharmaceutical dosage form releases a pharmaceutical agent based on diffusion of the pharmaceutical agent from a material containing the pharmaceutical agent. In some embodiments, the oral pharmaceutical dosage form releases a pharmaceutical agent based on erosion of an erodible material containing the pharmaceutical agent. In some embodiments, the oral pharmaceutical dosage form comprises a multi-layer structure comprising multiple layers of a first erodible material intermixed with the pharmaceutical agent. An example of an oral pharmaceutical dosage form based on erosion is described in U.S. Pat. No. 10,350,822, which is incorporated herein by reference in its entirety. In some embodiments, the oral pharmaceutical dosage form is configured to release the pharmaceutical agent from a compartment. In some embodiments, the contents of the compartment are exposed to the external environment by opening and / or rupturing the compartment. Examples of compartment-based oral pharmaceutical dosage forms are described in U.S. Pat. Nos. 10,143,626 and 10,363,220 and WO 2018137686, which are incorporated herein by reference in their entireties.

[0095] Using the disclosures herein, oral pharmaceutical dosage forms can be designed and produced to achieve any desired PK profile. In some embodiments, the oral pharmaceutical dosage form includes multiple compartments designed to achieve a complex desired PK profile. For example, in some embodiments, the multi-compartment oral pharmaceutical dosage form is configured to release a pharmaceutical agent (and optionally, any functional excipients) based on a simulated release profile. In some embodiments, the compartments include a pharmaceutical agent. In some embodiments, the compartments include an excipient, e.g., a functional excipient. In some embodiments, the compartments include a pharmaceutical agent and an excipient, e.g., a functional excipient. In some embodiments, each compartment of the multi-compartment oral pharmaceutical dosage form can release its contents, e.g., a pharmaceutical agent, at a desired time and / or at a desired rate after administration. In some embodiments, the compartments of the multi-compartment oral pharmaceutical dosage form are coordinated to release their contents in a coordinated manner, thereby achieving the desired PK profile.

[0096] The pharmaceutical dosage forms of the present invention may be of any size, shape, or weight suitable for oral administration to a particular individual, e.g., a child or an adult. In some embodiments, the size, shape, or weight of the oral pharmaceutical dosage form is selected based on an attribute of the individual to whom the oral pharmaceutical dosage form is to be administered. In some embodiments, the attribute of the individual is one or more of body length, weight, age, or biochemical parameters. In some embodiments, the shape of the oral pharmaceutical dosage form includes a cylindrical, oval, bullet, arrow, triangle, arc-triangle, square, arc-square, rectangle, arc-rectangle, diamond, pentagon, hexagon, octagon, half-moon, almond, or combinations thereof. In some embodiments, the size and shape of the oral pharmaceutical dosage form are suitable for oral administration to an individual.

[0097] In some embodiments, the oral pharmaceutical dosage form has a cross-sectional size, e.g., measured across the exterior surface of the oral pharmaceutical dosage form (e.g., the largest cross-sectional size across the surface of the oral pharmaceutical dosage form), that is less than about 22 mm, e.g., less than any one of about 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the pharmaceutical dosage form has a cross-sectional size, e.g., measured across the exterior surface of the oral pharmaceutical dosage form (e.g., the maximum cross-sectional size across the surface of the oral pharmaceutical dosage form), that is between about 1 mm and about 22 mm, e.g., any one of about 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, or 2 mm.

[0098] In some embodiments, the thickness of the oral pharmaceutical dosage form is about 1 mm to about 25 mm, e.g., about 2 mm to about 10 mm, about 5 mm to about 12 mm, about 8 mm to about 15 mm, about 5 mm to about 10 mm, or about 7 mm to about 9 mm. In some embodiments, the thickness of the dosage unit is less than about 25 mm, e.g., less than about 24 mm, 23 mm, 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, or 1 mm. In some embodiments, the thickness of the oral pharmaceutical dosage form is greater than about 1 mm, for example, greater than about any one of 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm. In some embodiments, the thickness of the oral pharmaceutical dosage form is greater than about any one of 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, or 25 mm.

