CN1283249C - Oral disintegrated and/or oral soluble solid hydrocyclo-benzenenonate - Google Patents
Oral disintegrated and/or oral soluble solid hydrocyclo-benzenenonate Download PDFInfo
- Publication number
- CN1283249C CN1283249C CN 200310103553 CN200310103553A CN1283249C CN 1283249 C CN1283249 C CN 1283249C CN 200310103553 CN200310103553 CN 200310103553 CN 200310103553 A CN200310103553 A CN 200310103553A CN 1283249 C CN1283249 C CN 1283249C
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- China
- Prior art keywords
- benzene ring
- nonyl ester
- ring nonyl
- cyclodextrin
- oral
- 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.)
- Expired - Lifetime
Links
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- 238000002360 preparation method Methods 0.000 claims abstract description 38
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 201000003152 motion sickness Diseases 0.000 claims abstract description 11
- 229920000642 polymer Polymers 0.000 claims abstract description 8
- -1 benzene ring nonyl ester Chemical class 0.000 claims description 61
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- AUKYHFFECJXLHI-HCMPJQJDSA-N [(1s,5r)-3-methyl-3-azabicyclo[3.3.1]nonan-9-yl] 2-cyclopentyl-2-hydroxy-2-phenylacetate;hydrochloride Chemical compound Cl.C1([C@@H]2CCC[C@H]1CN(C2)C)OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 AUKYHFFECJXLHI-HCMPJQJDSA-N 0.000 abstract 1
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- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 2
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Abstract
The present invention relates to a phencynonate hydrochloride orally disintegrated and/or orally dissolved solid preparation for treating motion sickness. The orally disintegrated and/or orally dissolved preparation of the present invention comprises methacrylic acid polymer or cyclodextrin and derivatives thereof, such as beta-cyclodextrin. The preparation can be disintegrated and/or dissolved within 1 to 30 seconds in an oral cavity without needing to drink water, and thus, the compliance of patients is increased.
Description
Technical field
The present invention relates in the oral cavity disintegrate or dissolved benzene ring nonyl ester Orally disintegrating and/or Orally dissolving novel solid preparation rapidly, described preparation can be used for anti-motion sickness as carsick, seasick, airsick etc.
Background technology
Benzene ring nonyl ester (chemical name: be the maincenter anticholinergic agent benzyl ring amyl group hydroxyacetic acid-N-methyl-3-azabicyclo [3,3, the 1] ninth of the ten Heavenly Stems-9 α ester hydrochloride), can enter in the brain by blood brain barrier.In the rabbit that the reversibility cholinesterase inhibitor causes reverse turn-take syndrome and two kinds of animal movement disease models of cat motion sickness sample syndrome, show the prevention of motion sickness effect.Its energy blockage of acetylcholine is to the agonism of M-ChR in the brain (m receptor) and nicotine receptor (n receptor).On mice its can antagonism the convulsions that causes of the endogenous acetylcholine that produces of cholinesterase inhibitor, what can antagonism m receptor agonist cause trembles and convulsions that the n receptor agonist causes, can also strengthen the syngignoscism of pentobarbital sodium.Benzene ring nonyl ester has the agonism of periphery blockage of acetylcholine to m receptor, shrinks as suppressing ileum, enlarges pupil, suppresses salivary gland secretion.Heavy dose can also speed heart rate and breathing rate.Respiratory depth and blood pressure are not had obvious influence, the periphery n receptor is not had obvious antagonism.
Benzene ring nonyl ester oral administration post-absorption is fast, can detect in blood after 15 minutes.Blood drug level peaked in 1～1.5 hour, and blood drug level is kept higher level in 4 hours, about 3.3 hours of biological half-life.Zoopery shows this product, and it can be distributed to each tissue of health, and is more with liver, lung, kidney, does not have a certain tissue phenomenon that concentrates especially.This product reaches peak time the earliest in brain.This product mainly through kidney by homaluria, discharged by urine in 24 hours and to reach 88.6%, no cumulative action.
Be used for the treatment of the oral ordinary tablet of carsick, seasick, airsick benzene ring nonyl ester and go on the market, but must use the water delivery service medicine when taking this medicine.In water-stressed conditions or for patient that dysphagia is arranged or child, compliance is relatively poor.
