Solid dispersion containing dimethyl sulfone and application thereof

Abstract

The invention relates to a solid dispersion containing dimethyl sulfone and application thereof, the solid dispersion contains a dispersing agent dimethyl sulfone and at least one medicine, and preferably, the solid dispersion is substantially composed of the dispersing agent dimethyl sulfone and at least one medicine. The preparation method comprises the following three methods: the first method comprises the following steps: uniformly dispersing dimethyl sulfone in a molten clarified state and a medicine to obtain a dispersion system in a molten state; and cooling the dispersion system in the molten state to obtain the solid dispersion. A second method comprises the following steps: uniformly dispersing dimethyl sulfone in a molten clarified state, a third solvent mixture and a medicine to obtain a molten dispersion system; and cooling the dispersion system in the molten state, and removing the third solvent to obtain the solid dispersion, a third method comprises the following steps: extruding or grinding dimethyl sulfone and the medicine, stirring, melting, mixing and cooling. The solid dispersion can be used for preparing a pharmaceutical preparation.

Description

Technical Field

[0001] The invention relates to solid dispersion, and belongs to the technical field of medical preparations. Background Art

[0002] Literature reports show that among the drugs currently in the research and development stage, the proportion of poorly soluble drugs is as high as 90%. How to improve the solubility and bioavailability of poorly soluble drugs is one of the specific challenges faced by pharmaceutical workers. Solid dispersion technology is one of the many feasible methods. Currently, about 49 drugs using solid dispersion technology have been marketed ( Marta F et al. "Hot-melt extrusion in the pharmaceutical industry: towardfiling a new drug application." Drug discovery today vol.24,9(2019):1749-1768.doi:10.1016 / j.drudis.2019.05.013; Bhujbal, Sonal V et al. "Pharmaceuticalamorphous solid dispersion: A review of manufacturing strategies." Actapharmaceutica Sinica.B vol.11,8(2021):2505-2536.doi:10.1016 / j.apsb.2021.05.014).

[0003] Solid dispersions (SD) refer to solid dispersion systems formed by drugs, especially poorly soluble solid drugs, being highly dispersed in suitable carrier materials in the form of molecules, colloids, microcrystals or amorphous states. They are also called solid dispersions. The preparation technology used to make drugs into solid dispersions is called solid dispersion technology.

[0004] According to whether the drug is dispersed in the carrier material (dispersant) in a saturated state and the form of the drug after supersaturation: molecular, colloidal, microcrystalline or amorphous, the solid dispersion finally prepared can be divided into the following solid solutions, coprecipitates, and low eutectic mixtures (Chiou, WL, and S Riegelman. "Pharmaceutical applications of solid dispersion systems." Journal of pharmaceutical sciences vol. 60, 9 (1971): 1281-302. doi: 10.1002 / jps.2600600902):

[0005] Solid solution, the drug is dissolved in the solid carrier in molecular state to form a homogeneous system. The dispersion of the drug in the solid solution is often higher than that in the eutectic mixture, so its dissolution rate is particularly large. In this case, the concentration (content) of the drug in the carrier is equal to or less than the solubility of the carrier for the drug.

[0006] Coprecipitate, a non-crystalline amorphous substance formed by solid drug and carrier in an appropriate proportion. The commonly used carrier is a polyhydroxy compound. In this case, the concentration (content) of the drug in the carrier is greater than the solubility of the carrier for the drug.

[0007] Low eutectic mixture, the drug and the carrier are melted into a completely miscible liquid, stirred evenly, and quickly cooled and solidified to become a dispersion. The drug is dispersed in the carrier in the form of microcrystals to form a physical mixture. In this case, the concentration (content) of the drug in the carrier is greater than the solubility of the carrier in the drug.

[0008] The carrier materials used in the existing drugs marketed using solid dispersion technology are mostly high molecular weight polymers and surfactants, such as high molecular weight polymers: polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polymethacrylate, and polymers based on natural products mainly include hydroxypropyl methylcellulose (HPMC), ethyl cellulose, hydroxypropyl cellulose or starch derivatives such as dextrin, surfactants: poloxamer 407, Tween-80 and Gelucire44 / 14 (polyethylene glycol laurate), etc.

[0009] Most of these carriers are high molecular weight polymers. Although the prepared solid dispersions have a good solubilizing effect when used in oral preparations, the ultimate drug loading capacity is still limited due to the large difference between high molecular weight polymers and small molecules of orally effective drugs.

[0010] On the other hand, since the structures of target drugs vary greatly, in order to find suitable excipients as dispersants for solid dispersions, screening is often required. In other words, these high-molecular polymer excipients are not universal. In other words, if a substance can be found that can form a solid dispersion with most drugs, it will greatly solve the above problems.

[0011] More importantly, using the above-mentioned high molecular polymers as dispersants often fails to truly dissolve the drug into a molecular state (even in a molten state, the high molecular polymers cannot truly dissolve the drug molecules into a true solution), so the solubility and dissolution rate are still not high enough.

[0012] Therefore, it is necessary to select small molecule excipients to develop a new universal solid dispersion system, which has universal applicability and can form solid dispersions or even solid solutions with a variety of drugs, thereby better improving the solubility and dissolution rate of the drugs. Summary of the invention

[0013] Based on many years of research and development experience, the inventors of the present application creatively proposed the use of dimethyl sulfone (Methyl SulfonylMet hane, abbreviated as MSM) as a dispersant for a new solid dispersion. After experiments, a universal dimethyl sulfone solid dispersion system was preliminarily determined. The system can melt, clarify and dissolve / disperse drugs at a relatively low temperature (below 110°C) using a direct melting method or other methods to ultimately form a solid dispersion. Preliminary experiments have shown that the system can be applied to a variety of drugs with different polarities and can improve solubility and dissolution rate.

[0014] Since dimethyl sulfone has a melting point of 107-109°C and is a crystalline substance, it has good fluidity and low viscosity after melting into a liquid. Its solubility in drug molecules of different polarities at the melting temperature is greater than that of general organic solvents, water and high molecular polymers. Therefore, this system has the potential to be developed into a universal solid dispersion.

[0015] To this end, the applicant provides a technical solution of a solid dispersion containing dimethyl sulfone and its application.

[0016] The solid dispersion containing dimethyl sulfone contains dimethyl sulfone as a dispersant and at least one drug; preferably, it essentially consists of dimethyl sulfone as a dispersant and at least one drug.

[0017] A method for preparing a solid dispersion containing dimethyl sulfone, wherein the solid dispersion is substantially composed of a dispersant dimethyl sulfone and at least one drug.

[0018] Method 1:

[0019] The dimethyl sulfone in a molten clear state is evenly dispersed with the drug to obtain a dispersed system in a molten state;

[0020] Cooling the molten dispersion to obtain the solid dispersion;

[0021] Method 2:

[0022] uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a dispersed system in a molten state;

[0023] The solid dispersion is obtained by cooling the molten dispersion system and removing the third solvent;

[0024] Method 3:

[0025] The dimethyl sulfone and the drug are extruded or ground, stirred, melted and mixed, and then cooled to obtain the product. Preferably, a third solvent is added to the dimethyl sulfone and the drug for extrusion or grinding and stirring;

[0026] Method 4:

[0027] The molten mixture of dimethyl sulfone and high molecular polymer is prepared, and the drug is added and uniformly dispersed when the molten mixture is in a molten state.

[0028] A method for preparing a solid solution containing dimethyl sulfone, wherein the solid solution is substantially composed of a dispersant dimethyl sulfone and at least one drug.

[0029] Method 1:

[0030] The dimethyl sulfone in a molten clear state is uniformly dispersed and dissolved with the drug to obtain a molten clear solution;

[0031] Cooling the molten clarified solution to obtain the solid solution;

[0032] The amount of drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state.

[0033] Method 2:

[0034] uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a molten clear solution;

[0035] The molten solution is cooled and the third solvent is removed to obtain the solid solution;

[0036] The amount of drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state.

[0037] Method 3:

[0038] The dimethyl sulfone and the drug are hot-melt extruded, and the mixture is in a molten clear state during the hot-melt extrusion; or the dimethyl sulfone, the drug and a third solvent are hot-melt extruded, and the mixture is in a molten clear state during the hot-melt extrusion.

[0039] The amount of the drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state, or the amount of the drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state.

[0040] Method 4:

[0041] The method comprises preparing a molten clarified mixture of dimethyl sulfone and a high molecular polymer, and adding a drug to the molten clarified mixture when the molten mixture is in a molten clarified state to obtain the molten clarified mixture.

[0042] The amount of the drug added should be less than or equal to the saturated drug solubility of the dimethyl sulfone and high molecular polymer mixed system in a molten clear state, or the amount of the drug added should be less than or equal to the saturated drug solubility of dimethyl sulfone in a molten clear state.

[0043] The solid dispersion contains dimethyl sulfone and at least one drug, wherein the drug is a raw material drug API.

[0044] API refers to the raw material drugs used in the production of various preparations. It is the active ingredient in the preparations. It is a variety of powders, crystals, extracts, etc. used as medicines prepared by chemical synthesis, plant extraction or biotechnology, but is a substance that patients cannot take directly.

[0045] In this application, APIs refer to registered APIs that have been approved for marketing by various countries and regions (marketed APIs) and APIs that are in the research stage and are expected to be approved for marketing (candidate APIs).

[0046] In the present application, drugs in marketed APIs and candidate APIs include human drugs (medicines) and drugs for other animals (veterinary drugs), plant protection drugs, animal control drugs (pesticides), etc. In short, the drug preparations here are broad, including traditional medicines, veterinary drugs and pesticides. Correspondingly, the same applies to marketed APIs and candidate APIs.