[0099] In some embodiments, the oral pharmaceutical dosage form contains a metered amount of pharmaceutical agent ranging from about 2000 mg to about 0.01 mg. In some embodiments, the oral pharmaceutical dosage form comprises an amount of pharmaceutical agent that is less than about 2000 mg, for example, less than any one of about 1900 mg, 1800 mg, 1700 mg, 1600 mg, 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 75 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, 0.25 mg, or 0.1 mg. In some embodiments, the oral pharmaceutical dosage form comprises an amount of pharmaceutical agent of about any one of about 2000 mg, 1900 mg, 1800 mg, 1700 mg, 1600 mg, 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, 900 mg, 800 mg, 700 mg, 600 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 75 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.75 mg, 0.5 mg, 0.25 mg, or 0.1 mg.

[0100] In some embodiments, the total weight of the oral pharmaceutical dosage form is from about 50 mg to about 2500 mg, for example, from about 50 mg to about 150 mg, from about 150 mg to about 250 mg, from about 250 mg to about 350 mg, from about 350 mg to about 450 mg, from about 450 mg to about 550 mg, from about 550 mg to about 650 mg, from about 650 mg to about 750 mg, from about 750 mg to about 850 mg, from about 850 mg to about 950 mg, from about 950 mg to about 1050 mg, from about 1050 mg to about 1150 mg, from about 1150 mg to about 1250 mg. 50 mg, about 1250 mg to about 1350 mg, about 1350 mg to about 1450 mg, about 1450 mg to about 1550 mg, about 1550 mg to about 1650 mg, about 1650 mg to about 1750 mg, about 1750 mg to about 1850 mg, about 1850 mg to about 1950 mg, about 1950 mg to about 2050 mg, about 2050 mg to about 2150 mg, about 2150 mg to about 2250 mg, about 2250 mg to about 2350 mg, or about 2350 mg to about 2450 mg. In some embodiments, the total weight of the oral pharmaceutical dosage form is at least about 50 mg, for example, at least about any one of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, or 2500 mg. In some embodiments, the total weight of the oral pharmaceutical dosage form is less than about 2500 mg, for example, less than any one of about 2400 mg, 2300 mg, 2200 mg, 2100 mg, 2000 mg, 1900 mg, 1800 mg, 1700 mg, 1600 mg, 1500 mg, 1400 mg, 1300 mg, 1200 mg, 1100 mg, 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, or 50 mg.

[0101] In some embodiments, the oral pharmaceutical dosage form comprises multiple pharmaceutical agents. In some embodiments, when the oral pharmaceutical dosage form comprises multiple pharmaceutical agents, the oral pharmaceutical dosage form is formulated and configured to provide a desired PK profile for each pharmaceutical agent.

[0102] In some embodiments, the oral pharmaceutical dosage form further comprises another agent, such as any one or more of a solubility enhancer, a permeability enhancer, an efflux pump inhibitor, or an agent that stabilizes the pharmaceutical agent in the GI tract. In some embodiments, the oral pharmaceutical dosage form is configured and formulated to controllably release the other agent (e.g., in a controlled amount and at a controlled location). In some embodiments, the other agent is mixed with the pharmaceutical agent in the oral pharmaceutical dosage form. In some embodiments, the other agent is contained separately from the pharmaceutical agent in the oral pharmaceutical dosage form, for example, in a separate compartment.

[0103] IV. Methods for Preparing Oral Pharmaceutical Dosage Forms In some aspects, the present disclosure provides methods for manufacturing, e.g., three-dimensional (3D) printing, oral pharmaceutical dosage forms designed by the methods described herein. In some examples, the oral pharmaceutical dosage forms are configured and formulated to release a drug based on a simulated drug release profile, where the simulated drug release profile is designed to achieve a target PK profile.

[0104] In some embodiments, a method for manufacturing an oral pharmaceutical dosage form is provided, the method comprising printing the oral pharmaceutical dosage form, wherein the oral pharmaceutical dosage form is designed to provide a target pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the design method comprising: (a) determining a simulated drug release profile configured to obtain the target PK profile, wherein the simulated drug release profile includes an amount of the pharmaceutical agent released from the oral pharmaceutical dosage form at a plurality of time points over a predetermined time course, and wherein each time point in the simulated drug release profile is determined based on the amount of the pharmaceutical agent absorbed at that time point, a permeability value of the pharmaceutical agent at a gastrointestinal (GI) location associated with that time point, and a fluid volume in the GI tract at the location associated with that time point; and (b) designing the oral pharmaceutical dosage form to release the pharmaceutical agent based on the simulated drug release profile, thereby designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile.

