WO2008150196A1 - Oxygen-transferring blood substitute - Google Patents
Oxygen-transferring blood substitute Download PDFInfo
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- WO2008150196A1 WO2008150196A1 PCT/RU2008/000158 RU2008000158W WO2008150196A1 WO 2008150196 A1 WO2008150196 A1 WO 2008150196A1 RU 2008000158 W RU2008000158 W RU 2008000158W WO 2008150196 A1 WO2008150196 A1 WO 2008150196A1
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- blood substitute
- blood
- oxygen
- substitute according
- hemoglobin
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/795—Porphyrin- or corrin-ring-containing peptides
- C07K14/805—Haemoglobins; Myoglobins
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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
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- 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
Definitions
- the invention relates to medicine, namely to blood substitutes based on polyhemoglobin.
- the invention can be used for the production of blood-replacing solutions comparable in gas transport efficiency (for oxygen transfer) with human blood red blood cells.
- the main disadvantage of the known blood substitute is its relatively high cost, which is due to the fact that an expensive biologically active reagent, pyridoxal-5-phosphate (PF), is used to obtain the blood substitute. There is also the risk of free PF entering the final product, which can lead to undesirable consequences.
- PF pyridoxal-5-phosphate
- the known blood substitute "Gelenpole" / RU 2132687, A61K35 / 18, A61K38 / 42, 1999 / is a mixture of hemoglobin tetramer and oligomers with different chain lengths. Oligomers were prepared by crosslinking hemoglobin tetramers with glutaraldehyde and modified with glutamic acid. This blood substitute is taken as a prototype.
- the disadvantages of the prototype include the fact that in the blood substitute there is a fairly large percentage of hemoglobin tetramer, which in the blood dissociates into dimers causing a nephrotoxic effect.
- the tetramer also causes a vasoconstrictor effect, binding nitric oxide, in addition, the tetramer is rapidly eliminated from the bloodstream, not having time to perform the gas transport function.
- the objective of the invention is the creation of a blood substitute devoid of these disadvantages.
- a blood substitute with oxygen transfer function is proposed, the basis of which is hemoglobin polymerized by modified glutaraldehyde.
- a distinctive feature of the proposed blood substitute is that polyhemoglobin consists exclusively of oligomers containing from 2 to 6 hemoglobin molecules.
- the blood substitute be made in the form of a dry substance, for example, in the form of a powder or granules with a moisture content of not more than 10%.
- the proposed blood substitute may additionally contain glucose and / or ascorbic acid.
- polyhemoglobin consists exclusively of oligomers containing from 2 to 6 hemoglobin molecules can improve the quality of the blood substitute by eliminating undesirable side effects.
- the implementation of the blood substitute in the form of a dry substance can increase the shelf life of the product.
- a blood substitute is obtained from deoxygenated hemoglobin by polymerization with subsequent purification. Cleaning is carried out on two shut-off membranes to obtain the finished product in the range of molecular weight not more than 450 kDa and not less than 100 kDa. Then the product is concentrated to 10% polyhemoglobin and served for drying. The quality of the drug for compliance with the fractional composition of polyhemoglobin is controlled by electrophoresis and chromatography.
- the therapeutic efficacy of the obtained blood substitute was evaluated on a model of hemorrhagic shock in dogs.
- sterile lyophilized dried polyhemoglobin containing glucose and ascorbic acid The powder was diluted with saline.
- 10 outbred dogs - males weighing 18-20 kg, which artificially caused hemorrhagic shock in acute blood loss with prolonged hypotension.
- the volume of blood loss was 45-55 ml / kg, the duration of hypotension at the level of blood pressure equal to 40 mm RT.
- Intravenous administration of a hemoglobin polymerized with modified glutaraldehyde aldehyde solution began during a period of severe disorders of systemic hemodynamics, oxygen transport and the acid-base state of the body caused by massive blood loss and prolonged hypotension.
- the introduction of the drug obtained by the claimed method was carried out in the amount of blood loss. Out of 10, 9 dogs survived, and it was found that the infusion of a solution with a low concentration of polyhemoglobin (0.8 g dl "1 ) provides not only a stable restoration of systemic hemodynamics, but also a higher level of tissue oxygen consumption.
