CN115557867B - Disulfiram inclusion compound eutectic, and preparation method and application thereof - Google Patents
Disulfiram inclusion compound eutectic, and preparation method and application thereof Download PDFInfo
- Publication number
- CN115557867B CN115557867B CN202211316988.3A CN202211316988A CN115557867B CN 115557867 B CN115557867 B CN 115557867B CN 202211316988 A CN202211316988 A CN 202211316988A CN 115557867 B CN115557867 B CN 115557867B
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- CN
- China
- Prior art keywords
- disulfiram
- cyclodextrin
- crystal
- eutectic
- inclusion
- Prior art date
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- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
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- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
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- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C333/14—Dithiocarbamic acids; Derivatives thereof
- C07C333/30—Dithiocarbamic acids; Derivatives thereof having sulfur atoms of dithiocarbamic groups bound to other sulfur atoms
- C07C333/32—Thiuramsulfides; Thiurampolysulfides
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Health & Medical Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
The invention provides a disulfiram inclusion compound eutectic, which comprises a eutectic ligand and a medicine active ingredient which is included by the eutectic ligand; the active component of the medicine is disulfiram, and the eutectic ligand is cyclodextrin. The inclusion compound eutectic formed by disulfiram and cyclodextrin has better water solubility, better thermal stability and more definite crystal structure. In addition, the preparation method of the inclusion compound eutectic formed by disulfiram and cyclodextrin can be realized by combining proper heating temperature with the preparation method of nanoparticles by a fusion solvent injection method and anti-solvent crystallization, and is simple and feasible, and convenient to popularize and apply.
Description
Technical Field
The invention relates to the field of fine chemical engineering and application, in particular to a disulfiram inclusion compound eutectic, a preparation method and application thereof.
Background
Disulfiram, also known as alcohol-stopping and disulfide-stopping, is a generic name for alcohol-stopping drugs, is a drug for treating chronic alcoholism and alcoholism psychosis, and has been used in many countries as an alcohol-stopping drug, and has the molecular formula of C 10 H 20 N 2 S 4 The molecular weight was 296.5. The medicine has the functions of preventing the liver from decomposing or metabolizing alcohol after drinking alcohol, and can be orally taken once a day, and even if a small amount of alcohol is drunk after the medicine is taken, serious discomfort can be generated by the body, so that the purpose of stopping alcohol is achieved. Disulfiram can be associated with an enzyme called acetaldehyde dehydrogenase, which plays an important role in decomposing alcohol. Without this enzyme, alcohol cannot be metabolized or cleared as usual, resulting in discomfort or vomiting. The disulfiram medicine has the defect of poor water solubility and can be used for treating the eyeThe former is mainly to prepare inclusion compound to increase the solubility in water. However, disulfiram inclusion compounds have some drawbacks in themselves, such as the need to often add several times the amount of inclusion agent during the preparation process, but not to completely isolate the excess inclusion agent.
Cyclodextrins (CD) are a class of cyclic oligosaccharides produced from starch by the action of a glycosyltransferase, which is typically produced by certain species of the genus Bacillus. The cyclodextrin has a three-dimensional chiral cavity with an inner hydrophobic and an outer hydrophilic. The inner side of the cavity of the cyclodextrin structure is composed of two circles of hydrogen atoms and one circle of oxygen atoms of the glycosidic bond, which are under the shielding of the C-H bond, so that the inner cavity of the cyclodextrin is hydrophobic, and the outer side of the cyclodextrin molecule is hydrophilic due to the aggregation of hydroxyl groups. The cyclodextrin is composed of glucose, so that the cyclodextrin has the characteristics of no toxicity, no harm, no side effect, capability of being absorbed by human bodies and the like, has the general property of starch, can be used as a filler and a binder of medicines, and is widely applied to the fields of medicines, foods, chemical engineering, materials, environmental protection, analytical chemistry and the like.
Disclosure of Invention
Based on the above, the invention provides a disulfiram inclusion compound eutectic which has better water solubility and better thermal stability, can improve bioavailability, and has a definite crystal structure.
The invention is realized by the following technical scheme.
