CN113813372A - Heme composition, pharmaceutical composition and application thereof - Google Patents

Heme composition, pharmaceutical composition and application thereof Download PDF

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Publication number
CN113813372A
CN113813372A CN202111129448.XA CN202111129448A CN113813372A CN 113813372 A CN113813372 A CN 113813372A CN 202111129448 A CN202111129448 A CN 202111129448A CN 113813372 A CN113813372 A CN 113813372A
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Prior art keywords
heme
composition
iron deficiency
catalase
present application
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CN202111129448.XA
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Chinese (zh)
Inventor
莫德欢
蔡伟江
王瑶曦
梁灿林
夏烈文
陈刚
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Yunjin Huazhang Beijing Biotechnology Co ltd
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Yunjin Huazhang Beijing Biotechnology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/446—Superoxide dismutase (1.15)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y111/00—Oxidoreductases acting on a peroxide as acceptor (1.11)
    • C12Y111/01—Peroxidases (1.11.1)
    • C12Y111/01006—Catalase (1.11.1.6)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y115/00—Oxidoreductases acting on superoxide as acceptor (1.15)
    • C12Y115/01—Oxidoreductases acting on superoxide as acceptor (1.15) with NAD or NADP as acceptor (1.15.1)
    • C12Y115/01001—Superoxide dismutase (1.15.1.1)

Abstract

The application relates to the technical field of heme, and provides a heme composition, a pharmaceutical composition and application thereof. The present application provides a heme composition comprising: heme, superoxide dismutase and catalase. The application can effectively prevent heme from being decomposed and oxidized by adding superoxide dismutase and catalase in heme, thereby improving the stability of heme.

