Solid dispersion containing dimethyl sulfone, and use thereof

Abstract

A solid dispersion containing dimethyl sulfone and the use thereof. The solid dispersion contains a dispersant, i.e., dimethyl sulfone and at least one drug, and is preferably substantially composed of the dispersant dimethyl sulfone and at least one drug. The solid dispersion is prepared by means of the following four methods: method I: uniformly dispersing dimethyl sulfone and a drug in a molten clear state so as to obtain a dispersion system in a molten state, and cooling the dispersion system in a molten state so as to obtain a solid dispersion; method II: uniformly dispersing dimethyl sulfone in a molten clear state, a third solvent mixture and a drug so as to obtain a dispersion system in a molten state, cooling the dispersion system in a molten state, and removing the third solvent so as to obtain a solid dispersion; method III: extruding or grinding dimethyl sulfone and a drug, and then stirring, melting, mixing, and cooling same, so as to obtain a solid dispersion; and method IV: preparing a molten mixture of dimethyl sulfone and a high-molecular polymer, adding a drug when the melting mixture is in a molten state, and uniformly dispersing same, so as to obtain a solid dispersion. The solid dispersion can be used for preparing pharmaceutical preparations.

Description

Solid dispersion containing dimethyl sulfone and its application Technical Field

[0001] The invention relates to solid dispersions and belongs to the technical field of pharmaceutical 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 researchers. 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:toward filing 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."Pharmaceutical amorphous solid dispersion:A review of manufacturing strategies." Acta pharmaceutica Sinica.B vol.11,8(2021):2505-2536.doi:10.1016 / j.apsb.2021.05.014).

[0003] Solid dispersions (SDs) are solid dispersions of drugs, especially poorly soluble solid drugs, dispersed in a suitable carrier material in a highly dispersed state, either molecularly, colloidal, microcrystalline, or amorphously. The formulation technology used to create these drugs is called solid dispersion technology.

[0004] Depending on whether the drug is dispersed in the carrier material (dispersant) in a saturated state and the drug's form after supersaturation: molecular, colloidal, microcrystalline, or amorphous, the resulting solid dispersion can be classified into the following categories: solid solution, coprecipitate, and eutectic mixture (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] In a solid solution, the drug is dissolved in a solid carrier in a molecular state to form a homogeneous system. The drug dispersion in a solid solution is often higher than that in a eutectic mixture, resulting in a particularly rapid dissolution rate. In this case, the drug concentration (content) in the carrier is equal to or less than the carrier's solubility for the drug.

[0006] Coprecipitate, a non-crystalline amorphous material 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] In a low-melting mixture, the drug and the carrier are melted together into a completely miscible liquid, stirred evenly, and rapidly cooled and solidified to form 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 for the drug.

[0008] The carrier materials used in drugs currently 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 Gelucire 44 / 14 (polyethylene glycol glyceride) and the like.

[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 solid dispersions with most drugs, it will greatly solve the above problems.

[0011] More importantly, using the above-mentioned high molecular weight polymers as dispersants often fails to truly dissolve the drug into a molecular state (even in a molten state, the high molecular weight 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. This system 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.

[0013] Summary of the Invention

[0014] Based on years of research and development experience, the inventors of this application have creatively proposed the use of dimethyl sulfone (MSM) as a dispersant for a new solid dispersion. Through experiments, a universal dimethyl sulfone solid dispersion system has been preliminarily determined. This system can melt, clarify, and dissolve / disperse drugs at relatively low temperatures (below 110°C) using a direct melting method or other methods to ultimately form a solid dispersion. Preliminary experiments have demonstrated that this system is applicable to a variety of drugs of different polarities and can improve solubility and dissolution rate.

[0015] 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.

[0016] To this end, the applicant provides a technical solution for a solid dispersion containing dimethyl sulfone and its application.

[0017] The solid dispersion containing dimethyl sulfone contains dimethyl sulfone as a dispersant and at least one drug; preferably, it essentially consists of the dispersant dimethyl sulfone and at least one drug.

[0018] 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.

[0019] Method 1:

[0020] The dimethyl sulfone in the molten clear state is uniformly dispersed with the drug to obtain a dispersed system in the molten state;

[0021] Cooling the molten dispersion to obtain the solid dispersion;

[0022] Method 2:

[0023] uniformly dispersing dimethyl sulfone, a third solvent mixture and the drug in a molten clear state to obtain a molten dispersion system;

[0024] Cooling the molten dispersion system and removing the third solvent to obtain the solid dispersion;

[0025] Method 3:

[0026] The dimethyl sulfone and the drug are extruded or ground, stirred, melted and mixed, and then cooled. Preferably, a third solvent is added to the dimethyl sulfone and the drug, and the mixture is extruded or ground and stirred;

[0027] Method 4:

[0028] The method comprises preparing a molten mixture of dimethyl sulfone and a high molecular polymer, and adding the drug to the molten mixture and uniformly dispersing the drug when the molten mixture is in a molten state.

[0029] 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.

[0030] Method 1:

[0031] The dimethyl sulfone in a molten clear state is uniformly dispersed and dissolved with the drug to obtain a molten clear solution;

[0032] Cooling the molten clear solution to obtain the solid solution;

[0033] 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.

[0034] Method 2:

[0035] uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a molten clear solution;

[0036] Cooling the molten solution and removing the third solvent to obtain the solid solution;

[0037] 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.

[0038] Method 3:

[0039] 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.

[0040] The amount of drug added should be less than or equal to the saturated drug solubility of the mixed system of dimethyl sulfone and the third solvent in the molten clear state, or the amount of drug added should be less than or equal to the saturated drug solubility of dimethyl sulfone in the molten clear state.

[0041] Method 4:

[0042] Prepare a molten clear mixture of dimethyl sulfone and high molecular polymer, and add the drug to the molten clear mixture when the molten mixture is in a molten clear state to melt and clarify.

[0043] The amount of the added drug 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 added drug should be less than or equal to the saturated drug solubility of dimethyl sulfone in a molten clear state.

[0044] The solid dispersion contains dimethyl sulfone and at least one drug, wherein the drug is a raw material drug (API).

[0045] API refers to the raw material drug used in the production of various preparations. It is the active ingredient in the preparation. It is a substance prepared by chemical synthesis, plant extraction or biotechnology for various medicinal purposes, such as powders, crystals, extracts, etc., but cannot be taken directly by patients.

[0046] In this application, APIs refer to registered APIs that have been approved for marketing in various countries and regions (marketed APIs) and APIs that are in the research stage and are expected to be approved for marketing (candidate APIs).

[0047] In this application, the drugs in the marketed APIs and candidate APIs include human drugs (pharmaceuticals) and drugs for other animals (veterinary drugs), plant protection drugs, animal control drugs (pesticides), etc. In short, the pharmaceutical preparations here are broad in scope, including traditional medicines, veterinary drugs and pesticides. Correspondingly, the same applies to marketed APIs and candidate APIs.

[0048] Marketed active pharmaceutical ingredients for human use (active pharmaceutical ingredients 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.

[0049] Marketed veterinary drugs or animal health products (raw materials used in veterinary drug production) can be found on the official websites of veterinary drug or animal health product departments in various countries and regions, such as the 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.

[0050] Marketed pesticides (APIs used in veterinary drug production) can be found on the official websites of veterinary drug or animal health product departments in various countries and regions, such as the U.S. EPA, the Pesticide Control Institute of the Ministry of Agriculture and Rural Affairs of China, the European Food Safety Authority (EFSA), and the Pesticide Inspection Service (ACIS) of the Center for Agricultural, Forestry and Fisheries Consumer Safety (FAMIC) of the Ministry of Agriculture, Forestry and Fisheries of Japan (MAFF).

[0051] In certain embodiments, the solid dispersion "consists of xxx" 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, no other intentionally and artificially added substances are contained. However, trace amounts of impurities, environmental substances, etc. will inevitably exist.

[0052] This does not apply to the detection of other substances (environmental substances) during the manufacturing process due to contact or contamination of containers, pipes, or tools. Similarly, dimethyl sulfone and drug APIs are inevitably contaminated with impurities or other substances (impurities) in the environment; these impurities or environmental substances are also not subject to this restriction.

[0053] All other substances (environmental substances), dimethyl sulfone and drug raw materials detected due to contact or contamination of containers, pipes, tools, which are inevitably contaminated with impurities or other substances (impurities) in the environment, should be within the legal limits or comply with the corresponding product (pharmaceutical grade, medical grade or equivalent quality standards) quality standards.

[0054] In certain embodiments, in order to increase the solubility of the molten dimethyl sulfone in the drug substance or form a uniform dispersion system (emulsion or suspension), a small amount of high molecular polymer surfactant may be added, such as polysorbate (Tween, Tween type, including various brands) and polyethylene glycol (PEG, including various brands), anhydrous sorbitan fatty acid ester (Span, Span type, including various brands), polyoxyethylene polyoxypropylene ether block copolymer (Poloxamer, poloxamer, including various brands), polyvinyl pyrrolidone (PVP, including various brands), etc.

[0055] In some cases, for certain 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.

