Psilocybin compositions, methods of making and methods of using the same

Abstract

This disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of psilocybin and one or more pharmaceutically acceptable excipients. It also discloses methods for preparing the composition and its use in the treatment of depression.

Description

Technical Field

[0001] This disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of cyclophosphamide and one or more pharmaceutically acceptable excipients, a method for preparing the composition, and the use of the composition in the treatment of depression. [] [Cross-reference to related applications] This application claims priority to U.S. Provisional Application No. 63 / 168,055, filed March 30, 2021, the contents of which are incorporated herein by reference in their entirety. Prior Technology

[0002] Serocerabine belongs to the class of psychedelic drugs ("mind-manifesting" drugs). Specifically, serocerabine is considered a serotonergic (serotonergic) psychedelic, unlike other tryptamines (such as dimethyltryptamine (DMT)), ergolines (such as lysergic acid diethylamine (LSD)), and phenethylamines (such as mescaline). Serocerabine was initially isolated from the psilocybe mushroom and later synthesized in the laboratory.

[0003] To provide potential therapeutic applications, pharmaceutical compositions containing serocepin that meet approved drug regulatory standards (e.g., stability and acceptable content uniformity during product storage) are required in the relevant technical field. Summary of the Invention

[0004] Xelocillin is a challenging active pharmaceutical ingredient (API) to formulate due to its physical properties and potential chemical instability (e.g., its tendency to hydrolyze into psilocin). Crystalline psiloclin is a needle-like or rod-shaped crystal with a high aspect ratio, resulting in poor flowability (especially in its hydrated form), which is undesirable for direct mixing, scale-up formulations, and commercial manufacturing. Furthermore, during pharmaceutical development (see Example 1), the applicant found that storing the drug under ICH stability testing conditions with certain commonly used solid dosage forms containing silica excipients yielded undesirable results (e.g., discoloration and loss of potency without corresponding increases in psiloclin-related impurities). Finally, given the hallucinogenic properties of psiloclin, it should be administered as a low-dose drug (e.g., 1 mg of psiloclin may be used for some indications). Therefore, suitable formulations must allow for low API loadings while providing pharmaceutically acceptable homogeneity (through European Pharmacopoeia 2.96 or USP). <905> (Measured).

[0005] This disclosure relates to pharmaceutical compositions containing serocepin and their preparation methods.

[0006] In one embodiment, this disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of psilocybin; and one or more pharmaceutically acceptable excipients, wherein, under industrially and pharmaceutically acceptable storage conditions (e.g., European Pharmacopoeia, USP), the potency of psilocybin in the composition and the mass balance of psilocybin and related substances in the composition are maintained at industrially and pharmaceutically acceptable levels (e.g., European Pharmacopoeia, USP), and psilocybin is provided with pharmaceutically acceptable uniformity of content (via European Pharmacopoeia 2.96 or USP). <905> (Measured).

[0007] In one embodiment, this disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of cyclophosphamide; and one or more pharmaceutically acceptable excipients, wherein, after storage at 40°C and 75% relative humidity for one month, the potency of cyclophosphamide in the composition decreases by less than 5%, and the mass balance of cyclophosphamide and related substances is greater than 97%.

[0008] In one embodiment, this disclosure provides a method for preparing a pharmaceutical composition comprising: (a) directly mixing serocerabin with one or more pharmaceutically acceptable excipients to provide an admixture; and (b) filling a capsule with the admixture to provide the pharmaceutical composition, wherein the homogeneity of the composition conforms to European Pharmacopoeia 2.96 or USP. <905> . Simple Explanation of the Diagram

[0009] [] []

[0010] [[] [picture] [1]] The numbering structure formula of seroxibin.

[0011] [[] [picture] [2A] is an XRPD diffraction diagram of a homogeneous polymorph A.

[0012] [[] [picture] [2B] is an XRPD diffraction diagram of a homogeneous polymorph A'.

[0013] [[] [picture] [2C] is an XRPD diffraction diagram of a homogeneous polymorph B.

[0014] [[] [picture] [2D] XRPD diffraction diagram of hydrate A.

[0015] [[] [picture] [2E] is an XRPD diffraction pattern of an ethanol solvate.

[0016] [[] [picture] [2F] is the XRPD diffraction pattern (top) of the product obtained during method development, compared with diffraction patterns of polymorph A' (middle) and polymorph B (bottom).

[0017] [[] [picture] [3A] is a DSC and TGA thermal analysis diagram of a homogeneous polymorph A.

[0018] [[] [picture] [3B] DSC and TGA thermal analysis diagrams of the homogeneous polymorph A'.

[0019] [[] [picture] [3C] DSC thermal analysis diagram of homogeneous polymorph B.

[0020] [[] [picture] [3D] DSC and TGA thermal analysis diagrams of hydrate A.

[0021] [[] [picture] [3E] is a DSC and TGA thermal analysis chromatogram of an ethanol solvate.

[0022] [[] [picture] [4] is a formal phase diagram that shows the interrelationships of forms in a water-based system.

[0023] [[] [picture] [5] The 1H NMR spectrum of serocepin.

[0024] [[] [picture] [6] 13C NMR spectrum of seroxibin.

[0025] [[] [picture] [7] The FT-IR spectrum of serocepin.

[0026] [[] [picture] [8] Mass spectrometry of serocepin.

[0027] [[] [picture] [9] shows a non-limiting example of a process flow diagram for preparing the serocepin capsules disclosed herein.

[0028] [[] [picture]

[10] shows the average test chart of the control group product from the stability study of Example 4.

[0029] [[] [picture]

[11] shows the average test plot of the low-level SMCC composition from the stability study of Example 4.

[0030] [[] [picture]

[12] ] shows the average assay chart of the 1 mg capsule composition from the stability study of Example 4.

[0031] [[] [picture]

[13] shows the average assay chart of the 5 mg capsule composition from the stability study of Example 4. Implementation

[0032] [definition] [] []

[0033] Throughout this disclosure, various patents, patent applications, and publications (including non-patent publications) are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes, in order to provide a more comprehensive description of the prior art known to a person of ordinary skill in the art to which this disclosure pertains as of the date of filing. This disclosure addresses any inconsistencies between the cited patents, patent applications, and publications and this disclosure.

[0034] For convenience, certain terms used in the specifications, examples, and requests are included herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0035] The term "about" immediately preceding a numerical value refers to a range (e.g., plus or minus 10% of that value). For example, "about 50" could mean 45 to 55, "about 25,000" could mean 22,500 to 27,500, etc., unless the context of this disclosure provides otherwise or is inconsistent with such interpretation. For example, in a list of values ​​such as "about 49, about 50, about 55, ...", "about 50" means a range extending to less than half the interval between the preceding and following values, e.g., greater than 49.5 to less than 52.5. Furthermore, the phrase "less than about" or "greater than about" should be understood according to the definition of the term "about" provided herein. Similarly, the term "about" preceding a series of numerical values ​​or a range of values ​​(e.g., "about 10, 20, 30" or "about 10 to 30") refers to all values ​​in that series or the endpoints of that range, respectively.

[0036] As used herein, the term "mass balance of psilocybin and related substances" refers to the sum of psilocybin and related substances (i.e., xylose and unidentified impurities defined by their relative residence times (RRTs)) as determined by HPLC analysis. In some embodiments, the mass balance is determined based on weight percent (wt%). In some embodiments, the unidentified impurities defined by their relative residence times as determined by the related substances HPLC method are selected from the group consisting of approximately RRT 0.85, approximately RRT 1.25, approximately RRT 1.38, approximately RRT 1.44, and approximately RRT 1.51. The following HPLC conditions ("related substances HPLC method") can be used to determine the mass balance of psilocybin and related substances of the components disclosed herein: [] []

[0037] The terms "effective dose" and "therapeutic effective dose" are used interchangeably in this disclosure and refer to the amount of a compound, or its salt, solvate, or ester, that, when administered to a patient, produces the desired results. For example, an effective dose of serocepin is the amount required to alleviate at least one symptom of depression in a patient. The actual amount including "effective dose" or "therapeutic effective dose" will vary depending on various factors, including but not limited to the severity of the condition, the patient's body size and health status, and the route of administration. A skilled physician can easily determine the appropriate dose using methods known in the medical field.

[0038] As used in this article, "substantially non-existent" in an XRPD diffraction pattern means a peak whose relative intensity is less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the intensity of a reference peak present in the diffraction pattern, or that the peak is undetectable.

[0039] As used in this article, the terms "object" and "patient" are used interchangeably.

[0040] As used in this article, the term "treatment" refers to the improvement of at least one symptom of a patient's condition. Treatment may improve or at least partially improve the condition.

[0041] As used herein, the term "therapeutic effect" refers to the desired or beneficial effect provided by the method and / or its components. For example, a method for treating depression provides a therapeutic effect when it reduces at least one symptom of depression in a patient.

[0042] XRPD diffraction patterns and XRPD peak positions can be obtained using Cu Kα radiation.

[0043] DSC thermal analysis charts and TGA thermal analysis charts can be obtained using a heating rate of 20℃ / min.

[0044] All diseases and symptoms listed in this article are defined in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) published by the American Psychiatric Association or the International Classification of Diseases (ICD) published by the World Health Organization.

[0045] As used in this article, the following terms from the MedDRA (Medical Dictionary of Regulatory Activities) are considered to be psychedelic adverse events in nature: mood alteration, altered state of consciousness, voyeurism, delusional perception, loss of control behavior, dissociation, dissociative identity disorder, sleep state, mood disorder, hyperactivity, paresthesia, hallucination, hyperacusis, hypersensitivity, hyposensitivity, illusion, paranoia, olfactory inversion, photophobia, sensory disturbance, altered time perception, thought disorder, synesthesia, substance-induced psychic distress, and bodily hallucinations.

[0046] The following abbreviations are used in this article: DSC - Differential Scanning Calorimetry RT - Room temperature TBME - Methyl tert-butyl ether TGA - Thermogravimetric Analysis THF - Tetrahydrofuran RRT - Relative Residence Time wrt - About XRPD - X-ray powder diffraction [Crystalized form of seroside] [] []

[0047] The pharmaceutical composition disclosed herein may include at least one form of serocepin disclosed in U.S. Patent No. 10,519,175, which is incorporated herein by reference in its entirety for all purposes.

[0048] In some embodiments, this disclosure provides a pharmaceutical composition wherein xelosipin-based crystalline polymorph A (or "polymorph A").

[0049] According to this disclosure, the psilocybin used has pharmaceutically acceptable chemical purity. In some embodiments, the psilocybin used has pharmaceutically acceptable chemical purity and is amorphous. In some embodiments, the psilocybin used has pharmaceutically acceptable chemical purity and is crystalline. In some embodiments, the psilocybin used has pharmaceutically acceptable chemical purity and is crystalline polymorph A.

[0050] In some embodiments, crystalline seroxipen is characterized by one or more of the following: (a) The peaks in the XRPD diffraction diagram are at 11.5, 12.0, and 14.5°2θ ± 0.1°2θ; and / or (b) Endothermic events in the DSC thermal analysis diagram, having a first onset temperature between 145°C and 165°C, and a second onset temperature between 205°C and 220°C.

[0051] In some embodiments, crystalline seroxipen is further characterized by at least one other peak at 19.7, 20.4, 22.2, 24.3 or 25.7°2θ ± 0.1°2θ.

[0052] In some embodiments, crystalline serocepin is characterized by having either of the following: (a) a water content of <0.5% w / w; or (b) a loss of <0.5% w / w in the TGA thermal analysis chart between 25°C and 200°C.

[0053] In some embodiments, cyclophosphine has a chemical purity greater than 97% as determined by HPLC analysis and is free of single impurities greater than 1%. In some embodiments, cyclophosphine has a chemical purity greater than 97% as determined by HPLC and is free of single impurities greater than 1%, including phosphoric acid as measured by 31P NMR and xylose as determined by HPLC.

[0054] In some embodiments, phosphoric acid impurities and any other impurities that may be present are present in amounts of less than 0.5%, less than 0.4%, 0.3%, or 0.2% or lower.

