CN101856498A - A kind of anti-septic shock pharmaceutical composition and application thereof - Google Patents

Abstract

The invention discloses a pharmaceutical composition, which contains a muscarinic receptor blocker and a cholinesterase inhibitor. The pharmaceutical composition of the invention is used for anti-infection, especially endotoxin shock, has enhanced anti-shock effect, has remarkable effect, and has little toxic and side effects, and overcomes the side effects often caused by existing medicines. The application of the pharmaceutical composition of the present invention in the preparation of anti-infection drugs, especially anti-endotoxin shock drugs.

Description

A kind of anti-septic shock pharmaceutical composition and application thereof

technical field

The invention belongs to the field of pharmaceutical compositions, in particular to a pharmaceutical composition and its application.

Background technique

Septic shock can be seen in sepsis caused by various microorganisms (so it is also called septic shock), especially the infection of Gram-negative bacteria, and the shock caused by endotoxin (endotoxic shock). Endotoxin is a complex of lipopolysaccharide (Lipoply Saccharide) and trace protein (Protein) on the cell wall of Gram-negative bacteria. Endotoxic shock refers to a large amount of endotoxin acting on the immune system and blood coagulation system of the body, exceeding the clearance capacity of the body's own defense system, and producing a large amount of biologically active substances, such as tumor necrosis factor α, interleukin 1, histamine and kinin etc., leading to microcirculation disorder and coagulation dysfunction in the body, and a series of clinical symptoms appear.

In the prior art, there are many drugs for treating septic shock (endotoxic shock). Muscarinic receptor blockers are clinically used to treat circulatory shock, especially septic shock, such as treating fulminant meningitis and toxic bacillary dysentery with anisodamine (Wang S.T., Kuo N.L., Experience in emergency treatment of shock due to infection. Chin.Med.J.1978, 6: 497-500), the conventional dosage for the treatment of endotoxic shock is: 1mg/kg in the early stage of infection, 1-2mg/kg in the middle stage , 2-3mg/kg in the late stage, intravenous drip into a small pot, administered once every 10-15 minutes; its side effects are mainly dry mouth, flushed face, mild pupil dilation, blurred near vision, etc. Some patients have heart rate Fast and difficult urination.

Cholinesterase inhibitors are commonly used to treat acute peritonitis models induced by intestinal perforation, but they can cause accumulation of acetylcholine leading to side effects in the cardiovascular system and digestive system (Hofer S., Eisenbach C., Lukic I.K., Schneider L., Bode K. , Brueckmann M., Mautner S., Wente M.N., Encke J., Werner J., Dalpke A.H., Stremmel W., Nawroth P.P., Martin E., Krammer P.H., Bierhaus A., Weigand M.A., Pharmacologic cholinesterase inhibition improves experimental surivivalin sepsis. Crit. Care. Med. 2008, 36(2): 404-408).

However, the pharmaceutical composition of muscarinic receptor blockers and cholinesterase inhibitors used in combination has not been reported yet.

Contents of the invention

The technical problem to be solved by the present invention is to overcome that when the existing muscarinic receptor blockers are used to treat endotoxic shock, the dosage of the drug is large and the side effects are many, or the cholinesterase inhibitor will cause the accumulation of acetylcholine and cause cardiovascular disease. The system and digestive system have defects such as adverse reactions, and provide a pharmaceutical composition with significant anti-infective shock, especially endotoxin shock, and less toxic and side effects and its application.

The pharmaceutical composition of the present invention contains a muscarinic receptor blocker and a cholinesterase inhibitor.

The present invention finds through research that when the combination of muscarinic receptor blockers and cholinesterase inhibitors is used to treat endotoxic shock, the effect is remarkable, and the dose of medicine used is small, the anti-shock effect is greatly strengthened, and the toxicity is overcome. The side effects of muscarinic receptor blockers such as dry mouth, flushed face, mild pupil dilation, and blurred near vision, as well as the adverse effects of M receptor stimulation caused by the use of cholinesterase inhibitors on the cardiovascular system and digestive system reaction.

Wherein, the mass ratio of the muscarinic receptor blocker to the cholinesterase inhibitor is preferably 10-1.6×10 ⁴ , more preferably 2.5×10 ² -4.0×10 ³ .

Wherein, the muscarinic receptor blocker is a muscarinic receptor blocker routinely used in the art, preferably selected from anisodamine, plant extracts containing anisodamine, atropine, scopolamine, scopolamine-containing One or more of the plant extracts.

