CN105997887A - Tolterodine sustained release microsphere preparation containing small molecular additive and preparation method thereof - Google Patents
Tolterodine sustained release microsphere preparation containing small molecular additive and preparation method thereof Download PDFInfo
- Publication number
- CN105997887A CN105997887A CN201510612201.1A CN201510612201A CN105997887A CN 105997887 A CN105997887 A CN 105997887A CN 201510612201 A CN201510612201 A CN 201510612201A CN 105997887 A CN105997887 A CN 105997887A
- Authority
- CN
- China
- Prior art keywords
- tolterodine
- microsphere
- release
- preparation
- additive
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a tolterodine sustained release microsphere preparation containing a small molecular additive and a preparation method thereof. The method consists of: weighing tolterodine, the small molecular additive and polylactide-glycolide, dissolving them in 0.2-5ml of dichloromethane, under a homogeneous condition, injecting the mixture into an aqueous solution, maintaining the homogeneous condition for 5min, then conducting 1000rpm stirring to volatilize the solvent for 4h, performing filtering with sieves with a pore diameter of 25 micrometers and 125 micrometers respectively, washing the microspheres with distilled water three times, and performing freeze-drying. The invention utilizes fatty acid or fatty acid ester as the additive of the biological sustained release microsphere preparation, the drug release can last for nearly one month, thus greatly reducing the medication frequency, improving the drug bioavailability and therapeutic efficacy, reduce the toxic and side effect, and greatly alleviating the suffering of patients, and improving the quality of life. Encapsulation of tolterodine with polylactide-glycolide can delay the release of tolterodine and reach a sustained release effect. Adding of the small molecular additive changes the existence and distribution form of tolterodine in microspheres, further delays the release of tolterodine, and improves the drug loading capacity.
Description
Technical field
The invention provides a kind of toterodine slow released microball preparation containing micromolecule additive, additionally provide its preparation method simultaneously, belong to technical field of medicine preparation.
Background technology
Tolterodine belongs to 3,3-diphenylprop amine muscarinic receptor antagonist, and oral drug effect is low, and side effect is big, and such as xerostomia, constipation, dyspepsia, headache, dizziness, eye are dry, urine retention.Its unabsorbed part is by side effect before generation system or interacts (EP1077912), and first pass effect of hepar also causes drug effect to reduce, and side effect increases.Although can be administered by normal injection mode, but for urine incontinence long-term treatment, injection system one or more times daily will increase misery and the discomfort of patient.
Summary of the invention
The invention provides a kind of toterodine slow released microball preparation containing micromolecule additive, drug loading is higher, the nearlyest one month, greatly reduces times for spraying, improves bioavailability and the therapeutic effect of medicine.
Invention further provides the preparation method of a kind of toterodine slow released microball preparation containing micromolecule additive, it is adaptable to industrialized production.
A kind of toterodine slow released microsphere reagent containing micromolecule additive of the present invention, it is characterised in that be made up by ratio of weight and the number of copies of following medicine:
1%-20% tolterodine, 0.1%-10% micromolecule additive, surplus is the medicinal high polymer adjuvant of biodegradable.
Wherein,
Described micromolecule additive is that molecular weight is less than 500 daltonian little molecules of fatty acids or little molecular fat acid esters.
Described little molecules of fatty acids is stearic acid, Palmic acid, tetradecylic acid one therein.
Described biodegradable pharmaceutical polymers is from polylactide-co-glycolide, polylactic acid, polycaprolactone, Polyhydroxybutyrate-co-hydroxyvalerate copolymer one therein or two kinds of mixture (1:9-9:1) therein, and its molecular weight is 3000-50000 dalton
The preparation method of a kind of toterodine slow released microball preparation containing micromolecule additive of the present invention, comprises the following steps:
Weigh tolterodine, micromolecule additive and polylactide-co-glycolide according to the above ratio and join dissolving in 0.2-5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 0.3-3%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, microsphere is washed three times, lyophilizing with distillation.
Toterodine slow released microball preparation containing micromolecule additive prepared by the present invention, particle diameter is at 50-300 μm, envelop rate 40-90%.
