CN1239656A - Compound transdermal nicotine-clonidine paster for giving up smoking - Google Patents
Compound transdermal nicotine-clonidine paster for giving up smoking Download PDFInfo
- Publication number
- CN1239656A CN1239656A CN99102043A CN99102043A CN1239656A CN 1239656 A CN1239656 A CN 1239656A CN 99102043 A CN99102043 A CN 99102043A CN 99102043 A CN99102043 A CN 99102043A CN 1239656 A CN1239656 A CN 1239656A
- Authority
- CN
- China
- Prior art keywords
- nicotine
- clonidine
- smoking
- medicine
- patch
- 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
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention replaces smoking-reducing treatment process with nicotine associated with synchronously released clonidine to give up smoking, one dose being taken one day. The animal test with large and small doses separately for pathological models of heavy and light craving for tobacco shows that the compound trandermal nicotine-clonidine paster has giving up rate of 71.1% and 81.4% separately, obvisouly exceeding those of alone trandermal nicotine paster, 59.9% and 28.1%, or alone transdermal clonidine paster, 40.9% and 50.2%. Furthermore, the side effect of cloniodine to result in calm and thirst may be antagonized by nicotine to result in excitation and salivation. The present invention can ensure giving up smoking safely, comfortably and effectively.
Description
The invention belongs to the smoking cessation with the health care pharmaceutical product, contain two kinds of stop smoking medicines: one for (-)-nicotine (nicotine, (-)-(Nicotine), as the smoking cessation alternative medicine (Replacement therapy); One is clonidine (Clonidine), as the symptomatic treatment (Symptomatictreatment) that suppresses the smoking cessation malaise symptoms.Two medicines are made into compound nicotine and Catapres-TTS (hereinafter to be referred as the compound recipe patch), in conjunction with the synchronous release new technology of control two medicines, make it reach effective treatment concentration simultaneously, and produce collaborative smoking cessation effect.Through careful experiment of animal craving for tobacco pathological model and clinical principium checking, compound transdermal patch significantly surpasses nicotine or clonidine transdermal patch effective percentage, even reaches two medicine effective percentage sums.
Long-term smoking can form craving for tobacco (nicotine dependency).In case stop smoking, all malaise symptoms appear after about 1-2 hours, and comprise that (absent-minded) laxed in serious hope smoking, excitation (dejected or irritability), anxiety (upseting), thinking, work efficiency reduces and feel hungry osmium, weak.These withdrawal symptoms are everlasting and are reached the peak in 24 hours, disappear gradually in a few days to several weeks then; But it is more of a specified duration that psychic dependence (being reluctant to leave smoking) continues, as rigid inadequate ES, and success rate low (5%-10%) not only, and also relapse rate is difficult to give up up to 90% in 1 year.
The smoking addiction reason is after the brain cholinergic nerve cell is subjected to the long-term excitement of nicotine, and endogenous neurotransmitter acetylcholine (Acetylcholine) reduces, and nAChR (nAChR) increases (rise).After stopping smoking, after nicotine 1-2 half-life of blood concentration (1-2 hours), nAChR had both lacked exogenous nicotine excitement, lacked the excitement of endogenous acetylcholine again, the cholinergic nerve dysfunction occurred, was to produce all subjectivities and objective withdrawal symptom.Have only by smoking again (or giving nicotine) and could alleviate, thereby cause vicious cycle to form craving for tobacco (Zheng Mingqi, Gong Xuling: nicotine toxicology and smoking, Chinese drug dependence magazine 1998; 7 (2): 73).
The long-term smoking health risk is because of containing nicotine (addiction), carbon monoxide (anoxia), tar (carcinogenic) in the smog.Smoking can cause tracheitis, emphysema, pulmonary carcinoma, cardiovascular and cerebrovascular vessel disease medicine etc.These diseases cause smoker and involuntary smoker's premature dead on every side.Annual dead 3,000,000 people in the whole world, China 750,000 people account for 1/4.According to Sino-British medical expert's investigation in 1998, harmfulness of smoking belonged to long-term chronic process, because masses' economic condition improves, and rich " enjoyment " smoker increase year by year, now reached 3.2 hundred million people, man's smoking rate is up to 68.9% over nearly 20 years in China.Estimate that the year two thousand twenty China dies from " cigarette disease " person and will reach 2,000,000 people every year.As calculating with people's smoking 40 years (18-58 years old), 8,000 ten thousand people's early graves will be arranged, account for 3.2 hundred million smokers 1/4th; Wherein man's harm is stronger, even can reach 1/3rd.Along with various countries' Tobacco Control cry day is high, medicines and health protection knowledge is universal day by day, and giving up craving for tobacco gradually becomes numerous smoker's eager desires.
After proving that in the last thirty years craving for tobacco is the nicotine dependency, begin to have regular smoking deterent development listing.According to various countries' medical magazine and smoking deterent patent documentation report, mainly contain two big classes: a class is the nicotine preparation, is alternative medicine; Another kind of for suppressing the medicine of craving for tobacco withdrawal symptom, as clonidine or the like symptomatic treatment medicine.
The nicotine preparation have two kinds comparatively commonly used, one is nicotine gum nurse chewable tablet, one is the nicotine transdermal absorption patch.The smoking cessation effect of nicotine chewable tablet (1991) test 490 examples such as plants according to the Beijing-Tianjin cooperative groups father-in-law heart, chews every day and uses the 6-8 sheet, the medication 1-3 month, gives up 37.0% (placebo 19.1%).The smoking cessation effect of nicotine transdermal patch, (Lancet 1994 according to Silagy etc.; 343:319) comprehensive statistics 2215 examples, nicotine patch quit smoking rate are 20.5% (placebo 10.8%) only; Again according to (J Am Med Ass 1994 such as Fiore; 271:1940) comprehensive 17 pieces of document 5097 examples, about 8 weeks of the course of treatment, nicotine patch quit smoking rate 27.1% (placebo 13.1%.Wherein pasting with 24 hours persons every day was 27.9% (half a year 24.7%); Pasting with 16 hours persons was 25.0% (half a year 18.7).(referring to Zheng Mingqi, Gong Xuling: Chinese drug dependence control magazine 1997; (4): 158).
