CN112546061B - Heparin pharmaceutical composition, nasal spray, and preparation method and application thereof - Google Patents
Heparin pharmaceutical composition, nasal spray, and preparation method and application thereof Download PDFInfo
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- CN112546061B CN112546061B CN202110208917.0A CN202110208917A CN112546061B CN 112546061 B CN112546061 B CN 112546061B CN 202110208917 A CN202110208917 A CN 202110208917A CN 112546061 B CN112546061 B CN 112546061B
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- heparin
- arbidol
- pharmaceutical composition
- sodium
- nasal spray
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The invention discloses a heparin pharmaceutical composition, a nasal spray, and a preparation method and application thereof. The heparin medicine composition comprises heparin sodium and arbidol. The heparin pharmaceutical composition provided by the invention is combined with heparin sodium and arbidol for the first time, and the inhibition efficiency of the arbidol virus combined with common heparin sodium and more than 1 mu M/L is obviously higher than that of single common heparin sodium or single arbidol group (a)p<0.05）。
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a heparin pharmaceutical composition, a nasal spray, and a preparation method and application thereof.
Background
In 12 months in 2019, the epidemic situation of a novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) rapidly develops, and the coronavirus disease is prevalent in the global scope at present, so that huge economic loss is caused in the global. COVID-19 is highly contagious, the early symptoms are atypical, and no specific drug for treatment is available at present. The transmission pathway of the virus is currently believed to be respiratory droplets and close contact transmission, and there is the possibility of transmission via aerosols when exposed to high concentration aerosols for a long time in a relatively closed environment, the source of infection being mainly patients infected with the novel coronavirus. The 'pneumonia mask instruction for preventing novel coronavirus infection' issued by the national health committee indicates that the mask is an important defense line for preventing respiratory infectious diseases and can reduce the risk of novel coronavirus infection. The mask can prevent the patient from spraying droplets, reduce the droplet amount and the spraying speed, block droplet nuclei containing viruses and prevent the wearer from inhaling. However, because the types of masks on the market are various, common people are difficult to distinguish, the filtering effect of the masks cannot completely prevent viruses from entering respiratory tracts, and meanwhile, the wearing of the masks brings inconvenience to daily life, particularly work, so that the development of a novel method for preventing the infection of the new coronavirus is significant in public health.
In a significant scientific study published in the International Authority journal "cells", scientists at the medical college of North Carolina university and at the Gilins Global public health college of North Carolina university characterized the specific pattern of infection by SARS-CoV-2, a coronavirus responsible for COVID-19. The new coronaviruses infect the nasal cavity to a large extent, where they replicate specific cell types, and in cells in the lower respiratory tract (including the lungs), the ability to infect and replicate is increasingly poor.
The heparin and enoxaparin derivatives can effectively inhibit the attachment and the cell entry of SARS-CoV-2, and provide a new opportunity for the development of therapeutic and prophylactic drugs. Although both of the common heparin (UFH) and enoxaparin drugs have been widely used for anticoagulant therapy, both drugs have serious side effects, including bleeding. Enoxaparin, as a covi-19 antiviral therapeutic or prophylactic agent, has potential dangerous side effects and may cause serious complications in covi-19 anticoagulant therapy. It would therefore be of great interest to develop a method for non-systemic use of UFH or enoxaparin as an antiviral therapy or prophylaxis. At the same time, studies based on healthy volunteers found that serum bioavailability was very low even with the inhalation of very large doses of UFH and enoxaparin.
Arbidol (Arbidol) is an antiviral drug that has been used in our country and russia to prevent or treat influenza. Arbidol can prevent the virus from entering and fusing with cells by binding to hemagglutinin in influenza.
However, the prior art does not disclose the mode of combined administration of heparin sodium and arbidol and the drug effect thereof, so in order to further discover a pharmaceutical preparation with excellent antiviral effect (especially against COVID-19), the technical problem to be solved in the field of antiviral drug effect after the combined administration of different drugs is proved.
Disclosure of Invention
The invention aims to overcome the defects that the method for preventing the infection of the new coronavirus is single and the prevention effect is poor in the prior art, and provides a heparin pharmaceutical composition, a nasal spray, and a preparation method and application thereof.
The invention provides a heparin medicine composition which comprises heparin sodium and arbidol.
In the present invention, the heparin is a heterogeneous mixture of Heparan Sulfate (HS) glycosaminoglycans, which is a widely used anticoagulant. Each HS chain consists of repeating disaccharide units of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcA) or iduronic acid (IdoA). GlcNAc may be sulfated at three different sites (-6S, -NS, and-3S), while IdoA may be sulfated at one site (-2S). Normal heparin consists of HS chains of 30 sugars in length, whereas low molecular weight heparin consists of HS chains of 22 sugars or less. HS proteoglycans play a crucial role in maintaining and regulating various functions, including coagulation activity, inflammatory response and viral entry into target cells.
