CN101810565A - Tolterodine gel preparation and preparation method thereof - Google Patents
Tolterodine gel preparation and preparation method thereof Download PDFInfo
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- CN101810565A CN101810565A CN201010155310A CN201010155310A CN101810565A CN 101810565 A CN101810565 A CN 101810565A CN 201010155310 A CN201010155310 A CN 201010155310A CN 201010155310 A CN201010155310 A CN 201010155310A CN 101810565 A CN101810565 A CN 101810565A
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- gel
- tolterodine
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- free alkali
- ethanol
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- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 title claims abstract description 43
- 229960004045 tolterodine Drugs 0.000 title claims abstract description 43
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 239000003513 alkali Substances 0.000 claims abstract description 17
- 239000011159 matrix material Substances 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- 229920001971 elastomer Polymers 0.000 claims description 20
- 229920001296 polysiloxane Polymers 0.000 claims description 20
- 239000000806 elastomer Substances 0.000 claims description 19
- 239000012153 distilled water Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 12
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 12
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 8
- 230000008961 swelling Effects 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- 230000035515 penetration Effects 0.000 claims description 5
- 239000000080 wetting agent Substances 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229920000642 polymer Polymers 0.000 claims description 3
- -1 polysiloxanes Polymers 0.000 claims description 3
- 229920002545 silicone oil Polymers 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920005601 base polymer Polymers 0.000 claims description 2
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 24
- 230000035807 sensation Effects 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 9
- 239000010409 thin film Substances 0.000 abstract description 8
- 239000010408 film Substances 0.000 abstract description 6
- 230000035699 permeability Effects 0.000 abstract description 3
- 210000001015 abdomen Anatomy 0.000 abstract description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 210000000689 upper leg Anatomy 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 abstract 1
- 239000003906 humectant Substances 0.000 abstract 1
- 231100000435 percutaneous penetration Toxicity 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 49
- 210000003491 skin Anatomy 0.000 description 15
- 239000000243 solution Substances 0.000 description 12
- 229940085237 carbomer-980 Drugs 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 238000013019 agitation Methods 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 2
- 235000020778 linoleic acid Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000037317 transdermal delivery Effects 0.000 description 2
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 108010001237 Cytochrome P-450 CYP2D6 Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 241000053227 Themus Species 0.000 description 1
- 208000005946 Xerostomia Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical class O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000012644 addition polymerization Methods 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 210000004209 hair Anatomy 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000010224 hepatic metabolism Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008337 systemic blood flow Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 210000003462 vein Anatomy 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
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Abstract
The invention discloses a tolterodine gel preparation, which is mainly prepared from free alkali tolterodine, gel matrix, film-forming matrix, organosilicon elastic body, percutaneous penetration accelerators, pH regulators, humectants, and the like. During use, the gel preparation contains the film-forming matrix which can form a flexible film after being dried, and can be externally coated on the thigh, the belly, the upper arm or shoulder, and other parts; flexible and wear-resistant thin film can be rapidly formed in the selected skin region; the gel is prevented from being taken away by the clothes; and meanwhile, the application site is in an unsealed state and has good air permeability. The contained organosilicon elastic body can obviously improve the dispersibility, flexibility, wettability, glossiness, and other performances of the gel system. The prepared gel is smooth, crystal clear and fine, has no foreign body sensation on the skin after use, durable medicament and slow release, good percutaneous absorption effect, convenient use, and improves the patient compliance.
Description
Technical field
The present invention is the improvement to the tolterodine pharmaceutical dosage form, further is to disclose a kind of Tolterodine gel preparation, and the present invention also provides the preparation method of described preparation, belongs to medical science pharmaceutical technology field.