The symptomatic treatment smoking deterent mainly uses clonidine (Clonidine) also can comprise the similar medicine of clonidine: lofexidine (Lofexidine), cirazoline (Cirazoline), moxonidine (Moxonidine) S-3341 (Rilmenidine) etc.By excitomotor center imidazoline and α
2Adrenoceptor (Imidazoline and α
2-Adrenergic receptors), suppress the smoking cessation malaise symptoms; In addition, (Ann NY Acad Sci 1995 such as Musgrave; 763:272) report: clonidine ex hoc genus anne medicine still can directly suppress and the mutually link coupled Na of nicotine receptor
+, Ca
2+Ion channel makes the exciting nicotine type nicotinic of nicotine, and the neurocyte effect that causes during acetylcholinergic receptor (nAChR) is blocked by it.When we found the clinical smoking cessation on probation of compound nicotine of the present invention and clonidine transdermal patch, nearly half ES is reflected smoking insipidness after the medication, and was relevant when planting effect therewith.
When the clonidine oral tablet was used to give up smoking, because of blood medicine peak valley fluctuation of concentration is bigger, side effect was more, difficult the popularization.Now use the smoking cessation of clonidine percutaneous plaster instead, according to 7 pieces of documents, the 570 routine comprehensive statisticss that are provided with matched group both at home and abroad, 6 weeks of the course of treatment, Clonidine Patch quit smoking rate 41.3% (placebo patches 23.9%) more.(referring to Covey and Glassman:Brit J Addict 1991,86:991).
Because the effect of smoking deterent commonly used is still dissatisfied, is scheme of combination drug therapy to occur.(Eur Respir J 1993 such as Kornitzer; 6 (S17): 630s) use in conjunction nicotine transdermal paster and nicotine gum nurse chewable tablet, 12 weeks of the course of treatment, 149 examples give up 34.9%, and single quit smoking rate 24% with nicotine patches 150 examples, two groups relatively, marked difference (P＜0.05) is arranged, and placebo group 75 examples give up 17.3%, compare no marked difference (P＞0.2) with the nicotine patches group with single.
Sees etc. (1989) are use in conjunction clonidine percutaneous plaster and nicotine gum nurse chewable tablet once, as the incidental smoking cessation treatment of a free narcotic house, thinks that this is a kind of effective and comfortable smoking abstention method, but lacks concrete routine number of smoking cessation and quit smoking rate report.
Wu Risheng reports at Chinese invention patent publication number CN1144088A (1997), use long-acting Clonidine Patch to paste weekly, rise morning every day to paste with nicotine patches and share 5 weeks of the course of treatment in 16 hours with 1, try to give up in 30 examples 24 examples (80%), but establish corresponding matched group for its shortcoming.Wu Risheng etc. (1997) report in national preparation capable of permeating skin academic conference that again single quit smoking rate with Clonidine Patch is 30%-70%, and the quit smoking rate of use in conjunction Clonidine Patch and nicotine patches is 61%-80%.Do not report the concrete example number,, fail still fully to prove that the smoking cessation effect of two kinds of pasters of use in conjunction is significantly better with nicotine or Clonidine Patch than single without statistical procedures.And used two kinds of paster drug release rates such as Wu are asynchronous, need just can reach effective Css after 3 days as imitating Clonidine Patch week; And the film controlling type nicotine patches that every exhibition was pasted with 16 hours needs just to reach the blood peak concentration of drug in back 8 hours in subsides, and all the morning blood drug level is on the low side.Because two kinds of principal agent blood concentrations are asynchronous, certainly will influence collaborative smoking cessation effect.
The collaborative smoking cessation effect of compound nicotine of the present invention and clonidine transdermal administration at first is fully to prove by animal craving for tobacco (nicotine dependency) pathological model.Experiment is with growing up and the juvenile Wistar rat, and the beginning average weight is respectively 212 grams and 23 grams.Male and female half and half are fed with dried pellet, and long-term drink nicotine aqueous solution (10-30 mg/litre) progressively forms the nicotine dependency.In strengthening process, a discrimination test (Discrimination test) is carried out at the end weekly, provides each one bottle of clear water and nicotine 10 mg/litre solution during discrimination test, no matter animal is freely selected.Occur positively until the 15th, 16 all double discrimination tests, be i.e. when nicotine solution reinforcement group and intact animal organize the active selectivity and take the photograph duty nicotine solution amount marked difference (P＜0.05) is arranged, prove and set up craving for tobacco (nicotine dependency) pathological model.Then the craving for tobacco animal is divided into 4 groups at random, difference transdermal administration nicotine, clonidine, compound nicotine and three kinds of patches of clonidine and excipient (Vehicle) patch, be administered once morning every day, and continuous 10 days is a course of treatment.
Laboratory animal nicotine degree of dependence has the weight amphitypy.Light-duty craving for tobacco: with 24 of adult rats, nicotine strengthened for 16 weeks, initiatively chose the nicotine amount and Duoed 14 times than normal rat; Heavy craving for tobacco: with 24 of adult rats, nicotine strengthened for 22 weeks, initiatively chose the nicotine amount and Duoed 20 times than normal rat; And use the extra-heavy duty type craving for tobacco: childhood, rat was 8, only strengthened for 13 weeks with nicotine, initiatively chose the nicotine amount than nearly 80 times of normal rats.Gently, heavy addiction animal is divided into 4 groups all at random.
