CN1110299C - Triazazole nucleoside aerosol and its preparing method - Google Patents

Abstract

The present invention relates to a ribavirin aerosol and a preparation method thereof. The ribavirin aerosol of the present invention comprises ribavirin as active components and medicinal carriers. The ribavirin aerosol can be sucked in through mouth or nose to reach to focus positions directly, inhibit virus replication effectively. The stimulation of gastrointestinal tract is avoided because of direct administration; besides, the ribavirin aerosol has the advantages of low dosage and minimal side effect. The present invention provides the preparation method.

Description

Triazazole nucleoside aerosol and preparation method thereof

The present invention relates to triazazole nucleoside aerosol and preparation method thereof.

The upper respiratory tract infection disease that is caused by viral infection is a kind of very general multiple disease, and it is few at present to treat and improve the medicine of symptom fast and effectively for this type of disease.Ribavirin, chemical name: 1-β-D-ribofuranose-1,2,4 triazoles-3-carboxylic acid amides have another name called ribavirin, and it is a kind of broad-spectrum antiviral new drug, multiple DNA and RNA viruses there is inhibitory action, can stop duplicating of virus, and be better than medicines such as vidarabine, cytosine arabinoside and amantadine, referring to what reported in " medical science reference material " 1976 the 10th phase 440-443 page or leaf " a new antiviral antineoplastic nucleoside compound-Virazole ".Ribavirin oral formulations reaction effect clinically is not obvious, and gastrointestinal side effect is big; Though the atomized inhalation effect is obvious, only be applicable to the inpatient; Can flow into throat during the nasal drop administration and swallow or flow out, thereby influence therapeutic effect from nasal cavity through esophagus.Therefore, the objective of the invention is to overcome above-mentioned weak point, use the advantage of aerosol spray administration, invent a kind of new triazazole nucleoside aerosol.

The invention provides a kind of ribavirin (ribavirin) aerosol.Triazazole nucleoside aerosol of the present invention is by forming as the ribavirin of active ingredient and pharmaceutical carrier, and wherein the proportioning of active ingredient and pharmaceutical carrier can be formed 100% composition by any proportioning that contains active ingredient ribavirin 0.01-30% and contain medicinal carrier 99.9-70%.

Above-mentioned pharmaceutical carrier is propellant such as fluoro trichloromethane, dichlorodifluoromethane or tetrafluorodichloroethane etc.; Dispersant is as three oleic acid sorbitol anhydrides, sorbitol half oleate, oleic acid, oleyl alcohol, phospholipid or monostearate sucrose fat etc.

Triazazole nucleoside aerosol of the present invention is as follows through the clinical test results of Huashan Hospital, Attached to Shanghai Medical Univ., Ruijin Hospital Attached to Shanghai Medical Univ No.2, Shanghai Medical Univ's pediatric hospital, Shanghai City Children Hospital:

(1) case is selected:

1, flu patient: adult patient 14-65 year, child patient is below 13 years old.

2, tool heating, headache, whole body extremities aching pain, three above symptoms such as throat pain, nasal obstruction, watery nasal discharge, sneeze, cough.

3, the course of disease is within 48 hours, and other antiviral had not been used in this morbidity.Bring down a fever, the cough medicine person.

4, periphery WBC counting is less than 10,000.

(2) observed result:

One, adult group:

1, three groups of transference cure situations relatively.(according to the case statistics of following up a case by regular visits at 48 hours) sees Table 1.

Three groups of transference cure situations of table 1 adult are (48 hours) relatively

