CN105193947A - Chinese patent medicine ear-drop preparation containing Shuanghuangliang and andrographolide - Google Patents

Abstract

The invention discloses a Chinese patent medicine ear-drop preparation containing Shuanghuangliang and andrographolide. Furacilin ear drops are external use local antibacterial agents which are frequently used clinically in the ear-nose-throat department of a hospital in China. Furacilin ear drops which are prepared through a traditional method have the following defects that stability is poor, the color can be darkened easily in the storage and clinical use process, and pale brown crystals can be precipitated from furacilin easily under the low-temperature condition in winter; heating and long-term stirring are needed during preparation; the content of the furacilin can be lowered at varying degrees along with the number of the crystals, so that the clinical effect is lowered, and the furacilin cannot be used. The furacilin ear drops prepared through the method are greatly optimized in technology. The phenomena of crystallization, turbidness and the like cannot happen to the obtained product through observation of reserved samples for 24 months, and high stability is achieved. The content of the furacilin is determined through the ultraviolet-visible spectrophotometry, the content is not changed obviously during the period of storage, and the content loss percentage is smaller than 1%.

Description

A kind of Chinese patent medicine [Dan preparation containing SHUANGHUANLIAN and andrographolide

The application is application number: 2013103058705, and the applying date is: 2013-07-22, and name is called: " utilizing ultrasonic-microwave to prepare the method for nitrofural [Dan preparation fast ", the divisional application of Chinese invention patent.

Technical field

The present invention relates to field of pharmaceutical preparations, specifically nitrofural [Dan preparation method.

Background technology

Nitrofural [Dan is the clinical conventional local external use's antibacterials of domestic hospitals department of otorhinolaryngology, and its treatment otitis media and otitis externa determined curative effect, clinical practice is extensive.

At present, nitrofural [Dan is prepared voluntarily by each hospital usually, main component is the nitrofural of recipe quantity, ethanol and glycerol (Liu Huiyi, the preparation of nitrofural [Dan and assay, " Journal of Chinese Hospital Pharmacy "), its outward appearance is yellow clear and bright oily liquids, mildly bitter flavor.Its Main Function is interference antibacterial glycometabolic commitment, causes bacterial metabolism disorderly and dead.Its antimicrobial spectrum is comparatively wide, has antibacterial action, also have effect to anaerobe to multiple Grain-positive and negative bacterium, to bacillus pyocyaneus and Diplococcus pneumoniae active force weak, have drug resistance, to fungus to Pseudomonas and Proteus, mycete is invalid, but is still effective to mould microbial bacteriological infection.The bacteriocidal concentration of its sensitive organism is 13-20 μ g/ml, and Mlc is 5-10 μ g/ml.

At present, the preparation method of " Chinese Hospitals preparation specification " is as follows: accurately weighed nitrofural 2g is mixed homogeneously with 250ml ethanol, slowly join again in appropriate glycerol, abundant stirring makes it dissolve, heat if desired, after it dissolves completely, be chilled to room temperature, then add glycerol to full dose 1000ml, mixing, to obtain final product.

Traditional preparation methods is prepared nitrofural [Dan and be there are some shortcomings: first, and owing to relying on agitating device to provide limited shearing force, mixing time is long, and the preparation amount of preparation more than 500ml is comparatively difficult, is more difficult to the preparation amount preparing more than 1000ml.Secondly, in a series of process for preparation such as stirring, whole solution system is spacious to be put, and easily causes medicine by outside contamination.Again, the meeting that light, dirt in air and oxygen molecule, metal ion produce in process of production produces certain impact to drug quality, such as makes it darken, accelerates crystallization generation etc.To sum up, existing nitrofural [Dan poor stability, just there is the phenomenon of variable color, muddiness or crystallization in lay up period of being everlasting, especially in the winter time preparation and the easier crystallization of long-term storage.Thus reduce curative effect, therefore namely current compound method can only join i.e. use, short-term is deposited.

Summary of the invention

The nitrofural [Dan preparation that the object of the invention is to provide a kind of good stability, is easy to a large amount of production, preserves for a long time, is applicable to medical institutions, pharmacy corporation large-scale production.

