Immediate release formulations of d-lysergic acid diethylamide for therapeutic applications

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

[0002] 2.Background technology Oral solution formulations are convenient for studies with limited numbers of patients at a few sites, primarily early development studies, but may not be suitable for late-stage development studies conducted at multiple centers across a wide geographic area and may not be commercially viable due to product stability and supply chain challenges, e.g., potential requirements for cold chain storage.

[0003] Solid oral formulations as tablets or capsules are more common in late stage clinical development and commercially because of advantages in production, supply chain, and patient convenience. Solid oral formulations can be immediate release, instantly dissolving 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 chosen to improve absorption or for patient populations with swallowing difficulties (Lindgren et al., 1993) and is also suitable for use in geriatric and pediatric patients, or patients suffering from conditions such as dysphagia (Sastry et al., 2000).

[0005] LSD is derived from its German name LysergSaeureDiethylamid (lysergic acid diethylamide). Lysergides belong to a family of indole alkylamines that includes psilocin (the active moiety of psilocybin) and a number of 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 aid in psychotherapy for many indications, including anxiety, depression, addiction, personality disorders, and others, and can 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 can include altered thinking, emotions, awareness of surroundings, dilated pupils, elevated blood pressure, and elevated body temperature. Therapeutic uses of LSD have shown promising results for treating a variety of neurological and behavioral disorders. However, due to its potency, there can be challenges in developing and manufacturing solid oral formulations of LSD to meet pharma- ceutically acceptable limits for content uniformity and chemical stability.

[0007] Clinical trials with LSD have focused on oral solution formulations. Formulation development studies for LSD have been nearly nonexistent. Historically, oral solutions have been used, and nearly all older studies and preliminary data involve oral solutions or impregnated papers / cartons.

[0008] There is a need for LSD dosage forms and formulations that are commercially attractive to a broad patient population and meet expectations for 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 currently exist as marketed products or have been reported in the literature. For therapeutic doses of LSD expected to be in the tens to hundreds of μg range, challenges exist 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). Summary of the Invention [Problem to be solved by the invention]

[0009] In addition to achieving a uniform and stable immediate release formulation, the final formulation must be in a form that is 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 solid oral immediate release formulations of LSD, including formulations of LSD intended for capsule, tablet, or orally disintegrating tablet dosage forms.

[0011] The present invention further provides a method of making a solid oral immediate release formulation of LSD using processes such as granulation and mixing that is uniform, chemically stable, and rapidly dissolving.

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

[0013] Description of the drawings Other advantages of the present invention will be readily appreciated as they become more fully understood by reference to the following detailed description when considered in connection with the accompanying drawings, in which: [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 is a representation of D-LSD D-tartrate. [Diagram 2] FIG. 2 is a graph of content uniformity of LSD from a solid oral capsule formulation made by granulation. [Diagram 3] FIG. 3 is a graph showing the immediate release of LSD from a solid oral capsule formulation made by granulation. [Figure 4] FIG. 4 is a graph showing the chemical stability of LSD when mixed with lactose, microcrystalline cellulose, or mannitol as solid drug crystals. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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" is a mechanism that delivers the drug immediately (similar to immediate release dosage) as opposed to a delay (delayed release dosage) or extended period (extended release (ER, XR, XL) dosage) or to a specific target in the body (targeted release dosage) after its administration. Preferably, it refers to minimal time-dependent release in an oral dosage formulation. The present invention provides a composition that dissolves relatively quickly once orally ingested, preferably comprising LSD as its active, or one of its active ingredients. This provides a therapeutic effect that is easy to administer yet is predicted to be effective and efficacious.

[0016] LSD may be in free base form or salt form, as a crystalline or amorphous solid. The salt may be, but is not limited to, hydrochloride, hydrobromide, maleate, tartrate (including D-tartrate and meso-tartrate), 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 0.01-1 mg (10-1000 μg). However, administration may be adjusted according to the indication, age, weight, and other factors affecting pharmacology, physiology, and drug / drug interactions in a given patient.

[0017] Solid oral formulations typically contain secondary ingredient components known as excipients which may include, but are not limited to, fillers / bulking agents, binders, absorbents, disintegrants, glidants, lubricants, pH modifiers / buffers, preservatives, antioxidants, permeation enhancers, colorants, and sweeteners / flavorants. Examples of each are listed below, and some common excipients serve more than one function.

[0018] Examples of fillers used in solid oral formulations include lactose (including anhydrous), mannitol, dicalcium phosphate, calcium sulfate, starch (starch as used herein may include dry or pregelatinized starch), cellulose (including microcrystalline cellulose), kaolin, sodium chloride, sorbitol, trehalose, sucrose, and the like.