Description

Heme composition, pharmaceutical composition and application thereof
Technical Field
The application relates to the technical field of heme, in particular to a heme composition, a pharmaceutical composition and application thereof.
Background
Iron is an important nutrient element essential to the human body, is mainly present in hemoglobin and myoglobin, and plays an important role in conveying oxygen, catalyzing the oxidation of organic matters, decomposing peroxides and transferring electrons in blood. Currently, the prevention and treatment of iron deficiency anemia is mainly realized by iron supplement. The common iron supplement agents comprise ferrous sulfate, ferrous chloride, ferrous gluconate, ferrous lactate, ferrous succinate, ferrous fumarate and the like, and although the iron supplement agents have high iron content and good iron supplement effect, the iron supplement agents have low utilization rate in vivo, have large toxic and side effects and special metal rust taste and are difficult to take for a long time.
The heme iron in the heme is an organic iron, can be directly absorbed by intestinal mucosa cells, does not produce digestive tract stimulation symptoms, and has high bioavailability. However, heme iron is unstable and easily decomposed by oxidation, thereby affecting its stability.
Disclosure of Invention
The present application aims to provide a hemoglobin composition which can effectively prevent hemoglobin in hemoglobin from being oxidized and decomposed, thereby improving the stability of the hemoglobin composition.
In a first aspect, the present application provides a heme composition comprising: heme, superoxide dismutase and catalase.
In some embodiments, the ratio of the mass of heme, the enzymatic activity of the superoxide dismutase, and the enzymatic activity of the catalase is 5 g: 3000-6000 IU: 1000-.
In a second aspect, the present application provides the use of a heme composition as provided in the first aspect of the present application for the preparation of a medicament for the prevention or treatment of an iron deficiency-related disorder.
In some embodiments, the iron deficiency-related disorder comprises iron deficiency anemia.
In a third aspect, the present application provides a pharmaceutical composition comprising the heme composition provided in the first aspect of the present application and a pharmaceutically acceptable carrier, diluent, or excipient.
In some embodiments, the dosage form is an oral dosage form.
In some embodiments, the oral dosage form is selected from one of oral liquid, syrup, granules, capsules, tablets, powders, pills and drop pills.
In a fourth aspect, the present application provides a use of the pharmaceutical composition provided in the third aspect of the present application in the preparation of a medicament for preventing or treating a disease associated with iron deficiency.
In some embodiments, the iron deficiency-related disorder comprises iron deficiency anemia.
The heme composition provided by the application can effectively prevent heme from being oxidized and decomposed by adding superoxide dismutase and catalase in heme, so that the stability of heme is improved.
Of course, not all advantages described above need to be achieved at the same time in the practice of any one product or method of the present application.
Detailed Description
The technical solutions in the present application will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present application, and not all embodiments. All other embodiments that can be derived by one of ordinary skill in the art from the description herein are intended to be within the scope of the present disclosure.
In a first aspect, the present application provides a heme composition comprising: heme, superoxide dismutase and catalase.
Superoxide dismutase is an important antioxidant enzyme in organisms, and can clear excessive oxygen free radicals generated in the metabolic process of the organisms and delay the aging of the organisms. Catalase is one of the key enzymes of the biological defense system established in the biological evolution process, and the biological function of the catalase is to catalyze the decomposition of hydrogen peroxide in cells and prevent degreasing and peroxidation.
The inventor finds in research that the combination of heme, superoxide dismutase and catalase can effectively prevent the low-valence iron in the heme from being oxidized into high-valence iron, thereby improving the stability of heme; it is difficult to effectively prevent the low-valent iron in hemoglobin from being oxidized into high-valent iron by mixing only hemoglobin and superoxide dismutase or only hemoglobin and catalase. In addition, the heme is mixed with superoxide dismutase and catalase, so that the obtained heme composition has the functions of supplementing iron, resisting oxidation, maintaining beauty, keeping young, delaying senescence and the like.
In some embodiments of the present application, the ratio of the mass of heme, the enzymatic activity of superoxide dismutase, and the enzymatic activity of catalase is 5 g: 3000-6000 IU: 1000-.
The inventor finds in the research that the combination of the heme, the superoxide dismutase and the catalase according to the proportion can effectively prevent the low-valence iron in the heme from being oxidized into high-valence iron, thereby improving the stability of the heme.
In a second aspect, the present application provides the use of a heme composition as provided in the first aspect of the present application for the preparation of a medicament for the prevention or treatment of an iron deficiency-related disorder.
In some embodiments of the present application, the iron deficiency-related disorder comprises iron deficiency anemia.
The iron deficiency anemia described herein may be selected from one or more of iron deficiency anemia in pregnant women, latent iron deficiency anemia in children and adolescents, iron deficiency anemia due to gastrointestinal disorders, iron deficiency anemia due to blood loss, iron deficiency anemia due to menstruation, iron deficiency anemia due to injury, iron deficiency anemia due to sprue, iron deficiency anemia in cancer patients, iron deficiency anemia due to chemotherapy, iron deficiency anemia due to inflammation, iron deficiency anemia due to chronic heart failure, iron deficiency anemia due to rheumatoid arthritis, iron deficiency anemia due to systemic lupus erythematosus, and iron deficiency anemia due to inflammatory bowel disease.