The technical scheme adopted for realizing the invention object is such, and a kind of method utilizing ultrasonic-microwave to prepare nitrofural [Dan preparation fast, comprises the following steps:

1) taking recipe quantity nitrofural adds in glass container, in described glass container, add recipe quantity ethanol.In this step, under normal circumstances, nitrofural and ethanol press portion rate for (2:250); (gram) and volume (milliliter) are than being (1:125) by weight, and the prescription recorded as certain pharmacopeia is: nitrofural 2g, ethanol 250ml.As preferably, this step 1) in glass container be can open/airtight container with the glass jar of stopper or other, after containing nitrofural and ethanol, described glass container can seal.Further, before containing nitrofural and ethanol, described brown glass container and stopper thereof are through disinfecting.

2) add water in the rinse bath of ultrasonic cleaner, the described glass container filling nitrofural and ethanol is put into rinse bath.In this step, described ultrasonic cleaner can use the ultrasonic cleaner of medical field or domestic, it has the rinse bath of an accommodation cleanout fluid (the present invention can use water), the friendship that supersonic generator sends is signal frequently, is converted to friendship frequency mechanical oscillation and propagates in described cleanout fluid by transducer.

3) setting up procedure 2) described in ultrasonic cleaner, ultrasonic dissolution assisting at least 2 minutes.Namely the glass container in described rinse bath is applied to the ultrasound wave of certain frequency, its objective is and the nitrofural in described glass container is dissolved in ethanol, and affect its performance.Meanwhile, the beaker filling glycerol is put into microwave oven, by the glycerol microwave heating to 70 in described beaker DEG C ~ 75 DEG C.In the present invention, the amount of the glycerol in described beaker is recipe quantity, and described ethanol and glycerol press portion rate for (1:3), and the prescription recorded as certain pharmacopeia is: nitrofural 2g, ethanol 250ml, glycerol are about 750ml, total amount 1000ml.What deserves to be explained is, owing to having hydroxyl in glycerol molecule structure, therefore, it is possible to adopt microwave oven to carry out Fast Heating to it, reach fabulous technique effect.

4) water in the rinse bath of described ultrasonic cleaner is heated to 60 DEG C, namely make described glass container be in 60 DEG C of water-baths.By through step 3) glycerol that processes joins in the glass container filling nitrofural and ethanol, namely obtains nitrofural [Dan after mix homogeneously.As preferably, glycerol joins in the process of glass jar by this step, and described ultrasonic cleaner does not cut out, and namely described glass container is still in and step 3) in identical environment, just when adding glycerol, need the stopper opening described glass container.Further, this step is slowly joined in glass jar by glycerol, namely adopts the mode of dropping, until nitrofural all dissolve clear and bright after, the glycerol in beaker is all joined in glass jar, after jolting glass jar, covers stopper, keep in Dark Place.

As preferably, above-mentioned steps 1 ~ 4 is carried out under lucifuge condition.

The present invention has following advantage: the first, simple to operate, without the need to many lengthy and tedious processes such as electromagnetic agitation, decreases the contact with the external world, make products obtained therefrom cleaner, and preparation time is short, process; The second, significantly improve the stability of nitrofural in prescription, make the product of gained stable in properties in long time stored process, almost without situations such as content decline, crystallization, variable colors; 3rd, improve uniformity of dosage units, improve shelf index, thus enhance the safety and efficacy of clinical application.

Accompanying drawing explanation

The nonlimiting examples that the device of the invention can be provided by accompanying drawing further illustrates.

Fig. 1 is the nitrofural [Dan ultraviolet detection collection of illustrative plates adopting the inventive method to prepare;

Fig. 2 is the nitrofural [Dan ultraviolet detection collection of illustrative plates adopting traditional method to prepare;

Fig. 3 adopts the nitrofural [Dan prepared of the inventive method in microcosmic (under microscope 400 ×) the property stability observed result of first month;

Fig. 4 is microcosmic (in microscope under 400 ×) the property stability observed result of the nitrofural [Dan prepared of traditional method at first month;

Fig. 5 adopts the nitrofural [Dan prepared of the inventive method microcosmic (under microscope 400 ×) the property stability observed result of six month;

Fig. 6 is the nitrofural [Dan prepared of traditional method microcosmic (under microscope 400 ×) the property stability observed result of six month;