[0047] Marketed APIs for human use (APIs used in pharmaceutical production) can be obtained from the official websites of pharmaceutical regulatory authorities in various countries and regions, such as the US FDA, China NMPA, Europe EMA, Japan PMDA, etc.

[0048] Veterinary drugs or animal health products that have been marketed (raw materials used in the production of veterinary drugs) can be found on the official websites of veterinary drug or animal health product departments in various countries and regions, such as CVM under the U.S. FDA, the Animal Husbandry and Veterinary Bureau under the Ministry of Agriculture and Rural Affairs of China, the European EMA, and the Animal Drug Inspection Institute of the Ministry of Agriculture, Forestry and Fisheries of Japan.

[0049] Pesticides that have been marketed (raw materials used in the production of veterinary drugs) can be found on the official websites of veterinary drug or animal health product departments in various countries and regions, such as the US EPA, the Pesticide Control Institute of the Ministry of Agriculture and Rural Affairs of China, the European Food Safety Authority EFSA, the Ministry of Agriculture, Forestry and Fisheries of Japan (MAFF) Agricultural, Forestry and Fisheries Consumer Safety Technology Center (FAMIC) Pesticide Inspection Service (ACIS), etc.

[0050] In certain embodiments, the solid dispersion "consists of certain substances" refers to substances that are intentionally and artificially added during preparation (these substances must be contained and can be detected by analytical testing instruments). Apart from these substances, it no longer contains other intentionally and artificially added substances, but trace amounts of impurities, environmental substances, etc. will inevitably exist.

[0051] Other substances (environmental substances) detected during the preparation process due to contact or contamination of containers, pipes, and tools are not subject to this restriction. Similarly, dimethyl sulfone and drug APIs are inevitably mixed with impurities or substances (impurities) in other environments, and these impurities or environmental substances are also not subject to this restriction.

[0052] All other substances (environmental substances), dimethyl sulfone and drug raw materials detected due to contact or contamination of containers, pipes, tools are inevitably mixed with impurities or other substances (impurities) in the environment. The content range should be within the legal limit or meet the corresponding product (pharmaceutical grade, medical grade or equivalent quality standard) quality standards.

[0053] In certain embodiments, in order to increase the solubility of molten dimethyl sulfone in the drug substance or form a uniform dispersion system (emulsion or suspension), a small amount of high molecular polymer type surfactant may be added, such as polysorbate (Tween, Tween type, including various brands) and polyethylene glycol (PEG, including various brands), sorbitan fatty acid ester (Span, Spans, including various brands), polyoxyethylene polyoxypropylene ether block copolymer (Poloxamer, poloxamer, including various brands), polyvinyl pyrrolidone (polyvinyl pyrrolidone, PVP, including various brands), etc.

[0054] In some cases, for some drugs, the mass ratio of the added surfactant acting as a cosolvent to dimethyl sulfone may reach 1:9, or even higher, up to 1:1.

[0055] In certain embodiments, a third solvent may be added to lower the melting temperature of dimethyl sulfone so that a drug substance with poor thermal stability can be melted after being added.

[0056] Whether a surfactant or a third solvent is added, the solid dispersion will contain other substances in addition to drugs and dimethyl sulfone.

[0057] The solid dispersion can be prepared by at least one of the following four methods:

[0058] Method 1:

[0059] The dimethyl sulfone in a molten clear state is evenly dispersed with the drug to obtain a dispersed system in a molten state;

[0060] Cooling the molten dispersion to obtain the solid dispersion;

[0061] Method 2:

[0062] uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a dispersed system in a molten state;

[0063] The solid dispersion is obtained by cooling the molten dispersion system and removing the third solvent;

[0064] Method 3:

[0065] The dimethyl sulfone and the drug are extruded or ground, stirred, melted and mixed, and then cooled to obtain the product. Preferably, a third solvent is added to the dimethyl sulfone and the drug for extrusion or grinding and stirring;

[0066] Method 4:

[0067] The molten mixture of dimethyl sulfone and high molecular polymer is prepared, and the drug is added and uniformly dispersed when the molten mixture is in a molten state.

[0068] Depending on whether the amount of drug raw materials added during preparation reaches saturation, the prepared solid dispersion can be further divided into solid solutions and co-precipitates and low eutectic mixtures of non-solid solutions. When the amount of drug raw materials added is less than or equal to the saturated amount, the prepared solid dispersion is a solid solution; and when the amount of drug raw materials added is greater than the saturated amount, the prepared solid dispersion is a non-solid solution: a co-precipitate and a low eutectic mixture.

[0069] Obviously, correspondingly, the solid solution can be prepared by at least one of the following four methods:

[0070] Method 1:

[0071] The dimethyl sulfone in a molten clear state is uniformly dispersed and dissolved with the drug to obtain a molten clear solution;

[0072] Cooling the molten clarified solution to obtain the solid solution;

[0073] The amount of drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state.

[0074] Method 2:

[0075] uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a molten clear solution;

[0076] The molten solution is cooled and the third solvent is removed to obtain the solid solution;

[0077] The amount of drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state.

[0078] Method 3:

[0079] The dimethyl sulfone and the drug are hot-melt extruded, and the mixture is in a molten clear state during the hot-melt extrusion; preferably, a third solvent is added to the dimethyl sulfone and the drug for hot-melt extrusion, and the mixture is in a molten clear state during the hot-melt extrusion.

[0080] The amount of the drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state, or the amount of the drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state.

[0081] Method 4:

[0082] The method comprises preparing a molten clarified mixture of dimethyl sulfone and a high molecular polymer, and adding a drug to the molten clarified mixture when the molten mixture is in a molten clarified state to obtain the molten clarified mixture.

[0083] The amount of the drug added should be less than or equal to the saturated drug solubility of the dimethyl sulfone and high molecular polymer mixed system in a molten clear state, or the amount of the drug added should be less than or equal to the saturated drug solubility of dimethyl sulfone in a molten clear state.

[0084] Since dimethyl sulfone is a small molecule organic substance and is crystalline (white needle-shaped crystals), its melting point is 107-111° C. The melting point is relatively low, so the solid dispersion can be prepared by the melting method and the grinding and extrusion method.

[0085] When preparing by the melting method, dimethyl sulfone needs to be heated, and after it is melted and clarified, the drug API is added and stirred to dissolve or disperse. In some cases, in order to reduce the heating temperature during melting, a third solvent can be appropriately added to dimethyl sulfone to obtain a semi-solid mixture, and then the drug API is added and stirred after heating and melting.

[0086] In some cases, a solid dispersion of dimethyl sulfone can also be prepared by extrusion or grinding and stirring. For example, the drug and dimethyl sulfone are ground and extruded in a mortar, or the drug and dimethyl sulfone are directly put into a hot-melt extrusion (Hot-Melt Extrusion technique, HME) device for preparation. Similar to the melting method, a third solvent or a surfactant can also be added during the extrusion or grinding and stirring process.

[0087] Preferably, in method 1, dimethyl sulfone is heated at a temperature T1, the melting point of dimethyl sulfone, until it is melted and clear, and then the drug is added, and the drug can withstand the high temperature T1 without deterioration;

[0088] In the second method, the mixture of dimethyl sulfone and the third solvent is heated at a temperature T2 which is higher than or equal to the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone until it is melted and clarified, and then the drug is added, and the drug can withstand the high temperature T2 without deterioration;

[0089] In method three, dimethyl sulfone and the drug are extruded or ground under heating conditions, stirred, melted and mixed, and then cooled to obtain the product.

[0090] Obviously, when heated to the melting point T1 of dimethyl sulfone, if the added drug raw material quickly deteriorates and breaks down at this temperature, then this drug raw material is not suitable for preparation using this method. Therefore, the drug raw material added after heating to T1 temperature, i.e. the melting point of dimethyl sulfone, should be able to withstand the high temperature of T1 without deterioration. To be precise, drugs that can be stable for a period of time at T1 temperature should be screened through experiments. The period of time should not be less than the time it takes for the drug to be added to the molten dimethyl sulfone and stirred to dissolve until it is clarified.

[0091] In some embodiments, a third solvent is added to reduce the heating temperature T2 for dimethyl sulfone to melt and clarify. Since the addition of the third solvent will partially dissolve the dimethyl sulfone in the solid state, the final melting temperature of dimethyl sulfone will be lower than its melting point T1. Similarly, in this case, to be precise, the drug that can be stable for a period of time at the temperature T2 should be screened through experiments, and the period of time should not be less than the time it takes for the drug to be added to the molten dimethyl sulfone-third solvent and stirred to dissolve until it is clarified.

[0092] When a third solvent is added, preferably the boiling point of the third solvent should be lower than the melting point T1 of dimethyl sulfone, and the heating temperature T2 should be between the temperature of the third solvent and the melting point T1 of dimethyl sulfone. In this case, the third solvent will be in a reflux state.

[0093] In order to make the dimethyl sulfone melt faster during the extrusion, grinding or stirring process, heating can also be used.

[0094] More preferably, in method three, a third solvent is added during extrusion, grinding or stirring, and the third solvent is selected from solvents that can dissolve dimethyl sulfone.

[0095] More preferably, the mixture is heated and squeezed or ground and stirred at a temperature T2 which is higher than the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone.

[0096] In method 2 and method 3, the third solvent is selected from water, methanol, ethanol, acetone, N,N-dimethylacetamide, N,N-dimethylformamide, acetone, ethyl acetate, and tetrahydrofuran.

[0097] The solid dispersion finally prepared can be obtained into powder by pulverizing to facilitate subsequent preparation processing.