Background technology
Medicine tolterodine (R)-N, (2-hydroxy-5-methyl base phenyl)-the 3-phenylpropylamine is a muscarinic receptor antagonist to N-diisopropyl-3-, can be used to treat the over-activity of bladder.Clinical research proves, the tolterodine oral administration is converted into the different metabolic thing through enzyme CYP2D6 after entering in the body in liver, because the difference of hepatic metabolism enzyme between individuality, cause that the interior metabolism product composition is different with content, cause different patient's drug effect differences very big, be unfavorable for the control of dosage, and cause untoward reaction such as xerostomia, constipation.If adopt the administration of normal injection mode, as the long-term treatment medicine, once a day or injection system repeatedly obviously will increase patient's misery and discomfort.Therefore, need a kind of non-oral tolterodine dosage form of exploitation, can discharge medicine equably, increase curative effect, avoid or reduce untoward reaction, increase drug bioavailability.
Transdermal delivery system (trandermal therapeutics systems, TTS) be a kind of novel form of percutaneous dosing, said preparation is in the skin surface administration, make medicine enter the systemic blood circulation through skin by the blood capillary absorption and reach effective blood drug concentration, and play treatment or prophylactic effect at each tissue or diseased region with constant speed (or near constant speed).
The dosage form that percutaneous dosing is commonly used is patch (Patch), and it has impervious skin, strippable protective layer and contains the substrate of active component or contain active component and contain the bank of semipermeable membrane.But, need continue the medicine that carries out for the administration process, patch needs for a long time incessantly and contact skin in the therapeutic process, and patch itself has the characteristics of sealing, and breathability is bad, can cause untoward reaction such as skin pruritus, and patient's compliance is bad.
Medicine is carried out the skin external administration with the form of gel, use more conveniently than patch, and agents area is non-air-tight state, and is also little to the stimulation of skin.But most of gels are smeared back unprotect layer and are existed, and preparation can be taken away by medicated clothing etc., causes that drug effect reduces, and easily pollutes.Therefore, need be optimized gel-type vehicle, it is rapidly dry to make it be coated with the back, forms flexible thin film, medicine can stablize, percutaneous discharges constantly, and gel is answered smooth exquisiteness simultaneously, with after skin do not have foreign body sensation.Also less to the report of relevant substrate at present, be necessary further investigation.
The pharmaceutical grade elastomer silicone, be also referred to as the silicon gel, it is the novel high molecular polymer elastomer that forms through the addition polymerization of platinum catalyst system and catalyzing by pharmaceutical grade ethenyl blocking polysiloxanes and containing hydrogen silicone oil, has excellent through performance, can improve the permeability of active medicine component on skin, thereby improved bioavailability of medicament, this advantage makes it be suitable for very much medicament slow release, controlled release formulation system.In transdermal delivery system, framework material adopts the hydrophobic organosilicon elastomer gel, can make the drug slow infiltration, improves releasing properties.
Summary of the invention
The invention provides a kind of Tolterodine gel preparation, percutaneous dosing is smeared in external, has solved to overcome the shortcoming that the oral formulations bioavailability is low, untoward reaction is many.
The present invention also provides the preparation method of Tolterodine gel agent, is applicable to suitability for industrialized production.
Tolterodine gel preparation provided by the invention mainly comprises following component (quality %):
1～5% free alkali tolterodine, 0.5～10% gel-type vehicle, 0.5～10% one-tenth membrane matrix, 0.5～5% elastomer silicone, 1～20% transdermal penetration promoter, 0～10%pH regulator, 5～20% wetting agents, the distilled water of 10～30% ethanol and surplus.
Described one-tenth membrane matrix is the hydroxy alkyl cellulose base polymer;
Described elastomer silicone is ethenyl blocking polysiloxanes and the containing hydrogen silicone oil polymer through the platinum catalyst system and catalyzing.
Described transdermal penetration promoter, the pH regulator agent, wetting agent and solvent can be selected the conventional reagent that often uses in the transdermal gel preparation.