Fig. 7 adopts the nitrofural [Dan prepared of the inventive method microcosmic (under microscope 400 ×) the property stability observed result of the 12 month;

Fig. 8 is the nitrofural [Dan prepared of traditional method microcosmic (under microscope 400 ×) the property stability observed result of the 12 month;

Fig. 9 is the nitrofural [Dan prepared of traditional method microcosmic (under microscope 400 ×) the property stability observed result of the 24 month;

Figure 10 is the observation image of the nitrofural [Dan prepared of the traditional method crystallization of separating out at the 24 month (400 ×) under the microscope.

Detailed description of the invention

Below in conjunction with embodiment, the invention is described further, but should not be construed the above-mentioned subject area of the invention and be only limitted to following embodiment.Without departing from the technical idea of the present inventions, according to ordinary skill knowledge and customary means, make various replacement and change, all should be included in the protection domain of the invention.

Embodiment 1

Prescription forms:

Composition	Consumption
		Nitrofural	2g
Ethanol	250ml
		Glycerol	About 750ml
Full dose	1000ml

Take nitrofural 2g, accurately weighed, proceeded in the glass jar of tool plug.Adding 250ml ethanol mix homogeneously to described glass jar is placed in the rinse bath of ultrasonic cleaner, ultrasonic dissolution assisting 2min, namely opens described ultrasonic cleaner (ultrasonic power 500W, frequency 40KHz).Meanwhile, the 1000ml beaker filling glycerol is put into microwave oven, heat 70s with high fire (microwave output power 700W, microwave frequency 2450Hz) and make its temperature reach 70 DEG C ~ 75 DEG C.Under ultrasound condition, slowly hot glycerol is added in glass jar, continues ultrasonic 6min, period bath temperature be arranged on 60 DEG C, until nitrofural all dissolve clear and bright after, record the ultrasonic time.Add glycerol to full dose 1000ml, after jolting evenly, obtain nitrofural [Dan preparation.As preferably, the present embodiment said process carries out under lucifuge condition.

This prescription prepares 1000ml by the inventive method, total 12min consuming time (wherein ultrasonic 8min), and products obtained therefrom is clear and bright yellow oily liquid.

Embodiment 2

Prescription forms:

Composition	Consumption
		Nitrofural	20g
Ethanol	2500ml
		Glycerol	About 7500ml
Full dose	10000ml

Preparation method: take nitrofural 20g, accurately weighed, proceed in the glass jar of tool plug, add 2500ml ethanol mix homogeneously and be placed in ultrasonic cleaner, ultrasonic dissolution assisting 5min.Period, successively the 1000ml beaker filling recipe quantity glycerol is put into microwave oven, heat 70s with high fire (microwave output power 700W, microwave frequency 2450Hz) and make its temperature reach 70 DEG C-75 DEG C.Under ultrasound condition, slowly hot glycerol is added in glass jar, continues ultrasonic 40min, period bath temperature be arranged on 60 DEG C, until nitrofural all dissolve clear and bright after, record the ultrasonic time.Add glycerol to full dose 10000ml (namely altogether adding about 7500ml glycerol), agitation as appropriate is even, to obtain final product.Said process carries out under lucifuge condition.

This prescription prepares 10000ml by the inventive method, total 53min consuming time (wherein ultrasonic 45min), and products obtained therefrom is clear and bright yellow oily liquid.

Embodiment 3

As optimal way step 1 of the present invention) in, take after recipe quantity nitrofural adds glass container, in described glass container, add compound recipe.Compound recipe described in the present embodiment is the mixture of SHUANGHUANLIAN, andrographolide, and its ratio as in the table below.

Compound recipe nitrofural [Dan has the plurality of advantages that common nitrofural [Dan does not have, and prove through subsequent experimental of the present invention, the stability adding gained preparation of compound recipe, curative effect are obviously better than the preparation of traditional method.

The present embodiment discloses a kind of prescription composition, i.e. compound recipe nitrofural [Dan, this prescription, except principal agent nitrofural, also add the Chinese medicine compound such as SHUANGHUANLIAN and andrographolide composition, and these compositions have definite meaning to the curative effect, prevention of recurrence etc. that improve nitrofural [Dan.

