CN102028801A - Radix Rehmanniae oligosaccharide lung dosing traditional Chinese medicinal preparation as well as preparation method and application thereof - Google Patents
Radix Rehmanniae oligosaccharide lung dosing traditional Chinese medicinal preparation as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the pharmaceutical field of the traditional Chinese medicine and relates to a lung dosing traditional Chinese medicinal preparation, in particular to a Radix Rehmanniae oligosaccharide lung dosing traditional Chinese medicinal preparation as well as a preparation method and an application thereof. The pharmacodynamic experimental research shows that the Radix Rehmanniae oligosaccharide obtained in the invention has the function of obviously inhibiting the rat lung inflammation induced by lipopolysaccharide and can enter the lung through the respiratory tract; the medicine is easy to absorb fast through the alveolar surface; and the first-pass effect of the liver can be avoided. The oligosaccharide can be used to prepare medicines for curing chronic obstructive pulmonary diseases, lung inflammation and pulmonary fibrosis, wherein the medicine-containing micropowder with the average particle size of 0.5-7mu m accounts for more than 90% and the micropowder can enter the lung through the respiratory tract through a special inhalant dosing device. The lung dosing traditional Chinese medicinal preparation in the invention can be used to send Radix Rehmanniae to the lung directly and effectively, have low irritation to the respiratory tract, be easy to store and convenient to use and have good patient compliance.
Description
Technical field
The invention belongs to field of traditional Chinese medicine pharmacy, relate to, be specifically related to a kind of dried rehmannia root oligosaccharide through lung administration Chinese medicine preparation and its production and application through lung administration Chinese medicine preparation.
Background technology
Chronic obstructive pulmonary disease (chronic obstructive pulmonary disease, COPD, be called for short chronic obstructive pulmonary disease) be a kind of flow limitation and incomplete reversible chronic airway disorders, be slowly, development progressively, comprise chronic bronchitis and (or) emphysema etc.COPD is a feature to spread all over air flue, pulmonary parenchyma and pulmonary vascular chronic inflammatory disease.Modern study shows, COPD and pulmonary are relevant to the abnormal inflammatory reaction of harmful gas such as smoke from cigarette or deleterious particle, are a kind of destructive pulmonary disease that weakens the patient respiratory function gradually, have a strong impact on patient's work capacity and quality of life.Smoking is the most important inducement of its development.According to The World Health Organization's 2007 annual reports, the existing COPD patient's quantity in the whole world reaches 2.10 hundred million people; The whole world reached 3,000,000 people because of this disease death person in 2005.WHO estimates that to the year two thousand thirty, COPD will become the whole world the 4th cause of death.
Clinical treatment COPD is primarily aimed at COPD flow limitation and inflammatory reaction at present, adopts bronchodilator (β
2Receptor stimulating agent, anticholinergic agent, theophylline etc.), anti-inflammatory agent (glucocorticoid, phosphodiesterase inhibitor etc.), expectorant and oxygen therapy etc.Western medicine mainly is to reduce symptom and complication, does not still have medicine and can effectively control the decline of carrying out property of COPD pulmonary function.Because COPD is chronic disease, long-term prescription can increase incidence rate of adverse reaction, and Western medicine preparation commonly used costs an arm and a leg, and treatment is restricted, as: even the very high β of selectivity
2Receptor stimulating agent also has certain excitation to heart, and prolonged application can cause β
2Function of receptors downward modulation and airway reactivity increase; The effective blood drug concentration of theophylline with cause that the blood concentration of toxic reaction is approaching, its side reaction comprises that gastrointestinal symptom (feel sick, vomiting), cardiovascular system symptom (tachycardia, heart rate disorder), idol can make and breathes excitedly that severe patient can cause twitches and dead.Sucking anticholinergic can not alleviate speed that antigen causes and send out and reach tardy phase reaction mutually.In general, continue to use β for the stable phase patient
2Receptor stimulating agent or anticholinergic agents nebulae inhalation are inappropriate.The local side effects that sucks glucocorticoid comprises pars oralis pharyngis monilial infection, hoarseness and cough, and life-time service can cause systemic side effects such as osteoporosis.Even the safety of the dose-effect relationship of suction glucocorticoid and prolonged application is still unknown among the COPD patient.Studies show that, COPD patient's pathophysiological change has reflected that present doctor trained in Western medicine changes at " dense, sticking, coagulate, poly-" that the treatment of its stable phase can not improve the blood samples of patients physical property, can not the microcirculation improvement obstacle, and still lacking competent evidence, the medicine of enhancing immunity (as vaccine, immunomodulator etc.) supports its widespread usage in COPD patient.
The traditional Chinese medical science is seted forth one's views with deficiency in origin and excess in superficiality to COPD, adopts strengthening the body resistance and the eliminating evil Therapeutic Method of taking into account, and clinical practice shows, has obtained better therapeutic effect, and few side effects.
Radix Rehmanniae is the dried root of Scrophulariaceae herbaceos perennial Radix Rehmanniae Rehmannia glutinosa Libosch, and the beginning is stated from Shennong's Herbal.The Radix Rehmanniae complex chemical composition is got more than 70 monomer so far, and main component is glycoside, saccharide, aminoacid and the trace element based on iridoid glycoside.Oligosaccharide composition in its saccharide mainly contains sucrose, Raffinose, mannotriose, stachyose, verbascose, verbascose etc.The pharmacological action of Radix Rehmanniae is extensive, as regulate immunity, anticancer, regulate central nervous system etc., wherein the pharmacological research of oligosaccharide mainly concentrate on and regulate immunity, antitumor, to aspects such as the influence of hemopoietic function, blood sugar lowering, current research shows, the oligosaccharide composition has effect (Liu Li, Tang Lan, the Xu Desheng that suppresses rat interstitial lung fibroblast I, the expression of III Collagen Type VI, Deng. the effect [J] that the Radix Rehmanniae is expressed rat interstitial lung fibroblast I, III Collagen Type VI. Chinese patent medicine, 2008; 30 (2): 175-178), further animal experiment shows that the oligosaccharide position of the Radix Rehmanniae has obvious Chinese People's Anti-Japanese Military and Political College enterobacteria lipopolysaccharide to cause the pulmonary inflammatory effect of rat.