Wherein the Low Molecular Weight Heparins (LMWHs) are fragments of native heparin produced by enzymatic or chemical depolymerization of unfractionated heparin (UFH). There are currently 3 major LMWHs approved by the FDA in the united states for marketing: low molecular weight heparin sodium produced by the nitric acid depolymerization method, namely enoxaparin (enoxaparin) obtained by base depolymerization of delteparin and benzyl ester, and low molecular weight heparin calcium produced by enzymatic depolymerization with heparinase, namely nadroparin (saproparin) ". The average molecular mass of the low molecular heparin sodium is 6000 daltons at most, the molecular mass of the low molecular heparin calcium is 4500 daltons less, and the molecular mass of the enoxaparin is 4200 daltons at least.
In the invention, the heparin sodium can be common heparin sodium or enoxaparin sodium.
Wherein the common heparin sodium is generally extracted from porcine intestinal mucosa or bovine lung, and can also be purchased from Roen.
Wherein the sodium heparin may be 185USP units/mg sodium heparin.
In the invention, preferably, the concentration of the heparin sodium in the heparin pharmaceutical composition is 0.6mg/L-400g/L or 1.5-6 μ g/L, such as 6 μ g/L, 3 μ g/L, 1.5 μ g/L.
In the invention, when the heparin pharmaceutical composition comprises arbidol, the concentration of the arbidol is preferably more than or equal to 1 mu M/L; more preferably, the concentration of said arbidol in said heparin-like pharmaceutical composition is 1-4. mu.M/L, such as 4. mu.M/L, 2. mu.M/L, 1. mu.M/L.
In a preferred embodiment of the present invention, the heparin pharmaceutical composition comprises the following components:
common heparin sodium 6 mu g/L and arbidol 4 mu M/L;
or common heparin sodium 3 mu g/L and arbidol 4 mu M/L;
or common heparin sodium 1.5 mu g/L and arbidol 4 mu M/L;
or common heparin sodium 6 mu g/L and arbidol 2 mu M/L;
or common heparin sodium 3 mu g/L and arbidol 2 mu M/L;
or common heparin sodium 1.5 mu g/L and arbidol 2 mu M/L;
or common heparin sodium 6 mu g/L and arbidol 1 mu M/L;
or common heparin sodium 3 mu g/L and arbidol 1 mu M/L;
or common heparin sodium 1.5 mu g/L and arbidol 1 mu M/L.
The invention also provides a preparation method of the heparin pharmaceutical composition, which comprises the following steps of mixing the heparin sodium and the arbidol.
The invention also provides a heparin nasal spray, which comprises the heparin pharmaceutical composition, an osmotic pressure regulator and water.
The osmotic pressure regulator may be, among others, an osmotic pressure regulator conventional in the art, such as sodium chloride.
The amount of the osmotic pressure regulator is selected according to the type of the osmotic pressure regulator, for example, when the osmotic pressure regulator is sodium chloride, the mass concentration of the osmotic pressure regulator in the heparin pharmaceutical composition is 0.9%.
The invention also provides a preparation method of the heparin nasal spray, which comprises the following steps of mixing the heparin pharmaceutical composition, the osmotic pressure regulator and water.
The invention also provides application of the heparin medicine composition or the heparin nasal spray in preparing a medicine for preventing and/or treating virus infection.
Wherein the virus may be SARS-COV-2.
The positive progress effects of the invention are as follows:
(1) the heparin pharmaceutical composition of the invention combines heparin sodium and arbidol for the first time, and the inhibition efficiency of the combination of common heparin sodium and arbidol virus (such as SARS-COV-2) with the concentration of more than 1 mu M/L is obviously higher than that of single common heparin sodium or single arbidol group (p is less than 0.05).
(2) The application scene of the nasal spray of the invention can be as follows: the nasal spray can be sprayed before entering a crowd gathering place or on necessary occasions every time to prevent new coronavirus infection, and even can have potential prevention effect on influenza virus infection.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
1. Material
Plain heparin sodium was purchased from Roen (185USP units/mg), arbidol (98% pure, purchased from alatin), 293T cells overexpressing ACE2, and pseudoviruses of SARS-Cov-2S protein were purchased from Changshou jejuni Huaxiang Biotech Ltd.
