CN1977826A - Method for increasing prodrug bioavailability using solid lipid nano granule - Google Patents
Method for increasing prodrug bioavailability using solid lipid nano granule Download PDFInfo
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Abstract
This invention disclosed method to advance prodrug biology use ratio lymphatic system target absorb advance biology use ratio. The method to produce prodrug solid lipide nm granule.
Description
Technical field
Technical field of the present invention relates to through the absorption of lymphsystem targeting, improves the method for prodrug bioavailability.This technical field also relates to solid lipid nano-particles of prodrug and preparation method thereof.
Background of invention
The appearance of new drug development and triage techniques has improved the effectiveness of molecule, but also brings the problem of more physics and chemistry and biological aspect simultaneously, and for example poorly soluble and lipotropy are low.By oral route gives medicine many advantages, but the curative effect of the medicine of oral administration mainly depends on effectiveness and the system's availability or the bioavailability of medicine.Pharmaceutical efficacy is influenced by the chemistry of this medicine or molecular structure to a great extent, is the intrinsic property of individual molecular.Bioavailability is subjected to multiple factor affecting, for example physics and chemistry, preparation and patient's correlation circumstance.Because drug bioavailability is subjected to multiple factor affecting, thus can improve drug bioavailability by the preparation strategy that application relates to the biological respinse of modified medicaments physicochemical property and some degree, to obtain high as far as possible bioavailability and therapeutic effect.Yet, understand drug molecule (i) processing (ii) store and (iii) the behavior of administration after-stage be important.To the systemic circulation, the medicine of oral administration must successfully overcome complicated gastrointestinal tract (GIT) environment of being made up of different pH scopes and digestive enzyme in drug absorption.
In order to improve the low bioavailability of medicament of poorly soluble and lipotropy, prior art has been put down in writing several different methods.But these method rough segmentations are two classes, comprising: improvement and dosage form to molecular structure of chemistry are improved.Changing the formation of molecular structure, preparation prodrug and salt, is the method that is included in the chemical modification of drug molecule.Using dissolution enhancers or absorption enhancer, formation inclusion complex and size is reduced to micron even nanometer level, is to be included in the method for the dosage form that improves bioavailability in improving.
The prodrug preparation is to improve the well-known method of bioavailability.Prodrug is meant any pharmaceutically acceptable ester of active part, salt or other derivant of ester, and when giving the experimenter, it can easily provide active part by enzyme or non-enzymatic pathway.Prodrug is designed to improve the solubility and the permeability of molecule, comprises extremely weak key in its structure.These weak bonds help in intestinal epithelial cell or blood, make prodrug easily be converted into the reactive precursor part, but meanwhile these weak bonds also make prodrug responsive to pipe intestinal digesting enzyme and pH effect, the degraded before causing absorbing, thus the purpose of prodrug design is failed.When prodrug demonstrates when intestinal wall is discharged rapidly, this problem is further aggravated, and wherein prodrug absorbs well, but it is easy to be converted into active part after entering enterocyte, and flows back to intestinal again rather than enter blood circulation, thereby reduces effective bioavailability.Cefpodoxime proxetil (Cefpodoxime proxetil) is the prototype example of this type of prodrug, the problem that it has the preceding degraded of a large amount of absorptions and discharges mechanism (efflux machanism).Compare with the cefpodoxime sodium injection for intravenous injection, the absolute bioavailability of the commercial cefpodoxime proxetil tablet that uses is reduced to thus only has an appointment 50%.Need cautiously quote preparation technique, to obtain better result in this case.