[0055] In some embodiments, the seroxibin-based homomorphic polymorph A is characterized by at least one other peak at 17.5°2θ±0.1°2θ in the XRPD diffraction pattern, the relative intensity of which is at least 5% compared to the peak at 14.5°2θ±0.1°2θ.

[0056] In some embodiments, the seroxibin-based homomorphic polymorph A is characterized by at least one other peak at 17.5°2θ±0.1°2θ in the XRPD diffraction pattern, the relative intensity of which is at least 5%, at least 6%, at least 7%, at least 8%, and 9% to at least 10% compared to the peak at 14.5°2θ±0.1°2θ.

[0057] In some embodiments, xelocepin is a polymorph A, characterized by XRPD peaks at 11.5±0.1, 12.0±0.1, 14.5±0.1, 17.5±0.1, and 19.7±0.1°2θ. In some embodiments, xelocepin is a polymorph A, characterized by XRPD peaks at 11.5±0.1, 12.0±0.1, 14.5±0.1, 17.5±0.1, and 19.7±0.1°2θ, and xelocepin has a chemical purity greater than 97% as determined by HPLC analysis, and is free of single impurities greater than 1%.

[0058] In some embodiments, serosibin is a homogeneous polymorph A, and has: (a) substantially as [picture] [2A] The XRPD diffraction diagram shown; and / or (b) substantially as [picture] [3A] shows the DSC diffraction diagram.

[0059] In some embodiments, the seroxibin polymorph A has relatively large, uniform rod-shaped crystals ranging in size from 50 to 200 micrometers.

[0060] In some embodiments disclosed herein, pyrosene isomorph A exhibits an XRPD diffraction pattern, characterized by the diffraction pattern summarized in Table 1. In some embodiments described herein, crystalline pyrosene isomorph A contains at least 3 peaks (±0.1°2θ) as shown in Table 1. In some embodiments, crystalline pyrosene isomorph A contains at least 4 peaks (±0.1°2θ) as shown in Table 1. In some embodiments, crystalline pyrosene isomorph A contains at least 5 peaks (±0.1°2θ) as shown in Table 1. In some embodiments, crystalline pyrosene isomorph A contains at least 6 peaks (±0.1°2θ) as shown in Table 1. In some embodiments, crystalline pyrosene isomorph A contains at least 8 peaks (±0.1°2θ) as shown in Table 1. In some embodiments, crystalline pyrosene isomorph A contains at least 10 peaks (±0.1°2θ) as shown in Table 1. In some embodiments, crystalline thelosine polymorph A comprises at least 15 peaks (±0.1°2θ) as shown in Table 1. A peak at approximately 17.5°2θ±0.1°2θ distinguishes thelosine polymorph A from polymorph A', which is absent or substantially absent in polymorph A' (i.e., its relative intensity is less than 2% or less than 1% compared to the peak at 14.5°2θ±0.1°2θ). [] []

[0061] In some embodiments, the crystalline xelosine isomorph A is characterized by XRPD diffraction peaks at 11.5, 12.0, 14.5, and 17.5°2θ±0.1°2θ. In some embodiments, the crystalline xelosine isomorph A is further characterized by at least one additional peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ. In some embodiments, the crystalline xelosine isomorph A is further characterized by at least two additional peaks at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ. In some embodiments, the crystalline xelosine isomorph A is further characterized by at least three additional peaks at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ. In other embodiments, the crystalline seroceridine polymorph A exhibits the same characteristics as... [picture] The XRPD diffraction diagram shown in [2A] is essentially the same as the XRPD diffraction diagram. []

[0062] In some embodiments, the crystalline thelosine polymorph A is characterized by XRPD diffraction peaks at 14.5 and 17.5°2θ ± 0.1°2θ, wherein the peak intensity at 17.5°2θ is at least 5%, or at least 6%, at least 7%, at least 8%, at least 9%, to at least 10% of the peak intensity at 14.5°2θ.

[0063] In some embodiments, the crystalline thelosine polymorph A does not exist or substantially does not have an XRPD diffraction peak at 10.1°2θ. "Substantially does not exist" means that any XRPD diffraction peak at 10.1°2θ is less than 2% of the peak intensity at 14.5°2θ, such as less than 1%, or is undetectable in the XRPD diffraction pattern.

[0064] In some embodiments, the crystalline thelosine polymorph A is characterized by an endothermic event in the DSC thermal analysis diagram having a first onset temperature between 145°C and 165°C (e.g., between 145°C and 160°C, or between 145°C and 155°C), and a second onset temperature between 205°C and 220°C (e.g., between 210°C and 220°C, or between 210°C and 218°C, or between 210°C and 216°C).

[0065] In some embodiments, crystalline seroxipen isomorph A exhibits the same characteristics as... [picture] The DSC thermal analysis diagram in [3A] is essentially the same as the DSC thermal analysis diagram.

[0066] In some embodiments, crystalline xelosine polymorph A is characterized by having a water content of <0.5% w / w, such as <0.4% w / w, such as <0.3% w / w, such as <0.2% w / w, or such as <0.1% w / w. Those skilled in the art will know methods for determining the water content of a compound, such as Karl Fischer titration. In some embodiments, crystalline xelosine polymorph A is characterized by a loss of <0.5% w / w, such as <0.4% w / w, such as <0.3% w / w, such as <0.2% w / w, or such as <0.1% w / w, in a TGA thermal analysis chart between ambient temperature (such as about 25°C) and 200°C. In some embodiments, crystalline xelosine polymorph A exhibits a loss on drying of less than 2% by weight, such as less than 1% by weight, such as less than 0.5% by weight. The loss on drying test is performed at 70°C.

[0067] In some embodiments, crystalline thelosine isomorphous polymorph A is a white to off-white solid.

[0068] In some embodiments, crystalline xelosine isoform A has a pharmaceutically acceptable chemical purity, for example, crystalline xelosine isoform A has a chemical purity greater than 97%, such as greater than 98%, or such as greater than 99%, as determined by HPLC. In some embodiments, crystalline xelosine isoform A does not have a single impurity greater than 1%, greater than 0.5%, greater than 0.4%, or 0.3% to 0.2% or less, including phosphoric acid as measured by 31P NMR and xelosine as measured by HPLC. In some embodiments, crystalline xelosine isoform A has a chemical purity greater than 97 area%, greater than 98 area%, or greater than 99 area%, as determined by HPLC. In some embodiments, crystalline xelosine isoform A does not have a single impurity greater than 1 area%, greater than 0.5 area%, greater than 0.4 area%, or 0.3% to 0.2% or less, as measured by HPLC. In some embodiments, crystalline xeloceline polymorph A is free of xeloceline at levels greater than 1 area%, greater than 0.5 area%, greater than 0.4 area%, or 0.3 area% to 0.2 area% or less as measured by HPLC. In some embodiments, crystalline xeloceline polymorph A is free of phosphoric acid at levels greater than 1 wt%, greater than 0.5 wt%, greater than 0.4 area%, or 0.3 area% to 0.2 area% or less as measured by 31P NMR. In some embodiments, crystalline xeloceline polymorph A has a chemical assay of at least 95 wt%, such as at least 96 wt%, or such as at least 98 wt%. Polymorph A'

[0069] Alternatively, crystalline seroceridine may exist as a polymorph A', characterized by one or more of the following: (a) The peaks in the XRPD diffraction diagram are at 11.5, 12.0, and 14.5°2θ±0.1°2θ, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent; (b) Having a first starting temperature between 145°C and 165°C and a second starting temperature between 205°C and 220°C.

[0070] The peak at 17.5°2θ±0.1°2θ is not substantially meaningful. Compared to the peak at 14.5°2θ±0.1°2θ, the relative intensity of the peak at 17.5°2θ±0.1°2θ (if present) is less than 5%, and in some embodiments, less than 4%, less than 3%, up to 2%, 1% or less.

[0071] In some embodiments, the crystalline pyrosene isomorph A' exhibits an XRPD diffraction pattern, characterized by the diffraction pattern summarized in Table 2. In some embodiments described herein, the crystalline pyrosene isomorph A' contains at least three peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, the crystalline pyrosene isomorph A' contains at least four peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, the crystalline pyrosene isomorph A' contains at least five peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, crystalline pyrosene isomorph A' contains at least 6 peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, crystalline pyrosene isomorph A' contains at least 8 peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, crystalline pyrosene isomorph A' contains at least 10 peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, crystalline pyrosene isomorph A' contains at least 15 peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, the crystalline thelosine polymorph A' comprises at least 20 peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent. In some embodiments, the crystalline thelosine polymorph A' comprises at least 25 peaks (±0.1°2θ) as shown in Table 2, but the peak at 17.5°2θ±0.1°2θ is absent or substantially absent.

[0072] In some embodiments, the crystalline xelosine isomorph A' is characterized by XRPD diffraction peaks at 11.5, 12.0, and 14.5°2θ±0.1°2θ, but the peak at 17.5°2θ±0.1°2θ is substantially absent. In some embodiments, the crystalline xelosine isomorph A' is further characterized by at least one additional peak at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ. In some embodiments, the crystalline xelosine isomorph A' is further characterized by at least two additional peaks at 19.7, 20.4, 22.2, 24.3, or 25.7°2θ±0.1°2θ. In some embodiments, the crystalline xelosine isomorph A' is further characterized by and differs from isomorph A in that it has a peak at 10.1°2θ±0.1°2θ. In other embodiments, the crystalline seroceridine polymorph A' exhibits the same characteristics as... [picture] The XRPD diffraction diagram shown in [2B] is essentially the same as the XRPD diffraction diagram.

[0073] In some embodiments, the crystalline thelosine polymorph A' is characterized by XRPD diffraction peaks at 14.5 and 17.5°2θ ± 0.1°2θ, wherein the peak intensity at 17.5°2θ is less than 5%, such as less than 4%, such as less than 3%, such as less than 2%, such as less than 1%, or such as about 1%, of the peak intensity at 14.5°2θ.

[0074] In some embodiments, the crystalline thelosine polymorph A' is characterized by XRPD diffraction peaks at 10.1 and 14.5°2θ ± 0.1°2θ, wherein the peak intensity at 10.1°2θ is at least 1%, such as at least 2%, such as at least 3%, or such as about 4% of the peak intensity at 14.5°2θ.

[0075] In some embodiments, the crystalline xelosine polymorph A' is characterized by an endothermic event in the DSC thermal analysis plot, having a first onset temperature between 145°C and 165°C (e.g., between 145°C and 160°C, or between 145°C and 155°C), and a second onset temperature between 205°C and 220°C (e.g., between 210°C and 220°C, or between 210°C and 218°C, or between 210°C and 216°C). In some embodiments, the crystalline xelosine polymorph A' exhibits a similar... [picture] The DSC thermal analysis diagram in [3B] is essentially the same as the DSC thermal analysis diagram.

[0076] In some embodiments, the crystalline xelosine polymorph A' is characterized by having a water content of <0.5% w / w, such as <0.4% w / w, such as <0.3% w / w, such as <0.2% w / w, or such as <0.1% w / w. Those skilled in the art will know methods for determining the water content of a compound, such as Karl Fischer titration. In some embodiments, the crystalline xelosine polymorph A' is characterized by a loss of <0.5% w / w, such as <0.4% w / w, such as <0.3% w / w, such as <0.2% w / w, or such as <0.1% w / w, in a TGA thermal analysis chart between ambient temperature (such as about 25°C) and 200°C. In some embodiments, the crystalline xelosine polymorph A' loses less than 2% by weight, such as less than 1% by weight, such as less than 0.5% by weight, in a loss-on-drying test. The loss-on-drying test is performed at 70°C.

[0077] In some embodiments, crystalline thelosine polymorph A' is a white to off-white solid.