Chinese patent [application number] 2005101124248 discloses the preparation method of dried rehmannia root oligosaccharide, and the dried rehmannia root oligosaccharide of mainly forming that makes by trisaccharide and tetrose, used Sephadex, Superose, the Superdex type gel of wherein disclosed purge process is filler inlet, cost an arm and a leg, so this preparation method cost height, production cycle are longer, suitability for industrialized production can't be adapted to, also dried rehmannia root oligosaccharide can't be prepared in a large number.
In addition, because dried rehmannia root oligosaccharide is oral in gastrointestinal absorption seldom, bioavailability is very low, and drug administration by injection mode life-time service, patient's compliance is poor, and be a kind of drug delivery system that integrates targeting and non-infringement through respiratory tract administration, therefore be the ideal style of treatment pulmonary disease, but at home and abroad there is no the dried rehmannia root oligosaccharide that is used for the treatment of pulmonary disease research report at present through the relevant dosage form of lung administration through the lung administration.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, provide a kind of dried rehmannia root oligosaccharide through lung administration Chinese medicine preparation, the Chinese medicine preparation through lung or nose administration of the effective ingredient in Chinese dried rehmannia root oligosaccharide of especially a kind of treatment chronic obstructive pulmonary disease (COPD).
Dried rehmannia root oligosaccharide of the present invention shows through pharmacodynamic experiment through lung or nose administration Chinese medicine preparation, has the pulmonary inflammatory effect of the inductive rat of obvious inhibition e. coli lipopolysaccharide, can enter pulmonary through respiratory tract, medicine easily passes through the alveolar surface by fast Absorption, and can avoid the liver first-pass effect.Wherein pastille micropowder mean diameter 0.5～7 μ m accounts for more than 90%, can enter pulmonary through respiratory tract by the inhalant doser of special use, and is little to the stimulation of respiratory tract, easily stores, and it is convenient to use, and patient's compliance is good.
Dried rehmannia root oligosaccharide of the present invention is made up of the dried rehmannia root oligosaccharide effective site and 30%～90% pharmaceutic adjuvant of 10%～70% percentage by weight through lung administration Chinese medicine preparation; Described dried rehmannia root oligosaccharide effective site, its molecular weight ranges mainly are made up of stachyose, cottonseed sugar, mannose and sucrose 200～1000, and the percentage by weight that accounts for described dried rehmannia root oligosaccharide effective site is 85～90%.
Among the present invention, in the described dried rehmannia root oligosaccharide effective site: the molecular weight of stachyose is 666, and the molecular weight of cottonseed sugar, mannotriose is 504, and the molecular weight of sucrose is 342, and wherein impurity is based on monosaccharide.
Further purpose of the present invention is to provide the preparation method of described dried rehmannia root oligosaccharide through pulmonary or pernasal preparation.
The present invention is a raw material with Radix Rehmanniae medical material, after carrying, water obtains Radix Rehmanniae total sugar, obtain the dried rehmannia root oligosaccharide position by membrane separation technique then, measure and show, described dried rehmannia root oligosaccharide position mainly is made up of four kinds of oligosaccharide, detect through 1H-NMR, 13C-NMR and LC-MS, be respectively stachyose, cottonseed sugar, mannotriose and sucrose.
Among the present invention, described dried rehmannia root oligosaccharide effective site prepares by following method and step:
Adopting molecular weight is that 1000 film carries out ultrafiltration to Radix Rehmanniae activated carbon decolorizing liquid, and to remove molecular weight in the feed liquid greater than 1000 impurity, reuse 150-200 NF membrane is carried out nanofiltration to ultrafiltrate, holds back material and then purification and concentrated 200 below.
Get section of Radix Rehmanniae medical material or pulverizing, add 8～16 times of water extraction 2～4 times, merge the water extract, it is 1.03～1.08 (60 ℃) that filtrate decompression is concentrated into relative density, and centrifugal or natural subsidence is got supernatant and passed through macroporous adsorptive resins, the water eluting, eluent is behind activated carbon decolorizing, and concentrating under reduced pressure obtains the total sugar juice of the Radix Rehmanniae; Getting the total sugar juice of the Radix Rehmanniae is that 1000 ultrafilter membrane and molecular cut off are the NF membrane of 150-200 by molecular cut off successively, hold back the material below 200, after purified and concentrated, obtain the nanofiltration concentrated solution, drying promptly gets dried rehmannia root oligosaccharide effective site, after measured, wherein mainly contain by stachyose, cottonseed sugar, mannose and sucrose, the percentage by weight that accounts for the oligosaccharide position is 85～90%.。
In the above-mentioned preparation method, described macroporous adsorbent resin is a nonpolar macroporous adsorption resin, be selected from a kind of among AB8, D101, HPD100, HPD450, HZ801, the HZ816, the post blade diameter length ratio is 1: 4～1: 8, liquor strength is every milliliter and contains medical material 0.2～0.5g, the water eluting, the eluent of 3～6 times of resin bed volumes of collection.A kind of among preferred HPD100, D101, HZ801 or the HZ816.
In the described activated carbon decolorizing, activated carbon dosage is 0.1～3%, boils, and can decolour 1～3 time.
In the described membrane separating method, the ultrafilter membrane material can select for use organic ultrafilter membrane to comprise cellulose family, polyamide-based, the aromatic heterocycle class, polysulfones, TPO, silicone rubber kinds, high molecular polymer films such as fluoro containing polymers class, concrete has: polysulfones, cellulose acetate, phthalein side group polysulfones, polyacrylonitrile, cyanoethyl cellulose, SPSF, quaternary ammoniated polysulfones, polyamide, Kynoar, poly-carbon vinegar ester, polyacrylonitrile, polyether sulfone, chitosan, the naphthyridine ketone structure polyether sulfone, nylon, polyvinyl alcohol, the porous polyether sulfone, acrylonitrile, acrylamide, styrene copolymer; Inorganic ultrafilter membrane comprises ceramic membrane (Al
2O
3, ZrO
2, TiO
2, Kaolin), metal film, glass-film, zeolite, charcoal element, silicate.NF membrane can select for use organic membrane to comprise aromatic polyamides class composite membrane, poly-piperazine acidamide composite nanometer filtering film, sulfonated polyether sulfone class composite nanometer filtering film, mixed type composite nanometer filtering film, and concrete has: polysulfones, cellulose acetate, polyamide, polyvinyl alcohol, SPSF, sulfonated polyether sulfone, polrvinyl chloride, melamine/phenolic resins, melamine/polypropylene etc.; Inoranic membrane comprises ceramic membrane (γ-Al
2O
3, ZrO
2, TiO
2, anodised aluminium, hafnium oxide), metal film, glass-film; And organic and inorganic mineral film.The film shape adopts rolling, tubular type, flat or doughnut formula.Selecting molecular cut off for use is that 1000 ultrafilter membrane carries out ultrafiltration, and feed concentration is every liter and contains raw medicinal herbs 10～20g, and pressure is 0.5Mpa～1.0Mpa, temperature≤40 ℃; Ultrafiltrated permeation liquid carries out nanofiltration through the NF membrane of molecular cut off 150～200, and pressure is 0.8～1.0Mpa, and temperature is≤40 ℃.