[0098] In certain embodiments, in order to obtain a solid dispersion with a high drug content, a surfactant may be added to the molten dimethyl sulfone to increase the solubility or improve the dispersion if the drug substance fails to completely dissolve and clarify, thereby increasing the final drug content; of course, adding an appropriate amount of a third solvent to form a composite solvent of a third solvent-dimethyl sulfone melt can also increase the solubility.

[0099] In certain embodiments, if a third solvent is added to prepare a solid dispersion, the solid dispersion can be subsequently crushed into powder and then vacuum-heated and dried to remove the third solvent. The drying temperature is preferably not more than 60°C, and the recommended temperature is 45-55°C.

[0100] When the solid dispersion is a solid solution, its melting point is 106.5-110.5°C. After X-ray powder diffraction test, Cu-Kα radiation, the characteristic peaks of the X-ray powder diffraction pattern expressed by the diffraction angle 2θ are 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1°.

[0101] Since dimethyl sulfone is a crystalline substance, when it is melted, the drug raw material is added to dissolve and form a clear molten liquid. Finally, after cooling, what is obtained is a solid solution, which is also a crystalline substance. The melting point and XRD diffraction pattern characteristics shown by experiments have special melting points and characteristic peaks.

[0102] The drug is selected from sildenafil and tadalafil.

[0103] The sildenafil-dimethyl sulfone solid dispersion is a solid solution, which is essentially composed of a dispersant dimethyl sulfone and a drug sildenafil, wherein the mass percentage of the drug is not greater than 14.2%, preferably 5.0%, 7.5% and 10.0%; and its melting point is 106.5-108.5°C for initial melting and 109.5-110.5°C for final melting.

[0104] The prepared dimethyl sulfone sildenafil solid solution was subjected to X-ray powder diffraction test, Cu-Kα radiation, and the characteristic peaks of the X-ray powder diffraction pattern represented by the diffraction angle 2θ were 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1°.

[0105] Experimental tests have shown that sildenafil has good stability in a molten dimethyl sulfone solution and will not undergo significant deterioration, damage or degradation for at least 2 hours at a melting temperature of 108°C. Therefore, it is not necessary to add a third solvent to help lower the melting temperature during preparation.

[0106] In particular, it was found through testing that the mass percentage of sildenafil in the sildenafil saturated solution of dimethyl sulfone in the molten state is no more than 14.2%.

[0107] If one wants to prepare a solid solution with a higher content, a surfactant can be added to dimethyl sulfone and sildenafil for solubilization, thereby increasing the solubility of sildenafil in molten dimethyl sulfone.

[0108] Tadalafil-dimethyl sulfone solid dispersion, which is a solid solution, substantially composed of dispersant dimethyl sulfone and drug tadalafil, the mass percentage of the drug is not more than 10.7%, preferably 5.0%, 7.5% and 10.0%;

[0109] Its melting point is 107.5-108.5°C for initial melting and 109.5-110.5°C for final melting;

[0110] or

[0111] The prepared dimethyl sulfone tadalafil solid solution was subjected to X-ray powder diffraction test, Cu-Kα radiation, and the characteristic peaks of the X-ray powder diffraction pattern represented by the diffraction angle 2θ were 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1°.

[0112] Experimental tests have shown that tadalafil is not very stable in molten dimethyl sulfone solution. It quickly undergoes obvious deterioration, destruction and degradation at a melting temperature of 108°C. Therefore, a third solvent, such as ethanol, should be added during preparation to help lower the melting temperature.

[0113] In particular, it was found through testing that the mass percentage of tadalafil in a saturated solution of tadalafil in dimethyl sulfone in a molten state is no more than 10.7%.

[0114] In the actual heating and melting process, the volume mass ratio of the added ethanol to dimethyl sulfone is 1.0 ml: 3.0-5.0 g. The corresponding heating temperature is preferably 80°C.

[0115] The invention discloses an application of a solid dispersion containing dimethyl sulfone in the preparation of a pharmaceutical preparation. The solid dispersion is substantially composed of a dispersant dimethyl sulfone and at least one drug.

[0116] The pharmaceutical preparation contains a solid dispersion of dimethyl sulfone, wherein the solid dispersion is substantially composed of a dispersant dimethyl sulfone and at least one drug.

[0117] The medicine or preparation in the present application may also contain pharmaceutically acceptable adjuvants or excipients. Of course, the solid dispersion powder may also be directly compressed to prepare tablets or granulated to prepare granules or capsules.

[0118] The drug can be in any dosage form for clinical administration, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orodisintegrating tablets, capsules, sugar-coated tablets, granules, dry powders, oral solutions, small needles for injection, lyophilized powders for injection or large infusions.

[0119] Since solid dispersions have better oral absorption characteristics than drug substances, they may be more advantageous when prepared as oral dosage forms.

[0120] Depending on the specific dosage form and mode of administration, the pharmaceutically acceptable excipients or vehicles in the drug may include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, encapsulating agents, and pigments, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0121] Figure 1 XRD comparison diagrams of 5% sildenafil + MSM melt sample, 5% sildenafil + MSM physical mixed sample, MSM sample, and sildenafil sample, wherein the middle diagram is an enlarged diagram of 2θ refraction angle (X-axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper diagrams;

[0122] Figure 2XRD comparison diagrams of 7.5% sildenafil + MSM melt sample, 7.5% sildenafil + MSM physical mixed sample, MSM sample, and sildenafil sample, wherein the middle diagram is an enlarged diagram of 2θ refraction angle (X-axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper diagrams;

[0123] Figure 3 XRD comparison diagrams of 10% sildenafil + MSM melt sample, 10% sildenafil + MSM physical mixed sample, MSM sample, and sildenafil sample, wherein the middle diagram is an enlarged diagram of the 2θ refraction angle (X-axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper diagrams;

[0124] Figure 4 XRD comparison diagrams of 5% tadalafil + MSM melt sample, 5% tadalafil + MSM physical mixed sample, MSM sample, and tadalafil sample, wherein the middle diagram is an enlarged diagram of 2θ refraction angle (X axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of 2θ refraction angle (X axis) and peak height intensity (Y axis) relative to the middle and upper diagrams;

[0125] Figure 5 XRD comparison diagrams of 7.5% tadalafil + MSM melt sample, 7.5% tadalafil + MSM physical mixed sample, MSM sample, and tadalafil sample, wherein the middle diagram is an enlarged diagram of 2θ refraction angle (X axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of 2θ refraction angle (X axis) and peak height intensity (Y axis) relative to the middle and upper diagrams;

[0126] Figure 6 XRD comparison diagrams of 10% tadalafil + MSM melt sample, 10% tadalafil + MSM physical mixed sample, MSM sample, and tadalafil sample, wherein the middle diagram is an enlarged diagram of 2θ refraction angle (X axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of 2θ refraction angle (X axis) and peak height intensity (Y axis) relative to the middle and upper diagrams;

[0127] Figure 7 XRD comparison diagrams of 5% tadalafil + MSM ground sample, 5% tadalafil + MSM physical mixed sample, MSM sample, and tadalafil sample, wherein the middle diagram is an enlarged diagram of 2θ refraction angle (X axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of 2θ refraction angle (X axis) and peak height intensity (Y axis) relative to the middle and upper diagrams;

[0128] Figure 8 XRD comparison diagrams of 10% tadalafil + MSM ground sample, 10% tadalafil + MSM physical mixed sample, MSM sample, and tadalafil sample, wherein the middle diagram is an enlarged diagram of 2θ refraction angle (X axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of 2θ refraction angle (X axis) and peak height intensity (Y axis) relative to the middle and upper diagrams;

[0129] Fig. 9 XRD comparison diagrams of nifedipine, dimethyl sulfone, 10% nifedipine + MSM solid solution sample, and nifedipine: dimethyl sulfone (1:9) physical mixed sample, wherein the middle diagram is an enlarged diagram of the 2θ refraction angle (X axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of the 2θ refraction angle (X axis) and peak height intensity (Y axis) relative to the middle and upper diagrams;

[0130] Fig.10 XRD comparison diagrams of nifedipine, dimethyl sulfone, PEG4000, nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) solid solution, and nifedipine: dimethyl sulfone: PEG4000 (2:9:9) physical mixed sample, wherein the middle diagram is an enlarged diagram of the 2θ refraction angle (X-axis) relative to the upper diagram, and the lower diagram is an enlarged diagram of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper diagrams;

[0131] Fig.11 The figure is a full wavelength (200-700nm) scan of UV-visible absorbance of nifedipine, polyethylene glycol and dimethyl sulfone, wherein the upper left figure is the scan result of a blank sample, the upper right figure is the scan result of a dimethyl sulfone sample, the lower left figure is the scan result of a polyethylene glycol (PEG4000) sample, the lower right figure is the scan result of a nifedipine sample, and the bottom figure is the result of superimposing the above four scan results in the same coordinate graph;

[0132] Fig.12 The dissolution curves of nifedipine bulk drug, 10% by mass nifedipine MSM solid solution, 20% by mass nifedipine MSM solid solution, and 30% by mass nifedipine MSM solid solution in pure water;

[0133] Fig.13 The dissolution curves of 10% by mass nifedipine MSM solid solution and nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) solid solution in an aqueous solution with added surfactant.

[0134] Fig.14 The figure is a full wavelength (200-700nm) scan of the ultraviolet-visible light absorbance of sildenafil and tadalafil aqueous solutions, wherein the upper figure is sildenafil and the lower figure is tadalafil;

[0135] Fig.15 The dissolution curves of sildenafil API and 7.5% by mass sildenafil MSM solid solution in pure water;

[0136] Fig.16 The figure shows the dissolution curve of tadalafil bulk drug and 7.5% by mass tadalafil MSM solid solution in pure water. DETAILED DESCRIPTION

[0137] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0138] The description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of the claims attached to the present invention.

