CN103432101B - Nanometer suspension osmotic pump type controlled release system of a kind of insoluble drug and preparation method thereof - Google Patents
Nanometer suspension osmotic pump type controlled release system of a kind of insoluble drug and preparation method thereof Download PDFInfo
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- CN103432101B CN103432101B CN201310394268.3A CN201310394268A CN103432101B CN 103432101 B CN103432101 B CN 103432101B CN 201310394268 A CN201310394268 A CN 201310394268A CN 103432101 B CN103432101 B CN 103432101B
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Abstract
The invention belongs to technical field of medicine, nanometer suspension osmotic pump type controlled release system disclosing a kind of insoluble drug and preparation method thereof.It by with drug release hole semipermeability capsule shells and be loaded in the inside content form.Content comprises the nano suspension powder of pharmacological active substance, suspending agent, penetrating agent and fluidizer, its percentage by weight is: the nano suspension powder 5%-50% of pharmacological active substance, suspending agent 20%-80%, penetrating agent 0%-40%, fluidizer 0%-5%, the nano suspension powder of pharmacological active substance is by obtaining after the pharmacological active substance drying solidification after nanorize; Semipermeability capsule shells, by forming volatilizing in capsule material perfusion to mould, is made up of capsule cap and capsule body; Content is directly loaded in powder form, and with capsule material liquid by capsule cap and the sealing of capsule body, spiles at any one of capsule simultaneously.The present invention, while raising insoluble drug bioavailability, reduces blood concentration fluctuation in body.
Description
Technical field
The invention belongs to technical field of medicine, nanometer suspension osmotic pump type controlled release system relating to a kind of insoluble drug and preparation method thereof.
Background technology
Dissolubility stomach function regulating intestinal membrane permeation is the key factor affecting drug bioavailability and body absorption.Medicament high flux screening technology is widely applied in recent years, but the most molecular weight of the reactive compound filtered out is large, and hydrophobicity is strong.According to statistics current more than 40% there is poorly soluble problem grinding medicine.Therefore, the focus that the dissolubility of insoluble drug and bioavailability have become Recent study is improved.The technology such as at present conventional cosolvent solubilising, cyclodextrin inclusion compound and Emulsion have certain limitation, such as, when cosolvent exists organic solvent toxic and side effects, the compatibility problem such as medicine precipitation; The size of cyclodextrin inclusion compound to drug molecule has particular/special requirement; Emulsion then requires that medicine has higher dissolubility in oil phase.
M ü ller in 1994 etc. propose the concept of nano suspension (Nanosuspensions) first, it is the Stabilization utilizing the stabilizing agent such as surfactant or high molecular polymer, by drug particle dispersion in water, by pulverizing or control the stable nanometer colloidal dispersion system that crystallize technology is formed.No matter be insoluble in the medicine of water or be not only insoluble in water but also be insoluble in oily medicine, corresponding nano suspension can be prepared by the method.As a kind of intermediate dosage form, nano suspension can be prepared into applicable oral, injection or the pharmaceutical dosage form of other administration route further, thus improves absorption and the bioavailability of medicine.And nano suspension can improve the medicament contg in preparation, be particularly suitable for the oral and drug administration by injection of heavy dose, insoluble drug.In addition, owing to not containing carrier and cosolvent in prescription, the toxic and side effects of drug administration by injection is very low.
But the nano suspension of report mostly is quick releasing formulation at present, the release of medicine is all very fast, generally can make the C of medicine
maxincrease, T
maxshorten.This point is for some special diseases, and such as the patient of the special disease such as hypertension and diabetes is disadvantageous beyond doubt, and the great fluctuation process excessively of blood drug level can increase the toxic and side effects of medicine.Therefore, find a kind of excellent slowly released and controlled-drug delivery system and combine with nanometer suspension system, make it can either play the effect improving drug bioavailability, can discharge medicine slowly is again significantly.
Oral osmotic pump controlled release administration system is chief motivation with osmotic pressure, take zero-order release as a class controlled release formulations for oral administration of basic feature.It has constant speed release medicine, affect by gastrointestinal tract variable factor hardly, In vitro-in vivo correlation is good, can the advantage such as controlled release multi-medicament simultaneously, be therefore acknowledged as current optimal oral controlled-release medication, and become the focus competitively studied both at home and abroad.
