CN103432101A - Nanosuspension osmotic pump type sustained-release system of insoluble drugs and preparation method thereof - Google Patents
Nanosuspension osmotic pump type sustained-release system of insoluble drugs and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and discloses a nanosuspension osmotic pump type sustained-release system of insoluble drugs and a preparation method thereof. The system is composed of a semipermeable capsule shell and contents, wherein the semipermeable capsule shell is provided with a drug release hole, and the contents are loaded in the semipermeable capsule shell. The contents include the following components in percentage by weight: 5-50% of nanosuspension powder of pharmacological active substances, 20-80% of a suspending aid, 0-40% of a penetration enhancer, and 0-5% of a flow aid, the nanosuspension powder of the pharmacological active substances is prepared through drying and solidifying nanocrystallized pharmacological active substances; the semipermeable capsule shell is prepared through filling capsule wall material liquid into a die and then volatilizing the liquid, and composed of a capsule cap and a capsule body; and the contents are directly loaded in a powder mode, the capsule cap and the capsule body are sealed by using the capsule wall material liquid, and a small hole is drilled at any end of the capsule. According to the invention, the bioavailability of insoluble drugs is improved, and the concentration fluctuation of blood in the body is reduced.
Description
Technical field
The invention belongs to technical field of medicine, relate to nanometer suspension osmotic pump type controlled release system of a kind of insoluble drug and preparation method thereof.
Background technology
Dissolubility and gastrointestinal tract mucous permeability are to affect drug bioavailability and the systemic key factor of body.The medicament high flux screening technology is widely applied in recent years, but the most molecular weight of reactive compound filtered out is large, and hydrophobicity is strong.More than 40%, there is poorly soluble problem grinding medicine at present according to statistics.Therefore, improve the dissolubility of insoluble drug and the focus that bioavailability has become Recent study.At present the technology such as cosolvent solubilising, cyclodextrin inclusion compound and Emulsion commonly used have certain limitation, and while such as cosolvent, having organic solvent toxic and side effects, compatibility, medicine such as separates out at the problem; Cyclodextrin inclusion compound has specific (special) requirements to the size of drug molecule; Emulsion requires medicine that higher dissolubility is arranged in oil phase.
M ü ller in 1994 etc. have proposed the concept of nano suspension (Nanosuspensions) first, it is the Stabilization that utilizes the stabilizing agents such as surfactant or high molecular polymer, drug particles is dispersed in water, by pulverizing or control the stable nanometer colloidal dispersion system that the crystallize technology forms.No matter be insoluble in the medicine of water or not only be insoluble in water but also be insoluble in oily medicine, can prepare corresponding nano suspension by the method.As a kind of intermediate dosage form, nano suspension can further be prepared into the pharmaceutical dosage form that is applicable to oral, injection or other administration route, thereby 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, and 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 the patient of special diseases 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 good slowly released and controlled-drug delivery system and combine with the nanometer suspension system, make it can either bring into play the effect that improves drug bioavailability, it is very significant can discharging slowly again medicine.
The oral osmotic pump controlled release administration system is to take osmotic pressure as chief motivation, the class controlled release formulations for oral administration that the zero-order release of take is basic feature.It has constant speed release medicine, be subject to that the gastrointestinal tract variable factor affects hardly, the inside and outside dependency is good, the advantage such as controlled release multi-medicament simultaneously, therefore is acknowledged as current optimal oral controlled-release medication, and becomes both at home and abroad the competitively focus of research.
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 coacted by Theeuwes and Alza company in 1974, structure to osmotic pump preparation is simplified, invent primary osmotic pump, just made 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. have designed a kind of push-pull osmotic pump with double-layer tablet cored structure, the label of this osmotic pumps consists 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, separate, label outer wrap one deck semi permeability clothing film, play a drug release hole in medicated layer one side of clothing film.After biofluid enters the sheet core inner through the clothing film, medicated layer water suction aquation, the suspension of formation medicine; While boosting layer hydration swelling, thus drug suspension is released from drug release hole.On this basis, the research worker simplifies push-pull osmotic pump and improves, and has removed the barrier film between medicated layer and boosting layer, still can form sharp interface between two-layer, reach desirable release effect, becoming at present the most frequently used is also the most classical insoluble drug osmotic pumps dosage form.Yet double-decker is higher to the technological requirement of tabletting and punching, this has hindered 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 technology to be combined with Oros type controlled-release technology and the nanometer suspension osmotic pumps sustained and controlled release medicament transmission system of a kind of novel hard-soluble medicine of obtaining, by changing the release behavior of medicine, reduce blood concentration fluctuation in body; By the nanometer suspension technology, the improvement of drug solubility is solved to the difficult point that insoluble drug is prepared into mono-layer osmotic pump simultaneously, maximize favourable factors and minimize unfavourable ones, bring into play the advantage of two kinds of preparation techniques simultaneously.
