CN102860979A - Multi-component drug composite particle administration system and preparation method - Google Patents
Multi-component drug composite particle administration system and preparation method Download PDFInfo
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Abstract
The invention belongs to the medicine technical field, and discloses a composite particle administration system suitable for multi-component drug combination delivery. According to the difference from physicochemical properties of each component, a twice encapsulation method is employed to prepare composite particle. A structure of the composite particle is characterized in that two particles with different molding mechanisms, structural characteristics and/or pharmacokinetic characteristics are mutually composited, the internal particle is core particle, and the external particle is shell particle. The particle size of the composite particle is between 5nm-2000nm, the external shell particle coats and/or encapsulates the shell particle. The composite particle administration system enables the entrapment rate of each drug component to tend to be consistent, thereby each component cooperates in proportion to generate the biological effect. An application of the administration system comprises the drug administration approaches through injection, oral administration, cavity, skin and the like for the composite particle preparations composited by chemical drugs, traditional Chinese medicine effective parts or components or chemical drugs and the traditional Chinese medicine components.
Description
Technical field
The present invention relates to medical technical field, more particularly relate to a kind of drug-supplying system and preparation method thereof.
Background technology
In recent years, be accompanied by the fast development of Drug therapy, drug regimen uses becomes the problem that people pay special attention to gradually, and especially for Chinese medicine preparation, multicomponent is its basic feature, and each composition can be worked in coordination with in proportion and be produced biological effect.
By utilizing the dynamic change in vivo of new technology and method regulating medicine, to obtain best therapeutic effect, Here it is drug-supplying system (drug delivery system, DDS).Utilize the effect of drug-supplying system, can improve medicine absorption, reduce poisonous side effect of medicine, improve medicine in the abundance of pathological tissues, realize the attenuation synergistic purpose.
Pharmaceutics is divided into two large classes: Nano medication and nano-carrier usually with the sizing 1nm-1000nm of nanoparticle.Nano medication refers to directly crude drug is processed into nanoparticle by technology such as micronizations.Nano-carrier is the various nanoparticles of medicine parcel, dissolving, dispersion.Composite particles of the present invention is composited mutually by two kinds of microgranules with different moulding mechanisms, architectural feature and/or characteristics of pharmacokinetics, so the particle diameter of composite particles increases to some extent, and the maximum particle diameter scope is 5nm-2000nm.
The applying nano microgranule is as carrier, and is comparatively deep in the research of chemical synthetic drug formulation art and application, such as solid dispersion technology, emulsifying technology, inclusion technique, liposome technology of preparing, polymer fabrication technology etc.The nanoparticle carrier can roughly be divided into two classes, take lipid as the liposome on basis and take the nanoparticle of polymer as the basis.The liposome biocompatibility is good, targeting is high, the pharmacokinetics behavior is controlled, and can improve behavior in the body by finishing, yet the liposome drug loading is low, and the easy oxidation deterioration of phospholipid material easily produces medicine and reveals less stable in storage and the transportation.Nanoparticle consists of with the aliphatic polyester shaped material with good biocompatibility and biodegradability, such as polylactic acid (PLA), PLGA (PLGA), polycaprolactone (PCL), and two blocks, the segmented copolymer of they and hydrophilic class material chitosan or hydrophilic segment Polyethylene Glycol (PEG) and derivant thereof.Recently form the nano-micelle of " nuclear-shell " structure with amphipathic nature polyalcohol (such as mPEG-PLGA, PLGA-Lethcin-PEG etc.) self assembly, the outside lipophilic end of its water-wet side is inside, can load various medicines, DNA, albumen etc. in the nuclear.Nanoparticle has been applied to polypeptide protein class, Antigens and the larger medicine of other untoward reaction as a kind of emerging medicine-feeding technology that has potentiality, and have following advantage: 1. the volume ultra micro is little, can pass interstice; 2. can effectively protect medicine, avoid degraded and reveal the body internal stability of raising medicine; 3. can control the release of medicine, prolong Half-life in vivo; 4. easily realize targeting and location.Especially can pass gastrointestinal tract through the M cell traffic of common enterocyte bypass and PayerShi knot behind the nanoparticles oral, optionally targeting is organized in aggregated lymphatic follicles, enter systemic circulation, adopt hydrophilic material that nanoparticle is carried out finishing, can improve its surface hydrophilicity, increase sterically hindered, prolong nanoparticle circulation time in vivo, improve bioavailability.