About the bibliographical information of osmotic pump preparation first appeared in nineteen fifty-five, due to its blank complex structure, be not easy to suitability for industrialized production, until 1974 are coacted by Theeuwes and Alza company, the structure of osmotic pump preparation is simplified, invent primary osmotic pump, just make the development of osmotic pump preparation reach a new milestone.But because primary osmotic pump is only applicable to soluble drug, therefore nineteen eighty-two Cortese and Theeuwes etc. devise a kind of push-pull osmotic pump with double-layer tablet cored structure, the label of this osmotic pumps is made up of with the boosting layer with expansion impetus the medicated layer of carrying active medicine, between two-layer with the elastic barrier film of one deck separately, label outer wrap one deck semi permeability clothing film, plays a drug release hole in the medicated layer side of clothing film.After biofluid enters sheet core inner through clothing film, medicated layer water suction aquation, forms the suspension of medicine; Boosting layer hydration swelling simultaneously, thus drug suspension is released from drug release hole.On this basis, research worker simplifies push-pull osmotic pump and improves, and eliminates the barrier film between medicated layer and boosting layer, still can form sharp interface between two-layer, reach desirable release effect, becoming the most frequently used at present is also the most classical insoluble drug osmotic pump dosage form.But the technological requirement of double-decker to tabletting and punching is higher, which prevent the process of osmotic pump preparation suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention is the nanometer suspension osmotic pumps sustained and controlled release medicament transmission system of a kind of novel hard-soluble medicine nanometer suspension technology being combined with oral osmotic pump-type controlled-release technology and obtain, by changing the release behavior of medicine, reduce blood concentration fluctuation in body; Solve by the improvement of nanometer suspension technology to drug solubility the difficult point that insoluble drug is prepared into mono-layer osmotic pump simultaneously, maximize favourable factors and minimize unfavourable ones, play the advantage of two kinds of preparation techniques simultaneously.
The present invention is achieved through the following technical solutions:
The present invention by with drug release hole semipermeability capsule shells and be loaded in the inside content form.
Described semipermeability capsule shells be a kind of by capsule material perfusion in mould, the putamina of volatile dry, refers to Fig. 1.Its formation basic theory is: containing cellulosic polymer, porogen, plasticizer and solvent thereof in capsule material liquid, fill mould solvent volatilization under preference temperature of capsule material liquid, when the gravity of capsule material liquid is equal to the adhesion of mold wall with it, solvent constantly evaporates into certain speed and is drying to obtain.Capsule material liquid is by weight percentage containing, for example lower component: cellulosic polymer 5%-15%, solvent 70%-90%, porogen 0.5%-10%, plasticizer 0%-5%.More preferred composition is: cellulosic polymer 6.5%-9.5%, solvent 70%-90%, porogen 1.5%-5%, plasticizer 0.5%-2.5%.Wherein cellulosic polymer is selected from one or more in cellulose acetate, ethyl cellulose, acetylbutyrylcellulose; One or more in described solvent selected from acetone, ethanol, isopropyl alcohol, butanols, capryl alcohol, ethyl acetate or dichloromethane; Described porogen is selected from one or more in Macrogol 200, PEG400 or Macrogol 600; Described plasticizer is selected from one or more in triethyl citrate, dimethyl phthalate, diethyl phthalate, dioctyl phthalate or DMEP.
The concrete preparation method of described semipermeability capsule shells is:
(1) prepare capsule liquid: take the cellulosic polymer of recipe quantity, porogen and plasticizer respectively, be placed in conical flask, add solvent in right amount, sealing, stir, after all dissolving, ultrasonic 5min, obtains capsule liquid.
(2) pour in mould by capsule liquid, at 4 DEG C, drying more than 12 hours, then cuts into suitable length as required.
The nano suspension powder of pharmacological active substance and adjuvant directly pour in semipermeability capsule body by the present invention in powder form, and with capsule material liquid by capsule cap and the sealing of capsule body, make a call to an aperture at any one of capsule simultaneously.
Content is made up of the nano suspension powder of pharmacological active substance, suspending agent, penetrating agent and fluidizer.Wherein pharmacological active substance is selected from anti-arrhythmic, vasodilation, antihypertensive, beta-blocker, oral antidiabetic, antirheumatic, antibiotic medicine, antidepressants, diuretic, antuepileptic, tranquilizer, antibiotic, analgesic, vitamin, hormone, antibacterial, polypeptide, enzyme and mucopolysaccharide, Chinese medicine extract.The nano suspension powder of pharmacological active substance is by obtaining being prepared into the pharmacological active substance after nano suspension after lyophilization or spray-dired mode solidification.One or more in suspending agent is selected from copolyvidone, polyvidone, molecular weight are 100000 ~ 500000 polyoxyethylene, arabic gum, sodium alginate or hydroxypropyl methylcellulose; Penetrating agent is selected from one or more in sodium chloride, potassium chloride, magnesium sulfate, sodium sulfate, sucrose, lactose or mannitol; Fluidizer is selected from one or more in magnesium stearate, micropowder silica gel or Pulvis Talci.The percentage by weight of the nano suspension powder of pharmacological active substance, suspending agent, penetrating agent and fluidizer is: the nano suspension powder 5%-50% of pharmacological active substance, suspending agent 20%-80%, penetrating agent 0%-40%, fluidizer 0%-5%.More preferred composition is: the nano suspension powder 10%-45% of pharmacological active substance, suspending agent 25%-65%, penetrating agent 5%-30%, fluidizer 0.5%-3%.Described drug release hole is that to make a call to a diameter be the aperture of 0.3-0.5mm any of capsule.