Lymphsystem is the subsystem of blood circulation.Lymphsystem is similar to blood circulation, and wherein lymphatic vessel branch is just as tremulous pulse and the vein all sites by health, and what only lymphsystem carried is colourless liquid rather than the blood that is called lymph.Lymphoid anatomy is different with the physiology at each position of health.The characteristics of small intestinal lymph are that the lacteal vessel that is positioned at central authorities is arranged in each fine hair.Lacteal vessel is connected into cisterna chyli by mesentery lymphatic vessel and lymphatic capillaries/drainage tube (drain) pipe Cong Xianglian.Lymph fluid from cisterna chyli is discharged from thoracic duct, and jugular vein and left subclavian vein place directly empty in the global cycle in a left side.The lymphoid tissue that digestive tract is relevant, comprise: lymphocyte and plasma cell that the lymph aggregation in tonsil, gland sample body (waldeyer ring, Waldeyer ' s ring), Peyer aggregate nodules, vermiform appendix and the large intestine, stomach distribute with disperse in lymphoid tissue, esophagus primary lymphedema aggregation and the digestive tract lamina propria of age accumulation.The Peyer aggregate nodules are bigger aggregations of lymphoid tissue of finding in the small intestinal.The epithelium that is covered with " dome " includes a large amount of intraepithelial lymphocytes.Some epithelial cells have complicated little folding on its surface.These cells are called as the M cell, it is believed that they play an important role the antigen from enteric cavity to the Peyer aggregate nodules shifts.
Therefore, because the anatomy and the physiology characteristic of lymphsystem uniqueness, there are the potentiality of utilizing the optional method that lymphsystem sends as medicine.Target administration to lymphsystem has certain advantage.These advantages comprise can avoid first pass metabolism, directly medicine is delivered to the specific region (for example under the situation of treatment disease) of lymph circulation, and regulates the probability that medicine is delivered to the efficient of systemic circulation.The principal element that influences apparent lymph transhipment comprises: the physics and chemistry and the metabolisming property of route of administration, drug delivery system design and medicine.Macromole and colloidal particle (for example Chylomicron) are optionally absorbed by the gap through lymphsystem.Nano-particle enters lymphsystem by the ad hoc approach that is called cell endocytic.Exist under the situation of absorption enhancer, with medicine and the compound close lymph delivery system of high molecular carrier (for example dextran sulfate), the selectivity lymph that strengthens cancer therapy drug is sent.
Prior art has been instructed the multiple formulation method that dissolubility improves that is primarily aimed at, and expectation helps improving bioavailability by this usually.A kind of such method relates to the drug use lipid system to poorly soluble.The preparation of lipid system comprises micron or nano-emulsion, liposome, self-emulsifying drug delivery systems and solid lipid nano-particles.
United States Patent (USP) 4,880,634 disclose the lipid nanoparticle (nano-pellet) that is used for the relatively poor medicine of orally give bioavailability.It discloses the excipient systems of the oral administration medicine that comprises the lipid nanoparticle that exists with superfine liquid state, gluey suspensions, this lipid nanoparticle comprises lipid and surfactant, wherein the particle diameter of nanoparticle is at 50-1, in the 000nm scope, the ratio of lipid and surfactant is 1 in lipid nanoparticle: 0.1-1: in 2.2 scopes, wherein lipid nanoparticle exists with the concentration of 1-20 weight % in suspension.Pharmaceutically active substances can be provided with lipid nanoparticle, this just makes raising oral administration bioavailability become possibility.
United States Patent (USP) 5,785,976 relate to the suspension of biodegradable lipid solid particle under the room temperature, preferably glycerine three esters, it can be used as the carrier of poorly water soluble drugs or other bioactive agents and can be used for particulate suspension.
Eldem etc. (Pharm.Res., 8, (1991) 47-54) have described the lipid micropill (micropellet) that spray drying and spray congealing method prepare.The spherical pellet that obtains has slick surface.
United States Patent (USP) 5,250,236 disclose the method for preparing solid lipid nano-particles with microemulsion technology, may further comprise the steps: the lipid matter that melts is added in the mixture of being made up of water, surfactant and optional surface activity auxiliary agent, form microemulsion, microemulsion is scattered in the water, saturating drainage is washed, lyophilization obtains finished product.
United States Patent (USP) 6; 337; 092 discloses the submicron that is coated with a natural phospholipid granule or the microgranule to the micron size, and wherein said granule is by being used in combination static and stereoscopic stable agent, respectively from least a powered surfaces dressing agent and the preparation of at least a block copolymer.This particulate generation and storage stability are subjected to the influence of this static and stereoscopic stable agent combination.
Summary of the invention
Lipid nanometer granule known in the art can improve the bioavailability of some hydrophobic drug.Yet, we find that solid lipid nano-particles can be used as preparation the delivery system that absorbs preceding degraded (in gastrointestinal cavity or at enterocyte or epithelial cell) and/or discharge the prodrug of mechanism problem is arranged now, thereby by absorb the bioavailability of this prodrug of enhancing through lymphoid targeting.