For the multicomponent composite reagent, especially Chinese medicine preparation, because its complicated component, each active component physicochemical properties differs, such as pH value, Determination of oil-water partition coefficient, molecular weight, light durability, temperature stability etc., therefore when the preparation particulate carrier, the envelop rate of each active component can't reach unanimity, yet the generation of optimum biological effect depends on according to a certain ratio synergism of each active component, and this has limited the performance of drug regimen pharmacological action to a certain extent.
Summary of the invention
In sum, in order effectively to address the above problem, make the envelop rate of each active component reach synchronous raising, improve the bioavailability of medicine, reduce drug toxicity, the advantage of any two kinds of pharmaceutical carriers such as comprehensive liposome, nanoparticle, micelle, microcapsule, Emulsion, the present invention is intended to adopt the microgranule of different moulding mechanisms, architectural feature and/or characteristics of pharmacokinetics mutually compound, a kind of drug-supplying system is provided, and in addition, the present invention also provides the preparation method of this drug-supplying system.
For achieving the above object, the invention provides following technical scheme.
First aspect present invention provides a kind of drug-supplying system, and its mesochite microgranule is sealed again to the free composition of envelop rate not in the karyomicrosome preparation process, can realize the purpose that each different constituent envelop rate of physicochemical property reaches unanimity.The architectural feature of this drug-supplying system is can wrap up at least one karyomicrosome in the shell microgranule; Or several at least one karyomicrosomes of shell particle encapsulation; Or the shell microgranule carries out again package/parcel to the karyomicrosome that is wrapped by/wraps up and covers, and its structure is illustrated in fig. 1 shown below.
Definition:
" composite particles ": according to the present invention, term " composite particles " refers to that the acceptable particulate carrier in pharmaceutics field is wrapped and/or is coated on the microgranule that forms in the another kind of carrier, also can be described as the larger microgranule parcel of particle diameter and/or coat the less microgranule of particle diameter, the architectural feature of this composite particles is mutually to be composited by two kinds of microgranules with different moulding mechanisms, architectural feature and/or characteristics of pharmacokinetics.The difference of two kinds of microgranules is that concrete orientation is different.Composite particles can comprise at least two kinds of active component.
" karyomicrosome ": according to the present invention, term " karyomicrosome " refers to be positioned at a kind of particulate carrier of acceptable particulate carrier inside, pharmaceutics field, also can be described as the less microgranule of particle diameter.
" shell microgranule ": according to the present invention, term " shell microgranule " refers to be positioned at a kind of particulate carrier of acceptable particulate carrier outside, pharmaceutics field, also can be described as the larger microgranule of particle diameter.
" parcel ": be contained at least one karyomicrosome in the shell microgranule.
" coating ": several shell microgranules are by physics or chemical bonding, be uniformly distributed at least one karyomicrosome around.
The inventor finds by lot of experiments, prepares on the basis at the nano-carrier of prior art, and the nano-carrier (karyomicrosome) that obtains is carried out again parcel and/or coating, forms the Novel Drug Delivery Systems that is applicable to the multicomponent pharmaceutical combination.Twice of karyomicrosome sealed to play two kinds of effects, the one, the drug regimen of larger difference is arranged for physicochemical property, can seal by non-encapsulated free drug in the karyomicrosome is carried out secondary, improve entrapment efficiency, reach and make the purpose that the envelop rate of each ingredient reaches unanimity in the combination; Two is existence of the particulate carrier of two kinds of different moulding mechanisms, architectural feature and/or characteristics of pharmacokinetics, makes each heterogeneity of sealing can obtain unified envelop rate, can realize the control to heterogeneity rate of release and degree synchronicity.