[0139] General Information

[0140] Sildenafil, tadalafil (tadalafil), and nifedipine are all free bases, and their specific chemical structures are as follows:

[0141]

[0142] All were purchased from the market and were of pharmaceutical grade.

[0143] Unless otherwise specified in the following experiments, the methods, instruments and other information for testing or inspection are as follows:

[0144] X-ray powder diffraction XRD, testing instrument: Netherlands PANalytical-X'Pert 3 Powder, Cu-Kα test, temperature 25°C, humidity 35%, the sample is evenly ground through 100 mesh, and the refraction angle is expressed in 2θ to obtain the X-ray powder diffraction spectrum, the error is <0.01°, and the scanning range is 3.0 to 60.0°.

[0145] Melting point measurements were made using the capillary method and the first and last melts were recorded.

[0146] HPLC purity test, calculated using the area normalization method after HPLC detection.

[0147] The specific HPLC detection methods for sildenafil and tadalafil are as follows:

[0148] Sildenafil was determined using the content determination method for Sildenafil Citrate Tablets Ws1-(X-010)-2010Z issued by the China Food and Drug Administration; or using the “related substance” method in “Sildenafil Citrate” on page 3786 of the European Pharmacopoeia.

[0149] Tadalafil is determined using the “related substance” method in the European Pharmacopoeia page 3957 “Tadalafifilum”.

[0150] The mass percentage of the saturated solution was determined using the above-mentioned HPLC method, and the mass percentage was calculated using the external standard method for quantitative detection.

[0151] The UV absorption and full-band UV scanning spectrum of the compound were measured using a Thermo Fisher Evolution 201 / 220 UV-visible spectrophotometer.

[0152] 1. Preparation and characterization of sildenafil solid solution - melting method

[0153] Preparation of Sildenafil Solid Solution by Direct Melting Method

[0154] In a dry 50 ml two-necked bottle, under nitrogen protection, add 9.5 g of dimethyl sulfone, stir, heat in an oil bath and control the temperature to 120-125 ° C, dissolve and clarify, add 0.5 g of sildenafil, stir and dissolve until clear, after 10 minutes, quickly transfer the solution to a watch glass, wrap it with a sealed bag, and cool it naturally to room temperature. It is a waxy translucent solid. Samples are taken from different parts and tested. The samples are marked as "5% sildenafil + MSM melt".

[0155] In a dry 50 ml two-necked bottle, under nitrogen protection, add 9.0 g of dimethyl sulfone, stir, heat in an oil bath and control the temperature to 120-125 ° C, dissolve and clarify, add 1.0 g of sildenafil, stir and dissolve until clear, after 10 minutes, quickly transfer the solution to a watch glass, wrap it with a sealed bag, and cool it naturally to room temperature. It is a waxy translucent solid. Samples are taken from different parts and tested. The samples are marked as "10% sildenafil + MSM melt".

[0156] In a dry 50 ml two-necked flask, under nitrogen protection, add 9.25 g of dimethyl sulfone, stir, heat in an oil bath and control the temperature to 120-125°C, dissolve and clarify, add 0.75 g of sildenafil, stir and dissolve until clear, after 10 minutes, quickly transfer the solution to a watch glass, wrap it with a sealed bag, and cool it naturally to room temperature. It is a waxy translucent solid, take a sample, and mark the sample as "7.5% sildenafil + MSM melt".

[0157] In a dry 50ml two-necked flask, nitrogen protection, add 8.0g of dimethyl sulfone, stir, heat in an oil bath and control the temperature to 120-125°C, dissolve and clarify, add 2.0g of sildenafil, stir, it is difficult to dissolve, solids precipitate at the bottom of the container, and it still cannot be completely dissolved after stirring. This shows that the amount of sildenafil that dimethyl sulfone can dissolve in the molten state is limited. Take the upper clear liquid of the above molten solution and accurately weigh the mass to determine and calculate its saturated concentration, which is 14.2% by mass of sildenafil.

[0158] Homogeneity test of sildenafil solid solution prepared by direct melting method

[0159] Different parts of the waxy solid block of the 5% sildenafil + MSM molten sample and the 10% sildenafil + MSM molten sample were sampled for HPLC detection. The results of the uniformity detection of the sildenafil solid solution are shown in Table 1 below.

[0160] Table 1: HPLC purity test results of 5 different samples of 5% and 10% sildenafil dimethyl sulfone solid solution

[0161]

[0162] The mixed sample refers to a sample obtained by grinding and mixing the entire waxy translucent solid.

[0163] The results in Table 1 show that the sample has excellent uniformity, which shows that during the preparation process by the melting method, no sildenafil precipitation occurs in the molten and clear sildenafil dimethyl sulfone solution during the cooling process, and the prepared solid is a solid solution of dimethyl sulfone sildenafil.

[0164] High temperature stability test of sildenafil solid solution prepared by direct melting method

[0165] In order to further verify the feasibility of large-scale preparation of solid solution of sildenafil in dimethyl sulfone, the stability experiment of sildenafil in dimethyl sulfone solution of sildenafil with different melting times was carried out.

[0166] In a dry 50 ml two-necked flask, under nitrogen protection, add 9.0 g of dimethyl sulfone, stir, heat in an oil bath to 120-125 ° C, dissolve and clarify, add 1.0 g of silderafil, stir and dissolve (red kerosene thermometer, detect the solution temperature at 120 ° C), and obtain a purple clear liquid. Continue to keep warm and stir, and intermittently sample: 30 min, 1 h, 2.5 h, 3.5 h for detection as shown in Table 2 below.

[0167] Table 2: HPLC purity test results of sildenafil stability test in sildenafil dimethyl sulfone molten solution with different melting times

[0168] Duration Main peak purity% Maximum single impurity % As is 99.96 Not detected 30min 99.03 0.97 1h 97.42 1.81 2.5h 96.01 3.13 3.5h 94.21 3.98

[0169] From the experimental results in Table 2, it can be seen that within 30 minutes, the molten sildenafil dimethyl sulfone solution has good stability at a high melting temperature (about 120°C); as the time is prolonged, the impurities increase significantly. Therefore, lowering the melting temperature can prolong the heating and melting time, which is more conducive to large-scale production.

[0170] Solid solution XRD detection

[0171] In order to further prove that the final solid is a solid solution, an X-ray powder diffraction experiment was performed.

[0172] XRD detection was performed on sildenafil, dimethyl sulfone, 5% sildenafil + MSM melt sample, 7.5% sildenafil + MSM melt sample, 10% sildenafil + MSM melt sample and the corresponding physical mixing control groups of 5% sildenafil + MSM physical mixing, 7.5% sildenafil + MSM physical mixing, and 10% sildenafil + MSM physical mixing samples.

[0173] Among them, sildenafil, dimethyl sulfone, 5% sildenafil + MSM molten sample, 7.5% sildenafil + MSM molten sample, and 10% sildenafil + MSM molten sample were all ground in a white porcelain mortar and passed through a 100-mesh sieve, while the physically mixed sample was obtained by first grinding sildenafil and dimethyl sulfone separately through a 100-mesh sieve and then physically shaking and mixing.

[0174] 5% sildenafil + MSM melt sample, the specific results are as follows Figure 1 Show.

[0175] 7.5% sildenafil + MSM melt sample, the specific results are as follows Figure 2 Show.

[0176] 10% sildenafil + MSM melt sample, the specific results are as follows Figure 3 Show.

[0177] analyze Figure 1-3 It can be seen that the XRD characteristic peaks of sildenafil raw material are 7.40°, 8.18°, 10.35°, and 14.51°. Figure 1 , 2 , 3 all disappeared in the melted samples, while the corresponding physical mixtures all existed. It can be seen that sildenafil in the samples prepared after melting no longer shows crystalline characteristics.

[0178] Further comparison Figure 1 , 2 From the molten sample and the dimethyl sulfone sample in 3, it can be seen that the XRD characteristic peaks of the molten sample, namely the characteristic peaks of sildenafil dimethyl sulfone solid solution, are 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1. Combined with the fact that it is completely dissolved in the dimethyl sulfone melt during melting, it can be seen that after cooling, it is completely dissolved and dispersed in dimethyl sulfone in molecular form.

[0179] Solid solution powder melting point detection

[0180] The melting point test results of the above 5% sildenafil + MSM melting sample, 7.5% sildenafil + MSM melting sample, 10% sildenafil + MSM melting sample and sildenafil are as follows:

[0181] 5% sildenafil + MSM melting sample, initial melting 108°C, final melting 110°C;

[0182] 7.5% sildenafil + MSM melting sample, initial melting 107°C, final melting 110°C;

[0183] 10% sildenafil + MSM melting sample, initial melting 107°C, final melting 110°C;

[0184] Sildenafil, initial melting point 189°C, final melting point 190°C;

[0185] According to the literature, the melting point of dimethyl sulfone is 107-109°C, which is close to that of the above-mentioned solid solution. In other words, the melting point of the prepared solid solution may be closer to dimethyl sulfone, which is similar to the comparison results of the XRD spectrum.

[0186] 2. Preparation and characterization of tadalafil solid solution - melt preparation by adding a third solvent

[0187] Homogeneity test of tadalafil solid solution prepared by direct melting method

[0188] Based on the successful preparation of sildenafil solid solution by direct melting method, a feasibility study on the preparation of tadalafil solid solution by direct melting method was conducted to investigate the purity of tadalafil at different sampling sites after melting and cooling, and a uniformity test was performed for this purpose.