[0078] In some embodiments, crystalline xelocetin polymorph A' has a pharmaceutically acceptable chemical purity, for example, xelocetin has a chemical purity greater than 97%, greater than 98%, greater than 98.5%, greater than 99%, greater than 99.1%, greater than 99.2%, greater than 99.3%, greater than 99.4%, greater than 99.5%, greater than 99.6%, greater than 99.7%, greater than 99.8%, or greater than 99.9% as determined by HPLC. In some embodiments, crystalline xelocetin polymorph A' does not have a single impurity greater than 1% or greater than 0.5%, including phosphoric acid as measured by 31P NMR and xelocetin as measured by HPLC. In some embodiments, crystalline xelocetin polymorph A' has a chemical purity greater than 97% area%, greater than 98% area%, greater than 98.5% area%, greater than 99% area%, and / or greater than 99.5% area as determined by HPLC. In some embodiments, crystalline xeloceline isomorph A' does not have a single impurity greater than 1 area%, greater than 0.75 area%, or greater than 0.5 area%, as measured by HPLC. In some embodiments, crystalline xeloceline isomorph A' does not contain xeloceline at levels greater than 1 area%, greater than 0.75 area%, or greater than 0.5 area%, as measured by HPLC. In some embodiments, crystalline xeloceline isomorph A' does not contain phosphoric acid at levels greater than 1 wt%, more preferably greater than 0.5 wt%, as measured by 31P NMR. In some embodiments, crystalline xeloceline isomorph A' has a chemical assay of at least 95 wt%, such as at least 96 wt%, or such as at least 98 wt%.

[0079] XRPD diffraction patterns and XRPD peak positions were obtained using Cu Kα radiation.

[0080] DSC and TGA thermal analysis maps can be obtained using a heating rate of 20℃ / min.

[0081] In some embodiments, a high-purity crystalline thelosine polymorph A or polymorph A' is provided, which exhibits substantially the same characteristics as... [picture] [2A] or [picture] [2B] shows the XRPD diffraction diagram and its actual properties as follows: [picture] [3A] or [picture] [3B] DSC thermal analysis diagram or a combination thereof.

[0082] In some embodiments, the crystalline selenociline polymorph A exhibits as follows: [picture] [2A] shows the XRPD diffraction diagram and as follows [picture] [3A] shows the DSC thermal analysis diagram.

[0083] In some embodiments, the crystalline thelosine polymorph A' exhibits substantially as [picture] [2B] shows the XRPD diffraction diagram and its actual properties as follows: [picture] [3B] shows the DSC thermal analysis diagram.

[0084] In some embodiments, the high-purity crystalline thelosine polymorph A is characterized by being substantially as [picture] [2A] shows the XRPD diffraction diagram and its actual properties as follows: [picture] [3A] shows the DSC thermal analysis diagram.

[0085] In some embodiments, the high-purity crystalline thelosine polymorph A is characterized by, as [picture] [2B] shows the XRPD diffraction diagram and as follows [picture] [3B] shows the DSC thermal analysis diagram.

[0086] Homogeneous polymorph A (including its isomorphous variant, homogeneous polymorph A') [picture] [2A] and [picture] [2B]) is different from the homogeneous polymorph B ( [picture] [2C]), hydrate A ( [picture] [2D]) and ethanol solvates ( [picture] [2E]: Solvate A), the relationships between some different forms are illustrated in [picture] [4] in.

[0087] Crystalline xeloceline polymorph A or polymorph A' is a white to off-white solid and / or has a chemical purity greater than 97% as determined by HPLC, greater than 98% in some embodiments, and greater than 99% in some embodiments, and is free from single impurities greater than 2%, greater than 1.75%, greater than 1.5%, greater than 1.25%, greater than 1%, greater than 0.75%, greater than 0.5%, greater than 0.4%, greater than 0.3% to greater than 0.2% or less, including phosphoric acid as measured by 31P NMR and xeloceline as measured by HPLC. In some embodiments, high-purity crystalline xeloceline polymorph A or polymorph A' is provided. In some embodiments, crystalline xeloceline polymorph A or polymorph A' has a chemical purity greater than 97% area%, greater than 98% area%, and greater than 99% area% as determined by HPLC. In some embodiments, crystalline xelocebin polymorph A or polymorph A' does not have a single impurity of greater than 2 area%, greater than 1.75 area%, greater than 1.5 area%, greater than 1.25 area%, 1 area%, greater than 0.5 area%, greater than 0.4 area%, or 0.3 area% to 0.2 area% or less. In some embodiments, crystalline xelocebin polymorph A or polymorph A' does not contain xelocecin at levels greater than 2 area%, greater than 1.75 area%, greater than 1.5 area%, greater than 1.25 area%, greater than 1 area%, greater than 0.5 area%, greater than 0.4 area%, or 0.3 area% to 0.2 area% or less as measured by HPLC. In some embodiments, crystalline xelocebin polymorph A or polymorph A' does not contain phosphoric acid at levels greater than 1 wt%, greater than 0.5 wt%, greater than 0.4 area%, or greater than 0.3 area% to greater than 0.2 area% or less as measured by 31P NMR. In some embodiments, crystalline thelosine polymorph A or polymorph A' has a chemical assay of at least 95% by weight, such as at least 96% by weight, or such as at least 98% by weight.

[0088] Heating of polymorph A or A' results in an endothermic event with an onset temperature of approximately 150°C, corresponding to the solid-solid transformation from polymorph A or A' to polymorph B. Further heating of the resulting solid (i.e., polymorph B) leads to a second endothermic event, corresponding to a melting point with an onset temperature between 205 and 220°C (see [link to endothermic event]). [picture] [3A] and [picture] [3B]).

[0089] In some embodiments, a crystalline form of serocepin, hydrate A, is provided, characterized by one or more of the following: (a) The peaks in the XRPD diffraction diagrams are at 8.9, 12.6, and 13.8°2θ ± 0.1°2θ; and / or (b) The endothermic event in the DSC thermal analysis diagram has a first initiation temperature between 90°C and 100°C, a second initiation temperature between 100°C and 120°C, and a third initiation temperature between 210°C and 220°C.

[0090] The XRPD diffraction pattern may show at least one other peak at 6.5, 12.2, 19.4, 20.4, or 20.8°2θ ± 0.1°2θ. [Hydrate] [A] []

[0091] In some embodiments, serozepine hydrate A exhibits an XRPD diffraction pattern, characterized by the diffraction pattern summarized in Table 3. In some embodiments described herein, crystalline serozepine hydrate A contains at least 3 peaks (±0.1°2θ) as shown in Table 3. In some embodiments, crystalline serozepine hydrate A contains at least 4 peaks (±0.1°2θ) as shown in Table 3. In some embodiments, crystalline serozepine hydrate A contains at least 5 peaks (±0.1°2θ) as shown in Table 3. In some embodiments, crystalline serozepine hydrate A contains at least 8 peaks (±0.1°2θ) as shown in Table 3. In some embodiments, crystalline serozepine hydrate A contains at least 10 peaks (±0.1°2θ) as shown in Table 3. []

[0092] In some embodiments, crystalline xelosine hydrate A is characterized by XRPD diffraction peaks at 8.9, 12.6, and 13.8°2θ±0.1°2θ. In some embodiments, crystalline xelosine hydrate A is further characterized by at least one peak at 6.5, 12.2, 19.4, 20.4, or 20.8°2θ±0.1°2θ. In some embodiments, crystalline xelosine hydrate A is further characterized by at least two peaks at 6.5, 12.2, 19.4, 20.4, or 20.8°2θ±0.1°2θ. In yet other embodiments, crystalline xelosine hydrate A exhibits... [picture] The XRPD diffraction diagram shown in [2D] is essentially the same as the XRPD diffraction diagram.

[0093] In some embodiments, crystalline seroxipen hydrate A is characterized by an endothermic event in the DSC thermal analysis plot, having a first onset temperature between 85°C and 105°C (e.g., between 90°C and 100°C, e.g., at about 96°C); a second onset temperature between 100°C and 120°C (e.g., between 105°C and 115°C, e.g., at about 109°C); and a third onset temperature between 205°C and 220°C (e.g., between 210°C and 220°C, e.g., between 210°C and 218°C, or e.g., between 210°C and 216°C, e.g., at about 216°C). In some embodiments, crystalline seroxipen hydrate A exhibits the same characteristics as... [picture] The DSC thermal analysis diagram in [3D] is essentially the same as the DSC thermal analysis diagram.

[0094] In some embodiments, crystalline serocerabine hydrate A is characterized by having a water content between 10% and 18%, such as between 12% and 16%, or such as about 13%. Those skilled in the art will know methods for determining the water content of a compound, such as Karl Fischer titration. In some embodiments, crystalline serocerabine hydrate A is characterized by having a weight loss in a TGA thermal analysis plot between ambient temperature (such as about 25°C) and 120°C, between 10% and 18%, such as between 12% and 16%, or such as about 13%.

[0095] In some embodiments, crystalline xelocebin hydrate A has a pharmaceutically acceptable chemical purity, for example, xelocebin has a chemical purity greater than 97%, such as greater than 98%, or such as greater than 99% as determined by HPLC. In some embodiments, crystalline xelocebin hydrate A is free from single impurities greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3% to greater than 0.2% or less, including phosphoric acid as measured by 31P NMR and xelocebin as measured by HPLC. In some embodiments, crystalline xelocebin hydrate A has a chemical purity greater than 97% area, more preferably greater than 98% area, and most preferably greater than 99% area as determined by HPLC. In some embodiments, crystalline xelocebin hydrate A is free from single impurities greater than 1% area, greater than 0.5% area, greater than 0.4% area, greater than 0.3% area to greater than 0.2% area or less as measured by HPLC. In some embodiments, crystalline xeloceline polymorph B is free of xeloceline at levels greater than 1 area%, greater than 0.5 area%, more preferably greater than 0.4 area%, greater than 0.3 area% to greater than 0.2 area% or less, as measured by HPLC. In some embodiments, crystalline xeloceline hydrate A is free of phosphoric acid at levels greater than 1 wt%, greater than 0.5 wt%, greater than 0.4 area%, greater than 0.3 area% to greater than 0.2 area% or less, as measured by 31P NMR. In some embodiments, crystalline xeloceline hydrate A has a chemical assay of at least 95 wt%, such as at least 96 wt%, or such as at least 98 wt%. [Homogeneous Polymorph] [B]

[0096] In some embodiments, a crystalline form of serocerin, polymorph B, is provided, characterized by one or more of the following: (a) The peaks in the XRPD diffraction diagram are at 11.1, 11.8, and 14.3°2θ ± 0.1°2θ; and / or (b) A single endothermic event in the DSC thermal analysis diagram, which has an initial temperature between 205 and 220 °C.

[0097] The XRPD diffraction pattern may show at least one other peak at 14.9, 15.4, 19.3, 20.0, or 20.6°2θ ± 0.1°2θ.

[0098] In some embodiments, the XRPD diffraction system is substantially as follows: [picture] As shown in [2C].

[0099] In some embodiments, the DSC diffraction pattern is substantially as follows: [picture] As shown in [3C].

[0100] In some embodiments, pyrosene isomorph B exhibits an XRPD diffraction pattern, characterized by the diffraction pattern summarized in Table 4. In some embodiments described herein, crystalline pyrosene isomorph B contains at least 3 peaks (±0.1°2θ) from Table 4. In some embodiments, crystalline pyrosene isomorph B contains at least 4 peaks (±0.1°2θ) from Table 4. In some embodiments, crystalline pyrosene isomorph B contains at least 5 peaks (±0.1°2θ) from Table 4. In some embodiments, crystalline pyrosene isomorph B contains at least 8 peaks (±0.1°2θ) from Table 4. In some embodiments, crystalline pyrosene isomorph B contains at least 10 peaks (±0.1°2θ) from Table 4. []

[0101] In some embodiments, the crystalline serozepine isomorph B is characterized by XRPD diffraction peaks at 11.1, 11.8, and 14.3°2θ±0.1°2θ. In some embodiments, the crystalline serozepine isomorph B is further characterized by at least one peak at 14.9, 15.4, 19.3, 20.0, or 20.6°2θ±0.1°2θ. In some embodiments, the crystalline serozepine isomorph B is further characterized by at least two peaks at 14.9, 15.4, 19.3, 20.0, or 20.6°2θ±0.1°2θ. In yet other embodiments, the crystalline serozepine isomorph B exhibits the same characteristics as... [picture] The XRPD diffraction diagram shown in [2C] is essentially the same as the XRPD diffraction diagram.