The present invention is achieved through the following technical solutions:
The present invention by the semipermeability capsule shells with drug release hole and be loaded in the inside content form.
Described semipermeability capsule shells be a kind of by capsule material perfusion in mould, the putamina that volatile dry forms, refer to Fig. 1.Its formation principle is: in capsule material liquid, contain cellulosic polymer, porogen, plasticizer and solvent thereof, fill mould solvent evaporates under preference temperature of capsule material liquid, when the gravity of capsule material liquid equates with its adhesion to mold wall, solvent constantly evaporates into and is drying to obtain with certain speed.Capsule material liquid contains following component by weight percentage: 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; Described solvent is selected from one or more in 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) preparation capsule liquid: take respectively cellulosic polymer, porogen and the plasticizer of recipe quantity, be placed in conical flask, add solvent appropriate, sealing, stir, and after all dissolving, ultrasonic 5min, obtain capsule liquid.
(2) capsule liquid is poured in mould, dry more than 12 hours under 4 ℃, then cut into as required suitable length.
The present invention directly pours into the nano suspension powder of pharmacological active substance and adjuvant in semipermeability capsule body with powder type, and with capsule material liquid, capsule cap and capsule body is sealed, and any at capsule makes a call to an aperture simultaneously.
Content is comprised of nano suspension powder, suspending agent, penetrating agent and the fluidizer of pharmacological active substance.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 that the pharmacological active substance by being prepared into after nano suspension obtains after lyophilization or spray-dired mode solidification.Suspending agent is selected from one or more in polyoxyethylene, arabic gum, sodium alginate or the hydroxypropyl methylcellulose that copolyvidone, polyvidone, molecular weight are 100000～500000; 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 nano suspension powder, suspending agent, penetrating agent and the fluidizer of pharmacological active substance 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 any at capsule makes a call to the aperture that a diameter is 0.3-0.5mm.
The nano suspension powder of described pharmacological active substance is under the protective effect of suitable stabilizing agent; by the medium milling method 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.Prepared nano suspension carries out solidification with lyophilization or spray-dired mode after adding excipient, is 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, the medium milling method is first the stabiliser solution of dispersion medicine and abrasive media to be put into to medium grinder, abrasive media is high speed rotating under the motor effect, make, between drug particle and with abrasive media, grinding chamber inwall, fierce collision occurs, thereby make drug particle be ground into nanoparticle; Abrasive media is generally glass particle, Zirconium oxide powder or special high polymer as polyoxyethylene deriv etc.Control the sedimentation method and be by medicine dissolution is formed to drug solution in a certain amount of and the molten good solvent of water, by drug solution, with certain speed, add in the water that contains stabilizing agent, medicine is because reaching rapidly crystallization of supersaturation in water, then can disperse by high shear, ultrasonic, microjet method controls precipitation.High pressure homogenization method is that micronized medicine is suspended in the aqueous solution that contains stabilizing agent, again by this coarse dispersion through high pressure homogenize combineds effect such as produced shearing force and void effect that repeatedly circulate, make after drug particle cracking fragmentation to obtain the drug crystallization of desired particle size.Controlling precipitation associating high pressure homogenization method is that the first suspension will obtained by the control sedimentation method is used high pressure homogenizer further all to turn to the method for desired particle size drug crystallization, the method can be converted into stable crystalline state by the particle of controlling sedimentation method acquisition, thereby the drug particle size that keeps the sedimentation method to obtain, can overcome on the other hand the sedimentation method and obtain particle diameter problem pockety, increase the physical stability of final products, can reduce the risk that the high pressure homogenizer slit stops up simultaneously.
