CN114209660A - Application process of rapamycin in intracranial medicine balls - Google Patents
Application process of rapamycin in intracranial medicine balls Download PDFInfo
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- CN114209660A CN114209660A CN202210062707.XA CN202210062707A CN114209660A CN 114209660 A CN114209660 A CN 114209660A CN 202210062707 A CN202210062707 A CN 202210062707A CN 114209660 A CN114209660 A CN 114209660A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0085—Brain, e.g. brain implants; Spinal cord
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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Abstract
The invention discloses an application process of rapamycin in a intracranial medicinal ball, wherein the application process of rapamycin in the intracranial medicinal ball comprises the following steps: preparing a rapamycin mixed solution; carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain a drug microcrystal of rapamycin; re-dissolving the drug microcrystals and obtaining a drug suspension; and spraying the drug suspension to the intracranial drug spheres under the action of a spraying force, and precipitating drug microcrystals of rapamycin again to ensure that the drug microcrystals of rapamycin are retained in the intracranial drug spheres, wherein the rapamycin mixed solution undergoes crystallization-dissolution-recrystallization, and the drug microcrystals of rapamycin are attached to the intracranial drug spheres, so that the adhesion capacity of the drug microcrystals of rapamycin attached to the intracranial drug spheres is improved, and in addition, the drug microcrystals of rapamycin are slowly released outwards by taking the intracranial drug spheres as carriers, so that the narrow parts are convenient to be unblocked.
Description
Technical Field
The invention relates to the technical field of an application process of rapamycin, in particular to an application process of rapamycin in a intracranial medicinal ball.
Background
With the development of science and technology, the intracranial medicinal balls are gradually applied to vascular therapy, and the rapamycin is attached to the intracranial medicinal balls only in a liquid form and is delivered to a diseased region through the intracranial medicinal balls, wherein the rapamycin is easy to lose in the delivery process of the intracranial medicinal balls, so that the rapamycin cannot reach the diseased region.
Disclosure of Invention
In order to solve the technical problems, the invention adopts the following technical scheme:
according to one aspect of the invention, the invention provides a process for applying rapamycin to an intracranial drug balloon, which comprises the following steps:
preparing a rapamycin mixed solution;
carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain a drug microcrystal of rapamycin;
re-dissolving the drug microcrystals and obtaining a drug suspension;
and spraying the drug suspension to the intracranial drug spheres under the action of the spraying force, and precipitating the drug microcrystals of the rapamycin again so that the drug microcrystals of the rapamycin are kept in the intracranial drug spheres.
Optionally, the rapamycin mixed solution is butylated hydroxytoluene-rapamycin mixed solution.
Optionally, the low-temperature ultrasonic treatment of the rapamycin mixed solution to obtain the drug microcrystal of rapamycin includes:
swirling the rapamycin mixture;
performing ultrasonic treatment on the basis of the rapamycin mixed solution after vortex treatment;
and carrying out vacuum treatment on the rapamycin mixed solution after ultrasonic treatment to obtain the drug microcrystal of rapamycin.
Optionally, the low-temperature ultrasonic treatment of the rapamycin mixed solution is performed to obtain the drug microcrystal of rapamycin, further comprising:
the vortex speed was 2500rpm, the vacuum was 99.9%, the ultrasonic frequency was 40Hz, and the temperature was-18 ℃.
Optionally, the re-dissolving the drug microcrystals and obtaining a drug suspension comprises:
the drug microcrystals were redissolved and vortexed and sonicated to obtain a drug suspension.
Optionally, the spraying the drug suspension to the intracranial pellets under the action of a spraying force, and precipitating the drug microcrystals of rapamycin again, so that the drug microcrystals of rapamycin remain in the intracranial pellets, comprising: spraying the drug suspension to the intracranial pellets under a spraying force, wherein the drug suspension adheres to the outer surface of the intracranial pellets; the drug suspension on the outer surface of the intracranial drug pellet is recrystallized such that the drug crystallites of rapamycin remain in the intracranial drug pellet.
Optionally, the application process of rapamycin in the intracranial drug ball further comprises the following steps: (ii) passing said intracranial pellets with said drug microcrystals of rapamycin attached along a blood vessel to a site of stenosis; the intracranial drug ball stays to the lesion site and releases the drug microcrystal of the rapamycin; the stricture site is gradually smoothened under the pharmacological action of the drug microcrystal of rapamycin, so that the stricture site is unblocked.
According to the technical scheme, the embodiment of the invention at least has the following advantages and positive effects:
in the application process of the rapamycin in the intracranial medicinal ball, the rapamycin mixed solution is prepared; carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain a drug microcrystal of rapamycin; re-dissolving the drug microcrystals and obtaining a drug suspension; the drug suspension is sprayed to the intracranial drug spheres under the action of the spraying force, and drug microcrystals of the rapamycin are precipitated again, so that the drug microcrystals of the rapamycin are kept in the intracranial drug spheres, wherein the rapamycin mixed solution undergoes crystallization-dissolution-recrystallization, and the drug microcrystals of the rapamycin are attached to the intracranial drug spheres, so that the adhesion capacity of the drug microcrystals of the rapamycin attached to the intracranial drug spheres is improved, the loss rate of the drug microcrystals of the rapamycin in the delivery process of the intracranial drug spheres is reduced, in addition, the drug microcrystals of the rapamycin are slowly released outwards by taking the intracranial drug spheres as carriers, the time of the drug acting on narrow parts is prolonged, and the narrow parts are convenient to be unblocked.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the structures shown in the drawings without creative efforts.
FIG. 1 is a schematic diagram of the process for applying rapamycin to intracranial drug balls in accordance with the present invention;
the implementation, functional features and advantages of the objects of the present invention will be further explained with reference to the accompanying drawings.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It should be noted that all the directional indicators (such as up, down, left, right, front, and rear … …) in the embodiment of the present invention are only used to explain the relative position relationship between the components, the movement situation, etc. in a specific posture (as shown in the drawing), and if the specific posture is changed, the directional indicator is changed accordingly.
In the present invention, unless otherwise expressly stated or limited, the terms "connected," "secured," and the like are to be construed broadly, and for example, "secured" may be a fixed connection, a removable connection, or an integral part; can be mechanically or electrically connected; they may be directly connected or indirectly connected through intervening media, or they may be connected internally or in any other suitable relationship, unless expressly stated otherwise. The specific meanings of the above terms in the present invention can be understood by those skilled in the art according to specific situations.
In addition, if there is a description of "first", "second", etc. in an embodiment of the present invention, the description of "first", "second", etc. is for descriptive purposes only and is not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In addition, the meaning of "and/or" appearing throughout includes three juxtapositions, exemplified by "A and/or B" including either A or B or both A and B. In addition, technical solutions between various embodiments may be combined with each other, but must be realized by a person skilled in the art, and when the technical solutions are contradictory or cannot be realized, such a combination should not be considered to exist, and is not within the protection scope of the present invention.
With the development of science and technology, the intracranial medicinal balls are gradually applied to vascular therapy, and the rapamycin is attached to the intracranial medicinal balls only in a liquid form and is delivered to a diseased region through the intracranial medicinal balls, wherein the rapamycin is easy to lose in the delivery process of the intracranial medicinal balls, so that the rapamycin cannot reach the diseased region.
Referring to fig. 1, the present invention provides a process for applying rapamycin to intracranial pellets, which comprises:
step S11, preparing rapamycin mixed solution;
s12, carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain a drug microcrystal of rapamycin;
step S13, dissolving the drug microcrystal again and obtaining drug suspension;
and step S14, spraying the medicine suspension to the intracranial medicine balls under the action of the spraying force, and precipitating the medicine microcrystals of the rapamycin again so that the medicine microcrystals of the rapamycin are remained in the intracranial medicine balls.
In the application process of the rapamycin in the intracranial medicinal ball, the rapamycin mixed solution is prepared; carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain a drug microcrystal of rapamycin; re-dissolving the drug microcrystals and obtaining a drug suspension; the drug suspension is sprayed to the intracranial drug spheres under the action of the spraying force, and drug microcrystals of the rapamycin are precipitated again, so that the drug microcrystals of the rapamycin are kept in the intracranial drug spheres, wherein the rapamycin mixed solution undergoes crystallization-dissolution-recrystallization, and the drug microcrystals of the rapamycin are attached to the intracranial drug spheres, so that the adhesion capacity of the drug microcrystals of the rapamycin attached to the intracranial drug spheres is improved, the loss rate of the drug microcrystals of the rapamycin in the delivery process of the intracranial drug spheres is reduced, in addition, the drug microcrystals of the rapamycin are slowly released outwards by taking the intracranial drug spheres as carriers, the time of the drug acting on narrow parts is prolonged, and the narrow parts are convenient to be unblocked.
In step S11: preparing a rapamycin mixed solution, wherein the rapamycin mixed solution is a butylated hydroxytoluene-rapamycin mixed solution; rapamycin is a macrolide immunosuppressant produced by streptomyces hygroscopicus, is a white to off-white powder, is readily soluble in chloroform, acetone and acetonitrile, is insoluble in water, and has the molecular formula: C51H79NO13, molecular weight: 914.2g/mol, CAS number: 53123-88-9, rapamycin blocks signaling through different cytokine receptors, blocks the progression of T lymphocytes and other cells from G1 to S phase, and thus exerts immunosuppressive effects.
In step S12: and carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain the drug microcrystal of the rapamycin.
The method comprises the following specific steps: swirling the rapamycin mixture; performing ultrasonic treatment on the basis of the rapamycin mixed solution after vortex treatment; and carrying out vacuum treatment on the rapamycin mixed solution after ultrasonic treatment to obtain the drug microcrystal of rapamycin.
Wherein the vortex speed is 2500rpm, the vacuum degree is 99.9%, the ultrasonic frequency is 40Hz, and the temperature is-18 ℃.
In step S13: re-dissolving the drug microcrystals and obtaining a drug suspension;
the method comprises the following specific steps: the drug microcrystals are redissolved and vortexed and sonicated to obtain a drug suspension, wherein a substantial portion of the drug microcrystals remain in the drug suspension to facilitate later processing of the drug suspension.
At step S14, the drug suspension is sprayed onto the intracranial pellets under the spraying force, and the drug crystallites of rapamycin are precipitated again, so that the drug crystallites of rapamycin remain in the intracranial pellets:
the method comprises the following specific steps: spraying the drug suspension to the intracranial pellets under a spraying force, wherein the drug suspension adheres to the outer surface of the intracranial pellets; the drug suspension on the outer surface of the intracranial drug pellet is recrystallized such that the drug crystallites of rapamycin remain in the intracranial drug pellet.
The rapamycin mixed solution is subjected to crystallization-dissolution-recrystallization, and the rapamycin drug microcrystal is attached to the intracranial drug spheres, so that the adhesion capacity of the rapamycin drug microcrystal attached to the intracranial drug spheres is improved, the loss rate of the rapamycin drug microcrystal in the intracranial drug sphere delivery process is reduced, in addition, the rapamycin drug microcrystal is slowly released outwards by taking the intracranial drug spheres as carriers, the time of the drug action on the narrow part is prolonged, and the narrow part is convenient to be unblocked.
In addition, the loss of the rapamycin drug coating in the delivery process is lower (< 20%), and the loss rate of paclitaxel coated pellets on the same type which are already on the market reaches 50%; the transfer rate of the drug to the vascular wall is higher (more than 10 percent) and is superior to that of the similar paclitaxel coating drug ball (8 percent); the proportion of drug remaining on the pellets after treatment was low (< 5%), indicating that the drug has been substantially completely released in vivo; the dissolution rate of rapamycin drug coatings in methyl- β -cyclodextrin aqueous solutions was low (< 20%), indicating that the drug was retained in vascular tissue for a longer period of time; rapamycin is a macrolide cytostatic agent, does not cause apoptosis of cells per se, and does not cause inflammatory reaction on local parts of vascular intima; the toxicity is lower, the safety is higher (the paclitaxel medicament has certain carcinogenicity, and 2018FDA issues the carcinogenic risk of the paclitaxel medicament balloon.
In addition, the application process of the rapamycin in the intracranial medicinal balls further comprises the following steps: (ii) passing said intracranial pellets with said drug microcrystals of rapamycin attached along a blood vessel to a site of stenosis; the intracranial drug ball stays to the lesion site and releases the drug microcrystal of the rapamycin; the stricture site is gradually smoothened under the pharmacological action of the drug microcrystal of rapamycin, so that the stricture site is unblocked.
According to the technical scheme, the embodiment of the invention at least has the following advantages and positive effects:
in the application process of the rapamycin in the intracranial medicinal ball, the rapamycin mixed solution is prepared; carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain a drug microcrystal of rapamycin; re-dissolving the drug microcrystals and obtaining a drug suspension; the drug suspension is sprayed to the intracranial drug spheres under the action of the spraying force, and drug microcrystals of the rapamycin are precipitated again, so that the drug microcrystals of the rapamycin are kept in the intracranial drug spheres, wherein the rapamycin mixed solution undergoes crystallization-dissolution-recrystallization, and the drug microcrystals of the rapamycin are attached to the intracranial drug spheres, so that the adhesion capacity of the drug microcrystals of the rapamycin attached to the intracranial drug spheres is improved, the loss rate of the drug microcrystals of the rapamycin in the delivery process of the intracranial drug spheres is reduced, in addition, the drug microcrystals of the rapamycin are slowly released outwards by taking the intracranial drug spheres as carriers, the time of the drug acting on narrow parts is prolonged, and the narrow parts are convenient to be unblocked.
The above description is only an alternative embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications and equivalents of the present invention, which are made by the contents of the present specification and the accompanying drawings, or directly/indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (7)
1. An application process of rapamycin in intracranial medicine balls is characterized by comprising the following steps:
preparing a rapamycin mixed solution;
carrying out low-temperature ultrasonic treatment on the rapamycin mixed solution to obtain a drug microcrystal of rapamycin;
re-dissolving the drug microcrystals and obtaining a drug suspension;
and spraying the drug suspension to the intracranial drug spheres under the action of the spraying force, and precipitating the drug microcrystals of the rapamycin again so that the drug microcrystals of the rapamycin are kept in the intracranial drug spheres.
2. The process for applying rapamycin to a intracranial drug balloon as in claim 1, wherein the rapamycin mixture is butylated hydroxytoluene-rapamycin mixture.
3. The process for applying rapamycin to a intracranial drug balloon as defined in claim 1, wherein the low-temperature ultrasonication of the rapamycin mixture to obtain the drug microcrystals of rapamycin comprises:
swirling the rapamycin mixture;
performing ultrasonic treatment on the basis of the rapamycin mixed solution after vortex treatment;
and carrying out vacuum treatment on the rapamycin mixed solution after ultrasonic treatment to obtain the drug microcrystal of rapamycin.
4. The process for applying rapamycin to intracranial drug delivery balloons as recited in claim 3, wherein the low-temperature ultrasonic treatment of the rapamycin mixture to obtain the drug microcrystals of rapamycin further comprises:
the vortex speed was 2500rpm, the vacuum was 99.9%, the ultrasonic frequency was 40Hz, and the temperature was-18 ℃.
5. The process for the use of rapamycin in intracranial drug delivery balloons, as in claim 1, wherein said redissolving the drug microcrystals and obtaining a drug suspension comprises:
the drug microcrystals were redissolved and vortexed and sonicated to obtain a drug suspension.
6. The process for applying rapamycin to intracranial drug delivery balloons as defined in claim 1, wherein said injecting said suspension of rapamycin into said intracranial drug delivery balloons under the action of an injection force and re-precipitating the drug crystallites of rapamycin such that the drug crystallites of rapamycin remain in said intracranial drug delivery balloons comprises:
spraying the drug suspension to the intracranial pellets under a spraying force, wherein the drug suspension adheres to the outer surface of the intracranial pellets;
the drug suspension on the outer surface of the intracranial drug pellet is recrystallized such that the drug crystallites of rapamycin remain in the intracranial drug pellet.
7. The process for applying rapamycin to a intracranial balloon as defined in claim 6, further comprising:
(ii) passing said intracranial pellets with said drug microcrystals of rapamycin attached along a blood vessel to a site of stenosis;
the intracranial drug ball stays to the lesion site and releases the drug microcrystal of the rapamycin;
the stricture site is gradually smoothened under the pharmacological action of the drug microcrystal of rapamycin, so that the stricture site is unblocked.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105025947A (en) * | 2013-03-07 | 2015-11-04 | 雅培心血管系统公司 | Method of fabricating an implantable medical device comprising a rapamycin derivative |
| CN112704686A (en) * | 2020-12-28 | 2021-04-27 | 浙江大学 | Preparation method of calcium phosphate-rapamycin composite medicine, preparation method of medicine coating balloon and medicine coating balloon |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105025947A (en) * | 2013-03-07 | 2015-11-04 | 雅培心血管系统公司 | Method of fabricating an implantable medical device comprising a rapamycin derivative |
| CN112704686A (en) * | 2020-12-28 | 2021-04-27 | 浙江大学 | Preparation method of calcium phosphate-rapamycin composite medicine, preparation method of medicine coating balloon and medicine coating balloon |
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