CN1293955A

CN1293955A - Anti-infective, antipyretic and antalgic medicine able to treat ophthalmopathy

Info

Publication number: CN1293955A
Application number: CN 00120513
Authority: CN
Inventors: 王建蓉
Original assignee: Individual
Current assignee: Individual
Priority date: 2000-10-27
Filing date: 2000-10-27
Publication date: 2001-05-09

Abstract

A medicine with anti-infective, antipyretic and antalgic function for treating ophthalmopathy contains chlorogenic acid and andrographolide or relative water-soluble derivative in weight ratio of (1-20):1.

Description

Have infection and antipyretic effect and can be used for the medicine of ophthalmic

What the present invention relates to is a kind ofly to have antibiotic, viral infection resisting and antipyretic effect, and can be suitable for the medicine of ophthalmic external.

It is existing many to be used for the treatment of infection that pathogenic microorganism such as antibacterial, virus cause and/or the medicine with antipyretic effect, and its indication, range of application and characteristics are respectively arranged; The medicine that can be used for Eye disease treatings such as acute conjunctivitis also has many.In the various medicines, the complete medicine that is active component by natural medicinal raw material or its effective component extracts of single or mixed form is wherein one type.Though the present more general a kind of situation of being made up of natural medicinal raw material of this class medicine is that it all can have wide pharmacology subject range usually fully, but application forms is comparatively single, particularly all directly use or contain medicinal raw material composition medicine without separation and Extraction, its application forms is many can only to be the form of peroral dosage form or body surface medicine for external use, and its valuable pharmacological drug effect subject range can not be played one's part to the full with the more applications dosage form and/or in more treatment field.Simultaneously, directly using the medicinal raw material composition, both strengthened the dosage when using, also is a kind of waste to the medicinal raw material resource in a sense.

At above-mentioned situation, it is simple that purpose of the present invention at first provides a kind of composition, and have infection and antipyretic effect and can be used for the medicine of Eye disease treating by what the effective component extracts of the effective ingredient of natural medicinal raw material or its medicinal raw material combined, make its active constituent content height, produce effects is fast, toxic and side effects is little, and can make multiple dosage forms such as oral, injection and eye external, to give full play to its multiple pharmacological effect effect.Further aim of the present invention is on this basis, can increase at least to select the types of drugs scope used as required for doctor and/or patient when infection, antipyretic-antalgic and Eye disease treating.

The present invention has infection and antipyretic effect and can be used for the medicine of ophthalmic, its effective medicinal ingredient is made up of chlorogenic acid and andrographolide or its corresponding soluble derivative, and its weight portion proportion of composing is a chlorogenic acid: andrographolide=(1～20): 1.The structure of chlorogenic acid is shown in formula I; The structure of andrographolide is shown in formula II.Chlorogenic acid, and andrographolide or its corresponding soluble derivative-as the alkali metal salt compounds composition that the most frequently used potassium salt, sodium salt etc. are allowed in pharmacopedics, be to have the pharmacologically active effective medicinal components in the medicine of the present invention.These effective medicinal components in medicine of the present invention, except that can using its single compound form, according to its source, mode and/or the different needs in different preparations and process thereof, allow also to contain other unavoidable impurity, complementary adding ingredient or can not cause adverse effect and/or interferential composition the drug action of this effective ingredient.

