CN105078928A - Nisoldipine ethosome controlled-released patch and preparation method thereof - Google Patents
Nisoldipine ethosome controlled-released patch and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a nisoldipine ethosome controlled-released patch and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The nisoldipine ethosome controlled-released patch consists of a back lining, a frame type medicated storage cavern layer and an anti-adhesion layer, and the frame type medicated storage cavern layer contains nisoldipine ethosomes, pressure-sensitive adhesives, penetration enhancer, crosslinking agents, plasticizer and humectants. The ethosomes serve as transdermal drug delivery carriers, percutaneous permeation of the nisoldipine is improved, release of drug is controlled by the frame type pressure-sensitive adhesives, and the nisoldipine transdermal delivery patch is prepared. Compared with a nisoldipine oral preparation, the nisoldipine ethosome controlled-released patch can overcome shortcomings that a first-pass effect of oral delivery is obvious, bioavailability is low, and untoward effects of a digestive tract are obvious. Compared with a common nisoldipine patch, the nisoldipine ethosome controlled-released patch has the advantages that a controlled-released characteristic is good in a percutaneous penetration process, the percutaneous penetration rate of drug is increased for five times at least, stable high blood concentration can be maintained for a long time, relative bioavailability is improved for 4 times almost.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of Percutaneously administrable preparation of Cardiovarscular, be specifically related to a kind of nisoldipine ethosome control-released plaster and preparation method thereof.
Background technology
Nisoldipine (nisoldipine) is a kind of dihydropyridine class calcium channel blocker, chemical constitution is similar to nifedipine, the carboxylic acid methyl of nifedipine 3 or 5 is replaced with carboxyl isobutyl group, fat-soluble enhancing, pharmacological action is 4 ~ 10 times of the latter, is one of the strongest known calcium antagonist at present.Its main pharmacological is for suppressing Ca
2+enter excitatory cells, optionally cause the expansion of peripheral blood vessel and arteria coronaria blood vessel, and on myocardial contraction, conducting system of heart without impact.Nisoldipine also can suppress potassium ion, and fall out effect is stronger 100 times than verapamil, diltiazem, but does not produce inhibitory action to the vasoconstriction that norepinephrine brings out.Therefore, the pharmacological action of nisoldipine was both different from diltiazem, was also different from nifedipine, and it has higher selectivity to the effect of blood vessel.Clinically, nisoldipine is mainly used in ischemic heart desease, congestive heart failure and hypertensive treatment, is particularly useful for hypertensive patients patients with coronary heart disease, is the common drug of Cardiovarscular.
At present, the multiple dosage form listing of domestic existing nisoldipine, has ordinary tablet, capsule, soft capsule, soft gelatin capsule, slow releasing tablet and slow releasing capsule, and within 2008, U.S. FDA have approved the listing of nisoldipine controlled release tablet, is oral digestion canal drug administration dosage form.After nisoldipine oral administration, within about 1.5 hours, reach blood medicine peak value, at intrahepatic metabolism, 70% is discharged by urine, blood drug level is dose dependent, and the half-life is 2 ~ 15h, has obvious liver first-pass effect, also metabolism is had at little intestinal segment, therefore its bioavailability very low (4% ~ 8%).And nisoldipine is through digestive tract administration, also can causes the side effect of digestive tract such as colitis, diarrhoea, gastrointestinal hemorrhage, oral ulcer, seriously constrain the performance of its clinical application and drug effect.Therefore, walk around first pass effect, avoid digestive tract administration again, parenteral digestive tract administration becomes the research direction of nisoldipine secondary development.
Transdermal drug delivery system take skin as route of administration, by drug delivery to skin surface or body circulation, plays the effect of local skin or whole body therapeutic.The Percutaneously administrable preparation of active ingredient is planted in oneself approval more than ten of current U.S. FDA, comprises scopolamine, clonidine, estradiol, nicotine, fentanyl, lignocaine, Rivastigmine, granisetron etc.Ethosome is a kind of novel carrier for transdermal delivery with imitated vesicle structure, is made up of, namely in the prescription of conventional liposome, adds high concentration alcohol phospholipid, cholesterol, ethanol, water, and its transdermal mechanism is also different from conventional liposome.It not only has efficient encapsulating and good percutaneous abilities, and effectively can carry drug molecule and penetrate horny layer and even arrive skin more deep layer, is a kind of efficient transdermal carrier.Have been reported the ethosome transdermal patch research of analgesic naloxone, antirheumatic colchicine, antimicrobial drug enoxolone, resisting hypertension cyclovirobuxinum D etc., in body or experiment in vitro demonstrate good percutaneous abilities, be that infiltration means urged by a kind of emerging medicine.
It is dynamic that the present invention follows the tracks of domestic and international new drug development, and be closely connected clinical application present situation and the market demand, and research nisoldipine transdermal administration plaster, has given full play to the advantage of patch without first pass effect of hepar; Principal agent is modified into novel transdermal administration carrier ethosome, improves the Transdermal absorption of medicine and enter the ability of blood circulation; Select New Pressure-Sensitive Adhesion to be framework material, in conjunction with adjuvants such as cross-linking agent, promoter, plasticizer, wetting agents, preparation has the transdermal patch of controlled release properties.