[0102] In some embodiments, crystalline xelosine polymorph B is characterized by a single endothermic event in the DSC thermal analysis diagram, having an initial temperature between 205 and 220°C, such as between 210 and 220°C, such as between 210 and 218°C, or such as between 210 and 216°C. In some embodiments, crystalline xelosine polymorph B exhibits a similarity to... [picture] The DSC thermal analysis diagram in [3C] is essentially the same as the DSC thermal analysis diagram.

[0103] In some embodiments, crystalline xelosine polymorph B is characterized by having a water content of <0.5% w / w, such as <0.4% w / w, such as <0.3% w / w, such as <0.2% w / w, or such as <0.1% w / w. Those skilled in the art will know methods for determining the water content of a compound, such as Karl Fischer titration. In some embodiments, crystalline xelosine polymorph B is characterized by a loss of <0.5% w / w, such as <0.4% w / w, such as <0.3% w / w, such as <0.2% w / w, or such as <0.1% w / w, in a TGA thermal analysis chart between ambient temperature (such as about 25°C) and 200°C. In some embodiments, crystalline xelosine polymorph B exhibits a loss of less than 2% by weight, such as less than 1% by weight, such as less than 0.5% by weight, in a loss-on-drying test. The loss-on-drying test is performed at 70°C.

[0104] In some embodiments, crystalline xelocetin isoform B has a pharmaceutically acceptable chemical purity, for example, xelocetin has a chemical purity greater than 97%, such as greater than 98%, or such as greater than 99%, as determined by HPLC. In some embodiments, crystalline xelocetin isoform B is free from single impurities greater than 1%, greater than 0.5%, greater than 0.4%, greater than 0.3% to greater than 0.2% or less, including phosphoric acid as measured by 31P NMR and xelocetin as measured by HPLC. In some embodiments, crystalline xelocetin isoform B has a chemical purity greater than 97% area, more preferably greater than 98% area, and most preferably greater than 99% area, as determined by HPLC. In some embodiments, crystalline xelocetin isoform B is free from single impurities greater than 1% area, more preferably greater than 0.5% area, more preferably greater than 0.4% area, and greater than 0.3% to greater than 0.2% area, as measured by HPLC. In some embodiments, crystalline xeloceline polymorph B is free of xeloceline at levels greater than 1 area%, more preferably greater than 0.5 area%, more preferably greater than 0.4 area%, and greater than 0.3 area% to greater than 0.2 area% or less, as measured by HPLC. In some embodiments, crystalline xeloceline polymorph B is free of phosphoric acid at levels greater than 1 area%, more preferably greater than 0.5 area%, more preferably greater than 0.4 area%, and greater than 0.3 area% to greater than 0.2 area% or less, as measured by 31P NMR. In some embodiments, crystalline xeloceline polymorph B has a chemical assay of at least 95% by weight, such as at least 96% by weight, or such as at least 98% by weight.

[0105] Cerosibine in the form of a homogeneous polymorph A or A' has the general properties shown in Table 5 below: [] [] Table 5. Appearance: White to off-white solid The main endothermic events in DSC (initial temperature) (corresponding to melting): 210-215℃ Hygroscopicity: Serocerin forms hydrate A when exposed to high humidity or added to water, but the hydrated water is rapidly lost upon drying. Therefore, an anhydrous form was developed. Crystallization form: Anhydrous homomorphic polymorphs A and / or A' pKa (calculated value): 1.74, 6.71, 9.75 solubility Approximately 15 mg / ml in water

[0106] Serocerin conforms to the spectra listed in Table 6 below, and is plotted on... [picture] [5] to [picture] [8] in the spectrum. [] [surface] [6.] [] technology in conclusion Proton (¹H) and carbon (¹³C) NMR Proton spectroscopy [picture] [5]) and carbon spectrum ( [picture] [6]) The determination is consistent with that of Cerosib. FT-IR spectroscopy FT-IR spectroscopy [picture] [7]) The determination is consistent with that of Cerosib. Mass spectrometry (MS) Mass spectrometry (MS) [picture] [8]) The determination is consistent with that of Cerosib.

[0107] High purity is achieved by carefully controlling reaction conditions to ensure a significant reduction in potential organic impurities.

[0108] Known and potential impurities in serocepin are shown in Table 7 below: [, , ] [] [surface] [7.] [] impurities Relative Residence Time (RRT) structure source Selosin 1.65 Starting material (Stage 3). Also produced by the hydrolysis of selociline. Significant impurities were observed only in selociline batches. Phase 4A The initial product formed in stage 4 of the reaction. It is converted to stage 4 upon stirring in THF. It is converted to seroxipen in stage 5. Phase 4 2.74 intermediate N-Benzylation Phase 4 In stage 4, it is identified by MS. In stage 5, it is converted into seroside. Phase 4 acid anhydride impurities In stage 4, identification is achieved through MS. In stage 5, it is converted into stage 5 pyrophosphate impurities. Phase 5 Pyrophosphate impurities Identification via MS It is formed from the acid anhydride in stage 4. It is removed in the recrystallization in stage 6 by a combination of hydrolysis to thiosylbenzene and increased solubility due to the additional phosphate ester group. Phase 5 (Intermediate) 1.89 and 2.45 Two intermediates are formed during hydrogenation. These are subsequently converted into the product (based on its chemical structure). Monitoring and control are performed during the fifth stage of the reaction. [] [Pharmaceutical ingredients disclosed herein] []

[0109] This disclosure provides pharmaceutical compositions containing serocepin, which are stable during long-term storage. [] []

[0110] In some embodiments, this disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of psilocybin; and one or more pharmaceutically acceptable excipients, wherein, under industrially and pharmaceutically acceptable storage conditions (e.g., European Pharmacopoeia, USP), the potency of psilocybin in the composition and the mass balance of psilocybin and related substances in the composition are maintained at industrially and pharmaceutically acceptable levels (e.g., European Pharmacopoeia, USP), and psilocybin is provided with pharmaceutically acceptable uniformity of content (via European Pharmacopoeia 2.96 or USP). <905> (Measured).

[0111] In some embodiments, this disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of cyclophosphine; and one or more pharmaceutically acceptable excipients, wherein after storage at 40°C and 75% relative humidity for one month, the potency of cyclophosphine in the composition decreases by less than 5%, and the mass balance of cyclophosphine and related substances is greater than 97%. [] []

[0112] In some embodiments, after storage at 40°C and 75% relative humidity for two, three, four, five, or six months, the potency of psilocybin in the composition decreases by less than 5%, and the mass balance of psilocybin and related substances is greater than 97%. In some embodiments, after storage at 40°C and 75% relative humidity for two months, the potency of psilocybin in the composition decreases by less than 5%, and the mass balance of psilocybin and related substances is greater than 97%. In some embodiments, after storage at 40°C and 75% relative humidity for the disclosed time period, the potency of psilocybin in the composition decreases by less than 5%, less than 4%, less than 2%, or less than 1%, and the mass balance of psilocybin and related substances is greater than 97%. In some embodiments, after storage at 40°C and 75% relative humidity for the disclosed time period, the potency of psilocybin in the composition decreases by less than 5%, less than 4%, less than 2%, or less than 1%, and the mass balance of psilocybin and related substances is greater than 98% or 99%. [] []

[0113] In some embodiments, the composition comprises about 1% to 10% by weight of serodecidine, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1% to 15% by weight of serodecidine, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1 mg to 40 mg of cilostabene, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, or 40 mg, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1 mg to 25 mg of cilostabene, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, or 25 mg, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1 mg to 10 mg of cyclophosphamide, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1 mg of cyclophosphamide. In some embodiments, the composition comprises about 5 mg of cyclophosphamide. In some embodiments, the composition comprises 10 mg of cyclophosphamide. In some embodiments, the composition comprises 15 mg of cyclophosphamide. In some embodiments, the composition comprises about 20 mg of cyclophosphamide. In some embodiments, the composition comprises about 25 mg of cyclophosphamide. [] []

[0114] In some embodiments, the chemical purity of oxycepin in the composition is determined by HPLC analysis to be not less than 97%, not less than 98%, or not less than 99%. In some embodiments, the chemical purity of oxycepin in the composition is determined by HPLC analysis to be not less than 97%. [] []

[0115] In some embodiments, serozepine comprises crystalline serozepine. In some embodiments, crystalline serozepine is the crystalline serozepine disclosed in U.S. Patent No. 10,519,175, which is incorporated herein by reference in its entirety for all purposes. In some embodiments, crystalline serozepine is crystalline serozepine polymorph A. In some embodiments, crystalline serozepine is crystalline serozepine hydrate A. In some embodiments, crystalline serozepine is crystalline serozepine polymorph A'. In some embodiments, crystalline serozepine is crystalline serozepine polymorph B. [] []

[0116] In some embodiments, serocebin comprises amorphous serocebin. [] [] [Pharmaceutical-acceptable excipients:] [] []

[0117] In some embodiments, the composition comprises at least one pharmaceutically acceptable excipient. [] []

[0118] In some embodiments, the composition comprises at least one pharmaceutically acceptable excipient that does not substantially interact chemically or physically with the functional groups of xelocebin. In some embodiments, the composition comprises at least one pharmaceutically acceptable excipient that does not substantially interact chemically or physically with the phosphate ester of xelocebin. In some embodiments, the composition comprises at least one pharmaceutically acceptable excipient that does not substantially form covalent and / or hydrogen bonds with the phosphate ester of xelocebin. [] []

[0119] In some embodiments, the composition does not contain pharmaceutically acceptable excipients that substantially interact chemically or physically with the functional groups of selocillin. In some embodiments, the composition does not contain pharmaceutically acceptable excipients that substantially interact chemically or physically with the phosphate ester of selocillin. In some embodiments, the composition does not contain pharmaceutically acceptable excipients that substantially form covalent bonds and / or hydrogen bonds with the phosphate ester of selocillin. In some embodiments, the composition does not contain inorganic silicates, silica, or silicified excipients. In some embodiments, the composition does not contain calcium aluminum silicate, calcium silicate, diatomaceous earth, magnesium silicate, perlite, potassium silicate, silica aerogel, silica, sodium aluminosilicate, sodium calcium aluminosilicate, sodium silicate, talc (basic magnesium silicate), or tricalcium silicate. In some embodiments, the composition does not contain silicified microcrystalline cellulose. [] []

[0120] In some embodiments, the composition does not contain polyhydroxylated excipients, such as sugar alcohols or sugars. In some embodiments, the composition does not contain polyols, mannitol, xylitol, sucrose, sorbitol, or fructose. [] []

[0121] In some embodiments, the composition does not contain calcium base. In some embodiments, the composition does not contain calcium carbonate or calcium phosphate. [] []

[0122] As stated above, the composition disclosed herein contains one or more pharmaceutically acceptable excipients. [] [] Diluent: [] []

[0123] In some embodiments, the composition includes a diluent. In some embodiments, the diluent is a starch-based material. [] []

[0124] In some embodiments, the diluent is pregelatinized starch. As mentioned herein, the term "pregelatinized starch" refers to starch that is fully or partially pregelatinized. In some embodiments, the pregelatinized starch is partially pregelatinized.

[0125] In some embodiments, pregelatinized starch comprises natural starch and precompacted starch powder. In some embodiments, pregelatinized starch is produced by a method comprising the steps of: fluidizing a mixture comprising natural starch and precompacted starch powder; and spraying a slurry comprising precompacted starch powder onto the fluidized mixture. The precompacted starch powder is also characterized by being partially pregelatinized. However, this differs from fully or completely pregelatinized starch because a significant amount of intact natural starch is retained in the precompacted starch powder.

[0126] The term "natural starch" refers to starch directly derived from any of several plant sources. Natural starch is extracted from plant sources (e.g., corn) and its granular structure remains substantially intact. The term "pre-compacted starch powder" refers to a product obtained by physically compacting ungelatinized, granular natural starch, possibly while simultaneously incorporating heat. After compaction, the starch is ground and sieved to produce a free-flowing powder.

[0127] In some embodiments, the pregelatinized starch system is derived from corn starch, potato starch, wheat starch, or a combination thereof. In some embodiments, the pregelatinized starch system is derived from corn starch. In some embodiments, the pregelatinized starch system is derived from potato starch. In some embodiments, the pregelatinized starch system is derived from wheat starch.