The nano suspension powder of described pharmacological active substance is under the protective effect of suitable stabilizing agent; by media milling process or control the sedimentation method or high pressure homogenization method or control that precipitation associating high pressure homogenization method is prepared from; the percentage by weight of each composition is: pharmacological active substance 0.001%-10%; stabilizing agent 0.1%-30%; good solvent 0%-30%; excipient 0.1%-20%, distilled water surplus.More preferred composition is: pharmacological active substance 0.5%-8%, stabilizing agent 0.1%-15%, good solvent 0%-30%, excipient 0.1%-20%, distilled water surplus.Described stabilizing agent is selected from one or more in polyvidone, Polyethylene Glycol, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamer F68, Poloxamer 127, Tween 80, phospholipid, sodium lauryl sulphate, NaTDC, vitamin e succinate and TPGS 1000.Described good solvent is selected from one or more in acetone, ethyl acetate, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide, dimethyl formamide, chloroform and glyceryl triacetate.Carry out solidification with lyophilization or spray-dired mode after prepared nano suspension adds excipient, be beneficial to the preparation of target formulation.Described excipient is selected from one or more in mannitol, lactose, sucrose, maltose, sorbitol, trehalose, dextran, glucose, micropowder silica gel and microcrystalline Cellulose.
In the preparation method of described pharmacological active substance nano suspension, media milling process first the stabiliser solution of dispersion medicine and abrasive media is put into medium grinder, abrasive media is high speed rotating under motor effect, make to occur fiercely to collide between drug particle and with abrasive media, grinding chamber inwall, thus make drug particle be ground into nanoparticle; Abrasive media is generally glass particle, Zirconium oxide powder or special high polymer as polyoxyethylene deriv etc.Controlling the sedimentation method is by medicine dissolution is formed drug solution in a certain amount of good solvent molten with aqueous phase, drug solution is added in the water containing stabilizing agent with certain speed, medicine is rapid crystallization because reaching supersaturation in water, then by high shear dispersion, ultrasonic, microjet method control precipitation.High pressure homogenization method is suspended in by micronized medicine in the aqueous solution containing stabilizing agent, repeatedly circulate this coarse dispersion through high pressure homogenize the combineds effect such as produced shearing force and void effect again, obtains the drug crystallization of desired particle size after making drug particle cracking fragmentation.Controlling precipitation associating high pressure homogenization method is use high pressure homogenizer all to turn to the method for desired particle size drug crystallization further the first suspension obtained by controlling the sedimentation method, the particle controlling sedimentation method acquisition can be converted into stable crystalline state by the method, thus keep the drug particle size that the sedimentation method obtain, can overcome the sedimentation method obtains particle diameter problem pockety on the other hand, increase the physical stability of final products, the risk of high pressure homogenizer slit blocking can be reduced simultaneously.
Common permeable pump-type sustained-release preparation is that further coating forms by tabletted after pharmacological active substance and adjuvant Homogeneous phase mixing.The present invention then simulates the structure of common permeable pump sheet, after capsule is placed in release medium, moisture in medium diffuses into capsule gradually, make capsule 's content aquation, due to the dissolving of osmotic pressure active substance and medicament nano particle, the hydration swelling of polymer, the homogeneous medicament nano suspension that osmotic pressure is very high is formed in capsule, because softgel shell is rigid structure, as permeable pressure head inside and outside the softgel shell of release power by maintain moisture continue enter, cause the formation of sheet in-core hydrostatic pressing, thus medicament nano suspendible dispersion liquid is constantly disengaged uniformly from small delivery aperture.Medicine constant release process will last till that content dissolves completely, only remain solution in semipermeable membrane.Remaining medicine, by with the speed declined gradually release, until osmotic pressure is equal inside and outside film, is shown in Fig. 2.With common permeable pump sheet unlike, first pharmacological active substance is prepared into nano suspension by the present invention, improve drug solubility, improve its bioadhesive, promote gastrointestinal absorption and then improve drug bioavailability, overcome insoluble drug osmotic pumps system drug release incomplete simultaneously, the defect that bioavailability is not high, and then be prepared into osmotic pump capsule, effectively prevent the peak valley phenomenon (see figure 3) of blood drug level in medicine body, decrease drug side effect, improve the compliance of patient.
