Pharmaceutical dosage forms and methods of use

Pharmaceutical dosage forms of D1/D5 receptor antagonists, and related methods of their use, are disclosed.

1. 11. A pharmaceutical dosage form for intra-oral absorption of ecopipam, comprising ecopipam or a pharmaceutically acceptable salt thereof and a pH modifier, the pH modifier being present in amount such that the pharmaceutical dosage form has a pH of about 2 to about 4, wherein when the dosage form is in solid form, the pH is as measured after dissolving the dosage form in 30 g of artificial saliva having a pH of 6.72, wherein the pH modifier comprises one or more of citric acid, hydrochloric acid, ascorbic acid, and acetic acid or a salt thereof.
2. 22. The pharmaceutical dosage form of claim 1, comprising ecopipam HCl.
3. 33. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form comprises about 0.01 to about 0.8 wt % pH modifier based on the total weight of the formulation.
4. 44. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form has a pH of about 2 to about 3.5.
5. 55. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form is a tablet, powder, sachet, film, gel, gum, aerosol, oral lyophilizate, oravescent, sprayable liquid, wafer, mouthwash, or lozenge.
6. 66. The pharmaceutical dosage form of claim 5, wherein the tablet is an orally dissolvable tablet, a fast-dissolving tablet, a buccal tablet, or a sublingual tablet, or wherein the film is a bioadhesive film, mucoadhesive film, or bucco adhesive film.
7. 77. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form comprise one or more excipients selected from the group an absorption enhancer (also called permeation enhancer), an antioxidant, a binder, a carrier, a colorant, a diluent, a disintegrant, a flavor, a lubricant, a pH modifier, a plasticizer, a preservative, a sweetener, a taste masking agent, a taste modulating agent, a viscosity modifier, a lyophilization agent, and nitrosamine scavengers, and including one or more from each group of excipients.
8. 88. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form comprises an absorption enhancer selected from one or more in the group of chelators; nonionic surfactants; cationic surfactants; anionic surfactants; fatty acids; non-surfactants; enzymes, chitosan, trimethyl chitosan, poly-l-arginine, l-lysine, chondroitinase ABC, 1-dodecylazacycloheptan-2-one, and quillajasaponin.
9. 99. The pharmaceutical dosage form of claim 1, wherein upon administration, the pharmaceutical dosage form reduces a pH of saliva of a subject by at least 1 pH unit.
10. 1010. The pharmaceutical dosage form of claim 1, wherein upon administration, the pharmaceutical dosage form reduces a pH of saliva of a subject to 6.5 or less, 6 or less, 5.5 or less, 5 or less, 4.5 or less, or 4 or less.
11. 1111. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form comprises one or more compounds selected from AB block copolymers of oligo(methyl methacrylate) and PAA, acacia, and polyvinyl alcohol, anionic types, Carbopol e.g. 934P, cationic types, chitosan, copolymers of PAA and PEG monoethylether monomethacrylate, epoxy resins, Eudragit polymers, gelatin, gellan gum, glycol, guar gum, hyaluronic acid, hydrogels of poly(N N-dimethylaminoethyl methacrylate-co-methyl methacrylate), hydrophilic pressure-sensitive adhesives (PSAs), hydroxyethyl cellulose, hydroxyethyl methacrylate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, a modified starch-polyacrylic acid mixture, monomeric alpha-cyanoacrylate, PAA complexed with PEGylated drug conjugate, pectin, poly(acrylic acid/divinyl benzene), polyacrylates, polymethacrylates, polycarbophil, polyethylene carboxymethyl cellulose, polymers with thiol groups, polymethyl vinyl ether-maleic anhydride, polystyrenes, polyurethanes, polyvinyl pyrrolidone, psyllium amberlite-200 resin, sodium alginate, sodium alginate, tamarind gum, thermally modified starch, tragacanth, and xanthan gum.
12. 1212. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form comprises an amount of ecopipam or a pharmaceutically acceptable salt thereof, of about 1 wt % to about 40 wt % based on the total weight of the pharmaceutical dosage form.
13. 1313. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical dosage form comprises an amount of ecopipam or a pharmaceutically acceptable salt thereof, of about 1 mg to about 200 mg.
14. 1414. A method of improving a safety profile of ecopipam, comprising administering to a subject in need thereof the pharmaceutical dosage form of claim 1, wherein the ecopipam is intraorally absorbed, wherein the safety profile is improved as compared to an oral dosage form of ecopipam or pharmaceutically acceptable salt in which ecopipam is absorbed in the GI tract.
15. 1515. The method of claim 14, wherein the improved safety profile is improved cardiac safety.
16. 1616. The method of claim 15, wherein administering the pharmaceutical dosage form reduces risk of QT prolongation.
17. 1717. A method of reducing one or more first pass metabolite concentrations in plasma when administering to a subject in need thereof the pharmaceutical dosage form of claim 1 for intraoral absorption of the ecopipam, wherein the one or more first pass metabolite concentrations are reduced after administration of the pharmaceutical dosage from as compared to after administration of an oral dosage form of ecopipam or pharmaceutically acceptable salt in which ecopipam is absorbed in the GI tract.
18. 1818. The method of claim 17, wherein the one or more first pass metabolites comprises ecopipam glucuronide.
19. 1919. The method of claim 18, wherein a concentration of ecopipam glucuronide is reduced by 75% to 85% after administration of the pharmaceutical dosage form as compared to a concentration of ecopipam glucuronide after administration of the oral dosage form.
20. 2020. The method of claim 17, wherein the first pass metabolites comprise EBS-101-40853 and/or EBS-101-40853 glucuronide.
21. 2121. The method of claim 20, wherein a concentration of EBS-101-40853 is reduced by 48% to 55% after administration of the pharmaceutical dosage form as compared to a concentration of EBS-101-40853 after administration of the oral dosage form and/or wherein a concentration of EBS-101-40853 glucuronide is reduced by 60% to 76% after administration of the pharmaceutical dosage form as compared to a concentration of EBS-101-40853 glucuronide after administration of the oral dosage form.
22. 2222. A method of administering a pharmaceutical dosage form of claim 1 to a subject in need thereof with a UGT inhibitor, or on a dosing schedule that overlaps a dosing schedule of a UGT inhibitor schedule.
23. 2323. A method of administering a pharmaceutical dosage form of claim 1 to a subject in need thereof with a CYP3A4 inducers, or on a dosing schedule that overlaps a dosing schedule of a CYP3A4 inducer schedule.
24. 2424. The method of claim 14, wherein the subject in has one or more disorders selected from the group of Tourette syndrome, transient tic disorder, chronic tic disorder, childhood onset fluency disorder (stuttering), Restless Legs Syndrome, refractory Restless Leg Syndrome, Restless Legs Syndrome with Augmentation, Augmentation associated with Restless Legs Syndrome, or a speech disorder selected from one or more of expressive language disorder, mixed receptive-expressive language disorder, phonological disorder and communication disorder not-otherwise-specified.
25. 2525. The method of claim 24, wherein the subject has Tourette syndrome.
26. 2626. The method of claim 24, wherein the subject has one or more disorders selected from the group of childhood onset fluency disorder (stuttering).
27. 2727. The method of claim 24, wherein the subject has one or more disorders selected from the group of Restless Legs Syndrome, refractory Restless Leg Syndrome, Restless Legs Syndrome with Augmentation, or Augmentation associated with Restless Legs Syndrome.
28. 2828. The method of claim 14, comprising administering the pharmaceutical dosage form to achieve a total daily dose of less than 2 mg/kg, 1.5 mg/kg or less, 1 mg/kg or less, or 0.5 mg/kg or less.
29. 2929. The method of claim 14, comprising administering the pharmaceutical dosage form to achieve a total daily dose of at least 25% less, or at least 50% less, or at least 75% less than a total daily dose needed for an oral dosage form which provides for absorption of ecopipam in the GI tract.
30. 3030. A method of treating of treating a disorder comprising administering to a subject in need thereof the pharmaceutical dosage form of claim 1, wherein the subject has one or more disorders selected from the group of Tourette syndrome, transient tic disorder, chronic tic disorder, childhood onset fluency disorder (stuttering), Restless Legs Syndrome, refractory Restless Leg Syndrome, Restless Legs Syndrome with Augmentation, Augmentation associated with Restless Legs Syndrome.

CROSS-REFERENCE TO RELATED APPLICATION
This application is a Continuation of International Application No. PCT/US25/20111, filed Mar. 14, 2025, which claims the benefit or priority to U.S. Provisional Patent Application No. 63/565,834 filed Mar. 15, 2024, which are hereby claimed and the disclosures are incorporated herein by reference in their entirety.


BACKGROUND
Field of the Disclosure
The disclosure relates generally to pharmaceutical dosage forms containing a D1/D5 receptor antagonist, for example ecopipam, or a salt of derivative thereof, and methods of using such dosage forms. More particularly, the disclosure relates to pharmaceutical dosage forms for use in delivering ecopipam in a dosage form that provides for intraoral absorption of the ecopipam while maintaining a reduced pH in the oral cavity.
Brief Description of Related Technology
D1/D5 receptor antagonists are described in U.S. Pat. Nos. 4,973,586, 6,262,049, 7,211,574, 7,504,391, 9,949,983, and 11,298,361 and International (PCT) Patent Application Publication WO 2014/012063 A1.
SUMMARY
One aspect of the disclosure provides a pharmaceutical dosage form for intra-oral absorption of ecopipam, comprising ecopipam or a pharmaceutically acceptable salt thereof and a pH modifier, the pH modifier being present in amount such that the pharmaceutical dosage form has a pH of 2 to 4, wherein when the dosage form is in solid form, the pH is as measured after dissolving the dosage form in 30 g of artificial saliva having a pH of 6.72.
One aspect of the disclosure provides a pharmaceutical dosage form for use in delivering an active pharmaceutical agent (API) in a manner other than oral systemic delivery, wherein the API is selected from one or more of those in Table I







TABLE I













 













Col. 3




Col.
Col.
stereo-




1
2
chemistry
Col. 4
Col. 5


Q
n
of 7a and 7b H's
X
Y





CH2
1
cis
CH3O
OH


CH2
1
cis
HO
CH3O


CH2
1
trans
CH3O
OH


CH2
1
trans
HO
CH3O


CH2
1
trans
Cl
OH


CH2
1
7b(S):7a(R)(+)
Cl
OH


CH2
1
7b(R):7a(S)(−)
Cl
OH


CH2
1
cis
Cl
OH


CH2
1
trans
H
OH


CH2
2
trans
CH3O
OH


CH2
2
trans
HO
CH3O


CH2
1
trans
CH3
OH


CH2
1
trans
Cl
NH2


O
1
trans
H
OH


CH2
0
trans
Cl
OH





;






or

    
    
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-3-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3-chloro-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,6a,7,8,9,13b-hexahydro-12-methoxy-7-methyl[1]benzopyrano[4,3-a][3]benzazepine;
        6,6a, 7,8,9,13b-hexahydro-7-methyl[1]benzopyrano[4,3-a][3]benzazepin-12-ol;
        6,6a,7,8,9,13b-hexahydro-3-hydroxy-2-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        2-hydroxy-3-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        3-hydroxy-2-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-methoxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-amino-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3,7-dimethyl-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-7-cyclopropylmethyl-2-hydroxy-benz[d]indeno[2,1b]azepine;
        5,6,7,7a,8,12b-hexahydro-7-allyl-3-chloro-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-2-hydroxy-7,8,8-trimethyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,11b-hexahydro-3-chloro-7-methylthieno[2′,3′:4,5]cyclopenta[1,2-a][3]benzazepine-2-ol;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-benz[d]indeno[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H-benzo[d]naphtho[2,1-b]azepine; or
        6,7,7a,8,9,13b-hexahydro-2-amino-3-trifluoromethyl-7-methyl-5H-benzo[d]naphtho[2,1b]azepine;
        or SCH23390 and compounds related thereto, including SCH 12679 and the compounds described in U.S. Pat. No. 4,477,378 (which is hereby incorporated by reference in the present application in its entirety), BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136, A69024, and NNC687. D1/D5 partial agonists include SKF38393, fenoldapam; SKF75670A; SKF 81297; SKF82958; or dinapsoline; or
    
    









    
    
        or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing.
    