[0128] In some embodiments, the diluent is Colorcon Starcap®, Roquette Lycatab® C, Roquette Lycatab® PGS, Grain Processing Corporation (GPC) Spress® B820, Cargil C☆PharmGel™, Insta-starch, Seppic Sepistab™ ST 200, or DFE Pharma Prejel PAH P5. Starcap® is a partially pregelatinized corn starch with engineered physical properties. Starcap® can be described by its physical properties, such as a Carr's index of about 21, a flow rate of about 5.6 g / sec, and an average particle size of about 90 micrometers. In some embodiments, the composition disclosed herein comprises Starcap®. Starcap® is described in U.S. Patent No. 7,186,293 and European Patent No. 1,861,427, which are incorporated herein by reference in their entirety for all purposes.

[0129] In some embodiments, the composition disclosed herein comprises a diluent characterized by its average particle size. In some embodiments, the average particle size of the diluent is about 40 to about 200 micrometers, for example, about 40 micrometers, about 45 micrometers, about 50 micrometers, about 55 micrometers, about 60 micrometers, about 65 micrometers, about 70 micrometers, about 75 micrometers, about 80 micrometers, about 85 micrometers, about 90 micrometers, about 95 micrometers, about 100 micrometers, about 105 micrometers, about 110 micrometers, about 115 micrometers, about 120 micrometers, about 125 micrometers, about 130 micrometers, about 135 micrometers, about 140 micrometers, about 145 micrometers, about 150 micrometers, about 155 micrometers, about 160 micrometers, about 165 micrometers, about 170 micrometers, about 175 micrometers, about 180 micrometers, about 185 micrometers, about 190 micrometers, about 195 micrometers, or about 200 micrometers, including all ranges and values ​​therein. In some embodiments, the average particle size of the diluent is about 50 to about 120 micrometers. In some embodiments, the average particle size of the diluent is about 60 to about 120 micrometers. In some embodiments, the average particle size of the diluent is about 90 micrometers. In an embodiment, the average particle size of the diluent is about 100 micrometers. In an embodiment, the average particle size of the diluent is about 150 micrometers.

[0130] In some embodiments, the composition disclosed herein includes a diluent characterized by its flow properties, such as the Carr index, Hausner ratio, or flow rate.

[0131] In some embodiments, the Karl Fischer index of the diluent is about 12 to about 25, for example, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24, including all ranges and values ​​therein. In some embodiments, the Karl Fischer index of the diluent is less than about 11. In some embodiments, the Karl Fischer index of the diluent is about 12 to about 16. In some embodiments, the Karl Fischer index of the diluent is about 18 to about 21. In some embodiments, the Karl Fischer index of the diluent is less than about 24. In some embodiments, the Karl Fischer index of the diluent is about 16. In some embodiments, the Karl Fischer index of the diluent is about 17. In some embodiments, the Karl Fischer index of the diluent is about 20. In some embodiments, the Karl Fischer index of the diluent is about 21.

[0132] In some embodiments, the hausnab ratio of the diluent is from about 1.0 to about 1.6, for example, about 1.00, about 1.05, about 1.10, about 1.15, about 1.20, about 1.25, about 1.30, about 1.35, about 1.40, about 1.45, about 1.50, about 1.55, or about 1.60, including all ranges and values ​​therein. In some embodiments, the hausnab ratio of the diluent is less than about 1.6. In some embodiments, the hausnab ratio of the diluent is less than about 1.2. In some embodiments, the hausnab ratio of the diluent is 1.29.

[0133] In some embodiments, the flow rate of the diluent, measured using a Sotax FT300 flowability tester (vibration set to 1.7 g), is approximately 2 g / sec to approximately 10 g / sec, for example, approximately 2.00 g / sec, approximately 2.25 g / sec, approximately 2.50 g / sec, approximately 2.75 g / sec, approximately 3.00 g / sec, approximately 3.25 g / sec, approximately 3.50 g / sec, approximately 3.75 g / sec, approximately 4.00 g / sec, approximately 4.25 g / sec, approximately 4.50 g / sec, approximately 4.75 g / sec, approximately 5.00 g / sec, approximately 5.25 g / sec, approximately 5.50 g / sec, approximately 5.75 g / sec, approximately 6.00 g / sec. The flow rate is approximately 6.25 g / sec, approximately 6.50 g / sec, approximately 6.75 g / sec, approximately 7.00 g / sec, approximately 7.25 g / sec, approximately 7.50 g / sec, approximately 7.75 g / sec, approximately 8.00 g / sec, approximately 8.25 g / sec, approximately 8.50 g / sec, approximately 8.75 g / sec, approximately 9.00 g / sec, approximately 9.25 g / sec, approximately 9.50 g / sec, approximately 9.75 g / sec, or approximately 10.00 g / sec, including all ranges and values ​​therein. In some embodiments, the flow rate of the diluent is approximately 3.6 g / sec. In some embodiments, the flow rate of the diluent is approximately 5.6 g / sec. In some embodiments, the flow rate of the diluent is approximately 8.5 g / sec.

[0134] In some embodiments, the composition disclosed herein includes a diluent, characterized by its bulk density. In some embodiments, the bulk density of the diluent is from about 0.40 g / mL to about 0.70 g / mL, for example, about 0.40%, about 0.41%, about 0.42%, about 0.43%, about 0.44%, about 0.45%, about 0.46%, about 0.47%, about 0.48%, about 0.49%, about 0.50%, about 0.51%, about 0.52%, about 0.53%, about 0.54%, about 0.55%, about 0.56%, about 0.57%, about 0.58%, about 0.59%, about 0.60%, about 0.61%, about 0.62%, about 0.63%, about 0.64%, about 0.65%, about 0.66%, about 0.67%, about 0.68%, about 0.69%, or about 0.70%, including all ranges and values ​​therein. In some embodiments, the bulk density of the diluent is about 0.47 g / mL. In some embodiments, the bulk density of the diluent is about 0.63 g / mL.

[0135] In some embodiments, the composition disclosed herein comprises a diluent, characterized by its water content. In some embodiments, the water content of the diluent is from about 1% to 20%, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, including all ranges and values ​​therein. In some embodiments, the water content of the diluent is about 6%. In some embodiments, the water content of the diluent is less than about 15%.

[0136] In some embodiments, the composition comprises about 85 to 99% by weight of a diluent, such as about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including all ranges and values ​​therein.

[0137] In some embodiments, the diluent is pregelatinized starch. In some embodiments, the composition comprises about 85% to about 99% pregelatinized starch, for example, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 98% pregelatinized starch. In some embodiments, the composition comprises about 94% pregelatinized starch. In some embodiments, the composition comprises about 89% pregelatinized starch. Lubricant: [] []

[0138] In some embodiments, the composition includes a lubricant. In some embodiments, the lubricant is selected from the group consisting of: sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl styrosinate, glyceryl palmitate, magnesium lauryl stearate, stearic acid, talc, and hydrogenated castor oil. In some embodiments, the lubricant is sodium stearyl fumarate. [] []

[0139] In some embodiments, the composition comprises about 0.5 to 2.0% by weight of a lubricant, for example, about 0.50%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 1.00%, about 1.10%, about 1.20%, about 1.30%, about 1.40%, about 1.50%, about 1.60%, about 1.70%, about 1.80%, about 1.90%, or about 2.00%, including all ranges and values ​​therein.

[0140] In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the composition comprises about 0.5% to about 2.0% sodium stearyl fumarate, for example, about 0.50%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 1.00%, about 1.10%, about 1.20%, about 1.30%, about 1.40%, about 1.50%, about 1.60%, about 1.70%, about 1.80%, about 1.90%, or about 2.00%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1% sodium stearyl fumarate.

[0141] In some embodiments, the composition comprises about 0.5 to 2% by weight of a lubricant, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, including all ranges and values ​​therein. Lubricant:

[0142] In some embodiments, the composition includes a lubricant. In some embodiments, the lubricant is selected from the group consisting of: calcium phosphate trihydrate, calcium silicate, cellulose, powdered colloidal silica, magnesium silicate, silica, starch, talc, and combinations thereof.

[0143] In some embodiments, the lubricant is calcium silicate. In some embodiments, the composition comprises about 0.5% to about 2% calcium silicate, for example, about 0.50%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 1.00%, about 1.10%, about 1.20%, about 1.30%, about 1.40%, about 1.50%, about 1.60%, about 1.70%, about 1.80%, about 1.90%, or about 2.00%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1% calcium silicate.

[0144] In some embodiments, the lubricant is silica. In some embodiments, the lubricant is colloidal silica. In some embodiments, the composition comprises about 1% to about 0.5% silica, for example, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, or about 0.50%, including all ranges and values ​​therein.

[0145] In some embodiments, the lubricant is magnesium silicate. In some embodiments, the composition comprises about 0.5% to about 2% magnesium silicate, for example, about 0.50%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 1.00%, about 1.10%, about 1.20%, about 1.30%, about 1.40%, about 1.50%, about 1.60%, about 1.70%, about 1.80%, about 1.90%, or about 2.00%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 1% magnesium silicate.

[0146] In some embodiments, the lubricant is talc. In some embodiments, the composition contains about 1% to about 10% talc, for example, about 1.00%, about 2.00%, about 3.00%, about 4.00%, about 5.00%, about 6.00%, about 7.00%, about 8.00%, about 9.00%, or about 10.00%, including all ranges and values ​​therein. Disintegrant:

[0147] In some embodiments, the composition includes a disintegrant. In some embodiments, the disintegrant is selected from the group consisting of: starch (e.g., pregelatinized starch), sodium starch glycolate, povidone, crospovidone, croscarmellose sodium, polcarin, methylcellulose, hydroxypropyl cellulose (HPC), microcrystalline cellulose, carboxymethyl cellulose, sodium alginate, calcium alginate, magnesium aluminum silicate, cellulose, chitosan, colloidal silica (SiO2), docusate sodium, guar gum, and combinations thereof. In some embodiments, the composition comprises about 0.1% to about 98% of a disintegrant, for example, about 0.10%, about 0.20%, about 0.30%, about 0.40%, about 0.50%, about 0.60%, about 0.70%, about 0.80%, about 0.90%, about 1.00%, about 1.10%, about 1.20%, about 1.30%, about 1.40%, about 1.50%, about 1.60%, or about 1.70%. Approximately 1.80%, approximately 1.90%, approximately 2.00%, approximately 2.20%, approximately 2.40%, approximately 2.60%, approximately 2.80%, approximately 3.00%, approximately 3.20%, approximately 3.40%, approximately 3.60%, approximately 3.80%, approximately 4.00%, approximately 4.20%, approximately 4.40%, approximately 4.60%, approximately 4.80%, approximately 5.00%, approximately 5.50%, approximately 6.00%, approximately 6.50%, approximately 7. 0.00%, approximately 7.50%, approximately 8.00%, approximately 8.50%, approximately 9.00%, approximately 9.50%, approximately 10.00%, approximately 11.00%, approximately 12.00%, approximately 13.00%, approximately 14.00%, approximately 15.00%, approximately 16.00%, approximately 17.00%, approximately 18.00%, approximately 19.00%, approximately 20.00%, approximately 22.00%, approximately 24.00%, approximately 26.00% Approximately 28.00%, approximately 30.00%, approximately 33.00%, approximately 36.00%, approximately 39.00%, approximately 42.00%, approximately 46.00%, approximately 50.00%, approximately 54.00%, approximately 58.00%, approximately 62.00%, approximately 68.00%, approximately 74.00%, approximately 80.00%, approximately 86.00%, approximately 92.00%, or approximately 98.00%, including all ranges and values ​​therein.

[0148] In some embodiments, the disintegrant is starch. In some embodiments, the starch is pregelatinized starch. In some embodiments, the composition comprises about 50% to about 98% starch, for example, about 50%, about 52%, about 54%, about 56%, about 58%, about 60%, about 62%, about 64%, about 66%, about 68%, about 70%, about 72%, about 74%, about 76%, about 78%, about 80%, about 82%, about 84%, about 86%, about 88%, about 90%, about 92%, about 94%, about 96%, or about 98%, including all ranges and values ​​therein.