At present, have the novel form that multiple patent literature nisoldipine is relevant, patent CN1436535 discloses nisoldipine capsule composition, patent CN1439372 discloses Nisoldipine double layer penetrated pump control releasing tablets, patent CN1552323 discloses monolayer osmotic pump controlled releasing tablets of nimodipine, patent CN1562013 discloses the Nisoldipine oral disintegration tablet and preparation method that are used for the treatment of hypertension, patent CN1695616 discloses a kind of nisoldipine dispersible tablet and preparation method thereof, patent CN101516352 discloses the controlled release solid oral preparation comprising nisoldipine, patent CN102406608A discloses Nisoldipine liposome solid preparation, patent CN102406623A discloses a kind of Nisoldipine controlled release tablet and preparation method thereof.The correlation technique of what these patents provided be nisoldipine oral formulations, the same with the nisoldipine oral formulations gone on the market, inevitably there is the drawbacks such as the low and side effect of digestive tract of first pass effect, bioavailability.
Patent CN103006620A discloses a kind of Nisoldipine controlled-release patch and preparation method thereof, described Nisoldipine controlled-release patch is made up of backing layer, drug-carrying polymer layer and adherent layer, wherein being directly mixed by medicine nisoldipine, drug-carrying polymer, penetrating agent and plasticizer of drug-carrying polymer layer, the not modified direct transdermal administration of nisoldipine.
The key of Percutaneously administrable preparation exploitation is the barrier action overcoming skin, makes medicine transdermal penetration amount within a certain period of time reach therapeutic dose.In fact nisoldipine is soluble in the organic solvent such as acetone, chloroform, and it is almost insoluble in water, it is a kind of fat-soluble medicine, be difficult to the horny layer structure through skin densification, make medicine transdermal penetration dose within a certain period of time limited, also be difficult in blood reach higher drug concentration levels, from the performance and the treatment use that affect drug effect.
The present invention is directed to the many drawbacks existed in nisoldipine oral formulations Clinical practice, take ethosome as the carrier of nisoldipine transdermal administration, nisoldipine is encapsulated in ethosome, improve the percutaneous permeation of medicine, be conducive to drug absorption and enter body circulation, thus play whole body therapeutic effect.Again with various new pharmaceutic adjuvant, prepare the control-released plaster of tool zero order kinetics drug release characteristic, stable high blood drug level is provided for a long time, play the drug effect continued, there is wide potential applicability in clinical practice.
Summary of the invention
The object of the invention is to the deficiency for existing nisoldipine preparation technique, a kind of nisoldipine ethosome control-released plaster is provided.The present invention take ethosome as the carrier of nisoldipine transdermal administration, transdermal penetration enhancer is added in matrix type pastille storage layer, the percutaneous permeation of nisoldipine can be significantly improved, medicine is made to maintain high blood drug level in long-time, ensure the lasting performance of drug effect, side reaction, administration number of times can be reduced, increase the compliance of patient.
The present invention also aims to the preparation method that a kind of nisoldipine ethosome control-released plaster is provided.
Nisoldipine ethosome control-released plaster of the present invention, be made up of backing layer, matrix type pastille storage layer and adherent layer, wherein matrix type pastille storage layer specifically forms and with weight ratio is: nisoldipine ethosome 20 ~ 100 parts, pressure sensitive adhesive 10 ~ 50 parts, penetrating agent 1 ~ 10 part, cross-linking agent 0 ~ 2 part, plasticizer 1 ~ 10 part and wetting agent 1 ~ 5 part.
Further preferably, matrix type pastille storage layer specifically forms and with weight ratio is: nisoldipine ethosome 30 ~ 60 parts, pressure sensitive adhesive 12 ~ 20 parts, penetrating agent 2 ~ 6 parts, cross-linking agent 0.5 ~ 1.5 part, plasticizer 2 ~ 6 parts and wetting agent 2 ~ 4 parts.
Described backing layer in order to be supported for matrix type pastille storage layer, and has certain for permeability and photophobism, and available backing layer has mylar, polyethylene film and clad aluminum foil etc.; The material that described adherent layer usable surface energy is low, if surface is through poly-third vinyl film, polycarbonate membrane and the separate paper etc. of silicone oil process.
Described nisoldipine ethosome specifically forms: nisoldipine 0.1 ~ 1.0%, phosphatidase 1 % ~ 5%, cholesterol 0.1 ~ 1.0%, ethanol 30 ~ 50% and aqueous phase 50 ~ 70%.
Further preferably, nisoldipine ethosome specifically forms and with percentage by weight is: nisoldipine 0.2 ~ 0.6%, phosphatidase 2 % ~ 4%, cholesterol 0.2 ~ 0.6%, ethanol 35 ~ 45% and aqueous phase 55 ~ 65%.
Described phospholipid is selected from the one in soybean phospholipid, egg yolk lecithin; Described aqueous phase is to the stable dilute acid soln of nisoldipine, is selected from the one in the glacial acetic acid of 0.2%, phosphate buffer (pH5.0).Described nisoldipine ethosome, can be wrapped in ethosome by nisoldipine, and circle or ellipse in rule, particle diameter, between 50 ~ 500nm, includes high concentration ethanol.