The structural formula of described anisodamine is as shown in formula 1, and it is the esters that are formed by tropic acid and organic base, and structure is similar with atropine and scopolamine, and there is asymmetry on the 6 carbon atoms of tropic base. hydroxyl.

Formula 1

The structural formula of the atropine is shown in formula 2.

Formula 2

The structural formula of the scopolamine is shown in formula 3.

Formula 3

Wherein, the cholinesterase inhibitor is a cholinesterase inhibitor commonly used in the art, preferably neostigmine and/or physostigmine.

The structural formula of the neostigmine is shown in Formula 4.

Formula 4

The structural formula of the physostigmine is shown in formula 5.

Formula 5

In the present invention, the anisodamine and scopolamine can also be extracted from plants. The anisodamine can be extracted from the plant Anisodamine, and the extraction method can refer to the literature "Simultaneous analysis of hyoscyamine, scopolamine, 6β-hydroxyhyoscyamine and apoatropine in Solanaceous hairy roots by reversed-phase high-performance liquid chromatography" (Journal of Chromatography 5 A, 20 , 1091(1-2):32-39). Scopolamine can be extracted from Solanaceae plants, and the extraction method can refer to the literature "Analysis of tropane and related alkaloids" (Journal of Chromatography A, 2002, 978(1-2): 1-35).

In a preferred embodiment of the present invention, the muscarinic receptor blocker is anisodamine, and the cholinesterase inhibitor is neostigmine. The mass ratio of the described anisodamine to neostigmine is preferably 250.

All raw materials or reagents mentioned in the present invention are commercially available.

The preparation method of the pharmaceutical composition of the present invention may be to mix the existing commercially available above-mentioned compounds, or extracts containing the above-mentioned compounds extracted from plants, according to the proportion, and mix them by conventional methods in the art.

The pharmaceutical composition of the present invention may also contain other existing drugs for treating shock, such as dopamine or phentolamine, as active ingredients.

The pharmaceutical composition of the present invention may also include a pharmaceutically acceptable carrier as needed. Described pharmaceutically acceptable carrier refers to the conventional drug carrier in the field of pharmacy, wherein, diluent such as starch, powdered sugar, dextrin, microcrystalline cellulose, mannitol, lactose and soybean oil etc.; Vinylpyrrolidone or hydroxypropyl cellulose, etc.; disintegrants such as sodium carboxymethyl cellulose or low-substituted hydroxypropyl cellulose, etc.; lubricants such as magnesium stearate or talc, etc.; stabilizers such as sodium carboxymethyl cellulose Or cyclodextrin, etc.; preservatives such as ethyl p-hydroxybenzoate or sodium benzoate, etc. In addition, other adjuvants such as flavoring agents and/or sweeteners such as sucrose, fructose and aspartame can also be added to the pharmaceutical composition. The active ingredient of the pharmaceutical composition is the pharmaceutical composition of the muscarinic receptor blocker and the cholinesterase inhibitor of the present invention in a therapeutically effective amount. The pharmaceutical composition can adopt conventional methods in the medical field to prepare the active ingredients and pharmaceutically acceptable carriers into various dosage forms. When used for oral administration, it can be prepared into conventional solid preparations such as tablets, capsules, soft capsules, liquid preparations, granules, decoctions, pills, dripping pills, suspensions, dispersions, syrups or suppositories, etc.; When used for injection, it can be prepared as injection solution. Each pharmaceutical composition of the present invention can be administered to patients in need of such treatment by intravenous injection, subcutaneous injection or oral administration in dosage form. The general dose applied to patients in need of treatment is 1-100mg/kg for muscarinic receptor blockers, and 6.25-100ug/kg for cholinesterase inhibitors; preferred doses for muscarinic receptor blockers The dosage is 12.5-50mg/kg, and the cholinesterase inhibitor is 12.5-50ug/kg; the optimal dosage is 12.5mg/kg of anisodamine and 50ug/kg of neostigmine. In the specific use process, it can also be changed as appropriate according to the age and condition of the patient.

The reagents and raw materials used in the present invention are all commercially available.

The positive progressive effect of the present invention is that: the present invention provides a pharmaceutical composition and its application. The medicinal composition is used for treating anti-infective shock, especially anti-endotoxin shock, has enhanced anti-shock effect, has remarkable effect, has little toxic and side effects, and overcomes the side effects often caused by existing medicines.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples.