In a third aspect, the present application provides a pharmaceutical composition comprising the heme composition provided in the first aspect of the present application and a pharmaceutically acceptable carrier, diluent, or excipient.
The pharmaceutically acceptable carrier, diluent or excipient in the pharmaceutical compositions of the present application may be any conventional carrier, diluent or excipient in the art of pharmaceutical formulation, the selection of a particular carrier, diluent or excipient being dependent upon the mode of administration or the type and state of the disease being treated in a particular patient. The preparation of pharmaceutical compositions for specific modes of administration is well within the knowledge of those skilled in the pharmaceutical art. For example, as a pharmaceutically acceptable carrier, diluent or excipient, there may be mentioned starch, powdered sugar, dextrin, creamer, starch slurry, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, vitamin C, lactose, magnesium stearate, aerosil, talc, hydrogenated vegetable oil, polyethylene glycol and magnesium lauryl sulfate, etc., which are conventional in the pharmaceutical field.
In some embodiments of the present application, the dosage form is an oral dosage form.
In some embodiments of the present application, the oral dosage form is selected from one of oral liquid, syrup, granules, capsules, tablets, powders, pills and drop pills.
For different types of oral dosage forms, different carriers, diluents or excipients may be selected, which are conventional technical means in the art. For example, in the case of capsules, lactose, magnesium stearate, starch, powdered sugar, etc. can be used; when tablets are prepared, sodium carboxymethylcellulose, dextrin and the like can be used.
The pharmaceutical compositions in the above various dosage forms can be prepared according to conventional methods in the pharmaceutical field.
In a fourth aspect, the present application provides a use of the pharmaceutical composition provided in the third aspect of the present application in the preparation of a medicament for preventing or treating a disease associated with iron deficiency.
In some embodiments of the present application, the iron deficiency-related disorder comprises iron deficiency anemia.
The content of "iron deficiency anemia" in the fourth aspect of the present application is the same as the corresponding content in the second aspect, and the description thereof will not be repeated here.
Terms used herein have their ordinary meanings as known to those skilled in the art, if not explicitly stated or defined.
As used herein, the term "treatment" has its ordinary meaning, such as treating an individual who may or is at risk of suffering from an iron deficiency-related disease with a pharmaceutical composition of the present application in an effort to treat, cure, alleviate, etc. the disease. Similarly, as used herein, the term "prevention" has its ordinary meaning, such as treatment of a subject who may or is at risk of suffering from an iron deficiency-related disease with a pharmaceutical composition of the present application, in order to prevent, arrest, abrogate, etc. the disease.
As used herein, the term "pharmaceutical composition" has its ordinary meaning and, in this application, can refer to a formulation, e.g., a pharmaceutical formulation, into which the heme composition of the present application is further processed. In addition, the "pharmaceutical composition" of the present application may also be present or provided in the form of a health product, a functional food, a food additive, or the like. The pharmaceutical compositions of the present application may be prepared by employing conventional techniques in the pharmaceutical arts, particularly in the formulation arts, optionally in admixture with one or more pharmaceutically acceptable carriers, diluents or excipients, and then formulated into the desired dosage form.
When the pharmaceutical compositions of the present application are administered to a human or animal subject, they may be administered as such, i.e. without any of the above-mentioned pharmaceutically acceptable carriers, diluents or excipients, by directly administering the pharmaceutical compositions of the present application to the patient in their raw form; or may be administered to a human or animal subject in a pharmaceutical composition containing, for example, 1% to 99% or in combination with a pharmaceutically acceptable carrier, diluent or excipient.
The actual dosage level and the time course of administration of the pharmaceutical composition or active ingredients in the pharmaceutical compositions of the present application can be adapted so that the amount of active ingredient is effective to achieve the desired therapeutic response without toxicity to the subject for the particular subject, composition, and method of administration.
The present application will be described in detail with reference to specific examples.
Example 1
5g of heme, 3000IU of superoxide dismutase and 1000IU of catalase were mixed to obtain a heme composition.
Example 2
5g of heme, 6000IU of superoxide dismutase and 3000IU of catalase are mixed to obtain the heme composition.
Example 3
5g of heme, 4500IU of superoxide dismutase and 2000IU of catalase were mixed to obtain a heme composition.
Example 4
5g of heme, 1g of sodium carboxymethylcellulose, 4500IU of superoxide dismutase and 2000IU of catalase were mixed to obtain a mixture.
Adding 10 wt% dextrin into the mixture to obtain soft mass, tabletting, and drying to obtain tablet.
Example 5
5g of heme, 1g of lactose, 0.5g of magnesium stearate, 25g of starch, 15g of powdered sugar, 4500IU of superoxide dismutase and 2000IU of catalase were mixed to obtain a mixture.
Wetting the mixture with 60% ethanol water solution by volume fraction, and making into granule; drying, and encapsulating the obtained granules into enteric-coated capsules to obtain capsules.
Example 6
The same procedure as in example 5 was repeated, except that the amount of superoxide dismutase was 1000IU and the amount of catalase was 4000 IU.
Example 7
The same procedure as in example 5 was repeated, except that the amount of superoxide dismutase was 7000IU and the amount of catalase was 500 IU.