6 of light addiction animal per groups adopt little system amount smoking cessation preparation transdermal medicine for treating, contain nicotine 2mg/kg.d respectively, clonidine 12 μ g/kg.d, compound nicotine 2mg/kg.d and clonidine 12 μ g/kg.d, and excipient matched group.2 of 6 of heavy addiction animal per groups and extra heavy addiction animal per groups adopt heavy dose of smoking cessation preparation transdermal medicine for treating, contain nicotine 4mg/kg.d respectively, clonidine 24 μ g/kg.d, compound nicotine 4mg/kg.d and clonidine 24 μ g/kg.d, and excipient matched group.10 days courses of treatment, last 3 days, promptly the 8th, 9,10 day, carry out discrimination test respectively, every group of each animal of parallel observations be selectivity picked-up nicotine solution amount initiatively, to judge the smoking cessation therapeutic effect.
The low dose of smoking deterent of table 1. to the light addiction of the result for the treatment of of light addiction animal low dose of rat test initiatively choose between nicotine amount group for several times efficient comparison of number μ g/kg.d conspicuousness [1] Normal group 8 16 17 ± 19---[1: 2] 14 times of [2] excipient control groups 61 232 ± 201 0% [2: 1] P＜0.001[3 of difference cutaneous penetration group] nicotine 2mg/kg organizes 6 18 93 ± 74 59.9% [3: 2] P＜0.01[4] clonidine 12 μ g/kg organize 6 18 137 ± 117 40.9% [4: 2] P＞0.05[5] nicotine 2mg/kg adds 6 18 67 ± 46 71.1% [5: 2] P＜0.01 clonidine, 12 μ g/kg [5: 3] P＞0.05 compound group [5: 4] P＜0.05
Compound preparation smoking cessation best results (effective percentage 71.1% as seen from Table 1; Significantly surpass clonidine group effective percentage 40.9%); Also slightly surpass nicotine group (effective percentage 59.9%).It is better that low dose of nicotine is treated light addiction animal effect, (Eur Respir J 1996 such as this and Paoletti; 9:643) clinical observation result is similar.They use nicotine patches 15mg/16h, in 18 weeks of the course of treatment, treat light-duty craving for tobacco (blood plasma nicotine metabolism thing cotinine≤250mg/ml), 60 examples, quit smoking rate 28%; With placebo group 60 routine quit smoking rate 9%, marked difference (P＜0.01) is arranged.
For several times efficient conspicuousness [1] Normal group 8 16 17 ± 19---[1: 2] 35 times of [2] excipient control groups 8 24 590 ± 599 0% [2: the 1] P＜0.001[3 that compares of number μ g/kg.d of difference cutaneous penetration group is initiatively chosen between nicotine amount group in the heavy dose of rat test of the heavy addiction of the result for the treatment of of the heavy dose of smoking deterent counterweight of table 2. addiction animal] nicotine 4mg/kg organizes 8 24 424 ± 513 28.1% [3: 2] P＞0.05[4] clonidine 24 μ g/kg organize 8 24 294 ± 247 50.2% [4: 2] P＜0.05[5] nicotine 4mg/kg adds 8 24 110 ± 74 81.4% [5: 2] P＜0.001 clonidine, 24 μ g/kg [5: 3] P＜0.01 compound group [5: 4] P＜0.01
Heavy dose of smoking deterent is treated heavy craving for tobacco (every composition year rat 6) and extra-heavy duty type craving for tobacco (every group childhood rat 2), and similar effect is all arranged.Wherein effective percentage all significantly surpasses folk prescription nicotine transdermal patch group (28.1%, P＜0.01) with compound recipe group (the 5th group in table 2) the highest (81.4%); Folk prescription clonidine transdermal patch group (50.2%, P＜0.01), the effective percentage of compound recipe patch are still a little more than two folk prescription effective percentage sums (78.3%).The heavy dose of patch of folk prescription clonidine (the 4th group in table 2) is compared with the excipient matched group also has remarkable result (P＜0.05); But the low dose of patch effect not good enough (the 4th group in table 1) of clonidine is reported similar to (1998) such as Wang Dapeng etc. (1994) and Chen Shiming.
Heavy dose of nicotine patch group counterweight addiction animal effective percentage only 28.1% is compared no marked difference (P＞0.05) with the excipient matched group.This result is similar to the result of (1996) clinical trial nicotine transdermal pasters such as Paoletti.They with the heavy craving for tobacco of two kinds of dosage nicotine transdermal patch treatment (blood plasma cotinine＞250ng/ml) all to no effect, paste 15mg/16h every day, main 12 weeks of the course of treatment, 6 weeks of decrement again, during to 18 weeks, the quit smoking rate of 90 examples only 11%; Strengthen nicotine patches dosage to 25mg/16h, the quit smoking rate 9% of 87 examples is with 9% nothing else difference of placebo 60 examples.This experimentation though heavy dose of nicotine patch does not have remarkable effect (P＞0.05) to heavy craving for tobacco animal, still has remarkable synergy (the 5th group of P＜0.01st of table 2) when share with clonidine.
Set up the experiment of craving for tobacco pathological model as for the long-term oral nicotine of rat, Clark MSG (Brit J Pharmacol 1969 is arranged in one's early years; 35:367) with Sanger DJ (Pharmacol BiochemBehav 1978; 8:343) report; Glick SD et al (Psychopharmacol (Berl) 1996 is arranged again in recent years; 128 (4): 426) report all successfully forms animal self administration behavior, i.e. selectivity picked-up nicotine solution initiatively during discrimination test.Similar to experimental technique of the present invention.Robinson SF etc. can absorb nicotine (Psychopharmacol (Berl) 1996 by the active selectivity after still reporting 6 strain mice continuous oral nicotine; 124 (4): 332).But do not see and utilize any animal craving for tobacco pathological model to carry out nicotine, clonidine or the dependent report of two recurrence due to taking drug side's experimental therapy nicotine both at home and abroad.