Described pressure sensitive adhesive is selected from one or more mixture of polyisobutylene class, acrylic resin apoplexy due to endogenous wind; Described penetrating agent is selected from one or more mixture in azone, menthol, eucalyptus oil, oleic acid, IPM and N-Methyl pyrrolidone; Described cross-linking agent is selected from the one in succinic acid, adipic acid and tartaric acid; Described plasticizer is selected from the one in triethyl citrate, citric acid glyceride and ethyl sebacate; Described wetting agent is selected from one or more mixture in glycerol, propylene glycol.
The preparation method of described nisoldipine ethosome control-released plaster comprises the steps:
(1) preparation of nisoldipine ethosome
Nisoldipine, phospholipid, cholesterol, dehydrated alcohol is taken by recipe quantity, be stirred to and dissolve completely, under rapid mixing conditions, slowly be instilled in the recipe quantity aqueous phase of 30 DEG C of insulations, obtain ethosome crude product, by ultrasonic or homogeneous dispersion, then through 0.22 μm of filtering with microporous membrane, obtained even-grained nisoldipine ethosome liquid.
(2) preparation of control-released plaster
Pressure sensitive adhesive and cross-linking agent is taken by recipe quantity, add recipe quantity nisoldipine ethosome liquid, be stirred to complete swelling, then add recipe quantity penetrating agent, plasticizer and wetting agent, stir and ultrasonicly make it mix homogeneously and bubble-free, coat equably on adherent layer, room temperature is placed to surface and is solidified with elasticity, baking oven 30 DEG C ~ 60 DEG C dry 6h ~ 12h, take out surface and be covered with backing layer, cutting divided dose, sealing is kept in Dark Place, and obtains nisoldipine ethosome control-released plaster.
Relative to prior art, the present invention has the following advantages:
(1) sheet is led to the existing nisoldipine gone on the market, capsule, soft capsule, soft gelatin capsule, slow releasing tablet, slow releasing capsule, the oral digestion canal drug administration preparation such as controlled release tablet and the nisoldipine Patents reported is compared, nisoldipine ethosome control-released plaster can avoid first pass effect of hepar obvious, bioavailability low (4% ~ 8%), and colitis, diarrhoea, gastrointestinal hemorrhage, the side effect of digestive tract such as oral ulcer, there is administration number of times few, dosage is by sticking area to control, even if there is discomfort can stop administration at any time, good patient compliance, be applicable to the long-term prevention and therapy of cardiovascular disease.
(2) compared with Nisoldipine controlled-release patch disclosed in existing patent CN103006620A, nisoldipine ethosome control-released plaster Chinese medicine nisoldipine is using ethosome as transdermal administration carrier, the transdermal penetration rates of medicine can be significantly improved, the drug level in blood is made to reach treatment concentration, thus fast onset drug effect, adapt to the feature of cardiovascular disease acute attack, quick curing.
Ligustrazine hydrochloride test confirms, compared to the direct transdermal administration of nisoldipine, ethosome can improve nisoldipine transdermal penetration amount more than 5 times.Medicine dynamic experiment display in rat body, ethosome can significantly improve the blood drug level of nisoldipine, and relative bioavailability improves nearly 4 times.Therefore, nisoldipine is encapsulated in ethosome, its percutaneous permeation can be strengthened, improve the transdermal penetration rates of medicine, be conducive to drug absorption to enter body circulation and reach medicine concentration, thus play whole body therapeutic effect, meet the clinical needs of Drugs for Cardiovascular Diseases quick acting; And be prepared into control-released plaster further with nisoldipine ethosome, stable high blood drug level can be maintained for a long time, meet the needs of the long-term preventive and therapeutic action of cardiovascular disease.
Accompanying drawing explanation
Fig. 1 nisoldipine ethosome control-released plaster structural representation
Fig. 2 nisoldipine suspension, ethosome Ligustrazine hydrochloride curve
The common patch of Fig. 3 nisoldipine, ethosome control-released plaster Ligustrazine hydrochloride release profiles
Blood concentration-time curve in Fig. 4 nisoldipine tablet, common patch and ethosome control-released plaster rat body
Detailed description of the invention
Below in conjunction with specific embodiment, the invention will be further described, skilled person can be made more fully to understand the present invention, but do not limit the present invention in any way.
The key instrument used in the invention process and material:
Instrument RYJ-6A percutaneous dispersion test instrument (Shanghai Huanghai Sea medicine inspection instrument plant, effective diffusion area (S) 2.8cm
2, acceptance pool volume (V) 6.5mL); Agilent1100HPLC (Agilent company of the U.S.); FA25 homogenizer (German Fu Luke company); JEM-1010 transmission electron microscope (NEC Optical Co., Ltd); Nano-ZS90 laser diffraction particle size instrument (Malvern company of Britain) SB-100YTD ultrasonic washing unit (Xin Zhi bio tech ltd, Ningbo); SH23-2 constant temperature blender with magnetic force (Mei Ying Pu, Shanghai instrument and meter Manufacturing Co., Ltd).