[0056] In certain embodiments, a third solvent may be added to lower the melting temperature of dimethyl sulfone, thereby allowing the drug substance with slightly poor thermal stability to melt after addition.

[0057] Whether a surfactant or a third solvent is added, the solid dispersion will contain other substances in addition to drugs and dimethyl sulfone.

[0058] Solid dispersions can be prepared by at least one of the following four methods:

[0059] Method 1:

[0060] The dimethyl sulfone in the molten clear state is uniformly dispersed with the drug to obtain a dispersed system in the molten state;

[0061] Cooling the molten dispersion to obtain the solid dispersion;

[0062] Method 2:

[0063] uniformly dispersing dimethyl sulfone, a third solvent mixture and the drug in a molten clear state to obtain a molten dispersion system;

[0064] Cooling the molten dispersion system and removing the third solvent to obtain the solid dispersion;

[0065] Method 3:

[0066] The dimethyl sulfone and the drug are extruded or ground, stirred, melted and mixed, and then cooled. Preferably, a third solvent is added to the dimethyl sulfone and the drug, and the mixture is extruded or ground and stirred;

[0067] Method 4:

[0068] The method comprises preparing a molten mixture of dimethyl sulfone and a high molecular polymer, and adding the drug to the molten mixture and uniformly dispersing the drug when the molten mixture is in a molten state.

[0069] Depending on whether the amount of drug substance added during preparation reaches saturation, the prepared solid dispersion can be further divided into solid solution and coprecipitate and low eutectic mixture of non-solid solution. When the amount of drug substance added is less than or equal to the amount of solubility saturation, the prepared solid dispersion is a solid solution; when the amount of drug substance added is greater than the amount of solubility saturation, the prepared solid dispersion is a non-solid solution: coprecipitate, low eutectic mixture.

[0070] Obviously, correspondingly, the solid solution can be prepared by at least one of the following four methods:

[0071] Method 1:

[0072] The dimethyl sulfone in a molten clear state is uniformly dispersed and dissolved with the drug to obtain a molten clear solution;

[0073] Cooling the molten clear solution to obtain the solid solution;

[0074] 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.

[0075] Method 2:

[0076] uniformly dispersing dimethyl sulfone, a third solvent mixture and a drug in a molten clear state to obtain a molten clear solution;

[0077] Cooling the molten solution and removing the third solvent to obtain the solid solution;

[0078] 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.

[0079] Method 3:

[0080] 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.

[0081] The amount of drug added should be less than or equal to the saturated drug solubility of the mixed system of dimethyl sulfone and the third solvent in the molten clear state, or the amount of drug added should be less than or equal to the saturated drug solubility of dimethyl sulfone in the molten clear state.

[0082] Method 4:

[0083] Prepare a molten clear mixture of dimethyl sulfone and high molecular polymer, and add the drug to the molten clear mixture when the molten mixture is in a molten clear state to melt and clarify.

[0084] The amount of the added drug 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 added drug should be less than or equal to the saturated drug solubility of dimethyl sulfone in a molten clear state.

[0085] Since dimethyl sulfone is a small molecule organic compound and is crystalline (white needle-shaped crystals), its melting point is 107-111°C. Since its melting point is relatively low, it can be prepared by melting method and grinding extrusion method for solid dispersion.

[0086] The melt method involves heating dimethyl sulfone. Once the solution is molten and clear, the API is added and stirred to dissolve or disperse the solution. In some cases, to lower the melting temperature, a third solvent can be added to the dimethyl sulfone to create a semisolid mixture. The mixture is then heated again to melt, and the API is added and stirred to mix.

[0087] In some cases, solid dispersions of dimethyl sulfone can be prepared by extrusion or by mixing with grinding and stirring. For example, the drug and dimethyl sulfone can be ground and extruded in a mortar or directly fed into a hot-melt extrusion (HME) apparatus. Similar to the melt method, a third solvent or surfactant can be added during the extrusion, grinding, or stirring process.

[0088] Preferably, in method 1, dimethyl sulfone is heated at the melting point T1 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;

[0089] 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 clear, and then the drug is added, and the drug can withstand the high temperature T2 without deterioration;

[0090] In the third method, dimethyl sulfone and the drug are extruded or ground under heating conditions, stirred, melted, mixed, and then cooled to obtain the product.

[0091] In the fourth method, the high molecular weight polymer is selected from high molecular weight polymer type surfactants.

[0092] Obviously, if the added drug substance quickly deteriorates and breaks down when heated to the melting point of dimethyl sulfone, T1, then this method is unsuitable for its preparation. Therefore, the drug substance added after heating to T1, the melting point of dimethyl sulfone, should be able to withstand the high temperature of T1 without deteriorating. More precisely, experimental screening should be conducted to identify drugs that are stable at T1 for a period of time, which should be no less than the time it takes for the drug to dissolve in the molten dimethyl sulfone and stir until it becomes clear.

[0093] In some embodiments, a third solvent is added to lower the heating temperature T2 required for dimethyl sulfone to melt and clear. This is because the addition of the third solvent partially dissolves the solid dimethyl sulfone, resulting in a final melting point lower than its melting point T1. Similarly, in this case, experimental screening should be conducted to identify drugs that are stable at T2 for a period of time, which should be no less than the time it takes for the drug to dissolve in the molten dimethyl sulfone-third solvent mixture and stir until it clears.

[0094] 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.

[0095] In order to make dimethyl sulfone melt faster during the extrusion, grinding or stirring process, heating can also be used.

[0096] 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.

[0097] More preferably, the mixture is heated 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 and subjected to extrusion, grinding, or stirring.

[0098] 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.

[0099] In the fourth method, the high molecular polymer is selected from polysorbate, polyethylene glycol, sorbitan fatty acid ester, polyoxyethylene polyoxypropylene ether block copolymer, and polyvinyl pyrrolidone.

[0100] The final solid dispersion can be pulverized to obtain powder for subsequent preparation processing.

[0101] In certain embodiments, in order to obtain a solid dispersion with a high drug content, if the drug substance fails to completely dissolve and clarify after being added to molten dimethyl sulfone, a surfactant may be added to increase the solubility or improve the dispersion, thereby increasing the final drug content. Of course, adding an appropriate amount of a third solvent to form a composite solvent of the third solvent and dimethyl sulfone melt can also increase the solubility.

[0102] 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-dried to remove the third solvent. The drying temperature is preferably not more than 60°C, and the recommended temperature is 45-55°C.

[0103] 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°.

[0104] Since dimethyl sulfone is a crystalline substance, when it is melted, the drug raw material is added to dissolve it to 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 the experiment have a special melting point and characteristic peaks.

[0105] The drug is selected from sildenafil, tadalafil, nifedipine, finasteride, celecoxib, and verapamil hydrochloride.

[0106] Sildenafil-dimethyl sulfone solid dispersion is a solid solution, which is essentially composed of the dispersant dimethyl sulfone and the drug sildenafil. The mass percentage of the drug is not more than 14.2%, preferably 5.0%, 7.5% and 10.0%; its melting point is 106.5-108.5℃ for initial melting and 109.5-110.5℃ for final melting.

[0107] The prepared dimethyl sulfone sildenafil solid solution was tested by X-ray powder diffraction using Cu-Kα radiation. The characteristic peaks of the X-ray powder diffraction pattern expressed 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°.

[0108] Experimental tests have shown that sildenafil has good stability in a molten dimethyl sulfone solution and will not undergo obvious 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.

[0109] In particular, it was found through testing that the mass percentage of sildenafil in a sildenafil saturated solution of dimethyl sulfone in a molten state is no more than 14.2%.

[0110] 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.

[0111] Tadalafil-dimethyl sulfone solid dispersion, which is a solid solution consisting essentially of dimethyl sulfone as the dispersant and tadalafil as the drug, with the mass percentage of the drug not exceeding 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 dissolution;

[0112] The prepared dimethyl sulfone tadalafil solid solution was tested by X-ray powder diffraction using Cu-Kα radiation. The characteristic peaks of the X-ray powder diffraction pattern expressed 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°.

[0113] Experimental testing has shown that tadalafil is not very stable in molten dimethyl sulfone solution, quickly undergoing significant deterioration, destruction, and degradation at a melting temperature of 112°C. Therefore, a third solvent, such as ethanol, should be added during preparation to help lower the melting temperature. Adding an appropriate amount of a third solvent, such as ethanol, can lower the melting temperature of the mixed system to 80°C, where it remains stable even after heating for two hours.

[0114] In particular, after testing, it was found that the mass percentage of tadalafil in a saturated solution of tadalafil in molten dimethyl sulfone after adding an appropriate amount of ethanol was no more than 10.7%. Similarly, a grinding method can also be used for preparation.

[0115] Nifedipine-dimethyl sulfone solid dispersion is a solid solution, which is essentially composed of dispersant dimethyl sulfone and drug nifedipine, with the mass percentage of the drug being no more than 30%.

[0116] The prepared dimethyl sulfone nifedipine solid solution was tested by X-ray powder diffraction using Cu-Kα radiation. The characteristic peaks of the X-ray powder diffraction pattern expressed 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°.