The positive effect of the present invention is:Fatty acid or fatty acid ester is utilized to do the additive of biological slow-released microball preparation, make medicine can discharge nearly one month and greatly reduce times for spraying, improve drug bioavailability and therapeutic effect, reduce toxic and side effects, thus greatly alleviate the misery of extensive patients, improve its quality of life.Polylactide-co-glycolide encapsulating tolterodine, has delayed the release of tolterodine, has played the effect of slow release.The addition of micromolecule additive changes tolterodine at the existence within microsphere and distribution form, delays the release of tolterodine further, and improves drug loading.
Accompanying drawing explanation
Fig. 1 is the form photo under the scanning electron microscope of embodiment 4 thus obtained microsphere；
Fig. 2 is the microsphere broken line graph of preparation in simulation release liquid of embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment 5 gained；
Fig. 3 is the microsphere broken line graph of preparation in simulation release liquid of embodiment 6, embodiment 7, embodiment 8, embodiment 9, embodiment 10 gained；
Fig. 4 is the broken line graph of the microsphere preparation in simulation release liquid of real embodiment 11, embodiment 12, embodiment 13, embodiment 14, embodiment 15 gained；
Fig. 5 is the microsphere broken line graph of preparation in simulation release liquid of embodiment 16, embodiment 17, embodiment 18, embodiment 19, embodiment 20, embodiment 21, embodiment 22 gained；
Fig. 6 is microsphere Drug-time curve in beasle dog body of embodiment 4, embodiment 23 gained；
Fig. 7 is the broken line graph of the sustained-release micro-spheres accumulative release rate in beasle dog.
Specific embodiment mode
Preparation method and the slow release effect of a kind of toterodine slow released microsphere containing micromolecule additive of the present invention will be further illustrated by embodiment below, but following example do not constitute any restriction to the present invention.In following example, the particle diameter of microsphere uses L2000 familiar to the person skilled in the art
Type fully-automatic laser particle size analyzer (Beckman coulter company) measures.Content uses high performance liquid chromatography (HPLC) to measure, and method, such as can be according to Chinese Journal of New Drugs according to literature method, and 2012,21 (23) is disclosed.Determination of plasma concentration use LC-MS-MS method, such as can according to China Medicine University's journal, 2005,36 (6): 546-550.
Embodiment
1
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, joins dissolving in 0.5 ml dichloromethane by the above-mentioned material that weighs, is injected into 50 ml under the conditions of homogenizing (6000-8000rpm)
In aqueous solution 0.5%PVA(w/w), keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, be sieved through filter by aperture 25 μm and 125 μm, wash microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 8.6%, embedding rate 57%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 2.
Embodiment
2
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 0.3 mg stearic acid, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 9.4%, embedding rate 63%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 2.
Embodiment
3
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 1.5 mg butyl stearates, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.It is prepared into pastille 10.3%
Microsphere, embedding rate 68.7%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 2.
Embodiment
4
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 3 mg butyl stearates, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.It is prepared into pastille 13.3%
Microsphere, embedding rate 89%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 2.Sustained-release micro-spheres Drug-time curve in beasle dog is shown in Fig. 6.The broken line graph of the sustained-release micro-spheres accumulative release rate in beasle dog is shown in Fig. 7.Sustained-release micro-spheres stereoscan photograph is shown in Fig. 1.
Embodiment
5
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 30 mg butyl stearates, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.It is prepared into pastille 10.5%
Microsphere, embedding rate 70%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 2.
Embodiment
6
Weigh 52.9mg tolterodine, 300.0
Mg 5050 5E PLGA, joins dissolving in 0.5 ml dichloromethane by the above-mentioned material that weighs, is injected into 50 ml under the conditions of homogenizing (6000-8000rpm)
In aqueous solution 0.5%PVA(w/w), keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, be sieved through filter by aperture 25 μm and 125 μm, wash microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 7.8%, embedding rate 52%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 3.
Embodiment
7
Weigh 52.9mg tolterodine, 300.0
Mg 5050 5E PLGA, 0.3 mg butyl stearate, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 7.2%, embedding rate 48%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 3.
Embodiment
8
Weigh 52.9mg tolterodine, 300.0
Mg, 5050 5E PLGA, 1.5 mg butyl stearates, join 0.5 by the above-mentioned material that weighs
Ml dichloromethane dissolves, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, microsphere is washed three times, lyophilizing with distillation.Being prepared into the microsphere of pastille 8.1%, embedding rate 54%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 3.
Embodiment
9
Weigh 52.9mg tolterodine, 300.0
Mg 5050 5E PLGA, 3 mg butyl stearates, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 9.3%, embedding rate 62%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 3.