A disulfiram inclusion co-crystal comprising a co-crystal ligand, and a pharmaceutically active ingredient that is included by the co-crystal ligand; the active pharmaceutical ingredient is disulfiram, and the eutectic ligand is cyclodextrin.
In one embodiment, the cyclodextrin is β -cyclodextrin or γ -cyclodextrin.
In one embodiment, the X-ray powder diffraction pattern of the disulfiram/beta cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
6.6 ° ± 0.2 °, 6.7 ° ± 0.2 °, 9.9 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.6 ° ± 0.5 °, 17.3 ° ± 0.2 °, 17.7 ° ± 0.2 °, 19.9 ° ± 0.2 °, 20.3 ° ± 0.2 ° and 23.8 ° ± 0.2 °;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
7.4 ° ± 0.2 °, 11.5 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.2 ° ± 0.2 °, 14.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 16.6 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.6 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.4 ° ± 0.2 °, 26.8 ° ± 0.2 ° and 34.9 ° ± 0.2 °.
In one embodiment, the X-ray powder diffraction pattern of the disulfiram/beta cyclodextrin inclusion complex co-crystal is substantially as shown in figure 5;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion complex co-crystal is substantially as shown in figure 5.
In one embodiment, the disulfiram/beta cyclodextrin inclusion eutectic has a melting point of 251 ℃ ± 5 ℃;
the melting point of the disulfiram/gamma cyclodextrin inclusion compound eutectic is 209+/-5 ℃.
In one embodiment, the mass percentage of disulfiram in the disulfiram inclusion eutectic is 7.0-9.0% in the disulfiram/beta cyclodextrin inclusion eutectic;
the mass percentage of disulfiram in the disulfiram/gamma cyclodextrin inclusion compound eutectic is 9.2-11.2%.
The invention also provides a preparation method of the disulfiram inclusion compound eutectic, which comprises the following steps:
mixing disulfiram with a first solvent to prepare a disulfiram solution;
mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;
heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the disulfiram solution to prepare a mixed solution;
cooling the mixed solution, standing and collecting precipitated solid;
wherein the first solvent is a water-miscible organic solvent.
In one embodiment, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.
In one embodiment, the volume ratio of the first solvent to water in the mixed solution is 3 (7-60).
In one embodiment, the molar ratio of disulfiram to cyclodextrin in the mixed solution is 1 (1-20).
In one embodiment, the process of adding the disulfiram solution satisfies one or more of the following conditions:
(1) Controlling the adding time to be 0.5-30 min according to 1-5 mL of the disulfiram solution;
(2) The aqueous cyclodextrin solution is stirred at a speed of 100rpm to 1000rpm.
The invention also provides application of the disulfiram inclusion compound eutectic in preparing chemical preparations, medicaments or foods.
Compared with the prior art, the disulfiram inclusion eutectic has the following beneficial effects:
the invention obtains the inclusion compound eutectic formed by disulfiram and cyclodextrin through research and preparation. Compared with the traditional inclusion compound, the inclusion compound eutectic formed by the disulfiram and the cyclodextrin has better water solubility, and the oral bioavailability of the disulfiram is also improved; meanwhile, compared with disulfiram, the melting point of the inclusion compound eutectic is obviously increased, which indicates that the thermal stability of the disulfiram/cyclodextrin inclusion compound eutectic is improved. In addition, inclusion eutectic also has a more definite crystal structure. Unlike the conventional eutectic preparation process in which crystal is formed through hydrogen bond, electrostatic effect, etc. between active medicine component and eutectic ligand, the clathrate eutectic of the present invention has cyclodextrin and disulfiram to form clathrate, and the cyclodextrin and disulfiram are assembled into clathrate eutectic to raise the water solubility of disulfiram.
Furthermore, the preparation method of the inclusion compound eutectic formed by disulfiram and cyclodextrin can be realized by combining proper heating temperature with the preparation of nanoparticles by a fusion solvent injection method and the crystallization by an anti-solvent method, and is simple and feasible, and convenient to popularize and apply.
