5-Hydroxytryptophan gastric retention dosage form

Abstract

A gastroretentive sustained release dosage form is described, which comprises 5-hydroxytryptophan (5-HTP) as an active ingredient and low-dose carbidopa.For example, the dosage form can be provided as a bilayer tablet comprising a swelling layer and a modified release layer, and both 5-HTP and carbidopa are contained in the modified release layer.The dosage form provides essentially parallel release of 5-HTP and carbidopa, for example, releasing 80% of 5-HTP and carbidopa in about 5 hours to about 12 hours.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of U.S. Provisional Patent Application No. 63 / 227,915, filed July 30, 2021, the disclosure of which is incorporated by reference in its entirety herein.

[0002] The subject matter of the present disclosure relates to gastroretentive sustained release dosage forms for 5-hydroxytryptophan (5-HTP) and methods of using said dosage forms to treat disorders of the body. [Background technology]

[0003] The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the prior art or is common general knowledge.

[0004] 5-Hydroxytryptophan (5-HTP) is the natural, rate-limiting precursor of serotonin in the mammalian body (Jacobsen et al., 2016b). Serotonin is a signaling molecule present in many tissues of the body, including the brain and gut. Oral administration of exogenous 5-HTP to the mammalian body can increase plasma levels of 5-HTP and brain levels of serotonin (Jacobsen et al., 2016b). In humans, 5-HTP has been used experimentally to treat depression (van Praag, 1982), anxiety (Kahn and Westenberg, 1985), myoclonus (Magnussen et al., 1977), fibromyalgia (Caruso et al., 1990), migraine (Santucci et al., 1986), headache (Bono et al., 1984), obesity (Cangiano et al., 1992), Parkinson's disease depression (Meloni et al., 2020a), L-DOPA dyskinesia in Parkinson's disease (Meloni et al., 2020b), sleep disorders (Birdsall, 1998), certain childhood developmental disorders (Ramaekers et al., 2001), and ataxic disorders (Trouillas et al., 1988), among other diseases.

[0005] 5-HTP drugs may also have therapeutic relevance in indications known to be responsive to pro-serotonergic drugs, including, but not limited to, social anxiety, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder (OCD), mood symptoms and agitation associated with neurological disorders (e.g., Alzheimer's disease, Parkinson's disease), stroke recovery, premenstrual dysphoria, post-traumatic stress disorder, postpartum depression, depression after interferon treatment, eating disorders, obesity, irritable bowel syndrome-constipation, idiopathic constipation and other constipation disorders.In addition, 5-HTP drugs may have therapeutic relevance in indications whose etiology is associated with low brain serotonin, including but not limited to, impulse control disorders, aggression, suicidal ideation, borderline personality disorder, autism, phenylketonuria and tetrahydrobiopterin deficiency.

[0006] However, natural 5-HTP in an immediate release dosage form (hereinafter referred to as "natural 5-HTP immediate release", i.e., the naturally occurring molecular form of 5-HTP formulated for immediate release without compounds that may enhance 5-HTP bioavailability) has insufficient pharmacokinetics for practical therapeutic use. For example, natural 5-HTP immediate release has a short half-life (T 1 / 2 Approximately 2 hours; typically reported to be 1.5-3 hours (Gijsman et al., 2002)), and require frequent dosing, e.g., 3 or more times a day, to provide a reasonably stable exposure (Thombre, 2005; van Praag, 1982). Furthermore, natural 5-HTP immediate release has a rapid absorption (T Max 1 hour), rapid C Max It is accompanied by associated adverse events (Lowe et al., 2006; van Praag, 1982). Furthermore, in many treatment scenarios, the low oral bioavailability of natural 5-HTP immediate release (e.g., about 20% in one study (WO2019245925)) can lead to the use of high daily doses, and therefore large dosage forms or many dosage forms taken per day, making treatment cumbersome or impractical.

[0007] The animal data demonstrate that sustained-release 5-HTP administration (modeled using either osmotic mini-pump or dietary administration) can (i) provide sustained elevated 5-HTP plasma levels; (ii) enhance brain serotonin synthesis, levels and function; and (iii) significantly reduce adverse events normally associated with natural immediate-release 5-HTP. Furthermore, the animal data demonstrate that adverse events associated with natural immediate-release administration are reduced by 5-HTP plasma C Max Not only related to C Max These results suggest that the steepness of the gradient to the

[0008] Thus, sustained release drug technologies for 5-HTP, such as those observed with natural 5-HTP immediate release administration, may be used to improve 5-HTP plasma T Max can be effectively delayed, and therefore C Max There is a need for a dosage form that can reduce the steepness of the gradient to 5-HTP and / or provide sustained 5-HTP plasma levels within the therapeutic range, ideally with once or twice daily dosing. Such technology can have broad therapeutic relevance across central and non-central nervous system disorders, for example, by providing a more effective ability to increase endogenous serotonin synthesis, serotonin levels (intracellular and / or extracellular), serotonin neurotransmission and serotonin function in the brain or periphery, depending on the indication. Dosage forms based on such technology can be used as monotherapy or as adjunctive therapy for other serotonergic enhancers, for example, adjunctive therapy for serotonin reuptake inhibitors. Furthermore, such dosage forms can be used as adjunctive therapy for other treatments that have only partial or no serotonin modulating pharmacology. Summary of the Invention

[0009] This summary lists some aspects of the subject matter of the present disclosure, and often lists variations and permutations of these aspects. This summary is merely illustrative of many different aspects. Mention of one or more representative features of a given aspect is also exemplary. Such aspects can typically exist with or without the mentioned features, and similarly, those features may be applied to other aspects of the subject matter of the present disclosure, whether or not they are listed in this summary. To avoid excessive repetition, this summary does not list or suggest all possible combinations of such features.

[0010] In some embodiments, the subject matter of the present disclosure provides a gastroretentive dosage form comprising a tablet, the tablet comprising two layers: (a) a swelling layer comprising one or more hydrophilic polymers, each of the one or more hydrophilic polymers being capable of swelling in the presence of gastric fluid; and (b) a modified release layer, the modified release layer comprising 5-hydroxytryptophan (5-HTP) and carbidopa, wherein the time period during which 80% by weight of 5-HTP is released from the dosage form in a dissolution test is within about 2 hours of the time period during which 80% by weight of carbidopa is released from the dosage form. In some embodiments, the time period during which 80% by weight of one or both of 5-HTP and carbidopa is released from the dosage form in a dissolution test is from about 5 hours to about 12 hours.

[0011] In some embodiments, the modified release layer comprises one or more hydrophilic polymers selected from the group comprising low viscosity hydroxypropyl methylcellulose (HPMC), medium viscosity HPMC, high viscosity HPMC, low molecular weight (MW) polyethylene oxide (PEO), medium MW PEO, high MW PEO and high viscosity hydroxyethyl cellulose. In some embodiments, the modified release layer comprises about 14% (w / w) to about 37% (w / w) of one or more hydrophilic polymers, based on the total weight of the modified release layer. In some embodiments, the modified release layer comprises about 5% (w / w) of medium MW PEO or high MW PEO and about 13% (w / w) to about 32% (w / w) of low viscosity HMPC, medium viscosity HPMC, or a mixture of medium viscosity HPMC and high viscosity HPMC, based on the total weight of the modified release layer.

[0012] In some embodiments, the modified release layer comprises, based on the total weight of the modified release layer, (i) about 50% (w / w) 5-HTP; (ii) about 0.0625% (w / w) to about 5% (w / w) carbidopa; or (iii) about 50% (w / w) 5-HTP and about 0.0625% (w / w) to about 5% (w / w) carbidopa. In some embodiments, the modified release layer further comprises about 5% (w / w) to about 30% (w / w) of one or more ductile fillers, based on the total weight of the modified release layer, and optionally the ductile filler comprises or consists of microcrystalline cellulose (MCC). In some embodiments, the modified release layer further comprises about 0.5% (w / w) to about 3% (w / w) of a lubricant, based on the total weight of the modified release layer, optionally selected from the group including sodium stearyl fumarate (SSF), glyceryl behenate, stearic acid, magnesium stearate, and mixtures thereof. In some embodiments, the modified release layer further comprises about 0.01% (w / w) to about 1% (w / w) of an antioxidant, based on the total weight of the modified release layer, optionally selected from the group including butylated hydroxytoluene (BHT), butylated hydroxyanisole, tocopherol, tocopherol acetate, ascorbic acid, sodium sulfite, sodium metabisulfite, and mixtures thereof.

[0013] In some embodiments, the swell layer comprises high MW PEO and high viscosity HPMC, optionally the swell layer comprises a weight ratio of high MW PEO:high viscosity HPMC of about 1:1. In some embodiments, the swell layer further comprises up to about 5% (w / w) of a lubricant, based on the total weight of the swell layer, optionally the lubricant comprises or consists of sodium stearyl fumarate (SSF).

[0014] In some embodiments, the swelling layer and the modified release layer have approximately the same weight. In some embodiments, the total weight of the tablet is about 500 milligrams (mg) to about 2000 mg, and optionally, the total weight of the tablet is about 1000 mg. In some embodiments, the tablet contains about 250 mg of 5-HTP and about 0.3125 mg to about 25 mg of carbidopa.

[0015] In some embodiments, the modified release layer comprises, based on the total weight of the modified release layer, about 50% (w / w) 5-HTP; about 0.06% (w / w) to about 5.4% (w / w) carbidopa; about 5.7% (w / w) to about 25.1% (w / w) MCC; about 5% (w / w) medium or high MW PEO; about 7% (w / w) to about 18% (w / w) medium viscosity HPMC; about 0% (w / w) to about 25% (w / w) high viscosity HPMC; about 0.2% (w / w) BHT, about 0.1% (w / w) colloidal silica, and about 1.5% (w / w) SSF. In some embodiments, the modified release layer comprises, based on the total weight of the modified release layer, about 50% (w / w) 5-HTP; about 0.06% (w / w) to about 5.4% (w / w) carbidopa; about 19.8% (w / w) to about 25.1% (w / w) MCC, about 5% (w / w) medium or high MW PEO; about 18% (w / w) medium viscosity HPMC; about 0.2% (w / w) BHT, about 0.1% (w / w) colloidal silica, and about 1.5% (w / w) SSF.

[0016] In some embodiments, the swelling layer swells in an aqueous solution to at least about 150% of the dry volume of the swelling layer. In some embodiments, the tablet remains in the stomach for about 5 hours after oral administration to a human. In some embodiments, the modified release layer remains stable for at least 70 days when stored protected from light at 15° C. to about 25° C. In some embodiments, the modified release layer and the swelling layer are stable according to the USP 100001 standard using a disk. <701> In some embodiments, the modified release layer remains attached to one another for at least 8 hours during disintegration testing according to U.S.P. <905> In a content uniformity test conducted in accordance with the present invention, the product has an acceptance value (AV) of about 15 or less and a relative standard deviation (RSD) of about 3 or less.

[0017] In some embodiments, administration of the tablet once or twice daily to a mammalian subject, optionally a human, results in a maximum plasma concentration (T) of 5-HTP that is delayed on average by about 4 hours compared to an immediate release dosage form of native 5-HTP. Max In some embodiments, administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides about 1-fold to about 10-fold increased 5-HTP plasma exposure compared to an immediate release natural 5-HTP dosage form containing the same weight amount of 5-HTP, wherein said immediate release natural 5-HTP dosage form does not contain carbidopa.

[0018] In some embodiments, administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides a steady state average 5-HTP plasma level of about 25 nanograms per milliliter (ng / ml) or greater, optionally a steady state average 5-HTP plasma level of about 50 ng / ml or greater, optionally a steady state average 5-HTP plasma level of about 100 ng / ml or greater, and optionally a steady state average 5-HTP plasma level of between 100 ng / ml and 500 ng / ml. In some embodiments, administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides a steady state average carbidopa plasma level of about 25 ng / ml or less, optionally about 20 ng / ml or less, and even optionally about 10 ng / ml or less. In some embodiments, administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides a steady state average maximum carbidopa plasma level (C) of about 25 ng / ml or less, optionally about 20 ng / ml or less, and even optionally about 10 ng / ml or less. Max ) is provided.

[0019] In some embodiments, administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides an increased 5-HTP half-life compared to the 5-HTP half-life when natural 5-HTP is administered in immediate release form, and optionally an increase in 5-HTP half-life of about 10% to about 200% compared to the 5-HTP half-life when natural 5-HTP is administered in immediate release form. In some embodiments, the dosage form is configured to provide the same release rate for 5-HTP and / or the same release rate for carbidopa over a range of carbidopa contents from 0.3125 mg to 25 mg when the total combined weight of carbidopa and microcrystalline cellulose is held constant.