Embodiment
10
Weigh 52.9mg tolterodine 300.0
Mg, 5050 5E PLGA, 30 mg butyl stearates, join 0.5 by the above-mentioned material that weighs
Ml dichloromethane dissolves, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, microsphere is washed three times, lyophilizing with distillation.It is prepared into pastille 10.7%
Microsphere, embedding rate 71%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 3.
Embodiment
11
Weigh 52.9mg tolterodine, 300.0
Mg 5050 4.5A PLGA, joins dissolving in 0.5 ml dichloromethane by the above-mentioned material that weighs, is injected into 50 ml under the conditions of homogenizing (6000-8000rpm)
In aqueous solution 0.5%PVA(w/w), keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, be sieved through filter by aperture 25 μm and 125 μm, wash microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 9.5%, embedding rate 634%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 4.
Embodiment
12
Weigh 52.9mg tolterodine, 300.0
Mg 5050 4.5A PLGA, 0.3 mg isopropyl palmitate, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 9.1%, embedding rate 61%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 4.
Embodiment
13
Weigh 52.9mg tolterodine, 300.0
Mg 5050 4.5A PLGA, 3 mg isopropyl palmitates, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 8.4%, embedding rate 56%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 4.
Embodiment
14
Weigh 52.9mg tolterodine, 300.0
Mg 5050 4.5A PLGA, 30mg isopropyl palmitate, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 8.6%, embedding rate 57%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 4.
Embodiment
15
Weigh 52.9mg tolterodine, 300.0
Mg 5050 4.5A PLGA, 10mg butyl stearate, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 7.9%, embedding rate 53%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 4.
Embodiment
16
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 10mg butyl stearate, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.It is prepared into pastille 12.4%
Microsphere, embedding rate 82%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 5.
Embodiment
17
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 3 mg tetradecylic acids, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 7.7%, embedding rate 51%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 5.
Embodiment
18
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 10 mg tetradecylic acids, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 7.2%, embedding rate 48%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 5.
Embodiment
19
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 3 mg stearic acid, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 7.3%, embedding rate 49%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 5.
Embodiment
20
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 10 mg stearic acid, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 8.5%, embedding rate 57%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 5.
Embodiment
21
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 3 mg Palmic acids, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 8.2%, embedding rate 55%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 5.
Embodiment
22
Weigh 52.9mg tolterodine, 300.0
Mg 7525 7E PLGA, 10 mg Palmic acids, the above-mentioned material that weighs is joined dissolving in 0.5 ml dichloromethane, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.Being prepared into the microsphere of pastille 7.9%, embedding rate 52%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 5.
Embodiment
23
Weigh 52.9mg tolterodine, 300.0
Mg 503H PLGA, 3 mg butyl stearates, join 0.5 by the above-mentioned material that weighs
Ml dichloromethane dissolves, under the conditions of homogenizing (6000-8000rpm), be injected into 50 ml 0.5%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm solvent flashing 4 hours, it is sieved through filter by aperture 25 μm and 125 μm, microsphere is washed three times, lyophilizing with distillation.Being prepared into the microsphere of pastille 6.2%, embedding rate 41%, recording particle diameter is 50-300 μm.The broken line graph of sustained-release micro-spheres preparation in simulation release liquid is shown in Fig. 4.The broken line graph of the sustained-release micro-spheres accumulative release rate in beasle dog is shown in Fig. 6.The broken line graph of the sustained-release micro-spheres accumulative release rate in beasle dog is shown in Fig. 7.
The positive effect of the present invention is proved by following experimental example:
, deenergized period the most steady as the tolterodine long-acting slow-release microball preparation release that additive, drug loading are 15% with little molecular fat acid esters and fatty acid was extended to 40 days by original two weeks.
By emulsion-solvent evaporation method prepare with 7525 7E PLGA as substrate, add the extracorporeal releasing test of tolterodine microsphere of butyl stearate, use embodiment 1-5 and the microsphere of embodiment 16, carry out release test by condition in analogue body, see accompanying drawing 2 and accompanying drawing 5.
By emulsion-solvent evaporation method prepare with 5050 5E PLGA as substrate, add the extracorporeal releasing test of tolterodine microsphere of butyl stearate, use the microsphere of embodiment 6-10, carry out release test by condition in analogue body, see accompanying drawing 3.