Reagent nisoldipine (Shandong Boyuan Pharmaceutical Co., Ltd., content > 99.1%); Injection stage soybean lecithin (Shanghai Taiwei Pharmaceutical Co., Ltd., PC >=92.6%); Cholesterol (Chemical Reagent Co., Ltd., Sinopharm Group); Nisoldipine (Li Nuoke peak, Shandong pharmaceutical Co. Ltd, 5mg/ sheet); EUDRAGITE100, EPO, RLPO, S100, L100 (German Romo Co., Ltd); Other pharmaceutical adjuncts are pharmaceutical grade, reagent is analytical pure.
Laboratory animal Kunming mouse, male, weight (20 ± 2) g; SD rat, male, weight (250 ± 20) g, provides by Nanfang Medical Univ's medical experiment animal center.
Embodiment 1
Nisoldipine ethosome control-released plaster is made up of backing layer, matrix type pastille storage layer and adherent layer, and its preparation method is:
(1) precision takes nisoldipine 0.4g, phosphatidase 3 .0g and cholesterol 0.3g, add dehydrated alcohol 45ml and be stirred to dissolving completely, under rapid mixing conditions, slowly be instilled into 30 DEG C insulation containing 0.2% glacial acetic acid aqueous solution 55ml in, obtain ethosome crude product, ultrasonic disperse 30min, then through 0.22 μm of filtering with microporous membrane, obtained even-grained nisoldipine ethosome liquid.
(2) precision takes EUDRAGITE100 (pressure sensitive adhesive) 14.0g and adipic acid 0.7g, add nisoldipine ethosome liquid 50ml, be stirred to pressure sensitive adhesive complete swelling, add azone 2.0ml, menthol 1.0g, triethyl citrate 2.0ml and glycerol 3.0ml again, stir, ultrasonic to mixed liquor bubble-free, be spread evenly across 4 × 10cm
2in poly-third vinyl film, room temperature is placed to surface and is solidified with elasticity, baking oven 30 DEG C of dry 12h, takes out surface and is covered with polyethylene film, cut into 4 × 2.5cm
2/ block, in patch, nisoldipine content is 5mg/cm
2, sealing is kept in Dark Place, and obtains nisoldipine ethosome control-released plaster.
Embodiment 2
Nisoldipine ethosome control-released plaster is made up of backing layer, matrix type pastille storage layer and adherent layer, and its preparation method is:
(1) precision takes nisoldipine 0.4g, phosphatidase 2 .0g and cholesterol 0.4g, add dehydrated alcohol 40ml and be stirred to dissolving completely, under rapid mixing conditions, slowly be instilled in phosphate-containing buffer (pH5.0) 60ml of 30 DEG C of insulations, obtain ethosome crude product, homogeneous dispersion 10min, then through 0.22 μm of filtering with microporous membrane, obtained even-grained nisoldipine ethosome liquid.
(2) precision takes EUDRAGITEPO (pressure sensitive adhesive) 6.0g, EUDRAGITRLPO (pressure sensitive adhesive) 7.0g and adipic acid 0.6g, add nisoldipine ethosome liquid 50ml, be stirred to pressure sensitive adhesive complete swelling, add azone 1.0ml, eucalyptus oil 1.5ml, citric acid glyceride 3.0ml, glycerol 1.0ml and propylene glycol 1.0ml again, stir, ultrasonic to mixed liquor bubble-free, be spread evenly across 4 × 10cm
2on polycarbonate membrane, room temperature is placed to surface and is solidified with elasticity, baking oven 40 DEG C of dry 10h, takes out surface and is covered with polyethylene film, cut into 4 × 2.5cm
2/ block, in patch, nisoldipine content is 5mg/cm
2, sealing is kept in Dark Place, and obtains nisoldipine ethosome control-released plaster.
Embodiment 3
Nisoldipine ethosome control-released plaster is made up of backing layer, matrix type pastille storage layer and adherent layer, and its preparation method is:
(1) precision takes nisoldipine 0.4g, phosphatidase 4 .0g and cholesterol 0.45g, add dehydrated alcohol 45ml and be stirred to dissolving completely, under rapid mixing conditions, slowly be instilled into 30 DEG C insulation containing 0.2% glacial acetic acid aqueous solution 55ml in, obtain ethosome crude product, ultrasonic disperse 30min, then through 0.22 μm of filtering with microporous membrane, obtained even-grained nisoldipine ethosome liquid.
(2) precision takes EUDRAGITS100 (pressure sensitive adhesive) 7.0g, EUDRAGITL100 (pressure sensitive adhesive) 6.0g and succinic acid 0.8g, add nisoldipine ethosome liquid 50ml, be stirred to pressure sensitive adhesive complete swelling, add azone 1.0ml, oleic acid 2.0ml, ethyl sebacate 2.5ml, glycerol 2.0ml and propylene glycol 1.0ml again, stir, ultrasonic to mixed liquor bubble-free, be spread evenly across 4 × 10cm
2on separate paper, room temperature is placed to surface and is solidified with elasticity, baking oven 40 DEG C of dry 12h, takes out surface and is covered with clad aluminum foil, cut into 4 × 2.5cm
2/ block, in patch, nisoldipine content is 5mg/cm
2, sealing is kept in Dark Place, and obtains nisoldipine ethosome control-released plaster.