[0020] It is therefore an object of the presently disclosed subject matter to provide a gastroretentive dosage form or modified / sustained release of 5-HTP and carbidopa. The objects of the presently disclosed subject matter set forth hereinabove are achieved in whole or in part by the presently disclosed subject matter, and other objects will become apparent as the description proceeds when taken in conjunction with the accompanying figures and examples, which are best described herein below.

[0021] So that the present disclosure may be readily understood and put to practical effect, reference will now be made to the illustrated embodiments, taken in conjunction with the accompanying drawings, which together with the present description serve to further illustrate aspects of the invention and explain various principles and advantages. [Brief description of the drawings]

[0022] [Figure 1] Figures 1A-1D: In vitro dissolution study of 5-HTP / low dose carbidopa gastroretentive tablets - 5-HTP release from "fast" vs. "slow" tablets. 5-HTP release over 18 hours. (Figure 1A) "Fast" bilayer tablet, 250 mg 5-HTP, 0.3125 mg carbidopa. (Figure 1B) "Fast" bilayer tablet, 250 mg 5-HTP, 25 mg carbidopa. (Figure 1C) "Slow" bilayer tablet, 250 mg 5-HTP, 0.3125 mg carbidopa. (Figure 1D) Slow bilayer tablet, 250 mg 5-HTP, 25 mg carbidopa. Conditions: USP III (reciprocating cylinder) dissolution bath. 250 mL 0.1 M HCl + 0.02% disodium EDTA. 37°C ± 0.5. [Diagram 2] Figure 2: In vitro dissolution study of "fast" 5-HTP / low dose carbidopa gastroretentive tablets - Effect of carbidopa level on 5-HTP release. Conditions: USP III (reciprocating cylinder) dissolution bath. 250 mL 0.1 M HCl + 0.02% disodium EDTA. 37°C ± 0.5. [Diagram 3] Figures 3A-3C: In vitro dissolution study of "fast" 5-HTP / low dose carbidopa gastroretentive tablets - parallel release of 5-HTP and carbidopa in various formulations. (Figure 3A) "Fast" bilayer tablet 250 mg 5-HTP 25 mg carbidopa. (Figure 3B) "Slow" bilayer tablet 250 mg 5-HTP 25 mg carbidopa. (Figure 3C) "Intermediate" bilayer tablet 250 mg 5-HTP 5 mg carbidopa. Conditions: USP III (reciprocating cylinder) dissolution bath. 250 mL 0.1 M HCl + 0.02% disodium EDTA. 37°C ± 0.5. [Figure 4]Figure 4: A pair of photographic images showing swelling of a "fast" 5-HTP / low-dose carbidopa gastric retention tablet. (Left image) Baseline. (Right image) 8 hour time point. Copley disintegration tester with discs. [Diagram 5] Figures 5A-5E: Dissolution study of "fast" 5-HTP / low dose carbidopa gastroretentive tablets during 70 day stability study. (Figures 5A-5C) 5-HTP release. (Figures 5D-5E) Carbidopa release. Carbidopa release at the 0.625 mg carbidopa level could not be assessed as the carbidopa level was too low to be reliably quantified. Conditions: USP III (reciprocating cylinder) dissolution bath. 250 mL 0.1 M HCl + 0.02% disodium EDTA. 37°C ± 0.5. [Figure 6] Figures 6A-6D: Pharmacokinetic evaluation of 5-HTP / low-dose carbidopa gastroretentive tablets in human healthy volunteers - 5-HTP plasma profile. Comparison with 250 mg of native 5-HTP immediate release after a high-fat, high-calorie (HF) meal. (Figure 6A) Plasma 5-HTP profile after a single dose of different carbidopa doses of 5-HTP / low-dose carbidopa gastroretentive tablets compared to 5-HTP immediate release after a HF meal. (Figure 6B) Plasma 5-HTP profile after a single dose of 250 mg 5-HTP / 15 mg carbidopa gastroretentive tablets after a medium fat, medium calorie (MF) meal compared to after a HF meal, relative to 5-HTP immediate release after a HF meal. (FIG. 6C) Plasma 5-HTP profile over 24 hours at steady state after multiple administration of different carbidopa doses of 5-HTP / low-dose carbidopa gastroretentive tablets, modeled by nonparametric superposition; compared to 5-HTP immediate release. (FIG. 6D) AUC0h-12h plasma 5-HTP levels at steady state after multiple administration of different carbidopa doses of 5-HTP / low-dose carbidopa gastroretentive tablets, modeled by nonparametric superposition; compared to 5-HTP immediate release. [Figure 7]Figures 7A-7D: Pharmacokinetic evaluation of 5-HTP / low-dose carbidopa gastroretentive tablets in human healthy volunteers - carbidopa plasma profiles. Note that the absence of data for a given carbidopa dose level indicates insufficient data above the lower limit of quantification. (Figure 7A) Plasma carbidopa profiles after single administration of different carbidopa doses of 250 mg 5-HTP / carbidopa gastroretentive tablets. (Figure 7B) Plasma carbidopa profiles after single administration of 250 mg 5-HTP / 15 mg carbidopa gastroretentive tablets after a moderate fat, moderate calorie (MF) meal compared to after a HF meal. (Figure 7C) Plasma carbidopa levels over 24 hours at steady state after multiple administration of carbidopa levels of 5 mg and 15 mg 5-HTP / low-dose carbidopa gastroretentive tablets modeled by non-parametric superposition. (Figure 7D) AUC0h-12h plasma carbidopa levels at steady state following multiple dosing of carbidopa dose levels of 5 mg and 15 mg 5-HTP / low-dose carbidopa gastroretentive tablets modeled by nonparametric superposition. [Figure 8] FIG. 8: Gastric retention and colonic transit time of 5-HTP / low-dose carbidopa gastric retention tablets in human healthy volunteers. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The subject matter of the present disclosure will now be described more fully hereinafter with reference to the accompanying drawings and examples, in which representative embodiments are shown. However, the subject matter of the present disclosure may be embodied in different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the embodiments to those skilled in the art.

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0025] I. Definition Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to facilitate description of the subject matter of the present disclosure.

[0026] Following long-standing patent law convention, the terms "a," "an," and "the" when used in this application, including the claims, refer to "one or more." Thus, for example, a reference to "an agent" or "a polymer" includes a plurality of such agents or polymers, and so forth.

[0027] Unless otherwise indicated, all numbers expressing quantities of sizes, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[0028] As used herein, the term "about" when referring to a value or amount of size (i.e., diameter), weight, concentration or percentage is meant to encompass variations from the specified amount, in one example ±20% or ±10%, in another example ±5%, in another example ±1%, and in yet another example ±0.1%, as such variations are suitable for carrying out the disclosed methods.

[0029] As used herein, the term "and / or," when used in the context of a list of entities, refers to the presence of those entities either alone or in combination. Thus, for example, the phrase "A, B, C, and / or D" includes A, B, C, and D individually, but also all combinations and subcombinations of A, B, C, and D.

[0030] The term "comprising" is synonymous with "including," "containing," or "characterized by" and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. "Comprising" is a term used in claim language that means that the specified elements are required, but that other elements can be added and still form a construct that is within the scope of the claim.

[0031] As used herein, the phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. When the phrase "consists of" appears in a clause in the body of a claim rather than immediately following the preamble, it limits only the elements recited in that clause and does not exclude other elements from the claim as a whole.

[0032] As used herein, the phrase "consisting essentially of" limits the claim to those specified materials or steps, in addition to materials or steps that do not materially affect the basic and novel characteristics of the claimed subject matter.

[0033] With regard to the terms "comprising," "consisting of," and "consisting essentially of," when one of these three terms is used in this specification, the subject matter disclosed and claimed herein can include the use of either of the other two terms.

[0034] As used herein, the term "exposure" refers to the range of (AUC 0h~無限大 ) or within a defined period (e.g., AUC 0h~12h ) refers to the total blood / plasma / serum / body level of a drug integrated over time, usually expressed as the area under the curve. Exposure is often used interchangeably with "level".

[0035] As used herein, a 1 fold change (eg, a 1 fold increase) refers to an increase of 100% of a baseline value added to the baseline value, resulting in 200% of the baseline.

[0036] As used herein, the term "treatment" includes reference to curative or palliative treatment of patients / animals in need of such treatment, as well as prophylactic treatment and / or diagnosis of patients / animals susceptible to the relevant condition, to the extent that prophylactic treatment and / or diagnosis of the patient / animal is possible.

[0037] The terms "patient" and "patients" include reference to mammalian (e.g., human) patients. As used herein, the terms "subject" or "patient" are well recognized in the art and are used interchangeably herein to refer to mammals, including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject may be a normal subject. The term does not denote a particular age or sex. Thus, it is intended to encompass adult, juvenile and neonatal subjects, whether male or female, or not identified as a particular sex.

[0038] As used herein, the term "gastric retentive dosage form" refers to a dosage form (e.g., an oral dosage form such as a tablet or capsule) that is retained in the stomach for a period of time and releases a substantial percentage of an active pharmaceutical ingredient or active pharmaceutical ingredients into the gastric acid and other stomach contents from which the active pharmaceutical ingredient or ingredients can travel by bulk flow through the pyloric sphincter into the upper intestine (duodenum, jejunum, ileum) for absorption. After leaving the pylorus, the gastric retentive dosage form can release a portion of the active pharmaceutical ingredient or ingredients into the intestine where further absorption can occur.

[0039] The term "immediate release" refers to a dosage form that ensures that at least 85% of the active pharmaceutical ingredient (API) content of the dosage form is dissolved in an aqueous dissolution medium of sufficient volume and solubility within a short time interval, such that the medium is not dissolution rate limiting, and the resulting pharmacokinetic profile for that dosage form is not functionally different compared to, for example, if the API were delivered as an oral bolus (and provided that the API from the oral bolus does not precipitate when delivered), as an unformulated powder, or in solution.

[0040] The terms "immediate release natural 5-HTP", "immediate release natural 5-HTP", "immediate release dosage form of natural 5-HTP" and the like refer to immediate release administrations / formulations of 5-HTP that do not use compounds that enhance the bioavailability of 5-HTP.

[0041] The term "steady state" as used herein refers to a pharmacokinetic steady state measured in a mammalian subject during repeated dosing over several days or longer, or extrapolated from a single dose of a compound or compounds in a mammal using an appropriate mathematical model. If the compounds are administered using the same dose and dosage form and the same route (e.g., oral, intravenous, etc.) and mode of administration (e.g., fasted / fed, time of day), at steady state, the plasma exposure profile and average levels of the compound do not change functionally across different treatment days. Thus, in pharmacokinetics, and as used herein, "steady state" can refer to a situation in which the overall intake of a pharmacoactive compound is in a fairly dynamic equilibrium with its elimination. The average plasma level of the compound remains at roughly the same level from day to day, although there may be diurnal variations associated with dosing and elimination. In practice, for most drugs, it typically takes about 4 to about 6 half-lives to reach steady state after regular dosing is initiated.

[0042] The term "extended release" refers to a delayed T of a delivered active pharmaceutical ingredient compared to when said active pharmaceutical ingredient is delivered in its immediate release form. Max , decreased C Max "Sustained release" refers to a significantly extended drug delivery of one or more active pharmaceutical ingredients, such as producing elevated plasma levels of the active ingredient and / or a sustained release. "Sustained release" can have synonyms, non-limiting examples of which include "slow release," "extended release," "controlled release," or "modified release."

[0043] The term "serotonin reuptake inhibitor" refers to any compound that functionally inhibits the serotonin transporter, i.e., blocks the reuptake of serotonin into cells via the serotonin transporter, causing an increase in extracellular serotonin in a tissue or compartment of the body, at plasma exposure levels observed during dosing at therapeutic doses. Non-limiting examples of serotonin reuptake inhibitors include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, certain tricyclic antidepressants, vilazodone, vortioxetine, trazodone, nefazodone, methylphenidate, dextromethorphan, amphetamine, and fenfluramine.

[0044] The term "matrix" as used herein refers to its well-known meaning in the pharmaceutical art, i.e., a solid material providing swelling or structural support, optionally with an active ingredient incorporated therein.

[0045] II. General Considerations 5-HTP has moderate bioavailability in the upper intestine (e.g., about 20% according to one study), but low bioavailability in the colon (e.g., about 4% according to one study) (WO2019245925). Thus, according to one aspect of the subject matter of the present disclosure, a gastroretentive sustained release dosage form is provided that delivers 5-HTP to the upper intestine over an extended period of time to achieve oral sustained release delivery of 5-HTP. In a further aspect, a compound that improves the bioavailability of 5-HTP, such as carbidopa, is delivered together with 5-HTP for the gastroretentive sustained release dosage form.