The maximum particle diameter scope of karyomicrosome is 1nm-1000nm, and is wrapped and/or is coated in the shell microgranule.Karyomicrosome is by any material and the methods known in the art preparation of polymer (such as PLGA, polyester, polyamide, polyureas etc.), lipid, protein, polysaccharide.Medicine can carry out medicine carrying by being wrapped in the microgranule or being adsorbed on microparticle surfaces.
For forming the composite particles drug delivery system, karyomicrosome can form by vesicle parcel and/or the coating that is formed by materials such as capsomeric particular polymers, lipids.The shell microgranule is by any material and the methods known in the art preparation of polymer (such as PLGA, polyester, polyamide, polyureas etc.), lipid, protein, polysaccharide.
Lipid described in the drug-supplying system of the present invention comprises natural, semi-synthetic, complete synthesis phospholipid and derivant thereof.Preferred scheme is that described phospholipid is selected from but is not limited to following soybean phospholipid; Ovum Gallus domesticus Flavus lecithin; EPG; polyene phosphatidylcholine; phosphatidic acid; cardiolipin; sphingomyelins; the phosphatidic acid serine; phosphatidylinositols; PHOSPHATIDYL ETHANOLAMINE; hydrogenated soy phosphatidyl choline; hydrogenated yolk lecithin; complete synthesis phospholipid; various synthetic phospholipids such as C3-C30; such as distearoyl phosphatidylcholine (DSPC); dipalmitoyl phosphatidyl choline (DPPC); DOPC (DOPC); dimyristoyl phosphatidyl choline (DMPC); DLPC (DLPC); DSPG (sodium salt DSPG); DPPG (sodium salt DPPG); L-a-GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (sodium salt DMPG); PE (DLPG); DSPE (DSPE); DPPE (DPPE); DOPE (DOPE); DMPEA (DMPE); two lauroyl PHOSPHATIDYL ETHANOLAMINE (DLPE); two DSPGs (sodium salt); two DPPGs (sodium salt); two GLYCEROL,DIMYRISTOYL PHOSPHATIDYLs (sodium salt); two PEs; the distearyl phosphatidylinositols; two palmityl phosphatidylinositols; dioleoyl phospholipid acyl inositol; two myristoyl phosphatidylinositols; two lauroyl phosphatidylinositols; POPC; the inferior oleoyl phosphatidylcholine of palmityl; the inferior oleoyl phosphatidylcholine of stearoyl; stearoyl oleoyl phosphatidylcholine; stearoyl arachidonic phosphatidyl choline; 1; 2-two hexanoyl lecithin; 1; the 2-DLPC; 1; 2-two lauroyl PHOSPHATIDYL ETHANOLAMINE; 1; 2-myristoyl lecithin; 1; 2-myristoyl PHOSPHATIDYL ETHANOLAMINE; 1,2-myristyl lecithin etc.
Because phospholipid dispersibility and dissolved substance limited in one's ability in water or in the oil phase, drug-supplying system of the present invention can add suitable oil substances or other lipid material, at least a as in medium chain triglyceride (MCT), tocopherol, oleic acid, soybean oil, olive oil, sad and esters, certain herbaceous plants with big flowers acid and esters, Palmic acid and esters thereof, linoleic acid and esters thereof, linoleic acid and esters thereof, the plant volatile oil.
Drug-supplying system of the present invention can add other lipids such as cholesterol and derivant thereof, NaTDC, sitosterol.Preparation phospholipid phase time, cholesterol, NaTDC, sitosterol are assisted phospholipid load lipophilic substance as the additives of liposome or Emulsion.
Drug-supplying system of the present invention can add the targeting agent, comprises part, antibody.Wherein said part is selected from galactose derivative, transferrins derivant, folic acid and derivant thereof, glucosamine derivant, various RGD and derivant thereof etc.; Described antibody is selected from the antibody in various people source, Mus source, recombination human source, Mus source, realizes the initiatively purpose of target administration.
For increasing medicine, especially the stability of Chinese medicine ingredients, guarantee that preparation is in rational pH scope, drug-supplying system of the present invention can add pH adjusting agent, such as organic acid, organic base or mineral acid, inorganic base, such as in citric acid, fumaric acid, tartaric acid, gluconic acid, sorbic acid, succinic acid, maleic acid, ascorbic acid, oxalic acid, benzoic acid, glutamic acid, aspartic acid, hydrochloric acid, phosphoric acid, sodium hydroxide, the phosphate etc. one or more.