[0149] In some embodiments, the disintegrant is sodium glycolate starch. In some embodiments, the composition comprises about 2% to about 8% sodium glycolate starch, for example, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, or about 8.0%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 4% sodium glycolate starch.

[0150] In some embodiments, the disintegrant is provitamin. In some embodiments, the composition comprises about 0.5% to about 5% provitamin, about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5.0%, including all ranges and values ​​therein.

[0151] In some embodiments, the disintegrant is crosoprevone. In some embodiments, the composition comprises about 2% to about 5% crosoprevone, for example, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5.0%, including all ranges and values ​​therein.

[0152] In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the composition comprises about 10% to about 25% croscarmellose sodium, for example, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 17.5% croscarmellose sodium.

[0153] In some embodiments, the disintegrant is polcarin potassium. In some embodiments, the composition contains about 2% to about 10% polcarin potassium, for example, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0%, including all ranges and values ​​therein. In some embodiments, the composition contains about 2% to about 3% polcarin potassium.

[0154] In some embodiments, the disintegrant is methylcellulose. In some embodiments, the composition comprises about 2% to about 10% methylcellulose, for example, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 5% methylcellulose.

[0155] In some embodiments, the disintegrant is hydroxypropyl cellulose. In some embodiments, the composition comprises about 2% to about 5% hydroxypropyl cellulose, for example, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, or about 5.0%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 2% to about 3% hydroxypropyl cellulose.

[0156] In some embodiments, the disintegrant is microcrystalline cellulose. In some embodiments, the composition comprises about 5% to about 15% microcrystalline cellulose, for example, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 10% microcrystalline cellulose.

[0157] In some embodiments, the disintegrant is carboxymethyl cellulose. In some embodiments, the composition comprises about 1% to about 6% carboxymethyl cellulose, for example, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, or about 6.0%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 2% to about 3% carboxymethyl cellulose.

[0158] In some embodiments, the disintegrant is sodium alginate. In some embodiments, the composition comprises about 2.5% to about 10% sodium alginate, for example, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 4% to about 5% sodium alginate.

[0159] In some embodiments, the disintegrant is potassium alginate. In some embodiments, the composition comprises about 2.5% to about 10% potassium alginate, for example, about 2.5%, about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0%, including all ranges and values ​​therein. In some embodiments, the composition comprises about 4% to about 5% potassium alginate.

[0160] In some embodiments, the disintegrant is magnesium aluminum silicate.

[0161] In some embodiments, the disintegrant is chitosan.

[0162] In some embodiments, the disintegrant is colloidal silica. In some embodiments, the composition comprises about 0.1% to about 0.55% colloidal silica, for example, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, or about 0.55%, including all ranges and values ​​therein.

[0163] In some embodiments, the disintegrant is cellulose. In some embodiments, the composition comprises about 5% to about 15% cellulose, for example, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, including all ranges and values ​​therein.

[0164] In some embodiments, the disintegrant is sodium docusate. In some embodiments, the composition comprises about 0.1% to about 1.0% sodium docusate, for example, about 0.10%, about 0.15%, about 0.20%, about 0.25%, about 0.30%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, or about 1.00%. In some embodiments, the composition comprises about 0.5% sodium docusate. [] [Dosage Form:] [] []

[0165] According to this disclosure, pharmaceutical compositions may be in any pharmaceutically acceptable form, maintaining the integrity and potency of the serocepin contained therein and providing pharmaceutically acceptable uniformity of content (as per European Pharmacopoeia 2.96 or USP). <905> (Measured). In some embodiments, the pharmaceutical composition is in solid form. In some embodiments, the pharmaceutical composition is an oral dosage form. In some embodiments, the pharmaceutical composition is a solution (e.g., an aqueous solution). In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the pharmaceutical composition is a powder.

[0166] In some embodiments, the pharmaceutical composition comprises seroxipen; about 85 to 99% by weight of a diluent and about 0.5 to 2% by weight of a lubricant.

[0167] In some embodiments, the composition comprises: seroxipen; about 85 to 99% by weight of a diluent, for example, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including all ranges and values ​​therein; and about 0.5 to 2% by weight of a lubricant, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, including all ranges and values ​​therein.

[0168] In some embodiments, the composition comprises: seroceridine; about 85 to 99% by weight of pregelatinized starch (Starcap), for example, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including all ranges and values ​​therein; and about 0.5 to 2% by weight of sodium stearyl fumarate, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, including all ranges and values ​​therein.

[0169] In some embodiments, the composition comprises about 1% by weight of serocerin, about 98% by weight of a diluent, and about 1% by weight of a lubricant. In some embodiments, the composition comprises about 1% by weight of serocerin, about 98% by weight of pregelatinized starch (Starcap), and about 1% by weight of sodium stearyl fumarate.

[0170] In some embodiments, the composition comprises about 5% by weight serocepin, about 94% by weight diluent, and about 1% by weight lubricant. In some embodiments, the composition comprises about 5% by weight serocepin, about 94% by weight pregelatinized starch (Starcap), and about 1% by weight sodium stearate fumarate.

[0171] In some embodiments, the composition comprises about 10% by weight of serodecidine, about 89% by weight of a diluent, and about 1% by weight of a lubricant. In some embodiments, the composition comprises about 10% by weight of serodecidine, about 89% by weight of pregelatinized starch (Starcap), and about 1% by weight of sodium stearyl fumarate.

[0172] In some embodiments, the pharmaceutical composition is a capsule. In some embodiments, the capsule material comprises methylcellulose, gellan gum, carrageenan, pectin, glycerin, hydroxypropyl (HP) starch, plasticizer, buffer (e.g., phosphate buffer), amorphous starch (e.g., amylopectin), softener, or a combination thereof. In some embodiments, the capsule material comprises hydroxypropyl methylcellulose. In some embodiments, the capsule material comprises starch (e.g., hydroxypropyl starch or amylopectin). In some embodiments, the capsule material is VcapsPlus®, Vcaps®, Quali-V®, EMBROCaps®-VG, VegiCaps®, SeaGel™, or VegaGels®.

[0173] In some embodiments, the capsule material contains about 1% to about 7% water content, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, or about 7%, including all ranges and values ​​therein. In some embodiments, the capsule material contains less than about 6% water content. In some embodiments, the capsule material contains about 3% to about 7% water content. In some embodiments, the capsule material contains about 4% to about 6% water content.

[0174] In some embodiments, the content uniformity of the components disclosed herein conforms to European Pharmacopoeia 2.96 or USP. <905> . [Powder Blend:] [] []

[0175] In some embodiments, the compositions disclosed herein comprise a powder blend suitable for capsules (i.e., a mixture of serocerabin and one or more pharmaceutically acceptable excipients). In some embodiments, the compositions disclosed herein comprise a powder blend suitable for direct compression to provide tablets.

[0176] In some embodiments, the powder blends disclosed herein are characterized by their flow properties, such as the Carr index or Hausner ratio.

[0177] In some embodiments, the Karl Fischer index of the powder blend is from about 12 to about 25, for example, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24, including all ranges and values ​​therein. In some embodiments, the Karl Fischer index of the powder blend is less than about 11. In some embodiments, the Karl Fischer index of the powder blend is from about 12 to about 16. In some embodiments, the Karl Fischer index of the powder blend is from about 18 to about 21. In some embodiments, the Karl Fischer index of the powder blend is less than about 24. In some embodiments, the Karl Fischer index of the powder blend is about 16. In some embodiments, the Karl Fischer index of the powder blend is about 17. In some embodiments, the Karl Fischer index of the powder blend is about 20. In some embodiments, the Karl Fischer index of the powder blend is about 21.

[0178] In some embodiments, the hausner ratio of the powder blend is from about 1.0 to about 1.6, for example, about 1.00, about 1.05, about 1.10, about 1.15, about 1.20, about 1.25, about 1.30, about 1.35, about 1.40, about 1.45, about 1.50, about 1.55, or about 1.60, including all ranges and values ​​therein. In some embodiments, the hausner ratio of the powder blend is less than about 1.6. In some embodiments, the hausner ratio of the powder blend is less than about 1.2. In some embodiments, the hausner ratio of the powder blend is 1.29.

[0179] In some embodiments, the powder admixture disclosed herein is characterized by its bulk density. In some embodiments, the bulk density of the powder admixture is from about 0.40 g / mL to about 0.70 g / mL, for example, about 0.40 g / mL, about 0.41 g / mL, about 0.42 g / mL, about 0.43 g / mL, about 0.44 g / mL, about 0.45 g / mL, about 0.46 g / mL, about 0.47 g / mL, about 0.48 g / mL, about 0.49 g / mL, about 0.50 g / mL, about 0.51 g / mL, about 0.52 g / mL, about 0.53 g / mL, and about... The concentrations are 0.54 g / mL, about 0.55 g / mL, about 0.56 g / mL, about 0.57 g / mL, about 0.58 g / mL, about 0.59 g / mL, about 0.60 g / mL, about 0.61 g / mL, about 0.62 g / mL, about 0.63 g / mL, about 0.64 g / mL, about 0.65 g / mL, about 0.66 g / mL, about 0.67 g / mL, about 0.68 g / mL, about 0.69 g / mL, or about 0.70 g / mL, including all ranges and values ​​therein. In some embodiments, the bulk density of the powder blend is from about 0.44 g / mL to 0.52 g / mL. In some embodiments, the bulk density of the powder blend is from about 0.45 g / mL to 0.55 g / mL. In some embodiments, the bulk density of the powder blend is about 0.47 g / mL. In some embodiments, the bulk density of the composition is about 0.63 g / mL.

[0180] In some embodiments, the powder blend disclosed herein is characterized by the ratio of its natural starch to pre-compacted starch. In some embodiments, the ratio of natural starch to precompacted starch is from about 70:30 to about 99:1, for example, about 70:30, about 71:29, about 72:28, about 73:27, about 74:26, about 75:25, about 76:24, about 77:23, about 78:22, about 79:21, about 80:20, about 81:19, about 82:18, about 83:17, about 84:16, about 85:15, about 86:14, about 87:13, about 88:12, about 89:11, about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, or about 99:1, including all ranges and values ​​therein. In some embodiments, the ratio of natural starch to precompacted starch is from about 85:15 to about 95:5.

[0181] In some embodiments, the powder blend comprises: seroxipen; about 85 to 99% by weight of a diluent; and about 0.5 to 2% by weight of a lubricant.

[0182] In some embodiments, the powder blend comprises: seroxipen; about 85 to 99% by weight of a diluent, for example, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including all ranges and values ​​therein; and about 0.5 to 2% by weight of a lubricant, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, including all ranges and values ​​therein.

[0183] In some embodiments, the powder blend comprises: seroceridine; about 85 to 99% by weight of pregelatinized starch (Starcap), for example, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%, including all ranges and values ​​therein; and about 0.5 to 2% by weight of sodium stearyl fumarate, for example, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%, including all ranges and values ​​therein.

[0184] In some embodiments of this method, the powder blend comprises about 1% to 10% by weight of serodecidine, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, including all ranges and values ​​therein. In some embodiments, the powder blend comprises about 1% to 15% by weight of serodecidine, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, including all ranges and values ​​therein.

[0185] In some embodiments, the powder blend comprises about 1% by weight of serocepin, about 98% by weight of a diluent, and about 1% by weight of a lubricant. In some embodiments, the powder blend comprises about 1% by weight of serocepin, about 98% by weight of pregelatinized starch (Starcap), and about 1% by weight of sodium stearyl fumarate.

[0186] In some embodiments, the powder blend comprises about 5% by weight serocepin, about 94% by weight diluent, and about 1% by weight lubricant. In some embodiments, the powder blend comprises about 5% by weight serocepin, about 94% by weight pregelatinized starch (Starcap), and about 1% by weight sodium stearate fumarate.

[0187] In some embodiments, the composition comprises about 10% by weight of serodecidine, about 89% by weight of a diluent, and about 1% by weight of a lubricant. In some embodiments, the powder blend comprises about 10% by weight of serodecidine, about 89% by weight of pregelatinized starch (Starcap), and about 1% by weight of sodium stearyl fumarate. In some embodiments, the content uniformity of the powder admixtures disclosed herein conforms to European Pharmacopoeia 2.96 or USP. <905> . [] [Method for preparing the pharmaceutical composition disclosed herein]

[0188] In some embodiments, this disclosure provides a method for preparing a pharmaceutical composition, comprising: (a) directly mixing serocerabin with one or more pharmaceutically acceptable excipients to provide an admixture, and (b) filling a capsule with the admixture to provide the pharmaceutical composition, wherein the composition exhibits uniformity in content conforming to European Pharmacopoeia 2.96 or USP. <905> .