[0046] For potent pharmacological enhancement of brain serotonin, relatively high plasma levels of 5-HTP, i.e., ≥ 50 ng / ml, appear to be required [(Gijsman et al., 2002; Lowe et al., 2006; Meltzer et al., 1997; Sargent et al., 1998; Shenker et al., 1985) and (WO2019245925)], meaning that previous 5-HTP treatments typically involved frequent, large doses of 5-HTP. This can pose challenges, and is even more so for sustained release formulations, where possible dose loading is often more limited due to the presence of release-modifying additives in the dosage form. In previous exploratory studies of 5-HTP in humans, peripheral decarboxylase inhibitors (PDIs) were co-administered to increase the bioavailability of 5-HTP (Turner et al., 2006). PDIs inhibit the enzyme aromatic amino acid decarboxylase (AAAD). In the human body, both 5-HTP (the natural direct precursor of serotonin) and L-DOPA (the natural direct precursor of dopamine and norepinephrine) are metabolized by AAAD to serotonin and dopamine, respectively.

[0047] Common PDIs include carbidopa and benserazide. Carbidopa and benserazide are used in regulatory approved pharmaceuticals with L-DOPA to treat Parkinson's disease. PDIs are typically used at saturating doses of 75-150 mg / day, which inhibit most or essentially all of the systemic amino acid decarboxylase activity, but not brain amino acid decarboxylase activity. When 5-HTP has been administered previously in the published medical literature, the PDI (usually carbidopa, but sometimes benserazide) was always administered in one dosage form, whereas 5-HTP was administered in a different dosage form. The dose of PDI given with 5-HTP is typically similar to the PDI dose used in the treatment of Parkinson's disease, i.e., ≥100 mg / day [see, e.g., (Magnussen et al., 1982; van Praag, 1982)].

[0048] Even high doses of PDI (≧100 mg / day) when given with high doses of L-DOPA (≧400 mg / day) do not prevent a significant proportion of L-DOPA from being metabolized to dopamine, adrenaline and noradrenaline in the periphery, thereby preserving the peripheral hormone and transmitter functions of dopamine, adrenaline and noradrenaline (Eisenhofer et al., 2014). However, there is evidence that long-term treatment with high doses of PDI to humans not treated with L-DOPA may involve health risks, for example, by affecting dopamine, adrenaline and noradrenaline or other transmitter systems and biological processes [discussed in (WO2019148087); see also (Allen et al., 2009; Garfinkel et al., 1977; Rauws et al., 1982)]. Thus, when a PDI is chronically administered to a human or another mammal in the absence of exogenously administered L-DOPA, it may be desirable to use the lowest possible PDI dose.

[0049] Recently, it has been shown that under certain conditions, i.e., when carbidopa is administered via a sustained release format in close temporal and spatial proximity to 5-HTP, carbidopa is unexpectedly effective in enhancing the bioavailability of 5-HTP (U.S. Patent No. 11,337,963). Without being bound by any theory, it is believed that to achieve parallel delivery in humans or other mammals using solid dosage forms such as sustained release tablets, 5-HTP and carbidopa are released at similar or nearly similar rates from the same dosage form. However, when designing a dosage form for similar or nearly similar release rates of 5-HTP and carbidopa (e.g., low-dose carbidopa), there are several factors to consider. The first consideration is that drug delivery from most matrices depends to a significant extent on diffusion. Thus, parallel delivery of two compounds with different aqueous solubilities from the same matrix is ​​unpredictable and in fact is generally not expected. This consideration applies to the co-delivery of 5-HTP and carbidopa by sustained release, since 5-HTP is sparingly soluble (aqueous solubility about 15 mg / ml) while carbidopa is only sparingly soluble (aqueous solubility about 1.5 mg / ml). A second consideration with achieving a sustained release dosage form of 5-HTP at medium to high doses (≧200 mg per tablet) using low doses of carbidopa (<10 mg per tablet, <5 mg per tablet, or <1 mg per tablet) is achieving content uniformity for the low doses of carbidopa. For example, given the need for release-modifying additives, the total weight of the drug delivery layer may be about twice the weight of the active pharmaceutical ingredient. When formulating low doses of carbidopa, in many cases this means that the carbidopa content is about 1% w / w or less of the total drug delivery layer weight. A third consideration is that since no validated / regulatory approved pharmaceuticals containing 5-HTP and carbidopa are currently available, the stability of carbidopa in the presence of 5-HTP and vice versa cannot generally be assumed. A fourth consideration is that when formulating solid dosage forms that retain large API levels, such as for 5-HTP, different dose levels / strengths may involve different, separate formulations to achieve roughly similar drug delivery profiles.Matching the delivery profiles of two separate formulations in vitro and in vivo can be difficult, cumbersome, expensive, and is not always possible. Furthermore, different formulations at different dose strengths for the same drug can burden drug development and drug manufacturing.

[0050] An additional consideration with formulation compositions of two or more active pharmaceutical ingredients within the same dosage form is ensuring the stability of the active pharmaceutical ingredients together, as well as with the selected excipients. This can be particularly problematic for carbidopa, which can be chemically unstable under some conditions, e.g., in solution or suspension (Donnelly, 2016).

[0051] Previous studies have been published using different dose combinations of 5-HTP and carbidopa in separate dosage forms for 5-HTP and carbidopa to obtain various plasma levels of 5-HTP in the human body. These studies used fixed daily doses of carbidopa, typically 100 mg / day to 300 mg / day, along with various doses of 5-HTP ranging from 250 mg / day to 2800 mg / day [see, for example, (Magnussen et al., 1982; van Hiele, 1980; van Praag, 1982)].

[0052] As mentioned above, both 5-HTP and L-DOPA are metabolized by AAAD in the body. Carbidopa, a PDI, is used clinically to enhance systemic plasma exposure of L-DOPA. Extended release formulations of L-DOPA and carbidopa are known in the art, typically using doses of 25 mg or more of carbidopa per tablet and a 4:1 L-DOPA:carbidopa ratio. For example, L-DOPA / carbidopa tablets sold under the trade name SINEMET® CR (Organon & Co., Jersey City, New Jersey, United States of America) are supplied as conventional (non-gastroretentive) extended release tablets containing either 50 mg of carbidopa and 200 mg of L-DOPA, or 25 mg of carbidopa and 100 mg of L-DOPA. The starting dose of SINEMET® CR is 200 mg / 50 mg L-DOPA / carbidopa twice daily for a total starting daily dose of 400 mg / 100 mg L-DOPA / carbidopa. Similarly, gastroretentive tablets of L-DOPA / carbidopa containing 200 mg L-DOPA and 50 mg carbidopa for twice daily dosing have been described (U.S. Patent No. 9,161,911) for a total daily dose of 400 mg L-DOPA and 100 mg carbidopa.

[0053] III. Gastric retention sustained release tablet formulation of 5-HTP In some embodiments, the subject matter of the present disclosure provides a gastroretentive dosage form for 5-HTP and carbidopa (e.g., low-dose carbidopa).In some embodiments, the gastroretentive dosage form is a gastroretentive sustained release dosage form for 5-HTP and carbidopa.In some embodiments, the dosage form is a tablet.

[0054] In some embodiments, the gastroretentive dosage form (e.g., tablet) of the present disclosure is configured to provide elevated 5-HTP plasma levels (i.e., maintained above baseline levels) for much of the day when the dosage form is administered to a mammal, such as a human. In some embodiments, the dosage form is configured to provide elevated 5-HTP plasma levels for much of the day upon twice-daily administration of the dosage form to a mammal. In some embodiments, the dosage form is configured to provide elevated 5-HTP plasma levels upon once-daily administration of the dosage form to a mammal. In some embodiments, the dosage form is configured to provide elevated 5-HTP plasma levels when the dosage form is administered for three or more daily doses to a mammal. In some embodiments, the dosage forms of the present disclosure are configured to provide 5-HTP plasma levels that are elevated above baseline by about 25 ng / ml, about 50 mg / ml, about 75 ng / ml, or about 100 ng / ml for much of the day (e.g., at least about 14, about 16, about 18, about 20, or about 22 hours of each 24-hour period) or for all of the day. In some embodiments, the 5-HTP plasma exposure following administration of the dosage forms of the present disclosure (e.g., once or twice daily) is elevated by about 1-fold to about 10-fold (e.g., about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or about 10-fold) compared to administration of natural 5-HTP immediate release at the same 5-HTP dose (e.g., an immediate release dosage form of natural 5-HTP that does not contain carbidopa).

[0055] In some embodiments, the gastroretentive dosage forms (e.g., tablets) of the present disclosure exhibit a reduced time required to achieve a maximum plasma concentration of 5-HTP (T) (e.g., with once or twice daily dosing) compared to administration of native 5-HTP immediate release. Max ) by about 1 to about 10 times. Max is delayed by about 1 to about 5 times. Max is delayed by about 4-fold. Maxis delayed by about 3 hours to about 10 hours (e.g., about 3 hours, about 3.5 hours, about 4.0 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, or about 10 hours) compared to administration of natural 5-HTP immediate release. Max In some embodiments, T is delayed by about 2 hours to about 6 hours or about 3 hours to about 5 hours. Max will be delayed by approximately four hours.

[0056] In some embodiments, the gastroretentive dosage form of the present disclosure comprises, consists essentially of, or consists of a tablet having a total weight of about 500 mg to about 2000 mg (e.g., a gastroretentive sustained release bilayer tablet) having a total weight of about 500 mg to about 2000 mg (e.g., a gastroretentive sustained release bilayer tablet). In some embodiments, the total weight of the tablet is about 1000 mg to about 2000 mg. In some embodiments, the total weight of the tablet is about 800 mg to about 1200 mg. In some embodiments, the total weight of the tablet is about 1000 mg to about 1200 mg. In some embodiments, the total weight of the tablet is about 1000 mg. In some embodiments, the total weight of the tablet is about 1200 mg to about 1600 mg. In some embodiments, the total weight of the tablet is about 500 mg to about 1000 mg, In some embodiments, the total weight of the tablet is about 700 mg to about 850 mg.

[0057] In some embodiments, the tablet comprises a swelling layer and a modified release layer. In some embodiments, the tablet is a bilayer tablet. In some embodiments, the swelling layer comprises one or more hydrophilic polymers (e.g., one or more hydrophilic polymers capable of swelling in the presence of gastric fluid). In some embodiments, the modified release layer comprises 5-HTP and carbidopa (e.g., low-dose carbidopa). In some embodiments, the swelling layer does not contain 5-HTP or carbidopa. In some embodiments, only the modified release layer contains 5-HTP and carbidopa. In some embodiments, the modified release layer comprises 5-HTP, carbidopa, and one or more polymers capable of providing modified release of 5-HTP and / or carbidopa. In some embodiments, the swelling layer imparts a majority of the volume (e.g., about 60%, 70%, 80%, 90% or more) of the total volume of the tablet when the tablet is exposed to an aqueous medium (e.g., after administration of the tablet to a mammal or exposure of the tablet to gastric fluid or another aqueous medium). In some embodiments, the swelling layer and the modified release layer have about equal sizes (e.g., about equal weights) when the tablet is dry. In some embodiments, the sizes (e.g., weights) of these layers are different when the tablet is dry.

[0058] In some embodiments, the gastroretentive dosage form of the present disclosure is provided as an oval or rectangular tablet. In some embodiments, the tablet has chamfered or rounded corners. In some embodiments, the tablet is about twice as long as it is wide before swelling. In some embodiments, before swelling, the tablet is about 19 mm long, about 9.5 mm wide, and about 7 mm deep.

[0059] In some embodiments, the dosage per gastroretentive dosage form (e.g., tablet) is about 250 mg of 5-HTP. Thus, in some embodiments, the modified release layer comprises about 250 mg of 5-HTP. In some embodiments, the modified release layer also contains carbidopa. In some embodiments, the dosage per dosage form of carbidopa is about 0.3125 mg to about 25 mg. Thus, in some embodiments, the modified release layer comprises about 0.3125 mg to about 25 mg of carbidopa. In some embodiments, the dosage of carbidopa is about 0.3125 mg, about 0.625 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg or about 25 mg.