Common osmotic pump type sustained-release preparation is that pharmacological active substance and adjuvant are evenly mixed to rear compacting in flakes, and further coating forms.The present invention has simulated the structure of common osmotic pump tablet, after capsule is placed in release medium, moisture in medium diffuses into capsule gradually, make the capsule 's content aquation, dissolving due to osmotic pressure active substance and medicament nano particle, the hydration swelling of polymer, form the very high homogeneous medicament nano suspension of osmotic pressure in capsule, because softgel shell is rigid structure, as permeable pressure head inside and outside the softgel shell of release power will maintain moisture continue enter, cause the formation of sheet in-core hydrostatic pressing, thereby medicament nano suspendible dispersion liquid is constantly disengaged uniformly from small delivery aperture.Medicine constant release process will last till that content dissolves fully, only remain solution in semipermeable membrane.Remaining medicine will discharge with the speed descended gradually, until the inside and outside osmotic pressure of film is equal, sees Fig. 2.Different from common osmotic pump tablet is, at first the present invention is prepared into nano suspension by pharmacological active substance, improve drug solubility, improved its bioadhesive, promoted gastrointestinal absorption and then improved drug bioavailability, overcome insoluble drug osmotic pumps system drug release incomplete simultaneously, the defect that bioavailability is not high, and then it is prepared into to osmotic pump capsule, effectively avoided the peak valley phenomenon (see figure 3) of blood drug level in the medicine body, reduce drug side effect, improved patient's compliance.
Pharmacokinetic studies in Beagle dog body
The test preparation that is subject to of choosing is carvedilol nanometer suspension osmotic pump capsule prepared by embodiment 1, and the reference preparation of choosing is commercially available Carvedilol Tablets.8 Beagle dogs are divided into to two groups at random, on an empty stomach lower Beagle dog (fasting 12h before administration) is carried out to single-dose, the clean phase in each cycle is one week, and dosage is 50mg.Administration the last fortnight and experimental session must not be taken any other medicine, during administration, freely drink water, and unified feed after administration 4h.Concrete dosage regimen sees the following form:
Reference preparation and be subject to test preparation respectively at administration after 0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,12,14 and 24 h get forelimb venous blood 3 mL, and move into and scribble in the test tube of heparin immediately, centrifugal 10 minutes of 4000 rpm, separated plasma, then put-20 ° of C Refrigerator stores stand-by.During plasma treatment, precision measures 200 μ L plasma samples, is placed in centrifuge tube at the bottom of 2.5 mL tool plug tips, adds the inner mark solution 40 μ L of 40 μ g/mL, NaOH solution (0.1 mol/L) 80 μ L, vortex mixed 1 min on the vortex agitator.Then add 320 μ L ether, vortex 5 min, centrifugal 5 min of 10,000 * g, separate organic layer to another conical centrifuge tube, in 40 ° of C water-baths, nitrogen dries up, the gained enriched substance is dissolved with 80 μ L mobile phases, vortex 3 min, then with 10, centrifugal 5 min of 000 * g, get supernatant 20 μ L and inject high performance liquid chromatograph.Record chromatogram and peak area, by the peak area ratio substitution standard curve of determinand and internal standard substance, calculate each time point sample Chinese medicine concentration.
The determination of plasma concentration result is as following table:
Its plasma concentration curve is shown in Fig. 4.By DAS software, data are processed, drawn following result: in the 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; Being subject to each mean parameter in the test preparation body is T
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, with ordinary preparation, compare, the nanometer suspension osmotic pump capsule has been avoided the peak valley phenomenon of blood drug level in body effectively, has reduced drug side effect, has extended the release time of medicine, has played slow controlled-release effect; Simultaneously, the medicament nano particle has effectively improved release and the gastrointestinal absorption of medicine, thereby bioavailability is significantly improved.
The accompanying drawing explanation
Fig. 1 is semipermeability capsule outside drawing
Fig. 2 is nanometer suspension osmotic pump capsule drug release schematic diagram
Fig. 3 is the cumulative in vitro release profiles according to the carvedilol nanometer suspension osmotic pump capsule of embodiment 1 preparation
Fig. 4 be according to the blood drug level of the carvedilol nanometer suspension osmotic pump capsule of embodiment 1 preparation and commercially available Carvedilol Tablets through the time curve.