The molecular formula C of said chlorogenic acid in the mentioned component ₁₆H ₁₈O ₉, semihydrate is acicular crystal (water), and 110 ℃ become anhydrous compound, and fusing point is 208 ℃.25 ℃ make that dissolubility is 4% in the water, and dissolubility is bigger in the hot water, is soluble in ethanol and acetone, atomic molten dried ethyl acetate.It is one of main component that can be used as the Flos Lonicerae that common drug and medicinal raw material use, act on resisting pathogenic microbes, to as golden Portugal bacterium, Hemolytic streptococcus, bordetella pertussis, gram positive bacteria and dysentery bacteriums such as Diplococcus pneumoniae, escherichia coli, vibrio cholera, Bacillus typhi, Salmonella paratyphi, bacillus pyocyaneus, the inhibitory action of gram negative bacterias such as meningococcus, its infusion is to rust microspore tinea bacterium, star nocardia, trichophyton, the inhibitory action of dermatophytess such as oidium schoenleinii epidermophyton rubrum, to influenza virus, Orphan virus, the inhibitory action of skin ulcer exanthema virus etc., and suppress and delay aspect such as its cytopathic effect that pharmacological effect is all arranged.In addition, at aspects such as raise immunity, antiinflammatory, analgesic, blood fat reducing, antifertilities corresponding pharmacological action is arranged also.In said medicine of the present invention to the use of this composition, can be for by the chemosynthesis mode, or, also can be this chemical compound purification composition that obtains through extraction, separation and purification by natural medicinal raw material Flos Lonicerae after chemical modification is transformed by the chemical compound that other related compound is obtained.Different according to the route of administration of prepared medicine and dosage form can also directly be used the extract of the natural medicinal raw materials such as Flos Lonicerae that contain above-mentioned significant proportion amount.The preparation of this Flos Lonicerae extract, can " the existing method of existing report be carried out in the document such as chemical composition of Chinese materia medica extraction separation handbook with reference to China Traditional Chinese Medicine Publishing House, as, with Flos Lonicerae decocting liquid concentrating under reduced pressure and after adding adjusting PH with base about 10, centrifugalize adds ethanol with precipitate and wears into thin pulp and transfer about pH3 with sulphuric acid, centrifugalize again, water intaking solution also uses adjusting PH with base 6 backs to reclaim ethanol, and the decompression oven dry obtains crude extract; Water-soluble and accent pH2 uses ethyl acetate extraction with it, with extracting liquid decoloration, concentrated, drying under reduced pressure, can obtain the chlorogenic acid product again.When water extract that directly uses natural medicinal raw material or above-mentioned crude extract, wherein can have other composition that ratio does not wait simultaneously inevitably, as long as it does not have a negative impact to the drug action of the above-mentioned effective ingredient of medicine of the present invention, and meet the requirement specific in the corresponding preparations and the restriction of allowed band, can allow it to be present in the medicine.For example, in above-mentioned Flos Lonicerae extract, except that chlorogenic acid, also often contain another main effective ingredient isochlorogenic acid, and composition such as volatile oil chemical compound.These compositions generally can not influence and disturb the drug action of chlorogenic acid in said medicine of the present invention, thereby guaranteeing under the prerequisite of above-mentioned chlorogenic acid usage ratio can to allow these compositions to exist with suitable form and/or ratio according to the requirement of concrete pharmaceutical technology and preparation.

Said andrographolide is the crystallization of colourless square, rectangle or prism-shaped in the mentioned component, odorless, and bitter in the mouth, fusing point are 224-230 ℃, and be water insoluble and be dissolved in the ethanol that boils, and slightly is dissolved in methanol or ethanol.Existing known this composition can have the pharmacologically active of aspects such as infection and antipyretic-antalgic, analgesia, analgesic, antiulcer, diuresis, and is useful on the report of Eye disease treating.This composition equally also can be for passing through the complete synthesis mode of chemistry, or the chemical compound that after chemical modification is transformed, is obtained by other related compound, this chemical compound composition that also can serve as reasons and obtain through ethanol extraction, separation as the Herba Andrographis of natural medicinal raw material, even can also use the ethanol extraction of the Herba Andrographis raw material of the andrographolide that contains the significant proportion amount to replace.When needs are made the water solublity dosage form, can use the soluble derivative commonly used of its corresponding potassium salt, sodium salt or other appropriate format that is prepared into according to a conventional method.When its ethanol extraction of direct use was replaced, this extract normally comprised this lactone and makes at interior total andrographolides.In like manner, as long as other wherein contained composition can not have a negative impact to the effect of effective ingredient in the said medicine of the present invention, and, also need not ask and its separation is removed and allow it to exist simultaneously with suitable form and/or ratio according to the requirement and the allowed band of different preparations.

Medicine of the present invention in the preparation, by after the said mixed, respectively by different dosage form preparation requirement, standard separately, and regulations such as processing, detection method are made the medicine of corresponding dosage form according to required dosage form with above-mentioned effective medicinal ingredient.As: after adding the composition of suitable auxiliary, interpolation property, can be made into solid oral dosage forms such as corresponding tablet, pill, capsule, or the medicine of liquid oral dosage forms such as electuary, syrup, extractum; By the requirement and the processing method of injection routine, can make the medicine of corresponding intramuscular injection or intravenous form; By the preparation requirement of eye medicinal dosage form, can make corresponding external medicament for the eyes.

Being mixed with andrographolide by Flos Lonicerae extract, and make wherein chlorogenic acid: the proportional quantities of andrographolide is 4: 1 said medicine of being formed of the present invention, is prepared into the test specimen medicine, has carried out the toxicity test of animal:

Acute toxicity test: get 20 of mices, by the dosage of 10.20 gram/kilograms (be equivalent to clinical consumption 1000 times), every day, 2 gastric infusions were observed none animal dead continuously 8 days.Fail to record its median lethal dose(LD 50) LD ₅₀

Long term toxicity test: get 22 of rat, by 1.02 gram/kilograms (be equivalent to clinical consumption 100 times) dosage, gastric infusion is 30 days continuously, except that the animal subject body weight gain shows slightly slowly, and organ no abnormality seens such as the heart, liver, spleen, lung, kidney.The result shows that medicine of the present invention does not have overt toxicity.