When zoopery proof nicotine and clonidine share, toxic action did not increase.Acute median lethal dose(LD 50) (LD50) as the oral nicotine solution of adult mice is 58.7mg/kg; And compound recipe LD50 is nicotine 59.3mg/kg and clonidine hydrochloride 0.87mg/kg (containing clonidine 0.77mg/kg) (two pharmaceutical quantities ratios are with reference to clinical treatment amount ratio).Compound recipe toxicity reduces by 1%, no marked difference.During acute toxic test, two treated animal poisoning symptoms are all the tonic convulsion that nicotine causes.The oral LD50 of clonidine mice is 328mg/kg, and the acute poisoning symptom is that maincenter suppresses, blood pressure reduces.
Normal rat, nicotine preparation transdermal administration, minimum lethal dose is 160mg/kg (dead 1/6); Behind multiple dosing, animal tolerance nicotine acute poisoning amount (LD50) can improve 10 times.For long-term smoker, nicotine transdermal absorbs its blood drug level of therapeutic dose (21mg/24h) 17ng/ml, be lower than smoking bleeding from anus nicotinic density (20-50ng/ml), so no important systemic side effects (TNS group; J Am Med Ass1991; 266:3133).
Clonidine has the calm side effect of maincenter, and a few peoples are drowsiness; Suppress the salivation amount and feel xerostomia; Slight blood vessel dilating, bring high blood pressure down and decreased heart rate.The nicotine side effect is then opposite, and the central excitation effect is arranged; Promote salivation; Vasoconstrictive, increase heart rate and rising blood pressure.When two medicines share, these major side effects still can be alleviated mutually, and are all lighter than arbitrary folk prescription patch, and this is another advantage (table 3) of compound nicotine and clonidine patch.
The interaction pharmacological action nicotine clonidine addiction of table 3. nicotine and clonidine does not have for the smoking addiction composition; Can smoking cessation, alleviating alcohol addiction, therapy is unstable as calm (drowsiness) sleep state sleep of symptomatic treatment mental status excitement (regaining consciousness) as an alternative in ring opium smoking cessation effect, dreaminess is slept peacefully, and few dream increased heart rate vasoconstriction diastolic blood pressure that slows down raises and reduces knock-on property reaction buck-boost saliva and increase (sialorrhea) and reduce (xerostomia)
Compound nicotine and clonidine transdermal patch were once openly solicited the aspiration ES and were carried out preliminary clinical trial, finished 3 all person's 17 examples course of treatment (women 1 example), and 44.2 years old mean age, 23.4 lengths of smoking, every day, suction strainer was chewed 15.1 of cigarettes.Fill in individual smoking history during registration.Collective's explanation harmfulness of smoking, the effect of plaster for giving up smoking, usage and the side effect that may occur before the smoking cessation.Measure pulse, blood pressure, and issued for first week and use 7 of large size sheets.Return visit is once measured pulse, blood pressure more weekly, reclaims useless sheet inspection and has or not leakage to paste, and issues and uses medium size sheet and small size sheet next week.Three kinds of specification patches discharge nicotine 21,14,7mg and clonidine 210,140,70 μ g respectively.Require no longer smoking as far as possible during pasting medicine.After finish 3 courses of treatment in week, give up 12 examples (70.6%) in 17 examples fully; Do not give up 5 routine smoking capacities and also reduce to 4.0 (reducing 80%) by original 19.6.Everyone adds this 5 example and use for 1 week, uses large stretch of 3 days successively, in, small pieces respectively 2 days, smoking capacity is still about 4 of every days as a result.
The mean age of not giving up 5 examples is big (51.8 years old), and the length of smoking grow (30.8), and once repeatedly attempt is given up smoking and failed to give up, former smoking capacity more (19.4), and craving for tobacco is heavier, and it is lack confidence to give up smoking.It is that the layman supervises down participation smoking cessation reluctantly that 3 people are arranged in 5 examples, and it is little to be determined.To these heavy addiction persons, still dislike the dosage and the course of treatment not enough.
The side effect aspect: calm 4 examples, xerostomia 3 examples are arranged in 17 examples, all relevant with contained clonidine; Have 2 examples when first all smoking, to be sick in the stomach, may nicotine transdermal absorb reach Css after, during smoking, the nicotine that absorbs through lung causes the blood concentration superelevation again.Have 4 examples skin in pasting medicine 1,2 hours that of short duration gargalesthesia is arranged, but local skin does not all have any objective variation.Systolic blood is pressed with slight reduction, but not statistically significant.
From now on, still to be undertaken about 300 examples, at random, double blinding, controlled trial by Ministry of Public Health (office) designated hospital.Light addiction person intended with 4 courses of treatment in week of usual amounts: large size sheet (18cm
2, discharge nicotine 18mg and clonidine 180 μ g every day) and 2 weeks; Reuse medium size sheet (12cm
2) and small size sheet (6cm
2) each 1 week.Heavy addiction person intended with heavy dose of 5 courses of treatment in week: large size sheet (24cm
2, discharge nicotine amount 24mg and clonidine 240 μ g every day) and 3 weeks, reuse medium size sheet (16cm
2) and small size sheet (8cm
2) each 1 week.The objective indicator of smoking cessation preferably adopts the expiration determination of carbon monoxide, is examined.
Three kinds of Transdermal absorption controlled release forms at present commonly used, as matrix type, viscose glue control release type and membrane controlled release type, all applicable (referring to Gong Xuling, Zheng Mingqi: China Dispensary 1994; 5 (6): 29).No matter with the sort of Transdermal absorption dosage form, no matter also use which kind of macromolecule controlled-release material, as long as can be by clinical smoking cessation requirement, control compound nicotine of the present invention and Catapres-TTS, discharge certain drug dose person every day (24 hours), promptly requiring to discharge every day the nicotine amount is 5-45mg and clonidine 0.05-0.5mg person, all can use.
