CN102626386B - Bacilli calmette-gurin polysaccharide nucleic acid inhalation aerosol and preparation method and application thereof - Google Patents
Bacilli calmette-gurin polysaccharide nucleic acid inhalation aerosol and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a bacilli calmette-gurin polysaccharide nucleic acid inhalation aerosol and a preparation method and an application thereof. The aerosol consists of bacilli calmette-gurin polysaccharide nucleic acid, a propellant, a cosolvent, a surfactant and a preservative, wherein the propellant is prepared from 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane. The aerosol is prepared with a pressure filling method or a cover filling method and the like; and an aerosol tank is provided with a quantifying valve which can be used for quantitatively releasing a medicament. Due to the adoption of the bacilli calmette-gurin polysaccharide nucleic acid inhalation aerosol provided by the invention, the bacilli calmette-gurin polysaccharide nucleic acid can be directly distributed into nasal cavities, trachea, bronchus and lungs, and is taken as a medicament for treating allergic asthma/or allergic rhinitis.
Description
Technical field
The invention belongs to technical field of medicine, in particular, relate to a kind of metered dose inhalation aerosol, Preparation method and use of BCG vaccine polysaccharide nucleic acid.
Background technology
Aerosol means containing drug solns, emulsion or suspension and suitable propellant and is jointly loaded in the pressure vessel with special valve system, content is spray ejection by pressure by propellant when use, sucks or be directly sprayed onto the preparation of tract mucosa, skin and space disinfection for pulmonary.Can be divided into inhalation aerosol, non-inhalation aerosol and aerosol for external use by route of administration; Can be divided into two-phase aerosol (gas phase and liquid phase) and three-phase aerosol (gas phase, liquid phase, solid phase or liquid phase) by prescription composition; By administration quantitatively whether, can be divided into quantitative aerosol and non-quantitation aerosol, referring to 2010 editions second annex I L of Chinese Pharmacopoeia.
Inhalation aerosol preparation is a kind of by the preparation of respiratory tract administration approach, make medicine can be penetrated into pulmonary and be deposited on the regions such as respiratory tract, there is quick-acting, target spot administration, avoid gastrointestinal tract and liver first-pass effect, the advantage such as side effect is little, dosage is little, gain international recognition.
Bcg-polysaccharides nucleic acid (BCG-polysaccharide nucleic acid, BCG-PSN) be by bacill calmette-guerin bacterial cell disruption, hot phenol processing, the refining polysaccharide forming of warp and the mixture of nucleic acid, for the immunologic active material in bacill calmette-guerin, there is immunomodulating and antiinflammatory action.Think at present Th1/Th2 unbalance be the key that causes cellular immune abnormality, also be to cause immunologic hypofunction, autoimmune disease and allergic main cause, Th1/Th2 cell is one of important Immunological Pathogenesis of bronchial asthma at the proportional imbalance of number, activation degree and function aspects.Research over nearly 10 years shows, the Th1 type cell immune response that BCG-PSN can specificity enhancing body, suppresses Th2 type cell immune response, and then maintain balance between the two; Can directly regulate peripheral blood, peripheral immune organ (spleen) and central immune organ (thymus) CD4
+t, CD4
+cD8
+the maturation of T cell and differentiation, and then maintain CD4
+t, CD8
+balance between T cell two subgroups, makes low immunologic function be recovered normal; Can increase the expression of IL-2 on T cell and splenocyte film, promote T cell clone propagation and T cell colony to form, can also increase the secretion of activating T cell IFN-γ, strengthen macrophage function, and then regulate immunity of organism level, treatment.In addition, the antiinflammatory action of BCG-PSN is relevant with NF-B approach, BCG-PSN shows as dual regulation to the impact of NF-kB, as IL-2 β, activate on the one hand person monocytic cell NF-kB, the latter's promoter sequence special with it combines, and on the other hand, again can the activation of anti-il-i-beta short of money to NF-B, referring to the peaceful Yunshan Mountain, Jiang Dejian, Liu Shanshan. the immunoregulation effect of bacillus calmette-guerin vaccine and BCG polysaccharide nucleic acid extractive and clinical practice. Products in China is learned magazine, 2008,21 (1): 74-77.Also studies have found that, BCG-PSN can stablize mastocyte, and sealing IgE function, reduces de-granular cell release of active agent, and have the bronchospasm effect due to anti-acetylcholine, reaches antiallergic and antiasthmatic effect.Therefore, BCG-PSN has good curative effect improving aspect immunologic function, antiallergic, antiinflammatory, clinically for panimmunity imbalance or immune level declines and the treatment of anaphylactic disease.