Symptom		Aerosol (snuffing formula) group	Aerosol (mouthful suction formula) group		Matched group
						The case load routine number % that disappears	The case load routine number % that disappears		The case load routine number % that disappears
		Watery nasal discharge	Gently	16 14 87.5	9 9 100					25 24 96.3
In	33 29 87.9						30 25 83.3		23 18 78.3
			Heavy	16 14 87.5	18 18 100					12 10 83.3
Add up to	65 57 87.7						57 52 91.2		60 52 86.7
			Nasal obstruction	Gently	17 11 64.7	13 8 61.5				18 8 44.4
In	34 18 60	30 17 56.7						32 15 46.9
				Heavy	18 8 44.4	20 10 50			16 6 37.5
Add up to	65 37 56.9	63 35 55.6						36 29 80.6
				Pharyngalgia	Gently	26 17 65.4	29 18 62.1		30 10 33.3
In	22 14 63.6	19 12 63.2								17 5 29.4
					Heavy	4 2 2/4	6 3 3/6		3 1 1/3
Add up to	52 33 63.5	54 33 61.1								50 16 32
					Cough	Gently	19 9 47.3	18 8 44.4			17 5 35.5
In	23 11 47.3	32 13 40.6		22 7 31.8
						Heavy	8 3 3/8	5 2 2/5		7 2 2/7
Add up to	50 23 46	55 23 41.8		46 14 30.4
						Headache	Gently	28 18 64.3	24 16 61.5		27 18 66.7
In	15 9 60	24 12 60		15 9 60
					Heavy		3 2 2/3	4 2 2/4		3 2 2/3
Add up to	46 29 63	50 30 60		45 29 64.4
					Systemic pain		Gently	35 25 71.4	28 21 75		27 20 24.1
In	8 5 62.5	15 10 46.7		10 6 64
						Heavy	2 1 1/2	4 2 2/4		3 2 2/3
Add up to	45 31 68.9	47 33 70.2		40 28 70

2, three groups of fever times relatively see Table 2

Three groups of fever times of table 2 adult are (unit two hours) relatively

Heating	Aerosol (snuffing formula) group	Aerosol (mouthful suction formula) group	Matched group
				Slightly	26.67±6.1	28.8±7.1	29.1±6.9
Moderate	34.67±7.7	36.7±8.6	36±7.2
				Severe	49.2±8.9	51.6±8.1	53.3±5.6

Through t check, in the above-mentioned table three groups light, in, P＞0.05 between severe fever patient's fever time.Three groups of fever time no significant differences are described.

(2) child's group:

1, three groups of transference cure situations of child relatively see Table 3

Three groups of transference cure situations of table 3 child relatively

Three groups of transference cure situations of table 3 child relatively

Symptom		Aerosol (snuffing formula) group	Aerosol (mouthful suction formula) group	Matched group
					The case load routine number % that disappears	The case load routine number % that disappears	The case load routine number % that disappears
		Watery nasal discharge	Gently	21 15 71.4				17 17 100	20 20 100
In	15 15 100				9 9 9/9	13 13 100
			Heavy	0 0 0			1 1 1/1	0 0 100
Add up to	36 30 83.3				27 27 100	0 0 0
			Nasal obstruction	Gently			17 12 70.6	18 12 66.7	16 8 50
In	9 6 6/9	7 5 5/7			12 5 41.7
				Heavy		3 2 2/3	1 1 1/1	1 1 1/1
Add up to	29 20 68.9	26 18 69.2			29 14 48.3
				Beat and sneeze		Gently	12 8 60.7	9 6 6/9	29 14 48.3
In	7 5 5/7	7 5 5/7	6 3 3/6
					Heavy	0 0 0	0 0 0	1 1 100
Add up to	19 13 68.4	16 11 68.8	19 12 63.2
					Pharyngalgia	Gently	19 13 60.4	17 12 70.6	15 6 40
In	10 6 6/10	8 5 5/8	9 4 4/9
				Heavy		0 0 0	0 0 0	0 0 0
Add up to	29 19 65.5	25 17 68.0	24 10 41.7
				Cough		Gently	17 10 58.8	8 5 5/8	10 5 50
In	7 4 4/7	7 4 4/7	10 4 40
					Heavy	8 4 4/8	6 3 3/6	8 3 3/8
Add up to	32 18 56.3	18 17 94.4	28 12 42.9
					Headache	Gently	19 14 73.7	17 12 70.6	15 11 73.3
In	10 7 7/10	8 5 5/8	9 6 6/9
				Heavy		0 0 0	0 0 0	0 0 0
Add up to	29 21 72.4	25 17 68	24 17 74.8
				Systemic pain		Gently	5 4 4/5	8 6 6/8	8 5 5/8
In	2 1 1/2	2 2 2/2	6 4 4/6
					Heavy	0 0 0	0 0 0	1 1 100
Add up to	7 5 5/7	10 8 8/10	15 10 68.77