Comparatively ideal stop smoking medicine dynamic metabolism, preferably daytime, blood drug level was higher, and blood drug level was lower when slept evening, half that to give a new paster precontract inferior morning be peak concentration.Viscose glue control release type percutaneous absorption patch comparatively meets this requirement.And the membrane controlled release type patch, blood drug level was too constant in 24 hours, certainly will influence sleep in night (nicotine can cause sleep shakiness, dreaminess), also easily made body produce tachyphylaxis (Tachyphylaxis), reduced drug effect.As for the matrix type patch, very fast because of drug release rate, it is also fast that per hour release amount descends, so inferior morning, blood drug level was on the low side; With 16 hours patches this shortcoming is arranged more and paste every day; All require the smoking cessation treatment that morning, WA will the smoker unfavorable to heavy craving for tobacco.In addition, viscose glue control release type compound recipe patch two medicine release rate peak times are 5 hours, and than 8 hours weak points of membrane controlled release type, onset is very fast.
The macromolecular material that the used control principal agent of compound nicotine and clonidine transdermal patch discharges has high low-molecular-weight polyisobutylene, polyacrylate, polysiloxanes etc.These medical high-molecular additives commonly used, bigger to skin-friendliness, generally can not cause contact hypersensitivity, but and double as adhere to the pressure sensitive adhesive adjuvant of skin (referring to Liang Bingwen chief editor " percutaneous drug administration preparation " 1992:208-249; Zheng Jun democracy is compiled " percutaneous dosing novel form " 1997:3-35).
Percutaneous plaster often has local skin reaction, occurs that heavier reaction such as hillock rash still appears in slight erythema (39%), pruritus (53%) a few peoples and therapy discontinued person reaches 9.5% (ResearchGroup:Brit Med J 1993 as commercially available nicotine patches; 306:1304); The dermoreaction rate of commercially available Clonidine Patch (Catapres TTS) has 10%-20%.Ito reports (Am J Med 1991; 91 (1) A:42s), before using Clonidine Patch, local skin uses 0.5% tixocortol (Hydrocortisone) cream 0.25g to handle in advance, can significantly alleviate the local skin irritant reaction.Compound nicotine of the present invention and clonidine patch are added with low dose of local steroidal anti-inflammatory medicine (Tropial steroidal anti-inflammatory drugs), as fluocinonide (Fluocinonide), are prevented.But should note using any local steroidal anti-inflammatory medicine, should use least effective dose (LED), in order to avoid Transdermal absorption causes side effect.
Nicotine contacts with tissue, can make the generation of oxygen-derived free radicals (Oxyyen free radical) increase several times, and pair cell has detrimental effect (Wetacher GJ, et al:Dig Dis Sci 1995; 40:853).In compound recipe patch of the present invention, be added with the vitamin E (a-Tocopherols) that to remove oxygen-derived free radicals, to alleviate the infringement of nicotine to skin.Vitamin E and low dose of steroidal anti-inflammatory medicine coordinating protection skin effects are excellent.Paste with 3-4 weeks continuously among the 17 example aspiration ESs above-mentioned the examination, never find any dermal inflammatory reaction.
Add in compound nicotine and Catapres-TTS with low dose of local steroidal anti-inflammatory medicine and vitamin E and share, not seeing has similar report both at home and abroad.Not seeing that more nicotine patches or Clonidine Patch are added with the report of local steroidal anti-inflammatory medicine and/or vitamin E, also is that the present invention initiates.
Three kinds of percutaneous absorption patchs that accompanying drawing is suitable for for the present invention: matrix type (3 layers), viscose glue control release type (4 layers), and the cross section structure sketch map of membrane controlled release type (5 layers).See accompanying drawing 1, Fig. 2, Fig. 3 successively.
1 matrix-type transdermal patch: comprise back sheet, medicine glue skeleton layer, 3 layers of antiseized protective layers etc. 1. backing Layer: be the impervious aluminum-plastic composite membrane of medicine, available aluminium foil and polyester (poly terephthalic acid ethylene glycol ester (Polyterephthalyl-glycolate) composite membrane; Also available aluminium foil and fine and close polyethylene (Dense Polyethylene) composite membrane, the plastics face is made skin color.
2. medicine glue skeleton layer: this layer drug storage warehouse, the main medicine of control discharge the functions such as speed, pressure-sensitive glue melt for One, technology is simple, and cost is low. It is to discharge by one-level dynamics constant proportion that only main medicine discharges, and it discharges speed With the positive correlation of skeleton layer content of dispersion, speed is very fast when beginning to discharge, and when reducing along with content of dispersion in the skeleton, releases It is slack-off to put speed. Its skeletal matrix high molecular polymer.
3. antiseized protective layer: be the medicine compound protective layer with thick polyester film, interior silication is antiseized. Guarantor before use tears Sheath sticks skin to the medicine glue-line, flattens with palm.
2. viscose glue control release type transdermal patch comprises back sheet, drug storage warehouse layer, pressure-sensitive adhesive layer, antiseized protective layer Deng 4 layers.
1. back sheet: with the matrix type patch.
2. drug storage warehouse layer: matrix is high molecular polymer, includes main medicine and complementary material. Rate of releasing drug with Matrix and the positive correlation of medicine concentration.
3. pressure-sensitive adhesive layer: polyisobutene commonly used or polyacrylate pressure-sensitive (Presure sensitive Adhesives). Include transdermal penetrating agent, antioxidant, oxygen radical removing agent, anti-scorching agent, also Contain a small amount of main medicine of certain proportion, absorb to accelerate drug transdermal, shorten medicine blood concentration peak time (Tmax). Pressure-sensitive adhesive layer adheres to the skin function except having, still have certain control drug storehouse layer medicine by close to The effect that zero level dynamics constant discharges.
4. antiseized protective layer: same matrix type.
3 membrane controlled release type transdermal patches: comprise back sheet, drug storage warehouse layer, release-controlled film pressure-sensitive adhesive layer, antiseized 5 layers of protective layers etc.