Embodiment 4
Nisoldipine ethosome control-released plaster is made up of backing layer, matrix type pastille storage layer and adherent layer, and its preparation method is:
(1) precision takes nisoldipine 0.4g, phosphatidase 3 .0g and cholesterol 0.4g, add dehydrated alcohol 40ml and be stirred to dissolving completely, under rapid mixing conditions, slowly be instilled in phosphate buffer (pH5.0) 60ml of 30 DEG C of insulations, obtain ethosome crude product, homogeneous dispersion 10min, then through 0.22 μm of filtering with microporous membrane, obtained even-grained nisoldipine ethosome liquid.
(2) precision takes EUDRAGITEPO (pressure sensitive adhesive) 7.0g, EUDRAGITRLPO (pressure sensitive adhesive) 7.0g and tartaric acid 1.2g, add nisoldipine ethosome liquid 50ml, be stirred to pressure sensitive adhesive complete swelling, add menthol 2.0g, IPM 1.5ml, triethyl citrate 3.0ml and glycerol 4.0ml again, stir, ultrasonic to mixed liquor bubble-free, coat 4 × 10cm equably
2in poly-third vinyl film, room temperature is placed to surface and is solidified with elasticity, baking oven 30 DEG C of dry 12h, takes out surface and is covered with mylar, cut into 4 × 2.5cm
2/ block, in patch, nisoldipine content is 5mg/cm
2, sealing is kept in Dark Place, and obtains nisoldipine ethosome control-released plaster.
Embodiment 5
Nisoldipine ethosome control-released plaster is made up of backing layer, matrix type pastille storage layer and adherent layer, and its preparation method is:
(1) precision takes nisoldipine 0.4g, phosphatidase 2 .0g and cholesterol 0.45g, add dehydrated alcohol 45ml and be stirred to dissolving completely, under rapid mixing conditions, slowly be instilled into 30 DEG C insulation containing 0.2% glacial acetic acid aqueous solution 55ml in, obtain ethosome crude product, ultrasonic disperse 30min, then through 0.22 μm of filtering with microporous membrane, obtained even-grained nisoldipine ethosome liquid.
(2) precision takes EUDRAGITE100 (pressure sensitive adhesive) 16.0g and adipic acid 0.8g, add nisoldipine ethosome liquid 50ml, be stirred to pressure sensitive adhesive complete swelling, add eucalyptus oil 1.0ml, N-Methyl pyrrolidone 1.0ml, citric acid glyceride 2.0ml and glycerol 3.0ml again, stir, ultrasonic to mixed liquor bubble-free, coat 4 × 10cm equably
2on polycarbonate membrane, room temperature is placed to surface and is solidified with elasticity, baking oven 30 DEG C of dry 12h, takes out surface and is covered with polyethylene film, cut into 4 × 2.5cm
2/ block, in patch, nisoldipine content is 5mg/cm
2, sealing is kept in Dark Place, and obtains nisoldipine ethosome control-released plaster.
For the transdermal effect of objective evaluation nisoldipine ethosome provided by the invention and control-released plaster thereof, respectively with the common patch of nisoldipine suspension/nisoldipine for reference preparation, the nisoldipine ethosome control-released plaster prepared with embodiment 3 is for being subject to test preparation, carry out the comparative study of experiment in vivo and vitro: one, nisoldipine ethosome transdermal penetration experiment, analyze nisoldipine suspension, nisoldipine ethosome transdermal penetration rates and infiltration capacity, evaluate the transdermal penetration performance of nisoldipine ethosome; Two, nisoldipine ethosome control-released plaster transdermal penetration experiment, analyzes the common patch of nisoldipine, nisoldipine ethosome control-released plaster transdermal penetration rates and infiltration capacity, evaluates nisoldipine ethosome control-released plaster transdermal penetration performance; Three, nisoldipine ethosome control-released plaster rat Internal pharmacokinetics experiment, analyze drug-time curve and pharmacokinetic parameters in nisoldipine, the common patch of nisoldipine and nisoldipine ethosome control-released plaster rat body, evaluate blood drug level change and the bioavailability of nisoldipine ethosome control-released plaster.
Reference preparation nisoldipine suspension, its preparation method is:
Precision takes nisoldipine 0.4g, adds in the carboxymethylcellulose sodium solution of 100mL5%, and magnetic stirring apparatus 900r/min stirs 30min, obtains 0.4% nisoldipine suspension.
The common patch of reference preparation nisoldipine, its preparation method is:
Precision takes EUDRAGITE100 (pressure sensitive adhesive) 16.0g, adipic acid 0.8g and nisoldipine 0.2g, add 50% ethanol 50ml, be stirred to pressure sensitive adhesive complete swelling, add eucalyptus oil 1.5ml, N-Methyl pyrrolidone 1.0ml, citric acid glyceride 2.0ml and glycerol 3.0ml again, stir, ultrasonic to mixed liquor bubble-free, coat 4 × 10cm equably
2on polycarbonate membrane, room temperature is placed to surface and is solidified with elasticity, baking oven 30 DEG C of dry 12h, takes out surface and is covered with polyethylene film, cut into 4 × 2.5cm
2/ block, in patch, nisoldipine content is 5mg/cm
2, sealing is kept in Dark Place, and obtains the common patch of nisoldipine.