In present field of pharmaceutical preparations, variously knownly be used for oral pharmaceutical dosage form and exist although have, still insufficient for the exploitation of the dosage form of being taken by the patient easily.For example, with regard to the tablet and capsule that are commonly used for oral formulations, old age that many swallows are more weak and child patient just are reluctant to take these solid preparations, and the complaint medicine is difficult to swallow and maybe can sticks in one's throat or esophagus, and masticable tablet also is not suitable for more weak old man of the ability of chewing and child.With regard to powder or granule, they are difficult to swallow, because they are easy to stay in the oral cavity, thereby produce unhappy sensation in mouth.Sometimes, the old man can because of the powder dysphagia or because granule be embedded in feels pain or discomfort in the artificial tooth.In addition, powder and granule need use after tearing each packaging bag, maybe a part of content can be trickled down but old man or child often are difficult to tear packaging bag.And taking these oral formulations needs drinking-water, and in many cases, old man or child especially need to take a large amount of water, because their dysphagia.But, can only drink water in right amount owing to the puzzlement of factors such as urinating night.In addition, the patient for needs continue to take oral formulations in daily life owing to be difficult to obtain water in some cases, also can cause compliance to descend sometimes.Syrup etc. are considered to be fit to old man and child's desirable dosage form, but can not expect to be difficult to measure volume required old man and the child can use these preparations by correct dosage.In addition, because many gerontal patients almost can not send into liquor in the mouth on one's own account, except the patient can require situation that the nurse helped, this dosage form always was not considered to dosage form that old man and child are fit to.Therefore, the preparation that the practicality that especially can make things convenient for old people and children taking can be conveniently taken in exploitation is just becoming a kind of urgent needs, oral rapidly disintegrating or oral instant tablet are the desirable dosage forms that satisfies this demand, the said preparation technology has become one of contemporary medical high-tech, is with a wide range of applications.
In addition, the benzene ring nonyl ester taste is extremely bitter, directly places the oral cavity patient to accept.
Summary of the invention
Prepare oral rapidly disintegrating or the oral instant preparation that need not water when taking after the objective of the invention is to resist motion sickness medicine benzene ring nonyl ester to handle by effective taste masking.All can conveniently take medicine in water-stressed conditions or for old people that dysphagia is arranged or child, thereby can increase patient's compliance.
Therefore, an aspect of of the present present invention relates to benzene ring nonyl ester oral rapidly disintegrating and/or the oral instant tablet that is used for anti-motion sickness, and it comprises benzene ring nonyl ester, odor mask and a kind of or various pharmaceutic adjuvant for oral use.
Another aspect of the present invention relates to the benzene ring nonyl ester oral rapidly disintegrating that is used for anti-motion sickness and/or the preparation method of oral instant tablet, it comprises at first benzene ring nonyl ester is mixed with odor mask, then gained mixture or complex is mixed with one or more oral pharmaceutic adjuvants.
Term used herein " Orally disintegrating and/or Orally dissolving solid preparation " is meant and only keeps in the mouth and do not need just fully disintegrate and by saliva dissolves and the solid preparation of suitable stiffness is arranged of water.Term used herein " can fully disintegrate and dissolving " be meant said preparation in the oral cavity inherent about 1-120 in second, preferably at 1-60 in second, more preferably in about 1-30 disintegrate or dissolving in second.Term " suitable hardness " is meant that said preparation has can be in preparation process and the disruptive enough hardness of distribution phase.
According to the present invention, used term " odor mask " can be the odor mask various for oral use that pharmaceutical field is used among the present invention, say for example as methacrylate polymer or cyclodextrin or derivatives thereof, wherein methacrylate polymer is selected from Youteqi E or Youteqi EPO, the cyclodextrin or derivatives thereof is selected from beta-schardinger dextrin-or beta-cyclodextrin derivative, preferred beta-schardinger dextrin-, HP-, ethyl cyclodextrin, DM-, TM-.
According to the present invention, used term among the present invention " pharmaceutic adjuvant for oral use " but the pharmaceutic adjuvant any for oral use that uses in the pharmaceutical field say for example, as mannitol, sucrose, gelatin, hydroxyethyl-cellulose, glucose, sodium bicarbonate, citric acid, saccharin sodium, aspartame, crospovidone.