[0117] Nifedipine-dimethyl sulfone solid dispersion is a solid solution, which is essentially composed of dispersant dimethyl sulfone, high molecular polymer, and drug nifedipine, with the mass percentage of the drug being no more than 30%.

[0118] The prepared dimethyl sulfone nifedipine solid solution was subjected to X-ray powder diffraction test, Cu-Kα radiation, and the characteristic peaks of the X-ray powder diffraction pattern expressed 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°.

[0119] Preferably, the high molecular weight polymer is selected from high molecular weight polymer type surfactants,

[0120] More preferably, the high molecular polymer is selected from polysorbate, polyethylene glycol, sorbitan fatty acid ester, polyoxyethylene polyoxypropylene ether block copolymer, and polyvinyl pyrrolidone.

[0121] The addition of such polymers may increase the solubility of the API during melting, thereby preparing a solid solution with a higher drug loading. It may also improve or enhance the dissolution profile during subsequent dissolution, thereby better achieving controlled release (immediate or sustained release). The selection and dosage of such materials require experimental exploration.

[0122] Experimental testing has shown that nifedipine exhibits good stability in molten dimethyl sulfone solution, with no significant deterioration, damage, or degradation occurring at a melting temperature of 120°C. Therefore, the addition of a third solvent to lower the melting temperature is unnecessary during preparation. However, the addition of an appropriate amount of a third solvent, such as ethanol, can lower the melting temperature of the mixed system.

[0123] In particular, it has been found through testing that the mass percentage of nifedipine in a saturated solution of nifedipine in molten dimethyl sulfone is no more than 30%.

[0124] Finasteride-dimethyl sulfone solid dispersion, which is a solid solution consisting essentially of dimethyl sulfone as the dispersant and finasteride as the drug, with the drug percentage by weight not exceeding 13%; its melting point is 106.5-108.5°C for initial melting and 109.5-110.5°C for final melting;

[0125] The prepared dimethyl sulfone finasteride solid solution was tested by X-ray powder diffraction using Cu-Kα radiation. The characteristic peaks of the X-ray powder diffraction pattern expressed 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°.

[0126] Experimental testing has shown that finasteride exhibits good stability in molten dimethyl sulfone solution, with no significant deterioration, damage, or degradation occurring within a short period of time at a melting temperature of 122°C. Therefore, the addition of a third solvent to lower the melting temperature is unnecessary during preparation. However, the addition of an appropriate amount of a third solvent, such as ethanol, can reduce the melting temperature of the mixed system to 100°C.

[0127] In particular, it was found through testing that the mass percentage of finasteride in the finasteride saturated solution of dimethyl sulfone in the molten state is no more than 13%.

[0128] Celecoxib-dimethyl sulfone solid dispersion is a solid solution consisting essentially of dimethyl sulfone as a dispersant and celecoxib as a drug, with the mass percentage of the drug being no more than 27%. It has an initial melting point of 106.5-108.5°C and a final melting point of 109.5-110.5°C.

[0129] The prepared dimethyl sulfone celecoxib solid solution was tested by X-ray powder diffraction using Cu-Kα radiation. The characteristic peaks of the X-ray powder diffraction pattern expressed 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°.

[0130] Experimental testing has shown that celecoxib exhibits good stability in molten dimethyl sulfone solution, with no significant deterioration, damage, or degradation occurring within a short period of time at a melting temperature of 124°C. Therefore, the addition of a third solvent to lower the melting temperature is unnecessary during preparation. However, the addition of an appropriate amount of a third solvent, such as ethanol, can reduce the melting temperature of the mixed system to 100°C.

[0131] In particular, it was found through testing that the mass percentage of celecoxib in a saturated solution of celecoxib in molten dimethyl sulfone was no more than 27%.

[0132] Verapamil hydrochloride-dimethyl sulfone solid dispersion is a solid solution consisting essentially of dimethyl sulfone as the dispersant and verapamil hydrochloride as the drug, with the mass percentage of the drug being no more than 9%. It has a melting point of 106.5-108.5°C for initial melting and 109.5-110.5°C for final dissolution.

[0133] The prepared dimethyl sulfone verapamil hydrochloride solid solution was tested by X-ray powder diffraction using Cu-Kα radiation. The characteristic peaks of the X-ray powder diffraction pattern expressed 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°.

[0134] Experimental testing has shown that verapamil hydrochloride exhibits good stability in molten dimethyl sulfone solution, with no significant deterioration, damage, or degradation occurring within a short period of time at a melting temperature of 122°C. Therefore, the addition of a third solvent to lower the melting temperature is unnecessary during preparation. However, the addition of an appropriate amount of a third solvent, such as ethanol, can reduce the melting temperature of the mixed system to 100°C.

[0135] In particular, it has been found through testing that the mass percentage of verapamil hydrochloride in a saturated solution of verapamil hydrochloride in molten dimethyl sulfone is no more than 27%.

[0136] During the actual heating and melting process, the volume-to-mass ratio of ethanol to dimethyl sulfone is 1.0 ml: 3.0-5.0 g. This volume-to-mass ratio dissolves dimethyl sulfone into a thick paste, which yields a clear solution upon heating. The corresponding heating temperature is preferably 80°C-100°C.

[0137] The invention relates to an application of a solid dispersion containing dimethyl sulfone in the preparation of a pharmaceutical preparation. The solid dispersion is essentially composed of a dispersant dimethyl sulfone and at least one drug.

[0138] The pharmaceutical preparation contains a solid dispersion of dimethyl sulfone, which is essentially composed of a dispersant dimethyl sulfone and at least one drug.

[0139] The medicine or preparation in this application may further contain pharmaceutically acceptable excipients or excipients. Of course, the solid dispersion powder may also be directly compressed to prepare tablets or granulated to prepare granules or capsules.

[0140] The drug can be in any dosage form for clinical administration, such as tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated tablets, granules, dry powders, oral solutions, small needles for injection, lyophilized powders for injection, or large infusions.

[0141] Since solid dispersions have better oral absorption properties than drug substances, they may be more advantageous when prepared as oral dosage forms.

[0142] Depending on the specific dosage form and mode of administration, the pharmaceutically acceptable excipients or excipients 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.

[0143] In particular, unless otherwise specified, all numerical values ​​in the specification have a range of ±10%. That is, if a numerical range in the specification is 2-3, then in fact, due to the existence of measurement errors, random errors, and systematic errors, if the actual measurement is 1.8-3.3, it should also be deemed to fall within the above-mentioned range of 2-3, which also meets the requirements. BRIEF DESCRIPTION OF THE DRAWINGS

[0144] Figure 1 is a comparative XRD graph of a 5% sildenafil + MSM melt sample, a 5% sildenafil + MSM physical mixture sample, an MSM sample, and a sildenafil sample, wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0145] Figure 2 is a comparative XRD graph of a 7.5% sildenafil + MSM melt sample, a 7.5% sildenafil + MSM physical mixture sample, an MSM sample, and a sildenafil sample, wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0146] Figure 3 is a comparative XRD graph of a 10% sildenafil + MSM melt sample, a 10% sildenafil + MSM physical mixture sample, an MSM sample, and a sildenafil sample, wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0147] Figure 4 is a comparison of XRD patterns of a 5% tadalafil + MSM melt sample, a 5% tadalafil + MSM physical mixture sample, an MSM sample, and a tadalafil sample, wherein the middle graph is an enlarged view of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged view of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0148] Figure 5 is a comparative XRD graph of a 7.5% tadalafil + MSM melt sample, a 7.5% tadalafil + MSM physical mixture sample, an MSM sample, and a tadalafil sample, wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0149] Figure 6 is a comparative XRD graph of a 10% tadalafil + MSM melt sample, a 10% tadalafil + MSM physical mixture sample, an MSM sample, and a tadalafil sample, wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0150] Figure 7 is a comparative XRD graph of a 5% tadalafil + MSM ground sample, a 5% tadalafil + MSM physical mixture sample, an MSM sample, and a tadalafil sample, wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0151] Figure 8 is a comparative XRD graph of a 10% tadalafil + MSM ground sample, a 10% tadalafil + MSM physical mixture sample, an MSM sample, and a tadalafil sample, wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0152] Figure 9 is a comparative XRD pattern of nifedipine, dimethyl sulfone, a 10% nifedipine + MSM solid solution sample, and a nifedipine: dimethyl sulfone (1:9) physical mixture sample, wherein the middle figure is an enlarged view of the 2θ refraction angle (X-axis) relative to the upper figure, and the lower figure is an enlarged view of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper figures;

[0153] Figure 10 is a comparison of XRD patterns of nifedipine, dimethyl sulfone, PEG4000, a solid solution of nifedipine:dimethyl sulfone:PEG4000 (2:9:9, formulation 2), and a physical mixture of nifedipine:dimethyl sulfone:PEG4000 (2:9:9), wherein the middle figure is an enlarged view of the 2θ refraction angle (X-axis) relative to the upper figure, and the lower figure is an enlarged view of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper figures;

[0154] Figure 11 is a full-wavelength (200-700 nm) scan of the 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, and the lower right figure is the scan result of a nifedipine sample. The bottom figure is the result of superimposing the above four scan results on the same coordinate graph;

[0155] Figure 12 shows 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;

[0156] FIG13 shows the dissolution curves of a 10% by mass nifedipine MSM solid solution and a nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) solid solution in an aqueous solution containing a surfactant.