Therefore, one total aspect, the invention provides by absorb the method that improves the prodrug bioavailability through lymphoid targeting.
Another total aspect, the invention provides 1.25 times or more method using solid lipid nano-particles the bioavailability of prodrug to be brought up to conventional peroral dosage form.
Another total aspect, the invention provides the solid lipid nano-particles of the prodrug that comprises prodrug and lipid carrier, the bioavailability of the solid lipid nano-particles of this prodrug is brought up to 1.25 times of conventional peroral dosage form or more.
Another total aspect, the invention provides the preparation method of the solid lipid nano-particles of prodrug, this method comprises the prodrug dissolution in the mixture of lipid carrier and stabilizing agent and the step that further is processed as dosage forms.
Description of drawings
Figure 1 shows that the curve chart of time to the formation percentage ratio (%) of cefpodoxime acid.
Figure 2 shows that the curve chart of time to the percentage ratio (%) of residue cefpodoxime proxetil.
Time shown in Figure 3 is to the curve chart of the concentration (mmol/gm) of cefpodoxime proxetil in the epithelial cell.
Figure 4 shows that the curve chart of time to the concentration (mmol/gm) of cefpodoxime acid in the epithelial cell.
The specific embodiment
The medicine that belongs to II, III, the biological medicine of IV class of solubility and/or permeability problems is arranged, and is the target of prodrug preparation.Known prodrug can improve this bioavailability of medicament by dissolubility and/or the permeability that improves the poorly soluble medicine.Can be hydrolyzed to parent fraction at intestinal wall/endochylema by enzyme or non-enzyme effect in intestinal absorption after it is believed that the prodrug oral administration.But in some cases, independent prodrug preparation can not address this problem.Although improved dissolubility and permeability are arranged, these prodrugs still demonstrate relatively poor bioavailability, and this is caused by the degraded before absorbing and the ileal lumen that overflows rapidly.A kind of method that improves this prodrug bioavailability is the targeting lymphsystem, and wherein prodrug directly enters lymph, thereby degrades before not absorbing and discharge mechanism.Lymphsystem also provides some other advantage, makes overall bioavailability be enhanced.
Cefpodoxime proxetil is an example of prodrug, and the absolute bioavailability that the commercial oral tablet that uses demonstrates only is 50% of intravenous injection.Carry out systematic Study to determine the possible cause of cefpodoxime proxetil bioavailability difference.
Carry out solubility and stability study under condition of different pH, find that cefpodoxime proxetil is the dissolubility and the stability of pH dependent form, the both descends along with the increase of pH.Although solubility reduces, the solubility expection during intestinal pH enough obtains the trap of expectation.Therefore, at the stability rather than the dissolubility of intestinal, may be one of possible cause of bioavailability reduction.
Further study with external Mus intestinal " eversion bladder (Everted Sac) " method, to determine effective infiltration coefficient of cefpodoxime and cefpodoxime proxetil.The infiltration coefficient that is surprisingly found out that cefpodoxime and cefpodoxime proxetil is similar.This is unexpected, because think cefpodoxime proxetil than cefpodoxime lipophilic more, the design cefpodoxime proxetil is in order to improve permeability and trap.Therefore, seem the infiltration coefficient that obtained to be subjected to the influence (for example having the mechanism of discharge) of X factor these factors and then reduced bioavailability.
The mechanism of discharging role in reducing overall bioavailability is confirmed by external Mus intestinal " eversion bladder " method, wherein the stability of the cefpodoxime proxetil of existence under the jejunal segment is studied.Observed result shows that about 90% cefpodoxime proxetil that exists was converted into cefpodoxime acid in 15 minutes, almost completely transformed, as shown in Figure 1 and Figure 2 in 30 minutes.Find that it is cefpodoxime proxetil metabolic problems to the absorption of cefpodoxime acid in the enterocyte that cefpodoxime proxetil is converted into the reason that is exposed to epithelial cefpodoxime rapidly, with and overflow and be back to the problem of enteric cavity.
