CN108721219A - A kind of bioadhesive lung inhales Nano Composite Particles and preparation method thereof - Google Patents
A kind of bioadhesive lung inhales Nano Composite Particles and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology field, it is related to a kind of bioadhesive compound lung and inhales Nano Composite Particles and its preparation.The Nano Composite Particles are the nanocrystals of the anti-asthma and chronic obstructive pulmonary disease drug by one or two kinds of water-soluble anti-asthma and chronic obstructive pulmonary disease drug and another slightly solubility while being mounted to formed in the framework material with bioadhesive.The composite particles use spray drying technology, it can be achieved that：1. improving the dissolution rate of insoluble drug, realizes the synchronous release of several different solubility property drugs, preferably play its synergistic effect；2. ensureing the uniform mixing of the larger several drugs of dose difference, the technical process of preparation is greatly simplified, improves drug quality, reduces cost, reduces energy consumption；3. the application of bioadhesive material is effective against the scavenging effect of pulmonary mucus cilium, extends lung's residence time, improve the drug concentration of lesions position, delay the absorption of drug, reaches the generation for improving curative effect, reducing whole body toxic side effect.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of bioadhesive compound lung and inhales Nano Composite Particles and its preparation
Method further relates to application of the composite particles in preparing treatment asthma and chronic obstructive pulmonary disease.
Background technology
Pulmonary inhalation is the treatment optimal approach of pulmonary disease.Drug may be deposited directly to lesion portion after sucking
Position, energy rapid-onset, easily reaches higher lung local drug concentration.Compared with the systemic administrations mode such as intravenous injection, oral,
Lung's sucking can also reduce or even avoid the toxic side effect to other non-drug site of action.Asthma and chronic obstructive pulmonary disease
Glucocorticoid and beta-receptor agonist and/or m receptor antagonist is used in combination it is also preferred that lung suction approach administration in clinical treatment more
Come act synergistically (two or three compound preparations), inflammation in air flue is eliminated while expansion bronchus.
Currently, lung's sucking preparation of Clinical practice includes three kinds of aerosol, powder spray (Foradil Aerolizer formoterol fumarate) and water mist agent.
Wherein, Foradil Aerolizer formoterol fumarate is a kind of respiratory tract administration dosage form of newer type.It the advantage is that：1. can come by the air-breathing of user
Drug is delivered, the probability for improving proper use of sucking product is conducive to；2. the powder spray of solid dry powder has drug substance stable
Property it is high, environmentally safe, the advantages that preservative without stimulation mucous membrane.The conventional flowsheet of Foradil Aerolizer formoterol fumarate includes raw material
The crushing of medicine, mixing, filling etc..Since dosage is small, each active medicine of compound is formed in dosage, physicochemical property side
Face difference is again very huge, can face the non-uniform problem of mixing when using dry powder powder spray of the common process to prepare lung suction,
Thus increase the difficulty, complexity and the cost of production of technique.In addition, the conventional micro mist poor fluidity being grinding to obtain,
It needs during inhalation well to disperse by bulky grain carrier as lactose, the pulmonary deposition ratio of drug is relatively low.
Further, since the amount of pulmonary mucus is very limited, the glucocorticoid medicine of slightly solubility is very slow in lung's dissolving, with water
It is extremely difficult to synchronous release after the stronger beta-receptor agonist of dissolubility and/or m receptor antagonist class drug composition compound, hinders him
Preferably play synergistic effect.Along with there is many intrinsic purge mechanisms, such as mucociliary clearance, macrophage in lung
Phagocytosis, metabolism, absorbed into serum etc., these purge mechanisms remove the transpulmonary drug granule for sucking and being deposited on lung from lung,
Drug is shortened in the residence time of lung, reduces local drug concentration.
Be concentrated mainly at present with the relevant research work of powder spray by improve dry powder particle dry jet mixing pile as
The size of grain, form, roughness, interaction force between drug granule and carrier etc. come improve particle lung deposition
Rate, and the research that sustained-release preparation is inhaled based on the lung of bioadhesive high molecular material is considerably less.
Invention content
The purpose of the invention is to overcome the deficiencies of existing technologies, one kind is provided and can effectively solve the problem that dosage, physics and chemistry
The compound lung suction dust cloud preparation medicine dissolution rate for the drug composition that matter differs greatly is inconsistent, hybrid technique difficulty is big and makes
Agent is low in pulmonary deposition ratio, and the bioadhesive compound lung that the residence time is short, drug eliminates the problems such as fast inhales Nano Composite Particles
Powder spray.
The present invention is achieved by the following technical solutions：
It includes active medicine and bioadhesive material that bioadhesive lung of the present invention, which inhales Nano Composite Particles,.
The active medicine is formed by water soluble drug and insoluble drug are nanocrystalline；Including the anti-asthma of 2-3 kinds and slow lung
The drug of resistance wherein at least contains a kind of glucocorticoids medicine of slightly solubility and one or two kinds of water-soluble beta-receptor agonisms
Agent and/or M- receptor antagonists.