The dried rehmannia root oligosaccharide position that the present invention obtains can be made the preparation of dried rehmannia root oligosaccharide through lung or nose administration with pharmaceutic adjuvant through proper method in further dry back, and described preparation can be made into and sucks powder spray, aerosol and atomized inhalation etc.
Dried rehmannia root oligosaccharide of the present invention is that 10%～70% dried rehmannia root oligosaccharide position and 30%～90% pharmaceutic adjuvant are formed through the preparation of lung administration by percentage by weight.Among the present invention, different dosage form is respectively by following method preparation:
(1) preparation powder spray
Dried rehmannia root oligosaccharide and pharmaceutic adjuvant (sugar alcohol, saccharide, aminoacid, other adjuvant etc.) are mixed, carry out micronization, get the pastille micropowder; Or dried rehmannia root oligosaccharide carried out micronization, with an amount of pharmaceutic adjuvant by equivalent incremental method mixing, prepare the pastille micropowder.Be convenient and use, can be with the direct fill of pastille micropowder in dry powder dosing device such as Turbuhaler inhaler, or pack into single dose capsule or vesicle preserve, during use by the administration of powder spray inhaler.
Described powder spray constituent content is pressed following percentage by weight:
Described pharmaceutic adjuvant is selected one or more of sugar alcohol, saccharide, aminoacid, other adjuvant for use.
Described aminoacid can be selected glycine, Aspartic Acid, alanine, tyrosine, tryptophan, leucine, isoleucine, threonine, glutamic acid, phenylalanine, cystine, proline for use; Described sugar alcohol can be selected mannitol, xylitol, maltose alcohol etc. for use; Described saccharide can be selected lactose, crystallization lactose, spray-dried lactose, inhalac70, inhalac120, inhalac230, trehalose, dextran, starch, chitosan for use; Described other adjuvant comprises lubricant, fluidizer, antistatic additive etc., can select dipalmitoyl-phosphate ester phatidylcholine (DPPC), two lauroyl phosphatldylcholines, cholesterol, poloxamer, magnesium stearate and beta-schardinger dextrin-and derivant, Polyethylene Glycol etc. for use.
Above-mentioned method of micronization is selected one or more in spray drying method, lyophilization+ball mill comminuting method, the comminution by gas stream for use.
The pastille micropowder of selecting for use spray drying method to obtain, be with dried rehmannia root oligosaccharide and auxiliary materials and mixing, be dissolved in water, filter, the spray-dried pastille micropowder that obtains particle diameter for＜10 μ m of filtrate, preferable particle size is 0.5～7 μ m, wherein at least 90% diameter of particle is 0.5～7 μ m in the pastille micropowder, packing, promptly.
It is soluble in water by dried rehmannia root oligosaccharide and pharmaceutic adjuvant selecting the micropowder that lyophilization+the ball mill comminuting method obtains for use, stirs, and lyophilization gets dry powder, and the reuse high energy ball mill is pulverized, sieve the pastille micropowder of mean diameter＜10 μ m, packing, promptly.
The micropowder of selecting for use comminution by gas stream to obtain is that dried rehmannia root oligosaccharide and adjuvant are entered pulverizing chamber by nozzle, contacts pulverizing with high velocity air, and operating pressure is 0.5～0.7mpa, and temperature is 5～30 ℃.Obtaining particle diameter is the pastille powder body of 1～7 μ m, packing, promptly.
By the dried rehmannia root oligosaccharide position make through powder spray for lung inhalation, its pastille micropowder also comprises liposome, solid lipid nanoparticle etc., is to be prepared by membrane process by dried rehmannia root oligosaccharide, film material, additives and other adjuvants.
Described film material is selected for use in lecithin, fabaceous lecithin, kephalin, cholesterol acetyl fat, di(2-ethylhexyl)phosphate spermaceti fat, natrii tauroglycocholas, phosphatidyl ethanolamine or other synthetic phospholipids a kind of, or their mixture.Described additives are selected a kind of in cholesterol, 18-amine. or the phosphatidic acid for use.Described other adjuvants are selected a kind of in tween 80, vitamin E or the Polyethylene Glycol for use
(2) preparation aerosol
With dried rehmannia root oligosaccharide micropowder and the abundant mixing of adjuvant, make stable solution, suspension or emulsion, quantitatively be sub-packed in the aerosol pressure vessel, repress is gone into propellant, makes aerosol.Described adjuvant comprises additives and propellant.
Among the present invention, get 10～40% dried rehmannia root oligosaccharide and 60～90% adjuvants, be sub-packed in the aerosol pressure vessel.
One or more of the optional water of described additives, ethanol, glycerol, propylene glycol, lecithin, fabaceous lecithin, kephalin, cholesterol acetyl fat, di(2-ethylhexyl)phosphate spermaceti fat, natrii tauroglycocholas, phosphatidyl ethanolamine, span20, span60, span80, span85, tween20, tween80, Brij 30, Brij 35, PEG300, Pulvis Talci, sodium sulfate, sodium chloride, vitamin C, sodium pyrosulfite, sodium sulfite etc.
Described propellant can be selected a kind of in HFA134a, HFA227ea, HFC152a, dimethyl ether, propane, butane, iso-butane, pentane, isopentane, tetrafluoroethane, carbon dioxide, nitrous oxide, compressed air and the nitrogen or their mixture for use.