Discharge the available fresh jejunum ring that turns up of mechanism, confirm by the intestinal tissue Absorption Study.The jejunum ring shows, at the initial stage that is lower than 1 minute, has a large amount of cefpodoxime proxetils in the enterocyte.But its concentration consumes rapidly in epithelial cell, passes the appearance of having observed cefpodoxime concentration in time.When general former times, ester carried out Absorption Study to cefpodoxime, the time of observing its trace in tissue only had 5 minutes.This shows the cefpodoxime proxetil rapid permeability, but is converted into cefpodoxime rapidly, flows to top side (apical side) rather than base side, reduces thereby cause absorbing.Pass in time, cumulative cefpodoxime is absorbed, but slowly until lower degree.When carrying out similar research with cefpodoxime, showed the constant absorption rate of tissue, the concentration that provides ascendant trend is to time diagram.Result of study is shown among Fig. 3 and Fig. 4.The degraded, this discharge mechanism has further reduced bioavailability before absorbing.
Before being absorbed into systemic circulation, the conversion from prodrug to active component is still a difficult problem in all conventional peroral dosage forms.Therefore, need the preparation of preparation prodrugs (for example cefpodoxime proxetil), said preparation can make prodrug by intestinal contents and provide enough protections to make it exempt from the degraded of intestinal contents and enterocyte enzyme.Through the solid lipid nano-particles that lymph absorbs, be a selection preferably in this case.Solid lipid nano-particles does not enter blood flow, but is absorbed into lymph by the special persorption process (persorption) that is called cell endocytic, and droplet or solid particle also enter Lymph flow thus by intestinal wall whereby.Because prodrug does not enter the enterocyte of degraded prodrug, secondly owing to having avoided directly contacting, so the chance of degraded was lower before prodrug absorbed with gastrointestinal tract environment.And lymphsystem absorbs prodrug, without any first pass effect (if the words that have), has therefore further improved bioavailability.
The solid lipid nano-particles of prodrug of the present invention is compared with conventional peroral dosage form, can improve 1.25 times of bioavailability or more, particularly 1.5 times or more.Compare with regular dosage form, reach the medicine blood plasma level, the prodrug that needs still less.Therefore, solid lipid nano-particles will have cost benefit, can reduce chance and relevant toxicity problem that dosage is removed (dumping).
Solid lipid nano-particles is by forming with the compound prodrug of lipid carrier, and is made into the globular solids granule of nanometer range, particularly in the 100-500nm scope.Solid lipid nano-particles has been gathered the advantage of polymer nano granules, fat milk and liposome, but has avoided their some shortcoming simultaneously.Size, character, Zeta potential, the constructive method of lipid carrier and the nutritional labeling that provides all are the factors that influences the solid lipid nano-particles performance.Therefore, on the one hand, solid lipid nano-particles of the present invention comprises prodrug and lipid carrier.
Solid lipid nano-particles can be used for because of degraded before absorbing and/or discharge mechanism problem that the prodrug that hangs down bioavailability is arranged.The example of prodrug comprises cefpodoxime proxetil, Ro-15-8075, cefditoren, CEFUROXIME AXETIL, cut down Xi Luowei, valganciclovir, azidothymidine AZT, capecitabine, famciclovir, nabumetone, pivampicillin, irinotecan, terfenadine, enalapril, ramipril, dipivefrine, omeprazole, sulfasalazine, Olsalazine, hexamethylenamine (methanamie), bambuterol, allopurinol, gemcitabine, fludarabine, cladribine, simvastatin, ftorafur, fosphenytoin, with Wella rice fourth (viramidine).Preceding dose can account for about 5%w/w of solid lipid nano-particles to about 90%w/w, and particularly about 10%w/w is to about 40%w/w.