Specifically, the active medicine is by water-soluble beta-receptor stimulating agent and/or M- receptor antagonists and slightly solubility sugar
Corticoid medicament nano crystalline substance forms.
The beta-receptor agonist and/or m receptor antagonist is bronchodilator, including salbutamol, propionic acid times
Chlorine rice pine, bricalin, datro, Formoterol, SCH 1000, salmeterol, plug support bromine ammonium, Vilantro,
One or more combinations in Procaterol, bambuterol, clenbuterol, Fino Tero, Levosalbutamol.
The glucocorticoid medicine is selected from：Budesonide, fluticasone propionate, fluticasone furoate, propionic acid times
One or more mixing in chlorine rice pine, pednisone, hydrocortisone, prednisolone, prednisone, methylprednisolone.
Water-soluble beta-the receptor stimulating agent and/or m receptor antagonist accounts for the 1%-50% of drug total amount, and slightly solubility
The summation of the nanocrystalline 50-99% for accounting for drug total amount of glucocorticoid, the two account for 10~83% (g/ of composite particles total weight
g)；
Preferably, water-soluble beta-receptor stimulating agent and/or m receptor antagonist account for the 2.7%-50% of drug total amount, indissoluble
Property glucocorticoid nanocrystal accounts for the 50-97.3% of medicine gross weight, and the summation of the two accounts for the 16.8- of composite particles gross weight
60.7%.
The nanocrystalline grain size of the slightly solubility glucocorticoid medicine is within the scope of 50-1000nm, it is highly preferred that grain size
For 100~400nm.
The bioadhesive material is selected from：Hyaluronic acid, cellulose, natural gum, hydroxypropyl cellulose, chitosan, Portugal
One or more mixtures in poly- carbohydrates and their derivative；
Bioadhesive material accounts for 17~90% (g/g) of particle total weight.
Further, bioadhesive material accounts for the 39.3-83.2% of particle total weight.
The bioadhesive material is preferably：The mixture of hyaluronic acid, chitosan or the two.
When bioadhesive material is the mixture of hyaluronic acid and chitosan, the ratio of hyaluronic acid and chitosan is
6:1~1:2.With this condition, the composite particles of preparation have stronger lung's mucous membrane adhesiveness, can block water solubility well
The quick release of drug, and with preferably aerodynamic property, can get higher pulmonary drug deposition.
Water soluble drug is 1 with the nanocrystalline weight ratio of insoluble drug:2~1:36.
The weight ratio of water soluble drug and bioadhesive material is：1:0.6~1:329.
Further, the weight ratio of water soluble drug and bioadhesive material is 1:2~1:181.
The nanocrystalline weight ratio with bioadhesive material of insoluble drug is：1:0.3~1:9.
Further, the nanocrystalline weight ratio with bioadhesive material of insoluble drug is 1:1~1:5.
Then it is 1 with the weight ratio of bioadhesive material when water soluble drug is short-acting beta-receptor agonist:2~1:
15；
When water soluble drug is long-acting beta-ceptor agonist formoterol, it is with the weight ratio of bioadhesive material then
1:146~1:181；
When water soluble drug is other long-acting beta-receptor stimulating agents, such as salmeterol, when Vilantro, with bioadhesion
Property material weight ratio be 1:20~1:54；
When water soluble drug is m receptor antagonist, the ratio with bioadhesive material is 1:18-1:49.
The short-acting beta-receptor agonist is selected from：Salbutamol sulfate or bricalin；
Long-acting beta-the receptor stimulating agent is selected from：Formoterol；
Other long-acting beta-receptor stimulating agents are selected from：Salmeterol, Vilantro, datro, salmeterol, dimension
One kind in Lactel sieve, Procaterol, bambuterol, clenbuterol, Fino Tero, Levosalbutamol；
The m receptor antagonist is selected from：Ipratropium Bromide, plug support bromine ammonium.
It is to be formed while being wrapped up by spray drying technology that the bioadhesive compound lung of the present invention, which inhales Nano Composite Particles,
The inhalable bioadhesive microspheres dry powder of drug molecule and medicament nano crystal.It is prepared via a method which：
First, bioadhesive polymer is dispersed in appropriate vehicle, is stirred to dissolve, water-soluble β-is then added
Receptor stimulating agent and/or m receptor agonist component, make it fully dissolve, then by the nanometer of slightly solubility glucocorticoid medicine
Crystalline substance is dispersed in the solution of bioadhesive polymer, and being made finally by spray drying technology has jujube cake fluid mosaic model structure special
Levy, be suitable for the bioadhesion composite particles of lung suction.