[0060] In some embodiments, the gastroretentive dosage forms (e.g., tablets) of the present disclosure are configured such that the release of 5-HTP and carbidopa from the modified release layer is essentially parallel. For example, in some embodiments, the dosage form is configured such that a given percentage of the total weight of 5-HTP in the dosage form is released from the dosage form (e.g., as measured by dissolution testing in aqueous media) within about 2 hours (e.g., within about 2 hours, about 1.5 hours, about 1 hour, or about 30 minutes) of the period during which a corresponding percentage of the total weight of carbidopa in the dosage form is released from the dosage form under the same conditions. For example, the dosage form can be configured such that the time period for release of 80% of the weight of one of 5-HTP and carbidopa (in dissolution testing, T=80%, T=80% or T80%) (i.e., the time it takes for 80% of the weight of 5-HTP or carbidopa to be released from the dosage form after the dosage form is introduced into an aqueous medium) is within about 2 hours of T=80% of the other. In some embodiments, the time period for release of 50% of the weight of 5-HTP or carbidopa (dissolution T=50%, T=50% or T50%) is within about 2 hours of T=50% of the other. In some embodiments, the time period for release of 50% of the weight of 5-HTP or carbidopa (dissolution T=50%, T=50% or T50%) is within about 2 hours of T=50% of the other. (5-HTP) and T=80% (5-HTP) ) are the T = 50% and T = 80% for carbidopa (T = 50% (カルビドパ) and T=80% (カルビドパ)) within about 2 hours of T = 80%. In some embodiments, T = 80% and T = 50% are measured by dissolution testing using a United States Pharmacopeia (USP) Apparatus III (Reciprocating Cylinder) in an appropriate volume of an appropriate aqueous medium (e.g., 250 mL of 0.1 Molar (M) hydrochloric acid (HCl) and 0.02% disodium ethylenediaminetetraacetate (EDTA)) at 37°C. Thus, in some embodiments, T = 80% (5-THP) and T = 80% (carbidopa) are measured by dissolution testing using a USP Apparatus III (Reciprocating Cylinder) in 250 mL of 0.1 Molar (M) hydrochloric acid (HCl) and 0.02% disodium ethylenediaminetetraacetate (EDTA)). (5-HTP) ) is T=80% of carbidopa (T=80% (カルビドパ) ) or less than 2 hours greater or less than 2 hours. In some embodiments, the dissolution T=50% and T=80% for 5-HTP is within about 1 hour of the T=50% and T=80% for carbidopa, respectively. In some embodiments, the dissolution T=50% and T=80% for 5-HTP is within about 0.5 hours of the T=50% and T=80% for carbidopa, respectively.

[0061] In some embodiments, the time period during which 80% by weight of one or both of the 5-HTP and carbidopa are released from the dosage form (i.e., T=80% (5-HTP) , T=80% (カルビドパ) Or T=80% (5-HTP) and T=80% (カルビドパ) (both) is about 4 hours to about 15 hours. In some embodiments, T=80% (5-HTP) and / or T=80% (カルビドパ) In some embodiments, T=80% is about 5 hours to about 12 hours. (5-HTP) and T=80% (カルビドパ)is about 5 hours to about 12 hours (e.g., about 5 hours, about 5.5 hours, about 6 hours, about 6.6 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, or about 12 hours).

[0062] As mentioned above, in some embodiments, the swelling layer of the gastroretentive dosage form comprises one or more hydrophilic polymers that swell in aqueous medium (e.g., gastric juice).In this regard, as the molecular weight increases, the number of intertwinings between polymers in the hydrophilic polymer can increase.These intertwinings can act like physical crosslinks and form a matrix.When water is absorbed into the matrix, the matrix can form a gel with a volume larger than the dry volume of the swelling layer.

[0063] In the context of using hydrophilic polymers for modified release of APIs (e.g., in the modified release layer of the tablet of the present disclosure), higher molecular weights can cause more polymer entanglement and slow the rate of polymer dissolution in aqueous media, so that erosion is typically slower than desired for drug delivery for APIs with low aqueous solubility. For lower molecular weight hydrophilic polymers, erosion can dominate and release can be rapid. For intermediate molecular weight hydrophilic polymers, erosion can be the primary release mechanism for poorly water-soluble or water-insoluble APIs, providing sufficient swollen gel for diffusion of more soluble APIs.

[0064] Polyethylene oxide is a representative class of hydrophilic polymers. Thus, in some embodiments, the swelling layer and / or modified release layer of the gastroretentive dosage form (e.g., tablet) disclosed herein comprises one or more polyethylene oxide (PEO) polymers, such as those available under the trade name POLYOX® (Dow Chemical Company, Midland, Michigan, United States of America). In some embodiments, the swelling layer can comprise one or more PEO polymers, and each of the PEO polymers, if more than one, can have a different molecular weight (MW). In some embodiments, the swelling layer comprises a high MW PEO.

[0065] As used herein, "high molecular weight PEO" or "high MW PEO" refers to a PEO having an average molecular weight of about 4 million or more (e.g., about 4 million to about 8 million) (as measured by a suitable method, e.g., by rheological measurements). Exemplary high MW PEOs include, but are not limited to, POLYOX® WSR 301 (which may also be referred to as PEO WSR 301) having an average MW of about 4 million; POLYOX® WSR Flocculant (which may also be referred to as POLYOX® Coag) having an average MW of about 5 million; POLYOX® WSR 303 having an average MW of about 7 million; and PEO 308 having an average MW of about 8 million. As used herein, "medium molecular weight PEO" or "medium MW PEO" refers to a PEO having an average MW of about 900,000 to about 4 million. Exemplary medium MW PEOs include, but are not limited to, PEO WSR 1105 having an average MW of about 900,000; PEO WSR N12K having an average MW of about 1 million; PEO WSR N60K having an average MW of about 2 million; and PEO WSR 301. Thus, PEO WSR 301 can be considered as a medium and / or high MW PEO as used herein. Exemplary "low molecular weight PEOs" or low "MW PEOs" as used herein include PEOs having an average MW of about 900,000 or less, such as, but not limited to, PEO WSR N10 having an average MW of about 100,000 and PEO WSR 1105 having an average MW of about 900,000. Thus, PEO WSR 1105 can be considered as a low and / or medium MW PEO according to the subject matter of the present disclosure.

[0066] Alkyl-substituted celluloses, with substituted alkyl groups of 1 to 3 carbons, are a representative class of hydrophilic polymers. Representative alkyl-substituted cellulose polymers for swelling are hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC or hypromellose), and carboxymethyl cellulose (CMC). Specific representative alkyl-substituted celluloses include HPMC and HEC. HPMC can be characterized by the viscosity of a 2% aqueous solution at 20°C, and HEC (NATROSOL™) can be characterized by the viscosity of a 1% solution at 25°C, with a typical Brookfield viscosity of 3400 to 5000 MPa-s. For HPMC, it is convenient to define "low", "medium" and "high" viscosity ranges. "Low" viscosity HPMC is defined as about 2 MPa-s to 500 MPa-s. Examples of low viscosity HPMC are METHOCEL™ K3LV, having a viscosity of 2.4-3.6 MPa-s, K100LV, having a viscosity of 100-120 MPa-s, and E5-LV, having a viscosity of 7-12 MPa-s. "Medium" viscosity HPMC is defined as about 550 MPa-s to about 30,000 MPa-s. Specific examples of medium viscosity HPMC are METHOCEL™ K4M, having a viscosity of 2,663 MPa-s to 4,970 MPa-s, K15M, having a viscosity of 13,275 MPa-s to 24,780 MPa-s, and E4M, having a viscosity of 2,663 MPa-s to 4,970 MPa-s. "High" viscosity HPMC is defined as about 30,000 MPa-s to about 200,000 MPa-s. An example of a high viscosity HPMC is METHOCEL™ K100M, which has a viscosity of 75,000 MPa-s to 140,000 MPa-s.

[0067] In some embodiments, the swelling layer of the gastroretentive dosage form (e.g., tablet) comprises high viscosity HPMC. Various HPMC are available under the trade names BENECEL™ from Ashland Inc. (Wilmington, Delaware, United States of America) and METHOCEL™ (Dupont de Nemours, Inc., Wilmington, Delaware, United States of America).

[0068] An example of a high viscosity HPMC is HPMC K100M, a 2% aqueous solution at 20°C has a viscosity of 75,000 MPa-s to 140,000 MPa-s, K indicates a methoxy substitution of 19.0% to 24.0%. A medium viscosity HPMC used as a binder for granulation and erodible drug release is HPMC K4M, a 2% aqueous solution at 20°C has a viscosity of 2,663 MPa-s to 4,970 MPa-s, K indicates a methoxy substitution of 19.0% to 24.0%. HPMC K100 LVCR is an example of a low viscosity HPMC used for sustained release, a 2% aqueous solution at 20°C has a viscosity of 80 MPa-s to 120 MPa-s, K indicates a methoxy substitution of 19.0% to 24.0%. In some embodiments, the swelling layer comprises a high viscosity hydroxyethyl cellulose (HEC), such as that sold under the trade name NATROSOL™ 250 HX Pharm from Ashland Inc. (Wilmington, Delaware, United States of America), having a viscosity of 1,500 MPa-s to 2,500 mPa-s; NATROSOL™ 250 HHX Pharm from Ashland Inc. (Wilmington, Delaware, United States of America), having a viscosity of 3,500 MPa-s to 5,500 mPa-s for a 1% aqueous solution at 25° C.; or CELLOSIZE™ 15000H from Dow Chemical Company (Midland, Michigan, United States of America), having a viscosity of 1% aqueous solution of 1,100 cP to 1,500 cP.

[0069] In some embodiments, the swelling layer of the gastroretentive sustained release dosage form (e.g., tablet) comprises a high molecular weight hydrophilic polymer and a gas generating agent such as sodium bicarbonate, calcium carbonate or magnesium carbonate, and optionally an organic acid such as citric acid, fumaric acid, maleic acid or another common organic acid suitable as a pharmaceutical excipient.

[0070] In some embodiments, the swelling layer of the gastroretentive dosage form (e.g., tablet) is made from a blend of polymers comprising approximately equal parts (by weight or volume) of high MW PEO and high viscosity HPMC. In some embodiments, the swelling layer comprises a weight ratio of about 1:1 high MW PEO:high viscosity HPMC. In some embodiments, the swelling layer comprises high MW PEO. In some embodiments, the swelling layer comprises up to about 50% (w / w) high MW PEO and up to about 50% (w / w) high viscosity HPMC (e.g., based on the total weight of the swelling layer).

[0071] In some embodiments, the swelling layer further comprises a lubricant. In some embodiments, the lubricant is present at less than about 5%, about 3%, about 1%, or about 0.5% (w / w) (i.e., based on the total weight of the swelling layer). In some embodiments, the lubricant comprises sodium stearyl fumarate, glyceryl behenate, stearic acid, magnesium stearate, or mixtures thereof. In some embodiments, the lubricant comprises or consists of sodium stearyl fumarate (SSF). In some embodiments, the swelling layer further comprises a glidant. In some embodiments, the swelling layer further comprises an antioxidant. Suitable antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole, tocopherol, tocopherol acetate, ascorbic acid, sodium sulfite, sodium metabisulfite, and mixtures thereof. In some embodiments, the antioxidant is BHT.

[0072] In some embodiments, the swelling layer of the gastroretentive dosage form (e.g., tablet) swells to about 200% or more of its dry volume when immersed in water, gastric juice, or another aqueous medium. In some embodiments, the swelling layer swells to about 150% of its dry volume. In some embodiments, the swelling layer is swelled according to the USP 1000002 ... <701> During disintegration testing according to the method of claim 1, the composition is still essentially intact (e.g., one substantially undisintegrated mass) after about 8 hours or more.

[0073] In some embodiments, the carbidopa of the gastroretentive dosage form (e.g., tablet) is delivered along with 5-HTP from the same modified release layer (i.e., modified release layer of a bilayer tablet). In some embodiments, the swelling layer is attached / adhered to the modified release layer without a binder or tie layer between the modified release layer and the swelling layer. In some embodiments, the modified release layer and the swelling layer are delivered according to the USP <701> and remain attached to one another for at least 8 hours during disintegration testing according to . In some embodiments, the modified release layer includes PEO, for example, to enhance adhesion between the modified layer and the swelling layer. In some embodiments, the PEO is present in the modified release layer at about 1% (w / w) to about 10% (w / w), based on the total weight of the modified release layer. In some embodiments, the modified release layer remains directly or indirectly attached to the swelling layer throughout substantially the entire drug release period.

[0074] In some embodiments, the modified release layer of the gastroretentive dosage form (e.g., tablet) comprises about 50% (w / w) 5-HTP based on the total weight of the modified release layer. In some embodiments, the modified release layer comprises about 0.0625% (w / w) to about 5% (w / w) carbidopa based on the total weight of the modified release layer. In some embodiments, the modified release layer comprises about 50% (w / w) 5-HTP and about 0.0625% (w / w) to about 5% (w / w) carbidopa based on the total weight of the modified release layer. Thus, in some embodiments, for example, when the dosage form is a bilayer tablet having a total weight of about 1000 mg, and the modified release layer and the swelling layer have approximately the same weight, the tablet (e.g., modified release layer) comprises about 250 mg 5-HTP. In some embodiments, the tablet (e.g., modified release layer) contains about 0.3125 mg to about 25 mg of carbidopa. In some embodiments, the tablet (e.g., modified release layer) contains about 250 mg of 5-HTP and about 0.3125 mg to about 25 mg of carbidopa.