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Public Health (AREA)
- Gastroenterology & Hepatology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Genetics & Genomics (AREA)
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- Biochemistry (AREA)
- Diabetes (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention relates to an oxygen-transferring blood substitute comprising a polymerised glutaric dialdehyde-modified hemoglobine. The inventive blood substitute is characterised in that said hemoglobine exclusively consists of oligomers containing from 2 to 6 hemoglobine molecules.
Description
Кровезаменитель с функцией переноса кислорода Blood oxygen substitute
Изобретение относится к медицине, а именно к кровезаменителям на основе полигемоглобина. Изобретение может быть использовано для производства кровезамещающих растворов, сопоставимых по эффективности газового транспорта (по переносу кислорода) с эритроцитами крови человека.The invention relates to medicine, namely to blood substitutes based on polyhemoglobin. The invention can be used for the production of blood-replacing solutions comparable in gas transport efficiency (for oxygen transfer) with human blood red blood cells.
Известен кровезаменитель / L. R. Sеhgаl, A. L. Rоsеп, S. А. Gоuld, Н.L. Sеhgаl, G.S. Моss / Тrапsfusiоп. - 1983. - v. 23. - N 2. - P. 158-162/, представляющий собой полимерный гемоглобин.The known blood substitute / L. R. Sehgal, A. L. Rosep, S. A. Gould, N.L. Sehgal, G.S. Moss / Trapsfusiop. - 1983. - v. 23. - N 2. - P. 158-162 /, which is a polymer hemoglobin.
Основным недостатком известного кровезаменителя является его относительно высокая стоимость, которая обусловлена тем, что для получения кровезаменителя используется дорогостоящий биологически активный реагент - пиpидoкcaль-5-фocфaт (ПФ). Существует также опасность попадания свободного ПФ в конечный продукт, что может привести к нежелательным последствиям.The main disadvantage of the known blood substitute is its relatively high cost, which is due to the fact that an expensive biologically active reagent, pyridoxal-5-phosphate (PF), is used to obtain the blood substitute. There is also the risk of free PF entering the final product, which can lead to undesirable consequences.
Известен кровезаменитель «Гeлeнпoл» /RU 2132687, A61K35/18, A61K38/42, 1999/ представляющий собой смесь тетрамера гемоглобина и олигомеров с различной длиной цепи. Олигомеры получены путём сшивания тетрамеров гемоглобина глутаровым альдегидом и модифицированы глутаминовой кислотой. Данный кровезаменитель принят за прототип.The known blood substitute "Gelenpole" / RU 2132687, A61K35 / 18, A61K38 / 42, 1999 / is a mixture of hemoglobin tetramer and oligomers with different chain lengths. Oligomers were prepared by crosslinking hemoglobin tetramers with glutaraldehyde and modified with glutamic acid. This blood substitute is taken as a prototype.
К недостаткам прототипа относится то, что в кровезаменителе находится достаточно большой процент тетрамера гемоглобина, который в крови диссоциирует на димеры обусловливающие нефротосксический эффект. Тетрамер также вызывает вазоконстрикторное действие, связывая оксид азота, кроме того, тетрамер быстро элиминируется из кровяного русла, не успевая выполнить газотранспортную функцию.
Задачей изобретения является создание кровезаменителя, лишённого указанных недостатков.The disadvantages of the prototype include the fact that in the blood substitute there is a fairly large percentage of hemoglobin tetramer, which in the blood dissociates into dimers causing a nephrotoxic effect. The tetramer also causes a vasoconstrictor effect, binding nitric oxide, in addition, the tetramer is rapidly eliminated from the bloodstream, not having time to perform the gas transport function. The objective of the invention is the creation of a blood substitute devoid of these disadvantages.
Для решения поставленной задачи предлагается кровезаменитель с функцией переноса кислорода, основу которого составляет полимеризованный модифицированным глутаровым альдегидом гемоглобин. Отличительной особенностью предлагаемого кровезаменителя является то, что полигемоглобин состоит исключительно из олигомеров содержащих от 2 до 6 молекул гемоглобина.To solve this problem, a blood substitute with oxygen transfer function is proposed, the basis of which is hemoglobin polymerized by modified glutaraldehyde. A distinctive feature of the proposed blood substitute is that polyhemoglobin consists exclusively of oligomers containing from 2 to 6 hemoglobin molecules.