According to the present invention, the weight ratio of benzene ring nonyl ester and methacrylate polymer is 1: 1-1: 20, preferred 1: 4-1: 10; 1 of the mol ratio of benzene ring nonyl ester and cyclodextrin or derivatives thereof: 1-1: 20, preferred 1: 3-1: 8.Active ingredient hydrochloric acid benzene ring pelargonate wherein needs coated or enclose is handled.Active component content is respectively by benzene ring nonyl ester: every of 0.5mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg or 3mg/.According to the present invention, the preferred following three kinds of combinations of the adjuvant that uses in this preparation preparation:
(a) mannitol 5-80%, sucrose 5-80%, gelatin 0.1-10%, hydroxyethyl-cellulose 0.1-7.5%; Or
(b) glucose 10-50%, compressibility sorbitol 10-50%, mannitol 10-40%, sucrose 10-40%, sodium bicarbonate 5-20%, citric acid 5-10%, saccharin sodium 0.01-0.08%, aspartame 0.01-0.08%; Or
(c) microcrystalline Cellulose 10-40%, lactose 10-40%, mannitol 10-40%, crospovidone 2-8%, saccharin sodium 0.01-0.08%, aspartame 0.01-0.08%.
The benzene ring nonyl ester oral rapidly disintegrating and/or the oral instant tablet of above-mentioned anti-motion sickness can prepare by the following method: principal agent is suspended in the hydroxyethyl cellulose aqueous solution, form solution A, press the prescription in the adjuvant (a), gelatin, mannitol and sucrose mixed dissolution, form solution B, solution A and solution B are mixed, and add the dilution of an amount of water, make its abundant mixing, join sharp freezing in the mould, put into the freeze dryer evacuation, ice sublimes up into the material bone dry, press seal, packing are the lyophilizing sheet.
Perhaps, principal agent and eight kinds of pharmaceutical excipients are pressed prescription mix homogeneously in the adjuvant (b), add wetting agent or binding agent and make soft material, sieve, oven dry, granulate adds tabletting behind the lubricant, packing, is compressed tablet.
Perhaps, principal agent and six kinds of pharmaceutical excipients are pressed prescription mix homogeneously in the adjuvant (c), add lubricant after, direct compression, packing.
" principal agent " mentioned in the context of the invention is meant the mixture or the complex of benzene ring nonyl ester and odor mask such as Youteqi E (Eudragit E) or Youteqi EPO (Eudragit EPO) or cyclodextrin or cyclodextrin derivative.
Described benzene ring nonyl ester mixes with odor mask and comprises:
(1) with benzene ring nonyl ester and beta-schardinger dextrin-, under the certain reaction temperature, be dissolved in water, the regulator solution pH value is closely neutral, stirs 8-10 hour, and left standstill 24 hours at cold place, filter, or lyophilization; Or
(2) the 500g benzene ring nonyl ester is pulverized, crossed 80 mesh sieves, use equipment coatings such as ebullated bed or fluid bed.Coating material is selected Eudragit E for use, and water is mixed with the dispersion of 2-10% aqueous dispersion or uses dissolve with ethanol, is aided with an amount of plasticizer and lubricant.Coating under temperature of charge 25-50 ℃, the condition of atomizing pressure 2.0-3.0bar, feed liquor speed 5-30ml/min, coating weightening finish 30-100%; Or
(3) select for use in neutrality or meta-alkalescence insoluble, and in acidic aqueous solution dissolved pharmaceutical polymers, with suitable organic solvent such as dissolve with ethanol, principal agent is added and dissolving, vacuum drying or lyophilization make it to solidify, or directly as medicinal adhesive, get final product.
Relative prior art, the present invention has following advantage: all need not take medicine by water with benzene ring nonyl ester oral rapidly disintegrating and/or oral instant tablet that three kinds of preparation methoies make.The lyophilizing sheet is put into oral cavity disintegrate below 5 seconds.Compressed tablet is disintegrate below 30 seconds in the oral cavity, and it is easy to take medicine, and saves the trouble with the water delivery service medicine, treats timely and effective.The weight of pharmaceutical preparation of the present invention is variable.Product of the present invention is mainly used in anti-motion sickness as carsick, seasick, airsick etc.