By emulsion-solvent evaporation method prepare with 5050 4.5A PLGA as substrate, add isopropyl palmitate or add the extracorporeal releasing test of tolterodine microsphere of butyl stearate, use the microsphere of embodiment 11-15, carry out release test by condition in analogue body, see accompanying drawing 4.
By emulsion-solvent evaporation method prepare with 7525 7E PLGA as substrate, add the extracorporeal releasing test of the tolterodine microsphere of tetradecylic acid or stearic acid or Palmic acid, use the microsphere of embodiment 17-22, carry out release test by condition in analogue body, see accompanying drawing 5.
The beasle dog experiment in vivo of tolterodine microsphere, uses embodiment 4 and 23, it can be deduced that conclusion, and the main cause that in two batch microspheres, release behavior is different is that PLGA model is different, and secondary cause is to add difference, sees accompanying drawing 6 and accompanying drawing 7.
Research according to the present inventor etc., use the buffer solution (phosphate buffered solution) of certain pH value (pH 7.4), drug release behavior is similar with internal, thus while its environment is incomplete same with human internal environment, but substantially thinks and can show internal release mode.
Experimental apparatus: constant temperature oscillator, centrifuge.
Experiment condition: temperature: 37 ± 0.5 DEG C, rotating speed: 120rpm.
Experimental technique: precision weighs laboratory sample about 1.5, is placed in the tool lid plastic centrifuge tube that volume is 50 ml, adds 40 ml release medium (pH=7.4
Phosphate buffered solution) it is placed in constant-temperature table, maintain certain temperature and rotating speed, temporally put sampling.
Sampling method: centrifuge tube is centrifugal 5min under the conditions of 4500 rpm, accurately draws 20 ml solution, adds the release medium of 20ml simultaneously in centrifuge tube again, takes out liquid HPLC and detects.
Sampling time point (my god): 0,0.125,1,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,38,42,46,50 wherein refer to the drug level being administered before the administration on the same day on the 0th day.
Conclusion: utilize fatty acid or the fatty acid ester of this experiment invention do the additive of biological slow-released microball preparation, make medicine can discharge nearly one month, greatly reduce times for spraying, improve therapeutic effect, reduce toxic and side effects, thus greatly alleviate the misery of extensive patients, improve its quality of life.
Claims (2)
1. the toterodine slow released microsphere reagent containing micromolecule additive, it is characterised in that be made up by ratio of weight and the number of copies of following medicine:
1%-20% tolterodine, 0.1%-10% micromolecule additive, surplus is the medicinal high polymer adjuvant of biodegradable；
Described micromolecule additive is that molecular weight is less than 500 daltonian little molecules of fatty acids or little molecular fat acid esters；
Described little molecules of fatty acids is stearic acid, Palmic acid, tetradecylic acid one therein；
Described biodegradable pharmaceutical polymers is from polylactide-co-glycolide, polylactic acid, polycaprolactone, Polyhydroxybutyrate-co-hydroxyvalerate copolymer one therein or two kinds of mixture (1:9-9:1) therein, and its molecular weight is 3000-50000 dalton.
2. the preparation method of a kind of toterodine slow released microball preparation containing micromolecule additive that claim 1 is stated, comprises the following steps:
Weigh tolterodine, micromolecule additive and polylactide-co-glycolide according to the above ratio and join 0.2-5 ml
In dichloromethane dissolve, under the conditions of homogenizing (6000-8000rpm), be injected into 0.3-3%PVA(w/w) aqueous solution in, keep above-mentioned processing condition 5 minutes, then to stir 1000rpm
Solvent flashing 4 hours, is sieved through filter by aperture 25 μm and 125 μm, washes microsphere three times with distillation, lyophilizing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510612201.1A CN105997887A (en) | 2015-09-24 | 2015-09-24 | Tolterodine sustained release microsphere preparation containing small molecular additive and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510612201.1A CN105997887A (en) | 2015-09-24 | 2015-09-24 | Tolterodine sustained release microsphere preparation containing small molecular additive and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105997887A true CN105997887A (en) | 2016-10-12 |
Family
ID=57082572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510612201.1A Pending CN105997887A (en) | 2015-09-24 | 2015-09-24 | Tolterodine sustained release microsphere preparation containing small molecular additive and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105997887A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111728957A (en) * | 2020-07-06 | 2020-10-02 | 济南大学 | Tolterodine long-acting sustained-release microsphere and preparation method thereof |