[0075] In some embodiments, the modified release layer comprises one or more hydrophilic polymers selected from low viscosity HPMC, medium viscosity HPMC, high viscosity HPMC, low MW PEO, medium MW PEO, high MW PEO and high viscosity hydroxyethyl cellulose. The modified release layer can comprise a single hydrophilic polymer or a combination of two, three or more of low viscosity HPMC, medium viscosity HPMC, high viscosity HPMC, low MW PEO, medium MW PEO, high MW PEO and high viscosity hydroxyethyl cellulose. The modified release layer can also comprise multiple polymers of the same type (e.g., two or more medium viscosity HPMC). In some embodiments, the modified release layer has a molecular weight of about 14% (w / w) to about 37% (w / w) (based on the total weight of the modified release layer) (e.g., about 14% (w / w), 15% (w / w), 16% (w / w), 17% (w / w), 18% (w / w), 19% (w / w), 20% (w / w), 21% (w / w), 22% (w / w), 23% (w / w), or more. %(w / w), 24%(w / w), 25%(w / w), 26%(w / w), 27%(w / w), 28%(w / w), 29%(w / w), 30%(w / w), 31%(w / w), 32%(w / w), 33%(w / w), 34%(w / w), 35%(w / w), 36%(w / w) or about 37%(w / w). For example, in some embodiments, the release rate of 5-HTP and carbidopa in the modified release layer of the gastroretentive tablet formulation is controlled by the level of medium viscosity HPMC, such as HPMC K4M. In some embodiments, a mixture (i.e., blend) of medium viscosity and high viscosity hydroxypropyl methylcellulose, such as HPMC K100M, controls the release rate. Thus, in some embodiments, HPMC is present in the modified release layer at about 10% to about 35% (w / w), based on the total weight of the modified release layer. In some embodiments, the modified release layer comprises about 15% (w / w) to about 35% (w / w) HPMC. In some embodiments, the medium to high MW PEO in the modified release layer controls the release of the drug. Thus, in some embodiments, the modified release layer comprises medium and / or high MW PEO.In some embodiments, the modified release layer comprises about 5% (w / w) medium MW PEO and / or high MW PEO and about 13% (w / w) to about 32% (w / w) of low viscosity HMPC, medium viscosity HPMC, or a mixture (i.e., a blend) of medium viscosity HPMC and high viscosity HPMC.

[0076] In some embodiments, the modified release layer of the gastroretentive dosage form (e.g., tablet) comprises a filler. In some embodiments, the filler comprises or consists of microcrystalline cellulose (MCC) or another ductile (i.e., non-brittle) filler, such as, but not limited to, calcium sulfate, cellulose, dicalcium phosphate, kaolin, lactose, mannitol, sodium chloride, sorbitol, starch, sucrose, or mixtures thereof. In some embodiments, the filler can improve tablet properties (e.g., hardness) in addition to maintaining a larger tablet size while having a neutral effect on drug release. In some embodiments, the modified release layer comprises about 5% (w / w) to about 30% (w / w) MCC (e.g., about 5% (w / w), 10% (w / w), 15% (w / w), 20% (w / w), 25% (w / w) or about 30% (w / w) MCC) based on the total weight of the modified release layer. In some embodiments, the modified release layer comprises about 20% (w / w) MCC based on the total weight of the modified release layer. In some embodiments, the modified release layer comprises about 25% (w / w) MCC based on the total weight of the modified release layer.

[0077] In some embodiments, the modified release layer of the gastroretentive sustained release dosage form further comprises a lubricant. In some embodiments, the lubricant comprises or consists of an SSF. In some embodiments, the modified release layer comprises about 0.5% (w / w) to about 3% (w / w) of a lubricant (e.g., SSF) based on the total weight of the modified release layer. Other exemplary lubricants include, but are not limited to, glyceryl behenate, stearic acid, or magnesium stearate.

[0078] In some embodiments, the modified release layer of the gastroretentive extended release tablet formulation further comprises an antioxidant. In some embodiments, the antioxidant comprises or consists of butylated hydroxytoluene (BHT). In some embodiments, the modified release layer comprises about 0.05% (w / w) to about 1% (w / w) based on the total weight of the modified release layer. Other exemplary antioxidants include, but are not limited to, butylated hydroxyanisole, tocopherol, tocopherol acetate, ascorbic acid, sodium sulfite, sodium metabisulfite, and others listed in the Handbook of Pharmaceutical Excipients.

[0079] In some embodiments, the presently disclosed subject matter provides a gastroretentive bilayer tablet comprising a swelling layer and a modified release layer, the modified release layer comprising, based on the total weight of the modified release layer, about 50% (w / w) 5-HTP; about 0.06% (w / w) to about 5.4% (w / w) carbidopa; about 5.7% (w / w) to about 25.1% (w / w) MCC, about 5% (w / w) medium or high MW PEO; about 7% (w / w) to about 18% (w / w) medium viscosity HPMC; about 0% (w / w) to about 25% (w / w) high viscosity HPMC; about 0.2% (w / w) BHT, about 0.1% (w / w) colloidal silica, and about 1.5% (w / w) SSF. In some embodiments, the modified release layer comprises, based on the total weight of the modified release layer, about 50% (w / w) 5-HTP; about 0.06% (w / w) to about 5.4% (w / w) carbidopa; about 19.8% (w / w) to about 25.1% (w / w) MCC; about 5% (w / w) medium or high MW PEO; about 18% (w / w) medium viscosity HPMC; about 0.2% (w / w) BHT; about 0.1% (w / w) colloidal silica; and about 1.5% (w / w) SSF. In some embodiments, the swelling layer comprises, based on the total weight of the swelling layer, about 49.55 (w / w) high MW PEO, about 49.5% (w / w) high viscosity HPMC, and about 1% (w / w) lubricant (e.g., SSF). In some embodiments, the weight of the modified release layer and the swelling layer is approximately the same. In some embodiments, the weight of the tablet is about 800mg to about 1200mg. In some embodiments, the weight of the table is about 1000mg. Thus, in some embodiments, the weight of each of the swelling layer and the modified release layer is about 500mg.

[0080] In some embodiments, the gastroretentive dosage form (e.g., tablet) is coated to enhance swallowing. In some embodiments, the coating has no or minimal functional impact on tablet swelling and drug delivery. In some embodiments, the coating adds color. In some embodiments, the coating masks taste.

[0081] In some embodiments, the tablet hardness of the gastroretentive tablet is about 22 kilopounds (Kp) to about 28 Kp. In some embodiments, the tablet hardness is about 24 Kp to about 26 Kp. In some embodiments, the tablet hardness is about 25 Kp.

[0082] United States Pharmacopeia ("USP") <905> “Uniformity of Dosage Units” (2011) and USP <701> Methods for determining disintegration and content uniformity are known in the art, including the methods described in “Disintegration” (2016), each of which is incorporated herein by reference for all purposes.

[0083] In some embodiments, the uniformity of the 5-HTP and carbidopa content in the gastroretentive dosage form (e.g., tablet) is measured according to USP <905> “Uniformity of Dosage Units”, 2011. In some embodiments, the modified release layer meets the requirements of the USP 1995 Standards for Pharmaceuticals and Medical Devices (USP 1995 Standards for Pharmaceuticals and Medical Devices), which meet the requirements of the USP 1995 Standards for Pharmaceuticals and Medical Devices (USP 1995 Standards for Pharmaceuticals and Medical Devices), and meets the requirements of the USP 1995 Standards for Pharmaceuticals and Medical Devices (USP 1995 Standards for Pharmaceuticals and Medical Devices). In some embodiments, the modified release layer meets the requirements of the USP 1995 Standards for Pharmaceuticals and Medical Devices (USP 1995 Standards for Pharmaceuticals and Medical Devices), which meet the requirements of the USP 1995 Standards for Pharmaceuticals and Medical Devices (USP 1995 Standards for Pharmaceuticals and Medical Devices), and meets the requirements of the USP 1995 Standards for Pharmaceuticals and Medical <905> (calculated according to). In some embodiments, the modified release layer has a relative standard deviation (RSD) of about 3% or less in a content uniformity test. In some embodiments, the modified release layer has an AV of about 15 or less and an RSD of about 3% or less in a content uniformity test. In some embodiments, the modified release layer remains stable (e.g., physically and / or chemically stable) for at least 70 days when stored at 15°C to about 25°C and protected from light. In some embodiments, the gastroretentive dosage form (e.g., tablet) remains physically and chemically stable for at least 70 days when stored at 15°C to about 25°C and protected from light.

[0084] While the time that a gastric retentive dosage form remains in the stomach may vary from individual to individual, in some embodiments, the gastric retentive dosage form (e.g., a tablet) swells in the stomach (e.g., in the fed state, i.e., when the dosage form is orally administered to a human concurrently with or within about 15 minutes after a meal) and is retained in the stomach for an average of about 4 hours to about 6 hours across a group of subjects, as assessed by scintigraphy. In some embodiments, the dosage form is retained in the stomach for about 5 hours.

[0085] In some embodiments, the delivery rate of 5-HTP from the gastroretentive extended release tablet formulation is not affected by the level of carbidopa.For example, the dose of carbidopa in the modified release layer can be adjusted (e.g., from about 0.3125 mg to about 25 mg) without affecting the release rate of 5'-HTP by adjusting the level of ductile filler (e.g., MCC) so that the total combined weight of carbidopa and ductile filler remains constant.For example, at higher carbidopa content, the modified release layer can contain less ductile filler, whereas at lower carbidopa content, the modified release layer can contain more ductile filler.In other words, the dosage form can be configured to maintain the same 5-THP release rate over a range of different carbidopa content values ​​by inversely adjusting the amount of ductile filler based on carbidopa content. In some embodiments, the dosage form is configured to provide the same release rate for 5-HTP and / or the same release rate for carbidopa over a range of carbidopa contents from 0.3125 mg to 25 mg when the total combined weight of carbidopa and microcrystalline cellulose is held constant. Thus, in some embodiments, the T=80% of carbidopa and / or 5-HTP is the same regardless of whether the dosage form contains 0.3125 mg of carbidopa or 25 mg of carbidopa or any value therebetween.

[0086] In some embodiments, the 5-HTP dose per gastroretentive dosage form (e.g., tablet) is fixed while the carbidopa dose per tablet varies to obtain various plasma 5-HTP levels that meet the requirements of the treatment scenario. In some embodiments, the 5-HTP dose is fixed at about 250 mg per tablet while the carbidopa dose varies from about 0.3125 mg to about 25 mg. In some embodiments, the fixed dose of 5-HTP is less than 250 mg, and in some embodiments, the fixed dose of 5-HTP is higher than 250 mg. In some embodiments, the fixed dose of 5-HTP per tablet is about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg or about 500 mg while the carbidopa dose per tablet varies.

[0087] In some embodiments, the carbidopa dose per gastroretentive dosage form (e.g., tablet) enhances 5-HTP plasma exposure from a given fixed dose of 5-HTP by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of natural 5-HTP immediate release form. In some embodiments, the carbidopa dose enhances 5-HTP plasma exposure from a given fixed dose of 5-HTP by about 0.5-fold to about 3-fold compared to the plasma exposure resulting from the same dose of natural 5-HTP immediate release form. In some embodiments, the carbidopa dose enhances 5-HTP plasma exposure from a given fixed dose of 5-HTP by about 3-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its natural 5-HTP immediate release form.

[0088] In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose in a gastroretentive dosage form (e.g., tablet) enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels are at steady state with an average C of about 5 ng / ml or less. MaxIn some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose enhances 5-HTP plasma exposure by about 1-fold to about 10-fold, while carbidopa plasma levels reach an average steady-state C value of about 5 ng / ml or less. In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose in a gastroretentive dosage form (e.g., tablet) enhances 5-HTP plasma exposure by about 1-fold to about 10-fold, while carbidopa plasma levels reach an average steady-state C value of about 10 ng / ml or less, compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form. Max In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels average at steady state below about 10 ng / ml.

[0089] In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose in a gastroretentive dosage form (e.g., tablet) enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels are at steady state with an average C of about 15 ng / ml or less. Max In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels average at steady state below about 15 ng / ml.

[0090] In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose in a gastroretentive dosage form (e.g., tablet) enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels are at steady state with an average C of about 20 ng / ml or less. Max In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels average at steady state below about 20 ng / ml.

[0091] In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose in a gastroretentive dosage form (e.g., tablet) enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels are at steady state with an average C of about 20 ng / ml or less. Max In some embodiments, the dose range of carbidopa used with a fixed 5-HTP dose enhances 5-HTP plasma exposure by about 1-fold to about 10-fold compared to the plasma exposure resulting from the same dose of 5-HTP administered in its native 5-HTP immediate release form, while carbidopa plasma levels average at steady state below about 25 ng / ml.

[0092] In some embodiments, the 5-HTP plasma exposure generated by the gastroretentive dosage form (e.g., tablet) increases with higher carbidopa dose in the modified release layer containing 5-HTP and carbidopa, compared to its natural immediate release form of 5-HTP.In some embodiments herein, the relationship between the increase in carbidopa dose and the increase in 5-HTP plasma exposure is nonlinear.In some embodiments herein, the relationship between the increase in carbidopa dose and the increase in 5-HTP plasma exposure is linear at lower carbidopa doses and nonlinear at higher carbidopa doses.