A second aspect of the present invention provides the preparation method of above-mentioned drug-supplying system, comprises following step:
(1) preparation of karyomicrosome and the processing that homogenizes;
(2) take karyomicrosome as to be wrapped and/or coating water, shell particulate carrier material is oil phase;
(3) capsomeric preparation and the processing that homogenizes.
A third aspect of the present invention is that the medicine that can design comprises at least two kinds of pharmacological active substancies, comprises the combination of chemicals combination, effective ingredient in Chinese or composition combination or chemicals and Chinese medicine ingredients.Described pharmacological active substance comprises medicine (sense stricto), diagnostic reagent and nutrient substance, and its Chinese medicine is selected from anti-malignant tumor, cardiovascular and cerebrovascular disease, neurodegenerative diseases, diabetes, psychotic disorder, autoimmune disease, drug resistance pathogenic bacterial infection, pulmonary tuberculosis, disease of viral infection medicine etc.
A fourth aspect of the present invention provides the pharmaceutical composition with composite particles of the present invention.Said composition can also contain the acceptable adjuvant of other medicines, can take the forms such as injection, granule, tablet, capsule, spray, ointment, realize the administrations such as injection (comprising vein, tremulous pulse, articular cavity, subcutaneous, Intradermal, intramuscular injection etc.), oral (comprising Sublingual, oral mucosa etc.), tract (comprising eyes, nasal cavity, trachea, auditory meatus, pulmonary, rectum, vagina, urethra etc.), skin.
Specific embodiment
Be described more specifically the present invention below in conjunction with embodiment.Should be appreciated that the following examples are used to illustrate content of the present invention and non-limiting content of the present invention, any pro forma variation and/or change all will fall within the scope of protection of the present invention.
Take Radix Notoginseng total arasaponins as model drug.Mainly contain Panax Notoginseng saponin R in the Radix Notoginseng total arasaponins (Panax notoginseng saponins, PNS)
1, ginsenoside Rb
lAnd ginsenoside Rg
lDeng, the order of the logP value of three kinds of index compositions is Rg among the PNS
1R
1Rb
1, Rb
1Hydrophilic is the strongest, and relative molecular weight is maximum.
Embodiment 1
High pressure homogenization method prepares the PNS composite particles
| PNS | 100mg |
| mPEG-PLGA | 80mg |
| Soybean lecithin | 2000mg |
| Cholesterol | 500mg |
| PVA | 500mg |
| PBS(pH7.4) extremely | 100 ml |
(1) preparation of PNS karyomicrosome
Get in the PBS solution that PNS is dissolved in pH=7.4 in right amount, as interior water W
1Get mPEG-PLGA and be dissolved in right amount in the dichloromethane, as oil phase O; The PVA aqueous solution is outer water W
2Mixed W
1With O phase (W
l: O=1:5, v/v), jolting disperses, and then adopts high pressure homogenizer high pressure 400bar, circulates 5 times, makes W
1/ O Emulsion is with above-mentioned W
1/ O Emulsion adds the outer water W of certain volume
2In (W
1/ O:W
2=1:2, v/v), with high pressure homogenizer high pressure 400bar, circulate 5 times, namely get W
l/ O/W
2Emulsion continues to be stirred to the dichloromethane volatilization fully, namely gets the obvious nattier blue nanoparticle colloid solution of opalescence.The mean diameter of gained nanoparticle is 125nm.Three kinds of leading indicator compositions of PNS Panax Notoginseng saponin R
1, ginsenoside Rb
1, the ginsenoside Rg
1Envelop rate differ, be respectively 26.2%, 52.3%, 40.6%.