[0105] In some embodiments, a method for manufacturing an oral pharmaceutical dosage form is provided, the oral pharmaceutical dosage form configured and formulated to provide a target PK profile of a pharmaceutical drug in an individual, the method comprising: (a) determining a simulated drug release profile configured to obtain the target PK profile, wherein the simulated drug release profile includes an amount of the pharmaceutical drug released from the oral pharmaceutical dosage form at a plurality of time points over a predetermined time course, and wherein each time point in the simulated drug release profile is determined based on the amount of the pharmaceutical drug absorbed at that time point, a permeability value of the pharmaceutical drug at a gastrointestinal (GI) location associated with that time point, and a fluid volume in the GI tract at the location associated with that time point; and (b) designing the oral pharmaceutical dosage form, wherein the oral pharmaceutical dosage form is formulated and configured to provide the target PK profile, by designing the oral pharmaceutical dosage form to release the pharmaceutical drug based on the simulated drug release profile; and printing the oral pharmaceutical dosage form based on the design of the oral pharmaceutical dosage form.

[0106] In some embodiments, the method comprises 3D printing an oral pharmaceutical dosage form described herein.

[0107] As used herein, "printing," "three-dimensional printing," "3D printing," "additive manufacturing," or their equivalents refer to the process of using a digital design to fabricate a three-dimensional object (e.g., a pharmaceutical dosage form) layer by layer. The basic process of three-dimensional printing is described in U.S. Patent Nos. 5,204,055, 5,260,009, 5,340,656, 5,387,380, 5,503,785, and 5,633,021. Other U.S. patents and patent applications related to three-dimensional printing include U.S. Patent Nos. 5,490,962, 5,518,690, 5,869,170, 6,530,958, 6,280,771, 6,514,518, 6,471,992, and 8,828,411, and U.S. Publication Nos. 2002 / 0015728, 2002 / 0106412, 2003 / 0143268, 2003 / 0198677, and 2004 / 0005360, the contents of which are incorporated by reference in their entirety.

[0108] In some embodiments, additive manufacturing techniques are used to manufacture the oral pharmaceutical dosage forms described herein. In some embodiments, layer-by-layer techniques are used to manufacture the oral pharmaceutical dosage forms described herein.

[0109] Various 3D printing methods have been developed for pharmaceutical dosage form manufacturing in terms of raw materials, equipment, and solidification. These 3D printing methods include binder deposition (Gibson et al., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing, 2nd ed. Springer, New York, 2015; Katstra et al., Oral dosage forms fabricated by three dimensional printing, J Control Release, 66, 2000; Katstra et al., Fabrication of complex oral delivery forms by three dimensional printing, Dissertation in Materials Science and Engineering, Massachusetts Institute of Technology, 2001; Lipson et al., Fabricated: The New World of 3D printing, John Wiley & Sons, 2001). Sons, Inc.), 2013; Jonathan, Karim, 3D printing in pharmaceutics: a new tool for designing customized drug delivery systems, Int J Pharm, 499, 2016), material jetting (Jonathan, Karim, 3D printing in pharmaceutics: a new tool for designing customized drug delivery systems, Int J Pharm, 499, 2016), extrusion (Gibson et al., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Additive manufacturing techniques: 3D printing, rapid prototyping and direct digital manufacturing, 2nd ed. Springer, New York, 2015), and photopolymerization (see Melchels et al., A review on stereolithography and its application in biomedical engineering, Biomaterials, 31, 2010).

[0110] In some embodiments, the oral pharmaceutical dosage forms described herein are 3D printed using an extrusion method. In some embodiments, the 3D printing method includes using a twin-screw extrusion method. In the extrusion process, material is extruded from a robotically actuated print head through a print nozzle. Unlike binder deposition, which requires a powder bed, extrusion methods can print on any substrate. A variety of materials can be extruded for three-dimensional printing, including the thermoplastic materials disclosed herein, pastes and colloidal suspensions, silicones, and other semi-solids. One common extrusion printing type is fused deposition modeling, which uses solid polymer filaments for printing. In fused deposition modeling, a gear system delivers the filament to a heated nozzle assembly for extrusion (see Gibson et al., Additive Manufacturing Technologies: 3D Printing, Rapid Prototyping, and Direct Digital Manufacturing, 2nd ed. Springer, New York, 2015).