(3) preparation atomized inhalation
Atomized inhalation is made up of 10～70% dried rehmannia root oligosaccharide and 30～90% adjuvant.After getting dried rehmannia root oligosaccharide and being dissolved in water, add antiseptic and antioxidant, filter, quantitatively packing, during use by special-purpose inhaler administrations such as nebulizers.Its liquor strength scope is 2%～10%.This atomized inhalation also can not add any adjuvant.
Described antioxidant can be selected in receiving one or more of vitamin C, sodium pyrosulfite, bisulfite for use.Described antiseptic can be selected one or more in parabens, benzoic acid (sodium), the sorbic acid (potassium) for use.
Studies show that through pharmacodynamic experiment, the dried rehmannia root oligosaccharide that the present invention obtains has the pulmonary inflammatory effect of the inductive rat of obvious inhibition e. coli lipopolysaccharide (LPS), can enter pulmonary through respiratory tract, medicine easily passes through the alveolar surface by fast Absorption, and can avoid the liver first-pass effect.Wherein dried rehmannia root oligosaccharide powder spray pastille micropowder mean diameter 0.5～7 μ m accounts for more than 90%, can enter pulmonary with dry powder form through respiratory tract by the powder spray doser of special use, can be used for the medicine of preparation treatment chronic obstructive pulmonary disease (COPD), pneumonia and pulmonary fibrosis.
The dried rehmannia root oligosaccharide position powder spray that the present invention makes is characterized in that preparation is simple, and preparation equipment is not had specific (special) requirements, is suitable for industrialized great production.Dried rehmannia root oligosaccharide sucks powder spray visible its pastille micropowder under optical microscope and is the spheroidal fine particle, favorable dispersibility, the visible powder of scanning electron microscopic observation is spheroidal, the good fluidity of powder, hygroscopicity is less, powder can atomize rapidly, meets every specification requirement of the suction powder spray of Chinese Pharmacopoeia regulation.
The present invention sucks powder spray can directly effectively send to pulmonary with dried rehmannia root oligosaccharide, has more advantage: 1. the patient initiatively sucks medicated powder, and dosage is controlled easily; 2. propellant such as non-freon can be avoided to atmospheric pollution with to the stimulation of respiratory tract; 3. medicine stores with dry powder, is difficult for degraded; 4. do not contain antiseptic or ethanol equal solvent; 5. it is convenient to use, and patient's compliance is good.
Description of drawings
The HPLC collection of illustrative plates of Fig. 1 dried rehmannia root oligosaccharide RGOS.
The structural relation figure of Fig. 2 chemical compound stachyose, cottonseed sugar, mannotriose and sucrose.
Fig. 3 pathological section figure H-E dyeing, digital photography, * 100 times.
Fig. 4 powder spray micropowder scanning electron microscope (* 3000).
Following embodiment is for further specifying the present invention, but do not limit the scope of protection of present invention.
The specific embodiment
Embodiment 1 preparation dried rehmannia root oligosaccharide
Get the Radix Rehmanniae decoction pieces and add 10 times of water gagings, soak 60min, decoct 2 times, each 60min, filter, merging filtrate, it is 1.05 (60 ℃) that filtrate decompression is concentrated into relative density, natural subsidence 24h, get supernatant and be settled to every milliliter of medicinal liquid and contain medical material 0.2g, be splined on the D101 macroporous adsorptive resins, the post blade diameter length ratio is 1: 7, water is eluting solvent, collects the eluent of 4 times of column volumes.Add 0.1% active carbon, boiling decoloring 2 times, sucking filtration, filtrate is made into every liter of feed liquid that contains medical material 10g concentration, and selecting relative molecular weight 1000, material for use is the flat ultrafilter membrane of cellulose acetate, and at pressure 0.5Mpa, temperature is to carry out ultrafiltration under 20 ℃; Ultrafiltrated permeation liquid is that the flat NF membrane of sulfonated polyether sulfone is carried out nanofiltration through relative molecular weight 150, material, and pressure is 0.8Mpa, and temperature is 20 ℃.The nanofiltration trapped fluid is through concentrating, and lyophilization obtains dried rehmannia root oligosaccharide.
Embodiment 2 preparation dried rehmannia root oligosaccharides
Get the Radix Rehmanniae decoction pieces, pulverize, add 8 times of water gagings, decoct 2 times, each 30min filters, merging filtrate, it is 1.05 (60 ℃) that filtrate decompression is concentrated into relative density, and high speed centrifugation is got supernatant and is settled to every milliliter of medicinal liquid and contains medical material 0.2g, be splined on the HZ801 macroporous adsorptive resins, the post blade diameter length ratio is 1: 5, adds water elution, collects the eluent of 5 times of column volumes.Add 0.1% active carbon, boiling decoloring 3 times, sucking filtration, filtrate is made into every liter of feed liquid that contains medical material 10g concentration, and selecting relative molecular weight 1000, material for use is the doughnut formula ultrafilter membrane of polyamide, and at pressure 0.6Mpa, temperature is to carry out ultrafiltration under 30 ℃; Ultrafiltrated permeation liquid is that the doughnut formula NF membrane of polyamide is carried out nanofiltration through relative molecular weight 200, material, and pressure is 0.8Mpa, and temperature is 30 ℃.The nanofiltration trapped fluid is through concentrating, and lyophilization obtains dried rehmannia root oligosaccharide.
Embodiment 3 preparation dried rehmannia root oligosaccharides
Get the Radix Rehmanniae decoction pieces and add 12 times of water gagings, decoct 3 times, each 45min filters, merging filtrate, filtrate vacuum concentration to relative density is 1.08 (60 ℃), and natural subsidence 24h, supernatant are settled to every milliliter of medicinal liquid and contain medical material 0.5g, medicinal liquid is splined on the HZ816 macroporous adsorbent resin, the post blade diameter length ratio is 1: 8, and water is eluting solvent, collects the eluent of 6 times of column volumes.Add 0.3% activated carbon decolorizing, sucking filtration, filtrate is made into every liter of feed liquid that contains medical material 15g concentration, select for use relative molecular weight 1000, material be polyether sulfone tubular ultra-filtration membrane, at pressure 0.5Mpa, temperature is to carry out ultrafiltration under 25 ℃; Ultrafiltrated permeation liquid is that the tubular type NF membrane of polyether sulfone is carried out nanofiltration through relative molecular weight 200, material, and pressure is 0.8Mpa, and temperature is 35 ℃.The nanofiltration trapped fluid concentrates, and lyophilization obtains dried rehmannia root oligosaccharide.