[0019] Binders can also be included which are polymeric, natural, or synthetic materials that impart adhesive properties to the powdered materials. Binders must be non-toxic and have a good compatibility profile. Materials commonly used as binders include gum acacia, methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, tragacanth, polyvinylpyrrolidone (PVP), starch, and the like. Microcrystalline cellulose is also considered as a dry binder.

[0020] Excipients such as starch, colloidal or mesoporous silicon dioxide (i.e., silica), sodium starch glycolate, and microcrystalline cellulose can act as solvent absorbents or disintegrants by absorbing solvents such as water while increasing formulation hydration. Some of these excipients may be preferred as absorbents for either disintegrant properties, but may also include other properties. For example, partially pregelatinized starch (e.g., Starch 1500) is often used as a disintegrant, but is also used as an absorbent to remove moisture and "hide" moisture from drugs that are sensitive to it. When Starch 1500 is used as an absorbent in moisture-activated dry granulation (MADG), it loses some of its disintegrant performance, but if it is added after the absorbent stage, it can function as a disintegrant. Colloidal (or mesoporous) silicon dioxide can be a good absorbent, but a weak disintegrant. Sodium starch glycolate can be a good disintegrant. Microcrystalline cellulose can be a good absorbent and have disintegrant properties. Croscarmellose sodium, crospovidone, sodium starch glycolate (which are disintegrants) and starch swell in the presence of liquid, thereby facilitating tablet disintegration by increasing 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 concentrations less than 2% w / w to minimize any adverse 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 oils, etc.

[0023] Buffers are added to target a particular pH of the formulation. Currently, three buffers, citrate, phosphate, and acetate, account for the majority of buffers used in FDA approved pharmaceuticals, but less prevalent excipients are available specifically for use in commercial dosage forms. The pH of the formulation can alternatively be adjusted with a non-buffered acid (i.e., hydrochloric acid) or a non-buffered 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 one chemical 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 sensitive to light, and therefore their formulations may degrade during manufacture, storage, and administration. Photostability of a drug substance can be defined as the response of a drug or formulation to exposure to sunlight, UV, and visible light in solid, semi-solid, or liquid states, which causes physical or chemical changes. Excessive light exposure can result in reduced 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. For example, liposomes are microscopic and submicroscopic phospholipid vesicles with a bilayer membrane structure. Photostabilization of a drug substance by entrapment in liposomes is one such method to improve its photostability.

[0026] Photodegradation may also occur in combination with oxygen exposure, resulting in photooxidative degradation. Some of the antioxidants commonly used to protect against photooxidation are ascorbic acid, alpha-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), L-histidine, propyl gallate, and sulfur compounds. Ascorbic acid, alpha-tocopherol, beta-carotene, and BHT act as free radical scavengers and singlet oxygen quenchers, thus inhibiting photosensitization reactions. If the drug substance acts as a photosensitizer and initiates a chain reaction in the formulation, some of the excipients may be oxidized, while the drug may be protected from photodegradation.

[0027] The formulation may also contain permeation enhancers to increase the extent and / or rate of absorption. Examples of such enhancers are sulfoxides (such as dimethyl sulfoxide, DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone, 2P), alcohols and alkanols (ethanol, or decanol), glycols (e.g., propylene glycol, PG, a common excipient in topical dosage forms), surfactants (also common in dosage forms), and terpenes.

[0028] Coloring, sweetening, and flavoring agents can be added to solid oral formulations to improve patient perception and acceptance.

[0029] The immediate release formulations made by granulation can contain, but are not limited to, the fillers / bulking agents, binders, absorbents, disintegrants, glidants, and lubricants of solid oral formulations, as well as buffers, antioxidants, absorption enhancers, and colorants and flavoring agents, as described above. One such granulation process is high shear granulation, where powders (active ingredients, dry binders, fillers, etc.) are loaded into a closed vessel containing blending / mixing components, such as impellers and choppers. In high shear wet granulation (hereafter referred to as wet granulation), powders are wetted with a binder solution / suspension, while blending allows particle adhesion and granule growth. Additional excipients (fillers, glidants, disintegrants, lubricants, etc.) can be added and blended with the granules after the addition of the binder solution / suspension. Depending on the concentration of the active ingredient, it is typically either added as a dry ingredient before the addition of the binder solution / suspension (typically higher concentrations of active ingredient, typically greater than 1-10% by weight) or is included in the binder solution / suspension to ensure homogeneity (typically lower concentrations of active ingredient, typically less than 1-10% by weight). In wet granulation, where the active ingredient is added in solution or suspension, the liquid vehicle is removed by active drying. Alternatively, in a process called moisture-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 the introduction of an active drying step.