[0189] Add 9 g of dimethyl sulfoxide to a dry two-necked bottle, protect with nitrogen, heat in an oil bath until dissolved and clear, the internal temperature is 112°C, and there is sublimation. Add 1 g of tadalafil and stir until clear. After 10 minutes, quickly transfer the dissolved solution to a watch glass, wrap it in a sealed bag, and cool it naturally to room temperature. It is a waxy translucent solid. Take samples from different parts and test them.

[0190] Sampling from different parts was performed for HPLC testing. The results of the uniformity test of the tadalafil solid solution are shown in Table 3 below.

[0191] Table 3: HPLC purity test results of 10% tadalafil dimethyl sulfone solid solution (112°C) of 5 different samples

[0192]

[0193] The results in Table 3 show that the sample homogeneity is poor, and in the preparation process of the melting method, the molten and clear tadalafil dimethyl sulfone solution deteriorates during the heating and cooling process: since the heating process is unevenly heated in various parts, the degree of deterioration also increases significantly. The high-temperature direct melting method is not suitable for preparing tadalafil dimethyl sulfone solid solution.

[0194] High temperature stability test of tadalafil solid solution prepared by adding a third solvent

[0195] By consulting relevant data and literature, we know that water, methanol, ethanol, acetone, N, N-dimethylacetamide, N, N-dimethylformamide, acetone, ethyl acetate, tetrahydrofuran and other solvents can dissolve dimethyl sulfone well. Considering that adding an appropriate amount of such solvents in advance may melt dimethyl sulfone into a paste so as to facilitate the melting of dimethyl sulfone at a lower temperature, ethanol, which is commonly used and easy to remove by subsequent heating, is used for experiments.

[0196] In a dry two-necked bottle, add 9 g of dimethyl sulfoxide, protect with nitrogen, add 18 ml of ethanol, heat in an oil bath until dissolved and clear, the internal temperature is 80°C, add 1 g of tadalafil, stir until clear, and take samples intermittently: 5 min, 10 min, 30 min, 60 min, 120 min for detection as shown in Table 4 below.

[0197] Table 4: HPLC purity test results of tadalafil stability test in tadalafil dimethyl sulfone ethanol molten solution with different melting times

[0198] Duration Main peak purity% Maximum single impurity % As is 99.85 Not detected 5min 99.75 Not detected 10min 99.74 0.07 30min 99.31 0.38 60min 99.31 0.40 120min 99.81 0.60

[0199] It can be seen from the experimental results in Table 4 that within 120 minutes, the molten tadalafil dimethyl sulfone ethanol solution has good stability at the high melting temperature (about 80° C.); as the time is extended, the impurity growth is not obvious.

[0200] From the experiments and data in Table 3, it can be seen that adding the third solvent can reduce the melting temperature of the mixture system, thereby prolonging the heating and melting time, which is more conducive to large-scale production.

[0201] Homogeneity test of tadalafil solid solution (80℃, 120℃) prepared by adding a third solvent

[0202] According to the experimental data in Table 4, after adding an appropriate amount of ethanol, the dimethyl sulfone ethanol mixed system can be melted and clarified at a temperature of 80°C, and tadalafil will not undergo obvious deterioration within at least 120 minutes after adding tadalafil. Therefore, for raw materials with poor stability, solid solutions can be prepared by melting at a lower temperature with the addition of a third solvent.

[0203] In order to further verify the uniformity of the prepared solid solution, a uniformity test experiment was conducted by adding a third solvent to prepare a tadalafil solid solution.

[0204] In a dry two-necked bottle, add 9 g of dimethyl sulfoxide, protect with nitrogen, add 18 ml of ethanol, heat in an oil bath until dissolved and clarified, the internal temperature is 80°C, add 1 g of tadalafil, stir until clarified, keep warm and stir for 2 hours, transfer to a watch glass, wrap with a sealed bag, cool naturally to room temperature, it is a waxy translucent solid, take samples from different parts and test.

[0205] Sampling from different parts was performed for HPLC testing. The results of the uniformity test of the tadalafil solid solution are shown in Table 5.

[0206] Table 5: HPLC purity test results of 10% tadalafil dimethyl sulfone-ethanol solid solution (80°C, 120 min) of 5 different parts of the sample homogeneity

[0207]

[0208] In a dry two-necked bottle, add 9 g of dimethyl sulfoxide, protect with nitrogen, add 18 ml of ethanol, heat in an oil bath until dissolved and clarified, the internal temperature is 80°C, add 1 g of tadalafil, stir until clarified, keep warm and stir for 5 minutes, quickly transfer to a watch glass, wrap with a sealed bag, and cool naturally to room temperature. It is a waxy translucent solid. Samples are taken from different parts for testing.

[0209] Sampling from different parts was performed for HPLC testing. The results of the uniformity test of the tadalafil solid solution are shown in Table 6 below.

[0210] Table 6: HPLC purity test results of 7 different sample homogeneity of 10% tadalafil dimethyl sulfone-ethanol solid solution (80°C, 5min)

[0211]

[0212] The results in Tables 5 and 6 show that the samples have excellent uniformity, which shows that during the preparation of the tadalafil dimethyl sulfone-ethanol solid solution, no tadalafil precipitation occurred in the molten and clear tadalafil dimethyl sulfone-ethanol solution during the cooling process, and the prepared solid is a solid solution of dimethyl sulfone tadalafil.

[0213] During the preparation process, the dissolution process is completed in a very short time (5 minutes) after heating, melting and clarification to obtain a uniform solution, and the solid solution prepared after cooling has excellent uniformity.

[0214] XRD Detection of Tadalafil Dimethyl Sulfone-Ethanol Solid Solution

[0215] Add 9.5g of dimethyl sulfone to a dry 50ml two-necked flask and replace it with a nitrogen atmosphere. Set the oil bath to 100°C, add about 2.5ml of anhydrous ethanol to the reaction flask, turn on stirring and start heating. The solid in the reaction flask begins to melt slowly at an internal temperature of about 80°C until all the solids are dissolved. Add 0.5g of tadalafil at an internal temperature of 85°C and stir rapidly until clear. Quickly transfer the dissolved solution to a watch glass, wrap it in a sealed bag, and cool it naturally to room temperature. It is a waxy translucent solid. Detect it and mark the sample as "5% tadalafil + MSM melt".

[0216] Add 9.0g of dimethyl sulfone to a dry 50ml two-necked flask and replace it with a nitrogen atmosphere. Set the oil bath to 100°C, add about 2.5ml of anhydrous ethanol to the reaction flask, turn on stirring and start heating. The solid in the reaction flask begins to melt slowly at an internal temperature of about 80°C until all the solids are dissolved. Add 1.0g of tadalafil at an internal temperature of 85°C and stir rapidly until clear. Quickly transfer the dissolved solution to a watch glass, wrap it in a sealed bag, and cool it naturally to room temperature. It is a waxy translucent solid. Detect it and mark the sample as "10% tadalafil + MSM melt".

[0217] Add 9.25g of dimethyl sulfone to a dry 50ml two-necked flask and replace it with a nitrogen atmosphere. Set the oil bath to 100°C, add about 2.5ml of anhydrous ethanol to the reaction flask, turn on stirring and start heating. The solid in the reaction flask begins to melt slowly at an internal temperature of about 80°C until all the solids are dissolved. Add 0.75g of tadalafil at an internal temperature of 85°C and stir rapidly until clear. Quickly transfer the dissolved solution to a watch glass, wrap it in a sealed bag, and cool it naturally to room temperature. It is a waxy translucent solid. Detect it and mark the sample as "7.5% tadalafil + MSM melt".

[0218] In a dry 50ml two-necked flask, 9.0g of dimethyl sulfone was added and replaced with a nitrogen atmosphere. The oil bath was set to 100°C, about 2.5ml of anhydrous ethanol was added to the reaction flask, stirring was turned on and heating was started. The solid in the reaction flask began to melt slowly at an internal temperature of about 80°C until all the solids were dissolved. 1.5g of tadalafil was added at an internal temperature of 85°C, stirred, and was difficult to dissolve. Solids precipitated at the bottom of the container, and still could not be completely dissolved after stirring. This shows that the amount of tadalafil that dimethyl sulfone-ethanol can dissolve in the molten state is limited. Take the upper clear liquid of the above-mentioned molten solution and accurately weigh the mass and then determine and calculate its saturation concentration to be 10.7% by mass of tadalafil.

[0219] XRD detection was performed on tadalafil, dimethyl sulfone, 5% tadalafil + MSM melt sample, 7.5% tadalafil + MSM melt sample, 10% tadalafil + MSM melt sample and the corresponding physical mixing control groups of 5% tadalafil + MSM physical mixing, 7.5% tadalafil + MSM physical mixing, and 10% tadalafil + MSM physical mixing samples.

[0220] Among them, tadalafil, dimethyl sulfone, 5% tadalafil + MSM molten sample, 7.5% tadalafil + MSM molten sample, and 10% tadalafil + MSM molten sample were all ground in a white porcelain mortar and passed through a 100-mesh sieve, while the physically mixed sample was obtained by first grinding tadalafil and dimethyl sulfone separately through a 100-mesh sieve and then physically shaking and mixing.

[0221] Among them, the 5% tadalafil + MSM melt sample, the 7.5% tadalafil + MSM melt sample, and the 10% tadalafil + MSM melt sample were transferred to a single-mouth bottle after grinding, and the ethanol was removed by vacuum under room temperature (vacuuming for about 30 minutes) before detection.

[0222] 5% Tadalafil + MSM melt sample, the specific results are as follows Figure 4 Show.

[0223] 7.5% Tadalafil + MSM melt sample, the specific results are as follows Figure 5 Show.

[0224] 10% Tadalafil + MSM melt sample, the specific results are as follows Figure 6 Show.