Дополнительно предлагается кровезаменитель выполнить в виде сухой субстанции, например, в виде порошка или гранул с влажностью не более 10%.In addition, it is proposed that the blood substitute be made in the form of a dry substance, for example, in the form of a powder or granules with a moisture content of not more than 10%.
Предлагаемый кровезаменитель может дополнительно содержать глюкозу и/или аскорбиновую кислоту.The proposed blood substitute may additionally contain glucose and / or ascorbic acid.
То, что полигемоглобин состоит исключительно из олигомеров содержащих от 2 до 6 молекул гемоглобина позволяет повысить качество кровезаменителя за счет исключения нежелательных побочных эффектов.The fact that polyhemoglobin consists exclusively of oligomers containing from 2 to 6 hemoglobin molecules can improve the quality of the blood substitute by eliminating undesirable side effects.
Выполнение кровезаменителя в виде сухой субстанции позволяет повысить сроки хранения продукта.The implementation of the blood substitute in the form of a dry substance can increase the shelf life of the product.
Таким образом, достигается технический результат.Thus, a technical result is achieved.
Кровезаменитель получают из дезоксигенированного гемоглобина путём его полимеризации с последующей очисткой. Очистку ведут на двух отсекающих мембранах с получением готового продукта в диапазоне по молекулярной массе не более 450 кДа и не менее 100 кДа. Затем продукт концентрируют до 10 % полигемоглобина и подают на сушку. Качество препарата на предмет соответствия фракционному составу полигемоглобина контролируют электрофорезом и хроматографией.A blood substitute is obtained from deoxygenated hemoglobin by polymerization with subsequent purification. Cleaning is carried out on two shut-off membranes to obtain the finished product in the range of molecular weight not more than 450 kDa and not less than 100 kDa. Then the product is concentrated to 10% polyhemoglobin and served for drying. The quality of the drug for compliance with the fractional composition of polyhemoglobin is controlled by electrophoresis and chromatography.
Лечебную эффективность полученного кровезаменителя оценивали на модели геморрагического шока у собак. Для исследований применяли
стерильный лиофильно высушенный полигемоглобин, содержащий глюкозу и аскорбиновую кислоту. Порошок разводили солевым раствором. Для опыта использовали 10 беспородных собак - самцов массой 18-20 кг, у которых искусственно вызывали геморрагический шок при острой кровопотере с длительной гипотензией. Объём кровопотери составлял 45-55 мл/кг, длительность гипотензии на уровне артериального давления, равном 40 мм рт. Ст. 60 - 70 мин. Внутривенное введение раствора полимеризованного модифицированным глутаровым альдегидом гемоглобина начинали в период выраженных расстройств системной гемодинамики, транспорта кислорода и кислотно-основного состояния организма, вызванных массивной потерей крови и длительной гипотензией. Введение препарата, полученного заявляемым методом, осуществляли в объёме кровопотери. Из 10 выжило 9 собак, при этом выявлено, что вливание раствора с низкой концентрацией полигемоглобина (0,8 г. дл"1) обеспечивает не только стойкое восстановление системной гемодинамики, но и более высокий уровень потребления тканями кислорода.
The therapeutic efficacy of the obtained blood substitute was evaluated on a model of hemorrhagic shock in dogs. For research used sterile lyophilized dried polyhemoglobin containing glucose and ascorbic acid. The powder was diluted with saline. For the experiment we used 10 outbred dogs - males weighing 18-20 kg, which artificially caused hemorrhagic shock in acute blood loss with prolonged hypotension. The volume of blood loss was 45-55 ml / kg, the duration of hypotension at the level of blood pressure equal to 40 mm RT. Art. 60 - 70 minutes Intravenous administration of a hemoglobin polymerized with modified glutaraldehyde aldehyde solution began during a period of severe disorders of systemic hemodynamics, oxygen transport and the acid-base state of the body caused by massive blood loss and prolonged hypotension. The introduction of the drug obtained by the claimed method was carried out in the amount of blood loss. Out of 10, 9 dogs survived, and it was found that the infusion of a solution with a low concentration of polyhemoglobin (0.8 g dl "1 ) provides not only a stable restoration of systemic hemodynamics, but also a higher level of tissue oxygen consumption.