Last table as seen, two groups of aerosols are in watery nasal discharge, the disappearance rate of symptoms such as nasal obstruction, pharyngalgia, cough is bigger than oral group, wherein the disappearance rate of watery nasal discharge symptom relatively, two groups all more oral group big of aerosol, (P＜0.06) shows three kinds of aerosols susceptible people's on improving watery nasal discharge, nasal obstruction, and pharyngalgia, the aspect effect of cough symptom are very fast than oral liquid.

2, three groups of fever times of child relatively see Table 4 (unit: hour)

Three groups of fever times comparisons of table 4 child (unit: hour)

Heating	Aerosol (snuffing formula) group	Aerosol (mouthful suction formula) group	Matched group
				Slightly	30.1±6.7	22.4±7.4	27.9±8.1
Moderate	36.2±10.8	34.3±8.8	34.8±7.8
				Severe	50.67±9.4	53.2±9.7	52.36±11.4

Above-mentioned three groups light, in, the fever time of severe learns by statistics and handles P＞0.03 and show that three groups of situations of bringing down a fever of child are similar.

(5) efficacy result:

1, adult group

Three groups the curative effect of being grown up relatively sees Table 5

Three groups of comprehensive therapeutic effects of table 5 adult relatively

Group	The example number	Recovery from illness	Produce effects	Take a turn for the better	Invalid	Effective percentage (%)
							Aerosol (snuffing formula) group	70	39	15	13	3	77.1
Aerosol (mouthful suction formula) group	70	37	18	12	3	78.6
							Matched group	70	36	22	8	4	82.8

Through chi-square statistics X ²=1.05, P＞0.05, people's curative effects are formed in demonstration three does not have significant difference.

(2) child's group, the curative effect that the child is three groups relatively sees Table 6

Three groups of child's curative effects of table 6 relatively

Group	The example number	Recovery from illness	Produce effects	Take a turn for the better	Invalid
						Aerosol (snuffing formula) group	42	19	20	0	3
Aerosol (mouthful suction formula) group	40	17	21	0	2
						Matched group	40	15	18	2	5

Through chi-square statistics X ²=89.72, P＞0.05, people's curative effects are formed in demonstration three does not have significant difference.

Five, dosage is relatively:

The ribavirin glucoside oral liquid about 450mg of average consumption every day that is grown up, average everyone consumption every day of child is 200-250mg, and aerosol (comprises the snuffing formula, mouth suction formula), everyone every day of average consumption 20-30mg is grown up, child's consumption is a little less than the adult, so the ribavirin consumption of aerosol only reaches 10-16/one of oral liquid consumption.

Six, side effect is relatively:

1, adult's side effect relatively sees Table 7

Table 7 three is formed people's side effect relatively

Group	The example number	Feel sick	Poor appetite	Diarrhoea	The side reaction rate
						Aerosol (snuffing formula) group	70	0	0	0	0
Aerosol (mouthful suction formula) group	70	0	0	0	0
						Matched group	70	1	2	0	4.29％

2, child's side effect relatively sees Table 8

Three groups of child's side effect of table 8 relatively

Group	The example number	Feel sick	Poor appetite	Diarrhoea	The side reaction rate
						Aerosol (snuffing formula) group	42	1	0	0	2.5％
Aerosol (mouthful suction formula) group	40	0	0	1	2.5％
						Matched group	40	2	3	1	15％

The adult uses two kinds of aerosols to have no side effect as seen from the table, uses oral liquid that a small amount of gastral side effect is arranged.A small amount of side effect when the child uses aerosol, but use the side effect of oral liquid little than the child.

