Compositions and methods for increasing the bioavailability of 5-hydroxytryptophan

Abstract

Provided are methods for increasing the bioavailability of enterally administered 5-hydroxytryptophan (5-HTP) in a human subject in need thereof, comprising enterally co-administering low-dose carbidopa with the 5-HTP, and pharmaceutical formulations useful therefor. In some embodiments, the 5-HTP and / or low-dose carbidopa are provided as sustained-release formulations.

Description

[Technical Field]

[0001] [Statement of government support] This invention was made with government support under Federal Grant No. 2R01MH079201-06A1 awarded by the NIH. The government has certain rights in this invention. [Background technology]

[0002] 5-Hydroxytryptophan (5-HTP) is the natural, direct precursor of serotonin (also known as 5-hydroxytryptamine, 5-HT). 5-HTP has been reported to have therapeutic potential in a variety of disorders related to central nervous system function (Turner et al., 2006a), but in humans, it is not rapidly absorbed (T Max approximately 1 hour) and rapid excretion (T 1 / 2 5-HTP as a single molecule exhibits rapid-acting C (approximately 2 hours) upon administration (Gijsman et al., 2002; Westenberg et al., 1982). Max Pharmacotherapy may be unsuitable due to associated adverse events and the need for four to six doses per day to maintain reasonably stable 5-HTP exposure, a dosing requirement that is unrealistic and impractical in a typical treatment setting (Jacobsen et al., 2016a).

[0003] Carbidopa and benserazide are peripheral inhibitors (PDIs) of aromatic amino acid decarboxylase (AAAD). In humans, PDI cotreatment has been used to increase the bioavailability of the dopamine precursor levodopa for the treatment of Parkinson's disease (Freitas et al., 2016) and the 5-HT precursor 5-HTP for experimental therapeutic purposes (Turner et al., 2006b). With regard to 5-HTP, PDI cotreatment can also reduce human GI adverse events associated with the conversion of 5-HTP to 5-HT in the gastrointestinal (GI) tract, such as nausea, diarrhea, upset stomach, and vomiting (Byerley et al., 1987).

[0004] Both benserazide and carbidopa are commonly used with levodopa in a 4:1 levodopa:PDI ratio (Merck, 2017; Roche, 2015). However, benserazide is a more potent PDI inhibitor than carbidopa. For example, after oral administration, benserazide is a 10-fold more potent inhibitor of AAAD in peripheral organs than carbidopa (Da Prada et al., 1987). Therefore, the starting dose of benserazide is approximately half that of carbidopa (Merck, 2017; Roche, 2015), and benserazide and carbidopa cannot be simply dose-substituted.

[0005] In chronic human studies, reports of the use of PDIs, primarily carbidopa, with 5-HTP have used doses of PDI ranging from 150 mg / day to 1000 mg / day. Such PDI doses produce robust systemic inhibition of AAAD in all peripheral tissues (i.e., all tissues outside the brain). Reported 5-HTP:PDI ratios are typically 4:1 to 10:1, similar to the ratio when PDIs are used with levodopa to treat Parkinson's disease. Previous chronic clinical studies using oral 5-HTP and PDI treatment have used PDI doses greater than 2 mg / kg / day (assuming a patient weight of 70 kg), which produce robust inhibition of AAAD in all systemic peripheral tissues. Reports of human chronic studies using carbidopa and 5-HTP (e.g., Kahn and Westerberg, 1985; van Hiele, 1980; van Praag, 1982) would result in mean carbidopa plasma levels above 25 ng / ml, based on extrapolation between the references cited therein (Verhagen Metman et al., 2015; Yeh et al., 1989).

[0006] When PDIs are given in systemically active doses (e.g., carbidopa 1 mg / kg / day to 2 mg / kg / day) along with levodopa to patients with Parkinson's disease who are unlikely to recover, it has been impossible to attribute adverse events specifically to PDI treatment because it is difficult to distinguish between the effects of PDIs and levodopa when administered together. The safety profile of PDI therapy in the absence of levodopa is even more difficult to assess because the effects of PDI treatment on peripheral dopamine, adrenaline, and noradrenaline (which inhibit synthesis) are counteracted by concomitant levodopa administration (which enhances synthesis) (Rose et al., 1988).

[0007] PDIs are not specific inhibitors of AAADs; they can also inhibit enzymes in the kynurenine pathway, the abnormalities of which are associated with CNS, metabolic, and immune disorders (Badawy and Bano, 2016). Furthermore, in animals, chronic PDI treatment without levodopa, i.e., carbidopa or benserazide, can cause severe toxic effects, including renal dysfunction and growth abnormalities (Rauws et al., 1982; Yoshimura et al., 1987). Furthermore, in humans, congenital amino acid decarboxylase deficiency causes severe autonomic, motor, and other symptoms, indicating that long-term PDI treatment can potentially have widespread toxic effects (Manegold et al., 2009).

[0008] In summary, the long-term stability of PDI treatment without levodopa in otherwise healthy humans has not been established, and the pharmacology of PDIs carries the risk of negative effects on various peripheral physiological systems. Therefore, human therapy with 5-HTP and low doses of PDIs, such as carbidopa, would be preferable if possible. Summary of the Invention

[0009] As demonstrated in the accompanying figures, it has been unexpectedly discovered that low doses of carbidopa, particularly those with high 5-HTP:PDI ratios, can substantially increase 5-HTP oral bioavailability (greater than 100%) without causing systemic carbidopa plasma levels in the therapeutically active range.

[0010] Accordingly, one embodiment of the present disclosure provides a method of increasing the bioavailability of 5-HTP in a subject (e.g., a human subject), comprising, consisting of, or consisting essentially of co-administering to the subject a therapeutically effective amount of 5-HTP and a low dose of carbidopa, thereby increasing the bioavailability of 5-HTP in the subject.

[0011] In some embodiments, low-dose carbidopa provides subclinical carbidopa plasma levels, whereby carbidopa acts only locally in the intestinal tract, enhancing the bioavailability of 5-HTP and thereby minimizing the risk of toxicity and other undesirable physiological effects associated with systemic carbidopa exposure.