The preferred Tolterodine gel preparation of the present invention comprises following component (quality %):
1～5% free alkali tolterodine, 0.5～2% carbomer, 1～3% hydroxypropyl cellulose, 0.5～3% elastomer silicone, 5～10%N-methyl pyrrolidone, 0.5～3% triethanolamine, 5～10% glycerol, the distilled water of 10～30% ethanol and surplus.
The preparation method of Tolterodine gel preparation of the present invention may further comprise the steps:
Free alkali tolterodine is added in the ethanol, and the vortex vibration is fully dissolved it, adds wetting agent, transdermal penetration promoter and distilled water wiring solution-forming then; With gel-type vehicle, one-tenth membrane matrix and elastomer silicone mixing, be sprinkled into together in the above-mentioned solution again, stir 24h under the 100rpm speed, drip the pH regulator agent and regulate pH value to 7, promptly to complete swelling.
The invention has the beneficial effects as follows:
1, tolterodine can absorb by percutaneous, and the untoward reaction of oral generation is avoided or reduced to the performance general action.
2, contain the one-tenth membrane matrix that can form flexible membranes after the drying in the gel preparation, external is applied in positions such as thigh, abdominal part, upper arm or shoulder, can form pliable and tough attrition resistant thin film at selected skin area rapidly, the drawback of having avoided ordinary gel to be taken away by medicated clothing, agents area is non-air-tight state simultaneously, good permeability.See effect embodiment 1 for details.
3, contain special adjuvant elastomer silicone in the gel-type vehicle, it can significantly improve the character such as dispersibility, pliability, wettability, glossiness of gel rubber system, the gel of preparation is smooth, sparkling and crystal-clear, fine and smooth, there is not foreign body sensation with back skin, medicine is lasting slowly to be discharged, the percutaneous good absorbing effect, easy to use, improve patient's compliance.See effect embodiment 2 for details.
Description of drawings
Fig. 1 is embodiment 1 preparation gel transdermal test in vitro cumulative release amount-time graph.
Fig. 2 is embodiment 2 preparation gel transdermal test in vitro cumulative release amount-time graphs.
Fig. 3 is embodiment 3 preparation gel transdermal test in vitro cumulative release amount-time graphs.
Fig. 4 smears blood drug level-time graph behind embodiment 3 preparation gels and the intravenous injection tolterodine solution to rabbit.
The specific embodiment
Specific implementation method of the present invention illustrated by following embodiment, but protection scope of the present invention is not limited to this.
Embodiment 1
Tolterodine gel preparation
Prepare gel (by 100g) by following prescription:
Free alkali tolterodine 1g, carbomer 980 1.5g, azone 5g, glycerol 10g, sodium hydroxide 2.5g, ethanol 30ml, surplus is a distilled water.
Free alkali tolterodine is added in the ethanol, and the vortex vibration is fully dissolved it, adds glycerol, azone and distilled water wiring solution-forming then; Other takes by weighing the carbomer 980 of recipe quantity, and it is sprinkled in the above-mentioned solution, and mechanical agitation 24h adds sodium hydroxide and regulates pH value to 7, promptly to complete swelling under the 100rpm speed.
Tolterodine gel preparation
Prepare gel (by 100g) by following prescription:
Free alkali tolterodine 3g, hydroxypropyl cellulose 3g, linoleic acid 5g, propylene glycol 10g, ethanol 10ml, surplus is a distilled water.
Free alkali tolterodine is added in the ethanol, and the vortex vibration is fully dissolved it, adds propylene glycol, linoleic acid and distilled water wiring solution-forming then; Other takes by weighing the hydroxypropyl cellulose of recipe quantity, and it is sprinkled in the above-mentioned solution, and mechanical agitation 24h is to complete swelling, promptly under the 100rpm speed.
Embodiment 3
Tolterodine gel preparation
Prepare gel (by 100g) by following prescription:
Free alkali tolterodine 3g, hydroxypropyl cellulose 1.5g, carbomer 980 1g, elastomer silicone (Pharmat, Guangzhou BioMax Pharmaceutical Co., Ltd.) 0.5g, N-Methyl pyrrolidone 5g, glycerol 10g, triethanolamine 2g, ethanol 10ml, surplus is a distilled water.