Description of drawings
Fig. 1 represents with of the present invention Orally disintegrating/dissolving preparation the release result in different artificial body fluid of benzene ring nonyl ester as active component.
The specific embodiment
Can be sure of, those skilled in the art can according to aforesaid content maximum magnitude utilize the present invention.Therefore, following embodiment only is in order to illustrate, and does not limit the present invention in any way.
Embodiment 1
Get the 1g benzene ring nonyl ester, add water 30ml, add the 9g beta-schardinger dextrin-s as 80 ℃ at a certain temperature, about regulator solution pH value 6.0-7.0, stirred 8-10 hour, left standstill 24 hours at cold place, filter, get benzene ring nonyl ester/cyclodextrin clathrate or complex, finish taste masking and handle.
Embodiment 2
Get 10gEudragit EPO powder,, add the 2g benzene ring nonyl ester with the dissolving of 30mL ethanol slight fever, the slight fever dissolving, other gets 10g and crosses 80 order Icing Sugar, in the mode of spraying aforesaid liquid is sprayed on the Icing Sugar, and drying makes it non-caked while spraying, and finishes taste masking and handles.
The principal agent of mentioning in following examples is meant and adopts the excellent Youteqi EPO of excipient (Eudragit EPO) that benzene ring nonyl ester is carried out complex after taste masking is handled.
Embodiment 3
In 1.0 gram principal agent (by benzene ring nonyl ester) suspendibles, 3 gram hydroxyethyl-celluloses, make solution A, then 7 gram gelatin, 80 gram sucrose and 10 gram mannitol mixed dissolutions, make solution B, solution A and solution B are mixed, add the suitable quantity of water mixing, put into the mould sharp freezing, evacuation in freeze dryer, ice sublimes up into material bone dry, press seal, packing.Make 1000, every contains 1.0 milligrams of benzene ring nonyl ester meters of principal agent. and this sheet is the lyophilizing sheet.
Embodiment 4
2 gram principal agents (by benzene ring nonyl ester), 2.5 gram gelatin, 7.5 gram hydroxyethyl-celluloses, 65 gram mannitol and 25 gram sucrose replace to be implemented the raw material consumption in 1, method is with embodiment 1, make 1000, every contains 2.0 milligrams of principal agents (by benzene ring nonyl ester).This sheet is the lyophilizing sheet.
Embodiment 5
Glucose 30 grams, compressibility sorbitol 10 grams, mannitol 20 grams, sucrose 20 grams, sodium bicarbonate 10 grams, citric acid 9.9 grams, saccharin sodium 0.05 gram, aspartame 0.05 gram be totally eight kinds of adjuvant 100 grams, with principal agent 2.0 gram (by benzene ring nonyl ester) mix homogeneously, add binding agent and make soft material, sieve, oven dry, granulate, tabletting behind the adding lubricant is suppressed 1000 altogether.Every contains 2.0 milligrams of principal agents (by benzene ring nonyl ester), and this sheet is a compressed tablet.
Embodiment 6
Microcrystalline Cellulose 30 grams, lactose 22 grams, mannitol 40 grams, crospovidone 6 grams, saccharin sodium 0.05 gram, aspartame 0.05 gram be totally six kinds of adjuvant 100 grams, with principal agent 2.0 gram (by benzene ring nonyl ester) mix homogeneously, direct compression behind the adding lubricant, suppress 1000 altogether, every contains 2.0 milligrams of principal agents (by benzene ring nonyl ester), and this sheet is a compressed tablet.
The test of embodiment 7 disintegrations
The tablet of embodiment 6 preparations is carried out the disintegrate investigation.
Because this sheet disintegrate is too fast, measure the difference that can't observe between each prescription with conventional disintegration tester, the present invention adopts dissolving device basket method to measure this sheet disintegration time.100ml water, 37 ℃, stirring arm rotating speed 100rpm, basket are 720 μ m stainless (steel) wires, with stopwatch record tablet scatter fully and granule the time by basket is the disintegration time of tablet fully.(annotate: the disintegrate environment of this method relaxes very much, is 10 minutes tablet with conventional disintegration tester mensuration disintegration time, in this disintegrate device 30 minutes can disintegrate).Measurement result sees Table 1.As seen this product disintegration time is in 30 seconds.