[0012] In some embodiments, a method for increasing the bioavailability of enterally administered 5-HTP in a human subject in need thereof comprises enterally co-administering low-dose carbidopa, provided at a daily dose of about 0.1 mg / kg / day or about 0.2 mg / kg / day to about 0.5 mg / kg / day, about 0.6 mg / kg / day, or about 0.8 mg / kg / day (alternatively, about 5 mg or about 10 mg to about 35 mg, about 50 mg, or about 60 mg per day), with the 5-HTP, thereby increasing the bioavailability of the enterally administered 5-HTP.

[0013] In some embodiments, 5-HTP and carbidopa are administered in a daily dosage ratio of 5-HTP:carbidopa of 100:1, 80:1, 60:1, or 50:1 to 40:1, 30:1, or 20:1.

[0014] In some embodiments, when low dose carbidopa is co-administered enterally, the subject has a plasma level of carbidopa of less than 25 ng / ml, 20 ng / ml, 15 ng / ml, 10 ng / ml, 5 ng / ml, or 2 ng / ml.

[0015] In some embodiments, the 5-HTP and low-dose carbidopa are administered once, twice, or three times per day.

[0016] In some embodiments, the formulation is administered in a manner selected from the group consisting of an oral immediate release formulation, an oral sustained release formulation, an oral enteral gel, a rectal suppository, and combinations thereof.

[0017] In some embodiments, the 5-HTP and carbidopa are provided in the same dosage form or in separate dosage forms as sustained release (SR) formulations of 5-HTP and low dose carbidopa.

[0018] In some embodiments, the subject is in need of treatment for a psychiatric and / or neurological disorder, such as a mood disorder or an abnormality in impulse control or aggression control. In some embodiments, the subject is in need of treatment for depression, social anxiety disorder, panic disorder, generalized anxiety disorder, OCD, impulse control disorder, suicidality, borderline personality disorder, fibromyalgia, ataxia, mood, cognitive, or behavioral symptoms and restlessness associated with neurological disorders (e.g., Alzheimer's disease, Parkinson's disease), stroke recovery, autism, migraine, sleep disorders, premenstrual dysphoria, post-traumatic stress disorder, postpartum depression, or depression after interferon treatment. In some embodiments, the subject is in need of treatment for depression, anxiety, suicidality, obsessive-compulsive disorder, or ADHD. In some embodiments, the subject is in need of treatment for depression, major depressive disorder, or treatment-resistant depression (not completely remitted after treatment with a serotonin reuptake inhibitor).

[0019] In some embodiments, the method comprises monotherapy with 5-HTP and low-dose carbidopa. In some embodiments, the method comprises adjunctive therapy with 5-HTP and low-dose carbidopa together with a serotonin enhancer. In some embodiments, the serotonin enhancer is selected from the group consisting of serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, triple reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin agonists, amphetamines, serotonin precursors, serotonin prodrugs, intermediates in the biosynthesis of serotonin, and pharmaceutically acceptable salts thereof. In some embodiments, the serotonin enhancer is a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the serotonin enhancer is selected from the group consisting of citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, vilazodone, vortioxetine, zimelidine, and combinations thereof.

[0020] In some embodiments, 5-HTP and low-dose carbidopa are administered orally, optionally in the same dosage form or in separate dosage forms.

[0021] In some embodiments, low-dose carbidopa is provided at a daily dosage of about 0.1 mg / kg / day or about 0.2 mg / kg / day to about 0.5 mg / kg / day (alternatively, about 5 mg or about 10 mg to about 35 mg per day).

[0022] In some embodiments, 5-HTP is provided in a daily dosage of about 0.1 grams, about 0.2 grams, about 0.5 grams, or about 0.75 grams to about 1 gram, about 4 grams, or about 6 grams per day.

[0023] Also provided is a pharmaceutical formulation or kit-of-parts suitable for enteral administration comprising 5-HTP and low-dose carbidopa, said formulation being suitable for administration once, twice or three times daily.

[0024] In some embodiments, the low-dose carbidopa in the pharmaceutical formulation or kit-of-parts is provided at a daily dosage of about 0.1 mg / kg / day or about 0.2 mg / kg / day to about 0.5 mg / kg / day, about 0.6 mg / kg / day or about 0.8 mg / kg / day (alternatively, about 5 mg or about 10 mg to about 35 mg, about 50 mg or about 60 mg per day).

[0025] In some embodiments, 5-HTP and low-dose carbidopa are provided in the pharmaceutical formulation or kit-of-parts in a 5-HTP:carbidopa dosage ratio of 100:1, 80:1, 60:1, or 50:1 to 40:1, 30:1, or 20:1.

[0026] In some embodiments, the formulation is a solid dosage form suitable for oral or rectal administration.

[0027] In some embodiments, the formulation of 5-HTP and / or carbidopa is one tablet, capsule, or other formulation for daily dosing, or two tablets, capsules, or other formulations for twice-daily dosing.

[0028] In some embodiments, the formulation comprises a sustained release formulation of 5-HTP and / or carbidopa. In some embodiments, the sustained release formulation comprises a gastroretentive formulation. In some embodiments, the 5-HTP and low-dose carbidopa are co-administered with a meal (e.g., when provided as a gastroretentive formulation).

[0029] Also provided is the use of low-dose carbidopa as taught herein in a method of increasing the bioavailability of 5-HTP in a subject (e.g., a human subject), the method comprising, consisting of, or consisting essentially of co-administering a low dose of carbidopa with 5-HTP to the subject, thereby increasing the bioavailability of 5-HTP in the subject.

[0030] Further provided is the use of low-dose carbidopa as taught herein in a method for preparing a medicament for increasing the bioavailability of 5-HTP in a subject (e.g., a human subject).