[0157] Figure 14 is a full-wavelength (200-700 nm) scan of the UV-visible absorbance of sildenafil and tadalafil aqueous solutions, wherein the upper figure is sildenafil and the lower figure is tadalafil;

[0158] Figure 15 shows the dissolution curves of sildenafil API and 7.5% by mass sildenafil MSM solid solution in pure water;

[0159] Figure 16 is the dissolution curve of tadalafil API and 7.5% by mass of tadalafil MSM solid solution in pure water;

[0160] Figure 17 is the dissolution curve of tadalafil API and 7.5% by mass tadalafil MSM solid solution in 0.25% sodium lauryl sulfate aqueous solution;

[0161] Figure 18 is a comparative XRD graph of finasteride (FNXA-01), dimethyl sulfone, and FNXA-03 samples (prepared by melting at 122°C), wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0162] Figure 19 is a comparative XRD graph of finasteride (FNXA-01), dimethyl sulfone, and FNXA-04 samples (heated at 100°C and added with ethanol), wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0163] Figure 20 is a comparison of XRD patterns of celecoxib (SLXB-01), dimethyl sulfone, and SLXB-03 samples (prepared by melting at 124°C), wherein the middle figure is an enlarged view of the 2θ refraction angle (X-axis) relative to the upper figure, and the lower figure is an enlarged view of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper figures;

[0164] Figure 21 is a comparative XRD graph of celecoxib (SLXB-01), dimethyl sulfone, and SLXB-04 samples (heated at 100°C and ethanol added), wherein the middle graph is an enlarged graph of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged graph of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs;

[0165] FIG22 is a comparative XRD pattern of verapamil hydrochloride (YSWLPM-01), dimethyl sulfone, and YSWLPM-03 samples (prepared by melting at 122° C.), wherein the middle pattern is an enlarged view of the 2θ refraction angle (X-axis) relative to the upper pattern, and the lower pattern is an enlarged view of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper patterns;

[0166] Figure 23 is a comparison of XRD patterns of verapamil hydrochloride, dimethyl sulfone, and YSWLPM-04 samples (heated at 100°C and with the addition of ethanol), wherein the middle graph is an enlarged view of the 2θ refraction angle (X-axis) relative to the upper graph, and the lower graph is an enlarged view of the 2θ refraction angle (X-axis) and peak height intensity (Y-axis) relative to the middle and upper graphs. DETAILED DESCRIPTION

[0167] The present invention is described below with reference to specific examples. Those skilled in the art will appreciate 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.

[0168] The description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can 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.

[0169] General Information

[0170] Sildenafil, tadalafil (tadalafil), and nifedipine are all free bases, and their specific chemical structures are as follows:

[0171] All were purchased from the market and were of pharmaceutical grade.

[0172] Unless otherwise specified in the following experiments, the detection or examination methods, instruments, etc. are as follows:

[0173] X-ray powder diffraction (XRD) was performed using a PANalytical-X" Pert 3 Powder (Netherlands). The test was performed using Cu-Kα at 25°C and 35% humidity. The sample was uniformly ground through a 100-mesh grinder. The refraction angle was expressed in 2θ to obtain an X-ray powder diffraction spectrum with an error of <0.01° over a scanning range of 3.0 to 60.0°.

[0174] Melting point measurements were made using the capillary method, and the initial and final melting points were recorded.

[0175] HPLC purity test, calculated using the area normalization method after HPLC detection.

[0176] The specific HPLC detection methods for sildenafil and tadalafil are as follows:

[0177] Sildenafil was determined using the content determination method for Sildenafil Citrate Tablets Ws1-(X-010)-2010Z published by the China Food and Drug Administration; or using the "related substance" method in "Sildenafil Citrate" on page 3786 of the European Pharmacopoeia.

[0178] Tadalafil was determined using the "related substance" method in the European Pharmacopoeia page 3957 "Tadalafifilum".

[0179] The detection of nifedipine, finasteride, celecoxib, verapamil hydrochloride, etc. are all carried out using the HPLC method specified in the corresponding chapters of the Chinese Pharmacopoeia.

[0180] The mass percentage of the saturated solution was determined using the HPLC method described above, and the mass percentage was quantitatively determined and calculated using the external standard method.

[0181] The UV absorption and full-band UV scanning spectra of the compounds were measured using a Thermo Fisher Evolution 201 / 220 UV-visible spectrophotometer.

[0182] 1. Preparation and characterization of sildenafil solid solution - melting method

[0183] Preparation of Sildenafil Solid Solution by Direct Melting Method

[0184] In a dry 50 ml two-necked flask, under nitrogen protection, 9.5 g of dimethyl sulfone was added and stirred. The temperature was controlled at 120-125 ° C in an oil bath until the solution was clear. 0.5 g of sildenafil was added and stirred to dissolve until clear. After 10 minutes, the solution was quickly transferred to a watch glass, wrapped in a sealed bag, and cooled naturally to room temperature. It was a waxy translucent solid. Samples were taken from different parts of the body and tested. The samples were labeled "5% Sildenafil + MSM melt".

[0185] In a dry 50 ml two-necked flask, under nitrogen protection, 9.0 g of dimethyl sulfone was added and stirred. The temperature was controlled at 120-125 ° C in an oil bath until the solution was clear. 1.0 g of sildenafil was added and stirred to dissolve until clear. After 10 minutes, the solution was quickly transferred to a watch glass, wrapped in a sealed bag, and naturally cooled to room temperature. It was a waxy translucent solid. Samples were taken from different parts of the body and tested. The samples were labeled "10% sildenafil + MSM melt".

[0186] In a dry 50 ml two-necked flask, under nitrogen protection, add 9.25 g of dimethyl sulfone, stir, and heat in an oil bath at 120-125 ° C. until the solution is clear. Add 0.75 g of sildenafil and stir to dissolve until clear. After 10 minutes, the solution is quickly transferred to a watch glass, wrapped in a sealed bag, and naturally cooled to room temperature. A waxy translucent solid is obtained. Samples are taken and the samples are labeled "7.5% Sildenafil + MSM melt".

[0187] In a dry 50ml two-necked flask, under nitrogen protection, 8.0g of dimethyl sulfone was added, stirred, and heated in an oil bath at 120-125°C. After dissolution and clarification, 2.0g of sildenafil was added and stirred. It was difficult to dissolve clearly, and solids precipitated at the bottom of the container. After stirring, it still could not be completely dissolved. This shows that the amount of sildenafil that dimethyl sulfone can dissolve in the molten state is limited. The supernatant of the above molten solution was taken and accurately weighed, and its saturation concentration was calculated to be 14.2% by mass of sildenafil.

[0188] Homogeneity testing of sildenafil solid solution prepared by direct melting method

[0189] HPLC analysis was performed on different parts of the waxy solid block of the 5% sildenafil + MSM molten sample and the 10% sildenafil + MSM molten sample. The results of the homogeneity test of the sildenafil solid solution are shown in Table 1.

[0190] Table 1: HPLC purity test results of 5 different samples of 5% and 10% sildenafil dimethyl sulfone solid solution

[0191] The mixed sample refers to a sample obtained by grinding and mixing the entire waxy translucent solid.

[0192] The results in Table 1 show that the sample has excellent homogeneity. It can be seen that during the preparation process by the melting method, no sildenafil precipitation occurs in the molten clear sildenafil dimethyl sulfone solution during the cooling process, and the prepared solid is a solid solution of sildenafil dimethyl sulfone.

[0193] High temperature stability test of sildenafil solid solution prepared by direct melting method

[0194] 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 with different melting times was carried out.

[0195] 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.

[0196] Table 2: HPLC purity test results of sildenafil stability test in sildenafil dimethyl sulfone molten solutions with different melting times

[0197] The experimental results in Table 2 show that within 30 minutes, the molten sildenafil dimethyl sulfone solution at the high melting temperature (approximately 120°C) exhibited good stability; however, as the melting time increased, the impurity growth was significant. Therefore, lowering the melting temperature can extend the heating and melting time, which is more conducive to large-scale production.

[0198] Solid solution XRD detection

[0199] In order to further prove that the final solid is a solid solution, an X-ray powder diffraction experiment was performed.

[0200] 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.

[0201] 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.

[0202] 5% sildenafil + MSM melt sample, the specific results are shown in Figure 1.

[0203] 7.5% sildenafil + MSM melt sample, the specific results are shown in Figure 2.

[0204] 10% sildenafil + MSM melt sample, the specific results are shown in Figure 3.

[0205] From the analysis of Figures 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°, which all disappear in the melt samples in Figures 1, 2, and 3, while the corresponding physical mixtures all exist. This shows that the sildenafil in the samples prepared after melting no longer shows crystalline characteristics.

[0206] Further comparison of the molten samples and dimethyl sulfone samples in Figures 1, 2, and 3 shows that the XRD characteristic peaks of the molten samples are the characteristic peaks of sildenafil dimethyl sulfone solid solution: 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.