Table 1 disintegration time measurement result
| The sample sequence number | Disintegration time (second) |
| 123456 is average | 17 22 15 19 20 25 20 |
The test of embodiment 8 releases
The tablet of embodiment 6 preparations is carried out the release test of different pH value media.
Content assaying method: high performance liquid chromatography (HPLC).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; Acetonitrile: 0.146M phosphoric acid: water: triethylamine (350: 40: 110: 0.8) be mobile phase; Detect wavelength 220nm; Theoretical cam curve is calculated by the benzene ring nonyl ester chromatographic peak should be not less than 2000, and the separating degree of benzene ring nonyl ester peak and adjacent impurity peaks should meet the requirements.
The little agar diffusion method of algoscopy.37 ℃, 100rpm, the 100mL release medium, the regularly accurate sampling 5ml every 1 minute, precision is added the 5mL medium simultaneously.With 0.45 μ m filtering with microporous membrane, discard filtrate just, get subsequent filtrate, sample introduction 50 μ L under selected chromatographic condition, the record chromatogram, other prepares the benzene ring nonyl ester contrast liquid of 20 μ g/mL, with the method sample introduction, record chromatogram, external standard method calculating release amount of medicine.
Test medium one: neutral aqueous solution (artificial saliva).
The hydrochloric acid solution of test medium two: pH1.2 (simulated gastric fluid).
Test medium three: test with 99mL medium one (artificial saliva) earlier, add 1mL hydrochloric acid after 5 minutes, make it to become the hydrochloric acid solution (simulated gastric fluid) of pH1.2, proceed test.
The drug release determination result:
(1) tablet of the present invention is in artificial saliva, and medicine did not discharge in 5 minutes, and release in 10 minutes is lower than release in 3%, 20 minute and is lower than 5%.Its release profiles is seen accompanying drawing 1 with " ■ " expression.Results suggest, this product are put in the oral cavity, and medicine does not dissolve or discharges in 5 minutes, can reach the taste masking effect of expection.
(2) tablet of the present invention is in simulated gastric fluid, and 5 minutes drug releases are not less than to discharge in 30%, 10 minute and are not less than 80%, 15 minute drug release and are not less than 90%, 20 minute medicine and discharge fully, see accompanying drawing 1.Results suggest, after this product entered human body alimentary canal, medicine can rapid release, can reach the rapid release effect of expection.Its release profiles is represented with " ▲ ".
(3) tablet of the present invention is in artificial saliva, and medicine did not discharge in 5 minutes, continues to investigate in simulated gastric fluid, and medicine can discharge fully at 15-20 minute.Its release profiles is seen accompanying drawing 1 with " ● " expression.Results suggest, this product oral administration can be avoided insufferable bitterness behind Orally disintegrating, can guarantee the rapid release effect of medicine simultaneously again.
The test of embodiment 9 bioequivalences
The tablet of embodiment 6 preparations is carried out the bioequivalence test
Experiment material and instrument benzene ring nonyl ester oral cavity disintegration tablet (self-control); Benzene ring nonyl ester ordinary tablet (it is happy to fly plug, and Fourth Ring, Beijing pharmaceutical factory provides); [
2H
3] benzene ring nonyl ester (the synthetic chamber of Poison ﹠ Medicine Inst. of Military Medicial Sciences Academy provides); Beasle dog (♂, 11～14.5kg, Military Medical Science Institute's animal center); Mass spectrograph (HP5971A type, hewlette-packard); Gas chromatograph (HP5890II type, hewlette-packard).