Drawings
FIG. 1 is a schematic diagram of a preparation process of a disulfiram inclusion eutectic provided by the invention;
FIG. 2 is an optical micrograph (scale: 50 μm) of a disulfiram/beta cyclodextrin inclusion eutectic and a disulfiram/gamma cyclodextrin inclusion eutectic provided by the present invention;
FIG. 3 is an H-NMR spectrum of disulfiram, beta-cyclodextrin, gamma-cyclodextrin, disulfiram/beta-cyclodextrin inclusion co-crystal, and disulfiram/gamma-cyclodextrin inclusion co-crystal provided by the invention;
FIG. 4 is an infrared spectrum of disulfiram, beta-cyclodextrin, gamma-cyclodextrin, disulfiram/beta-cyclodextrin inclusion eutectic and disulfiram/gamma-cyclodextrin inclusion eutectic provided by the invention;
FIG. 5 is an XPRD spectrum (abscissa is angle 2 θ (°), ordinate is intensity) of a disulfiram, beta-cyclodextrin, gamma-cyclodextrin, disulfiram/beta-cyclodextrin inclusion eutectic, and disulfiram/gamma-cyclodextrin inclusion eutectic provided by the present invention;
FIG. 6 is a DSC plot (temperature (DEG C) on the abscissa and heat flow rate (W/g) on the ordinate) of disulfiram, beta-cyclodextrin, gamma-cyclodextrin, disulfiram/beta-cyclodextrin inclusion eutectic and disulfiram/gamma-cyclodextrin inclusion eutectic provided by the invention.
Detailed Description
In order that the invention may be readily understood, a more complete description of the invention will be rendered by reference to the appended drawings. The drawings illustrate preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include at least one such feature. In the description of the invention, the meaning of "plurality" means at least two, for example, two, three, etc., unless specifically defined otherwise. In the description of the present invention, the meaning of "several" means at least one, such as one, two, etc., unless specifically defined otherwise.
The words "preferably," "more preferably," and the like in the present invention refer to embodiments of the invention that may provide certain benefits in some instances. However, other embodiments may be preferred under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values for the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
All percentages, fractions and ratios are calculated on the total mass of the composition of the invention, unless otherwise indicated. All of the mass of the ingredients listed, unless otherwise indicated, are given to the active substance content and therefore they do not include solvents or by-products that may be included in commercially available materials. The term "mass percent" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless indicated otherwise. All formulations and tests herein take place in an environment of 25 ℃, unless otherwise indicated. The terms "comprising," "including," "containing," "having," or other variations thereof herein are intended to cover a non-closed inclusion, without distinguishing between them. The term "comprising" means that other steps and ingredients may be added that do not affect the end result. The compositions and methods/processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as additional or optional ingredients, components, steps, or limitations of any of the embodiments described herein. The terms "efficacy," "performance," "effect," "efficacy" are not differentiated herein.
By "pharmaceutically acceptable" is meant those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for administration to patients and commensurate with a reasonable benefit/risk ratio.
"pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
As used herein, "drug" includes any agent, compound, composition, or mixture that provides a physiological and/or pharmacological effect in vivo or in vitro, and often provides a beneficial effect. The range of physiological and/or pharmacological actions of the "drug" in vivo is not particularly limited, and may be systemic or local. The activity of the "drug" is not particularly limited, and may be an active substance capable of interacting with other substances or an inert substance which does not interact with other substances.
The dosage form and the mode of administration of the compound of the present invention or the pharmaceutical composition thereof are not particularly limited.
Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilisers, for example starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Such as suspensions, may contain suspending agents as, for example, particularly ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. Is prepared by mixing the active ingredient under aseptic condition with pharmaceutically acceptable carrier and any preservative, buffer or propellant as required.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The invention provides a disulfiram inclusion compound eutectic, which comprises a eutectic ligand and a medicine active ingredient which is included by the eutectic ligand; the active component of the medicine is disulfiram, and the eutectic ligand is cyclodextrin.
In a specific example, the cyclodextrin is β -cyclodextrin or γ -cyclodextrin.
In a specific example, the X-ray powder diffraction pattern of the disulfiram/beta cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
6.6°±0.2°, 6.7°±0.2°, 9.9°±0.2°, 11.2°±0.2°, 11.6°±0.5°, 17.3°±0.2°, 17.7°±0.2°, 19.9°±0.2°, 20.3°±0.2° and 23.8°±0.2°
In a specific example, the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
7.4 ° ± 0.2 °, 11.5 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.2 ° ± 0.2 °, 14.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 16.6 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.6 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.4 ° ± 0.2 °, 26.8 ° ± 0.2 ° and 34.9 ° ± 0.2 °.