At present, existing BCG polyose nuclear acid injection is clinically for regulating immunity of organism level, the infection of enhancing body and antiallergic ability, the diseases such as treatment chronic bronchitis, asthma, irritated class disease (as allergic rhinitis, allergic asthma, allergic dermatitis, urticaria), chronic obstructive pulmonary disease (COPD).But injection also has its limitation, bcg-polysaccharides nucleic acid needs long-term prescription, and needs of patients is injected to hospital, medication inconvenience; Long-time medication, the easy ulcer in injection site, scleroma, infection etc., cause suffering to patient.CN1669557A (200410016932.1) provides BCG vaccine polysaccharide nucleic acid spray and preparation method thereof, be made up of BCG vaccine polysaccharide nucleic acid, biological adhesive, Chymotrypsin, flavoring agent and normal saline, spray directly acts on oral cavity and nasal mucosa immune system.CN101623304A (200910006080.0) provides a kind of pharmaceutical composition for nasal-cavity administration, comprise solid preparation powder and dry powder doses, liquid preparation spray, Emulsion, suspensoid and nasal drop, and semi-solid preparation gel, ointment.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of bcg-polysaccharides nucleic acid inhalation aerosol, more specifically say a kind of by oral cavity or nasal-cavity administration, can quantitatively suck the aerosol of bcg-polysaccharides nucleic acid, directly bcg-polysaccharides nucleic acid is distributed in to nasal cavity, trachea, bronchus, pulmonary, act on affected part, play treatment rhinitis and antiasthmatic effect.
The present invention also provides the Preparation method and use of bcg-polysaccharides nucleic acid aerosol.
Technical scheme of the present invention is as follows:
A kind of bcg-polysaccharides nucleic acid inhalation aerosol, is made up of bcg-polysaccharides nucleic acid, propellant, cosolvent, surfactant and antiseptic, and wherein, bcg-polysaccharides nucleic acid content is 0.02～0.90wt%; Propellant content is 60～99wt%; Cosolvent content is 0～30wt%; Surface-active contents is 1～10wt%; Antiseptic content is 0.01～0.25wt%; Each constituent content percentage by weight sum is 100%.
Described bcg-polysaccharides nucleic acid, first carry out lyophilization or vacuum dehydrating at lower temperature processing, make its water content be less than 1%, adopt again high energy ball mill or jet mill crushing technology to carry out micronization processes, make bcg-polysaccharides nucleic acid grain diameter that its micropowder particle size distribution is 100% within the scope of 0.05 μ m-15 μ m, wherein 99% bcg-polysaccharides nucleic acid grain diameter is within the scope of 0.1 μ m-5 μ m.Micronized bcg-polysaccharides nucleic acid is general cryopreservation before making suspension, as-10 DEG C of preservations.
Described propellant is one of HFA 134a (HFA134a), HFC-227ea (HFA227) or combination; The consumption of propellant is preferably 80～99wt%, more preferably 90～99wt%.
Described cosolvent is selected from one of propane, normal butane, iso-butane, pentane, isopentane, neopentane, dehydrated alcohol, propylene glycol, glycerol or combination; The consumption of cosolvent is preferably 5～10wt%.
Described surfactant is one of oleic acid, sorbitan trioleate, Span60, sorbitan monooleate, Polyethylene Glycol-300 or combination; The consumption of surfactant is preferably 1～3wt%.
Described antiseptic is methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, butoben, benzoic acid or sodium benzoate.The consumption of antiseptic is preferably 0.02～0.25wt%.
The above-mentioned bcg-polysaccharides nucleic acid inhalation aerosol according to the present invention, is preferably as follows:
Described bcg-polysaccharides nucleic acid, in above-mentioned formula, content is preferably 0.04～0.50wt%, more preferably 0.04～0.20wt%.
Described propellant is preferably HFA 134a (HFA 134a).
Described cosolvent is propane, normal butane, iso-butane, pentane, isopentane, neopentane, dehydrated alcohol, propylene glycol or glycerol.More preferably normal butane, iso-butane or dehydrated alcohol.
Described surfactant is preferably oleic acid, sorbitan trioleate, Span60, sorbitan monooleate or Polyethylene Glycol-300.More preferably oleic acid, sorbitan trioleate or Span60.
Described antiseptic is preferably ethyl hydroxybenzoate, propylparaben or butoben.More preferably ethyl hydroxybenzoate or propylparaben.
According to the present invention, the preparation method of described bcg-polysaccharides nucleic acid inhalation aerosol, adopts one of following pharmaceutically acceptable method: the lower fill method of cold filling, two step fill methods, the canned method of pressurizeing or lid.