[0225] analyze Figure 4-6 It can be seen that the XRD characteristic peaks of tadalafil raw material are 7.33°, 10.71°, 12.57°, 13.51°, and 14.56°. Figure 4 , 5 , 6 are weakened or even disappear in the melt samples, while the corresponding physical mixing is obviously present. It can be seen that tadalafil in the samples prepared after melting no longer shows crystalline characteristics.

[0226] Further comparison Figure 4 , 5 , 6 and the dimethyl sulfone sample, it can be seen that the XRD characteristic peaks of the molten sample, namely the characteristic peaks of tadalafil dimethyl sulfone solid solution, are: 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, 33.1±0.1. Combined with the fact that it is completely dissolved in the dimethyl sulfone melt during melting, it can be seen that after cooling, it is completely dissolved and dispersed in dimethyl sulfone in molecular form.

[0227] Solid solution powder melting point detection

[0228] The melting point test results of the above 5% tadalafil + MSM melting sample, 7.5% tadalafil + MSM melting sample, 10% tadalafil + MSM melting sample and tadalafil are as follows:

[0229] 5% tadalafil + MSM melting sample, initial melting 108°C, final melting 110°C;

[0230] 7.5% tadalafil + MSM melting sample, initial melting 108°C, final melting 110°C;

[0231] 10% tadalafil + MSM melting sample, initial melting 108°C, final melting 110°C;

[0232] Tadalafil, initial melting point 289°C, final melting point 291°C;

[0233] According to the literature, the melting point of dimethyl sulfone is 107-109°C, which is close to that of the above-mentioned solid solution. In other words, the melting point of the prepared solid solution may be closer to dimethyl sulfone, which is similar to the comparison results of the XRD spectrum.

[0234] 3. Preparation and characterization of tadalafil solid solution - grinding method

[0235] 9.5 g of dimethyl sulfone and 0.5 g of tadalafil were added to a white porcelain mortar and ground manually using a white porcelain pestle for about 5 minutes. The sample was labeled as "5% tadalafil + MSM grinding".

[0236] 9.0 g of dimethyl sulfone and 1.0 g of tadalafil were added to a white porcelain mortar and ground manually using a white porcelain pestle for about 5 minutes. The sample was labeled as "10% Tadalafil + MSM Grinding".

[0237] After grinding, the product was passed through a 100-mesh sieve for XRD analysis.

[0238] 5% tadalafil + MSM grinding sample, the specific results are as follows Figure 7 Show.

[0239] 10% tadalafil + MSM grinding sample, the specific results are as follows Figure 8 Show.

[0240] contrast Figure 7 , 8 It can be seen that compared with the physically mixed sample, the diffraction peak of tadalafil at 7.33° in the ground sample is weakened, especially the diffraction peak of 10% tadalafil + MSM ground sample at 7.33° is weakened to less than 20% of the physically mixed sample, that is, grinding can dissolve tadalafil in dimethyl sulfone to form a solid solution.

[0241] Therefore, under sufficient grinding time, tadalafil can completely diffuse and dissolve into dimethyl sulfone and exist in molecular form to obtain a solid solution. The final solid solution will show the characteristic peaks of dimethyl sulfone, namely 6.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1, in its XRD characteristic peaks.

[0242] 4. Preparation and dissolution experiment of nifedipine solid solution

[0243] Preparation of 10%, 20%, and 30% nifedipine + MSM solid solutions

[0244] Weigh 8g of dimethyl sulfone and place it in a 100ml conical flask for later use. Set the oil bath temperature to 120°C. When the temperature reaches the set temperature, place the conical flask in an oil bath pot, carefully stir manually with a glass rod until it is completely melted, then add 2.00g of nifedipine and stir quickly to dissolve. Pour the mixed solution into a clean stainless steel plate, cool it to room temperature and freeze it in a -20°C refrigerator for 10 minutes, collect the material to obtain a 20% nifedipine + MSM solid solution sample (prescription 8). A similar operation is used to prepare a 10% nifedipine + MSM solid solution sample (9g dimethyl sulfone + 1g nifedipine, prescription 3), and a similar operation is used to prepare a 30% nifedipine + MSM solid solution sample (7g dimethyl sulfone + 3g nifedipine, prescription 9).

[0245] Preparation of Nifedipine: Dimethyl sulfone: PEG4000 (2:9:9, Prescription 2) Solid Solution

[0246] Weigh 9 g of PEG4000, 9 g of dimethyl sulfone, and 0.02 g of sodium docusate (CAS No. 577-11-7, a surfactant) in the prescribed amount, put them in a 100 ml conical flask, mix them evenly, and then put them in a 120 ° C oil bath. Adjust the height until the material at the bottom of the bottle is just immersed in the oil bath. Use a suitable glass rod to carefully stir manually until all the materials are melted, then pour the solution into a clean stainless steel plate, cool it to room temperature, and freeze it in a -20 ° C refrigerator for 10 minutes. Collect the material and grind it into fine powder.

[0247] Put 18.0 g of the prepared fine powder and 2 g of nifedipine into a conical flask, mix well and place in a 120°C oil bath. Adjust the height until the material at the bottom of the flask is just submerged in the oil bath. Use a suitable glass rod to carefully stir manually until all the mixture is melted.

[0248] During the experiment, it was observed that the material began to soften at an internal temperature of 90-100°C, and became liquid at 120°C and basically clarified after stirring.

[0249] The mixed solution was poured into a clean stainless steel dish, cooled to room temperature and then placed in a -20°C refrigerator for 10 minutes. The material was collected to obtain a yellow waxy solid with uniform color.

[0250] XRD Detection of Nifedipine Dimethyl Sulfone Solid Solution

[0251] XRD detection was performed on nifedipine, dimethyl sulfone, PEG4000, 10% nifedipine + MSM solid solution sample, nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) solid solution, nifedipine: dimethyl sulfone (1:9) physical mixture, and nifedipine: dimethyl sulfone: PEG4000 (2:9:9) physical mixture.

[0252] The test sample preparation process is similar to the above-mentioned sildenafil and tadalafil process.

[0253] 10% nifedipine + MSM solid solution sample, the specific results are as follows Fig. 9 Show.

[0254] Nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) solid solution sample, the specific results are as follows Fig.10 Show.

[0255] contrast Fig. 9 , 10 It can be seen that the diffraction characteristic peaks of nifedipine at 8.13° and 11.85° almost disappear in the solid solution, while the diffraction peaks at the corresponding positions of the physical mixed sample still exist; the final 10% nifedipine + MSM solid solution sample and nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) solid solution sample all have characteristic peaks of 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1, which are also the characteristic peaks of dimethyl sulfone. Combined with the fact that nifedipine is completely dissolved in the dimethyl sulfone melt during melting, it can be seen that after cooling, it is completely dissolved and dispersed in dimethyl sulfone in molecular form.

[0256] Dissolution curve test

[0257] The dissolution content was determined using the UV absorption method.

[0258] The UV absorption curves of related substances dimethyl sulfone, nifedipine, and PEG-4000 were scanned to explore whether it is feasible to determine the nifedipine content by UV spectrophotometry.

[0259] A 0.01 mg / ml aqueous solution of nifedipine, a 0.1 mg / ml aqueous solution of polyethylene glycol and dimethyl sulfone were prepared and the UV absorbance was scanned at the full wavelength. The specific results are as follows Fig.11shown.

[0260] According to the scanning results of the above three related substances, it can be known that the absorbance measured at the strongest absorption wavelength of nifedipine, 237nm, is not affected by polyethylene glycol and dimethyl sulfone.

[0261] According to the literature (Ye Junpeng, Huang Peiliang, Liao Zhener, et al. Determination of the content of nifedipine slow-release and controlled-release tablets by ultraviolet spectrophotometry [J]. Journal of Tropical Medicine, 2003, 3(4): 2. DOI: 10.3969 / j.issn.1672-3619.2003.04.018.), the absorbance was measured at a wavelength of 237 nm. Since the final standard curve was c = FA + b, where b was small relative to the F value and could be ignored, that is, c = FA, the working curve was simplified to a single reference substance value, that is, the nifedipine reference substance was accurately weighed before each test and prepared into 50 ml of solution, and then the absorbance was measured. Thus, F = reference substance mass × content percentage ÷ 50 ÷ A was obtained.

[0262] Pure water dissolution test

[0263] Weigh the equivalent of 100 mg of nifedipine, place it in a 250 ml conical flask, add 250 ml of water heated to 37±0.2℃, stir at 300 rpm, sample 5 ml at 5 minutes, 20 minutes, 40 minutes, 60 minutes, and 120 minutes, replenish 5 ml of solution, take samples to test dissolution, and draw a dissolution curve of dissolution amount over time.

[0264] The dissolution amount was determined by ultraviolet spectrophotometry. In each test, about 20 mg of nifedipine reference substance was accurately weighed and dissolved in 50 ml of pure water, and the absorbance at 237 nm (the wavelength was set to 235 nm in actual operation) was measured twice. The formula F = nifedipine reference substance mass × content ÷ 50 ÷ absorbance was used to calculate the F value, and the F mean of the two tests was calculated.

[0265] Then, calculation was performed according to the formula: mass of nifedipine = absorbance × F mean × volume of dissolution medium.

[0266] The pure water dissolution experimental parameters of prescriptions 3, 8, and 9 and the F-mean determination data by UV spectrophotometry are shown in Table 7.

[0267] Table 7: Pure water dissolution experimental parameters of solid solution powders of prescriptions 3, 8, and 9 and F-mean value determination data table by UV spectrophotometry

[0268]

[0269] F value calculation example: 21.49×0.98485÷50÷4.146=0.102095642.