By test preparation nisoldipine ethosome control-released plaster, prepare by embodiment 3, its quality examination is as follows:
The average envelop rate of hplc determination ethosome is (68.01 ± 1.45) %.Transmission electron microscope observing ethosome form, the vesicle of the rounded or similar round of visible ethosome, structural integrity.Laser light scattering instrument measures particle diameter, and mean diameter is (123.7 ± 41.5) nm, and polydispersity is 0.196, even particle size distribution.30d is preserved in 4 DEG C of sealings, and ethosome outward appearance is light yellow translucent liquid, without layering, turbid phenomenon.By nisoldipine ethosome prepared by embodiment 3, surface structure is good, even particle size distribution, and envelop rate is higher, and illustrate that preparation method is reasonable, process stabilizing is feasible.
One, nisoldipine ethosome transdermal penetration experiment
(1) Kunming mouse of preparing of rat skin in vitro takes off neck execution, shaves except ventral seta, is separated complete skin of abdomen, reject subcutaneous fat and blood vessel, use normal saline rinsed clean, blot the water of skin keratin aspect, be cut into suitable size.
(2) mouse skin is put on Franz diffusion cell by percutaneous penetration, and acceptable solution is 6.5ml normal saline, makes liquid level and skin inner layer close contact, and water bath with thermostatic control (32 ± 0.5) DEG C, with 300r/min magnetic agitation.Pipette nisoldipine suspension, each 0.5ml of nisoldipine ethosome liquid is spread evenly across on keratodermatitis, and seal.Extract acceptable solution 2ml in the stipulated time (2,4,6,8,12,16,20 and 24h), and supplement the fresh acceptable solution 2ml of equality of temperature immediately, obtain transdermal test in vitro sample, 4 DEG C of Refrigerator stores.Transdermal sample after filtration with dilution after, then filter with 0.22 μm of filter membrane, subsequent filtrate enters hplc determination, unit of account area accumulation infiltration dose Q
r, Steady penetration rate J
si is compared with anatonosis
eR, Q
rfor drug per unit area transdermal penetration cumulative amount during 24h, I
eRfor ethosome group J
swith suspension group J
sratio.
(3) the transdermal penetration interpretation of experimental result nisoldipine suspension, ethosome is in table 1, with each time point Q
rfor vertical coordinate and sample time t be that abscissa draws Ligustrazine hydrochloride curve (see Fig. 2).Both percutaneous rate J
swith accumulative infiltration dose Q
r, through t inspection, P < 0.05, has significant difference, illustrates that ethosome can significantly improve the percutaneous rate J of medicine
swith accumulative infiltration dose Q
r.Compared to nisoldipine suspension, the percutaneous permeation of nisoldipine ethosome improves 11.66 times, and ethosome strengthens the transdermal penetration Be very effective of nisoldipine.
The transdermal penetration parameter of table 1 nisoldipine suspension, ethosome
Two, nisoldipine ethosome control-released plaster transdermal penetration experiment
(1) isolated skin is prepared rat and is taken off neck and put to death, and shaves clean ventral seta, is separated complete skin of abdomen, reject subcutaneous fat and blood vessel, clean, blot the water of skin keratin aspect, be cut to suitable size skin with normal saline.
(2) rat skin is put on Franz diffusion cell by percutaneous penetration, acceptable solution is ethanol-PEG200-normal saline (volume ratio 3: 2: 5) 6.5ml, make liquid level and skin inner layer close contact, water bath with thermostatic control (32 ± 0.5) DEG C, with 300r/min magnetic agitation.Get the common patch of nisoldipine, nisoldipine ethosome control-released plaster is cut into proper area, be affixed on the stratum corneum side of skin respectively, after guaranteeing close contact bubble-free, be fixed on diffusion cell.In 1,2,3,4,6,8,10,12,16 and 24 time, extract acceptable solution 2ml, and supplement the fresh acceptable solution 2ml of equality of temperature immediately, obtain transdermal test in vitro sample, 4 DEG C of Refrigerator stores.Transdermal sample after filtration with dilution after, then filter with 0.22 μm of filter membrane, subsequent filtrate enters hplc determination, unit of account area accumulation infiltration dose.
(3) experimental result is with the common patch of nisoldipine, each time point Q of nisoldipine ethosome control-released plaster
rfor vertical coordinate and sample time t be abscissa, make linear regression (see table 2).Two kinds of patch regression equation r are respectively 0.9821,0.9967, the r > 0.99 of nisoldipine ethosome control-released plaster, illustrate that nisoldipine accumulation infiltration capacity and time are better linear relationship, the Ligustrazine hydrochloride behavior fit zero-order equation of medicine, shows good controlled release properties.
The transdermal penetration regression parameter of the common patch of table 2 nisoldipine, ethosome control-released plaster
The slope of regression equation is the percutaneous rate J of patch
s, be respectively 1.0927 μ g (cm
2/ h), 6.4925 μ g (cm
2/ h).Compared to the common patch in Buddhist nun's rope ground, nisoldipine ethosome control-released plaster can significantly improve the Steady penetration rate of medicine, improves the transdermal penetration rates 5.75 times of nisoldipine, and ethosome strengthens the transdermal penetration Be very effective of nisoldipine.