The chromatographic condition chromatographic column is 12m * 0.2mm * 0.3m HP-1 capillary column; Carrier gas is a helium; Flow velocity is 0.8ml/min; 250 ℃ of injector temperatures; 300 ℃ of detector temperatures; The furnace temperature heating schedule is 100 ℃ and keeps 1min that the speed with 25 ℃/min rises to 250 ℃ again; Electron bombard energy 70E.Sample introduction 1 μ L
4 beasle dogs of experimental technique are divided into two groups at random, intersection single oral benzene ring nonyl ester oral cavity disintegration tablet and ordinary tablet.Twice dosing interval (purification phase) 10 days, dosage 2mg (1)/dog.Beasle dog is 12h on an empty stomach, and in the morning of experiment day last oral hydrochloride benzene ring pelargonate oral cavity disintegration tablet or ordinary tablet, the about 10mL of ordinary tablet water sweeps away, and oral cavity disintegration tablet places the dog oral cavity, with fixing about 5 minutes of the dog mouth of hands.3 hours hello breakfast after the administration.Take medicine back 0.25,0.5,0.75,1,1.25,1.5,2,3 .4,6,8,12h by retreating venous blood collection 3mL, centrifugal separation plasma 1mL, 1mL blood plasma add 0.1mL interior mark liquid ([
2H
3] benzene ring nonyl ester 100ng), the NaOH of the 0.5N of 0.2mL mixes ethyl acetate-chloroform (6: the 1) shake well of back with 4mL, and centrifugalize is got upper organic phase in another test tube, uses N in 50 ℃ of water-baths
2Dry up.Ethyl acetate-chloroform (6: 1) of the water reuse 4mL of lower floor extracts, and gets organic layer in above-mentioned test tube, adds the HCL of 1mL0.01N, and is centrifugal behind the shake well, discards organic layer.The NaOH that adds the 0.5N of 0.2mL in aqueous phase, ethyl acetate-chloroform mixed liquor shake well with 2.5mL, centrifugalize, get organic layer in the 5mL centrifuge tube, adding 2.5mL ethyl acetate-chloroform mixed liquor in lower floor's aqueous phase again extracts once, merge twice organic facies in above-mentioned centrifuge tube, in 50 ℃ of water-baths, use N
2Dry up,, get 1 μ L and carry out the GC-MS analysis, measure the blood drug level of beasle dog different time with 50 μ L dissolve with methanol residues.
Date processing
Blood drug level-the time data that records is carried out the compartment model match with 3P87 pharmacokinetics program, calculates corresponding pharmacokinetic parameter (AUC is tried to achieve by trapezoidal method), and with the t check of self pairing design data parameter is carried out statistical test.
The benzene ring nonyl ester oral cavity disintegration tablet is calculated by following formula the relative bioavailability of ordinary tablet:
Two kinds of preparations are differentiated with method of analysis of variance and two one-side t method of inspection (AUC and CMAX warp are to number conversion) in the intravital bioequivalence of beasle dog.
Experimental result
Benzene ring nonyl ester oral cavity disintegration tablet, the blood drug level of two kinds of preparations of ordinary tablet after beasle dog is taken see Table 2.Two kinds of preparations see Table 3 at the intravital main pharmacokinetic parameter of beasle dog.Relative bioavailability the results are shown in Table 4.
The blood drug level result of two kinds of preparations of table 2 after beasle dog is taken
| Time (h) | Benzene ring nonyl ester blood drug level (ng/ml) (n=4) | |
| Oral cavity disintegration tablet | Ordinary tablet | |
| 0.25 0.5 0.75 1 1.25 1.5 2 3 4 6 8 12 | 0.44±0.22 2.49±1.91 6.14±3.36 5.93±3.70 4.75±1.39 3.88±1.27 2.93±1.33 1.62±0.44 1.30±0.50 0.72±0.23 0.46±0.14 0.10±0.05 | 0.68±0.83 2.59±2.89 4.98±3.78 4.47±1.21 3.99±1.35 3.46±1.38 2.35±0.51 1.53±0.36 0.93±0.20 0.72±0.19 0.12±0.07 0.10±0.07 |
Two kinds of preparations of table 3 the intravital main pharmacokinetic parameter of beasle dog (X ± SD, n=4)
| Parameter | Unit | Oral cavity disintegration tablet | Ordinary tablet |
| t 1/2 ka t 1/2 α t 1/2 β Tmax Cmax AUC | h h h h ng·ml -1 ng·ml -1·h -1 | 0.343±0.093 0.416±0.154 2.728±0.611 1.048±0.400 4.993±1.987 15.101±2.810 | 0.242±0.176 0.265±0.281 1.906±0.460 0.973±0.299 4.676±2.298 12.065±2.957 |
Table 4 benzene ring nonyl ester oral cavity disintegration tablet is to the relative bioavailability result of ordinary tablet
| NO | AUC(ng·ml -1·h -1) | F(％) | |
| Oral cavity disintegration tablet | Ordinary tablet | ||
| 1 2 3 4 X±SD | 11.621 18.308 14.250 160226 15.101±2.81 | 7.850 14.644 13.373 12.391 12.065±2.957 | 148.04 125.02 106.56 130.95 127.460±17.110 |
Conclusion:
1, benzene ring nonyl ester oral cavity disintegration tablet and ordinary tablet absorb in the beasle dog body comparatively fast, can detect benzene ring nonyl ester in the 0.25h blood plasma after the administration, peak about 1h, reduce to 1/50 of peak concentration behind the 12h approximately.Plasma concentration-time graph all meets one-level and absorbs two-compartment model.Two kinds of preparations are at the intravital absorption of beasle dog, distribution and elimination process basically identical.