Cold filling: according to recipe quantity, bcg-polysaccharides nucleic acid, surfactant, propellant, antiseptic are cooled to-30 DEG C and add below in same container, stir, suspendible is even, is filled in aerosol container, adds a cover and tightens.
Two step fill methods: according to recipe quantity, first, by bcg-polysaccharides nucleic acid, surfactant and cosolvent suspendible, add antiseptic, stir, suspendible is even, then gained suspension is filled in aerosol container, add a cover after compression, the valve by propellant on aerosol container is filled with in aerosol container.
One of the canned method of described pressurization is the following step:
The canned method 1 of pressurizeing (using pretreatment solvent): according to recipe quantity, surfactant is dissolved in to pretreatment solvent, add bcg-polysaccharides nucleic acid, stir, make surfactant disperse to be fully attached to the surface of bcg-polysaccharides nucleic acid micro powder granule, then pretreatment solvent is removed in decompression, gained residue transfers in pressure vessel, add propellant, antiseptic, suspendible is even, and the valve on aerosol container under pressure of the medicinal liquid in pressure vessel is charged in the aerosol container that presses lid.
The canned method 2 of pressurizeing (without pretreatment solvent): according to recipe quantity, below-30 DEG C, by even bcg-polysaccharides nucleic acid, surfactant, propellant suspendible in pressure vessel, add again antiseptic, suspendible, the medicinal liquid in pressure vessel under pressure on aerosol container valve be charged in aerosol container.
Under described lid, canned method one of is the following step:
The lower fill method 1 of lid (using pretreatment solvent): according to recipe quantity, by surfactant dissolves in pretreatment solvent, add bcg-polysaccharides nucleic acid, stir, make surfactant disperse to be fully attached to the surface of bcg-polysaccharides nucleic acid micro powder granule, then pretreatment solvent is removed in decompression, gained residue is transferred in pressure vessel, add again propellant, antiseptic, suspendible is even, liquid medicine filling in pressure vessel, to the aerosol container of evacuation, is added a cover to compress and is made aerosol.
The lower fill method 2 (without pretreatment solvent) of lid: according to recipe quantity, below-30 DEG C, by even bcg-polysaccharides nucleic acid, surfactant, propellant suspendible in pressure vessel, add again antiseptic, suspendible, liquid medicine filling in pressure vessel, to the aerosol container of evacuation, is added a cover and is compressed and make aerosol.
In above-mentioned preparation method, the preferably lower fill method of two step fill methods, the canned method of pressurizeing and lid.The canned method 1 of more preferably pressurizeing and the lower fill method 1 of lid.
In above-mentioned preparation technology, described pretreatment solvent is selected the one in butane, iso-butane, pentane, isopentane, neopentane.Pretreatment solvent is different from the effect of cosolvent in formula, and pretreatment solvent is mainly used in making surfactant to disperse fully and be attached to the surface of bcg-polysaccharides nucleic acid micro powder granule, is then removed, and does not contain pretreatment solvent in final product.While carrying out pretreatment sample with pretreatment solvent, under pressure, surfactant is dissolved in pretreatment solvent as Span60, add micronized bcg-polysaccharides nucleic acid, fully stir, make surfactant disperse fully and be attached to the surface of bcg-polysaccharides nucleic acid micro powder granule, then remove pretreatment solvent, the method for removing pretreatment solvent can adopt low-temperature vacuum drying, the pressure reducing and steaming solvent method such as cold drying again.Gained residue is the bcg-polysaccharides nucleic acid microgranule of surfactant parcel, has both increased the mobility of bcg-polysaccharides nucleic acid microgranule, has increased again the suspension of bcg-polysaccharides nucleic acid microgranule in propellant.
In above-mentioned preparation technology, aerosol container for fill bcg-polysaccharides nucleic acid inhalation aerosol need to be selected suitable aerosol valve, preferably release scope is the quantitative aerosol valve of 25 μ l～250 μ l, the more preferably quantitative aerosol valve of 50 μ l, 63 μ l and 100 μ l, most preferably the quantitative aerosol valve of 50 μ l and 100 μ l.
Bcg-polysaccharides nucleic acid is made after inhalation aerosol, sucked by oral cavity or nasal cavity, can directly bcg-polysaccharides nucleic acid be distributed in to nasal cavity, trachea, bronchus, pulmonary, absorb rapidly and play a role, be suitable for treatment of allergic rhinitis, allergic asthma.
The medical usage of bcg-polysaccharides nucleic acid inhalation aerosol of the present invention, for the preparation of the medicine for the treatment of allergic asthma and/or allergic rhinitis.To be furnished with the aerosol container fill of quantitative aerosol valve.Packaging process is by prior art.