Embodiment 4 preparation dried rehmannia root oligosaccharides
Get the Radix Rehmanniae decoction pieces and add 16 times of water gagings, soak 60min, decoct 3 times, each 60min, filter, merging filtrate, filtrate vacuum concentration to relative density is 1.03 (60 ℃), centrifugal, supernatant is settled to every milliliter of medicinal liquid and contains medical material 0.5g, and medicinal liquid is splined on the HPD100 macroporous adsorbent resin, and the post blade diameter length ratio is 1: 7, the water eluting, the eluent of 4 times of column volumes of collection.Add 0.1% active carbon, boiling decoloring 3 times, sucking filtration, filtrate is made into every liter of feed liquid that contains medical material 15g concentration, and selecting relative molecular weight 1000, material for use is the rolling ultrafilter membrane of polysulfones, and at pressure 0.5Mpa, temperature is 20 ℃ and carries out ultrafiltration; Ultrafiltrated permeation liquid is that the rolling NF membrane of polysulfones is carried out nanofiltration through relative molecular weight 150, material, and pressure is 0.8Mpa, and temperature is 20 ℃.The nanofiltration trapped fluid concentrates, and lyophilization obtains dried rehmannia root oligosaccharide.
Embodiment 5 preparation dried rehmannia root oligosaccharides
Get the Radix Rehmanniae decoction pieces and add 14 times of water gagings, decoct 3 times, each 60min filters, merging filtrate, filtrate vacuum concentration to relative density is 1.06 (60 ℃), and is centrifugal, and supernatant is settled to every milliliter of medicinal liquid and contains medical material 0.25g, medicinal liquid is splined on the D101 macroporous adsorbent resin, the post blade diameter length ratio is 1: 6, water eluting, the eluent of 5 times of column volumes of collection.Add 0.1% active carbon, boiling decoloring 3 times, sucking filtration, filtrate is made into every liter of feed liquid that contains medical material 20g concentration, and selecting relative molecular weight 1000, material for use is the rolling ultrafilter membrane of polysulfones, and at pressure 0.5Mpa, temperature is 25 ℃ and carries out ultrafiltration; Ultrafiltrated permeation liquid is that the rolling ultrafilter membrane of polysulfones carries out nanofiltration through relative molecular weight 200, material, and pressure is 0.8Mpa, and temperature is 30 ℃.The nanofiltration trapped fluid concentrates, and lyophilization obtains dried rehmannia root oligosaccharide.
The pharmacological evaluation of embodiment 6 dried rehmannia root oligosaccharide aerosol inhalations
Dried rehmannia root oligosaccharide aerosol inhalation is induced the pulmonary inflammatory influence research of rat to LPS
1 sets up model
After the SD rat was weighed, the chloral hydrate anesthesia rat with 10% was pressed the 3.5ml/kg intraperitoneal injection.Postanesthetic rat immediate surgery exposes trachea, directly splashes into LPS (3mg/kg) from air flue with microsyringe, puts to death rat after splashing into LPS 6h, collects bronchoalveolar lavage fluid (BALF), gets lung tissue and do pathological section.
2 medications
8 rats are put into a closed box, and ventilation mist pipeline in the closed box is packed medicinal liquid 8ml (300mg/ml) in the liquid medicine cup into, and with the continuous aerosol 20min of aerosolizer, 0.4ml/min is till medicinal liquid has sprayed.Administration 2 times delivers medicine to for the first time air flue and splashes into 5min before the LPS, after delivering medicine to air flue for the second time and splashing into LPS 3h.
3 experimental techniques and detection index
Total white blood cells and neutrophilic granulocyte number in the bronchoalveolar lavage fluid, tumor necrosis factor (TNF-α), leukotriene B
4(LTB
4), neutrophilic granulocyte myeloperoxidase (MPer) content (MPO).
4 results
4.1 to the accumulative influence of inflammatory cell
Dried rehmannia root oligosaccharide aerosol inhalation can obviously suppress the inductive total white blood cells of LPS and the neutrophilic granulocyte number raises, and the plymphomonocyte number is not had obvious influence, sees Table 1.
The accumulative influence of the inductive induced lung BALF inflammatory cell of table 1 couple LPS (n=8, x ± SD)
Compare * P＜0.05, * * P＜0.01, * * * P＜0.001 with model group
4.2 influence to the TNF-alpha levels
Dried rehmannia root oligosaccharide aerosol inhalation has certain inhibitory action, but handles no significant difference (P＞0.05) with the model group comparative statistics, sees Table 2.
The influence of TNF-alpha levels among the inductive induced lung BALF of table 2 couple LPS
4.3 to LTB
4The influence of level
Dried rehmannia root oligosaccharide aerosol inhalation can obviously suppress the inductive LTB of LPS
4Level raises, and sees Table 3.
LTB among the inductive induced lung BALF of table 3 couple LPS
4The influence of level
Compare * P＜0.05 with model group
4.4 influence to the MPO level
Dried rehmannia root oligosaccharide aerosol inhalation can obviously suppress the inductive MPO level of LPS and raise, and sees Table 4.
The influence of MPO level among the inductive induced lung BALF of table 4 couple LPS (n=7～8,
)
Compare * P＜0.05 with model group
4.5 pathological examination results
Dried rehmannia root oligosaccharide aerosol inhalation can obviously suppress the inductive lung tissue neutrophil infiltration of LPS, tracheal mucosa edema and tissue injury, sees Table 5 and Fig. 3.