Claims
1. Кровезаменитель с функцией переноса кислорода, включающий полимеризованный модифицированным глутаровым альдегидом гемоглобин, отличающийся тем, что полигемоглобин состоит исключительно из олигомеров содержащих от 2 до 6 молекул гемоглобина.1. Blood substitute with oxygen transfer function, including hemoglobin polymerized by modified glutaraldehyde, characterized in that polyhemoglobin consists exclusively of oligomers containing from 2 to 6 hemoglobin molecules.
2. Кровезаменитель по п.l, отличающийся тем, что он дополнительно содержит глюкозу.2. The blood substitute according to claim 1, characterized in that it additionally contains glucose.
3. Кровезаменитель по п.l, отличающийся тем, что он дополнительно содержит аскорбиновую кислоту.3. The blood substitute according to claim 1, characterized in that it further comprises ascorbic acid.
4. Кровезаменитель по п. 1, отличающийся тем, что представляет собой сухую субстанцию.4. The blood substitute according to claim 1, characterized in that it is a dry substance.
5. Кровезаменитель по п. 4, отличающийся тем, что представляет собой порошок с влажностью не более 10%.5. The blood substitute according to claim 4, characterized in that it is a powder with a moisture content of not more than 10%.
6. Кровезаменитель по п. 4, отличающийся тем, что представляет собой гранулы с влажностью не более 10%. 6. Blood substitute according to claim 4, characterized in that it consists of granules with a moisture content of not more than 10%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2007120889 | 2007-06-05 | ||
| RU2007120889/15A RU2340354C1 (en) | 2007-06-05 | 2007-06-05 | Blood substitute with function of oxygen transfer |
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| Publication Number | Publication Date |
|---|---|
| WO2008150196A1 true WO2008150196A1 (en) | 2008-12-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/RU2008/000158 WO2008150196A1 (en) | 2007-06-05 | 2008-03-19 | Oxygen-transferring blood substitute |
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| RU (1) | RU2340354C1 (en) |
| WO (1) | WO2008150196A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2504387C2 (en) * | 2012-04-12 | 2014-01-20 | Учреждение Российской академии наук Институт высокомолекулярных соединений РАН | Method for preparing polymer modified hemoglobin |
| WO2023022625A1 (en) * | 2021-08-19 | 2023-02-23 | Рахимджан Ахметджанович РОЗИЕВ | Use of polymerized haemoglobin for mobilizing reservoir blood in the case of haemorrhage |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5464814A (en) * | 1986-06-20 | 1995-11-07 | Northfield Laboratories, Inc. | Acellular red blood cell substitute |
| RU2072853C1 (en) * | 1990-01-02 | 1997-02-10 | Ажигирова Мария Алексеевна | Method of preparing the artificial oxygen carrier |
| RU2162707C2 (en) * | 1999-03-24 | 2001-02-10 | Российский научно-исследовательский институт гематологии и трансфузиологии | Blood substitute as oxygen transporter, composition for its preparing and method of polymeric modified hemoglobin preparing |
| US20020025343A1 (en) * | 1996-03-28 | 2002-02-28 | Richard E. De Woskin | Method and apparatus for preparing an acellular red blood cell substitute |
-
2007
- 2007-06-05 RU RU2007120889/15A patent/RU2340354C1/en active IP Right Revival
-
2008
- 2008-03-19 WO PCT/RU2008/000158 patent/WO2008150196A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5464814A (en) * | 1986-06-20 | 1995-11-07 | Northfield Laboratories, Inc. | Acellular red blood cell substitute |
| RU2072853C1 (en) * | 1990-01-02 | 1997-02-10 | Ажигирова Мария Алексеевна | Method of preparing the artificial oxygen carrier |
| US20020025343A1 (en) * | 1996-03-28 | 2002-02-28 | Richard E. De Woskin | Method and apparatus for preparing an acellular red blood cell substitute |
| RU2162707C2 (en) * | 1999-03-24 | 2001-02-10 | Российский научно-исследовательский институт гематологии и трансфузиологии | Blood substitute as oxygen transporter, composition for its preparing and method of polymeric modified hemoglobin preparing |
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| Publication number | Publication date |
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| RU2340354C1 (en) | 2008-12-10 |
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