Specifically,
1) a certain amount of bioadhesive polymer dry powder is added in appropriate solvent, is stirred at room temperature to abundant dissolving or swelling,
It is configured to the solution of a concentration of 0.1-3.0% (g/v)；
2) by water-soluble active medicine, i.e. beta-receptor agonist and/or m receptor agonist component adds to above-mentioned biological slime
It in attached agent solution, is sufficiently stirred, it is made fully to dissolve.Wherein, the weight of water-soluble active drug total amount and bioadhesive material
Amount is than being 1:2~1:181 ranges.Specifically, different and different according to the type of selected water soluble drug.
3) by nanocrystalline (the i.e. nanometer of glucocorticoid medicine of the slightly solubility glucocorticoid medicine prepared in advance
Suspension) it is quantitative, it adds in above-mentioned bioadhesion agent solution, is sufficiently stirred, keep its evenly dispersed.Wherein slightly solubility sugar cortical hormone
The weight ratio of plain nanocrystal and bioadhesive material is 1:1~1:5.
4) by water-soluble beta-receptor stimulating agent and/or m receptor antagonist, slightly solubility glucocorticoid medicine it is nanocrystalline
Nano Composite Particles are made by spray drying in the mixed system of body and bioadhesive polymer.
Solvent described in step 1) is selected from：Water, aqueous acetic acid, ethyl alcohol, acetone and their mixture.
Slightly solubility glucocorticoid medicine described in step 3) is nanocrystalline by method commonly used in the prior art,
Such as：The acquisitions such as media milling process, high pressure homogenization method, nanoprecipitation method, emulsion process, supercritical fluid technique.Wherein preferred medium
Polishing is prepared via a method which：Insoluble drug powder is scattered in the F68 aqueous solutions of 0.1-0.4%, ball milling is added
In tank, the ball milling pearl of a diameter of 0.5mm of 100g is added, ball grinder is covered, is fixed in ball mill, starts to grind, when grinding
Between 5-10min, intermittent time 2-3min, in total milling time obtain receiving for slightly solubility glucocorticoid medicine in 30-240min
Rice suspension.
For the particle size range of medicament nano crystalline substance within the scope of 50~1000nm, nanocrystalline particle size directly affects slightly solubility
The dissolution rate of drug, to influence its body absorption rate.It is nanocrystalline according to the solubility of selected slightly solubility glucocorticoid
Grain size is preferably 100~400nm.When nanocrystalline particle size range is within the scope of preferred 100~400nm, and it is nanocrystalline with it is raw
The weight ratio of object adhesive is 1:0.31~1:When 9.25, the buffered liquid of the particle that is adhered on lung mucous membrane rinse 1 hour after still
There is nearly 30% particle to be adhered to mucomembranous surface, and when the nanocrystalline weight ratio with bioadhesive polymer is 1:0.97~1:5.09
When, the buffered liquid of the particle that is adhered on lung mucous membrane has more than 40% particle after rinsing 1 hour is adhered to mucomembranous surface, can have
Effect improves the drug lung local retention time, and can effectively improve the release of insoluble drug and prevent the release of water soluble ingredient,
And then reach synchronous release.
Present invention combination nanotechnology, bioadhesive particles technology and particle engineering techniques, first lead to insoluble drug
Nanotechnology quick-release processed is crossed, is then uniformly mixed in solvent together with water soluble drug, it will be several by particle engineering techniques
Kind is distinct, dosage differs huge drug and is embedded in adhesion material, and it is multiple to form the inhalable nanometer with bioadhesive
Close particle.By optimizing drying process with atomizing parameter, higher drug pulmonary deposition ratio is obtained, simplifies technique, reduces cost, carry
The high quality of the pharmaceutical preparations；By adjusting nanocrystalline granularity, the type of adhesion material, the proportioning between each formulation ingredients is improving
On the basis of insoluble drug dissolution rate, synchronous absorption, more preferable performance synergistic effect are realized, while extending drug in lung
Residence time improves drug local drug concentration and duration, to improve drug therapeutic indices.
The present invention can with the rate of release of 1. regulating medicines, to realize different physicochemical properties drug synchronous release,
It is more preferable to play synergistic effect；2. effectively antagonizing pulmonary mucus cilium scavenging effect, extend lung's residence time, improves treatment and refer to
Number；3. particle has preferable mobility, easily disperse, aerodynamic size is moderate, is not necessarily to carrier, can get higher lung
Deposition.That is a composite particles solve various problems, and final realize improves drug part drug effect, reduce systemic drug exposure
Amount reduces toxic side effect, improves the purpose for the treatment of effect.