[0093] In some embodiments, a 1-fold increase in carbidopa dose results in a less than 1-fold increase in 5-HTP exposure.In some embodiments, a 1-fold increase in carbidopa dose results in about a 1-fold increase in 5-HTP exposure at lower carbidopa doses and a less than 1-fold increase in 5-HTP exposure at higher carbidopa doses.In some embodiments, a fold increase in carbidopa dose results in a smaller fold increase in 5-HTP exposure.

[0094] The 5-HTP plasma levels generated by the gastroretentive dosage form (e.g., when administered once or twice daily to a mammal, such as a human, optionally in a fed state) can average from about 25 ng / ml to about 1000 ng / ml at steady state, depending on the combination of 5-HTP and carbidopa doses. In some embodiments, at steady state, with twice daily dosing, the average 5-HTP plasma level is greater than about 25 ng / ml. In some embodiments, at steady state, with twice daily dosing, the average 5-HTP plasma level is greater than about 50 ng / ml. In some embodiments, at steady state, the average 5-HTP plasma level is greater than about 100 ng / ml. In some embodiments, at steady state, the average 5-HTP plasma level is greater than about 150 ng / ml. In some embodiments, at steady state, the average 5-HTP plasma level is greater than about 200 ng / ml. In some embodiments, at steady state, the average 5-HTP plasma level is greater than about 250 ng / ml. In some embodiments, at steady state, the average 5-HTP plasma level is greater than about 300 ng / ml. In some embodiments, the steady state average 5-HTP plasma level is greater than about 350 ng / ml. In some embodiments, the steady state average 5-HTP plasma level is greater than about 400 ng / ml.

[0095] In some embodiments, the average 5-HTP plasma T produced by the gastroretentive dosage form (e.g., tablet) Max is delayed by about 1-fold to about 7-fold compared to 5-HTP administered in its native immediate release form (e.g., based on once or twice daily administration to humans, optionally in a fed state). In some embodiments, the mean 5-HTP plasma T Max occurs at about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours. In some embodiments, administration of a once or twice daily dosage form (e.g., tablet) to a mammalian subject, optionally a human, results in a maximum plasma concentration (T) of 5-HTP that is delayed on average by about 4 hours compared to an immediate release dosage form of 5-HTP. Max ) to achieve the

[0096] The mean carbidopa plasma level produced by the gastroretentive dosage form (e.g., tablet) can be less than about 25 ng / ml at steady state. In some embodiments, the mean carbidopa plasma level can be less than about 20 ng / ml, less than about 15 ng / ml, less than about 10 ng / ml, less than about 5 ng / ml, less than about 2.5 ng / ml, or less than about 1 ng / ml. The mean carbidopa C produced by the gastroretentive dosage form can be less than about 25 ng / ml at steady state. In some embodiments, the mean carbidopa plasma level can be less than about 20 ng / ml, less than about 15 ng / ml, less than about 10 ng / ml, less than about 5 ng / ml, less than about 2.5 ng / ml, or less than about 1 ng / ml. Max The plasma level may be less than about 25 ng / ml at steady state. In some embodiments, the mean C produced by the subject matter of the present disclosure Max Plasma levels may be less than about 20 ng / ml, less than about 15 ng / ml, less than about 10 ng / ml, less than about 5 ng / ml, less than about 2.5 ng / ml or less than about 1 ng / ml at steady state.

[0097] The gastroretentive dosage forms (e.g., tablets) of the presently disclosed subject matter, in some embodiments, have a shorter terminal half-life (T ) compared to when 5-HTP is administered at a given dose in its native immediate release form. 1 / 2 ) can be increased. In some embodiments, administering a once or twice daily dosage form (e.g., tablet) to a mammalian subject, optionally a human, provides an increased 5-HTP half-life compared to the 5-HTP half-life when 5-HTP is administered in immediate release form. In some embodiments, the 5-HTP half-life is increased by about 10% to about 200% compared to the 5-HTP half-life when 5-HTP is administered in immediate release form. In some embodiments, the T 1 / 2 is extended by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100%. 1 / 2 is extended by about 100% to about 200%. 1 / 2 is about 3.2 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours or about 6 hours.

[0098] Thus, the gastroretentive dosage form of the present disclosure can be orally administered and can act therapeutically by increasing plasma 5-HTP levels above baseline continuously all or most of the time. In some embodiments, 5-HTP plasma levels are continuously increased with minimal fluctuations in levels over time. Without being bound by any theory, it is believed that since 5-HTP crosses the blood-brain barrier, increased plasma 5-HTP can increase (i) synthesis, (ii) levels, and (iii) neurotransmission of serotonin in the brain. More specifically, it is believed that increased levels of extracellular serotonin can cause increased stimulation of serotonin receptors. This total receptor stimulation can cause increased serotonin neurotransmission. As described herein above, there is support for the therapeutic relevance of increased serotonin neurotransmission using 5-HTP dosage forms in a wide range of human disorders.

[0099] Thus, in some embodiments, the subject of the present disclosure provides the use of the disclosed gastroretentive dosage form for therapeutic use in a subject in need thereof. In some embodiments, the subject is a human. The gastroretentive extended release tablet formulation can be administered once or twice a day. Administration can be performed at any time of day. In some embodiments, administration is performed in the morning and evening with or after breakfast and dinner (e.g., within about 15 minutes after breakfast and dinner), respectively. In some embodiments, the interval between administrations in twice-daily dosing is about 12 hours, but the interval can be longer or shorter. In some embodiments, the gastroretentive dosage form is administered to a subject in need thereof during or after a meal. In some embodiments, twice-daily administration is performed during or after morning and evening meals. In some embodiments, twice-daily administration is performed after the two highest calorie or fat content meals of the day, such as breakfast and dinner, lunch and dinner, or breakfast and lunch.

[0100] In some embodiments, the gastroretentive dosage form (e.g., a tablet) is administered once a day, for example, during or after the meal with the highest calorie content and / or during or after the meal with the highest fat content of the day.

[0101] In some embodiments, the gastroretentive dosage form (e.g., tablet) is administered once, twice, or three times daily. In some embodiments, the gastroretentive dosage form (e.g., tablet) is administered more than three times daily.

[0102] In some embodiments, the gastroretentive dosage forms (e.g., tablets) of the present disclosure are used therapeutically with one or more other drugs.

[0103] In some embodiments, the gastroretentive dosage form is used as an adjunct therapy to serotonin reuptake inhibitors when treatment with serotonin reuptake inhibitors alone provides insufficient therapeutic relief.It is known that 5-HTP synergizes with serotonin reuptake inhibitors in elevating extracellular serotonin in mammalian brains (Jacobsen et al., 2016a).That is, under some circumstances, the increase in brain extracellular serotonin as a result of co-administration of 5-HTP and serotonin reuptake inhibitors is greater than the sum of the increase in brain extracellular serotonin as a result of 5-HTP and serotonin reuptake inhibitors administered individually.Therefore, the gastroretentive dosage form of the present disclosure can be used to significantly enhance the pharmacological effect of serotonin reuptake inhibitor therapy.

[0104] In some embodiments, the effective therapeutic plasma 5-HTP level resulting from the administration of the gastroretentive dosage form of the present disclosure is lower when the gastroretentive dosage form is used as a monotherapy compared to when the gastroretentive dosage form is used as an adjunct to serotonin reuptake inhibitor therapy.In further embodiments, a lower dose of serotonin reuptake inhibitor can be used during combination therapy with the gastroretentive dosage form of the present disclosure to achieve therapeutic efficacy.In some embodiments, there is an interval between the administration of the gastroretentive dosage form of the present disclosure and the administration of the serotonin reuptake inhibitor to enhance the tolerability of the combination therapy.A convenient mode is to administer the serotonin reuptake inhibitor before a given meal and administer the gastroretentive dosage form after a given meal.In different embodiments, the interval is 0.5 hours, 1 hour, 2 hours, 3 hours or 4 hours or longer.

[0105] Some disorders may require high and sustained 5-HTP plasma exposure, in which case more than one unit per administration of a gastroretentive dosage form (e.g., tablet) may be required. In some embodiments, two, three, four or more dosage forms (e.g., tablets) can be administered once, twice, three or more times a day.

[0106] In some embodiments, a titration scheme can be used to gradually increase 5-HTP plasma levels over days, weeks or months to optimize the safety and / or tolerability of the gastroretentive dosage forms of the present disclosure in subjects in need of the gastroretentive dosage forms of the present disclosure. In some embodiments, titration is accomplished by initiating treatment with a tablet containing a lower level of carbidopa, e.g., 0.3125 mg, and after a first interval, a tablet containing a higher carbidopa level, e.g., 0.625 mg, is administered for a second interval. This titration approach can be extended for a third, fourth, fifth, etc. interval using tablets with increasing levels of carbidopa. The length of the interval can be one to several days or one to several weeks, as needed. In some embodiments, titration is individualized to the patient, e.g., to optimize the safety, tolerability and clinical response of the subject. In some instances, titration includes administering only one tablet per day for a first interval, followed by administering two or more tablets per day for a second and subsequent intervals.Similarly, titration can be achieved in subjects who require titration by administering tablets of decreasing carbidopa dose strength over one, two, three or several intervals, and / or by reducing the number of tablets administered per day.Tapering can minimize discontinuation symptoms for many pharmaceuticals, including serotonergic enhancers (Haddad, 1998).

[0107] In some embodiments, the gastroretentive dosage form is used to treat certain disorders, non-limiting examples of which include social anxiety, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder (OCD), mood symptoms and agitation associated with neurological disorders (e.g., Alzheimer's disease, Parkinson's disease), stroke recovery, premenstrual dysphoria, post-traumatic stress disorder, postpartum depression, depression after interferon treatment, eating disorders, obesity, irritable bowel syndrome-constipation, idiopathic constipation and other constipation disorders.Furthermore, in some embodiments, the gastroretentive dosage form is used to treat indications whose etiology is related to low brain serotonin, non-limiting examples of which include impulse control disorder, aggression, suicidal ideation, borderline personality disorder, autism, phenylketonuria and tetrahydrobiopterin deficiency. EXAMPLES

[0108] The following examples are included to provide guidance to those skilled in the art for carrying out representative aspects of the subject matter of the present disclosure. In light of this disclosure and the general level of skill in the art, those skilled in the art will appreciate that the following examples are intended to be illustrative only, and that numerous changes, modifications and alterations can be used without departing from the scope of the subject matter of the present disclosure.

[0109] Example 1 Manufacturing of 5-HTP / low-dose carbidopa gastric retention tablets Four compositions of the 5-HTP / low dose carbidopa gastroretentive tablet technology were formulated and manufactured as bilayer tablets. See Table 1 below. The tablet weight was approximately 1000 mg total. The shape of the dry tablet was oval, 18.9 mm long, 9.6 mm wide, 7 mm deep, with beveled edges. The weights of the swelling layer and modified release layer were both approximately 500 mg.

[0110] Tablets were made from separate blends for the swelling and modified release layers, with each layer being filled and compressed sequentially after the other in a tablet die to obtain bilayer tablets. Each excipient was sieved and added to the appropriate blend (swelling or modified release).

[0111] In the modified release layer blend, the 5-HTP and carbidopa ingredients were added to the filler and then dry rinsed. <905> To obtain uniformity of carbidopa content in the blend that meets the requirements of carbidopa content, carbidopa was mixed with a small amount of microcrystalline cellulose (MCC) to make a first "preblend". If necessary, i.e., at a lower level of carbidopa, the first preblend was mixed with an additional amount of MCC to make a second preblend. This process was optionally repeated several times to make several intermediate preblends to achieve uniformity of carbidopa content. The final MCC / carbidopa preblend was mixed with the remaining modified release layer additives except for 5-HTP and sodium stearyl fumarate. This mixture was sieved through a 600 μm sieve, and then sodium stearyl fumarate was added and mixed. This was the final modified release layer blend.

[0112] For the swelling layer blend, all additives were screened and mixed. This was the final swelling layer blend.

[0113] A manual tablet press (Natoli NP-RD10A, Natoli, Saint Charles, Missouri, United States of America) was used to produce tablets. First, the modified release blend was loaded into the die and compressed. Then, the swollen blend was loaded into the die and compressed on top of the modified release layer to obtain bilayer tablets. Tablet hardness was approximately 25 kp (22-28 kp).