    


Another aspect is a method of administering a pharmaceutical dosage form of the disclosure herein with a UGT inhibitor, or on a dosing schedule that overlaps a dosing schedule of a UGT inhibitor schedule.
Another aspect is a method of administering a pharmaceutical dosage form of the disclosure herein with a CYP3A4 inducer, or on a dosing schedule that overlaps a dosing schedule of a CYP3A4 inducer schedule.
Another aspect is a method of improving the safety profile of ecopipam comprising administering to a subject in need thereof the pharmaceutical dosage form of the disclosure.
Another aspect is a method of reducing one or more first pass metabolite concentrations in plasma comprising administering to a subject in need thereof the pharmaceutical dosage form of any one of the preceding claims. In such aspects, the first pass metabolite concentration can be an ecopipam glucuronide concentration. The glucuronide concentration can be reduced by 75-85% using pharmaceutical dosage forms in accordance with the disclosure as compared to an oral dosage form for oral systemic administration. For example, the first pass metabolite concentration can be an EBS-101-40853 concentration and the reduction can be about 48-55% as compared to an oral dosage form for oral systemic administration. For example, the first pass metabolite concentration can be an EBS-101-40853 glucuronide concentration and the reduction can be about 60-76% as compared to an oral dosage form for oral systemic administration.
In any of the aspects of the disclosure, the pharmaceutical dosage form can be administered in one or more doses. The pharmaceutical dosage forms of the disclosure can be administered using an initial dose titration schedule or without an initial dose titration schedule.
In any of the aspects of the disclosure, the pharmaceutical dosage form of the disclosure can be administered to a subject in need thereof to achieve a total daily dose of ecopipam or pharmaceutically acceptable salt thereof of about 1 mg to about 200 mg, or about 5 mg to about 100 mg. For example, a subject in need thereof can be administered the pharmaceutical dosage form to achieve a total daily dosage of ecopipam or pharmaceutically acceptable salt thereof of 200 mg or less, 125 mg or less, 100 mg or less, 50 mg or less. In any of the aspects of the disclosure, the pharmaceutical dosage form of the disclosure can be administered to a subject in need thereof to achieve a total daily dosage of ecopipam of pharmaceutically acceptable salt thereof in an amount of less than 2 mg/kg, 1.5 mg/kg or less, 1 mg/kg or less, 0.5 mg/kg or less, or any values therebetween.
Another aspect is a method of treating a subject in need of a dopamine D1 antagonist or a dopamine D1/D5 antagonist comprising administering to the subject a dosage form of any one of the disclosure herein or according to a method of any one of the disclosure herein.
Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description. While the dosage forms and methods are susceptible of embodiments in various forms, the description hereafter includes specific embodiments with the understanding that the disclosure is illustrative, and is not intended to limit the invention to the specific embodiments described herein.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic showing metabolism of ecopipam in humans.
FIG. 2 is a graph showing the effect of pH on solubility for ecopipam HCl.
FIG. 3 is a an XRPD overlay of Ecopipam HCl (EBS-101_after solubility test in pH buffers.
FIG. 4 is a schematic showing the absorption profiles simulated.
FIG. 5A is a graph showing predicted solubility of ecopipam HCl as a function of pH.
FIG. 5B is a graph showing Ecopipam HCl solubility as a function of pH.
FIG. 5C is a graph showing intraoral fraction absorption percentage as a function of saliva pH.
FIG. 6 is a graph showing intraoral fraction absorption percentage as a function of D50 particle size of the formulation.
FIG. 7 is a graph showing the predicted probabilities and 90% confidence interval for exposure-response of efficacy on Tourette's Disorder.



DETAILED DESCRIPTION
Pharmaceutical dosage forms in accordance with the disclosure provide for intra-oral absorption of an active pharmaceutical ingredient (API). The pharmaceutical dosage forms of the disclosure can include an active pharmaceutical ingredient and a pH modifier that is capable of modifying the pH of the oral cavity upon dissolution of the formulation to a pH at which the active pharmaceutical ingredient has improved solubility.
Embodiments of the pharmaceutical dosage forms of the disclosure are pharmaceutical dosage forms for intraoral absorption of ecopipam or a pharmaceutically acceptable salt thereof. It has been surprisingly found that ecopipam or pharmaceutically acceptable salt thereof has improved solubility in pH environments of about 2 to 4. In addition to improved solubility, the use of a pharmaceutical formulation that provides for intraoral absorption of the ecopipam or pharmaceutically acceptable salt thereof advantageously avoids first pass metabolism present with oral administration. As a result of reducing or entirely avoiding first pass metabolism, the dosage forms of the disclosure beneficially exhibit reduced side effects, with an improved safety profile, such as for example, a cardiac safety profile, as well as can have reduced drug-drug interactions as compared to an oral dosage form in which the API is absorbed in the GI tract (oral systemic administration). Dosage forms in accordance with the disclosure have also been observed to have improved bioavailability of ecopipam and/or improved central nervous system availability of ecopipam, which can improve efficacy and/or allow for reduced dosing amounts to be used as compared to oral dosage forms for oral systemic administration. This can be beneficial to patient compliance through a reduction of dosing burden.
The absolute bioavailability of ecopipam is unknown in humans, but likely low since only 1.67% of the radiolabeled dose was found as ecopipam in plasma. It has been found that ecopipam undergoes significant first-pass metabolism following oral absorption. FIG. 1 illustrates the metabolism of ecopipam in humans. It was observed that with oral administration, ecopipam is primarily eliminated through metabolism, with <1% of the dose excreted unchanged in the urine. The primary metabolite is ecopipam glucuronide, which accounted for ˜80% of radioactivity in plasma and 67% of radioactivity in the urine (Example 4). Ecopipam glucuronide has the highest concentration present in human and animal plasma after oral administration and iso the metabolite with the lowest safety margin, particularly for cardiac safety. Without intending to be bound by theory, it is believed that the intraorally absorbed pharmaceutical formulations in accordance with the disclosure exhibit improved bioavailability and/or reduced side effects, such as QT effects, at least in part by avoiding the first pass metabolism seen with oral administration; in addition, improved bioavailability may occur from improved solubility and absorbance of ecopipam intraorally as a result of the dosage form maintaining a reduced pH in the oral cavity upon administration. For example, the first pass metabolite concentration can be an ecopipam glucuronide concentration. The ecopipam glucuronide concentration can be reduced by 75-85% using pharmaceutical dosage forms in accordance with the disclosure as compared to an oral dosage form for oral systemic administration. For example, the first pass metabolite concentration can be an EBS-101-40853 concentration and the reduction can be about 48-55% as compared to an oral dosage form for oral systemic administration. For example, the first pass metabolite concentration can be an EBS-101-40853 glucuronide concentration and the reduction can be about 60-76% as compared to an oral dosage form for oral systemic administration.
For example, as a result of the reduced first pass metabolite concentrations, intraoral absorption of ecopipam is believed to have reduced side effects, such as concentration-related prolongation of the QT interval and reduced drug-drug interactions originating from the gastrointestinal tract. This can improve the safety profile of ecopipam, which in turn can allow for use in a wider variety of patient populations. For example, the improved safety profile and reduced drug-drug interactions can allow for use in patients with moderate to severe hepatic and renal impairment. For example, the dosage forms of the disclosure can allow ecopipam to be dosed with UGT inhibitors or CYP3A inducers. For example, orally dissolvable pharmaceutical formulations in accordance with the disclosure can reduce drug-drug interaction of ecopipam as a perpetrator including but not limited to effects of ecopipam inducing CYP3A, P-glycoprotein, and CYP2C enzymes as well as UGT1A1.
The results shown in Example 3 revealed that upon administration of ecopipam via the oral systemic route, only about 1.69% of that active entity circulates in plasma. Most of the administered dose of drug circulates as glucuronic metabolites. Ecopipam is glucuronidated in the gastrointestinal tract and in the liver. Accordingly, dosing ecopipam, and similar compounds, such as other fused benzazepines, by routes other than oral systemic administration (in which the API is absorbed in the GI tract), can result in equivalent plasma levels of ecopipam using smaller doses, e.g. on the order of ¾, ½, ⅓, ¼, ⅕, 1/10 or any value therebetween.
Pharmaceutical dosage forms for intraoral absorption of ecopipam can include ecopipam or pharmaceutically active salt thereof and a pH modifier included in an amount such that a pH of the dosage form is about 2 to about 4. When the dosage form is provided as a solid the pH is measured after the dosage form is dissolved in 30 g of artificial salvia having a pH of 6.72. In any of the formulations disclosed herein, the ecopipam can be in free base form or as a pharmaceutically acceptable salt, or a solvate, hydrate, or prodrug, or pharmaceutically acceptable salt of any of the foregoing. It has advantageously been observed that improved solubility of the API, in whatever form present, can be made by adjusting the pH of the oral cavity to a pH at which the API form has the best solubility levels. Such modification of the oral cavity to provide a pH environment in which the API has improved solubility is believed to contribute to improved Cmax as compared to an oral administration where absorption occurs in the GI tract. Reference herein to ecopipam and pharmaceutically acceptable salts thereof should be understood to include solvates, hydrates, and prodrugs thereof. It has advantageously been found that when the dosage form has a pH of about 2 to about 4, the pH of the saliva in the mouth can be lowered significantly after administration of the pharmaceutical dosage form, for example, at least 0.5, at least 1, or at least 2 pH units. For example, after administration, the salvia of the subject to whom the dosage form is administered can be reduced from the natural pH of around 6-7 (with average pH being 6.7) to a pH of 6.5 or less, 6 or less, 5.5 or less, 5 or less, 4.5 or less, or a 4 or less, which is advantageous for improved solubility of ecopipam during intraoral absorption. Any known excipients for use in orally disintegrating dosage forms can be used. For example, gelatin and non-gelatin excipients as base excipients for orally disintegrating dosage forms are known in the art and can be used in the dosage forms of the disclosure. For example, the base excipients used in the Zydis® (Catalent) orally disintegrating tablet dosage form can be used. Dosage forms in accordance with the disclosure being present in a Zydis matrix further include the adjustment of pH using a pH modifier to provide for a pH reduction in the mouth during disintegration of the dosage form. Inclusion of other excipients are also contemplated herein, including, but not limited to binders, fillers, disintegrants, flavoring agents, nitrosamine scavengers, and combinations thereof.
The pharmaceutical dosage form can be provided in various dosage forms for intraoral absorption including, but not limited to, powders, sachets, sublingual tablets, orally disintegrating tablets, gels, films, buccal patches/films/tablets, oral sprays, lozenges, and the like. Excipients useful in providing such dosage forms are contemplated for use in the formulations of the disclosure.
The pharmaceutical dosage forms and methods are contemplated to include any combination of one or more of the additional optional elements, features, and steps further described below, unless stated otherwise.
Definitions
In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a substance that a human subject will self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.
As used herein, the term “comprising” indicates the potential inclusion of other agents, elements, steps, or features, in addition to those specified.
Compounds
The active compounds for use in the dosage forms and methods described in here are referred to herein and throughout as the API, active pharmaceutical ingredient. The API for use in a dosage form and the methods described herein can include those in the generic formula in the table below.