Beagle dog Internal pharmacokinetics is studied
What choose is carvedilol nanometer suspension osmotic pump capsule prepared by embodiment 1 by test preparation, and the reference preparation chosen is commercially available Carvedilol Tablets.8 Beagle dogs are divided into two groups at random, and carry out single-dose to the lower Beagle dog (before administration fasting 12h) of empty stomach, the clean phase in each cycle is one week, and dosage is 50mg.Administration the last fortnight and experimental session must not take any other medicine, freely drink water during administration, unified feed after administration 4h.Concrete dosage regimen sees the following form:
Reference preparation and by test preparation respectively at after administration 0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,12,14 and 24h get foreleg vein blood 3mL, and immigration scribbles in the test tube of heparin immediately, centrifugal 10 minutes of 4000rpm, separated plasma, then puts-20 ° of C Refrigerator stores stand-by.During plasma treatment, precision measures 200 μ L plasma samples, is placed in 2.5mL tool plug conical centrifuge tube, adds the inner mark solution 40 μ L of 40 μ g/mL, NaOH solution (0.1mol/L) 80 μ L, vortex mixed 1min on turbula shaker.Then 320 μ L ether are added, vortex 5min, 10,000 × g centrifugal 5min, are separated organic layer in another conical centrifuge tube, in 40 ° of C water-baths, nitrogen dries up, gained enriched substance is dissolved with 80 μ L mobile phases, vortex 3min, then with 10, the centrifugal 5min of 000 × g, gets supernatant 20 μ L and injects high performance liquid chromatograph.Record chromatogram and peak area, substitute into standard curve by the peak area ratio of determinand and internal standard substance, calculate each time point sample drug concentration.
Determination of plasma concentration result is as following table:
Its plasma concentration curve is shown in Fig. 4.By DAS software, data are processed, draw following result: in reference preparation body, each mean parameter is T
1/2=4.17h, C
max=1062.61ng/ml, T
max=2.75h, AUC
(0-∞)=4657.86ng/mlh; Be T by mean parameter each in test preparation body
1/2=6.42h, C
max=706.59ng/ml, T
max=5.75h, AUC
(0-∞)=9013.95ng/mlh; Relative bioavailability=AUC
(0-∞) is tested/ AUC
(0-∞) reference=203.5%.
As can be seen here, compared with ordinary preparation, nanometer suspension osmotic pump capsule efficiently avoid the peak valley phenomenon of blood drug level in body, decreases drug side effect, extends the release time of medicine, serves slow controlled-release effect; Meanwhile, medicament nano particle effectively improves release and the gastrointestinal absorption of medicine, thus bioavailability is significantly improved.
Accompanying drawing explanation
Fig. 1 is semipermeability capsule appearance figure
Fig. 2 is nanometer suspension osmotic pump capsule drug release schematic diagram
Fig. 3 is the cumulative in vitro release profiles of the carvedilol nanometer suspension osmotic pump capsule according to embodiment 1 preparation
Fig. 4 be according to embodiment 1 prepare carvedilol nanometer suspension osmotic pump capsule and commercially available Carvedilol Tablets blood drug level through time curve.
Detailed description of the invention
embodiment 1
Nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (PlasdoneS-630) 180mg
Mannitol 100mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 8g
Diethyl phthalate 0.96g
PEG400 2.24g
Acetone 100mL
Preparation technology:
The preparation of A, semipermeability capsule shells:
(1) capsule liquid is prepared;
(2) capsule liquid is poured in mould, at 4 DEG C dry more than 12 hours, then according to time lag need cut into suitable length;
The preparation of B, nano suspension powder:
(1) carvedilol of recipe quantity and vitamin e succinate are dissolved in prepare organic facies in acetone jointly, ultrasonic, with the filtering with microporous membrane of 0.45 μm after fully dissolving, to remove the impurity that may exist in organic facies;
(2) sodium lauryl sulphate of recipe quantity is dissolved in distilled water to prepare anti-solvent phase;
(3) under 10 ° of C, the organic facies of 1mL is injected rapidly the anti-solvent of 50mL mutually, use high-shear emulsifying homogenizer to disperse 1min simultaneously under the shear rate of 10,000rpm;
(4) then by first dispersion liquid ultrasonic 3s of Probe Ultrasonic Searching 15min(under the power of 400W, interval 3s), with ice bath, sample temperature is controlled at 4-8 ° of C;
(5) in the sample of pre-lyophilizing, add the maltose of recipe quantity, sample after pre-freeze 12h, is carried out lyophilization in-75oC cryogenic refrigerator, thus obtains carvedilol nano suspension powder;
The preparation of C, nanometer suspension osmotic pump capsule:
(1) nano suspension and the adjuvant powder of 60 mesh sieves was taken respectively according to recipe quantity precision, mix homogeneously;
(2) the content powder of recipe quantity is loaded in capsule, capsule body and capsule cap is fastened and uses capsule material liquid sealing, finally making a call to the aperture of a 0.4mm with perforating needle in any side of capsule.