Composition	Consumption
		Nitrofural	20g
SHUANGHUANLIAN	150g
		Andrographolide	100g
Ethanol	2500ml
		Glycerol	About 7460ml
Full dose	10000ml

Preparation method: take nitrofural and be about 20g, SHUANGHUANGLIAN FENZHENJI 150g and andrographolide 100g (SHUANGHUANGLIAN FENZHENJI that the present embodiment adopts and andrographolide are commercially available, wherein, shuanghuanglian powder injection is the pure Chinese medicinal preparation used for intravenous injection obtained by Flos Lonicerae, Radix Scutellariae, Fructus Forsythiae extract, andrographolide is white crystals, system for raw material, take water-ethanol as the solid that Extraction solvent obtains with the Folium Andrographis medical material of drying).

Nitrofural, SHUANGHUANGLIAN FENZHENJI and andrographolide are proceeded in the glass jar of tool plug, add 2500ml ethanol mix homogeneously and be placed in ultrasonic cleaner, ultrasonic dissolution assisting 10min.Period, successively the 1000ml beaker filling recipe quantity glycerol is put into microwave oven, heat 70s with high fire (microwave output power 700W, microwave frequency 2450Hz) and make its temperature reach 70 DEG C-75 DEG C.Under ultrasound condition, slowly hot glycerol is added in glass jar, continues ultrasonic 45min, period bath temperature be arranged on 60 DEG C, until nitrofural, SHUANGHUANLIAN and andrographolide all dissolve clear and bright after, record the ultrasonic time.Add glycerol to full dose 10000ml, agitation as appropriate is even, to obtain final product.Said process carries out under lucifuge condition.

This prescription prepares 10000ml by the inventive method, total 60min consuming time (wherein ultrasonic 55min), and products obtained therefrom is clear and bright pale yellowish oil liquid, and getting its portion markings is sample 1, so that subsequent analysis.

Get the product that part obtains by method disclosed in embodiment 2, be labeled as sample 2.

Prepare nitrofural [Dan by the preparation method of " Chinese Hospitals preparation specification " and the formula of the present embodiment, be labeled as sample 3.

Prepare compound recipe nitrofural [Dan by the preparation method of " Chinese Hospitals preparation specification " and the formula of the present embodiment, be about to single nitrofural in " Chinese Hospitals preparation specification " and replace to the mixture of nitrofural, SHUANGHUANGLIAN FENZHENJI and andrographolide composition.Gained compound recipe nitrofural [Dan is labeled as sample 4.

1) stable content is investigated:

Choose sample 1 ~ 4 carry out first month, 12 months and 24 months time nitrofural assay, result is as follows:

The above results shows, sample 1 and 2 has similar stability.And sample 3 and 4 is difficult to long-term preservation.Particularly for compound preparation, to use conventional methods after preparation because of its poor stability, be difficult to the effect playing compound recipe.

Meanwhile, above-mentioned experiment shows no matter this method prepares nitrofural [Dan or compound recipe nitrofural [Dan, all can obtain good stability.

2) macroscopical character study on the stability:

The sample 1 prepared by the inventive method and sample 4, be yellow clear and bright oily liquids, without macroscopic muddiness and crystallization at the beginning of preparation.But the color of sample 4 is yellow oily liquid, be deeper than the color of sample 1, and have a small amount of precipitation.

After storage December, macroscopic crystallizations existing a large amount of in sample 4, and sample 1 has no the phenomenon such as crystallization and muddiness.

3) pharmacodynamic analysis

Clinical observation on the therapeutic effect:

Patient 1, man, and at the age 10, acute suppurative otitis media, otalgia, suppurates, adopt nitrofural [Dan (i.e. sample 3) prepared by the inventive method, ear is bathed, each 2 ~ 3, every day 3 times, two days later, otalgia, symptom of suppurating are alleviated to some extent, continue use three days, recovery from illness.

Patient 2, female, the age 43, chronic otitis media, otalgia, tinnitus, throughout the year with a small amount of yellow sticky discharge, prolonged do not heal (symptom comparatively patient 1 is serious).Adopt compound recipe nitrofural [Dan (i.e. sample 4) prepared by the inventive method, ear is bathed, and each 2 ~ 3, every day 3 times, after three days, all symptoms are alleviated to some extent, continues use one week, recovery from illness.