[0031] The foregoing aspects and other features of the present disclosure are explained in the following description, taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0032] [Figure 1] Effect of low-dose carbidopa on the 5-HTP plasma elevation induced by 5-HTP administration. Carbidopa dose-dependently increased the 5-HTP plasma elevation. The effect was similar in WT mice and 5-HTHypo mice (mice with selective and partial brain 5-HT deficiency due to a mutation in tryptophan hydroxylase (Beaulieu et al., 2008)). This likely reflects the fact that mice of the two genotypes have similar 5-HTP plasma levels at baseline. * indicates a statistically significant difference from the group treated with 5-HTP 200 mg / kg / day alone. One-way analysis of variance, Dunnett's post-hoc test. [Figure 2] Effect of low-dose carbidopa on the elevation of brain 5-HT tissue induced by 5-HTP administration. Carbidopa dose-dependently increased the elevation of 5-HT tissue induced by 5-HTP. The effect was proportionally more pronounced in 5-HTHypo mice, which had lower brain 5-HT levels at baseline due to lower endogenous brain 5-HT synthesis. * indicates a statistically significant difference from the group treated with 5-HTP 200 mg / kg / day alone. One-way analysis of variance, Dunnett's post-hoc test. [Figure 3]Effect of low-dose carbidopa on the elevation of brain 5-HIAA tissue levels induced by 5-HTP administration. Carbidopa dose-dependently increased the elevation of 5-HIAA tissue levels induced by 5-HTP. The effect was proportionally more pronounced in 5-HTHypo mice, which had lower brain 5-HIAA levels at baseline due to lower endogenous brain 5-HT synthesis. * indicates a statistically significant difference from the group treated with 5-HTP 200 mg / kg / day alone. One-way analysis of variance, Dunnett's post-hoc test. [Figure 4A] HPLC electrochemical quantification of carbidopa in plasma. 10 ng / ml standard in perchloric acid. Carbidopa peak is seen at 24 minutes. [Figure 4B] HPLC electrochemical quantification of carbidopa in plasma. Plasma extract from a mouse not treated with carbidopa. No carbidopa peak is observed. The baseline undulation at 24 minutes is detector noise. [Figure 4C] HPLC electrochemical quantification of carbidopa in plasma. Plasma extract from mice not treated with carbidopa but spiked with carbidopa to a concentration of 2 ng / ml prior to extraction. A carbidopa peak is seen at 24 minutes. [Figure 4D] HPLC electrochemical quantification of carbidopa in plasma. Plasma extract from mice treated with 10 mg / kg / day of carbidopa. No carbidopa peak is observed. The baseline undulation at 24 minutes as shown is detector noise. [Figure 5]Qualitative description of the mechanism of action of the present invention. Under baseline conditions (FIG. 5A), essentially no 5-HTP is present in the systemic circulation (at baseline, brain 5-HT is synthesized locally in the brain from tryptophan). 5-HTP treatment alone (FIG. 5B) modestly elevates 5-HTP in the systemic circulation and brain 5-HT. Coadministration with low-dose carbidopa (FIG. 5C) significantly inhibits amino acid decarboxylase locally in the intestine, reducing the first-pass metabolism of 5-HTP and allowing more 5-HTP to enter the systemic circulation, resulting in a more potent increase in brain 5-HT after 5-HTP treatment compared to treatment with 5-HTP alone. At the same time, carbidopa levels in the systemic circulation are too low to functionally inhibit AAAD. Symbols: ●, carbidopa; ◆, 5-HTP. DETAILED DESCRIPTION OF THE INVENTION

[0033] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to preferred embodiments and specific language will be used to describe the preferred embodiments. It will nevertheless be understood that no limitation of the scope of the present disclosure is intended herein, and that such changes and further modifications of the present disclosure as described herein are intended to be within the ordinary skill of those skilled in the art to which the present disclosure pertains.

[0034] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" means at least one element and may include more than one element.

[0035] "About" is used to provide flexibility in the endpoints of a numerical range by providing that the value given may be "slightly above" or "slightly below" the endpoint without affecting the desired result.

[0036] Use of the terms "comprising," "including," or "having," and variations thereof herein, is intended to include the subsequently listed elements and equivalents thereof, as well as additional elements. Embodiments recited as "comprising," "including," or "having" certain elements are also intended to "consist essentially of" and "consisting of" the certain elements.

[0037] Unless otherwise stated herein, the recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each individual value falling within that range, and each individual value is incorporated herein as if it were individually recited. For example, if a concentration range is stated as 1% to 50%, values ​​such as 2% to 40%, 10% to 30%, or 1% to 3%, are also intended to be expressly recited herein. These are merely examples of what is specifically intended, and all possible combinations of numerical values ​​between and including the recited minimum and maximum values ​​should be considered to be expressly recited in this disclosure.

[0038] As used herein, "treatment," "therapy," and / or "therapeutic regimen" refer to a clinical intervention undertaken in response to a disease, disorder, or physiological condition that manifests in a patient or to which the patient may be susceptible. The goals of treatment include reducing or preventing symptoms, slowing or halting the progression or worsening of the disease, disorder, or condition, and / or ameliorating the disease, disorder, or condition.

[0039] The term "effective amount" or "therapeutically effective amount" refers to an amount sufficient to bring about beneficial or desired biological and / or clinical results.

[0040] As used herein, the terms "subject" and "patient" are used interchangeably herein and refer to both human and non-human animals. The term "non-human animal" of the present disclosure includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.

[0041] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0042] <I.5-ヒドロキシトリプトファン> "5-Hydroxytryptophan" or "5-HTP" is the precursor of serotonin (also known as 5-hydroxytryptamine, 5-HT) in the body. In humans, 5-HTP is synthesized from dietary tryptophan by tryptophan hydroxylase (subtype 1 in the periphery and subtype 2 in most neurons) (Jacobsen et al., 2016a). 5-HTP is rapidly converted to 5-HT by aromatic amino acid decarboxylase (AAAD), a large-capacity, ubiquitously expressed enzyme that is unsaturated under baseline conditions (Bowsher, 1986). Therefore, 5-HTP is both a natural intermediate and a rate-limiting precursor of 5-HT.

[0043] [ka]

[0044] Exogenously administered 5-HTP, whether orally or parenterally, has been shown to significantly increase brain 5-HT synthesis and functional levels (i.e., extracellular 5-HT, 5-HT) in animal models (Jacobsen et al., 2016b; Perry and Fuller, 1993) and humans (Agren et al., 1991; Sargent et al., 1998). Ext ) to increase.