Free alkali tolterodine is added in the ethanol, and the vortex vibration is fully dissolved it, adds glycerol, N-Methyl pyrrolidone and distilled water wiring solution-forming then; Other takes by weighing hydroxypropyl cellulose, carbomer 980 and the elastomer silicone of recipe quantity, is sprinkled into together behind the mixing in the above-mentioned solution, and mechanical agitation 24h drips triethanolamine and regulates pH value, promptly to complete swelling under the 100rpm speed.
Tolterodine gel preparation
Prepare gel (by 100g) by following prescription:
Free alkali tolterodine 1g, hydroxypropyl cellulose 1g, carbomer 980 2g, elastomer silicone (Pharmat, Guangzhou BioMax Pharmaceutical Co., Ltd.) 3g, N-Methyl pyrrolidone 10g, glycerol 5g, triethanolamine 3g, ethanol 10ml, surplus is a distilled water.
Free alkali tolterodine is added in the ethanol, and the vortex vibration is fully dissolved it, adds glycerol, N-Methyl pyrrolidone and distilled water wiring solution-forming then; Other takes by weighing hydroxypropyl cellulose, carbomer 980 and the elastomer silicone of recipe quantity, is sprinkled into together behind the mixing in the above-mentioned solution, and mechanical agitation 24h drips triethanolamine and regulates pH value, promptly to complete swelling under the 100rpm speed.
Embodiment 5
Tolterodine gel preparation
Prepare gel (by 100g) by following prescription:
Free alkali tolterodine 5g, hydroxypropyl cellulose 3g, carbomer 980 0.5g, elastomer silicone (Pharmat, Guangzhou BioMax Pharmaceutical Co., Ltd.) 0.5g, N-Methyl pyrrolidone 5g, glycerol 10g, triethanolamine 1g, ethanol 30ml, surplus is a distilled water.
Free alkali tolterodine is added in the ethanol, and the vortex vibration is fully dissolved it, adds glycerol, N-Methyl pyrrolidone and distilled water wiring solution-forming then; Other takes by weighing hydroxypropyl cellulose, carbomer 980 and the elastomer silicone of recipe quantity, is sprinkled into together behind the mixing in the above-mentioned solution, and mechanical agitation 24h drips triethanolamine and regulates pH value, promptly to complete swelling under the 100rpm speed.
Effect experimental example 1
Gel outward appearance, film property, viscosity and smear the back dermal sensation
Investigate outward appearance, film property, the viscosity of gel preparation among the embodiment 1～5 and smear the back dermal sensation, the results are shown in following table:
| Outward appearance | Film property | Viscosity | Smear aftersensation | |
| Embodiment 1 | Milky, some is coarse | Do not form film | Less | Non-stimulated, some is |
| Embodiment | ||||
| 2 | Milky, the viscosity I flows | Form thin film | Little | Non-stimulated, no foreign body sensation |
| Embodiment 3 | Milky, smooth sparkling and crystal-clear | Form thin film | Less | Non-stimulated, comfortable, no foreign |
| Embodiment | ||||
| 4 | Milky, smooth sparkling and crystal-clear | Form thin film | Less | Non-stimulated, comfortable, no foreign body sensation |
| Embodiment 5 | Milky, smooth sparkling and crystal-clear | Form thin film | Less | Non-stimulated, comfortable, no foreign body sensation |
The result shows, hydroxypropyl cellulose can make gel have film property, reduce the foreign body sensation after smearing, but single when being gel-type vehicle with it, the gel viscosity that forms during low concentration is too small, after adding carbomer and elastomer silicone, make gel and both can form thin film, viscosity is also moderate, the smooth exquisiteness of gel, it is comfortable to smear the back dermal sensation, no foreign body sensation.