[0207] Solid solution powder melting point detection

[0208] The melting point test results of the above 5% sildenafil + MSM melt sample, 7.5% sildenafil + MSM melt sample, 10% sildenafil + MSM melt sample and sildenafil are as follows:

[0209] 5% sildenafil + MSM melting sample, initial melting 108 ° C, final melting 110 ° C;

[0210] 7.5% sildenafil + MSM melting sample, initial melting 107 ° C, final melting 110 ° C;

[0211] 10% sildenafil + MSM melting sample, initial melting 107 ° C, final melting 110 ° C;

[0212] Sildenafil, initial melting point 189°C, final melting point 190°C;

[0213] 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 XRD spectrum comparison results.

[0214] 2. Preparation and Characterization of Tadalafil Solid Solution - Melt Preparation by Adding a Third Solvent

[0215] Homogeneity testing of tadalafil solid solution prepared by direct melting method

[0216] Based on the successful preparation of sildenafil solid solution by direct melting method, the feasibility study of preparing tadalafil solid solution by direct melting method was carried out to investigate the purity of tadalafil in different sampling parts after melting and cooling, and a uniformity test was performed for this purpose.

[0217] Add 9 g of dimethyl sulfoxide to a dry two-necked flask, protect with nitrogen, and heat in an oil bath until the solution is dissolved and clear. When the internal temperature reaches 112°C and sublimation occurs, add 1 g of tadalafil and stir until the solution is clear. After 10 minutes, quickly transfer the solution to a watch glass, wrap it in a sealed bag, and cool it naturally to room temperature. It becomes a waxy translucent solid. Samples are taken from different parts of the body for testing.

[0218] Samples were taken from different parts of the body for HPLC testing. The results of the tadalafil solid solution uniformity test are shown in Table 3.

[0219] Table 3: HPLC purity test results of 5 different sample portions of 10% tadalafil dimethyl sulfone solid solution (112°C)

[0220] The results in Table 3 show poor sample homogeneity. Furthermore, during the melt method, the clear molten tadalafil dimethyl sulfone solution deteriorated during the heating and cooling process. Due to uneven heating of various parts during the heating process, the degree of deterioration increased significantly. The high-temperature direct melt method is not suitable for preparing tadalafil dimethyl sulfone solid solutions.

[0221] High temperature stability test of tadalafil solid solution prepared by adding a third solvent

[0222] Relevant information and literature revealed that dimethyl sulfone can be effectively dissolved in solvents such as water, methanol, ethanol, acetone, N,N-dimethylacetamide, N,N-dimethylformamide, acetone, ethyl acetate, and tetrahydrofuran. Considering that adding an appropriate amount of such solvents in advance might melt dimethyl sulfone into a paste, thereby facilitating its melting at a lower temperature, the experiment used ethanol, which is commonly used and easily removed by subsequent heating.

[0223] In a dry two-necked flask, add 9 g of dimethyl sulfoxide, protect with nitrogen, add 18 ml of ethanol, and heat in an oil bath until dissolved and clear. The internal temperature is 80°C. Add 1 g of tadalafil and stir until clear. Intermittent sampling: 5 min, 10 min, 30 min, 60 min, and 120 min for detection as shown in Table 4 below.

[0224] Table 4: HPLC purity test results of tadalafil stability test in tadalafil dimethyl sulfone ethanol molten solutions with different melting times

[0225] From the experimental results in Table 4, it can be seen 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 growth of impurities is not obvious.

[0226] From the experiments and data in Table 3, it can be seen that adding the third solvent can lower the melting temperature of the mixture system, thereby prolonging the heating and melting time, which is more conducive to large-scale production.

[0227] Homogeneity test of tadalafil solid solution (80℃, 120℃) prepared by adding a third solvent

[0228] According to the experimental data in Table 4, after adding an appropriate amount of ethanol, the dimethyl sulfone-ethanol mixture 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 the addition of 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.

[0229] 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.

[0230] In a dry two-necked flask, add 9 g of dimethyl sulfoxide, protect with nitrogen, add 18 ml of ethanol, and heat in an oil bath until dissolved and clear. When the internal temperature is 80°C, add 1 g of tadalafil and stir until clear. Keep stirring for 2 hours, 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 of the body and tested.

[0231] Samples were taken from different parts of the body for HPLC testing. The results of the tadalafil solid solution uniformity test are shown in Table 5.

[0232] Table 5: HPLC purity test results of 5 different sample portions of 10% tadalafil dimethyl sulfone-ethanol solid solution (80°C, 120 min)

[0233] In a dry two-necked flask, 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, 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 of the body and tested.

[0234] Samples were taken from different parts of the body for HPLC testing. The results of the tadalafil solid solution uniformity test are shown in Table 6 below.

[0235] Table 6: HPLC purity test results of 7 different sample portions of 10% tadalafil dimethyl sulfone-ethanol solid solution (80°C, 5 min)

[0236] The results in Tables 5 and 6 show that the samples have excellent homogeneity. It can be seen that during the preparation of the tadalafil dimethyl sulfone-ethanol solid solution, no tadalafil precipitation occurred in the molten clear tadalafil dimethyl sulfone-ethanol solution during the cooling process, and the prepared solid is a solid solution of dimethyl sulfone tadalafil.

[0237] During the preparation process, the dissolution process is completed in a very short time (5 minutes) after heating, melting and clarifying to obtain a uniform solution, and the solid solution prepared after cooling has excellent uniformity.

[0238] XRD analysis of tadalafil dimethyl sulfone-ethanol solid solution

[0239] Add 9.5g of dimethyl sulfone to a dry 50ml two-necked flask and replace the atmosphere with nitrogen. Set the oil bath to 100°C, add approximately 2.5ml of anhydrous ethanol to the reaction flask, start stirring, and begin heating. At an internal temperature of approximately 80°C, the solid in the reaction flask will begin to slowly melt until completely dissolved. At an internal temperature of 85°C, add 0.5g of tadalafil and stir rapidly until clear. Quickly transfer the solution to a watch glass, wrap in a sealed bag, and allow to cool naturally to room temperature. A waxy, translucent solid will be obtained for testing. Label the sample "5% Tadalafil + MSM Melted."

[0240] Add 9.0 g of dimethyl sulfone to a dry 50 ml two-necked flask and replace the atmosphere with nitrogen. Set the oil bath to 100°C, add approximately 2.5 ml of anhydrous ethanol to the reaction flask, start stirring, and begin heating. At an internal temperature of approximately 80°C, the solid in the reaction flask will begin to slowly melt until completely dissolved. At an internal temperature of 85°C, add 1.0 g of tadalafil and stir rapidly until clear. Quickly transfer the solution to a watch glass, wrap in a sealed bag, and allow to cool naturally to room temperature. The solution will be a waxy, translucent solid. This sample will be tested and labeled "10% Tadalafil + MSM Melted."

[0241] To a dry 50ml two-necked flask, add 9.25g of dimethyl sulfone and replace the atmosphere with nitrogen. Set an oil bath to 100°C, add approximately 2.5ml of anhydrous ethanol to the reaction flask, start stirring, and begin heating. The solid in the reaction flask will begin to slowly melt at an internal temperature of approximately 80°C until all the solid has dissolved. At an internal temperature of 85°C, add 0.75g of tadalafil and stir rapidly until clear. Quickly transfer the solution to a watch glass, wrap in a sealed bag, and allow to cool naturally to room temperature. The solution will be a waxy, translucent solid. This sample will be tested and labeled "7.5% Tadalafil + MSM Melted."

[0242] 9.0 g of dimethyl sulfone was added to a dry 50 ml two-necked flask, and the atmosphere was replaced with nitrogen. The oil bath was set to 100 ° C, and about 2.5 ml 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. 1.5 g of tadalafil was added at an internal temperature of 85 ° C, stirred, and it was difficult to dissolve. Solids precipitated at the bottom of the container and 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 molten solution and accurately weigh the mass to determine and calculate its saturation concentration, which is 10.7% by mass of tadalafil.

[0243] 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 5% tadalafil + MSM physical mixing, 7.5% tadalafil + MSM physical mixing, and 10% tadalafil + MSM physical mixing samples.

[0244] Among them, tadalafil, dimethyl sulfone, 5% tadalafil + MSM melt sample, 7.5% tadalafil + MSM melt sample, and 10% tadalafil + MSM melt sample were all obtained by grinding in a white porcelain mortar and passing through a 100-mesh sieve. 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.

[0245] 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-necked bottle after grinding, and the ethanol was removed by vacuum at room temperature (vacuuming for about 30 minutes) before testing.

[0246] 5% Tadalafil + MSM melt sample, the specific results are shown in Figure 4.

[0247] 7.5% Tadalafil + MSM melt sample, the specific results are shown in Figure 5.

[0248] 10% Tadalafil + MSM melt sample, the specific results are shown in Figure 6.

[0249] Analysis of Figures 4-6 shows that the XRD characteristic peaks of tadalafil raw material are 7.33°, 10.71°, 12.57°, 13.51°, and 14.56°, which are weakened or even disappeared in the melt samples in Figures 4, 5, and 6, while the corresponding physical mixing is clearly present. This shows that the tadalafil in the samples prepared after melting no longer shows crystalline characteristics.