2, the benzene ring nonyl ester oral cavity disintegration tablet is 127.46 ± 17.11% to the relative bioavailability of ordinary tablet.Three parameters such as Tmax, Cmax and AUC are used variance analysis to its test (wherein Cmax and AUC carry out the logarithm conversion earlier), test, as a result three parameters between handling, there are no significant during week and between individuality difference (P＞0.05).AUC to two kinds of preparations carries out two one-side t checks, and t1 (10.8730) and t2 (3.8073) value all greater than t (2.9199) value, shows benzene ring nonyl ester oral cavity disintegration tablet and ordinary tablet bioequivalence as a result.
Claims (6)
1, the benzene ring nonyl ester Orally disintegrating and/or the Orally dissolving solid preparation that are used for anti-motion sickness wherein contain benzene ring nonyl ester and odor mask methacrylate polymer or cyclodextrin or derivatives thereof as active component, and oral pharmaceutic adjuvant,
Wherein, the weight ratio of described benzene ring nonyl ester and methacrylate polymer is 1: 1-1: 20, and the mol ratio of described benzene ring nonyl ester and cyclodextrin or derivatives thereof is 1: 1-1: 20;
Described cyclodextrin or derivatives thereof is selected from beta-schardinger dextrin-, HP-, ethyl cyclodextrin, DM-and TM-;
Described pharmaceutic adjuvant is selected from one of following three kinds of combinations:
(a) mannitol 5-80%, sucrose 5-80%, gelatin 0.1-10%, hydroxyethyl-cellulose 0.1-7.5%; Or
(b) glucose 10-50%, compressibility sorbitol 10-50%, mannitol 10-40%, sucrose 10-40%, sodium bicarbonate 5-20%, citric acid 5-10%, saccharin sodium 0.01-0.08%, aspartame 0.01-0.08%; Or
(c) microcrystalline Cellulose 10-40%, lactose 10-40%, mannitol 10-40%, crospovidone 2-8%, saccharin sodium 0.01-0.08%, aspartame 0.01-0.08%;
Above consumption all by weight percentage, and the weight of benzene ring nonyl ester is 1: 100 or 2: 100 with the ratio of adjuvant gross weight.
2, the described preparation of claim 1, wherein methacrylate polymer is selected from Youteqi E or Youteqi EPO, and the cyclodextrin or derivatives thereof is selected from beta-schardinger dextrin-.
3, the described preparation of claim 1, the weight ratio of wherein said benzene ring nonyl ester and methacrylate polymer is 1: 4-1: 10.
4, the described preparation of claim 1, the mol ratio that it is characterized in that described benzene ring nonyl ester and cyclodextrin or derivatives thereof is 1: 3-1: 8.
5, the described preparation of claim 1 is characterized in that active component is respectively by its content of benzene ring nonyl ester: every of 0.5mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg or 3.0mg/.
6, claim 1 or 2 described preparations is characterized in that described preparation is tablet, drop pill or granule.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310103553 CN1283249C (en) | 2003-11-07 | 2003-11-07 | Oral disintegrated and/or oral soluble solid hydrocyclo-benzenenonate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310103553 CN1283249C (en) | 2003-11-07 | 2003-11-07 | Oral disintegrated and/or oral soluble solid hydrocyclo-benzenenonate |
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| CN1283249C true CN1283249C (en) | 2006-11-08 |
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| CN103284974B (en) * | 2013-04-03 | 2016-01-20 | 中国人民解放军广州军区武汉总医院 | Benzene ring nonyl ester double-layer osmotic pump controlled-release tablet and preparation method thereof |
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