1. back sheet: same matrix type.
2. drug storage warehouse layer: the matrix high molecular polymer includes main medicine and complementary material. Its drug release rate Limited by release-controlled film, so drug content need be brought up to some times of the release amount, release such as nicotine content and every day Medicine amount ratio is 5-6 to 1; Clonidine content and release every day amount ratio are 17-25 to 1.
3. release-controlled film: with ethene-vinyl acetate copolymer (Ethylene vinylacetate co-polymer, EVAc) better, also available pore type polypropylene (Microporous polypropylene) Make the film material.
4. press every glue-line: pressure-sensitive with high and low molecular weight polyisoprene isobutene (Oppanol B) or polyacrylate Glue. Include transdermal penetrating agent, antioxidant, oxygen radical removing agent, anti-scorching agent and contain certain ratio The a small amount of main medicine of example to accelerate Transdermal absorption, shortens medicine blood concentration peak time (Tmax).
The drug storage warehouse contained drug of membrane controlled release type transdermal patch is limit by release-controlled film and the less important adhesive-layer that is subjected to mainly Speed discharges, and can discharge by zero level dynamics constant, makes the blood concentration keep comparatively constant stable state concentration (Css).
5. antiseized protective layer: same matrix type.
4. external packing pouch (seeing Fig. 4):
Every a slice patch is all with a special small package bag sealing, the effects such as anti-oxidation, moisture proof, lucifuge, To improve the stability of patch contained drug, prolong the term of validity to two year. Especially nicotine has certain volatility, Easy oxidized destruction is more wanted good packaging again. We have compared nearly 10 kinds of packaging material, in conjunction with (60 ℃ of high temperature ), the conditions such as high wet (RH75%), high light, carry out accelerated stability test result on the 10th, with following three layers Composite membrane the best: internal layer be polyvinyl fluoride (Polyvinyl fluoride, PVF) film, middle level be aluminium foil, Skin is fine and close polyethylene film. The patch name of an article, main medicine every day (24 hours) release amount, subsides can be printed in the surface Sheet area, usage, points for attention, authentication code, product batch number, the term of validity, production unit etc.
Example 1
Matrix type compound nicotine and clonidine percutaneous plaster A
1. medicine glue skeleton
(1) low-molecular-weight polyisobutylene (Oppanol B-10) 25%-35%
(2) high molecular weight polyisobutylene (Oppanol B-100) 20%-25%
(3) white oil (Liguid paraffin) 25%-40%
(4) nicotine or its esters (Nicotine or its salts) 5%-25%
(5) clonidine or its esters (Clonidine or its salts) 0.05%-2%
Or equivalent clonidine class medicine, as lofexidine (Lofexidine), cirazoline
(Cirazoline), moxonidine (Moxonidine) or S-3341
Or its esters (Rilmenidine) etc.
(6) laurocapram (Laurocapram) 1%-3%
(7) vitamin E (Vitamine E) 0.1%-1.0%
(8) fluocinonide (Fluocinonide) 0.005%-0.025%
Above-mentioned each composition stirs evenly with organic solvent (normal heptane or chloroform) dissolving (salt suspendible), and froth breaking is filmed on backing, and room temperature or 40 ℃ are flung to organic solvent, cover antiseized protective layer, cutting, packing.
2. backing layer: aluminum-plastic composite membrane, mould the face colour of skin.
3. protective layer: polyester (polyterephthalyl-glycolate) film, the inner face silication is antiseized.
Example 2
Matrix type compound nicotine and clonidine transdermal patch B
1. medicine glue casing play:
(1) polyacrylate (polyacrylate) 60%-80%
(2) nicotine or its esters (Nicotine or its salts) 5%-35%
(3) clonidine or its esters (Clonidine or its salts) 0.05%-2%
Or the similar medicine of equivalent clonidine, with example 1.
(4) laurocapram (Laurocapram) 1%-3%
(5) vitamin E (Vitamine E) 0.1%-1%
(6) fluocinonide (Fluocinonide) 0.005%-0.025%
2. backing layer: with example 1.
3. protective layer: with example 1.
Preparation process is with example 1.
Example 3
Viscose glue control release type compound nicotine and clonidine transdermal patch A
1. drug storage warehouse layer:
(1) low-molecular-weight polyisobutylene (Oppanol B-10) 25%-35%
(2) high molecular weight polyisobutylene (Oppanol B-100) 20%-25%
(3) white oil (Liquid paraffin) 25%-40%
(4) nicotine or its esters (Nicotine or its salts) 5%-20%
(5) clonidine or its esters (Clonidine or its salts) 0.05%-2%
Or the similar medicine of equivalent clonidine, with example 1.
(6) laurocapram (Laurocapram) 0%-3%
(7) vitamin E (Vitamine E) 0.1%-1.0%
(8) fluocinonide (Fluocinonide) 0%-0.025%
2. pressure-sensitive adhesive layer:
(1) low-molecular-weight polyisobutylene (Oppanol B-10) 30%-40%
(2) high molecular weight polyisobutylene (Oppanol B-100) 15%-25%
(3) white oil (Liquid paraffin) 25%-35%
(4) nicotine or its esters (Nicotine or its salts) 1%-5%
(5) clonidine or its esters (Clonidine or its salts) 0.01%-0.04%
Or the similar medicine of equivalent clonidine, with example 1.
(6) laurocapram (Laurocapram) 2%-3%
(7) vitamin E (Vitamine E) 0.1%-0.5%
(8) fluocinonide (Fluocinonide) 0.01%-0.025%
The medicine glue of above-mentioned drug storage warehouse layer and pressure-sensitive adhesive layer is used organic solvent dissolution (salt suspendible) respectively, stirs evenly froth breaking.Be uniformly coated on backing layer and protective layer inner face respectively.Put room temperature or 40 ℃ and fling to organic solvent, two-layer then medicine glue is bonding mutually, cutting, packing.