[0250] Further comparison of the molten samples and the dimethyl sulfone samples in Figures 4, 5, and 6 shows that the XRD characteristic peaks of the molten samples are the characteristic peaks of tadalafil dimethyl sulfone solid solution: 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.

[0251] Solid solution powder melting point detection

[0252] The melting point test results of the above 5% tadalafil + MSM melt sample, 7.5% tadalafil + MSM melt sample, 10% tadalafil + MSM melt sample and tadalafil are as follows:

[0253] 5% tadalafil + MSM melting sample, initial melting 108 ° C, final melting 110 ° C;

[0254] 7.5% tadalafil + MSM melting sample, initial melting 108 ° C, final melting 110 ° C;

[0255] The melting sample of 10% tadalafil + MSM had an initial melting point of 108°C and a final melting point of 110°C;

[0256] Tadalafil, initial melting point 289°C, final melting point 291°C;

[0257] 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 XRD spectrum comparison results.

[0258] 3. Preparation and Characterization of Tadalafil Solid Solution - Grinding Method

[0259] 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 "5% Tadalafil + MSM Grind".

[0260] 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 "10% Tadalafil + MSM Grind".

[0261] After grinding, the product was passed through a 100-mesh sieve for XRD analysis.

[0262] 5% tadalafil + MSM grinding sample, the specific results are shown in Figure 7.

[0263] 10% tadalafil + MSM grinding sample, the specific results are shown in Figure 8.

[0264] Comparing Figures 7 and 8, it can be seen that the diffraction peak of tadalafil at 7.33° in the ground sample is weakened compared to the physically mixed sample, especially the diffraction peak of 10% tadalafil + MSM ground sample at 7.33° is weakened to less than 20% of the physically mixed sample, which means that grinding can dissolve tadalafil in dimethyl sulfone to form a solid solution.

[0265] Therefore, under the condition of sufficient grinding time, tadalafil can completely diffuse and dissolve into dimethyl sulfone and exist in molecular form to obtain a solid solution. The XRD characteristic peaks of 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°.

[0266] 4. Preparation and dissolution experiment of nifedipine solid solution

[0267] Preparation of 10%, 20%, and 30% nifedipine + MSM solid solutions

[0268] Weigh 8g of dimethyl sulfone into a 100ml Erlenmeyer flask and set aside. Set the oil bath temperature to 120°C. Once the temperature reaches the set point, place the flask in the oil bath and carefully stir manually with a glass rod until completely melted. Then add 2.00g of nifedipine and stir rapidly to dissolve. Pour the mixed solution into a clean stainless steel dish, cool to room temperature, and freeze in a -20°C refrigerator for 10 minutes. Collect the material to obtain a 20% nifedipine + MSM solid solution sample (Formula 8). Similar procedures were used to prepare a 10% nifedipine + MSM solid solution sample (9g dimethyl sulfone + 1g nifedipine, Formulation 3) and a 30% nifedipine + MSM solid solution sample (7g dimethyl sulfone + 3g nifedipine, Formulation 9).

[0269] Preparation of Nifedipine: Dimethyl Sulfone: PEG4000 (2:9:9, Prescription 2) Solid Solution

[0270] Weigh 9 g of PEG4000, 9 g of dimethyl sulfone, and 0.02 g of docusate sodium (CAS No. 577-11-7, a surfactant) in the prescribed amount in a 100 ml conical flask, mix well, and place in a 120°C oil bath. Adjust the height so that the bottom of the flask is just immersed in the oil bath. Use a suitable glass rod to carefully stir manually until all the materials are melted. Pour the solution into a clean stainless steel plate, cool to room temperature, and freeze in a -20°C refrigerator for 10 minutes. Collect the material and grind it into a fine powder.

[0271] 18.0 g of the prepared fine powder and 2 g of nifedipine were put into a conical flask, mixed evenly, and placed in a 120°C oil bath. The height was adjusted so that the bottom of the flask was just submerged in the oil bath. A suitable glass rod was used to carefully stir manually until all the mixture was melted.

[0272] During the experiment, it was observed that the material began to soften at an internal temperature of 90-100°C, became liquid at 120°C and became basically clear after stirring.

[0273] The mixed solution was poured into a clean stainless steel dish, cooled to room temperature and then frozen in a -20°C refrigerator for 10 minutes. The material was collected to obtain a yellow waxy solid with uniform color.

[0274] XRD detection of nifedipine dimethyl sulfone solid solution

[0275] 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.

[0276] The test sample preparation process is similar to the above-mentioned sildenafil and tadalafil process.

[0277] 10% nifedipine + MSM solid solution sample, the specific results are shown in Figure 9.

[0278] The specific results of the solid solution sample of nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) are shown in FIG10 .

[0279] Comparing Figures 9 and 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 the nifedipine: dimethyl sulfone: PEG4000 (2:9:9, prescription 2) solid solution sample all have characteristic peaks at 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 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.

[0280] Dissolution curve determination experiment

[0281] The dissolution content was determined using the UV absorption method.

[0282] 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.

[0283] A 0.01 mg / ml aqueous solution of nifedipine, and a 0.1 mg / ml aqueous solution of polyethylene glycol and dimethyl sulfone were prepared and subjected to full wavelength scanning of UV absorbance. The specific results are shown in FIG11 .

[0284] According to the scanning results of the above three related substances, it can be seen that the absorbance measured at the strongest absorption wavelength of nifedipine, 237 nm, is not affected by polyethylene glycol and dimethyl sulfone.

[0285] 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 and negligible relative to the F value, that is, c = FA, the working curve was simplified to a single reference value, that is, the nifedipine reference was accurately weighed before each test and prepared into 50 ml of solution, and then the absorbance was measured. Thus, F = reference mass × content percentage ÷ 50 ÷ A was obtained.

[0286] Pure water dissolution test

[0287] 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, take samples of 5 ml at 5 minutes, 20 minutes, 40 minutes, 60 minutes, and 120 minutes, replenish 5 ml of the solution, take samples to test the dissolution, and draw a dissolution curve of the dissolution amount over time.

[0288] Dissolution was determined using ultraviolet spectrophotometry. For each test, approximately 20 mg of nifedipine reference substance was accurately weighed and dissolved in 50 ml of pure water. The absorbance at 237 nm (235 nm was used for practical purposes) was measured twice. The F value was calculated using the formula F = mass of nifedipine reference substance × content ÷ 50 ÷ absorbance. The mean F value of the two tests was then calculated.

[0289] Then, calculation was performed according to the formula: nifedipine mass = absorbance × F mean × dissolution medium volume.

[0290] The pure water dissolution experimental parameters of prescriptions 3, 8, and 9 and the F-mean value determination data by UV spectrophotometry are shown in Table 7.

[0291] Table 7: Pure water dissolution experimental parameters of solid solution powders of prescriptions 3, 8, and 9 and F-mean value determination data by UV spectrophotometry

[0292] F-value calculation example: 21.49×0.98485÷50÷4.146=0.102095642.

[0293] The pure water dissolution test results of prescriptions 3, 8, and 9 are shown in Table 8 below, where F takes the average value of 0.101753203. The nifedipine dissolution mass of 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.

[0294] Table 8: Dissolution test results of solid solutions of prescriptions 3, 8, and 9 and the API in pure water

[0295] *, the API was tested at a different time period 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. The rest can be deduced similarly.

[0296] The experimental data in Table 8 were prepared into a dissolution curve, as shown in FIG12 .

[0297] According to Table 8 and Figure 12, after nifedipine was prepared as a dimethyl sulfone solid solution, its dissolution rate in pure water and the final dissolution percentage were significantly improved. Moreover, the solid solution with a relatively low drug loading had a higher dissolution percentage and a faster dissolution rate.

[0298] During the experiment, it was found that flocculent matter 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.

[0299] Dissolution test of aqueous solution with added surfactant

[0300] Weigh the equivalent of 100 mg of nifedipine into a 250 ml conical flask, add 250 ml of an aqueous solution of sodium dodecyl sulfate (mass ratio 0.25%) heated to 37±0.2°C, stir at 300 rpm, take 5 ml samples at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, and 120 minutes, replenish with 5 ml of solution, take samples for dissolution detection, and draw a dissolution curve of the dissolution amount over time.

[0301] The dissolution experimental parameters of sodium lauryl sulfate aqueous solution of prescriptions 2 and 3 and the F mean value determination data of ultraviolet spectrophotometry are shown in Table 9 below.

[0302] Table 9: Dissolution experimental parameters of solid solution powders of prescriptions 2 and 3 in sodium lauryl sulfate aqueous solution and F-mean value determination data by UV spectrophotometry

[0303] F-value calculation example: 23.36×0.98485÷50÷4.141=0.111113721.

[0304] The dissolution test results of the raw materials of prescriptions 2 and 3 in 0.25% sodium lauryl sulfate aqueous solution are shown in Table 10 below, 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.

[0305] Table 10: Dissolution test results of solid solutions of prescriptions 2 and 3 and the API in 0.25% sodium lauryl sulfate aqueous solution

[0306] The experimental data in Table 10 were prepared into a dissolution curve, as shown in FIG13 .