In one specific example, the X-ray powder diffraction pattern of the disulfiram/beta cyclodextrin inclusion co-crystal is substantially as shown in figure 5.
In one specific example, the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion co-crystal is substantially as shown in figure 5.
In one specific example, the differential scanning calorimetry curve of the disulfiram/beta cyclodextrin inclusion eutectic is substantially as shown in figure 6.
In one specific example, the differential scanning calorimetry curve of the disulfiram/gamma cyclodextrin inclusion eutectic is substantially as shown in figure 6.
In a specific example, the disulfiram/beta cyclodextrin inclusion co-crystal has a melting point of 251 ℃ ± 5 ℃.
It is understood that in the present invention, the melting point of the disulfiram/beta cyclodextrin inclusion eutectic includes, but is not limited to, 246 ℃, 247 ℃, 248 ℃, 249 ℃, 250 ℃, 251 ℃, 252 ℃, 253 ℃, 254 ℃, 255 ℃, or 256 ℃.
In a specific example, the disulfiram/gamma cyclodextrin inclusion co-crystal has a melting point of 209 ℃ ± 5 ℃.
It is understood that in the present invention, the melting point of the disulfiram/gamma cyclodextrin inclusion eutectic includes, but is not limited to 204 ℃, 205 ℃, 206 ℃, 207 ℃,208 ℃, 209 ℃, 210 ℃, 211 ℃, 212 ℃, 213 ℃, or 214 ℃.
In a specific example, the mass percent of disulfiram in the disulfiram/beta cyclodextrin inclusion eutectic is 7.0% -9.0%.
It is understood that in the present invention, the mass percent of disulfiram in the disulfiram/beta cyclodextrin inclusion co-crystal includes, but is not limited to, 7%, 7.2%, 7.4%, 7.6%, 7.8%, 8.0%, 8.2%, 8.4%, 8.6%, 8.8%, 9.0%.
In a specific example, the mass percent of disulfiram in the disulfiram/gamma cyclodextrin inclusion eutectic is 9.2% -11.2%.
It is understood that in the present invention, the mass percent of disulfiram in the disulfiram/gamma cyclodextrin inclusion co-crystal includes, but is not limited to, 9.2%, 9.4%, 9.6%, 9.8%, 10.0%, 10.2%, 10.4%, 10.6%, 10.8%, 11.0%, 11.2%.
In a specific example, the crystals of the disulfiram inclusion eutectic are in the form of a block.
In a specific example, the disulfiram inclusion eutectic size is 10 μm to 20 μm.
The invention also provides a preparation method of the disulfiram inclusion compound eutectic, which comprises the following steps of:
mixing disulfiram with a first solvent to prepare a disulfiram solution;
mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;
heating cyclodextrin water solution to 30-60 ℃, and then adding disulfiram solution to prepare mixed solution;
cooling the mixed solution, standing, and collecting precipitated solid;
wherein the first solvent is a water-miscible organic solvent.
The first solvent serves as a solvent for disulfiram and can serve as a diluent and a delivery medium for the drug. After the disulfiram solution is injected into the aqueous solution of cyclodextrin, the solvent can be quickly combined with water molecules, so that the dispersion of the disulfiram in the water and the formation of inclusion compound eutectic are promoted; on the other hand, the organic solvent can be used as a poor solvent of cyclodextrin to promote the precipitation of inclusion compound eutectic from the solution.
In a specific example, the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol, and ethylene glycol.
In a specific example, the volume ratio of the first solvent to water in the mixed solution is 3 (7 to 60).
It is understood that in the present invention, the volume ratio of the first solvent to water in the mixed liquor includes, but is not limited to, 3:7, 3:8, 3:9, 3:10, 3:11, 3:12, 3:13, 3:14, 3:15, 3:20, 3:25, 3:30, 3:35, 3:40, 3:45, 3:50, 3:55, 3:60.
