A kind of asarone inhalation aerosol and preparation method thereof
Technical field
The invention belongs to medical technical field, more specifically relate to a kind of alpha-ararin inhalation aerosol and preparation method thereof.
Technical background
Asarone (Asarone) has another name called α asarone or α-asaricin, chemical name 2,4,5-trimethoxy-1-propenylbenzene, be the Chinese medicine Rhizoma Acori Graminei mainly contain one of effective constituent.From the sixties; Asarone had both been carried out extensive studies both at home and abroad; Confirmed that it has very strong pharmacologically active; Tool calmness, cough-relieving, eliminate the phlegm, relieving asthma, spasmolytic and anticonvulsant action, Diplococcus pneumoniae, staphylococcus aureus and colibacillary growth are also had inhibitory action in various degree.Be mainly used in the treatment of bronchial asthma, chronic bronchitis, pneumonia and chronic obstructive pulmonary disease companion pulmonary acute inflammation etc. clinically.
According to investigations; Have 3,500 ten thousand above asthmatic patients at least in China; But the asthmatic patient that has only less than 5% was accepted normalized treatment; Prevent and treat situation in conjunction with China's asthma, member of Chinese Academy of Engineering, the president of Chinese Medical Association, respiratory disease credit meeting fame General Board understand Zhong Nanshan and point out at " world's the Asthma Day " eve: though asthma can not be effected a radical cure, implement " three steps " with disease assessment, disease treatment and the disease surveillance that is controlled to be purpose; Particularly use the combined treatment that confirms through global evidence-based medicine EBM, asthma can be controlled.In China, the key of control asthma is actively to encourage the patient to seek regular therapeutic scheme.New treating asthma guide is stressed anapnotherapy: it is high to suck the bronchus local drug concentration, and systemic adverse reactions is few, progressively makes the bronchial mucosa allergic inflammation controlled, from but asthma obtains lasting and even lifelong control.
Asarone is the synthetic antiinflammatory expelling phlegm for arresting cough antiasthmatics of domestic unique Chinese medicine monomer, and more obvious than the cough-relieving Zhichuan effect of pure Chinese medicinal preparation, it is better to compare therapeutic effect in the Western medicine prepn of chemosynthesis, and does not have any toxicity, side effect.
Nineteen eighty-two Liuzhou pharmaceutical factory first at home manual work successfully synthesize alpha-ararin, have tablet, capsule and injection to go through to put on market subsequently.The asarone tablets and the capsule that go on the market at present, because its water solublity extreme difference, oral back is difficult for disperseing stripping, and effective ratio area is little when contacting with body fluid, and for example the common oral preparation bioavailability is merely 2~5%, can't realize desired therapeutic effect at all; And the Asarone injection liquid that uses in clinical adopts cosolvent hydrotropies such as tween, PEG400, ethanol usually, and clinical use can produce a lot of side effect, like haemolysis, allergy etc.
Aerosol (aerosol) is contained in medicinal substances extract or fine drug powder and suitable propellant in the withstand voltage tight envelope container with special valve system, and the pressure by propellant during use makes the preparation of content with fine mist or the ejection of other forms.Be divided into inhalation aerosol (inhalation aerosol) by route of administration: refer to that the time spent is content the aerosol of vaporific ejection and suction pulmonary.Inhalation aerosol also can be divided into unit dose package or multiple-unit container.2) non-inhalation aerosol: the time spent directly is sprayed onto the aerosol of tract mucosa (oral cavity, nasal cavity, vagina etc.).(3) aerosol for external use: be meant the aerosol that is used for skin and space disinfection
Inhalation aerosol has the irreplaceable advantage of other dosage forms, in clinical treatment, occupies certain status.The advantage of aerosol mainly comprises: 1. have quick-acting and positioning action, can make drug particle directly get into pulmonary like the aerosol of treatment asthma, sucking 2min can produce effects; 2. it is aseptic that medicine is enclosed within the internal energy maintenance medicine cleaning of container, because container is light tight, directly do not contact in moisture with airborne oxygen, therefore increased stability of drug; 3. medicine absorbs through pulmonary and can avoid gastrointestinal to destroy the regulating liver-QI first pass effect; 4. anapnotherapy is the gold therapy of asthma and chronic obstructive pulmonary disease; 5. use quantitative valve can accurately control dosage; 6. easy to use.
