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Rh-epo nasal formulations with low sialic acid concentration for the treatment of diseases of the central nervous system

A technology of erythropoietin and sialic acid, which is applied in the field of biopharmaceutical industry, can solve the problem of not being able to promote the proliferation, differentiation and maturation of red blood cells

Inactive Publication Date: 2008-10-29
CENT DE INVESTIGACION & DESARROLLO DE MEDICAMENTOS CIDEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] Patent CIPO-2408685 covers different formulations of rhEPO, but in this case it is intended for them to be used in the treatment of anemia, so it is acidic rhEPO, because basic rhEPO does not promote the proliferation, differentiation and maturation of red blood cells

Method used

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  • Rh-epo nasal formulations with low sialic acid concentration for the treatment of diseases of the central nervous system
  • Rh-epo nasal formulations with low sialic acid concentration for the treatment of diseases of the central nervous system
  • Rh-epo nasal formulations with low sialic acid concentration for the treatment of diseases of the central nervous system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Purification of rhEPO with low content of sialic acid

[0047] In order to obtain basic erythropoietin with less than 40% sialic acid, three basic chromatographic steps were performed, starting from a material that was very complex and had a lot of contaminating proteins, since this material contained 5% fetal bovine serum. Additional steps are then performed to obtain the target isoform.

[0048] For diafiltration and concentration of basic rhEPO a laboratory scale ultrafiltration system (SARTOFLOW SLICE 200) connected to a peristaltic pump (IP55 Watson-Marlow) was used. A 10 kDa Hydrosart membrane was used. The work was performed at a flow rate of 1.9 ± 0.25 mL / min, a push pressure (P1) of 2.9 ± 0.25 bar, a retained fraction pressure (P2) of 0.65 ± 0.1 bar and a transmembrane (TM) pressure of 1.8 ± 0.2 bar. For the determination of protein concentration, an Ultrospec™ 3100 spectrophotometer was used at λ = 280 nm. For the diafiltration process, use NaH with a pH ...

Embodiment 2

[0052] A nasal formulation of rhEPO containing low sialic acid using HPMC as a bioadhesive polymer, histidine hydrochloride as a stabilizer, Tween 80 as a nonionic surfactant and benzalkonium chloride as a preservative.

[0053] Preparation:

[0054] The preparation of this solution starts with 30% by volume of water for injection in the total volume of the formulation. This volume is used to dissolve preservatives, buffers and isotonic agents. In addition, in a container of appropriate capacity, put water for injection with a volume equal to 15% of the total volume of the preparation, and heat to a temperature of 85 to 95° C., and disperse the polymer under vigorous and constant stirring. Once the polymer is wetted, the previously prepared solution is incorporated into it while shaking vigorously until all is homogenized. Shaking was then reduced for incorporation of corresponding amounts of basic rhEPO, non-ionic surfactant and protein stabilizer. Finally, the volume was ...

Embodiment 3

[0068] RhEPO nasal formulation with low sialic acid content similar to the previous example but using methylcellulose as the bioadhesive polymer

[0069] Preparation method: similar to Example 2.

[0070] The composition of the prepared preparation is as follows:

[0071] Component Ratio

[0072] Basic rhEPO 0.8mg / mL

[0073] Methylcellulose 3.0mg / mL

[0074] Histidine hydrochloride 1.0mg / mL

[0075] Sodium dihydrogen phosphate 2mg / mL

[0076] Disodium hydrogen phosphate 0.7mg / mL

[0077] Tween 80 0.25mg / mL

[0078] Sodium chloride 7.4mg / mL

[0079] Disodium EDTA 0.1mg / mL

[0080] Benzalkonium Chloride 0.2mg / mL

[0081] Water for injection 1ml

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Abstract

The invention relates to the biopharmaceutical industry and, in particular, to the development of a medicament which is intended for the treatment of cerebrovascular, neurodegenerative and psychiatric diseases and which contains, by way of active principle, recombinant human erythropoietin (rh-Epo) with a low sialic acid concentration. During rh-Epo production, the glycoprotein is obtained with a different sialic acid concentration when less than 40 % of the molecule thereof is protected with (basic) sialic acid, in which case it is not biologically active by systemic route and is inactivated by hepatic enzymes. Surprisingly, it was found that nasally-administered basic rh-Epo has greater therapeutic benefits than the acid.; The inventive basic rh-Epo nasal formulations include bioadhesive polymers which increase the residence time in the nasal cavity, thereby enhancing the therapeutic effect thereof. Said formulations also include other auxiliary substances, such as preservative substances, surfactants, pH regulators, isotonising agents and protein stabilisers.

Description

technical field [0001] The present invention relates to the biopharmaceutical industry, in particular to the preparation of rhEPO intranasal drug containing low content of (basic) sialic acid, which starts from Chinese hamster ovary cells by genetic engineering, for the treatment of cerebrovascular, neurodegenerative and psychiatric diseases. Background technique [0002] Erythropoietin (EPO) is a glycoprotein hormone with a molecular weight in the 34 kDa range; the protein moiety consists of approximately 166 amino acids; it is produced in cells of the kidney, liver, and central nervous system, and it participates in red blood cells and Proliferation, differentiation and maturation of other hematopoietic cells. [0003] In 1998, Sakanaka and coworkers reported the neuronal protective properties of rhEPO against ischemic injury in vivo following occlusion of the common carotid artery in gerbils (a model of global ischemia) followed by infusion of rhEPO into the lateral ventr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/72A61K38/18A61P9/10
CPCA61K9/0043A61K38/1816A61P9/00A61P9/10A61P25/00A61P25/08A61P25/28
Inventor A·马诺兹塞尔纳达J·C·加西亚罗德里古兹Y·纳恩兹费古尔利多Z·帕尔多卢兹J·D·加西亚塞尔曼I·索萨特斯特D·库尔贝罗罗德里古兹J·克鲁兹罗德里古兹N·苏比洛斯玛提内兹
Owner CENT DE INVESTIGACION & DESARROLLO DE MEDICAMENTOS CIDEM
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