[0270] The pure water dissolution test results of prescriptions 3, 8, and 9 are shown in Table 8, where F takes the average value of 0.101753203. The dissolution mass of nifedipine in the sample with a dissolution time of 5 minutes in prescription 3 is 1.129×0.101753203×250=28.71984, which is rounded to two digits to 28.72.

[0271] Table 8: Dissolution test results of solid solutions of prescriptions 3, 8, 9 and raw materials in pure water

[0272]

[0273] *, where the API was tested at different time periods from prescriptions 3, 8, and 9, and its corresponding F-mean was 0.01676. Therefore, the 5-minute dissolution amount of the API was 0.031×0.01676×250=0.12989, which is 0.13 to two significant figures, and the rest is similar.

[0274] The experimental data in Table 8 are made into a dissolution curve, such as Fig.12 shown.

[0275] According to Table 8 and Fig.12 It can be seen that after nifedipine is prepared as a dimethyl sulfone solid solution, its dissolution rate in pure water and the final dissolution percentage are significantly improved. Moreover, the solid solution with a relatively low drug loading has a higher dissolution percentage and a faster dissolution rate.

[0276] During the experiment, it was found that floccules and precipitation appeared in the subsequent solution. This may be due to crystallization after dissolution. This can explain the phenomenon that the solid solution dissolved quickly and reached a peak within the initial 5 minutes and then decreased.

[0277] Dissolution test of aqueous solution with added surfactant

[0278] Weigh the equivalent of 100 mg of nifedipine, place it in a 250 ml conical flask, add 250 ml of sodium dodecyl sulfate aqueous solution (mass ratio 0.25%) heated to 37±0.2°C, stir at 300 rpm, take samples of 5 ml at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, and 120 minutes, replenish 5 ml of the solution, take samples to detect dissolution, and draw a dissolution curve of the dissolution amount over time.

[0279] The dissolution experimental parameters of sodium dodecyl sulfate aqueous solution of prescriptions 2 and 3 and the F-mean value determination data of ultraviolet spectrophotometry are shown in Table 9.

[0280] Table 9: Dissolution experimental parameters of solid solution powders of prescriptions 2 and 3 in sodium dodecyl sulfate aqueous solution and F-mean value determination data table by UV spectrophotometry

[0281]

[0282] F value calculation example: 23.36×0.98485÷50÷4.141=0.111113721.

[0283] The dissolution test results of prescriptions 2 and 3 and the raw materials in 0.25% sodium dodecyl sulfate aqueous solution are shown in Table 10, where the F mean is taken as 0.111342738. The dissolution mass of nifedipine in the sample with a dissolution time of 5 minutes in prescription 2 is 2.246×0.111342738×250=62.518953, which is rounded to two digits to 62.52.

[0284] Table 10: Dissolution test results of solid solutions of prescriptions 2 and 3 and the API in 0.25% sodium dodecyl sulfate aqueous solution

[0285]

[0286]

[0287] The experimental data in Table 10 are made into a dissolution curve, such as Fig.13 shown.

[0288] According to Table 10 and Fig.13 It can be seen that after nifedipine is prepared as a dimethyl sulfone solid solution, its dissolution rate in the sodium dodecyl sulfate aqueous solution and the final dissolution percentage in pure water are significantly improved.

[0289] During the experiment, it was found that floccules and precipitation appeared in the subsequent solution. This may be due to crystallization after dissolution. This can explain the phenomenon that the solid solution dissolved quickly and reached a peak within the initial 5 minutes and then decreased.

[0290] 5. Dissolution test of 7.5% sildenafil and tadalafil solid solution

[0291] The dissolution curves were determined using the 7.5% sildenafil + MSM melt sample prepared in the first part "Preparation of sildenafil solid solution by direct melting method" and the 7.5% tadalafil + MSM melt sample prepared in the second part "XRD detection of tadalafil dimethyl sulfone-ethanol solid solution".

[0292] Dissolution curve test

[0293] The dissolution content was determined using the UV absorption method.

[0294] In the experiment in the previous part, the UV absorption curve of dimethyl sulfone has been scanned and it has no absorption.

[0295] Therefore, we only need to scan the ultraviolet absorption curves of the related substances sildenafil and tadalafil to explore their respective strongest absorption wavelengths.

[0296] A 0.01 mg / ml aqueous solution of sildenafil and tadalafil was prepared for full wavelength scanning of UV absorbance. The specific results are as follows Fig.14 shown.

[0297] According to the above scanning results, sildenafil has the strongest absorption at a wavelength of 292nm; and tadalafil has the strongest absorption at 283nm, so the wavelength of 292nm is selected as the wavelength of the ultraviolet spectrophotometer for measuring the dissolution curve experiment of sildenafil, and the wavelength of 283nm is selected as the wavelength of the ultraviolet spectrophotometer for measuring the dissolution curve experiment of tadalafil.

[0298] Pure water dissolution test

[0299] Weigh the calculated amount of 14 mg of sildenafil API, and about 100 mg of 7.5% sildenafil + MSM molten sample, 14 mg of tadalafil API, and about 100 mg of 7.5% tadalafil + MSM molten sample, and place them in 4 250 ml conical flasks respectively, add 250 ml of water heated to 37±0.2°C, stir at a stirring speed of 300 rpm, take 5 ml of samples at 10 minutes, 20 minutes, 30 minutes, 60 minutes, and 120 minutes, respectively, replenish 5 ml of solution, take samples for dissolution detection, and draw a dissolution curve of the dissolution amount over time.

[0300] Dissolution curve of 7.5% sildenafil solid solution

[0301] The dissolution amount was determined by ultraviolet spectrophotometry. In each test, about 20 mg of the sildenafil reference substance was accurately weighed and dissolved in 1000 ml of pure water, and the absorbance at 292 nm was measured twice. The formula F = sildenafil reference substance mass × content ÷ 1000 ÷ absorbance was used to calculate the F value, and the F mean of the two tests was calculated.

[0302] Then, the calculation was performed according to the formula: mass of sildenafil = absorbance × F mean × volume of dissolution medium.

[0303] The experimental parameters of the pure water dissolution of 7.5% sildenafil solid solution and the F mean value determination data of the ultraviolet spectrophotometry are shown in Table 7 below.

[0304] Table 11: 7.5% sildenafil solid solution powder pure water dissolution experimental parameters and UV spectrophotometry F mean value determination data table

[0305]

[0306] F value calculation example: 19.27×1÷1000÷0.410=0.047.

[0307] The results of the pure water dissolution test of 7.5% sildenafil solid solution are shown in Table 12, where F takes the average value of 0.047, and the sildenafil dissolution mass of the sample with a dissolution time of 10 minutes is 1.083×0.047×250=12.72525, which is rounded to two digits to 12.73.

[0308] Table 12: Dissolution test results of 7.5% sildenafil solid solution and API in pure water

[0309]

[0310] The experimental data in Table 12 are made into a dissolution curve, such as Fig.15 shown.

[0311] According to Table 12 and Fig.13 It can be seen that after sildenafil is prepared as a dimethyl sulfone solid solution, the solubility of the solid solution is higher when compared with the same period of time, and the solid solution has a solubilizing effect.

[0312] Dissolution curve of 7.5% tadalafil solid solution

[0313] The dissolution amount was determined by ultraviolet spectrophotometry. In each test, about 15 mg of tadalafil reference substance was accurately weighed and dissolved in 1000 ml of 50% acetonitrile aqueous solution, and the absorbance at 283 nm was measured twice. The formula F = mass of tadalafil reference substance × content ÷ 1000 ÷ absorbance was used to calculate the F value, and the F mean of the two tests was calculated.

[0314] Then, calculation was performed according to the formula: mass of tadalafil = absorbance × F mean × volume of dissolution medium.

[0315] The experimental parameters of the pure water dissolution of 7.5% tadalafil solid solution and the F-mean value determination data by UV spectrophotometry are shown in Table 13.

[0316] Table 13: 7.5% Tadalafil solid solution powder pure water dissolution experimental parameters and UV spectrophotometry F mean value determination data table

[0317]

[0318] F value calculation example: 14.98×1÷1000÷0.529=0.02831758.

[0319] The results of the pure water dissolution test of 7.5% tadalafil solid solution are shown in Table 14, where F takes the average value of 0.028344396, and the tadalafil dissolution mass of the sample with a dissolution time of 10 minutes is 0.005×0.028344396×250=0.03543, which is rounded to 0.04.

[0320] Table 14: Dissolution test results of 7.5% tadalafil solid solution and API in pure water

[0321]

[0322] The experimental data in Table 14 are made into a dissolution curve, such as Fig.16 shown.

[0323] According to Table 14 and Fig.16 It can be seen that after tadalafil is prepared as a dimethyl sulfone solid solution, the solubility of the solid solution is higher when compared with the same period of time, and the solid solution has a very significant solubilizing effect.

Claims

1. A solid dispersion containing dimethyl sulfone, comprising a dispersant dimethyl sulfone and at least one drug; preferably, the solid dispersion consists essentially of the dispersant dimethyl sulfone and at least one drug.