The aerodynamic size of the Nano Composite Particles of the present invention is 0.5~10 μm, preferably 1~5 μm, is had good
Mobility, dispersibility, be suitble to the administration of lung inhalation route, wherein particulate subfraction (fine particle fraction) reaches
30% or more, far above the requirement (i.e. 10%) to FPF under powder spray quality standard item in pharmacopeia.And preparation process step of the present invention
It is rapid few, and solve the problems, such as that the low dosage component uniformity is poor in the larger compound preparation of component ratio great disparity, improves
Drug quality simplifies technical process.In addition, Nano Composite Particles in the present invention are by insoluble drug glucocorticoid
On the basis of class drug quick-release, the drug for keeping two class physicochemical property differences larger by the control of adhesion material is with comparable speed
Degree release, absorbs, and extends the drug local retention time, ensures that they preferably play synergistic effect.
Description of the drawings
Fig. 1 is the photograph of sample state in lung mucoadhesive evaluating apparatus schematic diagram (A) and evaluation procedure in test example 1
Piece (B)；
Fig. 2 is lung mucosal adhesive linearity curve in embodiment 1；
Fig. 3 is the interior medicine dynamics curve that latter two drug is administered through bronchus of rat for composite particles in embodiment 1；
Fig. 4 is the stereoscan photograph for the composite particles being prepared in embodiment 2；
Fig. 5 is lung mucosal adhesive linearity curve in embodiment 2；
Fig. 6 is lung mucosal adhesive linearity curve in embodiment 3；
Fig. 7 is lung mucosal adhesive linearity curve in embodiment 4；
Fig. 8 is the release profiles of two kinds of drugs in vitro in embodiment 4；
Fig. 9 is lung mucosal adhesive linearity curve in embodiment 5；
Figure 10 is the interior medicine dynamics song that latter two drug is administered through bronchus of rat for composite particles in embodiment 5
Line；
Figure 11 is lung mucosal adhesive linearity curve in embodiment 6；
Figure 12 is rat trachea dosing techniques figure in test example 3,4.
Specific implementation mode
Embodiment 1：Including salbutamol sulfate (salbutamol sulfate, SAS) and budesonide
The bioadhesive compound lung of (budesodine, BUD) nanocrystal inhales the preparation of Nano Composite Particles (SAS-BUD-HA/MS)
Hyaluronic acid 0.5g is weighed, 100mL double distilled waters are added, magnetic agitation sequentially adds sand to abundant swelling, dissolving
Butylamine alcohol 250mg and grain size containing 100mg are the nanocrystalline suspension 2mL of the budesonide of 200 ± 2nm, and continuing stirring makes medicine
Object is uniformly dispersed, and is spray-dried.As a contrast, the bulk pharmaceutical chemicals of salbutamol sulfate and budesonide are proportionally added into weight
It steams in water (8%, w/v), is uniformly dispersed, is spray-dried.The condition of spray drying is：160 DEG C of inlet temperature, dry air
Flow 35m3/ h, atomizing pressure 414L/h, feed speed 4.5mL/min are prepared and are received comprising salbutamol and budesonide
The bioadhesive lung of meter Jing Ti inhales Nano Composite Particles.
Using ram of new generation (NGI) determine composite particles aerodynamic size and particle in grain size be less than 5
Fine particle score (FPF values), respectively 4.9 ± 2.3 μm and 33.7 ± 0.6%.
Particle be adhered on lung mucous membrane and buffered liquid rinse 1 hour after still there is nearly 50% particle to be trapped in mucous membrane table
Face shows that the composite particles have the longer residence time (Fig. 1,2) on isolated pig lung mucous membrane.
Rats pharmacokinetics experimental result (Fig. 3) shows that the skeleton of hyaluronic acid can effectively adjust water-soluble sand
The release of both budesonides of butylamine alcohol and water slightly solubility, the pharmacokinetic parameters for keeping its internal synchronize, and have similar up to peak
Time (Tmax) and similar internal residence time.
Embodiment 2：Including salmeterol (Salmeterol, ST) and fluticasone propionate (Fluticasone
Propionate, FP) nanocrystal bioadhesive lung inhale Nano Composite Particles (ST-FP-HA/MS) preparation
Hyaluronic acid 1.5g is weighed, 150mL redistilled waters are added, magnetic agitation makes it fully be swollen, dissolve, successively accurately
Salmeterol 120mg and average grain diameter containing 600mg is added as the nanocrystalline suspension of the fluticasone propionate of 200 ± 10nm
50mL continues to stir, and so that two kinds of drugs is uniformly dispersed in the solution, is spray-dried.As a contrast, by salmeterol and third
The bulk pharmaceutical chemicals of sour fluticasone are proportionally added into redistilled water (10%, w/v), are uniformly dispersed, and are spray-dried.Spray drying condition
It is：Spray drying condition is 120 DEG C of inlet temperature, dry air flow 35m3/ h, atomizing pressure 414L/h, feed speed
6.0mL/min is obtained and is inhaled Nano Composite Particles comprising the bioadhesive lung of salmeterol and fluticasone propionate.
The scanned Electronic Speculum observation of appearance of composite particles is as shown in Fig. 4.