Table 5-13 to the influence of the inductive induced lung inflammation of LPS pathological change (n=8,
)
Embodiment 7 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 10g, mannitol 36g, glycine 10g, be dissolved in water, making its concentration is 8%, sucking filtration, and filtrate is with 120 ℃ of inlet temperatures; 80 ℃ of outlet temperatures; Spray velocity 10%; The speed of evacuation 90%; The condition of nozzle air current speed 800Nl/min is carried out spray drying, obtains white powder, and direct fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, passes through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 17.8％ | 17.8％ | 64.4％ | 0％ |
Embodiment 8 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 10g, xylitol 30g, leucine 10g, mix, be dissolved in water, be made into 5% solution, sucking filtration, filtrate is with 90 ℃ of inlet temperatures; 60 ℃ of outlet temperatures; Spray velocity 10%; The speed of evacuation 100%; The condition of nozzle air current speed 800Nl/min is carried out spray drying, obtains white powder, and direct fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, passes through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 20％ | 20％ | 60％ | 0％ |
Embodiment 9 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 10g and mannitol 31g, abundant mixing, comminution by gas stream to mean diameter less than 10 μ m, wherein 80% particle diameter is less than 5 μ m.Get poloxamer 0.2g again, L-leucine 4.5g joins in the dried rehmannia root oligosaccharide medicine carrying micropowder by the equivalent incremental method, mixing, be ground to repeatedly evenly, the direct fill of powder is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, passes through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 22％ | 9.8％ | 67.8％ | 0.44％ |
Embodiment 10 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 15g, L-leucine 15g, mannitol 45g, be dissolved in water, making its concentration is 3%, sucking filtration, filtrate is with 120 ℃ of inlet temperatures, 80 ℃ of outlet temperatures, spray velocity 15%, the speed of evacuation 100%, the condition of nozzle air current speed 800Nl/min is carried out spray drying, prepares white powder, and directly fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, pass through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 20％ | 20％ | 60％ | 0％ |
Embodiment 12 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 10g, spray-dried lactose 23g, magnesium stearate 0.3g mixing, be dissolved in water, be made into 4% solution, sucking filtration, filtrate is with 90 ℃ of inlet temperatures; 60 ℃ of outlet temperatures; Spray velocity 10%; The speed of evacuation 100%; The condition of nozzle air current speed 800Nl/min is carried out spray drying, obtains white powder, and direct fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, passes through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and | Surfactant | |
| 30％ | 0％ | 69％ | 1％ |
Embodiment 13 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 17g, mannitol 24g, L-leucine 8g, be dissolved in water, stir, lyophilization 72h gets spongy dry powder (water content is controlled in 3%).Add the dipalmitoyl-phosphate ester phatidylcholine, pulverize with high energy ball mill, sieve the pastille micropowder of mean diameter＜10 μ m, directly fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preserve, during use by the administration of powder spray inhaler.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 34％ | 16％ | 48％ | 2％ |
Embodiment 14 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 11g, mannitol 33g, tyrosinase 15 .5g, add the 0.5g poloxamer simultaneously, be dissolved in water, stir, lyophilization gets lyophilized powder.Pulverize with high energy ball mill, sieve the pastille micropowder of mean diameter＜10 μ m, directly fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preserve, during use by the administration of powder spray inhaler.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 22％ | 11％ | 66％ | 1％ |
Embodiment 15 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 8.5g, add inhalac120 8.5g, tryptophan 7.5g, be dissolved in water, stir, lyophilization gets lyophilized powder.In lyophilized powder, add poloxamer 0.5g, pulverize with high energy ball mill, sieve the pastille micropowder of mean diameter＜10 μ m, directly fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, pass through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 34％ | 30％ | 34％ | 2％ |
Embodiment 16 preparation dried rehmannia root oligosaccharides suck powder spray
Getting dried rehmannia root oligosaccharide 3g is dissolved in the pH7.2 phosphate buffer, under nitrogen current, join by granulesten 12g, cholesterol 3g, di(2-ethylhexyl)phosphate spermaceti fat 1g and be dissolved in the solution that the 20ml chloroform makes, reduction vaporization is removed chloroform, residual liquid is through ultra-sonic dispersion, divide the liposome that sheds, add the appropriate amount of buffer solution dilution and promptly get the dried rehmannia root oligosaccharide liposome solutions.Get this solution spray drying, get white powder, direct fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, passes through the administration of powder spray inhaler during use.
Embodiment 17 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 9.5g and crystallization lactose 25g, mixing, comminution by gas stream to mean diameter less than 10 μ m, add spray-dried lactose 3.5g and poloxamer 0.1g by the equivalent incremental method, be ground to repeatedly evenly, sieve the micropowder of mean diameter＜10 μ m, directly fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, pass through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 25％ | 0％ | 74.8％ | 0.26％ |
Embodiment 18 preparation dried rehmannia root oligosaccharides suck powder spray
Get each 10g of dried rehmannia root oligosaccharide lactose, mixing, comminution by gas stream to mean diameter less than 10 μ m, the chitosan 20g that added 100 mesh sieves again grinds with high energy ball mill, sieve the pastille micropowder of mean diameter＜10 μ m, direct fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, passes through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 33.3％ | 0％ | 66.6％ | 0％ |
Embodiment 19 preparation dried rehmannia root oligosaccharides suck powder spray
Get dried rehmannia root oligosaccharide 10g, trehalose 15g and L-leucine 15g, dipalmitoyl-phosphate ester phatidylcholine 0.05g is dissolved in water, and filters, and filtrate is with 110 ℃ of inlet temperatures; 75 ℃ of outlet temperatures; Spray velocity 10%; The speed of evacuation 100%; The condition of nozzle air current speed 700Nl/min is carried out spray drying, prepares white powder, and direct fill is in the dry powder dosing device, or pack into single dose capsule or vesicle preservation, passes through the administration of powder spray inhaler during use.
| Dried rehmannia root oligosaccharide | Aminoacid | Sugar alcohol is or/and sugar | Surfactant |
| 25％ | 37.5％ | 37.5％ | 0.12％ |
Embodiment 20 dried rehmannia root oligosaccharides suck the evaluation index and the method for powder spray
1, the morphologic observation of powder: surface condition and the rounding property of observing micropowder with scanning electron microscope (SEM); With the form and the coherent condition of observation by light microscope micropowder, and the particle size distribution of employing ocular-net preliminary observation micropowder.
2, the particle size determination of micropowder: get powder of the present invention a little, adopt Mastersizer2000 type laser particle analyzer with dry method or wet method measurement volumes mean diameter, particle size distribution.Wherein wet method is measured behind the ultra-sonic dispersion 4min for being dispersion solvent with 400ml acetone.
3, measure the angle of repose of micropowder: adopt the fixed funnel method, it is that 5.0cm clips down in the funnel of pipe that powder of the present invention is loaded in diameter, is fixed on the iron stand, and the funnel upper limb is apart from table top 10cm.Gently add vibration, powder is slowly flowed down.The below is that the culture dish of 6.0cm collects the powder that shakes with diameter.The center that funnel flows out powder is aimed in the center of circle of culture dish, and abundant powder is shaken to fall, and forms cone on culture dish.The height of cone is designated as h, and the radius of culture dish is designated as r, then angle of repose=arctg (h/r).