The example of lipid carrier comprise the saturated straight chain fatty acid list of one or more 12-30 carbon atom-, two-, the Three-glycerol ester, described fatty acid is for for example: lauric acid, myristic acid, Palmic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, cerinic acid, and melissic acid; The ester of polyhydroxy-alcohol, described polyhydroxy-alcohol for example are: saturated ceryl alcohol such as tetracosanol, ceryl alcohol, hexacosanol and the melissyl alcohol of the saturated fat acid alcohol of ethylene glycol, propylene glycol, mannitol, sorbitol, a 12-22 carbon atom such as lauryl alcohol, myristyl alcohol, spermol, stearyl alcohol, arachidic alcohol and behenyl alcohol, a 24-30 carbon atom; Or the like.Other example comprises animal or plant phospholipid, for example lecithin and hydrogenated form thereof; Polypeptide, for example gelatin and modified forms thereof; Wax, for example Brazil wax and Cera Flava; Or the like.Used lipid, preferred fusing point is in about 30 ℃ of-100 ℃ of scopes.In the solid lipid nano-particles, the ratio of prodrug and lipid carrier can be about 1: 0.5-changes between about 1: 10.The amount of lipid carrier changes between about 90%w/w at about 5%w/w of solid lipid nano-particles, especially, changes between about 70%w/w at about 20%w/w.
In addition, solid lipid nano-particles of the present invention can further comprise one or more other pharmaceutically acceptable additive, for example stabilizing agent, cosolvent, cryoprotective agent, antiseptic or the like.
Usually, solid lipid nano-particles comprises that with the minimized stabilizing agent of electrostatic interaction in the time of in being scattered in gastrointestinal content, thereby described electrostatic interaction can cause particle agglutination to influence repeatability.The example of stabilizing agent comprises one or more any polymer and/or surfactants, thereby described polymer and/or surfactant can stop solid lipid nano-particles coagulation stable composition.The instantiation of polymer comprises polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone or the like.Surfactants can be ion-type or nonionic.The example comprises natural formation and synthetic phospholipid, its hydrogenated derivatives and mixture, aphingolipid, and glycosphingolipid; The bile salts of physiologically active, for example sodium cholate, Carachol, NaTDC, sodium glycocholate and sodium taurocholate; Saturated and undersaturated fatty acid or aliphatic alcohol; Ethoxylated fatty acid or aliphatic alcohol and their ester and ether; Alkyl aryl polyether alcohol, for example tyloxapol; The ester of sugar or sugar alcohol and fatty acid or aliphatic alcohol and ether; Acetyl group or ethyoxyl list-and two glyceride; Synthetic biodegradable polymer, for example polyoxyethylene polyoxypropylene oxide block copolymer; Sulfosuccinate, polyoxyethylene sorbitan esters, ethyoxyl sorbitan esters or anhydrosorbitol ether; Aminoacid, polypeptide and protein such as gelatin and albumin, lecithin, egg lecithin, polyoxyethylene aliphatic alcohol ether, Myrj 45, and polyoxyethylene ether and polyethenoxy ether (Pluronic for example
), the saturated glyceride of ethyoxyl (Labrafil for example
) and partial fatty acid glyceride and polyglycereol inner ether (Gelucire for example
) corresponding mixed condensate.
The example of cosolvent comprises one or more volatile solvents, as organic solvent, comprises chloroform, methanol, ethanol or the like.
Cryoprotective agent is used to prevent that compositions from damaging between pool period.The example comprises sugar, as sucrose, glucose, trehalose; Glycol (alcohol that contains at least two hydroxyls) is as ethylene glycol, propylene glycol, glycerol; Or the like.
The example of antiseptic comprises: benzyl alcohol, phenethanol, phenoxyethanol, sodium benzoate, methyl butex, propylparaben, oxybenzene butyl formate, propyl gallate, dolantin Kapp sieve (demercaprol), Butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid Petiolus Trachycarpi ester, sodium pyrosulfite, tocopherol and/or its ester or the like.
Solid lipid nano-particles can prepare with routine techniques known in the art, for example high pressure homogenize method (hot homogenize or cold homogenize), microemulsified-solidification method, solvent emulsion/evaporation or the like.
In one embodiment, the solid lipid nano-particles of prodrug is by the even method preparation of hot high pressure, and this method comprises:
(a) lipid is melted, with the prodrug dissolution in lipid;
(b) with load the lipid of prodrug be scattered in the hot water surfacant mixture;
(c) premixing forms thick pre-Emulsion;
(d) high pressure homogenize forms hot oil-in-water nanometer Emulsion; And
(e) by being cooled to room temperature, curing nano Emulsion obtains solid lipid nano-particles.