Animal experiment:

Adopt rat acute suppurative otitis media model, observe the situation after using the inventive method compound recipe nitrofural [Dan.

Model production method: by rat anesthesia, then inject streptococcus pneumoniae bacteria suspension to tympanum, wherein 1 ~ 4 day is acute infection period, tympanum is congested, and have a large amount of pus secretions, infection in 5 ~ 7 days is faded, within 7 days, later for infecting the later stage, symptom disappears substantially, and minority still has a small amount of secretions.

Change with observation post administration tympanum and tympanum: after modeling success, uses compound recipe nitrofural [Dan (experimental group uses sample 4) in acute infection period, and the normal saline adopting equivalent as a control group.Observe and find, matched group is seriously congested at acute infection period tympanum, has faint yellow to yellow pus secretions in tympanum; And the congested situation of experimental group is obviously comparatively light, pus secretory volume is less.Matched group after 14 days congested and pus disappears substantially; And experimental group in medication two days later, above-mentioned situation takes a turn for the better completely.

By above-mentioned test, demonstrating adding of SHUANGHUANLIAN can the effect of the scorching especially chronic otitis media of prevention of otitis media or auditory meatus or the recurrence of auditory meatus inflammation, can strengthen therapeutic effect with nitrofural coupling; Andrographolide has the pharmacological effect such as antibacterium and dermatophytes, antiviral, antiallergic action, adding of andrographolide has synergism to the antibacterial effect of nitrofural [Dan, the two is with nitrofural use in conjunction, can strengthen the effect to otitis media especially chronic sympton, and the stability of medicine is better.

Embodiment 4:

Prepare three batches of nitrofural [Dan preparations respectively by the method disclosed in embodiment 1 and formula, be labeled as sample 1, sample 2 and sample 3 respectively.

As a comparison, adopt traditional method, by the formula of embodiment 2, prepare nitrofural [Dan 10000ml, total 390min consuming time, products obtained therefrom is yellow oily liquid, is labeled as sample 4.

1) assay:

Precision measures the nitrofural [Dan 5.00ml in sample 1, is placed in 50ml measuring bottle, is diluted with water to scale, shake up.Precision measures diluent 2.00ml, is placed in 50ml measuring bottle, is diluted with water to scale, shake up, and according to ultraviolet visible spectrophotometry, measures absorbance, obtain ultraviolet detection collection of illustrative plates shown in accompanying drawing 1 at 375nm wavelength place.

Precision measures the nitrofural [Dan 5.00ml in sample 4, is placed in 50ml measuring bottle, is diluted with water to scale, shake up.Precision measures diluent 2.00ml, is placed in 50ml measuring bottle, is diluted with water to scale, shake up, and according to ultraviolet visible spectrophotometry, measures absorbance, obtain ultraviolet detection collection of illustrative plates shown in accompanying drawing 2 at 375nm wavelength place.

2) stable content is investigated:

Choose sample 1 ~ 4 carry out first month, 12 months and 24 months time nitrofural assay, result is as follows:

3) macroscopical character study on the stability:

The sample 1 ~ 3 prepared by the inventive method, with the sample 4 obtained by traditional method, is yellow clear and bright oily liquids, without macroscopic muddiness and crystallization at the beginning of preparation.But the color of sample 4 is yellow oily liquid, is slightly deeper than the color of sample 1 ~ 3, cause the reason of this phenomenon may be that traditional preparation methods is easily produced catabolite by illumination, oxygen molecule and metal ion catalysis and causes color burn.

After storage December, macroscopic crystallizations existing a large amount of in sample 4, and sample 1 ~ 3 has no the phenomenon such as crystallization and muddiness.Namely the product stability obtained by microwave-ultrasonic method is apparently higher than traditional preparation methods gained, and color is slightly shallow and more clarify.

4) microcosmic property stability is observed:

Choose sample 1 respectively and sample 4 is representative, under microscope (400 ×) carry out first month, the 6th month, the 12 month and the 24 month time microcosmic property stability observe.