The specific embodiment
embodiment 1
The nano suspension prescription:
carvedilol 0.6g
Vitamin e succinate 0.4g
sodium lauryl sulphate 0.5g
maltose 3.0g
Acetone 2mL
Distilled water 100mL
The content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (Plasdone S-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) preparation capsule liquid;
(2) capsule liquid is poured in mould, dry more than 12 hours under 4 ℃, then according to the needs of time lag, cut into suitable length;
The preparation of B, nano suspension powder:
(1) carvedilol of recipe quantity and vitamin e succinate are dissolved in jointly in acetone with the preparation organic facies, ultrasonic, after fully dissolving with the filtering with microporous membrane of 0.45 μ m, 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 to the anti-solvent phase of 50 mL, use the high-shear emulsifying homogenizer to disperse 1 min under the shear rate of 10,000 rpm simultaneously;
(4) then by ultrasonic 3 s of first dispersion liquid Probe Ultrasonic Searching 15min(under the power of 400W, 3 s intermittently), with ice bath, sample temperature is controlled to 4-8 ° of C;
(5) to the maltose that adds recipe quantity in the sample of pre-lyophilizing, sample after pre-freeze 12 h, is carried out to lyophilization in-75 oC cryogenic refrigerators, thereby obtain carvedilol nano suspension powder;
The preparation of C, nanometer suspension osmotic pump capsule:
(1) took respectively nano suspension and the adjuvant powder of 60 mesh sieves, mix homogeneously according to the recipe quantity precision;
(2) the content powder of recipe quantity is loaded in capsule, capsule body and capsule cap are fastened and use capsule material liquid sealing, finally with perforating needle, in any side of capsule, make a call to the aperture of 0.4 mm.
The mean diameter that records the carvedilol nano suspension is 212nm, and Zeta potential is-42mV; Osmotic pump capsule 12h cumulative release amount 90.99%, release curve linear correlation coefficient r is 0.9901.
embodiment 2
The nano suspension prescription:
Carvedilol 0.6g
Poloxamer F127 0.4g
Sodium lauryl sulphate 0.8g
Trehalose 2.0g
Acetone 2mL
Distilled water 100mL
The 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 jointly in acetone with the preparation organic facies, ultrasonic, after fully dissolving with the filtering with microporous membrane of 0.45 μ m, 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 to the anti-solvent phase of 50 mL, use the high-shear emulsifying homogenizer to disperse 1 min under the shear rate of 10,000 rpm simultaneously;
(4) then first dispersion liquid is carried out to high pressure homogenize, cycling condition be 200bar, 500bar and 1000bar each twice, 1300bar15 time;
(5) to the trehalose that adds recipe quantity in the sample of pre-lyophilizing, sample after pre-freeze 12 h, is carried out to lyophilization in-75 oC cryogenic refrigerators, thereby obtain carvedilol nano suspension powder;
The preparation of C, nanometer suspension osmotic pump capsule is with embodiment 1.
The mean diameter that records the carvedilol nano suspension is 358nm, and Zeta potential is-24mV; Osmotic pump capsule 12h cumulative release amount 87.38%, release curve linear correlation coefficient r is 0.9891.
embodiment 3
The nano suspension prescription:
Vinpocetine 1.2g
Poloxamer F68 0.25g
NaTDC 0.5g
Mannitol 5.0g
Distilled water 100mL
The content prescription:
Vinpocetine nano suspension powder 100mg
Polyvidone (PVP K30) 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
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) add the vinpocetine through comminution by gas stream, magnetic agitation 10min;
(3) then first dispersion liquid is carried out to high pressure homogenize, cycling condition be 150bar, 500bar and 1000bar each twice, 1500bar15 time;
(4) to the mannitol that adds recipe quantity in sample, after making it fully dissolve dispersion, carry out spray drying, thereby obtain the nano suspension powder of medicine;
The preparation of C, nanometer suspension osmotic pump capsule is with embodiment 1.