In another embodiment, the solid lipid nano-particles of prodrug is by the even method preparation of cold high pressure, and described method comprises:
(a) lipid is melted, with the prodrug dissolution in lipid;
(b) with load the lipid of prodrug in liquid nitrogen or dry ice, solidify;
(c) appropriate abrasive solid;
(d) it is scattered in the organic solvent solution/dispersion liquid of surfactant;
(e) mix, form thick pre-Emulsion; And
(f) room temperature or more high pressure homogenize under the low temperature obtain solid lipid nano-particles.
In another embodiment, the solid lipid nano-particles of prodrug is by solvent emulsion/evaporation preparation, and described method comprises:
(a) prodrug and lipid are dissolved in the organic solvent;
(b) be mixed into stabilizing agent; And
(c) homogenize and this solvent of evaporation obtain solid lipid nano-particles.
Perhaps, solid lipid nano-particles also can be by microemulsified-curing or multistep microemulsified-curing technology preparation.
As needs, solid lipid nano-particles and one or more medicinal inert excipient composition that as above prepares can be processed into conventional peroral dosage form, for example suspension, tablet, capsule, pill, sachet powder or the like.
The performance of solid lipid nano-particles, can analyze by some parameter shown in the assessment following table:
| Parameter | Expectation target |
| Particle diameter | Should be in nanometer range (upper limit 1000nm) |
| Grain shape | Spherical |
| The drug loading rate | At least 5% |
The present invention further specifies with following embodiment, but this embodiment does not constitute any restriction to the scope of the invention.
Embodiment
| Composition | Percentage ratio (w/w) | ||
| Embodiment 1 | Embodiment 2 | Embodiment 3 | |
| |
25 | 20 | 40 |
| Three Glyceryl Behenate (Compitrol 888) | 75 | 80 | 60 |
Technological process:
1. cefpodoxime proxetil and three Glyceryl Behenates (tribehenin) are dissolved in the chloroform, form solution.
2. keep under the 40-50 ℃ of continuous stirring, the solution of step 1 is dropwise joined in the aqueous solution that contains polyvinyl alcohol.
3. the homogeneous mixture of super centrifugal purification step 2 is collected filtrate.
4. with the filtrate lyophilization in the step 3, obtain solid lipid nano-particles.
The solid lipid nano-particles of above-mentioned preparation has more or less spherical, and mean diameter is in the 100-500nm scope.The about 5-20% of the load capacity of cefpodoxime proxetil in lipid.In addition, the solid lipid nano-particles of each compositions among the embodiment 1-3 is stored down at 40 ℃, with (validated) HPLC method of empirical tests in the time more than 2 weeks regular correct spore moor oxime ester of general former times and analyze.Found that cefpodoxime proxetil content is at least 95%.
Performance is with Cepodem in the body of solid lipid nano-particles (T)
TM100 (being sold by Ranbaxy Lab.Ltd.) tablet (R) is reference, in male Sprague-Dawely rat (weight: 250-275gm), with 10mg/kg body weight dosage (cefpodoxime acid equivalent), (freely drink water) under acceleration environment and assess.All zooperies and operation are all carried out according to the method for ethics committee of Zoological Society approval.With the oral metered entry needle along with saline, with each preparation of given dose orally give.0.5,1,1.5,2,3,4,6,8,12,24 hours, collect blood sample (0.4-0.5ml).Centrifugal sample separation blood plasma is analyzed medicament contg with the HPLC method of empirical tests.From obtaining data computation pharmacokinetic parameters C
Max(maximal plasma concentration), T
Max(reaching the time of maximal plasma concentration), AUC
0-t(plasma concentration from 0 hour to the final sample acquisition time is than area under the time graph) and AUC
0-∞(from 0 hour plasma concentration when infinitely great than area under the time graph).Use MS-Excel
TMWith nonlinear regression software PC-NONLIN
TMData are analyzed.Result of study is as shown in the table.
| Dosage form | C max (ng/ml) | T max(hour) | AUC 0-∞ | Bioavailability (T/R) relative percentage (%) |
| R | 3994±676 | 0.75±0.10 | 8372±1003 | 167.98 |
| T | 6780±2763 | 0.68±0.06 | 14063±4038 |
The above results clearlys show that solid lipid nano-particles is to improving the importance of the oral availability of prodrug.