The pharmacodynamic experiment of bcg-polysaccharides nucleic acid inhalation aerosol treatment allergic asthma of the present invention
Animal: 32 of Wistar male white rats, body weight 220～240g, is provided by Shandong University's Experimental Animal Center.
The foundation of Allergic Asthma in SD Rats model: reference literature method: Chi Lei etc. the foundation of Allergic Asthma in SD Rats model. Chongqing Medical, 2003,32 (4): 429-431.32 rats are divided into normal group, asthmatic model group, drug administration by injection group, inhalation group, every group of 8 rats.Latter three groups are done subcutaneous injection (every some 0.2ml), lumbar injection 0.2ml simultaneously with freshly prepared ovalbumin suspension (ovalbumin 1mg+ aluminium hydroxide 200mg+ normal saline 1ml) ditch, abdominal part, 5 positions of the both sides front foot sole of the foot as rat two flanks in the 1st day, the 8th day respectively at experiment.In the 15th day, rat is placed in to the hermetic container of 20cm × 20cm × 15cm size, carry out atomization suction with 1% ovalbumin and excite, each atomization 30 minutes, continuous 7 days.Normal rats is with equivalent physiologic saline for substitute ovalbumin, carries out same method, commensurability, same period above-mentioned same operation.
Medication: start on the same day administration from what carry out that atomization sucks that ovalbumin excites, often suck ovalbumin administration in first 30 minutes inferior to atomization.Drug administration by injection group: every day, lumbar injection gave BCG polyose nuclear acid injection 0.6ml/kg (containing bcg-polysaccharides nucleic acid 500 μ g/ml, Wanma Pharmaceutical Co., Ltd., Zhejiang produces), was equivalent to bcg-polysaccharides nucleic acid 0.3mg/kg.Inhalation group: reference literature fourth is vertical, the Zhang Jun longevity. the prescription screening of salbutamol sulfate/tetrafluoroethane aerosol and rats breathing road Absorption Study. China Medicine University's journal, 2009,40 (4): the medication of 332-336, adopt nasal intubation to spray into method, directly by extremely pharynx and trachea of drug conveying, the aerosol drug delivery that uses embodiment 1 to prepare, be administered once every day, dosage 0.288mg/kg.Normal group, asthmatic model group all adopt nasal intubation to spray into method, in the prescription that gives to prepare according to embodiment 1 except not containing all identical aerosols of other compositions bcg-polysaccharides nucleic acid.
Experimental result:
(1) whole animal is observed: asthmatic model group rat, and rapid breathing, the rhythm and pace of moving things is irregular, the breathing of nodding, mouth and nose cyanosis, is slow in action.Normal rats is without obvious above-mentioned performance.Drug administration by injection group, the above-mentioned performance of inhalation group are slight.
(2) bronchoalveolar lavage fluid inspection: bronchoalveolar lavage fluid (BALF) collection adopts literature method, Chi Lei etc., the foundation of Allergic Asthma in SD Rats model. Chongqing Medical, 2003,32 (4): 429-431.Analyze total white blood cells and eosinophilic granulocyte's sum in BALF, the results are shown in Table 1.With normal group comparison, asthmatic model group compared with normal group total white blood cells and eosinophilic granulocyte's sum have significance to raise, and show asthmatic model establishment; With the comparison of asthmatic model group, drug administration by injection group, inhalation group all have significance to reduce compared with asthmatic model group total white blood cells and eosinophilic granulocyte's sum, show that bcg-polysaccharides nucleic acid has good therapeutical effect to Brown-Norway rats with asthma; And total cellular score and eosinophilic granulocyte's sum there was no significant difference between drug administration by injection group, inhalation group illustrates that the therapeutical effect of drug administration by injection group and inhalation group is without showing property difference.