TABLE I













 
















Col. 3




















stereo-


Ki (nM)















Col. 
Col. 
chemistry
Col. 
Col. 
Col. 6
Col. 7
Col. 8


1
2
of 7a and 
4
5
3H-
3H-
CAR 


Q
n
7b H's
X
Y
23390
Spip
(MED)

















CH2
1
cis
CH3O
OH
6450
>100,000



CH2
1
cis
HO
CH3O
44,800
>100,000



CH2
1
trans
CH3O
OH
23
2500
   30 (po); 









0.3-1 (sc)


CH2
1
trans
HO
CH3O
2970
>100,000



CH2
1
trans
Cl
OH
5.5
11,500
   30 (po); 









  0.3 (sc)


CH2
1
7b(S):
Cl
OH
1800
>100,000
  >30 (po)




7a(R)(+)







CH2
1
7b(R):
Cl
OH
12
14,300
   30 (po)




7a(S)(−)







CH2
1
cis
Cl
OH
6200
>100,000



CH2
1
trans
H
OH
30
3500



CH2
2
trans
CH3O
OH
292
>100,000
   10 (sc)


CH2
2
trans
HO
CH3O
7730
>100,000
   10 (sc)


CH2
1
trans
CH3
OH
119
7200



CH2
1
trans
Cl
NH2
70
4175
    3 (po)


O
1
trans
H
OH
121
—



CH2
0
trans
Cl
OH
10
2600










Such compounds are known in the art and are more fully described in U.S. Pat. No. 4,973,586, which is hereby incorporated by reference in its entirety.
In one embodiment, the API can be a metabolite of ecopipam, or another API described herein. For example, the API can be a desmethyl compound, such as the desmethyl form of ecopipam, which has been referenced in the art as SCH 40853 or EBS-101-04853.
More specifically, the API can be:

    
    
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-3-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3-chloro-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,6a, 7,8,9,13b-hexahydro-12-methoxy-7-methyl[1]benzopyrano[4,3-a][3]benzazepine;
        6,6a,7,8,9,13b-hexahydro-7-methyl[1]benzopyrano[4,3-a][3]benzazepin-12-ol;
        6,6a, 7,8,9,13b-hexahydro-3-hydroxy-2-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        2-hydroxy-3-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        3-hydroxy-2-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-methoxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-amino-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine; 5,6,7,7a,8,12b-hexahydro-2-hydroxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3,7-dimethyl-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-7-cyclopropylmethyl-2-hydroxy-benz[d]indeno[2,1b]azepine;
        5,6,7,7a,8,12b-hexahydro-7-allyl-3-chloro-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-2-hydroxy-7,8,8-trimethyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,11b-hexahydro-3-chloro-7-methylthieno[2′,3′:4,5]cyclopenta[1,2-a][3]benzazepine-2-ol;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-benz[d]indeno[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H-benzo[d]naphtho[2,1-b]azepine; or
        6,7,7a,8,9,13b-hexahydro-2-amino-3-trifluoromethyl-7-methyl-5H-benzo[d]naphtho[2,1b]azepine.
    
    


The API can be in the form of a pharmaceutically acceptable salt and/or a trans isomer. An example D1/D5 receptor antagonist useful in the dosage forms and methods of the invention is SCH39166, which is also known as PSYRX101, EBS-101, or ecopipam (6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H-benzo[d]naphtho[2,1-b]azepine or, in trans form, (−)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H-benzo[d]naphtho[2,1-b]azepine). Ecopipam conforms to the structure:




Other D1/D5 receptor antagonists that are useful in the present methods include: SCH23390 and compounds related thereto, including SCH 12679 and the compounds described in U.S. Pat. No. 4,477,378 (which is hereby incorporated by reference in the present application in its entirety), BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136, A69024, and NNC687. D1/D5 partial agonists include SKF38393, fenoldapam; SKF75670A; SKF 81297; SKF82958; and dinapsoline.
The structures of some of these compounds are illustrated here:







A dosage form described herein can include pharmaceutically acceptable salts, solvate, hydrate, prodrug, structural analog, metabolite, or polymorphs of any of the foregoing APIs, or any other APIs described herein.
The chemical names of these APIs appear in the following Table:













SCH 39166
(−)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-


(ecopipam)
2-hydroxy-N-methyl-5H-benzo [d]-naphtho-



[2,1-b]azepine


SCH 23390
(d)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-



tetrahydro-1H-3-benzazepine maleate


BTS-73-947
1-[1-(2-chlorophenyl)cyclopropyl]-1,2,3,4-



tetrahydro-7-hydroxy-6-methoxy-2-methyl-(S)-



isoquinolinol


NNC-22-0010
(+)-5-(5-bromo-2,3-dihydro-7-benzofuranyl)-8-



chloro-2,3,4,5-tetrahydro-3-m ethyl-1H-3-



benzazepin-7-ol


JHS-271
8-chloro-3-[6-(dimethylamino)hexyl]-2,3,4,5-



tetrahydro-5-phenyl-1H-3-benzazepin-7-ol


JHS-198
8-chloro-3-[6-(dimethylamino)hexyl]2,3,4,5-



tetrahydro-5-phenyl-1H-3-benzazepin-7-ol with



boranecarbonitrile (1:1).


JHS-136
8-chloro-3-[4-(dimethylamino)butyl]-2,3,4,5-



tetrahydro-5-phenyl-1H-3-benzazepin-7-ol


A-69024
1-[(2-bromo-4,5-dimethoxyphenyl)methyl]-



1,2,3,4-tetrahydro-6-methoxy-2-met hyl-7-



isoquinolinol









Compounds useful in the present invention can be prepared in a variety of ways known to one of ordinary skill in the art of organic synthesis. Starting materials are readily available, and it will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures. Thus, the foregoing D1/D5 antagonists can be prepared by known methods. For example, one of ordinary skill in the art could synthesize APIs by the methods described in U.S. Pat. No. 5,302,716, which is hereby incorporated by reference in its entirety, and such APIs are useful in the present methods. One could also consult the published PCT applications WO 93/13073; WO 93/1702; WO 95/25102. One could also consult J. Med. Chem., 38 (21): 4284-4293, 1995. A D1/D5 partial agonist is SKF 38393, having the chemical name 2,3,4,5-tetrahydro-1-phenyl-1-H-3-benzazepine-7,8-diol. Other APIs useful in the present invention are those described in U.S. Pat. No. 4,477,378 (esters of substituted 8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines), which is hereby incorporated by reference herein in its entirety.
Ecopipam free base is a benzazepine derivative that is a selective antagonist of the D1 family of receptors. Ecopipam hydrochloride (SCH 39166 HCl; C19H20NOCl·HCl) has the chemical structure:




The APIs described herein, including those conforming to any formula, can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. The present APIs that contain asymmetrically substituted carbon atoms can be used in mixed form or isolated in optically active or racemic forms. An API useful in the dosage forms described herein can have a trans configuration. Methods for preparing optically active forms from optically active starting materials are known in the art. These methods include resolution of racemic mixtures and stereoselective synthesis. For example, one can conduct fractional recrystallization using a chiral resolving acid that is an optically active, salt-forming organic acid. Suitable resolving agents for use in these methods can be, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other useful resolving agents include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by one skilled in the art.
Cis and trans geometric isomers of the present APIs are described and may be isolated as a mixture of isomers or as separated isomeric forms. Compounds for use in the dosage forms described herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
Compounds for use in the dosage forms described herein also include all isotopes of atoms occurring in the intermediate or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.
The term “compound,” as used herein with respect to any compound conforming to one of the D1/D5 antagonists or partial agonists described above, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures referenced (e.g., depicted). All APIs, and all pharmaceutically acceptable salts thereof, can be used in a solvated or hydrated form. In some embodiments, the compounds for use the dosage form (regardless of form; e.g., salts) are “substantially isolated,” meaning that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99%, by weight, of a compound of the invention. Methods for isolating compounds and their salts are routine in the art.
As noted, the dosage forms described herein can include “pharmaceutically acceptable salts,” a term that generally refers to derivatives of the disclosed APIs wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. “Pharmaceutically acceptable” generally encompasses those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit:risk ratio. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts useful in the dosage forms described herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and the Journal of Pharmaceutical Science, 66:2, 1977.
In addition to, or instead of, ecopipam hydrochloride, ecopipam free base may be in the form of another pharmaceutically acceptable salt. Such salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
Dosage Forms
A pharmaceutical dosage form according to the present disclosure is one suitable for and preferably specifically designed for use in delivering such a D1/D5 antagonist described herein in a manner other than oral systemic delivery. A pharmaceutical dosage form according to the present disclosure is one suitable for and preferably specifically designed for use in delivering such an API for pulmonary, transdermal, or transmucosal delivery. Transmucosal routes contemplated include the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavities, especially the nasal, ocular and oral cavities (including sublingual or buccal), especially the nasal, and oral cavities. For example, in embodiments, the dosage form is for intraoral absorption of ecopipam. Oral dosage forms or oral tablets are made with reference herein to dosage forms which are for oral systemic administration, that is dosage forms administered orally for absorption of the API in the GI tract. By comparison, dosage forms in accordance with the disclosure are designed for absorption of the API by other means, e.g., intraoral, pulmonary, transdermal, or transmucosal.
The dosage form can include a bioadhesive, e.g. a mucoadhesive material, or a buccoadhesive material.
The bioadhesive material, mucoadhesive material, or buccoadhesive material can contain or be a polymer material. Bioadhesive polymers are polymers that can adhere to a biological substrate. Mucoadhesive materials adhere to a substrate which is mucosal tissue. The mucoadhesive polymer can have predominantly anionic hydrophilicity with hydrogen bond-forming groups. The mucoadhesive polymer can have suitable surface property for wetting mucus/mucosal tissue surfaces. The mucoadhesive polymer can have sufficient flexibility to penetrate the mucus network or tissue crevices Suitable bioadhesive materials include AB block copolymers of oligo(methyl methacrylate) and PAA, acacia, and polyvinyl alcohol, anionic types, Carbopol e.g. 934P, cationic types, chitosan (e.g. free or cross-linked by an anionic polymer), copolymers of PAA and PEG monoethylether monomethacrylate, epoxy resins, Eudragit polymers (e.g. Eudragit L-100, an anionic copolymer based on methacrylic acid and methyl methacrylate), gelatin, gellan gum, glycol, guar gum, hyaluronic acid, hydrogels of poly(N N-dimethylaminoethyl methacrylate-co-methyl methacrylate) e.g., poly(DMA/MMA) cross-linked with DVB, hydrophilic pressure-sensitive adhesives (PSAs), hydroxyethyl cellulose, hydroxyethyl methacrylate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, a modified starch-polyacrylic acid mixture, monomeric alpha-cyanoacrylate, PAA complexed with PEGylated drug conjugate, pectin, poly(acrylic acid/divinyl benzene), polyacrylates, polymethacrylates, polycarbophil, polyethylene carboxymethyl cellulose, polymers with thiol groups, polymethyl vinyl ether-maleic anhydride, polystyrenes, polyurethanes, polyvinyl pyrrolidone, psyllium amberlite-200 resin, sodium alginate, sodium alginate, tamarind gum, thermally modified starch, tragacanth, and xanthan gum.
A dosage form for oral cavity delivery/absorption can be designed for application or insertion in a specific region of the oral cavity, e.g. buccally or sublingually, or otherwise in the oral cavity.
A dosage form for buccal administration is inserted into the buccal pouch, the space between the lip and gum in the mouth. The dosage form can take any suitable shape, including oval, and are often relatively flat. The buccal dosage form can be hard tablet. The buccal dosage form can be formulated to dissolve slowly, or erode slowly. The buccal dosage form can be one that melts at body temperature to release an API as described herein, for example a matrix type dosage form, e.g. one in which an API as described herein is in solution as the matrix is cooled and solidified and when remelted the API is in solution and available for absorption. The buccal dosage form can be a patch. The buccal dosage form can be a compressed tablet. In addition or in the alternative, the buccal dosage form can include a bioadhesive material.
Sublingual dosage forms, e.g. tablets, are placed under the tongue. A sublingual tablet can be designed to dissolve rapidly, and the API thus released.
The dosage form for oral cavity delivery/absorption can take any suitable shape and consistency, and can be selected from one or more types in the group of a chewing gum, a chewable lozenge, a chewable tablet, a film, a gel, a liquid, a lozenge, a microporous hollow fiber, a mouthwash, an oral lyophilizate, an oral strip, an oravescent, an orodispersible, a patch, a powder, a semisolid, a sprayable liquid, a tablet, a tape, and a wafer.
The dosage form can have a monolithic design, e.g. a matrix, or can be designed with multiple functional regions and/or coatings. For example, the dosage form can be designed for unidirectional release (e.g. a unidirectional release tablet), a bilayer (e.g. a bilayer tablet with a bioadhesive layer containing API and a water impermeable coating), a triple layer (e.g. a triple layer tablet with a bioadhesive layer, an API layer, and a water impermeable coating) or with an API-containing mucoadhesive layer and an API-free backing layer (e.g. ethylcellulose). The dosage form can be a reservoir type, e.g. one that includes a cavity for the API and optional excipients separate from a bioadhesive, and optionally with an impermeable backing that can have one or more functions, e.g. to control the direction of API delivery, to reduce shape deformation, to reduce disintegration while in the mouth (e.g. as a saliva barrier). A bioadhesive can be used as an API carrier and/or as a bioadhesive for an API-loaded, non-adhesive layer. The API can be microencapsulated.
Bioadhesive microspheres can be used for buccal or nasal delivery of the API. Such microspheres can be made from albumin, chitosan, diethylaminoethyl (DEAE)-dextran, hyaluronic acid, starch, combinations thereof, and other suitable materials known in the art.
An API-loaded, optionally non-adhesive region, e.g. a layer, can be made of any suitable material, for example one or more in the group of an acrylic acid polymer, ethylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene oxide and polyvinyl pyrrolidone, poly(ethylacrylate methylmethacrylate), polyethyene glycol, and natural polymers including gaur-gum, pectins, starches, gelatin, and casein. The region can contain or be based on one or more excipients selected from lactose, glucose, sucrose, starch, crystalline cellulose, dextrin, cyclodextrin, silicic acid anhydride, aluminum silicate, talc, calcium stearate, magnesium stearate, beeswax, polyethylene glycol, and polyphosphate. The region can be water soluble, or water swellable, or water-degradable. The region can include a water soluble polymer in which the API is dispersed.
Orodispersible dosage forms include orally disintegrating tablets, and oral lyophilizates or wafers which present even faster disintegration than compressed counterparts, and thin films. Lyophilization can also produce buccal wafers that adhere to mucosa, including optionally for sustained API release.
A bioadhesive tablet is similar to conventional tablets and can be prepared by various methods, including wet granulation, dry granulation, and direct compression processes. In addition to mucoadhesive components, a tablet can contain a water-soluble excipient, e.g. a high molecular weight polyethylene glycol, or mannitol. A fast-dissolving tablet can include a mixture of a water-soluble polymer and a crystalline sugar. Mannitol and natural polysaccharides such as gelatin and alginates can be used.
A film dosage form is a solid, which dissolves in a relatively short period of time when placed in the mouth without drinking water or chewing. These can also be designed as buccal films, and can be referred to as fast dissolving oral films, and oral strips and tapes, and thin films. A bioadhesive film or patch can be prepared by solvent casting, with steps of dissolving the API in a casting solution, casting a film, and drying the film, and then optionally laminating with a backing layer or a release liner. A bioadhesive film or patch can be prepared by hot-melt extrusion method.
Chewable lozenges can be gummy-type lozenges. A chewable lozenge can be based on a modified suppository formula, e.g. including glycerin, gelatin, and water. These lozenges can be fruit-flavored and can have an acidic taste to cover the taste associated with glycerin. Soft lozenges can include ingredients such as PEG 1000 or 1450, or a sugar-acacia base. Silica gel can be added to prevent sedimentation. Soft lozenges can also include flavors and sweeteners to aid compliance, including in children and adolescents.
An adhesive gel can be based on a mixture of polyacrylic acid and polymethacrylate.
Chewing gums can include a tasteless, insoluble masticatory gum base that consists of natural or synthetic elastomers. The gum can include excipients such as fillers, softeners, and sweetening and flavoring agents. Natural gum bases include chicle and smoked natural rubber, and synthetic gum bases include styrene-butadiene rubber, polyethylene, and polyvinylacetate. The gum base can form about 20 wt. % to 80 wt. % of the gum, or 30 wt. % to 65 wt. % of the gum, or 35 wt. % to 50 wt. % of the gum, or 40 wt. % of the gum. The gum base can also include plasticizers, waxes, lipids, and emulsifiers.
The dosage form can include one or more excipients, for example selected from the groups of an absorption enhancer (also called permeation enhancer), an antioxidant, a binder, a carrier, a colorant, a diluent, a disintegrant, a flavor, a lubricant, a pH modifier, a plasticizer, a preservative, a sweetener, a taste masking agent, a taste modulating agent, and a viscosity modifier, including one or more from each group of excipients.
Antioxidants include ascorbic acid and sodium metabisulfite.
Binders include microcrystalline cellulose, mannitol, lactose, starches, including corn starch and pregelatinized starch, sorbitol, crospovidone, cross-linked povidone, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, and silicified microcrystalline cellulose.
Coating materials include carboxymethylcellulose, polyvinyl alcohol (PVA), and ethylcellulose.
Colorants include FD&C dyes and natural colorants.
Diluents (e.g. mannitol, lactose, sucrose, and sorbitol) can aid in the formulation of chewable tablets by compression. They can facilitate disintegration with chewing and can aid taste and mouth feel. A combination of microcrystalline cellulose and guar gum (Avicel CE-15) can lead to a dosage form with reduced grittiness, resulting in a creamier mouth feel.
Disintegrants include croscarmellose sodium, croscarmellose calcium, and cross-linked sodium carboxymethylcellulose.
Flavoring agents include mint and fruit flavors.
Lubricants include magnesium stearate and stearic acid.
Modifiers of pH include, for example, citric acid, ascorbic acid, acetic acid, hydrochloric acid, salts thereof, and combinations thereof. The modifier can be present, for example, in an amount based on the total weight of the dosage form of about 0.01 wt % to about 0.8 wt %., about 0.01 wt % to about 0.05 wt %, about 0.1 wt % to about 0.5 wt %, or about 0.05 wt % to about 0.4 wt %, and any values therebetween. For example, the pH modifier can be included in an amount based on the total weight of the formulation of about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8 wt % or any values therebetween or ranges defined by such values. The selection of the amount of pH modifier to include in the formulation can be made based on ordinary skill in the art to achieve a target pH. The target pH can be selected based on identification of a pH at which solubility of the API improves and the pH of the formulation needed to achieve and maintain the saliva at the target pH alter administration of the pharmaceutical dosage form. For example, pharmaceutical dosage forms for intraoral administration of ecopipam or a pharmaceutically acceptable salt thereof can include the pH modifier in an amount sufficient to achieve a pharmaceutical formulation pH of about 2 to about 4. This has advantageously been found to reduce the pH of saliva to less than 6.5, or 6 or less, or 5.5 or less, or 5 or less, or 4.5 or less, or 4 or less, which can advantageously improve solubility of the ecopipam or pharmaceutically acceptable salt thereof, and in particular ecopipam HCl.
Plasticizers include glycerin, propylene glycol, and polyethylene glycol.
Preservatives include benzalkonium chloride, methylparaben, and propylparaben.
Taste masking agents for blocking bitterness include adenosine monophosphate, lipoproteins, phospholipids, eriodictyol, homoeriodictyol, and sodium laurylsulfate.
Viscosity modifiers include hydroxypropyl methylcellulose and sodium alginate.
Microencapsulation of an API for taste masking can be achieved by phase separation or coacervation. The same technologies may be used to encapsulate an API for formulation into chewable, softchew, and fast dissolving dosage forms. Complexation of an API with an ion exchange resin can be used for taste masking.
Xylitol (a sweet sugar alcohol), has a high negative heat of solution, making it a good excipient for chewable tablets. A compressible sugar, e.g. containing sucrose granulated with a small amount of a modified dextrin, is useful for making compressed dosage forms such as tablets. In addition or in the alternative, spray-dried crystalline maltose and directly compressible sucrose (e.g., 95% sucrose and 5% sorbitol) can be used for compressed dosage forms such as tablets.
Permeation Enhancers can include chelators (e.g., citric acid, EDTA, EGTA, methoxy salicylates, sodium salicylate); surfactants, including nonionic, e.g., polyoxyethylene vegetable-based fatty ethers derived from lauryl, cetyl, stearyl or oleyl alcohols (e.g., Brij), dodecylmaltoside, laureth-9, ethoxylated fatty acids (e.g. Myrj), poloxamer, polysorbate 80, span, sucrose esters, Tween, cationic (e.g., benzalkonium chloride, cetylmethylammonium bromide, Cetyl pyridinium chloride), and anionic (e.g., sodium dodecyl glycocholate, sodium lauryl sulfate, laureth-9 sodium dodecylsulfate); bile salts and other steroidal detergents (e.g., sodium glycocholate, sodium taurocholate, saponins, sodium taurodeoxycholate, sodium taurodihydrofusidate, and sodium glycodihydrofusidate); fatty acids (e.g., Oleic acid, Caprylic acid, Lauric acid, Lyso phosphatidyl choline, Phosphatidyl choline, sodium myristate); non-surfactants (e.g., 1-dodecylazacycloheptane-2-one (Azone), salicylates, and sulfoxides); enzymes (e.g., phopholipases, hyaluronidases, neuraminidase, and chondroitinase ABC); and Cyclodextrins (e.g., α, β, γ, Cyclodextrin, methylated β-cyclodextrins, hydroxypropyl beta-cyclodextrin), chitosan, trimethyl chitosan, poly-l-arginine, l-lysine, chondroitinase ABC, 1-dodecylazacycloheptan-2-one, quillajasaponin.
Examples of commercial formulations identified by trade name and active agent include Ativan™ (lorazepam), Buprenex™ (buprenorphine), Cardilate™ (nitroglycerine), Ergostat™ (ergotamine tartrate), Imdur™ (isosorbide mononitrate), Nicorette™ (nicotine), Testred™ (methyl testosterone); bioadhesive tablets including Bonjela™ (choline salicylate), Corsodyl™ (chlorhexidine), and Taktarin™ (miconazole); Buccal mucosa formulations including Aftach™ (triamcinolone acetonide), Buccastem™ (prochlorperazine maleate), and Suscard™ (glycerin trinitrate); and Bucaal sprays including Ambien™ (zolpidem tartrate), Imitrex™ (sumatriptan succinate), and Sativex™ (Nabiximols-1:1 THC:CBD). It is contemplated that a D1/D5 receptor antagonist described herein, including ecopipam, can be formulated in the same or similar manners.
A dosage form according to the disclosure herein can be designed for controlled release, including sustained release, extended release, and prolonged release. In embodiments, a pharmaceutical dosage form for intraoral absorption of ecopipam is designed for immediate release and intraoral absorption. It has advantageously been found that first pass metabolism can be avoided or significantly reduced with such formulations.
Amounts and Dosing
The amount of a D1/D5 receptor antagonist described herein, including ecopipam, in a dosage form according to the disclosure herein can be relatively small, e.g. less than 5 wt. %, or less than 2 wt. %, or less than 1 wt. % or less than 0.5 wt. %, for example in a range of 0.0001 wt. % to 5 wt. %, or 0.001 wt. % to 2 wt. %, 0.001 wt. % to 1 wt. %.
In embodiments, the API is ecopipam and the dosage form includes about 1 mg to about 200 mg, about 5 mg to about 100 mg, about 50 mg to about 90 mg, or any values therebetween of ecopipam or a pharmaceutically acceptable salt thereof. For example, the dosage form can include about 200 mg or less, 100 mg or less, 50 mg or less, or 10 mg or less of ecopipam or a pharmaceutically acceptable salt thereof. For example, the dosage form can include about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg or any values therebetween or ranges defined by such values of ecopipam or pharmaceutically acceptable salt thereof.
For example, the dosage forms including ecopipam or pharmaceutically acceptable salt thereof can include the ecopipam or pharmaceutically acceptable salt thereof in an amount of 1 wt % to about 40 wt %, about 10 wt % to 20 wt %, about 15 wt % to 30 wt %, about 1 wt % to about 10 wt %, about 5 wt % to about 15 wt % or any values therebetween.
The pharmaceutical dosage forms in accordance with the disclosure may allow for administration of reduced total dosing amounts, while maintaining efficacy of dosage form as compared to an oral dosage form for oral systemic administration. For example, the dosage forms in accordance with the disclosure can provide for 5% or more, 10% or more, or 20% or more, or 25% or more, or 50% or more, or 75% or more reduction in the total daily dosing amounts as compared an oral dosage form for oral systemic administration, while maintaining the same efficacy as the oral dosage form for oral systemic administration.
In any of the aspects of the disclosure, the pharmaceutical dosage form can be administered in one or more doses. The pharmaceutical dosage forms of the disclosure can be administered using an initial dose titration schedule or without an initial dose titration schedule.
In any of the aspects of the disclosure, the pharmaceutical dosage form of the disclosure can be administered to a subject in need thereof to achieve a total daily dose of ecopipam or pharmaceutically acceptable salt thereof of about 1 mg to about 200 mg, or about 5 mg to about 100 mg. For example, a subject in need thereof can be administered the pharmaceutical dosage form to achieve a total daily dosage of ecopipam or pharmaceutically acceptable salt thereof of 200 mg or less, 179.3 mg or less, 125 mg or less, 89.6 mg or less, 44.2 mg or less. For example, the total daily dose of ecopipam or pharmaceutically acceptable salt thereof can be about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mg or any values therebetween or ranges defined by such values. In any of the aspects of the disclosure, the pharmaceutical dosage form of the disclosure can be administered to a subject in need thereof to achieve a total daily dosage of ecopipam of pharmaceutically acceptable salt thereof in an amount of less than 2 mg/kg, 1.5 mg/kg or less, 1 mg/kg or less, 0.5 mg/kg or less, or any values therebetween. For example, the total weight based daily dosing of ecopipam can be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or less than 2 mg/kg or any values therebetween or ranges defined by such values.
Co-Administration
The dosage forms described herein, including one including ecopipam or a salt thereof, can be administered with a UGT inhibitor, or on a dosing schedule that overlaps a dosing schedule of a UGT inhibitor schedule. The dosage forms described herein can be administered at the same dose amounts and schedules described above. Ecopipam is glucuronidated in the gastrointestinal tract and in the liver, and concomitant administration of oral ecopipam with general UGT inhibitors increases bioavailability of ecopipam by 50.8%. For this drug interaction, the increase in bioavailability due to general UGT inhibition in the GI tract after oral systemic administration would not be observed upon administration according to the dosage forms and methods described herein. Examples of UGT inhibitors are in the table below.