The mean diameter that records the vinpocetine nano suspension is 302nm, and Zeta potential is-31mV; Osmotic pump capsule 12h cumulative release amount 92.59%, release curve linear correlation coefficient r is 0.9886.
embodiment 4
the nano suspension prescription:
Itraconazole 0.05g
Hydroxypropyl methylcellulose E15 0.05g
Poloxamer F127 0.15g
Microcrystalline Cellulose 1g
Distilled water 100mL
The 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 Tween 80, hydroxypropyl methylcellulose E15 and the poloxamer F127 of recipe quantity, add in 100mL water, ultrasonic dissolution is complete;
(2) add the itraconazole through comminution by gas stream, magnetic agitation 10min;
(3) then first dispersion liquid is carried out to high pressure homogenize, cycling condition be 150bar, 500bar and 1000bar each twice, 1500bar15 time;
(4) to the microcrystalline Cellulose that adds recipe quantity in sample, after making it fully dissolve dispersion, carry out spray drying, thereby obtain the nano suspension powder of medicine;
The preparation of C, nanometer suspension osmotic pump capsule is with embodiment 1.
The mean diameter that records Itraconazole nanometer suspensions is 516nm, and Zeta potential is-23mV; Osmotic pump capsule 12h cumulative release amount 88.21%, release curve linear correlation coefficient r is 0.9907.。
embodiment 5
The nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
The content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (Plasdone S-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, obtain carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 85.32%, release curve linear correlation coefficient r is 0.9765.
The nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
The content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (Plasdone S-630) 180mg
Mannitol 100mg
Magnesium stearate 5mg
Capsule material liquid prescription:
Cellulose acetate 5g
PEG400 0.5g
Acetone 100mL
Preparation technology: preparation technology: with embodiment 1, obtain carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 96.87%, release curve linear correlation coefficient r is 0.9521.
embodiment 7
The nano suspension prescription:
Carvedilol 0.6g
Poloxamer F68 0.35g
Sodium lauryl sulphate 0.3g
Hydroxypropyl methylcellulose 0.05g
Trehalose 3.0g
Acetone 2mL
Distilled water 100mL
The content prescription:
Carvedilol nano suspension powder 90mg
Copolyvidone (Plasdone S-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, obtain carvedilol nanometer suspension osmotic pump capsule controlled release system; The mean diameter that records nano suspension is 533nm, and Zeta potential is-23mV; Osmotic pump capsule 12h cumulative release amount 87.47%, release curve linear correlation coefficient r is 0.9833.
The nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
The 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, obtain carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 86.23%, release curve linear correlation coefficient r is 0.9934.
embodiment 9
The nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
The content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (Plasdone S-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, obtain carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 82.96%, release curve linear correlation coefficient r is 0.9960.
The nano suspension prescription:
Carvedilol 0.6g
Vitamin e succinate 0.4g
Sodium lauryl sulphate 0.5g
Maltose 3.0g
Acetone 2mL
Distilled water 100mL
The content prescription:
Carvedilol nano suspension powder 95mg
Copolyvidone (Plasdone S-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, obtain carvedilol nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 89.85%, release curve linear correlation coefficient r is 0.9798.
embodiment 11
The nano suspension prescription:
Silymarin 0.001g
Hydroxypropyl cellulose 0.05g
Micropowder silica gel 0.02g
Mannitol 0.08g
Distilled water 100mL
The 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
Acetone 100mL
Preparation technology: preparation technology: with embodiment 3, obtain silymarin nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 93.44%, release curve linear correlation coefficient r is 0.9811.
The nano suspension prescription:
Celecoxib 10g
Poloxamer F127 5g
Sodium carboxymethyl cellulose 5g
Sodium lauryl sulphate 1g
Micropowder silica gel 1.5g
Lactose 10g
Distilled water 100mL
The 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
Acetone 100mL
Preparation technology: preparation technology: with embodiment 3, obtain celecoxib nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 88.91%, release curve linear correlation coefficient r is 0.9782.
embodiment 13
The nano suspension prescription:
Nitrendipine 5g
Poloxamer F127 1g
Polyvinyl alcohol 0.5g
Sodium lauryl sulphate 0.05g
Sucrose 2g
Mannitol 5g
Distilled water 100mL
The 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, obtain nitrendipine nanometer suspension osmotic pump capsule controlled release system; Osmotic pump capsule 12h cumulative release amount 86.71%, release curve linear correlation coefficient r is 0.9862.
embodiment 14
The carvedilol nanometer suspension osmotic pump capsule cumulative in vitro drug release determination of embodiment 1 preparation:
Adopt the device of dissolution method (2005 editions two appendix XC the second methods of Chinese Pharmacopoeia), temperature is controlled to 37 ± 0.5 ° of C, rotating speed is 100 rpm, capsule is placed in to 500 mL dissolution mediums (0.1 mol/L HCL), take out solution 5 mL at 2,4,6,8,10 and 12 h respectively, filter with 0.1 μ m microporous filter membrane, discard just filtrate, get subsequent filtrate standby, and immediately supplement blank medium solution 5 mL; Measure respectively trap by ultraviolet spectrophotometry (2005 editions two appendix XA of Chinese Pharmacopoeia) at 242 nm places after subsequent filtrate dilution suitable multiple, calculate respectively the dissolution of different time points by external standard method.