2. The solid dispersion according to claim 1 can be prepared by at least one of the following three methods: Method 1: The dimethyl sulfone in a molten clear state is evenly dispersed with the drug to obtain a dispersed system in a molten state; Cooling the molten dispersion to obtain the solid dispersion; Method 2: uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a dispersed system in a molten state; The solid dispersion is obtained by cooling the molten dispersion system and removing the third solvent; Method 3: The dimethyl sulfone and the drug are extruded or ground, stirred, melted and mixed, and then cooled to obtain the product. Preferably, a third solvent is added to the dimethyl sulfone and the drug for extrusion or grinding and stirring; Method 4: Prepare a molten mixture of dimethyl sulfone and a high molecular polymer, and add the drug to the molten mixture when it is in a molten state and evenly disperse it. Preferably, In method 1, dimethyl sulfone is heated at a temperature T1, the melting point of dimethyl sulfone, until it is melted and clear, and then the drug is added, and the drug can withstand the high temperature T1 without deterioration; In the second method, the mixture of dimethyl sulfone and the third solvent is heated at a temperature T2 which is higher than or equal to the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone until it is melted and clarified, and then the drug is added, and the drug can withstand the high temperature T2 without deterioration; In method three, dimethyl sulfone and the drug are squeezed or ground under heating conditions, stirred, melted and mixed, and then cooled to obtain the product. In method 4, the high molecular polymer is selected from a high molecular polymer type surfactant, More preferably, In the third method, a third solvent is added during extrusion, grinding or stirring, and the third solvent is selected from a solvent that can dissolve dimethyl sulfone. More preferably, the mixture is heated and squeezed or ground and stirred at a temperature T2 which is higher than the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone. In method 2 and method 3, the third solvent is selected from water, methanol, ethanol, acetone, N,N-dimethylacetamide, N,N-dimethylformamide, acetone, ethyl acetate, tetrahydrofuran, In method 4, the high molecular polymer is selected from polysorbate, polyethylene glycol, sorbitan fatty acid ester, polyoxyethylene polyoxypropylene ether block copolymer, and polyvinyl pyrrolidone.

3. The solid dispersion according to claim 1, which is a solid solution, can be prepared by at least one of the following three methods: Method 1: The dimethyl sulfone in a molten clear state is uniformly dispersed and dissolved with the drug to obtain a molten clear solution; Cooling the molten clarified solution to obtain the solid solution; The amount of drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state. Method 2: uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a molten clear solution; The molten solution is cooled and the third solvent is removed to obtain the solid solution; The amount of drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state. Method 3: The dimethyl sulfone and the drug are hot-melt extruded, and the mixture is in a molten clear state during the hot-melt extrusion; preferably, a third solvent is added to the dimethyl sulfone and the drug for hot-melt extrusion, and the mixture is in a molten clear state during the hot-melt extrusion. The amount of the drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state, or the amount of the drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state. Method 4: The method comprises preparing a molten clarified mixture of dimethyl sulfone and a high molecular polymer, and adding a drug to the molten clarified mixture when the molten mixture is in a molten clarified state to obtain the molten clarified mixture. The amount of drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone and high molecular polymer mixed system in the molten clear state, or the amount of drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state. Preferably, In method 1, dimethyl sulfone is heated at a temperature T1, the melting point of dimethyl sulfone, until it is melted and clear, and then the drug is added, and the drug can withstand the high temperature T1 without deterioration; In the second method, the mixture of dimethyl sulfone and the third solvent is heated at a temperature T2 which is higher than or equal to the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone until it is melted and clarified, and then the drug is added, and the drug can withstand the high temperature T2 without deterioration; In method three, dimethyl sulfone and the drug are squeezed or ground under heating conditions, stirred, melted and mixed, and then cooled to obtain the product. In method 4, the high molecular polymer is selected from a high molecular polymer type surfactant, More preferably, In the third method, a third solvent is added during extrusion, grinding or stirring, and the third solvent is selected from a solvent that can dissolve dimethyl sulfone. More preferably, Heating and extruding or grinding and stirring at a temperature T2 higher than the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone, In method 2 and method 3, the third solvent is selected from water, methanol, ethanol, acetone, N,N-dimethylacetamide, N,N-dimethylformamide, acetone, ethyl acetate, tetrahydrofuran, In method 4, the high molecular polymer is selected from polysorbate, polyethylene glycol, sorbitan fatty acid ester, polyoxyethylene polyoxypropylene ether block copolymer, and polyvinyl pyrrolidone.

4. The solid dispersion according to claim 1, which is a solid solution, has a melting point of 106.5-110.5°C, and is tested by X-ray powder diffraction, Cu-Kα radiation, and the characteristic peaks of the X-ray powder diffraction pattern represented by the diffraction angle 2θ are 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1°.

5. The solid dispersion according to claim 1, wherein The drug is selected from sildenafil, tadalafil, and nifedipine.

6. The solid dispersion according to claim 5, which is a solid solution, substantially composed of a dispersant, dimethyl sulfone, and a drug, sildenafil, wherein the mass percentage of the drug is not greater than 14.2%, preferably 5.0%, 7.5% and 10.0%; Its melting point is 106.5-108.5°C for initial melting and 109.5-110.5°C for final melting; or The prepared dimethyl sulfone sildenafil solid solution was subjected to X-ray powder diffraction test, Cu-Kα radiation, and the characteristic peaks of the X-ray powder diffraction pattern represented by the diffraction angle 2θ were 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1°.

7. The solid dispersion according to claim 5, which is a solid solution, substantially composed of a dispersant, dimethyl sulfone, and a drug, tadalafil, wherein the mass percentage of the drug is not greater than 10.7%, preferably 5.0%, 7.5% and 10.0%; Its melting point is 107.5-108.5°C for initial melting and 109.5-110.5°C for final melting; or The prepared dimethyl sulfone tadalafil solid solution was subjected to X-ray powder diffraction test, Cu-Kα radiation, and the characteristic peaks of the X-ray powder diffraction pattern represented by the diffraction angle 2θ were 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, and 33.1±0.1°.

8. A method for preparing a solid dispersion containing dimethyl sulfone, wherein the solid dispersion is essentially composed of a dispersant dimethyl sulfone and at least one drug. Method 1: The dimethyl sulfone in a molten clear state is evenly dispersed with the drug to obtain a dispersed system in a molten state; Cooling the molten dispersion to obtain the solid dispersion; Method 2: The dimethyl sulfone, the third solvent mixture and the drug in a molten clear state are uniformly dispersed to obtain a molten dispersion system; The solid dispersion is obtained by cooling the molten dispersion system and removing the third solvent; Method 3: The dimethyl sulfone and the drug are extruded or ground, stirred, melted and mixed, and then cooled to obtain the product. Preferably, a third solvent is added to the dimethyl sulfone and the drug for extrusion or grinding and stirring. Preferably, In method 1, dimethyl sulfone is heated at a temperature T1, the melting point of dimethyl sulfone, until it is melted and clear, and then the drug is added. The drug can withstand the high temperature T1 without deterioration. In the second method, the mixture of dimethyl sulfone and the third solvent is heated at a temperature T2 which is higher than or equal to the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone until it is melted and clarified, and then the drug is added, and the drug can withstand the high temperature T2 without deterioration. In method three, dimethyl sulfone and the drug are squeezed or ground under heating conditions, stirred, melted and mixed, and then cooled to obtain the product. More preferably, In the third method, a third solvent is added during extrusion, grinding or stirring, and the third solvent is selected from an organic solvent that can dissolve dimethyl sulfone. More preferably, Heating and extruding or grinding and stirring at a temperature T2 higher than the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone, In method 2 and method 3, the third solvent is selected from water, methanol, ethanol, acetone, N,N-dimethylacetamide, N,N-dimethylformamide, acetone, ethyl acetate, and tetrahydrofuran.

9. A method for preparing a solid solution containing dimethyl sulfone, wherein the solid solution is essentially composed of a dispersant dimethyl sulfone and at least one drug. Method 1: The dimethyl sulfone in a molten clear state is uniformly dispersed and dissolved with the drug to obtain a molten clear solution; Cooling the molten clarified solution to obtain the solid solution; The amount of drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state. Method 2: uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a molten clear solution; The molten solution is cooled and the third solvent is removed to obtain the solid solution; The amount of drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state. Method 3: The dimethyl sulfone and the drug are hot-melt extruded, and the mixture is in a molten clear state during the hot-melt extrusion; or the dimethyl sulfone, the drug and a third solvent are hot-melt extruded, and the mixture is in a molten clear state during the hot-melt extrusion. The amount of the drug added should be less than or equal to the saturated drug dissolution amount of the mixed system of dimethyl sulfone and the third solvent in the molten clear state, or the amount of the drug added should be less than or equal to the saturated drug dissolution amount of dimethyl sulfone in the molten clear state. Preferably, In method 1, dimethyl sulfone is heated at a temperature T1, the melting point of dimethyl sulfone, until it is melted and clear, and then the drug is added. The drug can withstand the high temperature T1 without deterioration. In the second method, the mixture of dimethyl sulfone and the third solvent is heated at a temperature T2 which is higher than or equal to the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone until it is melted and clarified, and then the drug is added, and the drug can withstand the high temperature T2 without deterioration. In method three, dimethyl sulfone and the drug are squeezed or ground under heating conditions, stirred, melted and mixed, and then cooled to obtain the product. More preferably, In the third method, a third solvent is added during extrusion, grinding or stirring, and the third solvent is selected from a solvent that can dissolve dimethyl sulfone. More preferably, Heating and extruding or grinding and stirring at a temperature T2 higher than the boiling point of the third solvent and lower than or equal to the melting point of dimethyl sulfone, In method 2 and method 3, the third solvent is selected from water, methanol, ethanol, acetone, N,N-dimethylacetamide, N,N-dimethylformamide, acetone, ethyl acetate, and tetrahydrofuran.

10. Use of a solid dispersion containing dimethyl sulfone in the preparation of a pharmaceutical preparation, wherein the solid dispersion essentially consists of a dispersant dimethyl sulfone and at least one drug.

11. A pharmaceutical preparation comprising a solid dispersion of dimethyl sulfone, wherein the solid dispersion consists essentially of a dispersant dimethyl sulfone and at least one drug.

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