Method for crystallishing a drug
By combining and incubating nucleation initiator, surfactant solution and amorphous drug, the amorphous drug was successfully converted into crystalline forms, solving the problems of drug stability and use effect. The crystalline material formed has high stability and low surface Active agent content.
Patent Information
- Application Number
- CN202411519720.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2020-03-27
- Filing Date
- 2021-03-12
- Publication Date
- 2025-02-14
AI Technical Summary
The prior art is difficult to effectively convert amorphous drugs into crystalline forms, affecting the stability and use effect of the drugs.
The drug is transformed from an amorphous form to a crystalline form by combining a nucleation initiator, a surfactant solution and an amorphous drug to form a drug precursor dispersion/suspension and incubating the liquid.
The crystallization conversion of the drug is achieved, the stability and use effect of the drug are improved, and the crystallization material formed is basically free of surfactants.
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Abstract
Description
[0001] This application is a divisional application of application number 202180038456.5, application date 2021.3.12, and application title “Method for crystallizing drugs”.
[0002] CROSS-REFERENCE TO RELATED APPLICATIONS
[0003] This application claims the benefit of priority under 35 U.S.C. §119 to U.S. Provisional Application Serial No. 63 / 000,861, filed on March 27, 2020, the entire contents of which are incorporated herein by reference. Technical Field
[0004] The present disclosure relates to crystallization methods, such as methods for crystallizing pharmaceuticals. Background Art
[0005] A variety of medical devices have been developed for medical use, such as intravascular use. Some of these devices include guide wires, catheters, balloons, stents, etc. These devices are manufactured by any of a variety of different manufacturing methods and can be used according to any of a variety of methods. Some of these medical devices may include drugs, such as drugs in crystalline form. In known medical devices and methods, each has certain advantages and disadvantages. There is a need to provide alternative medical devices and alternative methods for making and using medical devices. This may include forming crystalline materials (e.g., drugs in crystalline form). Summary of the invention
[0006] A method for crystallizing a drug is disclosed. The method comprises: combining a nucleation initiator, a surfactant solution and an amorphous drug to form a drug precursor dispersion / suspension; and incubating the drug precursor dispersion / suspension to transform the drug from an amorphous form to a crystalline form.
[0007] Alternatively or additionally to any of the above embodiments, the drug comprises everolimus.
[0008] Alternatively or additionally to any of the above embodiments, the nucleation initiator comprises everolimus.
[0009] Alternatively or additionally to any of the above embodiments, the nucleation initiator comprises everolimus microcrystals.
[0010] Alternatively or additionally to any of the above embodiments, the nucleation initiator, the surfactant solution, or both include a solvent.
[0011] Alternatively or additionally to any of the above embodiments, the solvent includes ethyl acetate, heptane, or both ethyl acetate and heptane.
[0012] Alternatively or additionally to any of the above embodiments, the solvent comprises ethyl acetate and heptane, and wherein the ratio of ethyl acetate to heptane is in a range of about 1:4 to 1:30.
[0013] Alternatively or additionally to any of the above embodiments, the solvent comprises ethyl acetate and heptane, and wherein the ratio of ethyl acetate to heptane is in a range of about 1:4 to 1:20.
[0014] Alternatively or additionally to any of the above embodiments, the solvent comprises ethyl acetate and heptane, and wherein the ratio of ethyl acetate to heptane is about 1:20.
[0015] Alternatively or additionally to any of the above embodiments, the surfactant solution includes polyoxyethylene (20) sorbitan monooleate.
[0016] Alternatively or additionally to any of the above embodiments, the surfactant solution includes polyoxyethylene (80) sorbitan monooleate.
[0017] As an alternative or supplement to any of the above embodiments, one or more of the following may also be included:
[0018] (a) filtering the crystalline form of the drug, (b) washing the crystalline form of the drug, and (c) drying the crystalline form of the drug.
[0019] As an alternative or in addition to any of the above embodiments, the crystalline drug material is substantially free of surfactant.
[0020] Alternatively or additionally to any of the above embodiments, wherein incubating the prodrug dispersion / suspension to convert the drug from an amorphous form to a crystalline form occurs without stirring the prodrug dispersion.
[0021] A method for converting amorphous everolimus into crystalline everolimus is disclosed. The method comprises: forming a prodrug dispersion / suspension by combining a nucleation initiator, a surfactant solution, and an amorphous form of everolimus; wherein the prodrug dispersion / suspension comprises a solvent comprising ethyl acetate and heptane; wherein the surfactant solution comprises polyoxyethylene sorbitan monooleate; and incubating the prodrug dispersion / suspension to convert the amorphous form of everolimus into everolimus microcrystals.