Inflammatory cell sum and eosinophilic granulocyte's sum in the each group of table 1 BALF of Rats
| Group | Rat quantity | Inflammatory cell sum (× 10 6/L) | Oxyphil cell's sum (× 10 5/L) |
| Normal group | 8 | 3.62±0.60 | 0.92±0.14 |
| Asthmatic model group | 8 | 11.37±0.79 ΔΔ | 10.72±1.31 ΔΔ |
| Drug administration by injection group | 8 | 5.25±0.84 ** | 2.08±0.38 ** |
| Inhalation group | 8 | 4.90±0.63 ** | 1.78±0.27 ** |
Note: with normal group comparison,
Δ Δp < 0.01; With the comparison of asthmatic model group,
*p < 0.01; Drug administration by injection group and inhalation group be P > 0.05 relatively
(3) mensuration of Cytokine of Serum IL-4 and IFN-γ: rat abdominal cavity aorta is got blood, centrifugal, gets upper serum, adopts ELISA method, according to test kit description, measures the content of Cytokine of Serum IL-4 and IFN-γ, the results are shown in Table 2.Asthmatic model group and normal group comparison, in asthmatic model group blood plasma, IL-4 concentration compared with normal group significantly raises, and IFN γ concentration significantly reduces, and shows asthmatic model establishment; With the comparison of asthmatic model group, in drug administration by injection group, inhalation group blood plasma, IL-4 concentration significantly reduces compared with asthmatic model group, and IFN-γ concentration significantly raises, and shows that bcg-polysaccharides nucleic acid has good therapeutical effect to Brown-Norway rats with asthma; And IL-4, IFN-γ concentration there was no significant difference between drug administration by injection group, inhalation group illustrate the therapeutical effect there was no significant difference of drug administration by injection group and inhalation group.
The mensuration of cytokine IL-4 and IFN-γ in the each group of table 2 rat blood serum
Note: with normal group comparison,
Δ Δp < 0.01; With the comparison of asthmatic model group,
*p < 0.01; Drug administration by injection group and the comparison of inhalation group, P > 0.05
Above-mentioned experimental result shows, bcg-polysaccharides nucleic acid inhalation aerosol of the present invention has good therapeutical effect to allergic asthma, similar to the therapeutical effect of BCG vaccine polysaccharide nucleic acid injection, there is the feature that medication is convenient, medicine goes directly focus simultaneously, therefore, BCG vaccine polysaccharide nucleic acid aerosol of the present invention is the medicine that is applicable to allergic asthma, allergic rhinitis.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described, but be not limited to this.Raw material, equipment used in embodiment are prior art, commercial product.
In embodiment, on bcg-polysaccharides nucleic acid inhalation aerosol aerosol container used, there is quantitative aerosol valve, can quantitatively discharge medicinal liquid.Micronized bcg-polysaccharides nucleic acid grain diameter 99% is distributed between 0.1～5 μ m, and moisture is less than 1%.
Embodiment 1: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, surfactant oleic acid 1.0g is dissolved in pretreatment solvent 15ml pentane, add again micronized bcg-polysaccharides nucleic acid 0.048g, stir 48 hours, pretreatment solvent pentane is removed in decompression, obtain residue, by this residue and propellant 1,1,1,2-tetrafluoroethane 100ml, antiseptic ethyl hydroxybenzoate 0.04g add in pressure vessel, suspendible is even, then the medicinal liquid in pressure vessel is filled with in the aerosol container that presses lid through valve under pressure, every tank 10ml, obtains 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 100 μ l, containing bcg-polysaccharides nucleic acid 48 μ g.Every bottle is always lifted number of times 100 times.
Click a medicine of spray and be called " lifting ", always lift number of times and refer to that every bottle of aerosol is from being sprayed onto the total degree spraying till medicine spray to the greatest extent for the 1st time, lower with.
Embodiment 2: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, by micronized bcg-polysaccharides nucleic acid 0.072g, surfactant sorbitan trioleate 1.5g, propellant 1,1,1,2,3,3,3-heptafluoro-propane 100ml, in-30 DEG C of pressure vessels, suspendible is even, then adds antiseptic methyl hydroxybenzoate 0.04g, suspendible, then the medicinal liquid in pressure vessel is filled with in the aerosol container that presses lid through valve under pressure, every tank adds medicinal liquid 10ml, obtains 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 7.2mg.Aerosol quantitative valve often lifts release 100 μ l, containing bcg-polysaccharides nucleic acid 72 μ g.Every bottle is always lifted number of times 100 times.
Embodiment 3: a kind of production method of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, surfactant sorbitan trioleate 1.0g is dissolved in cosolvent 8ml dehydrated alcohol, add again micronized bcg-polysaccharides nucleic acid 0.048g, stir 12 hours, in this solution, add propellant 1 again, 1,1,2-tetrafluoroethane 92ml, in-30 DEG C of pressure vessels, suspendible is even, then adds antiseptic propylparaben 0.04g, suspendible, then the medicinal liquid in pressure vessel is filled with in the aerosol container that presses lid through valve under pressure, every tank adds medicinal liquid 10ml, obtains 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 100 μ l, containing bcg-polysaccharides nucleic acid 48 μ g.Every bottle is always lifted number of times 100 times.