UGT




Isoform
Inhibitor









UGT1A1
Silybin,




atazanavir



UGT1A3
Ritonavir,




Quinidine



UGT1A4
Diclofenac,




Probenecid



UGT1A6
Diclofenac



UGT1A9
Diclofenac,




Mycophenolic, acid




Mefenamic acid



UGT2B7
Diclofenac,




Quinidine,




Probenecid



UGT2B15
Probenecid










Surprisingly it has been found that the dosage forms described herein including ecopipam or pharmaceutically acceptable salt thereof can be administered with a CYP3A4/5 inducer and/or with a CYP3A4/5 inhibitor, or on a dosing schedule that overlaps a dosing schedule of a CYP3A4/5 inducer. As detailed below, oral dosage forms (for oral systemic administration) of ecopipam were found to have adverse drug-drug interactions with CYP3A4 inducers co-administration was not advised. The pharmaceutical dosage forms for intraoral ecopipam advantageously avoid first pass metabolism, which results in glucuronide metabolites. Metabolism in the gastrointestinal tract to metabolites was identified as a source of the adverse drug-drug interaction. Thus, the ability of the intraorally absorbed formulation to reduce or avoid such metabolism was beneficially found to allow for co-administration with the CYP3A4 inducers.
CYP3A4 inducers include, for example, Apalutamide, Mitotane, Avasimibe, Rifampin, Enzalutamide, Rifapentine, Ivosidenib, St John's Wort extract, and Lumacaftor.
The dosage forms described herein, including one including ecopipam or a salt thereof, can be administered with a p-glycoprotein (PGP) inhibitor, or on a dosing schedule that overlaps a dosing schedule of a PGP inhibitor schedule. The dosage forms described herein, including one including ecopipam or a salt thereof, can be administered with a CYP3A4/5 inhibitor, or on a dosing schedule that overlaps a dosing schedule of a CYP3A4/5 inhibitor schedule.
PGP inhibitors include (for example) verapamil, cyclosporin A, reserpine, quinidine, yohimbine, tamoxifen and toremifene, dexverapamil, dexniguldipine, valspodar, and dofequidar fumarate, cyclopropyldibenzosuberane zosuquidar, laniquidar, mitotane, biricodar, elacridar, ONT-093, tariquidar, and HM30181.
CYP3A4 inhibitors include weak inhibitors, e.g. cimetidine; moderate inhibitors, e.g. amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan; and strong inhibitors, e.g. clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir.
CYP3A5 inhibitors include (for example) ketoconazole, erythromycin, nefazodone, itraconazole, clarithromycin, and mibefradil.
Diseases
The dosage form can be for the treatment of a patient in need thereof, or a patient in need of a dopamine D1 antagonist, or a patient in need of a dopamine D1/D5 antagonist. A dosage form disclosed herein containing ecopipam can be for the treatment of a patient in need of a selective dopamine D1 antagonist. A dosage form described herein, including one containing ecopipam, can be for the treatment of a tic disorder or movement disorder. The tic disorder can be Tourette Syndrome, a pediatric autoimmune disorder associated with streptococcal infection (PANDAS), a transient tic disorder, a chronic tic disorder, or a Tic Disorder Not Otherwise Specified (NOS). The subject can exhibit a motor tic (e.g., a complex motor tic), a vocal tic (e.g., a complex vocal tic), or a combination thereof. A dosage form described herein, including one containing ecopipam, can be for the treatment of Childhood Onset Fluency Disorder (stuttering). A dosage form described herein, including one containing ecopipam, can be for the treatment of Restless Legs Syndrome, refractory Restless Leg Syndrome, Restless Legs Syndrome with Augmentation, or for Augmentation associated with Restless Legs Syndrome. A dosage form described herein, including one containing ecopipam, can be for the treatment of obesity, including type 2 diabetic subjects.
The dosage forms disclosed herein are generally and variously useful for treatment of fluency disorders, including stuttering, which is also variously referred to as stammering. The dosage forms disclosed herein can also be administered for the treatment of stuttering induced as a side effect of a medication; stuttering associated with autism; and stuttering as a result of another disease or condition, such as a sporadic, genetic, or neurodegenerative disorder.
In other embodiments, the dosage forms disclosed herein are useful in the treatment of speech and language disorders including expressive language disorder, mixed receptive-expressive language disorder, phonological disorder, and communication disorder not-otherwise-specified (DSM-IV). In any given disorder, there may be impaired production of fluent and comprehensible speech, a phonological disorder, or developmental verbal dyspraxia, in which the coordination and motor control of the speech organs is compromised, or problems with morphology, syntax, semantics, or pragmatics. The term specific language impairment (SLI) is often used as an umbrella term for expressive language disorder, mixed receptive-expressive language disorder, and sometimes phonological disorder. The dosage forms disclosed herein can be used to alleviate these disorders.
The dosage forms disclosed herein are contemplated to be useful in treatment of mental disorders including psychoses, schizophrenia or depression in a mammal, or for the control of pain or anxiety in a mammal, or for the control of pain or anxiety in a mammal.
A sublingual dosage form and/or a buccal dosage form could lend themselves for acute treatment of these ailments, especially stuttering and Tourette's syndrome.
Certain D1/D5 receptor antagonist APIs disclosed herein are also active as renal vasodilators. Dosage forms disclosed herein containing one or more of these compounds can thus be used in methods for controlling hypertension by administering to a mammal a renal vasodilating effective amount of such a compound in a dosage form described herein, and/or according to a method described herein.
EXAMPLES
The following examples are provided for illustration and are not intended to limit the scope of the invention.
Example 1: pH Effect on BCS Solubility of Ecopipam
BCS solubility of Ecopipam HCl (EBS-101) was performed in five different pH buffers ranging from pH 1.2 to pH 6.8 and three bio-relevant media at 37° C. for up to 24 hours. Results demonstrated that the solubility of Ecopipam HCl (EBS-101) was pH-dependent, solubility increased from pH 1.2 to pH 3.0 buffers and reached the highest solubility in pH 3.0 citrate buffer (9.4 mg/mL), then solubility decreased from pH 4.5 to pH 6.8 buffers due to crystalline form change. In bio-relevant media, Ecopipam HCl (EBS-101) exhibited the highest solubility in FaSSGF (2.0 mg/mL), followed by moderate solubility in FeSSIF-V2 (0.66 mg/mL) and the lowest solubility in FaSSIF-V2 (0.05 mg/mL), and crystalline form after solubility test also changed in FaSSIF-V2 and FeSSIF-V2. In pH buffers, it was observed to be substantially stable in the five pH buffers (pH 1.2, pH 3.0, pH 4.5, pH 5.5 and pH 6.8) at 37° C. for up to 24 hours, while in bio-relevant media, it was only stable at 37° C. for up to 1 hour, as degradation occurred from 3 hours. The results are shown in the table below. Solubility and final pH were the average of three parallel values. Purity was that of 24 hours. N/A means not performed.
