[0111] In some embodiments, the 3D printing methods described herein include continuous feed methods.

[0112] In some embodiments, the 3D printing methods described herein include batch feeding methods.

[0113] In some embodiments, the 3D printing is performed by fused deposition modeling (FDM). In some embodiments, the 3D printing is performed by non-filament FDM. In some embodiments, the 3D printing is performed by melt extrusion deposition (MED). In some embodiments, the 3D printing is performed by inkjet printing. In some embodiments, the 3D printing is performed by selective laser sintering (SLS). In some embodiments, the 3D printing is performed by stereolithography (SLA or SL). In some embodiments, 3D printing is performed by PolyJet, MultiJet Printing Systems (MJP), Perfactory, Solid Object Ultraviolet Laser Printers, Bioplotter, 3D Bioprinting, Rapid Freeze Prototyping, Tabletop Systems, Selective Deposition Laser (SDL), Laminated Object Manufacturing (LOM), Ultrasonic Consolidation, Color Jet Printing (CJP), EOSINT Systems, Laser Engineered Net Shaping (LENS) and Aerosol Jetting Systems, Electron Beam Melting (EBM), Laser Cusing®, Selective Laser Melting (SLM), Phoenix PX™ Series, Micro-Sintering, Direct Part Marking (DPM), or VX Systems.

[0114] In some embodiments, the three-dimensional printing is performed by a 3D printing technique, such as hot melt extrusion in combination with FDM.

[0115] In some embodiments, three-dimensional printing is performed by melt extrusion deposition (MED). In some embodiments, melt extrusion deposition techniques involve preparing the materials to be dispensed, e.g., preparing a powder in a hot melt extruder, and feeding the materials into a MED print head. The MED print head then dispenses the materials to form the delayed-release oral pharmaceutical dosage form in a layer-by-layer manner (deposited layer by layer). In some embodiments, each component of the pharmaceutical dosage form, e.g., the first component and the swellable component, is dispensed by a different MED print head. In some embodiments, the MED print head dispenses the materials according to instructions compiled into one or more gcode files. Exemplary MED techniques are disclosed, for example, in WO 2019 / 137333, WO 2018137686, and U.S. Pat. No. 10,201,503, each of which is incorporated herein by reference in its entirety.

[0116] In some examples, the methods of manufacturing oral pharmaceutical dosage forms described herein include 3D printing techniques, for example, 3D printing in combination with another method, for example, a combination of injection molding and 3D printing.

[0117] Method instructions for 3D printing the pharmaceutical dosage forms disclosed herein can be generated in a variety of ways, including direct coding, derivation from a solid CAD model, or other means inherent to the 3D printer's computer interface and application software. These instructions may include information regarding the number and spatial location of droplets, as well as general 3D printing parameters (e.g., droplet spacing in each linear dimension (X, Y, Z), and fluid volume or mass per droplet). For a given material set, these parameters can be adjusted to improve the quality of the resulting structure. The overall resolution of the resulting structure is a function of powder particle size, droplet size, printing parameters, and material properties.

[0118] 3D printing is highly suitable for the production of oral pharmaceutical dosage forms with complex geometries and compositions according to the present invention, as it can process an array of pharmaceutical materials and locally control their composition and structure.

[0119] The oral pharmaceutical dosage forms and components thereof described herein can be printed on a commercial scale. For example, in some embodiments, the methods disclosed herein can be used to 3D print oral pharmaceutical dosage forms at reasonable commercial prices.

[0120] Producing pharmaceutical dosage forms using 3D printing methods is also advantageous for personalized medicine, which involves stratifying patient populations based on biomarkers to aid in treatment decisions and individualized dosage form design. It is easier to modify digital designs than physical devices. Furthermore, the operational costs of automated, small-scale 3D printing are negligible. Therefore, 3D printing can make multiple, small, personalized batches economically feasible, enabling personalized dosage forms with the goal of improving patient compliance.