More specifically, a fixed volume of disulfiram solution is injected into an aqueous cyclodextrin solution, and the ratio of organic solvent to water is controlled within a certain range, such as methanol: water=1:20-3:7; ethanol: water=1:20-3:7; acetonitrile: water=1:20-3:7; acetone: water=1:20-3:7; isopropanol: water=1:20-3:7; ethylene glycol water=1:20-3:7, and when the disulfiram solvent is insufficient, the blank solvent can be used to complement the ratio of solvent to water.
In a specific example, the molar ratio of disulfiram to cyclodextrin in the mixed solution is 1 (1-20).
It is understood that in the present invention, the molar ratio of disulfiram to cyclodextrin in the mixed liquor includes, but is not limited to, 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20.
In a specific example, the concentration of disulfiram in the disulfiram solution is from 1mg/mL to 15mg/mL.
It is understood that in the present invention, the concentration of disulfiram in the disulfiram solution includes, but is not limited to, 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, 12mg/mL, 15mg/mL.
In a specific example, the concentration of cyclodextrin in the aqueous cyclodextrin solution is 3mg/mL to 50mg/mL.
More specifically, the concentration of beta-cyclodextrin in the beta-cyclodextrin aqueous solution is 3 mg/mL-30 mg/mL. It will be appreciated that in the present invention, the concentration of beta-cyclodextrin in the aqueous beta-cyclodextrin solution includes, but is not limited to, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL, 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, 11mg/mL, 12mg/mL, 13mg/mL, 14mg/mL, 15mg/mL, 16mg/mL, 17mg/mL, 18mg/mL, 19mg/mL, 20mg/mL, 30mg/mL. Preferably, the concentration of beta-cyclodextrin is 10mg/mL.
It will be appreciated that in the present invention, the concentration of gamma-cyclodextrin in the aqueous gamma-cyclodextrin solution includes, but is not limited to, 3mg/mL, 5mg/mL, 7mg/mL, 10mg/mL, 11mg/mL, 12mg/mL, 13mg/mL, 14mg/mL, 15mg/mL, 16mg/mL, 17mg/mL, 18mg/mL, 19mg/mL, 20mg/mL, 25mg/mL, 30mg/mL, 35mg/mL, 40mg/mL, 45mg/mL, 50mg/mL. Preferably, the concentration of gamma-cyclodextrin in the aqueous gamma-cyclodextrin solution is 20mg/mL.
In a specific example, in the process of adding the disulfiram solution, the adding time is controlled to be 0.5-30 min according to 1-5 mL of the disulfiram solution.
It will be appreciated that in the present invention, during the addition of the disulfiram solution, the time of the addition is controlled to include, but not limited to, 0.5min, 0.6min, 0.7min, 0.8min, 1min, 1.2min, 1.4min, 1.5min, 1.6min, 1.7min, 1.8min, 1.9min, 2min, 2.1min, 2.2min, 2.3min, 2.4min, 2.5min, 3min, 4min, 5min, 6min, 7min, 8min, 10min, 15min, 20min, 25min, 30min based on 1mL to 5mL of the disulfiram solution. Preferably, the addition time is controlled to be 3 minutes.
In a specific example, during the addition of the disulfiram solution, the aqueous cyclodextrin solution is agitated at a speed of 100rpm to 1000rpm.
It is understood that in the present invention, the rotational speed of stirring the aqueous cyclodextrin solution during the addition of the disulfiram solution includes, but is not limited to, 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, 800rpm, 900rpm, 1000rpm.
In a specific example, the mixture is cooled to 4-30 ℃.
In one specific example, the mixture is left to stand for 4 to 72 hours.
In a specific example, the method further comprises the following steps after collecting the precipitated solid:
filtering the precipitated solid, washing the solid for 1 to 3 times by using ice water or precooled crystallization solvent, and collecting white solid; and then the white solid is dried for 1 to 24 hours at the temperature of between 30 and 60 ℃.
The invention also provides application of the disulfiram inclusion compound eutectic in preparing chemical preparations, medicaments or foods.
The disulfiram inclusion eutectic and the preparation method thereof of the present invention are described in further detail below with reference to specific examples. The raw materials used in the following examples are all commercially available products unless otherwise specified.