Claims (12)
1. method that improves the prodrug bioavailability, described method adopt solid lipid nano-particles that the prodrug bioavailability is brought up to 1.25 times of conventional peroral dosage form or more.
2. the method for raising prodrug bioavailability as claimed in claim 1, wherein, conventional peroral dosage form bioavailability is low because of degrading before absorbing and/or discharging machine-processed causing.
3. the solid lipid nano-particles of a prodrug, it comprises prodrug and lipid carrier, and the bioavailability that described nano-particle provides exceeds 1.25 times of conventional peroral dosage forms or more.
4. solid lipid nano-particles as claimed in claim 3, wherein, described prodrug is selected from down group: cefpodoxime proxetil, Ro-15-8075, Cefditoren pivoxil Cephalosporins, CEFUROXIME AXETIL, cut down Xi Luowei, valganciclovir, azidothymidine AZT, capecitabine, famciclovir, nabumetone, pivampicillin, irinotecan, terfenadine, enalapril, ramipril, dipivefrine, omeprazole, sulfasalazine, Olsalazine, hexamethylenamine, bambuterol, allopurinol, gemcitabine, fludarabine, cladribine, simvastatin, ftorafur, fosphenytoin or Wella rice fourth.
5. solid lipid nano-particles as claimed in claim 4, wherein, described prodrug accounts for about 5%w/w of described solid lipid nano-particles to about 90%w/w.
6. solid lipid nano-particles as claimed in claim 3, wherein, described lipid carrier be selected from down the list of the saturated straight chain fatty acid of group: a 12-30 carbon atom-, two-, the Three-glycerol ester; The ester of polyhydroxy-alcohol; The saturated ceryl alcohol of 24-30 carbon atom; Animal or plant phospholipid, for example lecithin, and hydrogenated form; Or polypeptide.
7. solid lipid nano-particles as claimed in claim 6, wherein, described lipid carrier accounts for about 5%w/w of described solid lipid nano-particles to about 90%w/w.
8. the described solid lipid nano-particles of arbitrary as described above claim; wherein; described solid lipid nano-particles further comprises one or more pharmaceutically acceptable excipient, and described excipient is selected from down group: stabilizing agent, cosolvent, cryoprotective agent or antiseptic.
9. the described solid lipid nano-particles of arbitrary as described above claim, it is to prepare by the method that comprises the following steps: the prodrug dissolution in the mixture of lipid carrier and stabilizing agent, is added into dosage forms then.
10. solid lipid nano-particles as claimed in claim 9, wherein, the dissolution prodrug is undertaken by high pressure homogenize technology, microemulsified-curing technology, multistep microemulsified-curing technology or solvent emulsion/evaporation technique.
11. solid lipid nano-particles as claimed in claim 9, wherein, described dosage form is selected from: suspension, tablet, capsule, pill or sachet powder.
12. this paper embodiment puts down in writing the method for the raising prodrug bioavailability of explanation.
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| IN3139/DEL/2005 | 2005-11-23 | ||
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102091044A (en) * | 2011-01-27 | 2011-06-15 | 海南美大制药有限公司 | Cefuroxime axetil lipid microsphere solid preparation |
| CN102218036A (en) * | 2010-07-29 | 2011-10-19 | 吴赣英 | Formula, preparation method and application of omeprazole sodium liposome composite medicament |
| CN106821996A (en) * | 2017-03-01 | 2017-06-13 | 华益药业科技(安徽)有限公司 | Enalapril maleate granule and preparation method thereof |
-
2006
- 2006-11-23 CN CNA2006100647341A patent/CN1977826A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102218036A (en) * | 2010-07-29 | 2011-10-19 | 吴赣英 | Formula, preparation method and application of omeprazole sodium liposome composite medicament |
| CN102091044A (en) * | 2011-01-27 | 2011-06-15 | 海南美大制药有限公司 | Cefuroxime axetil lipid microsphere solid preparation |
| CN102091044B (en) * | 2011-01-27 | 2012-05-23 | 海南美大制药有限公司 | Cefuroxime axetil lipid microsphere solid preparation |
| CN106821996A (en) * | 2017-03-01 | 2017-06-13 | 华益药业科技(安徽)有限公司 | Enalapril maleate granule and preparation method thereof |
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