Solubility
Final
Purity




Media
(mg/mL)
pH
(%)
Appearance
XRPD




















pH 1.2 HCl
1.56
1.23
99.87
White
No


buffer, 50 mM



suspension
change


pH 3.0 citrate
9.42
2.96
99.87
White
No


buffer, 100 mM



suspension
change


pH 3.0 phthalate
0.008
3.05

White
Changed


buffer, 50 mM



suspension


pH 4.5 acetate
3.30
4.50
99.85
White
Changed


buffer, 50 mM



suspension


pH 5.5 acetate
0.23
5.49
100.00
White
Changed


buffer, 50 mM



suspension


pH 6.8 phosphate
0.02
6.85
100.00
White
Changed


buffer, 50 mM



suspension


FaSSGF
2.02
1.61
N/A
Hazy
No






solution
change


FaSSIF-V2
0.05
6.49
N/A
White
Changed






suspension


FeSSIF-V2
0.66
5.84
N/A
White
Changed






suspension









FIG. 2 illustrates the trend of solubility for Ecopipam HCl (EBS-101) in the various pH buffers. It was surprisingly found that Ecopipiam HCl had significantly improved solubility in a citrate buffer at a pH of 3.05. Referring to FIG. 3, it was also observed that the Ecopipam HCl did not exhibit a change in crystallinity in citrate buffer.
Example 2: Modeling of Intraoral Absorption of Ecopipam
The intraoral absorption of ecopipam was modeled using physiologically-based pharmacokinetics (PBPK) (GastroPlus®). FIG. 4 illustrates absorption profiles simulated. The following input parameters were used in the simulation:














Parameter
Value



















logP
4.31



pKa
8.68 (a) and 7.25 (b)



Particle size D50 (μm)
2



Intraoral residence time (min)
0.5



Diffusivity (×10−7 cm2/s)
11.2



Fraction unbound in oral mucosa Fut
0.06










The predicted intraoral fraction absorbed for ecopipam was calculated to be 23% after administration of a 20 mg orally dissolvable tablet formulation with small particle size (2 μm) comprising ecopipam HCl. This represents a significant absorption amount. This significant amount of absorption achievable intraorally with the formulations of the disclosure combined with the avoidance of first-pass metabolism results in significant and beneficial influence on the total exposure.
Referring to FIGS. 5A to 5C, solubility of ecopipam, HCl at different pH was also examined through the model. It was observed that solubility of ecopipam HCl drops significantly at the natural pH of the mouth. The model predicted the best intraoral absorption of ecopipam to be at a saliva pH of 4 or lower.
Referring to FIG. 6, the particle size of the formulation was also found to affect intraoral absorption. In FIG. 6, a 22.4 mg dose was analyzed by the model and an average D50 particle size of 10 μm or lower were found to be beneficial to improve intraoral fraction absorption.
Example 3: Analysis of First Pass Metabolites After Oral Administration of Ecopipam
A Phase 1, Open-label Study of the Absorption, Metabolism, and Excretion of [14C]-Ecopipam Following a Single Oral Capsule Dose in Healthy Male Subjects
Healthy subjects of any ethnic origin, aged between 35 and 55 years, inclusive, with a body mass index between 18.0 and 30.0 kg/m2, inclusive, were selected for the study. Eight subjects were enrolled and dosed, and all 8 subjects completed the study as planned.
A single oral dose of [14C]-ecopipam HCl containing approximately 88.5 μCi of [14C] radioactivity was administered to subjects orally as a powder-filled capsule in the fasted state.
Following a single oral dose of 200 mg [14C]-ecopipam HCl, the arithmetic mean total radioactivity recovery in urine and feces was 91.6%. Renal excretion of metabolites was the principal route of elimination of [14C]-ecopipam, with an arithmetic mean of 83.3% of radioactivity recovered in urine and 8.27% of radioactivity recovered in feces.
The median time of the maximum observed concentration of ecopipam in plasma, total radioactivity in plasma, and total radioactivity in whole blood were similar at 2.00, 2.25, and 2.00 hours postdose, respectively. Appearance of the EBS-101-40853 metabolite in plasma peaked at 3.50 hours postdose.
The geometric mean apparent terminal elimination half-life (t½) of ecopipam and EBS-101-40853 were 17.3 and 25.6 hours, respectively. The geometric mean t½ for total radioactivity in plasma and whole blood were longer than ecopipam and EBS-101-40853, at 94.1 and 122 hours, respectively, indicating the presence of other persistent circulating metabolites.
The geometric mean area under the concentration-time curve (AUC) ratio of plasma ecopipam or EBS-101-40853 to plasma total radioactivity was 0.0169 and 0.00178, respectively, suggesting neither ecopipam nor EBS-101-40853 were the primary drug-related material in systemic circulation. Instead, ecopipam O-β-D-glucuronide was the major drug-related material in systemic circulation, accounting for 80% of radioactivity in plasma.
There was no preferential association of radioactivity with red blood cells based on the geometric mean AUC ratio of whole blood to plasma total radioactivity of 0.666.
The geometric mean percentage of dose excreted in urine as ecopipam and EBS-101-40853 was 0.115% and 0.0645%, respectively, corresponding to geometric mean renal clearance of 0.284 and 1.53 L/hour, respectively, which were lower than the typical glomerular filtration rate in the kidney.
The primary route of biotransformation of ecopipam was by glucuronidation to form ecopipam O-β-D-glucuronide, which is then excreted renally (accounting for 67% of radioactivity in the urine) along with other minor metabolites. EBS-101-40853 AUC from time zero extrapolated to infinity (AUC0-inf) accounted for 10.5% of ecopipam AUC0-inf. The main component in the feces was unchanged ecopipam, accounting for 6% of the total administered dose.
The estimated AUC of the metabolites associated with the trailing terminal phase accounts for 39.4% of the overall plasma total radioactivity AUC0-inf and triggered the post-hoc pooled metabolites analysis.
Most of the radioactivity in plasma (˜80%) was accounted for by ecopipam glucuronide, with 2.66% of the radioactivity identified as ecopipam, 0.26% identified as EBS-101-40853, and 3.09% identified as EBS-101-40853 glucuronide. There were 3 peaks of unidentified metabolites in plasma: P3 representing 2.27%, P4 representing 2.82%, and P5 (EBS-101-40853 sulfate) representing 8.62%.
The t1/2 for metabolites P3 (97.4 hours) and P5 (EBS-101-40853 sulfate; 122 hours) corrected for extraction efficiency from pooled PK samples closely resembled that observed in plasma total radioactivity (94.1 hours), indicating these are the persistent circulating metabolites accounting for the terminal phase of radioactivity. The estimated fractions of AUC0-inf values (equivalent to predicted AUC from time 0 to end of the dosing interval at steady state) for the corrected P3, P4, and P5 metabolites relative to plasma total radioactivity were 0.0462, 0.00243, and 0.0603, respectively, indicating none of these metabolites accounted for >10% of the total radioactivity in plasma.
Example 4: Mass Balance Study of Ecopipam
Referring to FIG. 1, a mass balance study of ecopipam along with in vitro studies showed the metabolic pathways for elimination of Ecopipam (FIG. 1). Ecopipam is primarily metabolized by UGT1A9 to Ecopipam glucuronide (which accounted for ˜80% of radioactivity in plasma and 67% of radioactivity in the urine). In addition, Ecopipam is metabolized by CYP3A4 to form EBS-101-40853, which accounted for 10.5% of ecopipam's area under the curve AUC∞. There were several minor metabolites, which all account for less than 10% of the radioactivity, and were therefore, not important.
After steady-state dosing with ecopipam 1.8 mg/kg using the proposed weight-based dosing paradigm, the predicted geometric mean Cmax (3968 [range: 1679-11731] ng/ml) and AUC(0-τ) (29671 [range: 14981-55254] ng*h/mL) of ecopipam glucuronide was much higher than ecopipam. The Cmax (4.1 [range: 1.37-9.9] ng/ml) and AUC (0-1) (140 [range: 47.7-351] ng*h/mL) of EBS-101-40853 was much lower than ecopipam. After steady-state dosing with ecopipam, the predicted Cmax and AUC (0-1) of EBS-101-40853 glucuronide were 92.1 (32.7-180) ng/ml and 2074 (707-5747) ng*h/mL, respectively.
Weight-Based Ecopipam Dosing Regimen for Pediatric Patients with TD (Target Dose=˜1.8 mg/kg/day)














Weight
Dose (mg)
Dose (mg)
Dose (mg)
Dose (mg)


(kg)
Week #1
Week #2
Week #3
Week #4 onward







≥18 to ≤23
11.2 a
22.4 b
33.6 d
 33.6 d


>23 to ≤34
11.2 a
22.4 b
33.6 d
 44.8 c


>34 to ≤44
11.2 a
22.4 b
44.8 c
 67.2 e


>44 to ≤68
22.4 b
44.8 c
67.2 e
 89.6 f


>68 to ≤83
22.4 b
44.8 c
89.6 f
134.4 g


>83
22.4 b
44.8 c
89.6 f
179.2 h





HCl = hydrochloride;


TD = Tourette's disorder


a Equivalent to ecopipam HCl 12.5 mg


b Equivalent to ecopipam HCl 25 mg


c Equivalent to ecopipam HCl 50 mg


d Equivalent to ecopipam HCl 37.5 mg


e Equivalent to ecopipam HCl 75 mg


f Equivalent to ecopipam HCl 100 mg


g Equivalent to ecopipam HCl 150 mg


h Equivalent to ecopipam HCl 200 mg






Example 5: Formulations for Intraoral Absorption of Ecopipam
Formulations in accordance with the disclosure were prepared by incorporating ecopipam HCl into a formulation premix. Premixes which were gelatin and non-gelatin based were tested. It was observed in preparing batches 1 and 2 that the ecopipam did not disperse easily in the premix. For batches 3-5, the ecopipam was manually wetted prior to bulk premix addition. For batches 2, 4, and 5, the pH modifier was then added to the suspension of ecopipam HCl in the premix to adjust the pH to a target pH of 3.30±0.2. The suspension was then filled into tablet molds and freezing was performed at −70° C. for 4 minutes. The samples were held at −15° C. or less for a minimum of 12 hours. The samples were then freeze dried at 0° C. for 12 hours to thereby produce the formulations in accordance with the disclosure in the form of a sublingual orally disintegrating tablet.
Sublingual Orally Disintegration Formulations













Amount of component (% w/w)












Component
Batch 1
Batch 2
Batch 3
Batch 4
Batch 5















Ecopipam HCl (free
8.37
8.37
8.37
8.37
8.37


base equivalent)
(7.47)
(7.47)
(7.47)
(7.47)
(7.47)


Bovine Gelatin
4.00
4.00
4.00
4.00
N/A


Pullulan Polysaccharide
N/A
N/A
N/A
N/A
4.00


Mannitol
3.00
3.00
3.00
3.00
3.00


Citric Acid Anhydrous
N/A
0.52
N/A
0.64
0.03


Purified Water
84.63
84.10
88.82
88.18
84.60


Total
100
100
100
100
100


Dose Strength (mg)
22.4
22.4
22.4
22.4
22.4


Wet fill (mg)
300.00
300.00
600.00
600.00
300.00









The pH of the suspension was tested after mixing and then again 24 hours post mixing. Batches 1 and 3 did not include the citric acid pH modifier. The pH when adjusted to the target remained stable when pH was adjusted by addition of the citric acid (batches 2, 4, 5). Batches 1 and 3, which were not adjusted for pH after mixing exhibited more pH variability 24 hours after mixing as compared to the pH adjusted samples.
pH Testing During Manufacturing Process























pH 24 hrs








pH at
after






Citric
conclusion
conclusion
Change



Initial
Target
Adjusted
Acid
of mixing
of mixing
SH0 −


Batch
pH
pH
pH
(w/w %)
(SH0)
(SH24)
SH24







1
—
—
—
—
5.32
4.78
−0.54


2
5.43
3.30 ± 0.20
3.50
0.52
3.48
3.52
+0.04


3
—
—
—
—
5.29
5.42
+0.13


4
5.40
3.30 ± 0.20
3.33
0.64
3.31
3.37
+0.06


5
4.38
3.30 ± 0.20
3.01
0.03
3.03
3.05
+0.02









Example 6: Pharmacokinetic Properties of Formulations for Intraoral Absorption of Ecopipam
Pharmacokinetic properties of the pharmaceutical formulations in accordance with the disclosure, which provide for intraoral absorption of ecopipam was studied in a Naïve minipigs animal model. The minipigs were 4-5 months old with a weight range within 10-15 kg at dosing. 3 male animals were used. The minipigs were dosed with an ecopipam HCl oral tablet (Ecopipam HCl IR Tablet) on day 1, and separately an ecopipam HCl sublingual tablet (Ecopipam HCl Zydis ODT tablet), which disintegrates intraorally, on day 8. The minipigs were observed for 10 days. Ecopipam HCl Zydis ODT tablet had the formulation as identified in Batch 4 in Example 5.












Group
1
1







API
Ecopipam HCl
Ecopipam HCl


Dose route
Oral (tablet)
Sublingual (Tablet)


Dose level
50 mg ecopipam HCl
25 mg ecopipam HCl


(mg/animal)
(44.8 mg ecopipam
(22.4 mg ecopipam



free base)
free base)


Animal Number
1255, 1256, 1257
1255, 1256, 1257









On dosing days, the animals were fed 1 hour post dose and then offered a second feed in the afternoon. Prior to dosing and immediately after dosing, the pH level of the salvia were tested. The pH of the minipig saliva was found to remain unchanged after dosing with the oral tablet. By comparison, the sublingual tablet in accordance with the disclosure reduced the pH of the minipig saliva significantly. As shown in the table below, the pH of the saliva after dosing with the sublingual tablet was reduced dramatically by 1-3 units. The minipig salvia prior to dosing is 1 to 3 pH units higher than the saliva of a human. It is anticipated that the formulations of the disclosure will reduce the pH of human saliva after dosing to 6.5 or less, 5 or less, or even 4 or less, providing for improved solubility of ecopipam in the human mouth.


