Though aerosol has above-mentioned advantage, to the indissoluble characteristics of different principal agent asarone, and select difficulty such as proper supplementary material, still there is not the good asarone inhalation aerosol of effect product in the market.
The research starting of China on inhalation aerosol is late, and the market of most domestic is all captured by foreign medicine at present.The homemade aerosol of China use mostly as dichlorodifluoromethan hydro carbons (claiming freon again) as propellant, it is low, easy to control that this type propellant has a boiling point; Stable in properties, nonflammable, tasteless; Basic odorless, toxicity is less, and is water insoluble; Can make the advantages such as solvent of fat-soluble medicine, be ideal medicinal propellant.But owing to the destruction of fluorochloroparaffins to atmospheric ozone layer, WHO has required to stop using.China has confirmed that it is time of inessential purposes to be December in 2015 31 days that aerosol uses with the dichlorodifluoromethan hydro carbons.
Its character of ejecting agent hydrofluoroalkane (HFA), boiling point and low boiling freon are similar, but its chemical stability is relatively poor, and polarity is littler.And because HFA and freon difference aspect physicochemical property is very remarkable, traditional freon preparation technique can not simply be transplanted dosage form to HFA.
Though it is stable that Hydrocarbon is made propellant, toxicity is little, and density is low, and boiling point is lower, and is inflammable, explosive, should not use separately.
Compressed Gas such as carbon dioxide, nitrogen and nitric oxide etc., do not react with medicine though its chemical property is stable as propellant, do not burn.But the boiling point after the liquefaction is very low, and vapour pressure is too high during room temperature, to having relatively high expectations of container withstand voltage properties.In aerosol basically need not, and be used for spray.
Summary of the invention
The present invention is directed to above-mentioned existing problems, a kind of new administering mode alpha-ararin aerosol is provided, it has good stability, and toxic and side effects is little, uses convenient carrying, can pass through the direct pulmonary administration of respiratory tract.
The technical scheme that realizes above-mentioned purpose is following:
A kind of alpha-ararin inhalation aerosol, it is made up of the raw material of following weight parts:
Said propellant is 1,1,1,2 ,-tetrafluoroethane (HFA-134a) or 1,1,1,2,3,3,3-heptafluoro-propane (HFA-227).
Preferably, the weight portion of above-mentioned alpha-ararin is 0.5-1.5 part, and the weight portion of said propellant is 8.5-10 part.
Another object of the present invention is the method for preparing that has been to provide a kind of above-mentioned alpha-ararin inhalation aerosol, and this method for preparing is simple, and is easy to operate.
In order to realize above-mentioned purpose, the present invention adopts following technical measures:
A kind of method for preparing of above-mentioned asarone inhalation aerosol, its step comprises:
A, cosolvent, correctives, antioxidant, antibacterial are mixed or mix to dissolving;
B, alpha-ararin is directly added pressure vessel, or add in the pressure vessel together with the solution among the A;
C, the pressure vessel that contains medicine of gained in the B step is plugged in valve, envelope valve, propellant fill, both.
Preferably, said cosolvent is wherein a kind of of ethanol, propylene glycol or their mixing.
Said correctives is wherein a kind of of Folium Stevlae Rebaudianae, citric acid, cyclamate, sucralose, xylitol, fructose, Oleum Cinnamomi, oleum Citri sinensis, menthol, flavoring orange essence, Fructus Citri Limoniae volatile oil or their mixture.
Said antioxidant is wherein a kind of of two fourth cresols, Butylated hydroxyanisole or their mixture.
Said antibacterial is wherein a kind of of benzyl alcohol, methyl hydroxybenzoate, ethyl hydroxybenzoate or their mixture
The present invention compares with prior art and has the following advantages:
1) said alpha-ararin inhalation aerosol good stability, dosage is accurate, uses simply, and is easy to carry, patient's better tolerance.It can arrive patient pulmonary rapidly through the direct administration of pulmonary, has avoided first pass effect, has reduced side effect, and local concentration is high, and medicine can better be played a role in vivo.