See accompanying drawing 3 ~ 10, (Fig. 3 is sample 1 first month observed result, Fig. 4 is sample 4 first month observed result, Fig. 5 is sample 1 six month observed result, Fig. 6 is sample 4 six month observed result, Fig. 7 is sample 1 the 12 month observed result, Fig. 8 is sample 4 the 12 month observed result, and Fig. 9 is sample 1 the 24 month observed result, and Figure 10 is sample 4 the 24 month observed result):

Can be observed from Fig. 3,4, two kinds of preparation methoies are showed no crystallization at the beginning of preparation.

Can be observed from Fig. 5,6, store under the same conditions after six months, though all without the visible crystallization of naked eyes, under amplification 400 × condition, traditional preparation methods has a small amount of crystallization, and no matter microwave-ultrasonic method is showed no crystallization under perusal or microscope.

Can be observed from Fig. 7,8, store after 12 months under the same conditions, traditional preparation methods has a large amount of macroscopic yellow crystal and separates out.And microwave-ultrasonic method is without macroscopic crystallization, and also there are no crystallization under amplification 400 × condition.

Can be observed from Fig. 9,10, store after 24 months under the same conditions, the crystallization quantity that traditional preparation methods is separated out increases further, and volume increases further, and crystallization color gradually becomes yellowish-brown.And microwave-ultrasonic method is still without macroscopic crystallization, and have not yet to see crystallization under amplification 400 × condition.

According to the relevant regulations of " Chinese Hospitals preparation specification ", the effect duration of nitrofural [Dan is 12 months, and nitrofural [Dan prepared by the present invention is at interim the stable of outward appearance and content that keep of the reserved sample observing reaching 24 months always, reach the relevant regulations about external preparation in " Chinese Pharmacopoeia " completely.Invention increases the shelf index of nitrofural [Dan, make the suitability for industrialized production of this medicine become possibility.

Claims (6)

1. contain a Chinese patent medicine [Dan preparation for SHUANGHUANLIAN and andrographolide, it is characterized in that, comprise the following steps:

1) taking recipe quantity nitrofural adds in glass container, in described glass container, add recipe quantity ethanol; Compound recipe is added in described glass container; Described compound recipe is the mixture of SHUANGHUANLIAN, andrographolide;

2) add water in the rinse bath of ultrasonic cleaner, the described glass container filling nitrofural and ethanol is put into rinse bath;

3) setting up procedure 2) described in ultrasonic cleaner, ultrasonic dissolution assisting at least 2 minutes; Meanwhile, the beaker filling glycerol is put into microwave oven, by the glycerol microwave heating to 70 in described beaker DEG C ~ 75 DEG C;

4) water in the rinse bath of described ultrasonic cleaner is heated to 60 DEG C, the glycerol through step 3) process is joined in the glass container filling nitrofural and ethanol, namely obtain nitrofural [Dan preparation.

2. a kind of Chinese patent medicine [Dan preparation containing SHUANGHUANLIAN and andrographolide according to claim 1, it is characterized in that: in step 1), described glass container is the brown glass tank with stopper.

3. a kind of Chinese patent medicine [Dan preparation containing SHUANGHUANLIAN and andrographolide according to claim 2, it is characterized in that: in step 4), joined by glycerol in the process of tool plug brown glass tank, described ultrasonic cleaner does not cut out.

4. a kind of Chinese patent medicine [Dan preparation containing SHUANGHUANLIAN and andrographolide according to claim 3, it is characterized in that: in step 4), glycerol is slowly joined in brown glass tank, until nitrofural all dissolve clear and bright after, glycerol remaining in beaker is all joined in brown glass tank, after stirring or jolting make solution mix homogeneously, cover stopper, keep in Dark Place.

5. a kind of Chinese patent medicine [Dan preparation containing SHUANGHUANLIAN and andrographolide according to 1 ~ 4 any one claim, is characterized in that: in step 1), takes after recipe quantity nitrofural adds glass container, in described glass container, adds compound recipe.

6. a kind of Chinese patent medicine [Dan preparation containing SHUANGHUANLIAN and andrographolide according to 1 ~ 4 any one claim, is characterized in that: step 1 ~ 4 are carried out under lucifuge condition.