Pre-dose
Post-dose



Animal
Dosing
Saliva pH
Saliva pH



Number
Occasion
level
level
















Ecopipam IR Tablet












1255
1
9
9



1256
1
9
9



1257
1
9
9







Ecopipam Zydis ODT Tablet












1255
2
8
5



1256
2
8
7



1257
2
9
6










The minipigs were also observed for central nervous system (CNS) activity. Clinical observations indicate a more pronounced CNS effect after dosing with the sublingual tablet as compared to the orally administered tablet formulation, despite administering half of the dosing amount in the sublingual formulation.













Animal

Dose



No.
Days
Administered
Observation







1255
1
Ecopipam IR
Decreased general activity




Tablet



2-7 
NONE
Normal - no remarkable





observation



8
Ecopipam Zydis
Decreased general activity,




ODT Tablet
whole body tremor



9-10
NONE
Normal - no remarkable





observation


1256
1
Ecopipam IR
Decreased general activity




Tablet



2-7 
NONE
Normal - no remarkable





observation



8
Ecopipam Zydis
Decreased general activity,




ODT Tablet
whole body tremor



9-10
NONE
Normal - no remarkable





observation


1256
1
Ecopipam IR
Decreased general activity




Tablet



2-7 
NONE
Normal - no remarkable





observation



8
Ecopipam Zydis
Decreased general activity,




ODT Tablet
whole body tremor



9-10
NONE
Normal - no remarkable





observation









Consistent with the clinical observations, concentration-time pharmacokinetic data indicated a more rapid and increased exposure to ecopipam after administration of the sublingual formulation as compared to the oral tablet. There was a dramatic decrease in the concentration of glucuronide metabolites observed after the sublingual formulation administration, as well.
The observance of CNS side effects demonstrates that ecopipam in a sublingual formulation has increased CNS availability as compared to the oral formulation. While CNS side effects are to be avoided in patients, this data is indicative of the improved efficacy of the sublingual formulation, which can result in reduced dosing amounts being needed for effective treatment of patients, particularly for acute use.
The reduction of glucuronide metabolites with the formulations of the disclosure can result in reduced side effects, such as those relating to cardiac safety concerns, as well as reduced potential drug-drug interactions.
The concentration-time data were normalized for differences in dose. The ratio of Cmax and AUC after SL:oral dosing is summarized below

















Ecopipam
EBS-
EBS-101-40853



Ecopipam
Glucuronide
101-40853
Glucuronide




















Ratio of
2.83
0.24
0.45
0.24


SL/oral Cmax


Ratio of
0.73
0.15
0.52
0.4


SL/oral AUC









The data demonstrates that the amount of ecopipam glucuronide metabolites is significantly reduced (76-85% reduction) after sublingual administration as compared to oral administration. There was also an observed reduction in other metabolites.
Example 7: Exposure Response Study for Efficacy in Tourette's Disorder
A Phase 2 [Clinical Study] showed that there was an exposure-response for efficacy in Tourette's Disorder (TD). A logistic regression model showed that combined steady-state AUC (0-1) of ecopipam and EBS-101-40835 (assuming equipotence) was a predictor of being a responder at week 12 (FIG. 2). Based on this model, the odds of being a responder at 12 weeks increase by 6.8% for each 100 unit increase in the combined steady-state AUC (0-1) of ecopipam and EBS-101-40853 (Dumetrescu, 2023). FIG. 7 shows a plot of predicted probabilities and 90% confidence interval for exposure-response of efficacy in Tourette's Disorder.
Exposure-response analyses have been conducted for safety using sedation as an endpoint and cardiac safety (QTc). There was no relationship between plasma Cmax or AUCinf and the choice reaction time or visual analogue scale for sedation. There was an exposure-response relationship for QTc.
A randomized, double-blind, single dose, 4-way crossover thorough QT study was conducted with an open-label active control (EBS-101-HV-105, 2024). Subjects received single doses of ecopipam 179.2 mg, ecopipam 537.6 mg, moxifloxacin 400 mg, and placebo. There is no effect of ecopipam on HR, QRS, or PR intervals, but there is an increase in QTcF after a single dose of ecopipam 537.6 mg.
The primary endpoint for this study was pre-specified to be based on C-QT analysis using the methods outlined in the white paper (Garnett C, 2018) (Garnett C B. P., 2018). Models were developed for each single analyte including ecopipam, EBS-101-40853, ecopipam glucuronide, and EBS-101-40853 glucuronide and for 4 combination models (2 metabolites each). The best model appeared to be the model with ecopipam glucuronide and EBS-101-40853.
The most appropriate model describing the concentration-QT effects of ecopipam at increased doses and exposures was consistent with the nonclinical hERG data in vitro, which has been used as a surrogate for predicting QT prolongation. The hERG IC50/free Cmax ratios for ecopipam and its main metabolites (indicative of the safety margins for predicting QT prolongation) were:



 
  Ecopipam
  =
  1166
 




 
  
   EBS
   -
   101
   -
   40853
  
  =
  7303
 




 
  
   Ecopipam
   ⁢
       
   glucuronide
  
  =
  
   62
   ⁢
       
   
    (
    
     
      lowest
      ⁢
          
      safety
      ⁢
          
      margin
     
     ,
     
      and
      ⁢
          
      highest
      ⁢
       
      

         
      concentrations
      ⁢
          
      in
      ⁢
          
      human
     
     ,
     
      and
      ⁢
          
      animal
      ⁢
          
      plasma
     
    
    )
   
  
 




 
  
   EBS
   -
   101
   -
   40853
   ⁢
       
   glucuronide
  
  =
  652
 



The study showed that a 10 msec increase in ΔΔQTcF interval can be ruled out after a single ecopipam dose at the top end of the range for the therapeutic dose (ecopipam 179.2 mg) but cannot be ruled out after a single dose at the top end of the high clinical exposure (ecopipam 179.2 mg+a general UGT inhibitor) using the primary model. After steady-state dosing of ecopipam 1.8 mg/kg using the clinical weight-based dosing paradigm, a 10 msec increase in ΔΔQTcF can be ruled out using the primary model and all but one (EBS-101-40853 glucuronide alone) of the secondary models.
For the high clinical exposure (steady-state dosing of ecopipam 1.8 mg/kg with a general UGT inhibitor), a 10 msec increase can be ruled out by 5 of 8 models, including the primary model. The other 3 of 8 models, which could not rule out a 10 msec increase, resulted in an upper 90% confidence interval of 10.06 to 11.64 msec, which is not considered clinically relevant. At higher doses, there is the potential for increases in the ΔΔQTcF interval with up to 20.4 msec predicted after administration of a single dose of ecopipam 537.6 mg.
Example 8: Drug-Drug Interaction Studies
Ecopipam when administered orally is metabolized to ecopipam glucuronide by UGT1A9 and to EBS-101-40853 by CYP3A4 and both ecopipam and EBS-101-40853 are P-gp substrates. Two clinical studies were conducted to assess the resulting effects of UGT inhibition or CYP3A induction on the pharmacokinetics of ecopipam and its metabolites. One study evaluated whether a specific UGT1A9 inhibitor (mefenamic acid) or a general UGT inhibitor (divalproate sodium) affected the PK of ecopipam or its metabolites. The other study evaluated whether CYP3A4 induction influenced the PK of ecopipam and its metabolites. The results from these studies are summarized in Table 7 below along with clinical recommendations.
Clinical Studies Conducted to Evaluate the PK of Orally Administered Ecopipam and its Metabolites in the Presence and Absences of Specific Inducers and Inhibitors












Concomitant

Clinical


Medication

Recommendations


[Inducer/Inhibitor]

for oral systemically


(Study Number)
Results
administered ecopipam







Rifampicin
When rifampicin is co-administered
Co-administration of


[strong inducer of
with ecopipam, there was a
ecopipam with an


CYP3A4 and P-gp,
substantially (72-77%) lower Cmax
inducer is not


moderate inducer of
and AUC∞ of ecopipam, a
recommended.


CYP2C8, CYP2C9, and
substantially (71%) higher Cmax with


CYP2C19]
no change in AUC∞ of EBS-101-


(EBS-101-HV-106)
40853, only a 22% lower Cmax and no



change in AUC∞ of ecopipam



glucuronide, and a more substantial



impact on EBS-101-40853



glucuronide (with an increase of 2.8x



in Cmax and 86% in AUC∞)


Divalproate Sodium
When divalproate sodium was co-
If ecopipam is


[General UGT
administered with ecopipam, there
administered


Inhibitor]
was a 40%-66% increases in Cmax of
concomitantly with


(EBS-101-HV-102)
ecopipam and EBS-101-40853 and a
general UGT inhibitors



23% and 32% lower Cmax of
(e.g., VPA), the



ecopipam glucuronide and EBS-101-
ecopipam dose should



40853 glucuronide, a ~2.1x increase
be decreased by 50%..



in AUC∞ of ecopipam, an ~86%



increase in AUC∞ of EBS-101-40853



and no changes in the AUC∞ for the



glucuronide conjugates


Mefenamic Acid
When mefenamic acid was co-
If ecopipam is


[Specific UGT1A9
administered with ecopipam, there
administered


Inhibitor]
was a small increase (12-21%) in the
concomitantly with a


(EBS-101-HV-102)
Cmax of ecopipam and EBS-101-
UGT1A9 inhibitor (e.g.,



40853 and a 15% and 12% lower
mefenamic acid), the



Cmax of ecopipam glucuronide and
ecopipam dose should



EBS-101-40853 glucuronide, a 42-
be decreased by 50%.



45% increase in the AUC∞ of



ecopipam and EBS-101-40853, no



change in the AUC∞ of ecopipam



glucuronide and a 14% increase in the



AUC∞ of EBS-101-40853



glucuronide









The intra-orally absorbing formulations in accordance with the disclosure can advantageously reduce such drug-drug interactions through bypass of the first pass metabolism.
The foregoing description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the invention may be apparent to those having ordinary skill in the art.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise” and variations such as “comprises” and “comprising” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Throughout the specification, where compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Likewise, where methods are described as including particular steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise. The invention illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.
The practice of a method disclosed herein, and individual steps thereof, can be performed manually and/or with the aid of or automation provided by electronic equipment. Although processes have been described with reference to particular embodiments, a person of ordinary skill in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For example, the order of various of the steps may be changed without departing from the scope or spirit of the method, unless described otherwise. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.
All patents, publications and references cited herein are hereby fully incorporated by reference. In case of conflict between the present disclosure and incorporated patents, publications and references, the present disclosure should control.
Aspects of the Disclosure
1. A pharmaceutical dosage form for use in delivering an active pharmaceutical agent (API) in a manner other than oral systemic delivery, wherein the API is selected from one or more of those in Table I, or


    
    
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-3-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3-chloro-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,6a,7,8,9,13b-hexahydro-12-methoxy-7-methyl[1]benzopyrano[4,3-a][3]benzazepine;
        6,6a,7,8,9,13b-hexahydro-7-methyl[1]benzopyrano[4,3-a][3]benzazepin-12-ol;
        6,6a, 7,8,9,13b-hexahydro-3-hydroxy-2-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        2-hydroxy-3-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        3-hydroxy-2-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-methoxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-amino-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3,7-dimethyl-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-7-cyclopropylmethyl-2-hydroxy-benz[d]indeno[2,1b]azepine;
        5,6,7,7a,8,12b-hexahydro-7-allyl-3-chloro-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-2-hydroxy-7,8,8-trimethyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,11b-hexahydro-3-chloro-7-methylthieno[2′,3′:4,5]cyclopenta[1,2-a][3]benzazepine-2-ol;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-benz[d]indeno[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H-benzo[d]naphtho[2,1-b]azepine;
        or
        6,7,7a,8,9,13b-hexahydro-2-amino-3-trifluoromethyl-7-methyl-5H-benzo[d]naphtho[2,1b]azepine;
        or SCH23390 and compounds related thereto, including SCH 12679 and the compounds described in U.S. Pat. No. 4,477,378 (which is hereby incorporated by reference in the present application in its entirety), BTS-73-947, NNC-22-0010, JHS-271, JHS-198, JHS-136, A69024, and NNC687. D1/D5 partial agonists include SKF38393, fenoldapam; SKF75670A; SKF 81297; SKF82958; or dinapsoline; or
    
    






    
    
        or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing.