3. backing layer: aluminum-plastic composite membrane, plastic cover are skin color.
4. protective layer: aluminum-plastic composite membrane or polyester (terylene) film, the inner face silication is antiseized.
Example 4
Viscose glue control release type compound nicotine and clonidine transdermal patch B.
1. drug storage warehouse layer:
(1) polyacrylate (Polyacrylate) 60%-80%
(2) nicotine or its esters (Nicotine or its salts) 5%-20%
(3) clonidine or its esters (Clonidine or its salts) 0.05%-2%
Or the similar medicine of equivalent clonidine, with example 1.
(4) laurocapram (Laurocapram) 1%-3%
(5) vitamin E (Vitamine E) 0.1%-0.5%
(6) fluocinonide (Fluocinonide) 0%-0.025%
2. pressure-sensitive adhesive layer:
(1) polyacrylate (Polyacrylate) 60%-80%
(2) nicotine or its esters (Nicotine or its salts) 1%-5%
(3) clonidine or its esters (Clonidine or its salts) 0.01%-0.05%
Or the similar medicine of equivalent clonidine, with example 1.
(4) laurocapram (Laurocapram) 2%-3%
(5) vitamin E (Vitamine E) 0.1%-0.5%
(6) fluocinonide (Fluocinonide) 0.01%-0.025%
3. backing layer: with example 1.
4. protective layer: with example 1.
Preparation patch step is with example 3.
Example 5
Membrane controlled release type compound nicotine and clonidine transdermal patch A
1. drug storage warehouse layer:
(1) low-molecular-weight polyisobutylene (Oppanol B-10) 25%-35%
(2) high molecular weight polyisobutylene (Oppanol B-100) 20%-25%
(3) white oil (Liquid paraffin) 25%-40%
(4) nicotine or its esters (Nicotine or its salts) 5%-25%
(5) clonidine or its esters (Clonidine ir its salts) 0.05%-2%
Or the similar medicine of equivalent clonidine, with example 1.
(6) vitamin E (Vitamine E) 0.5%-1%
2. pressure-sensitive adhesive layer:
(1) low-molecular-weight polyisobutylene (Oppanol B-10) 30%-40%
(2) high molecular weight polyisobutylene (Oppanol B-100) 15%-25%
(3) white oil (Liquid paraffin) 25%-35%
(4) nicotine or its esters (Nicotine or its salts) 1%-5%
(5) clonidine or its esters (Clonidine ir its salts) 0.01%-0.05%
Or the similar medicine of equivalent clonidine, with example 1.
(6) laurocapram (Laurocapram) 2%-3%
(7) vitamin E (Vitamine E) 0.5%-1%
(8) fluocinonide (Fluocinonide) 0.01%-0.025%
3. release-controlled film: ethylene-vinyl acetate copolymer (Ethylene-Vinylacetate Co-polymer) film or microporous polypropylene membrane (Microporous Polypropylene membrane) etc.Place between drug storage warehouse layer and the pressure-sensitive adhesive layer, form permeability slow release barrier film.
It is poly-with example 3 that drug storage warehouse layer and pressure-sensitive adhesive layer prepare the patch step.
4. backing layer: with example 1.
5. protective layer: with example 1.
Membrane controlled release type compound nicotine and clonidine transdermal patch B
1. drug storage warehouse layer:
(1) polyacrylate (polyacrylate) 60-80%
(2) nicotine or its esters (Nicotine or its salts) 5%-25%
(3) clonidine or its esters (Clonidine or its salts) 0.05%-2%
Or the similar medicine of equivalent clonidine, with example 1.
(4) vitamin E (Vtamine E) 0.5%-1%
2. pressure-sensitive adhesive layer:
(1) polyacrylate (Polyacrylate) 60%-90%
(2) nicotine or its esters (Nicotine or its salts) 1%-5%
(3) clonidine or its esters (Clonidine or its salts) 0.01%-0.05%
Or the similar medicine of equivalent clonidine, with example 1.
(4) laurocapram (Laurocapram) 2%-3%
(5) vitamin E (Vitamime E) 0.5-1%
(6) fluocinonide (Fluocinonide) 0.01%-0.025%
3. release-controlled film: with example 5.
4. backing layer: with example 1.
5. protective layer: with example 1.
Drug storage warehouse layer and pressure-sensitive adhesive layer preparation step are poly-with example 3 and 5.
Claims (7)
1. give up compound nicotine and the clonidine transdermal patch (The Transdermal Preparation of Nicotine and Clonidine Compoundfor Smoking Cessation) that craving for tobacco (abuse tobacco product) is used for one kind, include two kinds of main smoking deterents: one is that (nicotine (-)-Nicotine) or its salt 5%-35% discharge the nicotine amount every day to be calculated as 5-45 milligrams by base (-)-nicotine; One is clonidine (Clonidine) or its salt 0.05%-2%, discharges clonidine every day and is calculated as 0.05-0.5 milligram by base.
2. the clonidine in the claim 1, also available its similar medicine, i.e. imidazoline receptor and epinephrine α
2Receptor stimulating agent, as lofexidine (Lofexidine), cirazoline (Cirazoline), moxonidine (Moxonidine) or S-3341 (Eilmenidine) etc. and their salt, every patch content of dispersion and release every day amount, the clinical equivalent dosage range that all is equivalent to clonidine or its esters, for example lofexidine burst size every day is 0.1-1.0 milligrams.
3. the preparation type of compound nicotines and clonidine (or its similar medicine) transdermal patch of claim 1 and 2 preparations can adopt any system type administration of the present clinical multiple transdermal formulation commonly used of viscose glue control release type, skeleton disperse control release type or permeable membrane control release type or the like.