[0045] Overall, the biology and pharmacology of 5-HTP, like the 5-HT system, appear to be very similar between nonhuman mammalian species, such as rodents, and humans. For example, in both rodents and humans, the only known metabolic fate of 5-HTP is its conversion to 5-HT by AAAD (Jacobsen et al., 2016a), baseline 5-HTP plasma and tissue levels are very low (Gijsman et al., 2002; Jacobsen et al., 2016b), and exogenous 5-HTP alone only modestly elevates neuroendocrine biomarkers of brain 5-HT function, whereas exogenous 5-HTP potently synergizes with concurrent SSRI administration to elevate 5-HT function beyond the effects of the SSRI (Fuller and Snoddy, 1980; Sargent et al., 1998). Therefore, findings regarding the pharmacology of 5-HTP in rodents are fully transferable to humans.

[0046] 5-HTP is readily obtained from the seeds of the plant Griffonia simplicifolia and is commercially available. 5-HTP can also be obtained by chemical synthesis (see, for example, CN103554005A). Exogenous administration of 5-HTP has been reported to have therapeutic potential in experimental human trials in a variety of disorders, including depression as monotherapy (Takahashi et al., 1976), depression as adjunctive therapy (van Praag, 1982), anxiety (Kahn et al., 1987), obesity (Cangiano et al., 1992), ataxia (Trouillas et al., 1988), migraine (Nicolodi and Sicuteri, 1999), fibromyalgia (Caruso et al., 1990), insomnia (Soulairac and Lambinet, 1977), and night terrors (Bruni et al., 2004).

[0047] Furthermore, 5-HTP, as a monotherapy or adjunctive therapy, enhances 5-HT function in the brain, and 5-HTP, as a monotherapy or adjunctive therapy, has been shown to be effective in treating post-traumatic stress disorder (Connor et al, 1999), social phobia (Lader et al, 2004), anxiety disorders (Coric et al, 2010), Alzheimer's disease agitation (Viscogliosi et al, 2017), Alzheimer's disease-related dementia (Bartels et al, 2018), obsessive-compulsive disorder (Blier and Bergeron, 1996), premenstrual dysphoria (Steiner et al, 1995), postpartum depression (Appleby et al, 1997), bulimia (Jackson et al, 2010), binge eating disorder (Guerdjikova et al, 2008), stroke recovery (Mead et al, 2013), and / or emotional dysregulation disorders (Sloan et al, 2018). Further disorders known to be treatable by 5-HT agonists can be treated, including, but not limited to, impulse control disorders (Carver et al., 2008), borderline personality disorder (Brown et al., 1982), suicidality (Asberg, 1997), and / or autism (Veenstra-VanderWeele et al., 2012).

[0048] After oral administration, 5-HTP is rapidly absorbed from the upper intestine (T Max It is then rapidly eliminated (converted to 5-HT) with a half-life of approximately 2 hours (Gijsman et al., 2002; Westenberg et al., 1982). Rapid absorption is associated with side effects such as nausea, diarrhea, abdominal pain, and vomiting. Max5-HTP is associated with related gastrointestinal (GI) adverse events (Byerley et al., 1987; Lowe et al., 2006). These undesirable adverse events are caused by the unintended conversion of 5-HTP to 5-HT in the GI tract (Turner et al., 2006b). In fact, animal studies suggest that greater than 50% of exogenously administered 5-HTP is converted to 5-HT during transport across the intestinal wall (Shindo et al., 1977). 5-HT promotes GI motility, fluid secretion, and pain sensation (Gershon, 2013), which corresponds to the observed GI adverse events associated with 5-HTP administration (Turner et al., 2006b). To reduce 5-HTP-induced GI adverse events, the 5-HTP dose in most trials has had to be increased in multiple dose steps over multiple days or weeks (Alino et al., 1976; van Hiele, 1980; van Praag, 1982). This unfortunately complicates therapy, reduces compliance, and reduces overall clinical efficacy (Claxton et al., 2001). In summary, the rapid pharmacokinetics of 5-HTP makes it difficult to use its natural immediate-release form as a therapeutic agent. In fact, there are currently no Food and Drug Administration-approved formulations that use 5-HTP as the active moiety.

[0049] The short half-life of 5-HTP requires multiple daily doses, i.e., four to six, to maintain reasonably stable 5-HTP plasma exposure (Jacobsen et al., 2016a; van Praag, 1982). Such a regimen would be impractical in a real-world treatment setting, resulting in poor adherence and impaired therapeutic efficacy. Fortunately, sustained-release (SR) delivery can significantly and unexpectedly enhance the drug properties of 5-HTP (see U.S. Patent Nos. 9,468,627 and 8,969,400 to Jacobsen et al.), a finding supported by animal data (Jacobsen et al., 2016b). Furthermore, the oral bioavailability of 5-HTP appears to be moderate (Gijsman et al., 2002). When natural 5-HTP is administered alone, therapeutic studies often use high daily doses of 5-HTP, e.g., 900 mg / day for obesity (Cangiano et al., 1992). High 5-HTP doses are disadvantageous due to the large size of solid dosage forms and / or multiple tablets or capsules per dose.

[0050] As used herein, a "sustained release formulation of 5-HTP" refers to a formulation that is effective in reducing plasma T 1 / 2 is increased and / or T Max "Slow-release 5-HTP" refers to a formulation that has the ability to release 5-HTP at a slow rate, so that the release of 5-HTP is delayed. The terms "slow-release 5-HTP" and "slow-release 5-HTP" are used interchangeably and refer to the ability to release 5-HTP in a subject at a slower rate than when administered directly. See U.S. Patent No. 9,468,627 to Jacobsen et al., which is incorporated herein by reference in its entirety. Other terms that can be used for such formulations include, but are not limited to, "sustained-release", "controlled-release", "extended-release" and "time-release".

[0051] For example, immediate-release oral 5-HTP typically has a T of about 2 hours 1 / 2 and therefore, sustained-release 5-HTP provides a T of greater than 3, 4, 5, 6, or 7 hours. 1 / 2 In some embodiments, T 1 / 2 is at least 8 hours. 1 / 2 The time is 8, 10 or 12 hours to 24, 48 or 72 hours.