[0307] According to Table 10 and Figure 13, after nifedipine was prepared as a dimethyl sulfone solid solution, its dissolution rate in the sodium lauryl sulfate aqueous solution and the final dissolution percentage in pure water were significantly improved.

[0308] During the experiment, it was found that flocculent matter 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.

[0309] 5. Dissolution test of 7.5% sildenafil and tadalafil solid solution

[0310] 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".

[0311] Dissolution curve determination experiment

[0312] The dissolution content was determined using the UV absorption method.

[0313] In the experiment in the previous part, the UV absorption curve of dimethyl sulfone was scanned and it showed no absorption.

[0314] Therefore, it is only necessary to scan the ultraviolet absorption curves of the related substances sildenafil and tadalafil and explore their respective strongest absorption wavelengths.

[0315] Aqueous solutions of sildenafil and tadalafil at 0.01 mg / ml were prepared and subjected to full wavelength UV absorbance scanning. The specific results are shown in FIG14 .

[0316] According to the above scanning results, sildenafil has the strongest absorption at a wavelength of 292 nm; and tadalafil has the strongest absorption at 283 nm. Therefore, a wavelength of 292 nm was selected as the wavelength of the ultraviolet spectrophotometer for measuring the dissolution curve experiment of sildenafil, and a wavelength of 283 nm was selected as the wavelength of the ultraviolet spectrophotometer for measuring the dissolution curve experiment of tadalafil.

[0317] Pure water dissolution test

[0318] Weigh the calculated amount of 14 mg of sildenafil API, approximately 100 mg of a 7.5% sildenafil + MSM molten sample, 14 mg of tadalafil API, and approximately 100 mg of a 7.5% tadalafil + MSM molten sample into four 250 ml conical flasks, add 250 ml of water heated to 37 ± 0.2°C, stir at 300 rpm, and take 5 ml samples at 10, 20, 30, 60, and 120 minutes, respectively. Replenish the solution with 5 ml of the solution, take samples for dissolution testing, and draw a dissolution curve of the dissolution amount over time.

[0319] Dissolution curve of 7.5% sildenafil solid solution

[0320] Dissolution was determined using ultraviolet spectrophotometry. For each test, approximately 20 mg of the sildenafil reference substance was accurately weighed and dissolved in 1000 ml of pure water. The absorbance at 292 nm was measured twice. The F value was calculated using the formula F = mass of sildenafil reference substance × content ÷ 1000 ÷ absorbance, and the mean F value of the two tests was calculated.

[0321] Then, calculation was performed according to the formula: mass of sildenafil = absorbance × F mean × volume of dissolution medium.

[0322] The experimental parameters for the pure water dissolution of 7.5% sildenafil solid solution and the F-mean value determination data by UV spectrophotometry are shown in Table 7.

[0323] Table 11: 7.5% Sildenafil solid solution powder pure water dissolution experimental parameters and UV spectrophotometry F mean value determination data

[0324] F-value calculation example: 19.27×1÷1000÷0.410=0.047.

[0325] The results of the pure water dissolution test of 7.5% sildenafil solid solution are shown in Table 12 below, where F takes an average value of 0.047. 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.

[0326] Table 12: Dissolution test results of 7.5% sildenafil solid solution and API in pure water

[0327] The experimental data in Table 12 were prepared into a dissolution curve, as shown in FIG15 .

[0328] According to Table 12 and Figure 13, after sildenafil was prepared as a dimethyl sulfone solid solution, the solubility of the solid solution was higher when compared with the same period of time, and the solid solution had a solubilizing effect.

[0329] Dissolution curve of 7.5% tadalafil solid solution

[0330] Dissolution was determined using UV spectrophotometry. For each test, approximately 15 mg of the tadalafil reference substance was accurately weighed and dissolved in 1000 ml of 50% acetonitrile aqueous solution. The absorbance at 283 nm was measured twice. The F value was calculated using the formula F = mass of tadalafil reference substance × content ÷ 1000 ÷ absorbance, and the mean F value of the two tests was calculated.

[0331] Then, calculation was performed according to the formula: tadalafil mass = absorbance × F mean × dissolution medium volume.

[0332] The experimental parameters for 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.

[0333] Table 13: 7.5% Tadalafil solid solution powder pure water dissolution experimental parameters and UV spectrophotometry F mean value determination data

[0334] F-value calculation example: 14.98×1÷1000÷0.529=0.02831758.

[0335] The results of the pure water dissolution test of 7.5% tadalafil solid solution are shown in Table 14 below, where F takes the average value of 0.028344396. 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 two digits to 0.04.

[0336] Table 14: Dissolution test results of 7.5% tadalafil solid solution and API in pure water

[0337] The experimental data in Table 14 were prepared into a dissolution curve, as shown in FIG16 .

[0338] According to Table 14 and Figure 16, after tadalafil was prepared as a dimethyl sulfone solid solution, the solubility of the solid solution was higher when compared with the same period of time, and the solid solution had a very significant solubilization effect.

[0339] Dissolution curve of 7.5% tadalafil solid solution in 0.25% sodium lauryl sulfate aqueous solution

[0340] Dissolution was determined using UV spectrophotometry. For each test, approximately 15 mg of the tadalafil reference substance was accurately weighed and dissolved in 1000 ml of 50% acetonitrile aqueous solution. The absorbance at 283 nm was measured twice. The F value was calculated using the formula F = mass of tadalafil reference substance × content ÷ 1000 ÷ absorbance, and the mean F value of the two tests was calculated.

[0341] Then, calculation was performed according to the formula: tadalafil mass = absorbance × F mean × dissolution medium volume.

[0342] The dissolution experimental parameters of 7.5% tadalafil solid solution in 0.25% sodium lauryl sulfate aqueous solution and the F mean value determination data by UV spectrophotometry are shown in Table 15 below.

[0343] Table 15: Dissolution parameters of 7.5% tadalafil solid solution powder in 0.25% sodium lauryl sulfate aqueous solution and UV spectrophotometry F mean value determination data

[0344] F-value calculation example: 16.76×1÷1000÷0.544=0.030808824.

[0345] The dissolution test results of 7.5% tadalafil solid solution in 0.25% sodium lauryl sulfate aqueous solution are shown in Table 16 below, where F takes the average value of 0.030808824. The tadalafil dissolution mass of the sample with a dissolution time of 10 minutes is 0.549×0.030808824×500=8.45702, which is rounded to two digits to 8.46.

[0346] Table 16: Dissolution test results of 7.5% tadalafil solid solution and API in 0.25% sodium lauryl sulfate aqueous solution

[0347] The experimental data in Table 16 were prepared into a dissolution curve, as shown in FIG17 .

[0348] According to Table 16 and Figure 17, after tadalafil was prepared as a dimethyl sulfone solid solution, the solubility of the solid solution in a 0.25% sodium lauryl sulfate aqueous solution was higher when compared with the same period of time, and the solid solution had a very significant solubilizing effect.

[0349] VI. Preparation and Characterization of Finasteride, Celecoxib, and Verapamil Hydrochloride Solid Solutions

[0350] Preparation of solid solutions

[0351] To a dry 50ml two-necked flask, add 6.6g of dimethyl sulfone under nitrogen protection and stir. Heat in an oil bath to 122°C until the solution dissolves and becomes clear. Gradually add finasteride while stirring until it dissolves rapidly and becomes clear. Add 1.0g of finasteride. Quickly transfer the solution to a watch glass, wrap in a sealed bag, and cool naturally to room temperature. Samples from different parts of the body were mixed and tested to obtain a 13% concentration of finasteride / dimethyl sulfone mixture, designated FNXA-03.

[0352] To a dry 50ml two-necked flask, add 6.15g of dimethyl sulfone and 3ml of ethanol under nitrogen protection, stir, and dissolve in an oil bath until it is clear. Gradually add finasteride while stirring until it dissolves rapidly and becomes clear. Add 0.51g (continue stirring and dissolving for approximately 5 minutes, the same below). Quickly transfer the solution to a watch glass, wrap it in a sealed bag, and cool it naturally to room temperature. Samples from different parts of the body were mixed and tested to obtain a 7.6% concentration of finasteride / dimethyl sulfone mixture, designated FNXA-04.

[0353] Samples were taken from different parts and mixed before HPLC testing. The test results of the finasteride solid solution are shown in Table 17.

[0354] Table 17: HPLC purity test results of finasteride solid solution samples

[0355] A similar procedure was performed using 5.8 g of dimethyl sulfone, heated to 124°C in an oil bath, and then 2.4 g of celecoxib was added to obtain a 27% concentration of celecoxib / dimethyl sulfone mixture, which was designated as SLXB-03. A similar procedure was performed using 5.3 g of dimethyl sulfone and 3 ml of ethanol, heated to 100°C in an oil bath, and then 2.5 g of celecoxib was added to obtain a 32% concentration of celecoxib / dimethyl sulfone mixture, which was designated as SLXB-04.

[0356] Samples were taken from different parts and mixed before HPLC testing. The test results of the celecoxib solid solution are shown in Table 18.