The mean diameter recording carvedilol nano suspension is 212nm, and Zeta potential is-42mV; Osmotic pump capsule 12h cumulative release amount 90.99%, drug release profiles linearly dependent coefficient r is 0.9901.
embodiment 2
Nano suspension prescription:
Carvedilol 0.6g
Poloxamer F1270.4g
Sodium lauryl sulphate 0.8g
Trehalose 2.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 80mg
Polyoxyethylene (molecular weight 200,000) 120mg
Sodium chloride 60mg
Pulvis Talci 5mg
Capsule material liquid prescription:
Cellulose acetate 7g
Diethyl phthalate 0.64g
PEG400 2.32g
Acetone 100mL
Preparation technology:
The preparation of A, semipermeability capsule shells is with embodiment 1;
The preparation of B, nano suspension powder:
(1) carvedilol of recipe quantity and poloxamer F127 are dissolved in prepare organic facies in acetone jointly, ultrasonic, with the filtering with microporous membrane of 0.45 μm after fully dissolving, to remove the impurity that may exist in organic facies;
(2) sodium lauryl sulphate of recipe quantity is dissolved in distilled water to prepare anti-solvent phase;
(3) under 10 ° of C, the organic facies of 1mL is injected rapidly the anti-solvent of 50mL mutually, use high-shear emulsifying homogenizer to disperse 1min simultaneously under the shear rate of 10,000rpm;
(4) then first dispersion liquid is carried out high pressure homogenize, cycling condition is 200bar, 500bar and 1000bar each twice, 1300bar15 time;
(5) in the sample of pre-lyophilizing, add the trehalose of recipe quantity, sample after pre-freeze 12h, is carried out lyophilization in-75oC cryogenic refrigerator, thus obtains carvedilol nano suspension powder;
The preparation of C, nanometer suspension osmotic pump capsule is with embodiment 1.
The mean diameter recording carvedilol nano suspension is 358nm, and Zeta potential is-24mV; Osmotic pump capsule 12h cumulative release amount 87.38%, drug release profiles linearly dependent coefficient r is 0.9891.
embodiment 3
Nano suspension prescription:
Vinpocetine 1.2g
Poloxamer F680.25g
NaTDC 0.5g
Mannitol 5.0g
Distilled water 100mL
Content prescription:
Vinpocetine nano suspension powder 100mg
Polyvidone (PVPK30) 240mg
Polyoxyethylene (molecular weight 100,000) 50mg
Micropowder silica gel 5mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 9g
Triethyl citrate 0.56g
Macrogol 200 3.2g
Acetone 100mL
Preparation technology:
The preparation of A, semipermeability capsule shells is with embodiment 1;
The preparation of B, nano suspension powder:
(1) take poloxamer F68 and the NaTDC of recipe quantity, add in 100mL water, ultrasonic dissolution is complete;
(2) vinpocetine through comminution by gas stream is added, magnetic agitation 10min;
(3) then first dispersion liquid is carried out high pressure homogenize, cycling condition is 150bar, 500bar and 1000bar each twice, 1500bar15 time;
(4) in sample, add the mannitol of recipe quantity, after making it fully dissolve dispersion, carry out spraying dry, thus obtain the nano suspension powder of medicine;
The preparation of C, nanometer suspension osmotic pump capsule is with embodiment 1.
The mean diameter recording vinpocetine nano suspension is 302nm, and Zeta potential is-31mV; Osmotic pump capsule 12h cumulative release amount 92.59%, drug release profiles linearly dependent coefficient r is 0.9886.
embodiment 4
Nano suspension prescription:
Itraconazole 0.05g
Tween 80 0.05g
Hydroxypropyl methylcellulose E150.05g
Poloxamer F1270.15g
Microcrystalline Cellulose 1g
Distilled water 100mL
Content prescription:
Itraconazole nanometer suspensions powder 300mg
Arabic gum 300mg
Capsule material liquid prescription:
Cellulose acetate 8g
Ethyl cellulose 1g
PEG400 5g
Acetone 95mL
Ethyl acetate 5mL
Preparation technology:
The preparation of A, semipermeability capsule shells is with embodiment 1;
The preparation of B, nano suspension powder:
(1) take the Tween 80 of recipe quantity, hydroxypropyl methylcellulose E15 and poloxamer F127, add in 100mL water, ultrasonic dissolution is complete;
(2) itraconazole through comminution by gas stream is added, magnetic agitation 10min;
(3) then first dispersion liquid is carried out high pressure homogenize, cycling condition is 150bar, 500bar and 1000bar each twice, 1500bar15 time;
(4) in sample, add the microcrystalline Cellulose of recipe quantity, after making it fully dissolve dispersion, carry out spraying dry, thus obtain the nano suspension powder of medicine;
The preparation of C, nanometer suspension osmotic pump capsule is with embodiment 1.