Embodiment 4: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, surfactant sorbitan monooleate 1.5g is dissolved in pretreatment solvent 20ml absolute ether, add again micronized bcg-polysaccharides nucleic acid 0.072g, stir 48 hours, pretreatment solvent absolute ether is removed in decompression, obtain residue, again by this residue and propellant 1,1,1,2-tetrafluoroethane 100ml, antiseptic propylparaben 0.04g add in pressure vessel, suspendible is even, then the medicinal liquid in pressure vessel is filled with in the aerosol container of evacuation, and every tank adds medicinal liquid 10ml, add a cover compression, obtain 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 7.2mg.Aerosol quantitative valve often lifts release 100 μ l, containing bcg-polysaccharides nucleic acid 72 μ g.Every bottle is always lifted number of times 100 times.
Embodiment 5: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, by micronized bcg-polysaccharides nucleic acid 0.048g, surfactant Span60 1.0g, propellant 1,1,1,2,3,3,3-heptafluoro-propane 100ml, in-30 DEG C of pressure vessels, suspendible is even, then add antiseptic butoben 0.05g, suspendible, is then filled with the medicinal liquid in pressure vessel in the aerosol container of evacuation, and every tank adds medicinal liquid 10ml, then add a cover compression, obtain 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 24 μ g.Every bottle is always lifted number of times 200 times.
Embodiment 6: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, surfactant sorbitan trioleate 1.5g is dissolved in cosolvent anhydrous propylene glycol 7ml, then adds micronized bcg-polysaccharides nucleic acid 0.072g, stir 12 hours, again by this solution and propellant 1,1,1,2-tetrafluoroethane 93ml, antiseptic propylparaben 0.05g add in pressure vessel, suspendible is even, then the medicinal liquid in pressure vessel is filled with in the aerosol container of evacuation, and every tank adds medicinal liquid 10ml, add a cover compression, obtain 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 7.2mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 36 μ g.Every bottle is always lifted number of times 200 times.
Embodiment 7: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, first, by micronized bcg-polysaccharides nucleic acid 0.048g, surfactant oleic acid 1.0g and cosolvent iso-butane 10ml suspendible, stir 24 hours, then add antiseptic butoben 0.05g, suspendible, then suspension equivalent filling is entered in 10 aerosol containers, add a cover after compression, successively each aerosol container is filled with to propellant 1 through valve respectively, 1,1,2-tetrafluoroethane 9ml, obtains 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 24 μ g.Every bottle is always lifted number of times 200 times.
Embodiment 8: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, first, by micronized bcg-polysaccharides nucleic acid 0.072g, surfactant sorbitan trioleate 1.5g and cosolvent normal butane 10ml suspendible, stir 24 hours, add antiseptic ethyl hydroxybenzoate 0.03g, suspendible, then enters suspension equivalent filling in 10 aerosol containers again, add a cover after compression, successively each aerosol container is filled with to propellant 1,1 through valve respectively, 1,2,3,3,3-heptafluoro-propane 9ml, obtains 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 7.2mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 36 μ g.Every bottle is always lifted number of times 200 times.
Embodiment 9: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, surfactant Span60 1.0g is dissolved in pretreatment solvent 15ml isopentane, then adds micronized bcg-polysaccharides nucleic acid 0.048g, to stir 48 hours, pretreatment solvent isopentane is removed in decompression, obtains residue.In this residue, add antiseptic ethyl hydroxybenzoate 0.03g, cooling under-30 DEG C of conditions, then add the propellant 1 of liquid condition, 1,1,2,3,3,3-heptafluoro-propane 100ml, stirs 12 hours, then suspension equivalent filling is entered in 10 aerosol containers, add a cover compression, obtain 10 bottles of aerosols.Every bottle of aerosol container loading amount is 10ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 100 μ l, containing bcg-polysaccharides nucleic acid 48 μ g.Every bottle is always lifted number of times 100 times.
Embodiment 10: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, micronized bcg-polysaccharides nucleic acid is added in cosolvent 2.5ml Polyethylene Glycol-300 to stirring and dissolving, under-30 DEG C of conditions by cooling this solution, then add the propellant 1,1,1 of liquid condition, 2-tetrafluoroethane 47.5ml, add antiseptic propylparaben 0.02g, stirring and evenly mixing, then enters its equivalent filling in 10 aerosol containers again, add a cover compression, obtain canned amount and be 10 bottles of the aerosols of 5ml.Every bottle of aerosol container loading amount is 5ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 48 μ g.Every bottle is always lifted number of times 100 times.