[0052] As another example, immediate-release oral 5-HTP has a T of 1 to 2 hours. Max Thus, in some embodiments, the sustained release formulation of 5-HTP has the T max The drug is administered and / or formulated so that the time to peak plasma concentration after administration is at least 2 hours, or between 2 and 12 hours.

[0053] In some embodiments, 5-HTP is provided in a therapeutically effective amount in a formulation suitable for enteral administration.As used herein, the term " therapeutically effective amount " refers to the amount of 5-HTP that is sufficient to show benefit in subject.In some embodiments, the formulation is provided in a unit dose for once-daily or twice-daily use.See, for example, U.S. Patent No. 8,969,400 to Jacobsen et al., the entirety of which is incorporated herein by reference.

[0054] In some embodiments, a daily dose of 0.05 grams to 10 grams of 5-HTP can be provided (e.g., one tablet, capsule, or other dosage formulation for daily dosing, or two tablets, capsules, or other dosage formulations for twice-daily dosing, each half the daily dose). In some embodiments, the daily dose can be 0.01 grams, 0.05 grams, 0.1 grams, 0.2 grams, 0.5 grams, or 0.75 grams to 5 grams, 8 grams, or 10 grams per day. In some embodiments, the daily dose can be 1 gram to 5 grams per day. In some embodiments, the daily dose can be 1 gram to 3 grams per day.

[0055] In some embodiments, 5-HTP is administered to a human subject at a daily dosage of about 0.1 grams, about 0.2 grams, about 0.5 grams, or about 0.75 grams to about 1 gram, about 4 grams, or about 6 grams per day.

[0056] In some embodiments, 5-HTP is administered to achieve a plasma 5-HTP level averaging from 10 ng / ml to 100 ng / ml. In some embodiments, 5-HTP is administered to achieve a plasma 5-HTP level averaging from 100 ng / ml to 1000 ng / ml. In some embodiments, 5-HTP is administered to achieve a plasma 5-HTP level averaging from 1000 ng / ml to 10000 ng / ml.

[0057] <II. Low-dose carbidopa> Carbidopa inhibits aromatic amino acid decarboxylase (AAAD), an enzyme that catalyzes the conversion of 5-HTP to 5-HT, the conversion of levodopa to dopamine, and other similar metabolic reactions (Bowsher R.R., 1986). The maintenance dosage of carbidopa exceeds 1 mg / kg / day (assuming a patient weight of 70 kg) (Merck, 2017, Pahwa et al, 2014, van Praag, 1982). In a treatment regimen, at steady state, the average plasma level of maintenance-dose carbidopa is 25 ng / ml or greater (range: 25 ng / ml to 150 ng / ml) (Verhagen Metman et al, 2015, Yeh et al, 1989).

[0058] "Low-dose" carbidopa, as used herein, refers to a dose lower than the dose normally used clinically. AAAD, the enzyme that catalyzes the conversion of 5-HTP to 5-HT, is present in large amounts and is not saturated under baseline conditions (Bowsher RR, 1986). As a result, under baseline conditions, 5-HTP levels are very low, reflecting the rate-limiting step in 5-HT synthesis, the formation of 5-HTP from tryptophan, catalyzed by tryptophan hydroxylase (Jacobsen et al., 2012a). Minimal levels of PDI (e.g., an average carbidopa of less than 25 ng / ml (Verhagen Metman et al., 2015; Yeh et al., 1989)) result in virtually no effect on AAAD activity in systemic circulation and visceral organs.

[0059] In some embodiments, low-dose carbidopa is provided to a human subject at a daily dosage of about 0.1 mg / kg / day or about 0.2 mg / kg / day to about 0.5 mg / kg / day, about 0.6 mg / kg / day, or about 0.8 mg / kg / day (alternatively, about 5 mg or about 10 mg to about 35 mg, about 50 mg, or about 60 mg per day).

[0060] In some embodiments, the co-administration / dosage form of 5-HTP and low-dose carbidopa functions such that the conversion of 5-HTP to 5-HT is inhibited substantially only in the intestine, the site of 5-HTP absorption, while AAAD activity in the systemic circulation, viscera, and brain remains substantially and functionally uninhibited (see Figures 5A-5C).

[0061] Without wishing to be bound by theory, the selective inhibition of AAAD in the intestine by low-dose carbidopa as taught herein completely or partially protects 5-HTP from the conversion to 5-HT catalyzed by AAAD in the intestine.This then allows more 5-HTP to enter the systemic blood circulation and be transported to the brain where it can be converted to 5-HT, thereby enhancing brain 5-HT synthesis and 5-HT function.In addition, since most adverse events caused by 5-HTP are due to the conversion to 5-HT in the intestine (for example, diarrhea, nausea, GI discomfort, vomiting) (Byerley et al., 1987), the present invention has the ability to reduce such 5-HT-related GI adverse events.

[0062] Enhanced 5-HT function in the brain is associated with increased terminal 5-HT synaptic and extrasynaptic release and increased levels of extracellular 5-HT (5-HT Ext ) levels. This can be manifested as an increase in the level of serotonin receptors in the brain. This can lead to increased 5-HT neurotransmission through serotonin receptors in the brain, and this action can exert a therapeutic effect. The downstream mechanisms of serotonin receptors include, but are not limited to, neuroplasticity, electrophysiological changes, modulation of brain connectivity, changes in brain structural circuitry, changes in brain functional circuitry, changes in macroscopic brain structure, changes in neurite structure and complement, changes in neurotrophic factors, changes in neurogenesis, changes in neuron number and complement, changes in non-neuronal cell number and complement, and changes in apoptosis. In some embodiments, co-administration can further include the administration of another serotonergic therapeutic agent.

[0063] As used herein, a "sustained release formulation of carbidopa" refers to a formulation that is effective in reducing plasma T 1 / 2 is delayed and / or T MaxRefers to a formulation having the ability to release low-dose carbidopa at a slow rate such that the release of carbidopa is decreased. The sustained-release formulation of carbidopa may be supplied together with 5-HTP in the same dosage form or in separate dosage forms. The terms "slow-rate carbidopa" and "slow-release carbidopa" are used interchangeably and refer to the ability to release carbidopa in a subject at a slower rate than when administered directly in an immediate-release dosage form. See, e.g., U.S. Patent Application No. 2006 / 0013875 to Han et al. (Pahwa et al, 2014). Other terms that may be used for such formulations include, but are not limited to, "sustained release", "controlled release", "sustained-type release", and "sustained-release type release".