[0030] Dry blending of micronized or non-micronized crystalline API is an alternative approach to granulation for solid oral formulation and is further described in Example 2. Dry blending can use similar blending / mixing equipment as granulation or with single layer low shear mixing and can use similar excipient classes with minimal fillers. Dry blend formulations can be further processed into tablets, including orally disintegrating tablets, through direct compression or encapsulation. When formed in direct compression, the composition can include any of the binders, disintegrants, glidants, and lubricants described above depending on the processing needs.

[0031] The compounds of the present invention are administered and dosed taking into consideration the clinical condition of the individual patient, the site and method of administration, the administration schedule, the patient's age, sex, weight and other factors recognized by physicians. Therefore, the pharmacologic "effective amount" for purposes herein is determined by such considerations as are known in the art. The amount must be effective to achieve improvement, including, but not limited to, improved survival rate or faster recovery, or improvement or elimination of symptoms and other indicators as selected as appropriate measures by those skilled in the art.

[0032] In the method of the present invention, the compound of the present invention can be administered in various ways.It should be noted that it can be administered as a compound, and can be administered as an active ingredient alone or in combination with pharmaceutically acceptable carriers, diluents, adjuvants and vehicles.The patient being treated is a warm-blooded animal, particularly a mammal, including human.Pharmaceutically acceptable carriers, diluents, adjuvants and vehicles generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating materials that do not react with the active ingredient of the present invention.

[0033] Administration can be a single dose or multiple doses over several days. Treatment generally has a duration commensurate with the duration of the disease process and drug effectiveness and the patient species being treated.

[0034] Absorption of active drugs can be targeted. Drug absorption is determined by the physicochemical properties of the drug, the formulation, and the route of administration. Dosage forms (e.g., tablets, capsules, solutions) consisting of a drug plus other ingredients are formulated to be administered by various routes (e.g., oral, buccal, sublingual, rectal, parenteral, topical, inhalation). Regardless of the route of administration, the drug must be in solution to be absorbed. Therefore, solid forms (e.g., tablets, capsules) must be capable of disintegration and deagglomeration. Solid oral tablet and capsule formulations typically have gastric absorption, while ODT formulations can be formulated to target pregastric or buccal absorption, which can further enhance bioavailability.

[0035] The present invention provides methods for making solid oral immediate release formulations of LSD as a free base or in salt form by steps selected from: 1) granulating with excipients such as fillers, absorbents, binders, disintegrants, glidants, and / or lubricants and encapsulating or forming tablets; or 2) blending with excipients such as fillers, disintegrants, dry binders, glidants, and / or lubricants for direct compression into tablets with ODT or encapsulation. Each approach addresses the challenges associated with formulating a low dose product while maintaining the content uniformity and chemical integrity of LSD.

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

[0037] The condition or disease being treated may include, but is not limited to, anxiety disorders (including anxiety in advanced illnesses, e.g., cancer, and generalized anxiety disorder), 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 disorder and post-traumatic stress disorder), substance 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 disorders, eating disorders, and body dysmorphic disorders), pain, neurodegenerative disorders (such as dementia, Alzheimer's disease, Parkinson's disease), autism spectrum disorders, eating disorders, or 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 be limiting unless otherwise indicated. Therefore, the present invention should not be construed as being limited to the following examples in any way, but rather as embracing any and all variations that become evident 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 moisture-activated dry granulation (MADG) was used to formulate low-dose LSD to achieve suitable content uniformity and avoid a separate active drying step typically performed by wet granulation. For MADG, the method of making the LSD formulation includes: 1) making water (or other suitable solvent) as the stock liquid for the granulation liquid of LSD, and dissolution aids if necessary; 2) mixing the filler (i.e., mannitol) and binder (i.e., hydroxypropyl methylcellulose); 3) spraying the granulation liquid onto the dry mix, mixing, and forming agglomerates; 4) adding the moisture absorbent (i.e., starch) and mixing; and finally, 5) adding additional functional excipients such as disintegrants, glidants, and lubricants, mixing, and forming the final granulated powder. In the optimization process, sieving is not required since no lumps are present in the final granules. The final granulation can be encapsulated or formed into tablets.

[0040] Table 1 shows 25 μg LSD (equivalent to 36.6 μg d-LSD D-tartrate) formulations developed using microcrystalline cellulose and starch as absorbents in the MADG process. These formulations were encapsulated, placed under stability at 25° C., and tested for total impurities. Table 2 shows the total impurity results for the microcrystalline cellulose formulations, and Table 3 shows the total impurity results for the starch formulations. Additionally, Figure 3 shows the dissolution profiles for the starch-containing formulations, which show 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 the MADG formulation with microcrystalline cellulose as the adsorbent.