What Fig. 3 meaned is the 12 hours release percent-time graphs of nanometer suspension osmotic pump capsule cumulative in vitro release according to embodiment 1 preparation, and result shows that this system release is complete, and release profiles is linear good, presents the zero-order release feature.
Claims (8)
1. the nanometer suspension osmotic pump type controlled release system of an insoluble drug, it is comprised of the semipermeability capsule shells with drug release hole and the content that is loaded in the inside, it is characterized in that:
Described semipermeability capsule shells be a kind of by capsule material perfusion in mould, the putamina that volatile dry forms; It is comprised of capsule cap and capsule body; Content is directly loaded wherein with powder type, and with capsule material liquid, capsule cap and capsule body are sealed, any at capsule plays a drug release hole simultaneously;
Described capsule material liquid contains following component by weight percentage: cellulosic polymer 5%-15%, solvent 70%-90%, porogen 0.5%-10%, plasticizer 0%-5%;
Described content comprises nano suspension powder, suspending agent, penetrating agent and the fluidizer of pharmacological active substance, 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%;
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 drug release hole is that any at capsule makes a call to the aperture that a diameter is 0.3-0.5mm.
2. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1, it is characterized in that: described cellulosic polymer is selected from one or more in cellulose acetate, ethyl cellulose, acetylbutyrylcellulose; Described solvent is selected from one or more in acetone, ethanol, isopropyl alcohol, butanols, capryl alcohol, ethyl acetate and dichloromethane; 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.
3. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1, it is characterized in that: described 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.
4. 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 the medium milling method or control the sedimentation method or high pressure homogenization method or control that precipitation associating high pressure homogenization method is prepared from.
5. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1, it is characterized in that: described stabilizing agent be selected from polyvidone, Polyethylene Glycol,, one or more in 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.
6. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1 is characterized in that: described suspending agent is selected from one or more in polyoxyethylene, arabic gum, sodium alginate or the hydroxypropyl methylcellulose that copolyvidone, polyvidone, molecular weight are 100000～500000.
7. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1, it is characterized in that: described penetrating agent is selected from one or more in sodium chloride, potassium chloride, magnesium sulfate, sodium sulfate, sucrose, lactose or mannitol.
8. the nanometer suspension osmotic pump type controlled release system of insoluble drug according to claim 1, it is characterized in that: described fluidizer is selected from one or more in magnesium stearate, micropowder silica gel or Pulvis Talci.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN105147607A (en) * | 2015-10-14 | 2015-12-16 | 中国药科大学 | Celecoxib nanosuspension and preparation method thereof |
| CN105520917A (en) * | 2014-10-15 | 2016-04-27 | 美佳胜肽科技股份有限公司 | Vegetarian diet hole sealing capsule for gastrointestinal tract controlled release |
| CN105596215A (en) * | 2015-12-30 | 2016-05-25 | 新昌县捷奥激光制品有限公司 | Capsule punching equipment |
| 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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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784154A (en) * | 2014-01-21 | 2015-07-22 | 胡容峰 | Site-specific osmotic-pump controlled-release capsule shell and preparation method thereof |
| CN105520917A (en) * | 2014-10-15 | 2016-04-27 | 美佳胜肽科技股份有限公司 | Vegetarian diet hole sealing capsule for gastrointestinal tract controlled release |
| CN105147607A (en) * | 2015-10-14 | 2015-12-16 | 中国药科大学 | Celecoxib nanosuspension and preparation method thereof |
| CN105596215A (en) * | 2015-12-30 | 2016-05-25 | 新昌县捷奥激光制品有限公司 | Capsule punching equipment |
| 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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| CN103432101B (en) | 2015-12-23 |
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