[0121] Personalized pharmaceutical dosage forms allow for tailoring the amount of medication delivered depending on the patient's height, weight, biochemical parameters, genetics, or metabolism, and any combination thereof. 3D printed dosage forms can ensure accurate dosing for growing children or enable highly efficient personalized dosing of medications. Personalized dosage forms can also improve patient adherence and compliance with medications by consolidating all of a patient's medications into a single daily dose.

[0122] In some embodiments, a method for 3D printing includes designing an oral pharmaceutical dosage form described herein based on a simulated drug release profile configured to achieve a target PK profile, and printing the designed oral pharmaceutical dosage form. In some embodiments, the method includes inputting parameters of the simulated drug release profile and / or the oral pharmaceutical dosage form into a computer system. In some embodiments, the method includes providing one or more parameters to be printed, such as layer surface area, thickness, drug mass fraction, erosion rate, compartment size, and compartment release time. In some embodiments, the method includes creating a virtual image of the oral pharmaceutical dosage form to be printed. In some embodiments, the method includes creating a computer model including pre-determined parameters. In some embodiments, the method includes providing the pre-determined parameters to a 3D printer and printing an article based on such pre-determined parameters. In some embodiments, the method includes creating a 3D drawing of the article to be printed based on the pre-determined parameters, wherein the 3D drawing is created in a computer system. In some embodiments, the method includes converting (e.g., slicing) the 3D drawing into 3D printing code, such as G-code. In some embodiments, the method includes printing according to the methods described herein by executing 3D printing code using a computer system.

[0123] Those skilled in the art will recognize that several implementations are possible within the scope and spirit of the present disclosure. The present disclosure is further illustrated by the following examples, which should not be construed as limiting the scope or spirit of the disclosure to the specific processes described therein.

[0124] In some embodiments, a method for manufacturing an oral pharmaceutical dosage form is provided, the method comprising printing the oral pharmaceutical dosage form, wherein the oral pharmaceutical dosage form is designed to provide a target pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, the design method comprising: (a) generating a drug absorption rate profile of the pharmaceutical agent in the gastrointestinal (GI) tract based on mathematical deconvolution of the target PK profile and removing therefrom a treatment profile of the pharmaceutical agent (e.g., a treatment profile based on the PK profile of the pharmaceutical agent after intravenous bolus administration of the pharmaceutical agent); and (b) simulating drug concentration-permeability interactions as a function of time and / or location to identify a combination of drug concentration and permeability that satisfies the drug absorption rate profile, wherein the drug concentration (c) identifying combinations of drug concentration and permeability values ​​as technically feasible or undesirable; (d) determining a GI drug demand profile based on the drug concentration and permeability combinations that satisfy the drug absorption rate profile, the drug concentration time or location profile, and the GI fluid volume time or location profile, (e) designing an oral pharmaceutical dosage form formulated and configured to provide a target PK profile for the drug in the individual by determining a cumulative drug release profile based on the GI drug demand profile; and (f) designing the oral pharmaceutical dosage form based on the cumulative drug release profile, wherein the manufacturing method includes printing the designed oral pharmaceutical dosage form. In some embodiments, the oral pharmaceutical dosage form is a multi-compartment oral pharmaceutical dosage form configured to release the drug (and optional functional excipients, if desired) based on the cumulative drug release profile. In some embodiments, an optimization strategy is performed on the undesirable drug concentration and permeability value combinations to generate drug concentration and permeability combinations that satisfy the drug absorption rate profile. In some examples, the optimization strategy involves modulating (e.g., increasing) dissolution kinetics, modulating (e.g., enhancing) apparent permeability, or modulating (e.g., inhibiting) pharmaceutical degradation, or any combination thereof.In some embodiments, the pharmaceutical agent is an ionizable pharmaceutical agent, e.g., a weak acid or a weak base in the GI physiological pH range. In some embodiments, for an ionizable pharmaceutical agent, the total solubility is the sum of the solubilities of the ionized and non-ionized species balanced by the pH-pKa relationship (Henderson-Hasselbalch equation), where the non-ionized species has a much greater permeability than the ionized species of the pharmaceutical agent. In some embodiments, the pharmaceutical agent is a non-ionized pharmaceutical agent. In some embodiments, the pharmaceutical agent is a non-ionized pharmaceutical agent, where the total solubility is based on the non-ionized molecule. In some embodiments, the apparent permeability or net permeability may include a negative efflux pump effect. In some embodiments, the use of an efflux inhibitor can improve the apparent permeability. In some embodiments, the method further includes conducting in vitro testing (e.g., drug release studies in biorelevant media, e.g., simulating gastric and / or intestinal fluids) to optimize the oral pharmaceutical dosage form.