(6) conclusion:

1, clinical observation result:

Adult group: 70 routine ribavirin aerosols (snuffing formula) group effective percentage reaches 77.1%, 70 routine triazazole nucleoside aerosol (mouthful suction formula) group effective percentage and reaches 78.6%, and matched group 70 examples use ribavirin glucoside oral liquid effective percentage to reach 82.8%, P＞0.05.

Child's group: 42 routine triazazole nucleoside aerosols (snuffing formula) group effective percentage reaches 92.9%, 40 routine triazazole nucleoside aerosol (mouthful suction formula) effective percentage and reaches 95%, and it is 82.5% that matched group 40 examples are used ribavirin glucoside oral liquid effective percentage, P＞0.05.

Show that triazazole nucleoside aerosol (snuffing formula), (mouthful suction formula) are the medicines that the treatment viral upper respiratory tract infection has definite curative effect.

2, compare with oral liquid, the adult uses the disappearance of triazazole nucleoside aerosol (snuffing formula), (mouthful suction formula) treatment viral upper respiratory tract infection part local symptom such as pharyngalgia fast than oral liquid.The disappearance of watery nasal discharge symptom was also fast than oral liquid when the child used aerosol.Therefore, the use of ribavirin aerosol is in time used early stage (when only local symptom being arranged) of the infection of viral upper respiratory, the state of an illness more easy to control, it is more early good more to use.

3, compare with oral liquid, adult and child use the dosage of triazazole nucleoside aerosol that 10-15/one of oral liquid is arranged, and dosage is minimum.

4, becoming to use the side reaction rate of triazazole nucleoside aerosol is 0%, and oral liquid is 4.29%.It is 5% that the child uses the side reaction rate of triazazole nucleoside aerosol, and oral liquid is 15%.Therefore compare with ribavirin is oral, the side effect of application triazazole nucleoside aerosol is little.

5, triazazole nucleoside aerosol is easy to use and be easy to carry.

Triazazole nucleoside aerosol of the present invention is as follows through institute of materia medica, Chinese Academy of Sciences Shanghai test suction acute toxicity mucomembranous irritant test result:

One, triazazole nucleoside aerosol sucks the acute toxicity test report

Test objective: after observing disposable suction triazazole nucleoside aerosol, the acute toxic reaction that Cavia porcellus produced.

Be subjected to the reagent thing:

Title: triazazole nucleoside aerosol.

The unit of providing: Xinyi Pharmaceutical Factory

Lot number: 940901

Content, tire: every bottle contains 75mg, whenever presses 0.5mg.

Excipient: Xinyi Pharmaceutical Factory provides

Animal

The source: Cavia porcellus is provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.

Conclusion: during disposable suction triazazole nucleoside aerosol maximum 40mg/kg (approximately people clinical consumption 66 times), the phenomena of mortality and any acute toxic reaction do not appear in Cavia porcellus in 14 days.

Two, triazazole nucleoside aerosol sucks the acute irritation test report to mucosa

Test objective: behind the inferior more than a day inhalation of test triazazole nucleoside aerosol, to animal subject oral cavity and nasal membrane acute irritation response situation.

Be subjected to the reagent thing:

Title: triazazole nucleoside aerosol.

The unit of providing: Xinyi Pharmaceutical Factory

Lot number: 940901

Content, tire: every bottle contains 75mg, whenever presses 0.5mg.

Excipient: control vehicle is provided by Xinyi Pharmaceutical Factory

Animal

The source: Cavia porcellus is provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.

Conclusion: triazazole nucleoside aerosol repeatedly sucked in one day, when sucking total amount 20mg/kg, Cavia porcellus respiratory tract and gastrointestinal mucosal was all had no stimulation, and stolen goods in main are also had no side effect.

Three, triazazole nucleoside aerosol sucks the subacute irritant test report to mucosa

Test objective: test triazazole nucleoside aerosol one day 2 times, continuous 14 days inhalations are to the subacute irritant reaction situation of animal subject oral cavity and nasal membrane.

Be subjected to the reagent thing:

Title: triazazole nucleoside aerosol.