With each time point patch unit are accumulation infiltration dose Q
rwith unit are drug content in patch Q ratio, calculate each time point unit are accumulation percutaneous release Q%, with Q% be vertical coordinate and sample time t draw Ligustrazine hydrochloride release profiles (see Fig. 3) for abscissa.As seen from Figure 3, the unit are accumulation percutaneous release Q% of each time point nisoldipine ethosome control-released plaster, all apparently higher than the common patch of nisoldipine, illustrates that ethosome improves significantly nisoldipine percutaneous permeation.
Three, nisoldipine ethosome control-released plaster rat Internal pharmacokinetics experiment
(1) rat pretreatment and grouping SD rat 18, shave clean back fur, fasting drinking-water 1d.Be divided into three groups at random: common patch group, ethosome patch group and tablet group, each 6.
(2) administration and blood specimen collection
Common patch group, ethosome control-released plaster group administration rat sticks the common patch of nisoldipine at back or ethosome control-released plaster 1 pastes, and Breathable adhesive tape is fastened, every cage 2 sub-cage rearings.After administration 1,2,3,4,6,8,10,12,16,24,36 and 48h eye corner of the eyes venous plexus to take a blood sample the centrifugal 10min of about 0.5ml, 3000r/min, separated plasma, freezen protective.
Tablet group administration rat oral gavage is to nisoldipine 1.After administration 0.5,1,1.5,2,2.5,3,4,6,8,10,12 and 24h eye corner of the eyes venous plexus to take a blood sample the centrifugal 10min of about 0.5ml, 3000r/min, separated plasma, freezen protective.
After the process of plasma sample, Aspirate supernatant enters hplc determination.
(3) experimental result is according to each time point blood drug level C and t drafting blood concentration-time curve sample time (see Fig. 4).As seen from the figure, compared with nisoldipine tablet, blood drug level " peak valley " degree of fluctuation of the common patch of nisoldipine, ethosome control-released plaster reduces, wherein nisoldipine ethosome patch can maintain long-time higher blood drug level, release peak time extends, blood drug level is comparatively mild, and controlled-release effect is good.By main pharmacokinetic parameters in table 3.According to formula: F=AUC
0-t (T)/ AUC
0-t (R)× 100%, the bioavailability of the common patch of calculating nisoldipine, the relative nisoldipine tablet of ethosome control-released plaster is respectively 61.82%, 242.32%.Compared with the common patch of nisoldipine, the biological utilisation of nisoldipine ethosome control-released plaster improves 3.92 times.
Table 3 nisoldipine tablet, common patch and ethosome control-released plaster main pharmacokinetic parameters
The transdermal penetration experiment being contrast with nisoldipine suspension, shows that ethosome can significantly improve the percutaneous rate J of medicine
swith accumulative infiltration dose Q
r, the percutaneous permeation of ethosome improves 11.66 times.The transdermal penetration experiment being contrast with the common patch of nisoldipine, shows the Ligustrazine hydrochloride behavior fit zero-order equation of nisoldipine ethosome control-released plaster Chinese medicine, shows good controlled release properties.Rat Internal pharmacokinetics is tested, compared with nisoldipine tablet, blood drug level " peak valley " degree of fluctuation of the common patch of nisoldipine, ethosome patch reduces, wherein, nisoldipine ethosome control-released plaster can maintain long-time higher blood drug level, release peak time extends, and blood drug level is comparatively mild, and controlled-release effect is good; Compared with the common patch of nisoldipine, the biological utilisation of nisoldipine ethosome control-released plaster improves 3.92 times.
Comprehensive above-mentioned experiment in vivo and vitro result of study, take ethosome as transdermal administration carrier, the nisoldipine ethosome control-released plaster prepared with Novel framework type patch adjuvant again, percutaneous permeation and the bioavailability of nisoldipine can be significantly improved, be better than its oral formulations and common patch, clinic is applied.
Claims (10)
1. a nisoldipine ethosome control-released plaster, be made up of backing layer, matrix type pastille storage layer and adherent layer, wherein matrix type pastille storage layer specifically forms and with weight ratio is: nisoldipine ethosome 20 ~ 100 parts, pressure sensitive adhesive 10 ~ 50 parts, penetrating agent 1 ~ 10 part, cross-linking agent 0 ~ 2 part, plasticizer 1 ~ 10 part and wetting agent 1 ~ 5 part.
2. nisoldipine ethosome control-released plaster according to claim 1, is characterized in that: described backing layer is the one without permeability and in the mylar of lucifuge, polyethylene film and clad aluminum foil; Described adherent layer is the one of surface in poly-third vinyl film, polycarbonate membrane and the separate paper of silicone oil process.
3. nisoldipine ethosome control-released plaster according to claim 1, is characterized in that: described nisoldipine ethosome specifically forms and with percentage by weight is: nisoldipine 0.1 ~ 1.0%, phosphatidase 1 % ~ 5%, cholesterol 0.1 ~ 1.0%, dehydrated alcohol 30 ~ 50% and aqueous phase 50 ~ 70%.