Embodiment 11: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, micronized bcg-polysaccharides nucleic acid 0.048g is dissolved in 3.0ml Polyethylene Glycol-300, then adds antiseptic methyl hydroxybenzoate 0.01g, stirring and dissolving, again by this solution and propellant 1,1,1,2-tetrafluoroethane 47ml, in-30 DEG C of pressure vessels, mix, then the medicinal liquid mixing is filled with in the aerosol container that presses lid through valve under pressure, every tank is filled with medicinal liquid 5ml, obtains 10 bottles of aerosols.Every bottle of aerosol container loading amount is 5ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 48 μ g.Every bottle is always lifted number of times 100 times.
Embodiment 12: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, micronized bcg-polysaccharides nucleic acid 0.048g is dissolved in 4ml Polyethylene Glycol-300, then adds preservative benzoic acid 0.12g, stirring and dissolving, then by this solution and propellant 1,1,1,2,3,3,3-heptafluoro-propane 46ml mixes in-30 DEG C of pressure vessels, then medicinal liquid is filled with in the aerosol container of evacuation, every tank adds medicinal liquid 5ml, obtains 10 bottles of aerosols.Every bottle of aerosol container loading amount is 5ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 48 μ g.Every bottle is always lifted number of times 100 times.
Embodiment 13: a kind of bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
According to recipe quantity, micronized bcg-polysaccharides nucleic acid 0.048g is dissolved in 0.5ml distilled water, then adds surfactant Span60 5ml, stir 24 hours, under agitation slowly add the propellant 1 of liquid condition, 1,1,2-tetrafluoroethane 44.5ml, preservative sodium benzoate 0.12g, under-30 DEG C of conditions, stir 12 hours, be sub-packed in again in 10 aerosol containers, then add a cover and tighten, obtain 10 bottles of aerosols.Every bottle of aerosol container loading amount is 5ml, pastille 4.8mg.Aerosol quantitative valve often lifts release 50 μ l, containing bcg-polysaccharides nucleic acid 48 μ g.Every bottle is always lifted number of times 100 times.
Bcg-polysaccharides nucleic acid inhalation aerosol quality analysis of the present invention
Experimental example 1 every bottle always lift number of times inspection
Get test sample, in fume hood, operate, remove cap, shake well, pressure-lift valve, continuous injection is within adding the beaker of appropriate 50% ethanol water, and each injection interval is about 5 seconds, and slowly jolting, until spray is to the greatest extent.The injecting times of each test sample is in table 3.
Every bottle of theory of the each embodiment sample of table 3 always lifts number of times and reality is always lifted number of times
| Embodiment | Theory is always lifted number of times | Reality is always lifted number of times |
| Embodiment 1 | 100 | 99 |
| Embodiment 2 | 100 | 101 |
| Embodiment 3 | 100 | 98 |
| Embodiment 4 | 100 | 100 |
| Embodiment 5 | 200 | 200 |
| Embodiment 6 | 200 | 199 |
| Embodiment 7 | 200 | 199 |
| Embodiment 8 | 200 | 201 |
| Embodiment 9 | 100 | 101 |
| Embodiment 10 | 100 | 100 |
| Embodiment 11 | 100 | 99 |
| Embodiment 12 | 100 | 99 |
| Embodiment 13 | 100 | 101 |
Experimental example 2 often lifts the inspection of BCG vaccine polysaccharide nucleic acid content
The mensuration of contained BCG vaccine polysaccharide: get 1 bottle of test sample, shake well, remove block, examination spray 5 times, with the clean running-on of distilled water, fully dry, be inverted in the small beaker that adds a certain amount of distilled water, running-on is immersed under water liquid level at least 25mm, spray 20 times, each injection interval approximately 5 seconds, and slowly jolting.Take out test sample, clean inside and outside running-on with fresh distilled water, merge distilled water, be transferred in 50ml volumetric flask, be settled to scale with distilled water, carry out assay.Adopt phenolsulfuric acid algoscopy, measure its absorbance at 487nm place, calculate the content of its polysaccharide, measurement result is in table 4.
The mensuration of contained bacillus calmette-guerin vaccine nucleic acid: get 1 bottle of test sample, shake well, remove block, examination spray 5 times, with the clean running-on of phosphate buffer (PBS), fully dry, be inverted in the small beaker that adds a certain amount of PBS, running-on is immersed under PBS liquid level at least 25mm, spray 20 times, each injection interval approximately 5 seconds, and slowly jolting.Take out test sample, inside and outside the clean running-on of fresh PBS, merge PBS liquid, be transferred in 50ml volumetric flask, be settled to scale with PBS, carry out assay.Adopt ultraviolet spectrophotometry directly to measure its absorbance at 260nm place, calculate the content of its nucleic acid, measurement result is in table 4.