The unit of providing: Xinyi Pharmaceutical Factory

Lot number: 940901

Content, tire: every bottle contains 75mg, whenever presses 0.6mg.

Excipient: provide by Xinyi Pharmaceutical Factory.

Reference substance: provide by Xinyi Pharmaceutical Factory.

Animal

The source: Cavia porcellus is provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.

The result: the local observation: the triazazole nucleoside aerosol oral cavity is the same with the blank group with the excipient matched group with nasal cavity suction group, and oral cavity, nasal cavity, esophagus and tunica mucosa tracheae there is no phenomenons such as hyperemia, redness.

Histopathologic examination: under the light microscopic, each organizes all not pathological changes such as swollen, congested, hemorrhage and inflammatory cell infiltration of water breakthrough of trachea and esophagus.The also no abnormal pathological changes of viscera tissue such as the heart, lung, liver,spleen,kidney.

Conclusion: triazazole nucleoside aerosol sucks through oral cavity and nasal cavity, and successive administration 14 days when sucking total amount 112mg/kg, all has no stimulation to Cavia porcellus respiratory tract and gastrointestinal mucosal, and main internal organs are also had no side effect.

Triazazole nucleoside aerosol be three groups of suspension aerosols wherein the principal agent microgranule be to be suspended in the liquid phase propellant, medicine is deposited in bottle bottom with solid particle at ordinary times, does not contact with outside air, jolting becomes the suspendible shape during use.

Stability test research to this aerosol is as follows:

Test back color and luster white particles suspension white particles suspension suspendible situation suspendible was all right before table 9 was heated for 37 ± 2 ℃ and quickened the test of 3 months data of test test index; there is not caking; no glomerocryst is with the most of 5 μ m of the preceding particle diameter of test; less than 105 μ m, do not have long with before the test

Crystalline substance and glomerocryst phenomenon content (%) lot number 1 102.00 102.44

2 105.20 104.66

3 98.02 106.30

4 98.02 111.27

5 101.33 101.44

It is all right that the detection data that table 10 room temperature kept sample a year 07 months are investigated 1 year 07 months color and luster white suspension suspendibles of index situation suspendible, there is not caking, the most of 5 μ m of the same particle diameter of no glomerocryst, less than 10 μ m, do not have long the same

Crystalline substance and glomerocryst phenomenon content (%) lot number 1 101.52 102.42

2 100.42 102.42

3 97.32 96.88

The every detection data that table 11 room temperature kept sample 3 years investigate index after 3 years color and luster white suspension suspendible situation suspendible all right, there is not caking, there are not the most of 5 μ m of the same particle diameter of cohesion, less than 10 μ m, do not have long the same

Crystalline substance and glomerocryst phenomenon content (%) lot number 1 112.4 110.32

2 116.4 108.25

3 106.4 104.20

4 102.3 100.30

5 113.4 98.45

6 103.4 99.37

Four, the inspection of impurity speckle:

With thin layer chromatography 37 ℃ of three months and the samples in 3 years of room temperature are carried out study on the stability to the ribavirin aerosol, compare with raw material.Through chromatography developing, free from admixture speckle and decomposition speckle take place.

Test result:

(1) room temperature storage 1 year seven months sample test situation in addition:

Color and luster, particle diameter, suspendible situation: no change before and after the test, content: original average content average content 100.57% after 99.6%, a year 07 months.

(2) 3 years test results of room temperature storage:

1, is white suspension before and after the color and luster test.

2, the most 5 μ m of particle diameter less than 10 μ m, do not have long brilliant glomerocryst phenomenon, no change before and after the test.

3, suspendible situation test self-consistentency does not have caking, no coacervation.

4, average content 110.46% before the changes of contents test, test back average content 103.48%.

5, the impurity speckle is checked through thin layer chromatography, and sample is identical with the raw material speckle before and after the test, does not have other speckle and occurs.

It is 5 μ g that chromatography detects the minimum speckle concentration that detects of method.

Annotate:

1, since aerosol to be enclosed in aluminium pot packing little, product can not be subjected to illumination effect, so exposure experiments to light is not done.