[0064] <III. Formulations and Administration> The 5-HTP and / or carbidopa used in the present invention can be free bases; salts; conjugates (e.g., amino acid conjugates, hydrocarbon conjugates, lipid conjugates); conjugates that change absorption, distribution, metabolism and / or excretion characteristics; or isotope modifications that change absorption, distribution, metabolism and / or excretion characteristics. See U.S. Patent No. 4,658,038 to Tamir et al., U.S. Patent No. 7,101,912 to Xiang et al., and U.S. Patent No. 8,969,400 to Jacobsen et al., which are incorporated herein by reference in their entirety.

[0065] Solid pharmaceutical dosage forms suitable for enteral administration of 5-HTP and / or carbidopa can include tablets, capsules, or microparticles that can be prepared using standard pharmaceutical approaches known to those skilled in the art for making drug formulations. Examples include, but are not limited to, gastric retention formulations (Lopes et al, 2016), swellable matrix tablets (Verhagen Metman et al, 2015), erodible matrix tablets (Nokhodchi et al, 2012), osmotic tablets (Thombre et al, 2004), minitablets (Mitra et al, 2017), and microbeads (Freitas et al, 2016).

[0066] In some embodiments, the formulation is a sustained-release gastroretentive formulation of 5-HTP and low-dose carbidopa, either in the same dosage form or in separate dosage forms for simultaneous administration (see review (Lopes et al., 2016) and U.S. Patent Nos. 6,340,475, 6,635,280, 6,723,340, 9,161,911, and 9,980,903).

[0067] The 5-HTP and / or carbidopa dosage form can be administered with or without food, depending on the specific embodiment.In some embodiments, the dosage form should be taken / administered with food (e.g., with a meal, see U.S. Patent No. 7,438,927).In other embodiments, the dosage form should be taken / administered while fasting.

[0068] Solid dosage forms suitable for enteral administration can deliver 5-HTP and / or carbidopa primarily to the stomach, jejunum, ileum, colon, or rectum, or a combination thereof. 5-HTP and / or carbidopa can be released from the solid dosage over a period ranging from essentially instantaneous at the site of delivery to up to 24 hours, as appropriate for the indication in question. 5-HTP and / or carbidopa dosage forms can also be liquid, gel, or semi-solid, or such non-solids incorporating solid components.

[0069] In some embodiments, enteral dosage forms can be administered orally or rectally.Dose can be administered once, twice, or more frequently depending on the need of treatment.One or more units can be administered in each dose.5-HTP and / or carbidopa dosage forms can be administered immediately, for one day, several days, several weeks, several months, or irregularly depending on the treatment needs of the subject being treated.

[0070] In some embodiments, each sub-dose (e.g., the first of two or more total daily doses) contains one tablet, capsule, or other dosage form, while in other embodiments, each sub-dose contains two or more tablets, capsules, or other dosage forms.

[0071] The 5-HTP and / or carbidopa dose can be increased over days, weeks, or months up to the final dose, or the final dosage strength can be administered from the start of treatment.

[0072] The simultaneous administration of 5-HTP and carbidopa can be used therapeutically as a monotherapy, i.e., without other simultaneous serotonin enhancer therapy.Alternatively, the simultaneous administration of 5-HTP and carbidopa can be used therapeutically as an adjunct therapy, i.e., with other serotonergic therapy or serotonin enhancer, including but not limited to serotonin reuptake inhibitor, serotonin norepinephrine reuptake inhibitor, monoamine oxidase inhibitor, serotonin agonist, serotonin antagonist, serotonin receptor allosteric modulator, serotonin precursor, serotonin synthesis cofactor, and / or modulator of biological components in serotonin metabolic pathway.See U.S. Patent No. 9,468,627 to Jacobsen et al.

[0073] "Serotonin enhancer", as used herein, refers to any compound that directly or indirectly increases the availability of serotonin in the central nervous system to bind to serotonin receptors in postsynaptic membranes, or directly stimulates serotonin receptors, including, but not limited to, serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin agonists, amphetamines, serotonin precursors, serotonin prodrugs, intermediates in the biosynthesis of serotonin, cofactors, and pharmaceutically acceptable salts thereof. Such compounds can be administered alone or in combination with other serotonin enhancers.

[0074] The term " SSRI " or " selective serotonin reuptake inhibitor " refers to a compound that is usually used as an antidepressant, and is associated with increasing the extracellular level of the neurotransmitter serotonin by inhibiting the uptake of serotonin into presynaptic cells, thereby increasing the level of serotonin in the synaptic cleft that is available for binding to postsynaptic serotonin receptors.Suitable examples of SSRI include but are not limited to citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, vilazodone, vortioxetine, zimelidine and combinations thereof.

[0075] 5-HTP and low-dose carbidopa can be provided together in the same dosage form, or 5-HTP and low-dose carbidopa can be provided separately as a kit of parts containing separate dosage forms that can be subsequently combined for use in combination with each other in combination therapy as taught herein. 5-HTP and low-dose carbidopa can also be packaged and provided together as separate components of a kit of parts in adjunctive therapy with a serotonin enhancer (e.g., an SSRI).

[0076] The following non-limiting examples are provided to further describe and demonstrate the present invention. [Example]

[0077] <Method> Mice: Adult mice, wild-type (WT) mice with normal 5-HT levels and 5-HT mice with reduced brain 5-HT synthesis and levels. Hypo Both 5-HT and 5-HT-β mice were used (Beaulieu et al., 2008). Hypo The mouse is a naturalistic model of brain 5-HT deficiency, which is known to be a causative factor in several CNS disorders, such as depression and suicide.