2) said alpha-ararin inhalation aerosol adopts the pressure vessel aluminium pot, keeps in Dark Place, and stability of drug is improved greatly.Oral relatively and injection asarone, this product carries simply, and is easy to use.
3) experience of passing through inventor's accumulation is tested with a large amount of; Select only propellant and relevant proportioning; Said alpha-ararin inhalation aerosol can not need other adjuvants such as cosolvent, and good stability, can reduce toxic and side effects and make method for preparing more simple and reliable.
Figure of description
Fig. 1 is the high-efficient liquid phase chromatogram of alpha-ararin raw material;
Fig. 2 is the described asarone inhalation aerosol high-efficient liquid phase chromatogram of embodiment 7;
Fig. 3 is the UV scanning collection of illustrative plates of embodiment 2 described asarone inhalation aerosol.
The specific embodiment
Below further set forth asarone inhalation aerosol according to the invention through embodiment.
Embodiment 1:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight crude drug:
The method for preparing of above-mentioned asarone inhalation aerosol the steps include:
A, claim that citric acid, two fourth cresols, methyl hydroxybenzoate join in the ethanol, are stirred to dissolving by weight;
B, the asarone in will filling a prescription add in the pressure vessel, and add the solution of A step;
C, the pressure vessel that contains medicine of gained in the B step is loaded onto valve and tightened, be pressed into HFA-134a, both.
Embodiment 2:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Raw material weight (g)
Alpha-ararin 0.01
HFA-134a 10。
The method for preparing of said asarone inhalation aerosol the steps include:
A, the asarone in will filling a prescription add in the pressure vessel;
B, valve is loaded onto and tightened, be pressed into HFA-134a, both.
Embodiment 3:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight parts raw material:
Its preparation process is identical with embodiment 1.
Embodiment 4:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Its preparation process is identical with embodiment 1.
Embodiment 5:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Its preparation process is identical with embodiment 1.
Embodiment 6:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Its preparation process is identical with embodiment 1.
Embodiment 7:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Raw material weight (g)
Alpha-ararin 0.5
HFA-134a 10。
Its preparation process is identical with embodiment 2.
Embodiment 8:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Its preparation process is identical with embodiment 1.
Embodiment 9:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Its preparation process is identical with embodiment 1.
Embodiment 10:
The said suction asarone of present embodiment inhalation aerosol, it is processed by the following weight raw material:
Its preparation process is identical with embodiment 1.
Embodiment 11: stability study
The proportioning of the described asarone inhalation aerosol of the foregoing description 1-10 the stability test of 100 days room temperature, asarone having good stability in HFA-134a have been carried out.
By prescription preparation asarone aerosol, the asarone aerosol that makes was kept in Dark Place 100 days at normal temperatures.
Outward appearance is observed: aerosol is placed under the light examine.
HPLC
Chromatographic condition and system suitability test: C
18Post (250mm * 4.6mm, 5 μ m); Mobile phase: methanol-water (70: 30); Flow velocity 1.0mlmin-1; Detect wavelength: 258nm; Sample size: 20 μ l.
The preparation of reference substance solution: it is an amount of to get the asarone crude drug, and accurate the title decides, and does dissolution with solvents with methanol.Be transferred in the 100ml volumetric flask and be diluted to scale, shake up, be reference substance solution with methanol.
The preparation of need testing solution: in beaker, pour a certain amount of methanol into as lyosoption, aerosol is upside down in the beaker, methanol is flooded about aerosol 5CM, tube squeezing valve sprays medicine for several times downwards.Methanol in the beaker is transferred to the 100ml volumetric flask, is diluted to scale, shake up, be need testing solution with methanol.
Ultraviolet spectrophotometry
The ultra-violet absorption spectrum of asarone crude drug: get asarone crude drug 20mg, the accurate title, decide, and does dissolution with solvents with methanol.Be transferred in the 100ml volumetric flask and be diluted to scale, shake up, the dilution several times with methanol.Do blank with methanol, UV scanning at wavelength 200-400nm place.