2, aerosol pressure packing, heating back impelling pressure raises, and causes the packing blast to damage easily, and in the aerosol description clearly regulation require product to keep from heat, be kept at below 40 ℃, so the high temperature accelerated test is not carried out yet.

Preliminarily stabilised test and room temperature 19 months (lot number) that this preparation is heated and tested by 31 ℃ ± 2 ℃ acceleration, its color and luster of further test, the particle diameter of 36 months (three lot numbers), the suspendible situation, changes of contents, the impurity speckle all meets the requirements, illumination and high temperature are because the particularity of this preparation, so do not do, but the result who kept sample 3 years from its room temperature, and every index all changes not quite, illustrate and illumination and hot season, therefore think that this preparation is stable the not influence of this preparation.

Triazazole nucleoside aerosol of the present invention is a suspension aerosol, preserves in the sealed container that the quantitative valve system is arranged.The discriminating of this aerosol, assay, particle diameter and discharge rate test check etc. are all worked out by the requirement of Chinese Pharmacopoeia aerosol.

The key technical indexes:

1, contains discharge amplitude and be controlled at 90-120%

2, the discharge rate amplitude is controlled at 80-120%

3, stability requirement reaches shelf-life＞2 year

4, diameter of particle＜10 μ m

Another object of the present invention provides the preparation method of a kind of above-mentioned ribavirin (ribavirin) aerosol.This method comprises the following steps:

1, micronization technology:

The ribavirin raw material after 80 ℃ of dryings of vacuum, is put in the exsiccator and cooled off earlier, and is indoor in drying work, pulverizes with pulverizer, and the micropowder after the pulverizing is through sediments microscope inspection, and diameter of particle should reach 6 microns, as does not reach requirement, should pulverize once more.

2, adjust:

Allocate into by the amount of prescription and to adjust bucket, carry out circulating pump then and return stirring, wait to stir full and uniform after, carry out the intermediate content analysis, content is qualified, carries out fill.

3, fill:

After analysis of medium is qualified, carry out fill by theoretical amount.

4, press-fit:

Piezometric dress propellant by prescription.

5, packing:

Suction, two kinds of shower nozzles of snuffing and relevant packaging material in being equipped with are according to the requirement packing of aerosol packaging.

The triazazole nucleoside aerosol of method for preparing, wherein propellant is fluoro trichloromethane (F11) and dichlorodifluoromethane (F12) or tetrafluorodichloroethane etc., dispersant is three oleic acid sorbitol anhydrides, sorbitol half oleate, oleic acid, oleyl alcohol, phosphide or monostearate sucrose ester etc.; F11 and F12 can be used alone, but also also mix together, blended best proportioning be each 50%.

The triazazole nucleoside aerosol of making as stated above, each dosed administration 50 microlitres-75 microlitre, the dose of storage dress can be for spraying 160 times or 200 usefulness of taking second place in every bottle container, spray 75 milligrams of-1000 milligrams of medicinal liquids that are under the pressure at every turn, be equivalent to 0.5 milligram-1 milligram ribavirin.

Triazazole nucleoside aerosol of the present invention is the local directly dosage form of administration, and oral administration sucks or nasal cavity sucks through lesions position, can suppress virus replication effectively, can be used to prevent and treat respiratory virus infection.Because directly administration is avoided GI irritation, it is little therefore to have dosage, the advantage that side effect is little.Rapid-action, the advantage of convenient drug administration, and can carry.

Example 1, preparation triazazole nucleoside aerosol

Prepare 100 bottles of triazazole nucleoside aerosols, precision weighing 7.5 grams, through the ribavirin of micronization processes, the micropowder microgranule of this ribavirin should be below 10 microns.The three oleic acid sorbitol anhydrides of this micropowder and 4.5 grams and the even of fluoro trichloromethane of 360 grams are mixed, make ribavirin be dispersed in the fluoro trichloromethane uniformly, make suspension, this suspension is divided in the aerosol container, the every bottle of 3.5 gram suspensions of quantitatively packing into, load onto behind the aerosol quantitative valve of 50 microlitres hermetically enclosedly, under pressure, every bottle pours into dichlorodifluoromethane 7 grams.