(2) preparation of PNS composite particles
Cholesterol and lecithin (1:4) are dissolved in an amount of chloroform, and 37 ℃ of rotary evaporation in vacuo are removed chloroform, and film forming obtains W with preceding method
l/ O/W
2The PNS emulsion is water, adds in the round-bottomed flask, and concuss washes lipid film, and the gained suspension circulates 5 times through high pressure homogenizer high pressure 400bar, and low pressure 40bar circulates 5 times, obtains the PNS composite particles.The mean diameter of gained composite particles is 223.4nm, is evenly distributed.Three kinds of leading indicator compositions of PNS Panax Notoginseng saponin R
1, ginsenoside Rb
1, the ginsenoside Rg
1Envelop rate basically identical, be respectively 45.7%, 54.3%, 53.8%.
Embodiment 2
The standby PNS composite particles of Ultrasonic Pulverization legal system
| PNS | 100mg |
| mPEG-PLGA | 80mg |
| Soybean lecithin | 2000mg |
| Cholesterol | 500mg |
| PVA | 500mg |
| PBS(pH7.4) extremely | 100 ml |
(1) preparation of PNS karyomicrosome
Get in the PBS solution that PNS is dissolved in pH=7.4 in right amount, as interior water W
1Get mPEG-PLGA and be dissolved in right amount in the dichloromethane, as oil phase O; The PVA aqueous solution is outer water W
2Mixed W
1With O phase (W
l: O=1:5, v/v), jolting disperses, and then adopts ultrasonic 400W3min to make W
1/ O Emulsion is with above-mentioned W
1/ O Emulsion adds the outer water W of certain volume
2In (W
1/ O:W
2=1:2, v/v), namely get W with Ultrasonic Pulverization 400W3min
l/ O/W
2Emulsion continues to be stirred to the dichloromethane volatilization fully, namely gets the obvious nattier blue nanoparticle colloid solution of opalescence.
(2) preparation of PNS composite particles
Get cholesterol and lecithin (1:4, w/w) and be dissolved in an amount of chloroform, 37 ℃ of rotary evaporation in vacuo are removed chloroform, and film forming obtains W with preceding method
l/ O/W
2The PNS emulsion is water, adds in the round-bottomed flask, and concuss washes lipid film, and the gained suspension obtains the PNS composite particles behind ultrasonic 400W3min.The mean diameter of gained composite particles is 234nm, is evenly distributed.
Embodiment 3
Different mPEG-PLGA amount preparation PNS composite particles: prescription and method according to embodiment 2 prepare the PNS composite particles that different mPEG-PLGA measure, and measure its change of size and index components envelop rate, the results are shown in following table:
| MPEG-PLGA measures (%) | 0.02 | 0.08 | 0.1 | 0.12 |
| Particle diameter (nm) | 195.3 | 234 | 316.9 | 343.6 |
| Panax Notoginseng saponin R 1 | 20.8% | 45.7% | 49.2% | 49.2% |
| Ginsenoside Rb 1 | 47.8% | 54.3% | 53.1% | 52.2% |
| The ginsenoside Rg 1 | 31.3% | 53.1% | 52.9% | 54.2% |
Can find out that along with the increase of nanoparticulate carriers material mPEG-PLGA consumption, prepared PNS composite particles particle size growth amplitude increases, the envelop rate of three kinds of index components does not simply improve with the raising of polymer volume.
Embodiment 4
The water of different PVA concentration is on the impact of PNS composite particles particle diameter:
Prepare the PNS composite particles of different PVA concentration according to the prescription of embodiment 2 and method, measure its change of size, the results are shown in following table:
| PVA concentration (%) | 0.25 | 0.5 | 1 | 1.5 |
| Particle diameter (nm) | 186.6 | 234 | 296.4 | 288.7 |
Can find out that along with the increase of aqueous phase PVA concentration, prepared PNS composite particles particle size growth amplitude increases, when concentration greater than 1% the time, particle diameter no longer increases.
Embodiment 5
The different phosphate lipid concentration prepares the PNS composite particles
According to the PNS composite particles that prescription and the method for embodiment 2 prepares the different phosphate lipid concentration, measure its change of size and index components envelop rate, the results are shown in following table:
| Phospholipid concentration (%) | 0.5 | 1 | 2 | 3 |
| Particle diameter (nm) | 175.7 | 207.8 | 234 | 249.5 |
| Panax Notoginseng saponin R 1 | 32.2% | 43.3% | 45.7% | 46.1% |
| Ginsenoside Rb 1 | 43.7% | 44.6% | 54.3% | 53.6% |
| The ginsenoside Rg 1 | 35.2% | 46.8% | 53.1% | 55.1% |
Can find out that along with the increase of matrix material phospholipid concentration, prepared PNS composite particles particle size growth amplitude increases, the envelop rate of three kinds of index components does not simply improve with the raising of phospholipid consumption.