4, the bulk density of micropowder is measured: it is that 5.0cm clips down in the funnel of pipe that powder of the present invention is loaded in diameter, is fixed on the iron stand, and the funnel upper limb is apart from table top 10cm.Gently add vibration, powder is slowly flowed down.The below is V=9.75ml with volume, and height is 4.0cm, and bore is 1.2cm, the powder that the end directly shakes and falls for the fine taper bottle splendid attire of 2.5cm, and the powder that the taper bottleneck is unnecessary scrapes off, and weighs.Conical flask+powder gross weight is designated as W1, and conical flask heavily is designated as W2, then bulk density ρ
b=(W1-W2)/V.
5, the hygroscopicity of micropowder is measured: take by weighing about 0.5g powder of the present invention in the weighing botle of having weighed, the uncovered exsiccator of putting into of weighing botle is dried to constant weight, sample heavily is designated as W1, sample+weighing botle gross weight is designated as W2, transferring to relative humidity is in the hermetic container of 75% (saturated NaCl solution), and 25 ℃ of constant temperature are behind the placement 24h, taking-up is weighed and is designated as W3, then moisture absorption percentage rate=(W3-W2)/W1*100%.
6, uniformity of dosage units: get this product and measure content, the result should (2005 editions two appendix XE of Chinese Pharmacopoeia) up to specification.
7, atomization and Emptying Rate thereof are measured:
Atomization is investigated: adopt homemade atomising device, this device is made up of an atomizing bottle and vacuum pump, is connected by a flow meter between the two.Taking by weighing an amount of powder of the present invention loads in the 3# gelatine capsule, with the capsule punching two ends, when effusion meter to be adjusted makes throughput to 60L/min, capsule is placed atomizing bottle plug place, top, the interior i.e. atomizing in the atomizing bottle of medicated powder of capsule this moment, continuous 4 times, each 1.5 seconds, the dispersibility of observation powder.
Emptying Rate is measured: get 10 of this product, measure according to Emptying Rate algoscopy (2005 editions two appendix I L of Chinese Pharmacopoeia), every Emptying Rate should be not less than 90%.
8, deposition of drug in effective site is measured: measure according to deposition of drug in effective site algoscopy (2005 editions two appendix X H of Chinese Pharmacopoeia), sample number is 10, and the drug deposition amount should be no less than 10% of labelled amount.
The product inspection result:
1, the morphologic observation of powder: visible powder is the spheroidal fine particle under the optical microscope, favorable dispersibility, and the visible powder of electron microscopic observation is spheroidal.
2, the particle diameter of powder: 1～10 μ m, 90% is below the 7 μ m.
3, the angle of repose of powder: 28～42 degree.
4, the bulk density of powder: 0.21～0.37g/cm
3
5, the hygroscopicity of powder: 2.08～10.62%.
6, uniformity of dosage units: 6.14～8.94%.
7, atomization and Emptying Rate thereof: powder spray all can atomize rapidly, forms even smog, no granule or a small amount of granule sedimentation, and the atomization of powder is good.Emptying Rate is 93.3～97.6%.
8, the deposition of effective fraction medicine: 25.6～31.7%.
Other indexs all meet Chinese Pharmacopoeia about sucking the pertinent regulations of powder spray.
Embodiment 21 preparation dried rehmannia root oligosaccharide aerosols
Get the 4.5g dried rehmannia root oligosaccharide and add the 4ml water dissolution, add 1ml ethanol, 0.5g Arlacel-60 again, shake up, quantitatively be sub-packed in the aerosol pressure vessel, be pressed into dimethyl ether 9g, promptly.
Embodiment 22 preparation dried rehmannia root oligosaccharide aerosols
Get the 4.5g dried rehmannia root oligosaccharide and add 5ml water and 0.02ml tween80, quantitatively be sub-packed in the aerosol pressure vessel, be pressed into 7g HFA134a, promptly.
Embodiment 23 preparation dried rehmannia root oligosaccharide aerosols
The ethanol liquid and the 5g tetrafluoroethane of 120g lecithin are mixed into organic facies, and the 5% ethanol liquid that contains the 15g dried rehmannia root oligosaccharide is water, carries out cannedly, promptly makes the dried rehmannia root oligosaccharide liposome aerosols.
Embodiment 24 preparation dried rehmannia root oligosaccharide atomized inhalations
After getting the 7g dried rehmannia root oligosaccharide and adding the 10ml water dissolution, add 0.5g vitamin C and 0.001g benzoic acid, filter, quantitatively packing, before using by special-purpose inhaler administrations such as nebulizers.
Embodiment 25 preparation dried rehmannia root oligosaccharide atomized inhalation agent
After getting the 7g dried rehmannia root oligosaccharide and adding the 30ml water dissolution, add the 0.06g potassium sorbate, filter, quantitatively packing, before using by special-purpose inhaler administrations such as nebulizers.
Claims (19)
1. a dried rehmannia root oligosaccharide is characterized in that through the lung drug-delivery preparation, and said preparation is made up of the dried rehmannia root oligosaccharide effective site and the pharmaceutic adjuvant of following weight percentage ratio: dried rehmannia root oligosaccharide effective site: 10%～70%, and pharmaceutic adjuvant: 30%～90%; Described dried rehmannia root oligosaccharide effective site, its molecular weight ranges are 200～1000, and stachyose wherein, cottonseed sugar, mannose and cane sugar content account for 85～90% weight ratios of described dried rehmannia root oligosaccharide effective site.
2. dried rehmannia root oligosaccharide according to claim 1 is through the lung drug-delivery preparation, it is characterized in that wherein said dried rehmannia root oligosaccharide effective site prepares by following method: with Radix Rehmanniae medical material is raw material, after water is carried, obtain Radix Rehmanniae total sugar, make by membrance separation then, comprise the following steps:
Get section of Radix Rehmanniae medical material or pulverizing, add 8～16 times of water extraction 2～4 times, merge the water extract, it is 1.03～1.08 60 ℃ that filtrate decompression is concentrated into relative density, and centrifugal or natural subsidence is got supernatant and passed through macroporous adsorptive resins, the water eluting, eluent is behind activated carbon decolorizing, and concentrating under reduced pressure gets the total sugar juice of the Radix Rehmanniae; Getting the total sugar juice of the Radix Rehmanniae is that 1000 ultrafilter membrane and molecular cut off are the NF membrane of 150-200 by molecular cut off successively, obtains the nanofiltration concentrated solution, and drying promptly gets the dried rehmannia root oligosaccharide position.