Example 1
The embodiment provides a disulfiram inclusion compound eutectic, which is prepared by the following steps:
(1) Respectively preparing an aqueous solution of beta-cyclodextrin and a disulfiram solution. Wherein the solvent of disulfiram is acetonitrile with the concentration of 3mg/mL and the concentration of beta-cyclodextrin is 15mg/mL.
(2) Heating the cyclodextrin aqueous solution to 50 ℃; 1mL of the disulfiram solution was poured into 7mL of the cyclodextrin aqueous solution with stirring at 50rpm, the addition time was controlled to be 1 minute, 2mL of acetonitrile was additionally added, and stirring was continued for 0.5 minute.
(3) Stopping heating and stirring, and cooling the mixed solution of disulfiram and cyclodextrin to 30 ℃; standing for 8 hours until the crystals in the solution are completely separated out.
(4) Suction filtration to obtain white solid, washing 3 times with water at 4 ℃; and then drying the product at 40 ℃ for 48 hours to obtain the inclusion eutectic of disulfiram and cyclodextrin as white powder. The yield of the product was 80% in terms of disulfiram.
Example 2
The embodiment provides a disulfiram inclusion compound eutectic, which is prepared by the following steps:
(1) An aqueous solution of gamma-cyclodextrin and a disulfiram solution are prepared respectively. Wherein the solvent of disulfiram is acetone, the concentration of the solvent is 6mg/mL, and the concentration of gamma-cyclodextrin is 20mg/mL.
(2) Heating the cyclodextrin aqueous solution to 50 ℃; 1mL of the disulfiram solution was poured into 7mL of the cyclodextrin aqueous solution with stirring at 50rpm, the addition time was controlled to 2 minutes, 2mL of acetone was added, and stirring was continued for 0.5 minutes.
(3) Stopping heating and stirring, and cooling the mixed solution of disulfiram and cyclodextrin to 30 ℃; standing for 8 hours until the crystals in the solution are completely separated out.
(4) Suction filtration to obtain white solid, washing 3 times with water at 4 ℃; and then drying the product at 40 ℃ for 48 hours to obtain the inclusion eutectic of disulfiram and cyclodextrin as white powder. The yield of the product was 85% in terms of disulfiram.
Comparative example 1
This comparative example provides a preparation method for attempting to prepare beta-cyclodextrin crystals, specifically as follows:
(1) An aqueous solution of beta-cyclodextrin was prepared, wherein the concentration of beta-cyclodextrin was 15mg/mL.
(2) The cyclodextrin aqueous solution was heated to 50 ℃.
(3) Stopping heating, and cooling the cyclodextrin water solution to 30 ℃; after standing for 8 hours, no solid precipitated.
Comparative example 2
This comparative example provides a preparation method for attempting to prepare gamma-cyclodextrin crystals, specifically as follows:
(1) An aqueous solution of gamma-cyclodextrin was prepared, wherein the concentration of gamma-cyclodextrin was 20mg/mL.
(2) The cyclodextrin aqueous solution was heated to 50 ℃.
(3) Stopping heating, and cooling the cyclodextrin water solution to 30 ℃; after standing for 8 hours, no solid precipitated.
Characterization of the disulfiram inclusion eutectic prepared in example 1 above, including crystal morphology, H-NMR, infrared spectroscopy, X-ray powder diffraction (XRD) and Differential Scanning Calorimeter (DSC), is specifically as follows:
(1) Crystal morphology
The inclusion compound eutectic prepared in example 1 and example 2 was placed on a glass slide, and the morphology of each sample was observed and recorded under an optical microscope (10×20), and the results are shown in fig. 2: the eutectic crystal formed by the disulfiram and the cyclodextrin has definite crystal habit, and the eutectic crystal of the disulfiram/beta cyclodextrin and the eutectic crystal of the disulfiram/gamma cyclodextrin presents transparent bulk crystal which is about 10-20 mu m.