The mean diameter recording Itraconazole nanometer suspensions is 516nm, and Zeta potential is-23mV; Osmotic pump capsule 12h cumulative release amount 88.21%, drug release profiles linearly dependent coefficient r is 0.9907.。
embodiment 5
Nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (PlasdoneS-630) 180mg
Mannitol 100mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 15g
Diethyl phthalate 5g
PEG400 10g
Acetone 100mL
Preparation technology: with embodiment 1, obtains carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 85.32%, drug release profiles linearly dependent coefficient r is 0.9765.
embodiment 6
Nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (PlasdoneS-630) 180mg
Mannitol 100mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 5g
Macrogol 4000 .5g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 1, obtains carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 96.87%, drug release profiles linearly dependent coefficient r is 0.9521.
embodiment 7
Nano suspension prescription:
Carvedilol 0.6g
Poloxamer F680.35g
Sodium lauryl sulphate 0.3g
Hydroxypropyl methylcellulose 0.05g
Trehalose 3.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 90mg
Copolyvidone (PlasdoneS-630) 160mg
Mannitol 100mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 8g
Diethyl phthalate 0.96g
PEG400 2.24g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 1, obtains carvedilol nanometer suspension osmotic pump capsule controlled release system; The mean diameter recording nano suspension is 533nm, and Zeta potential is-23mV; Osmotic pump capsule 12h cumulative release amount 87.47%, drug release profiles linearly dependent coefficient r is 0.9833.
embodiment 8
Nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 95mg
Polyvidone 80mg
Polyoxyethylene (molecular weight 300,000) 60mg
Mannitol 100mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 8.0g
Diethyl phthalate 0.96g
PEG400 2.24g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 1, obtains carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 86.23%, drug release profiles linearly dependent coefficient r is 0.9934.
embodiment 9
Nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (PlasdoneS-630) 230mg
Mannitol 85mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 8g
Diethyl phthalate 0.96g
PEG400 2.14g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 1, obtains carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 82.96%, drug release profiles linearly dependent coefficient r is 0.9960.
embodiment 10
Nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
Content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (PlasdoneS-630) 170mg
Mannitol 85mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 8g
Diethyl phthalate 0.96g
PEG400 2.14g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 1, obtains carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 89.85%, drug release profiles linearly dependent coefficient r is 0.9798.
embodiment 11
Nano suspension prescription:
Silymarin 0.001g
Hydroxypropyl cellulose 0.05g
Tween 80 0.05g
Micropowder silica gel 0.02g
Mannitol 0.08g
Distilled water 100mL
Content prescription:
Silymarin nano suspension powder 40mg
Polyoxyethylene (molecular weight 300,000) 180mg
Micropowder silica gel 5mg
Capsule material liquid prescription:
Cellulose acetate 8.5g
Diethyl phthalate 1.0g
Macrogol 200 2.5g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 3, obtains silymarin nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 93.44%, drug release profiles linearly dependent coefficient r is 0.9811.
embodiment 12
Nano suspension prescription:
Celecoxib 10g
Poloxamer F1275g
Sodium carboxymethyl cellulose 5g
Sodium lauryl sulphate 1g
Phosphatidase 0 .5g
Micropowder silica gel 1.5g
Lactose 10g
Distilled water 100mL
Content prescription:
Celecoxib nano suspension powder 200mg
Polyoxyethylene (molecular weight 500,000) 80mg
Sodium chloride 20mg
Copolyvidone 60mg
Magnesium stearate 10mg
Capsule material liquid prescription:
Cellulose acetate 8.5g
Dimethyl phthalate 0.75g
Macrogol 600 2.8g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 3, obtains celecoxib nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 88.91%, drug release profiles linearly dependent coefficient r is 0.9782.
embodiment 13
Nano suspension prescription:
Nitrendipine 5g
Poloxamer F1271g
Polyvinyl alcohol 0.5g
Sodium lauryl sulphate 0.05g
Sucrose 2g
Mannitol 5g
Distilled water 100mL
Content prescription:
Nitrendipine nano suspension powder 120mg
Polyoxyethylene (molecular weight 200,000) 70mg
Potassium chloride 50mg
Polyvidone 30mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 9.5g
DMEP 2.5g
PEG400 4.2g
Isopropyl alcohol 1mL
Acetone 100mL
Preparation technology: preparation technology: with embodiment 3, obtains nitrendipine nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 86.71%, drug release profiles linearly dependent coefficient r is 0.9862.