Using ram of new generation (NGI) determine composite particles aerodynamic size and particle in grain size be less than 5
Fine particle score (FPF values), respectively.4.5 ± 3.3 μm and 43.1 ± 0.8%
Particle be adhered on lung mucous membrane and buffered liquid rinse 1 hour after still there is nearly 60% particle to be trapped in mucous membrane table
Face shows that the composite particles have the longer residence time (Fig. 5) on isolated pig lung mucous membrane.
Embodiment 3：Including Vilantro (Vilanterol, VT) and fluticasone furoate (Fluticasone
Furoate, FF) nanocrystal bioadhesive lung inhale Nano Composite Particles (VT-FF-CS/MS) preparation
Pharmaceutic adjuvant chitosan 1.0g is weighed, 0.5% aqueous acetic acid 150mL is added and stirs to dissolving, it is accurate successively to add
Enter Vilantro 67mg and the nanocrystalline suspension 50mL of fluticasone furoate containing 533mg, stirs evenly, be spray-dried.Make
For control, the bulk pharmaceutical chemicals of Vilantro and fluticasone furoate are pressed 1:8 ratio is scattered in redistilled water (5%, w/v) progress
Spray drying.Spray drying condition is：120 DEG C of inlet temperature, dry air flow 35m3/ h, atomizing pressure 357L/h, into liquid speed
4.5mL/min is spent, the bioadhesive lung comprising Itraconazole nanometer crystalline substance is obtained and inhales Nano Composite Particles.
Using ram of new generation (NGI) determine composite particles aerodynamic size and particle in grain size be less than 5
Fine particle score (FPF values), respectively 4.3 ± 2.3 μm and 39.4 ± 0.8%.
Particle be adhered on lung mucous membrane and buffered liquid rinse 1 hour after still there is nearly 55% particle to be trapped in mucous membrane table
Face shows that the composite particles have the longer residence time (Fig. 6) on isolated pig lung mucous membrane.
Embodiment 4：Including plug support bromine ammonium (Tiotriopium Bromide, TB) and fluticasone furoate
The bioadhesive lung of (Fluticasone furoate, FF) nanocrystal inhales Nano Composite Particles (TB-FF-CS-HA/MS)
Preparation
Pharmaceutic adjuvant chitosan 0.5g and hyaluronic acid 0.2g is weighed, 0.5% aqueous acetic acid 100mL is added and stirs to molten
Solution, swelling sequentially add the suspension 20mL of 0.023g plug support bromine ammonium and the nanocrystal of fluticasone furoate containing 0.257g, stir
It mixes, is uniformly mixed, is spray-dried.As a contrast, plug support bromine ammonium and fluticasone furoate bulk pharmaceutical chemicals are pressed 9:100 ratio
It is added in redistilled water (5%, w/v), is uniformly dispersed, is spray-dried, spray drying condition is：120 DEG C of inlet temperature, dry air
Flow 35m3/ h, atomizing pressure 357L/h, feed speed 4.5mL/min are obtained comprising plug support bromine ammonium and fluticasone furoate nanometer
Brilliant bioadhesive lung inhales Nano Composite Particles.
Using ram of new generation (NGI) determine composite particles aerodynamic size and particle in grain size be less than 5
Fine particle score (FPF values), respectively 5.6 ± 1.7 μm and 38.1 ± 0.8%.
Particle be adhered on lung mucous membrane and buffered liquid rinse 1 hour after still there is 59% particle to be trapped in mucomembranous surface,
Show that the composite particles have the longer residence time (Fig. 7) on isolated pig lung mucous membrane.
External drug release rate investigates result and shows that (Fig. 8) plug support bromine ammonium and the nanocrystalline of fluticasone can be with almost same
The speed of step is discharged from HA skeletons, realizes the synchronous release of two medicines.
Rats pharmacokinetics experimental result (Fig. 9) shows that the skeleton of hyaluronic acid can effectively adjust water-soluble plug
It asks the release of both fluticasone furoates of bromine ammonium and slightly water-soluble, the pharmacokinetic parameters for keeping its internal to synchronize, has similar
Peak time (Tmax) and similar internal residence time.
Embodiment 5：Including Ipratropium Bromide (Ipratropium Bromide, IB), Formoterol (Formoterol,
FT) and the bioadhesive lung of fluticasone furoate (Fluticasone furoate, FF) nanocrystal inhales Nano Composite Particles
(IB-FT-FF-HA/MS) preparation
Hyaluronic acid 1.0g is weighed, 100mL redistilled waters are added, magnetic agitation sequentially adds isopropyl to abundant swelling, dissolving
Bromine ammonium 17.8mg, Formoterol 4mg and the fluticasone furoate nanocrystal suspension 50mL containing 178.2mg are held in the palm, continues to stir
Mixing makes to be uniformly dispersed, and is spray-dried.As a contrast, by Ipratropium Bromide, Formoterol and fluticasone furoate bulk pharmaceutical chemicals
(8%, w/v) is scattered in redistilled water to be spray-dried.Spray drying condition is 150 DEG C of inlet temperature, dry air flow
35m3/ h, atomizing pressure 414L/h, feed speed 4.5mL/min are obtained comprising Ipratropium Bromide, Formoterol and furancarboxylic acid fluorine for card
The bioadhesive lung that loose nanocrystal Three doses differ larger drug inhales Nano Composite Particles.