(2)H-NMR
D for eutectic inclusion compound prepared in the above examples 1-2 by using disulfiram, beta-cyclodextrin and gamma-cyclodextrin 6 Hydrogen spectra were determined after DMSO dissolution and the results are shown in figure 3. The H-NMR data of the disulfiram/beta cyclodextrin inclusion compound eutectic simultaneously contain signals of the disulfiram and the beta cyclodextrin, and the crystal is proved to be composed of two components; the H-NMR data of the disulfiram/gamma cyclodextrin inclusion compound eutectic simultaneously contain signals of disulfiram and gamma cyclodextrin, and the crystal is proved to be composed of two components.
(3) Infrared spectrum
The infrared spectra of the inclusion compound eutectic prepared in the above examples 1-2 are shown in figure 4. Wherein the characteristic peak of disulfiram is 910cm -1 、964cm -1 、1192cm -1 、1270cm -1 、1347cm -1 、1375cm -1 、1415cm -1 、1494cm -1 Etc.; cyclodextrin has characteristic peak of 400-2000cm -1 Between them; compared with the raw materials, most of characteristic peaks of related disulfiram in the infrared spectrum of the eutectic of the disulfiram/beta cyclodextrin and the inclusion compound of the disulfiram/gamma cyclodextrin disappear, and the infrared spectrum is consistent with the cyclodextrin as a whole, which indicates that the medicine and the cyclodextrin form the inclusion compound, so that the characteristic peaks of the disulfiram in the structure are covered by the cyclodextrin.
(4)XRD
XPRD patterns of the eutectic of the inclusion compound prepared in the above examples 1-2 are shown in FIG. 5. The characteristic peaks of disulfiram crystals are 9.8 °, 11.7 °, 13.9 °, 14.4 °, 17.4 °, 19.5 °, 21.3 °, 24.7 °, 25.7 °, 29.8 °, 33.1 °, 40.4 °, XRD diffraction peaks of disulfiram/beta cyclodextrin co-crystals are 6.6 °, 6.7 °, 9.9 °, 11.2 °, 11.6 °, 17.3 °, 17.7 °, 19.9 °, 20.3 °, 23.8 °, XRD diffraction peaks of disulfiram/gamma cyclodextrin co-crystals are 7.4 °, 11.5 °, 11.7 °, 12.0 °, 12.6 °, 14.2 °, 14.9 °, 15.8 °, 16.6 °, 19.2 °, 20.3 °, 20.4 °, 21.1 °, 21.8 °, 22.4 °, 23.6 °, 24.2 °, 25.4 °, 26.8 °, 34.9 °. The XPRD of the products prepared in examples 1-2 above has a characteristic diffraction peak which is quite different from the starting materials, indicating that not a simple physical mixture is formed but a new crystal form, and HNMR results show that the crystal contains both cyclodextrin and disulfiram formation, and thus can be identified as a disulfiram/beta cyclodextrin co-crystal and a disulfiram/gamma cyclodextrin co-crystal.
(5)DSC
The DSC spectra (heating rate in DSC measurement: 10K/min) of the co-crystals of the inclusion compound prepared in examples 1-2 above are shown in FIG. 6. The melting point of disulfiram is 67.2 ℃, after the disulfiram forms eutectic with cyclodextrin, the melting points of inclusion compound eutectic are 251.3 ℃ (disulfiram/beta cyclodextrin eutectic) and 208.9 ℃ (disulfiram/gamma cyclodextrin eutectic), and the result shows that the heat stability of the disulfiram is obviously improved after the disulfiram forms inclusion compound eutectic.
The solubility measurement experiment was performed on disulfiram and the inclusion compound eutectic prepared in the above examples 1-2, and the results are as follows:
the cyclodextrin inclusion compound eutectic obviously improves the solubility of the medicine in water. The disulfiram is almost insoluble in water, the solubility is about 4 mug/mL, and the solubility of the two inclusion compound eutectic crystals in water is 400 mug/mL (disulfiram/beta cyclodextrin eutectic) and 100 mug/mL (disulfiram/gamma cyclodextrin eutectic) respectively, which are increased by 40 times and 25 times, and the water solubility is obviously increased.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples merely represent a few embodiments of the present invention, which facilitate a specific and detailed understanding of the technical solutions of the present invention, but are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. It should be understood that, based on the technical solutions provided by the present invention, those skilled in the art may obtain technical solutions through logical analysis, reasoning or limited experiments, which are all within the scope of protection of the appended claims. The scope of the patent is therefore intended to be covered by the appended claims, and the description and drawings may be interpreted as illustrative of the contents of the claims.