As follows with the part pharmacodynamics test that medicine of the present invention carries out:

With said medicine of the present invention respectively by chlorogenic acid: Herba Andrographis is the test specimen medicine that 2: 1 (sample 1), 4: 1 (sample 2), 8: 1 (sample 3) and 16: 1 (sample 4) are prepared into four kinds of different proportion forms, carried out external antibacterial activity contrast test with the conventional medicine ciprofloxacin, the part test result of minimum inhibitory concentration (MIC) is as shown in table 1.

The result of the test of table 1 clearlys show, and two of form kinds of drug study samples of the present invention that active component is formed in varing proportions all demonstrate clinical isolating common Gram-positive and negative pathogenic bacterium and to have certain antibacterial vigor.Show that through a large amount of experimental result statistics sample 1, sample 2, sample 3 and 4 four groups of effective ingredient of the sample example pharmaceuticals of form composition in varing proportions all have antibiotic preferably vigor to staphylococcus aureus, bacillus cloacae, bacillus pyocyaneus, aerobacteria, Bacillus proteus, Ke Shi pneumobacillus etc.; Antibacterial vigor to streptococcus pneumoniae, Hemolytic streptococcus is stronger.Bloodthirsty hemophilus influenza also there is certain antibacterial vigor.But to the escherichia coli DeGrain, all＞400.The result of table 1 also demonstrates, and the antibacterial activity in vitro of the laboratory sample medicine of three groups of different proportion forms is basic identical, but wherein sample 2, sample 3 and sample are better than 1 group in sample for 4 three groups slightly.Relevant test also shows, as Gram-positive, negative bacillus such as Gram-positives such as Diplococcus pneumoniae, meningococcus, negative cocci and dysentery bacterium, Bacillus typhi, Salmonella paratyphi, vibrio cholera, diphtheria corynebacterium, bordetella pertussis, and multiple pathogenic microorganism such as leptospira, Candida albicans, epidermophyton also all has bacteriostasis to said medicine of the present invention to other.

The test of table 1 antibacterial activity in vitro

The test organisms kind	MIC (mg/ml)
	MIC (mg/ml)					Sample 1 (2: 1)	Sample 2 (4: 1)	Sample 3 (8: 1)	Sample 4 (16: 1)	Ciprofloxacin (mcg/ml)
	The gold bacterium 99-1 of Portugal	????0.38	????0.78	????0.39	????0.32	Sample 1 (2: 1)	Sample 2 (4: 1)	Sample 3 (8: 1)	Sample 4 (16: 1)	Ciprofloxacin (mcg/ml)	????16
The gold bacterium 99-2 of Portugal	The gold bacterium 99-1 of Portugal	????0.38	????0.78	????0.39	????0.32	????0.38	????0.39	????0.39	????0.32	????16	????16
The gold bacterium 99-2 of Portugal	The gold ATCC25923 of Portugal	????0.56	????0.56	????0.39	????0.39	????0.38	????0.39	????0.39	????0.32	????16	????0.5
Escherichia coli 99-1	The gold ATCC25923 of Portugal	????0.56	????0.56	????0.39	????0.39	????＞400	????＞400	????＞400	????＞400	????32	????0.5
Escherichia coli 99-1	Escherichia coli 99-2	????＞400	????＞400	????＞400	????＞400	????＞400	????＞400	????＞400	????＞400	????32	????8
Bacillus cloacae 9894	Escherichia coli 99-2	????＞400	????＞400	????＞400	????＞400	????1.56	????1.56	????1.56	????1.54	????1	????8
Bacillus cloacae 9894	Bacillus cloacae 9896	????1.56	????1.56	????1.56	????1.56	????1.56	????1.56	????1.56	????1.54	????1	????1
Bacillus pyocyaneus 9926	Bacillus cloacae 9896	????1.56	????1.56	????1.56	????1.56	????3.00	????3.00	????3.12	????3.00	????0.03	????1
Bacillus pyocyaneus 9926	Aerobacteria 9885	????1.56	????1.56	????1.56	????1.50	????3.00	????3.00	????3.12	????3.00	????0.03	????1
Aerobacteria 9888	Aerobacteria 9885	????1.56	????1.56	????1.56	????1.50	????1.56	????1.56	????1.56	????1.56	????16	????1
Aerobacteria 9888	Bacillus proteus 9936	????1.56	????1.56	????3.12	????3.10	????1.56	????1.56	????1.56	????1.56	????16	????0.06
Streptococcus pneumoniae 1	Bacillus proteus 9936	????1.56	????1.56	????3.12	????3.10	????0.78	????0.78	????0.78	????0.79	????0.5	????0.06
Streptococcus pneumoniae 1	Streptococcus pneumoniae 4	????1.56	????1.56	????1.56	????1.56	????0.78	????0.78	????0.78	????0.79	????0.5	????2
Bloodthirsty hemophilus influenza 1	Streptococcus pneumoniae 4	????1.56	????1.56	????1.56	????1.56	????3.12	????1.56	????1.56	????1.58	????0.25	????2
Bloodthirsty hemophilus influenza 1	Bloodthirsty hemophilus influenza 4	????6.25	????6.25	????12.5	????11.0	????3.12	????1.56	????1.56	????1.58	????0.25	????1
Ke Shi pneumobacillus 9863	Bloodthirsty hemophilus influenza 4	????6.25	????6.25	????12.5	????11.0	????1.56	????3.10	????3.12	????3.10	????2	????1
Ke Shi pneumobacillus 9863	Ke Shi pneumobacillus 9864	????1.78	????1.78	????1.56	????1.50	????1.56	????3.10	????3.12	????3.10	????2	????0.25
Hemolytic streptococcus 991	Ke Shi pneumobacillus 9864	????1.78	????1.78	????1.56	????1.50	????6.25	????6.12	????6.25	????6.00	????1	????0.25
Hemolytic streptococcus 991	Hemolytic streptococcus 992	????6.12	????6.12	????6.25	????6.30	????6.25	????6.12	????6.25	????6.00	????1	????0.5