| JP2022528265A (en) * | 2019-03-27 | 2022-06-09 | エイチエルビー ファーマシューティカル カンパニー リミテッド | Dispersed phase composition for producing apixaban-containing fine granules and biocompatible polymer-based apixaban-containing fine granules produced from the composition. |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005107812A1 (en) * | 2004-05-07 | 2005-11-17 | Antares Pharma Ipl Ag | Permeation enhancing compositions for anticholinergic agents |
-
2015
- 2015-09-24 CN CN201510612201.1A patent/CN105997887A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005107812A1 (en) * | 2004-05-07 | 2005-11-17 | Antares Pharma Ipl Ag | Permeation enhancing compositions for anticholinergic agents |
Non-Patent Citations (2)
| Title |
|---|
| FENGYING SUN ET AL: "Studies on the preparation, characterization and pharmacological evaluation of tolterodine PLGA microspheres", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| 刘文华等: "托特罗定 PLGA 微球的制备及其体外释药的研究", 《中国新药杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2022528265A (en) * | 2019-03-27 | 2022-06-09 | エイチエルビー ファーマシューティカル カンパニー リミテッド | Dispersed phase composition for producing apixaban-containing fine granules and biocompatible polymer-based apixaban-containing fine granules produced from the composition. |
| JP7278413B2 (en) | 2019-03-27 | 2023-05-19 | エイチエルビー ファーマシューティカル カンパニー リミテッド | Dispersed Phase Composition for Making Apixaban-Containing Microspheres and Biocompatible Polymer-Based Apixaban-Containing Microspheres Made Therefrom |
| CN111728957A (en) * | 2020-07-06 | 2020-10-02 | 济南大学 | Tolterodine long-acting sustained-release microsphere and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2586306C2 (en) | Risperidone sustained release microsphere composition | |
| JPS59161316A (en) | Antiinflammatory composition | |
| KR101900482B1 (en) | A sustained-release injection having microspheres and manufacturing method thereof | |
| US20110250269A1 (en) | Highly efficient and long-acting slow-release formulation of poorly soluble drugs and preparation method thereof | |
| WO2003004024A1 (en) | Injectable sustained-release microspheres of huperzine a compounds | |
| US8962017B2 (en) | Formulation of silymarin with high efficacy and prolonged action and the preparation method thereof | |
| US9023388B2 (en) | Formulation of silibinin with high efficacy and prolonged action and the preparation method thereof | |
| CN105997887A (en) | Tolterodine sustained release microsphere preparation containing small molecular additive and preparation method thereof | |
| CN114748428B (en) | High-drug-loading-amount long-acting sustained-release microsphere of calicheazine hydrochloride and preparation method thereof | |
| CN103893129B (en) | Paliperidone sustained-release micro-spheres and injection thereof and the preparation method of this sustained-release micro-spheres | |
| Liang et al. | Study on the slow-release mometasone furoate injection of PLGA for the treatment of knee arthritis | |
| CN117281796A (en) | Cefquinome sulfate sustained release preparation for treating dairy cow mastitis and preparation method thereof | |
| JP6850371B2 (en) | Suspension of sustained release containing dezosin analog ester and method for producing the same | |
| CN1876173A (en) | Thymus pentapeptide slow-release microshpere formulation for injection and its preparation method | |
| CN104013578B (en) | A kind of Paliperidone derivant sustained release microsphere agents and preparation method | |
| CN114681406B (en) | Carilazine long-acting slow-release microsphere and preparation method thereof | |
| Karuppusamy et al. | Preformulation Parameters Characterization to Design, Development and Formulation of Miglitol Loaded Nanoparticles | |
| CN100475264C (en) | Slow release microphere for injection containing interferon or its analog, and preparation method thereof | |
| Anusha et al. | Preparation and evaluation of mefenamic acid loaded microspheres using synthetic and natural polymers | |
| CN103690933A (en) | Stem cell factor sustained-release microspheres and preparation method thereof | |
| CN113786393A (en) | Rivaroxaban microsphere and preparation method and application thereof | |
| CN108379227B (en) | Rutin-entrapped polymer micelle and preparation method thereof | |
| CN100528224C (en) | Slow release microphere for injection containing interferon alpha-1b and its preparation method | |
| CN106860425A (en) | A kind of chloramphenicol solid lipid nano granule | |
| Saini et al. | Formulation and in-vitro evaluation of Glipizide (Anti diabetic drug) Liposphere |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20161012 |