3. dried rehmannia root oligosaccharide according to claim 2 is through the lung drug-delivery preparation, it is characterized in that, in the preparation method at described dried rehmannia root oligosaccharide position, described macroporous adsorbent resin is a nonpolar macroporous adsorption resin, the post blade diameter length ratio is 1: 4～1: 8, liquor strength is every milliliter and contains medical material 0.2～0.5g, water elution, the eluent of 3～6 times of resin bed volumes of collection.
4. dried rehmannia root oligosaccharide according to claim 2 is characterized in that through the lung drug-delivery preparation described macroporous adsorbent resin is selected from AB8, D101, HPD100, HPD450, HZ801 or HZ816.
5. dried rehmannia root oligosaccharide according to claim 2 is characterized in that through the lung drug-delivery preparation described macroporous adsorbent resin is selected from HPD100, D101, HZ801 or HZ816.
6. dried rehmannia root oligosaccharide according to claim 2 is characterized in that through the lung drug-delivery preparation wherein said activated carbon dosage is 0.1～0.3%, decolours 1～3 time.
7. dried rehmannia root oligosaccharide according to claim 2 is characterized in that through the lung drug-delivery preparation in the described membrance separation, the ultrafilter membrane material of employing is selected from organic ultrafilter membrane, fluoro containing polymers family macromolecule polymeric film, inorganic ultrafilter membrane or NF membrane.
8. dried rehmannia root oligosaccharide according to claim 7 is characterized in that through the lung drug-delivery preparation, and in the wherein said membrance separation, organic ultrafilter membrane material is selected from cellulose family, polyamide-based, aromatic heterocycle class, polysulfones, TPO or silicone rubber kinds ultrafilter membrane.
9. dried rehmannia root oligosaccharide according to claim 8 is through the lung drug-delivery preparation, it is characterized in that wherein said organic ultrafilter membrane material is selected from: polysulfones, cellulose acetate, phthalein side group polysulfones, polyacrylonitrile, cyanoethyl cellulose, SPSF, quaternary ammoniated polysulfones, polyamide, Kynoar, poly-carbon vinegar ester, polyacrylonitrile, polyether sulfone, chitosan, naphthyridine ketone structure polyether sulfone, nylon, polyvinyl alcohol, porous polyether sulfone, acrylonitrile, acrylamide or styrene copolymer; Described inorganic ultrafilter membrane is selected from ceramic membrane, metal film, glass-film, zeolite, charcoal element or silicate.
10. dried rehmannia root oligosaccharide according to claim 7 is characterized in that through the lung drug-delivery preparation wherein said NF membrane is selected from organic membrane, inoranic membrane or organic and inorganic mineral film.
11. dried rehmannia root oligosaccharide according to claim 10 is through the lung drug-delivery preparation, it is characterized in that wherein said organic membrane is selected from aromatic polyamides class composite membrane, poly-piperazine acidamide composite nanometer filtering film, sulfonated polyether sulfone class composite nanometer filtering film, mixed type composite nanometer filtering film; Described inoranic membrane is selected from ceramic membrane, metal film, glass-film.
12. dried rehmannia root oligosaccharide according to claim 10 is through the lung drug-delivery preparation, it is characterized in that wherein said organic membrane is selected from: polysulfones, cellulose acetate, polyamide, polyvinyl alcohol, SPSF, sulfonated polyether sulfone, polrvinyl chloride, melamine/phenolic resins or melamine/polypropylene; Described ceramic membrane is selected from γ-Al
2O
3, ZrO
2, TiO
2, anodised aluminium or hafnium oxide.
13. through the lung drug-delivery preparation, it is characterized in that in the described membrance separation, the ultrafilter membrane of employing is shaped as rolling, tubular type, flat or doughnut formula by the described dried rehmannia root oligosaccharide of claim 7.
14. through the lung drug-delivery preparation, it is characterized in that by the described dried rehmannia root oligosaccharide of claim 1 described making through the lung drug-delivery preparation sucks powder spray, aerosol or atomized inhalation.
15. through the lung drug-delivery preparation, it is characterized in that by the described dried rehmannia root oligosaccharide of claim 14 described powder spray comprises the component of following weight percent:
16. dried rehmannia root oligosaccharide according to claim 15 is characterized in that through the lung drug-delivery preparation pharmaceutic adjuvant in the described powder spray is selected from one or more of sugar alcohol, saccharide, aminoacid or other adjuvant.
17. dried rehmannia root oligosaccharide according to claim 15 is characterized in that through the lung drug-delivery preparation described powder spray adds ball mill comminuting method or comminution by gas stream preparation by spray drying method, lyophilization.
18. through the lung drug-delivery preparation, it is characterized in that described aerosol is made up of 10～40% dried rehmannia root oligosaccharides and 60～90% adjuvants by the described dried rehmannia root oligosaccharide of claim 14; By the preparation of following method: after getting dried rehmannia root oligosaccharide and being dissolved in water, add adjuvant, filter, quantitatively packing, or get dried rehmannia root oligosaccharide and be dissolved in water, filtering, quantitatively packing is by the nebulizer administration; Described adjuvant comprises additives and propellant.
19. the dried rehmannia root oligosaccharide of claim 1 is through the application of lung drug-delivery preparation in preparation treatment chronic obstructive pulmonary disease medicine.
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| CN100354290C (en) * | 2005-05-23 | 2007-12-12 | 青岛国风药业股份有限公司 | Raffinoses oligosaccharide with stachyose as main materials and method for preparing same |
| CN100537583C (en) * | 2005-12-30 | 2009-09-09 | 上海中医药大学附属曙光医院 | Dried rehmannia root oligosaccharide and its preparation method and uses |
| CN100575357C (en) * | 2006-03-24 | 2009-12-30 | 厦门牡丹香化实业有限公司 | A kind of method of from glutinous rehmannia, extracting rehmannia root oligose and Dihuang polysaccharide simultaneously |
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