Immediate-release formulation of d-lysergic acid diethylamide for therapeutic use

Abstract

The present invention relates to a solid oral immediate release formulation of LSD comprising LSD contained in a capsule, tablet, or orally disintegrating tablet dosage form.The present invention relates to a method of making a solid oral immediate release formulation of LSD as a free base or in salt form by granulation, including moisture activated dry granulation or dry blending.The present invention relates to a method of treating an individual by administering a solid oral immediate release formulation of LSD to treat the individual.

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 carried out at multiple sites across a wide geographical area, 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 for the purpose of increasing the dissolution rate of pharmaceuticals and promoting 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 swallowing disorders (Sastry et al., 2000).

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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 project] [Problems that the invention aims to solve]

[0009] 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]

[0010] Summary of the Invention The present invention provides a solid oral immediate-release formulation of LSD, including an LSD formulation intended in the dosage form of capsules, tablets, or orally disintegrating tablets.

[0011] The present invention further provides a method for producing a solid oral immediate-release formulation of LSD using processes such as granulation and mixing that are homogeneous, chemically stable, and rapidly dissolving.

[0012] The present invention also provides a method for treating an individual by administering a solid oral immediate-release formulation of LSD.

[0013] 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]

[0014] [Figure 1] Figure 1 shows the presentation of D-LSD D-tartrate. [Figure 2] Figure 2 is a graph showing the uniformity of LSD content from solid oral capsule formulations produced by granulation. [Figure 3] Figure 3 is a graph showing the immediate release of LSD from solid oral capsule formulations produced by granulation. [Figure 4] Figure 4 is a graph showing the chemical stability of LSD when mixed with lactose, microcrystalline cellulose, or mannitol as solid drug crystals. [Modes for carrying out the invention]

[0015] Detailed description of the invention The present invention provides formulations of LSD in rapid or immediate-release dosage forms, such as capsules, tablets, or 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 or one of its active ingredients. This provides a therapeutic effect that is easy to administer but is expected to be effective and efficient.

[0016] 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.

[0017] Solid oral preparations typically contain known ingredient components as excipients, which may include, but are not limited to, fillers / bulkers, binders, absorbents, disintegrants, lubricants, pH modifiers / buffers, preservatives, antioxidants, permeation enhancers, colorants, and sweeteners / flavorings. Examples of each are listed below, and some common excipients serve two or more functions.

[0018] Examples of fillers used in solid oral preparations 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.

[0019] The material may also include a binder, which is a polymer, natural, or synthetic material that imparts adhesion to the powdered material. The binder must be non-toxic and have a good compatibility profile. Materials commonly used as binders include acacia gum, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, tragacanth, polyvinylpyrrolidone (PVP), and starch. Microcrystalline cellulose can also be used as a drying binder.

[0020] Excipients such as starch, colloidal or mesoporous silicon dioxide (i.e., silica), sodium starch glycolate, and microcrystalline cellulose can act as solvent absorbers or disintegrants by absorbing solvents such as water while increasing the formulation's water-solubility. Some of these excipients may be preferred as absorbers with any of the disintegrant properties, but may also include other properties. For example, partially pre-gelled starch (e.g., Starch 1500) is often used as a disintegrant, but is also used as an absorber to remove moisture and "hide" moisture from moisture-sensitive drugs. When Starch 1500 is used as an absorber in moisture-activated dry granulation (MADG), it loses some of its disintegrant performance, but if it is added after the absorber stage, it can function as a disintegrant. Colloidal (or mesoporous) silicon dioxide can be an excellent absorber but a weak disintegrant. Sodium starch glycolate can be an excellent disintegrant. Microcrystalline cellulose is an excellent absorber and can have disintegrant properties. Croscarmellose sodium, crospovidone, sodium starch glycolate (which are disintegrants) and starch swell in the presence of liquid, thereby promoting tablet disintegration due to increased internal pressure within the tablet matrix.