The asarone aerosol is placed 100 days ultra-violet absorption spectrums: in beaker, pour a certain amount of methanol into, aerosol is upside down in the beaker, methanol is flooded about aerosol 5CM, tube squeezing valve sprays medicine for several times downwards.Methanol in the beaker is transferred to the 100ml volumetric flask, is diluted to scale, shake up, be need testing solution with methanol.Same method with not containing the asarone principal agent, has only the aerosol of adjuvant to make blank, the UV scanning at wavelength 200-400nm place.
Outward appearance: the described asarone inhalation aerosol of embodiment 1-10 solution keeps clear always.
According to HPLC: as depicted in figs. 1 and 2, crude drug is consistent with the crest of embodiments of the invention 7 described asarone inhalation aerosol HPLC, and appearance time is consistent, does not have new impurity peaks to produce.
The high-efficient liquid phase chromatogram of other embodiment is consistent with Fig. 1 Fig. 2, all representes to have good stability.
The UV scanning collection of illustrative plates of embodiment 2 described asarone inhalation aerosol is as shown in Figure 3, at 258nm and 313nm place maximum absorption wavelength is arranged, and waveform is identical.The UV scanning collection of illustrative plates of the described asarone inhalation aerosol of other embodiment similarly, the Therefore, omited.
Embodiment 12: content detection
Press shown in the table 1 preparation A, two bottles of aerosols of B.In beaker, pour a certain amount of methanol into, aerosol is upside down in the beaker, methanol is flooded about aerosol 5CM, tube squeezing valve sprays medicine downwards.Spray altogether 10 times.Methanol in the beaker is transferred to the 100ml volumetric flask, is diluted to scale, shake up with methanol.Therefrom get 200 μ l to 10ml volumetric flasks, be diluted to scale, shake up, get again and be need testing solution, do blank with methanol with methanol.According to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2010 A), measure trap respectively in the wavelength of 313nm, calculate, promptly get; Medicine was kept in Dark Place 100 days at normal temperatures, measure its every spray medicament contg with method.
Table 1
A, two different prescriptions of B, after placing 100 days, their every spray medicament contg does not have to change (minor variations is because each ejection dose should be in a scope) basically, has explained that medicine has chemical stability in this propellant.
Embodiment 13: the aerosol characteristic research
Every spray medicament contg: in beaker, pour a certain amount of methanol into, aerosol is upside down in the beaker, methanol is flooded about aerosol 5CM, tube squeezing valve sprays medicine downwards.Spray altogether 10 times.Methanol in the beaker is transferred to the 100ml volumetric flask, is diluted to scale, shake up with methanol.Therefrom get 250 μ l to 10ml volumetric flasks, be diluted to scale, shake up, get again and be need testing solution, do blank with methanol with methanol.According to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2010 A), measure trap respectively in the wavelength of 313nm, calculate, promptly get.
Lung deposition (droplet distribution): press 2010 editions second appendix X H of Chinese Pharmacopoeia, detect droplet and distribute
The composition of said asarone inhalation aerosol: asarone 1g, propellant 10g.
Every spray labelled amount is: 5.602mg
Table 2
|
Medicine heavy (g) |
Propellant (g) |
Every spray medicament contg (mg) |
Account for labelled amount percentage ratio |
The lung deposition |
?1 |
0.9939 |
10.17 |
5.720 |
102.11% |
17.28% |
?2 |
0.9941 |
10.38 |
5.540 |
98.94% |
21.34% |
?3 |
0.9916 |
10.3 |
5.550 |
98.17% |
20.19% |
Description of the aerosol drug content per Chin Shih stable, in line with the pharmacopoeia requirements (accounting for 80-120% of the labeled amount); distribution of fog particles reach their pharmacopoeia requirements for inhalation aerosol (greater than 15%).
More than be to the specifying of possible embodiments of the present invention, but this embodiment is not in order to limiting claim of the present invention, does not allly break away from the equivalence that skill spirit of the present invention does and implement or change, all should be contained in the claim of the present invention.