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

Abstract

The present invention relates to a solid oral immediate release formulation of LSD, wherein the composition is produced by freeze-drying ingredients in a preformed mold to form an orally disintegrating tablet.The present invention relates to a method of making a solid oral immediate release formulation of LSD by freeze-drying a deep-frozen preservative of LSD and excipients including a non-gelling matrix former, a filler, a binder, and a buffer in a preformed mold to form an orally disintegrating tablet.The present invention relates to a method of treating an individual by administering a solid oral immediate release formulation of LSD, wherein the composition is produced by freeze-drying ingredients in a preformed mold to form an orally disintegrating tablet.

Description

Technical Field

[0001] Background of the Invention 1. Technical Field The present invention relates to the formulation of drugs. More specifically, the present invention relates to an immediate release formulation for pharmaceutical formulations of d-lysergic acid diethylamide (LSD).

Background Art

[0002] 2. Background Art Oral solution formulations are convenient for testing in a limited number of patients at a few sites, mainly in early development tests, but are not only unsuitable for late development tests conducted across a wide geographical area in multiple facilities, but also may not be commercially viable due to issues in product stability and the supply chain, such as potential requirements in cold chain storage.

[0003] Solid oral formulations as tablets or capsules are more common clinically and commercially due to advantages in production, the supply chain, and patient convenience. Solid oral formulations can be immediate release, instant solubility in the mouth or stomach, or sustained release where drug release is extended over time.

[0004] Orally disintegrating tablets (ODTs) are another solid dosage form formulated to increase the dissolution rate of pharmaceuticals and promote pre-gastric absorption. To achieve a rapid disintegration rate, ODT formulations must provide high porosity, low density, and low hardness (Berthoumieu et al., 2010; Bandari et al., 2008). This dosage form can be selected to improve absorption or for patient populations with difficulty swallowing (Lindgren et al., 1993), and is also suitable for use in the elderly and pediatric patients, or patients suffering from conditions such as dysphagia (Sastry et al., 2000).

[0005] 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 formulations are lyophilized oral solid dosage forms that disperse almost instantly in the mouth without the need for water.

[0006] 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 part 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.

[0007] LSD can be used to adjunct psychotherapy for many indications, including anxiety, depression, addiction, personality disorders, and others, and 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 increased 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 for content uniformity and chemical stability.

[0008] In clinical trials using LSD, oral solution formulations are attracting attention. Research into LSD formulation development was virtually nonexistent. Historically, oral solutions have been used, and almost all older trials and preliminary data involve oral solutions or impregnated paper / cartons.

[0009] 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. No commercially viable solid oral immediate-release pharmaceutical formulations of d-lysergic acid diethylamide (LSD) as a free base or in salt form exist on the market or have been reported in the literature. For therapeutic doses of LSD expected to be in the tens- to hundreds-of-gold μg range, 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). [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] In addition to achieving a uniform and stable immediate-release formulation, the final formulation needs to be in a form that can be easily administered to a wide range of patient populations, including, but not limited to, the elderly, children, and patients with conditions that may limit their ability to swallow. [Means for solving the problem]

[0011] The present invention provides a solid oral immediate-release formulation of LSD, comprising an LSD formulation intended in the dosage form of an orally disintegrating tablet, wherein the composition provides a solid oral immediate-release formulation produced by freeze-drying raw materials in a pre-formed mold to form an orally disintegrating tablet.

[0012] The present invention further provides a method for producing a solid oral immediate-release formulation of LSD by freeze-drying a rapidly cryopreserved LSD solution and excipients such as a non-gelling matrix-forming agent, filler, binder, and buffer, as well as additional excipients such as antioxidants, light stabilizers, permeability enhancers, and flavoring agents, in a pre-formed mold to form an orally disintegrating tablet.

[0013] The present invention also provides a method for treating an individual by administering a solid oral immediate-release formulation of LSD, wherein the composition is produced by freeze-drying raw materials in a pre-formed mold to form an orally disintegrating tablet.

[0014] Description of the drawing Other advantages of the present invention will be readily apparent when considered in conjunction with the following appended drawings, so that they may be better understood by reference to the following detailed description. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows the label for D-LSD D-tartrate. [Figure 2] Figure 2 is a photograph of Zydis ODT containing LSD. [Modes for carrying out the invention]

[0016] 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 orally administered formulation. The present invention provides a composition that dissolves relatively quickly once taken orally, preferably containing LSD as its active ingredient (active) or as one of its active ingredients. This provides a therapeutic effect that is easy to administer but is expected to be effective and efficient.