[0189] In some embodiments, the blend is prepared by mixing celecidine with one or more pharmaceutically acceptable excipients for approximately 15 to 60 minutes, for example, approximately 15 minutes, approximately 20 minutes, approximately 25 minutes, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, or approximately 60 minutes. In some embodiments, the blending system is carried out in one or more stages. In some embodiments, the blending system is carried out in two stages. In some embodiments, the blending system is carried out in three stages.

[0190] In some embodiments of this method, after the composition is stored at 40°C and 75% relative humidity for one month, the mass balance of psilocybin and related substances in the composition decreases by less than 3%. In some embodiments, after the composition is stored at 40°C and 75% relative humidity for two months, the mass balance of psilocybin and related substances in the composition decreases by less than 3%.

[0191] In some embodiments of this method, the blend comprises about 1% to 10% by weight of serodecidine, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, including all ranges and values ​​therein. In some embodiments, the blend comprises about 1% to 15% by weight of serodecidine, for example, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, including all ranges and values ​​therein. In some embodiments, the capsule contains 1 mg to 40 mg of cilostabene, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, or 40 mg, including all ranges and values ​​therein. In some embodiments, the capsule contains about 1 mg to 25 mg of cilostabene, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, or 25 mg, including all ranges and values ​​therein. In some embodiments, the capsule contains about 1 mg to 10 mg of cyclophosphamide, for example, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg, including all ranges and values ​​therein. In some embodiments, the capsule contains about 1 mg to 5 mg of cyclophosphamide, for example, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg, including all ranges and values ​​therein. In some embodiments, the capsule contains 1 mg, 5 mg, 10 mg, or 25 mg of cyclophosphamide. In some embodiments, the capsule contains 1 mg of cyclophosphamide. In some embodiments, the capsule contains 5 mg of cyclophosphamide. In some embodiments, the capsule contains 10 mg of cyclophosphamide. In some embodiments, the capsule contains 15 mg of cyclophosphamide. In some embodiments, the capsule contains 20 mg of cyclophosphamide. In some embodiments, the capsule contains 25 mg of cyclophosphamide.

[0192] In some embodiments of this method, the blend comprises one or more pharmaceutically acceptable excipients. In some embodiments, the one or more pharmaceutically acceptable excipients comprise a diluent. In some embodiments, the diluent is pregelatinized starch.

[0193] In some embodiments of this method, the blend further comprises a lubricant. In some embodiments, the lubricant is selected from the group consisting of: sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl styrosinate, glyceryl palmitate, magnesium lauryl stearate, stearic acid, talc, and hydrogenated castor oil. In some embodiments, the lubricant is sodium stearyl fumarate.

[0194] In some embodiments, the blend does not contain a lubricant.

[0195] In some embodiments, the method for preparing the pharmaceutical composition disclosed herein is... [picture] The method described in [9].

[0196] Unbound by any particular theory, it was surprisingly found that the revealed method for preparing pharmaceutical compositions by directly mixing serocillin with one or more pharmaceutically acceptable excipients still provides compositions with pharmaceutically acceptable content uniformity, even at low drug loading levels (according to European Pharmacopoeia 2.96 or USP). <905> (Measured). [] Methods for treating depression [] []

[0197] In some embodiments, the methods provided herein are used to treat a subject suffering from depression, comprising administering the components disclosed herein that are effective in treating the condition. In some embodiments, the methods provided herein are used to treat a subject suffering from a mood disorder, comprising administering the components disclosed herein that are effective in treating the condition. The components disclosed herein can be used to treat any condition or disorder that can be treated by administering seroxipen. The methods disclosed herein can be used to treat the conditions described in PCT Publications WO2020 / 212951, WO2020 / 212948 and WO2020 / 212952, which are hereby incorporated herein by reference in their entirety for all purposes.

[0198] In some embodiments, depression refers to major depressive disorder, atypical depression, bipolar disorder, catatonic depression, depression caused by a medical condition, postpartum depression, premenstrual dysphoric disorder, or seasonal affective disorder.

[0199] In some embodiments, depression includes a medical diagnosis based on the criteria and classifications in the Diagnostic and Statistical Manual of Medical Disorders, Fifth Edition (DSM-5). In some embodiments, depression includes a medical diagnosis based on independent medical evaluation.

[0200] In some embodiments, the methods described herein are provided to a subject suffering from treatment-resistant depression. In some embodiments, the subject is diagnosed with "treatment-resistant depression." The term "treatment-resistant depression" refers to depression that is unresponsive or resistant to at least one or more treatment attempts of sufficient dosage and duration. In some embodiments, the subject suffering from treatment-resistant depression is unresponsive to one, two, three, four, or five treatment attempts. In some embodiments, the subject suffering from treatment-resistant depression is diagnosed with major depressive disorder and is unresponsive to three or more treatment attempts. In some embodiments, the subject suffering from treatment-resistant depression is diagnosed with bipolar disorder and is unresponsive to one treatment attempt.

[0201] In some embodiments, the methods provided herein reduce at least one sign or symptom of depression. In some embodiments, the methods provided herein reduce at least one sign or symptom of depression by between about 5% and about 100% compared to before treatment, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, or more.

[0202] In some embodiments, after administration of serocepin, no other treatments were administered to the subject to reduce signs or symptoms of depression.

[0203] In some embodiments, the disclosed method further includes administering at least one additional therapeutic agent to the subject to reduce signs or symptoms of depression. In some embodiments, the at least one additional therapeutic agent is a selective serotonin reuptake inhibitor, a serotonin and norepinephrine reuptake inhibitor, a tricyclic antidepressant, a tetracyclic antidepressant, a dopamine reuptake inhibitor, a 5-HT1A receptor antagonist, a 5-HT2 receptor antagonist, a 5-HT3 receptor antagonist, a monoamine oxidase inhibitor, or a noradrenergic antagonist. In some embodiments, the at least one additional therapeutic agent is administered before, on the same day as, or after administration of selocillin.

[0204] In some embodiments, the subject with depression has additional comorbidities or conditions. In some embodiments, the additional comorbidities or conditions include anxiety disorder, obsessive-compulsive disorder, alcoholism, personality disorder, cardiovascular disease, neurological disease, or cancer. In some embodiments, the subject has dementia, Alzheimer's disease, or Parkinson's disease. In some embodiments, using the methods disclosed herein to reduce at least one sign or symptom of depression in the subject can prevent one or more of the subject's comorbidities or conditions. [] [Example] [] []

[0205] The following examples included in this document for illustrative purposes only are not intended to be limiting. [] [Example] [1] Composition and stability of cyclophosphamide tablets containing silicified microcrystalline starch.

[0206] After optimization of the formulation, a preparation with [surface] [8] The 1 mg and 5 mg tablets containing selociline were tested and a 6-month drug stability study was conducted.

[0207] Results: The storage conditions and results of the stability study are shown below. [surface] [9] and [surface]

[10] In this study, the tablets discolored and lost their API potency after storage. However, there was no significant corresponding increase in impurities associated with serocepin (e.g., xerocin) (i.e., a significant loss of mass balance). Therefore, even when the tablets were stored in the presence of a desiccant, the drug stability was deemed unsuitable for pharmaceutical products. [] []

[0208] Discussion: To determine the potential role of water in mass balance loss, a moisture-proof aqueous coating was applied to the tablets to reduce water penetration. However, the stability of the coated tablets was even lower. Another possibility is that an amorphous form may have formed during tablet compression. The amorphous form is less stable than its crystalline counterpart and degrades under certain conditions via different mechanisms, which could explain the lack of significant API degradation. This was also ruled out when low recoveries were found when the blends were manufactured by other methods, similarly without accompanying degradation. Furthermore, similar instability was observed in capsules prepared by filling empty capsules with tablet formulation blends (i.e., the excipient blends in Table 8). [] [Example] [2] [Composition and stability of cyclophosphamide capsules in the absence of silicon dioxide excipients] [] []

[0209] Experiments were conducted to explore whether the loss of mass balance observed during product storage was due to the interaction between silicated microcrystalline cellulose and / or colloidal silica (both added to enhance API flow) and serocepin (e.g., irreversible binding of serocepin to the excipient surface).

[0210] Unbound by any theory, it is assumed that xelocebin (via its phosphate group) can form strong interactions (e.g., H-bonds) with the siliconized surface, leading to a loss of efficacy, without a corresponding increase in xelocebin-related impurities.

[0211] Two capsule formulations using starch-based excipients, Starch 1500 and Starcap, were evaluated. Blends containing 1% (1 mg) and 10% (25 mg) serocepin were prepared using each excipient. [surface]

[11] The physical properties of each blend are shown. Starcap shows excellent filling and content uniformity, as shown below. []

[0212] Starcap formulations were selected for further development. [surface]

[12] Shows the composition of the capsule, and [picture] [9] shows the method for preparing the composition using a direct mixing method. The stability of these capsules was tested below.

[0213] [surface]

[13] Results of 1 mg capsules (with desiccant) stored at 25°C / 60% RH for one and two months are shown. The data show that the capsules were within specifications and met all measurement parameters at both time points.

[0214] [surface]

[14] Results of 1 mg capsules (with desiccant) stored at 40°C / 75% RH for one and two months are shown. The data show that the capsules were within specifications and met all measurement parameters at both time points. []

[0215] [surface]

[15] Results of 5 mg capsules (with desiccant) stored at 25°C / 60% RH for one and two months are shown. The data show that the capsules are within specifications and meet all measured parameters at both time points. []

[0216] [surface]

[16] Results of 5 mg capsules (with desiccant) stored at 40°C / 75% RH for one and two months are shown. The data show that the capsules are within specifications and meet all measured parameters at both time points. []

[0217] [surface]

[17] Results of 25 mg capsules (with desiccant) stored at 25°C / 60% RH for one and two months are shown. The data show that the capsules were within specifications and met all measured parameters at both time points.

[0218] [surface]

[18] Results of 25 mg capsules (with desiccant) stored at 40°C / 75% RH for one and two months are shown. The data show that the capsules were within specifications and met all measured parameters at both time points.

[0219] The HPLC data mentioned in this example were obtained using the relevant substance HPLC method described in this article. [] [Example] [3] [Composition and stability of psilocybin capsules formulated with silicon dioxide and other excipients] []

[0220] Under stability conditions similar to those used in Example 2 and with the recorded stability parameters for each xelosipine component, the following study will be conducted. [surface]

[19] The composition of xelosipine containing silicon dioxide excipient.

[0221] Under stability conditions similar to those used in Example 2 and with the recorded stability parameters for each xelosipine component, the following study will be conducted. [surface]

[20] The composition of serozepine, a sugar or polyol that forms hydrogen bonds. [] []

[0222] Under stability conditions similar to those used in Example 2 and with the recorded stability parameters for each xelosipine component, the following study will be conducted. [surface]

[21] is a composition of xelosipine, an excipient in the compound. [] [Example] [4] [Composition and stability of psilocybin capsules formulated with silicon dioxide excipients, pregelatinized starch, or a combination thereof]

[0223] As described in Examples 1 and 2, a loss of potency was observed in tablets and capsules prepared from the same blending composition. The blend contained silicated microcrystalline cellulose (SMCC) and colloidal silica (Aerosil).

[0224] In [Example] [2] studied the stability conditions under similar conditions to those used in the study, including those containing silicon dioxide excipients and [surface]

[22] The composition of psilocybin in pregelatinized starch. The stability results of each psilocybin composition were recorded.

[0225] [surface]

[22] The composition prepared contains 10% by weight of silicated microcrystalline cellulose (SMCC), 1% by weight of colloidal silicon dioxide (Aerosil) and 1% by weight of serosidine.

[0226] [surface] The composition described in

[23] was used as a control composition that did not contain silicon dioxide and contained 1% by weight of serocepin.