Example 2, preparation triazazole nucleoside aerosol

Prepare 100 bottles of triazazole nucleoside aerosols, precision weighing 10 grams are through the ribavirin of micronization processes, and the micropowder microgranule of this ribavirin should be below 10 microns.Soybean phospholipid and the fluoro trichloromethane of 420 grams and dichlorodifluoromethane uniform mixing in hermetic container of 1180 grams with drip micropowder and 6 grams, make suspension, with this suspension under the pressure every bottle quantitatively pour into 14 and restrain in the aerosol container of the hermetically enclosed good aerosol quantitative valve of loading onto 50 microlitres.

Example 3, preparation triazazole nucleoside aerosol

Prepare 100 bottles of triazazole nucleoside aerosols, precision weighing 7.6 grams are through the ribavirin of micronization processes, and the microgranule of this ribavirin micropowder should be below 10 microns.Make suspension in the fluoro trichloromethane with this micropowder and 3.5 gram oleic acid and 350 grams, this suspension is divided in the aerosol container, the every bottle of 3.5 gram suspensions of quantitatively packing into, the aerosol quantitative valve labour of loading onto 50 microlitres is hermetically enclosed, under pressure, every bottle quantitatively pours into dichlorodifluoromethane 7 grams.

Example 4, preparation triazazole nucleoside aerosol

Prepare 100 bottles of triazazole nucleoside aerosols, precision weighing 10 grams are through the ribavirin of micronization processes, and the micropowder of this ribavirin should be below 10 microns.With the fluoro trichloromethane of this micropowder and 6 gram three oleic acid Pyrusussuriensis acid anhydrides and 420 grams, the tetrafluorodichloroethane of 320 grams and dichlorodifluoromethane uniform mixing in hermetic container of 440 grams, make suspension, with this suspension under the pressure every bottle quantitatively pour into 11 and restrain in the aerosol container of the hermetically enclosed good aerosol quantitative valve of loading onto 75 microlitres.

Claims (3)

1, a kind of ribavirin (ribavirin) aerosol, it is characterized in that this aerosol is by forming as the ribavirin of active ingredient and pharmaceutical carrier, wherein the proportioning of active ingredient and pharmaceutical carrier can be formed 100% composition by any proportioning that contains active ingredient ribavirin 0.01-30% and contain medicinal carrier 99.9-70%, and wherein said pharmaceutical carrier is propellant fluoro trichloromethane, dichlorodifluoromethane or tetrafluorodichloroethane; Dispersant is three oleic acid sorbitol anhydrides, sorbitol half oleate, oleic acid, oleyl alcohol, phosphide or monostearate sucrose ester.

2, ribavirin according to claim 1 (ribavirin) aerosol, it is characterized in that wherein said pharmaceutical carrier propellant fluoro trichloromethane or dichlorodifluoromethane can use separately, also can mix use, the proportioning when mixing use is respectively to contain 50% amount.

3, the preparation method of a kind of a kind of ribavirin as claimed in claim 1 (ribavirin) aerosol is characterized in that this preparation method comprises the following steps: 1. micronization technologies:

The ribavirin raw material after 80 ℃ of dryings of vacuum, is put in the exsiccator and cooled off earlier, and is indoor in drying work, pulverizes with pulverizer, and the micropowder after the pulverizing is through sediments microscope inspection, and diameter of particle should reach 5 microns, as does not reach requirement, should pulverize once more; 2. adjust:

Allocate into by the amount of prescription and to adjust bucket, carry out circulating pump then and return stirring, wait to stir full and uniform after, carry out the intermediate content analysis, content is qualified, carries out fill; 3. fill:

After analysis of medium is qualified, carry out fill by theoretical amount; 4. press-fit:

Piezometric dress propellant by prescription; 5. pack:

Suction, two kinds of shower nozzles of snuffing and relevant packaging material in being equipped with are according to the requirement packing of aerosol packaging.