[0078] Drug treatment: Carbidopa was used as the PDI. To model oral drug delivery that occurs in humans during treatment regimens, 5-HTP and carbidopa were delivered via mouse chow (standard diet). This approach distributed drug delivery over time, providing a measure of "sustained-release" (also known as sustained-release, extended-release, sustained-release, or controlled-release) delivery. 5-HTP was administered at a dose of 200 mg / kg / day. Carbidopa was administered in addition to 5-HTP at doses of 2 mg / kg / day, 5 mg / kg / day, or 10 mg / kg / day to evaluate the effect of carbidopa on the outcome of 5-HTP treatment. To evaluate the effect of carbidopa alone, groups of mice were also administered the maximum carbidopa dose of 10 mg / kg / day without concurrent 5-HTP, compared with untreated mice. All treatments lasted 14 days, which is considered chronic in mouse studies.

[0079] Sample collection: During treatment, blood samples were collected to assess plasma levels of 5-HTP and carbidopa. At the end of treatment, mice were euthanized and brain tissue (frontal cortex) was collected.

[0080] Quantitative Analysis: Plasma 5-HTP, plasma carbidopa, brain 5-HT, and brain 5-hydroxyindoleacetic acid (5-HIAA, the major 5-HT metabolite) levels were quantified using HPLC as described (Jacobsen et al., 2012b). The detection limits for 5-HT and 5-HTP in plasma were 1 ng / ml, and for carbidopa, 2 ng / ml in plasma (Figure 4C).

[0081] <Results and Discussion> 5-HTP treatment increased plasma 5-HTP (Figure 1), brain 5-HT (Figure 2), and brain 5-HIAA (Figure 3) levels. Carbidopa alone without concurrent 5-HTP treatment had no effect. When administered in addition to 5-HTP, carbidopa potentiated the effects of 5-HTP treatment on all assessment criteria in a dose-dependent manner across many conditions. The effects of treatment on plasma 5-HTP were comparable in WT mice and 5-HT Hypo There was no difference between the 5HTHypo This was expected, since the mutation carried by the mice does not affect 5-HTP absorption and metabolism (Beaulieu et al., 2008). In contrast, the effects of 5HTP + / - carbidopa treatment on brain 5-HT and 5-HIAA were similar to those of 5-HT. Hypo This may partly reflect that WT mice already had high tissue levels of 5-HT at baseline. Previous data suggest that the slight increase in tissue levels of 5-HT and 5-HIAA in WT mice results in the accumulation of 5HT (5-HT Ext Note that this demonstrates a substantial increase in the level of the functionally active pool of ATP (Jacobsen et al., 2016b).

[0082] Overall, these findings suggest that this 5-HTP / low-dose carbidopa treatment regimen may be particularly important not only in diseases associated with brain 5-HT dysfunction, such as psychiatric disorders, but also in patients and disorders in which 5-HT levels are normal and general elevation and enhancement of 5-HT may be therapeutic. Plasma carbidopa levels were below the limit of detection, i.e., below 2 ng / ml, even at the highest dose of 10 mg / kg / day.

[0083] This demonstrates that carbidopa significantly enhances the bioavailability of 5-HTP even at doses that result in plasma exposure levels at least 12-fold lower than the normal systemically active level (i.e., 25 ng / ml, Verhagen et al., 2015; Yeh et al., 1989). The underlying mechanism is thought to be that carbidopa acts locally only in the upper intestine to protect 5-HTP from first-pass metabolism during transport through the intestinal wall. It is known that first-pass metabolism of exogenously administered 5-HTP is significant under normal circumstances (Shindo et al., 1977). Furthermore, adverse effects of 5-HTP are primarily caused by the conversion of 5-HTP to 5-HT in the intestine. These data suggest that this 5-HTP / low-dose carbidopa regimen will improve the safety and tolerability of 5-HTP therapy in humans.

[0084] Therefore, lower carbidopa doses than previously reported may enhance the bioavailability and pharmacodynamic (brain 5-HT) effects of 5-HTP. Furthermore, carbidopa, which is essentially only useful for inhibiting PDI activity locally in the intestine, may significantly enhance the bioavailability and pharmacodynamic (brain 5-HT) effects of 5-HTP. 5-HTP:carbidopa ratios of 20:1 to 100:1, much higher than previously reported, were effective in enhancing the bioavailability and pharmacodynamic (brain 5-HT) effects of 5-HTP.

[0085] These data demonstrate the feasibility of co-treatment with 5-HTP and low-dose carbidopa (e.g., doses of approximately 0.17 mg / kg / day to 0.83 mg / kg / day to enhance 5-HTP bioavailability) as a human treatment strategy. Note that due to approximately 12-fold higher metabolism in mice, a daily human dose would need to provide the same exposure as in mice. Thus, the "interspecies scaling factor" for mice versus humans is 1 / 12 (Sharma and McNeill, 2009).

[0086] These data also demonstrate the feasibility of co-treatment with HTTP:carbidopa ratios of 20:1 to 100:1 to increase 5-HTP bioavailability and reduce 5-HTP GI adverse events.

[0087] <References> [Table 1A] [Table 1B] [Table 1C] [Table 1D] [Table 1E] [Table 1F]

[0088] Any patents or publications mentioned in this specification are indicative of the level of those skilled in the art to which this invention pertains. These patents and publications are hereby incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. In case of conflict, the present specification, including definitions, will control.

[0089] Those skilled in the art will readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as the inherent properties inherent therein. The disclosure set forth herein is presently representative of preferred embodiments, is exemplary, and is not intended as a limitation on the scope of the invention. Modifications herein and other uses which are encompassed within the spirit of the invention as defined by the claims will occur to those skilled in the art.

Claims

1. 1. A pharmaceutical combination for increasing the bioavailability of orally administered 5-HTP in a human subject in need thereof, comprising: 5-HTP, low-dose carbidopa provided at a daily dosage of about 0.1 or about 0.2 mg / kg / day to about 0.5, about 0.6, or about 0.8 mg / kg / day (or about 5 or about 10 mg to about 35, about 50, or about 60 mg per day); thereby increasing the bioavailability of the orally administered 5-HTP; the 5-HTP and the low-dose carbidopa are provided in the medicament in a daily dosage of 5-HTP:carbidopa ratio of 100:1 to 20:1; the 5-HTP and the low-dose carbidopa are provided in the medicament as sustained-release (SR) formulations of the 5-HTP and the low-dose carbidopa; the 5-HTP and the low-dose carbidopa in the medicament are orally co-administered in the same dosage form or in separate dosage forms; and and co-administering said low dose carbidopa orally, said subject having a plasma level of carbidopa of less than 2 ng / ml. Combination medicines.