[0114] These tablets were prepared by a manual process, however the same process can be fully automated with an automated bilayer press, e.g., Manesty BB3B Bilayer Tablet Press (Manesty, Knowsley, United Kingdom). The granulation process and the addition of glidants can improve the flow of the powder for use in an automated process, and lubricated materials can be added to avoid sticking to machine parts. Additionally, although these tablets were produced by direct compression, tablet production is easily adapted to high shear granulation, fluid bed granulation or roller compaction to allow for the production of robust tablets and / or improve content uniformity, as well as to scale up production. The composition of the swelling layer and modified release layer are shown in Table 1 below. The 5-HTP level was kept constant at 250 mg per tablet. The carbidopa content was adjusted for the level of hydration of the carbidopa bulk drug. The levels of carbidopa per tablet (adjusted for the hydration of the carbidopa bulk drug) ranged from 0.3125 mg to 25 mg. The carbidopa content uniformity results are shown in Table 2 below. TIFF2024528125000002.tif255170TIFF2024528125000003.tif73170

[0115] The release rate of 5-HTP from the modified release layer when combined with the swelling layer in a bilayer tablet varied from T80% approx. 8 hours (h) ("fast", see Figures 1A-1B) to T80% approx. 11 hours ("slow") (see Figures 1C-1D) under dissolution testing using USP III equipment (Agilent BIO-DIS Reciprocating Cylinder Apparatus 3 / 7 System with 850-DS Dissolution Sampling Station (Autosampler)). T80% is the time when 80% of the compound (5-HTP or carbidopa) has been released from the dosage form. The release rate was controlled by varying the levels of HPMC K100M CR and HPMC K4M DC in the modified release layer and adjusting the MCC level to maintain a modified release layer weight of 500 mg. See Table 1. An increase or decrease in carbidopa level was compensated by decreasing or increasing the MCC level, respectively, to maintain a modified release layer weight of 500 mg. See Table 1. Carbidopa level did not affect 5-HTP release rate. See Figure 2. 5-HTP and carbidopa release rates were similar and parallel regardless of overall release rate ("fast", "slow" or "medium") and carbidopa level. See Figures 3A-3C. See also Table 6 in Example 3 below. For all compositional iterations of the bilayer tablet, the difference in T=80% for 5-HTP and carbidopa was less than 2 hours.

[0116] Disintegration test (USP <701> During disintegration testing (a Copley DTG 2000 disintegration tester equipped with a disk conforming to “Disintegration” (2019)), the swellable layer remained largely intact (i.e., in one piece and without significant erosion) and the modified release layer remained attached to the swellable layer (albeit reduced in size due to erosion) for at least 8 hours. See Figure 4.

[0117] Example 2 Short-term stability of 5-HTP / low-dose carbidopa gastroretentive tablets. Three different carbidopa loadings of bilayer tablets of 5-HTP / low dose carbidopa ("fast") gastroretentive composition were tested for short-term stability (T=0, T=7 days, T=35 days, and T=70 days). Modified release layers were defined as "stable" if they met all pass / fail criteria defined in Tables 3-5. The three bilayer tablets contained 250 mg 5-HTP / 0.625 mg carbidopa, 250 mg 5-HTP / 5 mg carbidopa, and 250 mg 5-HTP / 25 mg carbidopa. The assays and related substances for 5-HTP and carbidopa were determined on a single modified release monolayer because the swelling layer additives interfered with the assays and related substances for 5-HTP and carbidopa. The assays for 5-HTP and carbidopa were within 90.0-110.0% of nominal at all stability time points for all three tablets. The related substances of 5-HTP and carbidopa remained within the pass / fail criteria at all stability time points for all three tablets. Appearance remained unchanged as white to off-white bilayer tablets for all bilayer tablets. See Tables 3-5 below. The dissolution profiles of 5-HTP and carbidopa from the three bilayer tablets were tested using a USP III apparatus. See Figures 5A-5E. The dissolution profiles of 5-HTP for all three bilayer tablets at 70 days were indistinguishable from the profiles at T=0. See Figures 5A-5C and Tables 3-5. The dissolution profiles of carbidopa for the 250 mg 5-HTP / 5 mg carbidopa and 250 mg 5-HTP / 25 mg bilayer tablets were indistinguishable from the profiles at T=0 (carbidopa levels from the 250 mg 5-HTP / 0.625 mg carbidopa bilayer were too low to be reliably quantified). Please see Figures 5D and 5E. TIFF2024528125000004.tif255170TIFF2024528125000005.tif255170TIFF2024528125000006.tif255170

[0118] Example 3 Other 5-HTP / low-dose carbidopa gastroretentive tablet manufacturers To further broaden the scope of the 5-HTP / low-dose carbidopa gastroretentive tablet technology presented in Example 1, a series of 33 compositions of bilayer tablets with different swelling layers and modified release layers were prepared and characterized by dissolution testing as described in Example 1. See Table 6 below. Excipients not listed are the same as those listed in Table 1. In 29 of the 33 compositions tested for T=80% release, the difference between T=80% of 5-HTP and T=80% of carbidopa was less than 2 hours, demonstrating essentially parallel release of 5-HTP and carbidopa. TIFF2024528125000007.tif255170TIFF2024528125000008.tif109170

[0119] Formulations were prepared with 300 mg 5-HTP, 25 mg carbidopa for a total tablet weight of 1200 mg (swell layer 600 mg, modified release layer 600 mg) up until formulation 201140-082 series, where the tablet weight was subsequently reduced from 1200 mg to 1000 mg (swell layer 500 mg, modified release layer 500 mg) with 250 mg 5-HTP and 2.5 mg carbidopa.

[0120] Example 4 Additive compatibility An excipient compatibility study was conducted to examine the stability of 5-HTP and carbidopa mixed together, either with only the two APIs or in the presence of one or two excipients. Small aliquots of 5-HTP (300 mg) and carbidopa (25 mg) blended together with or without excipients were used to test stability (assay and impurity levels). See Table 7 below. The API / excipient ratios were based on the approximate composition of the 5-HTP and carbidopa gastroretentive tablets in Table 1. There was no significant increase in the impurity levels for any of the API / excipient combinations at T=0, 40° C., 7 days and 1 month storage. See Table 8 below. The maximum percentage increase of carbidopa (most prevalent single impurity) was 0.44%, 0.55% and 0.86% at T=0, 7 days and 1 month, respectively. The maximum percentage increases for 5-HTP were 0.27%, 0.48% and 0.49% at T=0, 7 days and 1 month, respectively. TIFF2024528125000009.tif191170TIFF2024528125000010.tif255170

[0121] Example 5 Evaluation of 5-HTP / low-dose carbidopa gastroretentive tablets in healthy human volunteers In a five-period, open-label pharmacokinetic study, "fast" 5-HTP (250 mg) / low-dose carbidopa (0.625 mg, 2.5 mg, 5 mg, or 15 mg) gastroretentive tablets were orally administered to subjects from a cohort of 16 healthy subjects in total. See Table 9. The subjects' mean age was approximately 50 years (range 33-60 years). All were Caucasian, with 11 males and 5 females. The mean weight was approximately 80 kg, and all had a body mass index (BMI) of 32.0 kg / m2. 2 The subjects were admitted to the clinic for the duration of the study. 111The tablets were radiolabeled with In to allow for parallel scintigraphic location of the tablets within the gastrointestinal tract. Tablets were administered in the morning, one tablet per dose, after intake of 80% or more of breakfast. Tablets were administered with 210 mL of water, followed by a radiolabeled drink (radiocontrast agent) containing up to 4 MBq Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) in 30 mL of water. Blood samples for 5-HTP and carbidopa plasma analysis were taken at predetermined time points over 36 hours after tablet administration.

[0122] In the first four periods, tablets were administered in the order of increasing doses of carbidopa after a standardized FDA high-fat, high-calorie meal (FDA, 2022). The highest carbidopa dose tablet, 5-HTP (250 mg) / carbidopa 15 mg, was repeated in period 5, but using an FDA medium-fat, medium-calorie meal to evaluate the effect of another meal type on 5-HTP and carbidopa pharmacokinetics of the "fast" gastroretentive tablet. See Table 9 below. Plasma 5-HTP and carbidopa were analyzed by liquid chromatography-mass spectrometry. Regarding the tablet 5-HTP profile, tablet pharmacokinetic 5-HTP data from the "fast" gastroretentive tablet were compared with plasma 5-HTP data from a separate cohort of 12 healthy volunteers recruited from the same geographic area who received 250 mg natural 5-HTP immediate release after a standardized FDA high-fat, high-calorie meal in a similarly designed study, within the same clinic, under similar experimental conditions as for the "fast" gastroretentive tablet. TIFF2024528125000011.tif60170

[0123] Plasma pharmacokinetic parameters were estimated using standard Phoenix WinNonlin methods. Data are shown as geometric mean ± SEM. 5-HTP plasma profile after single tablet administration after a high-fat meal is shown in Figure 6A. 5-HTP plasma profile after single tablet administration of the "fast" 5-HTP (250 mg) / low-dose carbidopa (15 mg) tablet after an FDA high-fat, high-calorie meal compared to an FDA medium-fat, medium-calorie meal is shown in Figure 6B. Data from periods 1-4 were fitted and simulated to extrapolate to the pharmacokinetic steady state at twice daily dosing (after a high-fat, high-calorie meal) using nonparametric overlay. See Figure 6C. Corresponding AUC at steady state at twice daily dosing extrapolated using nonparametric overlay 1~12h is shown in Figure 6D. Table 10 below summarizes key 5-HTP pharmacokinetic parameters following five gastroretentive tablet treatments: (i) native 5-HTP immediate release, (ii) "fast" 5-HTP(250 mg) / low dose carbidopa(0.625 mg) gastroretentive tablet, (iii) "fast" 5-HTP(250 mg) / low dose carbidopa(2.5 mg) gastroretentive tablet, (iv) "fast" 5-HTP(250 mg) / low dose carbidopa(5 mg) gastroretentive tablet, and (v) "fast" 5-HTP(250 mg) / low dose carbidopa(15 mg) gastroretentive tablet. TIFF2024528125000012.tif255170

[0124] Plasma pharmacokinetic data for carbidopa are shown in Figures 7A-7D. Carbidopa plasma was below the lower limit of quantification (1 ng / ml) at all time points for the 0.625 mg carbidopa dose strength and at most time points for the 2.5 mg carbidopa dose strength. Extrapolation to steady state was performed using nonparametric superposition possible only for the 5 mg and 15 mg carbidopa dose strengths. Table 11 below summarizes important carbidopa pharmacokinetic parameters following (i) a "fast" 5-HTP(250 mg) / low-dose carbidopa(2.5 mg) gastroretentive tablet, (ii) a "fast" 5-HTP(250 mg) / low-dose carbidopa(5 mg) gastroretentive tablet, and (iii) a "fast" 5-HTP(250 mg) / low-dose carbidopa(15 mg) gastroretentive tablet, and (iv) a "fast" 5-HTP(250 mg) / low-dose carbidopa(15 mg) gastroretentive tablet, the latter following a moderate fat meal. Carbidopa concentrations below the limit of quantification are not summarized in the table. A T of approximately 5 hours was observed. max was similar across all dose groups. TIFF2024528125000013.tif59170

[0125] Using swelling layer scintigraphy and 111In radiolabeling, gastric emptying times and colonic transit times were estimated by periodic scintigraphic imaging of subjects following administration of the gastroretentive tablets. See Figure 8. On average, tablets were retained in the stomach for approximately 5 hours, with colonic transit occurring at approximately 9 hours. A single dose of "fast" 5-HTP (250 mg) / low-dose carbidopa (15 mg) after a medium-fat, medium-calorie meal resulted in gastrointestinal transit of the radiolabeled tablet occurring slightly faster than that measured after a high-fat, high-calorie meal. When compared across all five administration periods, the mean gastric emptying (4.4 hours) and colonic transit (6.3 hours) times were approximately 1-2 hours faster after a medium-fat, medium-calorie meal than after a high-fat, high-calorie meal.