4. claim 1 smoking cessation is with compound nicotine and used complementary medicinal materials (1) backing of clonidine transdermal patch, with aluminium foil and polyester or polyethylene composite film; (2) medicine glue-line, the substrate that comprises drug storage warehouse layer and pressure-sensitive adhesive layer, use high molecular polymer, as polyisobutylene (Polyisobutylene), polyacrylate (Polyacrylate) or silicone pressure-sensitive adhesive (transdermal patch controlled release commonly used macromolecular material such as Silicone Pressure Sensitive Adhesive; (3) release-controlled film: with ethylene-vinyl acetate copolymer (Ethylene Vinylacetate co-polymer), or with capillary polypropylene membrane such as (MicroporousPoly-propylene); (4) antiseized protective layer, available silication polyester film etc.; (5) every packing pouch: with three layers of special composite membrane of the present invention: internal layer is polyvinyl fluoride (Polyvinyl fluoride); the middle level is an aluminium foil; skin is fine and close polyethylene (Dense polyethylene), better protects the stability of principal agent in the claim 12.
5. by described compound nicotine of claim 1 and clonidine transdermal patch, contain penetration enhancer, preferably use Laurel nitrogen ketone (Laurocapram) 1%-3% at the medicine glue-line.
6. according to described compound nicotine of claim 1 and clonidine transdermal patch, in the medicine glue-line, close the local steroidal anti-inflammatory medicine (Tropical steroidal anti-inflammatory drugs) of a small amount of (minimum effective drug concentration), fluocinonide (Fluocinonide) 0.005%-0.025% preferably, other local steroidal anti-inflammatory medicines that also available suitable antiinflammatory is tired are as halcinonidedcorten (Halcinonide) or Triamcinolone acetonide acetate (Triamcinolone acetate) etc.
7. the medicine glue-line according to described compound nicotine of claim 1 and clonidine transdermal patch contains antioxidant, the most handyly has the vitamin E of removing oxygen-derived free radicals concurrently (Vitamine E, α-Tocopherols) 0.1%-1.0%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99102043A CN1239656A (en) | 1999-02-10 | 1999-02-10 | Compound transdermal nicotine-clonidine paster for giving up smoking |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN99102043A CN1239656A (en) | 1999-02-10 | 1999-02-10 | Compound transdermal nicotine-clonidine paster for giving up smoking |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1239656A true CN1239656A (en) | 1999-12-29 |
Family
ID=5270749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99102043A Pending CN1239656A (en) | 1999-02-10 | 1999-02-10 | Compound transdermal nicotine-clonidine paster for giving up smoking |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1239656A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2806625A1 (en) * | 2000-03-23 | 2001-09-28 | Pf Medicament | MATRIX DEVICE FOR THE TRANSDERMAL DELIVERY OF RILMENIDINE AND ITS PREPARATION METHOD |
| WO2001080837A3 (en) * | 2000-04-15 | 2002-02-21 | Lohmann Therapie Syst Lts | Transdermal or transmucosal dosage forms with a nicotine-containing active substance combination for smoker disintoxication |
-
1999
- 1999-02-10 CN CN99102043A patent/CN1239656A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2806625A1 (en) * | 2000-03-23 | 2001-09-28 | Pf Medicament | MATRIX DEVICE FOR THE TRANSDERMAL DELIVERY OF RILMENIDINE AND ITS PREPARATION METHOD |
| WO2001070224A3 (en) * | 2000-03-23 | 2002-02-28 | Pf Medicament | Rilmenidine dressing and method for preparing same |
| WO2001080837A3 (en) * | 2000-04-15 | 2002-02-21 | Lohmann Therapie Syst Lts | Transdermal or transmucosal dosage forms with a nicotine-containing active substance combination for smoker disintoxication |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1131018C (en) | Drug-containing adhesive composite transdermal delivery device | |
| KR20070088823A (en) | Tamper-resistant transdermal dosage form comprising an active agent component and an adverse agent component at the distal site of the active agent layer | |
| RU2009137472A (en) | MELATONIN TABLET AND METHODS OF MANUFACTURE AND APPLICATION | |
| CN1714867A (en) | Triacetin as a transdermal penetration enhancer | |
| CN111315438B (en) | Transdermal drug delivery system | |
| CN1750822A (en) | Method of treating post operative nausea and vomiting | |
| CN1239656A (en) | Compound transdermal nicotine-clonidine paster for giving up smoking | |
| CN1899268A (en) | L-amlodipine besilate dripping pill and its preparing method | |
| CN1679676A (en) | Six-component saf-flower drops and preparation thereof | |
| CN1307977C (en) | Propolis dripping pills for treating toothache and its preparation method | |
| CN1660141A (en) | Drop pills of arenobufagin and preparation method | |
| CN1634509A (en) | Yitongshu drop pill for treating pain and its preparation method | |
| CN1633994A (en) | Compound control-released percutaneous medicine plaster for treating high blood pressure and its preparation method | |
| CN1634508A (en) | Saussurea involucrata drop pill and its preparation method | |
| CN1287771C (en) | Almond cough-relieving drop pills and preparation method thereof | |
| CN1301094C (en) | Throat pain relieving anti-inflammation drop pills for treating oral disease and preparation method thereof | |
| CN1316958C (en) | Caulis Erycibes drop-pill and its preparation method | |
| CN1301107C (en) | Xiyanping drop pills of possessing function of clearing away heat and toxic materia and preparation method | |
| CN1679675A (en) | Chuanhuang anti-inflammation drops for clearing away heat and detoxicating, and preparation thereof | |
| CN1679669A (en) | Polygala dropping balls and preparation thereof | |
| CN1316957C (en) | Yam rhizoma drop-pill and its preparation method | |
| CN1297256C (en) | Oral drop pills for treating coronary disease and preparation method thereof | |
| CN1634483A (en) | Musk precordial pain relieving drop pills and preparation method thereof | |
| CN1720975A (en) | Asari dripping pills and its preparation process | |
| CN1634507A (en) | Tripterygium total terpenoids drop pill and its preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |