CN113143854B - Application of human serum albumin in preparation of radioactive iodine-labeled hypericin pharmaceutical preparation - Google Patents
Application of human serum albumin in preparation of radioactive iodine-labeled hypericin pharmaceutical preparation Download PDFInfo
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- 102000008100 Human Serum Albumin Human genes 0.000 title claims abstract description 30
- 108091006905 Human Serum Albumin Proteins 0.000 title claims abstract description 30
- 229940005608 hypericin Drugs 0.000 title claims abstract description 18
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention belongs to the field of pharmaceutical preparations, and relates to a method for preparing a pharmaceutical preparation of radioiodine hypericin by applying human serum albumin for the first time; because albumin is a main carrier for a plurality of medicines after entering blood, the dissolution rate of hypericin can be obviously improved; the hypericin is also an inherent component in human blood, and the hypericin is used for assisting dissolution, and does not meet the requirements of pharmacopoeia and approval of drug administration like other externally added drug carriers or auxiliary materials; under the marking condition of the patent, solubilized hypericin can be efficiently marked by iodine, human serum albumin is not marked, and the marked product does not need to be purified, and the targeting and in-vivo metabolism modes of the original iodine-marked hypericin are not changed; therefore, the human serum albumin can be used as a substitute of DMSO, cyclodextrin and the like and applied to a radioiodinated hypericin preparation; the method for preparing the iodine standard hypericin preparation has the advantages of simple process, low cost and high preparation efficiency, and is suitable for industrialized operation.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to application of human serum albumin in preparation of a radioactive iodine label hypericin pharmaceutical preparation.
Background
Hypericin (Hypericin, abbreviated as Hyp) is an extract from Hypericum perforatum, has anti-inflammatory, antiviral, anti-AIDS effects, and even has been reported to be anticancer. Nearly thirty years ago, hyp superior "necrosis targeting" was discovered by the professor Yicheng Ni of belgium chinese scientist, and then did open up its unique application in the field of diagnosis and treatment of malignant solid tumors, but not directly treating tumors, but in combination with other drugs: hyp is self-labeled with radioactivity after other drugs (e.g., combretastatin disodium phosphate) destroy most of the cancer cells and cause a large number of tumor necrosis sites 131 I (i.eFormation of 131 I-Hyp), will, depending on its characteristic necrosis targeting 131 I is carried to necrotic tumor range and utilized 131 The high-energy beta rays of the I kill short-distance and residual living tumor cells, and have no harm to normal tissue cells at a longer distance, so that the targeting of cancer treatment is fully realized. At the same time 131 The I-Hyp releases low-energy gamma rays and can be used for positioning diagnosis and curative effect evaluation of nuclear medicine image tumor.
Hyp is poorly soluble in water, so it is not easy to prepare into solution for injection, but is often soluble in oil to prepare into oral preparation. However, if it is desired to inject into the body 131 I-Hyp, but not Hyp, must not be taken orally (alkaline environment of the intestinal tract causes de-labelling, 131 i will separate from Hyp, resulting in 131 I does not accumulate at necrotic tumor sites, losing targeted therapeutic properties) and is therefore the only, best choice for intravenous injection. In preclinical studies, hyp was initially solubilized and labeled using the universal solvent DMSO 131 I. Then diluted, prepared into solution and then injected intravenously. However, DMSO has the special property of being very permeable to skin, and can cause adverse reactions such as nausea, vomiting, rash, etc. to the user; in addition, DMSO has certain toxic action, acts with hydrophobic groups of proteins to cause protein denaturation, and has vascular toxicity, hemolysis, hepatorenal toxicity and the like. Therefore, DMSO is not the most desirable hypericin-based dissolver in the pharmacopoeia approved for injection. Chinese patent CN201310111593.4 uses cholate to solubilize the radioiodinated hypericum, but the cholate as an adjuvant drug is injected intravenously and related adjuvant lot is not obtained temporarily. Chinese patent CN107308455B adopts cyclodextrin as preparation 131 The solvent of I-Hyp and hydroxypropyl-beta-cyclodextrin are auxiliary materials approved by pharmacopoeia for intravenous injection, but the required cyclodextrin dose is larger, after all, the cyclodextrin is a foreign substance which is not an in-vivo component, and the use is also careful; in some non-academic journal discussion, there is also a negative status on the safety of hydroxypropyl-beta-cyclodextrin for intravenous injection. There is therefore a need for further improvements in the solvents for Hyp.
In the past we have only learned through research experience: 131 I-Hyp should be carried in combination with plasma proteins after intravenous blood. Is to take the effect of 131 When the injection of I-Hyp is too fast, the self-aggregation phenomenon can occur due to the too high concentration and insolubility in blood, and the self-aggregation phenomenon is deposited in a mononuclear megaphagy system such as liver, spleen, lung and the like, so that the traditional administration is carried out 131 I-Hyp) is always injected as slowly as possible, increasing the chance of binding to plasma proteins. Recently, we have determined that whichever solvent, it (Hyp +. 131 I-Hyp) are bound to albumin after intravenous blood, and therefore it is proposed to envisage: why do it have to be injected slowly, but not allow it to bind with albumin sufficiently in vitro?
Replacement of DMSO or hydroxypropyl-beta-cyclodextrin with albumin, solubilizing Hyp, and in vitro 131 I labelling, generation 131 I-Hyp, this operation is unprecedented. One of the reasons for this speculation may be that the searchable literature suggests that "albumin may be iodine labeled (e.g., by 125 I label) ", and thus appears to be deduced: in Hyp/albumin solution, add 131 I, will be generated at the same time 131 I-Hyp 131 I-albumin, which is not only an impurity component but is also detrimental to tumor treatment. However, in practice, the conditions for the radioiodination are different, and only Hyp may be labeled and albumin may not be labeled by utilizing the difference in chemical reaction conditions.
Disclosure of Invention
The invention solves the technical problems in the prior art, and provides application of human serum albumin in preparation of a radioactive iodine-labeled Hyp pharmaceutical preparation, a method for preparing the radioactive iodine-labeled Hyp pharmaceutical preparation by using the human serum albumin and the radioactive iodine-labeled Hyp preparation.
The application of human serum albumin in preparing radioactive iodine-marked Hyp medicine preparation as Hyp and iodine-marked Hyp solvent for injecting into human blood vessel, such as vein and artery.
Preferably, the human serum albumin is human serum albumin with the concentration of 5% -25% (5-25 g/100 mL).
A pharmaceutical preparation containing radioactive iodine labeled Hyp comprises human serum albumin, hyp and 131 i labeled Hyp; human serumThe protein is used as solvent to increase Hyp solubility, and can be used for intravenous injection and arterial injection.
A method of preparing a radioiodinated Hyp pharmaceutical formulation comprising the steps of:
1) Mixing Hyp with 5% -25% (5-25 g/100 mL) of human serum albumin solution, adding 0.01-1 mg of Hyp per milliliter of the human serum albumin solution, continuously and uniformly mixing at the temperature of 4-37 ℃, centrifuging at high speed after 8 hours, taking the supernatant, and filtering with a 0.22 mu m microporous filter membrane to obtain a human serum albumin-Hyp solution;
2) Purchased nuclide-Na 131 The specific activity of the solution I is 20-1000 mCi/mL, and the solution I is adjusted to be neutral by PBS buffer solution.
3) And (2) continuously and uniformly mixing the human albumin-Hyp solution and the solution prepared in the step (2) in a water bath at the temperature of 34-40 ℃ in the presence of a catalyst until the marking rate reaches more than 90%. Said human serum albumin-Hyp solution and Na 131 The amount of the solution I is added in the amount required to prepare the label.
Preferably, the catalyst is Iodogen or chloramine T with the dosage of 3-10 mug/mCi Na 131 I。
The advantages of the present invention over the prior art are as follows,
the invention applies the human serum albumin to prepare the radioactive iodine label Hyp preparation for the first time. Because the human serum albumin is an inherent component of human blood, is nontoxic and harmless, and does not exist the condition that the components added in vitro like auxiliary materials need to be in the range of pharmacopoeia record or need to be approved by a drug administration; meanwhile, as a carrier in blood of most medicines, the albumin can be greatly mentioned as Hyp water-solubility; under the marking condition of the patent, solubilized Hyp can be efficiently marked by iodine, but human serum albumin is not marked, and the marked product does not need to be purified and can not change the targeting and in-vivo metabolism modes of the original iodine-marked Hyp. Therefore, the human serum albumin can be used as a substitute of DMSO and cyclodextrin and applied to a radioactive iodine standard Hyp preparation;
the radioactive iodine standard Hyp preparation of the invention is prepared by using DMSO or hydroxypropyl-beta-cyclodextrin as a solvent 131 I-Hyp injection phaseThe method is more acceptable by the medical community, can ensure the marking efficiency of Hyp, basically does not change the necrosis targeting of the marker, has lower distribution in normal liver, spleen, kidney and blood, and can be used for tumor treatment;
the method for preparing the iodine standard Hyp preparation has the advantages of simple process, low cost and high preparation efficiency, and is suitable for industrialized operation.
Drawings
FIG. 1 is a graph showing the pH adjustment of human serum albumin-Hyp solution 131 I, detecting a result by the marked radioactive thin layer scanner;
FIG. 2 shows the pH adjustment of human blood albumin solution 131 After I labeling, carrying out a detection result of a radioactive thin layer scanner labeled with human serum albumin-Hyp solution under the same condition;
FIG. 3 shows Hyp in human serum albumin solution (left), DMSO solution (middle), hydroxypropyl-beta-cyclodextrin solution (right) 131 After the marking of the I, the marking is carried out, 131 injecting the I-Hyp solution into a necrotic animal model body, and detecting the obtained radioactive in-vivo distribution by SPECT-CT;
FIG. 4 shows Hyp in human serum albumin solution (left), DMSO solution (middle), hydroxypropyl-beta-cyclodextrin solution 131 After I marking (right), 131 Injecting the I-Hyp solution into a necrotic animal model body, and killing a section to obtain necrotic liver lobes (ascending); in vitro analysis results (downlink) of the radioactivity distribution obtained by adopting phosphorus screen self-development analysis; indicating that radioactivity is distributed only in necrotic tissue of the liver lobes.
Detailed Description
In the following description, ci is a unit describing the size of a radioactive source in terms of activity, curie;
131 I-Hyp is 131 I labeled Hyp.
Example 1:
with human serum albumin as solvent 131 Preparation of I-Hyp solution: weighing 1mg Hyp, adding 1mL of 20% (20 g/100 mL) human serum albumin solution in proportion, ultrasonically and continuously mixing at 4-37 ℃ and proper heating not more than 37 ℃ for 8 hours, centrifuging 10000g for 15min after light shielding, collecting supernatant, and,Filtering with 0.22 μm microporous membrane to obtain "human serum albumin-Hyp" solution. The catalyst Iodogen was previously applied to a 1.5mL EP tube (optimal ratio is 3-10. Mu.g Iodogen:1mCi Na) 131 I) About 1mL of "human serum albumin-Hyp" solution was added, followed by about 10. Mu.L of Na 131 Solution I (specific activity is 20-1000 mCi/mL, the half life of isotope is no more than 1 from production to use, the isotope is adjusted to be neutral by PBS buffer solution before adding), water bath is carried out at 34-40 ℃, the solution I is continuously mixed and detected by Thin layer chromatography (Thin-layer chromatography, TLC) and a radioactive Thin layer scanner are matched 131 I marking rate until the marking rate reaches more than 98% (figure 1), obtaining " 131 I-Hyp/human serum albumin. The blank control group is corresponding human serum albumin solution without Hyp, and experiments show that the human serum albumin solution cannot be used per se 131 I (FIG. 2). Will' 131 The I-Hyp/human serum albumin "solution was diluted with 10-50 mL of human serum albumin solution for the next injection.
Example 2:
preparation of a rat partial liver necrosis reperfusion model: male SD rats (250-300 g) were started 24 hours prior to surgery and were dosed with 0.5% KI solution instead of drinking water to block thyroid uptake of free iodine. On the day of the operation, the anesthesia and the abdominal opening are carried out, the right lobe necrosis reperfusion operation is carried out, and the magnetic resonance scanning is carried out within 24 hours to detect whether the local part of the liver is necrotic.
The partial liver necrosis rat model was divided into three groups and injected separately " 131 I-Hyp/human serum albumin "solution, traditional formulation" 131 I-Hyp/DMSO "solutions" 131 I-Hyp/hydroxypropyl-beta-cyclodextrin "solutions (the three solutions were labeled under identical conditions). 48h after injection, detection 131 Radioactivity distribution of I. Rats were first anesthetized and subjected to in vivo nuclide scanning (SPECT-CT) (see fig. 3), and the results showed that: 1) Each group of 131 I radioactivity aggregates at the liver lobe sites subjected to necrosis modeling, and the solvent albumin does not affect the necrosis targeting distribution of radioactivity (i.e. does not affect 131 Distribution of I-Hyp); 2) Another site of radioactivity gathering in the gut (due to unwanted unbound necrotic sites 131 I-Hyp is metabolized by liver and discharged from bile into intestinal tractAnd gradually discharged out of the body along with the feces after being mixed with chyme); 3) Other parts have almost no radioactivity distribution, which accords with 131 Physiological distribution of I-Hyp and absence of 131 The possibility of I-albumin distribution (left in FIG. 3). Rats were then sacrificed by overdose, intraoperative necrotic lobes were harvested, frozen sections were performed, and radioactivity was detected by phosphorus screen autoradiography to attach only to necrotic tissue sites in the lobes (fig. 4), and the results showed: the necrotic parts of the liver lobes of the three treatment groups show radioactivity distribution through phosphorus screen autoradiography, and the parts of the liver lobes which are not necrotic have no radioactivity distribution, which accords with 131 I-Hyp necrosis targeted distribution profile.
The above embodiments are only preferred embodiments of the present invention, and should not be construed as limiting the present invention, and the protection scope of the present invention should be defined by the claims, including the technical equivalents of the technical features in the claims, as the protection scope, that is, the equivalent replacement and improvement within the protection scope of the present invention.
Claims (3)
1. A method of preparing a radioiodinated hypericin pharmaceutical formulation comprising the steps of:
A. mixing hypericin with 0.05-0.25 g/mL human serum albumin solution, adding 0.01-1 mg hypericin per milliliter of the human serum albumin solution, carrying out ultrasonic and uniform mixing for 8 hours, centrifuging to obtain supernatant, and filtering to obtain human serum albumin-hypericin solution;
B. na is mixed with 131 The solution I is regulated to be neutral by PBS buffer solution;
C. the human serum albumin-hypericin solution and the solution prepared in the step B are continuously and evenly mixed in a water bath at the temperature of 34-40 ℃ in the presence of a catalyst until the marking rate reaches more than 90%; human serum albumin-hypericin solution and Na 131 The amount of the solution I is added according to the amount required for preparing the marker;
in the step A, the temperature of ultrasonic and uniform mixing is 4-37 ℃;
na in step B 131 The specific activity of the solution I is 20-1000 mCi/mL.
2. The method according to claim 1, wherein the filtering in step a comprises the steps of: the supernatant was filtered through a microporous membrane having a pore size of 0.22. Mu.m.
3. The method according to claim 1, wherein the catalyst in step C is Iodogen or chloramine T at a dose of 3-10 μg/mCi Na 131 I。
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| US4473544A (en) * | 1979-11-24 | 1984-09-25 | Machulla Hans Juergen | Radio-iodine-labelled omega phenyl fatty acids |
| CN108434468A (en) * | 2018-06-08 | 2018-08-24 | 厦门大学 | A kind of protein binding partner of radioiodination and its application |
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| WO1993014197A1 (en) * | 1992-01-16 | 1993-07-22 | New York University | Hypericin treatment of vaccine agents for improved immunogenicity |
| WO2014141289A1 (en) * | 2013-03-12 | 2014-09-18 | Amrita Vishwa Vidyapeetham University | Photo - chemo composition on the basis of microcapsules with a core -shell structure |
| CN104840424B (en) * | 2015-05-05 | 2017-09-15 | 中国农业科学院兰州畜牧与兽药研究所 | A kind of hypericin albumin nanoparticle Escherichia coli serum antibody compound and its preparation method and application |
| CN107308455B (en) * | 2017-06-27 | 2021-02-12 | 南京成至诚医药科技有限公司 | Application of cyclodextrin in preparation of radioiodine hypericum pharmaceutical preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4473544A (en) * | 1979-11-24 | 1984-09-25 | Machulla Hans Juergen | Radio-iodine-labelled omega phenyl fatty acids |
| CN108434468A (en) * | 2018-06-08 | 2018-08-24 | 厦门大学 | A kind of protein binding partner of radioiodination and its application |
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