[0126] References All references cited herein, including, but not limited to, all patents, patent applications and publications thereof, scientific journal articles and database entries, to the extent they supplement, describe, provide background for, or teach the methodologies, techniques and / or compositions used herein, are incorporated herein by reference in their entirety. Allen GF, Land JM, Heales SJ (2009). A new perspective on the treatment of aromatic L-amino acid decarboxylase deficiency. Mol Genet Metab 97(1):6-14. Birdsall TC(1998).5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev 3(4):271-280. Bono G, Micieli G, Sances G, Calvani M, Nappi G (1984). L-5HTP treatment in primary headaches: an attempt at clinical identification of responsive patients. Cephalalgia 4(3):159-165. Cangiano C, Ceci F, Cascino A, Del Ben M, Laviano A, Muscaritoli M, et al (1992). Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr 56(5):863-867. Caruso I,Sarzi Puttini P,Cazzola M,Azzolini V(1990).Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome.The Journal of international medical research 18(3):201-209. Donnelly,Ronald F(2016)Stability of Levodopa / Carbidopa Rectal Suspensions.Hosp Pharm.Dec;51(11):915-921. Eisenhofer G,Brown S,Peitzsch M,Pelzel D,Lattke P,Glockner S,et al(2014).Levodopa therapy in Parkinson’s disease:influence on liquid chromatographic tandem mass spectrometric-based measurements of plasma and urinary normetanephrine,metanephrine and methoxytyramine.Ann Clin Biochem 51(Pt 1):38-46. FDA(2022).Assessing the Effects of Food on Drugs in INDs and NDAs-Clinical Pharmacology Considerations Guidance for Industry. 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Jacobsen JPR,Oh A,Bangle R,Roberts WL,Royer EL,Modesto N,et al(2019).Slow-release delivery enhances the pharmacological properties of oral 5-hydroxytryptophan:mouse proof-of-concept.Neuropsychopharmacology 44(12):2082-2090. Kahn RS,Westenberg HG(1985).L-5-hydroxytryptophan in the treatment of anxiety disorders.J Affect Disord 8(2):197-200. Lowe SL,Yeo KP,Teng L,Soon DK,Pan A,Wise SD,et al(2006).L-5-Hydroxytryptophan augments the neuroendocrine response to a SSRI.Psychoneuroendocrinology 31(4):473-484. Magnussen I,Dupont E,Prange-Hansen A,de Fine Olivarius B(1977).Palatal myoclonus treated with 5-hydroxytryptophan and a decarboxylase-inhibitor.Acta Neurol Scand 55(3):251-253. Magnussen I,Mondrup K,Engbaek F,Lademann A,Olivarius BD(1982).Treatment of myoclonic syndromes with paroxetine alone or combined with 5-HTP.Acta Neurol Scand 66(2):276-282. Meloni M,Puligheddu M,Carta M,Cannas A,Figorilli M,Defazio G(2020a).Efficacy and safety of 5-hydroxytryptophan on depression and apathy in Parkinson’s disease:a preliminary finding.Eur J Neurol 27(5):779-786. Meloni M,Puligheddu M,Sanna F,Cannas A,Farris R,Tronci E,et al(2020b).Efficacy and safety of 5-Hydroxytryptophan on levodopa-induced motor complications in Parkinson’s disease:A preliminary finding.J Neurol Sci 415:116869. Meltzer H,Bastani B,Jayathilake K,Maes M(1997).Fluoxetine,but not tricyclic antidepressants,potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder.Neuropsychopharmacology 17(1):1-11. PCT Publication No.WO 2019 / 245925 by Jacobsen et al. Ramaekers VT,Senderek J,Hausler M,Haring M,Abeling N,Zerres K,et al(2001).A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa.Molecular genetics and metabolism 73(2):179-187. Rauws AG,Vos JG,Garbis-Berkvens JM,Peters PW,de Vries T,van Logten MJ(1982).Comparative 90-day toxicity of two decarboxylase inhibitors,benserazide and carbidopa,in the rat.Toxicol Appl Pharmacol 66(2):201-220. Santucci M,Cortelli P,Rossi PG,Baruzzi A,Sacquegna T(1986).L-5-hydroxytryptophan versus placebo in childhood migraine prophylaxis:a double-blind crossover study.Cephalalgia 6(3):155-157. Sargent PA,Williamson DJ,Cowen PJ(1998).Brain 5-HT neurotransmission during paroxetine treatment.Br J Psychiatry 172:49-52. Shenker Y,Gross MD,Grekin RJ(1985).Central serotonergic stimulation of aldosterone secretion.J Clin Invest 76(4):1485-1490. Thombre AG(2005).Assessment of the feasibility of oral controlled release in an exploratory development setting.Drug Discov Today 10(17):1159-1166. Trouillas P,Brudon F,Adeleine P(1988).Improvement of cerebellar ataxia with levorotatory form of 5-hydroxytryptophan.A double-blind study with quantified data processing.Arch Neurol 45(11):1217-1222. Turner EH,Loftis JM,Blackwell AD(2006).Serotonin a la carte:supplementation with the serotonin precursor 5-hydroxytryptophan.Pharmacol Ther 109(3):325-338. U.S.Patent No.9,161,911 to Hou. U.S.Patent No.11,337,963 to Jacobsen et al. van Hiele LJ(1980).l-5-Hydroxytryptophan in depression:the first substitution therapy in psychiatry? The treatment of 99 out-patients with ’therapy-resistant’ depressions.Neuropsychobiology 6(4):230-240. van Praag HM(1982).Serotonin precursors in the treatment of depression.Adv Biochem Psychopharmacol 34:259-286.

[0127] It will be understood that various details of the presently disclosed subject matter may be changed without departing from the scope of the presently disclosed subject matter. Further, the foregoing description is by way of example only and not by way of limitation.

Claims

1. 1. A gastroretentive dosage form comprising a tablet, said tablet comprising two layers: (a) a swelling layer comprising one or more hydrophilic polymers, each of said one or more hydrophilic polymers being swellable in the presence of gastric fluid; (b) a modified release layer, the modified release layer comprising 5-hydroxytryptophan (5-HTP) and carbidopa; Equipped with A gastroretentive dosage form, wherein the period during which 80% by weight of 5-HTP is released from said dosage form in a dissolution test is within about 2 hours of the period during which 80% by weight of carbidopa is released.

2. 2. The gastroretentive dosage form of claim 1, wherein 80% by weight of one or both of 5-HTP and carbidopa is released from the dosage form in a dissolution test over a period of about 5 to about 12 hours.

3. 3. The gastroretentive dosage form of claim 1 or 2, wherein the modified release layer comprises one or more hydrophilic polymers selected from the group consisting of low viscosity hydroxypropylmethylcellulose (HPMC), medium viscosity HPMC, high viscosity HPMC, low molecular weight (MW) polyethylene oxide (PEO), medium MW PEO, high MW PEO, and high viscosity hydroxyethylcellulose.

4. 4. The gastroretentive dosage form of claim 3, wherein the modified release layer comprises from about 14% (w / w) to about 37% (w / w) of one or more hydrophilic polymers, based on the total weight of the modified release layer.

5. 4. The gastric retentive dosage form of claim 3, wherein the modified release layer comprises about 5% (w / w) of a medium MW PEO or a high MW PEO, and about 13% (w / w) to about 32% (w / w) of a low viscosity HMPC, a medium viscosity HPMC, or a blend of a medium viscosity HPMC and a high viscosity HPMC, based on the total weight of the modified release layer.

6. the modified emissive layer comprises, based on the total weight of the modified emissive layer: (i) about 50% (w / w) 5-HTP; (ii) about 0.0625% (w / w) to about 5% (w / w) carbidopa; or (iii) about 50% (w / w) 5-HTP and about 0.0625% (w / w) to about 5% (w / w) carbidopa 3. The gastroretentive dosage form of claim 1 or 2, comprising:

7. 3. The gastroretentive dosage form of claim 1 or 2, wherein the modified release layer further comprises from about 5% (w / w) to about 30% (w / w) of one or more ductile fillers, based on the total weight of the modified release layer, and optionally the ductile filler comprises or consists of microcrystalline cellulose (MCC).

8. 3. The gastroretentive dosage form of claim 1 or 2, wherein the modified release layer further comprises about 0.5% (w / w) to about 3% (w / w) of a lubricant, based on the total weight of the modified release layer, and optionally the lubricant is selected from the group consisting of sodium stearyl fumarate (SSF), glyceryl behenate, stearic acid, magnesium stearate, and mixtures thereof.

9. 3. The gastroretentive dosage form of claim 1 or 2, wherein the modified release layer further comprises about 0.01% (w / w) to about 1% (w / w) of an antioxidant, based on the total weight of the modified release layer, and optionally the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole, tocopherol, tocopherol acetate, ascorbic acid, sodium sulfite, sodium metabisulfite, and mixtures thereof.

10. 3. The gastroretentive dosage form of claim 1 or 2, wherein the swelling layer comprises high MW PEO and high viscosity HPMC, and optionally, the swelling layer comprises a weight ratio of high MW PEO:high viscosity HPMC of about 1:

1.

11. 3. The gastroretentive dosage form of claim 1 or 2, wherein the swelling layer further comprises up to about 5% (w / w) of a lubricant, based on the total weight of the swelling layer, and optionally the lubricant comprises or consists of sodium stearyl fumarate (SSF).

12. 3. The gastroretentive dosage form of claim 1 or 2, wherein the swelling layer and the modified release layer have approximately the same weight.

13. 3. The gastroretentive dosage form of claim 1 or 2, wherein the tablet has a total weight of about 500 milligrams (mg) to about 2000 mg, optionally having a total tablet weight of about 1000 mg.

14. 3. The gastroretentive dosage form of claim 1 or 2, wherein the tablet comprises about 250 mg of 5-HTP and about 0.3125 mg to about 25 mg of carbidopa.

15. 3. The gastric retentive dosage form of claim 1, wherein the modified release layer comprises, based on the total weight of the modified release layer, about 50% (w / w) 5-HTP; about 0.06% (w / w) to about 5.4% (w / w) carbidopa; about 5.7% (w / w) to about 25.1% (w / w) MCC; about 5% (w / w) medium or high MW PEO; about 7% (w / w) to about 18% (w / w) medium viscosity HPMC; about 0% (w / w) to about 25% (w / w) high viscosity HPMC; about 0.2% (w / w) BHT; about 0.1% (w / w) colloidal silica; and about 1.5% (w / w) SSF.

16. 16. The gastric retentive dosage form of claim 15, wherein the modified release layer comprises, based on the total weight of the modified release layer, about 50% (w / w) 5-HTP; about 0.06% (w / w) to about 5.4% (w / w) carbidopa; about 19.8% (w / w) to about 25.1% (w / w) MCC, about 5% (w / w) medium or high MW PEO, about 18% (w / w) medium viscosity HPMC, about 0.2% (w / w) BHT, about 0.1% (w / w) colloidal silica, and about 1.5% (w / w) SSF.

17. 3. The gastroretentive dosage form of claim 1, wherein the swellable layer swells in an aqueous solution to at least about 150% of the dry volume of the swellable layer.

18. 3. The gastroretentive dosage form of claim 1, wherein the tablet remains in the stomach for about 5 hours after oral administration to a human.

19. 3. The gastroretentive dosage form of claim 1 or 2, wherein the modified release layer remains stable for at least 70 days when stored at 15°C to about 25°C protected from light.

20. 3. The gastric retentive dosage form of claim 1, wherein the modified release layer and the swelling layer remain adhered to each other for at least 8 hours during a disintegration test according to USP <701> using a circular disk.

21. 3. The gastroretentive dosage form of claim 1 or 2, wherein the modified release layer has an acceptance value (AV) of about 15 or less and a relative standard deviation (RSD) of about 3 or less in a content uniformity test according to USP <905>.

22. 3. The gastroretentive dosage form of claim 1 or 2, wherein administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides a time to achieve maximum plasma concentration (TMax) of 5-HTP that is delayed on average by about 4 hours compared to an immediate release dosage form of native 5-HTP.

23. 3. The gastroretentive dosage form of claim 1 or 2, wherein administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides about 1 to about 10 times the 5-HTP plasma exposure compared to an immediate release native 5-HTP dosage form containing the same weight of 5-HTP, wherein the immediate release native 5-HTP dosage form does not contain carbidopa.

24. 3. The gastroretentive dosage form of claim 1 or 2, wherein administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides a steady-state average 5-HTP plasma level of about 25 nanograms per milliliter (ng / ml) or greater, optionally a steady-state average 5-HTP plasma level of about 50 ng / ml or greater, optionally a steady-state average 5-HTP plasma level of about 100 ng / ml or greater, and optionally a steady-state average 5-HTP plasma level of 100 ng / ml to 500 ng / ml.

25. 3. The gastroretentive dosage form of claim 1 or 2, wherein administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides a steady-state average carbidopa plasma level of about 25 ng / ml or less, optionally about 20 ng / ml or less, and further optionally about 10 ng / ml or less.

26. 3. The gastroretentive dosage form of claim 1 or 2, wherein administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides a steady-state average maximum carbidopa plasma level (CMax) of about 25 ng / ml or less, optionally about 20 ng / ml or less, and further optionally about 10 ng / ml or less.

27. 3. The gastroretentive dosage form of claim 1 or 2, wherein administration of the tablet once or twice daily to a mammalian subject, optionally a human, provides an increased 5-HTP half-life compared to the 5-HTP half-life when native 5-HTP is administered in immediate release form, optionally with an increase in 5-HTP half-life of about 10% to about 200% compared to the 5-HTP half-life when native 5-HTP is administered in immediate release form.

28. 3. The gastroretentive dosage form of claim 1, wherein the dosage form is configured to provide the same release rate for 5-HTP and / or the same release rate for carbidopa over a range of carbidopa contents from 0.3125 mg to 25 mg when the total combined weight of carbidopa and microcrystalline cellulose is held constant.

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