Using ram of new generation (NGI) determine composite particles aerodynamic size and particle in grain size be less than 5
Fine particle score (FPF values), respectively 4.7 ± 2.1 μm and 43.8 ± 0.8%.
Particle be adhered on lung mucous membrane and buffered liquid rinse 1 hour after still there is nearly 68% particle to be trapped in mucous membrane table
Face shows that the composite particles have the longer residence time (Figure 10) on isolated pig lung mucous membrane.
Embodiment 6:Including the bioadhesive lung of formoterol fumarate (FF) and budesonide (BUD) nanocrystal is inhaled
The preparation of Nano Composite Particles (FF-BUD-HPC/MS)
Hydroxypropyl cellulose 0.7g is weighed, 150mL redistilled waters are added, magnetic agitation makes it fully be swollen, dissolve, successively
Formoterol fumarate 10mg and grain size containing 355.5mg is added as the nanocrystalline suspension of the budesonide of 350 ± 3nm
50mL continues to stir, and so that two kinds of drugs is uniformly dispersed in the solution, is spray-dried.As a contrast, by fumaric acid Fu Mote
The bulk pharmaceutical chemicals of sieve and budesonide are proportionally added into redistilled water (8%, w/v), are uniformly dispersed, are spray-dried.Spray drying item
Part is：150 DEG C of inlet temperature, dry air flow 35m3/ h, atomizing pressure 536L/h, feed speed 6.0mL/min must be wrapped
The bioadhesive lung of formoterol fumarate and budesonide nanocrystal inhales Nano Composite Particles.
Using ram of new generation (NGI) determine composite particles aerodynamic size and particle in grain size be less than 5
Fine particle score (FPF values), respectively 6.3 ± 3.3 μm and 29.7 ± 0.4%.
Particle be adhered on lung mucous membrane and buffered liquid rinse 1 hour after still there is nearly 40% particle to be trapped in mucous membrane table
Face shows that the composite particles have the longer residence time (Figure 11) on isolated pig lung mucous membrane.But it is poly- with hyaluronic acid or shell
The microballoon of sugar is compared, hold-up energy force difference, and grain size is big, and particulate subfraction is low.
Test example 1.：Complex microsphere aerodynamic size measures
By " fixture of new generation has/does not have preseparator for metered dose inhalation aerosol and powder spray " (《Europe
Pharmacopeia》7th edition device E (NGI)) it operates under item.Before measurement starts, by volume shown in table 1, respectively by coating solution (10% (v/
V) Tween-20 ethanol solution) catch trays at different levels are spread evenly across, catch tray is placed in clean draught cupboard, is placed about 30min and is volatilized
Ethyl alcohol forms uniform and thin coating.3#HPMC capsules 1 are taken, it is dry that inside loads about 10mg (embodiment 1-4) composite particles
Powder, dry powder quality in accurately weighed capsule.Each catch tray is sequentially placed into device, connects instrument, and by adjusting TPK2000
The throughput of NGI is set to reach 100 ± 5L/min.Capsule is fitted into suction apparatus, and shaking 10s keeps dry powder fully dispersed, by suitable
Orchestration connects suction apparatus and instrument, press device both sides button puncture capsule.It adjusts TPK2000 and enters program setting, often
Secondary pumping continues 2.4s, and each capsule is evacuated 3-5 times.Into test program, in pressure 4kPa, 100 ± 5L/min of pumping airflow
Under the conditions of, it is tested, measures a capsule every time, each prescription parallel determination is three times.After measuring every time, vacuum is closed
Pump removes device, with acetonitrile solution (30:70, v/v) it is respectively washed each catch tray, cleaning solution is collected into volumetric flask, is used
Acetonitrile solution (30:70, v/v) it is settled to scale, is shaken up.And high-efficient liquid phase analysis is carried out to solution in volumetric flask, it measures each
Budesonide content in catch tray.Catch trays at different levels retention grain size and the accumulation of particulates percentage being collected into return and divided
Analysis is gone out micro- less than 5 μm of grain sizes using regression equation calculation
The volume of NGI devices retention grain sizes at different levels and required coating solution under table 1 100 ± 5L/min throughputs
Grain content, is denoted as FPF values.Aerodynamic size is less than 5 μm of particles, can be deposited on lung, plays therapeutic effect,
Therefore the pulmonary deposition ratio of particle is indicated with FPF values.