Embodiment 6
The preparation of PNS composite particles eye drop
| PNS | 100mg |
| mPEG-PLGA | 80mg |
| Soybean lecithin | 2000mg |
| Cholesterol | 500mg |
| PVA | 500mg |
| EDTA-2Na | 2mg |
| Geramine | 3mg |
| PBS(pH7.4) extremely | 100 ml |
Concrete operations are with embodiment 1.Different is that EDTA-2Na is soluble in water, is made into water, obtains W
l/ O/W
2The PNS emulsion.Get cholesterol and lecithin (1:4, w/w) and be dissolved in an amount of chloroform, 37 ℃ of rotary evaporation in vacuo are removed chloroform, film forming take the PNS emulsion that obtains as water, adds in the round-bottomed flask, concuss washes lipid film, and gained suspension citric acid is regulated pH6-8, and sodium chloride is regulated osmotic pressure, microjet disperses, and through high pressure homogenizer high pressure 400bar, circulates 5 times, low pressure 40bar circulates 5 times, adds geramine, adjust volume to 100ml, mixing gets PNS composite particles eye drop.
Embodiment 7
In composite particles, insert long recycled material
Concrete operations are with embodiment 2.Different is adopts outer insertion with 0.2%-20%(w/v) DSPE-PEG, DMPE-PEG or DLPE-PEG(PEG molecular weight 100-20000) add above-mentioned preparation.The preparation stability of preparation gained PEG coating is good.
Embodiment 8
In the composite particles preparation, insert the lipophilic group part
Concrete operations are with embodiment 2.Different is the antibody that adopts insertion insertion galactose derivative, transferrins derivant, folic acid and derivant, glucosamine derivant, various RGD and derivant thereof, is selected from various people source, Mus source, recombination human source, Mus source, realizes the initiatively purpose of target administration.
Embodiment 9
Freeze-drying prepares the PNS composite particles
Prescription and method according to embodiment 1 prepare the PNS composite particles, and different is adds 5% mannitol (w/v) in prescription, namely add 50g mannitol in the 2000ml pharmaceutical liquid, according to following freeze-dry process:
Pre-freeze :-74 ℃, 8h; Evacuation carries out drying.Phase I is dry :-30 ℃, and 30min; Second stage is dry :-20 ℃, and 12h; Insulation: 15 ℃, 5h.Obtain containing the lyophilization composite particles of PNS, encapsulated or direct compression.
Embodiment 10
The extracorporeal releasing experiment of different PNS preparations
Adopt dialysis, precision pipettes the common nanoparticle of PNS composite particles, PNS, the PNS solution that embodiment 2 prepares and is respectively charged in the bag filter of having handled well, the bag filter two ends are tightened, place the 200mlpH7.4 phosphate buffered solution, keep sink condition, vessel port is airtight, constant temperature (37 ± 1) ℃, constant speed (100r/min) stirs, timing sampling 0.5ml, add simultaneously with the synthermal release medium of volume parallel three parts.From institute's sample thief, get 20 μ l sample introductions, calculate the cumulative release amount.The result shows with other two kinds of preparations and compares that preparation slow release effect of the present invention is more obvious.
Embodiment 11
The acute toxicity testing of PNS composite particles
Medicine: embodiment 9 preparations after the reconstruction
Animal: KM healthy mice, body weight 18g-22g, ♀ ♂ half and half
Route of administration: gavage is oral
Observing time: 14 days
Experiment repeats 3 times.
Found that: test omnidistance mice and be showed no obvious poisoning symptom, without animal dead, the results are shown in following table.
Can find out that MTD is greater than the 1.8g/kg body weight for PNS composite particles maximum tolerated dose, safety is stronger.