2. The pharmaceutical dosage form of aspect 1, wherein the API is selected from one or more of those in Table I or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing.

3. The pharmaceutical dosage form of aspect 1, wherein the API comprises 6,7,7a,8,9,13b-hexahydro-2-hydroxy-3-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;

        6,7,7a,8,9,13b-hexahydro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-hydroxy-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3-chloro-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-2-amino-3,7-dimethyl-5H-benzo[d]naphtho[2,1-b]azepine;
        6,6a, 7,8,9,13b-hexahydro-12-methoxy-7-methyl[1]benzopyrano[4,3-a][3]benzazepine;
        6,6a, 7,8,9,13b-hexahydro-7-methyl[1]benzopyrano[4,3-a][3]benzazepin-12-ol;
        6,6a, 7,8,9,13b-hexahydro-3-hydroxy-2-methoxy-7-methyl-5H-benzo[d]naphtho[2,1-b]azepine;
        2-hydroxy-3-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        3-hydroxy-2-methoxy-7-methyl-5,6,7,7a,8,9,10,14b-octahydro-benzo[d]benzo[3,4] cyclo-hepta[1,2-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-methoxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-amino-3-chloro-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-7-methyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3,7-dimethyl-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-7-cyclopropylmethyl-2-hydroxy-benz[d]indeno[2,1b]azepine;
        5,6,7,7a,8,12b-hexahydro-7-allyl-3-chloro-2-hydroxy-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,12b-hexahydro-3-chloro-2-hydroxy-7,8,8-trimethyl-benz[d]indeno[2,1-b]azepine;
        5,6,7,7a,8,11b-hexahydro-3-chloro-7-methylthieno[2′,3′:4,5]cyclopenta[1,2-a][3]benzazepine-2-ol;
        5,6,7,7a,8,12b-hexahydro-2-hydroxy-3-chloro-benz[d]indeno[2,1-b]azepine;
        6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-5H-benzo[d]naphtho[2,1-b]azepine;
        or
        6,7,7a,8,9,13b-hexahydro-2-amino-3-trifluoromethyl-7-methyl-5H-benzo[d]naphtho[2,1b]azepine
        or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing.

4. The pharmaceutical dosage form of aspect 1, wherein the API is selected from one or more of:

    
    









    
    
        or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph of any of the foregoing, or a pharmaceutically acceptable salt of any of the foregoing.

5. The pharmaceutical dosage form of aspect 1, wherein the API comprises ecopipam or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, structural analog, metabolite, or polymorph thereof, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is for pulmonary, transdermal, or transmucosal delivery.

7. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is for transmucosal delivery, (e.g., buccal and/or sublingual).

8. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is for delivery to the mucosal lining of the nasal, rectal, vaginal, ocular, or oral cavity.

9. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is for topical oral delivery.

10. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form comprises a bioadhesive.

11. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form comprises a mucoadhesive.

12. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form comprises a buccoadhesive.

13. The pharmaceutical dosage form of any one of aspects 1-12, wherein the pharmaceutical dosage form comprises one or more compounds selected from AB block copolymers of oligo(methyl methacrylate) and PAA, acacia, and polyvinyl alcohol, anionic types, Carbopol e.g. 934P, cationic types, chitosan (e.g. free or cross-linked by an anionic polymer), copolymers of PAA and PEG monoethylether monomethacrylate, epoxy resins, Eudragit polymers (e.g. Eudragit L-100, an anionic copolymer based on methacrylic acid and methyl methacrylate), gelatin, gellan gum, glycol, guar gum, hyaluronic acid, hydrogels of poly(N N-dimethylaminoethyl methacrylate-co-methyl methacrylate) e.g., poly(DMA/MMA) cross-linked with DVB, hydrophilic pressure-sensitive adhesives (PSAs), hydroxyethyl cellulose, hydroxyethyl methacrylate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, a modified starch-polyacrylic acid mixture, monomeric alpha-cyanoacrylate, PAA complexed with PEGylated drug conjugate, pectin, poly(acrylic acid/divinyl benzene), polyacrylates, polymethacrylates, polycarbophil, polyethylene carboxymethyl cellulose, polymers with thiol groups, polymethyl vinyl ether-maleic anhydride, polystyrenes, polyurethanes, polyvinyl pyrrolidone, psyllium amberlite-200 resin, sodium alginate, sodium alginate, tamarind gum, thermally modified starch, tragacanth, and xanthan gum.

14. The pharmaceutical dosage form of any one of aspects 10-13 wherein the bioadhesive, mucoadheasive, or bucco adhesive comprises the API dispersed therein.

15. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a dosage form selected from a chewing gum, a chewable lozenge, a chewable tablet, a film, a gel, a liquid, a lozenge, a microporous hollow fiber, a mouthwash, an oral lyophilizate, an oral strip, an oravescent, an orodispersible, a patch, a powder, a semisolid, a sprayable liquid, a tablet, a tape, and a wafer.

16. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a tablet.

17. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a fast-dissolving tablet.

18. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a buccal tablet.

19. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a nasal spray.

20. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a matrix dosage form.

21. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a unidirectional release dosage form.

22. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a bilayer tablet.

23. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form comprises a bioadhesive layer containing drug and a water impermeable coating.

24. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is a triple layer tablet.

25. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form comprises a bioadhesive layer, a drug layer, and a water impermeable coating.

26. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form comprises a microsphere containing the API.

27. The pharmaceutical dosage form of any one of the preceding aspects, wherein the microsphere comprises a mucoadhesive.

28. The pharmaceutical dosage form of any one of the preceding aspects, wherein a region of the pharmaceutical dosage form comprising the API comprises one or more materials selected from acrylic acid polymer, ethylcellulose, hydroxypropyl cellulose, methylcellulose, polyethylene oxide and polyvinyl pyrrolidone, poly(ethylacrylate methylmethacrylate), polyethyene glycol, and natural polymers including gaur-gum, pectins, starches, gelatin, and casein. The region can contain or be based on one or more excipients selected from lactose, glucose, sucrose, starch, crystalline cellulose, dextrin, cyclodextrin, silicic acid anhydride, aluminum silicate, talc, calcium stearate, magnesium stearate, beeswax, polyethylene glycol, and polyphosphate.

29. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form further comprises one or more excipients.

30. The pharmaceutical dosage form of aspect 29, wherein the one or more excipients are selected from the groups of an absorption enhancer (also called permeation enhancer), an antioxidant, a binder, a carrier, a colorant, a diluent, a disintegrant, a flavor, a lubricant, a pH modifier, a plasticizer, a preservative, a sweetener, a taste masking agent, a taste modulating agent, and a viscosity modifier, including one or more from each group of excipients.

31. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form comprises an absorption enhancer selected from one or more in the group of chelators (e.g., citric acid, EDTA, EGTA, methoxy salicylates, sodium salicylate); surfactants, including nonionic, e.g., polyoxyethylene vegetable-based fatty ethers derived from lauryl, cetyl, stearyl or oleyl alcohols (e.g., Brij), dodecylmaltoside, laureth-9, ethoxylated fatty acids (e.g. Myrj), poloxamer, polysorbate 80, span, sucrose esters, Tween, cationic (e.g., benzalkonium chloride, cetylmethylammonium bromide, Cetyl pyridinium chloride), and anionic (e.g., sodium dodecyl glycocholate, sodium lauryl sulfate, laureth-9 sodium dodecylsulfate); bile salts and other steroidal detergents (e.g., sodium glycocholate, sodium taurocholate, saponins, sodium taurodeoxycholate, sodium taurodihydrofusidate, and sodium glycodihydrofusidate); fatty acids (e.g., Oleic acid, Caprylic acid, Lauric acid, Lyso phosphatidyl choline, Phosphatidyl choline, sodium myristate); non-surfactants (e.g., 1-dodecylazacycloheptane-2-one (Azone), salicylates, and sulfoxides); enzymes (e.g., phopholipases, hyaluronidases, neuraminidase, and chondroitinase ABC); and Cyclodextrins (e.g., α, β, γ, Cyclodextrin, methylated β-cyclodextrins, hydroxypropyl beta-cyclodextrin), chitosan, trimethyl chitosan, poly-l-arginine, l-lysine, chondroitinase ABC, 1-dodecylazacycloheptan-2-one, and quillajasaponin.

32. The pharmaceutical dosage form of any one of the preceding aspects, wherein the API is microencapsulated.

33. The pharmaceutical dosage form of any one of the preceding aspects, wherein the API forms a complex with an ion exchange resin.

34. The pharmaceutical dosage form of any one of the preceding aspects, wherein the pharmaceutical dosage form is controlled release dosage form, optionally a sustained release, extended release, or prolonged release dosage form.

35. The pharmaceutical dosage form of any one of the preceding aspects, wherein the dosage form comprises an amount of API, e.g. ecopipam or a pharmaceutically acceptable salt thereof, about 1 wt % to about 40 wt %

36. The pharmaceutical dosage form of any one of the preceding aspects, wherein the dosage form comprises an amount of API, e.g. ecopipam or a pharmaceutically acceptable salt thereof, of about 1 mg to about 200 mg.

37. A method of administering a pharmaceutical dosage form of any one of the preceding aspects with a UGT inhibitor, or on a dosing schedule that overlaps a dosing schedule of a UGT inhibitor schedule.

38. A method of administering a pharmaceutical dosage form of any one of the preceding aspects with a CYP3A4 inducer, or on a dosing schedule that overlaps a dosing schedule of a CYP3A4 inducer schedule.

39. A method of administering a pharmaceutical dosage form of any one of aspects 37-38, wherein the dosage form comprises an amount of API, e.g. ecopipam or a pharmaceutically acceptable salt thereof, of about 1 mg to about 200 mg

40. A method of treating a subject in need of a dopamine D1 antagonist or a dopamine D1/D5 antagonist comprising administering to the subject a dosage form of any one of the preceding aspects 1-36 or according to a method of any one of aspects 37-39.

41. The method of aspect 40, wherein the subject has one or more disorders selected from the group of Tourette syndrome, transient tic disorder, chronic tic disorder, childhood onset fluency disorder (stuttering), Restless Legs Syndrome, refractory Restless Leg Syndrome, Restless Legs Syndrome with Augmentation, Augmentation associated with Restless Legs Syndrome, or a speech disorder selected from one or more of expressive language disorder, mixed receptive-expressive language disorder, phonological disorder and communication disorder not-otherwise-specified.

42. The method of aspect 41, wherein the subject has Tourette syndrome.

43. The method of aspect 41, wherein the subject has one or more disorders selected from the group of childhood onset fluency disorder (stuttering).

44. The method of aspect 41, wherein the subject has one or more disorders selected from the group of Restless Legs Syndrome, refractory Restless Leg Syndrome, Restless Legs Syndrome with Augmentation, or Augmentation associated with Restless Legs Syndrome.