JP-7856745-B2 - Lyophilized orally disintegrating tablet formulation of d-lysergic acid diethylamide for therapeutic use

Inventors

• マック，ピーター
• トレンクトログ，ティム
• メルトン，ダスティン
• ドティー，ベサニー アンバー
• シュローダー，ジョン
• ガレット，リサ マリー

Assignees

• デフィニウム セラピューティクス ユーエス， インコーポレイテッド

Dates

Publication Date

20260511

Application Date

20220817

Priority Date

20210819

Claims (19)

1. i. Lysergic acid diethylamide (LSD) or its salts; ii. Non-gelling matrix forming agents; iii. A tablet comprising a binder; and iv. a filler.
2. A tablet according to claim 1, comprising LSD tartrate.
3. A tablet according to claim 2, comprising d-LSD D-tartaric acid.
4. The tablet according to claim 1, wherein the non-gelling matrix-forming agent is non-gelling gelatin, maltodextrin, modified starch, starch ether, low molecular weight dextran, or low to medium molecular weight cellulose gum.
5. The tablet according to claim 4, wherein the non-gelling matrix-forming agent is maltodextrin.
6. The tablet according to claim 1, wherein the binder is acacia gum, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, tragacanth, polyvinylpyrrolidone, or starch.
7. The tablet according to claim 6, wherein the binder is hydroxypropyl methylcellulose.
8. The tablet according to claim 1, wherein the filler is lactose, mannitol, dicalcium phosphate, calcium sulfate, starch, cellulose, kaolin, sodium chloride, sorbitol, trehalose, or sucrose.
9. The tablet according to claim 8, wherein the filler is mannitol.
10. The tablet according to claim 1, which is an orally disintegrating tablet.
11. A tablet according to claim 1, for use in the manufacture of a drug for treating generalized anxiety disorder.
12. i. Lysergic acid diethylamide (LSD) or its salts; ii. Maltodextrin; iii. Hydroxypropyl methylcellulose; and iv. Mannitol, A tablet in which the relative amounts (weight ratio) of LSD or its salt, maltodextrin, hydroxypropyl methylcellulose, and mannitol are, respectively, <1:0.4 to 10:1:0.4 to 10 .
13. A tablet according to claim 12, comprising LSD tartrate.
14. A tablet according to claim 13, comprising d-LSD D-tartaric acid.
15. The tablet according to claim 12, which is an orally disintegrating tablet.
16. The tablet according to claim 13, which is an orally disintegrating tablet.
17. The tablet according to claim 14, which is an orally disintegrating tablet.
18. A tablet according to claim 12, for use in the manufacture of a drug for treating generalized anxiety disorder.
19. i. LSD or its salts; ii. Non-gelling matrix forming agents; iii. Binder; iv. A filler; and v. A method for producing tablets, comprising rapidly freezing a preservative solution containing water.

Description

Background of the Invention 1. Technical Field The present invention relates to the formulation of pharmaceuticals. More specifically, the present invention relates to an immediate-release formulation of d-lysergic acid diethylamide (LSD) for pharmaceutical formulations. 2. Background Technology Oral solution formulations are convenient for trials involving a limited number of patients at a few sites, mainly in early development trials. However, they are not only unsuitable for late-stage development trials conducted at multiple sites across a wide geographical area, but may also be unsuitable for commercialization due to product stability and supply chain challenges, such as potential requirements for cold chain storage. Solid oral dosage forms, such as tablets or capsules, are more common in late-stage clinical development and commercially due to their advantages in production, supply chain, and patient convenience. Solid oral dosage forms may offer immediate release, instantaneous dissolution in the mouth or stomach, or sustained release with extended drug release over time. Orally disintegrating tablets (ODTs) are another solid dosage form formulated to increase the dissolution rate of a drug and promote pregastric absorption. To achieve rapid disintegration, ODT formulations must offer high porosity, low density, and low hardness (Berthoumieu et al., 2010; Bandari et al., 2008). This dosage form can be chosen to improve absorption or for patient populations with dysphagia (Lindgren et al., 1993), and is also suitable for use in elderly and pediatric patients, or patients with conditions such as dysphagia (Sastry et al., 2000). From the standpoint of cost and simplicity, direct compression is a common method for preparing ODTs. However, the disintegration ability of ODTs prepared in this way is limited by the size and hardness of the resulting tablets. An alternative method for preparing ODTs is lyophilization. For example, Zydis® ODT (oral dissolving tablet) rapid dissolution formulation is a lyophilized oral solid dosage form that disperses almost instantaneously in the mouth without the need for water. LSD is derived from its German name, Lyserg-Saeure-Diethylamid (lysergic acid diethylamide). Lysergic acids belong to the indole alkylamine family, which includes bushilocycin (the active site of psilocybin) and numerous substituted tryptamines such as N,N-dimethyltryptamine (DMT). The IUPAC name for LSD is 9,10-didehydro-N,N-diethyl-6-methylergoline-8β-carboxamide. LSD can be used to adjunct psychotherapy for many indications, including anxiety, depression, addiction, personality disorders, and others. It can also be used to treat other disorders such as cluster headaches, migraines, and others (Passie et al., 2008; Hintzen et al., 2010; Nichols, 2016; Liechti, 2017). The effects of LSD may include altered thoughts, emotions, perception of the surroundings, dilated pupils, increased blood pressure, and elevated body temperature. The therapeutic uses of LSD have shown promising results for treating various neurological and behavioral disorders. However, due to its potency, there may be challenges in the development and manufacture of solid oral formulations of LSD in meeting pharmaceutically acceptable limits regarding content uniformity and chemical stability. In clinical trials using LSD, oral solution formulations are attracting attention. Research into LSD formulation development was virtually nonexistent. Historically, oral solutions were used, and almost all older trials and preliminary data involve oral solutions or impregnated paper/cartons. There is a need for LSD dosage forms and formulations that are commercially attractive to a broad patient population and meet expectations regarding regulatory/quality compliance and robustness. Commercially viable solid oral immediate-release pharmaceutical formulations of d-lysergic acid diethylamide (LSD) as a free base or in salt form are not currently available on the market or have only been reported in the literature. For therapeutic doses of LSD expected to be in the tens to hundreds of micrograms, there are challenges in achieving acceptable drug content uniformity and chemical stability. Furthermore, previous studies have shown that LSD in oral solutions is not stable at room temperature (Holze et al 2019). Figure 1 shows the labeling for D-LSD D-tartrate.Figure 2 is a photograph of Zydis ODT containing LSD. Detailed Description of the Invention The present invention provides formulations of LSD in rapid or immediate-release dosage forms, such as orally disintegrating tablets. The term "rapid-release tablet" refers to a mechanism that delivers the drug immediately (similar to immediate-release drug delivery), different from delayed (delayed-release) or extended-release (ER, XR, XL) drug delivery, or targeted delivery to a specific target in the body (targeted-release drug delivery). Preferably, it refers to the minimum time-dependent release in an