Effect experimental example 2 gelinites sturdy the testing of passing through inside
The disconnected neck of healthy mice is put to death, cuts its skin of abdomen at once, carefully wipe the Mus hair off with blade, and remove subcutaneus adipose tissue and mucous tissue, note not destroying horny layer, clean with normal saline, put preserve in the refrigerator standby.
According to embodiment 1～5 preparation gel.Take out Corium Mus from refrigerator, return to room temperature, wash Corium Mus repeatedly with normal saline, reuse filter paper is dried gently.Use the Franz diffusion cell, skin is fixed between supply chamber and the receiving chamber, make stratum corneum side to supply chamber, the effective contact area in two Room is 0.636cm
2Precision takes by weighing the gel of certain mass, puts in the supply chamber to smoothen, and contacts closely with skin.(pH 7.4 to add phosphate buffer (PBS) 5ml in receiving chamber, 10mmol/L), bath temperature is (32 ± 0.5) ℃, constant speed 200r/min, respectively at 1h, 2h, 4h, 6h, 8h, 10h and 12h timing sampling 5ml (refilling the 5ml fresh medium immediately), 0.45 measuring, μ m filtering with microporous membrane, HPLC receive liquid Chinese medicine concentration.Every batch of gel is done 6 groups of parallel laboratory tests.
The HPLC condition is: XDB C18 post 5 μ m, and 4.5mm * 250mm, 40 ℃ of column temperatures detect wavelength 283nm, and mobile phase is 10mmol/L acetate buffer solution (pH 3.0)-methanol (35: 65), flow velocity 1ml/min.
Calculate transdermal cumulative release amount Q (μ gcm according to following formula
-2):
In the formula, Q
nTransdermal cumulative release amount (μ gcm when being the n sub-sampling
-2), V is acceptable solution volume (ml), C
iReceive in the liquid when being the i sub-sampling and record drug level (μ gcm
-2Ml
-1), S is effective infiltrating area (cm
2).
Calculate transdermal steady-state permeation speed J according to following formula again
Ss(μ gcm
-2H
-1):
J
ss＝dQ/dt
In the formula, t is transdermal time (h).
Five crowdes of gel transdermal release results are as follows:
| ??J ss(μg·cm -2·h -1) | ??Q 12b(μg·cm -2) | |
| Embodiment 1 | ??72.44 | ??938.0±83.2 |
| |
??100.63 | ??1253.1±201.8 |
| Embodiment 3 | ??139.45 | ??1930.9±301.8 |
| |
??102.67 | ??1301.7±187.4 |
| Embodiment 5 | ??130.28 | ??1798.9±314.7 |
The result shows, five batches of gel transdermal speed differences, and wherein, embodiment 3 percutaneous rate maximums are better than making substrate with hydroxypropyl cellulose or carbomer separately, also are better than embodiment 4,5.Embodiment 1～3 preparation Gel Transdermal cumulative release amount-time graph is seen Figure of description 1～3.
Effect experimental example 3
The gel medicine is for experiment
Get the healthy mature male rabbit, weight is 1.5～2.5kg, is divided into intravenous injection (i.v.) group and gel group, every group of 3 rabbit.Test the previous day, intramuscular injection 30mg/kg pentobarbital sodium anesthesia gel group rabbit is removed back wool with shears then, and skin can not have breakage, and (size is 8 * 8cm with the marking pen labelling at the defeathering position
2), fasting 12h.During experiment, the gel that embodiment 3 is prepared spreads upon the defeathering position, notes smearing evenly, and is fixing around with gauze after the administration, prevents that animal from wiping medicine.Simultaneously to another group rabbit i.v. tolterodine solution.In the experimentation, rabbit is freely intake.