The combination concentration gradient set in this example was as follows:
sodium heparin: 6 mug/L, 3 mug/L and 1.5 mug/L;
arbidol: 4. mu.M/L, 2. mu.M/L, 1. mu.M/L
This example was formulated with the concentrations shown in Table 1.
TABLE 1
2. Experimental methods
Mixing 200 pseudoviruses expressing SARS-CoV-2S protein TCID50 with a series of drug combinations with different concentrations, and the total volume is 100 μ l; adding into 96-well cell culture plate, incubating at 37 deg.C for 1h, adding 100 μ l 293T cells containing 20000 over-expressed ACE 2; negative control group without drug(ii) a Equal amounts of pseudovirus were mixed with 293T overexpressing ACE 2; mixing background equivalent pseudoviruses with 293T cells; 5% CO at 37 ℃2After standing for 48h, the fluorescence intensity was measured.
Inhibition efficiency was 100% (experimental group-background)/(control-background).
3. Results
The test results are shown in table 2 below.
TABLE 2
The results show that the common heparin sodium and the arbidol have obvious inhibition effect on the new coronavirus, and the inhibition efficiency of the combination of the common heparin sodium and the arbidol SARS-CoV-2 with the concentration of more than 1 mu M/L is obviously higher than that of the single common heparin sodium or the single arbidol group (p is less than 0.05).
Claims (7)
1. A heparin pharmaceutical composition for preventing or treating SARS-COV-2 infection, which is characterized in that the heparin pharmaceutical composition comprises heparin sodium and arbidol, wherein the concentration of the heparin sodium in the heparin pharmaceutical composition is 1.5-6 mug/L; the concentration of the arbidol in the heparin pharmaceutical composition is 1 mu M/L or 4 mu M/L.
2. The heparin-based pharmaceutical composition of claim 1, wherein said heparin-based pharmaceutical composition comprises the following components:
heparin sodium 6 mu g/L and arbidol 4 mu M/L;
or heparin sodium is 3 mu g/L and arbidol is 4 mu M/L;
or heparin sodium is 1.5 mu g/L and arbidol is 4 mu M/L;
or heparin sodium 6 mu g/L and arbidol 1 mu M/L;
or heparin sodium is 3 mu g/L and arbidol is 1 mu M/L;
or heparin sodium 1.5 mu g/L and arbidol 1 mu M/L.
3. Use of the heparin-based pharmaceutical composition according to claim 1 or 2, wherein the virus is SARS-COV-2, for the preparation of a medicament for the prophylaxis and/or treatment of viral infections.
4. A heparin nasal spray, comprising the heparin-based pharmaceutical composition according to claim 1 or 2, an osmotic pressure regulator and water.
5. The heparin-based nasal spray of claim 4, wherein said tonicity modifier is sodium chloride.
6. The process for preparing the heparin-based nasal spray according to claim 4, wherein the process comprises the step of mixing the heparin-based pharmaceutical composition, the osmotic pressure regulator and water.
7. The use of the heparin-based nasal spray of claim 4, wherein the virus is SARS-COV-2, for the preparation of a medicament for the prophylaxis and/or treatment of viral infections.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110208917.0A CN112546061B (en) | 2021-02-25 | 2021-02-25 | Heparin pharmaceutical composition, nasal spray, and preparation method and application thereof |
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| CN202110208917.0A CN112546061B (en) | 2021-02-25 | 2021-02-25 | Heparin pharmaceutical composition, nasal spray, and preparation method and application thereof |
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| CN112546061A CN112546061A (en) | 2021-03-26 |
| CN112546061B true CN112546061B (en) | 2021-06-11 |
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| CN117379544A (en) * | 2023-10-11 | 2024-01-12 | 中南大学湘雅医院 | Antibody composition and application thereof in preparation of anti-new coronavirus drugs |
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| US9452227B2 (en) * | 2008-11-25 | 2016-09-27 | Alderbio Holdings Llc | Methods of treating or diagnosing conditions associated with elevated IL-6 using anti-IL-6 antibodies or fragments |
| CU24444B1 (en) * | 2014-02-10 | 2019-10-04 | Troikaa Pharmaceuticals Ltd | TOPICAL HEPARIN FORMULATIONS |
| US10925889B2 (en) * | 2014-05-12 | 2021-02-23 | Gholam A. Peyman | Method of treating, reducing, or alleviating a medical condition in a patient |
| CN111297838A (en) * | 2020-04-08 | 2020-06-19 | 宁波合康生物医药科技有限公司 | Inhalation spray of antiviral drug |
| CN112156074A (en) * | 2020-09-22 | 2021-01-01 | 中南大学湘雅三医院 | Arbidol hydrochloride spray and preparation method thereof |
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