The each embodiment sample of table 4 often lifts bcg-polysaccharides nucleic acid theoretical amount and the practical measurement amount released
Claims (5)
1. a bcg-polysaccharides nucleic acid inhalation aerosol, is characterized in that, is made up of bcg-polysaccharides nucleic acid, propellant, cosolvent, surfactant and antiseptic, and wherein, bcg-polysaccharides nucleic acid content is 0.02 ~ 0.90wt%; Propellant content is 80 ~ 99wt %; Cosolvent content is 5 ~ 10wt%; Surface-active contents is 1 ~ 10wt %; Antiseptic content is 0.01 ~ 0.25wt %; Each constituent content percentage by weight sum is 100%;
Described propellant is one of HFA 134a, HFC-227ea or combination;
Described bcg-polysaccharides nucleic acid water content is less than 1wt%, micronization processes makes bcg-polysaccharides nucleic acid grain diameter that its micropowder particle size distribution is 100% within the scope of 0.05 μ m-15 μ m, and wherein 99% bcg-polysaccharides nucleic acid grain diameter is within the scope of 0.1 μ m-5 μ m;
Described cosolvent is selected from one of propane, normal butane, iso-butane, pentane, isopentane, neopentane, dehydrated alcohol or combination;
Described surfactant is one of sorbitan trioleate, Span60, sorbitan monooleate, Polyethylene Glycol-300 or combination.
2. bcg-polysaccharides nucleic acid inhalation aerosol as claimed in claim 1, is characterized in that, described antiseptic is methyl hydroxybenzoate, ethyl hydroxybenzoate, propylparaben, butoben, benzoic acid or sodium benzoate.
3. bcg-polysaccharides nucleic acid inhalation aerosol as claimed in claim 1, is characterized in that, bcg-polysaccharides nucleic acid aerosol container is selected quantitative aerosol valve, and quantitative aerosol valve release scope is 25 μ L ~ 250 μ L.
4. a bcg-polysaccharides nucleic acid inhalation aerosol, writing out a prescription is:
Bcg-polysaccharides nucleic acid 0.048g
HFA 134a 100mL
Oleic acid 1.0g
Ethyl hydroxybenzoate 0.04g
Described bcg-polysaccharides nucleic acid is that micronized bcg-polysaccharides nucleic acid grain diameter 99% is distributed between 0.1 ~ 5 μ m, and moisture is less than 1%;
According to recipe quantity, surfactant oleic acid 1.0g is dissolved in pretreatment solvent 15mL pentane, add again micronized bcg-polysaccharides nucleic acid 0.048g, stir 48 hours, pretreatment solvent pentane is removed in decompression, obtain residue, by this residue and propellant 1,1,1,2-tetrafluoroethane 100mL, antiseptic ethyl hydroxybenzoate 0.04g add in pressure vessel, suspendible is even, then the medicinal liquid in pressure vessel is filled with in the aerosol container that presses lid through valve under pressure, every tank 10mL, obtains 10 bottles of aerosols; Every bottle of aerosol container loading amount is 10mL, pastille 4.8mg; Aerosol quantitative valve often lifts release 100 μ L, containing bcg-polysaccharides nucleic acid 48 μ g; Every bottle is always lifted number of times 100 times.
5. the pharmaceutical applications of the bcg-polysaccharides nucleic acid inhalation aerosol described in claim 1-4 any one, for the preparation of the medicine for the treatment of allergic asthma and/or allergic rhinitis.
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| CN1440295A (en) * | 2000-07-03 | 2003-09-03 | 马拉汉医学研究院 | Vaccine comprising active agent immunogenic acyl glyceryl phosphatidylinositol monno-oligosaccharide |
| CN102366405A (en) * | 2011-10-21 | 2012-03-07 | 江阴长风医药科技有限公司 | Fluticasone propionate aerosol preparation with hydrofluoroalkane as propellant |
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| CN1669557A (en) * | 2004-03-15 | 2005-09-21 | 通用技术集团医药控股有限公司 | Bacill calmette-guerin polysaccharide nucleic acid spraying agent and preparation method thereof |
| CN102362859A (en) * | 2011-10-27 | 2012-02-29 | 江阴长风医药科技有限公司 | Budesonide aerosol preparation using hydrofluoroalkane as propellent |
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| CN1440295A (en) * | 2000-07-03 | 2003-09-03 | 马拉汉医学研究院 | Vaccine comprising active agent immunogenic acyl glyceryl phosphatidylinositol monno-oligosaccharide |
| CN102366405A (en) * | 2011-10-21 | 2012-03-07 | 江阴长风医药科技有限公司 | Fluticasone propionate aerosol preparation with hydrofluoroalkane as propellant |
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