[0017] LSD may be available as a crystalline or amorphous solid, in the form of a free base or a salt. Salts may include, but are not limited to, hydrochloride, hydrobromide, maleate, tartrate (including D-tartrate and mesotartrate), citrate, phosphate, fumarate, sulfate, mesylate, acetate, oxalate, benzoate, benzenesulfonate, xinafoate, 1,5-naphthalenedisulfonate, ascorbate, and naphthalene-2-sulfonate. The dose of LSD may preferably be 0.01 to 1 mg (10 to 1000 μg). However, the dose may be adjusted according to the indications, age, weight, and other factors affecting pharmacology, physiology, and drug / drug interactions in a given patient.

[0018] Preferred solid oral formulations are orally disintegrating tablets (ODTs), such as those described in U.S. Patent No. 9,192,580B2, incorporated herein by reference, using ZYDIS® (Catalent, Inc.) technology. This is further illustrated in Example 1. A typical ZYDIS® ODT formulation comprises a non-gelling matrix-forming agent, fillers, binders, and pH modifiers (i.e., buffers). Furthermore, antioxidants, light stabilizers, transmission enhancers, colorants, and sweeteners / flavoring agents may be included in the ZYDIS® ODT formulation.

[0019] Examples of non-gelling matrix-forming agents used include, but are not limited to, non-gelling gelatin (including fish gelatin), maltodextrin, modified starch, starch ether, low molecular weight dextran, and low to medium molecular weight cellulose gum (U.S. Patent No. 10,548,839B2).

[0020] Examples of fillers used include lactose (including anhydrous), mannitol, dicalcium phosphate, calcium sulfate, starch (which may include dried or pre-gelled starch when used herein), cellulose (including microcrystalline cellulose), kaolin, sodium chloride, sorbitol, trehalose, and sucrose.

[0021] Examples of binders include acacia gum, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, tragacanth, polyvinylpyrrolidone (PVP), starch, and the like.

[0022] Buffers are added for targeting the formulation to a specific pH. Currently, three types of buffers, citrate, phosphate, and acetate, account for the majority of buffers used in parenteral pharmaceuticals approved by the FDA, but less-precedented excipients are particularly available for use in commercial dosage forms. The pH of the formulation can alternatively be adjusted with non-buffered acid (i.e., hydrochloric acid) or non-buffered base (i.e., sodium hydroxide).

[0023] To minimize degradation due to oxidative stress, antioxidants can be added to the formulation. The term oxidation can be defined as the incorporation of oxygen into the structure of a drug or the process of converting a chemical substance into another derivative with fewer electrons. Examples of such antioxidants are ascorbic acid, citric acid, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0024] Many drugs are photosensitive and, therefore, their formulations can decompose during manufacture, storage, and administration. The photostability of the parent can be defined as the response of the drug or formulation to exposure to sunlight, UV, and visible light in the solid, semi-solid, or liquid state that causes physical or chemical changes. Reverting light exposure can result in decreased potency, altered efficacy, and adverse biological effects. To minimize any degradation due to light exposure (i.e., photostabilizers), various additives or encapsulation methods and compositions can be used to protect the active product from light.

[0025] Photodegradation can also occur in combination with oxygen exposure, leading to photooxidative degradation. Some antioxidants commonly used to protect against photooxidation include ascorbic acid, α-tocopherol, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), L-histidine, propyl gallate, and sulfur compounds. Ascorbic acid, α-tocopherol, β-carotene, and BHT act as free radical scavengers and singlet oxygen quenchers, and therefore inhibit photosensitization reactions. When the active ingredient acts as a photosensitizer and initiates a chain reaction in the formulation, some excipients may be oxidized, while the drug may be protected from photodegradation.

[0026] The formulation may also contain permeation enhancers to increase the range and / or rate of absorption. Examples of such enhancers include sulfoxides (dimethyl sulfoxide, DMSO, etc.), azones (e.g., laurocaprum), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (e.g., propylene glycol, PG, a common excipient in topical formulations), surfactants (common in formulations as well), and terpenes.

[0027] To improve patient recognition and tolerance, colorants, sweeteners, and flavorings may also be added to solid oral formulations.

[0028] The compounds of the present invention are administered and taken in consideration of the individual patient's clinical condition, site and method of administration, schedule of administration, patient age, sex, weight, and other factors recognized by the physician. Therefore, the pharmaceutically effective dose as used herein is determined by considerations known in the art. The dose must be effective, but not limited to, achieving improvements including improved survival rates or faster recovery, or improvement or elimination of symptoms and other indicators that may be selected as appropriate measures by those skilled in the art.

[0029] In the methods of the present invention, the compounds of the present invention can be administered in a variety of ways. It should be noted that they can be administered as compounds, or as active ingredients alone or in combination with pharmaceutically acceptable carriers, diluents, adjuvants, and media. Patients under treatment are warm-blooded animals, mammals, particularly humans. Pharmaceutically acceptable carriers, diluents, adjuvants, and media generally refer to inert and non-toxic solid or liquid fillers, diluents, or encapsulating materials that do not react with the active ingredients of the present invention.