Claims (8)
1. A disulfiram inclusion co-crystal comprising a co-crystal ligand, and a pharmaceutically active ingredient that is included by the co-crystal ligand; the active pharmaceutical ingredient is disulfiram, and the eutectic ligand is cyclodextrin; the cyclodextrin is beta-cyclodextrin or gamma-cyclodextrin;
the X-ray powder diffraction pattern of the disulfiram/beta cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
6.6 ° ± 0.2 °, 6.7 ° ± 0.2 °, 9.9 ° ± 0.2 °, 11.2 ° ± 0.2 °, 11.6 ° ± 0.5 °, 17.3 ° ± 0.2 °, 17.7 ° ± 0.2 °, 19.9 ° ± 0.2 °, 20.3 ° ± 0.2 ° and 23.8 ° ± 0.2 °;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion co-crystal has characteristic diffraction peaks at the following 2θ (°) angles:
7.4 ° ± 0.2 °, 11.5 ° ± 0.2 °, 11.7 ° ± 0.2 °, 12.0 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.2 ° ± 0.2 °, 14.9 ° ± 0.2 °, 15.8 ° ± 0.2 °, 16.6 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.3 ° ± 0.2 °, 20.4 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.8 ° ± 0.2 °, 22.4 ° ± 0.2 °, 23.6 ° ± 0.2 °, 24.2 ° ± 0.2 °, 25.4 ° ± 0.2 °, 26.8 ° ± 0.2 ° and 34.9 ° ± 0.2 °.
2. The disulfiram clathrate co-crystal of claim 1, wherein the X-ray powder diffraction pattern of the disulfiram/beta cyclodextrin clathrate co-crystal is substantially as shown in figure 5;
the X-ray powder diffraction pattern of the disulfiram/gamma cyclodextrin inclusion complex co-crystal is substantially as shown in figure 5.
3. Disulfiram clathrate co-crystal according to claim 1, wherein the disulfiram/beta cyclodextrin clathrate co-crystal has a melting point of 251 ℃ ± 5 ℃;
the melting point of the disulfiram/gamma cyclodextrin inclusion compound eutectic is 209+/-5 ℃.
4. The disulfiram clathrate co-crystal of claim 1, wherein the mass percent of disulfiram in the disulfiram/beta cyclodextrin clathrate co-crystal is 7.0-9.0%;
the mass percentage of disulfiram in the disulfiram/gamma cyclodextrin inclusion compound eutectic is 9.2-11.2%.
5. A method of preparing a disulfiram inclusion co-crystal according to any one of claims 1 to 4, comprising the steps of:
mixing disulfiram with a first solvent to prepare a disulfiram solution;
mixing cyclodextrin with water to prepare cyclodextrin aqueous solution;
heating the cyclodextrin aqueous solution to 30-60 ℃, and then adding the disulfiram solution to prepare a mixed solution;
cooling the mixed solution to 4-30 ℃, standing, and collecting precipitated solid;
wherein the first solvent is an organic solvent miscible with water; the first solvent is selected from one or more of methanol, ethanol, acetonitrile, acetone, tetrahydrofuran, isopropanol and ethylene glycol; in the mixed solution, the volume ratio of the first solvent to the water is 3 (7-60).
6. The method for producing a disulfiram clathrate eutectic according to claim 5, wherein the molar ratio of disulfiram to cyclodextrin in the mixed solution is 1 (1-20).
7. A method of preparing a disulfiram clathrate co-crystal according to claim 5 or 6, wherein the process of adding the disulfiram solution satisfies one or more of the following conditions:
(1) Controlling the adding time to be 0.5-30 min according to 1-5 mL of the disulfiram solution;
(2) The aqueous cyclodextrin solution is stirred at a speed of 100rpm to 1000rpm.
8. Use of a disulfiram clathrate co-crystal according to any one of claims 1-4 in the preparation of a chemical formulation, a pharmaceutical or a food product.
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