[0357] Table 18: HPLC purity test results of celecoxib solid solution samples

[0358] A similar operation was performed using 5.0 g of dimethyl sulfone, heated to 122° C. in an oil bath, and then 0.5 g of verapamil hydrochloride was added to obtain a 9% verapamil hydrochloride / dimethyl sulfone mixture, which was recorded as YSWLPM-03. A similar operation was performed using 5.21 g of dimethyl sulfone and 3 ml of ethanol, heated to 100° C. in an oil bath, and then 0.52 g of verapamil hydrochloride was added to obtain a 9% verapamil hydrochloride / dimethyl sulfone mixture, which was recorded as YSWLPM-04.

[0359] Samples were taken from different parts and mixed before HPLC testing. The test results of the verapamil hydrochloride solid solution are shown in Table 19.

[0360] Table 19: HPLC purity test results of verapamil hydrochloride solid solution samples

[0361] Solid solution XRD detection

[0362] In order to further prove that the final solid is a solid solution, an X-ray powder diffraction experiment was performed.

[0363] XRD tests were performed on finasteride, dimethyl sulfone, FNXA-03, FNXA-04, celecoxib, dimethyl sulfone, SLXB-03, SLXB-04, and verapamil hydrochloride, dimethyl sulfone, YSWLPM-03, YSWLPM-04, respectively.

[0364] The specific results of the FNXA-03 sample are shown in Figure 18; the specific results of the FNXA-04 sample are shown in Figure 19; the specific results of the SLXB-03 sample are shown in Figure 20; the specific results of the SLXB-04 sample are shown in Figure 21; the specific results of the YSWLPM-03 sample are shown in Figure 22, and the specific results of the YSWLPM-04 sample are shown in Figure 23.

[0365] From the analysis of Figures 18 and 19, it can be seen that the XRD characteristic peaks of the finasteride raw material are 13.90°, 14.31°, 15.31°, 15.48°, 15.76°, 16.83°, 17.26°, 18.45°, 19.37°, 19.53°, 19.88°, 20.75°, 23.31°, and 25.09°. In Figures 18 and 19, the corresponding peaks of the FNXA-03 and FNXA-04 samples disappeared or were greatly weakened. This shows that the finasteride in the samples prepared after melting no longer shows crystalline characteristics.

[0366] Further comparison of the molten sample and the dimethyl sulfone sample in Figures 18 and 19 shows that the XRD characteristic peaks of the molten sample, namely the characteristic peaks of finasteride dimethyl sulfone solid solution: 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, 33.1±0.1°, are consistent with the characteristic peaks of dimethyl sulfone. 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 to form a solid solution.

[0367] From the analysis of Figures 20 and 21, it can be seen that the XRD characteristic peaks of celecoxib raw material are 5.42°, 10.78°, 11.07°, 13.09°, 14.91°, 16.16°, 17.98°, 18.46°, 18.78°, 19.72°, 21.42°, 21.58°, 22.17°, 22.45°, 23.31°, 23.53°, 25.44°, and 29.54°. In Figures 20 and 21, the corresponding peaks of SLXB-03 and SLXB-04 samples disappeared or greatly weakened. It can be seen that celecoxib in the samples prepared after melting no longer shows crystalline characteristics.

[0368] Further comparison of the molten sample and the dimethyl sulfone sample in Figures 20 and 21 shows that the XRD characteristic peaks of the molten sample, namely the characteristic peaks of celecoxib dimethyl sulfone solid solution: 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°, are consistent with the characteristic peaks of dimethyl sulfone. 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 to form a solid solution.

[0369] Analysis of Figures 22 and 23 shows that the XRD characteristic peaks of the verapamil hydrochloride raw material are 4.70°, 8.67°, 10.63°, 11.50°, 14.11°, 14.49°, 15.08°, 16.78°, 17.12°, 17.90°, 18.13°, 18.87°, 19.25°, 20.30°, 21.35°, 23.09°, 23.32°, 23.58°, 23.81°, 25.18°, 26.34°, and 26.58°. In Figures 22 and 23, the corresponding peaks of the YSWLPM-03 and YSW LPM-04 samples disappeared or were greatly weakened. This shows that celecoxib in the samples prepared after melting no longer shows crystalline characteristics.

[0370] Further comparison of the molten sample and the dimethyl sulfone sample in Figures 22 and 23 shows that the XRD characteristic peaks of the molten sample, namely the characteristic peaks of celecoxib dimethyl sulfone solid solution: 16.4±0.1°, 20.4±0.1°, 24.3±0.1°, 25.3±0.1°, 29.4±0.1°, 33.1±0.1, are consistent with the characteristic peaks of dimethyl sulfone. 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 to form a solid solution.

[0371] Solid solution powder melting point detection

[0372] The melting point test results of the above-mentioned finasteride, FNXA-03, FNXA-04, celecoxib, SLXB-03, SLXB-04, and verapamil hydrochloride, YSWLPM-03, and YSWLPM-04 are as follows:

[0373] FNXA-03 sample, initial melting point 108.6℃, final melting point 118℃;

[0374] FNXA-04 sample, initial melting point 107.6℃, final melting point 116.3℃;

[0375] Finasteride, initial melting point 257.3℃, final melting point 259.7℃.

[0376] Obviously, the melting point of the above-mentioned finasteride-dimethyl sulfone solid solution (initial melting 107.6-108.6°C, final melting 116.3-118°C) is close to the melting point of dimethyl sulfone (107-109°C), but far from the melting point of finasteride. In other words, the melting point of the prepared solid solution may be closer to dimethyl sulfone, which is also confirmed by the XRD spectrum results.

[0377] SLXB-03 sample, initial melting point 93.5℃, final melting point 98.6℃;

[0378] SLXB-04 sample, initial melting point 92.7℃, final melting point 97.3℃;

[0379] Celecoxib, initial melting point 158.6℃, final melting point 160.8℃.

[0380] Obviously, the melting point of the above-mentioned celecoxib-dimethyl sulfone solid solution (initial melting 92.7.6-93.5°C, final melting 97.3-98.6°C) is close to the melting point of dimethyl sulfone (107-109°C), but is far from the melting point of celecoxib. In other words, the melting point of the prepared solid solution may be closer to dimethyl sulfone, which is also confirmed by the XRD pattern results.

[0381] YSWLPM-03 sample, initial melting point 94.5℃, final melting point 106.8℃;

[0382] YSWLPM-04 sample, initial melting point 92.1℃, final melting point 105.8℃;

[0383] Verapamil hydrochloride, initial melting point 144.4℃, final melting point 144.9℃.

[0384] Obviously, the melting point of the above-mentioned verapamil hydrochloride-dimethyl sulfone solid solution (initial melting point 92.1-94.5°C, final melting point 105.8-106.8°C) is close to the melting point of dimethyl sulfone (107-109°C), but is far from the melting point of verapamil hydrochloride. In other words, the melting point of the prepared solid solution may be closer to dimethyl sulfone, which is also confirmed by the XRD pattern results.

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 four 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 four 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, nifedipine, finasteride, celecoxib, and verapamil hydrochloride.

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. The solid dispersion according to claim 5, which is a solid solution, substantially composed of a dispersant, dimethyl sulfone, and a drug, nifedipine, wherein the mass percentage of the drug is no more than 30%; or The prepared dimethyl sulfone nifedipine solid solution was 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 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°.

9. The solid dispersion according to claim 5, which is a solid solution, substantially composed of a dispersant dimethyl sulfone, a high molecular polymer, and a drug nifedipine, wherein the mass percentage of the drug is no more than 30%; or The prepared dimethyl sulfone nifedipine solid solution was subjected to X-ray powder diffraction test, Cu-Kα radiation, and the characteristic peaks of the X-ray powder diffraction pattern expressed 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°, 33.1±0.1°, Preferably, the high molecular polymer is selected from high molecular polymer type surfactants, More preferably, the high molecular polymer is selected from polysorbate, polyethylene glycol, sorbitan fatty acid ester, polyoxyethylene polyoxypropylene ether block copolymer, and polyvinyl pyrrolidone.

10. The solid dispersion according to claim 5, which is a solid solution, substantially composed of a dispersant, dimethyl sulfone, and a drug, finasteride, wherein the mass percentage of the drug is no more than 13%; Its melting point is 107.6-108.6°C for the initial melting point and 116.3-118 for the final melting point; or The prepared dimethyl sulfone finasteride 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°.

11. The solid dispersion according to claim 5, which is a solid solution, substantially composed of a dispersant, dimethyl sulfone, and a drug, celecoxib, wherein the mass percentage of the drug is no more than 27%; Its melting point is 92.7.6-93.5°C for initial melting and 97.3-98.6°C for final melting; or The prepared dimethyl sulfone celecoxib solid solution was 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 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°.

12. The solid dispersion according to claim 5, which is a solid solution, substantially composed of a dispersant, dimethyl sulfone, and a drug, verapamil hydrochloride, wherein the mass percentage of the drug is not greater than 9%; Its melting point is 92.1-94.5°C for initial melting and 105.8-106.8°C for final melting; or The prepared dimethyl sulfone verapamil hydrochloride solid solution was 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 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°.

13. 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: 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. 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 and 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, 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.

14. 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. 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. 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. 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.

15. 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.

16. 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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