embodiment 14
Carvedilol nanometer suspension osmotic pump capsule accumulative dissolution rate in vitro prepared by embodiment 1 measures:
Adopt the device of dissolution method (Chinese Pharmacopoeia 2005 editions two annex XC second methods), temperature is controlled at 37 ± 0.5 ° of C, rotating speed is 100rpm, capsule is placed in 500mL dissolution medium (0.1mol/LHCL), take out solution 5mL in 2,4,6,8,10 and 12h respectively, filter with 0.1 μm of microporous filter membrane, discard just filtrate, get subsequent filtrate for subsequent use, and instant supplementary blank medium solution 5mL; Measure trap by ultraviolet spectrophotometry (Chinese Pharmacopoeia 2005 editions two annex XA) respectively at 242nm place after subsequent filtrate dilution suitable multiple, calculate the dissolution of different time points by external standard method respectively.
What Fig. 3 represented is that the nanometer suspension osmotic pump capsule cumulative in vitro prepared according to embodiment 1 discharges 12 hours release percent-time graphs, and result shows that this system release is complete, and release profiles is linearly good, presents zero-order release feature.
Claims (5)
1. a nanometer suspension osmotic pump type controlled release system for insoluble drug, it by with drug release hole semipermeability capsule shells and be loaded in the inside content form, it is characterized in that:
Described semipermeability capsule shells be a kind of by capsule material perfusion in mould, the putamina of volatile dry; It is made up of capsule cap and capsule body; Content is directly loaded wherein in powder form, and with capsule material liquid by capsule cap and the sealing of capsule body, plays a drug release hole at any one of capsule simultaneously;
Described capsule material liquid is by weight percentage containing, for example lower component: cellulosic polymer 5%-15%, solvent 70%-90%, porogen 0.5%-10%, plasticizer 0%-5%; Described cellulosic polymer is selected from one or more in cellulose acetate, ethyl cellulose, acetylbutyrylcellulose; Described porogen is selected from one or more in Macrogol 200, PEG400 and Macrogol 600; Described plasticizer is selected from one or more in triethyl citrate, dimethyl phthalate, diethyl phthalate, dioctyl phthalate and DMEP; One or more in described solvent selected from acetone, ethanol, isopropyl alcohol, butanols, capryl alcohol, ethyl acetate and dichloromethane;
Described content comprises the nano suspension powder of pharmacological active substance, suspending agent, penetrating agent and fluidizer, its percentage by weight is: the nano suspension powder 5%-50% of pharmacological active substance, suspending agent 20%-80%, penetrating agent 0%-40%, fluidizer 0%-5%;
One or more in described suspending agent is selected from copolyvidone, polyvidone, molecular weight are 100000 ~ 500000 polyoxyethylene, arabic gum, sodium alginate or hydroxypropyl methylcellulose;
Described penetrating agent is selected from one or more in sodium chloride, potassium chloride, magnesium sulfate, sodium sulfate, sucrose, lactose or mannitol;
In described nano suspension powder, the percentage by weight of each composition is: pharmacological active substance 0.001%-10%, stabilizing agent 0.1%-30%, good solvent 0%-30%, excipient 0.1%-20%, distilled water surplus;
Described stabilizing agent is selected from one or more in polyvidone, Polyethylene Glycol, polyvinyl alcohol, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamer F68, Poloxamer 127, Tween 80, phospholipid, sodium lauryl sulphate, NaTDC, vitamin e succinate or TPGS 1000; Described good solvent is selected from one or more in acetone, ethyl acetate, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide, dimethyl formamide, chloroform or glyceryl triacetate; Described excipient is selected from one or more in mannitol, lactose, sucrose, maltose, sorbitol, trehalose, dextran, glucose, micropowder silica gel or microcrystalline Cellulose;
Described drug release hole is that to make a call to a diameter be the aperture of 0.3-0.5mm any of capsule;
Described pharmacological active substance is carvedilol.
2. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1; it is characterized in that: the nano suspension powder of described pharmacological active substance is under the protective effect of stabilizing agent, by media milling process or control the sedimentation method or high pressure homogenization method or control that precipitation associating high pressure homogenization method is prepared from.
3. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1, is characterized in that: described fluidizer is selected from one or more in magnesium stearate, micropowder silica gel or Pulvis Talci.