[0030] Administration may be a single dose or multiple doses over several days. Treatment generally has a duration and patient type that is commensurate with the disease course and the duration of drug effectiveness.

[0031] The absorption of active drugs is targetable. Drug absorption is determined by the physicochemical properties of the drug, its formulation, and its route of administration. Dosage forms consisting of a drug plus other components (e.g., tablets, capsules, solutions) are formulated to be administered via various routes (e.g., oral, buccal, sublingual, rectal, parenteral, topical, inhalation). Regardless of the route of administration, the drug must be present in a solution to be absorbed. Therefore, solid forms (e.g., tablets, capsules) must be able to disintegrate and deaggregate. While solid oral tablets and capsules typically undergo gastric absorption, ODT formulations can be formulated to target pregastric or buccal absorption, which can further enhance bioavailability.

[0032] The present invention provides a method for producing a solid oral immediate-release formulation of LSD, either as a free base or in salt form, by freeze-drying a rapidly frozen preservation solution of the drug and excipients in a pre-formed mold for forming orally disintegrating tablets. This method addresses the challenges associated with formulating low-dose products while maintaining the uniformity of LSD content and chemical integrity.

[0033] The present invention provides a method for treating an individual by administering a solid oral immediate-release formulation of LSD, wherein the composition is produced by freeze-drying raw materials in a pre-formed mold to form an orally disintegrating tablet.

[0034] The medical conditions or diseases being treated are not limited to, but include anxiety disorders (anxiety in advanced diseases, e.g., cancer, and Generality This may include anxiety disorders, depression (including postpartum depression, major depressive disorder, and treatment-resistant depression), headache disorders (including cluster headaches and migraines), obsessive-compulsive disorder (OCD), personality disorders (including conduct disorder), stress disorders (including adjustment disorders and post-traumatic stress disorder), drug disorders (including alcohol dependence or withdrawal, nicotine dependence or withdrawal, opioid dependence or withdrawal, cocaine dependence or withdrawal, methamphetamine dependence or withdrawal), other addictions (including gambling disorder, eating disorders, and body dysmorphic disorder), pain, neurodegenerative disorders (such as dementia, Alzheimer's disease, and Parkinson's disease), autism spectrum disorder, eating disorders, or neurological disorders (such as stroke).

[0035] The present invention will be described in more detail by reference to the following experimental examples. These examples are provided for illustrative purposes only and are not intended to limit the invention unless otherwise indicated. Accordingly, the present invention should not be construed to be limited to the following examples, but rather to encompass all variations that become apparent as a result of the teachings provided herein. [Examples]

[0036] Example 1: Freeze-drying of d-LSD D-tartrate preservative solution for formulation of orally disintegrating tablets A solid oral formulation of d-LSD D-tartrate in a rapidly dispersible orally disintegrating tablet (ODT) was prepared using the following method: A) preparing a stock solution containing d-LSD D-tartrate, a non-gelling matrix-forming excipient, a filling excipient, and a binder, completely dissolved in water; B) administering the preservative solution in a pre-formed mold; and C) lyophilizing the administered formulation and removing water by sublimation. The formulation compositions are shown in Table 1. An image of Formulation 1 is shown in Figure 2. All formulations that disintegrated in less than 60 seconds exhibited immediate release.

[0037] [Table 1]

[0038] These formulations were protected from moisture ingress, stabilized at 40°C, and tested for chemical degradation after one month. Total chemical impurities are shown in Table 2. These results demonstrate a small change in total impurities after one month of storage under accelerated conditions, illustrating the suitability of lyophilized d-LSD D-tartrate for ODT formulations.

[0039] [Table 2]

[0040] Throughout this application, various publications, including U.S. patents, are referenced by author and year, and patents by number. A complete list of publications is provided below. To better illustrate the cutting edge technology to which this invention relates, the complete disclosures of these publications and patents are incorporated herein by reference.

[0041] This invention is described in an illustrative manner, and it should be understood that the terms used are intended to be in the essence of the explanatory terms, rather than to be limiting.

[0042] Clearly, many modifications and variations of the present invention are possible by considering the teachings above. Therefore, it should be understood that the present invention is implementable within the scope of the appended claims, except as described in detail.

Claims

1. i. Lysergic acid diethylamide (LSD) or its salts; ii. Non-gelling matrix forming agents; iii. Binders; and iv. Fillers Tablets containing [this ingredient].

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 Includes, 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. Fillers; and v. water A method for manufacturing tablets, comprising rapidly freezing a preservation solution containing the same solution.

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