Antivirus test:

Above-mentioned experimental drug matter sample 3 is respectively 10 mg/ml (1 group) by total medicament contg, 5 mg/ml (2 groups), 2.5 mg/ml (3 groups) is four test group with the different dilution factors of 1.25 mg/ml (4 groups), the antivirus test result that done of four matched groups (1～4 group) that constituted with virazole medicine by the configuration of same dilution factor and blank group is as shown in table 2 respectively.

Table 2 antivirus test result

Test specimen	Virus	The drug level group				The virus control group	The cell matched group
		The drug level group						1 group	2 groups	3 groups	4 groups
		Medicine of the present invention	ADV ₃	????-	????-			1 group	2 groups	3 groups	4 groups	????-	????-	????3+	??-
ADV ₇	????-		ADV ₃	????-	????-	????-	????-	????-	????3+	??-		????-	????-	????3+	??-
ADV ₇	????-		RSV	????-	????-	????-	????-	????-	????3+	??-	????-	????-	????3+	??-
Virazole	ADV ₃		RSV	????-	????-	????-	????-	????-	????1+	????3+	????-	????-	????3+	??-	??-
	ADV ₃	ADV ₇	????-	????-	????1+	????-	????-	????-	????1+	????3+	????1+	????3+	??-		??-
	RSV	ADV ₇	????-	????-	????1+	????-	????-	????-	????2+	????3+	????1+	????3+	??-	??-
	RSV	Blank	ADV ₃	????3+	????3+	????-	????-	????-	????2+	????3+	????3+	????3+	????3+	??-	??-
ADV ₇	????3+		ADV ₃	????3+	????3+	????3+	????3+	????3+	????3+	??-	????3+	????3+	????3+		??-
ADV ₇	????3+		RSV	????3+	????3+	????3+	????3+	????3+	????3+	??-	????3+	????3+	????3+	??-

(annotate: no pathological changes in "-" expression cell in the table; How much "+" represents intracellular lesion degree.)

The experimental result of table 2 shows, each dilution group of experimental drug matter sample of the present invention all has in various degree inhibitory action to three kinds of viruses, and to ADV ₃, ADV ₇All be better than the control drug virazole with the inhibitory action of RSV.

Separate heat test:

With the SD rat is experimental animal, with the above-mentioned experimental drug matter sample 2 of the present invention, be the medicine positive controls with aspirin, with the negative matched group of carboxymethyl cellulose (CMC), all to irritate the administration of stomach mode, carry out the pharmacodynamics test to yeast powder pyrogenic action influence, the result is as shown in table 3.

The result of table 3 shows that aspirin can make the anus temperature of yeast powder pyrogenicity rat significantly reduce, and has tangible refrigeration function; Medicine of the present invention has tangible refrigeration function after with the test dose administration, and learn by statistics and handle, the two there was no significant difference, but significant difference is more all arranged with negative control group, and wherein: * is P＜0.05, and * * is P＜0.01, and * * * is P＜0.001.