4. a nanometer suspension osmotic pump type controlled release system for insoluble drug, is characterized in that:
Nano suspension prescription:
Vinpocetine 1.2g
Poloxamer F680.25g
NaTDC 0.5g
Mannitol 5.0g
Distilled water 100mL
Content prescription:
Vinpocetine nano suspension powder 100mg
Polyvidone PVPK30240mg
The polyoxyethylene 50mg of molecular weight 100,000
Micropowder silica gel 5mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 9g
Triethyl citrate 0.56g
Macrogol 200 3.2g
Acetone 100mL
Preparation technology:
The preparation of A, semipermeability capsule shells:
(1) capsule liquid is prepared;
(2) capsule liquid is poured in mould, at 4 DEG C dry more than 12 hours, then according to time lag need cut into suitable length;
The preparation of B, nano suspension powder:
(1) take poloxamer F68 and the NaTDC of recipe quantity, add in 100mL water, ultrasonic dissolution is complete;
(2) vinpocetine through comminution by gas stream is added, magnetic agitation 10min;
(3) then first dispersion liquid is carried out high pressure homogenize, cycling condition is 150bar, 500bar and 1000bar each twice, 1500bar15 time;
(4) in sample, add the mannitol of recipe quantity, after making it fully dissolve dispersion, carry out spraying dry, thus obtain the nano suspension powder of medicine;
The preparation of C, nanometer suspension osmotic pump capsule:
(1) nano suspension and the adjuvant powder of 60 mesh sieves was taken respectively according to recipe quantity precision, mix homogeneously;
(2) the content powder of recipe quantity is loaded in capsule, capsule body and capsule cap is fastened and uses capsule material liquid sealing, finally making a call to the aperture of a 0.4mm with perforating needle in any side of capsule.
5. a nanometer suspension osmotic pump type controlled release system for insoluble drug, is characterized in that:
Nano suspension prescription:
Itraconazole 0.05g
Tween 80 0.05g
Hydroxypropyl methylcellulose E150.05g
Poloxamer F1270.15g
Microcrystalline Cellulose 1g
Distilled water 100mL
Content prescription:
Itraconazole nanometer suspensions powder 300mg
Arabic gum 300mg
Capsule material liquid prescription:
Cellulose acetate 8g
Ethyl cellulose 1g
PEG400 5g
Acetone 95mL
Ethyl acetate 5mL
Preparation technology:
The preparation of A, semipermeability capsule shells:
(1) capsule liquid is prepared;
(2) capsule liquid is poured in mould, at 4 DEG C dry more than 12 hours, then according to time lag need cut into suitable length;
The preparation of B, nano suspension powder:
(1) take the Tween 80 of recipe quantity, hydroxypropyl methylcellulose E15 and poloxamer F127, add in 100mL water, ultrasonic dissolution is complete;
(2) itraconazole through comminution by gas stream is added, magnetic agitation 10min;
(3) then first dispersion liquid is carried out high pressure homogenize, cycling condition is 150bar, 500bar and 1000bar each twice, 1500bar15 time;
(4) in sample, add the microcrystalline Cellulose of recipe quantity, after making it fully dissolve dispersion, carry out spraying dry, thus obtain the nano suspension powder of medicine;
The preparation of C, nanometer suspension osmotic pump capsule:
(1) nano suspension and the adjuvant powder of 60 mesh sieves was taken respectively according to recipe quantity precision, mix homogeneously;
(2) the content powder of recipe quantity is loaded in capsule, capsule body and capsule cap is fastened and uses capsule material liquid sealing, finally making a call to the aperture of a 0.4mm with perforating needle in any side of capsule.
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| CN104784154A (en) * | 2014-01-21 | 2015-07-22 | 胡容峰 | Site-specific osmotic-pump controlled-release capsule shell and preparation method thereof |
| TW201613565A (en) * | 2014-10-15 | 2016-04-16 | Bio Peptide Enhancer Tech Co Ltd | Controlled release sealing capsule in stomach, duodenum, jejunum, ileum and colon |
| CN105147607A (en) * | 2015-10-14 | 2015-12-16 | 中国药科大学 | Celecoxib nanosuspension and preparation method thereof |
| CN105596215B (en) * | 2015-12-30 | 2019-02-15 | 新昌县捷奥激光制品有限公司 | A kind of punch device of capsule |
| CN105617393A (en) * | 2016-01-20 | 2016-06-01 | 西安赛邦生物技术有限公司 | Water-soluble puerarin composition and preparation method |
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Non-Patent Citations (2)
| Title |
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| Controlled delivery of nanosuspensions from osmotic pumps: Zero order and non-zero order kinetics;Alexandra Hill et al;《Journal of Controlled Release》;20111214;第158卷;摘要 * |
| Fabrication of Carvedilol Nanosuspensions Through the Anti-Solvent Precipitation–Ultrasonication Method for the Improvement of Dissolution Rate and Oral Bioavailability;Dandan Liu et al;《Pharm.Sci.Tech.》;20120113;第13卷(第1期);第296页右栏第2-31行 * |
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