[0043] [Table 2]

[0044] Table 3 shows the stability data for d-LSD D-tartrate using MADG formulations with pregelatinized starch as the absorbent, and FIG. 3 shows the dissolution data.

[0045] [Table 3]

[0046] An additional granulation formulation of d-LSD D-tartrate was made using moisture-activated dry granulation and pregelatinized starch as the absorbent, but omitting the lubricant. The composition is equivalent to the starch formulation in Table 1 without sodium stearyl fumarate.

[0047] Figure 2 shows the content uniformity of the pregelatinized starch formulation without lubricant. Process performance based on these results shows that capsules below 0.5 parts per million (ppm) are outside the label claim range of 85% to 115%. The data provides evidence that the uniformity of the final blend was satisfactory.

[0048] Table 4 shows the chemical stability data for pregelatinized starch formulations without lubricant at 25°C.

[0049] [Table 4]

[0050] Taken together, these data indicate that moisture-activated dry granulation can produce pharma- ceutically acceptable, uniform, stable immediate release formulations of LSD.

[0051] Example 2: Drug crystals of dry mixed d-LSD D-tartrate with excipients The method for making a dry mix formulation of LSD in a single pot involves adding minimal filler / carrier excipients such as mannitol, lactose, and microcrystalline cellulose with d-LSD D-tartrate to a mixing vessel and mixing until the drug is uniformly dispersed. The order of addition of the ingredients or portions of the ingredients can be adjusted as needed.

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

[0053] [Table 5]

[0054] The results show that drug crystals of d-LSD D-tartrate mixed with lactose, mannitol, and microcrystalline cellulose are stable. Figure 4 shows the % iso-LSD (a known LSD degradation product) versus condition and excipient. Throughout this application, various publications, including U.S. patents, are referenced by author and year, and the patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0055] The present invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of descriptive terms and not of limitation.

[0056] Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention can be practiced other than as specifically described.

Claims

1. An immediate release capsule dosage form comprising: The capsule is i. LSD or a salt thereof; ii. mannitol, iii. Hypromellose, and iv. Water in an amount of 1 to 5% by weight 1. An immediate release capsule dosage form comprising a granulated powder comprising:

2. A capsule dosage form as described in claim 1, wherein the granulated powder contains LSD tartrate.

3. The capsule dosage form of claim 2, wherein the LSD tartrate is d-LSD D-tartrate.

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

5. A capsule dosage form as described in claim 1, wherein the granulated powder contains LSD or a salt thereof in an amount of less than 1% by weight.

6. A capsule dosage form as described in claim 1, wherein the granulated powder contains mannitol in an amount of 10 to 90% by weight.

7. A capsule dosage form as described in claim 2, wherein the granulated powder contains LSD tartrate in an amount of less than 1% by weight.

8. The capsule dosage form of claim 3, wherein the granulated powder contains d-LSD D-tartrate in an amount less than 1% by weight.

9. A capsule dosage form as described in claim 1, wherein the granulated powder contains hypromellose in an amount of 1 to 5% by weight.

10. A capsule dosage form as described in claim 1, wherein the granulated powder contains purified water in an amount of 1 to 5% by weight.

11. The capsule dosage form of claim 4, wherein the granulated powder contains mesoporous silicon dioxide in an amount of less than 2% by weight.

12. A capsule dosage form as described in claim 4, wherein the granulated powder contains croscarmellose sodium in an amount of 1 to 25% by weight.

13. An immediate release capsule dosage form comprising: The capsule is i. d-LSD D-tartrate, ii. mannitol, iii. Hypromellose, iv. Partially pregelatinized starch; V. mesoporous silicon dioxide; V. Croscarmellose sodium, and Vii. Water in an amount of 1 to 5% by weight 1. An immediate release capsule dosage form comprising a capsule granulation powder comprising:

14. The capsule dosage form of claim 13, wherein the capsule granulation powder contains d-LSD D-tartrate in an amount less than 1% by weight.

15. The capsule dosage form of claim 13, wherein the capsule granulation powder comprises mannitol in an amount of 10 to 90% by weight.

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

17. The capsule dosage form of claim 13, wherein the capsule granulation powder contains purified water in an amount of 1 to 5% by weight.

18. The capsule dosage form of claim 13, wherein the capsule granulation powder contains mesoporous silicon dioxide in an amount of less than 2% by weight.

19. The capsule dosage form of claim 13, wherein the capsule granulation powder comprises croscarmellose sodium in an amount of 1 to 25% by weight.

20. A capsule dosage form according to any one of claims 1 to 19 for use in the manufacture of a medicament for treating generalized anxiety disorder.

Images