4. nisoldipine ethosome according to claim 3, is characterized in that: described phospholipid is selected from the one in soybean phospholipid, egg yolk lecithin; Described aqueous phase is to the stable dilute acid soln of nisoldipine, is selected from the one in 0.2% glacial acetic acid liquid, phosphate buffer (pH5.0).
5. nisoldipine ethosome according to claim 3, is characterized in that: be wrapped in by nisoldipine in ethosome, and circle or similar round in rule, particle diameter, between 50 ~ 500nm, includes the ethanol of high concentration.
6. nisoldipine ethosome according to claim 3, is characterized in that: described nisoldipine ethosome specifically forms and with percentage by weight is: nisoldipine 0.2 ~ 0.6%, phosphatidase 2 % ~ 4%, cholesterol 0.2 ~ 0.6%, ethanol 35 ~ 45% and aqueous phase 55 ~ 65%.
7. nisoldipine ethosome control-released plaster according to claim 1, is characterized in that: described pressure sensitive adhesive is selected from one or more mixture of polyisobutylene class, acrylic resin apoplexy due to endogenous wind; Described penetrating agent is selected from one or more mixture in azone, menthol, eucalyptus oil, oleic acid, IPM and N-Methyl pyrrolidone; Described cross-linking agent is selected from the one in succinic acid, adipic acid and tartaric acid.
8. nisoldipine ethosome control-released plaster according to claim 1, is characterized in that: described plasticizer is selected from the one in triethyl citrate, citric acid glyceride and ethyl sebacate; Described wetting agent is selected from one or more mixture in glycerol and propylene glycol.
9. nisoldipine ethosome control-released plaster according to claim 1, is characterized in that: described matrix type pastille storage layer specifically forms and with weight ratio is: nisoldipine ethosome 30 ~ 60 parts, pressure sensitive adhesive 12 ~ 20 parts, transdermal penetration enhancer 2 ~ 6 parts, cross-linking agent 0.5 ~ 1.5 part, plasticizer 2 ~ 6 parts and wetting agent 2 ~ 4 parts.
10. the preparation method of nisoldipine ethosome control-released plaster according to claim 1, is characterized in that: described preparation method comprises the steps:
(1) preparation of nisoldipine ethosome
Nisoldipine, phospholipid, cholesterol, dehydrated alcohol is taken by recipe quantity, be stirred to and dissolve completely, under rapid mixing conditions, slowly be instilled in the recipe quantity aqueous phase of 30 DEG C of insulations, obtain ethosome crude product, by ultrasonic or homogeneous dispersion, then through 0.22 μm of filtering with microporous membrane, obtained even-grained nisoldipine ethosome liquid.
(2) preparation of control-released plaster
Pressure sensitive adhesive and cross-linking agent is taken by recipe quantity, add recipe quantity nisoldipine ethosome liquid, be stirred to complete swelling, then add recipe quantity penetrating agent, plasticizer and wetting agent, stir and ultrasonicly make it mix homogeneously and bubble-free, coat equably on adherent layer, room temperature is placed to surface and is solidified with elasticity, baking oven 30 DEG C ~ 50 DEG C dry 6h ~ 12h, take out surface and be covered with backing layer, cutting divided dose, sealing is kept in Dark Place, and obtains nisoldipine ethosome control-released plaster.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600297A (en) * | 2003-09-23 | 2005-03-30 | 中国医学科学院药物研究所 | Loratadine paster of penetrating skin |
| CN1679589A (en) * | 2005-01-24 | 2005-10-12 | 浙江大学 | Ethinyl estradiol gas permeable absorbing paste |
| CN103006620A (en) * | 2013-01-05 | 2013-04-03 | 中国药科大学 | Nisoldipine controlled-release patch and preparation method thereof |
| CN103040795A (en) * | 2013-01-22 | 2013-04-17 | 云南中医学院 | Rotundine transdermal patch and preparation method thereof |
-
2014
- 2014-05-08 CN CN201410195182.2A patent/CN105078928A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600297A (en) * | 2003-09-23 | 2005-03-30 | 中国医学科学院药物研究所 | Loratadine paster of penetrating skin |
| CN1679589A (en) * | 2005-01-24 | 2005-10-12 | 浙江大学 | Ethinyl estradiol gas permeable absorbing paste |
| CN103006620A (en) * | 2013-01-05 | 2013-04-03 | 中国药科大学 | Nisoldipine controlled-release patch and preparation method thereof |
| CN103040795A (en) * | 2013-01-22 | 2013-04-17 | 云南中医学院 | Rotundine transdermal patch and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| A. ABDUL HASAN SATHALI ET AL: "STUDIES ON THE DEVELOPMENT OF TRANSDERMAL PATCHES OF NISOLDIPINE", 《J. CURR. CHEM. PHARM. SC.》 * |
| GAMAL M. EL MAGHRABY ET AL: "Skin delivery of nisoldipine from niosome proconcentrate", 《JOURNAL OF APPLIED PHARMACEUTICAL SCIENCE》 * |
| 聂阳等: "尼索地平醇质体的制备及体外经皮渗透研究", 《中国医院药学杂志》 * |
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