Comparative example 1
The procedure was as in example 5 except that 4500IU of superoxide dismutase was not added.
Comparative example 2
The procedure was as in example 5 except that 2000IU of catalase was not added.
Comparative example 3
The procedure of example 5 was repeated, except that 2000IU of catalase was not added and the amount of superoxide dismutase was 35000 IU.
Comparative example 4
The procedure was as in example 5 except that 4500IU of superoxide dismutase and 2000IU of catalase were not added.
Comparative example 5
The procedure was as in example 4 except that 4500IU of superoxide dismutase and 2000IU of catalase were not added.
Heme stability test
In order to determine the stability of heme in the products obtained in examples 1-7 and comparative examples 1-5, the products obtained in examples 1-7 and comparative examples 1-5 were tested for the actual content of heme by liquid chromatography.
1. Test conditions
A chromatographic column: agilent TC-C18 column (4.6mm 250mm, 5 μm).
Mobile phase: methanol: 0.6% by volume aqueous acetic acid solution 70: 30 (volume ratio).
Flow rate: 1.0 mL/min.
Temperature of the column: 35 ℃ is carried out.
Sample introduction amount: 20 μ L.
Detection wavelength: 399 nm.
2. Preparing standard working solution
27.39mg of hemin standard substance is precisely weighed, dissolved by 0.1mol/L sodium hydroxide solution and is added to a constant volume of 50mL, 1mL is absorbed, and the volume is added to 25mL by methanol.
The solution was precisely aspirated by 0.1mL, 0.2mL, 0.3mL, 0.4mL, and 0.5mL, and the volume was adjusted to 1mL with methanol, respectively, to prepare standard working solutions having concentrations of 2.1. mu.g/mL, 4.2. mu.g/mL, 6.3. mu.g/mL, 8.4. mu.g/mL, and 10.5. mu.g/mL.
3. Establishing a standard curve
And (3) respectively injecting the standard working solution according to the liquid chromatogram test conditions, and establishing a standard curve by taking the concentration as a horizontal coordinate and the peak area as a vertical coordinate.
4. Preparation of samples to be tested
After the products prepared in examples 1 to 7 and comparative examples 1 to 5 were allowed to stand for 0 day, 7 days, 14 days, 30 days and 60 days, appropriate amounts of samples were taken for preparing samples to be tested, respectively.
Taking a proper amount of the samples, respectively adding 30mL of 0.1mol/L sodium hydroxide solution, and dissolving by ultrasonic treatment for 20 min; and (3) adding 0.1mol/L sodium hydroxide solution to a constant volume of 100mL, centrifuging at 8000r/min for 5min, filtering with a water phase 0.45 mu m filter membrane, and collecting the obtained filtrate, namely the sample to be detected. For samples to be tested with a concentration higher than 10.5. mu.g/mL, the samples are diluted to a range of 2.1-10.5. mu.g/mL with 0.1mol/L NaOH solution.
5. Testing a sample to be tested
And respectively injecting samples to be detected according to liquid chromatogram testing conditions, and obtaining peak areas of the samples to be detected from the liquid chromatogram. All tests were repeated three times and the results were averaged.
6. Data analysis
According to the peak area of each sample to be detected, the corresponding concentration of each sample to be detected is obtained by using a standard curve, and according to the dilution ratio, the actual content of the heme of the products prepared in the examples 1-7 and the comparative examples 1-5 after being placed for 0 day, 7 days, 14 days, 30 days and 60 days is respectively obtained.
The ratio (%) of hemoglobin detection to actual content of hemoglobin/theoretical content of hemoglobin × 100%.
The higher the ratio of hemoglobin detection, the lower the proportion of hemoglobin that is oxidized and decomposed, and the more stable the hemoglobin.
7. Test results
The test results are shown in table 1 below.
TABLE 1 test results
Figure BDA0003280011680000081
From the results in table 1, it can be seen that the heme detection ratio of the products prepared in examples 1 to 5 is still over 97.5% after standing for 60 days, which indicates that the ratio of ferrous iron in heme oxidized into high-valence iron is small and heme is stable; therefore, the method proves that by adding a proper amount of superoxide dismutase and catalase into the heme, the heme iron in the heme can be effectively prevented from being oxidized, and the stability of the heme is improved.
As can be seen from the results after 7 days, 14 days, 30 days and 60 days of standing, the products obtained in examples 6-7 were less stable than the product obtained in example 5, indicating that superoxide dismutase and catalase were present together only in the proper ratio to effectively increase the stability of hemoglobin, and that too high or too low was not good for the stability.
The product prepared in comparative examples 1-5 had a heme detection ratio of 97.0% or less after being left for 30 days, and had a heme detection ratio of further significantly decreased after being left for 60 days, both of which were less than 94.0%, indicating that the ratio of ferrous iron in heme oxidized to high-valent iron was large and the heme stability was poor.
As can be seen from the results after standing for 60 days, the stability of the products prepared in comparative examples 1-3 was slightly better than that of the products obtained in comparative examples 4-5, but was significantly worse than that of example 5, indicating that the addition of a single enzyme of superoxide dismutase or catalase only slightly improves the stability of heme, and that the addition of both superoxide dismutase and catalase at the same time in a proper ratio is effective in improving the stability of heme significantly.
The above results indicate that the heme compositions and pharmaceutical compositions provided herein have high heme stability.
All the embodiments in the present specification are described in a related manner, and the same and similar parts among the embodiments may be referred to each other, and each embodiment focuses on the differences from the other embodiments.
The above description is only for the preferred embodiment of the present application and is not intended to limit the scope of the present application. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application are included in the protection scope of the present application.