Example 1-7

Table 1 shows the formulations of the pharmaceutical compositions of Examples 1 to 7 of the present invention. According to the components listed in Table 1 and their proportions, simply mix them uniformly to obtain each pharmaceutical composition.

The formula of table 1 pharmaceutical composition of the present invention

Note: The extraction method of the above-mentioned anisodamine plant extract can refer to the literature "Simultaneous analysis ofhyoscyamine, scopolamine, 6β-hydroxyhyoscyamine and apoatropine in Solanaceous hairyroots by reversed-phase high-performance liquid chromatography" (Journal of ChromatographyA, 2015, 109 2): 32-39); The extraction method of the scopolamine plant extract can refer to the literature "Analysis of tropane and related alkaloids" (Journal of Chromatography A, 2002, 978 (1-2): 1-35).

Effect Example 1

To investigate the therapeutic effect of the pharmaceutical composition of the present invention in treating endotoxic shock, for the convenience of calculation, the dosage is used for calculation. A model of endotoxin shock induced by intraperitoneal injection of endotoxin (25mg/kg) in mice (Borovikova L.V., Ivanova S., Zhang M., et al: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature, 2000, 405 : 458-462), followed by separate administration of different doses of muscarinic receptor blockers or cholinesterase inhibitors (comparative examples), or according to different ratios, giving muscarinic receptor blockers and then giving Combined therapy with cholinesterase inhibitors was administered by intraperitoneal injection. Then observe every 3 hours for a total of 72 hours, and record the survival of the animals.

Table 2 The therapeutic effect of the pharmaceutical composition of the present invention in the treatment of endotoxic shock

Conclusion: The effect example studies the pharmaceutical composition of the present invention for treating endotoxic shock, and observes the 72-hour survival rate of mice, and the results are shown in the table above. For example, comparing the effects of Example 6 and Comparative Examples 3 and 6, it was found that the combined use of 25mg/kg, ip anisodamine and 25ug/kg, ip neostigmine, the survival rate of mice is far greater than that of 25mg alone /kg, ip of anisodamine or 25ug/kg, ip of neostigmine, the survival rate. This shows that the 72-hour survival rate of endotoxin shock mice is much higher when the two drugs are used in combination, and the synergistic anti-shock effect of the two drugs is greatly enhanced. And, compared with the comparative example, it is found that the combination of the two types of drugs in small doses also significantly reduces the adverse reactions such as side effects when these two types of drugs are used alone.

Effect Example 2

Investigate the time window for using the pharmaceutical composition of the present invention to treat endotoxin shock, and use it at 0 hour, 3 hours, and 6 hours after the shock occurs, and the results are shown in the following table.

Table 3 The therapeutic effect of the pharmaceutical composition of the present invention administered at different times to treat endotoxic shock

Conclusion: The present invention investigates the time window of the pharmaceutical composition for treating endotoxic shock, as shown in the above table, the results show that the pharmaceutical composition of the present invention has an anti-shock effect after 3 hours and 6 hours after the occurrence of shock.

Claims (10)

1. pharmaceutical composition, it contains M-ChR blocker and cholinesterase inhibitor.

2. pharmaceutical composition as claimed in claim 1 is characterized in that: described M-ChR blocker is selected from Anisodamine, contain plant extract, atropine, the scopolamine of Anisodamine and contain in the plant extract of scopolamine one or more.

3. pharmaceutical composition as claimed in claim 1 is characterized in that: described cholinesterase inhibitor is neostigmine and/or physostigmine.

4. pharmaceutical composition as claimed in claim 1 is characterized in that: the quality ratio of described M-ChR blocker and cholinesterase inhibitor is 10-1.6 * 10 ⁴

5. pharmaceutical composition as claimed in claim 4 is characterized in that: the quality ratio of described M-ChR blocker and cholinesterase inhibitor is 2.5 * 10 ²-4.0 * 10 ³

6. pharmaceutical composition as claimed in claim 1 is characterized in that: described M-ChR blocker is an Anisodamine; Described cholinesterase inhibitor is a neostigmine.

7. pharmaceutical composition as claimed in claim 6 is characterized in that: the quality ratio of described Anisodamine and neostigmine is 250.

8. pharmaceutical composition as claimed in claim 1 is characterized in that: described pharmaceutical composition also comprises pharmaceutically acceptable carrier.

9. as the application of each described pharmaceutical composition of claim 1～8 in preparation anti-septic shock medicine.

10. application as claimed in claim 9 is characterized in that described anti-septic shock medicine is the antiendotoxin shock drug.