[0125] example Example 1 This example illustrates the design of an oral pharmaceutical dosage form, which is formulated and configured to provide a desired pharmacokinetic (PK) profile for a pharmaceutical agent in a human individual.

[0126] A reference PK profile (FIG. 2) was obtained over a 24-hour period for a dosing regimen of a reference oral pharmaceutical dosage form containing 5 mg of Drug A. The reference PK profile of Drug A represented the plasma concentration (ng / mL) of Drug A in an individual when the reference oral pharmaceutical dosage form was administered twice (BID, administration occurred at 0 and 12 hours) over a 24-hour period.

[0127] The target PK profile was determined based on the reference PK profile (Figure 2). The target PK profile was bioequivalent to the reference PK profile (same AUC 0-24 , C max and C 24where the target PK profile is based on once daily (QD) administration of an oral pharmaceutical dosage form containing 10 mg of Drug A.

[0128] As shown in Figure 3, the target PK profile was used to determine the drug absorption rate profile required to achieve the target PK profile. Specifically, the target PK profile was first deconvolved using mathematical deconvolution and the treatment profile of drug A. Deconvolution was performed using Matlab software. The treatment profile of drug A was obtained from a human clinical study after intravenous bolus (IV) administration of drug A. Considering the reported oral bioavailability of drug A, the intravenous dose of drug A is bioequivalent to the oral dose. As described above, a once-daily oral pharmaceutical dosage form was designed so that the total amount of drug A in the oral dosage form was 10 mg, resulting in the same total daily dose as the reference drug given as 5 mg BID. Drug A is known to have a bioavailability of approximately 43.1% in humans when administered orally. The drug absorption rate profile was determined using a time increment of one hour.

[0129] The calculated drug absorption rate profile was used to determine the time or position profile of drug A concentration. As shown in FIG. 5A, the time or position profile of drug concentration is based on the absorption rate profile of drug A and the time or position profile of drug permeability, where the time or position profile of drug permeability includes permeability values ​​of the drug at a GI tract location or a time after administration. As taught herein, the location of the drug in the GI tract can be related to a time after drug administration. As shown in FIG. 5B, the time or position profile of drug permeability may be based on location (e.g., based on residence time information of an oral pharmaceutical dosage form relative to a location along the GI tract) and / or time after administration. The time or position profile of drug A concentration was calculated using Equation II. Equation II is:

number

[0130] The permeability time or position profile was determined based on data obtained from a clinical study in which a specially designed dosage form was administered to study local GI absorption, the dosage form releasing the drug at a specific location in the GI tract and containing an oral solution of Drug A. The permeability values ​​of the drug permeability time or position profile indicated the intestinal surface area at the location in the GI tract associated with the permeability value. As described herein, the drug permeability time or position profile may be based on various states of an individual, including fed or fasted states. The drug A permeability time or position profile shown in Figures 5A and 5B was calculated based on fed-state conditions. Similar to the drug permeability time or position profile, the time after oral administration may be related to the desired location of the dosage form in the GI tract (see Figure 5A). As shown in Figures 5A and 5B, one-hour time increments were used to determine the drug A permeability time or position profile.

[0131] The concentration time or position profile was used to determine the GI drug demand profile. Specifically, as shown in Figure 6, the drug concentration time or position profile and the GI fluid volume time or position profile and Equation III were used to determine the GI drug demand profile. Equation III is:

number

[0132] The drug absorption rate profile of Drug A was used to determine the drug absorption amount profile of Drug A. Specifically, as shown in Figure 4, the drug absorption rate profile of Drug A was determined using Formula IV. Formula IV is:

number

[0133] Based on the drug absorption profile and the GI drug demand profile, a simulated drug release profile was then determined using Equation V, which is designed to achieve the target PK profile.

number

[0134] When the amount of Drug A to be released from the oral pharmaceutical dosage form at each time point was determined to obtain the desired PK profile, the cumulative amount of drug released from the oral pharmaceutical dosage form was determined. The cumulative amount of drug released was determined using Formula VI. Formula VI is:

number

number

[0135] The profile according to Figure 7 shows the total cumulative release of Drug A over time to achieve the target pK profile.