2. 2. The pharmaceutical combination of claim 1, wherein the 5-HTP and the low-dose carbidopa are administered once, twice, or three times per day.

3. The pharmaceutical combination according to claim 1 or 2, wherein the SR formulation is a gastroretentive formulation.

4. 4. The pharmaceutical combination of claim 3, wherein the 5-HTP and the low-dose carbidopa are administered concomitantly with a meal.

5. 5. The pharmaceutical combination of any one of claims 1 to 4, wherein the subject is in need of treatment for depression, social anxiety disorder, panic disorder, generalized anxiety disorder, OCD, impulse control disorder, suicidality, borderline personality disorder, fibromyalgia, ataxia, mood, cognitive or behavioral symptoms and restlessness associated with neurological disorders (e.g., Alzheimer's disease, Parkinson's disease), stroke recovery, autism, migraine, sleep disorders, premenstrual dysphoria, post-traumatic stress disorder, postpartum depression, or depression after interferon treatment.

6. The pharmaceutical combination according to any one of claims 1 to 4, wherein the subject is in need of treatment for a psychiatric and / or neurological disorder, such as a mood disorder or a disorder in impulse control or aggression control.

7. The pharmaceutical combination according to any one of claims 1 to 4, wherein the subject is in need of treatment for depression, anxiety, obesity, suicidality, obsessive-compulsive disorder, or ADHD.

8. The combination pharmaceutical of any one of claims 1 to 4, wherein the subject is in need of treatment for depression, major depressive disorder or treatment-resistant depression.

9. The pharmaceutical combination according to any one of claims 1 to 8, further comprising a serotonin enhancer.

10. 10. The pharmaceutical combination of claim 9, wherein the serotonin enhancer is selected from the group consisting of serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, triple reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, serotonergic agents, amphetamines, and pharmaceutically acceptable salts thereof.

11. 10. The pharmaceutical combination of claim 9, wherein the serotonin enhancer is a selective serotonin reuptake inhibitor (SSRI).

12. 10. The pharmaceutical combination of claim 9, wherein the serotonin enhancer is selected from the group consisting of citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, vilazodone, vortioxetine, zimelidine, and combinations thereof.

13. 13. The pharmaceutical combination of any one of claims 1 to 12, wherein the low-dose carbidopa is supplied in a daily dosage of from about 0.1 or about 0.2 mg / kg / day to about 0.5 mg / kg / day (or from about 5 or about 10 mg to about 35 mg per day).

14. 14. The pharmaceutical combination of any one of claims 1 to 13, wherein the 5-HTP is supplied in a daily dosage of from about 0.1, about 0.2, about 0.5, or about 0.75 grams per day to about 1, about 4, or about 6 grams per day.

15. 15. The pharmaceutical combination of any one of claims 1 to 14, wherein the formulation of 5-HTP and / or low-dose carbidopa is one tablet, capsule, or other formulation for daily dosing, or two tablets, capsules, or other formulations for twice-daily dosing (together to achieve the daily dosage).

16. 1. A pharmaceutical composition for increasing the bioavailability of 5-HTP in a human subject, comprising low-dose carbidopa, wherein said pharmaceutical composition is orally co-administered to said subject with said 5-HTP as low-dose carbidopa provided at a daily dosage of from about 0.1 or about 0.2 mg / kg / day to about 0.5, about 0.6, or about 0.8 mg / kg / day (alternatively, from about 5 or about 10 mg to about 35, about 50, or about 60 mg per day), thereby increasing said bioavailability of 5-HTP in said subject; the low-dose carbidopa is provided as a sustained release (SR) formulation for administration with an SR formulation of 5-HTP in a daily dosage of 100:1 to 20:1 5-HTP:carbidopa; the 5-HTP and the low-dose carbidopa in the medicament are administered orally in the same dosage form or in separate dosage forms; and and co-administering said low dose carbidopa orally, said subject having a plasma level of carbidopa of less than 2 ng / ml. Pharmaceutical compositions.

17. 17. The pharmaceutical composition of claim 16, wherein the formulation is a solid dosage form suitable for oral administration.

18. 18. The pharmaceutical composition of claim 16 or 17, wherein the formulation of the 5-HTP and / or the low-dose carbidopa is one tablet, capsule, or other formulation for daily dosing, or two tablets, capsules, or other formulations for twice-daily dosing (together to achieve the daily dosage).

19. The pharmaceutical composition according to any one of claims 16 to 18, wherein the SR formulation is a gastroretentive formulation.

20. 20. The pharmaceutical composition of any one of claims 16-19, wherein the low-dose carbidopa is provided in a daily dosage of from about 0.1 or about 0.2 mg / kg / day to about 0.5 mg / kg / day (or from about 5 or about 10 mg to about 35 mg per day).

21. 1. Use of low-dose carbidopa in a method for preparing a medicament for increasing the bioavailability of 5-HTP in a human subject, wherein the low-dose carbidopa, for oral administration, is provided in a daily dosage of about 0.1 or about 0.2 mg / kg / day to about 0.5, about 0.6, or about 0.8 mg / kg / day (or about 5 or about 10 mg to about 35, about 50, or about 60 mg per day); the low-dose carbidopa is provided as a sustained release (SR) formulation for administration with an SR formulation of 5-HTP in a daily dosage of 100:1 to 20:1 5-HTP:carbidopa; the 5-HTP and the low-dose carbidopa in the medicament are administered orally in the same dosage form or in separate dosage forms; and and co-administering said low dose carbidopa orally, said subject having a plasma level of carbidopa of less than 2 ng / ml. use.

22. 22. The use of claim 21, wherein the low-dose carbidopa is provided in a daily dosage of about 0.1 or about 0.2 mg / kg / day to about 0.5 mg / kg / day (or about 5 or about 10 mg to about 35 mg per day).

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