Claims (9)

1. A hemoglobin composition comprising: heme, superoxide dismutase and catalase.
2. The heme composition of claim 1, wherein the ratio of the mass of heme, the enzymatic activity of superoxide dismutase, and the enzymatic activity of catalase is 5 g: 3000-6000 IU: 1000-.
3. Use of a heme composition according to claim 1 or 2 for the preparation of a medicament for the prevention or treatment of an iron deficiency-related disease.
4. The use according to claim 3, wherein the iron deficiency-related disease comprises iron deficiency anemia.
5. A pharmaceutical composition comprising the heme composition of claim 1 or 2 and a pharmaceutically acceptable carrier, diluent, or excipient.
6. The pharmaceutical composition of claim 5, wherein the dosage form is an oral dosage form.
7. The pharmaceutical composition of claim 6, wherein the oral dosage form is one selected from the group consisting of oral liquid, syrup, granule, capsule, tablet, powder, pill and drop pill.
8. Use of the pharmaceutical composition of claim 5 for the manufacture of a medicament for the prevention or treatment of an iron deficiency-related disorder.
9. The use according to claim 8, wherein the iron deficiency-related disease comprises iron deficiency anemia.
CN202111129448.XA 2021-09-26 2021-09-26 Heme composition, pharmaceutical composition and application thereof Pending CN113813372A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020099175A1 (en) * 2000-11-29 2002-07-25 Privalle Christopher Thomas Methods for the synthesis of a modified hemoglobin solution
CN1686536A (en) * 2005-03-18 2005-10-26 覃世元 Blood nourishing body building composition and its production method
RU2010106522A (en) * 2010-02-24 2011-08-27 Государственное образовательное учреждение высшего профессионального образования "Воронежский государственный университет" (ГОУ ВПО POLYFUNCTIONAL POLYHEMOGLOBIN-ENZYME COMPLEX
CN102458451A (en) * 2009-06-09 2012-05-16 普罗朗制药有限责任公司 Hemoglobin compositions
WO2020073030A1 (en) * 2018-10-05 2020-04-09 Ampersand Biopharmaceuticals, Inc. Iron formulations for topical administration and methods of treatment of iron deficiency

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020099175A1 (en) * 2000-11-29 2002-07-25 Privalle Christopher Thomas Methods for the synthesis of a modified hemoglobin solution
CN1686536A (en) * 2005-03-18 2005-10-26 覃世元 Blood nourishing body building composition and its production method
CN102458451A (en) * 2009-06-09 2012-05-16 普罗朗制药有限责任公司 Hemoglobin compositions
RU2010106522A (en) * 2010-02-24 2011-08-27 Государственное образовательное учреждение высшего профессионального образования "Воронежский государственный университет" (ГОУ ВПО POLYFUNCTIONAL POLYHEMOGLOBIN-ENZYME COMPLEX
RU2432172C1 (en) * 2010-02-24 2011-10-27 Государственное образовательное учреждение высшего профессионального образования "Воронежский государственный университет" (ГОУ ВПО ВГУ) Polyfunctional polyhemoglobin-enzyme complex
WO2020073030A1 (en) * 2018-10-05 2020-04-09 Ampersand Biopharmaceuticals, Inc. Iron formulations for topical administration and methods of treatment of iron deficiency

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