After the administration, respectively 0,15,30min, 1,2,4,6,8,10,12,24,36, the 48h auricular vein is got blood, collects 1ml blood, put in the EP pipe that contains 20 μ l heparin, 13, the centrifugal 10min separated plasma of 000rpm is preserved to be measured in-20 ℃ of refrigerators.
Get 100 μ l blood plasma, add 100 μ l inner mark solutions respectively, and 100 μ l acetonitrile-waters (80: 20, v/v), solution adds 3ml and extracts reagent (ether: dichloromethane=3: 2, v/v), eddy current mixing 30s, vibration 10min, centrifugal 5min (3500rpm), get supernatant and dry up in 30 ℃ of following nitrogen, residue adds the dissolving of 150 μ l mobile phases, gets 20 μ l and carries out the LC/MS/MS analysis.
I.v. tolterodine and smear embodiment 3 preparation gels after, the rabbit medicine is as follows for experimental result:
| ??T max(h) | ??C max(nmol/ml) | ??AUC 0-48h(nmol/ml)) | Absolute bioavailability (%) | |
| Tolterodine i.v. | ??0.25 | ??19.74 | ??76.00 | ??100％ |
| ??T max(h) | ??C max(nmol/ml) | ??AUC 0-48h(nmol/ml)) | Absolute bioavailability (%) | |
| Embodiment 3 | ??1 | ??0.67 | ??9.41 | ??12.38％ |
The result shows that embodiment 3 made gels can steadily slowly discharge, and bioavailability is higher than 10%, has certain clinical use meaning.
Blood drug level-time graph is seen Figure of description 4 behind the medicine.
Claims (4)
1. Tolterodine gel preparation mainly comprises following component (quality %):
1～5% free alkali tolterodine, 0.5～10% gel-type vehicle, 0.5～10% one-tenth membrane matrix, 0.5～5% elastomer silicone, 1～20% transdermal penetration promoter, 0～10%pH regulator, 5～20% wetting agents, the distilled water of 10～30% ethanol and surplus.
2. gel according to claim 1 is characterized in that:
Described one-tenth membrane matrix is the hydroxy alkyl cellulose base polymer;
Described elastomer silicone is ethenyl blocking polysiloxanes and the containing hydrogen silicone oil polymer through the platinum catalyst system and catalyzing.
3. according to claim 1 or 2 described Tolterodine gel preparations, comprise following component (quality %): 1～5% free alkali tolterodine, 1～3% hydroxypropyl cellulose, 0.5～2% carbomer, 0.5～3% elastomer silicone, 5～10% N-Methyl pyrrolidone, 0.5～3% triethanolamine, 5～10% glycerol, 10～30% ethanol and the distilled water of surplus.
4. according to the preparation method of claim 1 or 2 described Tolterodine gel preparations, it is characterized in that: free alkali tolterodine is added in the ethanol, and the vortex vibration is fully dissolved it, adds wetting agent, transdermal penetration promoter and distilled water wiring solution-forming then; With gel-type vehicle, one-tenth membrane matrix and elastomer silicone mixing, be sprinkled into together in the above-mentioned solution again, stir 24h under the 100rpm speed, drip the pH regulator agent and regulate pH value to 7, promptly to complete swelling.
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| CN103142465A (en) * | 2013-03-19 | 2013-06-12 | 长春健欣生物医药科技开发有限公司 | Tolterodine film-forming hydrogel preparation and preparation method thereof |
| EP3099381A4 (en) * | 2014-01-28 | 2017-07-19 | Avon Products, Inc. | Extended release fragrance compositions |
| CN114748451A (en) * | 2022-05-20 | 2022-07-15 | 武汉大学 | Timolol maleate external preparation and preparation method thereof |
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| CN101395206A (en) * | 2006-03-21 | 2009-03-25 | 陶氏康宁公司 | Silicone elastomer gels |
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| CN101340884A (en) * | 2005-10-19 | 2009-01-07 | 曼尼·马纳舍·辛格尔 | Method for treating hyperhidrosis |
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