Embodiment 12
The PNS composite particles is to the vitro efficacy of cardiovascular and cerebrovascular disease
Adopting human umbilical vein endothelial HUVEC-12 is model cell, sets up anoxia _ reoxygenation cell injury model, adopts mtt assay and Annexin V-FITC staining technique to detect each experimental group cell viability and apoptosis situation, the results are shown in following table.
The PNS composite particles on the impact of anoxia _ reoxygenation cell HUVEC-12 damage model activity (n=8,
± SD)
| Group | Dosage (μ mol/L) | OD |
| Blank group | — | 0.622±0.041 |
| Model group | — | 0.311±0.127 ◆◆ |
| PNS solution group | 72 | 0.431±0.022 △ |
| Low dose group | 36 | 0.402±0.013 △ |
| Middle dosage group | 72 | 0.482±0.027 △▲ |
| High dose group | 144 | 0.601±0.014 △△▲▲ |
Compare with the blank group, ◆:
p＜0.05, ◆ ◆:
p＜0.01; Compare △ with model group:
p＜0.05, △ △:
p＜0.01;
Compare with PNS solution, ▲:
p＜0.05, ▲ ▲:
p＜0.01
The PNS composite particles on the impact of anoxia _ reoxygenation cell HUVEC-12 apoptosis (n=8,
± SD)
| Group | Dosage (μ mol/L) | Apoptosis rate (%) |
| Blank group | — | 14.55±4.21 |
| Model group | — | 45.36±5.14 ◆◆ |
| PNS solution group | 72 | 34.15±3.61 △ |
| Low dose group | 36 | 36.27±6.31 △ |
| Middle dosage group | 72 | 29.08±4.07 △△▲ |
| High dose group | 144 | 20.37±3.26 △△▲▲ |
Compare with the blank group, ◆:
p＜0.05, ◆ ◆:
p＜0.01; Compare △ with model group:
p＜0.05, △ △:
p＜0.01;
Compare with PNS solution, ▲:
p＜0.05, ▲ ▲:
p＜0.01
Can find out, by following table as can be known the PNS composite particles can obviously improve cell viability, reduce apoptosis rate.
Embodiment 13
Render a service in the body of PNS composite particles to cardiovascular and cerebrovascular disease
The mongolian gerbil random packet is set up the cerebral ischemia re-pouring model, and take PNS solution as matched group, the PNS composite particles is the administration group, gastric infusion 7d, and experimental result sees the following form.
The PNS composite particles on the impact of pallasiomy brain water content and Stroke Index (n=6,
± SD)
| Group | Dosage (mg/kg) | Brain water content (%) | Stroke Index |
| Sham operated rats | — | 74.22±1.31 | — |
| Model group | — | 81.03±2.03 ◆◆ | 21.48±0.11 |
| PNS solution group | 800 | 78.01±0.45 △ | 16.41±0.41 △ |
| Low dose group | 400 | 78.24±0.11 △ | 18.36±0.35 △ |
| Middle dosage group | 800 | 76.54±0.30 △△▲ | 14.40±0.36 △△▲ |
| High dose group | 1200 | 75.13±0.21 △△▲ | 13.37±0.14 △△▲▲ |
Compare with sham operated rats, ◆:
p＜0.05, ◆ ◆:
p＜0.01; Compare △ with model group:
p＜0.05, △ △:
p＜0.01;
Compare with PNS solution, ▲:
p＜0.05, ▲ ▲:
p＜0.01
Can find out that the PNS composite particles can significantly reduce the Stroke Index of brain water content and animal, embody the protective effect to the cerebral ischemia re-pouring animal.
Claims (12)
1. key in herein claim 1, a kind of multicomponent pharmaceutical composite particles drug-supplying system, it is characterized in that, composite particles is mutually to be composited by two kinds of microgranules with different moulding mechanisms, architectural feature and/or characteristics of pharmacokinetics, inner microgranule is called karyomicrosome, and outer particle is called the shell microgranule.
2. key in herein claim 2, the composite particles drug-supplying system is characterized in that as claimed in claim 1, and described karyomicrosome comprises: nanoparticle, microcapsule, liposome, micelle, Emulsion etc.; The shell microgranule comprises: nanoparticle, microcapsule, liposome, micelle, Emulsion etc.