Test example 2：Lung inhales the morphologic observation of Nano Composite Particles (embodiment 2)
The surface shape of particle is observed with scanning electron microscope (Scanning Electron Microscope, SEM)
State.Operating process is as follows：Appropriate sample to be tested is taken, sample stage is scattered in, dehydration sprays golden particle, metal spraying thickness control
In 10nm or so, the measurement of sample morphology, accelerating potential 15kV are carried out.
Test example 3:Lung inhales adhesivity evaluation of the Nano Composite Particles (embodiment 1-4) to lung mucous membrane
Take 10cm or so long, the fresh lung mucous membrane in vitro 1h cleans surface bloodstain with physiological saline.By known quantity
Drug containing lung inhales Nano Composite Particles (about 5mg) and the spray drying particle (about 5mg) of corresponding pure drug is scattered in respectively on this mucous membrane,
Diffusional area is about 2.25cm2, the mucous membrane is then cultivated into 30min in 90% constant humidity environment, then be fixed in respectively poly-
It on ethylene arc-like sheet, and is placed horizontal by 45 °, installation drawing is as shown in Figure 1.It is rinsed with 37 ± 0.5 DEG C of PBS of preheating
1h, flow velocity are controlled the concentration of the drug in 5mL/min, collection flushing liquor, Syrups by HPLC flushing liquor by peristaltic pump, obtained
To lung mucosal adhesive linearity curve.
The lung prepared in embodiment inhales Nano Composite Particles and all has preferable bioadhesive, and purer medicine microspheres are in lung
The residence time is more long on mucous membrane.
Test example 4：Compound salbutamol sulfate budesonide lung (embodiment 1) inhales Nano Composite Particles medicine in rat body
It is dynamic to learn research
It takes male SD rat 8, after fasting 12h, every rat is weighed, label.By 0.2mg budesonides,
The dosage of 0.5mg salbutamol sulfates/100g rats claims drug to Model DP-4-RTMDry powder drug administration device is inserted into containing sky
The syringe of air column, for use；It is fixed by rat anesthesia, it fixes rat oral cavity by laryngoscope and finds rat rima glottidis, will be administered
Device is inserted into rima glottidis, and insertion depth is that device leading portion conduit bending place is located at rat front tooth, bolus syringe piston,
Complete rat trachea administration.Intratracheal administration operation is as shown in figure 12.
Rat 0.083h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, for 24 hours and 48h after administration
Blood 0.5mL is taken respectively at retroorbital venous, centrifuges 5min under 4 DEG C, 14800rpm rotating speeds rapidly, takes upper plasma sample, it is high
It imitates liquid phase method and surveys plasma sample drug concentration, change over time as shown in Figure 3.
Test example 4：Compound plug support bromine ammonium and fluticasone furoate bioadhesion compound lung inhale Nano Composite Particles (embodiment
4) vitro drug release degree measures
10mg microballoons are weighed, 5mL is added to containing in 0.2% PBS (pH7.4) buffer solution, in the case where ensureing sink conditions, is placed in
The measurement of vitro release, hunting speed 200rmin are carried out in level-constant temperature oscillation instrument-1, drug release temperature is 37 DEG C.?
The time point of default settings, 4000rmin-1After centrifuging 1min, 1mL is taken out, is supplemented the warmed-up fresh of same volume
The solution of PBS, taking-up are analyzed with HPLC, obtain the In-vitro release curves of microballoon, as shown in Figure 8.
Test example 5:Compound plug support bromine ammonium and fluticasone furoate bioadhesion compound lung inhale Nano Composite Particles (embodiment
4) it is studied in rat Internal pharmacokinetics
It takes male SD rat 8, after fasting 12h, every rat is weighed, label.Support bromine is filled in by 0.03mg/100g
The dosage of ammonium and 0.30mg/100g fluticasone furoates claims drug to Model DP-4-RTMDry powder drug administration device is inserted into containing sky
The syringe of air column, for use；It is fixed by rat anesthesia, it fixes rat oral cavity by laryngoscope and finds rat rima glottidis, will be administered
Device is inserted into rima glottidis, and insertion depth is that device leading portion conduit bending place is located at rat front tooth, bolus syringe piston,
Complete rat trachea administration.Intratracheal administration operation is as shown in figure 11.
Rat 0.083h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 4h, 6h, 8h, 12h, for 24 hours and 48h after administration
Blood 0.5mL is taken respectively at retroorbital venous, centrifuges 5min under 4 DEG C, 14800rpm rotating speeds rapidly, takes upper plasma sample, it is high
It imitates liquid phase method and surveys plasma sample drug concentration, change over time as shown in Figure 9.