[0227] Will [surface] The composition described in

[24] is used to replicate the formulation previously used in 1% by weight serocepin tablets.

[0228] Will [surface]

[25] The composition is used to replicate the formulation previously used in 5% by weight serocepin tablets.

[0229] [Method:] Each of the above components was divided equally into 6 individual HDPE sample bottles. Three of these bottles contained a 1g desiccant packet. All bottles were sealed with caps and sealing film. The bottles were subjected to the following conditions: [surface] The conditions described in

[26] . [] Table 26. Storage conditions for stability Conditions for stability Desiccant T = 0* T = 2 weeks T = 1 month T = 3 months T = 6 months 25℃ / 60%RH have Y test / RS Y test / RS Y test / RS Y test / RS Y test / RS 40℃ / 75%RH have Y test / RS Y test / RS Y test / RS Y test / RS Y test / RS 60℃ have Y test / RS Y test / RS Y test / RS Y test / RS Y test / RS 25℃ / 60%RH none Y test / RS Y test / RS Y test / RS Y test / RS Y test / RS 40℃ / 75%RH none Y test / RS Y test / RS Y test / RS Y test / RS Y test / RS 60℃ none Y test / RS Y test / RS Y test / RS Y test / RS Y test / RS *Analysis of T = 2 weeks and T = 1 month combined

[0230] The water content of the components was analyzed using Karl Fischer (KF) assay, and... [surface] The conditions described in

[27] were analyzed by high performance liquid chromatography (HPLC). Analyses were performed at the start of the study (initial), 2 weeks, 1 month, 2 months, and 6 months.

[0231] [surface]

[28] and [picture]

[10] The results of Starcap control group products with and without desiccant storage for two weeks, one month, three months and six months at 25°C / 60% RH, 40°C / 75% RH and 60°C are shown. The water content of the composition at T=0 was determined to be 7.11% by Kelvin analysis.

[0232] [surface]

[29] and [picture]

[11] Results of 1 mg serocepin low-level SMCC composition with and without desiccant after storage at 25°C / 60% RH, 40°C / 75% RH, and 60°C for two weeks, one month, three months, and six months. The water content of the composition at T=0 was determined to be 6.77% by Karl Fischer analysis.

[0233] [surface]

[30] and [picture]

[12] Results of 1 mg serocepin tablets with and without desiccant after storage at 25°C / 60% RH, 40°C / 75% RH, and 60°C for two weeks, one month, three months, and six months. The water content of the composition at T=0 was determined to be 3.05% by Karl Fischer analysis.

[0234] [surface]

[31] and [picture]

[13] Results of 5% serocepin tablets with and without desiccant after storage at 25°C / 60%, 40°C / 75% RH, and 60°C for two weeks, one month, three months, and six months. The moisture content of the composition at T=0 was determined to be 2.72% by Kelfer analysis.

[0235] [surface]

[32] Shows the results of a stability study of a control sample of 1 mg serocepin capsules.

[0236] [Results:] The level of xelosin impurity remained constant throughout all studies.

[0237] Compared to the control group, the composition containing silicon dioxide excipients showed an increasing decreasing trend in the assay (see [reference]). [surface]

[33] ). In addition, [surface]

[33] The use of desiccants has a limited effect on the stability of the composition. * * * * * *

[0238] The embodiments illustrated and discussed in this specification are intended only to teach inventors, in accordance with the skill of the art, the best mode known for making and using the invention. As will be understood by those skilled in the art based on the foregoing teachings, modifications and variations of the above embodiments of the invention are possible without departing from the invention. Therefore, it should be understood that the invention may be practiced in ways other than those specifically described within the scope of the claims and their equivalents. [, , ] [] [Example] [] 1. A pharmaceutical composition comprising: Therapeutic effective doses of seroconvertin; and One or more pharmaceutically acceptable excipients, Among them, after the composition was stored at 40°C and 75% relative humidity for one month, the potency of selocillin in the composition decreased by less than 5%, and the mass balance of selocillin and related substances was greater than 97%. 2. The pharmaceutical composition of Example 1, wherein the composition comprises at least one pharmaceutically acceptable excipient that does not substantially interact chemically or physically with thelosidine phosphate. 3. A pharmaceutical composition as described in any of Examples 1 to 2, wherein the composition does not contain any pharmaceutically acceptable excipients that substantially interact chemically or physically with oxycepyl phosphate. 4. A pharmaceutical composition as described in any of Examples 1 to 3, wherein the composition does not contain inorganic silicates, silicon dioxide, or siliconized excipients. 5. A pharmaceutical composition as described in any of Examples 1 to 4, wherein the composition does not contain calcium aluminum silicate, calcium silicate, diatomaceous earth, magnesium silicate, perlite, potassium silicate, silica aerogel, silica, sodium aluminum silicate, sodium calcium aluminum silicate, sodium silicate, talc (basic magnesium silicate), or tricalcium silicate. 6. A pharmaceutical composition as described in any of Examples 1 to 5, wherein the composition does not contain silicated microcrystalline cellulose. 7. A pharmaceutical composition as described in any of Examples 1 to 6, wherein the composition does not contain polyols, mannitol, xylitol, sucrose, sorbitol, or fructose. 8. A pharmaceutical composition as described in any of Examples 1 to 7, wherein the composition does not contain calcium carbonate or calcium phosphate. 9. A pharmaceutical composition as described in any of Examples 1 to 8, wherein the composition does not contain a lubricating agent. 10. A pharmaceutical composition as described in any of Examples 1 to 9, wherein the one or more pharmaceutically acceptable excipients comprise a diluent. 11. A pharmaceutical composition as described in any of Examples 1 to 10, wherein the one or more pharmaceutically acceptable excipients comprise a lubricant. 12. A pharmaceutical composition as described in any of Examples 1 to 11, wherein the composition comprises the following: a) Approximately 85 to 99% by weight of the diluent; and b) Approximately 0.5 to 2.0% by weight of lubricant. 13. A pharmaceutical composition as described in any of Examples 1 to 12, wherein the composition comprises about 1% to 10% by weight of serocepin. 14. A pharmaceutical composition as described in any of Examples 10 to 13, wherein the diluent is pregelatinized starch. 15. A pharmaceutical composition as described in any of Examples 11 to 14, wherein the lubricant is selected from the group consisting of: sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl styrosinate, glyceryl palmitate, magnesium lauryl stearate, stearic acid, talc, and hydrogenated castor oil. 16. The pharmaceutical composition of Example 15, wherein the lubricant is sodium stearyl fumarate. 17. A pharmaceutical composition of any of Examples 1 to 16, wherein the chemical purity of cyclophosphine in the composition is not less than 97%, as determined by HPLC analysis. 18. A pharmaceutical composition as described in any of Examples 1 to 17, wherein the composition contains 1 mg to 40 mg of cyclophosphamide. 19. A pharmaceutical composition as described in any of Examples 1 to 17, wherein the composition contains 1 mg of cyclophosphamide. 20. A pharmaceutical composition as described in any of Examples 1 to 17, wherein the composition contains 5 mg of cyclophosphamide. 21. A pharmaceutical composition as described in any of Examples 1 to 17, wherein the composition contains 10 mg of cyclophosphamide. 22. A pharmaceutical composition as described in any of Examples 1 to 17, wherein the composition contains 25 mg of cyclophosphamide. 23. A pharmaceutical composition of any of Examples 1 to 22, wherein the selociline comprises crystalline selociline. 24. The pharmaceutical composition of Example 23, wherein the crystalline serocepin is a crystalline polymorph A. 25. The pharmaceutical composition of Example 23, wherein the crystalline selosine is a crystalline hydrate A. 26. The pharmaceutical composition of Example 23, wherein the crystalline serocepin is a crystalline polymorph A'. 27. The pharmaceutical composition of Example 23, wherein the crystalline serocepin is a crystalline polymorph B. 28. A pharmaceutical composition as described in any of Examples 1 to 22, wherein the serocepin is amorphous. 29. A pharmaceutical composition as described in any of Examples 1 to 28, wherein the composition is a capsule. 30. A pharmaceutical composition as described in any of Examples 1 to 28, wherein the composition is a tablet. 31. A pharmaceutical composition as described in any of Examples 1 to 22, wherein the composition is a solution. 32. A pharmaceutical composition as described in any of Examples 1 to 30, wherein the uniformity of the composition conforms to the European Pharmacopoeia 2.96 or USP. <905> . 33. A method for preparing a pharmaceutical composition, comprising: a) Directly mixing serocerabin with one or more pharmaceutically acceptable excipients to provide an admixture, and b) Filling capsules with the admixture to provide the pharmaceutical composition. The uniformity of the content of this component conforms to the European Pharmacopoeia 2.96 or USP. <905> . 34. The method of Example 33, wherein after the composition is stored at 40°C and 75% relative humidity for one month, the mass balance of serocepin and related substances in the composition decreases by less than 3%. 35. The method of any of Examples 33 to 34, wherein the blend comprises about 1% to about 10% by weight of seroconvertin. 36. The method of any of Examples 33 to 35, wherein the capsule contains 1 mg, 5 mg, 10 mg or 25 mg of serocepin. 37. The method of any of Examples 33 to 36, wherein the one or more pharmaceutically acceptable excipients comprises a diluent. 38. The method of any of Examples 33 to 37, wherein the blend further comprises a lubricant. 39. The method of any of Examples 33 to 38, wherein the blend does not contain a lubricant. 40. A pharmaceutical composition prepared by any one of the methods of Examples 33 to 39. 41. A method for treating mood disorders, comprising administering a therapeutically effective amount of any one of the components described in Examples 1 to 32 and 40.

Claims

1. A pharmaceutical composition comprising: a therapeutically effective amount of psilocybin; and 85 to 99% by weight of partially pregelatinized starch, wherein the potency of psilocybin in the pharmaceutical composition is reduced by less than 5%.

2. The pharmaceutical composition of claim 1 further includes a lubricant.

3. The pharmaceutical composition of claim 2, wherein the composition contains 0.5 to 2.0% by weight of a lubricant.

4. The pharmaceutical composition of claim 2 or 3, wherein the lubricant is sodium stearyl fumarate.

5. A pharmaceutical composition as claimed in claim 1 or 2, wherein the composition is a capsule.

6. A pharmaceutical composition as claimed in claim 1 or 2, wherein the composition contains 1% to 10% by weight of serocepin.

7. The pharmaceutical composition of claim 1 or 2, wherein the composition does not contain silicated microcrystalline cellulose.

8. A pharmaceutical composition as claimed in claim 1 or 2, wherein the composition contains 1 mg of cyclophosphamide.

9. A pharmaceutical composition as claimed in claim 1 or 2, wherein the composition contains 5 mg of cyclophosphamide.

10. A pharmaceutical composition as claimed in claim 1 or 2, wherein the composition contains 10 mg of cyclophosphamide.

11. A pharmaceutical composition as claimed in claim 1 or 2, wherein the composition contains 25 mg of cyclophosphamide.

12. A pharmaceutical composition as claimed in claim 1 or 2, wherein the composition contains 40 mg of cyclophosphamide.

13. A pharmaceutical composition comprising: 1% to 10% by weight of cyclophosphamide; 85% to 99% by weight of partially pregelatinized starch; and 0.5% to 2.0% by weight of sodium stearyl fumarate, wherein the potency of cyclophosphamide in the pharmaceutical composition is reduced by less than 5%.

14. The pharmaceutical composition of claim 13, wherein the composition does not contain silicated microcrystalline cellulose.

15. The pharmaceutical composition of claim 13, wherein the composition is a capsule.

16. A pharmaceutical composition as claimed in any of claims 13 to 15, wherein the composition contains 1 mg of cyclophosphamide.

17. A pharmaceutical composition as claimed in any of claims 13 to 15, wherein the composition contains 5 mg of cyclophosphamide.

18. A pharmaceutical composition as claimed in any of claims 13 to 15, wherein the composition contains 10 mg of cyclophosphamide.

19. A pharmaceutical composition as claimed in any of claims 13 to 15, wherein the composition contains 25 mg of cyclophosphamide.

20. A pharmaceutical composition as claimed in any of claims 13 to 15, wherein the composition contains 40 mg of cyclophosphamide.

Images