[0136] Techniques for optimizing the absorption of Drug A were also explored. As shown in Figure 8A, solubility was evaluated relative to the time or location profile of drug concentration. For most GI tract drug concentration time profiles, the concentration present in the GI tract is predicted to exceed the desired solubility of Drug A based on the design method described herein (Figure 8A). Therefore, the solubility of Drug A was adjusted using the optimization method described herein, resulting in an enhanced solubility limit that is higher than the desired GI tract concentration at all current time points (Figure 8A). Modifications and schedules of drug permeability were also explored to determine the impact on the time or location profile of drug concentration, as shown in Figure 8B. Figure 8B shows the effect of changes in Drug A permeability on the time or location profile of drug concentration when (a) permeability from 0 to 24 hours post-dose is enhanced to 1.4-fold the original permeability value, (b) permeability from 3 (jejunum) to 24 hours post-dose is enhanced to 1.4-fold the original permeability value, (c) permeability from 8 (colon) to 24 hours post-dose is enhanced to 1.4-fold the original permeability value, and (d) permeability from 8 (colon) to 24 hours post-dose is enhanced to 1.8-fold the original permeability value. These methods may be used alone or in combination with other optimization techniques.

[0137] Based on information regarding the release of Drug A from the oral pharmaceutical dosage form, the oral pharmaceutical dosage form was designed to release the drug accordingly, thereby providing an oral pharmaceutical dosage form formulated and configured to provide the desired PK profile.

Claims

1. 1. A method for designing an oral pharmaceutical dosage form formulated and configured to provide a desired pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, comprising: (a) determining a simulated drug release profile configured to obtain said target PK profile, wherein the simulated drug release profile comprises an amount of the drug released from the oral pharmaceutical dosage form at multiple time points over a predefined time course; and wherein each time point or location of the simulated drug release profile is determined based on the amount of the drug absorbed at that time point, a permeability value of the drug at a gastrointestinal (GI) tract location associated with that time point, and a liquid volume in the GI tract at the location associated with that time point; (b) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile.

2. 10. The method of claim 1, further comprising determining the amount of said pharmaceutical agent absorbed from said oral pharmaceutical dosage form at each time point.

3. the amount of the drug absorbed from the oral pharmaceutical dosage form at each time point is based on a drug absorption rate profile; wherein the drug absorption rate profile comprises the drug uptake rate at the multiple time points to obtain the target PK profile; and / or The amount of the pharmaceutical agent absorbed from the oral pharmaceutical dosage form is based on Formula IV: [0010] Formula IV, where Q abs (t) is the amount of the drug absorbed from the oral pharmaceutical dosage form as a function of time; and where q abs (t) is the absorption rate of the drug as a function of time. The method according to claim 1 or 2.

4. determining an absorption rate profile of the pharmaceutical agent; Optionally, the drug absorption rate profile is based on deconvolution of the target PK profile according to Formula I with a treatment profile of the drug; [0025] Formula I, where L and L −1 are the Laplace transform and the inverse Laplace transform, where q abs (t) is based on the drug absorption rate profile as a function of time, and where C p, oral (t) and C p, treatment (t) are based on the plasma level concentration profiles as a function of oral administration time and treatment time, respectively. The method according to claim 3.

5. 5. The method of any one of claims 1 to 4, further comprising determining an amount of the pharmaceutical agent required for absorption from the oral pharmaceutical dosage form at a location in the GI tract at said time or location, wherein the amount of pharmaceutical agent required for absorption from the oral pharmaceutical dosage form at a location in the GI tract at said time or location is based on a permeability value of the pharmaceutical agent at the location in the GI tract associated with said time or location, and a liquid volume in the GI tract at the location associated with said time or location.

6. 6. The method of claim 5, wherein the amount of drug required for absorption from the oral pharmaceutical dosage form at a location in the GI tract at the time or location is based on a time or location profile of drug concentration and a time or location profile of GI fluid volume.