Pyrogenic action influences result of the test to table 3 rat to yeast powder

Group	Dosage (g/kg)	Number of animals (only)	Anus temperature difference meansigma methods after the administration (℃)
								1 hour	2 hours	3 hours	4 hours	5 hours
			Of the present invention group	0．5	11	0．96**	0．64**	0．43***	0．40***	0．31**
Positive group	0．6	12	0．77**	0．16***	0．32***	0．56***	0．47***
Negative group	Equivalent 1%	12	2．26	2．51	2．11	2．42	2．45

The clinical treatment test:

Adopt the above-mentioned experimental drug matter sample 2 of the present invention, with oral 420 milligrams/time, every day 3 times dosed administration, the treatment of common diseases such as the flu that is used for causing, acute bronchitis, pneumonia, gingivitis, pharyngolaryngitis, the bacillary dysentery of XIS by above-mentioned paathogenic factor; With external eye drip drug treatment acute conjunctivitis, it was a course of treatment all by 3～7 days.Therapeutic trial patient's age 18～60 years old, average course of disease 8.19 days.By following standard the curative effect of test of cure is evaluated:

Recovery from illness: remove the cause of disease in 3 days, all diseases are disappeared, and the tongue arteries and veins is normal, no longer recurrence;

Effectively: basic solution removes the cause of disease in 3 days, and cardinal symptom alleviates, and the tongue arteries and veins is normal, but occurs mild again after the drug withdrawal, reuse medicine may command symptom;

Invalid: symptom does not have any alleviation in 3 days;

Increase the weight of: 3～5 days symptom reverse side of medication increase the weight of.

The observation of curative effect result of therapeutic trial is as shown in table 4.

Table 4 clinical observation on the therapeutic effect result

The curative effect case load	Flu	Acute bronchitis	Pneumonia	Gingivitis	Pharyngolaryngitis	Acute conjunctivitis	Acute bacillary dysentery
Recovery from illness	199	257	128	162	272	35	42
Effectively	120	111	24	42	130	5	4
Invalid	91	32	0	12	10	2	2
Increase the weight of	0	0	0	0	0	0	0
Total routine number	410	400	152	216	412	42	48

More than every result of the test is clear shows that said medicine of the present invention can have clinical common pathogenic microorganisms such as various bacteria, viruses, even produces obvious and stronger inhibitory action; To also all producing the better and/or ideal curative effect of taking stopgap measures, effecting a permanent cure by the multiple common diseases such as inside and outside section that it caused.Said medicine decapacitation of the present invention increases the doctor when being used for infection and analgesic analgesia therapy outside more alternative variety range and the leeway, also be grouped into simply because of its one-tenth, effective ingredient is concentrated, and can be made into the several formulations form, thereby the use amount of medicine is reduced relatively, and reduced waste to natural medicinal raw material, reduced cost, and make the scope of its occupation mode and/or patient's object more extensive, help promoting the use of on a large scale.

Claims

1. have infection and antipyretic effect and can be used for the medicine of ophthalmic, it is characterized in that effective medicinal ingredient is made up of chlorogenic acid and andrographolide or its corresponding soluble derivative, its weight portion proportion of composing is a chlorogenic acid: andrographolide=(1～20): 1.

2. medicine as claimed in claim 1, the soluble derivative that it is characterized in that andrographolide in the said composition are the alkali metal salt compounds that allows in the pharmacopedics.

3. medicine as claimed in claim 1 is characterized in that the chlorogenic acid in the said composition maybe can be the extraction composition from natural medicinal raw material Flos Lonicerae.

4. medicine as claimed in claim 1 is characterized in that the chlorogenic acid in the said composition or can be directly be the extract of the natural medicinal raw material Flos Lonicerae that contains significant proportion amount chlorogenic acid.

5. medicine as claimed in claim 1 is characterized in that the andrographolide in the said composition can be the ethanol extraction composition from natural medicinal raw material Herba Andrographis.

6. medicine as claimed in claim 1, it is characterized in that andrographolide in the said composition can be directly with the Herba Andrographis feed ethanol extract of the andrographolide that contains the significant proportion amount.

7. as the described medicine of one of claim 1 to 6, it is characterized in that said medicine is the medicine of peroral dosage form.

8. as the described medicine of one of claim 1 to 6, it is characterized in that said medicine is the medicine of injection type.

9. as the described medicine of one of claim 1 to 6, it is characterized in that said medicine is the medicine of eye with dosage form.