[0022] Alternatively or additionally to any of the above embodiments, the ratio of ethyl acetate to heptane in the solvent is in the range of about 1:4 to 1:20.
[0023] Alternatively or additionally to any of the above embodiments, the ratio of ethyl acetate to heptane in the solvent is about 1:20.
[0024] Alternatively or additionally to any of the above embodiments, the nucleation initiator comprises everolimus.
[0025] As an alternative or addition to any of the above embodiments, further comprising one or more of filtering the everolimus microcrystals, washing the everolimus microcrystals, and drying the everolimus microcrystals substantially free of surfactant.
[0026] A shelf-stable crystalline material is disclosed. The material comprises: everolimus microcrystals formed by crystallizing amorphous everolimus in the presence of a polyoxyethylene sorbitan monooleate surfactant; wherein the everolimus microcrystals are processed to be substantially free of the surfactant; and wherein the everolimus microcrystals have a width of less than about 3 microns, a thickness of less than about 1 micron, and a length of less than about 10 microns.
[0027] The above summary of some embodiments is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The following figures and detailed description more particularly exemplify these embodiments. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] The present disclosure may be more fully understood upon consideration of the following detailed description in conjunction with the accompanying drawings, in which:
[0029] Figure 1 is an example medical device.
[0030] Figure 2 is an example medical device.
[0031] Although the present disclosure may be modified and substituted in various forms, the details thereof have been shown by way of example in the accompanying drawings and will be described in detail. However, it should be understood that the purpose of the present invention is not to limit the present invention to the specific embodiments described. On the contrary, it is intended to cover all modifications, equivalents and substitutes that fall within the spirit and scope of the present disclosure. DETAILED DESCRIPTION
[0032] For the following defined terms, these definitions shall apply, unless a different definition is given in the claims or elsewhere in this specification.
[0033] It is assumed herein that all numerical values are modified by the term "about", whether or not explicitly indicated. The term "about" generally refers to a numerical range that one skilled in the art considers equivalent to the recited value (e.g., having the same function or result). In many cases, the term "about" may include numbers rounded to the nearest significant figure.
[0034] The recitation of numerical ranges by endpoints includes all numbers within that range (eg, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).
[0035] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term "or" is generally used in its sense including "and / or" unless the content clearly dictates otherwise.
[0036] It should be noted that references to "one embodiment", "some embodiments", "other embodiments", etc. in the specification indicate that the described embodiments may include one or more specific features, structures and / or characteristics. However, such a description does not necessarily mean that all embodiments include the specific features, structures and / or characteristics. In addition, whether explicitly described or not, when specific features, structures and / or characteristics are described in conjunction with one embodiment, it should be understood that these features, structures and / or characteristics may also be used in conjunction with other embodiments unless otherwise clearly stated.
[0037] The following detailed description should be read with reference to the accompanying drawings, in which similar elements in different drawings are labeled with the same numerals. The drawings, which are not necessarily drawn to scale, depict illustrative embodiments and are not intended to limit the scope of the invention.
[0038] Drug-coated medical devices, such as drug-coated stents, drug-coated balloons, etc., can be used to treat small vessel occlusions and / or vascular diseases. Some example drugs that can be used with such devices include paclitaxel, everolimus, etc. Applying the drug to the medical device may include applying the drug in crystalline form to the surface of the medical device. In at least some cases, the manufacturing process may include converting the drug in amorphous form into a crystalline form. Disclosed herein is a method for converting a material (e.g., a drug) in amorphous form into a crystalline form. In addition, disclosed herein is a medical device having such a coating applied thereto, a method for coating, etc.
[0039] Some exemplary methods for converting an amorphous form of a drug into a crystalline form may generally include:
[0040] (a) preparing a suitable solvent, (b) preparing a nucleation initiator with the solvent, (c) combining / mixing the nucleation initiator with the amorphous form of the drug to form a prodrug dispersion / suspension, and (d) incubating the prodrug dispersion / suspension to convert the amorphous form of the drug to a crystalline form of the drug. Suitable surfactants used with the prodrug dispersion / suspension can allow for the formation of drug crystals having a desired morphology, allow for the formation of drug crystals having a desired size and / or shape and / or aspect ratio, allow for the formation of a coating suspension having a desired stability, combinations thereof, and / or the like. Thus, at least some of the methods for converting an amorphous form of a drug to a crystalline form include: (a) preparing a suitable solvent,
[0041] (b) preparing a surfactant solution by combining / mixing the surfactant with a solvent, (c) preparing a nucleation initiator with a solvent, (d) combining / mixing the nucleation initiator with the surfactant solution and the amorphous form of the drug to form a prodrug dispersion / suspension, and (e) incubating the prodrug dispersion / suspension to allow conversion of the amorphous form of the drug into a crystalline form of the drug.
[0042] In some embodiments, the drug can be a macrolide immunosuppressive (limus) drug. In some embodiments, the macrolide immunosuppressive drug is rapamycin, biolimus A9, 40-O-(2-hydroxyethyl) rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl)benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxyethyl)]benzyl-rapamycin, 40-O-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4(S)-yl)-prop-2'-en-1'-yl]-rapamycin, (2':E,4'S)-40-O-(4',5'-dihydroxypentyl-2'-en-1'-yl)-rapamycin, 40-O-(2-hydroxy)ethoxy 40-O-(3-hydroxy)propyl-rapamycin, 40-O-(6-hydroxy)hexyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2-dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxypropionic acid-1-yl]-rapamycin, 40-O-(2-acetoxy)ethyl-rapamycin, 40-O-(2-nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N -Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-demethyl-39, 40-O,O-ethylene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-methyl-rapamycin, 40-O-(2-aminoethyl)-rapamycin, 40-O-(2-acetylaminoethyl)-rapamycin, 40-O-(2-nicotinamideethyl)-rapamycin, 40-O-(2-(N-methylimidazole)-2'-ylmethoxyacetamide)ethyl)-rapamycin, 40 -O-(2-ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-toluenesulfonamidoethyl)-rapamycin, 40-O-[2-(4',5'-diethoxy-1',2',3'-triazol-1'-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), 42-[3-hydroxy-2-(hydroxymethyl)-2-propionic acid methyl ester]rapamycin (sirolimus), (42S)-42-deoxy-42-(1H-tetrazol-1-yl)-rapamycin (zotarolimus) or their derivatives, isomers, racemates, diastereomers, prodrugs, hydrates, esters or analogs.Other drugs may include anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine and their analogs; anti-neoplastic agents / anti-proliferative agents / anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, thymidine kinase inhibitors and their analogs; anesthetics such as lidocaine, bupivacaine, ropivacaine and their analogs; anticoagulants; and growth factors.
[0043] As described herein, an exemplary method of converting an amorphous form of a drug into a crystalline form includes preparing a suitable solvent. When the solvent is a single material, preparing a suitable solvent can be as simple as placing the solvent in a suitable container. When the solvent is a mixture of materials, preparing a suitable solvent can include combining or mixing the solvents.
[0044] In at least some cases, the solvent may include alcohols, such as methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol or tert-butanol; acetonitrile (ACN); ethers, such as tetrahydrofuran (THF) isopropyl ether (IPE), diethyl ether (DEE); ketone solvents, such as acetone, 2-butanone (MEK) or methyl isobutyl ketone (MIBK); halogenated solvents, such as dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), ethyl trifluoroacetate (ETFA); aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons, such as toluene or xylene; and ester solvents, such as ethyl acetate. For example, mixed solvents such as ethyl acetate / heptane, acetone / water, IPA / water, IPA / THF, methanol / water, IPA / heptane or THF / heptane may also be used.
[0045] When a mixture of solvents is used, the mixture can have a suitable ratio of each material. For example, some exemplary solvents can include a mixture of ethyl acetate and heptane. The ratio of ethyl acetate to heptane can be in the range of about 1:4 to 1:30, or about 1:4 to 1:20, or about 1:20. Other mixtures and / or ratios are contemplated. Therefore, in some cases, the method of converting an amorphous form of a drug into a crystalline form can include preparing a solvent, such as by mixing ethyl acetate with heptane.
[0046] The method of converting an amorphous form of a drug into a crystalline form may include preparing a surfactant solution (e.g., preparing a surfactant solution with a solvent). In at least some cases, the surfactant may include TWEEN 20 TM (e.g., polysorbate 20, polyoxyethylene (20) sorbitan monooleate or PEG (20) sorbitan monooleate), TWEEN80 TM(e.g., polysorbate 80, polyoxyethylene (80) sorbitan monooleate) or PEG (80) sorbitan monooleate), SPAN TM 80. SPAN TM 20. TRITON TM X-100, TRITON TM 400. Nonionic surfactant and / or the like. The surfactant solution may have a suitable concentration. For example, the concentration of the surfactant solution may be about 0.01-1% (by weight), about 0.05-0.5% (by weight), or about 0.1% (by weight).
[0047] The method of converting an amorphous form of a drug into a crystalline form may include preparing a nucleation initiator (e.g., preparing a nucleation initiator with a solvent). This process or step may also be referred to as "seeding". In at least some cases, the nucleation initiator may include a crystalline form of the drug suspended in a suitable solvent (e.g., it may or may not be the same solvent used to dissolve the amorphous form of the drug). When the drug used is everolimus, the nucleation initiator may include a suitable amount of crystalline everolimus in a suitable solvent. The concentration of crystalline everolimus in the solvent may be about 0.1-10%, or about 0.1-2%, or about 0.5%. Crystalline everolimus may include everolimus microcrystals formed as described herein. Alternatively, crystalline everolimus may include everolimus crystals having different morphologies.
[0048] The method for converting the amorphous form of the drug into a crystalline form may include mixing and / or combining a nucleating initiator with a surfactant solution and the amorphous form of the drug to form a prodrug dispersion / suspension. The amount of the amorphous form drug added may be different. For example, about 0.5-100 mg of everolimus may be added / dispersed per milliliter (e.g., per milliliter of solvent), or about 1-50 mg of everolimus may be added / dispersed per milliliter, or about 10-30 mg of everolimus may be added / dispersed per milliliter, or about 20 mg of everolimus may be dissolved per milliliter. In at least some cases, the drug dispersion solution may be referred to as and / or be similar to a slurry.
[0049] The prodrug dispersion / suspension can be incubated so that the amorphous form of the drug can be converted into a crystalline form. In some cases, incubation can occur in a suitable time period of the order of several hours to several days. For example, the incubation time may exceed 24 hours. In some of these and other cases, incubation may include a high temperature or warm temperature incubation step at a suitable temperature (e.g., at about 20°C to 80°C, or about 40°C to 60°C, or about 50°C). In some cases, high temperature incubation may include stirring the prodrug dispersion (e.g., using a suitable device, such as an orbital oscillator). However, in other cases, the high temperature incubation step does not require stirring / agitation. The high temperature incubation step can be carried out in a suitable time period of the order of several hours to several days. For example, incubation may last for about two days. In some of these and other cases, incubation may also include a low temperature or cold temperature incubation step at a suitable temperature (e.g., at about -10°C to 10°C, or about 0°C to 5°C, or about 4°C). The low temperature incubation step can be carried out in a suitable time period of the order of several hours to several days. For example, incubation may last for several days.
[0050] In some cases, the method of converting the amorphous form of the drug to the crystalline form may include one or more of the following: (a) filtering the crystalline form of the drug, (b) washing the crystalline form of the drug, and (c) drying the crystalline form of the drug. For example, some methods are contemplated, including filtering, washing, and drying the crystalline form of the drug. When doing so, the solvent, the surfactant, or both can be substantially completely removed from the drug crystals.
[0051] The drug crystalline form (e.g., the crystalline form of everolimus) formed by the method may produce crystals with certain morphology, size and shape, so that the formed crystals are described as microcrystals. In particular, a surfactant is used in the crystallization process, together with a suitable solvent mixture mixed in a suitable ratio, resulting in the formation of microcrystals. For the purposes of this disclosure, microcrystals can be understood as crystals that can be described as relatively flat flakes. Some example sizes may include microcrystals with a width less than about 3 microns (e.g., having a non-zero width less than about 3 microns), a thickness less than about 1 micron (e.g., having a non-zero thickness less than about 1 micron) and a length less than about 10 microns (e.g., having a non-zero length less than about 10 microns). Microcrystals may be needed for a variety of reasons. For example, in some crystallization processes that form "larger", rod-shaped or "non-micro" crystals, the resulting crystals will settle rapidly when suspended in a coating material / dispersion. This may make it more challenging to apply drug crystals to medical devices. Microcrystals formed by the methods described herein can, for example, be suspended in a coating material / dispersion and remain suspended over a long period of time (e.g., several months or longer).
[0052] In some cases, the microcrystals formed by the methods disclosed herein may be suspended in a suitable coating material / dispersion. This may include the addition of a suitable excipient. An example excipient may include acetyl tributyl citrate (ATBC). In some cases, the drug microcrystals may be mixed with the excipient in a ratio of about 20:80 to about 90:10, or in a ratio of about 80:20. The coating material / dispersion may then be applied to the medical device using a suitable process. For example, the coating material / dispersion may then be applied to the medical device by dip coating, roller coating, via a syringe, and / or the like. Figure 1-2 Some exemplary drug-coated medical devices are schematically shown in FIG. Figure 1 A drug coated balloon device 10 is shown including a balloon 12 coupled to a catheter shaft 14. A drug coating 16 (eg, crystalline everolimus including everolimus microcrystals formed as disclosed herein) can be disposed along the balloon 12. Figure 2 A drug coated stent 110 is shown. A drug coating 116 (eg, crystalline everolimus comprising everolimus microcrystals formed as disclosed herein) can be disposed along the stent 110 .
[0053] Example
[0054] The present disclosure may be further clarified by reference to the following examples, which are intended to illustrate some embodiments but not to limit the present disclosure.
[0055] Example 1 - Solvent Preparation
[0056] Prepare the solvent by mixing 200 mL of heptane and 10 mL of ethyl acetate in a bottle.
[0057] Example 2 - Preparation of surfactant solution
[0058] By weighing 50 mg of TWEEN TM 80 mL of the surfactant solution was added to the container and 50 mL of the solvent prepared in Example 1 was added to the container. The surfactant solution was shaken / mixed until the surfactant (e.g., TWEEN TM 80) is well dispersed in the solvent. Optionally, the solution can be sonicated for 15 seconds. In addition, when reusing a previously prepared stock of surfactant solution, sonication can be used to redisperse the surfactant (e.g., TWEEN TM 80).
[0059] Example 3 - Nucleation Initiator
[0060] The nucleation initiator is prepared by weighing 5 mg of everolimus microcrystals (eg, from a previously performed crystallization process) into a vial and adding 10 mL of the solvent prepared in Example 1 to the vial.
[0061] Example 4 - Crystallization
[0062] 960 mg of amorphous everolimus was added to the vial containing the nucleation initiator prepared in Example 3.
[0063] 30 mL of the surfactant solution prepared in Example 2 was added to a vial (eg, the vial containing the nucleation initiator prepared in Example 3 and containing 960 mg of amorphous everolimus).
[0064] The final combination of nucleation initiator, surfactant, and amorphous everolimus can be understood as a prodrug dispersion.
[0065] The prodrug dispersion was sonicated in the vial for 1 minute.
[0066] Crystallization is allowed to occur by incubating the vials (eg, incubating the prodrug dispersion) at room temperature for 24 hours.
[0067] Following incubation, the vials may be sonicated for 1 minute.
[0068] The result of incubating the prodrug dispersion is the formation of everolimus microcrystals (eg, a microcrystal suspension).
[0069] The microcrystal suspension was filtered using a vacuum filtration system with a 0.45 micron polytetrafluoroethylene (PTFE) filter. This involved transferring the microcrystal suspension to the filtration system, rinsing the vial with heptane to transfer any remaining crystals to the filter, pulling a vacuum on the filtration system, and rinsing the microcrystals three times with heptane.
[0070] The filter with the microcrystals was transferred to a clean, pre-weighed vial. The microcrystals were then allowed to dry in a vacuum chamber overnight.
[0071] The dried microcrystals were weighed and the percent yield was calculated.
[0072] The dried crystallites were analyzed by differential scanning calorimetry to determine the percent crystallinity.
[0073] Store the dried microcrystals in a refrigerator for long term storage.
[0074] The filtration process may include placing a drop of the microcrystalline suspension on a disk for SEM analysis.
[0075] It should be understood that the present disclosure is in many respects illustrative only. Changes may be made in detail, particularly in shape, size, and arrangement of steps, without exceeding the scope of the present disclosure. This may include, within appropriate limits, using any feature of an example embodiment in other embodiments. Of course, the scope of the present invention is defined in the language of the appended claims.
Claims
1. A method for crystallizing a drug, the method comprising: combining a nucleation initiator, a surfactant solution, and an amorphous form of the drug to form a prodrug dispersion / suspension; and The prodrug dispersion / suspension is incubated to convert the drug from the amorphous form to a crystalline form.
2. The method of claim 1, wherein the drug comprises everolimus.
3. The method of claim 1 or 2, wherein the nucleation initiator comprises everolimus.
4. The method of claim 1 or 2, wherein the nucleation initiator comprises everolimus microcrystals.
5. The method of any one of claims 1-4, wherein the nucleation initiator, the surfactant solution, or both comprise a solvent.
6. The method of claim 5, wherein the solvent comprises ethyl acetate, heptane, or both ethyl acetate and heptane.
7. The method of claim 5, wherein the solvent comprises ethyl acetate and heptane, and wherein the ratio of ethyl acetate to heptane is in the range of about 1:4 to 1:
30.
8. The method of claim 5, wherein the solvent comprises ethyl acetate and heptane, and wherein the ratio of ethyl acetate to heptane is in the range of about 1:4 to 1:
20.
9. The method of claim 8, wherein the solvent comprises ethyl acetate and heptane, and wherein the ratio of ethyl acetate to heptane is about 1:
20.
10. The method of any one of claims 1-9, wherein the surfactant solution comprises polyoxyethylene (20) sorbitan monooleate.