7. The amount of the pharmaceutical agent required for absorption from the oral pharmaceutical dosage form at a given time or location in the GI tract is based on Formula III: [0030] Formula III, Here, Q ＧＩＴ (t / x) is the amount of the drug required for absorption from the oral pharmaceutical dosage form as a function of time or location; Here, C ＧＩＴ (t / x) is the concentration of the pharmaceutical agent that is soluble for absorption from the oral pharmaceutical dosage form as a function of time or location; and Here, V ＧＩＴ 7. The method of claim 6, wherein (t / x) is the liquid volume of the GI tract as a function of time or location.

8. 8. The method of claim 6 or 7, further comprising determining a time or location profile of said pharmaceutical concentration.

9. the drug concentration-location profile is based on the drug absorption rate profile and a time or location profile of drug permeability, wherein the time or location profile of drug permeability comprises permeability values ​​of the drug at a location in the GI tract associated with each time point of the plurality of time points, and optionally the drug concentration-location profile is based on Formula II; [0045] Formula II, where C(t / x) is the concentration of the drug that is soluble in the GI tract from the oral pharmaceutical dosage form as a function of time or location; where q abs (t / x) is the absorption rate of the drug as a function of time or location; and where P(t / x) is the transmittance as a function of time or position. The method according to any one of claims 6 to 8.

10. (a) further comprising designing the oral pharmaceutical dosage form based on adjusting the pharmaceutical solubility and / or permeability; (b) further comprising optimizing the simulated drug release profile; and / or (c) determining a cumulative drug release profile based on the simulated drug release profile. The method according to any one of claims 1 to 9.

11. 1. A method for designing an oral pharmaceutical dosage form formulated and configured to provide a desired pharmacokinetic (PK) profile of a pharmaceutical agent in an individual, comprising: (a) determining a drug absorption rate profile based on deconvolution of a target PK profile with a treatment profile and a total amount of drug in the oral pharmaceutical dosage form; (b) determining a drug absorption profile based on the drug absorption rate profile; and (c) determining a time or location profile of drug concentration based on the simulated drug absorption rate profile and the time or location profile of the drug permeability; (d) determining a GI drug requirement profile based on the drug concentration time or location profile and the GI fluid volume time or location profile; (e) determining a simulated drug release profile based on the drug absorption profile and the GI drug requirement profile, the simulated drug release profile being configured to obtain the target PK profile; wherein the simulated drug release profile comprises an amount of the drug released from the oral pharmaceutical dosage form to obtain the target PK profile; (f) designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile by designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile.

12. The method of claim 11, further comprising determining a cumulative drug release profile based on the simulated drug release profile.

13. 13. An oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, the oral pharmaceutical dosage form being formulated and configured to release the pharmaceutical agent according to a design obtained from the method of any one of claims 1 to 12.

14. 13. A method for preparing an oral pharmaceutical dosage form comprising a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, the method comprising three-dimensional (3D) printing said oral pharmaceutical dosage form based on a design of said oral pharmaceutical dosage form obtained from the method of any one of claims 1 to 12.

15. 1. A method for preparing an oral pharmaceutical dosage form containing a pharmaceutical agent formulated and configured to have a desired pharmacokinetic (PK) profile, comprising: (a) determining a drug absorption rate profile based on deconvolution of a target PK profile with a treatment profile and a total amount of drug in the oral pharmaceutical dosage form; (b) determining a drug absorption profile based on the drug absorption rate profile; and (c) determining a time or location profile of drug concentration based on the drug absorption rate profile and the permeability time or location profile of the drug; (d) determining a GI drug requirement profile based on the drug concentration time or location profile and the GI fluid volume time or location profile; (e) determining a simulated drug release profile based on the drug absorption profile and the GI drug requirement profile, the simulated drug release profile being configured to obtain the target PK profile; wherein the simulated drug release profile comprises an amount of the drug released from the oral pharmaceutical dosage form to obtain the target PK profile; (f) three-dimensionally (3D) printing the oral pharmaceutical dosage form based on a design of the oral pharmaceutical dosage form obtained from a method comprising: designing the oral pharmaceutical dosage form to release the drug based on the simulated drug release profile, thereby designing an oral pharmaceutical dosage form formulated and configured to provide the target PK profile.

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