3. composite particles drug-supplying system as claimed in claim 1 is characterized in that, can wrap up at least one karyomicrosome in the shell microgranule; Or several at least one karyomicrosomes of shell particle encapsulation; Or the shell microgranule again wraps up and/or coats the karyomicrosome that is wrapped by/wraps up.
4. composite particles drug-supplying system as claimed in claim 1 is characterized in that, described multicomponent pharmaceutical is number of chemical drug regimen, effective ingredient in Chinese or composition combination or chemicals and Chinese medicine ingredients combination.
5. composite particles drug-supplying system as claimed in claim 1 is characterized in that composite particles can improve the bioavailability of at least a composition, or reduces the toxicity of at least a composition.
6. composite particles drug-supplying system as claimed in claim 1, its preparation method is characterised in that the method comprises following step:
The preparation of karyomicrosome and the processing that homogenizes;
Take karyomicrosome as to be wrapped and/or coating water, shell particulate carrier material is oil phase;
Capsomeric preparation and the processing that homogenizes.
7. drug-supplying system as claimed in claim 1 is characterized in that the maximum particle diameter scope of composite particles is 5nm-2000nm.
8. preparation method as claimed in claim 6 is characterized in that, take karyomicrosome as to be wrapped and/or coating water, utilizes the required carrier material of shell microgranule molding that karyomicrosome is further wrapped up and/or coats; To the free composition of envelop rate not in the karyomicrosome preparation process, carry out secondary and seal, with the purpose that realizes that each different constituent envelop rate of physicochemical property reaches unanimity.
9. preparation method as claimed in claim 6 is characterized in that, the homogenizing of microgranule processed methods such as selecting at a high speed breast is even, high pressure homogenize, microjet, Ultrasonic Pulverization.
10. preparation method as claimed in claim 6, the composite particles carrier material is one or more in polymer, copolymer, the phospholipid, polymer and/or copolymer and/or phospholipid can consist of the composite particles structure jointly in the mode of chemistry or physical bond.
11. composite particles drug-supplying system as claimed in claim 1, it is characterized in that, can be according to the dosage form needs, further sterilize, lyophilization or spray drying treatment, lyophilization or spray drying can be selected at least a as additive in sucrose, lactose, glucose, mannitol, dextran, trehalose, xylitol, maltose, fructose, albumen, chitosan, glycine, citric acid, the sodium chloride.
12. composite particles drug-supplying system as claimed in claim 1, it is characterized in that, according to clinical needs, composite particles can be made into the different dosage forms such as injection, granule, tablet, capsule, spray, ointment, to satisfy route of administration needs such as comprising injection, oral, tract, skin.
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| CN 201110183945 CN102860979A (en) | 2011-07-03 | 2011-07-03 | Multi-component drug composite particle administration system and preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104225614A (en) * | 2014-09-22 | 2014-12-24 | 北京航空航天大学 | Chitosan grafted polylactic acid composite microsphere simultaneously carried with hydrophilic and hydrophobic biological molecules and preparation method of chitosan grafted polylactic acid composite microsphere |
| CN107474845A (en) * | 2017-09-20 | 2017-12-15 | 华中科技大学同济医学院附属协和医院 | A kind of nanometer microvesicle mixture that biology light source is provided and preparation method thereof |
-
2011
- 2011-07-03 CN CN 201110183945 patent/CN102860979A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104225614A (en) * | 2014-09-22 | 2014-12-24 | 北京航空航天大学 | Chitosan grafted polylactic acid composite microsphere simultaneously carried with hydrophilic and hydrophobic biological molecules and preparation method of chitosan grafted polylactic acid composite microsphere |
| CN104225614B (en) * | 2014-09-22 | 2016-11-30 | 北京航空航天大学 | With chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule and preparation method thereof |
| CN107474845A (en) * | 2017-09-20 | 2017-12-15 | 华中科技大学同济医学院附属协和医院 | A kind of nanometer microvesicle mixture that biology light source is provided and preparation method thereof |
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Application publication date: 20130109 |