Claims (10)
1. a kind of bioadhesive compound lung inhales Nano Composite Particles, which is characterized in that the composite particles include active drug
Object and bioadhesive material, the active medicine is formed by water soluble drug and insoluble drug are nanocrystalline, and is at least contained
There is a kind of slightly solubility glucocorticoid medicine nanocrystalline and one or two kinds of water soluble drug beta-receptor agonists and/or M-
Receptor antagonist；The nanocrystalline insoluble drug is that glucocorticoid medicine is nanocrystalline；The bioadhesive material
Material is selected from：One kind or more in hyaluronic acid, cellulose, natural gum, hydroxypropyl cellulose, chitosan, glucan and its derivative
Kind of mixture, the water soluble drug account for the 1%-50% of drug total amount, and the nanocrystalline drug total amount that accounts for of insoluble drug
50-99%, the summation of the two account for the 10~83% of composite particles total weight, bioadhesive material account for particle total weight 17~
90%.
2. bioadhesive compound lung according to claim 1 inhales Nano Composite Particles, it is characterised in that：The indissoluble
The nanocrystal of property glucocorticoid medicine includes budesonide, fluticasone propionate, fluticasone furoate, propionic acid times chlorine rice
One or more nanocrystals in pine, pednisone, hydrocortisone, prednisolone, prednisone, methylprednisolone
Combination；The beta-receptor agonist and/or m receptor antagonist is bronchodilator, including salbutamol, propionic acid times chlorine rice
One in pine, bricalin, datro, Formoterol, SCH 1000, salmeterol, plug support bromine ammonium, Vilantro
Kind or a variety of combinations.
3. bioadhesive compound lung according to claim 1 or 2 inhales Nano Composite Particles, it is characterised in that：Described
Bioadhesive material is in hyaluronic acid, cellulose, natural gum, hydroxypropyl cellulose, chitosan, glucan and its derivative
One or more mixtures, preferably：The mixture of hyaluronic acid, chitosan or the two.
4. the bioadhesive compound lung according to claim 1-3 any one inhales Nano Composite Particles, it is characterised in that：
Water soluble drug beta-receptor agonist and/or M- receptor antagonists and the nanocrystalline weight ratio of slightly solubility glucocorticoid medicine
It is 1:2~1:36, water-soluble beta-receptor stimulating agent and/or the weight ratio of M- receptor antagonists and bioadhesive material are：1:
0.6~1:329, the nanocrystalline weight ratio with bioadhesive material of slightly solubility glucocorticoid medicine is：1:0.3~1:9.
5. the bioadhesive lung according to claim 1-4 any one inhales Nano Composite Particles, it is characterised in that：Indissoluble
The property nanocrystalline particle size range of glucocorticoid medicine is within the scope of 50~1000nm, preferably 100~400nm.
6. bioadhesive lung according to claim 1 inhales the preparation method of Nano Composite Particles, it is characterised in that：
1) a certain amount of bioadhesive polymer dry powder is added in appropriate solvent, is stirred at room temperature to abundant dissolving or swelling, is prepared
At the solution of a concentration of 0.1-3.0% (g/v)；
2) that water-soluble active medicine beta-receptor agonist and/or m receptor agonist component are added to above-mentioned bioadhesive polymer is molten
It in liquid, is sufficiently stirred, it is made fully to dissolve；
3) the slightly solubility glucocorticoid medicine prepared in advance is nanocrystalline quantitative, add to above-mentioned bioadhesion agent solution
In, it is sufficiently stirred, keeps its evenly dispersed；
4) by water-soluble beta-receptor stimulating agent and/or m receptor antagonist, the nanocrystal of slightly solubility glucocorticoid medicine with
Nano Composite Particles are made by spray drying in the mixed system of bioadhesive polymer.
7. preparation method as claimed in claim 6, which is characterized in that water soluble drug beta-receptor agonist and/or M- receptors
Antagonist is 1 with the nanocrystalline weight ratio of slightly solubility glucocorticoid medicine:2~1:36, water soluble drug and bioadhesion
Property material weight ratio be 1:2~1:181；The nanocrystalline weight ratio with bioadhesive material of insoluble drug is：1:0.3~
1:9。
8. preparation method as claimed in claim 6, which is characterized in that the solvent in step 1) is water, aqueous acetic acid, second
Alcohol, acetone and their mixture；Slightly solubility glucocorticoid medicine described in step 3) is nanocrystalline to pass through medium milling
Method, high pressure homogenization method, nanoprecipitation method, emulsion process, supercritical fluid technique obtain.
9. preparation method as claimed in claim 6, which is characterized in that the process regulation of spray drying is as follows：Import temperature
Degree is 110-190 DEG C, atomizing pressure 357-601L/h, and dry air flow is 25-28m3/ h, liquid supply speed 5.0-
7.0mL/min.Optimum condition is that inlet temperature is 120 DEG C, dry air flow 27m3/ h, atomizing pressure 473L/h, feed flow
Speed is 6.0mL/min.
It is preparing while treating 10. the bioadhesive compound lung described in Claims 1 to 5 any one inhales Nano Composite Particles
Application in the drug of bronchial asthma and chronic obstructive pulmonary disease.
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