[0021] Lubricants enhance the flowability of the formulation. Typical lubricants include magnesium stearate, colloidal silicon dioxide, and the like.

[0022] Hydrophobic stearic acid and stearates, such as magnesium stearate and sodium stearyl fumarate, are the most widely used lubricants in oral formulations. They are typically added at a concentration of less than about 2% w / w to minimize any detrimental effects on the disintegration or dissolution of the formulation matrix. Other examples of lubricants used include polyethylene glycol (PEG), polyoxyethylene stearate, lauryl sulfate, talc, glyceryl behenate, glyceryl palmitostearate, calcium stearate, hydrogenated vegetable oil, and the like.

[0023] Buffers are added to target the formulation to a specific pH. Currently, three buffers, citrate, phosphate, and acetate, account for the majority of buffers used in FDA-approved pharmaceuticals, but less-precedented excipients are particularly available for use in commercial dosage forms. The pH of the formulation can alternatively be adjusted with unbuffered acid (i.e., hydrochloric acid) or unbuffered base (i.e., sodium hydroxide).

[0024] 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).

[0025] Many drugs are photosensitive and, therefore, their formulations can degrade during manufacture, storage, and administration. The photostability of the parent compound 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. Excessive light exposure can lead to a decrease in efficacy, a change in effectiveness, 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. For example, liposomes are microscopic and submicroscopic phospholipid vesicles having a bilayer structure. Photostabilization of the parent compound by encapsulation into liposomes is one way to improve its photostability.

[0026] 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.

[0027] 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.

[0028] To improve patient recognition and tolerance, colorants, sweeteners, and flavorings may also be added to solid oral formulations.

[0029] Immediate-release formulations produced by granulation may, but are not limited to, contain fillers / bulkers, binders, absorbents, disintegrants, lubricants, and buffers, antioxidants, absorption enhancers, and colorants and flavorings of solid oral formulations, as described above. One such granulation process is high-shear granulation, where powder (active ingredient, dry binder, filler, etc.) is loaded into a closed container containing mixing / combining components, such as an impeller and chopper. In high-shear wet granulation (hereinafter referred to as wet granulation), the powder is moistened with a binder solution / suspension while mixing allows for particle adhesion and granule growth. Additional excipients (fillers, lubricants, disintegrants, etc.) can be added after the binder solution / suspension is added and mixed with the granules. Depending on the concentration of the active ingredient, it is typically added as a dry component before the addition of the binder solution / suspension (typically for higher concentrations of the active ingredient, more than 1-10% by weight), or it is contained in the binder solution / suspension to ensure homogeneity (typically for lower concentrations of the active ingredient, less than 1-10% by weight). In wet granulation where the active ingredient is added in a solution or suspension, the liquid solvent is removed by active drying. Alternatively, in a process called water-activated dry granulation (MADG) in Example 1, the liquid (typically water) content is reduced and absorbed by an absorbent added to the formulation, rather than by introducing an active drying step.

[0030] Dry mixing of granulated or ungranulated crystalline APIs is an alternative method for solid oral formulation to granulation, as further described in Example 2. Dry mixing can be performed using similar mixing / combining equipment as for granulation or by a single low-shear mixing, and a similar class of excipients with minimal fillers can be used. Dry mixed formulations can be further processed into tablets, including orally disintegrating tablets, through direct compression or encapsulation. When formed by direct compression, the composition may contain any of the above-mentioned binders, disintegrants, lubricants, and additives, depending on the processing requirements.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] The present invention provides a method for preparing a solid oral immediate-release formulation of LSD, either as a free base or in salt form, by a step selected from: 1) granulating and encapsulating or forming tablets using excipients such as fillers, absorbents, binders, disintegrants, lubricants, and / or stimulants; or 2) directly compressing or encapsulating tablets containing ODT with excipients such as fillers, disintegrants, drying binders, lubricants, and / or stimulants. Each method addresses the challenges associated with formulating low-dose products while maintaining the uniformity and chemical integrity of LSD content.

[0036] The present invention provides a method for treating an individual by administering a solid oral immediate-release formulation of LSD to the individual.

[0037] The medical condition or disease being treated is not limited to, but includes anxiety disorders (in the case of advanced diseases, such as cancer). Anxiety, and Generality (including anxiety disorders), depression (postpartum depression, major depressive disorder and treatment resistance) (including antidepressant), headache disorders (including cluster headaches and migraines), obsessive-compulsive disorder (OCD), Personality disorders (including conduct disorder), stress disorders (adjustment disorder and post-traumatic stress disorder) Drug disorders (including harm), alcohol dependence or withdrawal, nicotine dependence or withdrawal, opioid dependence (including addiction or withdrawal, cocaine dependence or withdrawal, methamphetamine dependence or withdrawal), other Addiction (including gambling disorder, eating disorders, and body dysmorphic disorder), pain, neurodegenerative disorders (cognition) (Such as intellectual disability, Alzheimer's disease, Parkinson's disease, etc.), autism spectrum disorder, eating disorders, and This may include neurological disorders (such as stroke).

[0038] 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]

[0039] Example 1: Granulation of d-LSD D-tartrate with excipients A single-pot granulation process called water-activated dry granulation (MADG) was used for the formulation of low-dose LSD to achieve desirable content uniformity and avoid another activated drying step typically performed by wet granulation. In the case of MADG, the method for producing the LSD formulation includes: 1) preparing water (or other suitable solvent) as a storage solution for the LSD granulation liquid, and a solubilizer if necessary; 2) mixing a filler (i.e., mannitol) and a binder (i.e., hydroxypropyl methylcellulose); 3) spraying the granulation liquid onto the dry mixture, mixing, and forming aggregates; 4) adding and mixing a water absorbent (i.e., starch); and finally, 5) adding and mixing additional functional excipients such as disintegrants, lubricants, and saturants to form the final granulated powder. In the optimized process, sieving is not required as there are no lumps in the final granules. The final granules can be encapsulated or formed into tablets.

[0040] Table 1 shows formulations containing 25 μg of LSD (equivalent to 36.6 μg of d-LSD D-tartrate) developed using microcrystalline cellulose and starch as absorbents in the MADG process. These formulations were encapsulated, stabilized at 25°C, and tested for total impurities. Table 2 shows the results for total impurities for the microcrystalline cellulose formulation, and Table 3 shows the results for total impurities for the starch formulation. Furthermore, Figure 3 shows the solubility profile for the starch-containing formulation, which indicates immediate release of LSD or complete dissolution within 15 minutes.

[0041] [Table 1]

[0042] Table 2 shows the total impurity data for d-LSD D-tartrate using a MADG formulation with microcrystalline cellulose as an adsorbent.

[0043] [Table 2]

[0044] Table 3 shows the stability data for d-LSD D-tartrate using a MADG formulation with pre-gelled starch as an absorbent, and Figure 3 shows the dissolution data.

[0045] [Table 3]

[0046] An additional granulated formulation of d-LSD D-tartrate was prepared using water-activated dry granulation and pre-gelled starch as an absorbent, but the lubricant was omitted. The composition is equivalent to the starch formulation in Table 1 without sodium stearyl fumarate.

[0047] Figure 2 shows the content homogeneity of the pre-gelled starch formulation without lubricant. Process performance based on these results indicates that capsules containing less than 0.5 million parts per million (ppm) fall outside the label claim range of 85% to 115%. The data provides evidence that the homogeneity of the final mixture was satisfactory.

[0048] Table 4 shows the chemical stability data for pre-gelled starch formulations without lubricants at 25°C.

[0049] [Table 4]

[0050] Combining these data, it is demonstrated that water-activated dry granulation can produce pharmaceutically acceptable, uniform, and stable immediate-release formulations of LSD.

[0051] Example 2: Drug crystals of dry-mixed d-LSD D-tartrate with excipients A method for preparing a dry mixed formulation of LSD in a single pot comprises adding minimal fillers / carrier excipients, such as mannitol, lactose, and microcrystalline cellulose, and d-LSD D-tartrate to a mixing vessel, and mixing until the drug is uniformly dispersed. The order of addition of the components or parts of the components can be adjusted as necessary.

[0052] The chemical purity of d-LSD D-tartrate (Figure 4) was evaluated from the bulk formulation over extended periods (3 and 6 weeks) at 40°C when mixed with a solid excipient in a ratio of approximately 1:100 as solid drug crystals. Table 5 shows the chromatographic purity results for three dry-mixed d-LSD D-tartrate formulations at 40°C, which represent the minimum change in chemical purity for each of the packing / carrier excipients.

[0053] [Table 5]

[0054] The results demonstrate that drug crystals of d-LSD D-tartrate mixed with lactose, mannitol, and microcrystalline cellulose are stable. Figure 4 shows % iso-LSD (known LSD degradation products) in relation to the state and excipients. Throughout this application, various publications, including U.S. patents, are referenced by author and year, and patents by number. A complete citation of publications is listed 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.

[0055] This invention is described in an exemplary 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.

[0056] Clearly, many modifications and variations of the present invention are possible by taking into consideration 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. An immediate-release capsule formulation, The aforementioned capsule, i. LSD, or a salt thereof ii. Mannitol, iii. Hypromellose, and iV. 1-5% by mass of water An immediate-release capsule formulation containing granulated powder.

2. The capsule formulation according to claim 1, wherein the granulated powder contains LSD tartrate.

3. The capsule formulation according to claim 2, wherein the LSD tartrate is d-LSD D-tartrate.

4. The capsule formulation according to claim 1, wherein the granulated powder further comprises partially pre-gelled starch, mesoporous silicon dioxide, and croscarmellose sodium.

5. The capsule formulation according to claim 1, wherein the granulated powder contains less than 1% by weight of LSD or a salt thereof.

6. The capsule formulation according to claim 1, wherein the granulated powder contains 10 to 90% by weight of mannitol.

7. The capsule formulation according to claim 2, wherein the granulated powder contains less than 1% by weight of LSD tartrate.

8. The capsule formulation according to claim 3, wherein the granulated powder contains less than 1% by weight of d-LSD D-tartrate.

9. The capsule formulation according to claim 1, wherein the granulated powder contains hypromellose in an amount of 1 to 5% by weight.

10. The capsule formulation according to claim 1, wherein the granulated powder contains 1 to 5% by weight of purified water.

11. The capsule formulation according to claim 4, wherein the granulated powder contains less than 2% by weight of mesoporous silicon dioxide.

12. The capsule formulation according to claim 4, wherein the granulated powder contains 1 to 25% by weight of croscarmellose sodium.

13. An immediate-release capsule formulation, The aforementioned capsule, i. d-LSD D-tartrate, ii. Mannitol, iii. Hypromellose, iv. Partially pre-gelled starch, V. Mesoporous silicon dioxide, Vi. Croscarmellose sodium, and vii. 1-5% by mass of water An immediate-release capsule formulation containing capsule granulation powder.

14. The capsule formulation according to claim 13, wherein the capsule granulation powder contains less than 1% by weight of d-LSD D-tartrate.

15. The capsule formulation according to claim 13, wherein the capsule granulation powder contains 10 to 90% by weight of mannitol.

16. The capsule formulation according to claim 13, wherein the capsule granulation powder contains hypromellose in an amount of 1 to 5% by weight.

17. The capsule formulation according to claim 13, wherein the capsule granulation powder contains 1 to 5% by weight of purified water.

18. The capsule formulation according to claim 13, wherein the capsule granulation powder contains less than 2% by weight of mesoporous silicon dioxide.

19. The capsule formulation according to claim 13, wherein the capsule granule powder contains 1 to 25% by weight of croscarmellose sodium.

20. A capsule formulation according to any one of claims 1 to 19, for use in the manufacture of a drug for treating generalized anxiety disorder.

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